Patients with knee or hip osteoarthritis who newly initiated centrally acting analgesics had a higher hazard of knee or hip replacement than those who initiated selective serotonin reuptake inhibitors, according to findings from a population-based cohort study published in BMC Medicine.
The findings ran counter to the researchers’ original hypothesis that centrally acting analgesics might reduce progression to joint replacement by improving pain and function. However, the investigators emphasized that the observational findings should be interpreted cautiously because patients prescribed centrally acting analgesics may have had more severe pain, functional limitation, or structural osteoarthritis than patients prescribed selective serotonin reuptake inhibitors.
Using the IQVIA Medical Research Database, which incorporates data from The Health Improvement Network, the researchers evaluated patients aged 40 to 89 years with knee or hip osteoarthritis who newly initiated centrally acting analgesics or selective serotonin reuptake inhibitors (SSRIs) from 2000 to 2021. Centrally acting analgesics included tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and gabapentinoids.
SSRIs were selected as an active comparator because they are commonly used as first-line treatment for depression and are not known to have definitive analgesic effects. The study used a new-user, active-comparator design and propensity score matching within 1-year accrual blocks. The new-user and active-comparator design was intended to reduce immortal time bias and confounding by indication. Because death could preclude subsequent joint replacement, the researchers also used Fine-Gray models to account for death as a competing risk.
The primary outcome was total joint arthroplasty, defined as knee or hip replacement. Hip fracture–related arthroplasties were excluded. Patients were also excluded if they had prior joint replacement, rheumatoid arthritis, cancer, severe chronic kidney disease, end-stage liver disease, or missing data for body mass index, smoking status, or alcohol use. Patients were required to have at least 2 years of continuous general practitioner enrollment before study entry.
In the primary analysis, 11,734 patients who initiated centrally acting analgesics were propensity score–matched with 11,734 patients who initiated SSRIs. Over a median follow-up of 9.5 years in the centrally acting analgesic group and 9.1 years in the SSRI group, knee or hip replacement occurred in 617 patients (5.3%) and 327 patients (2.8%), respectively.
Centrally acting analgesic initiation was associated with an 81% higher hazard of knee or hip replacement in the propensity score–matched model. The estimate was similar after additional adjustment and accounting for death as a competing risk, increasing slightly from HR 1.80 to HR 1.87. Deaths were more common among SSRI initiators than centrally acting analgesic initiators in the matched cohort, occurring in 1,241 patients (11.0%) vs 831 patients (7.1%), respectively. In the model that also censored patients at drug class switching or discontinuation, the association was attenuated but persisted, with a 48% higher hazard of knee or hip replacement.
In a subgroup of patients with both osteoarthritis and depression, the association was smaller and less precise. Among 3,095 centrally acting analgesic initiators and 3,095 matched SSRI initiators, the propensity score–matched model showed a 59% higher hazard of knee or hip replacement with centrally acting analgesic initiation. In the fully adjusted model that accounted for competing risk of death and censored patients at switching or discontinuation, the point estimate still favored more knee or hip replacement with centrally acting analgesic initiation, but the estimate was attenuated to a 25% higher hazard and the confidence interval was wide (95% CI, 0.87-1.80), consistent with limited precision in the smaller subgroup.
Drug class–specific analyses showed a similar direction of association for tricyclic antidepressants and gabapentinoids. In the most adjusted models, tricyclic antidepressant initiation was associated with a 34% higher hazard of knee or hip replacement compared with SSRI initiation, and gabapentinoid initiation was associated with a 50% higher hazard. Analyses for serotonin-norepinephrine reuptake inhibitors were not reported because matching to the SSRI comparator group was unsuccessful due to low numbers. The researchers noted that this limitation is clinically relevant because duloxetine, a serotonin-norepinephrine reuptake inhibitor, is the only centrally acting analgesic approved by the US Food and Drug Administration for osteoarthritis pain.
“We did not find CAAs to be superior to SSRIs in preventing joint replacement,” wrote lead study author Zhiqiang Wang, of Southern Medical University and Boston University Chobanian & Avedisian School of Medicine, and colleagues. “These findings challenge the consideration of preference being given to antidepressants with purported centrally-acting pain mechanisms for OA pain management.”
The researchers cautioned that the study could not establish causality. Approximately three-quarters of patients in both groups did not have a recorded depression diagnosis, suggesting that many prescriptions may have been for other indications, including anxiety, sleep disorders, or off-label pain management.
The potential for residual confounding by indication remained despite these methods. The database did not capture pain severity, functional limitation, or radiographic osteoarthritis severity, and patients prescribed centrally acting analgesics may have had more severe symptoms at baseline. In an additional analysis adjusting for baseline intra-articular corticosteroid use, the association remained elevated and was only slightly attenuated (HR, 1.57; 95% CI, 1.21-2.04). Multiple-imputation analyses for missing body mass index, smoking, and alcohol-use data yielded similar estimates to the complete-case analysis.
The findings raise the possibility that management of depression may influence osteoarthritis symptoms indirectly through effects on pain perception and function, rather than through direct analgesic mechanisms alone. However, the authors emphasized that the observed association should be interpreted cautiously because residual confounding by indication remains possible; patients prescribed centrally acting analgesics may have had more severe pain, functional limitation, or structural osteoarthritis than those prescribed SSRIs. They also noted that it remains unclear how much apparent “pain relief” reflects centrally acting mechanisms versus improvement in depression with downstream effects on the pain experience.
Disclosures: The researchers reported no competing interests.
Source: BMC Medicine
