Mediating Effect of Pain Sensitization on the Paradoxical Relation of Taking Opioids to Pain Severity in Knee Osteoarthritis: The Multicenter Osteoarthritis Study

OBJECTIVE: One of the less understood adverse effects while taking opioids is the paradoxical increase in pain, known as opioid-induced hyperalgesia (OIH). We sought to determine whether pain sensitization mediates the relation of taking an opioid to pain severity in people with knee osteoarthritis (OA). METHODS: We included participants in a National Institutes of Health-funded cohort study of people with or at risk of knee OA. Participants were categorized into opioid and nonopioid analgesic groups at baseline. Western Ontario McMaster Universities OA Index (WOMAC) pain two years later was assessed as the outcome. We used causal mediation analysis to assess the mediating role of pain sensitization, quantified by changes in pressure pain threshold (PPT) at the wrist and patella over two years, on the effect of taking an opioid on WOMAC pain two years later. RESULTS: We included 296 participants who took opioids and 1,070 participants who took nonopioid analgesics. Compared with taking nonopioid analgesics, taking opioids was associated with greater pain two years later. This relation was mediated by 0.05- and 0.08-unit changes in wrist PPT (95% confidence interval [CI] 0.01-0.10) and patellar PPT (95% CI 0.02-0.14), respectively. When we assessed any worsening in WOMAC pain score over two years, taking opioids, compared with taking nonopioid analgesics, had 2% and 5% higher odds of experiencing any worsening pain mediated by changes in wrist PPT (95% CI 0.99-1.04) and patellar PPT (95% CI 1.01-1.09), respectively. CONCLUSION: Pain sensitization had small mediating effects on the paradoxical phenomenon of OIH, suggesting that pain sensitization may not play a major role and/or that PPT is an inadequate tool to assess OIH.