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 

• 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]
• 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]
• 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]
• 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 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]
• 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.

What this means in practice

• Morphine continues to be the recommended first line strong opioid 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 a superior analgesic to other opioids. [16,17] Choice of alternative opioids is best determined on first principles by the 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]
• Recommendations for managing breakthrough pain and titration of opioids for severe, uncontrolled pain continue to be largely based on expert opinion.
• Based on studies using the oral transdermal fentanyl lozenge for breakthrough pain, it seems that the ideal ratio of breakthrough dose to background dose is not fixed and should be individualized. [18]
• 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, and to recognise that opioid dose conversion ratios are not fixed. [18, 8]
• In relation to 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 and 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

• Fallon et al, Principles of control of cancer pain (BMJ 2006)  
• Auret and Pickstock  Pain management in palliative care: an update (AFP 2006)

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. British Journal of Cancer. 2001 Mar 2;84(5):587-93.  
2. Davis MP, Walsh D, Lagman R, LeGrand SB. Controversies in pharmacotherapy of pain management. Lancet Oncology. 2005 Sep;6(9):696-704.  
3. Nicholson AB. Methadone for cancer pain. Cochrane Database of Systematic Reviews. 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. Archives of Internal Medicine. 2006 Apr 24;166(8):837-843.  
5. Quigley C, Wiffen P. A systematic review of hydromorphone in acute and chronic pain. Journal of Pain & Symptom Management. 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. Current Medical Research and Opinion. 2004 Sep;20(9):1419-1428. 
7. Quigley C. Opioid switching to improve pain relief and drug tolerability. Cochrane Database of Systematic Reviews. 2004;(3):CD004847. 
8. Mercadante S, Bruera E. Opioid switching: a systematic and critical review. Cancer Treatment Reviews. 2006 Jun;32(4):304-15. 
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 of Systematic Reviews. 2006 Jan 25;(1 ):CD004311.  
11. Davis MP, Weissman DE, Arnold RM. Opioid dose titration for severe cancer pain: A systematic evidence-based review. Journal of Palliative Medicine. 2004 Jun;7(3):462-8. 
12. Eisenberg E, McNicol ED, Carr DB. Opioids for neuropathic pain. Cochrane Database of Systematic Reviews. 2006 Jul 19;3:CD006146.   
13. Hollingshead J, Dühmke RM, Cornblath DR. Tramadol for neuropathic pain. Cochrane Database of Systematic Reviews. 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. Journal of Pain and Symptom Management. 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. Journal of Pain and Symptom Management. 2000 Aug;20(2):S37-S43.  
16. Wiffen PJ, McQuay HJ. Oral morphine for cancer pain. Cochrane Database of Systematic Reviews. 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. Journal of Palliative Medicine. 2007 Feb;10(1):47-55. 

This page was created on 23 May 2008 and is due for review in May 2010