Composition containing an anesthetic and method of using the same

Abstract

The present disclosure relates to a pharmaceutical composition comprising a dopamine antagonist and a method of using the same to treat pain and prevent drug preference and opioid addiction.

Description

Technology Field

[0001] Cross-reference of related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 614,582, filed December 24, 2023, titled “Compositions Comprising Anesthesics and Methods of Using the Same,” and U.S. Provisional Application No. 63 / 703,160, filed October 3, 2024, titled “Compositions Comprising Anesthesics and Methods of Using the Same,” the entire contents of both applications are incorporated into this application.

[0003] Statements regarding federal government-funded research

[0004] This invention was made with government support under grant numbers NIH R01DA056593 and NIH R21DA048323 awarded by the National Institutes of Health (NIH). The government retains specific rights to this invention.

[0005] The present disclosure relates to compositions, pharmaceutical compositions, and methods of administering said compositions for preventing opioid-related disorders such as opioid use disorder and opioid addiction. Additionally, the present disclosure relates to a method of treating pain in a subject requiring pain treatment by administering a dopamine antagonist to the subject using one or more compositions disclosed herein. Background Technology

[0006] In the past year alone, more than 9 million Americans abused opioids, resulting in over 106,000 deaths in 2021. The cause of this crisis is rooted in the healthcare system itself, stemming from the point where patients first encounter opioids to manage pain resulting from medical procedures, including surgery. Of the approximately 51 million patients who undergo surgery in the United States annually, 76.2% received opioid prescriptions within seven days of discharge, and between 9% and 13% of them continue to take opioids for extended periods. More importantly, between 10% and 50% of these patients experience persistent and chronic pain after surgery, leading to opioid use disorders in 8% to 12% of them. There is no effective cure for opioid-related disorders, nor is there a safer pharmacological approach that can treat patients' pain while preventing opioid dependence.

[0007] The present disclosure relates to novel formulations and novel methods for managing, preventing, and treating opioid use disorders that are not addressed by existing methods or therapies. These novel therapeutic agents may improve patient prognosis when used alone or in combination with other therapies. Surprisingly, the methods and compositions of the present disclosure not only meet these requirements but also satisfy other purposes and advantages that will become apparent in the description below.

[0008] The present disclosure comprises compositions and formulations comprising compounds of formulas I through VI, which are useful for the treatment or prevention of pain and for the prevention of opioid disorders, including but not limited to conditions such as opioid dependence and drug preference. Some embodiments of the present disclosure comprise compositions useful for anesthetizing subjects requiring anesthesia and for enhancing the effects of opioids.

[0009] Additionally, the present disclosure comprises a method for treating pain or preventing opioid-related disorders, the method comprising the step of administering a therapeutically or prophylactically effective amount of a composition to a mammal requiring such treatment or prevention, wherein the composition comprises (i) one of a dopamine antagonist, a dopamine antagonist and an opioid, a compound of formulas I to VI, or a pharmaceutically acceptable salt or prodrug thereof; and (ii) a pharmaceutically acceptable carrier.

[0010] In some embodiments, the dopamine antagonist is a compound of formula (I),

[0011] Chemical Formula I

[0012] or includes a pharmaceutically acceptable salt thereof, an isomer thereof, or a prodrug thereof.

[0013] In some embodiments, the dopamine antagonist is a compound of formula (II),

[0014] Chemical Formula II

[0015] or includes a pharmaceutically acceptable salt thereof, an isomer thereof, or a prodrug thereof.

[0016] In some embodiments, the dopamine antagonist is a compound of formula (III),

[0017] Chemical Formula III

[0018] or includes a pharmaceutically acceptable salt thereof, an isomer thereof, or a prodrug thereof.

[0019] In some embodiments, the dopamine antagonist is a compound of formula (IV),

[0020] (IV)

[0021] In the above formula,

[0022] X1 is selected from H, Cl, F, I, O, OH, or NH2;

[0023] R2 is O, N, NH, Selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted alkylene groups, substituted or unsubstituted aryl groups, substituted or unsubstituted acyl groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted heteroacyl groups, substituted or unsubstituted cycloalkyl groups, or substituted or unsubstituted heterocycloalkyl groups;

[0024] R1 and R3 are O, N, NH, A compound individually selected from a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkylene group, a substituted or unsubstituted aryl group, a substituted or unsubstituted acyl group, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted heteroacyl group, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl;

[0025] or includes a pharmaceutically acceptable salt thereof, an isomer thereof, or a prodrug thereof.

[0026] In some embodiments, the dopamine antagonist is a compound of formula (V),

[0027] (V)

[0028] X1 is selected from H, Cl, F, I, O, OH, or NH2;

[0029] R2 is selected from a substituted or unsubstituted amine group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkylene group;

[0030] R1 and R3 are individually selected from O, N, NH, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted acyl groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted heteroacyl groups, substituted or unsubstituted cycloalkyl groups, or substituted or unsubstituted heterocycloalkyl groups;

[0031] X2 is selected from Cl, F, I, OH, or =O;

[0032] R4 is selected from substituted or unsubstituted amine groups or substituted or unsubstituted alkyl groups;

[0033] R7 is selected from substituted or unsubstituted amine groups, substituted or unsubstituted alkyl groups, or substituted or unsubstituted alkylene groups;

[0034] R5 and R6 are individually selected from O, N, NH, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkylene groups, substituted or unsubstituted aryl groups, substituted or unsubstituted acyl groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted heteroacyl groups, substituted or unsubstituted cycloalkyl groups and substituted or unsubstituted heterocycloalkyl groups, or R5 and R6 together form a compound that forms a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted cycloalkene; or comprise a pharmaceutically acceptable salt thereof, an isomer thereof, or a prodrug thereof.

[0035] In addition, the present disclosure is a compound of formula (VI), wherein

[0036] VI

[0037] In the above formula,

[0038] X1 is selected from halogen, H, O, OH, or NH2;

[0039] R2 is selected from substituted or unsubstituted amine groups, substituted or unsubstituted alkyl groups, or substituted or unsubstituted alkylene groups; and

[0040] R1 and R3 are O, N, NH, Individually selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted alkylene groups, substituted or unsubstituted aryl groups, substituted or unsubstituted acyl groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted heteroacyl groups, substituted or unsubstituted cycloalkyl groups, or substituted or unsubstituted heterocycloalkyl groups; and

[0041] X3 is a compound selected from H, O, OH, halogen, or NH2; or

[0042] The invention relates to a composition comprising a dopamine antagonist comprising a pharmaceutically acceptable salt thereof.

[0043] Additionally, the present disclosure relates to a composition comprising a dopamine antagonist, a pharmaceutically acceptable salt thereof, or a prodrug thereof. Additionally, the present disclosure relates to a composition comprising an opioid or a pharmaceutically acceptable salt thereof. In some embodiments, the composition of the present disclosure comprises a dopamine antagonist and an opioid or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises a dopamine antagonist, wherein the dopamine antagonist is selected from DD8, DD9, DD10, or a pharmaceutically acceptable salt thereof. In some embodiments, the dopamine antagonist is selected from prochlorperazine, haloperidol, quetiapine, droperidol, or a pharmaceutically acceptable salt thereof or a prodrug thereof. In some embodiments, the opioid is selected from morphine, codeine, oxycodone, hydrocodone, fentanyl, hydromorphone, levorphanol, oxymorphone, meperidine, methadone, tapentadol, tramadol, and pharmaceutically acceptable salts thereof.

[0044] The present disclosure relates to a composition comprising a dopamine antagonist or a pharmaceutically acceptable salt thereof and an opioid or a pharmaceutically acceptable salt thereof, wherein the opioid is a compound having a structure represented by the following chemical formula,

[0045]

[0046] or a pharmaceutically acceptable salt thereof. In some embodiments, the opioid is selected from morphine, codeine, hydromorphone, fentanyl, hydrocodone, levorphanol, meperidine, methadone, oxycodone, oxymorphone, tramadol, and the opioid is fentanyl or a pharmaceutically acceptable salt thereof, and the mass of fentanyl in the fentanyl formulation is about 100 micrograms to about 500 micrograms. In some embodiments, the dopamine antagonist is DD9 or a pharmaceutically acceptable salt thereof, and the mass of DD9 is about 0.1 milligrams to about 2 milligrams.

[0047] In some embodiments, the present disclosure also relates to a composition comprising a dopamine antagonist or a pharmaceutically acceptable salt thereof or a prodrug thereof. Additionally, the present disclosure relates to a composition comprising an opioid or a pharmaceutically acceptable salt thereof. In some embodiments, the composition of the present disclosure comprises a dopamine antagonist and an opioid or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises a dopamine antagonist, and the dopamine antagonist comprises DD12 or a pharmaceutically acceptable salt thereof. In some embodiments, the opioid is selected from morphine, codeine, oxycodone, hydrocodone, fentanyl, hydromorphone, levorphanol, oxymorphone, meperidine, methadone, tapentadol, tramadol, and pharmaceutically acceptable salts thereof. In some embodiments, the dopamine antagonist comprises DD12 but does not comprise DD9, DD10, variants thereof or salts thereof. In some embodiments, the composition comprises about 2 milligrams to about 200 milligrams of DD12. In some embodiments, the composition is an immediate-release formulation.

[0048] Additionally, the present disclosure relates to a pharmaceutical composition comprising (i) a dopamine antagonist or a prodrug thereof; (ii) an opioid or a prodrug thereof; and (iii) a pharmaceutically acceptable carrier. In some embodiments, the dopamine antagonist is a compound having a structure represented by formulas I, II, III, IV, V, VI, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical composition comprises an effective amount of a dopamine antagonist selected from DD8, DD9, DD10, and pharmaceutically acceptable salts or prodrugs thereof. In some embodiments, the pharmaceutical composition comprises an effective amount of a dopamine antagonist or a pharmaceutically acceptable salt or prodrug thereof selected from the compounds listed in Table X. In some embodiments, the mass of the dopamine antagonist, the pharmaceutically acceptable salt or prodrug thereof, wherein the mass of the dopamine antagonist is about 0.1 milligrams to about 2 milligrams. In some embodiments, the opioid is a compound having a structure represented by the formula VII, wherein

[0049] VII

[0050] R1 is a compound that is a six-membered carbon ring or a six-membered heterocycle, a pharmaceutically acceptable salt thereof, or a prodrug thereof. In some embodiments, the opioid is selected from morphine, codeine, hydromorphone, fentanyl, hydrocodone, levorphanol, meperidine, methadone, oxycodone, oxymorphone, tramadol, tapentadol, or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition comprises an opioid with a mass of about 100 micrograms to about 500 micrograms. In some embodiments, the pharmaceutical composition comprises a dopamine antagonist, which is administered at a dose of about 0.1 milligrams to about 24 milligrams. In some embodiments, the opioid is fentanyl, a pharmaceutically acceptable salt thereof, or a prodrug thereof, and the mass of fentanyl is about 100 micrograms to about 500 micrograms.

[0051] In some embodiments, the present disclosure also relates to a pharmaceutical composition comprising (i) a dopamine antagonist or a prodrug thereof; (ii) an opioid or a prodrug thereof; and (iii) a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises an effective amount of DD12, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical composition comprises DD12 but does not comprise DD9, DD10, variants thereof, or salts thereof. In some embodiments, the dopamine antagonist, a pharmaceutically acceptable salt thereof, or a prodrug thereof is present in the pharmaceutical composition in an amount of about 0.1 milligrams to about 2 milligrams.

[0052] The present disclosure relates to any pharmaceutical composition disclosed herein, the pharmaceutical composition is an oral formulation. The present disclosure relates to any pharmaceutical composition disclosed herein, the pharmaceutical composition is a liquid formulation. In some embodiments, the pharmaceutical composition is a single oral formulation comprising a dopamine antagonist and an opioid. In some embodiments, the pharmaceutical composition is a single oral formulation comprising DD9 and an opioid. In some embodiments, the pharmaceutical composition is a single oral formulation comprising DD10 and an opioid. In some embodiments, the pharmaceutical composition is a single oral formulation comprising DD12 and an opioid. In some embodiments, the pharmaceutical composition is an immediate-release formulation.

[0053] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a dopamine antagonist. In some embodiments, the pharmaceutical composition comprises about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 39 mg, about 31 mg, about 32 It contains approximately 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, and 50 mg of a dopamine antagonist. In some embodiments, the dopamine antagonist is DD12, and the pharmaceutical composition does not contain DD9, DD10, variants thereof, or salts thereof. In some embodiments, the dopamine antagonist is DD9, DD10, or DD12, and the pharmaceutical composition does not contain at least one of the other dopamine antagonists listed in Table X.

[0054] Another aspect of the present disclosure relates to a method for preventing opioid preference and / or opioid dependence, comprising the step of administering a pharmaceutical composition comprising an effective amount of opioid and an effective amount of dopamine antagonist to a subject requiring such a method. In some embodiments, the effective amount of the two compounds is a prophylactic effective amount or an amount necessary to prevent the onset of opioid preference and / or opioid dependence. In some embodiments, the amount of dopamine antagonist administered is sufficient to reduce an oscillation frequency of about 4 Hz to about 8 Hz when measured by EEG.

[0055] Additionally, the present disclosure relates to a method for treating pain comprising the step of administering the composition or pharmaceutical composition disclosed herein to a subject who requires treatment of pain. In some embodiments, the subject is administered an IV, oral, or liquid formulation containing a dopamine antagonist such as DD8, DD9, or DD10, with a total mass of about 2 milligrams to about 200 milligrams. In some embodiments, the dopamine antagonist is administered before or simultaneously with opioid administration. In some embodiments, administration is performed in one, two, three, or more doses during surgery, and about three additional doses are administered within 72 hours after surgery. In some embodiments, opioid administration is performed about once, about twice, about three, or about four times per day. In some embodiments, the formulation is an immediate-release formulation. Additionally, in some embodiments, the method comprises a step of administration including one or more administrations per day.

[0056] In some embodiments, the present disclosure also relates to a method for treating pain comprising the step of administering the composition or pharmaceutical composition disclosed herein to a subject who requires treatment of pain. In some embodiments, the subject is administered an IV formulation, an oral formulation, or a liquid formulation comprising a dopamine antagonist comprising DD12, with a total mass of about 0.2 milligrams to about 200 milligrams. In some embodiments, the dopamine antagonist comprises DD12 or an analog thereof, but does not comprise DD9, DD10, variants thereof, or salts thereof. In some embodiments, the dopamine antagonist is administered before or simultaneously with opioid administration. In some embodiments, administration is performed in one, two, three, or more doses during surgery, and about three additional doses are administered within 72 hours after surgery. In some embodiments, opioid administration is performed once, two, three, or four times per day. In some embodiments, the antagonist is administered once, twice, three, or four times daily. In some embodiments, the formulation is an immediate-release formulation.

[0057] In some embodiments, the dose of the dopamine antagonist is about 2 to about 24 milligrams in liquid or solid formulation. In some embodiments, the method of the present disclosure comprises the step of administering the dopamine antagonist daily, twice daily, or every other day for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days or more after surgery. In some embodiments, the method comprising the administration of the dopamine antagonist comprises the step of administering a low dose of the dopamine antagonist to a subject requiring it for about 1 to about 3 months after surgery, or at least during the period the subject is taking an opioid to treat postoperative pain. In some embodiments, a dopamine antagonist is administered in a dose sufficient to enhance the analgesic effect of the opioid in the same composition as the opioid (or two separate compositions administered within about 1 hour of opioid administration) and to prevent adverse effects of dopamine receptors and opioids (e.g., opioid addiction, drug preference, and opioid use disorder). Additionally, some embodiments of the present disclosure include a method for reducing opioid-induced respiratory and cardiovascular adverse effects by achieving a level of pain relief equivalent to that of a higher dose at a lower dose. In some embodiments, opioid administration is performed once, twice, three, or four times daily. In some embodiments, the antagonist is administered once, twice, three, or four times daily. In some embodiments, the formulation is an immediate-release formulation.

[0058] The present disclosure also relates to a kit comprising any disclosed composition or pharmaceutical composition and optionally a syringe or other device for administering the pharmaceutical composition. Brief explanation of the drawing

[0059] The following detailed description of embodiments is better understood when read together with the accompanying drawings. For illustrative purposes, specific embodiments are shown in the drawings. However, it is understood that embodiments of the present invention are not limited to the exact configurations and means shown in the drawings. In the drawings: Figures 1A–1D: EEG biomarkers indicating the effects of opioid drugs: Theta waves correlate with increasing fentanyl concentration. Changes in ESC and EEG caused by fentanyl. Subjects were administered a single dose of fentanyl (ideally 2 mcg per kg of body weight) up to three times at 2-minute intervals following the baseline period (F1, F2, and F3), and concentration levels were calculated using PK / PD modeling. Figure 1A shows the predicted ESC of a representative subject. Upon exposure to fentanyl, changes in the power spectrum—such as those shown in the spectrogram in Figure 1B and the EEG graph of the representative subject—were observed. Figure 1C shows spectra measured at various time points during the experiment, confirming that EEG theta band (4 to 8 Hz) power increases as the experiment progresses and fentanyl concentration increases. Figure 1D shows the correlation between EEG theta power and the concentration of fentanyl at the site of action. Figures 2A and 2B: Theta waves induced by fentanyl are observed in brain regions corresponding to the reward circuit. Figure 2A graphs the average difference in power (dB) compared to the baseline in the theta frequency band (4–8 Hz) after fentanyl injection, calculated for 824 channels across five subjects and plotted on a Colin 27 brain template. Lighter shades indicate increased power, darker shades indicate decreased power, and shaded colors indicate no change in power (where the confidence interval overlaps with 0). Figure 2B shows the changes in power in each part of the brain after fentanyl administration, along with confidence intervals. Figures 3A and 3B: The theta wave observed during remifentanil administration is attenuated upon administration of 1 mg of haloperidol. Figure 3A compares the EEG power spectra of two conditions, contrasting the baseline condition of total intravenous anesthesia (TIVA) based on remifentanil with the condition after administration of 1 mg of haloperidol. Examination of the EEG power spectrum reveals a clear and statistically significant decrease in power in the theta band (4 to 8 Hz) after haloperidol administration. Figure 3B shows the bootstrap sample and 99% confidence interval for the difference in theta power after haloperidol administration. Figure 4: The theta wave observed during fentanyl administration is attenuated upon administration of 1 mg of haloperidol. This figure compares the EEG power spectra of two conditions, contrasting the baseline condition, which is an anesthetic state during fentanyl administration, with the condition after administration of 1 mg of haloperidol. Looking at the EEG power spectrum, it is shown that the power in the theta band (4 to 8 Hz) decreased clearly and statistically significantly after administration of haloperidol. Fig. 5: The theta wave occurring during hydromorphone administration is attenuated by 1 mg of haloperidol. This figure compares the EEG power spectra of two conditions, contrasting the anesthetic state during hydromorphone administration (the reference condition) with the state after administration of 1 mg of haloperidol. Looking at the EEG power spectrum, it is shown that the power in the theta band (4 to 8 Hz) decreased clearly and statistically significantly after haloperidol administration. Fig. 6: Structure of the neural network used to learn the embeddings of the CPT and ICD-10 sets. For each patient, a code embedding matrix is ​​generated in the initial embedding layer by mapping ICD-10 and CPT codes into vectors. This matrix is ​​then passed to a multi-head self-attention layer with mean-pooling applied, where set embeddings are computed. This set of embeddings is combined with demographic variables and passed to a feedforward neural network, which contributes to exposure prediction. Figure 7: Distribution of fentanyl exposure during surgery. This figure shows the distribution of fentanyl exposure during surgery as average effect site concentrations in ng / mL, and is part of a causal inference analysis on the effects of dopamine antagonist administration on pain and opioid use. Figs. 8A and 8B: Distribution of timing of haloperidol and fentanyl administration throughout the preoperative course. Fig. 9: Adjusted odds ratios of intraoperative haloperidol, fentanyl, and interaction term (haloperidol * fentanyl) for primary and secondary outcomes. FIGS. 10A to 10F: Counterfactual estimates for short- and mid-term pain and opioid-related outcomes for an exposure variable called haloperidol dose per patient body weight (mg / kg). Here, counterfactual estimates are presented for maximum pain in the PACU (Fig. 10A), maximum pain at 24 hours post-surgery (Fig. 10B), maximum pain during hospitalization (Fig. 10C), total opioid dose (MME) in the PACU (Fig. 10D), total opioid dose at 24 hours post-surgery (Fig. 10E), and total opioid dose during hospitalization (Fig. 10F). Fig. 11: Distribution of fentanyl site of action concentrations. This figure shows the distribution of fentanyl exposure during surgery as average site of action concentrations in ng / mL units and is part of a causal inference analysis on the effects of dopamine antagonist administration on pain and oral opioid use. Figs. 12A and 12B: Distribution of timing of administration during surgery including haloperidol (Fig. 12A) and fentanyl (Fig. 12B). Fig. 13: Adjusted odds ratios of intraoperative haloperidol, fentanyl, and interaction term (haloperidol * fentanyl) for primary and secondary outcomes. Fig. 14: Plot showing the log-transformed mean effect site concentration of haloperidol in the PACU versus the amount of oxycodone (MME) administered in the PACU. This line represents a regression line with confidence intervals marked. Fig. 15: Estimated distribution of EEG theta (4-8 Hz) power changes induced by 1 mg morphine IV. Fig. 16: Estimated distribution of EEG theta (4-8 Hz) power changes induced by 1 mg haloperidol IV. Fig. 17. Estimated distribution of haloperidol dosage required to offset opioid-induced increase in EEG theta power. Fig. 18: Bootstrap distribution of theta power change after DD9 administration with new spectral analysis parameters applied. The vertical line represents the mean and 99% confidence interval of the distribution. Fig. 19: Distribution of DD9 doses required to offset the brain effects resulting from intravenous injection of 1 mg of morphine. The vertical line represents the mean and 99% confidence interval of the distribution. Fig. 20: Box plot including individual data points and connecting lines representing the average theta power (decibels, dB) measured under two conditions. These data points represent individual values ​​of theta power for each condition. The connecting lines represent the change in theta power during the transition from "steady-state remifentanyl" to "after DD12" for each subject. An asterisk indicates statistically significant results from a paired t-test. Fig. 21: Bootstrap distribution of theta power change after DD12 administration. The vertical line represents the mean and 99% confidence interval of the distribution. Fig. 22: Distribution of DD12 doses required to offset the brain effects resulting from intravenous injection of 1 mg of morphine. The vertical line represents the mean and 99% confidence interval of the distribution. Fig. 23: Distribution of theta power change after DD9 administration. The vertical dashed line represents the mean of the distribution. Fig. 24: Counterfactual estimate of the change in maximum pain score in PACU due to a decrease in EEG theta band power. Fig. 25: Counterfactual estimate of the change in maximum pain score 24 hours after surgery due to a decrease in EEG theta band power. Fig. 26: Counterfactual estimate of the change in maximum pain score during hospitalization due to a decrease in EEG theta band power. Fig. 27: Counterfactual estimate of change in PACU discharge rate due to decrease in EEG theta band power. Fig. 28: Counterfactual estimate of the change in hospital discharge rate due to a decrease in EEG theta band power. Fig. 29: Average concentration-time curve of DD10 in mouse plasma when 5 mg / kg of DD10 was administered orally, with or without 2 mg / kg of oxycodone. Fig. 30: Average concentration-time curve of DD12 in mouse plasma when 5 mg / kg of DD12 was administered orally, with or without 2 mg / kg of oxycodone. Fig. 31: Average concentration-time curve of oxycodone in mouse plasma when 2 mg / kg of oxycodone was administered orally, with or without co-administration of 5 mg / kg of DD10 or 5 mg / kg of DD12. Figs. 32A and 32B: Vertical counts by group administered oxycodone and DD10. 32A) Oxycodone 2 mg / kg and DD10 administered at the following doses: 0.01, 0.025, 0.05, 0.1 mg / kg. 32B) Oxycodone 2 mg / kg and DD10 administered at the following doses: 0.5, 1, 2.5, 5 mg / kg. Inferior activity, indicated by a significant decrease in vertical counts, was observed at doses of 0.5, 1, 2.5, and 5 mg / kg. Fig. 33: Vertical coefficients by group administered the following doses of DD10: 0.05, 0.1, 0.25, 0.5 mg / kg. Low activity, indicated by a significant decrease in the vertical coefficient, was observed with oxycodone + DD10 at doses of 0.1, 0.25, and 0.5 mg / kg. Fig. 34: Vertical counts by group administered the following doses of DD12: 5, 10, 20, and 40 mg / kg. No significant difference in vertical counts was observed between the vehicle group and the treatment group. Fig. 35: Vertical counts by group receiving vehicle, oxycodone (2 mg / kg), and oxycodone co-administered with DD12 at the following doses: 10, 20, 40, and 100 mg / kg. No significant difference in vertical counts was observed between the vehicle group and the treatment group. Fig. 36: Vertical counts of the vehicle, oxycodone (2 mg / kg), and the group administered oxycodone and DD12 100 mg / kg in combination. Fig. 37: Conditioning site preference for each treatment condition is indicated by the chamber residence times of vehicle, oxycodone (2 mg / kg), oxycodone + DD10 (0.005 mg / kg, PO), oxycodone + DD10 (0.025 mg / kg, PO), oxycodone + DD10 (0.05 mg / kg, PO), oxycodone + DD12 (20 mg / kg, PO), oxycodone + DD12 (30 mg / kg, PO), oxycodone + DD12 (40 mg / kg, PO), and oxycodone + DD12 (60 mg / kg, PO). Fig. 38: Relationship between DD10 dosage and oxycodone-induced conditioning site preference. For each DD10 administration condition, the mean values ​​are plotted along with the 95% CI calculated using the bootstrap method. The linear regression lines of the original data are superimposed. Fig. 39: Relationship between DD12 dosage and oxycodone-induced conditioning site preference. For each DD12 dosage condition, the mean values ​​are plotted along with the 95% CI calculated using the bootstrap method. The linear regression lines of the original data are superimposed. Fig. 40: Estimated plasma concentrations of olanzapine. For these models, equivalent doses of olanzapine of 2.5 and 30 mg were administered according to various dosing schedules to reflect the frequency of opioid administration for the treatment of acute and chronic pain. Curves for three body weights (50 kg, 70 kg, and 100 kg) are plotted. Since the plasma concentration model of olanzapine is not affected by body weight, all three curves are identical. Dotted horizontal lines are indicated at the plasma concentration locations corresponding to the side effects of olanzapine. Fig. 41: Estimated plasma concentrations of aripiprazole. For these models, 2.5 and 30 mg of olanzapine equivalent doses were administered according to various dosing schedules to reflect the frequency of opioid administration for the treatment of acute and chronic pain. Curves for three body weights (50 kg, 70 kg, and 100 kg) are plotted. Dotted horizontal lines are indicated at the plasma concentration locations corresponding to the side effects of olanzapine. Fig. 42: Estimated plasma concentrations of quetiapine. For these models, 2.5 and 30 mg of olanzapine equivalent doses were administered according to various dosing schedules to reflect the frequency of opioid administration for the treatment of acute and chronic pain. Curves for three body weights (50 kg, 70 kg, and 100 kg) are plotted. Since the plasma concentration model of quetiapine is not affected by body weight, all three curves are identical. Dotted horizontal lines are indicated at the plasma concentration locations corresponding to olanzapine side effects. Fig. 43: Estimated plasma concentrations of risperidone. For these models, 2.5 and 30 mg of olanzapine equivalent doses were administered according to various dosing schedules to reflect the frequency of opioid administration for the treatment of acute and chronic pain. Curves for three body weights (50 kg, 70 kg, and 100 kg) are plotted. Dotted horizontal lines are indicated at the plasma concentration locations corresponding to the side effects of olanzapine. Fig. 44: Estimated plasma concentrations of ziprasidone. For these models, 2.5 and 30 mg of olanzapine equivalent doses were administered according to various dosing schedules to reflect the frequency of opioid administration for the treatment of acute and chronic pain. Curves for three body weights (50 kg, 70 kg, and 100 kg) are plotted. Dotted horizontal lines are indicated at the plasma concentration locations corresponding to the side effects of olanzapine. Fig. 45: Estimated plasma concentrations of droperidol. For these models, oral doses of 0.08 mg, 4.29 mg, and 8.58 mg were administered according to various dosing schedules to reflect the frequency of opioid administration for the treatment of acute and chronic pain. Curves for three body weights (50 kg, 70 kg, and 100 kg) are plotted. Dotted horizontal lines are indicated at the plasma concentration locations corresponding to the side effects of olanzapine. Fig. 46: Estimated plasma concentrations of amyulfride. For these models, oral doses of 0.58 mg, 25.67 mg, and 51.34 mg were administered according to various dosing schedules to reflect the frequency of opioid administration for the treatment of acute and chronic pain. Curves for three body weights (50 kg, 70 kg, and 100 kg) are plotted. Dotted horizontal lines are indicated at the plasma concentration locations specified as reference values ​​where amyulfride levels are considered high according to laboratory guidelines. Fig. 47: Plasma amyulprid concentration in mice after oral administration of 5 mg / kg. Fig. 48: Estimated human plasma concentrations of amylphride at suggested doses when administered in combination with oxycodone. Human plasma concentrations were estimated after a single oral administration of amylphride within the lower and upper limits of the suggested doses for combination with generally prescribed oxycodone doses: 0.58 mg and 102.68 mg. Additionally, estimated mouse plasma concentrations of DD12 with oxycodone-induced behavioral effects canceled out were plotted: 30-60 mg / kg. Then, concentration ranges above 852 ng / mL, which are the initial sedative plasma concentrations in mice estimated based on mouse activity chamber results, were shaded. Fig. 49: Estimated human plasma concentrations of amylphride at suggested doses when administered in combination with hydrocodone. Human plasma concentrations were estimated after a single oral administration of amylphride within the lower and upper limits of the suggested doses for combination with generally prescribed hydrocodone doses: 0.39 mg and 84.71 mg. Additionally, estimated mouse plasma concentrations of DD12 with oxycodone-induced behavioral effects canceled out were plotted: 30-60 mg / kg. Then, concentration ranges above 852 ng / mL, which are the initial sedative plasma concentrations in mice estimated based on mouse activity chamber results, were shaded. Fig. 50: Estimated human plasma concentrations of amyulpride at suggested doses when administered in combination with morphine. Human plasma concentrations were estimated after a single oral administration of amyulpride at the lower and upper ranges of the suggested doses for combination with generally prescribed morphine doses: 0.77 and 101.66 mg. Additionally, estimated mouse plasma concentrations of DD12 with oxycodone-induced behavioral effects canceled out were plotted: 30-60 mg / kg. Then, concentration ranges above 852 ng / mL, which are the initial sedative plasma concentrations in mice estimated based on mouse activity chamber results, were shaded. Fig. 51: Estimated human plasma concentrations of amyulpride at the proposed maximum dose when administered in combination with commonly prescribed oral opioids. Human plasma concentrations were estimated after a single oral administration of amyulpride within the lower and upper limits of the maximum dose proposed for combination with commonly prescribed opioid doses: 169.42 mg and 338.86 mg. Additionally, estimated mouse plasma concentrations of DD12 with oxycodone-induced behavioral effects canceled out were plotted: 30-60 mg / kg. Then, concentration ranges above 852 ng / mL, which are the initial sedative plasma concentrations in mice estimated based on mouse activity chamber results, were shaded. Fig. 52: Plasma droperidol concentration in mice after oral administration of 5 mg / kg. Fig. 53: Estimated human plasma concentrations of droperidol at suggested doses for concomitant administration with oxycodone. We estimated human plasma concentrations after a single oral administration of droperidol at the lower and upper ranges of the suggested doses for concomitant administration with commonly prescribed oxycodone doses: 0.08 mg and 17.16 mg. We also plotted estimated mouse plasma concentrations of DD10 that eliminated oxycodone-induced behavioral effects: 0.005–0.05 mg / kg. Then, the concentration range above 44 ng / mL, which represents the initial sedative plasma concentration in mice estimated based on mouse activity chamber results, was shaded. Fig. 54: Estimated human plasma concentrations of droperidol at suggested doses when administered in combination with hydrocodone. Human plasma concentrations were estimated after a single oral administration of droperidol within the lower and upper limits of the suggested doses for combination with generally prescribed hydrocodone doses: 0.05 mg and 14.16 mg. Additionally, estimated mouse plasma concentrations of DD10 that eliminated oxycodone-induced behavioral effects were plotted: 0.005–0.05 mg / kg. Then, concentration ranges above 44 ng / mL, which are the initial sedative plasma concentrations in mice estimated based on mouse activity chamber results, were shaded. Fig. 55: Estimated human plasma concentrations of droperidol at suggested doses when administered in combination with morphine. Human plasma concentrations were estimated after a single oral administration of droperidol at the lower and upper ranges of the suggested doses for combination with generally prescribed morphine doses: 2.83 mg and 16.99 mg. Additionally, estimated mouse plasma concentrations of DD10 that eliminated morphine-induced behavioral effects were plotted: 0.005–0.05 mg / kg. Then, concentration ranges above 44 ng / mL, which are the initial sedative plasma concentrations in mice estimated based on mouse activity chamber experiment results, were shaded. Fig. 56: Plasma oxycodone concentration in mice after oral administration of 2 mg / kg. Fig. 57: Estimated human plasma concentrations of oxycodone after a single oral administration. Human plasma concentrations were estimated after a single oral administration of two doses of oxycodone: 2.5 mg and 40 mg. Additionally, estimated mouse plasma concentrations of oxycodone were plotted when the behavioral effects of oxycodone induced in mice by co-administration of amylphride were eliminated. Figs. 58A and 58B: Differences in visual analog scale scores and EEG theta power observed in patients receiving DD10 while receiving remifentanil continuous infusion. Figure 59 shows the research procedure. Specific details for implementing the invention

[0060] definition

[0061] Definitions of various terms used to describe the present disclosure are listed below. These definitions apply to how such terms are used throughout the specification, either individually in specific cases or as part of a larger group, unless otherwise limited.

[0062] As used herein, the terms “a” or “an” mean “at least one” or “more than one” unless otherwise clearly indicated in the context. The phrase “and / or” as used herein in the specification and claims should be understood to mean “one or both” of the elements thus combined, that is, elements that exist combined in some cases and separately in others. In addition to the elements specifically identified by the “and / or” clause, other elements may optionally exist, regardless of whether they are related to the elements specifically identified, unless otherwise clearly indicated. Thus, as a non-limiting example, when used with open language such as “comprising,” a reference to “A and / or B” may, in various embodiments, refer to A excluding B (optionally including elements other than B); in another embodiment, refer to B excluding A (optionally including elements other than A); in yet another embodiment, refer to both A and B (optionally including other elements), etc.

[0063] The term "or" as used herein shall be interpreted as indicating an exclusive alternative (i.e., "one of the two but not both") only when preceded by an exclusive term such as "either," "one of," "only one of," or "exactly one of."

[0064] The terms used herein “comprising” (and any form of “comprising” such as “comprise”, “comprises”, and “comprised”)), “having” (and any form of “having” such as “have” and “has”)), “including” (and any form of “including” such as “includes” and “include”)), or “containing” (and any form of “containing” such as “contains” and “contain”)) are inclusive or open and do not exclude any additional elements or method steps not mentioned.

[0065] As used herein, the term "approximately" means that the figures are approximations and that small variations do not have a significant effect on the practice of the disclosed embodiments. Where numerical limitations are used, unless otherwise specified in the context, "approximately" means that the figures may vary by ±10%, + / -5%, + / -4%, + / -3%, + / -2%, and + / -1% and are within the range of the disclosed embodiments.

[0066] The abbreviations used herein have their ordinary meanings within the fields of chemistry and biology. The chemical structures and formulas described herein are constructed according to the standard rules of chemical valence known in the field of chemistry.

[0067] References to weight parts of a specific element or component in a composition in the specification and concluding claims indicate a weight relationship between the element or component in the composition or article in which the weight part is expressed and any other element or component. Thus, in a compound containing 2 weight parts of component X and 5 weight parts of component Y, X and Y are present in a weight ratio of 2:5, and are present in this ratio regardless of whether additional components are included in the compound.

[0068] The weight percentage (wt. %) of an ingredient is based on the total weight of the formulation or composition containing the ingredient, unless otherwise specifically stated.

[0069] As used herein, the terms “optional” or “optional” mean that an event or situation described subsequently may or may not occur, and that such description includes cases where said event or situation occurs and cases where it does not occur.

[0070] As used herein, the term “diagnosed” means that a person has been physically examined by a skilled person, e.g., a physician, and is found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein. In some embodiments of the disclosed method, the subject is in a state of being diagnosed prior to the administration step as needing treatment for an opioid use-related disorder, such as opioid preference or opioid use disorder. As used herein, the phrase “identified as needing treatment for a specific disorder” or a similar expression means selecting a subject based on the need for treatment for said disorder. In some embodiments, identification is considered to be performed by a person different from the person making the diagnosis. Additionally, in further embodiments, it is considered that the person who performed the administration may also perform the administration thereafter.

[0071] As used herein, the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, vaginal administration, ophthalmic administration, ear administration, intracerebral administration, rectal administration, and parenteral administration (including injectables such as intravenous, arterial, intramuscular, and subcutaneous administration). Administration may be continuous or intermittent. In various embodiments, the preparation may be administered therapeutically; that is, to treat an existing disease or condition. In additional various embodiments, the preparation may be administered prophylactically; that is, to prevent a disease or condition.

[0072] As used herein, the term “contact” means placing the disclosed compound and the cell, target receptor, or other biological entity together in such a manner that the compound can influence the activity of the target (e.g., receptor, cell, etc.) directly, i.e., by interacting with the target itself, or indirectly, i.e., by interacting with other molecules, cofactors, factors, or proteins that depend on the activity of the target.

[0073] As used herein, "IC50" represents the concentration of a substance (e.g., a compound or drug) required to inhibit a biological process, or a component of a process including proteins, subunits, organelles, ribonucleoproteins, etc., by about 50%. In some embodiments, IC50 may represent the concentration of a substance required to inhibit about 50% in vivo, as further defined elsewhere in this invention. In some embodiments, IC50 may represent the concentration of a substance required to inhibit about 40% in vivo, as further defined elsewhere in this invention. In some embodiments, IC50 may represent the concentration of a substance required to inhibit about 30% in vivo, as further defined elsewhere in this invention. In some embodiments, IC50 may represent the concentration of a substance required to inhibit about 20% in vivo, as further defined elsewhere in this invention. In some embodiments, IC50 may represent the concentration of a substance required to inhibit about 10% in vivo, as further defined elsewhere in this invention. In some embodiments, IC50 may represent the concentration of a substance required for about 60% inhibition in vivo, as further defined elsewhere in this invention. In some embodiments, inhibition is inhibition of one or more of D1, D2, D3, D4 and / or D5 dopamine receptors.

[0074] As used herein, “EC50” indicates the concentration of a substance (e.g., a compound or drug) that induces half of the maximum reaction (i.e., 50% of the maximum reaction) for a biological process, or for a component of a process including proteins, subunits, organelles, ribonucleoproteins, etc. In some embodiments, EC50 may indicate the concentration of a substance required to achieve about 50% of the maximum reaction in vivo, as further defined elsewhere herein. In some embodiments, EC50 may indicate the concentration of a substance required to achieve about 10% of the maximum reaction in vivo, as further defined elsewhere herein. In some embodiments, EC50 may indicate the concentration of a substance required to achieve about 20% of the maximum reaction in vivo, as further defined elsewhere herein. In some embodiments, EC50 may indicate the concentration of a substance required to achieve about 30% of the maximum reaction in vivo, as further defined elsewhere herein. In some embodiments, EC50 may represent the concentration of a substance required to achieve about 40% of the maximum response in vivo, as further defined elsewhere in this invention. In some embodiments, EC50 may represent the concentration of a substance required to achieve about 60% of the maximum response in vivo, as further defined elsewhere in this invention. In some embodiments, EC50 may represent the concentration of a substance required to achieve about 70% of the maximum response in vivo, as further defined elsewhere in this invention. In some embodiments, the maximum response is determined by measuring the decrease in theta waves via electroencephalography (EEG). In some embodiments, the maximum response is determined by measuring a decrease in the brain's theta wave frequency of about 4 Hz to about 8 Hz during an EEG. In some embodiments, the decrease in theta waves is about 8 Hz. In some embodiments, the decrease in theta waves is about 7 Hz. In some embodiments, the decrease in theta waves is about 6 Hz.In some embodiments, the reduction of theta wave is about 5 Hz. In some embodiments, the reduction of theta wave is about 4 Hz. In some embodiments, the reduction of theta wave is about 4 Hz or more.

[0075] Compounds according to the present disclosure may form a prodrug at a hydroxyl or amino functional group using a group such as an alkoxy or amino acid as a prodrug-forming moiety. For example, a hydroxymethyl position may form a mono-, di-, or triphosphate, and these phosphates may again form a prodrug. The preparation of such prodrug derivatives is discussed in various literature sources (e.g., Alexander et al., J. Med. Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO 2000 / 041531, p. 30). When preparing these derivatives, the converted nitrogen functional group is one (or more) of the nitrogen atoms of the compounds of the present disclosure.

[0076] "Derivatives" of the compounds disclosed herein are pharmaceutically acceptable salts, prodrugs, deuteriumized forms, radiolabeled forms, isomers, solvates, and combinations thereof. In this context, "combinations" refer to derivatives belonging to two or more of the group of pharmaceutically acceptable salts, prodrugs, deuteriumized forms, radiolabeled forms, isomers, and solvates. Examples of radiolabeled forms include compounds labeled with tritium, phosphorus-32, iodine-129, carbon-11, fluorine-18, etc.

[0077] The term "leaving group" refers to an atom (or group of atoms) that has the ability to withdraw electrons and can be replaced as a stable species along with bonded electrons. Suitable examples of leaving groups include sulfonate esters, including trilates, mesylates, tosylates, and broxylates, as well as halides.

[0078] As used herein, the term “substituted” is considered to include all acceptable substituents of an organic compound. In broad embodiments, acceptable substituents include non-cyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and non-aromatic substituents of the organic compound. Exemplary substituents include those listed below, for example. One or more acceptable substituents may be the same or different for a suitable organic compound. For the purposes of this disclosure, a heteroatom such as nitrogen may have any acceptable substituent of the organic compound described herein that satisfies the hydrogen substituent and / or the valence of the heteroatom. This disclosure is not intended to be limited in any way by the acceptable substituents of the organic compound. Additionally, the terms “substituted” or “substituted” contain an implied meaning that such substitution follows the accepted valence of the substituted atom and the substituent, and that the substitution produces a stable compound, for example, a compound that does not undergo spontaneous modification by rearrangement, cyclization, removal, etc. In addition, in certain embodiments, individual substituents are considered to be optionally additionally substituted (i.e., additionally substituted or unsubstituted).

[0079] When defining various terms, "A1," "A2," "A3," and "A4" are used herein as general symbols to denote various specific substituents. These symbols may be any substituent, not limited to those disclosed herein, and when they are defined as specific substituents in one case, they may be defined as some other substituent in another case.

[0080] As used herein, the terms "halo" and "halogen" refer to atoms selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0081] As used herein, the terms “aliphatic” or “aliphatic group” refer to hydrocarbon moiety that may be linear (i.e., unbranched), branched, or cyclic (including fused, cross-linked, and spiro-fused polycycles), and may be fully saturated or contain one or more unsaturated units, but are not aromatic. Unless otherwise specified, an aliphatic group comprises 1 to 20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0082] As used herein, the term "alkyl" refers to a monovalent saturated straight-chain or branched-chain hydrocarbon radical having 1 to 6 carbon atoms, unless otherwise specified. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, tert-pentyl, neopentyl, sec-pentyl, 3-pentyl, sec-isopentyl, hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane, etc. The alkyl group may also be substituted or unsubstituted. For example, the alkyl group may be substituted with one or more groups, including but not limited to alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. The "lower alkyl" group is an alkyl group containing 1 to 6 (e.g., 1 to 4) carbon atoms. The term alkyl group may also be C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, etc., and includes up to C1-C24 alkyl.

[0083] Throughout the specification, “alkyl” is generally used to refer to both unsubstituted and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying specific substituent(s) on the alkyl group. For example, the terms “alkyl halide” or “haloalkyl” specifically refer to an alkyl group substituted with one or more halides, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group substituted with a single halide, e.g., fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group independently substituted with two or more halides, that is, each halide substituent does not need to be the same halide as another halide substituent, nor does it need to be on the same carbon in the case of multiple halide substituents. The term “alkoxyalkyl” specifically refers to an alkyl group substituted with one or more alkoxy groups, as described below. The term "aminoalkyl" specifically refers to an alkyl group substituted with one or more amino groups. The term "hydroxyalkyl" specifically refers to an alkyl group substituted with one or more hydroxy groups. Where "alkyl" is used in one case and a specific term such as "hydroxyalkyl" is used in another, it does not mean that the term "alkyl" does not refer to a specific term such as "hydroxyalkyl".

[0084] This practice is also applied to other groups described herein. That is, terms such as "cycloalkyl" refer to both unsubstituted and substituted cycloalkyl moiety, but substituted moiety may also be specifically identified herein; for example, a specific substituted cycloalkyl may be referred to, for example, as "alkylcycloalkyl." Similarly, a substituted alkoxy may be specifically referred to, for example, as "halogenated alkoxy," and a specific substituted alkenyl may be, for example, "alkenyl alcohol," etc. Again, the practice of using general terms such as "cycloalkyl" and specific terms such as "alkylcycloalkyl" does not imply that the general term does not include the specific term.

[0085] As used herein, the term “alkenyl” refers to a hydrocarbon group having 2 to 24 carbon atoms having a structural formula containing at least one carbon-carbon double bond. An asymmetric structure such as (A1A2)C=C(A3A4) is intended to include both E and Z isomers. This can be inferred from the structural formula in which the asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group may be substituted with one or more groups, including but not limited to, the alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol described herein.

[0086] As used herein, the term “alkynyl” is a hydrocarbon group having a structural formula containing at least one carbon-carbon triple bond and having 2 to 24 carbon atoms. The alkynyl group may be unsubstituted as described herein or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol.

[0087] As used herein, the term "heteroalkyl" refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, wherein nitrogen, phosphorus, and sulfur atoms are optionally oxidized and nitrogen heteroatoms are optionally quaternized. The heteroalkyl may be substituted with respect to the alkyl group as defined above.

[0088] The term "haloalkyl" includes mono, poly, and perhalalkyl groups in which the halogen is independently selected from fluorine, chlorine, bromine, and iodine.

[0089] "Alkoxy" is an alkyl group bonded to another group through an oxygen linker (-O(alkyl)). Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy.

[0090] "Haloalkoxy" is a haloalkyl group attached to another moiety via an oxygen atom, not limited to, for example, -OCHCF2 or -OCF3.

[0091] The term “9- or 10-membered carbon ring” refers to a 9- or 10-membered monocyclic (e.g., bridged or spirocyclic), polycyclic (e.g., tricyclic), or fused hydrocarbon ring system that is saturated or partially unsaturated. The term “9- or 10-membered carbon ring” also includes a saturated or partially unsaturated hydrocarbon ring fused with one or more aromatic rings or partially unsaturated hydrocarbon rings (e.g., dihydroindenyl and tetrahydronaphthalenyl). Cross-linked dicyclic cycloalkyl groups include, but are not limited to, bicyclo[4.3.1]decanyl, etc. Spirocyclic cycloalkyl groups include, for example, spiro[3.6]decanyl, spiro[4.5]decanyl, spiro[4.4]nonyl, etc. The fused cycloalkyl ring includes, for example, decahydronaphthalenyl, dihydroindeneyl, decahydroazulenyl, octahydroazulenyl, tetrahydronaphthalenyl, etc. Where specified, the optional substituent on the carbon ring (e.g., in the case of an optionally substituted cycloalkyl) may be present at any substitutable position, and it will be understood that, for example, the position to which the carbon ring is attached is included.

[0092] As used herein, the term "cycloalkyl" is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl. The term "heterocycloalkyl" is a type of cycloalkyl group as defined above and is included within the meaning of the term "cycloalkyl," wherein at least one of the carbon atoms of the ring is replaced by a heteroatom such as nitrogen, oxygen, sulfur, or phosphorus, but is not limited thereto. Cycloalkyl groups and heterocycloalkyl groups may be substituted or unsubstituted. Cycloalkyl groups and heterocycloalkyl groups may be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. In various aspects, cycloalkyl groups and heterocycloalkyl groups may be monocyclic, bicyclic (e.g., crosslinked type such as bicyclo[4.3.1]decanyl or spiro-type such as spiro[3.6]decanyl, spiro[4.5]decanyl, spiro[4.4]nonyl), polycyclic (e.g., tricyclic), or saturated or partially unsaturated fused hydrocarbon ring systems (e.g., decahydronaphthalenyl, dihydroindeneyl, decahydroazulenyl, octahydroazulenyl, tetrahydronaphthalenyl).

[0093] As used herein, the term "cycloalkenyl" is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bond, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, etc. The term "heterocycloalkenyl" is a type of cycloalkenyl group as defined above and is included within the meaning of the term "cycloalkenyl," wherein at least one of the carbon atoms of the ring is replaced by a heteroatom such as nitrogen, oxygen, sulfur, or phosphorus, but is not limited thereto. Cycloalkenyl groups and heterocycloalkenyl groups may be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group may be substituted with one or more groups including, but not limited to, the alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol described herein.

[0094] As used herein, the term "cycloalkynyl" is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bond. Examples of cycloalkynyl groups include, but are not limited to, cycloheptinyl, cyclooctinyl, cyclononinyl, etc. The term "heterocycloalkynyl" is a type of cycloalkenyl group as defined above and is included within the meaning of the term "cycloalkynyl," wherein at least one of the carbon atoms of the ring is replaced by a heteroatom such as nitrogen, oxygen, sulfur, or phosphorus, but is not limited thereto. Cycloalkynyl groups and heterocycloalkynyl groups may be substituted or unsubstituted. The cycloalkynyl group and the heterocycloalkynyl group may be substituted with one or more groups including, but not limited to, the alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol described herein.

[0095] As used herein, the terms “heterocycle” or “heterocyclil” may be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is not carbon. Accordingly, the terms include, but are not limited to, “heterocycloalkyl,” “heteroaryl,” “bicyclic heterocycle,” and “polycyclic heterocycle.” The heterocycle may be monocyclic, bicyclic (e.g., spiro or bridged), or polycyclic, or may be a saturated or partially saturated fused structure. Heterocycles include pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiaazole, pyrazol, oxazole, thiazole, imidazole, oxazole including 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole including 1,2,3-thiadiazole, 1,2,5-thiadiazole and 1,3,4-thiadiazole, triazole including 1,2,3-triazole and 1,3,4-triazole, tetrazole including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine including 1,2,4-triazine and 1,3,5-triazine, tetrazine including 1,2,4,5-tetrazole, pyrrolidine, It includes piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, etc. The term heterocyclil group may also include C2 heterocyclil, C2-C3 heterocyclil, C2-C4 heterocyclil, C2-C5 heterocyclil, C2-C6 heterocyclil, C2-C7 heterocyclil, C2-C8 heterocyclil, C2-C9 heterocyclil, C2-C10 heterocyclil, C2-C11 heterocyclil, etc., and includes up to C2-C18 heterocyclil. For example, C2 heterocyclil includes a group having two carbon atoms and at least one heteroatom, including but not limited to aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, tyranyl, etc.Alternatively, for example, a C5 heterocyclile comprises a group having five carbon atoms and at least one heteroatom, and is non-limiting to piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazephanyl, pyridinyl, etc. It is understood that the heterocyclile group may be bonded through a heteroatom within the ring, or through one of the carbons comprising the heterocyclile ring, where chemically possible.

[0096] As used herein, the terms “acyclic heterocycle” or “acyclic heterocyclile” refer to a ring system in which at least one of the ring members is not carbon. An acyclic heterocyclile includes a ring system in which an aromatic ring is fused to another aromatic ring or an aromatic ring is fused to a non-aromatic ring. An acyclic heterocyclile includes a ring system in which a benzene ring is fused to a 5- or 6-membered ring containing 1, 2, or 3 cyclic heteroatoms or a pyridine ring is fused to a 5- or 6-membered ring containing 1, 2, or 3 cyclic heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranil, quinolinil, quinoxalinil, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxynyl, 3,4-dihydro-2H-chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and 1H-pyrazolo[3,2-b]pyridin-3-yl.

[0097] As used herein, the term “heterocycloalkyl” refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system comprising a single ring and non- and tricyclic ring systems of about 3 to about 8 atoms. The heterocycloalkyl ring system comprises 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0098] The term "9-membered fused heterocyclile" means a 9-membered saturated or partially unsaturated fused heterocyclic ring comprising at least one oxygen heteroatom and optionally comprising 2 to 4 additional heteroatoms independently selected from N, O, and S. The terms "heterocycle," "heterocyclile," "heterocyclic ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein. The heterocyclic ring may be attached to a pendent group thereof at any heteroatom or carbon atom resulting in a stable structure. Examples of fused saturated or partially unsaturated heterocyclic radicals comprising at least one oxygen atom include, but are not limited to, dihydrobenzofuranyl, dihydropropyridinyl, octahydrobenzofuranyl, etc. Where it is specified that it can be optionally substituted, the heterocyclyl substituent (e.g., in the case of an optionally substituted heterocyclyl) may be present at all substitutable positions, including, for example, positions to which the heterocyclyl group is attached.

[0099] As used herein, the term “aromatic group” refers to a ring structure having a cyclic cloud of π electrons delocalized above and below the molecular plane, wherein the π cloud contains (4n+2)π electrons. Further discussion of aromaticity can be found in the literature incorporated herein by reference (Morrison and Boyd, Organic Chemistry (5th ed., 1987), Chapter 13, titled “Aromaticity,” pp. 477–497). The term “aromatic group” includes both aryl and heteroaryl groups.

[0100] As used herein, the term "aryl" is a group containing any carbon-based aromatic group, including but not limited to benzene, naphthalene, phenyl, biphenyl, anthracene, etc. The aryl group may be substituted or unsubstituted. The aryl group may be substituted with one or more groups, including but not limited to alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, -NH2, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term "biaryl" is a specific type of aryl group and is included in the definition of "aryl." Additionally, the aryl group may be a single ring structure, a fused ring structure, or a polycyclic structure attached through one or more crosslinking groups, such as carbon-carbon bonds. For example, the biaryl group may be two aryl groups that are joined together through a fused ring structure, as in naphthalene, or attached through one or more carbon-carbon bonds, as in biphenyl.

[0101] As used herein, the term “heteroaryl” refers to an aromatic group having at least one heteroatom incorporated into the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, wherein N-oxides, sulfur oxides, and dioxides are acceptable heteroatom substitutions. The heteroaryl group may be substituted or unsubstituted. The heteroaryl group may be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. The heteroaryl group may be a monocyclic or alternatively fused ring system. The heteroaryl group includes, but is not limited to, furil, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranil, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Additional non-limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl and pyrido[2,3-b]pyrazinyl.

[0102] The term "5- or 6-membered heteroaryl" refers to a 5- or 6-membered aromatic radical comprising 1 to 4 heteroatoms selected from N, O, and S. Non-limiting examples include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. Where specified, the optional substituent of the heteroaryl group may be present at any substitutable position, for example, including the position to which the heteroaryl is attached.

[0103] The term "aldehyde" as used herein is represented by the chemical formula ―C(O)H. Throughout this specification, "C(O)" is an abbreviation notation for a carbonyl group, i.e., C=O.

[0104] The terms “amine” or “amino” as used herein are represented by the chemical formula -NA1A2, wherein A1 and A2 may independently be hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl as described herein. A specific example of an amino is -NH2.

[0105] The term "alkylamino" as used herein is represented by the chemical formula ―NH(-alkyl), wherein the alkyl is as described herein. Representative examples include, but are not limited to, methylamino groups, ethylamino groups, propylamino groups, isopropylamino groups, butylamino groups, isobutylamino groups, (sec-butyl)amino groups, (tert-butyl)amino groups, pentylamino groups, isopentylamino groups, (tert-pentyl)amino groups, hexylamino groups, etc.

[0106] The term "dialkylamino" as used herein is represented by the chemical formula -N(-alkyl)2, wherein the alkyl is as described herein. Representative examples include, but are not limited to, dimethylamino groups, diethylamino groups, dipropylamino groups, diisopropylamino groups, dibutylamino groups, diisobutylamino groups, di(sec-butyl)amino groups, di(tert-butyl)amino groups, dipentylamino groups, diisopentylamino groups, di(tert-pentyl)amino groups, dihexylamino groups, N-ethyl-N-methylamino groups, N-methyl-N-propylamino groups, N-ethyl-N-propylamino groups, etc.

[0107] The term "carboxylic acid" as used herein is represented by the chemical formula ―C(O)OH.

[0108] The term “ester” as used herein is represented by the chemical formula ―OC(O)A1 or ―C(O)OA1, wherein A1 may be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “polyester” as used herein is represented by the chemical formula ―(A1O(O)C-A2-C(O)O)a― or ―(A1O(O)C-A2-OC(O))a―, wherein A1 and A2 may independently be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein, and “a” is an integer from about 1 to about 500. "Polyester" is a term used to describe a group produced by the reaction between a compound having at least two carboxylic acid groups and a compound having at least two hydroxyl groups.

[0109] The term "ether" as used herein is represented by the formula A1OA2, wherein A1 and A2 may independently be the alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groups described herein. The term "polyether" as used herein is represented by the formula ―(A1O-A2O)a―, wherein A1 and A2 may independently be the alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groups described herein, wherein "a" is an integer from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0110] As described herein, the compounds of the present disclosure may contain "optionally substituted" moiety. Generally, the term "substituted" means that one or more hydrogens of a designated moiety are replaced with suitable substituents, whether or not the term "optionally" precedes it. Unless otherwise specified, the "optionally substituted" group may have suitable substituents at each substitutable position of the group, and where more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. The combination of substituents envisioned in the present disclosure preferably results in the formation of a stable or chemically viable compound. In certain embodiments, unless otherwise explicitly indicated, it is also considered that individual substituents may be further optionally substituted (i.e., further substituted or unsubstituted).

[0111] In some embodiments, the structure of the compound may be represented by the following chemical formula:

[0112] ,

[0113] This is understood to be equivalent to the following equation:

[0114] ,

[0115] Here, n is generally an integer. That is, R n R is 5 independent substituents n (a) , R n (b) , R n (c) , R n (d) , R n (e) It is understood to represent. In each of these cases, 5 R n Each can be a hydrogen or a specified substituent. "Independent substituents" means that each R substituent can be defined independently. For example, in one case, R n (a) If is a halogen, R n (b) In that case, it is not necessarily a halogen.

[0116] In some additional embodiments, the structure of the compound may be represented by the following chemical formula:

[0117] ,

[0118] Here, R y For example, A 1 , A 2 and A 3 Represents 0 to 2 independent substituents selected from among, which are considered equivalent to groups represented by the following chemical formulas:

[0119] Here, R y represents 0 independent substituents.

[0120]

[0121] Here, R y represents one independent substituent.

[0122]

[0123] Here, R y represents two independent substituents.

[0124]

[0125] In other words, "independent substituents" means that each R substituent can be defined independently. For example, if Ry1 is A1 in one case, Ry2 is not necessarily A1 in that case.

[0126] In some additional embodiments, the structure of the compound may be represented by the following chemical formula, and

[0127] ,

[0128] Here, for example, Q consists of three substituents independently selected from hydrogen and A, which is understood to be equivalent to the following chemical formula:

[0129] .

[0130] In other words, "independent substituents" means that each Q substituent is independently defined as hydrogen or A, where Q consists of three substituents independently selected from H and A, which are considered equivalent to the groups in the following chemical formula:

[0131]

[0132] In some embodiments, the disclosed compound exists in geometric isomer forms. "Geometric isomer" refers to an isomer in which the arrangement of substituent atoms for the cycloalkyl ring differs, namely, a cis or trans isomer. Where the disclosed compound is named or represented by a structural formula without specifying a particular cis or trans geometric isomer form, such name or structural formula should be understood to encompass a single geometric isomer that does not contain other geometric isomers, a mixture of geometric isomers, or a mixture that is rich in a particular geometric isomer relative to said geometric isomer. Where a particular geometric isomer (i.e., cis or trans) is indicated, the indicated isomer has a purity of at least about 60%, 70%, 80%, 90%, 99%, or 99.9% by weight relative to the other geometric isomer.

[0133] The compounds described herein may exist in the form of pharmaceutically acceptable salts. For medicinal use, the salts of the compounds described herein refer to non-toxic "pharmaceutically acceptable salts." Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include, for example, salts of inorganic acids (e.g., hydrochloric acid, hydrobromide, phosphoric acid, nitric acid, and sulfuric acid) and salts of organic acids (e.g., acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid, and p-toluenesulfonic acid). Examples of pharmaceutically acceptable basic addition salts include, for example, sodium, potassium, calcium, ammonium, organic amine, or magnesium salts. Certain pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric acid, phosphoric acid, hydrobromide, malic acid, glycolic acid, fumaric acid, sulfuric acid, sulfamic acid, sulfanilic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, ethane disulonic acid, 2-hydroxyethylsulfonic acid, nitric acid, benzoic acid, 2-acetoxybenzoic acid, citric acid, tartaric acid, lactic acid, stearic acid, salicylic acid, glutamic acid, ascorbic acid, parmoic acid, succinic acid, fumaric acid, maleic acid, propionic acid, hydroxymaleic acid, hydroiodic acid, phenylacetic acid, alkanic acids, such as acetic acid, HOOC-(CH2)n-COOH (where n is about 0 to about 4).

[0134] The term “pharmaceuticalally acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compound being formulated. Pharmaceutically acceptable carriers, adjuvant, or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffering materials such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fats.

[0135] As used herein, the expression “pharmaceuticalally acceptable” means compounds, substances, compositions, and / or formulations suitable for use in contact with human and animal tissues within the scope of reasonable medical judgment. In some embodiments, “pharmaceutically acceptable” means approved by federal or state regulatory agencies or listed in the United States Pharmacopoeia or other generally accepted pharmacopoeias for use in animals, and more particularly in humans.

[0136] As used herein and unless otherwise specified, the term “pharmaceuticalally acceptable prodrug” means a derivative of a compound capable of producing the corresponding compound through hydrolysis, oxidation, or other reactions under biological conditions (in vitro or in vivo). Examples of prodrugs include, but are not limited to, compounds containing a biohydrolyzable moiety such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureates, and biohydrolyzable phosphate analogs. Other examples of prodrugs include compounds composed of oligonucleotides, peptides, lipids, aliphatic and aromatic groups, or NO, NO2, ONO, and ONO2 moiety. Prodrugs can typically be manufactured using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery, pages 172, 178, 949, 982 (edited by Manfred E. Wolff, 5th edition, 1995) and Design of Prodrugs (edited by H. Bundgaard, Elselvier, New York, 1985).

[0137] As used herein and unless otherwise specified, “biohydrolyzable amide,” “biohydrolyzable ester,” “biohydrolyzable carbamate,” “biohydrolyzable carbonate,” “biohydrolyzable urea,” and “biohydrolyzable phosphate” each mean an amide, ester, carbamate, carbonate, urea, or phosphate of a compound corresponding to any of the following: 1) a compound capable of conferring advantageous properties, such as absorption, duration of action, or expression of action in vivo, without interfering with the biological activity of the said compound; or 2) a compound that is biologically inactive but converts into a biologically active compound in vivo. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, lower acyloxyalkyl esters (acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl esters, etc.), lactonyl esters (phthalidyl and thiopthalidyl esters, etc.), lower alkoxyacyloxyalkyl esters (methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters, etc.), alkoxyalkyl esters, choline esters and acylaminoalkyl esters (acetamidomethyl esters, etc.). Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, amino acid amides, alkoxyacyl amides and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

[0138] Diseases, disabilities, and pathological conditions are used interchangeably at this institution.

[0139] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disease or disorder, or one or more of its symptoms, as described herein. In some embodiments, treatment, i.e., therapeutic treatment, may be administered after one or more symptoms have appeared. In other embodiments, treatment may be administered even in the absence of symptoms. For example, treatment, i.e., prophylactic treatment, may be administered to susceptible individuals before the onset of symptoms (e.g., considering the history of symptoms and / or exposure to specific organisms or other susceptibility factors). Treatment may be continued even after symptoms have resolved to delay recurrence.

[0140] As used herein, the terms “prevent” or “preventing” refer to excluding, avoiding, eliminating, preventing, stopping, or hindering something from occurring, particularly through prior action. Where reduction, inhibition, or prevention are used herein, the use of the other two words is also understood to be expressly disclosed, unless specifically otherwise stated. The term “prevention” refers to preventing the occurrence of a particular disease, disorder, or condition in a person or animal that is predisposed to such disease, disorder, or condition but has not yet been diagnosed with such disease, disorder, or / or condition, and / or inhibiting such disease, disorder, or condition, that is, preventing its progression.

[0141] The terms "effective dose" or "therapeutic effective dose" refer to an amount sufficient to achieve a desired result (e.g., inducing a biological or medical response in the subject; non-limiting examples include a dosage of about 0.01 to about 100 mg / kg body weight / day) or to affect an undesirable condition. For example, a "therapeutic effective dose" refers to an amount sufficient to achieve a desired therapeutic result or affect undesirable symptoms, but generally insufficient to cause adverse effects. A specific therapeutic effective dose level for any particular patient will depend on various factors, including the disorder being treated and its severity; the specific composition used; the patient's age, weight, general health, sex, and diet; the time of administration; the route of administration; the elimination rate of the specific compound used; the duration of treatment; drugs used in conjunction with or simultaneously with the specific compound used; and similar factors well known in the medical field. For example, starting a dose of a compound at a level lower than necessary to achieve a desired therapeutic effect and gradually increasing the dose until the desired effect is achieved is within the scope of the art. If desired, an effective daily dose may be divided into multiple doses for the purpose of administration. Thus, a single-dose composition may contain such an amount or a fraction thereof to constitute a daily dose. The individual physician may adjust the dosage in the event of any contraindications. Dosage varies and may be administered as one or more doses daily for one day or several days. Guidelines for appropriate dosages for a given class of medicines can be found in the literature. In various additional embodiments, the formulation may be administered as a "prophylactic effective dose," that is, an amount effective for the prevention of a disease or condition.

[0142] As used herein, the term “salt” refers to an acid salt or base salt of a compound used in the method of the present disclosure. Exemplary examples of acceptable salts include salts of inorganic acids (hydrochloric acid, hydrobromide, phosphoric acid, etc.), salts of organic acids (acetic acid, propionic acid, glutamic acid, citric acid, etc.), and salts of quaternary ammoniums (methyl iodide, ethyl iodide, etc.).

[0143] The terms “subject” and “patient” may be used interchangeably and refer to mammals requiring treatment, e.g., companion animals (e.g., dogs, cats, and similar ones), farm animals (e.g., cows, pigs, horses, sheep, goats, and similar ones), and laboratory animals (e.g., rats, mice, guinea pigs, and similar ones). In some embodiments, the subject is a human requiring treatment.

[0144] The terms “related” or “associated with” used in the context of a substance or the activity or function of a substance associated with a disorder (e.g., protein-related disease, symptoms associated with opioid preference, opioid use disorder, or symptoms associated with pain) mean that the said disease (e.g., opioid preference, opioid use disorder) is caused (wholly or partially) by the activity or function of the said substance or substance, or that the symptoms of said disease are caused (wholly or partially). For example, symptoms of a disease or condition associated with elevated dopamine receptor activity levels may be symptoms that appear (wholly or partially) due to the activation of dopamine receptor activity levels. As used herein, if what is described as associated with a disease is a causative substance, it may be a target for the treatment of the disease. For example, a disease associated with the stimulation or sustained stimulation of opioid receptors may be treated using agents (e.g., compounds described herein) that are effective in reducing opioid activity by binding to the said receptor or indirectly binding to other receptors such as dopamine receptors.

[0145] "Control group" or "control experiment" is used in its ordinary and common sense and refers to an experiment in which the subjects or reagents are treated as in a parallel experiment, except for the omission of experimental procedures, reagents, or variables. In some cases, the control group is used as a standard of comparison to evaluate experimental effects.

[0146] "Contact" is used in the general sense and refers to a process that allows at least two distinct species (e.g., compounds containing biomolecules or cells) to be close enough to react, interact, or physically contact each other. However, it should be understood that the resulting reaction product may be generated from a reaction between the added reagents or directly from an intermediate from one or more added reagents that may be generated in the reaction mixture. The term "contact" may include allowing two species to react, interact, or physically contact each other, wherein the two species may be compounds and proteins or enzymes (e.g., dopamine antagonists for dopamine receptors) as described herein. In an embodiment, contact involves allowing a compound described herein to interact with a protein or enzyme involved in a signaling pathway.

[0147] As defined herein, with respect to protein-modifier (e.g., antagonist) interactions, terms such as "inhibition," "to inhibit," and "inhibiting" mean having a negative effect (e.g., reducing) on ​​the activity or function of a protein compared to the activity or function of a protein in the absence of the modulator. In the embodiments, inhibition refers to a reduction in a disease or symptoms of a disease. In the embodiments, inhibition refers to a reduction in a signaling pathway or the activity of a signaling pathway. Thus, inhibition includes blocking a stimulus at least partially, partially or wholly, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating signaling or enzyme activity or the amount of a protein.

[0148] sign " " indicates the attachment point of a chemical moiety to the rest of the molecule or chemical formula.

[0149] As defined herein, terms such as “activation,” “to activate,” “activating,” etc., in relation to protein-activator (e.g., agonist) interactions, mean having a positive effect (e.g., increasing) on ​​the activity or function of a said protein (e.g., opioid receptors for opioids, dopamine receptors for dopamine agonists) compared to the protein activity or function in the absence of an activator (e.g., compounds described herein). In the embodiments, activation refers to an increase in the activity of a signaling pathway or a signaling pathway (e.g., an opioid receptor pathway). Thus, activation may include at least partially increasing stimulation, partially or wholly, increasing or enabling activation, or activating, sensitizing, or upregulating signaling or enzyme activity, or the amount of a protein, that has been reduced due to disease (e.g., a decrease in opioid receptor activity levels or protein levels associated with dopamine effects). Activation may include, at least in part, increasing stimulation partially or wholly, increasing or enabling activation, activating, sensitizing, or upregulating signal transduction or enzymatic activity, or increasing the amount of proteins (e.g., mu receptors (MOR), kappa receptors (KOR), delta receptors (DOR), nociceptors (NOR), and zeta receptors (ZOR)—selectively including mu1, mu2, mu3, kappa1, kappa2, kappa3, delta1, and delta2 within these various types), which may regulate the levels of other proteins or stimulate the release of additional neurotransmitters (e.g., an increase in opioid activity may increase the pain-relieving effect, which may or may not be accompanied by a decrease in opioid receptor function compared to a control group).

[0150] The term "modulator" refers to a composition that increases or decreases the concentration or function of a target molecule. In embodiments, the modulator is a modulator of mu receptors (MOR), kappa receptors (KOR), delta receptors (DOR), nociceptors (NOR), and / or zeta receptors (ZOR) in relation to opioids, or a modulator of D1, D2, D3, D4, and / or D5 in relation to dopamine antagonists. In embodiments, the modulator is an opioid receptor modulator and is a compound that reduces the severity of one or more symptoms of a disease or disorder related to drug preference (e.g., a reduction in the levels of D1, D2, D3, D4, and / or D5 activity or protein associated with drug preference or opioid disorder). In an embodiment, the modifier is a compound that reduces the severity of one or more symptoms of drug preference, pain, or opioid dependence, which are not caused or characterized by D1, D2, D3, D4, or D5, but can be improved through modulation of D1, D2, D3, D4, or D5 activity (e.g., increase in the level of activity).

[0151] The term "opioid-related disorder" refers to drug preference, opioid dependence, opioid use disorder, and persistent and / or newly developed persistent opioid use.

[0152] Drug "likability" is an indicator of how much a patient feels they like the effects of the drug. This is measured using a visual analog scale, which can be unipolar or bipolar (i.e., a form capable of quantifying both liking and disliking).

[0153] "Opioid dependence" generally refers to a persistent urge to continue using opioids despite the harm or negative consequences resulting from the repeated and long-term use of opioids.

[0154] The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) defines the diagnostic criteria for opioid use disorder as including the following elements or assessment items: 1) frequent use of opioids in larger amounts or for longer periods than intended; 2) a persistent desire to reduce or control opioid use, or failure of such attempts; 3) significant time required for activities necessary to obtain, use, or recover from the effects of opioids; 4) craving, that is, a strong desire or impulse to use opioids; 5) failure to fulfill primary role duties at work, school, or home due to repeated opioid use; 6) continued use of opioids despite persistent or recurring social or interpersonal problems caused or exacerbated by the effects of opioids; 7) giving up or reducing important social, occupational, or leisure activities due to opioid use; 8) Repeated use of opioids in physically dangerous situations; 9) Continued use of opioids despite knowing that there are persistent or recurring physical or psychological problems likely caused or aggravated by the substance; 10) Drug "tolerance" corresponding to any of the following: A) A state of addiction or the need to significantly increase the dosage of opioids to achieve the desired effect; B) Significantly reduced effectiveness when the same amount of opioids is continuously administered.

[0155] Continuous opioid use can be defined as at least one opioid prescription occurring between 90 and 180 days after any specific standard treatment, such as surgery. New continuous opioid use may mean at least one opioid prescription occurring between 90 and 180 days after any specific standard medical treatment, such as surgery, where no opioid prescriptions were made for 11 months prior to the treatment.

[0156] Clinical outcomes that may reflect a reduction in the risk of opioid-related disorders achieved by applying the techniques described herein may include: a decrease in preference for the drug; a decrease in drug intake (which may be measured in other units such as morphine equivalents (MME) or milligrams of a specific opioid); an opioid sparing effect measured in MME, milligrams, or as a percentage relative to a specific reference value or control group; the incidence of continued opioid use or new continued opioid use following specific indicator medical treatment, such as surgery; the severity of continued opioid use or new continued opioid use (measured in the amount of opioid continuously consumed or prescribed in MME or milligrams of a specific opioid, or other comparable severity measures); the incidence of opioid use disorder, or its severity measured by the number of DSM-V criteria items meeting the definition of opioid use disorder; the frequency or severity of any of the elements constituting the DSM-V criteria for opioid use disorder.

[0157] “Patient” or “subject requiring this” refers to a living organism suffering from or prone to a disease or condition that can be treated by the administration of a compound or pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, cattle, rats, pigs, mice, dogs, cats, monkeys, goats, sheep, dairy cows, deer, and other non-mammalians. In an embodiment, the patient is a human.

[0158] composition

[0159] The present disclosure relates to a composition comprising (i) a dopamine antagonist; and (ii) an opioid, wherein the dopamine antagonist is selected from any one of formulas I, II, III, or IV, its salt, or its prodrug. In some embodiments, the opioid is selected from any one of formulas V or VI, its salt, or its prodrug. The present disclosure also relates to a composition comprising (i) a dopamine antagonist; and (ii) an opioid, wherein the dopamine antagonist is selected from any dopamine antagonist, its salt, or its prodrug. In some embodiments, the opioid is selected from any one of formulas V or VI, its salt, or its prodrug. In some embodiments, the present disclosure relates to a composition comprising a single active ingredient that is a dopamine agonist. The composition comprises all disclosed dopamine antagonists and / or opioids, including but not limited to the molecules listed in Tables X, Y, and Z. In some embodiments, dopamine antagonists and / or opioids have masses, mass ranges, or concentrations provided herein, which include, but are not limited to, the masses and / or concentrations listed in any one of Tables X, Y, or Z.

[0160] The present disclosure relates to a composition comprising (i) a dopamine antagonist; and (ii) an opioid, wherein the total mass of the dopamine antagonist is about 0.1 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the composition comprises a dopamine antagonist having a total mass of about 0.2 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. The total mass of the dopamine antagonist is about 0.3 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. The total mass of the dopamine antagonist is about 0.4 to about 2.5 milligrams, where the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. The total mass of the dopamine antagonist is about 0.5 to about 2.5 milligrams; where, the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. The total mass of the dopamine antagonist is about 0.6 to about 2.5 milligrams; where, the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. The total mass of the dopamine antagonist is about 0.7 to about 2.5 milligrams; Here, the total mass of the opioid is about 0.2 milligrams to about 150 milligrams; the total mass of the dopamine antagonist is about 0.8 to about 2.5 milligrams; here, the total mass of the opioid is about 0.2 milligrams to about 150 milligrams; the total mass of the dopamine antagonist is about 0.9 to about 2.5 milligrams; here, the total mass of the opioid is about 0.2 milligrams to about 150 milligrams; the total mass of the dopamine antagonist is about 1.0 to about 2.5 milligrams; here, the total mass of the opioid is about 0.2 milligrams to about 150 milligrams; the total mass of the dopamine antagonist is about 1.1 to about 2.5 milligrams; here, the total mass of the opioid is about 0.2 milligrams to about 150 milligrams; the total mass of the dopamine antagonist is about 0.1 to about 2.5 milligrams; wherein the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the composition is an immediate-release formulation. In some embodiments, the present disclosure relates to a pharmaceutical composition comprising the composition described herein and a pharmaceutically acceptable carrier.

[0161] The present disclosure relates to a composition comprising (i) a dopamine antagonist comprising DD12; and (ii) an opioid, wherein the total mass of the dopamine antagonist is about 0.1 to about 2.5 milligrams; and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the composition does not comprise DD9, DD10, variants thereof, or salts thereof. In some embodiments, the total mass of the dopamine antagonist is about 0.2 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the total mass of DD12 is about 0.2 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the total mass of the dopamine antagonist is about 0.3 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the total mass of DD12 is about 0.3 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the total mass of the dopamine antagonist is about 0.4 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the total mass of DD12 is about 0.4 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the total mass of the dopamine antagonist is about 0.5 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the total mass of DD12 is about 0.5 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the total mass of the dopamine antagonist is about 0.6 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams.In some embodiments, the total mass of DD12 is about 0.6 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the total mass of the dopamine antagonist is about 0.7 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the total mass of DD12 is about 0.7 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the total mass of the dopamine antagonist is about 0.8 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the total mass of DD12 is about 0.8 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the total mass of the dopamine antagonist is about 0.9 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the total mass of DD12 is about 0.9 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the total mass of the dopamine antagonist is about 1.0 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the total mass of DD12 is about 1.0 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the total mass of the dopamine antagonist is about 1.1 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the total mass of DD12 is about 1.1 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams.In some embodiments, the total mass of the dopamine antagonist is about 0.1 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the total mass of DD12 is about 0.1 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. In some embodiments, the composition is an immediate-release formulation. In some embodiments, the present disclosure relates to a pharmaceutical composition comprising the composition described herein and a pharmaceutically acceptable carrier.

[0162] The present disclosure relates to a composition comprising (i) a dopamine antagonist; and (ii) an opioid, wherein the dopamine antagonist is amilphride. In some embodiments, the composition comprises a total mass of about 10 to about 800 milligrams of amilphride, wherein the composition contains about 1 milligram to about 2 milligrams of buprenorphine. In some embodiments, the composition comprises a total mass of about 10 to about 800 milligrams of amilphride, wherein the composition contains about 4 milligrams to about 8 milligrams of buprenorphine. In some embodiments, the composition comprises a total mass of about 1.5 to about 800 milligrams of amilphride, wherein the composition contains about 7.5 milligrams to about 15 milligrams of codeine. In some embodiments, the composition comprises a total mass of about 2.99 to about 800 milligrams of amyulfride, wherein the composition contains about 15 milligrams to about 30 milligrams of codeine. In some embodiments, the composition comprises a total mass of about 5.98 to about 800 milligrams of amyulfride, wherein the composition contains about 30 milligrams to about 60 milligrams of codeine. In some embodiments, the composition comprises a total mass of about 2.35 to about 800 milligrams of amyulfride, wherein the composition contains about 5 milligrams to about 10 milligrams of hydrocodone. In some embodiments, the composition comprises a total mass of about 4.7 to about 800 milligrams of amyulfride, wherein the composition contains about 10 milligrams to about 20 milligrams of hydrocodone. In some embodiments, the composition comprises a total mass of about 7.05 to about 800 milligrams of amyulfrid, wherein the composition contains about 15 milligrams to about 30 milligrams of hydrocodon. In some embodiments, the composition comprises a total mass of about 9.4 to about 800 milligrams of amyulfrid, wherein the composition contains about 20 milligrams to about 40 milligrams of hydrocodon.In some embodiments, the composition comprises a total mass of about 10 to about 800 milligrams of amyulfride, wherein the composition contains about 25 to about 50 milligrams of hydrocodon. In some embodiments, the composition comprises a total mass of about 10 to about 800 milligrams of amyulfride, wherein the composition contains about 30 to about 60 milligrams of hydrocodon. In some embodiments, the composition comprises a total mass of about 10 to about 800 milligrams of amyulfride, wherein the composition contains about 40 to about 80 milligrams of hydrocodon. In some embodiments, the composition comprises a total mass of about 10 to about 800 milligrams of amyulfride, wherein the composition contains about 50 to about 100 milligrams of hydrocodon. In some embodiments, the composition comprises a total mass of about 10 to about 800 milligrams of amyulfride, wherein the composition comprises about 100 milligrams to about 200 milligrams of hydrocodone. In some embodiments, the composition comprises a total mass of about 1.9 to about 800 milligrams of amyulfride, wherein the composition comprises about 1 milligram to about 2 milligrams of hydromorphone. In some embodiments, the composition comprises a total mass of about 3.79 to about 800 milligrams of amyulfride, wherein the composition comprises about 2 milligrams to about 4 milligrams of hydromorphone. In some embodiments, the composition comprises a total mass of about 7.58 to about 800 milligrams of amyulfride, wherein the composition comprises about 4 milligrams to about 8 milligrams of hydromorphone. In some embodiments, the composition comprises a total mass of about 5.27 to about 800 milligrams of amyulprid, wherein the composition contains about 1 milligram to about 2 milligrams of levolphanol. In some embodiments, the composition comprises a total mass of about 1.The composition comprises 18 to about 800 milligrams of amilphride, wherein the composition comprises about 25 milligrams to about 50 milligrams of meperidine. In some embodiments, the composition comprises a total mass of about 2.35 to about 800 milligrams of amilphride, wherein the composition comprises about 50 milligrams to about 100 milligrams of meperidine. In some embodiments, the composition comprises a total mass of about 2.35 to about 800 milligrams of amilphride, wherein the composition contains about 5 milligrams to about 10 milligrams of morphine. In some embodiments, the composition comprises a total mass of about 3.53 to about 800 milligrams of amilphride, wherein the composition contains about 7.5 milligrams to about 15 milligrams of morphine. In some embodiments, the composition comprises a total mass of about 7.05 to about 800 milligrams of amilphride, wherein the composition contains about 15 milligrams to about 30 milligrams of morphine. In some embodiments, the composition comprises a total mass of about 10 to about 800 milligrams of amilphride, wherein the composition contains about 30 milligrams to about 60 milligrams of morphine. In some embodiments, the composition comprises a total mass of about 10 to about 800 milligrams of amilphride, wherein the composition contains about 50 milligrams to about 100 milligrams of morphine. In some embodiments, the composition comprises a total mass of about 2.38 to about 800 milligrams of amilphride, wherein the composition contains about 2.5 milligrams to about 5 milligrams of methadone. In some embodiments, the composition comprises a total mass of about 4.75 to about 800 milligrams of amyulfride, wherein the composition contains about 5 milligrams to about 10 milligrams of methadone. In some embodiments, the composition comprises a total mass of about 1.78 to about 800 milligrams of amyulfride, wherein the composition contains about 2.5 milligrams to about 5 milligrams of oxycodone.In some embodiments, the composition comprises a total mass of about 2.67 to about 800 milligrams of amilphride, wherein the composition contains about 3.75 milligrams to about 7.5 milligrams of oxycodone. In some embodiments, the composition comprises a total mass of about 3.56 to about 800 milligrams of amilphride, wherein the composition contains about 5 milligrams to about 10 milligrams of oxycodone. In some embodiments, the composition comprises a total mass of about 5.34 to about 800 milligrams of amilphride, wherein the composition contains about 7.5 milligrams to about 15 milligrams of oxycodone. In some embodiments, the composition comprises a total mass of about 10 to about 800 milligrams of amilphride, wherein the composition contains about 15 milligrams to about 30 milligrams of oxycodone. In some embodiments, the composition comprises a total mass of about 10 to about 800 milligrams of amilphride, wherein the composition comprises about 20 to about 40 milligrams of oxycodone. In some embodiments, the composition comprises a total mass of about 3.56 to about 800 milligrams of amilphride, wherein the composition comprises about 2.5 to about 5 milligrams of oxymorphone. In some embodiments, the composition comprises a total mass of about 7.12 to about 800 milligrams of amilphride, wherein the composition comprises about 5 to about 10 milligrams of oxymorphone. In some embodiments, the composition comprises a total mass of about 2.32 to about 800 milligrams of amilphride, wherein the composition comprises about 32.5 to about 65 milligrams of propoxyphen. In some embodiments, the composition comprises a total mass of about 4.63 to about 800 milligrams of amyulfride, wherein the composition contains about 25 to about 50 milligrams of tapentadol. In some embodiments, the composition comprises a total mass of about 6.95 to about 800 milligrams of amyulfride, wherein the composition contains about 37.It contains 5 milligrams to about 75 milligrams of tapentadol. In some embodiments, the composition comprises a total mass of about 9.26 to about 800 milligrams of amilphride, wherein the composition contains about 50 milligrams to about 100 milligrams of tapentadol. In some embodiments, the composition comprises a total mass of about 1.07 to about 800 milligrams of amilphride, wherein the composition contains about 25 milligrams to about 50 milligrams of tramadol. In some embodiments, the composition comprises a total mass of about 2.14 to about 800 milligrams of amilphride, wherein the composition contains about 50 milligrams to about 100 milligrams of tramadol. In some embodiments, the composition comprises a total mass of about 4.27 to about 800 milligrams of amilphride, wherein the composition contains about 100 milligrams to about 200 milligrams of tramadol. In some embodiments, the composition comprises a total mass of about 6.41 to about 800 milligrams of amyulprid, wherein the composition comprises about 150 milligrams to about 300 milligrams of tramadol. In some embodiments, the composition is an immediate-release formulation. In some embodiments, the present disclosure relates to a pharmaceutical composition comprising the composition described herein and a pharmaceutically acceptable carrier.

[0163] Table W: Table of names of representative dopamine antagonists

[0164]

[0165] Table X: Dopamine antagonist table

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172] Table Y: Opioid Table

[0173]

[0174]

[0175] Table Z: Conversion ratios used to calculate dopamine antagonists and dosage ranges

[0176]

[0177] The composition of the present disclosure comprises a pharmaceutical composition comprising two active ingredients and a pharmaceutically acceptable carrier. The present disclosure relates to a pharmaceutical composition comprising an effective amount of a dopamine antagonist and an effective amount of an opioid, wherein the dopamine antagonist accounts for about 50% to about 70% of the total weight by mass percentage, and the opioid accounts for about 10% to about 30% of the total weight by mass percentage.

[0178] Embodiments of the present disclosure may be prepared in formulations that are easy to administer. The formulations of the present disclosure include solid or liquid formulations. In the case of solid formulations, embodiments of the present disclosure include formulations such as tablets or capsules through methods well known in the art. It is known that when preparing tablets containing analgesic formulations, the salts may be compressed into a homogeneous mixture and, if necessary, an inert diluent such as a tablet binder may be included. The tablet binder may be a pharmaceutically acceptable binder and is a binder that does not cause significant osmotic effects. Examples of useful binders include nonionic surfactants of the Pluronic™ series (e.g., Pluronic F-68™ (a trademark of BASF-Wyandotte Chemicals, defined as a condensate of ethylene oxide, propylene oxide, and propylene glycol)), related nonionic surfactants, mechanical adhesives such as polyvinyl alcohol and sodium carboxymethylcellulose, and numerous other examples. Microcrystalline cellulose (MCC) may also be used to improve compressibility when compressing all salts disclosed herein into tablet or capsule form. Soluble, non-fermentable binders that may be used in the compositions of the present disclosure include polyethylene glycol (PEG). The structural formula of PEG is as follows: HOCH2(CH2OCH2)mCH2OH, where m represents the average number of oxyethylene groups. Any PEG polymer may be used in the compositions considered herein. In some embodiments, the PEG polymer may be in a solid state at room temperature (i.e., 25°C) and / or may be soluble in water (or mixed with water) at room temperature. In some embodiments of the present disclosure, the average molecular weight of the PEG polymer is at least 200, at least 400, at least 600, at least 1,000, at least 1,540, at least 3,000, at least 4,000, or at least 8,000. In some embodiments of the present disclosure, the average molecular weight of the PEG polymer is about 7,000 to about 9,000.

[0179] The amount of binder may vary depending on the desired characteristics of the solid formulation and can be determined by a person skilled in the art. In some embodiments of the present disclosure, the content of the PEG binder is about 5% to about 20% by weight, in other embodiments about 7.5% to about 15%, and in yet another embodiment about 10%. In some embodiments of the present disclosure, the formulation does not contain a PEG binder.

[0180] In some embodiments of the present disclosure, the composition of the present disclosure does not contain an insoluble binder, or contains only an insoluble binder at a level that does not interfere with or impede the visualization of the large intestine. A person skilled in the art can readily modify the additive mixed with the dopamine antagonist and / or opioid salt according to the present disclosure to optimize the formulation for oral administration.

[0181] Solid formulations are well known in the industry. Solid formulations are easier for patients or caregivers to identify, handle, and administer. They are also non-invasive and offer high patient compliance. Solid formulations can be divided into several groups based on the route of drug delivery, including, for example, gastrointestinal (GI) administration, suppositories (rectal, vaginal, and urethral), and transdermal administration. Most solid formulations on the market are designed to deliver drugs through the gastrointestinal tract. GI administration is often simply referred to as "oral administration" because tablets or capsules are initially placed in the mouth and swallowed. However, these types of solid dosage forms are designed to dissolve within the GI tract.

[0182] In some embodiments, the present disclosure relates to an oral formulation in the form of a pharmaceutical composition comprising a dopamine antagonist and an opioid, and further comprising a pharmaceutically acceptable carrier. In some embodiments, the oral formulation comprises two active ingredients consisting of one dopamine antagonist listed in the table above and one opioid listed in the table above. In some embodiments, the pharmaceutical composition or formulation does not include non-opioid analgesics, barbiturate preparations, or stimulants. In some embodiments, the pharmaceutical composition or formulation does not include active ingredients other than a single dopamine antagonist and a single opioid. In some embodiments, the composition or pharmaceutical composition of the present disclosure does not include acetaminophen and naproxen.

[0183] The present disclosure relates to a composition comprising (i) a dopamine antagonist; and (ii) an opioid, wherein the dopamine antagonist is aripiprazole. In some embodiments, the composition comprises a total mass of about 2.91 to about 42.76 milligrams of aripiprazole, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 6 to about 171.05 milligrams of aripiprazole, wherein the composition comprises a total mass of about 4 milligrams to about 8 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 0.31 to about 4.49 milligrams of aripiprazole, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of codeine; In some embodiments, the composition comprises a total mass of about 0.61 to about 8.98 milligrams of aripiprazole, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 1.22 to about 17.96 milligrams of aripiprazole, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 0.48 to about 7.06 milligrams of aripiprazole, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 0.96 to about 14.11 milligrams of aripiprazole, wherein the composition comprises a total mass of about 10 milligrams to about 20 milligrams of hydrocodone; In some embodiments, the composition comprises a total mass of about 1.44 to about 21.17 milligrams of aripiprazole, wherein the composition comprises a total mass of about 15 to about 30 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 1.92 to about 28.The composition comprises 22 milligrams of aripiprazole, wherein the composition contains a total mass of about 20 milligrams to about 40 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 2.4 to about 35.28 milligrams of aripiprazole, wherein the composition contains a total mass of about 25 milligrams to about 50 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 2.88 to about 42.33 milligrams of aripiprazole, wherein the composition contains a total mass of about 30 milligrams to about 60 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 3.85 to about 56.45 milligrams of aripiprazole, wherein the composition contains a total mass of about 40 milligrams to about 80 milligrams of hydrocodon; In some embodiments, the composition comprises a total mass of about 4.81 to about 70.56 milligrams of aripiprazole, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 6 to about 141.11 milligrams of aripiprazole, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 0.39 to about 5.69 milligrams of aripiprazole, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 0.77 to about 11.38 milligrams of aripiprazole, wherein the composition comprises a total mass of about 2 milligrams to about 4 milligrams of hydromorphone; In some embodiments, the composition comprises a total mass of about 1.55 to about 22.75 milligrams of aripiprazole, wherein the composition comprises a total mass of about 4 milligrams to about 8 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 1.08 to about 15.The composition comprises 82 milligrams of aripiprazole, wherein the composition contains about 1 milligram to about 2 milligrams of levophanol by total mass; in some embodiments, the composition comprises about 0.24 to about 3.53 milligrams of aripiprazole by total mass, wherein the composition contains about 25 milligrams to about 50 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 0.48 to about 7.06 milligrams of aripiprazole by total mass, wherein the composition contains about 50 milligrams to about 100 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 0.48 to about 7.06 milligrams of aripiprazole by total mass, wherein the composition contains about 5 milligrams to about 10 milligrams of morphine by total mass; In some embodiments, the composition comprises a total mass of about 0.72 to about 10.58 milligrams of aripiprazole, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 1.44 to about 21.17 milligrams of aripiprazole, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 2.88 to about 42.33 milligrams of aripiprazole, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 4.81 to about 70.56 milligrams of aripiprazole, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of morphine; In some embodiments, the composition comprises a total mass of about 0.49 to about 7.13 milligrams of aripiprazole, wherein the composition contains a total mass of about 2.5 to about 5 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 0.97 to about 14.The composition comprises 26 milligrams of aripiprazole, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 0.36 to about 5.35 milligrams of aripiprazole, wherein the composition contains a total mass of about 2.5 milligrams to about 5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.55 to about 8.02 milligrams of aripiprazole, wherein the composition contains a total mass of about 3.75 milligrams to about 7.5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.73 to about 10.69 milligrams of aripiprazole, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of oxycodone; In some embodiments, the composition comprises a total mass of about 1.09 to about 16.04 milligrams of aripiprazole, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 2.18 to about 32.07 milligrams of aripiprazole, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 2.91 to about 42.76 milligrams of aripiprazole, wherein the composition comprises a total mass of about 20 milligrams to about 40 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.73 to about 10.69 milligrams of aripiprazole, wherein the composition comprises a total mass of about 2.5 milligrams to about 5 milligrams of oxymorphone; In some embodiments, the composition comprises a total mass of about 1.46 to about 21.38 milligrams of aripiprazole, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of oxymorphone; in some embodiments, the composition comprises a total mass of about 0.47 to about 6.The composition comprises 95 milligrams of aripiprazole, wherein the composition contains propoxyphen in a total mass of about 32.5 milligrams to about 65 milligrams; in some embodiments, the composition comprises aripiprazole in a total mass of about 0.95 to about 13.9 milligrams, wherein the composition contains tapentadol in a total mass of about 25 milligrams to about 50 milligrams; in some embodiments, the composition comprises aripiprazole in a total mass of about 1.42 to about 20.85 milligrams, wherein the composition contains tapentadol in a total mass of about 37.5 milligrams to about 75 milligrams; in some embodiments, the composition comprises aripiprazole in a total mass of about 1.89 to about 27.8 milligrams, wherein the composition contains tapentadol in a total mass of about 50 milligrams to about 100 milligrams; In some embodiments, the composition comprises a total mass of about 0.22 to about 3.21 milligrams of aripiprazole, wherein the composition comprises a total mass of about 25 milligrams to about 50 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 0.44 to about 6.41 milligrams of aripiprazole, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 0.87 to about 12.83 milligrams of aripiprazole, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 1.31 to about 19.24 milligrams of aripiprazole, wherein the composition comprises a total mass of about 150 milligrams to about 300 milligrams of tramadol.

[0184] Chlorpromazine

[0185] The present disclosure relates to a composition comprising (i) a dopamine antagonist; and (ii) an opioid, wherein the dopamine antagonist is chlorpromazine. In some embodiments, the composition comprises a total mass of about 58.26 to about 855.24 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 120 to about 3420.9 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 4 milligrams to about 8 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 6.12 to about 89.82 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of codeine; In some embodiments, the composition comprises a total mass of about 12.24 to about 179.58 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 24.48 to about 359.22 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 9.6 to about 141.12 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 19.2 to about 282.24 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 10 milligrams to about 20 milligrams of hydrocodone; In some embodiments, the composition comprises a total mass of about 28.86 to about 423.36 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 38.The composition comprises 46 to about 564.48 milligrams of chlorpromazine, wherein the composition contains about 20 milligrams to about 40 milligrams of hydrocodon by total mass; in some embodiments, the composition comprises about 48.06 to about 705.54 milligrams of chlorpromazine by total mass, wherein the composition contains about 25 milligrams to about 50 milligrams of hydrocodon by total mass; in some embodiments, the composition comprises about 57.66 to about 846.66 milligrams of chlorpromazine by total mass, wherein the composition contains about 30 milligrams to about 60 milligrams of hydrocodon by total mass; in some embodiments, the composition comprises about 76.92 to about 1128.9 milligrams of chlorpromazine by total mass, wherein the composition contains about 40 milligrams to about 80 milligrams of hydrocodon by total mass; In some embodiments, the composition comprises a total mass of about 96.12 to about 1411.14 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 120 to about 2822.28 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 7.74 to about 113.76 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of hydromorphone; In some embodiments, the composition comprises a total mass of about 15.48 to about 227.52 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 2 milligrams to about 4 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 31.02 to about 454.The composition comprises 98 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 4 milligrams to about 8 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 21.54 to about 316.44 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of levorphanol; in some embodiments, the composition comprises a total mass of about 4.8 to about 70.56 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 25 milligrams to about 50 milligrams of meperidine; in some embodiments, the composition comprises a total mass of about 9.6 to about 141.12 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of meperidine; In some embodiments, the composition comprises a total mass of about 9.6 to about 141.12 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 14.4 to about 211.68 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 28.86 to about 423.36 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 57.66 to about 846.66 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of morphine; In some embodiments, the composition comprises a total mass of about 96.12 to about 1411.14 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 9.72 to about 142.The composition comprises 62 milligrams of chlorpromazine, wherein the composition contains a total mass of about 2.5 milligrams to about 5 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 19.44 to about 285.24 milligrams of chlorpromazine, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 7.26 to about 106.92 milligrams of chlorpromazine, wherein the composition contains a total mass of about 2.5 milligrams to about 5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 10.92 to about 160.38 milligrams of chlorpromazine, wherein the composition contains a total mass of about 3.75 milligrams to about 7.5 milligrams of oxycodone; In some embodiments, the composition comprises a total mass of about 14.58 to about 213.78 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 21.84 to about 320.7 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 43.68 to about 641.4 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 58.26 to about 855.24 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 20 milligrams to about 40 milligrams of oxycodone; In some embodiments, the composition comprises a total mass of about 14.58 to about 213.78 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 2.5 to about 5 milligrams of oxymorphone; in some embodiments, the composition comprises a total mass of about 29.The composition comprises 16 to about 427.62 milligrams of chlorpromazine, wherein the composition comprises about 5 milligrams to about 10 milligrams of oxymorphone by total mass; in some embodiments, the composition comprises about 9.48 to about 138.96 milligrams of chlorpromazine by total mass, wherein the composition comprises about 32.5 milligrams to about 65 milligrams of propoxyphene by total mass; in some embodiments, the composition comprises about 18.96 to about 277.92 milligrams of chlorpromazine by total mass, wherein the composition comprises about 25 milligrams to about 50 milligrams of tapentadol by total mass; in some embodiments, the composition comprises about 28.38 to about 416.94 milligrams of chlorpromazine by total mass, wherein the composition comprises about 37.5 milligrams to about 75 milligrams of tapentadol by total mass; In some embodiments, the composition comprises a total mass of about 37.86 to about 555.9 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of tapentadol; in some embodiments, the composition comprises a total mass of about 4.38 to about 64.14 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 25 milligrams to about 50 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 8.76 to about 128.28 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of tramadol; In some embodiments, the composition comprises a total mass of about 17.46 to about 256.56 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 26.22 to about 384.84 milligrams of chlorpromazine, wherein the composition comprises a total mass of about 150 milligrams to about 300 milligrams of tramadol.

[0186] Clozapine

[0187] The present disclosure relates to a composition comprising (i) a dopamine antagonist; and (ii) an opioid, wherein the dopamine antagonist is clozapine. In some embodiments, the composition comprises a total mass of about 38.84 to about 570.16 milligrams of clozapine, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 80 to about 2280.6 milligrams of clozapine, wherein the composition comprises a total mass of about 4 milligrams to about 8 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 4.08 to about 59.88 milligrams of clozapine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of codeine; In some embodiments, the composition comprises a total mass of about 8.16 to about 119.72 milligrams of clozapine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 16.32 to about 239.48 milligrams of clozapine, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 6.4 to about 94.08 milligrams of clozapine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 12.8 to about 188.16 milligrams of clozapine, wherein the composition comprises a total mass of about 10 milligrams to about 20 milligrams of hydrocodone; In some embodiments, the composition comprises a total mass of about 19.24 to about 282.24 milligrams of clozapine, wherein the composition comprises a total mass of about 15 to about 30 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 25.64 to about 376.The composition comprises 32 milligrams of clozapine, wherein the composition contains a total mass of about 20 milligrams to about 40 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 32.04 to about 470.36 milligrams of clozapine, wherein the composition contains a total mass of about 25 milligrams to about 50 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 38.44 to about 564.44 milligrams of clozapine, wherein the composition contains a total mass of about 30 milligrams to about 60 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 51.28 to about 752.6 milligrams of clozapine, wherein the composition contains a total mass of about 40 milligrams to about 80 milligrams of hydrocodon; In some embodiments, the composition comprises a total mass of about 64.08 to about 940.76 milligrams of clozapine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 80 to about 1881.52 milligrams of clozapine, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 5.16 to about 75.84 milligrams of clozapine, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 10.32 to about 151.68 milligrams of clozapine, wherein the composition comprises a total mass of about 2 milligrams to about 4 milligrams of hydromorphone; In some embodiments, the composition comprises a total mass of about 20.68 to about 303.32 milligrams of clozapine, wherein the composition comprises a total mass of about 4 milligrams to about 8 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 14.36 to about 210.The composition comprises 96 milligrams of clozapine, wherein the composition contains about 1 milligram to about 2 milligrams of levophanol by total mass; in some embodiments, the composition comprises about 3.2 to about 47.04 milligrams of clozapine by total mass, wherein the composition contains about 25 milligrams to about 50 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 6.4 to about 94.08 milligrams of clozapine by total mass, wherein the composition contains about 50 milligrams to about 100 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 6.4 to about 94.08 milligrams of clozapine by total mass, wherein the composition contains about 5 milligrams to about 10 milligrams of morphine by total mass; In some embodiments, the composition comprises a total mass of about 9.6 to about 141.12 milligrams of clozapine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 19.24 to about 282.24 milligrams of clozapine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 38.44 to about 564.44 milligrams of clozapine, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 64.08 to about 940.76 milligrams of clozapine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of morphine; In some embodiments, the composition comprises a total mass of about 6.48 to about 95.08 milligrams of clozapine, wherein the composition contains a total mass of about 2.5 to about 5 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 12.96 to about 190.The composition comprises 16 milligrams of clozapine, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 4.84 to about 71.28 milligrams of clozapine, wherein the composition contains a total mass of about 2.5 milligrams to about 5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 7.28 to about 106.92 milligrams of clozapine, wherein the composition contains a total mass of about 3.75 milligrams to about 7.5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 9.72 to about 142.52 milligrams of clozapine, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of oxycodone; In some embodiments, the composition comprises a total mass of about 14.56 to about 213.8 milligrams of clozapine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 29.12 to about 427.6 milligrams of clozapine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 38.84 to about 570.16 milligrams of clozapine, wherein the composition comprises a total mass of about 20 milligrams to about 40 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 9.72 to about 142.52 milligrams of clozapine, wherein the composition comprises a total mass of about 2.5 milligrams to about 5 milligrams of oxymorphone; In some embodiments, the composition comprises a total mass of about 19.44 to about 285.08 milligrams of clozapine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of oxymorphone; in some embodiments, the composition comprises a total mass of about 6.32 to about 92.The composition comprises 64 milligrams of clozapine, wherein the composition contains propoxyphen in a total mass of about 32.5 milligrams to about 65 milligrams; in some embodiments, the composition comprises clozapine in a total mass of about 12.64 to about 185.28 milligrams, wherein the composition contains tapentadol in a total mass of about 25 milligrams to about 50 milligrams; in some embodiments, the composition comprises clozapine in a total mass of about 18.92 to about 277.96 milligrams, wherein the composition contains tapentadol in a total mass of about 37.5 milligrams to about 75 milligrams; in some embodiments, the composition comprises clozapine in a total mass of about 25.24 to about 370.6 milligrams, wherein the composition contains tapentadol in a total mass of about 50 milligrams to about 100 milligrams; In some embodiments, the composition comprises a total mass of about 2.92 to about 42.76 milligrams of clozapine, wherein the composition comprises a total mass of about 25 milligrams to about 50 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 5.84 to about 85.52 milligrams of clozapine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 11.64 to about 171.04 milligrams of clozapine, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 17.48 to about 256.56 milligrams of clozapine, wherein the composition comprises a total mass of about 150 milligrams to about 300 milligrams of tramadol.

[0188] Droperidol

[0189] The present disclosure relates to a composition comprising (i) a dopamine antagonist; and (ii) an opioid, wherein the dopamine antagonist is droperidol. In some embodiments, the composition comprises droperidol in a total mass of about 0.97 to about 14.25 milligrams, wherein the composition comprises buprenorphine in a total mass of about 1 milligram to about 2 milligrams; in some embodiments, the composition comprises droperidol in a total mass of about 2 to about 57.02 milligrams, wherein the composition comprises buprenorphine in a total mass of about 4 milligrams to about 8 milligrams; in some embodiments, the composition comprises droperidol in a total mass of about 0.1 to about 1.5 milligrams, wherein the composition comprises codeine in a total mass of about 7.5 milligrams to about 15 milligrams; In some embodiments, the composition comprises droperidol with a total mass of about 0.2 to about 2.99 milligrams, wherein the composition comprises codeine with a total mass of about 15 to about 30 milligrams; in some embodiments, the composition comprises droperidol with a total mass of about 0.41 to about 5.99 milligrams, wherein the composition comprises codeine with a total mass of about 30 to about 60 milligrams; in some embodiments, the composition comprises droperidol with a total mass of about 0.16 to about 2.35 milligrams, wherein the composition comprises hydrocodone with a total mass of about 5 to about 10 milligrams; in some embodiments, the composition comprises droperidol with a total mass of about 0.32 to about 4.7 milligrams, wherein the composition comprises hydrocodone with a total mass of about 10 to about 20 milligrams; In some embodiments, the composition comprises droperidol with a total mass of about 0.48 to about 7.06 milligrams, wherein the composition comprises hydrocodone with a total mass of about 15 to about 30 milligrams; in some embodiments, the composition comprises about 0.64 to about 9 milligrams with a total mass.It comprises 41 milligrams of droperidol, wherein the composition contains a total mass of about 20 milligrams to about 40 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 0.8 to about 11.76 milligrams of droperidol, wherein the composition contains a total mass of about 25 milligrams to about 50 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 0.96 to about 14.11 milligrams of droperidol, wherein the composition contains a total mass of about 30 milligrams to about 60 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 1.28 to about 18.82 milligrams of droperidol, wherein the composition contains a total mass of about 40 milligrams to about 80 milligrams of hydrocodon; In some embodiments, the composition comprises droperidol with a total mass of about 1.6 to about 23.52 milligrams, wherein the composition comprises hydrocodon with a total mass of about 50 milligrams to about 100 milligrams; in some embodiments, the composition comprises droperidol with a total mass of about 2 to about 47.04 milligrams, wherein the composition comprises hydrocodon with a total mass of about 100 milligrams to about 200 milligrams; in some embodiments, the composition comprises droperidol with a total mass of about 0.13 to about 1.9 milligrams, wherein the composition comprises hydromorphone with a total mass of about 1 milligram to about 2 milligrams; in some embodiments, the composition comprises droperidol with a total mass of about 0.26 to about 3.79 milligrams, wherein the composition comprises hydromorphone with a total mass of about 2 milligrams to about 4 milligrams; In some embodiments, the composition comprises droperidol with a total mass of about 0.52 to about 7.58 milligrams, wherein the composition comprises hydromorphone with a total mass of about 4 to about 8 milligrams; in some embodiments, the composition comprises about 0.36 to about 5 milligrams with a total mass.It comprises 27 milligrams of droperidol, wherein the composition contains about 1 milligram to about 2 milligrams of levolphanol by total mass; in some embodiments, the composition comprises about 0.08 to about 1.18 milligrams of droperidol by total mass, wherein the composition contains about 25 milligrams to about 50 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 0.16 to about 2.35 milligrams of droperidol by total mass, wherein the composition contains about 50 milligrams to about 100 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 0.16 to about 2.35 milligrams of droperidol by total mass, wherein the composition contains about 5 milligrams to about 10 milligrams of morphine by total mass; In some embodiments, the composition comprises droperidol with a total mass of about 0.24 to about 3.53 milligrams, wherein the composition comprises morphine with a total mass of about 7.5 milligrams to about 15 milligrams; in some embodiments, the composition comprises droperidol with a total mass of about 0.48 to about 7.06 milligrams, wherein the composition comprises morphine with a total mass of about 15 milligrams to about 30 milligrams; in some embodiments, the composition comprises droperidol with a total mass of about 0.96 to about 14.11 milligrams, wherein the composition comprises morphine with a total mass of about 30 milligrams to about 60 milligrams; in some embodiments, the composition comprises droperidol with a total mass of about 1.6 to about 23.52 milligrams, wherein the composition comprises morphine with a total mass of about 50 milligrams to about 100 milligrams; In some embodiments, the composition comprises droperidol with a total mass of about 0.16 to about 2.38 milligrams, wherein the composition contains methadone with a total mass of about 2.5 to about 5 milligrams; in some embodiments, the composition comprises about 0.32 to about 4 milligrams with a total mass.The composition comprises 75 milligrams of droperidol, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 0.12 to about 1.78 milligrams of droperidol, wherein the composition contains a total mass of about 2.5 milligrams to about 5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.18 to about 2.67 milligrams of droperidol, wherein the composition contains a total mass of about 3.75 milligrams to about 7.5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.24 to about 3.56 milligrams of droperidol, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of oxycodone; In some embodiments, the composition comprises droperidol with a total mass of about 0.36 to about 5.35 milligrams, wherein the composition comprises oxycodone with a total mass of about 7.5 milligrams to about 15 milligrams; in some embodiments, the composition comprises droperidol with a total mass of about 0.73 to about 10.69 milligrams, wherein the composition comprises oxycodone with a total mass of about 15 milligrams to about 30 milligrams; in some embodiments, the composition comprises droperidol with a total mass of about 0.97 to about 14.25 milligrams, wherein the composition comprises oxycodone with a total mass of about 20 milligrams to about 40 milligrams; in some embodiments, the composition comprises droperidol with a total mass of about 0.24 to about 3.56 milligrams, wherein the composition comprises oxymorphone with a total mass of about 2.5 milligrams to about 5 milligrams; In some embodiments, the composition comprises droperidol with a total mass of about 0.49 to about 7.13 milligrams, wherein the composition comprises oxymorphone with a total mass of about 5 to about 10 milligrams; in some embodiments, the composition comprises about 0.16 to about 2 milligrams with a total mass.The composition comprises 32 milligrams of droperidol, wherein the composition contains propoxyphen in a total mass of about 32.5 milligrams to about 65 milligrams; in some embodiments, the composition comprises droperidol in a total mass of about 0.32 to about 4.63 milligrams, wherein the composition contains tapentadol in a total mass of about 25 milligrams to about 50 milligrams; in some embodiments, the composition comprises droperidol in a total mass of about 0.47 to about 6.95 milligrams, wherein the composition contains tapentadol in a total mass of about 37.5 milligrams to about 75 milligrams; in some embodiments, the composition comprises droperidol in a total mass of about 0.63 to about 9.27 milligrams, wherein the composition contains tapentadol in a total mass of about 50 milligrams to about 100 milligrams; In some embodiments, the composition comprises droperidol with a total mass of about 0.07 to about 1.07 milligrams, wherein the composition comprises tramadol with a total mass of about 25 milligrams to about 50 milligrams; in some embodiments, the composition comprises droperidol with a total mass of about 0.15 to about 2.14 milligrams, wherein the composition comprises tramadol with a total mass of about 50 milligrams to about 100 milligrams; in some embodiments, the composition comprises droperidol with a total mass of about 0.29 to about 4.28 milligrams, wherein the composition comprises tramadol with a total mass of about 100 milligrams to about 200 milligrams; in some embodiments, the composition comprises droperidol with a total mass of about 0.44 to about 6.41 milligrams, wherein the composition comprises tramadol with a total mass of about 150 milligrams to about 300 milligrams.

[0190] Flupentisol

[0191] The present disclosure relates to a composition comprising (i) a dopamine antagonist; and (ii) an opioid, wherein the dopamine antagonist is flupentisol. In some embodiments, the composition comprises a total mass of about 0.97 to about 14.25 milligrams of flupentisol, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 2 to about 57.02 milligrams of flupentisol, wherein the composition comprises a total mass of about 4 milligrams to about 8 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 0.1 to about 1.5 milligrams of flupentisol, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of codeine; In some embodiments, the composition comprises a total mass of about 0.2 to about 2.99 milligrams of flupentisol, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 0.41 to about 5.99 milligrams of flupentisol, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 0.16 to about 2.35 milligrams of flupentisol, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 0.32 to about 4.7 milligrams of flupentisol, wherein the composition comprises a total mass of about 10 milligrams to about 20 milligrams of hydrocodone; In some embodiments, the composition comprises a total mass of about 0.48 to about 7.06 milligrams of flupentisol, wherein the composition comprises a total mass of about 15 to about 30 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 0.64 to about 9.It comprises 41 milligrams of flupentisol, wherein the composition contains a total mass of about 20 milligrams to about 40 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 0.8 to about 11.76 milligrams of flupentisol, wherein the composition contains a total mass of about 25 milligrams to about 50 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 0.96 to about 14.11 milligrams of flupentisol, wherein the composition contains a total mass of about 30 milligrams to about 60 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 1.28 to about 18.82 milligrams of flupentisol, wherein the composition contains a total mass of about 40 milligrams to about 80 milligrams of hydrocodon; In some embodiments, the composition comprises a total mass of about 1.6 to about 23.52 milligrams of flupentisol, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 2 to about 47.04 milligrams of flupentisol, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 0.13 to about 1.9 milligrams of flupentisol, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 0.26 to about 3.79 milligrams of flupentisol, wherein the composition comprises a total mass of about 2 milligrams to about 4 milligrams of hydromorphone; In some embodiments, the composition comprises a total mass of about 0.52 to about 7.58 milligrams of flupentisol, wherein the composition comprises a total mass of about 4 to about 8 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 0.36 to about 5.It comprises 27 milligrams of flupentisol, wherein the composition contains about 1 milligram to about 2 milligrams of levophanol by total mass; in some embodiments, the composition comprises about 0.08 to about 1.18 milligrams of flupentisol by total mass, wherein the composition contains about 25 milligrams to about 50 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 0.16 to about 2.35 milligrams of flupentisol by total mass, wherein the composition contains about 50 milligrams to about 100 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 0.16 to about 2.35 milligrams of flupentisol by total mass, wherein the composition contains about 5 milligrams to about 10 milligrams of morphine by total mass; In some embodiments, the composition comprises a total mass of about 0.24 to about 3.53 milligrams of flupentisol, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 0.48 to about 7.06 milligrams of flupentisol, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 0.96 to about 14.11 milligrams of flupentisol, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 1.6 to about 23.52 milligrams of flupentisol, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of morphine; In some embodiments, the composition comprises a total mass of about 0.16 to about 2.38 milligrams of flupentisol, wherein the composition contains a total mass of about 2.5 to about 5 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 0.32 to about 4.It comprises 75 milligrams of flupentisol, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 0.12 to about 1.78 milligrams of flupentisol, wherein the composition contains a total mass of about 2.5 milligrams to about 5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.18 to about 2.67 milligrams of flupentisol, wherein the composition contains a total mass of about 3.75 milligrams to about 7.5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.24 to about 3.56 milligrams of flupentisol, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of oxycodone; In some embodiments, the composition comprises a total mass of about 0.36 to about 5.35 milligrams of flupentisol, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.73 to about 10.69 milligrams of flupentisol, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.97 to about 14.25 milligrams of flupentisol, wherein the composition comprises a total mass of about 20 milligrams to about 40 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.24 to about 3.56 milligrams of flupentisol, wherein the composition comprises a total mass of about 2.5 milligrams to about 5 milligrams of oxymorphone; In some embodiments, the composition comprises a total mass of about 0.49 to about 7.13 milligrams of flupentisol, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of oxymorphone; in some embodiments, the composition comprises a total mass of about 0.16 to about 2.It comprises 32 milligrams of flupentisol, wherein the composition contains propoxyphen in a total mass of about 32.5 milligrams to about 65 milligrams; in some embodiments, the composition comprises about 0.32 to about 4.63 milligrams of flupentisol in a total mass, wherein the composition contains about 25 milligrams to about 50 milligrams of tapentadol in a total mass; in some embodiments, the composition comprises about 0.47 to about 6.95 milligrams of flupentisol in a total mass, wherein the composition contains about 37.5 milligrams to about 75 milligrams of tapentadol in a total mass; in some embodiments, the composition comprises about 0.63 to about 9.27 milligrams of flupentisol in a total mass, wherein the composition contains about 50 milligrams to about 100 milligrams of tapentadol in a total mass; In some embodiments, the composition comprises a total mass of about 0.07 to about 1.07 milligrams of flupentisol, wherein the composition comprises a total mass of about 25 milligrams to about 50 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 0.15 to about 2.14 milligrams of flupentisol, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 0.29 to about 4.28 milligrams of flupentisol, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 0.44 to about 6.41 milligrams of flupentisol, wherein the composition comprises a total mass of about 150 milligrams to about 300 milligrams of tramadol.

[0192] Fluphenazine

[0193] The present disclosure relates to a composition comprising (i) a dopamine antagonist; and (ii) an opioid, wherein the dopamine antagonist is fluphenazine. In some embodiments, the composition comprises a total mass of about 1.17 to about 17.1 milligrams of fluphenazine, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 2.4 to about 68.42 milligrams of fluphenazine, wherein the composition comprises a total mass of about 4 milligrams to about 8 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 0.12 to about 1.8 milligrams of fluphenazine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of codeine; In some embodiments, the composition comprises a total mass of about 0.24 to about 3.59 milligrams of fluphenazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 0.49 to about 7.18 milligrams of fluphenazine, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 0.19 to about 2.82 milligrams of fluphenazine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 0.38 to about 5.64 milligrams of fluphenazine, wherein the composition comprises a total mass of about 10 milligrams to about 20 milligrams of hydrocodone; In some embodiments, the composition comprises a total mass of about 0.58 to about 8.47 milligrams of fluphenazine, wherein the composition comprises a total mass of about 15 to about 30 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 0.77 to about 11.The composition comprises 29 milligrams of fluphenazine, wherein the composition contains a total mass of about 20 milligrams to about 40 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 0.96 to about 14.11 milligrams of fluphenazine, wherein the composition contains a total mass of about 25 milligrams to about 50 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 1.15 to about 16.93 milligrams of fluphenazine, wherein the composition contains a total mass of about 30 milligrams to about 60 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 1.54 to about 22.58 milligrams of fluphenazine, wherein the composition contains a total mass of about 40 milligrams to about 80 milligrams of hydrocodon; In some embodiments, the composition comprises a total mass of about 1.92 to about 28.22 milligrams of fluphenazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 2.4 to about 56.45 milligrams of fluphenazine, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 0.15 to about 2.28 milligrams of fluphenazine, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 0.31 to about 4.55 milligrams of fluphenazine, wherein the composition comprises a total mass of about 2 milligrams to about 4 milligrams of hydromorphone; In some embodiments, the composition comprises a total mass of about 0.62 to about 9.1 milligrams of fluphenazine, wherein the composition comprises a total mass of about 4 to about 8 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 0.43 to about 6.The composition comprises 33 milligrams of fluphenazine, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of levophanol; in some embodiments, the composition comprises a total mass of about 0.1 to about 1.41 milligrams of fluphenazine, wherein the composition comprises a total mass of about 25 milligrams to about 50 milligrams of meperidine; in some embodiments, the composition comprises a total mass of about 0.19 to about 2.82 milligrams of fluphenazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of meperidine; in some embodiments, the composition comprises a total mass of about 0.19 to about 2.82 milligrams of fluphenazine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of morphine; In some embodiments, the composition comprises a total mass of about 0.29 to about 4.23 milligrams of fluphenazine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 0.58 to about 8.47 milligrams of fluphenazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 1.15 to about 16.93 milligrams of fluphenazine, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 1.92 to about 28.22 milligrams of fluphenazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of morphine; In some embodiments, the composition comprises a total mass of about 0.19 to about 2.85 milligrams of fluphenazine, wherein the composition contains a total mass of about 2.5 to about 5 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 0.39 to about 5.The composition comprises 7 milligrams of fluphenazine, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 0.15 to about 2.14 milligrams of fluphenazine, wherein the composition contains a total mass of about 2.5 milligrams to about 5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.22 to about 3.21 milligrams of fluphenazine, wherein the composition contains a total mass of about 3.75 milligrams to about 7.5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.29 to about 4.28 milligrams of fluphenazine, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of oxycodone; In some embodiments, the composition comprises a total mass of about 0.44 to about 6.41 milligrams of fluphenazine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.87 to about 12.83 milligrams of fluphenazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 1.17 to about 17.1 milligrams of fluphenazine, wherein the composition comprises a total mass of about 20 milligrams to about 40 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.29 to about 4.28 milligrams of fluphenazine, wherein the composition comprises a total mass of about 2.5 milligrams to about 5 milligrams of oxymorphone; In some embodiments, the composition comprises a total mass of about 0.58 to about 8.55 milligrams of fluphenazine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of oxymorphone; in some embodiments, the composition comprises a total mass of about 0.19 to about 2.The composition comprises 78 milligrams of fluphenazine, wherein the composition contains propoxyphene in a total mass of about 32.5 milligrams to about 65 milligrams; in some embodiments, the composition comprises about 0.38 to about 5.56 milligrams of fluphenazine in a total mass, wherein the composition contains about 25 milligrams to about 50 milligrams of tapentadol in a total mass; in some embodiments, the composition comprises about 0.57 to about 8.34 milligrams of fluphenazine in a total mass, wherein the composition contains about 37.5 milligrams to about 75 milligrams of tapentadol in a total mass; in some embodiments, the composition comprises about 0.76 to about 11.12 milligrams of fluphenazine in a total mass, wherein the composition contains about 50 milligrams to about 100 milligrams of tapentadol in a total mass; In some embodiments, the composition comprises a total mass of about 0.09 to about 1.28 milligrams of fluphenazine, wherein the composition comprises a total mass of about 25 milligrams to about 50 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 0.18 to about 2.57 milligrams of fluphenazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 0.35 to about 5.13 milligrams of fluphenazine, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 0.52 to about 7.7 milligrams of fluphenazine, wherein the composition comprises a total mass of about 150 milligrams to about 300 milligrams of tramadol.

[0194] Haloperidol

[0195] The present disclosure relates to a composition comprising (i) a dopamine antagonist; and (ii) an opioid, wherein the dopamine antagonist is haloperidol. In some embodiments, the composition comprises haloperidol in a total mass of about 0.97 to about 14.25 milligrams, wherein the composition comprises buprenorphine in a total mass of about 1 milligram to about 2 milligrams; in some embodiments, the composition comprises haloperidol in a total mass of about 2 to about 57.02 milligrams, wherein the composition comprises buprenorphine in a total mass of about 4 milligrams to about 8 milligrams; in some embodiments, the composition comprises haloperidol in a total mass of about 0.1 to about 1.5 milligrams, wherein the composition comprises codeine in a total mass of about 7.5 milligrams to about 15 milligrams; In some embodiments, the composition comprises a total mass of about 0.2 to about 2.99 milligrams of haloperidol, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 0.41 to about 5.99 milligrams of haloperidol, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 0.16 to about 2.35 milligrams of haloperidol, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 0.32 to about 4.7 milligrams of haloperidol, wherein the composition comprises a total mass of about 10 milligrams to about 20 milligrams of hydrocodone; In some embodiments, the composition comprises a total mass of about 0.48 to about 7.06 milligrams of haloperidol, wherein the composition comprises a total mass of about 15 to about 30 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 0.64 to about 9.It comprises 41 milligrams of haloperidol, wherein the composition contains a total mass of about 20 milligrams to about 40 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 0.8 to about 11.76 milligrams of haloperidol, wherein the composition contains a total mass of about 25 milligrams to about 50 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 0.96 to about 14.11 milligrams of haloperidol, wherein the composition contains a total mass of about 30 milligrams to about 60 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 1.28 to about 18.82 milligrams of haloperidol, wherein the composition contains a total mass of about 40 milligrams to about 80 milligrams of hydrocodon; In some embodiments, the composition comprises a total mass of about 1.6 to about 23.52 milligrams of haloperidol, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 2 to about 47.04 milligrams of haloperidol, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 0.13 to about 1.9 milligrams of haloperidol, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 0.26 to about 3.79 milligrams of haloperidol, wherein the composition comprises a total mass of about 2 milligrams to about 4 milligrams of hydromorphone; In some embodiments, the composition comprises a total mass of about 0.52 to about 7.58 milligrams of haloperidol, wherein the composition comprises a total mass of about 4 to about 8 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 0.36 to about 5.It comprises 27 milligrams of haloperidol, wherein the composition contains about 1 milligram to about 2 milligrams of levophanol by total mass; in some embodiments, the composition comprises about 0.08 to about 1.18 milligrams of haloperidol by total mass, wherein the composition contains about 25 milligrams to about 50 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 0.16 to about 2.35 milligrams of haloperidol by total mass, wherein the composition contains about 50 milligrams to about 100 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 0.16 to about 2.35 milligrams of haloperidol by total mass, wherein the composition contains about 5 milligrams to about 10 milligrams of morphine by total mass; In some embodiments, the composition comprises a total mass of about 0.24 to about 3.53 milligrams of haloperidol, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 0.48 to about 7.06 milligrams of haloperidol, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 0.96 to about 14.11 milligrams of haloperidol, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 1.6 to about 23.52 milligrams of haloperidol, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of morphine; In some embodiments, the composition comprises a total mass of about 0.16 to about 2.38 milligrams of haloperidol, wherein the composition contains a total mass of about 2.5 to about 5 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 0.32 to about 4.The composition comprises 75 milligrams of haloperidol, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 0.12 to about 1.78 milligrams of haloperidol, wherein the composition contains a total mass of about 2.5 milligrams to about 5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.18 to about 2.67 milligrams of haloperidol, wherein the composition contains a total mass of about 3.75 milligrams to about 7.5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.24 to about 3.56 milligrams of haloperidol, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of oxycodone; In some embodiments, the composition comprises a total mass of about 0.36 to about 5.35 milligrams of haloperidol, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.73 to about 10.69 milligrams of haloperidol, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.97 to about 14.25 milligrams of haloperidol, wherein the composition comprises a total mass of about 20 milligrams to about 40 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.24 to about 3.56 milligrams of haloperidol, wherein the composition comprises a total mass of about 2.5 milligrams to about 5 milligrams of oxymorphone; In some embodiments, the composition comprises a total mass of about 0.49 to about 7.13 milligrams of haloperidol, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of oxymorphone; in some embodiments, the composition comprises a total mass of about 0.16 to about 2.The composition comprises 32 milligrams of haloperidol, wherein the composition contains propoxyphene with a total mass of about 32.5 milligrams to about 65 milligrams; in some embodiments, the composition comprises haloperidol with a total mass of about 0.32 to about 4.63 milligrams, wherein the composition contains tapentadol with a total mass of about 25 milligrams to about 50 milligrams; in some embodiments, the composition comprises haloperidol with a total mass of about 0.47 to about 6.95 milligrams, wherein the composition contains tapentadol with a total mass of about 37.5 milligrams to about 75 milligrams; in some embodiments, the composition comprises haloperidol with a total mass of about 0.63 to about 9.27 milligrams, wherein the composition contains tapentadol with a total mass of about 50 milligrams to about 100 milligrams; In some embodiments, the composition comprises a total mass of about 0.07 to about 1.07 milligrams of haloperidol, wherein the composition comprises a total mass of about 25 milligrams to about 50 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 0.15 to about 2.14 milligrams of haloperidol, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 0.29 to about 4.28 milligrams of haloperidol, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 0.44 to about 6.41 milligrams of haloperidol, wherein the composition comprises a total mass of about 150 milligrams to about 300 milligrams of tramadol.

[0196] Levomepromazine

[0197] The present disclosure relates to a composition comprising (i) a dopamine antagonist; and (ii) an opioid, wherein the dopamine antagonist is levomepromazine. In some embodiments, the composition comprises a total mass of about 38.84 to about 570.16 milligrams of levomepromazine, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 80 to about 2280.6 milligrams of levomepromazine, wherein the composition comprises a total mass of about 4 milligrams to about 8 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 4.08 to about 59.88 milligrams of levomepromazine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of codeine; In some embodiments, the composition comprises a total mass of about 8.16 to about 119.72 milligrams of levomepromazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 16.32 to about 239.48 milligrams of levomepromazine, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 6.4 to about 94.08 milligrams of levomepromazine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 12.8 to about 188.16 milligrams of levomepromazine, wherein the composition comprises a total mass of about 10 milligrams to about 20 milligrams of hydrocodone; In some embodiments, the composition comprises a total mass of about 19.24 to about 282.24 milligrams of levomepromazine, wherein the composition comprises a total mass of about 15 to about 30 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 25.64 to about 376.The composition comprises 32 milligrams of levomepromazine, wherein the composition contains a total mass of about 20 milligrams to about 40 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 32.04 to about 470.36 milligrams of levomepromazine, wherein the composition contains a total mass of about 25 milligrams to about 50 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 38.44 to about 564.44 milligrams of levomepromazine, wherein the composition contains a total mass of about 30 milligrams to about 60 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 51.28 to about 752.6 milligrams of levomepromazine, wherein the composition contains a total mass of about 40 milligrams to about 80 milligrams of hydrocodon; In some embodiments, the composition comprises a total mass of about 64.08 to about 940.76 milligrams of levomepromazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 80 to about 1881.52 milligrams of levomepromazine, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 5.16 to about 75.84 milligrams of levomepromazine, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of hydromorphone; In some embodiments, the composition comprises a total mass of about 10.32 to about 151.68 milligrams of levomepromazine, wherein the composition comprises a total mass of about 2 milligrams to about 4 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 20.68 to about 303.32 milligrams of levomepromazine, wherein the composition comprises a total mass of about 4 milligrams to about 8 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 14.The composition comprises 36 to about 210.96 milligrams of levomepromazine, wherein the composition comprises about 1 milligram to about 2 milligrams of levorphanol by total mass; in some embodiments, the composition comprises about 3.2 to about 47.04 milligrams of levomepromazine by total mass, wherein the composition comprises about 25 milligrams to about 50 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 6.4 to about 94.08 milligrams of levomepromazine by total mass, wherein the composition comprises about 50 milligrams to about 100 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 6.4 to about 94.08 milligrams of levomepromazine by total mass, wherein the composition comprises about 5 milligrams to about 10 milligrams of morphine by total mass; In some embodiments, the composition comprises a total mass of about 9.6 to about 141.12 milligrams of levomepromazine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 19.24 to about 282.24 milligrams of levomepromazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 38.44 to about 564.44 milligrams of levomepromazine, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 64.08 to about 940.76 milligrams of levomepromazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of morphine; In some embodiments, the composition comprises a total mass of about 6.48 to about 95.08 milligrams of levomepromazine, wherein the composition contains a total mass of about 2.5 to about 5 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 12.The composition comprises 96 to about 190.16 milligrams of levomepromazine, wherein the composition contains about 5 milligrams to about 10 milligrams of methadone by total mass; in some embodiments, the composition comprises about 4.84 to about 71.28 milligrams of levomepromazine by total mass, wherein the composition contains about 2.5 milligrams to about 5 milligrams of oxycodone by total mass; in some embodiments, the composition comprises about 7.28 to about 106.92 milligrams of levomepromazine by total mass, wherein the composition contains about 3.75 milligrams to about 7.5 milligrams of oxycodone by total mass; in some embodiments, the composition comprises about 9.72 to about 142.52 milligrams of levomepromazine by total mass, wherein the composition contains about 5 milligrams to about 10 milligrams of oxycodone by total mass; In some embodiments, the composition comprises a total mass of about 14.56 to about 213.8 milligrams of levomepromazine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 29.12 to about 427.6 milligrams of levomepromazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 38.84 to about 570.16 milligrams of levomepromazine, wherein the composition comprises a total mass of about 20 milligrams to about 40 milligrams of oxycodone; In some embodiments, the composition comprises a total mass of about 9.72 to about 142.52 milligrams of levomepromazine, wherein the composition comprises a total mass of about 2.5 milligrams to about 5 milligrams of oxymorphone; in some embodiments, the composition comprises a total mass of about 19.44 to about 285.The composition comprises 0.8 milligrams of levomepromazine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of oxymorphone; in some embodiments, the composition comprises a total mass of about 6.32 to about 92.64 milligrams of levomepromazine, wherein the composition comprises a total mass of about 32.5 milligrams to about 65 milligrams of propoxyphene; in some embodiments, the composition comprises a total mass of about 12.64 to about 185.28 milligrams of levomepromazine, wherein the composition comprises a total mass of about 25 milligrams to about 50 milligrams of tapentadol; in some embodiments, the composition comprises a total mass of about 18.92 to about 277.96 milligrams of levomepromazine, wherein the composition comprises a total mass of about 37.5 milligrams to about 75 milligrams of tapentadol; In some embodiments, the composition comprises a total mass of about 25.24 to about 370.6 milligrams of levomepromazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of tapentadol; in some embodiments, the composition comprises a total mass of about 2.92 to about 42.76 milligrams of levomepromazine, wherein the composition comprises a total mass of about 25 milligrams to about 50 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 5.84 to about 85.52 milligrams of levomepromazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of tramadol; In some embodiments, the composition comprises a total mass of about 11.64 to about 171.04 milligrams of levomepromazine, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 17.48 to about 256.56 milligrams of levomepromazine, wherein the composition comprises a total mass of about 150 milligrams to about 300 milligrams of tramadol.

[0198] Loxapin

[0199] The present disclosure relates to a composition comprising (i) a dopamine antagonist; and (ii) an opioid, wherein the dopamine antagonist is loxapine. In some embodiments, the composition comprises loxapine in a total mass of about 5.83 to about 85.52 milligrams, wherein the composition comprises buprenorphine in a total mass of about 1 milligram to about 2 milligrams; in some embodiments, the composition comprises loxapine in a total mass of about 12 to about 342.09 milligrams, wherein the composition comprises buprenorphine in a total mass of about 4 milligrams to about 8 milligrams; in some embodiments, the composition comprises loxapine in a total mass of about 0.61 to about 8.98 milligrams, wherein the composition comprises codeine in a total mass of about 7.5 milligrams to about 15 milligrams; In some embodiments, the composition comprises a total mass of about 1.22 to about 17.96 milligrams of loxapine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 2.45 to about 35.92 milligrams of loxapine, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 0.96 to about 14.11 milligrams of loxapine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 1.92 to about 28.22 milligrams of loxapine, wherein the composition comprises a total mass of about 10 milligrams to about 20 milligrams of hydrocodone; In some embodiments, the composition comprises a total mass of about 2.89 to about 42.34 milligrams of roxafine, wherein the composition comprises a total mass of about 15 to about 30 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 3.85 to about 56.It comprises 45 milligrams of loxapine, wherein the composition contains a total mass of about 20 milligrams to about 40 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 4.81 to about 70.55 milligrams of loxapine, wherein the composition contains a total mass of about 25 milligrams to about 50 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 5.77 to about 84.67 milligrams of loxapine, wherein the composition contains a total mass of about 30 milligrams to about 60 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 7.69 to about 112.89 milligrams of loxapine, wherein the composition contains a total mass of about 40 milligrams to about 80 milligrams of hydrocodon; In some embodiments, the composition comprises a total mass of about 9.61 to about 141.11 milligrams of loxapine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 12 to about 282.23 milligrams of loxapine, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 0.77 to about 11.38 milligrams of loxapine, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 1.55 to about 22.75 milligrams of loxapine, wherein the composition comprises a total mass of about 2 milligrams to about 4 milligrams of hydromorphone; In some embodiments, the composition comprises a total mass of about 3.1 to about 45.5 milligrams of roxafine, wherein the composition comprises a total mass of about 4 milligrams to about 8 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 2.15 to about 31.It comprises 64 milligrams of loxapine, wherein the composition contains about 1 milligram to about 2 milligrams of levolphanol by total mass; in some embodiments, the composition comprises about 0.48 to about 7.06 milligrams of loxapine by total mass, wherein the composition contains about 25 milligrams to about 50 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 0.96 to about 14.11 milligrams of loxapine by total mass, wherein the composition contains about 50 milligrams to about 100 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 0.96 to about 14.11 milligrams of loxapine by total mass, wherein the composition contains about 5 milligrams to about 10 milligrams of morphine by total mass; In some embodiments, the composition comprises a total mass of about 1.44 to about 21.17 milligrams of roxafine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 2.89 to about 42.34 milligrams of roxafine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 5.77 to about 84.67 milligrams of roxafine, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 9.61 to about 141.11 milligrams of roxafine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of morphine; In some embodiments, the composition comprises a total mass of about 0.97 to about 14.26 milligrams of roxafine, wherein the composition contains a total mass of about 2.5 to about 5 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 1.94 to about 28.The composition comprises 52 milligrams of loxapine, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 0.73 to about 10.69 milligrams of loxapine, wherein the composition contains a total mass of about 2.5 milligrams to about 5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 1.09 to about 16.04 milligrams of loxapine, wherein the composition contains a total mass of about 3.75 milligrams to about 7.5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 1.46 to about 21.38 milligrams of loxapine, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of oxycodone; In some embodiments, the composition comprises a total mass of about 2.18 to about 32.07 milligrams of loxapine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 4.37 to about 64.14 milligrams of loxapine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 5.83 to about 85.52 milligrams of loxapine, wherein the composition comprises a total mass of about 20 milligrams to about 40 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 1.46 to about 21.38 milligrams of loxapine, wherein the composition comprises a total mass of about 2.5 milligrams to about 5 milligrams of oxymorphone; In some embodiments, the composition comprises a total mass of about 2.92 to about 42.76 milligrams of roxafine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of oxymorphone; in some embodiments, the composition comprises a total mass of about 0.95 to about 13.9 milligrams of roxafine, wherein the composition comprises a total mass of about 32.It contains 5 milligrams to about 65 milligrams of propoxyphen; in some embodiments, the composition contains about 1.9 to about 27.79 milligrams of loxapine by total mass, wherein the composition contains about 25 milligrams to about 50 milligrams of tapentadol by total mass; in some embodiments, the composition contains about 2.84 to about 41.69 milligrams of loxapine by total mass, wherein the composition contains about 37.5 milligrams to about 75 milligrams of tapentadol by total mass; in some embodiments, the composition contains about 3.79 to about 55.59 milligrams of loxapine by total mass, wherein the composition contains about 50 milligrams to about 100 milligrams of tapentadol by total mass; In some embodiments, the composition comprises a total mass of about 0.44 to about 6.41 milligrams of loxapine, wherein the composition comprises a total mass of about 25 milligrams to about 50 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 0.88 to about 12.83 milligrams of loxapine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 1.75 to about 25.66 milligrams of loxapine, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 2.62 to about 38.48 milligrams of loxapine, wherein the composition comprises a total mass of about 150 milligrams to about 300 milligrams of tramadol.

[0200] Mesori-dajin

[0201] The present disclosure relates to a composition comprising (i) a dopamine antagonist; and (ii) an opioid, wherein the dopamine antagonist is mesoridazine. In some embodiments, the composition comprises a total mass of about 29.13 to about 427.62 milligrams of mesoridazine, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 60 to about 1710.45 milligrams of mesoridazine, wherein the composition comprises a total mass of about 4 milligrams to about 8 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 3.06 to about 44.91 milligrams of mesoridazine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of codeine; In some embodiments, the composition comprises a total mass of about 6.12 to about 89.79 milligrams of mesoridazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 12.24 to about 179.61 milligrams of mesoridazine, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 4.8 to about 70.56 milligrams of mesoridazine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 9.6 to about 141.12 milligrams of mesoridazine, wherein the composition comprises a total mass of about 10 milligrams to about 20 milligrams of hydrocodone; In some embodiments, the composition comprises a total mass of about 14.43 to about 211.68 milligrams of mesoridazine, wherein the composition comprises a total mass of about 15 to about 30 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 19.23 to about 282.The composition comprises 24 milligrams of mesoridazine, wherein the composition contains a total mass of about 20 milligrams to about 40 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 24.03 to about 352.77 milligrams of mesoridazine, wherein the composition contains a total mass of about 25 milligrams to about 50 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 28.83 to about 423.33 milligrams of mesoridazine, wherein the composition contains a total mass of about 30 milligrams to about 60 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 38.46 to about 564.45 milligrams of mesoridazine, wherein the composition contains a total mass of about 40 milligrams to about 80 milligrams of hydrocodon; In some embodiments, the composition comprises a total mass of about 48.06 to about 705.57 milligrams of mesoridazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 60 to about 1411.14 milligrams of mesoridazine, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 3.87 to about 56.88 milligrams of mesoridazine, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 7.74 to about 113.76 milligrams of mesoridazine, wherein the composition comprises a total mass of about 2 milligrams to about 4 milligrams of hydromorphone; In some embodiments, the composition comprises a total mass of about 15.51 to about 227.49 milligrams of mesoridazine, wherein the composition comprises a total mass of about 4 to about 8 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 10.77 to about 158.The composition comprises 22 milligrams of mesoridazine, wherein the composition contains about 1 milligram to about 2 milligrams of levophanol by total mass; in some embodiments, the composition comprises about 2.4 to about 35.28 milligrams of mesoridazine by total mass, wherein the composition contains about 25 milligrams to about 50 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 4.8 to about 70.56 milligrams of mesoridazine by total mass, wherein the composition contains about 50 milligrams to about 100 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 4.8 to about 70.56 milligrams of mesoridazine by total mass, wherein the composition contains about 5 milligrams to about 10 milligrams of morphine by total mass; In some embodiments, the composition comprises a total mass of about 7.2 to about 105.84 milligrams of mesoridazine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 14.43 to about 211.68 milligrams of mesoridazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 28.83 to about 423.33 milligrams of mesoridazine, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 48.06 to about 705.57 milligrams of mesoridazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of morphine; In some embodiments, the composition comprises a total mass of about 4.86 to about 71.31 milligrams of mesoridazine, wherein the composition contains a total mass of about 2.5 to about 5 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 9.72 to about 142.The composition comprises 62 milligrams of mesoridazine, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 3.63 to about 53.46 milligrams of mesoridazine, wherein the composition contains a total mass of about 2.5 milligrams to about 5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 5.46 to about 80.19 milligrams of mesoridazine, wherein the composition contains a total mass of about 3.75 milligrams to about 7.5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 7.29 to about 106.89 milligrams of mesoridazine, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of oxycodone; In some embodiments, the composition comprises a total mass of about 10.92 to about 160.35 milligrams of mesoridazine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 21.84 to about 320.7 milligrams of mesoridazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 29.13 to about 427.62 milligrams of mesoridazine, wherein the composition comprises a total mass of about 20 milligrams to about 40 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 7.29 to about 106.89 milligrams of mesoridazine, wherein the composition comprises a total mass of about 2.5 milligrams to about 5 milligrams of oxymorphone; In some embodiments, the composition comprises a total mass of about 14.58 to about 213.81 milligrams of mesoridazine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of oxymorphone; in some embodiments, the composition comprises a total mass of about 4.74 to about 69.The composition comprises 48 milligrams of mesoridazine, wherein the composition contains propoxyphene in a total mass of about 32.5 milligrams to about 65 milligrams; in some embodiments, the composition comprises about 9.48 to about 138.96 milligrams of mesoridazine in a total mass, wherein the composition contains about 25 milligrams to about 50 milligrams of tapentadol in a total mass; in some embodiments, the composition comprises about 14.19 to about 208.47 milligrams of mesoridazine in a total mass, wherein the composition contains about 37.5 milligrams to about 75 milligrams of tapentadol in a total mass; in some embodiments, the composition comprises about 18.93 to about 277.95 milligrams of mesoridazine in a total mass, wherein the composition contains about 50 milligrams to about 100 milligrams of tapentadol in a total mass; In some embodiments, the composition comprises a total mass of about 2.19 to about 32.07 milligrams of mesoridazine, wherein the composition comprises a total mass of about 25 milligrams to about 50 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 4.38 to about 64.14 milligrams of mesoridazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 8.73 to about 128.28 milligrams of mesoridazine, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 13.11 to about 192.42 milligrams of mesoridazine, wherein the composition comprises a total mass of about 150 milligrams to about 300 milligrams of tramadol.

[0202] money gathered

[0203] The present disclosure relates to a composition comprising (i) a dopamine antagonist; and (ii) an opioid, wherein the dopamine antagonist is molindone. In some embodiments, the composition comprises molindone in a total mass of about 9.71 to about 142.54 milligrams, wherein the composition comprises buprenorphine in a total mass of about 1 milligram to about 2 milligrams; in some embodiments, the composition comprises molindone in a total mass of about 20 to about 570.15 milligrams, wherein the composition comprises buprenorphine in a total mass of about 4 milligrams to about 8 milligrams; in some embodiments, the composition comprises molindone in a total mass of about 1.02 to about 14.97 milligrams, wherein the composition comprises codeine in a total mass of about 7.5 milligrams to about 15 milligrams; In some embodiments, the composition comprises a total mass of about 2.04 to about 29.93 milligrams of molindone, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 4.08 to about 59.87 milligrams of molindone, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 1.6 to about 23.52 milligrams of molindone, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 3.2 to about 47.04 milligrams of molindone, wherein the composition comprises a total mass of about 10 milligrams to about 20 milligrams of hydrocodone; In some embodiments, the composition comprises a total mass of about 4.81 to about 70.56 milligrams of molindone, wherein the composition contains a total mass of about 15 to about 30 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 6.41 to about 94.It comprises 0.8 milligrams of molindone, wherein the composition contains a total mass of about 20 milligrams to about 40 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 8.01 to about 117.59 milligrams of molindone, wherein the composition contains a total mass of about 25 milligrams to about 50 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 9.61 to about 141.11 milligrams of molindone, wherein the composition contains a total mass of about 30 milligrams to about 60 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 12.82 to about 188.15 milligrams of molindone, wherein the composition contains a total mass of about 40 milligrams to about 80 milligrams of hydrocodon; In some embodiments, the composition comprises a total mass of about 16.02 to about 235.19 milligrams of molindone, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 20 to about 470.38 milligrams of molindone, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 1.29 to about 18.96 milligrams of molindone, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 2.58 to about 37.92 milligrams of molindone, wherein the composition comprises a total mass of about 2 milligrams to about 4 milligrams of hydromorphone; In some embodiments, the composition comprises a total mass of about 5.17 to about 75.83 milligrams of molindone, wherein the composition comprises a total mass of about 4 milligrams to about 8 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 3.59 to about 52.It comprises 74 milligrams of molindone, wherein the composition contains about 1 milligram to about 2 milligrams of levophanol by total mass; in some embodiments, the composition comprises about 0.8 to about 11.76 milligrams of molindone by total mass, wherein the composition contains about 25 milligrams to about 50 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 1.6 to about 23.52 milligrams of molindone by total mass, wherein the composition contains about 50 milligrams to about 100 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 1.6 to about 23.52 milligrams of molindone by total mass, wherein the composition contains about 5 milligrams to about 10 milligrams of morphine by total mass; In some embodiments, the composition comprises a total mass of about 2.4 to about 35.28 milligrams of molindone, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 4.81 to about 70.56 milligrams of molindone, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 9.61 to about 141.11 milligrams of molindone, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 16.02 to about 235.19 milligrams of molindone, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of morphine; In some embodiments, the composition comprises a total mass of about 1.62 to about 23.77 milligrams of molindone, wherein the composition contains a total mass of about 2.5 to about 5 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 3.24 to about 47.It comprises 54 milligrams of molindone, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 1.21 to about 17.82 milligrams of molindone, wherein the composition contains a total mass of about 2.5 milligrams to about 5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 1.82 to about 26.73 milligrams of molindone, wherein the composition contains a total mass of about 3.75 milligrams to about 7.5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 2.43 to about 35.63 milligrams of molindone, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of oxycodone; In some embodiments, the composition comprises a total mass of about 3.64 to about 53.45 milligrams of molindone, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 7.28 to about 106.9 milligrams of molindone, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 9.71 to about 142.54 milligrams of molindone, wherein the composition comprises a total mass of about 20 milligrams to about 40 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 2.43 to about 35.63 milligrams of molindone, wherein the composition comprises a total mass of about 2.5 milligrams to about 5 milligrams of oxymorphone; In some embodiments, the composition comprises a total mass of about 4.86 to about 71.27 milligrams of molindone, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of oxymorphone; in some embodiments, the composition comprises a total mass of about 1.58 to about 23.16 milligrams of molindone, wherein the composition comprises a total mass of about 32.It contains 5 milligrams to about 65 milligrams of propoxyphen; in some embodiments, the composition contains a total mass of about 3.16 to about 46.32 milligrams of molindone, wherein the composition contains a total mass of about 25 milligrams to about 50 milligrams of tapentadol; in some embodiments, the composition contains a total mass of about 4.73 to about 69.49 milligrams of molindone, wherein the composition contains a total mass of about 37.5 milligrams to about 75 milligrams of tapentadol; in some embodiments, the composition contains a total mass of about 6.31 to about 92.65 milligrams of molindone, wherein the composition contains a total mass of about 50 milligrams to about 100 milligrams of tapentadol; In some embodiments, the composition comprises a total mass of about 0.73 to about 10.69 milligrams of molindone, wherein the composition comprises a total mass of about 25 milligrams to about 50 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 1.46 to about 21.38 milligrams of molindone, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 2.91 to about 42.76 milligrams of molindone, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 4.37 to about 64.14 milligrams of molindone, wherein the composition comprises a total mass of about 150 milligrams to about 300 milligrams of tramadol.

[0204] Olanzapine

[0205] The present disclosure relates to a composition comprising (i) a dopamine antagonist; and (ii) an opioid, wherein the dopamine antagonist is olanzapine. In some embodiments, the composition comprises olanzapine in a total mass of about 1.94 to about 28.51 milligrams, wherein the composition comprises buprenorphine in a total mass of about 1 milligram to about 2 milligrams; in some embodiments, the composition comprises olanzapine in a total mass of about 4 to about 114.03 milligrams, wherein the composition comprises buprenorphine in a total mass of about 4 milligrams to about 8 milligrams; in some embodiments, the composition comprises olanzapine in a total mass of about 0.2 to about 2.99 milligrams, wherein the composition comprises codeine in a total mass of about 7.5 milligrams to about 15 milligrams; In some embodiments, the composition comprises olanzapine with a total mass of about 0.41 to about 5.99 milligrams, wherein the composition comprises codeine with a total mass of about 15 milligrams to about 30 milligrams; in some embodiments, the composition comprises olanzapine with a total mass of about 0.82 to about 11.97 milligrams, wherein the composition comprises codeine with a total mass of about 30 milligrams to about 60 milligrams; in some embodiments, the composition comprises olanzapine with a total mass of about 0.32 to about 4.7 milligrams, wherein the composition comprises hydrocodone with a total mass of about 5 milligrams to about 10 milligrams; in some embodiments, the composition comprises olanzapine with a total mass of about 0.64 to about 9.41 milligrams, wherein the composition comprises hydrocodone with a total mass of about 10 milligrams to about 20 milligrams; In some embodiments, the composition comprises olanzapine with a total mass of about 0.96 to about 14.11 milligrams, wherein the composition comprises hydrocodone with a total mass of about 15 to about 30 milligrams; in some embodiments, the composition comprises about 1.28 to about 18 milligrams with a total mass.The composition comprises 82 milligrams of olanzapine, wherein the composition contains a total mass of about 20 milligrams to about 40 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 1.6 to about 23.52 milligrams of olanzapine, wherein the composition contains a total mass of about 25 milligrams to about 50 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 1.92 to about 28.22 milligrams of olanzapine, wherein the composition contains a total mass of about 30 milligrams to about 60 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 2.56 to about 37.63 milligrams of olanzapine, wherein the composition contains a total mass of about 40 milligrams to about 80 milligrams of hydrocodone; In some embodiments, the composition comprises olanzapine with a total mass of about 3.2 to about 47.04 milligrams, wherein the composition comprises hydrocodone with a total mass of about 50 milligrams to about 100 milligrams; in some embodiments, the composition comprises olanzapine with a total mass of about 4 to about 94.08 milligrams, wherein the composition comprises hydrocodone with a total mass of about 100 milligrams to about 200 milligrams; in some embodiments, the composition comprises olanzapine with a total mass of about 0.26 to about 3.79 milligrams, wherein the composition comprises hydromorphone with a total mass of about 1 milligram to about 2 milligrams; in some embodiments, the composition comprises olanzapine with a total mass of about 0.52 to about 7.58 milligrams, wherein the composition comprises hydromorphone with a total mass of about 2 milligrams to about 4 milligrams; In some embodiments, the composition comprises olanzapine with a total mass of about 1.03 to about 15.17 milligrams, wherein the composition comprises hydromorphone with a total mass of about 4 milligrams to about 8 milligrams; in some embodiments, the composition comprises about 0.72 to about 10 milligrams with a total mass.The composition comprises 55 milligrams of olanzapine, wherein the composition contains about 1 milligram to about 2 milligrams of levorphanol by total mass; in some embodiments, the composition comprises about 0.16 to about 2.35 milligrams of olanzapine by total mass, wherein the composition contains about 25 milligrams to about 50 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 0.32 to about 4.7 milligrams of olanzapine by total mass, wherein the composition contains about 50 milligrams to about 100 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 0.32 to about 4.7 milligrams of olanzapine by total mass, wherein the composition contains about 5 milligrams to about 10 milligrams of morphine by total mass; In some embodiments, the composition comprises olanzapine with a total mass of about 0.48 to about 7.06 milligrams, wherein the composition comprises morphine with a total mass of about 7.5 to about 15 milligrams; in some embodiments, the composition comprises olanzapine with a total mass of about 0.96 to about 14.11 milligrams, wherein the composition comprises morphine with a total mass of about 15 to about 30 milligrams; in some embodiments, the composition comprises olanzapine with a total mass of about 1.92 to about 28.22 milligrams, wherein the composition comprises morphine with a total mass of about 30 to about 60 milligrams; in some embodiments, the composition comprises olanzapine with a total mass of about 3.2 to about 47.04 milligrams, wherein the composition comprises morphine with a total mass of about 50 to about 100 milligrams; In some embodiments, the composition comprises olanzapine with a total mass of about 0.32 to about 4.75 milligrams, wherein the composition contains methadone with a total mass of about 2.5 to about 5 milligrams; in some embodiments, the composition comprises about 0.65 to about 9 milligrams with a total mass.The composition comprises 51 milligrams of olanzapine, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 0.24 to about 3.56 milligrams of olanzapine, wherein the composition contains a total mass of about 2.5 milligrams to about 5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.36 to about 5.35 milligrams of olanzapine, wherein the composition contains a total mass of about 3.75 milligrams to about 7.5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.49 to about 7.13 milligrams of olanzapine, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of oxycodone; In some embodiments, the composition comprises olanzapine with a total mass of about 0.73 to about 10.69 milligrams, wherein the composition comprises oxycodone with a total mass of about 7.5 milligrams to about 15 milligrams; in some embodiments, the composition comprises olanzapine with a total mass of about 1.46 to about 21.38 milligrams, wherein the composition comprises oxycodone with a total mass of about 15 milligrams to about 30 milligrams; in some embodiments, the composition comprises olanzapine with a total mass of about 1.94 to about 28.51 milligrams, wherein the composition comprises oxycodone with a total mass of about 20 milligrams to about 40 milligrams; in some embodiments, the composition comprises olanzapine with a total mass of about 0.49 to about 7.13 milligrams, wherein the composition comprises oxymorphone with a total mass of about 2.5 milligrams to about 5 milligrams; In some embodiments, the composition comprises olanzapine with a total mass of about 0.97 to about 14.25 milligrams, wherein the composition comprises oxymorphone with a total mass of about 5 to about 10 milligrams; in some embodiments, the composition comprises olanzapine with a total mass of about 0.32 to about 4.63 milligrams, wherein the composition comprises olanzapine with a total mass of about 32.It contains 5 milligrams to about 65 milligrams of propoxyphen; in some embodiments, the composition contains olanzapine with a total mass of about 0.63 to about 9.26 milligrams, wherein the composition contains tapentadol with a total mass of about 25 milligrams to about 50 milligrams; in some embodiments, the composition contains olanzapine with a total mass of about 0.95 to about 13.9 milligrams, wherein the composition contains tapentadol with a total mass of about 37.5 milligrams to about 75 milligrams; in some embodiments, the composition contains olanzapine with a total mass of about 1.26 to about 18.53 milligrams, wherein the composition contains tapentadol with a total mass of about 50 milligrams to about 100 milligrams; In some embodiments, the composition comprises olanzapine with a total mass of about 0.15 to about 2.14 milligrams, wherein the composition comprises tramadol with a total mass of about 25 milligrams to about 50 milligrams; in some embodiments, the composition comprises olanzapine with a total mass of about 0.29 to about 4.28 milligrams, wherein the composition comprises tramadol with a total mass of about 50 milligrams to about 100 milligrams; in some embodiments, the composition comprises olanzapine with a total mass of about 0.58 to about 8.55 milligrams, wherein the composition comprises tramadol with a total mass of about 100 milligrams to about 200 milligrams; in some embodiments, the composition comprises olanzapine with a total mass of about 0.87 to about 12.83 milligrams, wherein the composition comprises tramadol with a total mass of about 150 milligrams to about 300 milligrams.

[0206] paliperidon

[0207] The present disclosure relates to a composition comprising (i) a dopamine antagonist; and (ii) an opioid, wherein the dopamine antagonist is paliperidone. In some embodiments, the composition comprises a total mass of about 0.87 to about 12.82 milligrams of paliperidone, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 1.8 to about 51.29 milligrams of paliperidone, wherein the composition comprises a total mass of about 4 milligrams to about 8 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 0.09 to about 1.35 milligrams of paliperidone, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of codeine; In some embodiments, the composition comprises a total mass of about 0.18 to about 2.69 milligrams of paliperidone, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 0.37 to about 5.39 milligrams of paliperidone, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 0.14 to about 2.12 milligrams of paliperidone, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 0.29 to about 4.23 milligrams of paliperidone, wherein the composition comprises a total mass of about 10 milligrams to about 20 milligrams of hydrocodone; In some embodiments, the composition comprises a total mass of about 0.43 to about 6.35 milligrams of paliperidone, wherein the composition comprises a total mass of about 15 to about 30 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 0.58 to about 8.The composition comprises 46 milligrams of paliperidone, wherein the composition contains a total mass of about 20 milligrams to about 40 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 0.72 to about 10.58 milligrams of paliperidone, wherein the composition contains a total mass of about 25 milligrams to about 50 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 0.86 to about 12.69 milligrams of paliperidone, wherein the composition contains a total mass of about 30 milligrams to about 60 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 1.15 to about 16.93 milligrams of paliperidone, wherein the composition contains a total mass of about 40 milligrams to about 80 milligrams of hydrocodone; In some embodiments, the composition comprises a total mass of about 1.44 to about 21.16 milligrams of paliperidone, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 1.8 to about 42.31 milligrams of paliperidone, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 0.12 to about 1.71 milligrams of paliperidone, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 0.23 to about 3.41 milligrams of paliperidone, wherein the composition comprises a total mass of about 2 milligrams to about 4 milligrams of hydromorphone; In some embodiments, the composition comprises a total mass of about 0.47 to about 6.82 milligrams of paliperidone, wherein the composition comprises a total mass of about 4 to about 8 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 0.32 to about 4.The composition comprises 74 milligrams of paliperidone, wherein the composition contains about 1 milligram to about 2 milligrams of levophanol by total mass; in some embodiments, the composition comprises about 0.07 to about 1.06 milligrams of paliperidone by total mass, wherein the composition contains about 25 milligrams to about 50 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 0.14 to about 2.12 milligrams of paliperidone by total mass, wherein the composition contains about 50 milligrams to about 100 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 0.14 to about 2.12 milligrams of paliperidone by total mass, wherein the composition contains about 5 milligrams to about 10 milligrams of morphine by total mass; In some embodiments, the composition comprises a total mass of about 0.22 to about 3.17 milligrams of paliperidone, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 0.43 to about 6.35 milligrams of paliperidone, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 0.86 to about 12.69 milligrams of paliperidone, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 1.44 to about 21.16 milligrams of paliperidone, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of morphine; In some embodiments, the composition comprises a total mass of about 0.15 to about 2.14 milligrams of paliperidone, wherein the composition contains a total mass of about 2.5 to about 5 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 0.29 to about 4.The composition comprises 28 milligrams of paliperidone, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 0.11 to about 1.6 milligrams of paliperidone, wherein the composition contains a total mass of about 2.5 milligrams to about 5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.16 to about 2.4 milligrams of paliperidone, wherein the composition contains a total mass of about 3.75 milligrams to about 7.5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.22 to about 3.21 milligrams of paliperidone, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of oxycodone; In some embodiments, the composition comprises a total mass of about 0.33 to about 4.81 milligrams of paliperidone, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.65 to about 9.62 milligrams of paliperidone, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.87 to about 12.82 milligrams of paliperidone, wherein the composition comprises a total mass of about 20 milligrams to about 40 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.22 to about 3.21 milligrams of paliperidone, wherein the composition comprises a total mass of about 2.5 milligrams to about 5 milligrams of oxymorphone; In some embodiments, the composition comprises a total mass of about 0.44 to about 6.41 milligrams of paliperidone, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of oxymorphone; in some embodiments, the composition comprises a total mass of about 0.14 to about 2.The composition comprises 0.8 milligrams of paliperidone, wherein the composition comprises a total mass of about 32.5 milligrams to about 65 milligrams of propoxyphen; in some embodiments, the composition comprises a total mass of about 0.28 to about 4.17 milligrams of paliperidone, wherein the composition comprises a total mass of about 25 milligrams to about 50 milligrams of tapentadol; in some embodiments, the composition comprises a total mass of about 0.43 to about 6.25 milligrams of paliperidone, wherein the composition comprises a total mass of about 37.5 milligrams to about 75 milligrams of tapentadol; in some embodiments, the composition comprises a total mass of about 0.57 to about 8.33 milligrams of paliperidone, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of tapentadol; In some embodiments, the composition comprises a total mass of about 0.07 to about 0.96 milligrams of paliperidone, wherein the composition comprises a total mass of about 25 milligrams to about 50 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 0.13 to about 1.92 milligrams of paliperidone, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 0.26 to about 3.85 milligrams of paliperidone, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 0.39 to about 5.77 milligrams of paliperidone, wherein the composition comprises a total mass of about 150 milligrams to about 300 milligrams of tramadol.

[0208] Periciazine

[0209] The present disclosure relates to a composition comprising (i) a dopamine antagonist; and (ii) an opioid, wherein the dopamine antagonist is fericiazine. In some embodiments, the composition comprises a total mass of about 4.86 to about 71.27 milligrams of fericiazine, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 10 to about 285.08 milligrams of fericiazine, wherein the composition comprises a total mass of about 4 milligrams to about 8 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 0.51 to about 7.49 milligrams of fericiazine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of codeine; In some embodiments, the composition comprises a total mass of about 1.02 to about 14.97 milligrams of ferciazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 2.04 to about 29.94 milligrams of ferciazine, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 0.8 to about 11.76 milligrams of ferciazine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 1.6 to about 23.52 milligrams of ferciazine, wherein the composition comprises a total mass of about 10 milligrams to about 20 milligrams of hydrocodone; In some embodiments, the composition comprises a total mass of about 2.41 to about 35.28 milligrams of ferriciazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 3.21 to about 47.The composition comprises 0.4 milligrams of ferriciazine, wherein the composition contains a total mass of about 20 milligrams to about 40 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 4.01 to about 58.8 milligrams of ferriciazine, wherein the composition contains a total mass of about 25 milligrams to about 50 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 4.81 to about 70.56 milligrams of ferriciazine, wherein the composition contains a total mass of about 30 milligrams to about 60 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 6.41 to about 94.08 milligrams of ferriciazine, wherein the composition contains a total mass of about 40 milligrams to about 80 milligrams of hydrocodon; In some embodiments, the composition comprises a total mass of about 8.01 to about 117.6 milligrams of ferciazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 10 to about 235.19 milligrams of ferciazine, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 0.65 to about 9.48 milligrams of ferciazine, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 1.29 to about 18.96 milligrams of ferciazine, wherein the composition comprises a total mass of about 2 milligrams to about 4 milligrams of hydromorphone; In some embodiments, the composition comprises a total mass of about 2.59 to about 37.92 milligrams of ferriciazine, wherein the composition comprises a total mass of about 4 milligrams to about 8 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 1.8 to about 26.The composition comprises 37 milligrams of ferriciazine, wherein the composition contains about 1 milligram to about 2 milligrams of levophanol by total mass; in some embodiments, the composition comprises about 0.4 to about 5.88 milligrams of ferriciazine by total mass, wherein the composition contains about 25 milligrams to about 50 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 0.8 to about 11.76 milligrams of ferriciazine by total mass, wherein the composition contains about 50 milligrams to about 100 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 0.8 to about 11.76 milligrams of ferriciazine by total mass, wherein the composition contains about 5 milligrams to about 10 milligrams of morphine by total mass; In some embodiments, the composition comprises a total mass of about 1.2 to about 17.64 milligrams of ferciazine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 2.41 to about 35.28 milligrams of ferciazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 4.81 to about 70.56 milligrams of ferciazine, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 8.01 to about 117.6 milligrams of ferciazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of morphine; In some embodiments, the composition comprises a total mass of about 0.81 to about 11.89 milligrams of ferriciazine, wherein the composition contains a total mass of about 2.5 to about 5 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 1.62 to about 23.The composition comprises 77 milligrams of ferciazine, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 0.61 to about 8.91 milligrams of ferciazine, wherein the composition contains a total mass of about 2.5 milligrams to about 5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.91 to about 13.37 milligrams of ferciazine, wherein the composition contains a total mass of about 3.75 milligrams to about 7.5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 1.22 to about 17.82 milligrams of ferciazine, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of oxycodone; In some embodiments, the composition comprises a total mass of about 1.82 to about 26.73 milligrams of ferciazine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 3.64 to about 53.45 milligrams of ferciazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 4.86 to about 71.27 milligrams of ferciazine, wherein the composition comprises a total mass of about 20 milligrams to about 40 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 1.22 to about 17.82 milligrams of ferciazine, wherein the composition comprises a total mass of about 2.5 milligrams to about 5 milligrams of oxymorphone; In some embodiments, the composition comprises a total mass of about 2.43 to about 35.64 milligrams of ferriciazine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of oxymorphone; in some embodiments, the composition comprises a total mass of about 0.79 to about 11.The composition comprises 58 milligrams of ferriciazine, wherein the composition contains propoxyphene in a total mass of about 32.5 milligrams to about 65 milligrams; in some embodiments, the composition comprises about 1.58 to about 23.16 milligrams of ferriciazine in a total mass, wherein the composition contains tapentadol in a total mass of about 25 milligrams to about 50 milligrams; in some embodiments, the composition comprises about 2.37 to about 34.75 milligrams of ferriciazine in a total mass, wherein the composition contains tapentadol in a total mass of about 37.5 milligrams to about 75 milligrams; in some embodiments, the composition comprises about 3.16 to about 46.33 milligrams of ferriciazine in a total mass, wherein the composition contains tapentadol in a total mass of about 50 milligrams to about 100 milligrams; In some embodiments, the composition comprises a total mass of about 0.37 to about 5.35 milligrams of ferriciazine, wherein the composition comprises a total mass of about 25 milligrams to about 50 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 0.73 to about 10.69 milligrams of ferriciazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 1.46 to about 21.38 milligrams of ferriciazine, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 2.19 to about 32.07 milligrams of ferriciazine, wherein the composition comprises a total mass of about 150 milligrams to about 300 milligrams of tramadol.

[0210] Perphenazine

[0211] The present disclosure relates to a composition comprising (i) a dopamine antagonist; and (ii) an opioid, wherein the dopamine antagonist is perphenazine. In some embodiments, the composition comprises perphenazine in a total mass of about 2.91 to about 42.76 milligrams, wherein the composition comprises buprenorphine in a total mass of about 1 milligram to about 2 milligrams; in some embodiments, the composition comprises perphenazine in a total mass of about 6 to about 171.05 milligrams, wherein the composition comprises buprenorphine in a total mass of about 4 milligrams to about 8 milligrams; in some embodiments, the composition comprises perphenazine in a total mass of about 0.31 to about 4.49 milligrams, wherein the composition comprises codeine in a total mass of about 7.5 milligrams to about 15 milligrams; In some embodiments, the composition comprises a total mass of about 0.61 to about 8.98 milligrams of perphenazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 1.22 to about 17.96 milligrams of perphenazine, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 0.48 to about 7.06 milligrams of perphenazine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 0.96 to about 14.11 milligrams of perphenazine, wherein the composition comprises a total mass of about 10 milligrams to about 20 milligrams of hydrocodone; In some embodiments, the composition comprises a total mass of about 1.44 to about 21.17 milligrams of perphenazine, wherein the composition comprises a total mass of about 15 to about 30 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 1.92 to about 28.The composition comprises 22 milligrams of perphenazine, wherein the composition contains a total mass of about 20 milligrams to about 40 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 2.4 to about 35.28 milligrams of perphenazine, wherein the composition contains a total mass of about 25 milligrams to about 50 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 2.88 to about 42.33 milligrams of perphenazine, wherein the composition contains a total mass of about 30 milligrams to about 60 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 3.85 to about 56.45 milligrams of perphenazine, wherein the composition contains a total mass of about 40 milligrams to about 80 milligrams of hydrocodon; In some embodiments, the composition comprises a total mass of about 4.81 to about 70.56 milligrams of perphenazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 6 to about 141.11 milligrams of perphenazine, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 0.39 to about 5.69 milligrams of perphenazine, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 0.77 to about 11.38 milligrams of perphenazine, wherein the composition comprises a total mass of about 2 milligrams to about 4 milligrams of hydromorphone; In some embodiments, the composition comprises a total mass of about 1.55 to about 22.75 milligrams of perphenazine, wherein the composition comprises a total mass of about 4 to about 8 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 1.08 to about 15.The composition comprises 82 milligrams of perphenazine, wherein the composition contains about 1 milligram to about 2 milligrams of levolphanol by total mass; in some embodiments, the composition comprises about 0.24 to about 3.53 milligrams of perphenazine by total mass, wherein the composition contains about 25 milligrams to about 50 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 0.48 to about 7.06 milligrams of perphenazine by total mass, wherein the composition contains about 50 milligrams to about 100 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 0.48 to about 7.06 milligrams of perphenazine by total mass, wherein the composition contains about 5 milligrams to about 10 milligrams of morphine by total mass; In some embodiments, the composition comprises a total mass of about 0.72 to about 10.58 milligrams of perphenazine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 1.44 to about 21.17 milligrams of perphenazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 2.88 to about 42.33 milligrams of perphenazine, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 4.81 to about 70.56 milligrams of perphenazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of morphine; In some embodiments, the composition comprises a total mass of about 0.49 to about 7.13 milligrams of perphenazine, wherein the composition contains a total mass of about 2.5 to about 5 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 0.97 to about 14.The composition comprises 26 milligrams of perphenazine, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 0.36 to about 5.35 milligrams of perphenazine, wherein the composition contains a total mass of about 2.5 milligrams to about 5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.55 to about 8.02 milligrams of perphenazine, wherein the composition contains a total mass of about 3.75 milligrams to about 7.5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.73 to about 10.69 milligrams of perphenazine, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of oxycodone; In some embodiments, the composition comprises a total mass of about 1.09 to about 16.04 milligrams of perphenazine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 2.18 to about 32.07 milligrams of perphenazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 2.91 to about 42.76 milligrams of perphenazine, wherein the composition comprises a total mass of about 20 milligrams to about 40 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.73 to about 10.69 milligrams of perphenazine, wherein the composition comprises a total mass of about 2.5 milligrams to about 5 milligrams of oxymorphone; In some embodiments, the composition comprises a total mass of about 1.46 to about 21.38 milligrams of perphenazine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of oxymorphone; in some embodiments, the composition comprises a total mass of about 0.47 to about 6.The composition comprises 95 milligrams of perphenazine, wherein the composition contains propoxypheneine of a total mass of about 32.5 milligrams to about 65 milligrams; in some embodiments, the composition comprises perphenazine of a total mass of about 0.95 to about 13.9 milligrams, wherein the composition contains tapentadol of a total mass of about 25 milligrams to about 50 milligrams; in some embodiments, the composition comprises perphenazine of a total mass of about 1.42 to about 20.85 milligrams, wherein the composition contains tapentadol of a total mass of about 37.5 milligrams to about 75 milligrams; in some embodiments, the composition comprises perphenazine of a total mass of about 1.89 to about 27.8 milligrams, wherein the composition contains tapentadol of a total mass of about 50 milligrams to about 100 milligrams; In some embodiments, the composition comprises a total mass of about 0.22 to about 3.21 milligrams of perphenazine, wherein the composition comprises a total mass of about 25 milligrams to about 50 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 0.44 to about 6.41 milligrams of perphenazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 0.87 to about 12.83 milligrams of perphenazine, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 1.31 to about 19.24 milligrams of perphenazine, wherein the composition comprises a total mass of about 150 milligrams to about 300 milligrams of tramadol.

[0212] Pimozide

[0213] The present disclosure relates to a composition comprising (i) a dopamine antagonist; and (ii) an opioid, wherein the dopamine antagonist is pimozide. In some embodiments, the composition comprises a total mass of about 0.78 to about 11.4 milligrams of pimozide, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 1.6 to about 45.61 milligrams of pimozide, wherein the composition comprises a total mass of about 4 milligrams to about 8 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 0.08 to about 1.2 milligrams of pimozide, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of codeine; In some embodiments, the composition comprises a total mass of about 0.16 to about 2.39 milligrams of pimozide, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 0.33 to about 4.79 milligrams of pimozide, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 0.13 to about 1.88 milligrams of pimozide, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 0.26 to about 3.76 milligrams of pimozide, wherein the composition comprises a total mass of about 10 milligrams to about 20 milligrams of hydrocodone; In some embodiments, the composition comprises a total mass of about 0.38 to about 5.64 milligrams of pimozide, wherein the composition comprises a total mass of about 15 to about 30 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 0.51 to about 7.The composition comprises 53 milligrams of pimozide, wherein the composition contains a total mass of about 20 milligrams to about 40 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 0.64 to about 9.41 milligrams of pimozide, wherein the composition contains a total mass of about 25 milligrams to about 50 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 0.77 to about 11.29 milligrams of pimozide, wherein the composition contains a total mass of about 30 milligrams to about 60 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 1.03 to about 15.05 milligrams of pimozide, wherein the composition contains a total mass of about 40 milligrams to about 80 milligrams of hydrocodon; In some embodiments, the composition comprises a total mass of about 1.28 to about 18.82 milligrams of pimozide, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 1.6 to about 37.63 milligrams of pimozide, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 0.1 to about 1.52 milligrams of pimozide, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 0.21 to about 3.03 milligrams of pimozide, wherein the composition comprises a total mass of about 2 milligrams to about 4 milligrams of hydromorphone; In some embodiments, the composition comprises a total mass of about 0.41 to about 6.07 milligrams of pimozide, wherein the composition comprises a total mass of about 4 to about 8 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 0.29 to about 4.The composition comprises 22 milligrams of pimozide, wherein the composition contains about 1 milligram to about 2 milligrams of levophanol by total mass; in some embodiments, the composition comprises about 0.06 to about 0.94 milligrams of pimozide by total mass, wherein the composition contains about 25 milligrams to about 50 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 0.13 to about 1.88 milligrams of pimozide by total mass, wherein the composition contains about 50 milligrams to about 100 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 0.13 to about 1.88 milligrams of pimozide by total mass, wherein the composition contains about 5 milligrams to about 10 milligrams of morphine by total mass; In some embodiments, the composition comprises a total mass of about 0.19 to about 2.82 milligrams of pimozide, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 0.38 to about 5.64 milligrams of pimozide, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 0.77 to about 11.29 milligrams of pimozide, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 1.28 to about 18.82 milligrams of pimozide, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of morphine; In some embodiments, the composition comprises pimozide with a total mass of about 0.13 to about 1.9 milligrams, wherein the composition contains methadone with a total mass of about 2.5 to about 5 milligrams; in some embodiments, the composition comprises about 0.26 to about 3 milligrams with a total mass.The composition comprises 8 milligrams of pimozide, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 0.1 to about 1.43 milligrams of pimozide, wherein the composition contains a total mass of about 2.5 milligrams to about 5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.15 to about 2.14 milligrams of pimozide, wherein the composition contains a total mass of about 3.75 milligrams to about 7.5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.19 to about 2.85 milligrams of pimozide, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of oxycodone; In some embodiments, the composition comprises a total mass of about 0.29 to about 4.28 milligrams of pimozide, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.58 to about 8.55 milligrams of pimozide, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.78 to about 11.4 milligrams of pimozide, wherein the composition comprises a total mass of about 20 milligrams to about 40 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 0.19 to about 2.85 milligrams of pimozide, wherein the composition comprises a total mass of about 2.5 milligrams to about 5 milligrams of oxymorphone; In some embodiments, the composition comprises a total mass of about 0.39 to about 5.7 milligrams of pimozide, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of oxymorphone; in some embodiments, the composition comprises a total mass of about 0.13 to about 1.85 milligrams of pimozide, wherein the composition comprises a total mass of about 32.It contains 5 milligrams to about 65 milligrams of propoxyphene; in some embodiments, the composition comprises a total mass of about 0.25 to about 3.71 milligrams of pimozide, wherein the composition comprises a total mass of about 25 milligrams to about 50 milligrams of tapentadol; in some embodiments, the composition comprises a total mass of about 0.38 to about 5.56 milligrams of pimozide, wherein the composition comprises a total mass of about 37.5 milligrams to about 75 milligrams of tapentadol; in some embodiments, the composition comprises a total mass of about 0.5 to about 7.41 milligrams of pimozide, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of tapentadol; In some embodiments, the composition comprises a total mass of about 0.06 to about 0.86 milligrams of pimozide, wherein the composition comprises a total mass of about 25 milligrams to about 50 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 0.12 to about 1.71 milligrams of pimozide, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 0.23 to about 3.42 milligrams of pimozide, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 0.35 to about 5.13 milligrams of pimozide, wherein the composition comprises a total mass of about 150 milligrams to about 300 milligrams of tramadol.

[0214] Prochlorperazine

[0215] The present disclosure relates to a composition comprising (i) a dopamine antagonist; and (ii) an opioid, wherein the dopamine antagonist is prochlorperazine. In some embodiments, the composition comprises a total mass of about 8.49 to about 124.67 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 17.49 to about 498.67 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 4 milligrams to about 8 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 0.89 to about 13.09 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of codeine; In some embodiments, the composition comprises a total mass of about 1.78 to about 26.18 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 3.57 to about 52.36 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 1.4 to about 20.57 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 2.8 to about 41.14 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 10 milligrams to about 20 milligrams of hydrocodone; In some embodiments, the composition comprises a total mass of about 4.21 to about 61.71 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 5.61 to about 82.The composition comprises 29 milligrams of prochlorperazine, wherein the composition contains a total mass of about 20 milligrams to about 40 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 7.01 to about 102.85 milligrams of prochlorperazine, wherein the composition contains a total mass of about 25 milligrams to about 50 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 8.41 to about 123.42 milligrams of prochlorperazine, wherein the composition contains a total mass of about 30 milligrams to about 60 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 11.21 to about 164.56 milligrams of prochlorperazine, wherein the composition contains a total mass of about 40 milligrams to about 80 milligrams of hydrocodon; In some embodiments, the composition comprises a total mass of about 14.01 to about 205.71 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 17.49 to about 411.41 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 1.13 to about 16.58 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of hydromorphone; In some embodiments, the composition comprises a total mass of about 2.26 to about 33.17 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 2 milligrams to about 4 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 4.52 to about 66.The composition comprises 32 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 4 milligrams to about 8 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 3.14 to about 46.13 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of levorphanol; in some embodiments, the composition comprises a total mass of about 0.7 to about 10.29 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 25 milligrams to about 50 milligrams of meperidine; in some embodiments, the composition comprises a total mass of about 1.4 to about 20.57 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of meperidine; In some embodiments, the composition comprises a total mass of about 1.4 to about 20.57 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 2.1 to about 30.86 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 4.21 to about 61.71 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 8.41 to about 123.42 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of morphine; In some embodiments, the composition comprises a total mass of about 14.01 to about 205.71 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 1.42 to about 20.The composition comprises 79 milligrams of prochlorperazine, wherein the composition contains a total mass of about 2.5 milligrams to about 5 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 2.83 to about 41.58 milligrams of prochlorperazine, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 1.06 to about 15.59 milligrams of prochlorperazine, wherein the composition contains a total mass of about 2.5 milligrams to about 5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 1.59 to about 23.38 milligrams of prochlorperazine, wherein the composition contains a total mass of about 3.75 milligrams to about 7.5 milligrams of oxycodone; In some embodiments, the composition comprises a total mass of about 2.13 to about 31.16 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 3.18 to about 46.75 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 6.37 to about 93.5 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 8.49 to about 124.67 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 20 milligrams to about 40 milligrams of oxycodone; In some embodiments, the composition comprises a total mass of about 2.13 to about 31.16 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 2.5 to about 5 milligrams of oxymorphone; in some embodiments, the composition comprises a total mass of about 4.25 to about 62.The composition comprises 34 milligrams of prochlorperazine, wherein the composition contains about 5 milligrams to about 10 milligrams of oxymorphone by total mass; in some embodiments, the composition comprises about 1.38 to about 20.26 milligrams of prochlorperazine by total mass, wherein the composition contains about 32.5 milligrams to about 65 milligrams of propoxyphene by total mass; in some embodiments, the composition comprises about 2.76 to about 40.51 milligrams of prochlorperazine by total mass, wherein the composition contains about 25 milligrams to about 50 milligrams of tapentadol by total mass; in some embodiments, the composition comprises about 4.14 to about 60.78 milligrams of prochlorperazine by total mass, wherein the composition contains about 37.5 milligrams to about 75 milligrams of tapentadol by total mass; In some embodiments, the composition comprises a total mass of about 5.52 to about 81.03 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of tapentadol; in some embodiments, the composition comprises a total mass of about 0.64 to about 9.35 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 25 milligrams to about 50 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 1.28 to about 18.7 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 2.55 to about 37.4 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of tramadol; In some embodiments, the composition comprises a total mass of about 3.82 to about 56.1 milligrams of prochlorperazine, wherein the composition comprises a total mass of about 150 milligrams to about 300 milligrams of tramadol.

[0216] Quetiapin

[0217] The present disclosure relates to a composition comprising (i) a dopamine antagonist; and (ii) an opioid, wherein the dopamine antagonist is quetiapine. In some embodiments, the composition comprises a total mass of about 72.83 to about 1069.05 milligrams of quetiapine, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 150 to about 4276.13 milligrams of quetiapine, wherein the composition comprises a total mass of about 4 milligrams to about 8 milligrams of buprenorphine; in some embodiments, the composition comprises a total mass of about 7.65 to about 112.28 milligrams of quetiapine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of codeine; In some embodiments, the composition comprises a total mass of about 15.3 to about 224.48 milligrams of quetiapine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 30.6 to about 449.03 milligrams of quetiapine, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of codeine; in some embodiments, the composition comprises a total mass of about 12 to about 176.4 milligrams of quetiapine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 24 to about 352.8 milligrams of quetiapine, wherein the composition comprises a total mass of about 10 milligrams to about 20 milligrams of hydrocodone; In some embodiments, the composition comprises a total mass of about 36.08 to about 529.2 milligrams of quetiapine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of hydrocodone; in some embodiments, the composition comprises a total mass of about 48.08 to about 705.It comprises 6 milligrams of quetiapine, wherein the composition contains a total mass of about 20 milligrams to about 40 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 60.08 to about 881.93 milligrams of quetiapine, wherein the composition contains a total mass of about 25 milligrams to about 50 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 72.08 to about 1058.33 milligrams of quetiapine, wherein the composition contains a total mass of about 30 milligrams to about 60 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 96.15 to about 1411.13 milligrams of quetiapine, wherein the composition contains a total mass of about 40 milligrams to about 80 milligrams of hydrocodon; In some embodiments, the composition comprises a total mass of about 120.15 to about 1763.93 milligrams of quetiapine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 150 to about 3527.85 milligrams of quetiapine, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of hydrocodon; in some embodiments, the composition comprises a total mass of about 9.68 to about 142.2 milligrams of quetiapine, wherein the composition comprises a total mass of about 1 milligram to about 2 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 19.35 to about 284.4 milligrams of quetiapine, wherein the composition comprises a total mass of about 2 milligrams to about 4 milligrams of hydromorphone; In some embodiments, the composition comprises a total mass of about 38.78 to about 568.73 milligrams of quetiapine, wherein the composition comprises a total mass of about 4 milligrams to about 8 milligrams of hydromorphone; in some embodiments, the composition comprises a total mass of about 26.93 to about 395.It comprises 55 milligrams of quetiapine, wherein the composition contains about 1 milligram to about 2 milligrams of levolphanol by total mass; in some embodiments, the composition comprises about 6 to about 88.2 milligrams of quetiapine by total mass, wherein the composition contains about 25 milligrams to about 50 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 12 to about 176.4 milligrams of quetiapine by total mass, wherein the composition contains about 50 milligrams to about 100 milligrams of meperidine by total mass; in some embodiments, the composition comprises about 12 to about 176.4 milligrams of quetiapine by total mass, wherein the composition contains about 5 milligrams to about 10 milligrams of morphine by total mass; In some embodiments, the composition comprises a total mass of about 18 to about 264.6 milligrams of quetiapine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 36.08 to about 529.2 milligrams of quetiapine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 72.08 to about 1058.33 milligrams of quetiapine, wherein the composition comprises a total mass of about 30 milligrams to about 60 milligrams of morphine; in some embodiments, the composition comprises a total mass of about 120.15 to about 1763.93 milligrams of quetiapine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of morphine; In some embodiments, the composition comprises a total mass of about 12.15 to about 178.28 milligrams of quetiapine, wherein the composition contains a total mass of about 2.5 to about 5 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 24.3 to about 356.It comprises 55 milligrams of quetiapine, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of methadone; in some embodiments, the composition comprises a total mass of about 9.08 to about 133.65 milligrams of quetiapine, wherein the composition contains a total mass of about 2.5 milligrams to about 5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 13.65 to about 200.48 milligrams of quetiapine, wherein the composition contains a total mass of about 3.75 milligrams to about 7.5 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 18.23 to about 267.23 milligrams of quetiapine, wherein the composition contains a total mass of about 5 milligrams to about 10 milligrams of oxycodone; In some embodiments, the composition comprises a total mass of about 27.3 to about 400.88 milligrams of quetiapine, wherein the composition comprises a total mass of about 7.5 milligrams to about 15 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 54.6 to about 801.75 milligrams of quetiapine, wherein the composition comprises a total mass of about 15 milligrams to about 30 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 72.83 to about 1069.05 milligrams of quetiapine, wherein the composition comprises a total mass of about 20 milligrams to about 40 milligrams of oxycodone; in some embodiments, the composition comprises a total mass of about 18.23 to about 267.23 milligrams of quetiapine, wherein the composition comprises a total mass of about 2.5 milligrams to about 5 milligrams of oxymorphone; In some embodiments, the composition comprises a total mass of about 36.45 to about 534.53 milligrams of quetiapine, wherein the composition comprises a total mass of about 5 milligrams to about 10 milligrams of oxymorphone; in some embodiments, the composition comprises a total mass of about 11.85 to about 173.It comprises 7 milligrams of quetiapine, wherein the composition contains propoxyphene with a total mass of about 32.5 milligrams to about 65 milligrams; in some embodiments, the composition comprises quetiapine with a total mass of about 23.7 to about 347.4 milligrams, wherein the composition contains tapentadol with a total mass of about 25 milligrams to about 50 milligrams; in some embodiments, the composition comprises quetiapine with a total mass of about 35.48 to about 521.18 milligrams, wherein the composition contains tapentadol with a total mass of about 37.5 milligrams to about 75 milligrams; in some embodiments, the composition comprises quetiapine with a total mass of about 47.33 to about 694.88 milligrams, wherein the composition contains tapentadol with a total mass of about 50 milligrams to about 100 milligrams; In some embodiments, the composition comprises a total mass of about 5.48 to about 80.18 milligrams of quetiapine, wherein the composition comprises a total mass of about 25 milligrams to about 50 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 10.95 to about 160.35 milligrams of quetiapine, wherein the composition comprises a total mass of about 50 milligrams to about 100 milligrams of tramadol; in some embodiments, the composition comprises a total mass of about 21.83 to about 320.7 milligrams of quetiapine, wherein the composition comprises a total mass of about 100 milligrams to about 200 milligrams of tramadol; In some embodiments, the composition comprises a total mass of about 32.78 to about 481.05 milligrams of quetiapine, wherein the composition comprises a total mass of about 150 mil...

Claims

Claim 1 A composition comprising (i) a dopamine antagonist; and (ii) an opioid; wherein the total mass of the dopamine antagonist is about 0.1 to about 2.5 milligrams, and the total mass of the opioid is about 0.2 milligrams to about 150 milligrams. Claim 2 In claim 1, the dopamine antagonist is a compound having a structure represented by the following chemical formula I, I In the above formula, X1 is selected from halogen, H, O, OH, or NH2; R2 is O, N, NH, Selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted alkylene groups, substituted or unsubstituted aryl groups, substituted or unsubstituted acyl groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted heteroacyl groups, substituted or unsubstituted cycloalkyl groups, or substituted or unsubstituted heterocycloalkyl groups; R1 and R3 are O, N, NH, A composition comprising a compound individually selected from a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkylene group, a substituted or unsubstituted aryl group, a substituted or unsubstituted acyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted heteroacyl group, a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocycloalkyl, a pharmaceutically acceptable salt thereof, or a precursor drug thereof. Claim 3 A composition according to claim 1 or 2, wherein the dopamine antagonist is a compound selected from DD8, DD9 and DD10 or pharmaceutically acceptable salts thereof. Claim 4 In any one of claims 1 to 3, the opioid is a compound having a structure represented by the following chemical formula, wherein In the above formula, X1 is selected from H, Cl, F, I, O, OH, or NH2; R2 is selected from a substituted or unsubstituted amine group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkylene group; and R1 and R3 are O, N, NH, Individually selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted acyl groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted heteroacyl groups, substituted or unsubstituted cycloalkyl groups, or substituted or unsubstituted heterocycloalkyl groups; X2 is selected from Cl, F, I, OH, or =O; R4 is selected from substituted or unsubstituted amine groups or substituted or unsubstituted alkyl groups; R7 is selected from substituted or unsubstituted amine groups, substituted or unsubstituted alkyl groups, or substituted or unsubstituted alkylene groups; R5 and R6 are O, N, NH, A compound individually selected from a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkylene group, a substituted or unsubstituted aryl group, a substituted or unsubstituted acyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted heteroacyl group, a substituted or unsubstituted cycloalkyl and a substituted or unsubstituted heterocycloalkyl, or R5 and R6 together form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted cycloalkene; or a pharmaceutically acceptable salt thereof or a prodrug thereof. Claim 5 A composition according to any one of claims 1 to 4, wherein the opioid is selected from morphine, codeine, hydromorphone, fentanyl, hydrocodone, levorphanol, meperidine, methadone, oxycodone, oxymorphone, tramadol, tapentadol, or pharmaceutically acceptable salts thereof or precursor drugs thereof. Claim 6 A composition according to any one of claims 1 to 5, wherein the opioid is fentanyl or a pharmaceutically acceptable salt thereof, and the mass of fentanyl is about 100 micrograms to about 500 micrograms. Claim 7 A composition according to any one of claims 1 to 6, wherein the dopamine antagonist is DD9 or a pharmaceutically acceptable salt thereof, and the mass of DD9 is about 0.1 milligrams to about 2 milligrams. Claim 8 A pharmaceutical composition comprising: (i) a dopamine antagonist, a pharmaceutically acceptable salt thereof or a prodrug thereof; (ii) an opioid, a pharmaceutically acceptable salt thereof or a prodrug thereof; and (iii) a pharmaceutically acceptable carrier. Claim 9 A pharmaceutical composition according to claim 8, wherein the dopamine antagonist is a compound having a structure represented by chemical formulas I, II, III, and IV, or a pharmaceutically acceptable salt thereof or a prodrug thereof. Claim 10 A pharmaceutical composition according to claim 8 or 9, wherein the dopamine antagonist is a compound selected from DD8, DD9 and DD10 or pharmaceutically acceptable salts thereof. Claim 11 In any one of claims 8 to 10, the opioid is a compound having a structure represented by the following chemical formula, wherein A pharmaceutical composition, wherein R1 is a compound that is a substituted or unsubstituted six-membered carbon ring or a six-membered heterocycle, a pharmaceutically acceptable salt thereof, or a precursor drug thereof. Claim 12 A pharmaceutical composition according to any one of claims 8 to 11, wherein the opioid is selected from morphine, codeine, hydromorphone, fentanyl, hydrocodone, levorphanol, meperidine, methadone, oxycodone, oxymorphone, tramadol, tapentadol, pharmaceutically acceptable salts thereof, or precursor drugs thereof. Claim 13 A pharmaceutical composition according to any one of claims 8 to 12, wherein the opioid is fentanyl or a pharmaceutically acceptable salt thereof, and the mass of fentanyl is about 100 micrograms to about 500 micrograms. Claim 14 A pharmaceutical composition according to any one of claims 8 to 13, wherein the dopamine antagonist is DD9 or DD10 or a pharmaceutically acceptable salt thereof, and the mass of DD9 or DD10 is about 0.1 milligrams to about 2 milligrams. Claim 15 A pharmaceutical composition according to any one of claims 8 to 13, wherein the dopamine antagonist is DD9 or DD10 or a pharmaceutically acceptable salt thereof, the mass of DD9 or DD10 is about 0.1 milligrams to about 2 milligrams, and the opioid is fentanyl, codeine, morphine, oxycodone, methadone or a pharmaceutically acceptable salt thereof. Claim 16 A pharmaceutical composition according to any one of claims 8 to 15, wherein the pharmaceutical composition is an oral formulation. Claim 17 A method for preventing opioid dependence comprising the step of administering to a subject who needs to be prevented from opioid dependence, the step of administering to the subject a dopamine antagonist or a pharmaceutically acceptable salt thereof; or the step of administering to the subject a pharmaceutical composition of any one of claims 8 to 16. Claim 18 In claim 17, the method wherein the pharmaceutical composition comprises one or a combination of a dopamine antagonist and an opioid in a therapeutically effective amount. Claim 19 A method according to either claim 17 or 18, wherein the dopamine antagonist or the pharmaceutical composition is administered via oral administration, parenteral administration, sublingual administration, transdermal administration, rectal administration, transmucosal administration, local administration, inhalation, buccal administration, intrapleural administration, intravenous administration, intra-arterial administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, intranasal administration, intrathecal administration and intra-articular administration, or a combination thereof. Claim 20 A method according to any one of claims 17 to 19, wherein the subject is a mammal. Claim 21 A method in which, in any one of paragraphs 17 through 20, the subject is a human being. Claim 22 A method according to any one of claims 17 to 21, wherein the dopamine antagonist is administered simultaneously with opioid administration or before or after opioid administration. Claim 23 A method according to any one of claims 17 to 22, wherein the dopamine antagonist is administered in a dose of about 0.1 milligrams to about 2 milligrams. Claim 24 A method according to any one of claims 17 to 24, wherein the dopamine antagonist is administered before or after surgery or with an opioid dose. Claim 25 A method for treating pain in a subject who needs to be treated for pain, comprising the step of administering a dopamine antagonist or a pharmaceutically acceptable salt thereof to the subject; or the step of administering a pharmaceutical composition of any one of claims 8 to 16 to the subject. Claim 26 In claim 25, the pharmaceutical composition comprises a therapeutically effective amount of a dopamine antagonist and optionally an opioid. Claim 27 A method according to either claim 25 or 26, wherein the dopamine antagonist or the pharmaceutical composition is administered via oral administration, parenteral administration, sublingual administration, transdermal administration, rectal administration, transmucosal administration, local administration, inhalation, buccal administration, intrapleural administration, intravenous administration, intra-arterial administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, intranasal administration, intrathecal administration and intra-articular administration, or a combination thereof. Claim 28 A method according to any one of paragraphs 25 to 27, wherein the subject is a mammal. Claim 29 A method in which, in any one of paragraphs 25 through 28, the subject is a human being. Claim 30 A method according to any one of claims 25 to 29, wherein the dopamine antagonist is administered simultaneously with opioid administration or before or after opioid administration. Claim 31 A method according to any one of claims 25 to 30, wherein the dopamine antagonist is administered in a dose of about 0.1 milligrams to about 2 milligrams. Claim 32 A method according to any one of claims 25 to 31, wherein the dopamine antagonist is administered before or after surgery or with an opioid dose. Claim 33 A method for preventing drug preference, comprising the step of administering a dopamine antagonist or a pharmaceutically acceptable salt thereof to the subject; or the step of administering a pharmaceutical composition of any one of claims 8 to 16 to the subject. Claim 34 In paragraph 33, the method wherein the pharmaceutical composition comprises one or a combination of a dopamine antagonist and an opioid in a therapeutically effective amount. Claim 35 A method according to either claim 33 or 34, wherein the dopamine antagonist or the pharmaceutical composition is administered via oral administration, parenteral administration, sublingual administration, transdermal administration, rectal administration, transmucosal administration, local administration, inhalation, buccal administration, intrapleural administration, intravenous administration, intra-arterial administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, intranasal administration, intrathecal administration and intra-articular administration, or a combination thereof. Claim 36 A method according to any one of paragraphs 33 to 35, wherein the subject is a mammal. Claim 37 A method in which, in any one of paragraphs 33 through 36, the subject is a human being. Claim 38 A method according to any one of claims 33 to 37, wherein the dopamine antagonist is administered simultaneously with opioid administration or before or after opioid administration. Claim 39 A method according to any one of claims 33 to 38, wherein the dopamine antagonist is administered in a dose of about 0.1 milligrams to about 2 milligrams. Claim 40 A method according to any one of claims 33 to 39, wherein the dopamine antagonist is administered before or after surgery or with an opioid dose. Claim 41 A method for reducing event-related pain response, comprising the step of administering a dopamine antagonist or a pharmaceutically acceptable salt thereof to a subject; or the step of administering a pharmaceutical composition of any one of claims 8 to 16 to a subject. Claim 42 In claim 41, the pharmaceutical composition comprises a therapeutically effective amount of one or a combination of a dopamine antagonist and an opioid and a pharmaceutically acceptable carrier. Claim 43 A method according to either claim 41 or 42, wherein the dopamine antagonist or the pharmaceutical composition is administered via oral administration, parenteral administration, sublingual administration, transdermal administration, rectal administration, transmucosal administration, local administration, inhalation, buccal administration, intrapleural administration, intravenous administration, intra-arterial administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, intranasal administration, intrathecal administration and intra-articular administration, or a combination thereof. Claim 44 A method according to any one of paragraphs 41 to 43, wherein the subject is a mammal. Claim 45 A method in which, in any one of paragraphs 41 to 44, the subject is a human being. Claim 46 A method according to any one of claims 41 to 45, wherein the dopamine antagonist is administered simultaneously with opioid administration or before or after opioid administration. Claim 47 A method according to any one of claims 41 to 46, wherein the dopamine antagonist is administered in a dose of about 0.1 milligrams to about 2 milligrams. Claim 48 A method according to any one of claims 41 to 47, wherein the dopamine antagonist is administered before or after surgery or with an opioid dose. Claim 49 A method for preventing opioid use disorder, comprising the step of administering a dopamine antagonist or a pharmaceutically acceptable salt thereof to the subject; or the step of administering a pharmaceutical composition of any one of claims 8 to 16 to the subject. Claim 50 In claim 49, the method wherein the pharmaceutical composition comprises one or a combination of a dopamine antagonist and an opioid in a therapeutically effective amount. Claim 51 A method according to either claim 49 or 50, wherein the dopamine antagonist or the pharmaceutical composition is administered via oral administration, parenteral administration, sublingual administration, transdermal administration, rectal administration, transmucosal administration, local administration, inhalation, buccal administration, intrapleural administration, intravenous administration, intra-arterial administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, intranasal administration, intrathecal administration and intra-articular administration, or a combination thereof. Claim 52 A method according to any one of claims 49 to 51, wherein the subject is a mammal. Claim 53 A method in which, in any one of paragraphs 49 to 52, the subject is a human being. Claim 54 A method according to any one of claims 49 to 53, wherein the dopamine antagonist is administered simultaneously with opioid administration or before or after opioid administration. Claim 55 A method according to any one of claims 49 to 54, wherein the dopamine antagonist is administered in a dose of about 0.1 milligrams to about 2 milligrams. Claim 56 A method according to any one of claims 49 to 55, wherein the dopamine antagonist is administered before or after surgery or with an opioid dose. Claim 57 A method for anesthetizing a subject that requires anesthesia, comprising the step of administering a dopamine antagonist or a pharmaceutically acceptable salt thereof to the subject; or the step of administering a pharmaceutical composition of any one of claims 8 to 16 to the subject. Claim 58 In claim 57, the pharmaceutical composition comprises one or a combination of a dopamine antagonist and an opioid in a therapeutically effective amount. Claim 59 A method according to either claim 57 or 58, wherein the dopamine antagonist or the pharmaceutical composition is administered via oral administration, parenteral administration, sublingual administration, transdermal administration, rectal administration, transmucosal administration, topical administration, inhalation, buccal administration, intrapleural administration, intravenous administration, intra-arterial administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, intranasal administration, intrathecal administration and intra-articular administration, or a combination thereof. Claim 60 A method according to any one of paragraphs 57 to 59, wherein the subject is a mammal. Claim 61 A method in any one of paragraphs 57 through 60, wherein the subject is a human. Claim 62 A method according to any one of claims 57 to 61, wherein the dopamine antagonist is administered simultaneously with opioid administration or before or after opioid administration. Claim 63 A method according to any one of claims 57 to 62, wherein the dopamine antagonist is administered in a dose of about 0.1 milligrams to about 2 milligrams. Claim 64 A method according to any one of claims 57 to 63, wherein the dopamine antagonist is administered before or after surgery or with an opioid dose. Claim 65 A method for enhancing the analgesic effect of an opioid, comprising the step of administering a dopamine antagonist or a pharmaceutically acceptable salt thereof to the subject; or the step of administering a pharmaceutical composition of any one of claims 8 to 16 to the subject. Claim 66 In paragraph 65, the method wherein the pharmaceutical composition comprises one or a combination of a dopamine antagonist and an opioid in a therapeutically effective amount. Claim 67 A method according to either claim 65 or 66, wherein the dopamine antagonist or the pharmaceutical composition is administered via oral administration, parenteral administration, sublingual administration, transdermal administration, rectal administration, transmucosal administration, local administration, inhalation, buccal administration, intrapleural administration, intravenous administration, intra-arterial administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, intranasal administration, intrathecal administration and intra-articular administration, or a combination thereof. Claim 68 A method according to any one of paragraphs 65 to 67, wherein the subject is a mammal. Claim 69 A method in which, in any one of paragraphs 65 through 68, the subject is a human being. Claim 70 A method according to any one of claims 65 to 69, wherein the dopamine antagonist is administered simultaneously with opioid administration or before or after opioid administration. Claim 71 A method according to any one of claims 65 to 70, wherein the dopamine antagonist is administered in a dose of about 0.1 milligrams to about 2 milligrams. Claim 72 A method according to any one of claims 65 to 71, wherein the dopamine antagonist is administered before or after surgery or with an opioid dose. Claim 73 A method for inhibiting intracellular dopamine action, comprising the step of exposing the cell to a composition, wherein the cell is exposed to a dopamine antagonist or a composition of any one of claims 1 to 7. Claim 74 In paragraph 73, the above-mentioned exposure step is performed in a test tube, a method. Claim 75 In paragraph 73, the above-mentioned exposure step is performed in vivo, a method. Claim 76 A composition according to claim 1 or 2, wherein the dopamine antagonist is DD12 or a pharmaceutically acceptable salt thereof. Claim 77 In paragraph 76, the composition does not contain DD9, DD10, or pharmaceutically acceptable salts thereof. Claim 78 A composition according to any one of claims 1 to 7, 76 or 77, wherein the composition is an immediate-release formulation and / or an oral formulation. Claim 79 A pharmaceutical composition according to claim 8 or 9, wherein the dopamine antagonist is DD12 or a pharmaceutically acceptable salt thereof. Claim 80 In claim 79, the pharmaceutical composition does not include DD9, DD10, variants thereof, salts thereof, or analogs thereof. Claim 81 A pharmaceutical composition according to any one of claims 8 to 13, wherein the dopamine antagonist is DD12 or a pharmaceutically acceptable salt thereof and the mass of DD12 is about 0.1 milligrams to about 2 milligrams. Claim 82 In claim 81, the pharmaceutical composition does not include DD9, DD10, variants thereof, or salts thereof. Claim 83 A pharmaceutical composition according to claim 81 or 82, wherein the opioid is fentanyl, codeine, morphine, oxycodone, methadone, or a pharmaceutically acceptable salt. Claim 84 A pharmaceutical composition according to any one of claims 81 to 83, wherein the pharmaceutical composition is an oral formulation. Claim 85 A pharmaceutical composition according to any one of claims 8 to 16 and 79 to 84, wherein the pharmaceutical composition is an immediate-release formulation or an oral formulation. Claim 86 A method for preventing opioid dependence comprising the step of administering to a subject who needs to be prevented from opioid dependence, the step of administering DD12 or a pharmaceutically acceptable salt thereof to the subject; or the step of administering a pharmaceutical composition of any one of claims 81 to 85. Claim 87 In paragraph 86, the method wherein the DD12 does not include DD9, DD10, variants thereof, or salts thereof. Claim 88 A method according to either claim 86 or 87, wherein the DD12 or the pharmaceutical composition is administered via oral administration, parenteral administration, sublingual administration, transdermal administration, rectal administration, transmucosal administration, topical administration, inhalation, buccal administration, intrapleural administration, intravenous administration, intra-arterial administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, intranasal administration, intrathecal administration and intra-articular administration, or a combination thereof. Claim 89 A method according to any one of claims 86 to 88, wherein the subject is a mammal. Claim 90 A method in which, in any one of paragraphs 86 through 88, the subject is a human being. Claim 91 A method according to any one of claims 86 to 90, wherein the DD12 or the pharmaceutical composition is administered simultaneously with opioid administration or before or after opioid administration. Claim 92 A method according to any one of claims 86 to 91, wherein the DD12 is administered in a dose of about 0.1 milligrams to about 2 milligrams. Claim 93 A method according to any one of claims 86 to 92, wherein the DD12 or the pharmaceutical composition is administered before, after, or after surgery with an opioid dose. Claim 94 A method according to any one of claims 86 to 94, wherein the administration of DD12 is about 2 to about 6 times per day. Claim 95 A method for treating pain in a subject who needs to be treated for pain, comprising the step of administering DD12 or a pharmaceutically acceptable salt thereof to the subject; or the step of administering a pharmaceutical composition of any one of claims 79 to 84 to the subject. Claim 96 In paragraph 95, the method wherein the DD12 does not include DD9, DD10, variants thereof, or salts thereof. Claim 97 A method according to either claim 95 or 96, wherein the pharmaceutical composition comprises a therapeutically effective amount of a dopamine antagonist and optionally an opioid. Claim 98 A method according to any one of claims 95 to 97, wherein the dopamine antagonist or the pharmaceutical composition is administered via oral administration, parenteral administration, sublingual administration, transdermal administration, rectal administration, transmucosal administration, local administration, inhalation, buccal administration, intrapleural administration, intravenous administration, intra-arterial administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, intranasal administration, intrathecal administration and intra-articular administration, or a combination thereof. Claim 99 A method according to any one of claims 95 to 98, wherein the subject is a mammal. Claim 100 A method in any one of paragraphs 95 through 99, wherein the subject is a human. Claim 101 A method according to any one of claims 95 to 100, wherein the DD12 or the pharmaceutical composition is administered simultaneously with opioid administration or before or after opioid administration. Claim 102 A method according to any one of claims 95 to 101, wherein the DD12 is administered in a dose of about 0.1 milligrams to about 2 milligrams. Claim 103 A method according to any one of claims 95 to 102, wherein the DD12 or the pharmaceutical composition is administered before, after, or after surgery with an opioid dose. Claim 104 A method according to any one of claims 95 to 103, wherein the administration is about 2 to about 6 times per day. Claim 105 A method for preventing drug preference, comprising the step of administering DD12 or a pharmaceutically acceptable salt thereof to the subject; or the step of administering a pharmaceutical composition of any one of claims 79 to 85 to the subject. Claim 106 In claim 105, the method wherein the DD12 does not include DD9, DD10, variants thereof, or salts thereof. Claim 107 A method according to either claim 105 or 106, wherein the pharmaceutical composition comprises a therapeutically effective amount of DD12 and one or a combination thereof of an opioid. Claim 108 A method according to any one of claims 105 to 107, wherein the dopamine antagonist or the pharmaceutical composition is administered via oral administration, parenteral administration, sublingual administration, transdermal administration, rectal administration, transmucosal administration, local administration, inhalation, buccal administration, intrapleural administration, intravenous administration, intra-arterial administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, intranasal administration, intrathecal administration and intra-articular administration, or a combination thereof. Claim 109 A method according to any one of claims 105 to 108, wherein the subject is a mammal. Claim 110 A method in which, in any one of paragraphs 105 to 109, the subject is a human being. Claim 111 A method according to any one of claims 105 to 110, wherein the DD12 or the pharmaceutical composition is administered simultaneously with opioid administration or before or after opioid administration. Claim 112 A method according to any one of claims 105 to 111, wherein the DD12 is administered in a dose of about 0.1 milligrams to about 2 milligrams. Claim 113 A method according to any one of claims 105 to 112, wherein the DD12 or the pharmaceutical composition is administered before, after, or after surgery with an opioid dose. Claim 114 A method according to any one of claims 105 to 113, wherein the administration of DD12 is about 2 to about 6 times per day. Claim 115 A method for reducing an event-related pain response in a subject who needs to reduce an event-related pain response, comprising the step of administering a therapeutically effective amount of DD12 or a pharmaceutically acceptable salt thereof to the subject; or the step of administering a pharmaceutical composition of any one of claims 79 to 85. Claim 116 In paragraph 115, the method wherein the DD12 does not include DD9, DD10, variants thereof, or salts thereof. Claim 117 A method according to either claim 115 or 116, wherein the pharmaceutical composition comprises a therapeutically effective amount of one or a combination of a dopamine antagonist and an opioid and a pharmaceutically acceptable carrier. Claim 118 A method according to any one of claims 115 to 117, wherein the dopamine antagonist or the pharmaceutical composition is administered via oral administration, parenteral administration, sublingual administration, transdermal administration, rectal administration, transmucosal administration, local administration, inhalation, buccal administration, intrapleural administration, intravenous administration, intra-arterial administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, intranasal administration, intrathecal administration and intra-articular administration, or a combination thereof. Claim 119 A method according to any one of claims 115 to 118, wherein the subject is a mammal. Claim 120 A method in which, in any one of paragraphs 115 to 119, the subject is a human being. Claim 121 A method according to any one of claims 115 to 120, wherein the DD12 or the pharmaceutical composition is administered simultaneously with opioid administration or before or after opioid administration. Claim 122 A method according to any one of claims 115 to 121, wherein the DD12 is administered in a dose of about 0.1 milligrams to about 2 milligrams. Claim 123 A method according to any one of claims 115 to 122, wherein the dopamine antagonist is administered before or after surgery or with an opioid dose. Claim 124 A method according to any one of claims 115 to 123, wherein the administration is about 2 to about 6 times per day. A method for preventing opioid use disorder in a subject who needs to prevent opioid use disorder, comprising the step of administering DD12 or a pharmaceutically acceptable salt thereof to the subject; or the step of administering a pharmaceutical composition according to any one of claims 79 to 85 to the subject. Claim 125 In paragraph 124, the method wherein the DD12 does not include DD9, DD10 and / or analogs thereof. Claim 126 A method according to either claim 124 or 125, wherein the pharmaceutical composition comprises a therapeutically effective amount of DD12 and one or a combination thereof of an opioid. Claim 127 A method according to any one of claims 124 to 126, wherein the dopamine antagonist or the pharmaceutical composition is administered via oral administration, parenteral administration, sublingual administration, transdermal administration, rectal administration, transmucosal administration, local administration, inhalation, buccal administration, intrapleural administration, intravenous administration, intra-arterial administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, intranasal administration, intrathecal administration, and intra-articular administration, or a combination thereof. Claim 128 A method according to any one of claims 124 to 127, wherein the pharmaceutical composition is in an oral formulation. Claim 129 A method in which, in any one of paragraphs 124 to 128, the subject is a human being. Claim 130 A method according to any one of claims 124 to 129, wherein the DD12 or the pharmaceutical composition is administered simultaneously with opioid administration or before or after opioid administration. Claim 131 A method according to any one of claims 124 to 130, wherein the DD12 is administered in an oral or liquid formulation comprising about 0.1 milligrams to about 2 milligrams. Claim 132 A method according to any one of claims 124 to 131, wherein the DD12 or the pharmaceutical composition is administered before, after, or after surgery with an opioid dose. Claim 133 A method according to any one of claims 124 to 132, wherein the administering step comprises administering DD12 about 2 to about 6 times per day. Claim 134 A method for anesthetizing a subject requiring anesthesia, comprising the step of administering to the subject (i) a pharmaceutical composition comprising DD12 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, or (ii) a pharmaceutical composition of any one of claims 79 to 85. Claim 135 In paragraph 134, the pharmaceutical composition does not include DD9, DD10, variants thereof, or salts thereof. Claim 136 A method according to either claim 133 or 134, wherein the pharmaceutical composition comprises a therapeutically effective amount of DD12 and one or a combination thereof of an opioid. A method according to any one of claims 133 to 135, wherein the dopamine antagonist or the pharmaceutical composition is administered via oral administration, parenteral administration, sublingual administration, transdermal administration, rectal administration, transmucosal administration, topical administration, inhalation, buccal administration, intrapleural administration, intravenous administration, intra-arterial administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, intranasal administration, intrathecal administration, and intra-articular administration, or a combination thereof. Claim 137 A method according to any one of paragraphs 133 to 136, wherein the subject is a mammal. Claim 138 A method in which, in any one of paragraphs 133 to 137, the subject is a human being. Claim 139 A method according to any one of claims 133 to 138, wherein the DD12 or the pharmaceutical composition is administered simultaneously with opioid administration or before or after opioid administration. Claim 140 A method according to any one of claims 133 to 139, wherein the DD12 is administered in a dose of about 0.1 milligrams to about 2 milligrams. Claim 141 A method according to any one of claims 133 to 140, wherein the DD12 or the pharmaceutical composition is administered before, after, or after surgery with an opioid dose. Claim 142 A method according to any one of claims 133 to 141, wherein the administration of DD12 is about 2 to about 6 times per day. Claim 143 A method for enhancing the analgesic effect of an opioid, comprising the step of administering DD12 or a pharmaceutically acceptable salt thereof to the subject; or the step of administering a pharmaceutical composition of any one of claims 79 to 85 to the subject. Claim 144 In paragraph 143, the method wherein the DD12 does not include DD9, DD10, variants thereof, or salts thereof. Claim 145 A method according to either claim 143 or 144, wherein the pharmaceutical composition comprises a therapeutically effective amount of DD12 and one or a combination thereof of an opioid. Claim 146 A method according to any one of claims 143 to 145, wherein the dopamine antagonist or the pharmaceutical composition is administered via oral administration, parenteral administration, sublingual administration, transdermal administration, rectal administration, transmucosal administration, local administration, inhalation, buccal administration, intrapleural administration, intravenous administration, intra-arterial administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, intranasal administration, intrathecal administration and intra-articular administration, or a combination thereof. Claim 147 A method according to any one of claims 143 to 146, wherein the subject is a mammal. Claim 148 A method in which, in any one of paragraphs 143 to 147, the subject is a human being. Claim 149 A method according to any one of claims 143 to 148, wherein the DD12 or the pharmaceutical composition is administered simultaneously with opioid administration or before or after opioid administration. Claim 150 A method according to any one of claims 143 to 149, wherein the DD12 is administered in a dose of about 0.1 milligrams to about 2 milligrams. Claim 151 A method according to any one of claims 143 to 150, wherein the DD12 or the pharmaceutical composition is administered before, after, or after surgery with an opioid dose. Claim 152 A method according to any one of claims 143 to 151, wherein the administration of DD12 is about 2 to about 4 times per day. Claim 153 A method for inhibiting intracellular dopamine action, comprising the step of exposing the cell to a composition, the step of exposing the cell to DD12 and an opioid. Claim 154 In paragraph 153, the method wherein the composition does not include DD9, DD10, variants thereof, or salts thereof. Claim 155 A method according to either claim 153 or 154, wherein the composition comprises the DD12 in a total mass of about 0.1 to about 2.5 milligrams and the opioid in a total mass of about 0.2 milligrams to about 150 milligrams. Claim 156 A method according to any one of claims 153 to 155, wherein the opioid is selected from morphine, codeine, hydromorphone, fentanyl, hydrocodone, levorphanol, meperidine, methadone, oxycodone, oxymorphone, tramadol, tapentadol, or pharmaceutically acceptable salts thereof or precursor drugs thereof. Claim 157 A method according to any one of claims 153 to 156, wherein the opioid is fentanyl or a pharmaceutically acceptable salt thereof, and the mass of fentanyl is about 100 micrograms to about 500 micrograms. Claim 158 A method according to any one of claims 153 to 157, wherein the exposing step is performed in a test tube. Claim 159 A method according to any one of claims 153 to 158, wherein the exposing step is performed in vivo. Claim 160 A method according to any one of claims 153 to 159, wherein the administration of DD12 is about 2 to about 6 times per day. Claim 161 A pharmaceutical composition in the form of an oral formulation, wherein the pharmaceutical composition comprises a dopamine antagonist or a pharmaceutically acceptable salt thereof in an amount ranging from about 0.1 mg to about 19 mg. Claim 162 In claim 161, the dopamine antagonist is a pharmaceutical composition comprising DD12. Claim 163 In paragraph 162, the pharmaceutical composition is a pharmaceutical composition that does not contain DD9. Claim 164 A pharmaceutical composition according to claim 162 or 163, wherein the pharmaceutical composition does not contain DD10. Claim 165 In claim 161, the above-mentioned dopamine antagonist is a pharmaceutical composition comprising amyulprid. Claim 166 A pharmaceutical composition according to claim 165, comprising about 4 mg or less of risperidone. Claim 167 A pharmaceutical composition according to claim 165 or 166, comprising about 31 mg or less of olanzapine. Claim 168 A pharmaceutical composition according to any one of claims 165 to 167, wherein the composition does not contain risperidone. Claim 169 A pharmaceutical composition according to any one of claims 165 to 168, wherein the composition does not contain olanzapine. Claim 170 A pharmaceutical composition according to any one of claims 165 to 169, wherein the pharmaceutical composition does not include one or more of aripiprazole, asenapine, benperidol, chlorpromazine, clopentisol, chlorprotisene, clotiapine, clozapine, droperidol, flupentisol, fluphenazine, haloperidol, levomepromazine, loxapin, lurasidone, mesoridazine, metotrimeprazine, molindone, olanzapine, oxypertin, paliperidone, periciazine, perphenazine, pimozide, prochlorperazine, quetiapine, remoxiprid, risperidone, sertindol, sulfiride, thioridazine, thioticene, trifluoperazine, trifluperidol, triflupromazine, ziprasidone, zotepine, or zuclopentisol, or salts or derivatives thereof. Claim 171 In claim 170, the pharmaceutical composition does not comprise aripiprazole, asenapine, benperidol, chlorpromazine, clopentisol, chlorprotisene, clotiapine, clozapine, droperidol, flupentisol, fluphenazine, haloperidol, levomepromazine, loxapine, lurasidone, mesoridazine, metotrimeprazine, molindone, olanzapine, oxypertin, paliperidone, periciazine, perphenazine, pimozide, prochlorperazine, quetiapine, remoxiprid, risperidone, sertindol, sulfiride, thioridazine, thioticene, trifluoperazine, trifluperidol, triflupromazine, ziprasidone, zotepine, or zuclopentisol, or salts or derivatives thereof. Claim 172 A pharmaceutical composition according to claim 161, wherein the dopamine antagonist comprises at least one of amyulprid, aripiprazole, asenapine, benperidol, chlorpromazine, clopentisol, chlorprotisene, clotiapine, clozapine, droperidol, flupentisol, fluphenazine, haloperidol, levomepromazine, loxapine, lurasidone, mesoridazine, metotrimeprazine, molindone, olanzapine, oxypertin, paliperidone, periciazine, perphenazine, pimozide, prochlorperazine, quetiapine, remoxiprid, risperidone, sertindol, sulfiride, thioridazine, thioticene, trifluoperazine, trifluperidol, triflupromazine, ziprasidone, zotepine, or zuclopentisol. Claim 173 A pharmaceutical composition according to claim 161, wherein the dopamine antagonist comprises one of amyulprid, aripiprazole, asenapine, benperidol, chlorpromazine, clopentisol, chlorprotisene, clotiapine, clozapine, droperidol, flupentisol, fluphenazine, haloperidol, levomepromazine, loxapine, lurasidone, mesoridazine, metotrimeprazine, molindone, olanzapine, oxypertin, paliperidone, periciazine, perphenazine, pimozide, prochlorperazine, quetiapine, remoxiprid, risperidone, sertindol, sulfiride, thioridazine, thioticene, trifluoperazine, trifluperidol, triflupromazine, ziprasidone, zotepine, or zuclopentisol or a salt or derivative thereof. Claim 174 A pharmaceutical composition according to claim 161, wherein the dopamine antagonist is essentially composed of one of amyulprid, aripiprazole, asenapine, benperidol, chlorpromazine, clopentisol, chlorprotisene, clotiapine, clozapine, droperidol, flupentisol, fluphenazine, haloperidol, levomepromazine, loxapine, lurasidone, mesoridazine, metotrimeprazine, molindone, olanzapine, oxypertin, paliperidone, periciazine, perphenazine, pimozide, prochlorperazine, quetiapine, remoxiprid, risperidone, sertindol, sulfiride, thioridazine, thioticene, trifluoperazine, trifluperidol, triflupromazine, ziprasidone, zotepine, or zuclopentisol. Claim 175 A pharmaceutical composition according to claim 161, wherein the dopamine antagonist comprises one of amyulprid, aripiprazole, asenapine, benperidol, chlorpromazine, clopentisol, chlorprotisene, clotiapine, clozapine, droperidol, flupentisol, fluphenazine, haloperidol, levomepromazine, loxapine, lurasidone, mesoridazine, metotrimeprazine, molindone, olanzapine, oxypertin, paliperidone, periciazine, perphenazine, pimozide, prochlorperazine, quetiapine, remoxiprid, risperidone, sertindol, sulfiride, thioridazine, thioticene, trifluoperazine, trifluperidol, triflupromazine, ziprasidone, zotepine, or zuclopentisol. Claim 176 A pharmaceutical composition according to any one of claims 161 to 175, wherein the therapeutically effective amount of the dopamine antagonist is the total amount of all dopamine antagonists in the pharmaceutical composition. Claim 177 A pharmaceutical composition according to any one of claims 161 to 176, wherein the therapeutically effective amount of the dopamine antagonist is within the range of about 1 mg to about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, or about 18 mg. Claim 178 A pharmaceutical composition according to any one of claims 161 to 176, wherein the amount of the dopamine antagonist is within the range of about 2 mg to about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, or about 18 mg. Claim 179 A pharmaceutical composition according to any one of claims 161 to 178, further comprising an effective amount of opioid or a pharmaceutically acceptable salt thereof. Claim 180 A pharmaceutical composition according to claim 179, wherein the opioid comprises at least one of morphine, codeine, hydromorphone, hydromorphone, fentanyl, fentanyl, fentanyl, fentanyl, fentanyl, hydrocodone, levorphanol, meperidine, meperidine, methadone, oxycodone, oxymorphone, tramadol, or tapentadol. Claim 181 A pharmaceutical composition according to claim 179, wherein the opioid comprises one of morphine, codeine, hydromorphone, hydromorphone, fentanyl, fentanyl, fentanyl, fentanyl, fentanyl, hydrocodone, levorphanol, meperidine, meperidine, methadone, oxycodone, oxymorphone, tramadol, or tapentadol. Claim 182 A pharmaceutical composition according to claim 179, wherein the opioid is essentially composed of one of morphine, codeine, hydromorphone, hydromorphone, fentanyl, fentanyl, fentanyl, fentanyl, fentanyl, hydrocodone, levorphanol, meperidine, meperidine, methadone, oxycodone, oxymorphone, tramadol, or tapentadol. Claim 183 A pharmaceutical composition according to claim 179, wherein the opioid is one of morphine, codeine, hydromorphone, hydromorphone, fentanyl, fentanyl, fentanyl, fentanyl, fentanyl, fentanyl, hydrocodone, levorphanol, meperidine, meperidine, methadone, oxycodone, oxymorphone, tramadol, or tapentadol. Claim 184 A method for reducing an event-related pain response in a subject who needs to reduce an event-related pain response, comprising the step of administering a pharmaceutical composition of any one of claims 179 to 183 to the subject. Claim 185 A method for enhancing the analgesic effect of an opioid in a subject who needs to enhance the analgesic effect of an opioid, comprising the step of administering a pharmaceutical composition of any one of claims 179 to 183 to the subject. Claim 186 A method for anesthetizing a subject that requires anesthesia, comprising the step of administering a pharmaceutical composition of any one of claims 179 to 183 to the subject. Claim 187 A method for preventing opioid dependence, comprising the step of administering a pharmaceutical composition of any one of claims 161 to 183 to a subject who needs to be prevented from opioid dependence. Claim 188 A method for treating pain in a subject who needs pain treatment, comprising the step of administering a pharmaceutical composition of any one of claims 161 to 183 to the subject. Claim 189 A method for preventing drug preference in a subject for whom drug preference needs to be prevented, comprising the step of administering a pharmaceutical composition of any one of claims 161 to 183 to the subject. Claim 190 A method for preventing opioid use disorder in a subject who needs to prevent opioid use disorder, comprising the step of administering a pharmaceutical composition of any one of claims 161 to 183 to the subject. Claim 191 A method according to any one of claims 184 to 190, wherein the subject is a mammal. Claim 192 A method in which, in any one of paragraphs 184 to 190, the subject is a human being. Claim 193 A method in which, in any one of claims 184 to 192, the pharmaceutical composition of any one of claims 161 to 178 is administered simultaneously with opioid administration or before or after opioid administration. Claim 194 A method according to any one of claims 184 to 193, wherein the dopamine antagonist is administered in a dose of about 0.1 milligrams to about 2 milligrams. Claim 195 A method according to any one of claims 184 to 194, wherein the method has no serotonin release induced by the opioid and / or no hallucinogenic effect induced by the dopamine antagonist. Claim 196 A method for inhibiting intracellular dopamine action, comprising the step of exposing the cell to a pharmaceutical composition according to any one of claims 161 to 183. Claim 197 In paragraph 196, the above exposure is In a test tube Method being performed. Claim 198 In paragraph 196, the above exposure is In vivo Method being performed. Claim 199 A pharmaceutical composition comprising a dopamine antagonist or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the mass content of the dopamine antagonist is about 0.02 mg to about 495.30 mg. Claim 200 A pharmaceutical composition according to claim 199, further comprising an opioid, wherein the opioid has a mass content of about 1 mg to about 300 mg. Claim 201 A pharmaceutical composition according to claim 199 or 200, wherein the composition does not contain DD9. Claim 202 A pharmaceutical composition according to any one of claims 199 to 201, wherein the dopamine antagonist is amyulprid or a pharmaceutically acceptable salt thereof, and the mass content thereof is about 0.39 mg to about 410.73 mg. Claim 203 A method for treating or preventing opioid use disorder in a subject who needs to be treated or prevented from having opioid use disorder, comprising the step of administering a pharmaceutical composition of any one of claims 199 to 202 to the subject. Claim 204 A method according to claim 203, wherein the administering step is performed about 2 to about 6 times per day. Claim 205 A method for anesthetizing a subject that requires anesthesia, comprising the step of administering a pharmaceutical composition of any one of claims 199 to 202 to the subject. Claim 206 A method according to claim 205, wherein the administering step is performed about 2 to about 6 times per day. Claim 207 A method for treating or preventing opioid addiction in a subject who needs to be treated or prevented from opioid addiction, comprising the step of administering a pharmaceutical composition of any one of claims 199 to 202 to the subject.

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