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Naltrexone

Classification: A

Drug products: Mysimba, Nalorex, Naltrexon Molteni, Naltrexon Vitaflo, Naltrexone Accord, Naltrexone POA Pharma, Revia, Revia®, VIVITROL

ATC code: A08AA62, N07BB04

Substances: naltrexone, naltrexone hydrochloride

Summary

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 present evidence concerning differences between men and women is limited and do not motivate differentiation in dosing or treatment.

Additional information

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 [1].

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 [2].

Pharmacokinetics and dosing

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 [3].

Effects

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 [4].

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 [11].

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 [14].

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 [15].

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 [16].

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 [17]. 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) [16].

Adverse effects

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 [4]. 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 [11].

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 [16].

Reproductive health issues

Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).

Other information

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 [18].

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 [6].

A US 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 [19].

Updated: 2019-02-26

Date of litterature search: 2016-04-19

References

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  2. Folkhälsan i Sverige Årsrapport 2014. Folkhalsomyndigheten [www]. [updated 2015-12-28, cited 2016-04-19]. Länk
  3. Food and Drug Administration (FDA). Clinical Pharmacology and Biopharmaceutics Review - VIVTROL (naltrexone). Food and Drug Administration [www]. [updated 2006-04-13, cited 2016-04-01]. länk
  4. Garbutt JC, Kranzler HR, O'Malley SS, Gastfriend DR, Pettinati HM, Silverman BL et al. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. JAMA. 2005;293:1617-25. PubMed
  5. Anton RF, O'Malley SS, Ciraulo DA, Cisler RA, Couper D, Donovan DM et al. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006;295:2003-17. PubMed
  6. Greenfield SF, Pettinati HM, O'Malley S, Randall PK, Randall CL. Gender differences in alcohol treatment: an analysis of outcome from the COMBINE study. Alcohol Clin Exp Res. 2010;34:1803-12. PubMed
  7. Morley KC, Teesson M, Reid SC, Sannibale C, Thomson C, Phung N et al. Naltrexone versus acamprosate in the treatment of alcohol dependence: A multi-centre, randomized, double-blind, placebo-controlled trial. Addiction. 2006;101:1451-62. PubMed
  8. Morley KC, Teesson M, Sannibale C, Baillie A, Haber PS. Clinical predictors of outcome from an Australian pharmacological relapse prevention trial. Alcohol Alcohol. 2010;45:520-6. PubMed
  9. Kiefer F, Jahn H, Tarnaske T, Helwig H, Briken P, Holzbach R et al. Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind, placebo-controlled study. Arch Gen Psychiatry. 2003;60:92-9. PubMed
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  11. Setiawan E, Pihl RO, Cox SM, Gianoulakis C, Palmour RM, Benkelfat C et al. The effect of naltrexone on alcohol's stimulant properties and self-administration behavior in social drinkers: influence of gender and genotype. Alcohol Clin Exp Res. 2011;35:1134-41. PubMed
  12. NALTREXONE (naltrexonhydroklorid). Summary of Product Characteristics. Medical Products Agency (MPA); 2014.
  13. Food and Drug Administration (FDA). Labeling - NALTREXONE HYDROCHLORIDE (naltrexone hydrochloride). Food and Drug Administration [www]. [updated 2016-04-12, cited 2016-04-01]. länk
  14. Krupitsky E, Nunes EV, Ling W, Illeperuma A, Gastfriend DR, Silverman BL. Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial. Lancet. 2011;377:1506-13. PubMed
  15. Farley AC, Hajek P, Lycett D, Aveyard P. Interventions for preventing weight gain after smoking cessation. Cochrane Database Syst Rev. 2012;1:CD006219. PubMed
  16. King AC, Cao D, O'Malley SS, Kranzler HR, Cai X, deWit H et al. Effects of naltrexone on smoking cessation outcomes and weight gain in nicotine-dependent men and women. J Clin Psychopharmacol. 2012;32:630-6. PubMed
  17. King AC, Cao D, Zhang L, O'Malley SS. Naltrexone reduction of long-term smoking cessation weight gain in women but not men: a randomized controlled trial. Biol Psychiatry. 2013;73:924-30. PubMed
  18. Fonsi Elbreder M, de Souza e Silva R, Pillon SC, Laranjeira R. Alcohol dependence: analysis of factors associated with retention of patients in outpatient treatment. Alcohol Alcohol. 2011;46:74-6. PubMed
  19. Harris AH, Kivlahan DR, Bowe T, Humphreys KN. Pharmacotherapy of alcohol use disorders in the Veterans Health Administration. Psychiatr Serv. 2010;61:392-8. PubMed
  20. Socialstyrelsens statistikdatabas . Stockholm: Socialstyrelsen. 2014 [cited 2016-02-17.] Socialstyrelsens statistikdatabas

Authors: Maria Enghag

Reviewed by: Mia von Euler

Approved by: Karin Schenck-Gustafsson