Opioid tolerance and adherence and its relationship to cytokine concentrations among patients with non-cancer pain at pain clinics in three tertiary hospitals

Abstract

Introduction: Opioids are strong analgesics that have been used for centuries for the treatment of pain. The long-term use of opioid in chronic non-cancer pain (CNCP) is controversial as the available evidence is limited to short term efficacy and side effects. Several concerns are raised regarding the long-term use of opioids in CNCP, and most of these concerns were linked to unclear adherence to opioid therapy, increased risks of opioid tolerance, abuse, addiction, and opioid overdose death. Methods: This prospective cross-sectional study was conducted among patients with noncancer pain attending pain clinics at three tertiary hospitals in Malaysia from March 2016 to February 2017. Patients’ medical records and prescription records were assessed. Blood samples were also taken for the assessment of pro-inflammatory cytokine interleukin (IL-6) and anti-inflammatory (IL-10). The opioid plasma concentrations were also measured using LCMSMS. Patients were categorized into short-term opioid users and long-term opioid users based on the use of opioids >90 days. For long-term opioid users, they were further categorized into adherent and non-adherent based on medication possession ratio (MPR). Prevalence of patients with opioid therapy was also recorded. Opioid tolerance was investigated based on the significant increment in opioid dose throughout treatment. This measure of tolerance was then correlated with pro-inflammatory IL-6 and anti-inflammatory IL-10. Results: Prevalence of opioid use among 726 pain patients attending the pain clinic during the study period was 11.9% (n=87/726). Thirty-eight patients were recruited into the study. Of these, 24% (n=9/38) were short term opioid users, and 76% (n=29/38) were long-term, opioid users. Among 29 patients using opioids for long-term (> 90 days), 62% (n=18/29) of these patients were adherent to opioid therapy while 38% (n=11/29) of patients showed non-adherence to opioid therapy. The correlation between both cytokines showed a strong correlation for long- and short-term users, respectively. The opioid plasma concentrations revealed that the majority of long- and short-term users had their plasma concentration within the therapeutic range. Further correlation showed that the plasma concentration measure and the medication possession ratio have moderate strength correlation. The mean dose in oral morphine equivalence (OMEQ) for the long-term users was higher (42.8 ± 11.1 mg/day) than with short-term users (13.6 ± 2.7 mg/day) while the small opioid doses of less than 20 OMEQ was the most common doses prescribed for long- and short-term users. Opioid tolerance was common in long-term opioid users and to a lesser extent in short-term users. Moreover, the mean plasma concentration of anti-inflammatory IL-10 was significantly higher among opioid intolerant patients than among opioid-tolerant patients There was a significant positive correlation between the pro-inflammatory IL-6 concentration and pain intensity in the tolerant opioid users. Conclusion: The results of this study demonstrated that most patients used opioids for the long-term for their non-cancer pain, and the majority of long-term opioid users were adherent to their opioid therapeutic plan. The indirect measure of adherence using prescription refills calculated by medication possession ratio was found to be well correlated with the direct measure of adherence characterized by the opioid plasma concentrations. This study provides evidence for clinical practice to confidently use the indirect measure of adherence to assess patients’ behavior to opioid therapy and also further cautions clinician on the risk of opioid tolerance in patients with long-term opioid therapy.