An international, open-label, randomised trial comparing a two-step approach versus the standard three-step approach of the WHO analgesic ladder in patients with cancer

Worldwide, cancer pain management follows the World Health Organization (WHO) three-step analgesic ladder. Using weak opioids (e.g. codeine) at step 2 is debatable with low-dose strong opioids being potentially better, particularly in low- and middle-income countries where weak opioids are expensive. We wanted to assess the efficiency, safety and cost of omitting step 2 of the WHO ladder. We carried out an international, open-label, randomised (1 : 1) parallel group trial. Eligible patients had cancer, pain ≥4/10 on a 0-10 numerical rating scale, required at least step 1 (paracetamol) of the WHO ladder and were randomised to the control arm (weak opioid, step 2 of the WHO ladder) or the experimental arm (strong opioid, step 3). Primary outcome was time to stable pain control (3 consecutive days with pain ≤3). Secondary outcomes included distress, opioid-related side-effects and costs. The primary outcome analysis was by intention to treat and the follow-up was for 20 days. One hundred and fifty-three patients were randomised (76 control, 77 experimental). There was no statistically significant difference in time to stable pain control between the arms, P = 0.667 (log-rank test). The adjusted hazard ratio for the control arm was 1.03 (95% confidence interval 0.72-1.49). In the control arm, 38 patients (53%) needed to change to a strong opioid due to ineffective analgesia. The median time to change was day 6 (interquartile range 4-11). Compared to the control arm, patients in the experimental arm had less nausea (P = 0.009) and costs were less. This trial provides some evidence that the two-step approach is an alternative option for cancer pain management. •For decades the empirical WHO 3 step analgesic ladder has remained the keystone to cancer pain management education worldwide.•Debate has existed around the need for step 2 of the analgesic ladder which consists of weak opioids, such as codeine.•We examined pain and side-effects between the standard 3 step (weak to strong opioid) and a 2 step arm (no weak opioid).•Time to pain control equal in both arms, fewer side effects in 2 step arm, 50% in control arm needed strong opioid by day 7.•Important practical implications, particularly in LMICs where weak opioids (step 2) are expensive and switching complicated.