Fentanyl and fentanyl analogue overdose reversal

Abstract

Described herein are compositions, devices, and methods useful for treating (reversing) and / or preventing fentanyl overdose resulting in respiratory failure or airway obstruction (FIVCC). Compositions are provided that include optimized amounts and / or ratios of two active ingredients, including: an alpha 2 adrenergic receptor agonist (e.g., lofexidine, dexmedetomidine, clonidine) and a short acting mu opioid receptor antagonist (e.g., naloxone); an alpha 2 adrenergic receptor agonist and a long acting mu opioid receptor antagonist (nalmefene); and an alpha 2 adrenergic receptor agonist and a fentanyl opioid analgesic. Methods and devices for concurrent delivery of combined active ingredients are also provided.

Description

FENTANYL AND FENTANYL ANALOGUE OVERDOSE REVERSALCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of the earlier filing of U.S. Provisional Application No. 63 / 656,550, filed on June 5, 2024, and U.S. Provisional Application No. 63 / 735,276, filed December 17, 2024. Each of these earlier filed applications is incorporated by reference herein in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under contract R44DA056267 awarded by the National Institutes of Health. The government has certain rights in the invention.FIELD OF THE DISCLOSURE

[0003] This disclosure relates to compositions and methods to treat (e.g., reverse and / or prevent) opiate and opioid effects in a subject. It further relates to preventing or reversing opioid / opiate overdose.INTRODUCTION

[0004] According to the U.S. Centers for Disease Control, fentanyl is currently the most common cause (MCC) of overdose death in the U.S. and since 1999, fentanyl and its related analogues have been the cause of well over 700,000 deaths in the U.S. and since 2018 and 2021 , has been the MCC of overdose death and the MCC of overall death from all other types of accidental death combined (e.g., MVA and gun deaths), respectively. Fentanyl deaths continue to rise despite the widespread availability of naloxone I Narcan, the current standard for opioid overdose treatment. Since 2018, three years after the introduction of naloxone (nasal Narcan), nearly 300,000 Americans have lost their lives to fentanyl overdose, emphasizing the critical need for the development of more effective treatments for fentanyl overdose. The limited impact of naloxone on fentanyl deaths becomes quite clear when we compare the ongoing increase in fentanyl overdose deaths and the rapid rise in naloxone sales (Nasal Narcan). Since the introduction of Nasal Narcan in late 2015, fentanyl deaths have more than doubled, while the distribution of naloxone has increased by well over 300% (5 million units sold in 2018 versus > 21 million units sold in 2022) as calculated from U.S. total sales, with significant decreases in the cost per unit.

[0005] The response by the U.S. Food and Drug Administration (FDA), National Institute on Drug Abuse (NIDA), and pharmaceutical companies has been to increase the dose of naloxone available (from 0.4 mg to 8 mg for a single dose) and recently to approve a longer acting mu- opioid receptor agonist Nalmefene to prevent the event of re-narcotization (the recurrence of opioid overdose after initial opioid reversal due to longer half-life of opioid agonist thanantagonist). The continued presumption and consensus are that naloxone is an effective reversal agent for fentanyl overdose. However, little to no effort has been made to explore the fact that fentanyl and its related analogues are fully synthetic molecules that share very little common structure with morphine and morphine derived opiates resulting in lethal atypical effects unique to fentanyls and other potent synthetic opioids.OVERVIEW OF THE DISCLOSURE

[0006] The significant lack of shared structure between fentanyl and morphine derived drugs (such as heroin) results in fentanyl having unique pharmacological binding sites with specific lethal physiological effects unrelated to morphine. At low doses in therapeutic analgesia range, fentanyl (along with structurally similar compounds, alfentanil, remifentanil, sufentanil, carfentanil, and the like) behave just like morphine derived opiates and can cause respiratory depression leading to apnea, hypoxemia, and death. However, fentanyls also bind “off-site” (non-opioid receptor) targets, such as noradrenergic and cholinergic cells, which has not been fully explored or adequately researched to inform the research and clinical community.

[0007] The inventor of the herein-described technology is the first to demonstrate that fentanyl’s lethal effects on the airway causing asphyxiation are controlled directly by “off-site” (non-opioid receptor) targets; data in support of this is disclosed herein. The lack of knowledge by “experts” and “researchers” in the field of addiction medicine regarding the lethal effects of these previously undiscovered “off-site” (non-opioid receptor) targets has inadvertently contributed to the current opioid crisis, as fentanyl’s “off-site” (non-opioid receptor) targets have not been considered in the development of therapeutics specific to fentanyls, and naloxone (demonstrated by our data described herein) is inadequate to treat these lethal effects.Clinicians and Researchers in Addiction Medicine:

[0008] The binding of fentanyl to these “off-site” targets is not recognized in the field of Addiction Medicine. The concept of fentanyl having other pharmacological properties and lethal physiological effects, other than respiratory depression, has met with and continues to meet with considerable resistance from the research and clinical community. The contributing factor appears to be that, prior to the early 2000’s anesthesiologists were trained to administer high dose fentanyl induction for cardiac surgery; this was replaced by dexmedetomidine sometime after 2005. Anesthesiologists trained after that transition likely have not observed FIVCC or WCS. This transition occurred before fentanyls became part of the current opioid crisis. Researchers, in contrast, have no experience administering high dose fentanyls in human and consequently have no or little awareness of FIVCC or WCS.

[0009] Clinical studies have demonstrated the occurrence and dose range of WCS and FIVCC in humans (Grell et al., Anesth Analg,. 49(4):523-532, 1970; Streisand et al., Anesthesiology,78(4): 629-34. 1993; Bennett et al., Anesthesiology, 87(5):1070-1074, 1997; Arandia & Patil, Anesthesiology, 66(4):574-575, 1987). FIVCC resistance to IM naloxone is supported by recent reports from supervised injection site data showing 85% of illicit fentanyl overdose victims presenting with severe muscle rigidity are rescued by rapid IM administration of naloxone, but 15% present with upper airway obstruction that fails IM naloxone and skilled airway management (positive pressure ventilation, oxygen).

[0010] The result is that the clinicians administering fentanyl no longer give doses high enough to cause FIVCC or WCS, researchers have never seen the effect in humans or explored FIVCC in the animal model, but illicit fentanyl users are recreating these FIVCC and WCS effects in the community setting, and dying as a result.

[0011] This gap has subsequently created a vacuum for the development of effective therapeutics for fentanyl overdose.Alpha 1 adrenergic receptors and muscle rigidity induced by fentanyls:

[0012] Previous literature has demonstrated that fentanyl can bind alpha 1 adrenergic receptors (noradrenergic- NA receptors) in the Locus coeruleus (LC) and can cause chest wall rigidity, which impairs normal respiratory mechanics and can lead to hypoxemia and even death. Clinical literature has also demonstrated that high dose fentanyl's can cause sustained vocal cord closure also known as laryngospasm, that is widely recognized to be rapidly lethal (1 -3 minutes) without expert medical intervention. However, the underlying mechanism of fentanyl-induced vocal cord closure FIVCC, has not been explored in humans and has remained unexplored in animal models. The inventor was the first to demonstrate using a translational model of fentanyl overdose and FIVCC (Miner et al., Drug Alcohol Depend. 227:108974, 2021 ) that, although alpha 1 adrenergic receptors are involved in the fentanyl induced muscle rigidity (FIMR), they have no effect on FIVCC, indicating that FIVCC involves separate circuitry and receptors outside of the LC. The mechanism of FIVCC has remained unknown until our recent work identifying the CNS receptor targets controlling the effects of fentanyls on the upper airway (FIVCC) and has resulted in the development of formulations and identification of dose ranges and formulation ratios that increase survival from an LD o fentanyl overdose by 80% over naloxone as a single agent (FIGs.5 & 6).

[0013] As a clinician having seen this phenomenon in humans / clinically, WCS and FIVCC is easily treated with anesthesia induction agents (propofol), muscle relaxants (paralytics- Succinylcholine), and an endotracheal tube or an advanced airway device placed by those trained in invasive airway management. The window of intervention is exceedingly narrow (1-3 minutes, and likely 60-90 seconds in most cases). However, in the community setting these invasive measures are not immediately available and will likely result in the death of the overdose victim, but use of effective, accurately designed pharmacological interventions can provide life-saving restoration of respirations and relieve airway obstruction and can be rapidly administered by non-medical first responders.

[0014] Fentanyl interferes with cardiovascular, respiratory, and vocal cord function, with a unique pattern of changes that is dissimilar to and more rapidly lethal than the effects of morphine and other opioids. Until recently, data confirming the efficacy of naloxone or other mu opioid receptor antagonism for inhibiting the upper airway effects induced by high dose fentanyl has been lacking. Work in our animal model has demonstrated that intravenous (IV) naloxone fails to increase survival at 1 minute after FIVCC at doses 12 times the human equivalent dose and shows <50% survival in our translational model if administered 30 seconds after FIVCC occurs at the LD o dose of fentanyl (25 pg / kg) (FIGs. 5 & 6).

[0015] Provided herein in one embodiment is a composition formulated for use in reversing or preventing at least one symptom of fentanyl overdose in a human subject, the composition including: a therapeutic drug combination selected from the group consisting of: 0.5 mg lofexidine (LFX) and 5 mg naloxone (NLX); 0.5 mg LFX and 1 mg nalmefene (NF); 0.2 mg clonidine (CLON) and 5 mg NLX; 0.2 mg CLON and 1 mg NF; 0.1 mg dexmedetomidine (DEX) and 5 mg NLX; and 0.1 mg DEX and 1 mg NF; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0016] Another embodiment is a composition including: lofexidine and naloxone in a ratio of 1 :1 to a ratio of 1 :166 by weight (or 1 :5 to 1 :40 by weight, or 1 :1 , 1 :5, 1 :10, 1 :20, 1 :30, 1 :40, 1 :75, 1 :85, 1 :100, 1 :110, 1 :125, 1 :140, 1 :150, 1 :160, or 1 :166 by weight); and a pH balanced pharmaceutical carrier solution suitable for human administration. In various examples, the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0017] In examples of this embodiment, the composition includes 0.056 - 7 mg of lofexidine and 0.1 - 70 mg of naloxone; 0.1 - 3 mg lofexidine; or 0.1 - 7 mg naloxone; or both 0.1 - 3 mg lofexidine and 0.1 - 7 mg naloxone. In one specific example, the composition includes 0.145 mg lofexidine and 5.8 mg naloxone. By way of example, a single dose of examples of the composition include 0.05 mg to 7 mg of lofexidine (0.0007 mg / kg - 0.1 mg / kg for a 70 kg adult) and 0.1 - 70 mg of naloxone (0.0014 - 1 mg / kg for a 70 kg adult). Alternatively, a single dose of the composition includes 0.075 pg to 3 mg of lofexidine (1 -50 pg / kg for a 60 kg adult) and 0.1 - 10 mg of naloxone (1 -167 pg / kg for a 60 kg adult).

[0018] Also provided are uses of these compositions as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose. Such composition may be administered intramuscularly, intravenously, or intranasally. In specific examples, the composition is provided in a dosage of 0.0008 - 0.1 mg / kg lofexidine and 0.005 - 1.5 mg / kg naloxone; or in a dosage of 0.015 - 0.1 mg / kg lofexidine and 0.01 - 1 .5 mg / kg naloxone.

[0019] Provided in another embodiment is a composition including: clonidine and naloxone in a ratio of 1 :1 to a ratio of 1 :34 by weight (or a ratio of 1 :2 to a ratio of 1 :6 or a ratio of clonidine to naloxone is 1 :1 , 1 :2,1 :3, 1 :4, or up to 1 :34 by weight); and a pH balanced pharmaceutical carrier solution suitable for human administration; and a pH balanced pharmaceutical carrier solution suitable for human administration. In various examples, the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0020] In examples of this embodiment, the composition includes 0.05 - 3 mg of clonidine and 0.1 - 70 mg of naloxone; or 0.1 - 3 mg of clonidine and 0.1 - 10 mg of naloxone; or 0.56 mg clonidine and 5.8 mg naloxone; or 0.58 mg clonidine and 5.8 mg naloxone. By way of example, a single dose of the composition includes 0.05 mg to 3 mg of clonidine (0.0007 mg / kg - 0.043 mg / kg for a 70 kg adult) and 0.1 - 70 mg of naloxone (0.0014 mg / kg - 1 mg / kg for a 70 kg adult). Alternatively, a single dose of the composition includes 0.075 pg to 3 mg of clonidine (1 - 50 pg / kg for a 60 kg adult) and 0.5 - 10 mg of naloxone (1 -167 pg / kg for a 60 kg adult).

[0021] Also provided are uses of these compositions as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose. Such composition may be administered intramuscularly, intravenously, or intranasally. In specific examples, the composition is provided in a dosage of 0.008 - 0.175 mg / kg clonidine and 0.005 - 1 .5 mg / kg naloxone; or in a dosage of 0.01 - 0.5 mg / kg clonidine and 0.01 - 1 .5 mg / kg naloxone.

[0022] Yet another embodiment is a composition including: lofexidine and nalmefene in a ratio of 1 :1 to a ratio of 1 OO by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration. In various examples, the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0023] Another embodiment is a composition including: lofexidine and nalmefene in a ratio of 1 :1 to a ratio of 4:1 by weight (or a ratio of lofexidine to nalmefene is 1 :1 , 1 :2, 1 :20 or 1 :100 by weight; or the ratio of lofexidine to nalmefene is 4:1 by weight); and a pH balanced pharmaceutical carrier solution suitable for human administration. By way of example, a single dose of the composition includes 0.05 mg to 7 mg of lofexidine (0.0008 mg / kg - 0.1 mg / kg for a 70 kg adult) and 0.056 to 35 mg of nalmefene (0.0008 mg / kg - 0.5 mg / kg for a 70 kg adult). Alternatively, a single dose of the composition includes 0.9 mg to 2.4 mg of lofexidine (0.015 - 0.04 mg / kg for a 60 kg adult) and 0.6 - 1.2 mg of nalmefene (0.01 - 0.02 mg / kg for a 60 kg adult).

[0024] Also provided are uses of these compositions as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose. Such composition may be administered intramuscularly, intravenously, or intranasally. In specific examples, the composition is provided in a dosage of 0.0008 - 0.1 mg / kg lofexidine and 0.0008 mg / kg - 0.5 mg / kg nalmefene; or in a dosage of 0.015 - 0.1 mg / kg lofexidine and 0.001 - 0.2 mg / kg nalmefene.

[0025] Another embodiment is a composition including: lofexidine and naltrexone in a ratio of 1 :1 to a 1 :250 by weight (or in a ratio of 1 :1 to a 1 :70 by weight; or 1 :5, 1 :10, 1 :20, 1 :30, 1 :40, 1 :50, 1 :75, 1 :100, 1 :125, 1 :150, 1 :175, 1 :200, 1 :225, or 1 :250 by weight); and a pH balanced pharmaceutical carrier solution suitable for human administration. In various examples, the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0026] In examples of this embodiment, the composition includes 0.05 mg to 7 mg of lofexidine (0.0008 mg / kg - 0.1 mg / kg for a 70 kg adult) and 5 mg to 50 mg of naltrexone (0.07 mg / kg - 0.7 mg / kg for a 70 kg adult). In specific examples, the composition includes 0.5 mg of lofexidine and 25 mg of naltrexone; or 0.1 mg lofexidine and 5 mg naltrexone; or 0.58 mg lofexidine and 5.8 mg naltrexone.

[0027] Also provided are uses of these compositions as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose. Such composition may be administered intramuscularly, intravenously, or intranasally.

[0028] Another embodiment is a composition including: clonidine and nalmefene in a ratio of 1 :1 to a ratio of 10:1 by weight (or a ratio of 5:1 to a ratio of 10:1 by weight; or 1 :1 , 2:1 , 3:1 , 4:1 , 5:1 , 6:1 , 7:1 , 8:1 , 9:1 , or 10:1 by weight); and a pH balanced pharmaceutical carrier solution suitable for human administration. In various examples, the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0029] By way of example, a single dose of the composition includes 0.05 mg to 3 mg of clonidine (0.0007 - 0.04 mg / kg for a 70 kg adult) and 0.056 to 35 mg of nalmefene (0.0008 mg / kg - 0.5 mg / kg for a 70 kg adult). Alternatively, a single dose of the composition includes 9 mg of clonidine (0.15 mg / kg for a 60 kg adult) and 1.2 mg of nalmefene (0.02 mg / kg for a 60 kg adult).

[0030] Also provided are uses of these compositions as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose. Such composition may be administered intramuscularly, intravenously, or intranasally. In specific examples, the composition is provided in a dosage of 0.008 - 0.2 mg / kg clonidine and 0.0008 - 0.5 mg / kg nalmefene; or in a dosage of 0.01 - 0.5 mg / kg clonidine and 0.001 - 0.2 mg / kg nalmefene.

[0031] Yet another embodiment is a composition including: dexmedetomidine and nalmefene in a ratio of 1 :1 to a ratio of 20:1 by weight (or a ratio of 1 :5 to a ratio of 1 :10 by weight; or 1 :1 , 2:1 , 3:1 4:1 , 5:1 , 6:1 , 7:1 , 8:1 , 9:1 , 10:1 and all ratios up to 20:1 by weight); and a pH balanced pharmaceutical carrier solution suitable for human administration. In various examples, the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0032] In examples of this embodiment, a single dose of the composition includes 0.2 mg to 35 mg of dexmedetomidine (0.003 mg / kg - 0.5 mg / kg for a 70 kg adult) and 0.056 to 35 mg of nalmefene (0.0008 mg / kg - 0.5 mg / kg for a 70 kg adult). Alternatively, a single dose of thecomposition includes 6 mg of dexmedetomidine (0.1 mg / kg for a 60 kg adult) and 0.6 - 1 .2 mg of nalmefene (0.01 - 0.02 mg / kg for a 60 kg adult).

[0033] Also provided are uses of these compositions as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose. Such composition may be administered intramuscularly, intravenously, or intranasally. In specific examples, the composition is provided in a dosage of 0.003 - 0.5 mg / kg dexmedetomidine and 0.0008 - 0.5 mg / kg nalmefene; or in a dosage of 0.01 - 0.5 mg / kg dexmedetomidine and 0.001 - 0.2 mg / kg nalmefene.

[0034] By way of example, such compositions may be used as a reversal therapy in response to a fentanyl, F / FA or combination opiate overdose.

[0035] Another embodiment is a composition including: dexmedetomidine and naloxone in a ratio of 1 :1 to a ratio of 1 :33 by weight (or a ratio of 1 :2 to a ratio of 1 :5 by weight; or 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 :10, 1 :11 and all ratios up to 1 :33 by weight); and a pH balanced pharmaceutical carrier solution suitable for human administration. In various examples, the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0036] In examples of this embodiment, a single dose of the composition includes 0.2 mg to 35 mg of dexmedetomidine (0.003 mg / kg - 0.5 mg / kg for a 70 kg adult) and 0.1 - 70 mg of naloxone (0.001 - 1.5 mg / kg for a 70 kg adult). Alternatively, a single dose of the composition includes 6 mg of dexmedetomidine (0.1 mg / kg for a 60 kg adult) and 50 - 100 mg of naloxone (0.25 - 0.5 mg / kg for a 60 kg adult).

[0037] Also provided are uses of these compositions as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose. Such composition may be administered intramuscularly, intravenously, or intranasally. In specific examples, the composition is provided in a dosage of 0.003 mg / kg -0.5 mg / kg dexmedetomidine and 0.001 - 1 .5 mg / kg of naloxone; or in a dosage of 0.01 - 0.5 mg / kg dexmedetomidine and 0.01 - 1.5 mg / kg naloxone. In various examples, the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0038] By way of example, such compositions may be used as a reversal therapy in response to a fentanyl, F / FA or combination opiate overdose.

[0039] Another embodiment is a composition including: dexmedetomidine and naloxone in a ratio of 1 :1 to a ratio of 1 :50 by weight (or a ratio of 1 :1 to a ratio of 1 :7 by weight; or 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9 or 1 :10 up to 1 :50 by weight); and a pH balanced pharmaceutical carrier solution suitable for human administration. By way of example, a single dose of examples of the composition includes 0.42 mg to 35 mg of dexmedetomidine (0.006 - 0.5 mg / kg for a 70 kg adult) and 15 - 30 mg of naloxone (0.001 - 1.5 mg / kg of naloxone for a 70 kg adult). Alternatively, a single dose of the composition includes 4.5 mg to 9 mg of dexmedetomidine (0.075 - 0.15 mg / kg for a 60 kg adult) and 15 - 30 mg of naloxone (0.25 - 0.5 mg / kg for a 60 kg adult).

[0040] Also provided are uses of these compositions as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose. Such composition may be administered intramuscularly, intravenously, or intranasally. In specific examples, the composition is provided in a dosage of 0.006 - 0.5 mg / kg dexmedetomidine and 0.001 - 1 .5 mg / kg naloxone. In specific examples, the composition is provided in a dosage of 0.075 - 0.15 mg / kg dexmedetomidine and 0.01 - 1.5 mg / kg naloxone.

[0041] By way of example, such compositions may be used as a pretreatment therapy in response to a fentanyl, F / FA or combination opiate overdose.

[0042] Yet another embodiment is a composition including: dexmedetomidine and nalmefene in a ratio of 1 :1 to a ratio of 16:1 by weight (or a ratio of 3:1 to a ratio of 20:1 by weight; or 1 :1 , 2:1 , 3:1 , 4:1 , 10:1 , and all ratios up to 16:1 by weight); and a pH balanced pharmaceutical carrier solution suitable for human administration. In various examples, the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0043] 96 By way of example, a single dose of the composition includes 0.42 mg to 35 mg of dexmedetomidine (0.006 - 0.5 mg / kg for a 70 kg adult) and 0.056 to 35 mg of nalmefene (0.0008 mg / kg - 0.5 mg / kg for a 70 kg adult). Alternatively, a single dose of the composition includes 4.5 mg to 9 mg of dexmedetomidine (0.075 - 0.15 mg / kg for a 60 kg adult) and 0.6 - 1 .2 mg of nalmefene (0.01 - 0.02 mg / kg for a 60 kg adult).

[0044] Also provided are uses of these compositions as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose. Such composition may be administered intramuscularly, intravenously, or intranasally. In specific examples, the composition is provided in a dosage of 0.006 - 0.5 mg / kg dexmedetomidine and 0.0008 - 0.5 mg / kg nalmefene; or in a dosage of 0.006 - 0.5 mg / kg dexmedetomidine and 0.0008 - 0.5 mg / kg nalmefene.

[0045] By way of example, such compositions may be used as a pretreatment therapy in response to a fentanyl, F / FA or combination opiate overdose.BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Some of the drawings submitted herein may be better understood in color. Applicant considers the color versions of the drawings as part of the original and / or priority submission(s) and reserves the right to present color images of the drawings in later proceedings.

[0047] FIG. 1 Fentanyl effects on VCC and death: IV fentanyl has dose dependent effects on vocal cord function. All doses are noted below each bar and numbers above the bars represent the number of test animals corresponding to each dose. X” in the bar represents the % survival, “O” indicates death by either respiratory depression, apnea or hypotension and the “blank bar” represents death from VCC / Fl VCC. Increases in dose are positively correlated with VCC and VCC death (fentanyl -induced vocal cord closure - FIVCC).

[0048] FIG. 2. Fentanyl effects on VCC and death and on MAP, HR, RR. IV fentanyl has dose dependent effects on MAP, HR and RR in the graph above. Percent survival in response to fentanyl (0.005, 0.015, 0.025, 0.100 mg / kg) are noted as 1 -4. Numbers beside the graph lines represent the dose and MAP (millimeters of mercury; mmHg), HR (beats per minute; BPM), and RR (breaths per minute; BRPM) are noted for different doses of fentanyl. All measurements are reported as the mean ± SEM.

[0049] FIGs. 3A-3B. Naloxone effects on Fl VCC and death: IV naloxone has dose dependent, timing effects on survival and VCC death after FIVCC. Naloxone was delivered 15 seconds (FIG. 3A) or 45 seconds (FIG. 3B) after fentanyl dosing. Numbers above bars represent the number of animals for each dose. “X” in the bar represents % survival, “O” indicates death by either respiratory depression, apnea or hypotension and “blank bar” represents death from VCC I FIVCC.

[0050] FIGs. 4A-4B. IV naloxone reverses the effects of IV fentanyl-induced changes in vocal cord function, MAP, HR and RR in a dose and time dependent fashion. The graph lines represent % survival for naloxone IV at 15 seconds (FIG. 4A) or 45 seconds (FIG. 4B) after FIVCC over range of naloxone doses (0.007, 0.125, 0.500, 1 .0 mg / kg; labeled 1 , 2, 3, and 4, respectively). “F” indicates fentanyl delivery and “R” indicates delivery of the naloxone rescue drug naloxone.

[0051] FIGs. 5 & 6. Comparison of IV drug delivery for FIVCC reversal. IV naloxone (NLX), clonidine (CLON) or a combination (NLX + CLON or NLX+ LFX) was administered 45 sec after IV fentanyl (25 mcg / kg) to compare dose dependent, timing effects on survival and VCC death after FIVCC. FIG. 5. An n=8 animals were tested for each dose represented by lines numbered 1 -5 (respectively, naloxone, clonidine, Naloxone + Clonidine, Naloxone + Lofexidine). Compared to using naloxone alone, clonidine alone, or lofexidine alone: Formulations of Naloxone + clonidine, or Naloxone + lofexidine, improve survival efficacy. Naloxone depicted in FIG. 5 illustrates 5 % survival after an LD o dose of fentanyl (25 pg / kg) is administered by LV. to study animals in a model of fentanyl overdose and FIVCC. The LD o dose of fentanyl noted here consistently causes FIVCC in < 10 sec in all study animals. FIG. 6. The bar graph the “Percent Survival Over Time” for each drug or combination. Each drug alone has minimal survival versus the combinations for clonidine + naloxone ( 75% survival at 15”) and lofexidine + naloxone (70% survival at 15”). TMT-RX formulations that target opioid receptors and alpha 2 adrenergic receptors and lead to 80% increased survival over naloxone as a single agent. Each line and bar represent an n=8 study animals.

[0052] FIGs. 7 & 8. Comparison of IV naloxone, clonidine and combination (Naloxone + Clonidine and Naloxone + Lofexidine) for MAP (FIG. 7) and FIVCC reversal (VCA) (FIG. 8) comparison of naloxone, clonidine and naloxone + clonidine. FIG. 7 is a graph showing the effect of fentanyl and indicated treatments on blood pressure (hemodynamic stability). Combination treatment significantly improves blood pressure maintenance compared to naloxone alone at 1 minute aftertreatment. F=Time of fentanyl (25 pig / kg) IV injection; T=Time of treatment IV injection; dashed line at 30 minutes Hg denotes minimum blood pressure allowed for protocol inclusion. FIG. 8 is a graph illustrating that the return of “Vocal Cord Activity” which is critical to restoring respiration and survival, is reduced by 75% for both naloxone and clonidine as single agents, whereas the combination (green bar) demonstrates significantly greater return of “Vocal Cord Activity” if administered 45 seconds after FIVCC. Antagonism of these fentanyl effects using an alpha 2 adrenergic receptor agonist is therapeutic (reverses FIVCC and restores respiration) and allows for increased survival from fentanyl overdose when used in combination with a mu opioid receptor agonist. Each line (FIG. 7) and bar (FIG. 8) represent an n=8 study animals (4 male and 4 female).

[0053] FIG. 9. Comparison of IV naloxone, clonidine, and combination therapies (Naloxone + Clonidine, Naloxone + Lofexidine, Naloxone + Dexmedetomidine) for FIVCC reversal. IV naloxone (Nix), clonidine (Cion), dexmedetomidine (Dex), lofexidine (Lofex) were administered in combination (Nlx+ Cion, Dex +Nlx, Lofex + Nix) 45 sec after IV fentanyl (25 pg / kg) to compare dose dependent, timing effects on survival and VCC death after FIVCC. Numbers above bars represent the number of animals for each dose. “X” in the bar represents % survival, “O” indicates death from VCC / FIVCC.

[0054] FIG. 10. Comparison of IM Naloxone, Clonidine and Combination (Naloxone + Clonidine) for FIVCC Reversal. IM naloxone (Nix), clonidine (Cion) and combination (Nlx+ Cion) was administered immediately after IV fentanyl (25 pig / kg) dose dependent, timing effects on survival and VCC death after FIVCC. Numbers above bars represent the number of animals for each dose. “X” in the bar represents % survival, “O” indicates death from VCC / FIVCC and “blank bar” represents death by either respiratory depression, apnea or hypotension.

[0055] FIG. 11 A. MAP, HR, and RR for different treatments delivered 15 seconds after fentanyl- induced vocal cord closure. FIG. 11 B shows the same assessments as FIG. 1 1 A but grouped by the indicated survival status of each animal. Physiology normalizes after combination treatment in survivors but not non-survivors, as shown in FIG. 11 B. “F” indicates IV fentanyl and “R” indicates IM rescue. Results are reported as the mean ± SEM. Rescue of MAP and HR is correlated with return of respiration for survivors, demonstrating that the toxidrome is treated by combination therapy but not as single agents. Naloxone: N (1 mg / kg); Clonidine: C (1 mg / kg); Combination: NIxC (N 1 mg / ml + C 1 mg / kg).DETAILED DESCRIPTION OF REPRESENTATIVE EMBODIMENTS

[0056] The ultra-potent synthetic opioid fentanyl has become the most common cause of illicit drug overdose death in North America and has found further misuse as a chemical weapon against insurgents and civilian populations. The Moscow theater incident (in 2002) stands as a dark field demonstration of the potency of weaponized fentanyls and suggests a limited efficacy for conventional opioid reversal agents. The ability to develop more effective medicalcountermeasures for fentanyl and related analogues depends on a clearer understanding of fentanyl pharmacology and the clinical effects of fentanyls at high doses. Specifically, fentanyl and its related analogues cause respiratory depression at low doses in animals and humans, while higher doses cause the mechanical failure of respiration via chest wall rigidity ("wooden chest syndrome"- WCS) and airway obstruction from sustained vocal cord closure. Although respiratory depression and WCS can be lethal complications of fentanyl, fentanyl-induced vocal cord closure (FIVCC) is rapidly fatal without immediate intervention and is resistant to naloxone. However, while the mechanisms of respiratory depression and WCS are well defined, the mechanism(s) of FIVCC remains unknown. The emergence of fentanyl as the major cause of overdose death in the U.S., its ubiquitous presence, and its demonstrated potential for weaponization, have all increased the critical significance of understanding the mechanism(s) of FIVCC for developing effective therapeutics for fentanyl poisoning and overdose. An animal model that replicates the acute clinical effects of fentanyl on the upper airway has been used by our lab to test potential pharmacotherapeutic agents for reversal of fentanyl overdose and FIVCC. This model has been employed to study and elucidate unique aspects of synthetic opioid- mediated physiological dysfunction that overlaps in animals and humans. Original data from a translational model is described, which adds context and support to development of therapeutics.

[0057] Described herein are methods and compositions (formulations) to prevent or reverse the multiple opioid receptor and non-opioid receptor-based lethal effects that occur with fentanyl and related fentanyl analogues (F / FAs) (e.g., overdoses) that are not recognized or addressed by current opioid overdose treatments. Fentanyl, like all opiates and other synthetic opioids, can cause death by causing a failure of the respiratory system (e.g., respiratory depression) with secondary cardiovascular effects which are mediated by mu-opioid receptors at low doses of fentanyl. However, due to F / FAs unique and fully synthetic molecular structure, moderate to high clinical doses of F / FA engage non-opioid receptor mediated lethal effects on the airway. Therefore, a novel and non-obvious approach to treating F / FA overdose is required and proposed in this application to increase survival and decrease the ongoing death toll in current opioid crisis dominated by fentanyls.

[0058] This disclosure is focused on the respiratory component of fentanyl toxicity. Fentanyl causes respiratory failure in three different ways through three different receptor and neurocircuitry mechanisms, two identified (respiratory depression and chest wall rigidity) and one previously unidentified mechanism (FIVCC). The underlying receptor target of the most lethal of the mechanisms (FIVCC) has been unknown until this disclosure. Fentanyl causes: 1 ) respiratory depression mediated by Mu-opioid receptors; 2) impaired ventilation due to chest wall muscle rigidity that can result in respiratory failure mediated by alphal receptors and; 3) vocal cord closure or airway obstruction that is mediated by fentanyl’s functional effects on alpha 2 adrenergic receptors. This data was obtained by pharmacological demonstration in ourtranslational animal model, as illustrated in FIGs. 5-8, and by standard hybridization techniques with HEK cells and human adrenergic receptors demonstrating binding affinities of fentanyls at relevant targets.

[0059] Based on these precli nical, in vivo results of FIVCC rescue treatment shown in FIGs. 7 & 8 and human equivalency dosing calculations for naloxone and alpha 2 adrenergic receptor agonists (e.g., clonidine or lofexidine) (Reagan-Shaw et al., 2008; Nair et al., 2016; Zhu et al., 2016; Kang et al., 2022), the following ratios and dose ranges of the combination of naloxone with an alpha 2 adrenergic receptor agonist (e.g., clonidine or lofexidine) are provided as examples of formulations for the clinical treatment of FIVCC. Examples of the clinically comparable mu-opioid receptor antagonists nalmefene and naltrexone are provided, as their dose equivalencies are well established in the literature and provide broader dosing flexibility and duration with the alpha 2 adrenergic receptor antagonists disclosed. These are exemplary and do not constitute all of the possibilities suggested by this technology. Human Dose Equivalency (HED) has been correlated and calculated between rats and humans for the mu-opioid receptor antagonist naloxone, where 170 pg / kg (0.17 mg / kg) of naloxone in a rat model is equal to a 2 mg dose of naloxone in a 70 kg adult male (Kang et al., 2022; Nair et al., 2016).

[0060] Based on the preclinical model data presented here, a 500 pg / kg dose in a 70 kg adult male would have a HED of 5.8 mg total dose of naloxone to provide similar effects in humans, in this case for reversal of fentanyl overdose effects on the airway (FIVCC) when combined with an alpha2 agonist (Kang et al., 2022) (FIGs. 5-8). This data was gathered from anesthetized animals; anesthetization will lower the dose of fentanyl required to cause FIVCC effects, as 25 mcg / kg is lethal in our model, but in awake animal models the lethal dose of fentanyl when administered rapidly (IV bolus over 10 sec) is 50 mcg / kg (Lui et al., Anesthesiology, 70(6): 984-990, 1989). When considering these data along with clinical studies where FIVCC is induced in awake humans at fentanyl doses of 25-30 pg / kg, it can be useful to consider a modification of allometric conversion factors.

[0061] The data set presented herein is unique in that it provides the first data set necessary to quantitatively factor anesthetic (CNS sedative) effects when CNS sedatives are combined with fentanyl. This model, in effect, represents polysubstance dosing (additional CNS depressants similar to general anesthesia) versus awake dosing of fentanyl effects, which are well established in human clinical literature. The model not only replicates the effects of high dose fentanyls in humans but represents the closest clinical model of polysubstance overdose involving synthetic opioids. This allows for a broader determination of fentanyl effects when combined with CNS depressants and thus a broader characterization of the therapeutic agents tested (e.g. mu-opioid receptor antagonists and alpha2 adrenergic receptor agonists). Opioid dose conversions from rats to human normally use a factor of 6 (rat doses of opioids are 6x higher than in humans to cause similar physiological effects), but in this case it is more likely to be a factor of 2-3 to moreaccurately factor out anesthetic effects (Kang et al., 2022, Nair et al., 2016). The lower allometric limit of “2” was selected to allow for broadest and most clinically relevant therapeutic range for the calculations rendered and summarized in the Dosing Table that follows.

[0062] A practical application here is to extend the allometric conversion factor from 6 to a range of 2-6. The “awake” HED dose of mu-opioid receptor antagonists (MOR) and alpha2 adrenergic receptor (A2AR) agonists combined allometrically converted from an anesthetized rat dose of 0.5 mg / kg of IV naloxone, yields an “anesthetized to awake” range of be 5.8-17.5 mg IV in humans, indicating that extremely high doses of IV naloxone (e.g. >40 doses of intranasal naloxone) would be required to reverse FIVCC. Anesthesia (general anesthesia, “GA”), in this model, lowers the threshold for fentanyl to cause FIVCC and subsequently and artificially lowers the MOR antagonist dose. This means the “awake” HED of MOR is significantly higher and will decrease if fentanyl is combined with other CNS sedative agents. However, the ratio of the A2AR agonist and MOR antagonist remains relatively constant. This is an important advance of the described technology, as it has identified underlying mechanism(s) of FIVCC and has enabled the development of optimal ratio and ranges of these compounds for clinical use. The anesthetic used has allowed for us to replicate FIVCC at the same dose in which it is seen clinically in humans and offers a logical derivation of the dose range for the drugs and drug combinations tested as potential clinical interventions. On a more general note, this technology also indicates that most individuals dying from fentanyl may be dying from a combination of naloxone failure at current maximal dose ranges, incomplete CNS receptor targeting and atypical effects of fentanyl. The following example calculation demonstrates the allometric HED range in consideration of awake versus CNS depressants combined with fentanyl: Ex. 0.5 mg / kg IV naloxone x 70 kg adult male = 35 mg naloxone / 2 = 17.5 mg IV naloxone, or 5.8 mg of naloxone if divided by an allometric factor of 6.

[0063] In the case of an alpha 2 agonist such as dexmedetomidine, a dose of 2.5 pg / kg is equal to a 0.3 pg / kg dose in an adult human (factor of *8) (Reagan-Shaw et al., 2008; Nair et al., 2016; Zhu et al., 2016), where 100 pg / kg in a rat model is equal to a HED of 12 pg / kg. Again, when factoring anesthesia, a similar modified allometric conversion factor range of 2-6 or 2-8 can be used, and would consider that:

[0064] Ex. DEX 0.100 mg / kg : 100 pg / kg = 0.1 mg / kg : 0.1 mg / kg x 70 kg = 7 mg total / 8 = 0.875 mg HED or by wt. = 0.0125 mg / kg or 12 pg / kg

[0065] Ex. DEX 0.05 mg / kg : Low end dose (pretreatment) : 0.05 mg / kg x 70 kg. = 3.5 mg total dose / 2- *8 = HED. 0.44 mg-1 .75 mg total HED dose / By wt. 0.006 mg / kg - 0.025 mg / kg

[0066] DEX: high end dose (pretreatment): 0.15 mg / kg x 70 kg. = 10.5 mg total dose / 2- *8 = HED 1 .3 mg — 5.25 mg total HED dose / By wt. 0.02 mg / kg - 0.075 mg / kg

[0067] **HED DEX (pretreatment) Complete Dose range 0.44-5.25 mg / by weight (0.006 - 0.075 mg / kg).

[0068] Thus, a 70 kg awake or sedated adult would require an approximate dose range of 0.44- 5.25 mg I by weight (0.006-0.075 mg / kg) and with a general range 0.1 - 5 mg for similar effects in humans compared to rat model (e.g., reversal of fentanyl overdose effects on the airway -FIVCC). Anesthesia in the rat model creates a 1 :1 ratio for FIVCC effects where 25 g / kg fentanyl in rat and humans causes FIVCC.

[0069] The alpha 2 agonist lofexidine has a similar conversion equivalency, where 15 g / kg in a rat model is equal to a HED range (anesthetized to awake) of 1.8 -7.5 pg / kg in humans; and a 70 kg adult would require an approximate dose of 130-525 pg total dose for similar effects in humans (e.g., reversal of fentanyl overdose effects on the airway -FIVCC).

[0070] Neither of the two classes of molecules (mu-opioid receptor antagonist such as naloxone; alpha 2 adrenergic receptor agonist such as lofexidine, xylazine, dexmedetomidine, clonidine) in the data described herein, when administered as single agents, can significantly increase survival after an IV fentanyl LD o dose. In fact, when given as single agents in this model of fentanyl overdose, naloxone, lofexidine and clonidine all cause a catastrophic decrease in blood pressure within the first 2 minutes, that decreases survival after fentanyl overdose with an IV LDwo dose (FIG. 7). Additionally, naloxone, as a mu-opioid receptor antagonist, is expected to reverse all opioid / opiate overdose effects of fentanyl, while alpha 2 agonists are not expected to have any effect on opioid overdose effects whatsoever (respiratory depression or FIVCC).

[0071] Surprisingly, it is demonstrated herein that when naloxone is administered with an alpha 2 agonist (demonstrated herein using, for instance, lofexidine and clonidine) in an appropriate ratio, this combination results in a functional interaction, and the result of this interaction is a reversal of FIVCC and a significant increase in blood pressure that leads to a >75% increase in survival over any of the single agents, after an IV fentanyl LDwo dose is administered. The effect is unexpected, has not been previously described or predicted from the medical / scientific literature, and is the result of combining these two separate classes of drugs (that is, a mu-opioid receptor antagonist with an alpha 2 adrenergic receptor agonist) in an appropriate ratio, for instance in a single administration. The combination clearly yields atypical effects, an effect greater than either ingredient used alone and could not have been foreseen or predicted by an expert in the field.

[0072] Fentanyl, unlike morphine-derived opiates, causes respiratory failure by closing the vocal cords (FIVCC), the conduit of oxygen into the lungs, and inhibits the respiratory drive for the mechanical ventilation of the lungs. Each of these functions, controlling airway patency and respiration, are controlled by two separate neural circuits and receptor sets and addressing both is necessary for successful reversal of fentanyl overdose. Airway obstruction must be reversed, and respiratory drive must be restored to survive a fentanyl overdose. Unfortunately, the commonly held belief by experts in the field is that respiratory depression and renarcotization are the only effects which must be reversed (Averick et al., Front Psychiatry. 15:1366186, 2024. doi:10.3389 / fpsyt.2024.1366186). The mechanism of FIVCC has remained unknown, until the discovery described herein and the provision of optimal, experimentally determined drug formulation ratios as described. The specific dose, time course limitations, and ineffectiveness of the mu-opioid receptor antagonist naloxone (alone) for treating FIVCC has been definitively demonstrated (see FIGs. 5-8) and the demonstration that including an alpha 2 adrenergic receptor agonist(s) to reverse FIVCC is presented here for the first time.

[0073] Based on this data presented herein, an alpha 2 adrenergic receptor agonist (exemplified by lofexidine) can be combined with naloxone in a 1 :1 ratio up to a 1 :166 ratio, where an optimal dose ratio of 1 :40 is included within this range, as it overlaps with current U.S. FDA clinical guidelines for the two components separately (e.g., 0.145 mg lofexidine / 5.8 mg naloxone). However, broader ranges and ratios may be required to accommodate for increased and variable synthetic opioid potencies, increased dose requirements for IM and nasal administration and to control side effects by either drug class (e.g. increased A2AR agonist may be required to decrease withdrawal symptoms of a potent MOR antagonist or a higher dose of ratio of MOR antagonist to A2AR agonist may be required to limit hypotensive effects of A2AR agonists).

[0074] A combination of an MOR antagonist to A2AR agonist can be combined in a pH balanced, pharmaceutical carrier solution suitable for human administration and administered (e.g., via IM, IV, or Intranasal dosing delivery method) as a therapeutic treatment in the event of a fentanyl, F / FA or combination opiate overdose.

[0075] Lofexidine and naloxone are combined in one formulation with a range of formulations that include a combination of between 0.1 - 7 mg of lofexidine and 0.1 - 70 mg of naloxone. The dose of each agent in a formulation will be a minimum dose of 0.056 mg and maximum dose of 7 mg for lofexidine (0.0008 mg / kg - 0.1 mg / kg for a 70 kg adult) and 0.1 - 70 mg for naloxone (0.0014 mg / kg -1 mg / kg for a 70 kg adult). Ranges of HED are calculated from the range of efficacy of each drug in the animal model (e.g. naloxone effective dose range 0.035 mg / kg - 2 mg / kg). Additional ranges are discussed herein.

[0076] A number of alpha 2 adrenergic receptor agonists were tested for efficacy for reversal of FIVCC. All alpha 2 adrenergic receptor agonists tested were capable of reversing FIVCC, but each drug had a unique optimal dose based on relative potency, lipophilicity, physical properties, and functional binding affinity for alpha 2 adrenergic receptors for the same dose fentanyl dose (25 pg / kg) inducing FIVCC in this model. These relative potencies influence the preferred ratio of a particular alpha 2 agonist to the mu-opioid receptor antagonist selected (e.g., naloxone) and combination dosing will vary with the degree of potency of the synthetic opioid being treated. The dosing and ratio range also allow for variability in dose used for a particular ratio: Ex. 1 :1 = 5 mg: 5 mg or 0.5 mg: 0.5 mg, 1 :10 = 4 mg: 40 mg or 0.4 mg : 4 mg.

[0077] The alpha 2 agonist clonidine was tested in combination with naloxone for reversal of FIVCC. Based on this data, an alpha 2 adrenergic receptor agonist (clonidine) can be combinedwith naloxone in a 1 :1 ratio up to a 1 :34 ratio, where an optimized dose ratio of 1 :10 (e.g., 0.58 mg clonidine / 5.8 mg naloxone) would be combined in a pH balanced, pharmaceutical carrier solution suitable for human administration and administered via an (e.g., IM, IV, Intranasal) dosing delivery method as a therapeutic treatment in the event of a fentanyl, F / FA or combination opiate overdose. Clonidine and naloxone are combined in one formulation with a range of formulations that include a combination between 0.05 - 14 mg for clonidine and 0.1 - 70 mg for naloxone. The dose of each agent in formulation will be a minimum of 0.05 mg and a maximum of 14 mg for clonidine (0.0007 mg / kg — 0.2 mg / kg for a 70 kg adult) and a minimum of 0.1 mg naloxone and a maximum of 70 mg for naloxone (0.0014 mg / kg -1 mg / kg for a 70 kg adult). Additional ranges are discussed herein.

[0078] Similar rationale and proof of concept can be applied to a prophylaxis agent against fentanyl overdose that can be administered prior to exposure or even up to and including, immediately upon exposure to an F / FA. Ideally, such prophylaxis formulation(s) are administered 30-60 minutes prior to fentanyl exposure to optimize plasma levels and efficacy of the active ingredients. The inventor has demonstrated that alpha 2 adrenergic receptor agonists can prevent vocal cord closure induced by fentanyl (FIVCC), if administered prior to fentanyl exposure with multiple drugs in class, as demonstrated in Tables 1 A, 1 B, and 2 (clonidine, lofexidine, xylazine, dexmedetomidine). (Xylazine is an animal anesthetic not currently approved for human use; however, it is combined with fentanyl by drug cartels as a cost-effective adulterant / CNS depressant.) The doses required for prophylaxis as single agents are comparable to overdose reversal doses, with lofexidine more consistently effective for inhibiting FIVCC at doses of 40 pg / kg (HED range of 0.35 mg-1 .4 mg) for pre-treatment. Although pretreatment with the alpha 2 adrenergic receptor agonists will prevent FIVCC, they do not ultimately lead to increased survival without the addition of a mu-opioid receptor antagonist. In the case of an optimized prophylaxis agent against fentanyl overdose, alpha 2 adrenergic receptor agonist(s) and mu- opioid receptor antagonist(s) combined in formulation should have relatively long and comparable (to the other component(s) in the mixture) half-lives, to increase duration of plasma level for effective prophylaxis, for instance over a 12-24 hr period.

[0079] Beneficially, a mu opioid receptor antagonist with a longer half-life than naloxone (t > / 2= 30 - 45 minutes), such as nalmefene or naltrexone, could be used in combination with an alpha 2 adrenergic receptor agonist as an effective prophylaxis agent against fentanyl overdose or FIVCC resulting from accidental ingestion, poisoning, or toxic exposure. As in the previous alpha 2 agonist example, the optimal ratio will be influenced by the potency of the selected alpha 2 agonist relative to the selected mu-opioid receptor antagonist.

[0080] In the case of adult (70 kg) clinical dosing, nalmefene can be administered in a broad dose range of 0.007 mg-35 mg, with an ideal dose range of 0.5 mg-1 .5 mg, combined with an alpha 2 adrenergic agonist (i.e., lofexidine 0.1 -7 mg) in a ratio between Lofexidine 1 :1 Nalmefene- 1 :1 -100 and an ideal range of Lofexidine 1 :1 Nalmefene - Lofex 1 :2 Nalmefene (e.g., 0.5-1 mg lofexidine / 1 -2 mg nalmefene) in a pH balanced, pharmaceutical carrier solution suitable for human administration and administered (e.g., via IM, IV, Intranasal, oral, transdermal dosing delivery method) as an effective prophylaxis agent against fentanyl overdose or FIVCC resulting from accidental ingestion, poisoning or toxic exposure.

[0081] The higher dose of the alpha 2 agonist in this case of 0.5-1 mg for lofexidine is specifically to increase duration of plasma level for effective prophylaxis during a 12-24 hr period but would be effective in a 1 :20 ratio where 0.1 mg lofexidine is combined with 2 mg of nalmefene.

[0082] Naltrexone has a clinical dose range of 1-50 mg combined with an alpha 2 adrenergic agonist (i.e. lofexidine 0.1 -3 mg ) in a ratio between Lofexidine 1 :1 - 1 :70 Naltrexone and an ideal range of Lofexidine 1 :50 Naltrexone (e.g., 0.5 mg lofexidine / 25 mg naltrexone)

[0083] Naltrexone has a clinical dose range of 1-50 mg combined with an alpha 2 adrenergic agonist (i.e. lofexidine 0.1 -7 mg) in a ratio between Lofexidine 1 :1 - 1 :70 Naltrexone and an ideal range of Lofexidine 1 :50 Naltrexone (e.g., 0.5 mg lofexidine / 25 mg naltrexone) or in a smaller dose ratio that can be titrated to effect during a 24 hr period (e.g. 0.1 mg Lofexidine / 5 mg naltrexone) as a prophylaxis agent or pretreatment prior to fentanyl exposure in a pH balanced, pharmaceutical carrier solution suitable for human administration and administered via an (IM, IV, Intranasal, oral, transdermal) dosing delivery method as an effective prophylaxis agent against fentanyl overdose or FIVCC resulting from accidental ingestion, poisoning or toxic exposure. The higher dose of the alpha 2 agonist in this case of 0.5-1 mg for lofexidine is specifically to increase duration of plasma level for effective prophylaxis during a 12-24 hr period but would be effective in a 1 :250 ratio where 0.1 mg lofexidine is combined with 25 mg of naltrexone. Additional ranges are discussed below.

[0084] As new alpha 2 adrenergic agonists emerge, their potency relative to lofexidine and clonidine can be applied to determine appropriate ratios for use in combination with naloxone, nalmefene and naltrexone.

[0085] Table 1A Dexmedetomidine (Dex) 5 minute Pre-Treatment + Fentanyl 25 g / kg

[0086] Table 1 B Fentanyl 25 pg / kg + immediate (0 sec delay) Dexmedetomidine Rescue

[0087] As shown above, Dexmedetomidine at 0.1 mg / kg showed 100% survival with 5 min pretreatment (Table 1 A) and 75% survival with immediate rescue at the 0.1 mg / kg dose (Table 1 B).

[0088] Table 2: alpha 2 agonist (Xylazine) pretreatment effect on vocal cord closure withFentanyl (50 pg / kg)

[0089] Pretreatment with xylazine 30 seconds prior to IV fentanyl at 25 pg / kg showed no vocal cord closure (VCC) and 100% survival (Table 2), whereas 50 pg / kg showed no VCC in majority of animals but with no survival.

[0090] Data on Pre-exposure treatment for fentanyl toxic exposure (or overdose) and Postexposure treatment for fentanyl toxic exposure (or overdose), with formulations of mu-opioid receptor (Mu-OR) antagonists (with short and long half-lives) and alpha 2 adrenergic receptor (A2AR) agonists (with weak, moderate and strong binding affinity at A2AR-2A subtypes):

[0091] Fentanyl and related analogues (e.g., sufentanil, carfentanil, alfentanil, remifentanil) have atypical effects on the upper airway (vocal cords and laryngeal muscles) not seen with morphine opiates and not commonly known by researchers or practitioners in the field of opioid addiction and treatment. High dose fentanyls cause muscle rigidity (wooden chest syndrome-WCS) and induce laryngospasm (fentanyl-induced vocal cord closure-FIVCC) and dose ranges for these effects are well-defined in the anesthesiology clinical literature and considered highly lethal without immediate intervention. However, the mechanism for FIVCC has remained unknown until this disclosure. Our experimental data have confirmed that the class of drugs known as A2AR agonists, have proved generally effective in either prophylaxis against FIVCC or for reversal of FIVCC as single agents in human equivalent dose ranges (HED), at the fentanyl LDi00dose (25 pg / kg) in a translational (animal) model of fentanyl toxicity with FIVCC as the primary outcome variable. Of note, this LD o dose of fentanyl (25 pg / kg) in this model has been confirmed clinically to induce FIVCC in >95% of individuals exposed to this dose (25 pg / kg of fentanyl or equipotentdose of a fentanyl analogue). A2AR agonists vary in A2AR subtype receptor affinity (e.g., 2A, 2B, 2C) and this determines the efficacious dose range of a specific A2AR agonist to inhibit (prevent) or antagonize (reverse) the atypical effects of fentanyls (e.g., FIVCC).

[0092] Conversely, Mu-OR antagonists (e.g., naloxone, nalmefene), the “gold standard” treatment for opioid overdose reversal, are ineffective at HED to inhibit (prevent) or antagonize (reverse) the atypical effects of fentanyls (e.g., FIVCC) and at doses up to 100 times these HED (IV and IM) for reversal. This is due to the fact that FIVCC is mediated by non-opioid receptors.

[0093] However, we have found that when these two classes of drugs (A2AR agonists and mu- opioid receptor Mu-OR antagonists) are combined, they are between 50-80% more efficacious at increasing survival from FIVCC death than either agent alone, as they restore respiratory drive (Mu-OR mediated) and airway patency / reversal of FIVCC (A2AR mediated).

[0094] The optimal ratio of A2AR agonists with mu-opioid receptor (Mu-OR) antagonists will vary with the affinity of each agent at their respective targets. Our experimental data support the ratio examples listed in the following section divided into categories of:1 ) Weak A2AR agonist (>500 nM - 2500 nM binding affinity at the Alpha 2 AR - subtype 2A binding site);2) Moderate A2AR agonist (>50 nM - 500 nM binding affinity at Alpha 2 AR - subtype 2A binding site);3) Strong A2AR agonist (<50 nM binding affinity at Alpha 2 AR - subtype 2A binding site) (e.g., where 1 nM binding affinity > 50 nM); and(4) optimal subtype binding affinity ratio 2A: 2B ratio at: (2A) 1 -10 : 1 (2B) (e.g., (2A binding affinity 50 nM) 2:1 (2B binding affinity at 25 nM).

[0095] Ratios of A2AR agonists mu-opioid receptor Mu-OR antagonists may be influenced by: 1 ) binding affinity; 2) half-life; 3) treatment timing (pre or post fentanyl exposure) and 4) clinical effect (e.g., inhibition or antagonism of FIVCC and opioid-induced respiratory depression, prevention of re-narcotization and recurrence of FIVCC or WCS).

[0096] Categories of A2AR agonists: Ex. weak (e.g., xylazine), moderate (e.g., clonidine) and strong (e.g., lofexidine, dexmedetomidine).Weak A2AR agonist (>500 nM - 2500 nM at Alpha 2 AR - 2A binding)Prophylaxis (Pre-Treatment before fentanyl exposure) :

[0097] Indication: Reversal for short half-life opioids / opiates (e.g., <1-15 min half-life).

[0098] Weak A2AR agonist (>500 nM - 2500 nM) combined with Naloxone (short acting Mu-OR antagonist) = e.g., Xylazine 8 mg / kg : Naloxone 0.5 mg / kg

[0099] Ratio: Weak A2AR Ag 1 -16 : 1 Mu-OR antagonist

[0100] Ex: 1 -16 : 1 (e.g., 1 :1 , 2:1 , 3:1 , 4 :1 , up to 16:1 )

[0101] Indication: Reversal for long half-life opioids / opiates (e.g., > 15 min half-life)

[0102] Weak A2AR agonist (>500 nM - 2500 nM) combined with Nalmefene (long acting Mu-OR antagonist) = e.g., Xylazine 8 mg / kg : Nalmefene 0.075 mg / kg

[0103] Ratio: Weak A2AR Ag 1 -100 : 1 Mu-OR antagonist

[0104] (*Note: calculation converting naloxone to nalmefene is noted below and is based on the maximal HED for each drug from clinical literature and FDA regulatory guidelines on dosages of each drug).

[0105] Ex. HED Naloxone ( IV / IM dose: 0.1-10 mg for 70 kg adult) and Nalmefene ( IV / IM dose: 0.01 - 1.5 mg)

[0106] Max Naloxone (NLX) FDA approved IV dose for single administration period 10 mg / 1 .5 mg (maximal dose suggested by FDA regulatory guidelines for nalmefene-NF). NLX 10 mg / 1 .5 mg NF = *6.67 conversion factor. Conversion factor range based on single dose of each drug (Naloxone 2 mg IV / IM vs. Nalmefene 0.5 mg IV / IM) is NLX 2 mg / 0.5 mg NF and yields a factor of 4 with a range of 4-6.67.

[0107] Ex. Naloxone 10 mg / *6.67 = 1.499 mg Nalmefene or Naloxone 10 mg / *4 = 2.5 mg Nalmefene.Reversal:

[0108] Indication: Reversal for opioids / opiates.

[0109] Weak A2AR agonist (>500 nM - 2500 nM) combined with Naloxone = e.g., Xylazine (8 mg / kg) 16:1 Naloxone (0.5 mg / kg)

[0110] Ratio: Weak A2AR Agonist 1 -16 : 1 Mu-OR antagonist

[0111] Ex: 1-16 : 1 (e.g., 1 :1 , 2:1 , 3:1 , 4 :1 , up to 16:1 )

[0112] Indication: Reversal for opioids / opiates long half-life opioids / opiates with risk of renarcotization.

[0113] Reversal with Prophylaxis against re-narcotization and recurrence of FIVCC or WCS.Weak A2AR agonist (>500 nM - 2500 nM) combined with (c / w) Nalmefene (long acting Mu-OR antagonist) = e.g., Xylazine 8 mg / kg / 0.075—0.125 mg / kg Nalmefene.

[0114] Weak A2AR Agonist 50-100 : 1 Mu-OR antagonistModerate A2AR agonist (e.g., Clonidine)(>50 nM - 500 nM binding affinity at Alpha 2 AR - subtype 2A binding site) Prophylaxis:

[0115] Indication: prophylaxis for opioid / opiate overdose.

[0116] Moderate A2AR agonist (>50 nM - 500nM) combined with Naloxone (short acting Mu-OR antagonist) = e.g., Clonidine 0.15 mg / kg : Naloxone 0.5 mg / kg

[0117] Ratio: Moderate A2AR agonist 1 : 1 -34 Mu-OR antagonist

[0118] Indication: Reversal for opioids / opiates long half-life opioids / opiates with risk of renarcotization.

[0119] Moderate A2AR agonist (>50 nM - 500nM) combined with Nalmefene (long acting Mu- OR antagonist) = e.g., Clonidine (0.15 mg / kg) 2:1 Nalmefene (0.075 - 0.125 mg / kg).

[0120] Ratio: Moderate A2AR agonist 1 -10 : 1 Long acting Mu-OR antagonist

[0121] (e.g., 1:1, 2:1, 3:1, 4:1, 5:1 , 6:1 , 7:1 , 8:1 , 9:1 ,10:1 )Reversal:

[0122] Indication: Reversal for opioids / opiates overdose.

[0123] Moderate A2AR agonist (>50 nM - 500 nM) combined with Naloxone (short acting Mu- OR antagonist) = e.g., IV Clonidine 0.15 mg / kg : IV Naloxone 0.5 mg / kg. ‘Combo given at 45 sec yields > 80% survival.

[0124] Ratio: Moderate A2AR agonist 1 : 1 :34 Mu-OR antagonist

[0125] Indication: Reversal for opioids / opiates long half-life opioids / opiates with risk of renarcotization.

[0126] Reversal with continued Prophylaxis against re-narcotization and recurrence of FIVCC or WCS.

[0127] Moderate A2AR agonist (>50 nM - 500 nM) combined with (c / w) Nalmefene (long acting Mu-OR antagonist) = e.g., Clonidine (0.15 mg / kg) 2:1 Nalmefene (0.075 - 0.125 mg / kg).

[0128] Ratio: Moderate A2AR agonist 1-10 : 1 Long acting Mu-OR antagonistStrong A2AR agonist (<50 nM binding affinity at Alpha 2 AR - subtype 2A binding site) (e.g., where 1 nM binding affinity > 50 nM) ; (e.g., Lofexidine , Dexmedetomidine) Prophylaxis:

[0129] Indication: prophylaxis for opioid / opiate overdose.

[0130] Strong A2AR agonist (<50 nM binding affinity at Alpha 2 AR - subtype 2A binding site) combined with Naloxone (short acting Mu-OR antagonist) = e.g., Dexmedetomidine (0.01 mg / kg) 1 :10 Naloxone (0.1 - 0.5 mg / kg).

[0131] Ratio: Strong A2AR agonist 1 : 1-50 Mu-OR antagonist

[0132] Indication: prophylaxis for opioid / opiate overdose.

[0133] Strong A2AR agonist (<50 nM binding affinity at Alpha 2 AR - subtype 2A binding site) combined with Nalmefene (long acting Mu-OR antagonist) = e.g., Dexmedetomidine (0.01 mg / kg) 1 :1 Nalmefene (0.01 mg / kg).

[0134] Ratio: Strong A2AR agonist 1 -16: 1 Long acting Mu-OR antagonist (e.g., 1 :1 , 2:1 , 3:1 4:1 5:1 up to 16:1).Reversal:

[0135] Indication: Reversal for opioids / opiates overdose.

[0136] Strong A2AR agonist (<50 nM binding affinity at Alpha 2 AR - subtype 2A binding site) combined with Naloxone (short acting Mu-OR antagonist) = e.g., IV Lofexidine (0.015 mg / kg) 1 :33 IV Naloxone (0.5 mg / kg). *Combo yields >70% survival.

[0137] Ratio: Strong A2AR agonist 1 : 1 -166 Mu-OR antagonist (Ex. 1 : 5-40 e.g., 1 :5, 1 :10, 1 : 40. up to 1 :166)

[0138] Indication: Reversal for opioids / opiates overdose.

[0139] Reversal with continued Prophylaxis against re-narcotization and recurrence of FIVCC or WCS.

[0140] Strong A2AR agonist (<50 nM binding affinity at Alpha 2 AR - subtype 2A binding site) combined with Nalmefene (long acting Mu-OR antagonist) = e.g., Lofexidine (0.015 mg / kg) 1 :1 Nalmefene (0.015 mg / kg).

[0141] Ratio: Strong A2AR agonist 1 : 1-100 Long-acting Mu-OR antagonist (e.g.,. 1 : 1 , 1 :2, 1 :3 up to 1400)

[0142] Indication: Reversal for opioids / opiates overdose.

[0143] Strong A2AR agonist (<50 nM binding affinity at Alpha 2 AR - subtype 2A binding site) combined with Naloxone (short acting Mu-OR antagonist) = e.g., IV Dexmedetomidine (0.01 mg / kg) 1 :10 IV Naloxone (0.5 mg / kg).

[0144] Ratio: Strong A2AR agonist 1 : 1 -33 Mu-OR antagonist (Ex. 1 : 1 -33 e.g., 1 :1, 1 :2, 1 : 5, 1 :7 up 1 : 1 -33)

[0145] Indication: Reversal for opioids / opiates overdose.

[0146] Reversal with continued Prophylaxis against re-narcotization and recurrence of FIVCC or WCS.

[0147] Strong A2AR agonist (<50 nM binding affinity at Alpha 2 AR - subtype 2A binding site) combined with Nalmefene (long acting Mu-OR antagonist) = e.g., Dexmedetomidine (0.01 mg / kg) 1 :1 Nalmefene (0.01 mg / kg) or Dexmedetomidine (0.1 mg / kg) 10:1 Nalmefene (0.01 mg / kg).

[0148] Ratio: Strong A2AR agonist 1-20 : 1 Long-acting Mu-OR antagonist (Ex. 1-20 : 1 e.g., 1:1, 2:1, 3:1 , 4:1 , 10:1 up to 20:1 ).EXEMPLARY EMBODIMENTSEmbodiments Set 1:

[0149] 1. A formulation to treat (reverse) fentanyl overdose resulting in respiratory failure or airway obstruction (FIVCC). A therapeutic formulation consists of (as active ingredients) an alpha 2 adrenergic receptor agonist {e.g., lofexidine or clonidine) and a short acting mu opioid receptor antagonist e.g., naloxone) in selected ratio of an alpha 2 AR agonist (e.g., lofexidine) combined with naloxone in a ratio range of 1 :1 -1 :166, for instance using a dose ratio of Lofexidine 1 :40Naloxone (e.g., 0.145 mg lofexidine / 5.8 mg naloxone), which is combined in a pH balanced, pharmaceutical carrier solution suitable for human administration and administered via a suitable device (e.g., IM, IV, Intranasal).

[0150] 2. Lofexidine and naloxone combined to generate a range of formulations that include a combination of between 0.1 - 7 mg of lofexidine and 0.1 - 70 mg of naloxone. The dose of each agent in a formulation will be a minimum dose of 0.056 mg and maximum dose of 7 mg for lofexidine (0.0008 mg / kg - 0.1 mg / kg for a 70 kg adult) and 0.1 - 70 mg for naloxone (0.0014 mg / kg -1 mg / kg for a 70 kg adult). Ranges of HED are calculated from the range of efficacy of each drug in the animal model (e.g. naloxone effective dose range 0.035 mg / kg — 2 mg / kg).

[0151] 3. A formulation to treat (reverse) fentanyl overdose resulting in respiratory failure or airway obstruction (FIVCC). The therapeutic formulation consists of (as active ingredients) an alpha 2 adrenergic receptor agonist (e.g., clonidine) and a short acting mu opioid receptor antagonist (e.g., naloxone) in selected ratio of an alpha 2 adrenergic receptor agonist (e.g., clonidine) combined with naloxone in a 1 :1 ratio up to a 1 :34 ratio, for instance a dose ratio of 1 :10 (e.g., 0.58 mg clonidine / 5.8 mg naloxone), which is combined in a pH balanced, pharmaceutical carrier solution suitable for human administration and administered via an (e.g., IM, IV, Intranasal) dosing delivery method as a therapeutic treatment in the event of a fentanyl, F / FA or combination opiate overdose.

[0152] 4. Clonidine and naloxone are combined in one formulation with a range of formulations that include a combination between 0.05 - 14 mg for clonidine and 0.1 - 70 mg for naloxone. The dose of each agent in formulation will be a minimum of 0.05 mg and a maximum of 14 mg for clonidine (0.0007 mg / kg - 0.2 mg / kg for a 70 kg adult) and a minimum of 0.1 mg naloxone and a maximum of 70 mg for naloxone (0.0014 mg / kg -1 mg / kg for a 70 kg adult).

[0153] 5. A formulation for prophylaxis against fentanyl overdose or toxic exposure, wherein the therapeutic formulation consists of (as active ingredients) an alpha 2 adrenergic receptor agonist and a short acting (e.g., naloxone) or long acting (e.g., nalmefene) mu opioid receptor antagonist. In the case of adult (70 kg) clinical dosing, nalmefene can be administered in a broad dose range of 0.007 mg-35 mg, with an ideal dose range of 0.5 mg-1.5 mg, combined with an alpha 2 adrenergic agonist (i.e., lofexidine 0.1 -7 mg) in a ratio between Lofexidine 1 :1 Nalmefene - 1 :1 - 100 and an ideal range of Lofexidine 1 :1 Nalmefene - Lofexidine 1 :2 Nalmefene (e.g., 0.5-1 mg lofexidine / 1 -2 mg nalmefene) in a pH balanced, pharmaceutical carrier solution suitable for human administration and administered (e.g., via IM, IV, Intranasal, oral, transdermal dosing delivery method) as an effective prophylaxis agent against fentanyl overdose or FIVCC resulting from accidental ingestion, poisoning or toxic exposure.

[0154] 6. A formulation for a fentanyl opioid analgesic for medical use with prophylaxis against fentanyl overdose from FIVCC, wherein the therapeutic formulation consist of (as activeingredients) an alpha 2 adrenergic receptor agonist and a fentanyl opioid analgesic combined in ratio range of (1 :1 -1 :10) depending on the relative potency of the fentanyl analogue compared to fentanyl and the relative potency of the alpha 2 agonist compared to dexmedetomidine / lofexidine (e.g., lofexidine at 5 pg / kg combined with fentanyl at 25 pg / kg or Lofexidine (0.005 mg / kg) 1 :5 Fentanyl (0.25 mg / kg); the formulation delivered in a pH balanced, pharmaceutical carrier solution or delivery vehicle suitable for human administration and administered via an (IM, IV, Intranasal, oral, transdermal) dosing delivery method as an effective prophylaxis agent against fentanyl overdose or FIVCC resulting from accidental ingestion or overdose.

[0155] 7. An administration device for delivering a formulation as described herein in any embodiments, to treat (reverse) fentanyl overdose resulting in respiratory failure or airway obstruction (FIVCC), the device itself in embodiments involving a “dual injector” or insufflation device with separated active ingredients, a “single injector” or insufflation device with combined active ingredients, or a “single injector” or insufflation device with barrier separation of the active ingredients. In each case, the dosing and delivery method is to provide a therapeutic treatment in the event of a fentanyl, F / FA or combination opiate overdose.

[0156] 8. Alternatively, dosing of active ingredients can be separated as long as they are delivered concurrently and in the appropriate (described) ratio. In the case of oral dosing, active ingredients can be separated into blister packs or kits as long as they are delivered concurrently and in the appropriate ratio.Embodiments Set 2:

[0157] 1 . A composition including: lofexidine and naloxone in a ratio of 1 :5 to a ratio of 1 :40 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0158] 2. The composition of embodiment 1 , wherein the ratio of lofexidine to naloxone is 1 :5, 1 :10, or 1 :40 by weight.

[0159] 3. The composition of embodiment 1 , wherein the composition includes between 0.1 - 3 mg of lofexidine and 0.1 - 10 mg of naloxone.

[0160] 4. The composition of embodiment 1 , wherein the composition includes 0.145 mg lofexidine and 5.8 mg naloxone.

[0161] 5. The composition of embodiment 1 , wherein a single dose of the composition includes 0.075 pg to 3 mg of lofexidine (1 -50 pg / kg for a 60 kg adult) and 0.1 - 10 mg of naloxone (1 - 167 pg / kg for a 60 kg adult).

[0162] 6. The composition of any of embodiments 1-5, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0163] 7. Use of the composition of embodiment 1 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0164] 8. The use of embodiment 7, wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0165] 9. The use of embodiment 7, wherein the composition is provided in a dosage of 0.015 - 0.1 mg / kg lofexidine and 0.01 - 1 .5 mg / kg naloxone.

[0166] 10. A composition including: clonidine and naloxone in a ratio of 1 :2 to a ratio of 1 :6 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0167] 11. The composition of embodiment 10, wherein the ratio of clonidine to naloxone is 1 :2, 1 :3, 1 :4, or 1 :6 by weight.

[0168] 12. The composition of embodiment 10, wherein the composition includes between 0.1 - 3 mg of clonidine and 0.1 - 10 mg of naloxone.

[0169] 13. The composition of embodiment 10, wherein the composition includes 0.58 mg clonidine and 5.8 mg naloxone.

[0170] 14. The composition of embodiment 10, wherein a single dose of the composition includes 0.075 pg to 3 mg of clonidine (1-50 pg / kg for a 60 kg adult) and 0.5 - 10 mg of naloxone ( - 1- 167 pg / kg for a 60 kg adult).

[0171] 15. The composition of any of embodiments 10-14, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0172] 16. Use of the composition of embodiment 10 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0173] 17. The use of embodiment 16, wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0174] 18. The use of embodiment 16, wherein the composition is provided in a dosage of 0.01- 0.5 mg / kg clonidine and 0.01 - 1 .5 mg / kg naloxone.

[0175] 19. A composition including: lofexidine and nalmefene in a ratio of 1 :1 to a ratio of 4:1 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0176] 20. The composition of embodiment 19, wherein the ratio of lofexidine to nalmefene is 1 :1 , 2:1 or 4:1 by weight.

[0177] 21 . The composition of embodiment 19, wherein a single dose of the composition includes 0.9 mg to 2.4 mg of lofexidine (0.015 - 0.04 mg / kg for a 60 kg adult) and 0.6 - 1.2 mg of nalmefene (0.01 - 0.02 mg / kg for a 60 kg adult).

[0178] 22. The composition of any of embodiments 19-21 , wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0179] 23. Use of the composition of embodiment 19 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0180] 24. The use of embodiment 23, wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0181] 25. The use of embodiment 23, wherein the composition is provided in a dosage of 0.015- 0.1 mg / kg lofexidine and 0.001 - 0.2 mg / kg nalmefene.

[0182] 26. A composition including: lofexidine and naltrexone in a ratio of 1 :1 to a 1 :70 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0183] 27. The composition of embodiment 26, wherein the ratio of lofexidine to naltrexone is 1 :5, 1 :10, 1 :20, 1 :30, 1 :40, or 1 :50 by weight.

[0184] 28. The composition of embodiment 26, wherein the composition includes between 0.5 mg of lofexidine and 25 mg of naltrexone.

[0185] 29. The composition of embodiment 26, wherein the composition includes 0.58 mg lofexidine and 5.8 mg naltrexone.

[0186] 30. The composition of any of embodiments 26-29, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0187] 31 . Use of the composition of embodiment 26 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0188] 32. The use of embodiment 31 , wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0189] 33. A composition including: clonidine and nalmefene in a ratio of 5:1 to a ratio of 10:1 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0190] 34. The composition of embodiment 33, wherein the ratio of clonidine to nalmefene is 5:1 , 6:1 , 7:1 , 8:1 , 9:1 , or 10:1 by weight.

[0191] 35. The composition of embodiment 33, wherein a single dose of the composition includes 9 mg of clonidine (0.15 mg / kg for a 60 kg adult) and 1.2 mg of nalmefene (0.02 mg / kg for a 60 kg adult).

[0192] 36. The composition of any of embodiments 33-35, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0193] 37. Use of the composition of embodiment 33 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0194] 38. The use of embodiment 37, wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0195] 39. The use of embodiment 37, wherein the composition is provided in a dosage of 0.01- 0.5 mg / kg clonidine and 0.001 - 0.2 mg / kg nalmefene.

[0196] 40. A composition including: dexmedetomidine and nalmefene in a ratio of 1 :5 to a ratio of 1 :10 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0197] 41. The composition of embodiment 40, wherein the ratio of dexmedetomidine to nalmefene is 1 :5, 1 :7, or 1 :10 by weight.

[0198] 42. The composition of embodiment 40, wherein a single dose of the composition includes 6 mg of dexmedetomidine (0.1 mg / kg for a 60 kg adult) and 0.6 - 1 .2 mg of nalmefene (0.01 - 0.02 mg / kg for a 60 kg adult).

[0199] 43. The composition of any of embodiments 40-42, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0200] 44. Use of the composition of embodiment 40 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0201] 45. The use of embodiment 44, wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0202] 46. The use of embodiment 44, wherein the composition is provided in a dosage of 0.01- 0.5 mg / kg dexmedetomidine and 0.001 - 0.2 mg / kg nalmefene.

[0203] 47. A composition including: dexmedetomidine and naloxone in a ratio of 1 :2 to a ratio of 1 :5 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0204] 48. The composition of embodiment 47, wherein the ratio of dexmedetomidine to naloxone is 1 :2, 1 :3, 1 :4, or 1 :5 by weight.

[0205] 49. The composition of embodiment 47, wherein a single dose of the composition includes 6 mg of dexmedetomidine (0.1 mg / kg for a 60 kg adult) and 50 - 100 mg of naloxone (0.25 - 0.5 mg / kg for a 60 kg adult).

[0206] 50. The composition of any of embodiments 47-49, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0207] 51 . Use of the composition of embodiment 47 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0208] 52. The use of embodiment 51 , wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0209] 53. The use of embodiment 51 , wherein the composition is provided in a dosage of 0.01- 0.5 mg / kg dexmedetomidine and 0.01 - 1 .5 mg / kg naloxone.

[0210] 54. A composition including: dexmedetomidine and naloxone in a ratio of 1 :1 to a ratio of 1 :7 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0211] 55. The composition of embodiment 54, wherein the ratio of dexmedetomidine to naloxone is 1 :1 , 1 :2, 1 :3, 1 :4, or 1 :7 by weight.

[0212] 56. The composition of embodiment 54, wherein a single dose of the composition includes 4.5 mg to 9 mg of dexmedetomidine (0.075 - 0.15 mg / kg for a 60 kg adult) and 15 - 30 mg of naloxone (0.25 - 0.5 mg / kg for a 60 kg adult).

[0213] 57. The composition of any of embodiments 54-56, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0214] 58. Use of the composition of embodiment 54 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0215] 59. The use of embodiment 58, wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0216] 60. The use of embodiment 58, wherein the composition is provided in a dosage of 0.075 - 0.15 mg / kg dexmedetomidine and 0.01 - 1 .5 mg / kg naloxone.

[0217] 61. A composition including: dexmedetomidine and nalmefene in a ratio of 3:1 to a ratio of 20:1 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0218] 62. The composition of embodiment 61 , wherein the ratio of dexmedetomidine to nalmefene is 3:1 , 4:1 , 10:1 , or 20:1 by weight.

[0219] 63. The composition of embodiment 61 , wherein a single dose of the composition includes 4.5 mg to 9 mg of dexmedetomidine (0.075 - 0.15 mg / kg for a 60 kg adult) and 0.6 - 1 .2 mg of nalmefene (0.01 - 0.02 mg / kg for a 60 kg adult).

[0220] 64. The composition of any of embodiments 61 -63, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0221] 65. Use of the composition of embodiment 61 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0222] 66. The use of embodiment 65, wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0223] 67. The use of embodiment 65, wherein the composition is provided in a dosage of 0.075 - 0.15 mg / kg dexmedetomidine and 0.001 - 0.2 mg / kg nalmefene.Embodiments Set 3:

[0224] 1 . A composition including: lofexidine and naloxone in a ratio of 1 :1 to a ratio of 1 :166 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0225] 2. The composition of embodiment 1 , wherein the ratio of lofexidine to naloxone is 1 :1 , 1 :5, 1 :10, 1 :40 up to 1 :166 by weight.

[0226] 3. The composition of embodiment 1 , wherein the composition includes between 0.056 - 7 mg of lofexidine and 0.1 - 70 mg of naloxone.

[0227] 4. The composition of embodiment 1 , wherein the composition includes 0.145 mg lofexidine and 5.8 mg naloxone.

[0228] 5. The composition of claim 1 , wherein a single dose of the composition comprises 0.05 mg to 7 mg of lofexidine (0.0007 - 0.1 mg / kg for a 70 kg adult) and 0.1-70 mg of naloxone (0.0014 -1 mg / kg for a 70 kg adult).

[0229] 6. The composition of any of embodiments 1-5, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0230] 7. Use of the composition of embodiment 1 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0231] 8. The use of embodiment 7, wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0232] 9. A combination composition as described herein, and / or use of that combination composition in reversing or preventing (e.g., through pretreatment) one or more symptoms of opioid or opiate overdose.

[0233] 10. A composition including: clonidine and naloxone in a ratio of 1 :1 to a ratio of 1 :34 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0234] 11 . The composition of embodiment 10, wherein the ratio of clonidine to naloxone is 1 :1 , 1 :2, 1 :3, 1 :4, or up to 1 :34 by weight.

[0235] 12. The composition of embodiment 10, wherein the composition includes between 0.5 - 3 mg of clonidine and 0.1 - 70 mg of naloxone.

[0236] 13. The composition of embodiment 10, wherein the composition includes 0.56 mg clonidine and 5.8 mg naloxone.

[0237] 14. The composition of embodiment 10, wherein a single dose of the composition includes 0.05 mg to 3 mg of clonidine (0.0007 mg / kg -0.043 mg / kg for a 70 kg adult) and 0.1- 70 mg of naloxone (0.0014 mg / kg - 1 mg / kg for a 70 kg adult).

[0238] 15. The composition of any of embodiments 10-14, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0239] 16. Use of the composition of embodiment 10 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0240] 17. The use of embodiment 16, wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0241] 18. The use of embodiment 16, wherein the composition is provided in a dosage of 0.008 - 0.175 mg / kg clonidine and 0.005 - 1 .5 mg / kg naloxone.

[0242] 19. A composition including: lofexidine and nalmefene in a ratio of 1 :1 to a ratio of '1 :100 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0243] 20. The composition of embodiment 19, wherein the ratio of lofexidine to nalmefene is 1 :1 , 1 :2, 1 : 20 or up to 1 :100 by weight.

[0244] 21. The composition of embodiment 19, wherein a single dose of the composition comprises 0.05 mg to 7 mg of lofexidine (0.0008 mg / kg - 0.1 mg / kg for a 70 kg adult) and 0.056 to 35 mg of nalmefene (0.0008 mg / kg - 0.5 mg / kg for a 70 kg adult).

[0245] 22. The composition of any of embodiments 19-21 , wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0246] 23. Use of the composition of embodiment 19 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0247] 24. The use of embodiment 23, wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0248] 25. The use of embodiment 23, wherein the composition is provided in a dosage of 0.0008 - 0.1 mg / kg lofexidine and 0.0008 mg / kg - 0.5 mg / kg nalmefene.

[0249] 26. A composition including: lofexidine and naltrexone in a ratio of 1 :1 to a 1 :250 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0250] 27. The composition of embodiment 26, wherein the ratio of lofexidine to naltrexone is 1 :5, 1 :10, 1 :20, 1 :30, 1 :40, 1 :50 or up to 1 :250 by weight.

[0251] 28. The composition of embodiment 26, wherein the composition includes between 0.1 mg of lofexidine and 5 mg of naltrexone.

[0252] 29. The composition of embodiment 26, wherein the composition includes 0.58 mg lofexidine and 5.8 mg naltrexone.

[0253] 30. The composition of any of embodiments 26-29, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0254] 31 . Use of the composition of embodiment 26 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0255] 32. The use of embodiment 31 , wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0256] 33. A composition including: clonidine and nalmefene in a ratio of 1 :1 to a ratio of 10:1 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0257] 34. The composition of embodiment 33, wherein the ratio of clonidine to nalmefene is 1 :1 , 2:1 , 3:1 , 4:1 , 5:1 , 6:1 , 7:1 , 8:1 , 9:1 , or 10:1 by weight.

[0258] 35. The composition of embodiment 33, wherein a single dose of the composition comprises 0.05 mg to 3 mg of clonidine (0.0007- 0.04 mg / kg for a 70 kg adult) and 0.056 to 35 mg of nalmefene (0.0008 mg / kg - 0.5 mg / kg for a 70 kg adult).

[0259] 36. The composition of any of embodiments 33-35, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0260] 37. Use of the composition of embodiment 33 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0261] 38. The use of embodiment 37, wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0262] 39. The use of embodiment 37, wherein the composition is provided in a dosage of 0.008 - 0.2 mg / kg clonidine and 0.0008-0.05 mg / kg of nalmefene.

[0263] 40. A composition for Reversal including: dexmedetomidine and nalmefene in a ratio of 1 :1 to a ratio of 20:1 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0264] 41 . The composition of embodiment 40, wherein the ratio of dexmedetomidine to nalmefene is 1 :1 , 2:1 , 3:1 4:1 , 5:1 , 6:1 , 7:1 , 8:1 , 9:1 , 10:1 and all ratios up to 20:1 by weight.

[0265] 42. The composition of embodiment 40, wherein a single dose of the composition comprises 0.2 mg to 35 mg of dexmedetomidine (0.003 mg / kg-0.5 mg / kg for a 70 kg adult) and 0.056 to 35 mg of nalmefene (0.0008 mg / kg - 0.5 mg / kg for a 70 kg adult).

[0266] 43. The composition of any of embodiments 40-42, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0267] 44. Use of the composition of embodiment 40 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0268] 45. The use of embodiment 44, wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0269] 46. The use of embodiment 44, wherein the composition for Reversal is provided in a dosage of 0.003 - 0.5 mg / kg dexmedetomidine and 0.0008- 0.5 mg / kg nalmefene.

[0270] 47. A composition for Reversal including: dexmedetomidine and naloxone in a ratio of 1 :1 to a ratio of 1 :33 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0271] 48. The composition of embodiment 47, wherein the ratio of dexmedetomidine to naloxone is 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 :10, 1 :1 1 and all ratios up to 1 :33 by weight.

[0272] 49. The composition of embodiment 47, wherein a single dose of the composition comprises 0.2 mg to 35 mg of dexmedetomidine (0.003 mg / kg-0.5 mg / kg for a 70 kg adult) and 0.1 - 70 mg of naloxone (0.001 - 1 .5 mg / kg for a 70 kg adult).

[0273] 50. The composition of any of embodiments 47-49, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0274] 51 . Use of the composition of embodiment 47 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0275] 52. The use of embodiment 51 , wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0276] 53. The use of embodiment 51 , wherein the composition for Reversal is provided in a dosage of 0.003 mg / kg-0.5 mg / kg dexmedetomidine and 0.001 - 1 .5 mg / kg of naloxone.

[0277] 54. A composition for Pretreatment including: dexmedetomidine and naloxone in a ratio of 1 :1 to a ratio of 1 :50 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0278] 55. The composition of claim 54, wherein the ratio of dexmedetomidine to naloxone is 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9 or up to 1 :1 -50 by weight.

[0279] 56. The composition of claim 54, wherein a single dose of the composition comprises 0.42 mg to 35 mg of dexmedetomidine (0.006 - 0.5 mg / kg for a 70 kg adult) and 15 - 30 mg of naloxone (0.001 - 1 .5 mg / kg of naloxone for a 70 kg adult).

[0280] 57. The composition of any of embodiments 54-56, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0281] 58. Use of the composition of embodiment 54 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0282] 59. The use of embodiment 58, wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0283] 60. The use of embodiment 58, wherein the composition is provided in a dosage of 0.006 - 0.5 mg / kg dexmedetomidine and 0.001 - 1 .5 mg / kg naloxone.

[0284] 61 . A composition for Pretreatment including: dexmedetomidine and nalmefene in a ratio of 1 :1 to a ratio of 16:1 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0285] 62. The composition of embodiment 61 , wherein the ratio of dexmedetomidine to nalmefene is 1 :1 , 2:1 , 3:1 , 4:1 , 10:1 , and all ratios up to 16:1 by weight.

[0286] 63. The composition of embodiment 61 , wherein a single dose of the composition comprises 0.42 mg to 35 mg of dexmedetomidine (0.006 - 0.5 mg / kg for a 70 kg adult) and 0.056 to 35 mg of nalmefene (0.0008 mg / kg - 0.5 mg / kg for a 70 kg adult).

[0287] 64. The composition of any of embodiments 61 -63, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0288] 65. Use of the composition of embodiment 61 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0289] 66. The use of embodiment 65, wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0290] 67. The use of embodiment 65, wherein the composition for Pretreatment is provided in a dosage of 0.006 - 0.5 mg / kg dexmedetomidine and 0.0008 - 0.5 mg / kg nalmefene.Embodiments Set 4:

[0291] 1. A composition formulated for use in reversing or preventing at least one symptom of fentanyl overdose in a human subject, the composition including: a therapeutic drug combination selected from the group consisting of: 0.5 mg lofexidine (LFX) and 5 mg naloxone (NLX); 0.5 mg LFX and 1 mg nalmefene (NF); 0.2 mg clonidine (CLON) and 5 mg NLX; 0.2 mg CLON and 1 mg NF; 0.1 mg dexmedetomidine (DEX) and 5 mg NLX; and 0.1 mg DEX and 1 mg NF; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0292] 2. A composition including: lofexidine and naloxone in a ratio of 1 :1 to a ratio of 1 :166 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0293] 3. The composition of embodiment 2, wherein the ratio of lofexidine to naloxone is 1 :5 to 1 :40.

[0294] 4. The composition of embodiment 2, wherein the ratio of lofexidine to naloxone is 1 :1 , 1 :5, 1 :10, 1 :20, 1 :30, 1 :40, 1 :75, 1 :85, 1 :100, 1 :110, 1 :125, 1 :140, 1 :150, 1 :160, or 1 :166 by weight.

[0295] 5. The composition of embodiment 2, wherein the composition includes 0.056 - 7 mg of lofexidine and 0.1 - 70 mg of naloxone.

[0296] 6. The composition of embodiment 2, wherein the composition includes: 0.1 - 3 mg lofexidine; or 0.1 - 7 mg naloxone; or both 0.1 - 3 mg lofexidine and 0.1 - 7 mg naloxone.

[0297] 7. The composition of embodiment 2, wherein the composition includes 0.145 mg lofexidine and 5.8 mg naloxone.

[0298] 8. The composition of embodiment 2, wherein a single dose of the composition includes 0.05 mg to 7 mg of lofexidine (0.0007 mg / kg - 0.1 mg / kg for a 70 kg adult) and 0.1 - 70 mg of naloxone (0.0014 - 1 mg / kg for a 70 kg adult).

[0299] 9. The composition of embodiment 2, wherein a single dose of the composition includes 0.075 pg to 3 mg of lofexidine (1 -50 pg / kg for a 60 kg adult) and 0.1 - 10 mg of naloxone (1 - 167 pg / kg for a 60 kg adult).

[0300] 10. The composition of any of embodiments 2-9, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0301] 11 . Use of the composition of embodiment 2 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0302] 12. The use of embodiment 11 , wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0303] 13. The use of embodiment 11 , wherein the composition is provided in a dosage of 0.0008- 0.1 mg / kg lofexidine and 0.005 - 1 .5 mg / kg naloxone.

[0304] 14. The use of embodiment 11 , wherein the composition is provided in a dosage of 0.015- 0.1 mg / kg lofexidine and 0.01 - 1.5 mg / kg naloxone.

[0305] 15. A composition including: clonidine and naloxone in a ratio of 1 :1 to a ratio of 1 :34 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0306] 16. A composition including: clonidine and naloxone in a ratio of 1 :2 to a ratio of 1 :6 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0307] 17. The composition of embodiment 15, wherein the ratio of clonidine to naloxone is 1 :1 , 1 :2, 1 :3, 1 :4, or up to 1 :34 by weight.

[0308] 18. The composition of embodiment 15, wherein the composition includes 0.05 - 3 mg of clonidine and 0.1 - 70 mg of naloxone.

[0309] 19. The composition of embodiment 15, wherein the composition includes 0.1 - 3 mg of clonidine and 0.1 - 10 mg of naloxone.

[0310] 20. The composition of embodiment 15, wherein the composition includes 0.56 mg clonidine and 5.8 mg naloxone.

[0311] 21. The composition of embodiment 15, wherein the composition includes 0.58 mg clonidine and 5.8 mg naloxone.

[0312] 22. The composition of embodiment 15, wherein a single dose of the composition includes 0.05 mg to 3 mg of clonidine (0.0007 mg / kg - 0.043 mg / kg for a 70 kg adult) and 0.1 - 70 mg of naloxone (0.0014 mg / kg - 1 mg / kg for a 70 kg adult).

[0313] 23. The composition of embodiment 15, wherein a single dose of the composition includes 0.075 g to 3 mg of clonidine (1 -50 pg / kg for a 60 kg adult) and 0.5 - 10 mg of naloxone (1 - 167 pg / kg for a 60 kg adult).

[0314] 24. The composition of any of embodiments 15-23, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0315] 25. Use of the composition of embodiment 15 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0316] 26. The use of embodiment 25, wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0317] 27. The use of embodiment 25, wherein the composition is provided in a dosage of 0.008- 0.175 mg / kg clonidine and 0.005 - 1 .5 mg / kg naloxone.

[0318] 28. The use of embodiment 25, wherein the composition is provided in a dosage of 0.01- 0.5 mg / kg clonidine and 0.01 - 1 .5 mg / kg naloxone.

[0319] 29. A composition including: lofexidine and nalmefene in a ratio of 1 :1 to a ratio of 1 :100 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0320] 30. A composition including: lofexidine and nalmefene in a ratio of 1 :1 to a ratio of 4:1 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0321] 31. The composition of embodiment 29, wherein the ratio of lofexidine to nalmefene is 1 :1 , 1 :2, 1 :20 or 1 :100 by weight.

[0322] 32. The composition of embodiment 29, wherein the ratio of lofexidine to nalmefene is 4:1 by weight.

[0323] 33. The composition of embodiment 29, wherein a single dose of the composition includes 0.05 mg to 7 mg of lofexidine (0.0008 mg / kg - 0.1 mg / kg for a 70 kg adult) and 0.056 to 35 mg of nalmefene (0.0008 mg / kg - 0.5 mg / kg for a 70 kg adult).

[0324] 34. The composition of embodiment 29, wherein a single dose of the composition includes 0.9 mg to 2.4 mg of lofexidine (0.015 - 0.04 mg / kg for a 60 kg adult) and 0.6 - 1.2 mg of nalmefene (0.01 - 0.02 mg / kg for a 60 kg adult).

[0325] 35. The composition of any of embodiments 29-34, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0326] 36. Use of the composition of embodiment 29 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0327] 37. The use of embodiment 36, wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0328] 38. The use of embodiment 36, wherein the composition is provided in a dosage of 0.0008- 0.1 mg / kg lofexidine and 0.0008 mg / kg - 0.5 mg / kg nalmefene.

[0329] 39. The use of embodiment 36, wherein the composition is provided in a dosage of 0.015- 0.1 mg / kg lofexidine and 0.001 - 0.2 mg / kg nalmefene.

[0330] 40. A composition including: lofexidine and naltrexone in a ratio of 1 :1 to a 1 :250 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0331] 41 . A composition including: lofexidine and naltrexone in a ratio of 1 :1 to a 1 :70 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0332] 42. The composition of embodiment 40, wherein the ratio of lofexidine to naltrexone is 1 :5, 1 :10, 1 :20, 1 :30, 1 :40, 1 :50, 1 :75, 1 :100, 1 :125, 1 :150, 1 :175, 1 :200, 1 :225, or 1 :250 by weight.

[0333] 43. The composition of embodiment 40, wherein the composition includes 0.05 mg to 7 mg of lofexidine (0.0008 mg / kg - 0.1 mg / kg for a 70 kg adult) and 5 mg to 50 mg of naltrexone (0.07 mg / kg - 0.7 mg / kg for a 70 kg adult).

[0334] 44. The composition of embodiment 40, wherein the composition includes 0.5 mg of lofexidine and 25 mg of naltrexone.

[0335] 45. The composition of embodiment 40, wherein the composition includes 0.1 mg lofexidine and 5 mg naltrexone.

[0336] 46. The composition of embodiment 40, wherein the composition includes 0.58 mg lofexidine and 5.8 mg naltrexone.

[0337] 47. The composition of any of embodiments 40-45, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0338] 48. Use of the composition of embodiment 40 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0339] 49. The use of embodiment 48, wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0340] 50. A composition including: clonidine and nalmefene in a ratio of 1 :1 to a ratio of 10:1 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0341] 51 . A composition including: clonidine and nalmefene in a ratio of 5:1 to a ratio of 10:1 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0342] 52. The composition of embodiment 50, wherein the ratio of clonidine to nalmefene is 1 :1 , 2:1 , 3:1 , 4:1 , 5:1 , 6:1 , 7:1 , 8:1 , 9:1 , or 10:1 by weight.

[0343] 53. The composition of embodiment 50, wherein a single dose of the composition includes 0.05 mg to 3 mg of clonidine (0.0007 - 0.04 mg / kg for a 70 kg adult) and 0.056 to 35 mg of nalmefene (0.0008 mg / kg - 0.5 mg / kg for a 70 kg adult).

[0344] 54. The composition of embodiment 50, wherein a single dose of the composition includes 9 mg of clonidine (0.15 mg / kg for a 60 kg adult) and 1 .2 mg of nalmefene (0.02 mg / kg for a 60 kg adult).

[0345] 55. The composition of any of embodiments 50-54, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0346] 56. Use of the composition of embodiment 50 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0347] 57. The use of embodiment 56, wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0348] 58. The use of embodiment 56, wherein the composition is provided in a dosage of 0.008- 0.2 mg / kg clonidine and 0.0008 - 0.5 mg / kg nalmefene.

[0349] 59. The use of embodiment 56, wherein the composition is provided in a dosage of 0.01- 0.5 mg / kg clonidine and 0.001 - 0.2 mg / kg nalmefene.

[0350] 60. A composition including: dexmedetomidine and nalmefene in a ratio of 1 :1 to a ratio of 20:1 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0351] 61. A composition including: dexmedetomidine and nalmefene in a ratio of 1 :5 to a ratio of 1 :10 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0352] 62. The composition of embodiment 60, wherein the ratio of dexmedetomidine to nalmefene is 1 :1 , 2:1 , 3:1 4:1 , 5:1 , 6:1 , 7:1 , 8:1 , 9:1 , 10:1 and all ratios up to 20:1 by weight.

[0353] 63. The composition of embodiment 60, wherein a single dose of the composition includes 0.2 mg to 35 mg of dexmedetomidine (0.003 mg / kg - 0.5 mg / kg for a 70 kg adult) and 0.056 to 35 mg of nalmefene (0.0008 mg / kg - 0.5 mg / kg for a 70 kg adult).

[0354] 64. The composition of embodiment 60, wherein a single dose of the composition includes 6 mg of dexmedetomidine (0.1 mg / kg for a 60 kg adult) and 0.6 - 1 .2 mg of nalmefene (0.01 - 0.02 mg / kg for a 60 kg adult).

[0355] 65. The composition of any of embodiments 60-64, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0356] 66. Use of the composition of embodiment 60 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0357] 67. The use of embodiment 66, wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0358] 68. The use of embodiment 66, wherein the composition is provided in a dosage of 0.003- 0.5 mg / kg dexmedetomidine and 0.0008 - 0.5 mg / kg nalmefene.

[0359] 69. The use of embodiment 66, wherein the composition is provided in a dosage of 0.01- 0.5 mg / kg dexmedetomidine and 0.001 - 0.2 mg / kg nalmefene.

[0360] 70. Use of the composition of embodiment 60 as a reversal therapy in response to a fentanyl, F / FA or combination opiate overdose.

[0361] 71 . A composition including: dexmedetomidine and naloxone in a ratio of 1 :1 to a ratio of 1 :33 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0362] 72. A composition including: dexmedetomidine and naloxone in a ratio of 1 :2 to a ratio of 1 :5 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0363] 73. The composition of embodiment 71 , wherein the ratio of dexmedetomidine to naloxone is 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 :10, 1 :11 and all ratios up to 1 :33 by weight.

[0364] 74. The composition of embodiment 71 , wherein a single dose of the composition includes 0.2 mg to 35 mg of dexmedetomidine (0.003 mg / kg - 0.5 mg / kg for a 70 kg adult) and 0.1 - 70 mg of naloxone (0.001 - 1 .5 mg / kg for a 70 kg adult).

[0365] 75. The composition of embodiment 71 , wherein a single dose of the composition includes 6 mg of dexmedetomidine (0.1 mg / kg for a 60 kg adult) and 50 - 100 mg of naloxone (0.25 - 0.5 mg / kg for a 60 kg adult).

[0366] 76. The composition of any of embodiments 71-74, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0367] 77. Use of the composition of embodiment 71 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0368] 78. The use of embodiment 77, wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0369] 79. The use of embodiment 77, wherein the composition is provided in a dosage of 0.003 mg / kg -0.5 mg / kg dexmedetomidine and 0.001 - 1 .5 mg / kg of naloxone.

[0370] 80. The use of embodiment 77, wherein the composition is provided in a dosage of 0.01 - 0.5 mg / kg dexmedetomidine and 0.01 - 1 .5 mg / kg naloxone.

[0371] 81. Use of the composition of embodiment 71 as a reversal therapy in response to a fentanyl, F / FA or combination opiate overdose.

[0372] 82. A composition including: dexmedetomidine and naloxone in a ratio of 1 :1 to a ratio of 1 :50 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0373] 83. A composition including: dexmedetomidine and naloxone in a ratio of 1 :1 to a ratio of 1 :7 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0374] 84. The composition of embodiment 82, wherein the ratio of dexmedetomidine to naloxone is 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9 or 1 :10 up to 1 :50 by weight.

[0375] 85. The composition of embodiment 82, wherein a single dose of the composition includes 0.42 mg to 35 mg of dexmedetomidine (0.006 - 0.5 mg / kg for a 70 kg adult) and 15 - 30 mg of naloxone (0.001 - 1 .5 mg / kg of naloxone for a 70 kg adult).

[0376] 86. The composition of embodiment 82, wherein a single dose of the composition includes 4.5 mg to 9 mg of dexmedetomidine (0.075 - 0.15 mg / kg for a 60 kg adult) and 15 - 30 mg of naloxone (0.25 - 0.5 mg / kg for a 60 kg adult).

[0377] 87. The composition of any of embodiments 82-85, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0378] 88. Use of the composition of embodiment 82 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0379] 89. The use of embodiment 88, wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0380] 90. The use of embodiment 88, wherein the composition is provided in a dosage of 0.006- 0.5 mg / kg dexmedetomidine and 0.001 - 1 .5 mg / kg naloxone.

[0381] 91 . The use of embodiment 88, wherein the composition is provided in a dosage of 0.075 - 0.15 mg / kg dexmedetomidine and 0.01 - 1 .5 mg / kg naloxone.

[0382] 92. Use of the composition of embodiment 82 as a pretreatment therapy in response to a fentanyl, F / FA or combination opiate overdose.

[0383] 93. A composition including: dexmedetomidine and nalmefene in a ratio of 1 :1 to a ratio of 16:1 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0384] 94. A composition including: dexmedetomidine and nalmefene in a ratio of 3:1 to a ratio of 20:1 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

[0385] 95. The composition of embodiment 94, wherein the ratio of dexmedetomidine to nalmefene is 1 :1 , 2:1 , 3:1 , 4:1 , 10:1 , and all ratios up to 16:1 by weight.

[0386] 96. The composition of embodiment 94, wherein a single dose of the composition includes 0.42 mg to 35 mg of dexmedetomidine (0.006 - 0.5 mg / kg for a 70 kg adult) and 0.056 to 35 mg of nalmefene (0.0008 mg / kg - 0.5 mg / kg for a 70 kg adult).

[0387] 97. The composition of embodiment 94, wherein a single dose of the composition includes 4.5 mg to 9 mg of dexmedetomidine (0.075 - 0.15 mg / kg for a 60 kg adult) and 0.6 - 1 .2 mg of nalmefene (0.01 - 0.02 mg / kg for a 60 kg adult).

[0388] 98. The composition of any of embodiments 94-97, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

[0389] 99. Use of the composition of embodiment 94 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

[0390] 100. The use of embodiment 99, wherein the composition is administered intramuscularly, intravenously, or intranasally.

[0391] 101 . The use of embodiment 99, wherein the composition is provided in a dosage of 0.006- 0.5 mg / kg dexmedetomidine and 0.0008 - 0.5 mg / kg nalmefene.

[0392] 102. The use of embodiment 99, wherein the composition is provided in a dosage of 0.006- 0.5 mg / kg dexmedetomidine and 0.0008 - 0.5 mg / kg nalmefene.

[0393] 103. Use of the composition of embodiment 94 as a pretreatment therapy in response to a fentanyl, F / FA or combination opiate overdose.Clonidine Pretreatment and Reversal of Fentanyl overdose or toxicity:

[0394] Clonidine (CD) and Naloxone (NLX):

[0395] Based on preclinical data and Human Equivalency Dosing, the a2-adrenergic receptor agonist -Clonidine can be combined with Mu opioid receptor antagonist Naloxone (NLX) in a ratio of 1 part clonidine (CD) to 1 -34 parts naloxone.

[0396] The ratio range for this formulation: CD 1 :1 -34 NLX {e.g., 1 :1 , 1 :2,1 :3, 1 :4, or up to 1 :34.

[0397] This ratio can be used for either “pre-treatment” (Prophylaxis before fentanyl exposure) or “Reversal” (treatment after fentanyl exposure). See Chart for actual dose ranges in mg / kg for IV and IM use.

[0398] Clonidine (CD) and Nalmefene (NF):

[0399] In fentanyl overdose or toxicity exposure where a Mu opioid receptor antagonist with a long half-life is required {e.g., Nalmefene), the ratio will change based on the potency of the Mu opioid receptor antagonist. In this case, 1 -10 parts of clonidine can be combined with 1 part nalmefene (NF).The ratio range for this formulation: CD 1 -10 : 1 NF {e.g., 1 :1 , 2:1 , 3:1 , 4:1 , 5:1 , 6:1 , 7:1 , 8:1 , 9:1 , or 10:1 by weight).

[0400] This ratio can be used for either “pre-treatment” (Prophylaxis before fentanyl exposure) or “Reversal” (treatment after fentanyl exposure). See Chart for actual dose ranges in mg / kg for IV and IM use.Dexmedetomidine Pre-Treatment of Fentanyl overdose or toxicity:

[0401] Dexmedetomidine. (DEX) and Naloxone (NLX):

[0402] Other examples of a2-adrenergic receptor agonists based on preclinical data and Human Equivalency Dosing include Lofexidine and Dexmedetomidine.

[0403] Pre-Treatment (Prophylaxis before fentanyl exposure) with Dexmedetomidine with naloxone. Dexmedetomidine can be combined with Mu opioid receptor antagonist Naloxone (NLX) in a ratio of 1 part Dexmedetomidine (DEX) to 1 - 50 parts naloxone .

[0404] The ratio range for this formulation: DEX 1 : 2-5 NLX {e.g., 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 :10 up to 1 :50 by weight).

[0405] This ratio can be used for “pre-treatment” (Prophylaxis before fentanyl exposure).

[0406] Dexmedetomidine (DEX) and Nalmefene (NF):

[0407] In fentanyl overdose or toxicity exposure where a Mu opioid receptor antagonist with a long half-life is required {e.g., Nalmefene), the ratio will change based on the potency of the Mu opioid receptor antagonist. In this case 1 -16 parts of Dexmedetomidine (DEX) can be combined with 1 part nalmefene (NF).

[0408] The ratio range for this formulation: DEX 1 -16: 1 NF {e.g., 1 :1 , 2:1 , 3:1 , 4:1 , 10:1 , and all ratios up to 16:1 by weight.

[0409] This ratio can be used for “pre-treatment” (Prophylaxis before fentanyl exposure).Dexmedetomidine Reversal of Fentanyl overdose or toxicity:

[0410] Dexmedetomidine (DEX) and Naloxone (NLX):

[0411] Reversal (treatment after fentanyl exposure) with Dexmedetomidine and naloxone.

[0412] Dexmedetomidine can be combined with Mu opioid receptor antagonist Naloxone (NLX) in a ratio of 1 part Dexmedetomidine (DEX) to 1-33 parts naloxone.

[0413] The ratio range for this formulation: DEX 1 : 1-33 NLX (e.g., 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 :10, 1 :11 and all ratios up to 1 :33 by weight).

[0414] This ratio can be used for Reversal (treatment after fentanyl exposure).

[0415] Dexmedetomidine (DEX) and Nalmefene (NF):

[0416] Reversal (treatment after fentanyl exposure) with Dexmedetomidine (DEX) with nalmefene (NF). In fentanyl overdose or toxicity exposure where a Mu opioid receptor antagonist with a long half-life is required (e.g., Nalmefene), the ratio will change based on the potency of the Mu opioid receptor antagonist. Dexmedetomidine can be combined with Mu opioid receptor antagonist nalmefene in a ratio of 1 -20 parts Dexmedetomidine to 1 -part nalmefene.

[0417] The ratio range for this formulation: DEX 1-20 : 1 NF (e.g., 1 :1 , 2:1 , 3:1 4:1 , 5:1 , 6:1 , 7:1 , 8:1 , 9:1 , 10:1 and all ratios up to 20:1 by weight).

[0418] This ratio can be used for Reversal (treatment after fentanyl exposure).Lofexidine Reversal of Fentanyl overdose or toxicity:

[0419] Lofexidine (LFX) and Naloxone (NLX):

[0420] Reversal (treatment after fentanyl exposure) with Lofexidine and naloxone.

[0421] Lofexidine can be combined with Mu opioid receptor antagonist Naloxone (NLX) in a ratio of 1 part Lofexidine (LFX) to 1 -166 parts naloxone.

[0422] The ratio range for this formulation: LFX 1 : 1-166 NLX (e.g., 1 :1 , 1 :5, 1 :10, 1 :40, 1 :100 and all ratios up 1 :166 by weight).

[0423] This ratio can be used for Reversal (treatment after fentanyl exposure).

[0424] Lofexidine (LFX) and Nalmefene (NLX):

[0425] Reversal (treatment after fentanyl exposure) with Lofexidine (LFX) with nalmefene (NF). In fentanyl overdose or toxicity exposure where a Mu opioid receptor antagonist with a long halflife is required (e.g., Nalmefene), the ratio will change based on the potency of the Mu opioid receptor antagonist. Lofexidine can be combined with Mu opioid receptor antagonist nalmefene (NF) in a ratio of 1-4 parts Lofexidine (LFX) to 1-part nalmefene.

[0426] The ratio range for this formulation: LFX 1 : 1 -100 NF (e.g., 1 :1 , 1 :2, 1 : 20 or up to 1 :100 by weight).

[0427] This ratio can be used for Reversal (treatment after fentanyl exposure).

[0430] Key for Table 4: * These doses represent the effective dose range in the animal model for reversal or prophylaxis of FIVCC. **These doses represent an allometric conversion to a human equivalent dose (HED) representing the effective dose range in the animal model for reversal or prophylaxis of FIVCC. ***These doses represent an allometric conversion to a HED representing the effective dose range in the animal model for reversal or prophylaxis of FIVCC for comparable MOR antagonist. **** Broader dose range required to accommodate for IV / IM or IN dosing for synthetic opioids (5-10 times higher). *"”Ex. CD. (0.6 mg) 1 :10 (6 mg) NF. In the case of nasal delivery it may require increasing the dose of nalmefene (NF) and keeping the clonidine (CD) dose lower in order to minimize A2AR mediated vasoconstriction in nasal mucosa.

[0431] Pre-treatment: prophylaxis before fentanyl exposure. Reversal', treatment after fentanyl exposure.

[0432] Data used to develop the ratios described in the table above are detailed in the following examples (as well as the Appendices included in priority application US Provisional Application No. 63 / 735,276, which is incorporated by reference herein in its entirety, including the Appendices). These data were gathered using the methods of Miner et al. (“Fentanyl causes naloxone-resistant vocal cord closure: A platform for testing opioid overdose treatments.” Drug Alcohol Depend. 227:108974, 2021 ).Example 1 : Synthetic Opioids with Reduced Atypical Effects Profile.

[0433] Ratio for Safer Fentanyl when combined with alpha 2 adrenergic receptor agonists (e.g., FIVCC resistant fentanyl, FIVCC prophylaxed fentanyl, High analgesic capacity fentanyl).

[0434] Introduction: As per previous disclosures, fentanyl and related analogues (e.g., sufentanil, carfentanil, alfentanil, remi-fentanil) have atypical effects on the upper airway (vocal cords and laryngeal muscles) not seen with morphine opiates. High dose fentanyls cause muscle rigidity (wooden chest syndrome-WCS or fentanyl-induced muscle rigidity-FIMR) and induce laryngospasm (fentanyl-induced vocal cord closure-FIVCC) and dose ranges for these effects are well-defined in the anesthesiology clinical literature and considered highly lethal without immediate intervention. However, the mechanism for FIVCC has remained unknown until this disclosure. Experimental data have confirmed that the class of drugs known as alpha 2 adrenergic receptor agonists -A2AR agonists, have proved generally effective in either prophylaxis against FIVCC or for reversal of FIVCC as single agents in human equivalent dose ranges (HED), at the fentanyl LD o dose (25 |ag / kg) in a translational (animal) model of fentanyl toxicity with FIVCC as the primary outcome variable. Of note, this LD o dose of fentanyl (25 pg / kg) in this model has been confirmed clinically to induce FIVCC in >95% of individuals exposed to this dose (25 pg / kg of fentanyl or equipotent dose of a fentanyl analogue). A2AR agonists vary in their affinity to different A2AR receptor subtypes {e.g., 2A, 2B, 2C) and thisdetermines the efficacious dose range of a specific A2AR agonist to inhibit (prevent) or antagonize (reverse) the atypical effects of fentanyls (e.g., FIVCC).

[0435] In an effort to fulfill the unmet need of making safer fentanyls for clinical use, we have demonstrated that by combining fentanyl in a specific dose ratio with an alpha 2 adrenergic receptor agonist (A2AR agonist), we can significantly increase the dose of fentanyl that can be administered for improved analgesia but with increased safety and decreased risk of atypical lethal effects (FIVCC and FIMR). We have demonstrated in vivo, in a clinically correlated translational model of FIVCC, that a specific ratio of A2AR agonist, when administered with fentanyl, prevent FIVCC at the LDwo dose of fentanyl (25 pg / kg). This fentanyl LDwo dose in the translational model also correlates with clinical doses with >95% lethality.

[0436] Additionally, we have demonstrated that these ratios (Fentanyl: A2AR agonist) can dramatically increase the fentanyl LDwo by 5-8-fold (e.g., fentanyl LDwo = 25 pg / kg versus Fentanyl + A2AR agonist LDwo = > 200 pg / kg).

[0437] The following ratios generally vary as per the potency of the fentanyl analogue and A2AR agonist selected for formulation but will generally follow the ratios listed here:

[0438] Ratio for Safer Fentanyl (FIVCC resistant fentanyl, FIVCC prophylaxed fentanyl, High analgesic capacity fentanyl).

[0439] 1) Weak A2AR agonist (>500 nM - 2500 nM Ki binding at A2AR-2A receptor subtype):

[0440] Fentanyl, or equipotent analog dose can be combined with a weak A2AR agonist in a ratio range: Fentanyl (or equipotent analog dose) 1 : 10-300 Weak A2AR agonist (>500 nM - 2500 nM) (e.g., xylazine).

[0441] Ratio: Fentanyl (or equipotent analog dose in pg / kg) 1 : 10-300 Weak A2AR agonist (>500 nM - 2500 nM) (e.g., xylazine in mcg / kg). (e.g., Ratio in micrograms / kg (mcg / kg, pg / kg) : Fentanyl 25 pg-200 pg / kg : Weak A2AR agonist (xylazine) at 8000 pg / kg)

[0442] 2) Moderate A2AR agonist (e.g., Clonidine) (>50 nM - 500 nM binding affinity at Alpha 2 AR - subtype 2A binding site):

[0443] Fentanyl, or equipotent analog dose can be combined with a moderate A2AR agonist in a ratio range: Fentanyl (or equipotent analog dose in pg / kg) Fentanyl 1 : 4-20 Clonidine- Moderate A2AR agonist (>50 nM - 500 nM) (e.g., Clonidine in pg / kg).

[0444] Ratio: Fentanyl (or equipotent analog dose in pg / kg) 1 : 4-20 Clonidine Moderate A2AR agonist (>50 nM - 500 nM)

[0445] (e.g., Ratio in micrograms / kg (pg / kg): Fentanyl 25 pg-200 pg / kg : Clonidine at 150-350 pg / kg - Moderate A2AR agonist (>50 nM - 500 nM) )

[0446] 3) Strong A2AR agonist (<50 nM binding affinity at Alpha 2 AR - subtype 2A binding site) (e.g., where 1 nM binding affinity < 50 nM); (e.g., Lofexidine , Dexmedetomidine)

[0447] Fentanyl, or equipotent analog dose can be combined with a Strong A2AR agonist in a ratio range: Fentanyl (or equipotent analog dose in pg / kg) 1 : 2-6 Dexmedetomidine - StrongA2AR agonist (< 50 nM binding affinity at Alpha 2 AR - subtype 2A binding site) (e.g., Dexmedetomidine in pg / kg).

[0448] Ratio: Fentanyl (or equipotent analog dose in pg / kg) 1 : 2-6 Dexmedetomidine Strong A2AR agonist (< 50 nM binding affinity at Alpha 2 AR - subtype 2A binding site) (e.g., Ratio in micrograms / kg (pg / kg) : Fentanyl 25 pg-200 pg / kg : Dexmedetomidine at 100- 150 pg / kg - Strong A2AR agonist (< 50 nM binding affinity at Alpha 2 AR - subtype 2A binding site)).Subtype Ratio Optimization:

[0449] A2AR agonist efficacy for limiting atypical effects including cardiovascular effects (e.g., hypotension) (e.g., can be further enhanced by selecting a strong A2AR agonist with a receptor subtype specific ratio that favors a close Ki (binding affinity) ratio between the 2A and 2B subtypes. An optimal subtype binding affinity ratio for 2A: 2B ratio is: (2A)1-10 : 1 (2B) (e.g., (2A binding affinity 50 nM) 2:1 (2B binding affinity at 25 nM) (ex. 2A higher Ki (weaker binding) > 2B lower Ki (stronger binding). «Key Example for Ratio: 1-10 : 1 »

[0450] Ex. Dexmedetomidine Ki at 2A = 5 nM and Ki at 2B = 5 nM

[0451] "Ki" = "inhibition constant," which represents the concentration of a molecule (typically an inhibitor) required to occupy 50% of the binding sites on a target molecule (like an enzyme or receptor), essentially measuring how strongly that molecule binds to its target; a lower Ki value indicates a higher binding affinity.Example 2

[0452] Toxidrome: Description of the fentanyl toxidrome and descriptions of corresponding data from animal model.

[0453] Fentanyl toxidrome: All opiates impact respiratory and cardiovascular function to some degree. However, fentanyl, due to its high lipophilicity, potency, rapid CNS penetration and targeting of alphal and alpha2 adrenergic receptors can have profound effects on multiple physiologic symptoms (cardiovascular, respiratory, hepatic metabolism) when given at high doses (>15 pg / kg).

[0454] High dose fentanyl or fentanyl analogues (F / FAs), in contrast to morphine-based opiates, can cause an atypical toxidrome that includes respiratory failure from muscle rigidity in the chest wall and diaphragm (Wooden chest syndrome), airway obstruction from vocal cord closure (VCC), and severe cardiovascular (CV) dysfunction that can be lethal within 1 -3 minutes without medical intervention (Alalami et al., Pediatric Anesthesia 18(4):281 , 2008; Gavel & Walker, Continuing Education in Anaesthesia Critical Care & Pain, 14(2):47-51 , 2014; Bohringer, AHRQ Patient Safety Network (PSNet) Collection 2023, PMID: 40106627). This data is the first to show the overlap of these physiological systems and the time scale in which they overlap with catastrophic lethal effects. These atypical clinical effects are dose dependent, have a limited intervention window compared to morphine and have been demonstrated with both clinical andillicit fentanyl use. Autopsy, public health data and supervised injection site reports of F / FA overdose have characterized the atypical presentation as severe rigidity, rapid cyanosis, airway obstruction indicated by inability to mask ventilate or even open the mouth and limited fentanyl metabolism; all indicating pathophysiology consistent with respiratory failure and cardiovascular collapse versus effects limited to respiratory depression.

[0455] The data presented herein represents the first demonstration in the scientific literature of fentanyl effects on the upper airway in a (translational) animal model of fentanyl overdose using fiber optic endoscopy (Miner et al., 2021 ). The model was used to establish the potency for fentanyl-induced vocal cord closure (FIVCC) and test the efficacy of intravenous (IV) and intramuscular naloxone to reverse these effects.Fentanyl Causes Dose-Dependent Vocal Cord Closure (FIVCC)

[0456] FIG. 1 is a comparison of IV fentanyl effects on vocal cord function (VCC) and FIGs. 2A- 2B is a comparison of mean arterial pressure (MAP), heart rate (HR) and respiration rate (RR). Intravenous (IV) boluses of fentanyl were administered to test animals over a dose range as noted in the bar graph (FIG. 1 ). Effects on vocal cord patency were determined as per previous methods (Miner et al., 2021 ). Fentanyl caused VCC death at the low dose of 0.005 mg / kg but induced VCC death in 80% of animals at 0.015 mg / kg and 100% of animals at 0.20 mg / kg and above. Fentanyl showed dose-dependent effects on MAP, HR and RR in FIG. 2 .IV Naloxone Effects on VCC, MAP, HR and RR at 15 sec versus 45 sec after IV Fentanyl

[0457] The effects on airway and survival with increasing IV doses of naloxone after IV fentanyl (25 pg / kg) are noted in naloxone bar graph below (FIG. 3). Naloxone IV immediately (15 sec) after fentanyl showed VCC death in 100% of animals at the low dose (0.007 mg / kg / HED of 0.1 mg or 12.5 mcg / kg) and 100% survival at all doses greater than or equal to 0.5 mg / kg. Naloxone delayed (45 sec) after fentanyl showed 100% VCC death at the low doses (0.007- 0.06 mg / kg), 50% survival at 0.5 mg / kg and 100% VCC death at 1 mg / kg. MAP, HR and RR showed dose dependent effects on all physiology measured, with increased survival at doses greater than or equal to 0.125 mg / kg and with a decrease in VCC death. Immediate (15 sec) dosing showed increases in MAP, HR and RR with return to baseline values at all doses >0.125 mg / kg and biggest decreases at the lowest dose (0.007 mg / kg). MAP, HR and RR responses were all decreased with the time delay (45 sec) of naloxone administration with MAP most affected. Naloxone dosing delays increased VCC death.Data on IV Alpha 2 Adrenergic Receptor Agonists and Naloxone:

[0458] Initial studies comparing alpha 2 adrenergic agonists - dexmedetomidine, lofexidine and clonidine in their efficacy to reverse or inhibit VCC with either pre-treatment prior to fentanyl or immediately after FIVCC - are described in Appendix II of US Provisional Application No. 63 / 735,276 (incorporated by reference herein). Reversal of FIVCC, noted as vocal cord relaxation -“VCR”, was seen with each drug but varied in efficacy depending on the potency of each drug.These studies were later repeated using a similar dose range, invasive hemodynamic monitoring and an adequate sample size to more accurately determine effects of these alpha 2 adrenergic agonists.

[0459] The same Appendix shows initial studies comparing alpha 1 adrenergic antagonists tamsulosin and prazosin over a wide range of doses to assess their efficacy to reverse or inhibit VCC with either pre-treatment prior to fentanyl or immediately after FIVCC. None of these trials reversed or inhibited FIVCC or increased survival.

[0460] Also illustrated in that Appendix are initial studies of naloxone over a wide range of doses to assess efficacy to reverse or inhibit VCC with either pre-treatment prior to fentanyl or immediately after FIVCC. The general pattern demonstrated was that immediate rescue showed 100% survival, but delays in administration showed less survival and by 1 minute there was 0% survival even at the highest doses. Female animals did seem to tolerate a longer duration before administration with greater survival compared to males. These studies were later repeated using a wider dose range, invasive hemodynamic monitoring and an adequate sample size to more accurately determine effects of naloxone.Intravenous (IV) COMBO Data

[0461] Test animals were administered IV naloxone, clonidine and combination (Naloxone + Clonidine, Naloxone + Lofexidine) to compare effects on FIVCC reversal, survival and MAP. Methods used for fentanyl and naloxone dose response curves described for FIGs. 1 -4B were repeated for experiments in FIGs. 5-8. Each drug alone has minimal survival versus the combinations for clonidine + naloxone (75% survival at 15”) and lofexidine + naloxone (70% survival at 15”). Similarly, combination therapy rescued MAP whereas drugs given alone after IV fentanyl and FIVCC, significantly decreased MAP. This is an unexpected result as each drug given alone significantly decrease MAP and survival.

[0462] IV naloxone (Nix), clonidine (Cion) and combination (Nlx+ Cion or Nlx+ Lofex) was administered 45 sec after IV fentanyl (25 mcg / kg) to compare dose dependent, timing effects on survival and VCC death after FIVCC. An n=8 animals were tested for each dose represented by lines 1 -5. The bar graph in the slide shows the % Survival Over Time for each drug or combination. Each drug alone has minimal survival versus the combinations for clonidine + naloxone ( 75% survival at 15”) and lofexidine + naloxone (70% survival at 15”). Similar effects are seen in FIG. 2B where neither naloxone or clonidine alone significantly increase survival (FIVCC reversal = return of vocal cord activity “VCA”) when administered at 45 sec after IV fentanyl-induced vocal cord closure (FIVCC).Comparison of Survival and Reversal of FIVCC from Alpha 2 Agonists in Combination with Naloxone:

[0463] Test animals were administered IV naloxone, clonidine and combination (Naloxone + Clonidine, Naloxone + Lofexidine or Naloxone + Dexmedetomidine) to compare effects on FIVCCreversal and survival. Methods used for fentanyl and naloxone dose response curves described for FIGs. 1-4B were repeated for experiments in FIG. 9. A comparison of the three Alpha 2 Agonists (clonidine, lofexidine and dexmedetomidine) showed a significant difference in survival where dexmedetomidine (0.1 mg / kg or 100 mcg / kg) demonstrated 80% survival versus 60% survival for lofexidine (0.015 mg / kg or 15 mcg / kg) and 40% survival for clonidine (0.15 mg / kg or 150 pg / kg).Conversion from IV to IM dosing:

[0464] Preliminary IV data on alpha 2 agonists was done initially for target validation to determine the receptor / s involved with FIVCC. A shift to intramuscular (IM) dosing from IV was done specifically for the purpose of drug development. Individuals using illicit fentanyls / opioids tend to have poor IV access and IV access requires significant medical training. IM injection can be done with minimal training. IM injection of naloxone and alpha2 agonists alone were tested and in combination for efficacy to reverse FIVCC in the animal model. Neither drug alone administered IM increased survival, but in combination increased survival by 40% as noted in FIG. 5. A comparison of IM and IV naloxone efficacy as single agents at equipotent doses (0.500 mg / kg), showed 100% survival and FIVCC reversal with IV naloxone and 0% survival or reversal of VCC with IM naloxone. Similar rescue effects were demonstrated for MAP, HR and RR as seen with IV combination (Clonidine + naloxone, lofexidine + naloxone) compared to drugs administered alone (FIG. 10), where naloxone or alpha 2 agonists alone caused decreases in all parameters measured. Both IV and IM demonstrated an unexpected outcome of synergy between the naloxone and alpha2 agonists tested with significant increases in all cardiovascular parameters measured (MAP, HR) and reversal of all fentanyl toxidrome effects in survivors.Unexpected outcome and explanation of potential mechanisms:

[0465] Alpha 2 adrenergic receptor agonists (A2AR) (e.g. clonidine, lofexidine) are used to reduce opioid withdrawal symptoms (sympathetic activation) for individuals in active detoxification or preparing for opioid detoxification. A2ARs typically cause bradycardia and hypotension at low doses. They are not used in acute opioid overdose treatment and are relatively contraindicated, as acute opioid overdose victims are usually found in a state of hypotension and bradycardia with a high risk of cardiac arrest. High dose fentanyls antagonize alpha adrenergic receptors and causes vasodilation and bradycardia. A2AR agonists normally cause similar effects as high dose fentanyl but can effectively counteract these alpha-adrenergic receptors mediated cardiovascular effects when combined with naloxone. A2AR agonists combined with naloxone also reverse airway obstruction (FIVCC), chest wall rigidity and respiratory depression. The combination effect of these two drugs on the cardiovascular and respiratory systems and survival from fentanyl overdose, is an unexpected outcome as neither drug alone increases survival after 45 sec when given IV or immediately after FIVCC when given IM. These data are illustrated in FIGs. 5-1 1.Example 3: Exemplary dosing ranges for Combination Therapies

[0466] This example provides proposed beneficial doses for specific combination therapies, based on the data and information provided herein.Lofexidine + Naloxone:

[0467] An optimized initial dose of I V / 1 M lofexidine (LFX) combined with naloxone (NLX) is 0.5 mg LFX combined with 5 mg NLX for a 70 kg adult. An optimized dose range for initial dose of I V / 1 M lofexidine combined with naloxone is 0.5 mg-2 mg LFX combined with 0.5 mg-10 mg NLX for a 70 kg adult. This provides a ratio range for of: LFX 1 :1 -10 NLX (e.g. 1 :10, 1 :9, 1 :8, 1 :7, 1 :6, 1 :5, 1 :4, 1 :3, 1 :2 and 1 :1).

[0468] The following are additional specific example ratios and dosages:Lofexidine + Nalmefene:

[0469] An optimized initial dose for initial dose of IV / IM lofexidine (LFX) combined with nalmefene (NF) would be 0.5 mg LFX combined with 1 mg NF for a 70 kg adult. An optimized dose range for initial dose of IV / IM lofexidine combined with nalmefene is 0.5 mg-2 mg LFX combined with 0.1 mg-3 mg NF for a 70 kg adult. This provides a ratio range of: LFX 1 :1-6 NF (e.g. 1 :1 , 1 :2, 1 :3, 1 :4 ,1 :5 and 1-6). An additional specific example is: LFX 0.5 mg 1 :2 1 mg NF.Clonidine + Naloxone :

[0470] An optimized initial single dose of IV / IM clonidine (CLON) combined with naloxone (NLX) is 0.2 mg CLON combined with 5 mg NLX for a 70 kg adult. An optimized dose range for IV / IM CLON combined with NLX is 0.1 mg-2 mg CLON combined with 0.5 mg-10 mg NLX for a 70 kg adult. This provides a ratio range of: CLON 1 :1 -10 NLX (e.g. 1 :10, 1 :9, 1 :8, 1 :7, 1 :6, 1 :5, 1 :4, 1 :3, 1 :2 and 1 :1).Clonidine + Nalmefene:

[0471] An optimized initial single dose of IV / IM clonidine (CLON) combined with Nalmefene (NF) is 0.2 mg CLON combined with 1 mg of NF for a 70 kg adult. An optimized dose range for IV / IM CLON combined with NF would be 0.1 mg-2 mg CLON combined with 0.1 mg-3 mg NF for a 70 kg adult. This provides a ratio range of: CLON 1 :1 -10 NF (e.g. 1 :10, 1 :9, 1 :8, 1 :7, 1 :6, 1 :5, 1 :4, 1 :3, 1 :2 and 1 :1 ).Dexmedetomidine + Naloxone:

[0472] An optimized initial single dose of IV / IM dexmedetomidine (DEX) combined with naloxone (NLX) is 0.1 mg of DEX combined with 5 mg of NLX for a 70 kg adult. An optimized dose range for IV / IM DEX combined with NLX is 0.1 mg-1 mg DEX combined with 0.5 mg-10 mg NLX for a 70 kg adult. This provides a ratio range of: DEX 1 :1 -10 NLX (e.g. 1 :10, 1 :9, 1 :8, 1 :7, 1 :6, 1 :5, 1 :4, 1 :3, 1 :2 and 1 :1 ).Dexmedetomidine + Nalmefene:

[0473] An optimized initial single dose of IV / IM dexmedetomidine (DEX) combined with Nalmefene (NF) is 0.1 mg of DEX combined with 1 mg of NF for a 70 kg adult. An optimized dose range for IV / IM DEX combined with NF is 0.1 mg-1 mg DEX combined with 0.1 mg-3 mg NF for a 70 kg adult. This provides a ratio range of: DEX 1 :1 -15 NF (e.g. 1 :15, 1 :14, 1 :13, 1 :12, 1 :1 1 , 1 :10, 1 :9, 1 :8, 1 :7, 1 :6, 1 :5, 1 :4, 1 :3, 1 :2 and 1 :1 ).CLOSING PARAGRAPHS

[0474] As will be understood by one of ordinary skill in the art, each embodiment disclosed herein can comprise, consist essentially of, or consist of its particular stated element, step, ingredient or component. Thus, the terms “include” or “including” should be interpreted to recite: “comprise, consist of, or consist essentially of.” The transition term “comprise” or “comprises” means has, but is not limited to, and allows for the inclusion of unspecified elements, steps, ingredients, or components, even in major amounts. The transitional phrase “consisting of” excludes any element, step, ingredient, or component not specified. The transition phrase “consisting essentially of” limits the scope of the embodiment to the specified elements, steps, ingredients, or components and to those that do not materially affect the embodiment.

[0475] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinaryrounding techniques. When further clarity is required, the term “about” has the meaning reasonably ascribed to it by a person skilled in the art when used in conjunction with a stated numerical value or range, i.e. denoting somewhat more or somewhat less than the stated value or range, to within a range of ±20% of the stated value; ±19% of the stated value; ±18% of the stated value; ±17% of the stated value; ±16% of the stated value; ±15% of the stated value; ±14% of the stated value; ±13% of the stated value; ±12% of the stated value; ±1 1% of the stated value; ±10% of the stated value; ±9% of the stated value; ±8% of the stated value; ±7% of the stated value; ±6% of the stated value; ±5% of the stated value; ±4% of the stated value; ±3% of the stated value; ±2% of the stated value; or ±1 % of the stated value.

[0476] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0477] The terms “a,” “an,” “the” and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0478] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0479] Certain embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, andthe inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0480] Furthermore, numerous references have been made to patents, printed publications, journal articles, other written text, and web site content throughout this specification (referenced materials herein), including in the References list. Each of the referenced materials are individually incorporated herein by reference in their entirety for their referenced teaching(s), as of the filing date of the first application in the priority chain in which the specific reference was included. For instance, with regard to chemical compounds, nucleic acid, and amino acids sequences referenced herein that are available in a public database, the information in the database entry is incorporated herein by reference as of the date of an application in the priority chain in which the database identifier for that compound or sequence was first included in the text.

[0481] It is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.

[0482] The particulars shown herein are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of various embodiments of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for the fundamental understanding of the invention, the description taken with the drawings and / or examples making apparent to those skilled in the art how the several forms of the invention may be embodied in practice.

[0483] Definitions and explanations used in the present disclosure are meant and intended to be controlling in any future construction unless clearly and unambiguously modified in the example(s) or when application of the meaning renders any construction meaningless or essentially meaningless. In cases where the construction of the term would render it meaningless or essentially meaningless, the definition should be taken from Webster’s Dictionary, 11thEdition or a dictionary known to those of ordinary skill in the art, such as the Oxford Dictionary of Biochemistry and Molecular Biology, 2ndEdition (Ed. Anthony Smith, Oxford University Press, Oxford, 2006), and / or A Dictionary of Chemistry, 8thEdition (Ed. J. Law & R. Rennie, Oxford University Press, 2020).SELECT REFERENCES:Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J 2008; 22:659-61.Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016 Mar;7(2):27-31 .Zhu YJ, Peng K, Meng XW, Ji FH. Attenuation of neuroinflammation by dexmedetomidine is associated with activation of a cholinergic anti-inflammatory pathway in a rat tibial fracture model. Brain Res. 2016 Aug 1 ; 1644:1 -8.Pan S, Chen Y, Zhang X, Xie Y. The JAK2 / STAT3 pathway is involved in dexmedetomidine- induced myocardial protection in rats undergoing cardiopulmonary bypass. Ann Transl Med. 2020 Apr;8(7):483.Kang Y, O'Conor KA, Kelleher AC, Ramsey J, Bakhoda A, Eisenberg SM, Zhao W, Stodden T, Pearson TD, Guo M, Brown N, Liow JS, Fowler JS, Kim SW, Volkow ND. Naloxone's dosedependent displacement of [11C]carfentanil and duration of receptor occupancy in the rat brain. Sci Rep. 2022 Apr 19;12(1 ) :6429.Averick SE, Kassick AJ, Song D, Zhang B, Vigliaturo J, Luengas D, Silva-Ortiz P, Pravetoni M, Raleigh MD. Evaluating the rate of reversal of fentanyl-induced respiratory depression using a novel long-acting naloxone nanoparticle, cNLX-NP. Front Psychiatry. 2024 Mar 14;15:1366186.Miner NB, Schutzer WE, Zarnegarnia Y, Janowsky A, Torralva R. Fentanyl causes naloxone- resistant vocal cord closure: A platform for testing opioid overdose treatments. Drug Alcohol Depend. 2021 Oct 1 ;227:108974.WO 2020 / 041006WO 2021 / 102328WO 2021 / 174116

Claims

LISTING OF CLAIMSI claim:1 . A composition formulated for use in reversing or preventing at least one symptom of fentanyl overdose in a human subject, the composition comprising: a therapeutic drug combination selected from the group consisting of:0.5 mg lofexidine (LFX) and 5 mg naloxone (NLX);0.5 mg LFX and 1 mg nalmefene (NF);0.2 mg clonidine (CLON) and 5 mg NLX;0.2 mg CLON and 1 mg NF;0.1 mg dexmedetomidine (DEX) and 5 mg NLX; and0.1 mg DEX and 1 mg NF; and a pH balanced pharmaceutical carrier solution suitable for human administration.

2. A composition comprising: lofexidine and naloxone in a ratio of 1 :1 to a ratio of 1 :166 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

3. The composition of claim 2, wherein the ratio of lofexidine to naloxone is 1 :5 to 1 :40.

4. The composition of claim 2, wherein the ratio of lofexidine to naloxone is 1 :1 , 1 :5, 1 :10, 1 :20, 1 :30, 1 :40, 1 :75, 1 :85, 1 :100, 1 :110, 1 :125, 1 :140, 1 :150, 1 :160, or 1 :166 by weight.

5. The composition of claim 2, wherein the composition comprises 0.056 - 7 mg of lofexidine and 0.1 - 70 mg of naloxone.

6. The composition of claim 2, wherein the composition comprises:0.1 - 3 mg lofexidine; or0.1 - 7 mg naloxone; or both 0.1 - 3 mg lofexidine and 0.1 - 7 mg naloxone.

7. The composition of claim 2, wherein the composition comprises 0.145 mg lofexidine and 5.8 mg naloxone.

8. The composition of claim 2, wherein a single dose of the composition comprises 0.05 mg to 7 mg of lofexidine (0.0007 mg / kg - 0.1 mg / kg for a 70 kg adult) and 0.1 - 70 mg of naloxone (0.0014 - 1 mg / kg for a 70 kg adult).

9. The composition of claim 2, wherein a single dose of the composition comprises 0.075 pg to 3 mg of lofexidine (1 -50 pg / kg for a 60 kg adult) and 0.1 - 10 mg of naloxone (1-167 pg / kg for a 60 kg adult).

10. The composition of any of claims 2-9, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.11 . Use of the composition of claim 2 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

12. The use of claim 11 , wherein the composition is administered intramuscularly, intravenously, or intranasally.

13. The use of claim 11 , wherein the composition is provided in a dosage of 0.0008 - 0.1 mg / kg lofexidine and 0.005 - 1 .5 mg / kg naloxone.

14. The use of claim 11 , wherein the composition is provided in a dosage of 0.015 - 0.1 mg / kg lofexidine and 0.01 - 1 .5 mg / kg naloxone.

15. A composition comprising: clonidine and naloxone in a ratio of 1 :1 to a ratio of 1 :34 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

16. A composition comprising: clonidine and naloxone in a ratio of 1 :2 to a ratio of 1 :6 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

17. The composition of claim 15, wherein the ratio of clonidine to naloxone is 1 :1 , 1 :2, 1 :3, 1 :4, or up to 1 :34 by weight.

18. The composition of claim 15, wherein the composition comprises 0.05 - 3 mg of clonidine and 0.1 - 70 mg of naloxone.

19. The composition of claim 15, wherein the composition comprises 0.1 - 3 mg of clonidine and 0.1 - 10 mg of naloxone.

20. The composition of claim 15, wherein the composition comprises 0.56 mg clonidine and 5.8 mg naloxone.21 . The composition of claim 15, wherein the composition comprises 0.58 mg clonidine and 5.8 mg naloxone.

22. The composition of claim 15, wherein a single dose of the composition comprises 0.05 mg to 3 mg of clonidine (0.0007 mg / kg - 0.043 mg / kg for a 70 kg adult) and 0.1 - 70 mg of naloxone (0.0014 mg / kg - 1 mg / kg for a 70 kg adult).

23. The composition of claim 15, wherein a single dose of the composition comprises 0.075 pg to 3 mg of clonidine (1 -50 pg / kg for a 60 kg adult) and 0.5 - 10 mg of naloxone (1 - 167 pg / kg for a 60 kg adult).

24. The composition of any of claims 15-23, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

25. Use of the composition of claim 15 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

26. The use of claim 25, wherein the composition is administered intramuscularly, intravenously, or intranasally.

27. The use of claim 25, wherein the composition is provided in a dosage of 0.008 - 0.175 mg / kg clonidine and 0.005 - 1 .5 mg / kg naloxone.

28. The use of claim 25, wherein the composition is provided in a dosage of 0.01 - 0.5 mg / kg clonidine and 0.01 - 1 .5 mg / kg naloxone.

29. A composition comprising: lofexidine and nalmefene in a ratio of 1 :1 to a ratio of 1 :100 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

30. A composition comprising: lofexidine and nalmefene in a ratio of 1 :1 to a ratio of 4:1 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.31 . The composition of claim 29, wherein the ratio of lofexidine to nalmefene is 1 :1 , 1 :2, 1 :20 or 1 :100 by weight.

32. The composition of claim 29, wherein the ratio of lofexidine to nalmefene is 4:1 by weight.

33. The composition of claim 29, wherein a single dose of the composition comprises 0.05 mg to 7 mg of lofexidine (0.0008 mg / kg - 0.1 mg / kg for a 70 kg adult) and 0.056 to 35 mg of nalmefene (0.0008 mg / kg - 0.5 mg / kg for a 70 kg adult).

34. The composition of claim 29, wherein a single dose of the composition comprises 0.9 mg to 2.4 mg of lofexidine (0.015 - 0.04 mg / kg for a 60 kg adult) and 0.6 - 1 .2 mg of nalmefene (0.01 - 0.02 mg / kg for a 60 kg adult).

35. The composition of any of claims 29-34, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

36. Use of the composition of claim 29 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

37. The use of claim 36, wherein the composition is administered intramuscularly, intravenously, or intranasally.

38. The use of claim 36, wherein the composition is provided in a dosage of 0.0008 - 0.1 mg / kg lofexidine and 0.0008 mg / kg - 0.5 mg / kg nalmefene.

39. The use of claim 36, wherein the composition is provided in a dosage of 0.015 - 0.1 mg / kg lofexidine and 0.001 - 0.2 mg / kg nalmefene.

40. A composition comprising: lofexidine and naltrexone in a ratio of 1 :1 to a 1 :250 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.41 . A composition comprising: lofexidine and naltrexone in a ratio of 1 :1 to a 1 :70 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

42. The composition of claim 40, wherein the ratio of lofexidine to naltrexone is 1 :5, 1 :10, 1 :20, 1 :30, 1 :40, 1 :50, 1 :75, 1 :100, 1 :125, 1 :150, 1 :175, 1 :200, 1 :225, or 1 :250 by weight.

43. The composition of claim 40, wherein the composition comprises 0.05 mg to 7 mg of lofexidine (0.0008 mg / kg - 0.1 mg / kg for a 70 kg adult) and 5 mg to 50 mg of naltrexone (0.07 mg / kg - 0.7 mg / kg for a 70 kg adult).

44. The composition of claim 40, wherein the composition comprises 0.5 mg of lofexidine and 25 mg of naltrexone.

45. The composition of claim 40, wherein the composition comprises 0.1 mg lofexidine and 5 mg naltrexone.

46. The composition of claim 40, wherein the composition comprises 0.58 mg lofexidine and 5.8 mg naltrexone.

47. The composition of any of claims 40-45, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

48. Use of the composition of claim 40 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

49. The use of claim 48, wherein the composition is administered intramuscularly, intravenously, or intranasally.

50. A composition comprising: clonidine and nalmefene in a ratio of 1 :1 to a ratio of 10:1 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.51 . A composition comprising: clonidine and nalmefene in a ratio of 5:1 to a ratio of 10:1 by weight; anda pH balanced pharmaceutical carrier solution suitable for human administration.

52. The composition of claim 50, wherein the ratio of clonidine to nalmefene is 1 :1 , 2:1 , 3:1 , 4:1 , 5:1 , 6:1 , 7:1 , 8:1 , 9:1 , or 10:1 by weight.

53. The composition of claim 50, wherein a single dose of the composition comprises 0.05 mg to 3 mg of clonidine (0.0007 - 0.04 mg / kg for a 70 kg adult) and 0.056 to 35 mg of nalmefene (0.0008 mg / kg - 0.5 mg / kg for a 70 kg adult).

54. The composition of claim 50, wherein a single dose of the composition comprises 9 mg of clonidine (0.15 mg / kg for a 60 kg adult) and 1 .2 mg of nalmefene (0.02 mg / kg for a 60 kg adult).

55. The composition of any of claims 50-54, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

56. Use of the composition of claim 50 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

57. The use of claim 56, wherein the composition is administered intramuscularly, intravenously, or intranasally.

58. The use of claim 56, wherein the composition is provided in a dosage of 0.008 - 0.2 mg / kg clonidine and 0.0008 - 0.5 mg / kg nalmefene.

59. The use of claim 56, wherein the composition is provided in a dosage of 0.01 - 0.5 mg / kg clonidine and 0.001 - 0.2 mg / kg nalmefene.

60. A composition comprising: dexmedetomidine and nalmefene in a ratio of 1 :1 to a ratio of 20:1 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.61 . A composition comprising: dexmedetomidine and nalmefene in a ratio of 1 :5 to a ratio of 1 :10 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

62. The composition of claim 60, wherein the ratio of dexmedetomidine to nalmefene is 1 :1 , 2:1 , 3:1 4:1 , 5:1 , 6:1 , 7:1 , 8:1 , 9:1 , 10:1 and all ratios up to 20:1 by weight.

63. The composition of claim 60, wherein a single dose of the composition comprises 0.2 mg to 35 mg of dexmedetomidine (0.003 mg / kg - 0.5 mg / kg for a 70 kg adult) and 0.056 to 35 mg of nalmefene (0.0008 mg / kg - 0.5 mg / kg for a 70 kg adult).

64. The composition of claim 60, wherein a single dose of the composition comprises 6 mg of dexmedetomidine (0.1 mg / kg for a 60 kg adult) and 0.6 - 1.2 mg of nalmefene (0.01 - 0.02 mg / kg for a 60 kg adult).

65. The composition of any of claims 60-64, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

66. Use of the composition of claim 60 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

67. The use of claim 66, wherein the composition is administered intramuscularly, intravenously, or intranasally.

68. The use of claim 66, wherein the composition is provided in a dosage of 0.003 - 0.5 mg / kg dexmedetomidine and 0.0008 - 0.5 mg / kg nalmefene.

69. The use of claim 66, wherein the composition is provided in a dosage of 0.01 - 0.5 mg / kg dexmedetomidine and 0.001 - 0.2 mg / kg nalmefene.

70. Use of the composition of claim 60 as a reversal therapy in response to a fentanyl, F / FA or combination opiate overdose.71 . A composition comprising: dexmedetomidine and naloxone in a ratio of 1 :1 to a ratio of 1 :33 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

72. A composition comprising: dexmedetomidine and naloxone in a ratio of 1 :2 to a ratio of 1 :5 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

73. The composition of claim 71 , wherein the ratio of dexmedetomidine to naloxone is 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 :10, 1 :11 and all ratios up to 1 :33 by weight.

74. The composition of claim 71 , wherein a single dose of the composition comprises 0.2 mg to 35 mg of dexmedetomidine (0.003 mg / kg - 0.5 mg / kg for a 70 kg adult) and 0.1 - 70 mg of naloxone (0.001 - 1 .5 mg / kg for a 70 kg adult).

75. The composition of claim 71 , wherein a single dose of the composition comprises 6 mg of dexmedetomidine (0.1 mg / kg for a 60 kg adult) and 50 - 100 mg of naloxone (0.25 - 0.5 mg / kg for a 60 kg adult).

76. The composition of any of claims 71-74, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

77. Use of the composition of claim 71 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

78. The use of claim 77, wherein the composition is administered intramuscularly, intravenously, or intranasally.

79. The use of claim 77, wherein the composition is provided in a dosage of 0.003 mg / kg - 0.5 mg / kg dexmedetomidine and 0.001 - 1 .5 mg / kg of naloxone.

80. The use of claim 77, wherein the composition is provided in a dosage of 0.01 - 0.5 mg / kg dexmedetomidine and 0.01 - 1.5 mg / kg naloxone.81 . Use of the composition of claim 71 as a reversal therapy in response to a fentanyl, F / FA or combination opiate overdose.

82. A composition comprising: dexmedetomidine and naloxone in a ratio of 1 :1 to a ratio of 1 :50 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

83. A composition comprising: dexmedetomidine and naloxone in a ratio of 1 :1 to a ratio of 1 :7 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

84. The composition of claim 82, wherein the ratio of dexmedetomidine to naloxone is 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9 or 1 :10 up to 1 :50 by weight.

85. The composition of claim 82, wherein a single dose of the composition comprises 0.42 mg to 35 mg of dexmedetomidine (0.006 - 0.5 mg / kg for a 70 kg adult) and 15 - 30 mg of naloxone (0.001 - 1 .5 mg / kg of naloxone for a 70 kg adult).

86. The composition of claim 82, wherein a single dose of the composition comprises 4.5 mg to 9 mg of dexmedetomidine (0.075 - 0.15 mg / kg for a 60 kg adult) and 15 - 30 mg of naloxone (0.25 - 0.5 mg / kg for a 60 kg adult).

87. The composition of any of claims 82-85, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

88. Use of the composition of claim 82 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

89. The use of claim 88, wherein the composition is administered intramuscularly, intravenously, or intranasally.

90. The use of claim 88, wherein the composition is provided in a dosage of 0.006 - 0.5 mg / kg dexmedetomidine and 0.001 - 1 .5 mg / kg naloxone.

91. The use of claim 88, wherein the composition is provided in a dosage of 0.075 - 0.15 mg / kg dexmedetomidine and 0.01 - 1.5 mg / kg naloxone.

92. Use of the composition of claim 82 as a pretreatment therapy in response to a fentanyl, F / FA or combination opiate overdose.

93. A composition comprising: dexmedetomidine and nalmefene in a ratio of 1 :1 to a ratio of 16:1 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

94. A composition comprising: dexmedetomidine and nalmefene in a ratio of 3:1 to a ratio of 20:1 by weight; and a pH balanced pharmaceutical carrier solution suitable for human administration.

95. The composition of claim 94, wherein the ratio of dexmedetomidine to nalmefene is 1 :1 , 2:1 , 3:1 , 4:1 , 10:1 , and all ratios up to 16:1 by weight.

96. The composition of claim 94, wherein a single dose of the composition comprises 0.42 mg to 35 mg of dexmedetomidine (0.006 - 0.5 mg / kg for a 70 kg adult) and 0.056 to 35 mg of nalmefene (0.0008 mg / kg - 0.5 mg / kg for a 70 kg adult).

97. The composition of claim 94, wherein a single dose of the composition comprises 4.5 mg to 9 mg of dexmedetomidine (0.075 - 0.15 mg / kg for a 60 kg adult) and 0.6 - 1 .2 mg of nalmefene (0.01 - 0.02 mg / kg for a 60 kg adult).

98. The composition of any of claims 94-97, wherein the composition is formulated for administrating via intramuscular (IM), intravenous (IV), or intranasal delivery to a mammalian subject.

99. Use of the composition of claim 94 as a therapeutic treatment in response to a fentanyl, F / FA or combination opiate overdose.

100. The use of claim 99, wherein the composition is administered intramuscularly, intravenously, or intranasally.101 . The use of claim 99, wherein the composition is provided in a dosage of 0.006 - 0.5 mg / kg dexmedetomidine and 0.0008 - 0.5 mg / kg nalmefene.

102. The use of claim 99, wherein the composition is provided in a dosage of 0.006 - 0.5 mg / kg dexmedetomidine and 0.0008 - 0.5 mg / kg nalmefene.

103. Use of the composition of claim 94 as a pretreatment therapy in response to a fentanyl, F / FA or combination opiate overdose.

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