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Abstract
Introduction Gabapentinoids are among the most widely prescribed pain medications. However, there is growing evidence to suggest that gabapentinoids may be associated with dependence and misuse. The aim of this systematic review is to synthesise the qualitative literature on gabapentinoid misuse and symptoms of dependence. The findings of this study will inform efforts to mitigate emerging harms.
Methods and analysis A systematic review of qualitative research will explore lived experiences of misuse and symptoms of dependence among people who use gabapentinoids. Six databases (MEDLINE, Scopus, Web of Science, CINAHL, EMBASE and PsycINFO) and grey literature sources will be searched from inception to May 2023. Qualitative studies that include people with lived experiences of gabapentinoid misuse and symptoms of gabapentinoid dependence will be included. Reference lists of included studies will also be screened for additional studies. The methodological quality of included studies will be appraised using the Critical Appraisal Skills Programme qualitative checklist, and higher quality studies will be prioritised in the thematic synthesis. The GRADE-CERQual approach will be used to assess confidence in the overall findings of the review.
Ethics and dissemination Ethical approval is not required for this systematic review. The findings of this review will be disseminated in peer-reviewed journals, at conferences and on social media.
PROSPERO registration number CRD42023401832.
- Systematic Review
- QUALITATIVE RESEARCH
- Chronic Pain
- CLINICAL PHARMACOLOGY
- PAIN MANAGEMENT
- Substance misuse
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- Systematic Review
- QUALITATIVE RESEARCH
- Chronic Pain
- CLINICAL PHARMACOLOGY
- PAIN MANAGEMENT
- Substance misuse
STRENGTHS AND LIMITATIONS OF THIS STUDY
The review will follow the gold-standard guidelines for conducting and reporting systematic reviews of qualitative research (Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Enhancing Transparency of Reporting the Synthesis of Qualitative research).
The literature will be searched comprehensively and screened independently by two reviewers, with conflicts resolved by a third reviewer.
The methodological quality of included studies will be appraised, and higher quality research will be prioritised in the thematic synthesis.
Confidence in the review findings will be assessed and reported using the GRADE-CERQual approach.
The review will be limited by the exclusion of studies written in languages other than English.
Introduction
Over the past two decades, prescribing of gabapentinoids has more than tripled in the USA,1 the UK2 and Australia.3 4 The gabapentinoid drugs—gabapentin and pregabalin—are primarily approved for the treatment of epilepsy and neuropathic pain conditions.5 Pregabalin is also approved for the treatment of fibromyalgia in the USA and Canada and generalised anxiety disorder in the UK and European Union.5 However, off-label prescribing, particularly for non-neuropathic pain conditions, is widespread.2 6 7 In Australia, pregabalin has overtaken oxycodone to become the most widely prescribed pain medication.3 Likewise, both pregabalin and gabapentin are prescribed at much higher rates than oxycodone in primary care in England.8 In the year ending June 2022, the Australian government spent $A56 million subsidising pregabalin prescriptions, while the cost to consumers totalled $13 million.3 Over the same period, the National Health Service spent more than £68 million on gabapentinoids dispensed in the community in England.9
However, as gabapentinoid prescribing has grown in recent years, so too have concerns about the potential harms associated with these drugs.10 11 Despite being perceived as having minimal abuse liability, there is a growing body of research indicating gabapentinoids can cause dependence and are being misused.12 Pregabalin in particular has been found to produce euphoric and dissociative effects at high doses.13 Moreover, gabapentinoids are increasingly being detected in drug-related hospitalisations and deaths.12 While gabapentinoids rarely lead to serious sequalae of overdose alone,14 when used in combination with opioids and other sedating drugs there is an increased risk of central nervous system depression, which can lead to coma and death.15 16 This is troubling as concomitant prescribing of gabapentinoids with opioids and benzodiazepines is relatively common,2 17 18 particularly among those from disadvantaged communities.7 In response to rising deaths associated with gabapentinoid misuse, both pregabalin and gabapentin were reclassified as class C controlled substances in the UK in 2019.19 There is an urgent need to better understand the reasons for and harms associated with gabapentinoid dependence and misuse.
A preliminary search for existing systematic reviews and protocols in MEDLINE, and CINAHL found five on the topic of gabapentinoid dependence and misuse.12–14 20 21 These reviews primarily synthesise evidence from clinical and epidemiological studies. However, good clinical practice depends not only on data from quantitative research but on the rich knowledge gained through in-depth qualitative inquiry.22 Synthesised qualitative evidence can deepen understanding of the impact of medical treatments on both the individuals who receive them and the community more broadly.23 Moreover, qualitative evidence can shed light on the attitudes, values and lived experiences of patients, while revealing important individual and contextual influences.23
A recent evidence map of systematic reviews informing the optimal prescribing of drugs that can cause dependency found there was a dearth of evidence on gabapentinoids, identifying this as a priority area for future systematic reviews.24 The aim of this study is to systematically review and synthesise the qualitative literature on misuse and symptoms of dependence among people who use gabapentinoids. The findings of this study will improve understanding of emerging harms associated with these widely prescribed drugs and inform efforts to mitigate these harms.
Methods and analysis
The review will follow the Enhancing Transparency of Reporting the Synthesis of Qualitative research25 and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)26 guidelines. The review will commence in May 2023 and be completed by April 2024. Important protocol amendments will be documented with PROSPERO and reported in the published review.
Inclusion criteria
Types of participants
This review will consider studies that include people with experience (either past or present) of using gabapentinoids (both prescribed and non-prescribed) for any reason.
Phenomena of interest
The phenomena of interest for this review are the lived experiences of gabapentinoid misuse and symptoms of gabapentinoid dependence. This review will consider studies that explore either or both phenomena. Gabapentinoid drugs include pregabalin and gabapentin.
For the purpose of this review, symptoms of gabapentinoid dependence are defined in line with the International Classification of Diseases 11th Revision (ICD-11) criteria for substance dependence and the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) criteria for substance use disorder.27 We will consider symptoms of dependence to be any of the three central symptoms of dependence outlined in ICD-11 or any of the 11 symptoms of substance use disorder outlined in the DSM-5. Participants do not need to have a diagnosis of, or meet the diagnostic criteria for, substance dependence or substance use disorder.
For the purpose of this review, gabapentinoid misuse is defined as any use that is either (a) without a prescription, (b) in a manner or dose other than prescribed or (c) for reasons other than prescribed, regardless of the motive for use (ie, therapeutic or non-therapeutic).28 This may include using someone else’s prescribed medication, using medication purchased without prescription (ie, online or on ‘the street’), using higher than prescribed doses, using more frequently than prescribed, using outside of the prescribed duration, using via a route of administration other than prescribed, using for recreational purposes (ie, to experience euphoria or intoxication), using for self-harm or using in combination with other drugs to alter or enhance the effects of the drugs. This definition is purposefully broad in an effort to capture all forms of misuse that may be associated with harms.
Context
This review will consider any setting (medical or non-medical) including but not limited to primary care, tertiary care, pharmacy, addiction treatment, online and community settings.
Types of studies
This review will include qualitative studies or mixed-methods studies that include a qualitative component. A qualitative study uses both a qualitative method of data collection and a qualitative method of analysis.
Search strategy
The search strategy will aim to find both published and unpublished studies. While the search strategy will be tailored for each information source, it will generally include variations of the following keywords: gabapentinoids, misuse, dependence and qualitative. For example, see online supplemental file 1 for MEDLINE search strategy.
Supplemental material
Information sources
We will search databases including MEDLINE, Scopus, Web of Science, CINAHL, EMBASE and PsycINFO. The reference lists of all studies selected for inclusion will be screened for additional studies. The search for unpublished studies will include ProQuest Dissertations and Theses, Google Scholar and MedNar.
Limitations to the scope of searching
Databases will be searched from inception to May 2023. Searches will be re-run prior to the final analysis and any further studies identified will be retrieved for inclusion. There will be no geographical limits to the search. However, only studies published in English will be considered for inclusion due to lack of resources for translation.
Screening process
Records will be uploaded to Covidence web-based software for screening. Duplicates will be removed using the Covidence deduplication function. Prior to screening all records, two reviewers will pilot the screening process on a sample of 100 records to ensure consistency in the application of the eligibility criteria. The same two reviewers will then independently conduct both title/abstract and full-text screening, with conflicts resolved by discussion or a third reviewer. Decisions will be recorded in Covidence. The results of the screening process will be reported in a PRISMA flow diagram. Reasons for exclusion at the full-text review stage will also be recorded and reported.
Data extraction
Data extraction will be conducted by one reviewer and checked by a second reviewer. Study characteristics will be extracted into an Excel spreadsheet. Extracted characteristics will include, author/s, publication year, title, country, setting/context, sample size, sample characteristics, research aims, data collection method and data analysis method. Study findings will be extracted in NVivo software for analysis. All text under headings such as ‘Results’, ‘Findings’ or ‘Conclusions’ relevant to the review question will be extracted verbatim. If necessary, study authors will be contacted to obtain missing or additional data.
Quality appraisal
A modified 11-item version of the Critical Appraisal Skills Programme (CASP) checklist for qualitative research will be used to assess the methodological quality of each included study.29 The CASP items evaluate the conduct of the study, the reporting of the study and the utility of the findings. Quality appraisal will be conducted by two reviewers independently, with conflicts resolved by discussion or a third reviewer. The results of the quality appraisal will be used to inform the data analysis. Poorer quality studies will not be excluded from the review. Rather, the findings from higher quality studies will be prioritised (ie, weighted more heavily) in the synthesis.29 The results of the critical appraisal will be reported in narrative form and tables.
Data analysis
Data will be analysed using thematic synthesis.30 A thematic synthesis approach was chosen as the aim of the review is to provide practical implications to inform clinicians and policymakers rather than to develop a theory. Furthermore, thematic synthesis is well suited to reviews with broad and exploratory research questions where the aim is to generate common themes from studies with diverse aims, methodologies, participants and contexts.31 Thematic synthesis involves three stages: line-by-line inductive coding of the study findings, organising codes into related categories to construct descriptive themes and developing higher-order analytical themes. Themes will be illustrated using exemplar participant quotes from primary studies to demonstrate where the themes are embedded in the data. Disconfirmatory evidence and outliers (‘negative cases’) will also be represented in the reporting of themes.
To ensure analytical rigour, the thematic synthesis will be conducted collaboratively. A sample of data from the full dataset will initially be coded independently by two or more reviewers who will then compare their interpretations. The purpose of the comparison will not be to reach consensus but rather to seek multiple perspectives and encourage reflexivity when interpreting data. The remaining data will then be coded by the first author (AGM) who will meet regularly with the research team to receive feedback and identify potential biases. Members of the interdisciplinary research team—which includes a social psychologist (CA-J), a pharmacist (SN) and an addiction medicine physician (BM)—will provide input throughout the iterative process of developing themes.
Data contributed by higher quality studies will be prioritised in the synthesis (see the Quality appraisal section), as will data arising from more in-depth data collection methods. For example, interview and focus group data typically provide more ‘richness’ than survey data and thus will be weighted more favourably in the analysis. Importantly, the findings of the thematic synthesis will be embedded in their context to ensure appropriate implications can be drawn from the review. In addition, our review will include a table outlining the characteristics of each study so that readers can determine whether or not the contexts of the studies included in the review are similar to their own.
The analytic process will be guided by the principles of reflexivity.32 In order to maintain transparency, the review will include a detailed description of the methodology as well as a ‘Researcher reflexivity’ section outlining the assumptions informing the findings.
Confidence in the evidence
The GRADE-CERQual approach will be used to assess confidence in the evidence (ie, ‘the extent to which a review finding is a reasonable representation of the phenomenon of interest’).33 Confidence in the evidence is determined by (a) the methodological limitations of the included studies, (b) the coherence of the review finding (the fit between the data from the primary studies and the synthesised review finding), (c) the adequacy of the data supporting a review finding and (d) the relevance of the data from included studies to the context specified in the review question.33 The GRADE-CERQual assessment will be independently conducted by two authors, with conflicts resolved by discussion or a third reviewer. The overall CERQual assessment (high, moderate, low or very low) for each review finding (ie, each theme) will be reported in a Summary of Qualitative Findings table.
Patient and public involvement
The motivation for this review arose from interviews conducted with patients with lived experience of tapering off gabapentinoids who raised concerns about the potential for misuse and dependence associated with the drugs.34 While patients and members of the public were not directly involved in the planning or reporting of this protocol, a consumer partner will provide input on the interpretation and discussion of the clinical and policy implications of the review findings.
Ethics and dissemination
Ethical approval is not required for this review as no human participants will be involved and there will be no primary data collected. The findings of this review will be disseminated in peer-reviewed journals, at conferences and on social media.
Ethics statements
Patient consent for publication
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Twitter @AmyMcNeilage, @drsuzinielsen, @drashtonjames
Contributors AGM was responsible for the conceptualisation and design of the review with close supervision from SN, BM, and CA-J. AGM drafted the protocol manuscript with important intellectual input and revisions from SN, BM, and CA-J. All authors have read and approved this version of the manuscript. AGM and CA-J are guarantors.
Funding The first author (AGM) receives an Australian Government Research Training Program Scholarship and a supplementary PhD scholarship from the Pain Foundation. The funders had no role in the development of this protocol.
Competing interests SN has previously received funding from Seqirus to study pharmaceutical opioid poisoning, and was a named investigator on an implementation trial of buprenorphine depot funded by Indivior (neither SN nor her institution received funding for the trial).
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.