Nalmefene Hydrochloride: Potential Implications for Treating Alcohol and Opioid Use Disorder

Figures & data

Table 1 Binding Affinities (K_i) in nM of Therapeutic Agents at the Humanized μ/κ/δ-Opioid Receptors on Transfected Chinese Hamster Ovarian Cells.

Therapeutic Agents	Mechanism of Action	Human μ in Transfected CHO [^3H]DAMGO	Human δ in Transfected CHO [^3H]DPDPE	Human κ in Transfected CHO [^3H]U69,593
Buprenorphine	μOR: Partial agonist δOR: Antagonist κOR: Antagonist	1.5 ± 0.8	4.5 ± 0.4	0.8 ± 0.05
Fentanyl	μOR: Agonist δOR: Agonist κOR: Agonist	0.7 ± 0.3	152.7 ± 38.3	84.8 ± 19.4
Methadone	μOR: Agonist δOR: Antagonist κOR: Agonist	0.6 ± 0.2	132.2 ± 10.7	323.5 ± 18.3
Morphine	μOR: Agonist δOR: Agonist κOR: Agonist	1.1 ± 0.05	140 ± 1.5	46.8 ± 14.5
Naloxone	μOR: Antagonist δOR: Antagonist κOR: Antagonist	1.4 ± 0.05	67.5 ± 40	2.5 ± 0.3
Nalmefene	μOR: Antagonist δOR: Antagonist κOR: Partial agonist	0.3 ± 0.15	7.3 ± 3.6	0.3 ± 0.15
Naltrexone	μOR: Antagonist δOR: Antagonist κOR: Antagonist	0.2 ± 0.0	10.8 ± 3.0	0.4 ± 0.1

Notes: Data from Meeting C on P of DD (U. S). S, Abuse NI on D. Problems of Drug Dependence: proceedings of the. Annual Scientific Meeting, the College on Problems of Drug Dependence, Inc [Internet]. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute on Drug Abuse; 1997. Available from: https://books.google.com/books?id=hgj5eTyGTI4C.⁴¹

Abbreviations: μOR, mu-opioid receptor; κOR, kappa-opioid receptor; δOR, delta-opioid receptor; DAMGO, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin, selective µ-opioid receptor agonist; DPDPE, [D-Pen2,D-Pen5]- enkephalin, selective δ-receptor agonist; U69,593, selective κ-opioid receptor agonist.

Table 2 Route, C_max, T_max, t_1/2, V_d, and Systemic CL of Therapeutic Opioid Receptor Agents

Therapeutic Agent	Route	Cmax (ng/mL)	Tmax (h)	t1/2	Vd (L)	Systemic CL (L/h)	References
Buprenorphine	SQ	4–11.81	24	3–60 d	ND	ND	[72,73]
	Buccal	0.17–1.43	0.81–3.0	19.01–48 h	5598	711.9	[67]
	SL	1.25–2.65	0.67–3.5	31–36.5 h	6750	210.4	[74,75]
	Implant	0.5–1	12–24	24–48 h	ND	ND	[68,76,77]
	IV	19.3–137.7	ND	1.2–7.2 h	97–334.9	54.1–77.4	[64,66,78,79]
Buprenorphine + Naloxone	SL	Buprenorphine	Buprenorphine	Buprenorphine	Buprenorphine	Buprenorphine	[80]
		0.780–2.58	1.5	30.75–31.94 h	ND	ND
		Naloxone	Naloxone	Naloxone	Naloxone	Naloxone
		51.3–135.	0.75	5.15–7.65 h	ND	ND
Fentanyl	IV	1.46	0.17	3–18.03 h	420–833	42–53	[81,82]
	Oral	0.2–2.7	0.16–2	2.6–19 h	280	42–53	[83–87]
	Transdermal	0.38–3.36	20–72	3–27 h	833	3–80	[81,88]
Methadone	IV	0.29	~ 0.1	23 h	~ 251	7.42	[89,90]
	Oral	124–1255	1–7.5	8–59 h	70–560	1.4–126	[91,92]
Morphine	IV	33–40	0.16–0.3	1.5–4.5 h	70–329	60–84	[93–95]
	Oral	7.35–78	0.9–10	2–15 h	70–420	84–126	[93,95–98]
Nalmefene	IV	3.7–5.8	~ 2.3	~ 10.8 h	~ 602	~ 67	[33,99]
	Oral	16.5	~ 1.5	~ 12.5 h	~ 3200	~ 169	[33,100]
Naltrexone	Extended Release IM	25–28	2 h (first peak) 2–3 d (second peak)	5–10 d	~ 1350	~ 210	[101,102]
	Oral	8.6	1	4 h	ND	~ 94	[101,103]

Notes: C_max = maximum observed plasma drug concentration; T_max = time to maximum plasma drug concentration; t_1/2 = elimination half-life; V_d = volume of distribution; CL = clearance.

Abbreviations: IM, intramuscular; IN, intranasal; IV, intravenous; SL, sublingual; SQ, subcutaneous; ND, not determined or reported.

Table 3 Onset, T_max, t_1/2, and C_max for Nalmefene Intramuscular, Nalmefene Intranasal, Naloxone Intranasal, and Naltrexone + DDM Intranasal

Therapeutic Opioid Overdose Reversal Agent	Onset (min)	Tmax (h)	t1/2 (h)	Cmax (ng/mL)	References
Nalmefene, IM (2 mg / 2 mL)	5–15	0.33 (0.117–18.0)	10.60	1.50	[116]
Nalmefene + DDM, IN (2.7 mg)	2.5–5	0.27 (0.167–2.03)	11.40	4.45–9.75	[116,118]
Naloxone, IN (4 mg) (Narcan)	1–2	0.50 (0.17–1.00)	2.08	4.83	[127]
Naltrexone + DDM, IN (4 mg)	ND	0.20 (0.1‐0.3)	2.20	15.7	[128]

Notes: C_max = maximum observed plasma drug concentration; T_max = time to maximum plasma drug concentration; t_1/2 = elimination half-life.

Abbreviations: DDM, dodecyl maltoside; IM, intramuscular; IN, intranasal; ND, not determined or reported.

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