Chronic non-cancer pain – pain that lasts for at least three months and is not related to any other malignancy – is one of the most common pain-related conditions globally. Despite this, diagnosis is often difficult, and many current treatments achieve unsatisfactory relief. Chronic pain is associated with significant effects on mobility and quality of life and can have direct and indirect economic implications; estimates show that costs associated with chronic pain in Canada equate to approximately $7.2 billion annually.
Figures show that around 30% of patients with chronic non-cancer pain may be prescribed opioids. Furthermore, strong opioids are more commonly prescribed than weak opioids which may contribute to an increase in unwanted side effects. Despite this ongoing use and a high risk profile, evidence suggests that the use of opioids for chronic non-cancer pain only demonstrate modest benefits for both pain and physical function.
Most systematic reviews for opioids for chronic pain pool treatment effects across individual opioids under the assumption they provide similar benefits and harms. In order to better understand the individual effects of different opioids, the authors of a recent systematic review and meta-analysis examined the results of randomised controlled trials (RCTs) that enrolled patients with chronic non-cancer pain who were treated with different opioids, or opioids vs placebo.
Design and Methods
The researchers identified relevant studies using a medical librarian developed database-specific search strategies, for MEDLINE, EMBASE, CINAHL, and Cochrane Central Register of Controlled Trials. Databases were searched from inception to 20 March 2021. In addition, the researchers also reviewed the reference list of each included study to identify further relevant studies. Studies that assessed combination products containing a non-opioid component and trials or trial arms of opioids not currently approved for clinical use were excluded.
Opioids used in eligible RCTs were reviewed by a clinical pharmacologist who was blinded to the study results. Furthermore, the selection of adverse events used in the final analysis was guided by a systematic review of patients’ values and preferences. This review identified gastrointestinal (GI) events as the most important harms as considered by patients prescribed opioids for chronic pain. For this review, GI events included vomiting, constipation, and nausea.
All measures of pain intensity were converted to a 10cm visual analogue scale (VAS) and physical function to the 100-point 36-item Short Form Survey (SF-36) physical component summary (PCS) score. Researchers also assessed the certainty of evidence included in the review on an outcome-by-outcome basis and provided a rating for each comparison: high, moderate, low, or very low based on risk of bias, inconsistency, indirectness, publication bias, intransitivity, incoherence, and imprecision.
Results
In total, 80 articles were deemed to meet the eligibility criteria and were included in the review. Two of the articles reported two RCTs each, resulting in the inclusion of 82 eligible trials collectively enrolling 22,619 participants. A further 11 studies were included in the review but excluded from meta-analysis of effect estimates.
Nine studies included patients with mixed types of chronic pain, 34 included patients with nociceptive pain, 20 with neuropathic pain, and 20 with nociplastic pain. Twenty-one trials (26%) used an enriched enrolment design. The median duration of chronic pain was 97 months. Of the included studies, nine (11%) were judged to be at low risk of bias in all domains while all other studies (88%) had issues in domains of frequently missing outcome data (87%) or failure to blind patients (13%).
Outcomes for Pain Relief
Of the 82 RCTs included for review, 78 (21,906 participants) reported the effect of opioids on pain relief – including 22 direct comparisons. Low to very low certainty evidence suggests that extended-release (ER) and immediate-release (IR) opioids may provide similar benefits for pain relief. Moderate certainty evidence showed that that IR tramadol, ER morphine, sublingual buprenorphine, ER tapentadol, and ER tramadol were only superior to placebo, with pain reduction ranging from –0.80 to –1.09 cm on a 10-cm VAS. However, no opioid showed superiority over another.
Furthermore, low to very low certainty evidence suggested that that IR tramadol, ER morphine, sublingual buprenorphine, ER tapentadol, and ER tramadol were only superior to placebo. Overall, the SUCRA ranking suggested that ER codeine, ER oxymorphone, IR tramadol, and IR oxycodone were the best opioids for pain relief; however, their effect estimates were supported by only low certainty evidence.
Outcomes for Physical Function
Thirty-nine studies (13,134 participants) reported the effect of opioids on physical functioning. As seen with pain relief outcomes, low to very low certainty evidence suggests that IR and ER opioids may have similar benefits for physical functioning. While the researchers found no moderate or high certainty evidence for physical functioning, they did note that low to very low certainty evidence suggested that ER codeine and ER hydromorphone may improve physical functioning more than placebo.
Other low to very low certainty evidence suggested that some opioids are superior to others for the improvement of physical functioning; namely, ER tapentadol and ER oxycodone may be inferior to ER codeine and ER hydromorphone but superior to placebo for this outcome.
Gastrointestinal (GI) Adverse Events
Evidence reviewed by the researchers suggests that opioids may be associated with a higher risk of gastrointestinal harms, including vomiting, constipation and nausea. This was particularly true of ER oxycodone for which there was moderate certainty evidence of an increased risk of each of these events. Low to very low certainty evidence also suggested that most other opioids (both IR and ER medications) included in this review also increased the risk of adverse events when compared to placebo.
Whilst all opioids supported by moderate certainty evidence were shown to increase the risk of GI adverse events, none were more harmful than others. Low to very low certainty evidence suggests that ER vs IR opioids may result in similar GI harms.
Conclusions
Having reviewed the existing evidence on the benefits and harms of individual opioids, the researchers conclude that ER and IR opioids produced similar effects. This finding is in line with a 2014 qualitative systematic review of six trials which found insufficient evidence to suggest that individual opioids were more or less effective.
The authors also note that their findings build on previous evidence to suggest that individual opioids are similarly effective for pain relief and physical functioning. Individual opioids were also found to carry a similar risk of GI adverse events, including an increased risk of vomiting, constipation, and nausea.
