A lengthy and systematic process was used to identify and synthesize the literature and research that support this Treatment Improvement Protocol (TIP). This TIP literature search was built on—and expanded—a short pharmacotherapy literature review covering 2000–2005, which had been completed for the Center for Substance Abuse Treatment as part of the Screening, Brief Intervention, and Referral to Treatment program. The literature search, done through the National Institute of Medicine’s PubMed database, encompassed both clinical and administrative topics. For example, it identified articles concerning physicians’ use of pharmacotherapy for alcohol problems, as well as such barriers to use as practitioners’ attitudes and lack of knowledge about these medications. In addition, the Center for Substance Abuse Research (CESAR) conducted a literature search specific to alcohol-related disorders and acamprosate in April 2005 (for databases used, see the list below). This search identified 83 relevant articles in the period from 2000 to 2005. These preliminary searches, as well as the experience of literature searches done for earlier TIPs, demonstrated that it would not be necessary to conduct a separate literature search dedicated to administrative topics.

The series of comprehensive searches undertaken for this literature review was started in March 2006. The searches covered the period from 2000 to 2006, with selected articles also retrieved from 1998 to 1999, and focused on (1) research literature concerning medications approved by the Food and Drug Administration (FDA) for medical management of alcohol disorders, as well as combined pharmacotherapies, (2) use of these medications in primary care, including adverse events and selection of appropriate patients, and (3) need for further research and knowledge. The searches, conducted by a professional librarian from CESAR, used the following databases:

• PubMed. Search terms included
  • – Alcoholism/drug therapy
  • – Alcohol-related disorders/drug therapy
  • – Alcohol-related disorders AND each of the following:
    • ▪ Acamprosate/Campral (since April 2005)
    • ▪ Naltrexone
    • ▪ ReVia
    • ▪ Antabuse
    • ▪ Disulfiram
    • ▪ Odansetron
    • ▪ Topiramate
    • ▪ Nalmefene
    • ▪ Multiple substance abuse
    • ▪ Relapse prevention
    • ▪ Craving.
• PsycINFO. Search paths included
  • – (Alcoholism OR Alcohol abuse) AND (Pharmacotherapy OR Drug therapy OR Acamprosate/Campral [since April 2005] OR Naltrexone OR ReVia OR Antabuse OR Disulfiram OR Odansetron OR Topiramate OR Nalmefene) OR Multiple substance abuse OR Relapse prevention OR Craving.
• ETOH. (This Alcohol and Alcohol Problems Science Database, sponsored by the National Institute on Alcohol Abuse and Alcoholism, includes articles from 1972 through December 2003 only.) Search terms included
  • – Ti Pharmacotherapy OR
  • – Kw Drug therapy.
• Academic Search Elite, CINAHL, Health Source Academic, Psychology and Behavior Science, PsycArticles, Social Science Abstracts, Social Index.
  • Search terms included
  • – Alcoholism AND
  • – (Pharmacotherapy OR Drug therapy).

While the TIP on alcohol pharmacotherapies was being developed, Vivitrol^® (formerly Vivitrex^®), a long-acting injectable form of naltrexone, was in the final stages of approval by FDA. To keep apprised of emerging research and updates on the status of the FDA application, the FDA and the manufacturer’s Web sites as well as Web search engines were searched regularly for references to this new medication. In April 2006, a targeted literature search was carried out on long-acting naltrexone, which elicited 24 articles specific to this new form of the drug, including articles on an open-label trial, randomized controlled clinical trials, and a multicenter, randomized, placebo-controlled pilot study.

Using the search strategy developed for the comprehensive review, updates to this literature review were made in October 2006 and in April 2007. An additional update was made in October 2007, after the text for the literature review had been completed; that update appears as a separate section at the beginning of this Web-site literature review. Continuing updates will be made at 6-month intervals as long as the literature review remains available on the Web site of the Substance Abuse and Mental Health Services Administration’s Knowledge Application Program (KAP). Exhibit A-1 provides a tabulation of the articles identified during the initial literature search as well as during the updated searches.

Exhibit A-1

Articles Identified in Specific Categories by Year.

For each citation found, reference information and abstracts were reviewed by the literature reviewer and TIP editors. The reviewers eliminated any citations that focused on preclinical research, including animal studies, and on medications used for detoxification rather than medical management. Citations were also rejected when they concerned use of medications for mental or physical disorders occurring in conjunction with substance use disorders. For example, articles were omitted that focused on medications to treat depression in people with alcohol use disorders. Citations from foreign sources written in English were included because so much significant research on naltrexone and acamprosate has been done in foreign, particularly European, countries. The foreign literature on acamprosate was particularly crucial because acamprosate had been used in 26 countries (with 17 randomized, placebo-controlled clinical trials) before 2004, when it was approved for use in the United States. Citations addressing the future directions of pharmacologic treatment were also included, such as the promise of genetic-based research and of selected medications now under development.

After references were selected using these search procedures, the bibliographies or citation lists from these references were reviewed to find older, seminal literature appropriate for this topic. Because disulfiram has been used in the United States for more than 55 years, it was especially important to identify seminal research before 2000. Members of the TIP development panel were asked to suggest earlier research and other articles that would be relevant to the TIP, focusing on the disulfiram literature.

Potentially useful books were identified by chapters appearing in the literature searches and by the TIP chair.

Included with the literature review on the KAP Web site is a 50-item Annotated Bibliography that lists many major and seminal articles on the pharmacotherapy of alcohol disorders. This highly selective list covers articles on each medication currently approved for medical management of alcohol disorders. The literature reviewer assembled an initial list of candidates for this Annotated Bibliography, and the TIP consensus panel of experts reviewed the list and recommended additions and deletions. The Annotated Bibliography represents the final selections recommended by the TIP consensus panel. Because the Annotated Bibliography is limited to only 50 citations, many fine articles could not be included.