Method for preventing addiction to therapeutic opioids

Abstract

A technique for preventing addiction to an opioid while still allowing the beneficial effects of the opioid may be provided, the technique generally including providing two molecules to a subject: (i) a first molecule comprising the opioid (e.g., a pain-relieving opioid, such as oxycodone), and (ii) a second molecule comprising a compound for decreasing orexin neural signaling in the patient (e.g., an Orexin- 1 receptor antagonist). These molecules may be co-administered at every dose of the opioid.

Description

METHOD FOR PREVENTING ADDICTION TO THERAPEUTIC OPIOIDSCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of provisional patent application Serial No.63 / 462,132 filed on April 26, 2023, entitled METHOD FOR PREVENTING ADDICTION TO THERAPEUTIC OPIOIDS, which provisional patent application is incorporated herein by reference in its entirety.GOVERNMENT INTEREST

[0002] This invention was made with government support under grant number DA006214 awarded by the National Institutes of Health. The government has certain rights in the invention.TECHNICAL FIELD

[0003] The present disclosure is drawn to addiction prevention techniques, and specifically to techniques for preventing addiction to opioids that have been prescribed to patients for treating, e g., pain.BACKGROUND

[0004] This section is intended to introduce the reader to various aspects of art, which may be related to various aspects of the present invention that are described and / or claimed below. This discussion is believed to be helpful in providing the reader with background information to facilitate a better understanding of the various aspects of the present invention. Accordingly, it should be understood that these statements are to be read in this light, and not as admissions of prior art.

[0005] Opioids have long been prescribed to patients for pain management. However, use of opioids can lead to opioid dependence and addiction, captured under the term opioid use disorder (OUD). OUD is one of the most serious chronic and relapsing medical disorders. Each year, thousands of individuals die from an overdose of a opioid, having become addicted to opioids due to prescription opioids for, e.g., pain management.

[0006] In the past, methods of helping OUD patients consisted of treatments with methadone, buprenorphine and / or naltrexone. Naltrexone, however, does not help a patient with the severewithdrawal symptoms, and methadone on many occasions proved to be as much of an addiction as the original drug the patient abused. Buprenorphine or methadone also are ineffective against many side effects of opioids as they are in fact opioid drugs. Critically, all clinical approaches focus on treating opioid addiction after it has occurred, rather than preventing it in the first place.

[0007] Some treatments also interfere with the opioid’s ability to reduce pain in a patient; thus, what is needed is a method for preventing addiction in the first place, while still allowing the opioid to provide the treatment. Unfortunately, due to how the body changes due to addiction to opioids, the mechanisms and neurological pathways for treating addiction are necessarily distinct from those for preventing addiction, so the same techniques for treating addiction do not necessarily help prevent addiction.BRIEF SUMMARY

[0008] Various deficiencies in the prior art are addressed below by the disclosed compositions of matter and techniques.

[0009] In various aspects, a method for preventing addiction of an opioid may be provided. The method may include providing a treatment including two different molecules to a patient. The two different molecules include (i) the opioid; and (ii) a compound for decreasing orexin neural signaling in the patient.

[0010] In some embodiments, the treatment may comprise a first dose of a orexin antagonist coadministered with a second dose of the opioid. The orexin antagonist may be a dual orexin receptor antagonist (DORA), such as daridorexant, lemborexant, suvorexant, vomorexant, or a derivative or analog thereof. The orexin antagonist may be a single orexin receptor antagonist (SORA), such as an orexin-1 receptor (OxlR) antagonist. The opioid may be a non-peptide agonist, such as morphine, hydromorphone, fentanyl, sufentanil, alfentanil, remifentanil, buprenorphine, oxycodone, tramadol, etorphine, levorphanol, etonitazene, tilidine, nortilidine, loperamide or piritramide.

[0011] In some embodiments, the first dose may be smaller than the second dose, the same as the second dose, or larger than the second dose. In some embodiments, the second dose may be a sub -therapeutic dose.BRIEF DESCRIPTION OF DRAWINGS

[0012] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the present invention and, together with a general description of the invention given above, and the detailed description of the embodiments given below, serve to explain the principles of the present invention.

[0013] Figure 1 A is an illustration of a timeline for behavioral testing of animals.

[0014] Figure IB is a graph showing the effect of opioid use on paw withdrawal (hyperalgesia) in rats. ***p<0.001.

[0015] Figure 1C is a graph showing the effect of opioid use on body weight in rats. * p<0.05.

[0016] Figure ID is a graph showing the effect of opiod use on saccharine preference (a measure of anhedonia) in rats. ** p<0.01.

[0017] Figure IE is a graph showing the effect of opiod use on anxiety-like behavior on the elevated plus maze (EPM) test in rats. ** p<0.01.

[0018] Figure IF is a graph showing the effect of opiod use on mobility on the forced swim test (FST; a behavioral measure of despair) in rats. ** p<0.01.

[0019] Figure 1G is a graph showing a composite affect severity score established using normalized z-scores from each affective measure in rats for opioid use. ** p<0.01.

[0020] Figure 2A shows low- and high-magnification (inset) images of orexin (red) in the hypothalamus of a saline (top panel) and oxycodone treated animal (bottom panel) sacrificed 24h after receiving their final saline or oxycodone treatment in one example test in rats.

[0021] Figures 2B and 2C are graphs showing the impact of oxycodone on orexin-expressing neurons in rats in both dorsomedial hypothalamus (MH) (Figure 2B) and lateral hypothalamus (LH) (Figure 2C) at 24h, Iwk, and 4wks of abstinence. * p<0.05, ** p<0.01.

[0022] Figure 2D is a graph showing orexin cell numbers in oxycodone treated rats sacrificed at 24h of abstinence correlate with the affect / withdrawal severity score.

[0023] Figure 2E is a graph showing the lack of relationship between lateral orexin cell numbers and affect / withdrawal severity.

[0024] Figure 2F is a high-magnification image showing MH orexin (green) and delta-FosB (red) from a rat given saline (left) or oxycodone (right).

[0025] Figure 2G is a graph showing percentage of orexin neurons that expressed delta-FosB- in MH at 24h, Iwk, and 4 wk of abstinence. * p<0.05, ** p<0.01.

[0026] Figure 2H is a graph showing percentage of orexin neurons that expressed delta-FosB- in LH at 24h, Iwk, and 4 wk of abstinence. * p<0.05, ** p<0.01.

[0027] Figure 3 A is an illustration of a timeline for testing of inhibition of orexin neurons during administration of oxycodone or saline. This is a test of ability to inhibit development of negative affect normally produced by chronic oxycodone, thought to be a key element in the development of OUD.

[0028] Figure 3B is a graph showing the effect of inhibiting orexin neural activity (hM4Di +CNO) on paw withdrawal (hyperalgesia) in rats. Note that inhibition of orexin neurons prevented the hyperalgesia that otherwise occurs after chronic oxycodone.

[0029] Figure 3C is a graph showing the effect of inhibiting orexin neural activity (hM4Di +CNO) on body weight in rats. Note that inhibition of orexin neurons partially prevented the decrease in body weight that otherwise occurs after chronic oxycodone.

[0030] Figure 3D is a graph showing the effect of inhibiting orexin neural activity (hM4Di) on saccharine preference. Note that inhibition of orexin neurons prevented decreased saccharine preference (anhedonia) that otherwise occurs after chronic oxycodone.

[0031] Figure 3E is a graph showing the effect of inhibiting orexin neural activity (hM4Di) on anxiety-like behavior in the EPM. Note that inhibition of orexin neurons prevented the elevated anxiety that otherwise occurs after chronic oxycodone.

[0032] Figure 4 is a graph showing the effect of co-treatment of suvorexant (orexin antagonist) with oxycodone. Note that such treatment prevents development of the negative affective signs of the addicted state.

[0033] Figure 5 is a graph showing that co-treatment of suvorexant (orexin antagonist) with oxycodone prevents development of the negative affective signs of the addicted state.

[0034] Figure 6 shows that co-treatment of chronic oxycodone with suvorexant prevents the increase in iv fentanyl consumption normally seen after chronic oxycodone.

[0035] Figure 7A is a graph showing economic demand for iv fentanyl following daily cotreatment with oxycodone and suvorexant (compared to vehicle). This suvorexant co-treatment prevented the increased consumption of fentanyl at null cost, a key indicator of opioid demand.

[0036] Figure 7B is a graph showing economic demand for iv fentanyl following daily cotreatment with oxycodone and suvorexant (compared to vehicle). The daily suvorexant cotreatment prevented low demand elasticity, reflecting decreased motivation for fentanyl.DETAILED DESCRIPTION

[0037] The following description and drawings merely illustrate the principles of the invention. It will thus be appreciated that those skilled in the art will be able to devise various arrangements that, although not explicitly described or shown herein, embody the principles of the invention and are included within its scope. Furthermore, all examples recited herein are principally intended expressly to be only for illustrative purposes to aid the reader in understanding the principles of the invention and the concepts contributed by the inventor(s) to furthering the art and are to be construed as being without limitation to such specifically recited examples and conditions. Additionally, the term, "or," as used herein, refers to a non-exclusive or, unless otherwise indicated (e.g., “or else” or “or in the alternative”). Also, the various embodiments described herein are not necessarily mutually exclusive, as some embodiments can be combined with one or more other embodiments to form new embodiments.

[0038] The numerous innovative teachings of the present application will be described with particular reference to the presently preferred exemplary embodiments. However, it should be understood that this class of embodiments provides only a few examples of the many advantageous uses of the innovative teachings herein. In general, statements made in the specification of the present application do not necessarily limit any of the various claimed inventions. Moreover, some statements may apply to some inventive features but not to others. Those skilled in the art and informed by the teachings herein will realize that the invention is also applicable to various other technical areas or embodiments.

[0039] A major concern with chronic opioid administration for pain relief is frequent development of dependence and progression to addiction behaviors. Disclosed is a combination of an orexin antagonist with an opioid to produce an analgesic with decreased propensity for leading to opioid addiction. Specifically, as one example, co-administering an orexin antagonist such as suvorexant with the opioid oxycodone. The co-administration limits the propensity for chronic use of the opioid to lead to addiction.

[0040] In various aspects, a method for preventing addiction of an opioid may be provided. The method may include providing a treatment including two different molecules to a patient. Thetwo different molecules include (i) the opioid; and (ii) a compound for decreasing orexin neural signaling in the patient.

[0041] In some embodiments, the treatment may comprise a first dose of a orexin antagonist coadministered with a second dose of the opioid.

[0042] The orexin antagonist may be a dual orexin receptor antagonist (DORA), such as daridorexant, lemborexant, suvorexant, vornorexant, or a derivative or analog thereof. As used herein, the term "derivative or analog thereof' refers to functional equivalents of a known orexin receptor antagonist, which can be obtained by substitution of atoms or molecular groups or bonds of the base molecular structure, whereby the basic or general structure is not changed, and which differ from the structure of the base molecular structure no more than a few positions (e.g., 1-3 positions); and includes, without limitation, pharmaceutically acceptable salts, prodrugs, stereoisomers, and isomers of the base molecular structure that function as an orexin receptor antagonist.

[0043] The orexin antagonist may be a single orexin receptor antagonist (SORA), such as an orexin-1 receptor (OxlR) antagonist or orexin 2 receptor (0x2R) antagonist. Non-limiting examples of such OxlR antagonists include, e.g., ACT-335827, SB-334867, SB-408124, and GSK1059865. Non-limiting examples of such Ox2R antagonists include, e.g., TCS OX2 29, LSN2424100 or Seltorexant (JNJ-42847922 / MIN-202).

[0044] As used herein the term “OxlR antagonist” refers to any compound that is able to inhibit the calcium-dependent signaling pathway induced by orexin. It is known that binding of an orexin to its receptor triggers an influx of calcium, which is coupled to activation of Erk. The receptors also couple to a phospholipase C (PLC)-mediated pathway that releases intracellular calcium stores. The utility of the compounds as orexin receptor 0X1R antagonists may be readily determined without undue experimentation by methodology well known in the art, including the “FLIPR Ca2+ Flux Assay” (Okumura et al, Biochem. Biophys. Res. Comm. 280:976-981, 2001).

[0045] It is envisioned that any opioid may be utilized in this technique. Non-limiting examples of such opioids include mu-opioid receptor agonists such as endogenous agonists, e.g. betaendorphin; endomorphins; small peptide agonists, e.g. DAMGO (D-Ala, N-Me-Phe, Gly-ol)- enkephalin or DALDA (H-Dmt-D-Arg-Phe-Lys-NH2); non-peptide agonists, such as morphine, hydromorphone, fentanyl and fentanyl analogues, such as sufentanil, alfentanil, remifentanil,buprenorphine, oxycodone, tramadol, etorphine, levorphanol, etonitazene and analogues, tilidine and analogues, e.g. the active metabolite nortilidine, loperamide and piritramide; delta-opioid receptor agonists, such as: endogenous agonists, e.g. met-enkephalin (Tyr-Gly-Gly-Phe-Met) and leu-enkephalin (Tyr-Gly-Gly-Phe-Leu); small peptides, e.g. DADLE (D-Ala 2, D-Leu 5) enkephalin or DPDPE (tyrosyl-2,6-3H(N)-(2-D-penicillamine-5-D-penicillamine)-enkephalin); non-peptide agonists, such as BW373U86 (±)-4-(a-R)-a(2S,5R)-4-allyl-2,5-dimethyl-l- piperazinyl)-3-hydroxybenzyl)- N,N-diethylbenzamide or SNC80 (±)-4-(a-R)-a(2S,5R)-4-allyl- 2, 5-dimethyl-l-piperazinyl)-3-methoxybenzyl)-N,N-di ethylbenzamide; and ORL-1 receptor agonists, such as: endogenous agonists, e.g., nociceptin; small peptides, e.g. Ro 64-6198 ((lS,3aS)-8-(2,3,3a,4,5,6-hexahydro-lH-phenalen-l-yl)-l-phenyl-l,3,8-triaza-spiro[4.5]decan-4- one).

[0046] In a preferred embodiment, the opioid may be a non-peptide agonist, such as morphine, hydromorphone, fentanyl, sufentanil, alfentanil, remifentanil, buprenorphine, oxycodone, tramadol, etorphine, levorphanol, etonitazene, tilidine, nortilidine, loperamide or piritramide.

[0047] In some embodiments, the first dose (e.g., the dose of the compound for decreasing orexin neural signaling) may be smaller than the second dose (e.g., the dose of the opioid). In some embodiments, the first dose may the same (or substantially the same, such as ± 10% by weight) as the second dose. In some embodiments, the first dose may be larger than the second dose.

[0048] The second dose may be a therapeutic dose. In some embodiments, the second dose may be a sub -therapeutic dose. In some embodiments, the first and / or second doses may be sub- therapeutic doses. For example, the second dose may comprise a dose normally deemed subtherapeutic by itself (e.g., such as a dose deemed approximately sufficient for the treatment of insomnia).

[0049] Preferably, the two compounds are always co-administered while the opioid is used to treat an affliction (e.g., pain management).

[0050] Administering an orexin antagonist with oxycodone may prevent addiction while still producing the analgesia effect that relieves pain.

[0051] The compounds for the two doses may be provided as a kit. That is, various embodiments provide a pharmaceutical kit for preventing addiction to an opioid while providing a treatment to a patient, the kit comprising a first pill comprising the opioid and a second pill comprising acompound for decreasing orexin neural signaling in the patient. For example, the kit may contain a pill of 5-10mg oxycodone plus a pill of 15-30mg of suvorexant. As discussed in detail herein, such a kit may comprise other orexin antagonists or opioid compounds, with relative doses adjusted according to pK and therapeutic efficacy.

[0052] Orexin inhibitors have been approved for, e.g., treating insomnia. There are currently three orexin inhibitors on the market for insomnia: (i) daridorexant, a dual OXi and OX2 antagonist approved for insomnia, (ii) lemborexant, a dual OXi and OX2 antagonist approved for insomnia and under development for circadian rhythm sleep disorders, chronic obstructive pulmonary disease, and sleep apnea, and (iii) suvorexant, a dual OXi and OX2 antagonist approved for insomnia and under development for delirium.

[0053] Our data (presented above) shows that co-administration of an orexin inhibitor, such as suvorexant, appears to limit the propensity for chronic oxycodone use to lead to addiction.

[0054] Studies have shown that chronic non-contingent oxycodone is associated with signs of negative affect during acute abstinence. Negative affect is a consequence of opioid administration that is thought to contribute to opioid addiction through a process known as negative reinforcement. Referring to FIG. 1A, one can see a timeline of behavioral testing, where Male Sprague Dawley (SD) rats were treated with saline (n=l 5) or oxycodone (n=l 6) twice daily for 21 days and assessed for signs of negative affect during acute abstinence. In FIGS. IB and 1C, one can see that, compared to saline control animals, oxycodone-treated rats exhibited lower paw withdrawal thresholds (e.g., increased hyperalgesia) (see FIG. IB) and had reduced weight gain across the 21 d treatment paradigm (see FIG. 1C). Oxycodone-treated animals also showed lower saccharine preference (a sign of anhedonia; FIG. ID), increased anxiety-like behavior on the elevated plus maze (EPM; FIG. IE) and reduced mobility in the forced swim test (FST, a test of depressive despair; FIG. IF). Referring to FIG. 1G, a composite affect severity score was established using normalized z-scores from each affective measure. Using this approach, oxycodone-treated rats showed greater negative affect severity compared to saline controls. In these figures, * p<0.05, ** p<0.01, ***p<0.001.

[0055] Studies have also shown that orexin cell number and activity are increased in oxycodone treated rats. Prior data indicate that this increase in orexin cell number is associated with addictive behaviors. Orexin expression and activity were assessed in saline (n=8) and oxycodone-treated rats (n=20) scarified following 24h, Iwk, and 4wks of abstinence. Referringto FIG. 2A, low- and high-magnification (inset) images can be seen of orexin (red) in the hypothalamus of a saline (top panel) and oxycodone treated animal (bottom panel) sacrificed 24h after receiving their final saline or oxycodone treatment. As seen in FIGS. 2B and 2C, compared to saline control animals, oxycodone-treated rats had a higher number of orexin- expressing neurons in both MH and LH at 24h, Iwk, and 4wks of abstinence. Referring to FIG. 2D, in MH, orexin cell numbers in oxycodone treated rats sacrificed at 24h of abstinence were highly correlated with affect severity, such that rats with more orexin neurons exhibit stronger negative affect during abstinence. Referring to FIG. 2E, no relationship was observed between lateral orexin cell numbers and affect severity. Activity of orexin neurons was assessed with the immediate early gene, delta-FosB. FIG. 2F shows a high-magnification image showing MH orexin (green) and delta-FosB (red) from a rat given saline (left) or oxycodone (right). As seen in FIGS. 2G and 2H, in MH, oxycodone treated rats a greater percentage of orexin neurons expressed delta-FosB- at Iwk and 4wk of abstinence, while in LH, oxycodone animals had a higher percentage of delta-FosB-expressing orexin neurons at 24h and Iwk of abstinence. In these figures, * p<0.05, ** p<0.01.

[0056] Chronic inhibition of orexin neurons prevents the development of negative affect and also prevents increased orexin cell number associated with acute abstinence from oxycodone. Referring to FIG. 3A, an illustration demonstrating an experimental timeline can be seen. In oxycodone-treated rats with hM4Di expressed in orexin neurons, inhibition of orexin neurons (by CNO-activation of hM4Di receptors induced specifically in orexin neurons) prior to each oxycodone treatment prevented changes in paw withdrawal thresholds (attenuated hyperalgesia) (see FIG. 3B) and increased weight gain (see FIG. 3C). Inhibition of orexin neurons in hM4Di rats also prevented deficits in saccharin preference (see FIG. 3D), and anxiety-like behavior in the EPM (see FIG. 3E).

[0057] Various modifications may be made to the systems, methods, apparatus, mechanisms, techniques and portions thereof described herein with respect to the various figures, such modifications being contemplated as being within the scope of the invention. For example, while a specific order of steps or arrangement of functional elements is presented in the various embodiments described herein, various other orders / arrangements of steps or functional elements may be utilized within the context of the various embodiments. Further, while modifications toembodiments may be discussed individually, various embodiments may use multiple modifications contemporaneously or in sequence, compound modifications and the like.

[0058] FIG. 4 shows that the analgesia (mechanical analgesia) seen with oxycodone following chronic pain is not affected by daily co-treatment with suvorexant. Following FCA treatment (Freund’s Complete Adjuvant injected into a rear paw), a decrease in paw withdrawal thresholds is seen indicating hyperalgesia, as expected. This index of pain is attenuated in rats given daily oxycodone and vehicle (n=10, as expected) or oxycodone and suvorexant (n=10) compared to saline controls (n=5). Mixed effects analysis with Tukey’s post-hoc test, *p<0.05.

[0059] FIG. 5 is a graph showing that co-treatment of suvorexant (orexin antagonist) with oxycodone prevents development of the negative affective signs of the addicted state. Daily suvorexant treatment prevents or attenuates global negative affect induced by oxycodone treatment following chronic pain. Negative affect severity scores are increased (greater negative values) in rats receiving twice-daily oxycodone compared to saline controls, indicative of heightened negative affect, which is prevented in rats given daily suvorexant treatment. Independent samples t-tests, *p<0.05.

[0060] FIG. 6 is a graph showing that co-treatment with suvorexant plus oxycodone prevents that increased consumption of iv fentanyl normally seen after chronic oxycodone administration. These results show that co-treatment with suvorexant prevents that increased consumption of fentanyl normally seen after chronic oxycodone administration. Specifically, FIG. 6 shows that increased iv fentanyl intake is prevented in rats given co-treatment with suvorexant with two weeks of oxycodone treatment. Compared to rats pretreated with saline, rats given oxycodone and vehicle show increased fentanyl intake during 5d of self-administration, which is prevented in rats given co-treatment of suvorexant with oxycodone treatment.

[0061] FIG. 7A is a graph showing that daily suvorexant treatment compared to vehicle along with 2wks of oxycodone prevents increased iv fentanyl consumption at null cost (Qo); Qo is a measure of hedonic setpoint, or the amount of fentanyl subjects would consume at zero cost. This measure typically increases after chronic oxycodone due to, e g., tolerance. FIG. 7B is a graph showing that daily suvorexant treatment compared to vehicle along with 2wks of oxycodone showed increased demand elasticity for iv fentanyl (indicating less motivation for fentanyl). Thus, suvorexant co-admini strati on with oxycodone prevents increased demand for opioids after chronic oxycodone. Rats that received daily suvorexant treatment compared tovehicle along with 2wks of oxycodone showed decreased fentanyl demand, seen with A) decreased consumption at null cost and B) increased demand elasticity. Independent samples t- tests. Compare to the increased demand (increase in Qo and decrease in alpha) seen after chronic oxycodone alone (FIG. 7). It is believed that these trends will become statistically significant with greater number of subjects tested.

[0062] Aspects of various embodiments are specified in the claims. Those and other aspects of at least a subset of the various embodiments are specified in the following numbered clauses:

[0063] 1. A method for preventing addiction to an opioid, comprising providing a treatment comprising two molecules to a patient, the two molecules including one molecule comprising the opioid and another molecule comprising a compound for decreasing orexin neural signaling in the patient.

[0064] 2. The method according to clause 1, wherein the treatment comprises a dose of an orexin antagonist co-administered with a dose of the opioid.

[0065] 3. The method according to clause 2, wherein the orexin antagonist is a dual orexin receptor antagonist (DORA).

[0066] 4. The method according to clause 3, wherein the dual orexin receptor antagonist is daridorexant, lemborexant, suvor exant, vornor exant, or a derivative or analog thereof.

[0067] 5. The method according to clause 2, wherein the orexin antagonist is a single orexin receptor antagonist (SORA).

[0068] 6. The method according to clause 4, wherein the single orexin receptor antagonist is an orexin- 1 receptor (OxlR) or orexin-2 receptor (0x2R) antagonist.

[0069] 7. The method according to clause 4, wherein the single orexin receptor antagonist is an orexin-2 receptor (Ox2R) antagonist.

[0070] 8. The method according to clause 2, wherein the opioid is a non-peptide agonist.

[0071] 9. The method according to clause 8, wherein the non-peptide agonist is morphine, hydromorphone, fentanyl, sufentanil, alfentanil, remifentanil, buprenorphine, oxycodone, tramadol, etorphine, levorphanol, etonitazene, tilidine, nortilidine, loperamide or piritramide.

[0072] 10. The method according to clause 2, wherein the first dose of a orexin antagonist is smaller than the second dose of the opioid.

[0073] 11. The method according to clause 2, wherein the first dose of a orexin antagonist is larger than the second dose of the opioid.

[0074] 12. The method according to clause 2, wherein the first dose of the orexin antagonist is a sub -therapeutic dose.

[0075] 13. The method according to clause 2, wherein the second dose of the opioid is a sub- therapeutic dose.

[0076] 14. A pharmaceutical kit for preventing addiction to an opioid while providing a treatment to a patient, the kit comprising a first pill comprising the opioid and a second pill comprising a compound for decreasing orexin neural signaling in the patient.

[0077] 15. The pharmaceutical kit of clause 14, wherein the first pill comprises 5-10mg oxycodone and the second pill comprises 15-30mg of suvorexant.

[0078] 16. The pharmaceutical kit of clause 14, wherein the treatment comprises a first dose of a orexin antagonist co-administered with a second dose of the opioid.

[0079] 17. The pharmaceutical kit of clause 16, wherein the orexin antagonist is a dual orexin receptor antagonist (DORA).

[0080] 18. The pharmaceutical kit of clause 17, wherein the dual orexin receptor antagonist is daridorexant, lemborexant, suvorexant, vornor exant, or a derivative or analog thereof.

[0081] 19. The pharmaceutical kit of clause 16, wherein the orexin antagonist is a single orexin receptor antagonist (SORA).

[0082] 20. The pharmaceutical kit of clause 19, wherein the single orexin receptor antagonist comprises on or an orexin-1 receptor (OxlR) and an orexin-2 receptor (0x2R).

[0083] 21. The pharmaceutical kit of clause 16, wherein the opioid is a non-peptide agonist.

[0084] 22. The pharmaceutical kit of clause 21, wherein the non-peptide agonist is morphine, hydromorphone, fentanyl, sufentanil, alfentanil, remifentanil, buprenorphine, oxycodone, tramadol, etorphine, levorphanol, etonitazene, tilidine, nortilidine, loperamide or piritramide.

[0085] 23. The pharmaceutical kit of clause 16, wherein the first dose of a orexin antagonist is smaller than the second dose of the opioid.

[0086] 24. The pharmaceutical kit of clause 16, wherein the first dose of a orexin antagonist is larger than the second dose of the opioid.

[0087] 25. The pharmaceutical kit of clause 16, wherein the second dose of the opioid is a sub- therapeutic dose.

[0088] 26. The pharmaceutical kit of clause 16, wherein the first dose of the orexin antagonist is a sub-therapeutic dose.

[0089] Although various embodiments which incorporate the teachings of the present invention have been shown and described in detail herein, those skilled in the art can readily devise many other varied embodiments that still incorporate these teachings. Thus, while the foregoing is directed to various embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof. As such, the appropriate scope of the invention is to be determined according to the claims.

Claims

What is claimed is:

1. A method for preventing addiction to an opioid, comprising: providing a treatment comprising two molecules to a patient, the two molecules including a first molecule comprising the opioid and a second molecule comprising a compound for decreasing orexin neural signaling in the patient.

2. The method according to claim 1, wherein the treatment comprises a first dose of a orexin antagonist co-administered with a second dose of the opioid.

3. The method according to claim 2, wherein the orexin antagonist is a dual orexin receptor antagonist (DORA).

4. The method according to claim 3, wherein the dual orexin receptor antagonist is daridorexant, lemborexant, suvor exant, vornor exant, or a derivative or analog thereof.

5. The method according to claim 2, wherein the orexin antagonist is a single orexin receptor antagonist (SORA).

6. The method according to claim 5, wherein the single orexin receptor antagonist is an orexin- 1 receptor (OxlR).

7. The method according to claim 5, wherein the single orexin receptor antagonist is an orexin-2 receptor (0x2R) antagonist.

8. The method according to claim 2, wherein the opioid is a non-peptide agonist.

9. The method according to claim 8, wherein the non-peptide agonist is morphine, hydromorphone, fentanyl, sufentanil, alfentanil, remifentanil, buprenorphine, oxycodone, tramadol, etorphine, levorphanol, etonitazene, tilidine, nortilidine, loperamide or piritramide.

10. The method according to claim 2, wherein the first dose of the orexin antagonist is smaller than the second dose of the opioid.

11. The method according to claim 2, wherein the first dose of the orexin antagonist is larger than the second dose of the opioid.

12. The method according to claim 2, wherein the second dose of the opioid is a sub- therapeutic dose .

13. The method according to clause 2, wherein the first dose of the orexin antagonist is a sub- therapeutic dose.

14. A pharmaceutical kit for preventing addiction to an opioid while providing a treatment to a patient, the kit comprising a first pill comprising the opioid and a second pill comprising a compound for decreasing orexin neural signaling in the patient.

15. The pharmaceutical kit of claim 14, wherein the first pill comprises 5-10mg oxycodone and the second pill comprises 15-30mg of suvorexant.

16. The pharmaceutical kit of claim 14, wherein the treatment comprises a first dose of a orexin antagonist co-administered with a second dose of the opioid.

17. The pharmaceutical kit of claim 16, wherein the orexin antagonist is a dual orexin receptor antagonist (DORA).

18. The pharmaceutical kit of claim 17, wherein the dual orexin receptor antagonist is daridorexant, lemborexant, suvorexant, vornor exant, or a derivative or analog thereof.

19. The pharmaceutical kit of claim 16, wherein the orexin antagonist is a single orexin receptor antagonist (SORA).

20. The pharmaceutical kit of claim 19, wherein the single orexin receptor antagonist comprises on or an orexin-1 receptor (OxlR) and an orexin-2 receptor (0x2R).

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