The results of a randomised parallel group study provide some evidence that a two-step approach is an alternative option for cancer pain management and may be less expensive than a three-step approach. For decades the empirical World Health Organization (WHO) 3 step analgesic ladder has remained the keystone to cancer pain management with debate around the need for step 2 which consists of weak opioids. The study examined pain and side effects between the standard three-step (weak to strong opioid) and a two-step arm (no weak opioid). Time to pain control was equal in both arms with fewer side effects in two-step arm, but 50% in control arm needed strong opioid by day 7. The authors led by Prof. Marie T. Fallon of the Edinburgh Cancer Research Centre, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital in Edinburgh, UK wrote in December 2022 issue of the Annals of Oncology that the study has important implications for the practice, in particular in low- and middle-income countries where weak opioids are expensive and switching complicated.

The authors wrote in the background that almost four decades ago, the WHO published the analgesic ladder for treatment of cancer pain that recommends using non-opioids such as non-steroidal anti-inflammatory drugs and paracetamol (acetaminophen) for mild pain and which constitutes first step; the second step of the ladder is to add an opioid for mild-to-moderate pain (codeine, tramadol); and the third step constitutes an opioid for moderate-to-severe pain (morphine) which is titrated to pain relief or to occurrence of dose-limiting adverse events. Validation studies have shown that the WHO analgesic ladder can provide pain control in up to 80% of patients.

However, since its inception, there has been a call for randomised controlled studies to explore whether it would be beneficial for patients to move directly from step 1 to step 3, omitting step 2. Hypothesis of this randomised controlled study was that moving to a strong opioid directly from non-opioid analgesia and omitting the weak opioid step achieves quicker pain control without additional side-effects. 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. Therefore, the study investigators assessed the efficiency, safety and cost of omitting step 2 of the WHO ladder.

In this open-label, randomised (1:1) parallel group study, eligible patients had cancer, pain ≥4/10 on a 0-10 numerical rating scale, required at least step 1 of the WHO ladder and were randomised to the control arm with weak opioid (step 2 of the WHO ladder) or the experimental arm with strong opioid (step 3). Primary outcome was time to stable pain control defined as 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.

In total, 153 patients were randomised, 76 in control and 77 in experimental arm. 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.

The authors concluded that although underpowered, their study demonstrated several findings. Three-step approach (direct to a strong opioid) did not result in faster pain relief than two-step approach (weak opioid step). In the control arm of two-step approach more than half of the patients required to switch from a weak to a strong opioid to achieve stable pain control. Furthermore, moving from a non-opioid to a strong opioid in this study was safe. However, the cost of the three-step approach arm was less than that of the two-step approach. In countries where strong opioids are limited, such as in low- and middle-income countries, weak opioids are usually very expensive, and findings of this study may help to make a case for increased access to strong opioids globally.

The authors commented that this is the first assessment of the WHO analgesic ladder which has undertaken a cost comparison. The main limitation of the health economic analysis is that the differences for the economic outcomes between two-step and three-step ladders did not achieve statistical significance possibly due to low statistical power. 

In an accompanied editorial, professors Patricia S. Bramati and Eduardo Bruera of the Department of Palliative Care, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center in Houston, TX, US pointed out that the original study plan was to recruit 400 participants with 200 in each arm. Unfortunately, after 3 years of slow recruitment, the study was closed after including 153 patients only. They emphasized that cancer-related pain encompasses a wide range of pain disorders that frequently require opioids, either alone or in combination with additional treatments and that all physicians treating patients with cancer pain should feel confident starting morphine or similar opioids.

Current guidelines and the results or recent randomised controlled studies do not support the use of weak opioids such as codeine because low-dose morphine or another strong opioid typically provides a faster and better relief from cancer pain. The question then is whether weak opioids still have a role in the management of cancer pain. In many countries, weak opioids are subjected to lower levels of regulatory prescription barriers compared with strong opioids. Furthermore, in some institutions they are the only available opioids, and any opioid is better than no opioid when patients with cancer pain do not respond to non-opioids according to the editorialists. In addition, weak opioids might provide a temporary measure for physicians who are less at ease prescribing strong opioids until patients can be referred to physicians with expertise in pain management.

The study was supported by Doreen McGuire Endowment Fund and a Mundipharma Educational Grant.


Fallon M, Dierberger K, Leng M, et al. 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. Annals of Oncology 2022;33(12):1296-1303.

Bramati PS, Bruera E. The end of the second step of the World Health Organization analgesic ladder? Annals of Oncology 2022;33(12):1212-1213.