Acamprosate
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Maintenance of abstinence from alcohol in patients with alcohol dependence who are abstinent at treatment initiation | Adults; safety and efficacy not established in pediatrics; geriatric data limited | Adjunctive — must be part of a comprehensive program including psychosocial support | FDA Approved (2004) |
Acamprosate is a first-line maintenance pharmacotherapy for alcohol use disorder (AUD). It is intended for patients who have already completed alcohol withdrawal and achieved abstinence — efficacy was not demonstrated in patients who continued to drink at baseline or in polysubstance users. The drug does not treat acute withdrawal, does not produce a disulfiram-like reaction, and is not associated with abuse or dependence. Both the American Psychiatric Association and the VA/Department of Defense clinical practice guidelines recommend acamprosate alongside naltrexone as a first-line option for moderate-to-severe AUD; choice between the two is individualized, with acamprosate often preferred when patients have hepatic disease, are taking opioids, or want to focus specifically on abstinence maintenance.
Reduction of heavy drinking days in patients who are not fully abstinent at initiation — limited evidence; FDA labelling specifies abstinence at initiation. Evidence quality: low to moderate.
Combination therapy with naltrexone — the COMBINE trial did not demonstrate added benefit of acamprosate when added to naltrexone plus medical management; concurrent use is not routinely recommended outside specialist care. Evidence quality: high (negative result).
Cocaine, methamphetamine, or other substance use disorders — investigational; current evidence does not support routine use. Evidence quality: low.
Dosing
Acamprosate is dosed three times daily because of its short clinical action despite a longer terminal half-life. The 333 mg enteric-coated tablet is the only available strength; the standard 666 mg dose therefore requires two tablets per administration. Treatment should begin as soon as possible after the patient achieves abstinence (typically immediately following supervised withdrawal) and should be continued even if the patient relapses, in conjunction with psychosocial support.
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Standard AUD maintenance — normal renal function (CrCl >50 mL/min) | 666 mg PO TID (two 333 mg tablets three times daily) | 666 mg PO TID | 1998 mg/day (FDA recommended dose) | Initiate after abstinence is achieved; continue if relapse occurs Steady state in ~5 days; do not crush or chew tablets |
| Moderate renal impairment (CrCl 30–50 mL/min) | 333 mg PO TID (one tablet three times daily) | 333 mg PO TID | 999 mg/day | FDA PI: peak concentrations were ~2-fold higher and half-life ~1.8-fold longer in moderate impairment vs healthy |
| Severe renal impairment (CrCl ≤30 mL/min) | Contraindicated | Peak concentrations ~4-fold higher and half-life ~2.6-fold longer in severe impairment per FDA PI | ||
| Patient with relapse during treatment | No dose change | Continue current dose; do not discontinue | Same as standard | FDA PI specifies treatment should be maintained even if the patient relapses |
| Lower-dose option (selected patients) | — | FDA PI states a lower dose may be effective in some patients | — | Consider in patients with prominent diarrhoea or borderline tolerance; not specifically defined in PI |
Population-specific adjustments
| Population | Adjustment | Notes |
|---|---|---|
| Pediatrics | Safety and efficacy not established | FDA PI: no pediatric PK or efficacy data |
| Geriatric (≥65 years) | No fixed adjustment, but monitor renal function and reduce per CrCl criteria as appropriate | FDA PI: only 41 of 4,234 trial subjects were ≥65; renal function declines with age, so the renal dose-reduction criteria become particularly relevant |
| Pregnancy | Use only if benefit justifies risk | Former Pregnancy Category C — teratogenic in rats at the human-equivalent dose (mg/m²) and in rabbits at ~3× human dose; human data limited |
| Hepatic impairment (mild–moderate, Child-Pugh A/B) | No dose adjustment | Acamprosate is not metabolized; PK unchanged in mild–moderate impairment per FDA PI |
| Severe hepatic impairment (Child-Pugh C) | No specific PK data in FDA PI | Use caution; concurrent severe renal impairment is more likely in this population and would contraindicate use |
| Dialysis | Not addressed in FDA PI; severe renal impairment is a contraindication | Acamprosate is renally excreted unchanged; clearance characteristics on dialysis not well characterized |
The three-times-daily regimen is acamprosate’s biggest practical limitation. Adherence drops substantially compared with once- or twice-daily regimens, and missed doses partly explain weaker real-world effectiveness compared with the controlled-trial efficacy. Tying doses to consistent daily anchors — breakfast, lunch, and dinner — improves adherence; pill-counters or smartphone reminders help. In patients who cannot manage TID dosing, naltrexone (oral once daily or extended-release injectable monthly) is a reasonable alternative.
Pharmacology
Mechanism of Action
Acamprosate’s mechanism is incompletely understood. Chronic alcohol exposure produces neuroadaptations that disrupt the balance between excitatory glutamate and inhibitory GABA neurotransmission — protracted post-withdrawal hyperglutamatergic activity is thought to drive cravings, dysphoria, and relapse risk. Preclinical and human data suggest acamprosate modulates these systems, partly by attenuating glutamatergic NMDA-receptor activity and possibly by enhancing GABAergic tone, restoring the disrupted excitation–inhibition balance. Acamprosate is a structural analogue of the endogenous amino-acid taurine and the GABA-related compound homotaurine. Importantly, the drug has no anxiolytic, anticonvulsant, antidepressant, or sedative activity at clinical doses, does not produce a disulfiram-like reaction, does not block alcohol’s effects, and is not associated with abuse or dependence.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Absolute oral bioavailability ~11%; Tmax 3–8 h; steady state in ~5 days; food reduces Cmax by ~42% and AUC by ~23% but not clinically significant per FDA PI | Low and variable bioavailability — adherence and TID dosing are critical; tablets are enteric-coated and must be swallowed whole; can be taken with or without food |
| Distribution | Vd ~72–109 L (~1 L/kg) following IV administration; plasma protein binding negligible | Negligible protein binding effectively eliminates protein-binding-mediated drug interactions |
| Metabolism | None — acamprosate does not undergo metabolism. No CYP induction or inhibition (CYP1A2, 2C9, 2C19, 2D6, 2E1, 3A4) | Hepatic disease does not require dose adjustment; minimal pharmacokinetic drug-interaction potential |
| Elimination | Renal excretion of unchanged drug; terminal half-life 20–33 h; clearance is linearly related to creatinine clearance | Renal function determines dosing; severe renal impairment (CrCl ≤30 mL/min) is a contraindication; moderate renal impairment requires dose halving |
Side Effects
The incidence figures below are taken directly from the FDA prescribing information adverse-reactions table for the standard 1998 mg/day dose vs placebo (Campral 1998 mg/day, N=1539; placebo, N=1706). Acamprosate is overall well tolerated; diarrhoea is the only adverse effect reliably more frequent than placebo and the only one that meaningfully drives discontinuation. Many of the other “common” effects occurred at rates similar to or below placebo and likely reflect the alcohol-dependent population rather than the drug.
| Adverse Effect | Incidence (placebo) | Clinical Note |
|---|---|---|
| Diarrhoea | 17% (10%) | The only adverse effect reliably more frequent than placebo; usually dose-related and often improves; main reason for discontinuation |
| Adverse Effect | Incidence (placebo) | Clinical Note |
|---|---|---|
| Asthenia (weakness/fatigue) | 5% (5%) | Similar to placebo; usually does not warrant discontinuation |
| Insomnia | 6% (7%) | Similar to placebo; sleep hygiene first-line; avoid sedative-hypnotics where possible in AUD |
| Anxiety / nervousness | 5% (6%) | Similar to placebo; consider underlying anxiety disorder or post-acute withdrawal symptoms |
| Depression | 4% (5%) | Similar to placebo; depression is highly comorbid with AUD; screen and treat as appropriate |
| Nausea | 4% (3%) | Usually mild and transient |
| Flatulence | 4% (2%) | Class GI effect |
| Pain (any location) | 4% (3%) | Includes back pain, abdominal pain, generalized pain |
| Pruritus | 4% (3%) | Usually mild; topical antipruritic if needed |
| Dizziness | 3% (3%) | Similar to placebo |
| Accidental injury | 3% (3%) | FDA PI category includes events coded as “fracture”; similar to placebo overall |
| Anorexia | 2% (3%) | Similar to placebo |
| Sweating | 2% (2%) | Similar to placebo |
| Paresthesia | 2% (2%) | Similar to placebo |
| Dry mouth | 1% (2%) | Similar to placebo |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Suicidal ideation / suicide attempts | 1.4% vs 0.5% in studies ≤6 months; 2.4% vs 0.8% in year-long studies (Campral vs placebo per FDA PI) | Variable; often associated with relapse | Monitor for emerging depression and suicidality at baseline and throughout treatment; evaluate context of any relapse; involve mental health support |
| Completed suicide | 0.13% (3/2272) vs 0.10% (2/1962) in pooled controlled trials per FDA PI | Variable | Active suicide-risk assessment; safety planning; prompt referral when risk emerges |
| Acute kidney failure | Postmarketing — at least 3 cases reported outside the US per FDA PI | Variable | Discontinue acamprosate; evaluate volume status, drug history, and other nephrotoxic exposures; supportive care |
| Hypersensitivity reactions | Rare | Any time | Permanent discontinuation; prior hypersensitivity is a labelled contraindication |
| Other serious events reported in the FDA PI (uncommon to rare) | Infrequent / rare | Variable | Includes pancreatitis, GI haemorrhage, hepatitis, convulsion, and others reported during premarketing surveillance — most occurred at frequencies comparable to or below placebo |
Diarrhoea is the predictable and dose-related adverse effect. Most cases are mild and improve over the first 1–2 weeks; supportive measures (hydration, dietary adjustment, brief loperamide if needed) usually suffice. If diarrhoea is persistent or interferes with daily life, the FDA PI explicitly notes that a lower dose may be effective in some patients — consider trialling 333 mg TID (one tablet) rather than abandoning therapy. Discontinuing acamprosate over a manageable GI side effect risks losing an evidence-based AUD treatment in a population where any ongoing pharmacotherapy is associated with better outcomes.
Drug Interactions
Acamprosate has a notably clean drug-interaction profile: it is not metabolized, has negligible plasma protein binding, and neither induces nor inhibits CYP enzymes. The only PK interaction noted in the FDA PI is with naltrexone, and this does not require dose adjustment. Pharmacodynamic considerations — additive GI effects, additive CNS effects in polysubstance use — are clinically more relevant than PK changes.
Monitoring
Acamprosate is one of the lowest-monitoring-burden chronic medications in psychiatry: no required laboratory monitoring beyond renal function, no QTc concerns, no metabolic monitoring, and no titration. The most important “monitoring” is the clinical encounter itself — assessing drinking, mood, suicidality, adherence, and the broader recovery context.
-
Drinking behaviour and abstinence
Every visit (weekly–biweekly during initial phase; monthly when stable)
Routine Number of drinks, drinking days, heavy-drinking days, cravings (validated tools: PACS, OCDS); biomarkers (PEth, %CDT, GGT) where available; do not stop acamprosate after relapse -
Renal function (creatinine, eGFR, CrCl)
Baseline; periodically — particularly in elderly or comorbid patients
Routine Adjust dose per CrCl criteria; discontinue if CrCl falls to ≤30 mL/min -
Mood & suicidality (PHQ-9, suicide screening)
Baseline; each visit during initial phase; periodically when stable
Routine FDA PI requires monitoring for emergence of depression and suicidality; engage family/caregivers; safety plan as needed -
Treatment adherence
Every visit
Routine TID dosing is the major adherence challenge; pillboxes, alarms, anchoring to meals; consider naltrexone if TID not feasible -
Liver function (AST, ALT, GGT)
Baseline; per general AUD care
Routine Not required by acamprosate labelling, but standard AUD care given high prevalence of alcohol-related liver disease; informs choice between acamprosate (preferred in significant hepatic disease) and naltrexone -
Engagement in psychosocial treatment
Every visit
Routine FDA PI: acamprosate efficacy demonstrated as adjunct to comprehensive psychosocial care, not as monotherapy -
Diarrhoea / GI tolerability
First 1–4 weeks; thereafter as needed
Trigger-based If persistent, consider dose reduction (333 mg TID) before discontinuing -
Pregnancy testing / contraception counselling
As clinically indicated in patients of reproductive potential
Trigger-based Animal teratogenicity at human-equivalent doses; discuss risk–benefit and preferred contraception during therapy
Contraindications & Cautions
Per the FDA prescribing information, adverse events of a suicidal nature were more common in acamprosate-treated patients than in placebo-treated patients in controlled trials (1.4% vs 0.5% in studies ≤6 months; 2.4% vs 0.8% in year-long studies). Completed suicide rates were similar between groups (0.13% vs 0.10%). Most events occurred in the context of relapse, and the relationship between acamprosate, alcohol dependence, depression, and suicidality is complex and not fully understood. The FDA PI requires that patients, families, and caregivers be alerted to monitor for emerging depression or suicidal thinking and to report symptoms promptly.
Renal impairment: Acamprosate is contraindicated in severe renal impairment (CrCl ≤30 mL/min) and requires dose halving in moderate renal impairment (CrCl 30–50 mL/min). Renal function should be assessed at baseline and periodically — particularly in older adults.
Alcohol withdrawal: Acamprosate does not treat acute alcohol withdrawal. Withdrawal must be managed with appropriate agents (typically benzodiazepines) before initiating acamprosate.
Absolute Contraindications (FDA PI)
- Severe renal impairment (CrCl ≤30 mL/min) — peak concentrations are ~4-fold higher and half-life ~2.6-fold longer than in healthy subjects
- Hypersensitivity to acamprosate calcium or any component of the formulation
Relative Contraindications (Specialist Input Recommended)
- Active alcohol withdrawal — manage withdrawal first; acamprosate has no role in withdrawal symptom control
- Pregnancy — animal teratogenicity at human-equivalent doses; use only if benefit justifies risk and after shared decision-making
- Active suicidal ideation — coordinate with mental health services and consider whether the medication is appropriate at this time; not a strict contraindication
- Continued heavy drinking at initiation — the FDA-labelled indication requires abstinence at treatment start; efficacy was not demonstrated in non-abstinent or polysubstance-using populations
Use with Caution
- Moderate renal impairment (CrCl 30–50 mL/min) — start at the reduced dose (333 mg TID) per FDA PI
- Elderly patients — age-related reduction in renal function may require dose adjustment; geriatric trial data are very limited (only 41 of 4,234 trial subjects were ≥65)
- Comorbid depression or anxiety — assess and treat concurrently; acamprosate itself is not antidepressant or anxiolytic
- Lactation — human data unavailable; acamprosate is excreted in animal milk; weigh benefit vs. risk
- Concurrent nephrotoxic medications — monitor renal function more frequently
Patient Counselling
Purpose of Therapy
Acamprosate is a medication that helps the brain re-balance after years of alcohol use. Long-term drinking shifts the brain’s chemistry in ways that drive cravings, mood swings, and sleep problems for weeks or months after the last drink — acamprosate gently nudges that chemistry back toward normal. It is not a substitute for alcohol, does not produce a high, is not addictive, and does not cause a sick feeling if you drink. It works best as part of a treatment plan that includes counselling, mutual-support groups (AA, SMART Recovery, etc.), and medical follow-up. Many patients take it for 6–12 months or longer; the longer you stay on it, the better the chances of staying sober.
How to Take It
Take two 333 mg tablets three times a day — six tablets total daily. Many people anchor doses to breakfast, lunch, and dinner to help remember; you can take the tablets with or without food. Swallow the tablets whole, do not crush or chew them — they have a special coating that lets them work properly. If you miss a dose, take it as soon as you remember unless your next dose is close; do not double up. It usually takes a few days to a week for the medication to reach steady levels in your system.
Sources
- Campral (acamprosate calcium) Delayed-Release Tablets — US Prescribing Information. Forest Pharmaceuticals, Inc. Revised January 2012. accessdata.fda.gov/drugsatfda_docs/label/2012/021431s015lbl.pdf Primary US regulatory document — source for indications, dosing, contraindications, drug interactions, and adverse-reaction frequencies cited in this monograph.
- Acamprosate Calcium Delayed-Release Tablets — US Prescribing Information (generic). DailyMed. dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fe6f754f-62b4-4c86-805d-221332409516 Current generic labeling, identical in core content to the discontinued Campral brand label.
- Anton RF, O’Malley SS, Ciraulo DA, et al; COMBINE Study Research Group. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006;295(17):2003-2017. doi.org/10.1001/jama.295.17.2003 Largest US trial of pharmacotherapy for AUD; naltrexone plus medical management showed clinically meaningful benefit; acamprosate did not show added benefit over placebo or as add-on to naltrexone.
- Mason BJ, Goodman AM, Chabac S, Lehert P. Effect of oral acamprosate on abstinence in patients with alcohol dependence in a double-blind, placebo-controlled trial: the role of patient motivation. J Psychiatr Res. 2006;40(5):383-393. doi.org/10.1016/j.jpsychires.2006.02.002 US pivotal trial supporting Campral approval; demonstrated greater abstinence rates with acamprosate vs placebo, particularly in motivated, abstinent-at-baseline patients.
- Sass H, Soyka M, Mann K, Zieglgänsberger W. Relapse prevention by acamprosate. Results from a placebo-controlled study on alcohol dependence. Arch Gen Psychiatry. 1996;53(8):673-680. doi.org/10.1001/archpsyc.1996.01830080023006 Foundational European trial establishing acamprosate’s efficacy in maintaining abstinence in detoxified alcohol-dependent patients.
- Rösner S, Hackl-Herrwerth A, Leucht S, Lehert P, Vecchi S, Soyka M. Acamprosate for alcohol dependence. Cochrane Database Syst Rev. 2010;(9):CD004332. doi.org/10.1002/14651858.CD004332.pub2 Cochrane meta-analysis of 24 randomized trials (~7,000 patients) confirming acamprosate’s efficacy in promoting abstinence and reducing risk of any drinking; NNT around 9.
- Jonas DE, Amick HR, Feltner C, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA. 2014;311(18):1889-1900. doi.org/10.1001/jama.2014.3628 AHRQ-commissioned meta-analysis comparing AUD pharmacotherapies; acamprosate and naltrexone both supported by moderate-strength evidence with comparable effect sizes.
- Reus VI, Fochtmann LJ, Bukstein O, et al. The American Psychiatric Association Practice Guideline for the Pharmacological Treatment of Patients With Alcohol Use Disorder. Am J Psychiatry. 2018;175(1):86-90. doi.org/10.1176/appi.ajp.2017.1750101 APA practice guideline supporting acamprosate or naltrexone as first-line pharmacotherapy for moderate-to-severe AUD in patients who prefer pharmacotherapy or have not responded to non-pharmacologic treatment.
- US Department of Veterans Affairs / Department of Defense. VA/DoD Clinical Practice Guideline for the Management of Substance Use Disorders. Version 4.0. 2021. healthquality.va.gov/guidelines/MH/sud/ Most recent US federal guideline for AUD pharmacotherapy; recommends acamprosate or naltrexone as first-line; guides choice based on hepatic, renal, and concurrent opioid considerations.
- Substance Abuse and Mental Health Services Administration. Medication for the Treatment of Alcohol Use Disorder: A Brief Guide. SAMHSA Publication. store.samhsa.gov/product/medication-for-the-treatment-of-alcohol-use-disorder-a-brief-guide/sma15-4907 Practical SAMHSA guidance on AUD pharmacotherapy in primary-care and addiction-medicine settings.
- Mason BJ, Heyser CJ. Acamprosate: a prototypic neuromodulator in the treatment of alcohol dependence. CNS Neurol Disord Drug Targets. 2010;9(1):23-32. doi.org/10.2174/187152710790966641 Mechanistic review covering acamprosate’s modulation of glutamate and GABA neurotransmission and the neuroadaptive changes that follow chronic alcohol exposure.
- Spanagel R, Vengeliene V, Jandeleit B, et al. Acamprosate produces its anti-relapse effects via calcium. Neuropsychopharmacology. 2014;39(4):783-791. doi.org/10.1038/npp.2013.264 Influential preclinical study proposing the calcium ion as the active moiety responsible for acamprosate’s anti-relapse effects — a hypothesis that has stimulated debate but has not changed clinical practice.
- Saivin S, Hulot T, Chabac S, Potgieter A, Durbin P, Houin G. Clinical pharmacokinetics of acamprosate. Clin Pharmacokinet. 1998;35(5):331-345. doi.org/10.2165/00003088-199835050-00001 Comprehensive PK review covering the low oral bioavailability, lack of metabolism, renal elimination, and dose adjustment in renal impairment.
- Maisel NC, Blodgett JC, Wilbourne PL, Humphreys K, Finney JW. Meta-analysis of naltrexone and acamprosate for treating alcohol use disorders: when are these medications most helpful? Addiction. 2013;108(2):275-293. doi.org/10.1111/j.1360-0443.2012.04054.x Meta-analysis suggesting acamprosate is most effective at promoting abstinence and naltrexone at reducing heavy drinking — supports differential drug selection in clinical practice.