Drug products: Mysimba, Nalorex, Naltrexon Hydrochloride Accord, Naltrexon Molteni, Naltrexon Vitaflo, Naltrexone Accord, Naltrexone POA Pharma, Naltrexonhydrochlorid Accord, VIVITROL
ATC code: A08AA62, N07BB04
Substances: naltrexone, naltrexone hydrochloride
Reports on sex differences in effect and adverse effects of naltrexon are contradictory in alcohol dependence. For treatment of opiate dependence similar results have been reported in men and women.
The risk of alcohol use according to the Global Burden of Disease Study 2010, was ranked as number three in men and number twelve in women. Disability-adjusted life years were three times higher in men than in women and alcohol related deaths were twice as common in men as in women .
In Sweden, hospital care due to alcohol related diagnoses were twice as common in men compared to women in 2012 and alcohol related deaths were more common in men than in women .
According to studies conducted by the manufacturer’s (285 men, 168 women), Cmax of naltrexone and the active metabolite 6-β-naltrexol was approximately 30% lower in women after an injection of a single dose naltrexone extended release (ER) of 380 mg, while AUC showed no sex differences. Despite this pharmacokinetic difference in Cmax, the clinical studies have shown similar effect using the same doses in men and women and therefore no sex differentiation in dosing has been suggested .
Studies show conflicting results regarding sex differences.
Alcohol dependenceA randomized placebo-controlled study of 380 mg injected naltrexone ER every fourth week during 24 weeks in alcohol dependent individuals (423 men, 201 women) showed that heavy drinking was reduced in men (hazard ratio 0.56), but not in women .In a placebo controlled study (COMBINE), patients with alcohol dependence (955 men, 428 women) were randomized to naltrexone, acamprosate or naltrexone + acamprosate, with or without supportive counseling during 16 weeks. Drug treatment was effective in men as well as in women [5,6]. Similarly a post-hoc analysis of a randomized double-blind placebo-controlled study of naltrexone (38 men, 15 women) and acamprosate (42 men, 13 women) in alcohol dependent individuals during 12 weeks showed similar relapse and abstinence rates in men and women [7,8].However, a post-hoc analysis of another randomized double-blind, placebo-controlled trial of naltrexone, acamprosate, or a combination (118 men, 42 women) showed that naltrexone improved abstinence more in women than in men. Outcome was measured in time to first drink (69 vs 39 days), and time to relapse to heavy drinking (77 vs 44 days) [9,10].In a randomized cross-over study, social drinkers (20 men, 20 women) received naltrexone or placebo and were offered alcohol. Naltrexone reduced the euphoric effect of alcohol in women but not in men. Despite women’s reduced euphoria, the ingested amount alcohol did not decrease. Furthermore, naltrexone reduced the euphoric effect of alcohol in carriers of the -/G-allele of the mu opioid receptor gene (OPRM1) but not in carriers of the A/A-allele. According to the authors, the lack of naltrexone effect seen in some clinical trials could be explained by both sex/gender and genotype which are factors needed to be studied simultaneously to reveal possible sex/gender differences .
Opioid dependenceNaltrexone is approved for opioid dependence in the US but not in Sweden [12,13].A randomized placebo-controlled study of 380 mg injectable naltrexone ER every fourth week during 24 weeks in opioid dependent individuals (220 men, 30 women, in all) showed similar abstinence rate in men and women .
SmokingNaltrexone is not approved for smoking cessation or reduction of post smoking cessation weight gain neither in Sweden nor in the US [12, 13].According to a Cochrane review without sex analysis, no pharmacological treatment affected smoking cessation rate. However, there was some evidence that addition of naltrexone to standard smoking cessation treatment reduced post cessation weight gain (-0.8 kg) at the end of 12 week treatment, but not 6 or 12 months after smoking cessation .During four weeks after smoking cessation, the participants in a placebo-controlled study (147 men, 168 women, in all) received nicotine patch and supportive counseling and were subsequently randomized to treatment with naltrexone or placebo. After 12 weeks of naltrexone treatment men had a better outcome than women, measured in number of cigarettes smoked weekly (32 vs 39) and quit rate (30% vs 20%). An observation is that among women, there was a lower quit rate in the naltrexone than in the placebo group (20% vs 28%). Follow-up at 26 and 52 weeks post treatment showed a similar quit rate in men and women .A pooled analysis of two randomized placebo-controlled trials of naltrexone treatment during 6 months (78 men, 77 women) and 12 months (54 men, 57 women) showed that post smoking cessation weight gain was reduced in women but not in men. Furthermore, in the placebo group, women had a higher weight gain than men . Follow-up one year after smoking cessation (76 men, 85 women) showed that naltrexone treated women had a lower weight gain than men (1 kg vs 2.2 kg) .
In a randomized placebo-controlled study, alcohol dependent patients (423 men, 201 women) received 190 or 380 mg injectable naltrexone ER every fourth week during 24 weeks. The treatment caused decreased libido in men only, and the 190 mg dose caused more nausea in women . A similar finding was shown in a cross-over study of social drinkers (20 men, 20 women) randomized to naltrexone or placebo and exposed to alcohol. Men did not report nausea. Women carrying the A/A-allele of the mu opioid receptor gene (OPRM1) reported more nausea from naltrexone than from placebo. Among women carrying the -/G-allele, alcohol-induced nausea was more frequent when receiving naltrexone than placebo .In a double-blind study where smokers were randomized to 12 weeks treatment with naltrexone or placebo (147 men, 168 women, in all), ratings of adverse effects were similar in men and women .
Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
A retrospective cross-sectional study of patients with alcohol dependence (833 men, 218 women) treated with supportive counseling and disulfiram or naltrexone showed that the duration of treatment was similar in men and women .In a placebo controlled study of patients with alcohol dependence (955 men, 428 women) randomized to naltrexone, acamprosate or naltrexone + acamprosate, with or without supportive counseling during 16 weeks showed a similar medication adherence in men and women .A U.S. study based on data from Veterans Health Administration (VHA) of treatment of alcohol misuse (270 774 men, 9 319 women) showed that women were more likely than men to receive a prescription of acamprosate (1% vs 0.6%), naltrexone (2.9% vs 1.6%), disulfiram (1.8% vs 1.1%), or any medication (5.2% vs 3%). The odds ratio for receiving any of these medications was 1.58 in women compared to men .
Date of litterature search: 2016-04-19
Reviewed by: Mia von Euler
Approved by: Karin Schenck-Gustafsson