TITLE: Long-term Use of Acamprosate Calcium for Alcoholism: A Review of the Clinical Effectiveness, Safety, and Guidelines DATE: 29 May 2015 CONTEXT AND POLICY ISSUES Alcoholism or alcohol dependence is a chronic and often progressive disease with genetic, psychosocial, and environmental factors influencing its development and manifestation. 1,2 It is a major public health problem impacting individuals, their families and society. The worldwide annual estimate of deaths attributed to alcoholism is 2.5 million, which represents approximately 4% of all mortality. 3 It was estimated in 2012, that 3.2% of the population in Canada of age 15 years or older, abused or were dependent on alcohol. 4 The major challenge in management of alcohol dependence is maintenance of abstinence after detoxification and prevention of relapse. 5 Treatment for alcohol dependence includes psychotherapy and pharmacotherapy. Acamprosate is one of the drugs used for treatment of individuals with alcohol dependence. Acamprosate, or N-acetyl homotaurine appears to modulate the N-methyl-D-aspartate (NMDA) receptor. 6 During alcohol withdrawal there is an increased influx of calcium through the NMDA receptors and acamprosate appears to inhibit the calcium influx and thereby restore the balance between inhibitory and excitatory neurotransmitters. 7 Its exact mechanism of action is however still unclear. 6,7 Systematic reviews have shown that, generally, acamprosate was an effective treatment for supporting abstinence after detoxification in adults with alcohol dependence. 6-9 The most common adverse event associated with acamprosate was transient diarrhea but acamprosate was generally considered to be well tolerated and safe. 10,11 The long term effectiveness of acamprosate is unclear as the durations of acamprosate use were 1 year in the studies included in these systematic reviews. The purpose of this report is to review the available evidence on the clinical effectiveness and safety for long term (> 1 year) use of acamprosate to treat adults with alcoholism and to review evidence-based guidelines on the use of acamprosate for treating alcoholism. Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material and may contain material in which a third party owns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a web site, redistributed by email or stored on an electronic system without the prior written permission of CADTH or applicable copyright owner. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.
RESEARCH QUESTIONS 1. What is the clinical effectiveness and safety of long-term (> 1 year) acamprosate calcium use for adults with alcoholism? 2. What are the evidence-based guidelines regarding the use of acamprosate calcium for the treatment of alcoholism? KEY FINDINGS No relevant studies were identified on the clinical effectiveness and safety of long-term (> 1 year) acamprosate use for adults with alcoholism. Three evidence-based guidelines recommended that acamprosate be initiated in individuals with alcoholism after assisted withdrawal and in combination with psychological or psychosocial therapy but do not provide recommendations regarding use beyond one year. METHODS Literature Search Strategy A limited literature search was conducted on key resources including PubMed, MEDLINE, Embase, PsycINFO, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2005 and April 28, 2015. Selection Criteria and Methods One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1. Population Intervention Comparator Outcomes Study Designs Table 1: Selection Criteria Adults with alcoholism Acamprosate calcium (Campral) for longer than one year Any comparator (placebo, no treatment, other active treatment) No comparator Clinical effectiveness (e.g. alcohol abstinence) Safety Evidence-based guidelines for use Health technology assessment (HTA), systematic review (SR), metaanalysis (MA), randomized controlled trial (RCT), and non-randomized study (NRS) Long-term Use of Acamprosate Calcium 2
Exclusion Criteria Studies were excluded if they did not satisfy the selection criteria, if they were duplicate publications, or were published prior to 2005. Guidelines were excluded, if the methodology used was unclear. Critical Appraisal of Individual Studies Critical appraisal of a study was conducted based on an assessment tool appropriate for the particular study design. The AGREE II checklist 12 was used for appraising the guidelines. For the critical appraisal, a numeric score was not calculated. Instead, the strength and limitations of the study were described. SUMMARY OF EVIDENCE Quantity of Research Available A total of 515 citations were identified in the literature search. Following screening of titles and abstracts, 469 citations were excluded and 46 potentially relevant reports from the electronic search were retrieved for full-text review. Three potentially relevant publications were retrieved from the grey literature search. Of these 49 potentially relevant articles, 46 publications were excluded for various reasons, while three publications 13-15 met the inclusion criteria and were included in this report. These three publications 13-15 were evidence-based guidelines. No relevant HTAs, SRs, RCTs or NRSs were identified. Appendix 1 describes the PRISMA flowchart of the study selection. Summary of Study Characteristics Characteristics of the included guidelines are summarized below and details are provided in Appendix 2. Guidelines Three relevant evidence-based guidelines 13-15 were identified. One guideline 15 was specifically on alcohol use disorders whereas the other two guidelines 13,14 were on substance use disorders and included a section on alcohol use disorder. The National Institute for Health and Clinical Excellence (NICE) guideline 15 on alcohol-use disorders was published in 2011 from the United Kingdom (UK). The Department of Veterans Affairs and Department of Defense (VA/DoD) guideline 14 on substance use disorders was published in 2009 from United States of America (USA). The American Psychiatric Association (APA) guideline 13 for substance use disorders was published in 2006 from USA. Summary of Critical Appraisal The strength and limitations of the included guidelines are summarized below and details are provided in Appendix 3. Three relevant evidence-based guidelines 13-15 were identified. Overall the guidelines were of good quality. For all three guidelines the scope was clearly stated, the guideline development Long-term Use of Acamprosate Calcium 3
group comprised of individuals with relevant expertise such as psychiatrists and academics, the guideline development process included a systematic literature search, external review of the draft and a process for updating the guideline and the recommendations were clearly stated. The methodology for selection of studies retrieved from the literature search was unclear in the guidelines. In all three guidelines 13-15 it was unclear if patient input was sought, however one 15 of these guidelines included a lay person and a carer representative in the guideline development group. Implementation issues were not described. Cost implications were considered in one guideline 15 but did not appear to be considered in two guidelines. 13,14 In one guideline 15 the level of evidence and the recommendation category for the specific recommendation were not explicitly stated however it was mentioned that the GRADE method was used. In the second guideline 14 the level of evidence was not explicitly stated and the category of recommendation was sometimes stated however a process for grading was in place. In the third guideline 13 the category of recommendation was stated but the level of evidence was not explicitly stated. Of the three guidelines, in two 13,15 it was mentioned that the guideline development group members were required to provide disclosures of conflict of interest and in one guideline 14 it was unclear. Summary of Findings The findings are summarized below and the details are provided in Appendix 4. What is the clinical effectiveness of and safety of long-term (> 1 year) acamprosate calcium use for adults with alcoholism? No HTAs, SRs, RCTs or NRSs were identified on the clinical effectiveness of and safety of longterm (> 1 year) acamprosate use for adults with alcoholism. What are the evidence-based guidelines regarding the use of acamprosate calcium for the treatment of alcoholism? Three relevant evidence based guidelines 13-15 were identified. The NICE guidelines 15 provided some recommendations for treatment with acamprosate for individuals with alcohol dependence. It was recommended that after successful withdrawal, acamprosate or oral naltrexone in combination with individual psychological interventions or behavioural couples therapy in case of individuals with partners, should be considered. If acamprosate is used, it was recommended to be started as soon as possible after assisted withdrawal. The recommended daily dose of acamprosate was 1998 mg for individuals with weight 60 kg and a maximum daily dose of 1,332 mg for individuals with weight < 60 kg. It was to be prescribed for up to six months, or longer for those benefiting from it and who were willing to continue. It was recommended that acamprosate be stopped if drinking persists for four to six months after starting the drug. The VA/DoD guidelines 14 stated that treatment with acamprosate should be considered for patients with alcohol dependence, be initiated after abstinence, and be combined with psychosocial therapy. The APA guidelines 13 stated that acamprosate may reduce alcohol craving in abstinent individuals and may also be used as an effective adjunct together with psychosocial treatment in motivated individuals. In summary, the guidelines recommend that acamprosate be initiated in individuals with alcoholism after assisted withdrawal and in combination with psychological or psychosocial therapy. There was no recommendation regarding the maximum duration of acamprosate use. Long-term Use of Acamprosate Calcium 4
Limitations No HTAs, SRs, RCTs or NRSs on the long term (> 1 year) clinical effectiveness and safety of acamprosate for the treatment of alcoholism were identified. No guideline on long term (> 1 year) use of acamprosate for treating adults with alcoholism was identified No Canadian evidence-based guideline was identified but the recommendations from the guidelines published from UK and USA are likely to apply for individuals with alcoholism in Canada. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING No relevant studies were identified on the clinical effectiveness and safety of long-term (> 1 year) acamprosate use for adults with alcoholism. The evidence-based guidelines recommend that acamprosate be initiated in individuals with alcoholism after assisted withdrawal and in combination with psychological or psychosocial therapy, but do not provide recommendations regarding use beyond one year. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca Long-term Use of Acamprosate Calcium 5
REFERENCES 1. Mayo Clinic Staff. Alcoholism [Internet]. Rochester (MN): Mayo Clinic; 2014 Dec 5. [cited 2015 May 12]. Available from: http://www.mayoclinic.org/diseasesconditions/alcoholism/basics/definition/con-20020866 2. Morse RM, Flavin DK. The definition of alcoholism. The Joint Committee of the National Council on Alcoholism and Drug Dependence and the American Society of Addiction Medicine to Study the Definition and Criteria for the Diagnosis of Alcoholism. JAMA. 1992 Aug 26;268(8):1012-4. 3. Jaurigue MM, Cappell MS. Therapy for alcoholic liver disease. World J Gastroenterol [Internet]. 2014 Mar 7 [cited 2015 May 1];20(9):2143-58. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc3942819/pdf/wjg-20-2143.pdf 4. Canadian drug summary: alcohol [Internet]. Ottawa: Canadian Centre on Substance Abuse; 2014. [cited 2015 May 12]. Available from: http://www.ccsa.ca/resource%20library/ccsa-canadian-drug-summary-alcohol-2014- en.pdf 5. Mason BJ, Heyser CJ. The neurobiology, clinical efficacy and safety of acamprosate in the treatment of alcohol dependence. Expert Opin Drug Saf. 2010 Jan;9(1):177-88. 6. Witkiewitz K, Saville K, Hamreus K. Acamprosate for treatment of alcohol dependence: mechanisms, efficacy, and clinical utility. Ther Clin Risk Manag [Internet]. 2012 [cited 2015 May 1];8:45-53. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc3277871/pdf/tcrm-8-045.pdf 7. Rosner S, Hackl-Herrwerth A, Leucht S, Lehert P, Vecchi S, Soyka M. Acamprosate for alcohol dependence. Cochrane Database Syst Rev. 2010 Sep 8;(9):CD004332. 8. Jonas DE, Amick HR, Feltner C, Bobashev G, Thomas K, Wines R, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA. 2014 May 14;311(18):1889-900. 9. Donoghue K, Elzerbi C, Saunders R, Whittington C, Pilling S, Drummond C. The efficacy of acamprosate and naltrexone in the treatment of alcohol dependence, Europe versus the rest of the world: a meta-analysis. Addiction. 2015 Jun;110(6):920-30. 10. Crowley P. Long-term drug treatment of patients with alcohol dependence. Aust Prescr [Internet]. 2015 [cited 2014 May 1];38(2):41-3. Available from: http://www.australianprescriber.com/magazine/38/2/article/1557.pdf 11. Yahn SL, Watterson LR, Olive MF. Safety and efficacy of acamprosate for the treatment of alcohol dependence. Subst Abus [Internet]. 2013 [cited 2015 May 1];6:1-12. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc3565569/pdf/sart-7-2013-001.pdf 12. Brouwers M, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, et al. AGREE II: advancing guideline development, reporting and evaluation in healthcare. CMAJ [Internet]. Long-term Use of Acamprosate Calcium 6
2010 Dec [cited 2015 May 12];182(18):E839-E842. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc3001530/pdf/182e839.pdf 13. Work Group on Substance Use Disorders. Practice guideline for the treatment of patients with substance use disorders [Internet]. 2nd edition. Arlington (VA): American Psychiatric Association; 2006. [cited 2015 May 11]. Available from: http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/substanc euse.pdf 14. The Management of Substance Use Disorders Working Group. VA/DoD practice guideline for management of substance use disorders (SUD) [Internet]. Version 2.0. Washington (DC): Department of Veterans Affairs, Department of Defense; 2009. [cited 2015 May 11]. (Clinical practice guideline). Available from: http://www.healthquality.va.gov/guidelines/mh/sud/sud_full_601f.pdf 15. National Collaborating Centre for Mental Health. Alcohol-use disorders: the NICE guideline on diagnosis, assessment and management of harmful drinking and alcohol dependence [Internet]. London (UK): The British Psychological Society and the Royal College of Psychiatrists; 2011. [cited 2015 May 11]. (National clinical practice guideline 115). Available from: http://www.nice.org.uk/guidance/cg115/evidence/cg115-alcoholdependence-and-harmful-alcohol-use-full-guideline3 16. American Psychiatric Association. Practice guideline development process. Arlington (VA): The Association; 2014. Long-term Use of Acamprosate Calcium 7
ABBREVIATIONS APA GRADE HTA MA NICE NRS RCT SR UK USA VA/DoD American Psychiatric Association Grading of Recommendations: Assessment, Development and Evaluation Health Technology Assessment Meta-analysis National Institute for Health and Clinical Excellence non-randomized study Randomized Controlled Trial Systematic review United Kingdom United States of America Veterans Affairs/ Department of Defense Long-term Use of Acamprosate Calcium 8
APPENDIX 1: Selection of Included Studies 515 citations identified from electronic literature search and screened 469 citations excluded 46 potentially relevant articles retrieved for scrutiny (full text, if available) 3 potentially relevant reports retrieved from other sources (grey literature, hand search) 49 potentially relevant reports 46 reports excluded: - irrelevant treatment duration (33) - guidelines with no specific recommendation regarding acamprosate (4) - non-english article (1) - other (review article, commentary) (8) 3 reports included in review Long-term Use of Acamprosate Calcium 9
APPENDIX 2: Grading of Recommendations and Levels of Evidence Guideline Society, Country, Year NICE, 15 UK, 2011 Recommendation grade Level of Evidence Guidelines were drafted based on the clinical summaries and GRADE profiles VA/DoD, 14 USA, 2009 APA, 13 USA, 2006 A: A strong recommendation that the clinicians provide the intervention to eligible patients. Good evidence was found that the intervention improves important health outcomes and concludes that benefits substantially outweigh harm. P.96 B: A recommendation that clinicians provide (the service) to eligible patients. At least fair evidence was found that the intervention improves health outcomes and concludes that benefits outweigh harm. P.96 C: No recommendation for or against the routine provision of the intervention is made. At least fair evidence was found that the intervention can improve health outcomes, but concludes that the balance of benefits and harms is too close to justify a general recommendation. P.96 D: Recommendation is made against routinely providing the intervention to asymptomatic patients. At least fair evidence was found that the intervention is ineffective or that harms outweigh benefits. P.96 I: The conclusion is that the evidence is insufficient to recommend for or against routinely providing the intervention. Evidence that the intervention is effective is lacking, or poor quality, or conflicting, and the balance of benefits and harms cannot be determined.. P.96 Level 1: Recommended with substantial clinical confidence. P. 9 Level II: Recommended with I: At least one properly done RCT P.95 II-1: Well-designed controlled trial without randomization P. 95 II-2: Well-designed cohort or case-control analytic study, preferably from more than one source P. 95 II-3: Multiple time series evidence with/without intervention, dramatic results of uncontrolled experiment P.95 III: Opinion of respected authorities, descriptive studies, case reports, and expert committees P.95 [A] Randomized, double-blind clinical trial. A study of an intervention in which subjects are prospectively followed over time; there Long-term Use of Acamprosate Calcium 10
Guideline Society, Country, Year Recommendation grade moderate clinical confidence. P. 9 Level III: May be recommended on the basis of individual circumstances. P. 9 Level of Evidence are treatment and control groups; subjects are randomly assigned to the two groups; and both the subjects and the investigators are blind to the assignments. [A ] Randomized clinical trial. Same as above but not double blind. [B] Clinical trial. A prospective study in which an intervention is made and the results of that intervention are tracked longitudinally. Does not meet standards for a randomized clinical trial. [C] Cohort or longitudinal study. A study in which subjects are prospectively followed over time without any specific intervention. [D] Control study. A study in which a group of patients and a group of control subjects are identified in the present and information about them is pursued retrospectively or backward in time. [E] Review with secondary data analysis. A structured analytic review of existing data, e.g., a meta-analysis or a decision analysis. [F] Review. A qualitative review and discussion of previously published literature without a quantitative synthesis of the data. [G] Other. Opinion-like essays, case reports, and other reports not categorized above. P. 3 of Practice Guideline development Process 16 APA = American Psychiatric Association, GRADE = Grading of Recommendations: Assessment, Development and Evaluation, NICE = National Institute for Health and Clinical Excellence, UK = United Kingdom, USA = United States of America, VA/DoD = Veterans Affairs/ Department of Defense, Long-term Use of Acamprosate Calcium 11
APPENDIX 3: Summary of Strengths and Limitations Guideline Society, Country, Year Strengths Guideline NICE, 15 UK, 2011 The scope was clearly stated. The guideline development group comprised of individuals from relevant areas such as clinical psychologist, psychiatrist, nurse specialist, academics, health economist, lay person, and carer representative Guideline development method was systematic. Literature search methods, criteria for selecting evidence, strength and limitations were described. The guideline draft was externally reviewed. A process for updating the guideline was in place Cost implications and implementation issues were considered Recommendations were clear Disclosure statements from all committee members had been received Limitations Unclear if patient input was sought but the guideline development group included a lay person and a carer representative The recommendation category and level of evidence for the specific recommendation was not explicitly stated however it was mentioned that the GRADE system was used VA/DoD, 14 USA, 2009 The scope was clearly stated. The guideline development group comprised of individuals from relevant areas such as psychiatrists, clinical pharmacist, and academics Guideline development method was systematic. Literature search methods, criteria for selecting evidence, strength and limitations were described. The guideline draft was externally reviewed. The guidelines were to be updated whenever possible. Recommendations were clear APA, 13 USA, 2006 The scope was clearly stated. The guideline development group comprised of individuals from relevant areas such as psychiatrists, and academics Guideline development method was systematic. Literature search Unclear if patient input was sought Cost implications were not discussed. The recommendation category was stated sometimes and the level of evidence for the specific recommendation was not explicitly stated however a process for grading recommendations was in place. Unclear if disclosure statements from all committee members had been received Unclear if patient input was sought Cost implications were not discussed. The level of evidence for the specific recommendation was not explicitly stated however the Long-term Use of Acamprosate Calcium 12
Guideline Society, Country, Year Strengths methods, criteria for selecting evidence, strength and limitations were described but not in detail. The guideline draft was externally reviewed. A process for updating the guideline was in place Recommendations were clear Guideline development group members were required to disclose conflict of interest. Limitations category of the recommendation was stated APA = American Psychiatric Association, NICE = National Institute for Health and Clinical Excellence, UK = United Kingdom, USA = United States of America, VA/DoD = Veterans Affairs/ Department of Defense, Long-term Use of Acamprosate Calcium 13
APPENDIX 4: Guidelines and Recommendations Guideline Society, Country, Year NICE, 15 UK, 2011 Recommendations For harmful drinkers and people with mild alcohol dependence who have not responded to psychological interventions alone, or who have specifically requested a pharmacological intervention, consider offering acamprosate[63] or oral naltrexone[64] in combination with an individual psychological intervention (cognitive behavioural therapies, behavioural therapies or social network and environment-based therapies) or behavioural couples therapy P.451 After a successful withdrawal for people with moderate and severe alcohol dependence, consider offering acamprosate or oral naltrexone[71] in combination with an individual psychological intervention (cognitive behavioural therapies, behavioural therapies or social network and environment-based therapies) focused specifically on alcohol misuse P. 454 After a successful withdrawal for people with moderate and severe alcohol dependence, consider offering acamprosate or oral naltrexone in combination with behavioural couples therapy to service users who have a regular partner and whose partner is willing to participate in treatment P.454 Before starting treatment with acamprosate, oral naltrexone[73] or disulfiram, conduct a comprehensive medical assessment (baseline urea and electrolytes and liver function tests including gamma glutamyl transferase [GGT]). In particular, consider any contraindications or cautions (see the SPC), and discuss these with the service user. P. 455 If using acamprosate, start treatment as soon as possible after assisted withdrawal. Usually prescribe at a dose of 1,998 mg (666 mg three times a day) unless the service user weighs less than 60 kg, and then a maximum of 1,332 mg should be prescribed per day. Acamprosate should: usually be prescribed for up to 6 months, or longer for those benefiting from the drug who want to continue with it[74] be stopped if drinking persists 4 6 weeks after starting the drug. P.455 Service users taking acamprosate should stay under supervision, at least monthly, for 6 months, and at reduced but regular intervals if the drug is continued after 6 months. Do not use blood tests routinely, but consider them to monitor for recovery of liver function and as a motivational aid for service users to show improvement. P.455 ( [63] Note that the evidence for acamprosate in the treatment of harmful drinkers and people who are mildly alcohol dependent is less robust than that for naltrexone. At the time of publication of the NICE guideline (February 2011), acamprosate did not have UK marketing authorisation for this indication. Informed consent should be obtained and documented. [64]At the time of publication of the NICE guideline (February 2011), oral naltrexone did not have UK marketing authorisation for this indication. Informed consent should be obtained and documented. [71]At the time of publication of the NICE guideline (February 2011), oral naltrexone did Long-term Use of Acamprosate Calcium 14
Guideline Society, Country, Year Recommendations not have UK marketing authorisation for this indication. Informed consent should be obtained and documented. [73]At the time of publication of the NICE guideline (February 2011), oral naltrexone did not have UK marketing authorisation for this indication. Informed consent should be obtained and documented. [74]At the time of publication of the NICE guideline (February 2011), acamprosate did not have UK marketing authorisation for use longer than 12 months. Informed consent should be obtained and documented P. 451, 454 and 455.) VA/DoD, 14 USA, 2009 Routinely consider oral naltrexone, an opioid antagonist, and/or acamprosate for patients with alcohol dependence. [A] P.67 Treatment with acamprosate should be initiated after abstinence and should be combined with psychosocial therapy. APA, 13 USA, 2006 Acamprosate, a γ-aminobutyric acid (GABA) analog that may decrease alcohol craving in abstinent individuals, may also be an effective adjunctive medication in motivated patients who are concomitantly receiving psychosocial treatment (Level 1), P. 13 APA = American Psychiatric Association, NICE = National Institute for Health and Clinical Excellence, UK = United Kingdom, USA = United States of America, VA/DoD = Veterans Affairs/ Department of Defense Long-term Use of Acamprosate Calcium 15