Approximately 60% of cancer patients experience pain, and 25% to 30% have severe pain. With some cancers, opioids will be needed before chemotherapy begins and may be more frequently prescribed than chemotherapy. Given the frequency with which pain management is necessary in cancer patients, all oncologists should be familiar with opioid prescribing principles. This article reviews the World Health Organization recommendations for analgesic therapy in this setting, as well as guidelines for opioid therapy in patients with renal failure or hepatic failure, assessment of pain, dosing strategies in both acute and chronic pain, management of opioid overdose, pain associated with dose-limiting side effects, and pain in the actively dying.
Cancer is present in 160/100,000 males and 186/100,000 females worldwide, with some variability in frequency between countries. The majority of these individuals (60%) experience pain, and 25% to 30% will have severe pain.[2,3] Those with common malignancies (eg, pancreatic or lung cancer) are likely to have pain at presentation to an oncologist or with their initial diagnosis. It is also likely that with certain cancers, opioids will be needed before chemotherapy treatment is started and that opioids will be more frequently prescribed than chemotherapy.
Several myths surround the use of opioids (Table 1). These either hinder optimal opioid dosing or lead to miscommunication between clinician and patient. Analgesic prescribing errors are common among clinicians, despite the wide acceptance of the World Health Organization (WHO) "three-step ladder" guidelines. In our experience, > 50% of patients will have received opioid therapy with dosing errors when first referred to palliative services. Common errors are outlined in Table 2.
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Parkin D, Bray F, Ferlay J, et al: Estimating the world cancer burden: Globocan 2000. Int J Cancer 94:153-156, 2001.
2. Rustoen T, Fossa SD, Skarstein J, et al: The impact of demographic and disease specific variables on pain in cancer patients. J Pain Symptom Manage 26:696-704, 2003.
3. Shvartzman P, Friger M, Shani A, et al: Pain control in ambulatory cancer patients—can we do better? J Pain Symptom Manage 26:716-722, 2003.
4. Forbes K: Opioids: Beliefs and myths. J Pain Palliat Care Pharmacother 20:33-35, 2006.
5. Kochhar R, Legrand SB, Walsh D, et al: Opioids in cancer pain: Common dosing errors. Oncology (Williston Park) 17:571-579 (incl discussion), 2003.
6. Burton AW, Cleeland CS: Cancer pain: Progress since the WHO guidelines. Pain Pract 1:236-242, 2001.
7. Stjernsward J, Collelau SM, Ventafridda V: The World Health Organization Cancer Pain and Palliative Care Program. Past, present and future. J Pain Symptom Manage 12:65-72, 1996.
8. Stjernsward J: WHO cancer pain relief programme. Cancer Surv 7:195-208, 1988.
9. Ventafridda V, Stjernsward J: Pain control and the World Health Organization analgesic ladder. JAMA 20:853-856, 1996.
10. Ventafridda V, Tamburini M, Caraceni A, et al: A validation study of the WHO method for cancer pain relief. Cancer 59:850-856, 1987.
11. Zech DF, Grond S, Lynch J, et al: Validation of World Health Organization Guidelines for cancer pain relief: A 10-year prospective study. Pain 63:65-76, 1995.
12. Zernikow B, Smale H, Michel E, et al: Paediatric cancer pain management using the WHO analgesic ladder—results of a prospective analysis from 2265 treatment days during a quality improvement study. Eur J Pain 10:587-595, 2006.
13. Grond S, Zech D, Lynch J, et al: Validation of World Health Organization guidelines for pain relief in head and neck cancer. A prospective study. Ann Otol Rhinol Laryngol 102:342-348, 1993.
14. Grond S, Zech D, Schug SA,et al: Validation of World Health Organization guidelines for cancer pain relief during the last days and hours of life. J Pain Symptom Manage 6:411-422, 1991.
15. World Health Organization: Cancer Pain Relief, 2nd ed. Geneva, WHO, 1996.
16. Austin K, Stapleton JV, Mather LE: Relationship between blood meperidine concentrations and analgesic response: A preliminary report. Anesthesiology 53:460-466, 1980.
17. Austin K, Stapleton JV, Mather LE: Multiple intramuscular injections: A major source of variability in analgesic response to meperidine. Pain 8:47-62, 1980.
18. Tamsen A, Hartvig P, Dahlstrom B, et al: Patient controlled analgesic therapy in the early postoperative period. Acta Anaesthesiol Scand 23:462-470, 1979.
19. Tamsen A, Hartvig P, Fagerlund C, et al: Patient controlled analgesic therapy, part II: Individual analgesic demand and analgesic plasma concentrations of pethidine in post operative pain. Clin Pharmacokinet 7:164-175, 1982.
20. Dahlstrom B, Tamsen A, Paalzow L, et al: Patient controlled analgesic therapy, part IV: Pharmacokinetics and analgesic plasma concentrations of morphine. Clin Pharmacokinet 7:266-279, 1982.
21. Expert Working Group of the European Association for Palliative Care: Morphine in cancer pain: Modes of administration. BMJ 312:823-826, 1996.
22. Hanks G, Reid C: Contribution to variability in response to opioids. Support Care Cancer 13:145-152, 2005.
23. Klepstad P, Kaasa S, Cherny N, et al: Pain and pain treatments in European palliative care units. A cross sectional survey from the European Association for Palliative Care Research Network. Palliat Med 19:477-484, 2005.
24. Schug SA, Zech D, Grond S: Adverse effects of systemic opioid analgesics. Drug Saf 7:200-213, 1992.
25. Hanks G, de Conno F, Cherny N, et al: Morphine and alternative opioids in cancer pain: The EAPC recommendations. Br J Cancer 84:587-593, 2001.
26. Klepstad P, Kaasa S, Skauge M, et al: Pain intensity and side effects during titration of morphine to cancer patients using a fixed schedule dose escalation. Acta Anaesthesiol Scand 44:656-664, 2000.
27. Cherny N, Ripamonti C, Pereira J, et al: Strategies to manage the adverse effects of oral morphine: An evidence-based report. J Clin Oncol 19:2542-2454, 2001.
28. Ross JRR, Welsh D, Joel K, et al: Clinical response to morphine in cancer patients and genetic variation in candidate genes. Pharmacogenomics J 5:324-336, 2005.
29. Lotsch J, Geisslinger G: Current evidence for a genetic modulation of the response to analgesics. Pain 121:1-5, 2006.
30. Romberg RR, Olofsen E, Bijl H, et al: Polymorphism of mu-opioid receptor gene (OPRM1:c.118A>G) does not protect against opioid-induced respiratory depression despite reduced analgesic response. Anesthesiology 102:522-530, 2005.
31. Fainsinger RL, Nekolaichuk CL, Lawlor PG, et al: A multicenter study of the revised Edmonton Staging System for classifying cancer pain in advanced cancer patients. J Pain Symptom Manage 29:224-237, 2005.
32. Riley J, Ross JR, Rutter D, et al: No pain relief from morphine? Support Care Cancer 14:56-64, 2006.
33. Uceyler N, Rogausch JP, Toyka KV, et al: Differnetial expression of cytokines in painful and painless neuropathies. Neurology 69:42-49, 2007.
34. Guo W, Wang H, Watanabe M, et al: Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J Neurosci, 27:6006-6018, 2007.
35. Arriagada O, Constandil L, Hernandez A, et al: Effects of interleukin-1beta on spinal cord nociceptive transmission in intact and propentofylline-treated rats. Int J Neurosci 117:617-625, 2007.
36. Simopoulos TT, Smith HS, Peeters-Asdourian C, et al: Use of meperidine in patient-controlled analgesia and the development of a normeperidine toxic reaction. Arch Surg 137:84-88, 2002.
37. Hemstapat K, Monteith GR, Smith D, et al: Morphine-3-glucuronide's neuro-excitatory effects are mediated via indirect activation of N-methyl-D-aspartic acid receptors: Mechanistic studies in embryonic cultured hippocampal neurones. Anesth Analg 97:494-505, 2003.
38. Lee MA, Leng ME, Tiernan EJ: Retrospective study of the use of hydromorphone in palliative care patients with normal and abnormal urea and creatinine. Palliat Med 15:26-34, 2001.
39. Lugo RA, Satterfield KL, Kern SE: Pharmacokinetics of methadone. J Pain Palliat Care Pharmacother 19:13-24, 2005.
40. Murtagh FE, Addington-Hall JM, Donohoe P, et al: Symptom management in patients with established renal failure managed without dialysis. Edtna Erca J 32:93-98, 1006.
41. Filitz J, Griessinger N, Sittl R, et al: Effects of intermittent hemodialysis on buprenorphine and norbuprenorphine plasma concentrations in chronic pain patients treated with transdermal buprenorphine. Eur J Pain 10:743-748, 2006.
42. Kirvela M, Lindgren L, Seppala T, et al: The pharmacokinetics of oxycodone in uremic patients undergoing renal transplantation. J Clin Anesth 8:13-18, 1996.
43. Penson RT, Joel SP, Bakhshi K, et al: Randomized placebo-controlled trial of the activity of the morphine glucuronides. Clin Pharmacol Ther 68:667-676, 2000.
44. Portenoy RK, Foley KM, Stulman J, et al: Plasma morphine and morphine-6-glucuronide during chronic morphine therapy for cancer pain: Plasma profiles, steady-state concentrations and the consequences of renal failure. Pain 47:13-19, 1991.
45. Tegeder I, Lotsch J, Geisslinger G: Pharmacokinetics of opioids in liver disease. Clin Pharmacokinet 37:17-40, 1999.
46. Furlan V, Demirdjian S, Bourdon O, et al: Glucuronidation of drugs by hepatic microsomes derived from healthy and cirrhotic human livers. J Pharmacol Exp Ther 289:1169-1175, 1999.
47. Desmond PV, Smyth FE, Mashford ML: Release of latent glucuronosyltransferase activity contributes to the sparing of glucuronidation in experimental liver injuries. J Gastroenterol Hepatol 9:350-354, 1994.
48. George J, Murray M, Byth K, et al: Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease. Hepatology 21:120-128, 1995.
49. Mehdizadeh A, Toliate T, Rouini MR, et al: Design and in vitro evaluation of new drug-in-adhesive formulations of fentanyl transdermal patches. Acta Pharm 54:301-317, 2004.
50. Roy SD, Gutierrez M, Flynn GL, et al: Controlled transdermal delivery of fentanyl: characterizations of pressure-sensitive adhesives for matrix patch design. J Pharm Sci 85:491-495, 1996.
51. Watanabe S, Pereira J, Hanson J, et al: Fentanyl by continuous subcutaneous infusion for the management of cancer pain: A retrospective study. J Pain Symptom Manage 16:323-326, 1998.
52. Mystakidou K, Befon S, Tsilika E, et al: Use of TTS fentanyl as a single opioid for cancer pain relief: A safety and efficacy clinical trial in patients naive to mild or strong opioids. Oncology 62:9-16, 2002.
53. Jeal W, Benfield P: Transdermal fentanyl. A review of its pharmacological properties and the therapeutic efficacy in pain control. Drugs 53:109-138, 1997.
54. van Seventer R, Smit JM, Schipper RM, et al: Comparison of TTS fentanyl with sustained release oral morphine in the treatment of patients not using opioids for mild to moderate pain. Curr Med Res Opin 19:457-469, 2003.
55. Davis M, Walsh D, Lagman R, et al: Controversies in pharmacotherapy of pain management. Lancet Oncol 6:696-704, 2005.
56. Larsen RH, Nielsen F, Sorensen JA, et al: Dermal penetration of fentanyl: Inter- and intraindividual variations. Pharmacol Toxicol 93:244-248, 2003.
57. Ripamonti C, Fagnoni E, Campa T, et al: Is the use of transdermal fentanyl inappropriate according to the WHO guidelines and the EAPC recommendations? A study of cancer patients in Italy. Support Care Cancer 14:400-407, 2006.
58. Clemens K, Klaschik E: Clinical experience with transdermal and orally administered opioids in palliative care patients—a retrospective study. Jpn J Clin Oncol 37:302-309, 2007.
59. Davis MP, Walsh D: Methadone for relief of cancer pain: A review of pharmacokinetics, pharmacodynamics, drug interactions and protocols of administration. Support Care Cancer 9:73-83, 2001.
60. Dale O, Sheffels P, Kharasch ED: Bioavailabilities of rectal and oral methadone in healthy subjects. Br J Clin Pharmacol 58:156-162, 2004.
61. Zimmermann C, Seccareccia D, Booth CM, et al: Rotation to methadone after opioid dose escalation: How should individualization of dosing occur? J Pain Palliat Care Pharmacother 19:25-31, 2005.
62. Soares LG: Methadone for cancer pain: What have we learned from clinical studies? Am J Hosp Palliat Care 22:223-227, 2005.
63. Manfredi PL, Houde RW: Prescribing methadone, a unique analgesic. J Support Oncol 1:216-220, 2003.
64. Ripamonti C, Groff L, Brunelli C, et al: Switching from morphine to oral methadone in treating cancer pain: What is the equianalgesic dose ratio? J Clin Oncol 16:3216-3221, 1998.
65. Crettol S, Deglon JJ, Besson J, et al: Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment. Clin Pharmacol Ther 78:593-604, 2005.
66. Crettol S, Deglon JJ, Besson J, et al: ABCB1 and cytochrome P450 genotypes and phenotypes: Influence on methadone plasma levels and response to treatment. Clin Pharmacol Ther 80:668-681, 2006.
67. Elfrink EJ, van der Rijt CC, van Boxtel RJ, et al: Problem solving by telephone in palliative care: Use of a predetermined assessment tool within a program of home care technology. J Palliat Care 18:105-110, 2002.
68. Appel PR, Bleiberg J, Noiseux J: Self-regulation training for chronic pain: Can it be done effectively by telemedicine? Telemed J E Health 8:361-368, 2002.
69. Carlson LE, Speca M, Hagen N, et al: Computerized quality-of-life screening in a cancer pain clinic. J Palliat Care 17:46-52, 2001.
70. Allard P, Maunsell E, Labbe J, et al: Educational interventions to improve cancer pain control: A systematic review. J Palliat Med 4:191-203, 2001.
71. Miaskowski C, Dodd M, West C, et al: Randomized clinical trial of the effectiveness of a self-care intervention to improve cancer pain management. J Clin Oncol 22:1713-1720, 2004.
72. Gordon DB, Dahl JL, Miaskowski C, et al: American pain society recommendations for improving the quality of acute and cancer pain management: American Pain Society Quality of Care Task Force. Arch Intern Med 165:1574-1580, 2005.
73. Serlin RC, Mendoza TR, Nakamura Y, et al: When is cancer pain mild, moderate or severe? Grading pain severity by its interference with function. Pain 61:277-284, 1995.
74. Zalon ML: Comparison of pain measures in surgical patients. J Nurs Meas 7:135-152, 1999.
75. Tittle MB, McMillan SC, Hagan S: Validating the brief pain inventory for use with surgical patients with cancer. Oncol Nurs Forum 30:325-330, 2003.
76. Farrar JT, Berlin JA, Strom BL: Clinically important changes in acute pain outcome measures: A validation study. J Pain Symptom Manage 25:406-411, 2003.
77. Cepeda MS, Polo R, Alcala R, et al: What decline in pain intensity is meaningful to patients with acute pain? Pain 105:151-157, 2003.
78. Jensen MP: The validity and reliability of pain measures in adults with cancer. J Pain 4:2-21, 2003.
79. Davis MP: Acute pain in advanced cancer: An opioid dosing strategy and illustration. Am J Hosp Palliat Care 21:47-50, 2004.
80. Upton RN, Semple TJ, Macintyre PE: Pharmacokinetic optimisation of opioid treatment in acute pain therapy. Clin Pharmacokinet 33:225-244, 1997.
81. Mercadante S: Opioid rotation for cancer pain: Rationale and clinical aspects. Cancer 86:1856-1866, 1999.
82. Kumar KS, Rajagopal MR, Naseema AM: Intravenous morphine for emergency treatment of cancer pain. Palliat Med 14:183-188, 2000.
83. Harris JT, Suresh Kumar K, Rajagopal MR: Intravenous morphine for rapid control of severe cancer pain. Palliat Med 17:248-256, 2003.
84. Mercadante S, Villari P, Ferrera P, et al: Rapid titration with intravenous morphine for severe cancer pain and immediate oral conversion. Cancer 95:203-208, 2002.
85. Davis MP, Weissman DE, Arnold RM: Opioid dose titration for severe cancer pain: A systematic evidence-based review. J Palliat Med 7:462-468, 2004.
86. Donnelly S, Davis MP,Walsh D, et al: Morphine in cancer pain management: A practical guide. Support Care Cancer 10:13-35, 2002.
87. Walsh D: Pharmacological management of cancer pain. Semin Oncol 27:45-63, 2000.
88. McQuay HJ, Jadad AR: Incident pain. Cancer Surv 21:17-24, 1994.
89. Zeppetella G, Ribeiro MD: Opioids for the management of breakthrough (episodic) pain in cancer patients. Cochrane Database Syst Rev 1:CD004311, 2006.
90. Portenoy RK, Hagen NA: Breakthrough pain: Definition, prevalence and characteristics. Pain 41:273-281, 1990.
91. Walsh D, Rivera N, Davis MP, et al: Strategies for pain management: Cleveland Clinic Foundation for opioid dosing for cancer pain. Support Cancer Therapy 1:157-164, 2004.
92. Klepstad P, Kaasa S, Jystad A, et al: Immediate- or sustained-release morphine for dose finding during start of morphine to cancer patients: A randomized, double-blind trial. Pain 101:193-198, 2003.
93. Mercadante S, Villari P, Ferrera P, et al: Transmucosal fentanyl vs. intravenous morphine in doses proportional to basal oioid regimen for episodic breakthrough pain. Br J Cancer 96:1828-1833, 2007.
94. Wasiak J, Clavisi O: Is subcutaneous or intramuscular naloxone as effective as intravenous naloxone in the treatment of life threatening heroin overdose? Med J Aust 176:495, 2002.
95. Watson WA, Steele MT,Muelleman RL, et al: Opioid toxicity recurrence after an initial response to naloxone. J Toxicol Clin Toxicol 36:11-17, 1998.
96. McNicol E, Horowicz-Mehler N, Fisk RA, et al: Management of opioid side effects in cancer-related and chronic noncancer pain: A systematic review. J Pain 4:231-256, 2003.
97. Mao J: NMDA and opioid receptors: Their interactions in antinociception, tolerance and neuroplasticity. Brain Res Brain Res Rev 30:289-304, 1999.
98. Ossipov MH, Lai J,King T, et al: Underlying mechanisms of pronociceptive consequences of prolonged morphine exposure. Biopolymers 80:319-324, 2005.
99. Chang G, Chen L, Mao J: Opioid tolerance and hyperalgesia. Med Clin North Am 91:199-211, 2007.
100. Rajagopal A, Vassilopoulou-Sellin R, Palmer JL, et al: Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer 100:851-858, 2004.
101. Paice JA, Penn RD, Ryan WG: Altered sexual function and decreased testosterone in patients receiving intraspinal opioids. J Pain Symptom Manage 9:126-131, 1994.
102. Rajagopal A, Bruera ED: Improvement in sexual function after reduction of chronic high-dose opioid medication in a cancer survivor. Pain Med 4:379-383, 2003.
103. Beattie DT, Cheruvu M, Mai N, et al: The in vitro pharmacology of the peripherally restricted opioid receptor antagonists, alvimopan, ADL 08-0011 and methylnaltrexone. Naunyn Schmiedebergs Arch Pharmacol 375:205-220, 2007.
104. Banach T, Ferreira CE,Weisbrodt NW, et al: Mechanisms of intestinal dysmotility in morphine dependence: Whether central or peripheral? Folia Med Cracov 46:75-82, 2005.
105. Dahan A: Respiratory depression with opioids. J Pain Palliat Care Pharmacother 21:63-66, 2007.
106. Christo PJ: Opioid effectiveness and side effects in chronic pain. Anesthesiol Clin North America 21:699-713, 2003.
107. Quigley C: Opioid switching to improve pain relief and drug tolerability. Cochrane Database Syst Rev 3:CD004847, 2004.
108. Doorley J, McNeal W: The role of neuroleptics in managing morphine-induced terminal delirium: Implications for the clinical nurse specialist. Clin Nurse Spec 18:183-185, 2004.
109. Lawlor PG: The panorama of opioid-related cognitive dysfunction in patients with cancer: A critical literature appraisal. Cancer 94:1836-1853, 2002.
110. Mercadante S: Pathophysiology and treatment of opioid-related myoclonus in cancer patients. Pain 74:5-9, 1998.
111. Ersek M, Cherrier MM,Overman SS, et al: The cognitive effects of opioids. Pain Manag Nurs 5:75-93, 2004.
112. Davis M: The opioid bowel syndrome: A review of pathophysiology and treatment. J Opioid Manag 1:153-161, 2005.
113. White C, McCann MA, Jackson N: First do no harm... Terminal restlessness or drug-induced delirium. J Palliat Med 10:345-351, 2007.
114. Mercadante S, Portenoy RK: Opioid poorly-responsive cancer pain. Part 2: Basic mechanisms that could shift dose response for analgesia. J Pain Symptom Manage 21:255-264, 2001.
115. Kalso E: Improving opioid effectiveness: From ideas to evidence. Eur J Pain 9:131-135, 2005.
116. Mercadante S, Bruera E: Opioid switching: A systematic and critical review. Cancer Treat Rev 32:304-315, 2006.
117. Lonergan E, Britton A, Luxenberg J, et al: Antipsychotics for delirium. Cochrane Database Syst Rev 2:CD005594, 2007.
118. Estfan B, Yavuzsen T, Davis MP: Development of opioid induced delirium while on olanzapine: A two case report. Letters 29:330-332, 2005.
119. Krames ES, Gershow J,Glassberg A, et al: Continuous infusion of spinally administered narcotics for the relief of pain due to malignant disorders. Cancer 56:696-702, 1985.
120. Glavina MJ, Robertshaw R: Myoclonic spasms following intrathecal morphine. Anaesthesia 43:389-390, 1988.
121. Eisele JH Jr, Grigsby EJ, Dea G: Clonazepam treatment of myoclonic contractions associated with high-dose opioids: Case report. Pain 49:231-232, 1992.
122. Holdsworth MT, Adams VR,Chavez CM, et al: Continuous midazolam infusion for the management of morphine-induced myoclonus. Ann Pharmacother 29:25-29, 1995.
123. Wilson RK, Weissman DE: Neuroexcitatory effects of opioids: Treatment #58. J Palliat Med 7:580-581, 2004.
124. Wilson RK, Weissman DE: Neuroexcitatory effects of opioids: Patient assessment #57. J Palliat Med 7:579, 2004.
125. Slatkin NE, Rhiner M, Bolton TM: Donepezil in the treatment of opioid-induced sedation: Report of six cases. J Pain Symptom Manage 21:425-438, 2001.
126. Sykes NP: An investigation of the ability of oral naloxone to correct opioid-related constipation in patients with advanced cancer. Palliat Med 10:135-144, 1996.
127. Yuan C, Israel R: Methylnaltrexone, a novel peripheral opioid receptor. Expert Opin Investig Drugs 15:541-552, 2006.