Mediating Effect of Pain Sensitization on the Paradoxical Relation of Opioid Use to Pain Severity in Knee Osteoarthritis: The MOST Study

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 opioid use to pain severity in people with knee OA.We included participants in a NIH-funded cohort study of people with or at risk of knee OA. Participants were categorized into opioid and non-opioid analgesic groups at baseline. WOMAC pain 2 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 2 years, on the effect of opioid use on WOMAC pain 2 years later.We included 296 opioid users and 1070 non-opioid analgesic users. Compared with non-opioid analgesic use, opioid use was associated with greater pain 2 years later. This relation was mediated by 0.05 and 0.08 unit changes in wrist PPT (95%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 2 years, opioid use, compared with non-opioid analgesic use, had a 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.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. This article is protected by copyright. All rights reserved.