Background: Recent observational studies suggest gabapentinoids associate with an increased risk of fractures. The potential for confounding inherent to non-randomised studies of interventions, however, alongside the conflicting findings of these studies (with some reporting an increased risk [1] and others no relationship [2] mean further confirmatory research is needed. We therefore conducted a case-control study in people with inflammatory arthritis (IA) – a population often suffering fractures and widely prescribed gabapentinoids – in which all people had received a gabapentinoid at some point, minimising confounding by indication.

Objectives: To determine the risk of fractures in people with IA currently and recently receiving a gabapentinoid prescription, compared to those receiving one in the remote past.

Methods: We used data from CPRD Aurum (primary care electronic health record database covering 20% of England) and linked Hospital Episode Statistics Admitted Patient Care data. Adults meeting validated criteria for a rheumatoid arthritis/psoriatic arthritis/axial spondyloarthritis diagnosis and contributing data to Aurum between 01/01/2004 and 31/12/2022, entered the cohort on first receipt of an oral gabapentinoid prescription. Cases had a coded diagnosis of an incident fracture after cohort inclusion. Risk set sampling matched them to up to five controls (on age, gender, and gabapentinoid type).

Gabapentinoid exposure was categorised as: (a) current (prescription overlapped with fracture date); (b) recent (prescription ended 1 to 60 days pre-fracture date); and (c) remote (prescription ended >60 days pre-fracture date). Conditional logistic regression models determined odds ratios (ORs) with 95% confidence intervals (CIs) for fractures with current or recent gabapentinoid use vs. remote use, adjusting for confounding variables age, gender, IA type, previous fragility fracture(s)/presence of osteoporosis, presence of CKD stage III/IV/V, prednisolone use, and receipt of a current opioid prescription. Analysis was repeated stratifying exposure by gabapentinoid type and dose, and duration of current use.

Results: 2,529 cases and 12,466 controls were included. More cases received gabapentin (1,526) than pregabalin (941) and more were remote (65.0%) than current (29.5%) or recent (5.5%) users (similar patterns in controls). Current any gabapentinoid use (vs. remote use) associated with a significantly increased fracture risk (OR 1.35 [95% CI 1.22, 1.50]). Similar risks were seen with gabapentin (OR 1.31 [1.13, 1.52]) and pregabalin (OR 1.44 [1.22, 1.70]). Recent use of any gabapentinoid, gabapentin, and pregabalin also associated with a significantly increased fracture risk with ORs of 1.47 (1.20, 1.81), 1.38 (1.04, 1.81), and 1.61 (1.13, 2.30). Examining risk by dosing showed that for gabapentin, the association was only observed with low dose current use (OR 1.42 [1.15, 1.75]); this may have arisen from confounding by use duration (with gabapentin requiring up-titration, and therefore low dose use more likely in those starting gabapentin more recently). For pregabalin, a significantly increased risk of fractures was seen for low (OR 1.68 [1.27, 2.24]), moderate (OR 1.35 [1.09, 1.67]), and high (OR 1.40 [1.06, 1.85]) dose current use. Examining risk by duration of use revealed strongest associations for those currently using gabapentinoids for <12-months.

Conclusion: In people with IA, the risk of fractures is significantly increased in those currently using gabapentinoids, after accounting for both measured (through model adjustment) and time-invariant unmeasured (through comparing risk to remote gabapentinoid users) confounding. When considered alongside a lack of evidence for efficacy and widespread prescribing - with 10% of people with IA in England prescribed a gabapentinoid in 2020 (3) - our findings support the role of existing safer gabapentinoid prescribing initiatives, particularly in people with IA.

REFERENCES: [1] Rentsch CT, et al. Alcohol Clin Exp Res. 2020;44(9):1807–15.

[2] Vangala C, et al. J Am Soc Nephrol JASN. 2020;31(6):1325–34.

[3] Scott IC, et al. Rheumatology. 2023 [Epub ahead of print].

Acknowledgements: This study is based in part on data from the Clinical Practice Research Datalink (CPRD) obtained under licence from the UK Medicines and Healthcare products Regulatory Agency. The data is provided by patients and collected by the NHS as part of their care and support. The interpretation and conclusions contained in this study are those of the authors alone. HES data copyright © 2022, re-used with the permission of The Health & Social Care Information Centre. All rights reserved. The study was approved by the CPRD Research Data Governance Process (ref 20_000244). This study was funded by the National Institute for Health and Care Research (NIHR; Advanced Research Fellowship awarded to ICS [NIHR300826]). SM and KPJ are partly funded by the NIHR Applied Research Collaboration West Midlands. CDM is partly funded by the NIHR Applied Research Collaboration West Midlands and the NIHR School for Primary Care Research. The views expressed are those of the author(s) and not necessarily those of the NIHR, NHS or the Department of Health and Social Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Disclosure of Interests: None declared.