TITLE: Abuse and Misuse Potential of Dimenhydrinate: A Review of the Clinical Evidence DATE: 01 December 2015 CONTEXT AND POLICY ISSUES Dimenhydrinate (marketed as Gravol in Canada and Dramamine in the United Kingdom and the United States) is an over-the-counter (OTC) antihistamine indicated for the prevention and relief of nausea and vomiting from a number of causes. It is an H1 receptor antagonist that demonstrates anticholinergic activity. 1 Abuse of dimenhydrinate has been reported, and often involves ingestion of high doses to induce psychotropic effects, including hallucinations and euphoria. 1-3 Psychiatric patients may also abuse dimenhydrinate to achieve an anti-anxiety effect. 1,2 In addition to frank abuse, OTC medications, including dimenhydrinate, may be misused when taken in higher doses or for a longer duration than indicated on the product monograph. 4 Potential for drug dependence is also a concern in situations of dimenhydrinate abuse or misuse. 2 Given these potential risks, some jurisdictions have chosen to store and sell dimenhydrinate under pharmacist supervision; 5 however, it is available without any restrictions in other jurisdictions. The purpose of this report is to identify the recent clinical evidence on the potential misuse or abuse of dimenhydrinate, in order to inform decision making regarding appropriate access to this drug within the pharmacy. RESEARCH QUESTION What is the clinical evidence for the potential misuse or abuse of dimenhydrinate? KEY FINDINGS One cross-sectional questionnaire-based study regarding the potential misuse or abuse of antihistamines, including dimenhydrinate, was identified. No cases of misuse or abuse of dimenhydrinate were reported in this study. 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 review s. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts w ithin the time allow ed. Rapid responses should be considered along w ith 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 w hich little information can be found, but w hich 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 ef fect. 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 w hich a third party ow ns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a w eb site, redistributed by email or stored on an electronic system w ithout the prior w ritten permission of CADTH or applicable copyright ow ner. Links: This report may contain links to other information available on the w ebsites 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.
METHODS Literature Search Methods A limited literature search was conducted on key resources including PubMed, 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 November 5, 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 Patients of any age Dimenhydrinate Not applicable Drug abuse, illicit use, misuse, abuse potential, drug diversion, psychoactive or other side effects Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, non-randomized studies Exclusion Criteria Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, or were published prior to 2005. Critical Appraisal of Individual Studies The included non-randomized study was critically appraised using the Centre for Evidence Based Medicine s critical appraisal tool for surveys. 6 Summary scores were not calculated for the included study; rather, a review of the strengths and limitations were described. SUMMARY OF EVIDENCE Quantity of Research Available A total of 360 citations were identified in the literature search. Following screening of titles and abstracts, 338 citations were excluded and 22 potentially relevant reports from the electronic search were retrieved for full-text review. One potentially relevant publication was retrieved from the grey literature search. Of these potentially relevant articles, 22 publications were excluded for various reasons (15 studies did not specifically address dimenhydrinate, four were review articles, two were case reports, and one was a clinical practice guideline). One publication met Dimenhydrinate Abuse Potential 2
the inclusion criteria and was included in this report. Appendix 1 describes the PRISMA flowchart of the study selection. Additional references of potential interest are provided in Appendix 5. Summary of Study Characteristics Study Design One cross-sectional, questionnaire-based pilot study was included in this report. 7 The objective of the pilot study was to assess the feasibility of a pharmacy-led method for monitoring patientreported abuse and misuse of OTC medications for psychoactive effects. The study was conducted in community pharmacies over the course of two months. Patient Population The study was conducted in 74 community pharmacies in France. Adult patients visiting the participating community pharmacies who requested one of the studied drugs were offered a questionnaire. No other inclusion or exclusion criteria were reported. Interventions and Comparators Patients were asked about the use of medications from four drug classes known for their abuse potential and psychoactive effects: codeine in analgesics, dextromethorphan, pseudoephedrine and sedative antihistamines. Dimenhydrinate was one of the included antihistamines addressed by the questionnaire. Patients were also asked about the abuse or misuse of antacid drugs as a control group. Outcomes Outcomes assessed by the questionnaire were: abuse (defined as the recurrent and excessive use of a drug leading to clinically significant impairment or distress ), misuse (excessive or regular use), non-medical use (use with the intent of achieving a psychoactive effect), and drug dependence (negative consequences of drug use and continued use of drug despite these consequences, as well as significant time spent on acquiring the drug). Excessive use meant use of a dose higher than the maximum recommended dose, and regular use meant use for longer than 10 days in the past month. Additional details regarding study characteristics are provided in Appendix 2. Summary of Critical Appraisal The study design and objectives were clearly presented, but a sample size calculation was not performed to ensure enough patients were recruited to identify a difference between groups, should a true difference exist. All patients who requested the studied drugs from the pharmacist were offered the questionnaire, and the reasons for refusal to participate in the study were provided. However, 32% of patients who accepted the questionnaire did not complete it, and the reasons for this are unclear. It is also unclear how valid and reliable self-report of drug abuse or misuse on this questionnaire was. Dimenhydrinate Abuse Potential 3
Additional critical appraisal points are provided in Appendix 3. Summary of Findings A total of 817 patients were offered a questionnaire, 778 accepted, 530 completed the questionnaire, and 491 responses were analyzed (39 questionnaires were excluded due to irrelevant drug use and patient age under 18 years). Of the 491 analyzed patients, 99 reported use of antihistamines, and 60 patients reported use of antihistamines in the past month. The types of antihistamines used were not reported; therefore, it is unclear how many patients, if any, reported the use of dimenhydrinate. One case of non-medical antihistamine use was identified: one patient reported using oxomemazine for sleep aid. No reports of dimenhydrinate misuse, abuse, non-medical use, or dependence were identified. Additional details regarding study findings are provided in Appendix 4. Limitations Given that the identified cross-sectional study was designed to be a pilot study with a short duration, it had a limited set of results for antihistamine use, and it is unclear whether any patients used dimenhydrinate at all. Furthermore, the types of patient-reported results that were received may be biased due to the potential for stigma associated with OTC medication abuse or misuse. Some patients may have chosen not to return the questionnaire for the same reason. Both cases could have led to underreporting of OTC drug abuse or misuse. No eligible studies regarding the abuse or misuse of dimenhydrinate in children or adolescents were identified for inclusion in this report. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING One cross-sectional study evaluating the abuse or misuse of OTC medications, including dimenhydrinate, was identified. No cases of dimenhydrinate abuse or misuse were reported in this study; however, these results should be interpreted with caution due to the small sample size and potential for bias in patient self-reporting. Another study that evaluated the abuse and misuse potential of dimenhydrinate and other antihistamines demonstrated that there is some evidence of this problem for this drug class; however, results specific to dimenhydrinate were not reported separately. 4 Additional references regarding abuse or misuse of antihistamines that do not specify inclusion of dimenhydrinate are provided in Appendix 5. No additional information was identified to inform decisions on access to dimenhydrinate in pharmacies to limit abuse or misuse of this drug. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca Dimenhydrinate Abuse Potential 4
REFERENCES 1. Lessenger JE, Feinberg SD. Abuse of prescription and over-the-counter medications. J Am Board Fam Med [Internet]. 2008 Jan [cited 2015 Nov 16];21(1):45-54. Available from: http://www.jabfm.org/content/21/1/45.full.pdf+html 2. Reeves RR, Ladner ME, Perry CL, Burke RS, Laizer JT. Abuse of medications that theoretically are without abuse potential. South Med J. 2015 Mar;108(3):151-7. 3. Conca AJ, Worthen DR. Nonprescription drug abuse. J Pharm Pract. 2012 Feb;25(1):13-21. 4. Roussin A, Bouyssi A, Pouche L, Pourcel L, Lapeyre-Mestre M. Misuse and dependence on non-prescription codeine analgesics or sedative H1 antihistamines by adults: a crosssectional investigation in France. PLoS ONE [Internet]. 2013 [cited 2015 Nov 9];8(10):e76499. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc3789666 5. Prince Edward Island Pharmacy Board. Policy regarding dimenhydrinate sale entry into the Drug Information System (DIS) [Internet]. Crapaud (PEI): Prince Edward Island Pharmacy Board; 2011 [cited 2015 Nov 23]. Available from: http://napra.ca/content_files/files/pei/dimenhydrinatepolicyjanuary2011.pdf 6. Critical appraisal of a survey [Internet]. Oxford (UK): CEBMa center for Evidence-Based Management; 2011 [cited 2015 Nov 27]. Available from: http://www.cebma.org/wpcontent/uploads/critical-appraisal-questions-for-a-survey.pdf Adapted from Crombie, The Pocket Guide to Critical Appraisal; the critical appraisal approach used by the Oxford Centre for Evidence Medicine, checklists of the Dutch Cochrane Centre, BMJ editor's checklists and the checklists of the EPPI Centre. 7. Orriols L, Gaillard J, Lapeyre-Mestre M, Roussin A. Evaluation of abuse and dependence on drugs used for self-medication: a pharmacoepidemiological pilot study based on community pharmacies in France. Drug Saf. 2009;32(10):859-73. Dimenhydrinate Abuse Potential 5
APPENDIX 1: Selection of Included Studies 360 citations identified from electronic literature search and screened 338 citations excluded 22 potentially relevant articles retrieved for scrutiny (full text, if available) 1 potentially relevant report retrieved from other sources (grey literature, hand search) 23 potentially relevant reports 22 reports excluded: -irrelevant intervention (15) -other (review articles, guidelines, case reports, editorials) (7) 1 report included in review Dimenhydrinate Abuse Potential 6
APPENDIX 2: Characteristics of Included Publications First Author, Publication Year, Country Orriols 2009, 7 France Table A1: Characteristics of Included Clinical Studies Patient Characteristics Study Design Crosssectional study Adult patients requesting one of the drugs from the five studied drug classes Offered questionnaire: n = 817; completed questionnaire: n = 491 Intervention(s) Comparator(s) Clinical Outcomes Questionnaire assessing use of codeine in analgesics, dextromethorphan, pseudoephedrine and sedative antihistamines (including dimenhydrinate) Assessment of use of antacid drugs Misuse, abuse, nonmedical use, dependence Dimenhydrinate Abuse Potential 7
APPENDIX 3: Critical Appraisal of Included Publications Table A2: Strengths and Limitations of Surveys using the CEBM Critical Appraisal Tool 6 Strengths Limitations Orriols 2009 7 The study addressed a clearly focused Sample size calculation not performed question Low patient response rate of 65% The study design was appropriate for answering the research question Unclear validity and reliability of patientreported drug abuse or misuse data Method of patient selection described Confidence intervals not presented All patients who requested the studied Unclear confounding factors drugs were offered the questionnaire Details of specific drugs reported for cases Reasons for refusal to participate (by pharmacies and patients) provided of abuse or misuse but not for any use Statistical significance of results compared with the control antacid group presented CEBM = Centre for Evidence Based Medicine Dimenhydrinate Abuse Potential 8
APPENDIX 4: Main Study Findings and Author s Conclusions Table A3: Summary of Findings of Included Studies Main Study Findings Author s Conclusions Orriols 2009 7 491/817 questionnaires were completed and analyzed, mean age 45.8 ± 15.1 a years (range 19 85 years), 64.8% female 99/491 patients reported use of antihistamines, mean age 49.0 years ± 16.0 a years (range 19 83 years), 76.8% female 60/99 antihistamine users reported use in the past month 1/60 patients reported non-medical use of an antihistamine in the past month (oxomemazine) No abuse, misuse, non-medical use of, or dependence on dimenhydrinate reported OTC = over-the-counter. a standard deviation A patient questionnaire provided by community pharmacies is a valuable method to obtain data on inappropriate use of OTC medications. Dimenhydrinate Abuse Potential 9
APPENDIX 5: Additional References of Potential Interest Case Reports White RF, Honer WG, Procyshyn RM, Vila-Rodriguez F. Dimenhydrinate use disorder with chronic psychosis. J Clin Psychopharmacol. 2015 Feb;35(1):105-7. Kaya FD. A Patient with dimenhydrinate dependence: a case report [Internet]. Bull Clin Psych; 2014 [cited 2015 Nov 30] 24(2):184-7. Available from: http://www.psikofarmakoloji.org/pdf/24_2_13.pdf Abuse and Misuse of Antihistamines (Not Specific to Dimenhydrinate) Albsoul-Younes A, Wazaify M, Yousef AM, Tahaineh L. Abuse and misuse of prescription and nonprescription drugs sold in community pharmacies in Jordan. Subst Use Misuse. 2010 Jul;45(9):1319-29. Ajuoga E, Sansgiry SS, Ngo C, Yeh RF. Use/misuse of over-the-counter medications and associated adverse drug events among HIV-infected patients. Res Social Adm Pharm. 2008 Sep;4(3):292-301. Clinical Practice Guidelines Scharman EJ, Erdman AR, Wax PM, Chyka PA, Caravati EM, Nelson LS, et al. Diphenhydramine and dimenhydrinate poisoning: an evidence-based consensus guideline for out-of-hospital management [Internet]. Clin Toxicol. 2006 [cited 2015 Nov 30];44(3):205-23. Available from: http://www.tandfonline.com/doi/pdf/10.1080/15563650600585920 See Literature Review: Dimenhydrinate: Acute Exposures in Patients 6 Years of Age and Older; Dimenhydrinate: Chronic Exposures in Patients 6 Years of Age and Older, page 213 Dimenhydrinate Abuse Potential 10