Oral morphine is the standard strong opioid used in cancer pain, and it continues to be the benchmark 'step 3' analgesic in the World Health Organization (WHO) analgesic ladder against which newer drugs are measured. [1] A number of alternative strong opioids are available in Australia, including oxycodone, hydromorphone, fentanyl, methadone, and buprenorphine. Further research is needed to clarify the most appropriate clinical role of each drug, and each formulation, in the management of pain in palliative care patients. [2]

What is known 

• Alternative opioids
  There is evidence that alternative strong opioids such as methadone, [3] oxycodone, [4] hydromorphone [5] and fentanyl [6] are effective alternatives to morphine, although there are few trials which have been designed to allow direct comparison between different opioids. [1] 
   
• Opioid switching
  The practice of 'opioid switching' is done to improve analgesia in the minority of patients who do not respond to increasing doses or who have severe adverse effects. However the practice is not supported by strong evidence. [7] Studies which have been done have methodological problems, but suggest that 50% of patients who are switched may experience some clinical improvement. [8] One challenging area of practice relates to opioid rotation to and from methadone, as there are a number of different protocols available in the literature. A study of conversion rations used to convert patients to methadone from other opioids revealed that, of the many methods in clinical use, none seems to be superior to any other. [20]
   
• Managing "breakthrough" pain
  The practice of providing an immediate-release opioid to be used as needed as a 'rescue dose' for breakthrough pain is well established clinically, and is recommended in all guidelines on cancer pain management. [1,9] However the available studies do not allow the identification of an ideal breakthrough regimen, either in terms of the ratio of breakthrough dose to the regular dose, or how frequently it should be made available. The only opioid preparation which has been studied for use as a breakthrough medication is the oral transdermal fentanyl lozenge, and it was shown to be effective. [10]
   
• Managing "crescendo" pain
  There is little good evidence to guide the practice of escalating opioid doses for severe or 'crescendo' cancer pain, and a range of strategies of combining fixed and variable doses, at different intervals, are used. [11] Whilst the dosing strategies used in the studies varied, and so no evidence-based recommendations can be made, all the strategies studied were safe and effective in relieving pain in the majority of patients within 24 hours. 
   
• Neuropathic pain
  Neuropathic pain is a significant problem for many palliative care patients, and has been thought to be only partially responsive to opioids. However, in a recent systematic review opioids were effective in relieving neuropathic pain in patients followed over eight to ten weeks. [12] Adverse effects were common but not severe. Tramadol has also been shown to be effective at treating neuropathic pain in a recent systematic review. [13] A systematic review of methadone in cancer pain provided no evidence that methadone has particular benefits for treating neuropathic pain beyond other opioids. [3] 
   
• Routes of administration for opioids
  A review which compared transdermal opioids (fentanyl and buprenorphine) with slow release oral morphine suggested that the overall adverse effect profile was not significantly different, although specific adverse effects, particularly constipation, may possibly be less with transdermal opioids. [21]  Topical opioids have been studied for use in ulcers (both malignant and non-malignant) and in oropharyngeal mucositis, and appear likely to be effective, although the evidence is of varied quality, and further investigation is needed. [22] Spinal and intrathecal routes of analgesia are sometimes used for difficult pain management problems. A survey and systematic review of the literature revealed considerable variation in practice, scant evidence to support clinical decision making, and little consensus on the medications to be used. [14,15] These reviews do not provide any guidance about the indications for choosing the intraspinal route for analgesia 
   
• Adverse effects
  Managing the adverse effects of opioids, whether by preventing or treating them, is an important aspect of clinical practice. The prevalence of drug interactions with methadone was studied, [23] but little information was available that specifically related to a palliative care population. Problems such as cognitive changes associated with opioids have been studied, [24] and these have been demonstrated objectively.

What this means in practice

• First line strong opioid: Morphine continues to be the recommended due to its efficacy, easy availability, versatility, cost, and the extensive clinical experience of using it in palliative care patients; however there is no evidence that it is superior to other opioids. [16-17] 
   
• Alternative opioids: Choice is based on specific properties of the drug and preparation (eg, risk of metabolite accumulation in renal impairment, versatility of various routes of administration, availability of sustained and immediate release formulations, cost to the patient and the healthcare system). [2] 
   
• Morphine, oxycodone and hydromorphone all have metabolites that are likely to accumulate in renal impairment. Methadone and fentanyl are safer in this situation. However methadone has complex pharmacokinetics and a long and unpredictable half-life, and fentanyl has less versatility in the preparations which are available, and significant potential for drug interactions. [2] 
   
• Breakthrough pain and opioid titration: Recommendations continue to be largely based on expert opinion. 
   
• Based on studies using the oral transdermal fentanyl lozenge for breakthrough pain, it may be that the ideal ratio of breakthrough dose to background dose is not fixed and should be individualized. [18] 
   
• Opioid rotation: Inter-individual genetic differences are likely to be significant in patients’ individual responses to opioid medications. This may be a rationale for opioid rotation. [17] Based on studies of opioid switching, it is important to individualise opioid conversion. Opioid dose conversion ratios are not fixed. [18,8] 
   
• Intraspinal analgesia: The best evidence is for morphine as a first line drug. There is also limited evidence to support use of morphine / bupivicaine if the pain has a neuropathic component, or of morphine / clonidine, and hydromorphone. [15] For other medications and combinations the evidence is not strong, and further research is required.

Finding out more
Guidelines

• Guideline for the management of cancer pain in adults and children.
  American Pain Society (Clinical practice guideline, no. 3) 2005.

Links to prescribing information
NB Prescribing information may not yet have been updated to include the most recent evidence

• Online Palliative Medicine Handbook
  Click on “Notes on Prescribing”
  This prescribing information is from the UK - some medications may not be available in Australia. Diamorphine is not used in Australia
• Therapeutic Guidelines for Palliative Care
  An Australian source of prescribing information not available directly online through CareSearch, but can be accessed online in most hospitals, or purchased.

Overview articles

• Opioids in Cancer Pain: New Considerations
  King T, Porreca F. IASP Pain: Clinical Updates. 2010 Feb;XVIII(1).
  Principles of control of cancer pain
  Fallon M, Hanks G, Cherny N. BMJ. 2006 Apr 29;332(7548):1022-4. 
• Pain management in palliative care: an update
  Auret K, Pickstock S. Aust Fam Physician. 2006 Oct;35(10):762-5. 

Related CareSearch pages
List of assessment tools
Health service issues in pain management
Radiotherapy and adjuvants
Non-pharmacological approaches to pain management

References

1. Hanks GW, Conno F, Cherny N, Hanna M, Kalso E, McQuay HJ, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer. 2001 Mar 2;84(5):587-93.
2. Davis MP, Walsh D, Lagman R, LeGrand SB. Controversies in pharmacotherapy of pain management. Lancet Oncol. 2005 Sep;6(9):696-704.
3. Nicholson AB. Methadone for cancer pain. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003971.
4. Reid CM, Martin RM, Sterne JA, Davies AN, Hanks GW. Oxycodone for cancer-related pain: meta-analysis of randomized controlled trials. Arch Intern Med. 2006 Apr 24;166(8):837-43.
5. Quigley C, Wiffen P. A systematic review of hydromorphone in acute and chronic pain. J Pain Symptom Manage. 2003 Feb;25(2):169-78.
6. Clark AJ, Ahmedzai SH, Allan LG, Camacho F, Horbay GL, Richarz U, 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 Sep;20(9):1419-28.
7. Quigley C. Opioid switching to improve pain relief and drug tolerability. Cochrane Database Syst Rev. 2004;(3):CD004847.
8. Mercadante S, Bruera E. Opioid switching: a systematic and critical review. Cancer Treat Rev. 2006 Jun;32(4):304-15. Epub 2006 Apr 19. 
9. Miaskowski C, Cleary J, Burney R, Coyne P, Finley R, Foster R, et al. Guideline for the management of cancer pain in adults and children. Clinical practice guideline no.3. Glenview (IL): American Pain Society; 2005.
10. Zeppetella G, Ribeiro MD. Opioids for the management of breakthrough (episodic) pain in cancer patients. Cochrane Database Syst Rev. 2006 Jan 25;(1 ):CD004311.
11. Davis MP, Weissman DE, Arnold RM. Opioid dose titration for severe cancer pain: a systematic evidence-based review. J Palliat Med. 2004 Jun;7(3):462-8.
12. Eisenberg E, McNicol ED, Carr DB. Opioids for neuropathic pain. Cochrane Database Syst Rev. 2006 Jul 19;3:CD006146.
13. Hollingshead J, Dühmke RM, Cornblath DR. Tramadol for neuropathic pain. Cochrane Database Syst Rev. 2006 Jul 19;3:CD003726.
14. Bennett G, Serafini M, Burchiel K, Buscher E, Classen A, Deer T, et al. Evidence-based review of the literature on intrathecal delivery of pain medication. J Pain Symptom Manage. 2000 Aug;20(2):S12-36.
15. Bennett G, Burchiel K, Buscher E, Classen A, Deer T, Du Pen S, et al. Clinical guidelines for intraspinal infusion: report of an expert panel. J Pain Symptom Manage. 2000 Aug;20(2):S37-43.
16. Wiffen PJ, McQuay HJ. Oral morphine for cancer pain. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003868.
17. Ross JR, Riley J, Quigley C, Welsh KI. Clinical pharmacology and pharmacotherapy of opioid switching in cancer patients. Oncologist. 2006 Jul-Aug;11(7):765-73.
18. Hagen NA, Fisher K, Victorino C, Farrar JT. A titration strategy is needed to manage breakthrough cancer pain effectively: observations from data pooled from three clinical trials. J Palliat Med. 2007 Feb;10(1):47-55. 
19. Riley J, Eisenberg E, Müller-Schwefe G, Drewes AM, Arendt-Nielsen L. Oxycodone: a review of its use in the management of pain. Curr Med Res Opin. 2008 Jan;24(1):175-92.
20. Weschules DJ, Bain KT. A systematic review of opioid conversion ratios used with methadone for the treatment of pain. Pain Med. 2008 Jul-Aug;9(5):595-612. Epub 2008 Jun 28.
21. Tassinari D, Sartori S, Tambiurini E, Scarpi E, Raffaeli W, Tombesi P, et al. Adverse effects of transdermal opiates treating moderate –severe cancer pain in comparison to long acting morphine: a meta-analysis and systematic review of the literature. J Palliat Med. 2008 Apr;11(3):492-501.
22. LeBon B, Zeppetella G, Higginson IJ. Effectiveness of topical administration of opioids in palliative care: a systematic review. J Pain Symptom Manage. 2009 May;37(5):913-7. Epub 2009 Mar 24.
23. Weschules DJ, Bain KT, Richeimer S. Actual and potential drug interactions associated with methadone. Pain Med. 2008 Apr;9(3):315-44.
24. Kurita GP, Lundorff L, Pimenta CA, Sjøgren P. The cognitive effects of opioids in cancer: a systematic review. Support Care Cancer. 2009 Jan;17(1):11-21. Epub 2008 Sep 2.

This page was created on 23 May 2008
Last updated 14 October 2010