Title: Trends in gabapentinoid prescribing and risk of adverse events: an observational study in UK primary care using the Clinical Practice Research Datalink.
Funder: Department of Health and Social Care

Abstract: Background Gabapentin and pregabalin (gabapentinoids) are licensed for epilepsy, neuropathic pain, and pregabalin also for anxiety. Marked year-on-year increases in gabapentinoid prescribing suggest widespread off-label prescribing for other pain conditions, despite limited evidence of effectiveness. Increasing reports of misuse and gabapentinoid-related deaths have resulted in plans to reclassify gabapentinoids as controlled drugs. However, most reported adverse events occur in high-risk populations and the risk of gabapentinoid-related adverse events in the wider patient population is unknown. Aims and Objectives Our objectives are to investigate patterns and trends in gabapentinoid prescribing, including prescribing indications and to determine the risks and risk factors for fracture, drug misuse and overdose in primary care patients. Methods We will use the Clinical Practice Research Datalink (CPRD), a large anonymised UK primary care database, linked to Hospital Episode Statistics (HES) providing details of NHS hospital care. Work Package 1 Prevalence study: We will identify patients aged &ge;18 years in CPRD practices and issued &ge;1 gabapentinoid prescription between 1995 and 2018. Repeated cross-sectional analyses will calculate point and period prevalence of gabapentinoid prescribing each year, stratified by age and gender. Cohort study: In patients with incident gabapentinoid prescriptions and &ge;5 years follow-up data, we will extract information on licensed indications (epilepsy, neuropathic pain, anxiety), chronic pain conditions representing unlicensed indications (expert consensus), and concurrent prescribing (opioids, benzodiazepines, hypnotics, antidepressants). We will identify the proportions with licensed/non-licensed indications and describe therapy dose/duration, prior prescribing pathway and concurrent prescribing using descriptive statistics. Work Package 2 Matched cohort study: We will compare patients with incident gabapentinoid prescriptions to patients not prescribed gabapentinoids regarding incidence of fracture, drug misuse, and overdose. Self-controlled case-series methodology will be used to better account for between-person confounding. Gabapentinoid users with adverse events will be identified from our cohort study. These patients will be used as their own controls to assess the impact of drug exposure on adverse outcomes using a conditional Poisson regression model. Work Package 3 Cohort study: We will assess potential risk factors for adverse events in patients prescribed gabapentinoids, including socio-demographics, social class, smoking/alcohol status, body mass index, comorbidities, cancer, gabapentinoid dose, substance misuse, mental health disorders, previous overdose, and co-prescribed medication, using multivariable cox regression to examine associations between potential risk factors and adverse events. Anticipated impact and dissemination Gabapentinoids are expensive and potentially harmful medications. Understanding the current clinical context and risks will inform resource and intervention development to improve patient safety and support clinicians treatment choices e.g. patient resources explaining gabapentinoids risk/benefit profile, clinician education packages, prescribing quality improvement tools and pharmacist-led interventions. Study findings will be relevant to patients, clinicians, healthcare commissioners and policy makers. Our Impact Accelerator Unit will support wide dissemination to all stakeholders, with outputs made freely available and easy to access at no cost. Patient partners will advise on easily understandable messages for dissemination to the wider public. Strong professional, patient and NHS links will facilitate influence of national/international clinical guidelines, healthcare professional and patient resources, undergraduate/postgraduate medical education and translation into clinical practice.

Lay abstract: Gabapentin and pregabalin ( gabapentinoids ) are medicines used to treat epilepsy and nerve pain. Pregabalin is also approved to treat anxiety. Use of gabapentin and pregabalin has increased considerably. In the UK, around 12 million gabapentinoid prescriptions were issued in 2016 compared to 1.5 million in 2006. This increase may partly be due to clinical guidelines recommending gabapentinoids as first choice treatments for nerve pain. However, other uses for gabapentinoids have been suggested and widespread off-label prescribing for other pain conditions is suspected. Gabapentinoids are commonly prescribed in the UK yet little is known about the patients taking them or why they are prescribed, although pain is thought to be the commonest reason. Research shows that gabapentinoids benefit only one-fifth of people with nerve pain and there is little research evidence that they are effective for other pain conditions. Studies show that they do not help people with chronic back pain. Around six in every ten people experience side-effects with gabapentinoids, including dizziness, feeling sleepy and unsteadiness. There are also increasing reports that gabapentinoids are being misused or abused. Overdoses involving gabapentinoids are increasing and, in the UK, deaths involving gabapentinoids rose from 12 in 2012 to 170 in 2016. Following concerns about rising use and misuse of gabapentin and pregabalin, the UK government plans to classify gabapentinoids as controlled substances . However, most reports of abuse are in high risk groups, such as people who are addicted to opioids (like morphine or heroin) and prison inmates. Most deaths linked to gabapentinoids also involve opioids. Little is known about the risks to patients, without a history of drug abuse, who are legitimately prescribed gabapentinoids. This study will use a database called the Clinical Practice Research Datalink (CRPD) which contains anonymised electronic health records of patients from hundreds of GP practices across the UK to investigate: Trends and patterns of gabapentin and pregabalin prescribing in UK primary care. The risk of serious adverse events (fractures, drug misuse/addiction and overdose) in patients prescribed gabapentinoids by their GP. The factors that are linked to increased risk of these adverse events. If successful, this research will benefit patients and the NHS by: Providing new evidence regarding: How and why gabapentinoids are prescribed in UK primary care. The risks of gabapentinoids across a wide range of patients. Helping doctors identify patients who are at higher risk from gabapentinoids and who should avoid these treatments or be monitored more closely. Informing patient information, prescribing guidelines and development of interventions to ensure safe and appropriate gabapentinoid prescribing. We will involve patients to advise on: What the results mean to patients. Easily understandable messages to explain the study findings and how best to widely publicise them Priorities for future research.

Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;7.1 INDIVIDUAL CARE NEEDS
Health categories: MENTAL HEALTH;GENERIC HEALTH RELEVANCE