TITLE:
Efficacy and Tolerability of Long-Acting Injectable Formulation of Nalmefene (Nalmefene Consta 393.1 mg) for Opioid Relapse Prevention: A Multicentre, Open-Label, Randomised Controlled Trial
AUTHORS:
Sead Kadric, Hanns Mohler, Olli Kallioniemi, Karl Heinz Altmann
KEYWORDS:
Nalmefene Consta, Long-Acting Depot Formulations of Nalmefene, Opioid Dependence, Long-Term Delivery, PLGA Polymers
JOURNAL NAME:
World Journal of Neuroscience,
Vol.9 No.3,
July
15,
2019
ABSTRACT: Objective: To determine the efficacy and
tolerability of a long-acting intramuscular formulation of Nalmefene (Nalmefene
Consta 393.1 mg) for the treatment of opioid-dependent patients. Design,
Setting, and Participants: A 12 weeks, open-label, randomised controlled trial
conducted between June 2009-July 2011, at 14 Hospital-based drug clinics, in
the 12 countries. Participants were 18 years or older, had Diagnostic and
Statistical Manual of Mental Disorders-5 opioid use disorder. Of the 3200
individuals screened, 3000 (93.7%) adults were randomized 1500 participants to
receive injections of Long-acting depot formulations ofNalmefene (Nalmefene
Consta 393.1 mg) given intramuscularly once in 12 weeks and 1500participants to
receive extended-release Naltrexone (Vivitrol 380 mg), administered
intramuscularly every fourth week for 12 weeks. Main Outcomes and Measures: The
primary endpoints (protocol) were: Confirmed Opioid abstinence (percentage i.e. the number of patients who achieved complete abstinence during week 12).
Confirmed abstinence or “opioid-free” was defined as a negative urine drug test
for opioids and no self-reported opioid use. Weeks 1 - 4 were omitted from this
endpoint to allow for stabilization of abstinence. Secondary end points
included a number of days in treatment, treatment retention and craving. The
study also investigated, on 275 participants, degree and time course of
mu-opioid receptor occupancy following single doses of Nalmefene
extended-release injection (Nalmefene Consta 393.1 mg) as well as the plasma
concentration of Nalmefene and Nalmefene-3-O-glucuronide. Safety was assessed
by adverse event reporting. Results: Of 3000 participants, mean (SD) age was
27.1 (±4.8) years and 831 (27.7%) were women. 1500 individuals were randomized
to receive injections of Long-acting depot formulations of Nalmefene (Nalmefene
Consta 393.1 mg) and 1500 to receive injections of extended-release Naltrexone
(Vivitrol 380 mg); 2088 participants (69.6.0%) completed the trial. Primary
endpoints: Confirmed Opioid Abstinence: Complete abstinence was sustained by
86% (n = 1290) of Nalmefene patients (patients treated with Nalmefene Consta
393.1 mg, long-acting depot formulations) compared with 43% (n = 645) of
patients treated with extended-release Naltrexone 380 mg (Vivitrol), during
weeks 5 - 12 (χ2 = 672.34, P Secondary Endpoint: Craving: A
statistically and clinically significant reduction in opioid craving was
observed with Nalmefene (Nalmefene Consta 393.1 mg, long-acting depot
formulations) vs. Naltrexone (extended-release Naltrexone, Vivitrol 380 mg) by
week 4 (P =0.0048), which persisted every week through 12 (P Secondary Endpoint: Treatment Retention: Long-acting intramuscular formulation
of Nalmefene (Nalmefene Consta 393.1 mg) helped significantly more patients
complete 12 weeks treatment (n = 1245, 83%) compared with extended-release
Naltrexone (Vivitrol 380 mg) (n = 570, 38%) (χ2 = 635.53, P Concentrations of Nalmefene and
Nalmefene-3-O-Glucuronide in Plasma: Analyses were made of 275 study sample.
There was no statistically significant difference for plasma nalmefene
concentrations between days 2 and 84 (p = 0.416). The plasma concentration of
Nalmefene were 20.3 and 28.5 ng/ml and concentrations of
nalmefene-3-O-glucuronide were 2.1 and 4.1 ng/ml, respectively. Plasma levels
of Nalmefene remained above 20 ng/ml for approximately 12 weeks after
administration of Nalmefene, long-acting depot formulations (Nalmefene Consta
393.1 mg). PET Assessments: Very high mu-opioid receptor occupancy by Nalmefene
was detected 1 day after treatments at which time point the occupancy was
100.0% after Nalmefene injection (Nalmefene Consta 393.1 mg). Nalmefene Consta
393.1 mg injection (long-acting intramuscular formulation of Nalmefene) led to
a very high occupancy ofmu-opioid receptors in all brain areas examined; the
thalamus, caudate nucleus, and frontal cortex. Depending on the brain area
mu-opioid receptor occupancy varied between 83.0% and 85.8% 84 days after
dosing. Adverse Reactions: Adverse events were similar in opioid-dependent
patients treated with long-acting intramuscular formulation of Nalmefene
(Nalmefene Consta 393.1 mg) vs. patients treated with extended-release
Naltrexone (Vivitrol 380 mg). Conclusions and Relevance: Long-acting depot formulations
of Nalmefene (Nalmefene Consta 393.1 mg) was more effective then
extended-release Naltrexone (Vivitrol 380 mg) in maintaining short-term
abstinence from heroin and should be considered as a treatment option for
opioid-dependent individuals.