Individualizing cancer pain therapy

With Professor Sam Ahmedzai  |  8 Dec 2015  |  Print

Individualizing cancer pain therapy

Submitted by Professor Sam H Ahmedzai, Professor of Palliative Medicine, Academic Unit of Supportive Care, School of Medicine and Biomedical Sciences, University of Sheffield, UK

The paradox of cancer pain

More than half of surveyed cancer patients experienced moderate to severe pain at least monthly and more than two thirds reported pain-related difficulties with everyday activities.[1]Persistent pain is widely acknowledged to reduce function and overall quality of life, and is also demoralizing and debilitating for both patients and their carergivers. [2].Indeed, cancer pain is described as the most feared symptom by many patients, one that is intricately connected to other cancer symptoms (such as insomnia, fatigue, nausea and constipation), and yet cancer pain is the one of the most treatable of cancer complaints. Pain may be well-controlled in the majority of cases using pharmacotherapy (such as opioid analgesics) and other interventions.[3]

The paradox of cancer pain is that, despite its acknowledged burden and the availability of effective treatment options, unrelieved cancer pain continues to be a substantial worldwide public health concern, particularly in parts of Asia, with nearly half of cancer patients undertreated.[4][5]Therapy improvements mean that cancer patients are living longer and more people are becoming cancer survivors.[6] With this comes a responsibility to prioritize pain management and optimize the quality of life of these patients.

21st century cancer pain management: Toward an individualized approach

Before the introduction of the World Health Organization (WHO) ‘analgesic ladder’ in the 1980s, cancer pain was either ignored or treated on an ad hoc basis. The WHO ‘analgesic ladder’ provided a standardized paradigm of care for managing cancer pain, which championed oral opioids, especially morphine (Figure 1) [7]. It is a simple three-step approach based on the belief that cancer is a terminal disease and that cancer pain in the palliative setting requires a straightforward solution, a ‘one-size-fits-all’ approach.

Figure 1. The WHO 3-step ladder for managing cancer pain[7]

140530_APPROVED_HCP_Individualizing cancer_v1_1

As cancer treatments have improved, however, so have mortality rates, to the extent that many cancers are no longer considered terminal diseases, rather chronic diseases that increasing numbers of patients are living with for many years.[6] While the simple three-step approach of the ‘analgesic ladder’ may be appropriate in the last days or weeks of life, problems arise when patients require treatment for longer periods with the disease. Increasingly, cancer survivors are living with chronic pain arising from surgery or other forms of cancer therapy. The simple model is no longer sophisticated enough to address the complex problem of cancer pain in such populations.

Like modern anti-cancer treatment itself, cancer pain management strategies have become more sophisticated in recent years. We now know that:

Use of multimodal therapy (a combination of therapies and interventions tailored to the needs of an individual) may be required as the disease progresses, to optimize pain management through additive or synergistic improvements in pain, while minimalizing toxicity.

Opioid switching can exploit incomplete cross-tolerance, as oncology does with second- and third-line cytotoxic chemotherapy. Not all opioids are pharmacologically equal; for example, the intrinsic receptor activation profiles and physicochemical properties of oxycodone and fentanyl differ from those of morphine. Oxycodone acts at the μ and κ opioid receptors while morphine acts solely on μ receptors. It has a higher bioavailability with reduced interpatient variability than morphine, produces no clinically significant metabolites and has a short half-life that allows rapid dose titration.8-11 Fentanyl causes fewer side effects than morphine, particularly with respect to constipation, nausea and somnolence.12 Applying such readily accessible knowledge from the laboratory, large clinical trials and meta-analyses can be used to make more informed treatment choices for individual patients.

Targeted prevention of the causes of pain as well as management of treatment-related adverse effects maximizes patient benefits. For example, one of the side effects that most frequently results in cessation of opioid therapy, constipation, can be managed with specific μ-opioid receptor antagonists, such as naloxone or methylnaltrexone.13

Addressing opioid-induced constipation with oxycodone/naloxone combination

Constipation is highly prevalent among cancer patients, especially those who receive opioid therapy,14 and is associated with lower health-related quality of life.15 Oral prolonged release oxycodone/naloxone as a fixed dose combination causes blockade of peripheral gastrointestinal opioid receptors while allowing centrally mediated analgesia. This novel combination has been shown to significantly improve bowel function compared with prolonged release oxycodone alone, in patients with moderate to severe cancer pain (Figure 2), without compromising analgesic efficacy, or provoking opioid withdrawal.15 A statistically significant improvement in bowel function was observed after 1 week compared with oxycodone alone and, after 4 weeks, the improvement was both statistically significant and clinically relevant. After 4 weeks, constipation-related quality of life also improved, as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) constipation subscore.15

Figure 2. Prolonged release oxycodone/naloxone improves bowel function compared with prolonged release oxycodone in cancer pain15

140530_APPROVED_HCP_Individualizing cancer_v1_2

Our evolving understanding of the mechanisms of cancer pain

In the last decade, our understanding of the mechanisms that drive different types of cancer pain has advanced substantially. For example, bone cancer models have demonstrated that pain signal transduction is initiated and maintained through multiple inflammatory mechanisms at the interface of cancer and host immune cells in the bone trabeculae. Transient receptor potential vanilloid subfamily 1 (TRPV1), nerve growth factor (NGF) and various cytokines, chemokines and prostaglandins appear to be key components in these mechanisms.16 Such findings may lead to novel strategies for the treatment of bone cancer pain, which would be another step toward the goal of individualized pain management in cancer patients.

What does the future hold for cancer pain management?

Developing mechanism-based therapies for cancer pain will be crucial to advancing this field of medicine. As cancer patients are living longer, future treatments must suit more active and demanding lifestyles, and offer side-effect profiles that are acceptable in long-term use. Cancer treatment is increasingly driven by testing for cell surface receptors and their genetic variations, facilitating personalized treatment plans. Personalized pain therapy is already showing potential promise and could yield greater quality of life gains for longer periods with the use of targeted drugs.17


1. Breivik H, Cherny N, Collett B, et al. Cancer-related pain: a pan-European survey of prevalence, treatment, and patient attitudes. Ann Oncol 2009;20:1420-1433.

2. Induru RR, Lagman RL. Managing cancer pain: frequently asked questions. Cleve Clin J Med 2011;78:449-464.

3. Cleary JF. The pharmacologic management of cancer pain. J Palliat Med 2007;10:1369-1394.

4. Deandrea S, Montanari M, Moja L, Apolone G. Prevalence of undertreatment in cancer pain. A review of published literature. Ann Oncol 2008;19:1985-1991.

5. Cleary J, Radbruch L, Torode J, Cherny NI. Formulary availability and regulatory barriers to accessibility of opioids for cancer pain in Asia: a report from the Global Opioid Policy Initiative (GOPI). Ann Oncol 2013;24 (Suppl 11):xi24-xi32.

6. Coleman MP, Forman D, Bryant H, et al. Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK, 1995-2007 (the International Cancer Benchmarking Partnership): an analysis of population-based cancer registry data. Lancet 2011;377:127-138.

7. Azevedo São Leão Ferreira K, Kimura M, Jacobsen Teixeira M. The WHO analgesic ladder for cancer pain control, twenty years of use. How much pain relief does one get from using it? Support Care Cancer 2006;14:1086-1093.

8. McDonald J, Lambert DG. Opioid receptors. Contin Educ Anaesth Crit Care Pain 2005;5:22-25.

9. Riley J, Eisenberg E, Müller-Schwefe G, et al. Oxycodone: a review of its use in the management of pain. Curr Med Res Opin 2008;24:175-192.

10. Colucci RD, Swanton RE, Thomas GB, Kaiko RF. Relative variability in bioavailability of oral controlled-release formulations of oxycodone and morphine. Am J Ther 2001;8:231-236.

11. Lalovic B, Kharasch E, Hoffer C, Risler L, Liu-Chen LY, Shen DD. Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clin Pharm Ther 2006;79:461-479.

12. Clark AJ, Ahmedzai SH, Allan LG, et al. Efficacy and safety of transdermal fentanyl and sustained-release oral morphine in patients with cancer and chronic non-cancer pain. Curr Med Res Opin 2004;20:1419-1428.

13. Ahmedzai SH, Boland J. Constipation in people prescribed opioids. Clin Evid (Online) 2010;2010:2407.

14. Woolery M, Bisanz A, Lyons HF, et al. Putting evidence into practice: evidence-based interventions for the prevention and management of constipation in patients with cancer. Clin J Oncol Nurs 2008;12:317-337.

15. Ahmedzai SH, Nauck F, Bar-Sela G, Bosse B, Leyendecker P, Hopp M. A randomized, double-blind, active-controlled, double-dummy, parallel-group study to determine the safety and efficacy of oxycodone/naloxone prolonged-release tablets in patients with moderate/severe, chronic cancer pain. Palliative Med 2012;26:50-60.

16. Luger NM, Mach DB, Sevcik MA, Mantyh PW. Bone cancer pain: from model to mechanism to therapy. J Pain Symptom Manag 2005;29(5 Suppl):S32-S46.

17. Ahmedzai SH. Personalized medicine — one size fits one: tailoring pain therapy to individuals’ needs. J Pain Palliat Care Pharmacother 2013;27:83-85.