Peer Reviewed

Cancer pain management: what are the controversies?

Taylan Gurgenci, Phillip Good, Janet R. Hardy

Adequate pain relief in people with advanced cancer can usually be achieved using an evidence-based, multidisciplinary approach. However, some patients experience refractory cancer pain, with clinicians then understandably turning to controversial therapeutic options. This article considers some of these therapeutic options and the evidence supporting or cautioning against their use.

Key Points
  • The benefit of the World Health Organization analgesic ladder in facilitating pain relief in patients with cancer outweighs the criticisms.
  • The prescription of opioid analgesia should be individualised to the needs and preferences of patients.
  • Methadone can be a useful drug in refractory cancer pain but is best left to specialists in view of the potential for harm.
  • The use of ketamine for chronic cancer pain is not supported by the existing evidence.
  • Given the lack of high-quality evidence of clinical benefit, it is hard to recommend medicinal cannabis as standard practice for cancer pain management.

Pain is a major source of distress in patients with advanced cancer. Almost half of all patients with metastatic cancer report moderate-to-severe pain with increasing prevalence prior to death.1 Adequate pain relief can usually be achieved using an evidence-based, multidisciplinary approach.2 Nevertheless, 10 to 20% of patients will experience refractory cancer pain.2 

Clinicians will understandably turn to controversial therapeutic options once standard care fails. Controversial therapies are defined in this article as those that have produced considerable disagreement in the palliative care literature, particularly regarding the degree to which they are supported by evidence. The evidence base behind most of these second-line practices is often reliant on anecdote and/or personal experience and often supported by reports of significant benefit. This article considers some of these contentious pharmacological options and the evidence supporting or cautioning against their use and includes the authors’ opinion as to their value.

World Health Organization analgesic ladder 

There is little controversy about the historical benefit of the World Health Organization (WHO) ladder per se and its significant role in bringing pain relief to many people worldwide. However, there has been much discussion about its relevance in recent times and concerns have been raised about its deleterious effect in the management of nonmalignant pain. The comments in this article relate to its use in cancer pain.

The WHO analgesic ladder was first published in 1986 as an approach to cancer pain management relevant to both developed and developing health services.3 It is simple, easy to understand and utilises a small number of commonly used analgesics. A three-step approach to cancer management is advocated, corresponding to three levels of pain severity (mild, moderate, severe).

  • Step 1: start a nonopioid (e.g. paracetamol) with or without an adjuvant analgesic, then
  • Step 2: add a weak opioid (e.g. codeine, tramadol) with or without an adjuvant analgesic, then
  • Step 3: replace the weak opioid with a strong opioid (e.g. morphine, oxycodone).

To place these recommendations in the appropriate historical context, the first hospice was opened in 1967, the term ‘palliative care’ was first coined in 1974, and the first slow-release opioid was introduced in 1980.4-6

Options for cancer pain are now more plentiful and pain management more complex, leading many authors to suggest that the WHO ladder needs modification to avoid obsolescence.7 For example, it does not take into account the mechanism, type or cause of pain, it does not consider interventional pain procedures and it suggests a one-way escalation of opioids.8 

One major European guideline suggests that low-dose strong opioids should be used as first-line agents for moderate cancer pain rather than the WHO ladder’s recommendation of weak opioids at step 2.1 This is echoed in a regularly updated Australian guideline.9 As others have noted, this approach seemingly transforms the WHO ladder into the WHO elevator, where the patient proceeds directly to the appropriate level rather than climbing one rung at a time.7

A multicentre, open-label randomised controlled trial (RCT) in adults with moderate cancer pain showed low-dose morphine resulted in a 20% pain intensity reduction for 88.2% of patients versus 57.7% in the weak opioid group.10 Another RCT supported the omission of step 2, although there were some questions around study methodology.11,12

The reliance on opioids in the WHO ladder raises issues around opioid dependency as survival is more prolonged.13 Moreover, it has received a portion of the blame for current opioid epidemics following its use in patients with chronic nonmalignant pain.14 Radiotherapy, chemotherapy, surgery or interventional pain procedures may all decrease the daily opioid requirement. Patients who have improved pain control after these treatments should be considered for gradual opioid dose reduction.

Authors’ opinion: the benefit of this simple tool in facilitating pain relief in patients with cancer outweighs the criticisms. There is evidence to support the common practice of omitting the second level of the WHO ladder (use of a weak opioid) in the management of cancer pain.

Regular long-acting or as-required opioids 

Regular dosing ‘by the clock’ is one of the recommendations of most international analgesic guidelines. Usual practice is to titrate short-acting opioids upwards until pain control is achieved, at which time the total opioid dose used can be converted to a long-acting preparation to be taken regularly every day. Pain varies, however, and many patients prefer to take analgesia only when required. Moreover, several guidelines now recommend titration with either long- or short-acting opioids.1

A systematic review of RCTs that compared regular with  as-required analgesia did not demonstrate superiority of regular analgesia.15 Moreover, regular dosing was associated with significantly higher total opioid doses. This is relevant for patients wishing to maintain full cognitive function. 

Authors’ opinion: the prescription of opioid analgesia should be individualised to the needs and preferences of patients.


Methadone is a synthetic opioid developed in the 1930s. Its main use today is in methadone maintenance programs, as the long half-life of the drug allows for once-daily delivery. In palliative care, methadone is generally reserved for patients with pain that is difficult to manage with standard analgesia. It is thought by many that methadone is more efficacious than other opioids, especially in the management of neuropathic pain. Based on low-quality evidence, a 2017 updated Cochrane review concluded that methadone has similar analgesic benefits to morphine.16 In this 2017 Cochrane review, the drawbacks of methadone were pointed out and included ‘high potential for accumulation leading to delayed toxicity, highly variable pharmacokinetics between individuals, relative ease of use of modified-release morphine preparations, possible drug interactions, and concerns over dose titration and conversion from other opioids’.17 Similarly, the evidence of benefit in patients with neuropathic pain is limited and of low quality.17

Many clinicians prefer to use methadone as an adjuvant because conversion from other opioids is notoriously difficult. Multiple conversion methods have been published, resulting in widely differing doses of methadone when compared head-to-head.18

Authors’ opinion: methadone can be a useful drug in refractory cancer pain but is best left to specialists in view of the potential for harm. 

Opioid rotation

Opioid rotation is the act of switching from one opioid to another to improve pain control or decrease adverse effects. There are multiple anecdotal reports of benefit after such switching. The purported mechanism underlying the benefit of opioid rotation remains unclear. The original hypothesis of toxic metabolite reduction remains unconfirmed. Incomplete cross-tolerance has been suggested as an alternative mechanism. This theory suggests that although patients become generally tolerant to opioids with regular dosing, the tolerance incompletely carries over when another opioid is prescribed.19 Differential agonism of opioid receptor subtypes has also been proposed.19

Opioid rotation was first evaluated in a retrospective cohort study of 191 consecutive palliative patients.20 From this cohort, 80 patients underwent opioid rotation. The indications were persistent pain as well as other symptoms of opioid toxicity such as cognitive decline or myoclonus. The rationale for trialling opioid rotation was the potential to improve symptoms by reducing the concentration of accumulated toxic metabolites. The mean reduction in pain following rotation was 0.8 points on a visual analogue scale (from 4.4 to 3.6 points) and the mean reduction in daily oral morphine equivalents was 241 mg, both of which were statistically significant. 

The most recent Cochrane review assessing opioid rotation was published in 2004.21 No RCTs were available for inclusion. The authors concluded that although opioid rotation may be the only option for symptomatic relief for patients with refractory cancer pain, the evidence is based on a combination of anecdote and uncontrolled studies. 

Multiple systematic reviews on opioid rotation have been published since the Cochrane review.22,23 They cautiously suggest opioid rotation as an option for refractory cancer pain while acknowledging the absence of prospective RCT evidence. 

There are still no prospective, placebo-controlled trials to guide clinical practice. The only available prospective studies compared opioid rotation with different opioids or other options for refractory pain, but not with a placebo control.22,23 In a randomised study of 50 participants with persistent pain who were taking at least 100 mg of oral morphine equivalents per day, participants were randomised to either rotation to transdermal fentanyl or a combination of 50% of the fentanyl dose that the other group received plus regular oral oxycodone.24 Each group had a statistically significant improvement in pain scores. 

Authors’ opinion: opioid rotation is less relevant in modern practice when many patients receive a combination of different opioids to optimise their pain control. It is likely, however, that certain opioids are more suited to individuals than others on the basis of multiple factors (e.g. preference, route of delivery, cost, convenience). It is common practice in palliative care to rotate to a different opioid if there is a perceived lack of efficacy or signs of opioid toxicity. Dose reduction should be considered when doing so and palliative specialist advice sought if there is any uncertainty. 


Ketamine is a phencyclidine derivative used primarily as an anaesthetic agent.25 It acts principally as an N-methyl-D-aspartate receptor antagonist. It is often used in perioperative and chronic nonmalignant pain and the approach has been extrapolated to those with malignant pain. Ketamine for palliative cancer pain management continues to inspire a great deal of controversy. 

In an Australian RCT of 185 palliative patients with advanced cancer, subcutaneous ketamine infusion was no better than placebo when used in a dose-escalating regimen over five days.26 The doses achieved were consistent with clinical practice and the population under study had the characteristics of those in a palliative care practice. Another multicentre RCT of 214 patients with cancer-related neuropathic pain showed ketamine was equivalent to placebo.27 

Two smaller RCTs also did not demonstrate benefit of ketamine compared with placebo in patients with advanced cancer.28,29 Ketamine was better than placebo in one small, single-institution study of 10 patients.30 This study assessed pain scores every 30 minutes for a total of only three hours. No rescue analgesia was given. Thus, the only RCT showing a benefit was both very small and least resembled the actual use of ketamine in clinical practice. Despite this, a Cochrane review claims insufficient evidence to assess the benefits and harms of ketamine as an adjuvant to opioids for the relief of refractory cancer pain.31 

Case series and observational studies continue to be published. One recent case series of 47 patients with refractory cancer-related pain treated with subanaesthetic ketamine in an ambulatory context showed improvement from baseline pain levels.32 

Separately, a retrospective cohort study of 70 patients measured a mean pain score improvement from 7.0 to 4.0 on the numerical rating scale.33 The median opioid dose reduction was 25.5% and patients needed to be taking more than 300 mg oral morphine equivalent per day to be eligible. The authors posited there may be an unidentified ‘good responder’ group to account for the discrepancy from the RCTs. 

The question is whether the positive cohort studies and case series outweigh the negative, large RCTs. Further observational studies will not provide that information.34 

Authors’ opinion: the use of ketamine for chronic cancer pain is not supported by the existing evidence.

Medicinal cannabis

Medicinal cannabis is sometimes prescribed for cancer pain management. Tetrahydrocannabinol (THC) and cannabidiol (CBD) are generally accepted as the clinically relevant compounds. However, some claim this ignores the so-called entourage effect, whereby the combination of multiple cannabinoids plus terpenes found in the cannabis plant act together to provide the desired effect.35 THC is a partial agonist of CB1 and CB2 receptors. CBD is a negative allosteric modulator of CB1 receptor and may act on other receptors.36 If medicinal cannabis has a role in cancer pain, the pathophysiological explanation remains elusive. Early studies were suggestive of an antinociceptive effect.37,38 The results of modern, higher-quality studies have been mixed.    

A two-week, parallel-group trial of 177 patients comparing THC:CBD extract, THC extract and placebo found a statistically significant change from baseline in mean pain numerical rating scale scores in favour of the THC:CBD extract compared with placebo (improvement of −1.37 vs −0.69).39 Medication doses were determined by self-titration. Breakthrough opioid use was similar across the three groups. A similarly large study showed a reduction in average daily pain score with use of nabiximols (a specific THC:CBD 1:1 extract) compared with placebo.40  

In contrast, both an RCT of 399 patients and a withdrawal design RCT of 406 patients  failed to demonstrate that the use of nabiximols was superior to placebo.41 The results of an RCT of 380 participants were similarly contradictory.42 So too was a smaller pilot RCT in 16 patients investigating nabiximols for the treatment of chemotherapy-induced peripheral neuropathy.43

A 2021 systematic review and meta-analysis of RCTs concluded that there was moderate to high certainty that medicinal cannabis provides a small or very small improvement in pain relief in patients with chronic pain.44 Another recent meta-analysis showed no benefit of medicinal cannabis for pain in adults with advanced cancer.45

Authors’ opinion: medicinal cannabis may provide a small benefit in cancer pain for some adults. The clinical significance of this is uncertain. Given the lack of high-quality evidence of clinical benefit it is hard to recommend medicinal cannabis as standard practice for cancer pain management.


RCTs provide the highest level of evidence when assessing the efficacy of a drug or intervention. RCTs in patients receiving palliative care, although demonstrably possible, are difficult to orchestrate, in part due to the unique population characteristics leading to significant attrition. Many controversial issues in palliative care are difficult to resolve. Other pain management options not covered in this article include lignocaine infusion, clonidine and NSAIDs or corticosteroids alone or in combination with opioids. Evidence-based care should be prioritised in this specialty as much as in others.    PMT





1.    Fallon M, Giusti R, Aielli F, et al. Management of cancer pain in adult patients: ESMO Clinical Practice Guidelines. Ann Oncol 2018; 29(Suppl 4): iv166-iv191.
2.    Afsharimani B, Kindl K, Good P, Hardy J. Pharmacological options for the management of refractory cancer pain – what is the evidence? Support Care Cancer 2015; 23: 1473-1481.
3.    Ventafridda V, Tamburini M, Caraceni A, De Conno F, Naldi F. A validation study of the WHO method for cancer pain relief. Cancer 1987; 59: 850-856.
4.    Oransky I. Dame Cicely Mary Strode Saunders. Lancet 2005; 366: 628.
5.    Mount B. Ten thousand crossroads: the path as I remember it. McGill-Queen’s University Press-MQUP; 2021 Jan 16.
6.    Leslie S, Rhodes A, Black F. Controlled release morphine sulphate tablets – a study in normal volunteers. Br J Clin Pharmcol 1980; 9: 531-534.
7.    Eisenberg E, Shifrin A. Reassessing the need for step 2 of the WHO analgesic ladder. J Pain Palliat Care Pharmacother 2011; 25: 288-290.
8.    Vayne-Bossert P, Afsharimani B, Good P, Gray P, Hardy J. Interventional options for the management of refractory cancer pain – what is the evidence? Support Care Cancer 2015; 24: 1429-1438.
9. Australian Adult Cancer Pain Management Guideline Working Party. Cancer pain management in adults. Sydney: Australian Adult Cancer Pain Management Guideline Working Party. Available online at: (accessed June 2022).
10. Bandieri E, Romero M, Ripamonti CI, et al. Randomized trial of low-dose morphine versus weak opioids in moderate cancer pain. J Clin Oncol 2016;  34: 436-442.
11. Marinangeli F, Ciccozzi A, Leonardis M, et al. Use of strong opioids in advanced cancer pain: a randomized trial. J Pain Symptom Manage 2004;  27: 409-416.
12. Hanks GW, Reid C, Forbes K. Re: Use of strong opioids in advanced cancer pain. J Pain Symptom Manage 2005; 29: 113-114.
13. Pergolizzi JV, Magnusson P, Christo PJ, et al. Opioid therapy in cancer patients and survivors at risk of addiction, misuse or complex dependency. Front Pain Res (Lausanne) 2021; 2: 691720.
14. Ballantyne JC, Kalso E, Stannard C. WHO analgesic ladder: a good concept gone astray. BMJ 2016; 352: i20-i20.
15. Edler-Buggy S, Birtwistle J, ElMokhallalati Y, Kindl K, Good P, Bennett MI. Regular dosing compared with as-needed dosing of opioids for management of chronic cancer pain: systematic review and meta-analysis. Pain 2020; 161: 703-712.
16. Nicholson AB, Watson GR, Derry S, Wiffen PJ, Nicholson AB. Methadone for cancer pain. Cochrane Database Syst Rev 2017; (3): CD003971.
17. McNicol ED, Ferguson MC, Schumann R. Methadone for neuropathic pain in adults. Cochrane Database Syst Rev; 2017; (5): CD012499.
18. Lukin B, Greenslade J, Kearney AM, et al. Conversion of other opioids to methadone: a retrospective comparison of two methods. BMJ Support Palliat Care 2020; 10: 201-204.
19. Pasternak GW. Opiate pharmacology and relief of pain. J Clin Oncol 2014; 32: 1655-1661.
20. De Stoutz ND, Bruera E, Suarez-Almazor M. Opioid rotation for toxicity reduction in terminal cancer patients. J Pain Symptom Manage 1995; 10:  378-384.
21. Quigley C. Opioid switching to improve pain relief and drug tolerability. Cochrane Database Syst Rev 2004; (3): CD004847.
22. Schuster M, Bayer O, Heid F, Laufenberg-Feldmann R. Opioid rotation in cancer pain treatment – a systematic review. Dtsch Ärztebl Int 2018; 115:  135-142.
23. Dale O, Moksnes K, Kaasa S. European Palliative Care Research Collaborative pain guidelines: opioid switching to improve analgesia or reduce side effects. A systematic review. Palliat Med 2011; 25: 494-503.
24. Kim H-J, Kim YS, Park SH. Opioid rotation versus combination for cancer patients with chronic uncontrolled pain: a randomized study. BMC Palliat Care 2015; 14: 41.
25. Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI. Ketamine: a review of clinical pharmacokinetics and pharmacodynamics in anesthesia and pain therapy. Clin Pharmacokinet 2016; 55: 1059-1077.
26. Hardy J, Quinn S, Fazekas B, et al. Randomized, double-blind, placebo-controlled study to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain. J Clin Oncol 2012; 30: 3611-3617.
27. Fallon MT, Wilcock A, Kelly CA, et al. Oral ketamine vs placebo in patients with cancer-related neuropathic pain: a randomized clinical trial. JAMA Oncol 2018; 4: 870-872.
28. Salas S, Frasca M, Planchet-Barraud B, et al. Ketamine analgesic effect by continuous intravenous infusion in refractory cancer pain: considerations about the clinical research in palliative care. J Palliat Med 2012; 15: 287-293.
29. Ishizuka P, Garcia JBS, Sakata RK, Issy AM, Mülich SL. Assessment of oral S+ ketamine associated with morphine for the treatment of oncologic pain. Rev Bras Anestesiol 2007; 57: 19-31.
30. Mercadante S, Arcuri E, Tirelli W, Casuccio A. Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study. J Pain Symptom Manage 2000; 20: 246-252.
31. Bell RF, Eccleston C, Kalso EA. Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database Syst Rev 2017; (6): CD003351.
32. Chung M, Benkli B, Roldan C, Qing Y, Wang J, Huh B. Subanesthetic ketamine in the ambulatory setting for refractory cancer pain: a 6-year retrospective at a cancer center. Pain Management 2021; 11: 267-276.
33. Cheung KWA, Chan PC, Lo SH. The use of ketamine in the management of refractory cancer pain in a palliative care unit. Ann Palliat Med 2020; 9:  4478-4489.
34. Senn S. Individual response to treatment: is it a valid assumption? BMJ 2004; 329: 966-968.
35. Cogan PS. The ‘entourage effect’ or ‘hodge-podge hashish’: the questionable rebranding, marketing, and expectations of cannabis polypharmacy. Expert Rev Clin Pharmacol 2020; 13: 835-845.
36. Shahbazi F, Grandi V, Banerjee A, Trant JF. Cannabinoids and cannabinoid receptors: the story so far. iScience 2020; 23: 101301.
37. Noyes Jr R, Brunk SF, Baram DA, Canter A. Analgesic effect of delta-9-tetrahydrocannabinol. J Clin Pharmacol 1975; 15: 139-143.
38. Noyes R, Brunk SF, Avery DH, Canter A. The analgesic properties of delta‐9‐tetrahydrocannabinol and codeine. Clin Pharmacol Therapeutics 1975; 18: 84-89.
39. Johnson J, Burnell-Nugent M, Lossignol D, Ganae-Motan E, Potts R, Fallon M. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of thc:cbd extract and thc extract in patients with intractable cancer-related pain. J Pain Symptom Manage 2010; 39: 167-179.
40. Portenoy RK, Ganae-Motan ED, Allende S, et al. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain 2012; 13: 438-449.
41. Fallon MT, Albert Lux E, McQuade R, et al. Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies. Br J Pain 2017; 11: 119-133.
42. Lichtman AH, Lux EA, McQuade R, et al. Results of a double-blind, randomized, placebo-controlled study of nabiximols oromucosal spray as an adjunctive therapy in advanced cancer patients with chronic uncontrolled pain.  J Pain Symptom Manage 2018; 55: 179-188.e1.
43. Lynch ME, Cesar-Rittenberg P, Hohmann AG. A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain.  J Pain Symptom Manage 2014; 47: 166-173.
44. Wang L, Hong PJ, May C, et al. Medical cannabis or cannabinoids for chronic non-cancer and cancer related pain: a systematic review and meta-analysis of randomised clinical trials. BMJ 2021; 374: n1034.
45. Boland EG, Bennett MI, Allgar V, Boland JW. Cannabinoids for adult cancer-related pain: systematic review and meta-analysis. BMJ Support Palliat Care 2020; 10: 14-24.
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