Peach, Emily J.
(2020)
Investigating the association between opioid analgesics and the risk of bone fracture.
PhD thesis, University of Nottingham.
Abstract
Background
Opioids have been increasingly prescribed to people with pain; despite limited evidence to support their effectiveness and safety in the long-term. Opioids may increase the risk of bone fracture due to effects on the central nervous system (CNS) and on bone mineral density (BMD). The aim of this research was to examine the utilisation of opioids in the UK and to explore the relationship between opioids and fractures.
Methods
A systematic review was conducted to identify observational studies relating to opioids and fractures. Methodological approaches were appraised, and pooled risk estimates were synthesised by meta-analysis. People prescribed opioids were identified in the Clinical Practice Research Datalink (CPRD) and opioid prescription records were prepared to generate a time-varying measure of opioid exposure and dose. A repeat cross-sectional study and a retrospective cohort study of people prescribed opioids was conducted to describe population- and patient-level trends in opioid utilisation. Fracture events among new users of opioids were identified in the CPRD and Hospital Episode Statistics (HES) databases to estimate the incidence rate of fractures. Finally, a self-controlled case series (SCCS) study was conducted to compare the incidence of fractures during opioid exposure and non-exposure; assessing the effects of opioid duration and dose.
Results
Prior opioid-fracture association studies
A total of 26 studies were included in the systematic review; these varied by study design, population, exposure definitions and potential for confounding. Of these, 21 studies that compared opioid use to non-use were meta-analysed; pooled hazard ratios (HRs) showed that opioids significantly increased the risk of fracture (pooled HR: 1.39; 95% confidence interval (CI): 1.20, 1.62).
Trends in opioid utilisation
1,790,046 people registered in the CPRD were prescribed opioids between 2008 and 2017. The proportion of CPRD registrants prescribed opioids increased from 14.5% to 15.9%, and the proportion of strong opioid users doubled from 3.0% to 6.6%. In 2008, strong opioid users were prescribed a median oral morphine equivalent (OMEQ) dose of 60mg/day for a median duration of 155 days, whereas weak opioid users were prescribed 18mg/day for 30 days. Of 957,664 new opioid users, most (97.5%) were initiated on weak opioids and were prescribed opioids for short durations; half discontinued opioids within 16 days. A small proportion (4.1%) of people were persistent users within one year of initiation.
Fracture incidence in people prescribed opioids
Of 539,369 new opioid users who had linkage to the HES database, 67,622 sustained ≥1 fracture. The overall rate of fracture in the cohort was 218 per 10,000 person-years; double that of the general UK population.
Risk of fracture during opioid use
67,622 people with fractures were included in the SCCS study. Opioid use was associated with a significant increase in the risk of fracture compared to non-exposure (incidence rate ratio (IRR): 3.9; 95%CI: 3.8, 4.0). The risk of fracture was greatest in the first week of use (IRR: 7.8; 95%CI: 7.4, 8.3) and declined with increasing duration of use. Re-starting opioids increased the risk of fracture and fracture-risk was greater when the OMEQ dose was ≥50mg/day compared to when the OMEQ dose was <50mg/day.
Conclusions
Opioid prescribing has increased in the UK, and a greater proportion of people were prescribed strong opioids. Although most people are prescribed weak opioids for short durations, they remain at an increased risk of fracture; the risk is greatest during the first week of use. This research complements existing evidence to suggest a causal association between opioids and fracture. Policy makers and healthcare providers need to be aware of the potential for opioids to increase the risk of fracture, particularly at initiation.
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