Patients with opioid use disorder receiving agonist therapy, such as methadone or buprenorphine, were found to have a 52% reduction in pain tolerance compared to healthy controls, according to a recent systematic review and meta-analysis published in JAMA Psychiatry.
Researchers evaluated the potential association between hyperalgesia and opioid use in patients with opioid use disorder (OUD), analyzing data from 39 studies involving 1,385 patients with OUD and 741 control patients. The literature search was conducted between March 1, 2023, and April 12, 2024, across Web of Science, PubMed, and Embase databases, focusing specifically on cold pressor test (CPT) pain responses.
The analysis revealed that patients undergoing opioid agonist therapy exhibited increased sensitivity to cold pain compared to controls, with a 22% reduction in pain threshold and a 52% reduction in pain tolerance.
Patients receiving opioid agonist therapy exhibited a mean pain threshold that was 2 to 3 seconds shorter compared to healthy controls (95% confidence interval [CI], −4 to −1; t test P = .01; %Δ, −22%; Hedges g = −0.5). Additionally, these patients showed a pain tolerance that was 29 seconds less than that of the control group (95% CI, −39 to −18; t test P < .001; %Δ, −52%; Hedges g = −0.9). However, cold pain intensity did not significantly differ between patients receiving opioid agonist therapy and healthy control subjects (mean difference [MD], 1.0; 95% CI, −19.4 to 21.4; t test P = .92; %Δ, 1.7; Hedges g = 0.0).
Patients evaluated before starting treatment for OUD showed a significantly lower tolerance for cold pain compared to healthy controls (MD, −24.0; 95% CI, −47.3 to −0.6; t test P < .05; %Δ, −52%; Hedges g = −0.8), while their pain threshold did not significantly differ (MD, 0.6; 95% CI, −39.8 to 40.9; t test P = .89; %Δ, 17.8; Hedges g = 0.1).
Despite these findings, the evidence linking hyperalgesia directly to opioid use remains inconclusive. The study's meta-regressions did not show consistent associations between hyperalgesia and measures of opioid tolerance, withdrawal, or abstinence. This suggests that factors other than opioid use could contribute to the observed pain sensitivity in this patient population.
No significant differences in cold pain threshold, tolerance, or intensity were found when comparing abstinent patients to healthy controls or to patients receiving opioid agonist therapy. Interestingly, patients receiving opioid antagonist therapy, such as naltrexone, demonstrated a significantly higher cold pain threshold (MD, 13.3; 95% CI, 8.9 to 17.6; t test P < .001; %Δ, 52%; Hedges g = 1.5) and pain tolerance (MD, 27.3; 95% CI, 15.5 to 39.0; t test P < .001; %Δ, 41%; Hedges g = 1.2) compared to healthy controls.
The researchers attempted to test the hypothesis that chronic pain rates are positively correlated with cold pain sensitivity in patients receiving opioid agonist treatment, but this analysis yielded inconclusive results.
The study authors noted several limitations, including potential sources of bias such as inadequate sample matching and participant dropout. Additionally, the cross-sectional nature of most included studies and the focus solely on cold pain limit the generalizability of the findings.
The authors recommend further investigation to elucidate the underlying mechanisms of hyperalgesia in patients with OUD, with particular emphasis on its impact on treatment outcomes and patient well-being. They suggest investigating the predictive value of hyperalgesia for important patient outcomes, including abstinence, treatment retention, well-being, and social functioning.
This work was supported by grants from the South-Eastern Norway Regional Health Authority (project No. 2018035). The authors reported no conflicts of interest.