Is naltrexone more effective than acamprosate at treating alcohol use disorder?

Is naltrexone more effective than acamprosate at treating alcohol use disorder?

Comment by InpharmD Researcher

Both naltrexone and acamprosate are recommended treatments for alcohol use disorder, with the American Psychiatric Association endorsing their use. While comparative data from various sources show mixed results, indicating no significant differences between the drugs in improving alcohol consumption outcomes, naltrexone demonstrates a slightly higher risk of nausea and vomiting compared to acamprosate. However, naltrexone, particularly in combination with behavioral intervention, appears to offer better outcomes in reducing alcohol consumption, especially in individuals with low levels of clinical depression and alcohol dependence severity.

Background

A 2018 guideline published by the American Psychiatric Association (APA) recommends either naltrexone or acamprosate for patients with moderate to severe alcohol use disorder (AUD). Both agents are deemed to have clinical benefits that outweigh potential harms of treatment or harms of continued alcohol use. Acamprosate has demonstrated small benefit on the outcome of returning to any drinking and number of drinking days while naltrexone is associated with small benefits for returning to any drinking, returning to heavy drinking, frequency of drinking days, and frequency of heavy drinking days. In regards to comparative efficacy, the APA guidelines reference the Healthcare Research and Quality (AHRQ) report below where results were inconclusive. However, the U.S. COMBINE study reported better drinking outcomes for naltrexone compared to acamprosate. The result from this singular study was insufficient to change the APA guideline recommendations. [1]

The 2014 Agency for AHRQ report on pharmacotherapy for adults with AUD discusses comparative data between acamprosate and naltrexone. The report also included a meta-analysis specifically for adverse events between acamprosate and naltrexone. Four trials with a total of over 1,000 participants compared acamprosate and naltrexone for alcohol dependence treatment. Doses and treatment durations ranged from 12-16 weeks. Meta-analyses found no significant differences between the drugs on return to any drinking, return to heavy drinking, drinking days, or heavy drinking days. Two trials reported drinks per drinking day but did not provide enough data for quantitative synthesis. Overall, the studies found no evidence that acamprosate or naltrexone was more effective than the other for improving alcohol consumption outcomes. [2]

In the safety meta-analysis, the risks of nausea and vomiting were slightly higher for those treated with naltrexone compared to acamprosate. However, there was no significant difference between the drugs in withdrawal due to adverse events, dizziness, insomnia, diarrhea, headache, or other outcomes reported. [2]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Is naltrexone more effective than acamprosate at treating alcohol use disorder?

Level of evidence

B - One high-quality study or multiple studies with limitations Read more→

Please see Tables 1-2 for your response.

Naltrexone versus acamprosate in the treatment of alcohol dependence: a multi-centre, randomized, double-blind, placebo-controlled trial
Design	Double-blind, randomized, placebo-controlled trial N= 169
Objective	To compare the efficacy of acamprosate and naltrexone in the treatment of alcohol dependence
Study Groups	Placebo (n= 61) Acamprosate (n= 55) Naltrexone (n= 53)
Inclusion Criteria	18 to 65 years, Diagnostic and Statistical Manual version IV (DSM-IV) diagnosis of alcohol dependence or abuse, abstinence from alcohol for 3-21 days with resolution of any withdrawal symptoms, sufficient English comprehension skills to provide informed consent and complete questionnaires
Exclusion Criteria	Advanced liver disease, previous treatment with naltrexone or acamprosate within 3 months of randomization, any other drug dependence, severe current psychiatric disorder associated with psychosis and significant suicide risk, pregnancy/breastfeeding
Methods	Patients were randomized to receive either naltrexone 50 mg/day, acamprosate 1998 mg/day, or placebo for 12 weeks. All patients were also offered compliance therapy targeting.
Duration	Treatment duration: 12 weeks Study duration: 24 weeks
Outcome Measures	Primary: Time to relapse (≥ four drinks for women, ≥ six drinks for men) Secondary: Cumulative days abstinent, number of drinks per drinking day, Alcohol Dependence Scale (ADS) score, Penn Alcohol Craving Scale (PACS) craving score
Baseline Characteristics		Placebo (n= 61)	Acamprosate (n= 55)	Naltrexone (n= 55)
	Age, years	42.4	45.2	47.6
	Female	36%	23.6%	28.3%
	Married	33.3%	38.9%	34.0%
	Partnership	53.3%	48.2%	47.2%
	Education, years	12.43	14.2	12.9
	Drinks per drinking day	14.3	16.0	14.1
	Total intensity of withdrawal (AWS, 0-5)	0.57	0.42	0.47
Results	Endpoint	Placebo (n= 61)	Acamprosate (n= 55)	Naltrexone (n= 55)
	Patients who developed relapse	43 (73%)	40 (74%)	39 (75%)
	Time to first lapse, days Time to first relapse, days	24.6 ± 32.1 33.4 ± 34.9	24.1 ± 32.9 33.6 ± 34.6	24.3 ± 31.7 39.2 ± 32.3
	Cumulative days abstinent	56.7 ± 31.4	66.3 ± 25.2	57.8 ± 29.2
	Number of drinks per drinking day	7.1 ± 6.0	7.5 ± 6.1	5.9 ± 6.1
	ADS score	9.7 ± 9.7	9.3 ± 9.6	10.1 ± 9.6
	PACS craving score	10.9 ± 8.6	10.9 ± 8.5	11.1 ± 8.6
	A significant beneficial treatment effect on time to first relapse was revealed for subjects with ‘no depression’ allocated to naltrexone (n = 56; p< 0.01). A significant beneficial treatment effect was revealed in subjects with ‘low dependence’ allocated to naltrexone (n = 34; p< 0.05).
Adverse Events	No serious adverse events were reported.
Study Author Conclusions	The results of this study support the efficacy of naltrexone in the relapse prevention of alcoholism amongst those with low levels of clinical depression and alcohol dependence severity. No effect of acamprosate was found in our sample.
InpharmD Researcher Critique	The study has a relatively small sample size, which may limit the detection of significant effects, especially when analyzing subgroups. Therefore, the advantages that naltrexone may have over acamprosate should be interpreted with caution.

References:

Morley KC, Teesson M, Reid SC, et al. Naltrexone versus acamprosate in the treatment of alcohol dependence: A multi-centre, randomized, double-blind, placebo-controlled trial. Addiction. 2006;101(10):1451-1462. doi:10.1111/j.1360-0443.2006.01555.x

Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (The COMBINE Study)
Design	Randomized controlled trial N= 1,383
Objective	To evaluate the efficacy of medication, behavioral therapies, and their combinations for treatment of alcohol dependence and to evaluate placebo effect on overall outcome
Study Groups	Naltrexone (n= 154) Acamprosate (n= 152) Naltrexone + Acamprosate (n= 148) Placebo (n= 153)
Inclusion Criteria	Alcohol dependence, determined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria; 4 to 21 days of abstinence; more than 14 drinks (women) or 21 drinks (men) per week, with at least 2 heavy drinking days (defined as ≥4 drinks/d for women and ≥5 drinks/d for men) during a consecutive 30-day period within the 90 days prior to baseline evaluation
Exclusion Criteria	History of other substance abuse (other than nicotine or cannabis) by DSM-IV criteria in the last 90 days (6 months for opiate abuse) or by urine drug screen; psychiatric disorder requiring medication; unstable medical conditions (eg, serum liver enzyme levels >3 times the upper limit of normal)
Methods	Patients were randomized into nine different groups. Four groups received medication only, including naltrexone (100 mg/day), acamprosate (3 g/day), naltrexone + acamprosate, or placebo. Four other groups received the same active medications (or placebo) combined with a behavioral intervention (CBI), while one group received CBI alone (no pills). Participants in each group were assigned blister cards and took up to 8 pills daily for 16 weeks. The appearance of all pills was identical to maintain blinding. Naltrexone and its placebo were taken once daily as 2 pills, while acamprosate and placebo were taken three times daily. Doses could be adjusted based on tolerability.
Duration	January 2001 to January 2004
Outcome Measures	Percent days abstinent from alcohol and time to first heavy drinking day
Baseline Characteristics		Naltrexone (n= 154)	Acamprosate (n= 152)	Naltrexone + Acamprosate (n= 148)	Placebo (n= 153)
	Age, years	44.4 ± 9.93	44.0 ± 10.97	44.2 ± 10.83	44.2 ± 9.15
	Male	105 (68.2%)	105 (69.1%)	106 (71.6%)	103 (67.3%)
	Race White Black Hispanic	108 (70.1%) 18 (11.7%) 25 (16.2%)	122 (80.3%) 10 (6.6%) 15 (9.9%)	117 (79.1%) 11 (7.4%) 15 (10.1%)	120 (78.4%) 10 (6.5%) 17 (11.1%)
	Current smoker	83 (53.9%)	74 (48.7%)	91 (61.5%)	81 (52.9%)
	Percent days abstinent	29.8 ± 24.70	24.6 ± 24.78	22.9 ± 24.70	24.3 ± 24.74
	Drinks per drinking day	12.7 ± 7.69	12.2 ± 7.77	12.4 ± 7.66	12.6 ± 7.67
	Overall drinks per day	8.9 ± 6.45	9.1 ± 6.41	9.5 ± 6.45	9.6 ± 6.43
	Heavy drinking days*	19.0 ± 8.56	19.6 ± 8.51	20.1 ± 8.52	20.1 ± 8.53
	DSM-IV symptoms	5.5 ± 1.27	5.7 ± 1.34	5.7 ± 1.38	5.5 ± 1.28
	ADS score	17.5 ± 7.92	17.6 ± 7.38	16.8 ± 7.70	16.5 ± 7.15
	OCDS score	24.6 ± 7.57	26.3 ± 7.64	25.3 ± 7.66	24.5 ± 7.55
	DrInC score	48.1 ± 20.10	52.1 ± 20.10	47.5 ± 20.19	46.5 ± 20.16
	Abbreviations: ADS= Alcohol Dependence Scale; DrInC= Drinker Inventory of Consequences; DSM-IV= Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; OCDS= Obsessive Compulsive Drinking Scale Baseline characteristics presented are for the medical management (No CBI) groups 30 days prior to randomization was the baseline timeframe used for percent days abstinent, drinks per drinking day, overall drinks per day, and heavy drinking days *Heavy drinking days defined as ≥4 drinks/d for women and ≥ 5 drinks/d for men
Results	Endpoint	Naltrexone (n= 154)	Acamprosate (n= 152)	Naltrexone + Acamprosate (n= 148)	Placebo (n= 153)	p-value
	Percent days abstinent	80.0 ± 26.06	75.6 ± 26.01	80.5 ± 25.91	73.8 ± 25.98	--
	Return to heavy drinking	104 ± 67.5	108 ± 71.1	96 ± 64.9	115 ± 75.2	--
	Good clinical outcome	87 ± 73.7	79 ± 60.8	91 ± 78.4	71 ± 58.2	--
	Adverse events during treatment by medication group* Nausea Vomiting Decreased appetite Somnolence Alcohol detoxification Withdrawals due to adverse events	101 (34%) 45 (15%)‡ 92 (31%)‡ 63 (21%) 112 (37%)† 6 (2%) 12 (4%)	72 (24%) 27 (9%) 193 (65%)† 57 (19%) 94 (31%)§ 11 (4%)‡ 9 (3%)	125 (42%)† 52 (18%)§ 165 (56%)† 75 (25%)† 91 (31%)‡ 11 (4%)‡ 13 (4%)‡	65 (21%) 26 (9%) 108 (35%) 41 (13%) 72 (24%) 3 (1%) 4 (1%)	<0.001 <0.001 <0.001 0.002 0.003 0.58 0.09
	Results presented are for the medical management (No CBI) groups *CBI + medical management groups also included: Acamprosate (n= 303), Naltrexone (n= 309), Acamprosate + Naltrexone (n = 305), and Placebo (n= 309) †P.001 or placebo vs active drug comparison ‡P.05 for placebo vs active drug comparison §P.01 for placebo vs active drug comparison
Adverse Events	See results
Study Author Conclusions	Patients receiving medical management with naltrexone, CBI, or both fared better on drinking outcomes, whereas acamprosate showed no evidence of efficacy, with or without CBI. No combination produced better efficacy than naltrexone or CBI alone in the presence of medical management. Placebo pills and meeting with a health care professional had a positive effect above that of CBI during treatment. Naltrexone with medical management could be delivered in healthcare settings, thus serving alcohol-dependent patients who might otherwise not receive treatment.
InpharmD Researcher Critique	Although the study suggests the benefits of naltrexone and CBI, and the lack of efficacy with acamprosate, further research is needed to assess the efficacy and safety of long-term therapy beyond 16 weeks.

References:

Anton RF, O'Malley SS, Ciraulo DA, et al. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006;295(17):2003-2017. doi:10.1001/jama.295.17.2003