Abstract
Control of malignant pain and related symptoms is paramount to clinical success in caring for cancer patients. To achieve the best quality of life for patients and families, oncologists and palliative care clinicians must work together to understand problems related to psychologic, social, and spiritual pain. Pain is the primary problem targeted for control using the World Health Organization’s (WHO) analgesic ladder. This article focuses on increased knowledge of analgesic action that may enable expansion of the WHO analgesic ladder to fulfill the broader objectives of palliative medicine. We discuss clinical experience with several classes of drugs that are currently used to treat cancer pain: 1) nonsteroidal anti-inflammatory drugs, with emphasis on cyclooxygenase-2 inhibitors; 2) opioid analgesics, with specific emphasis on methadone and its newly recognized value in cancer pain; 3) ketamine, an antagonist at N-methyl-D-aspartate receptors; and 4) bisphosphonates, used for pain resulting from bone metastases. New concepts that compare molecular actions of morphine at excitatory opioid receptors, and methadone at nonopioid receptor systems, are presented to underscore the importance of balancing central nervous system excitatory (anti-analgesic) versus inhibitory (analgesic) influences.
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References and Recommended Reading
World Health Organization: Cancer Pain Relief. Geneva, Switzerland; 1986.
Stijernsward J, Colleau S, Ventafridda V: The World Health Organization cancer pain and palliative care program. J Pain Symptom Manage 1996, 12:65–72.
Joishy SK, Walsh D: The opioid-sparing effects of intravenous ketorolac as an adjuvant analgesic in cancer pain: application in bone metastases and the opioid bowel syndrome. J Pain Symptom Manage 1998, 16:334–336.
Mercadante S, Casuccio A, Agnello A, et al.: Analgesic effects of nonsteroidal anti-inflammatory drugs in cancer pain due to somatic or visceral mechanisms. J Pain Symptom Manage 1999, 17:351–356.
Jenkins CA, Bruera E: Nonsteroidal anti-inflammatory drugs as adjuvant analgesics in cancer patients. Palliat Med 1999, 13:183–196. Excellent overview of the use of NSAIDs in cancer patients.
Bjorkman D: Nonsteroidal anti-inflammatory drug-associated toxicity of the liver, lower gastrointestinal tract, and esophagus. Am J Med 1998, 105:17S-21S. Part of an excellent symposium, along with [7] below, on the general effect, side effects, and mechanism of action of NSAIDs.
Vane JR, Botting RM: Mechanism of action of nonsteroidal anti-inflammatory drugs. Am J Med 1998, 104:2S-8S, discussion 21S-22S.
Vane JR, Botting RM: Mechanism of action of anti-inflammatory drugs. Int J Tissue React 1998, 20:3–15.
Lashbrook JM, Ossipov MH, Hunter JC, et al.: Synergistic antiallodynic effects of spinal morphine with ketorolac and selective COX 1 and COX 2 inhibitors in nerve-injured rats. Pain 1999, 82:65–72.
Simon LS, Weaver DY, Graham AJ, et al.: Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis. JAMA 1999, 282:1921–1928.
Kaplan-Machlis B, Klostermeyer BS: The cyclooxygenase-2 inhibitors: safety and effectiveness. Ann Pharmacother 1999, 33:979–988.
Foley K: The treatment of cancer pain. N Engl J Med 1985, 313:84–95.
Portenoy RK: Cancer pain management. Semin Oncol 1993, 20:19–35.
Hanks GW, De Conno F, Ripamonti C: Morphine in cancer pain: modes of administration. BMJ 1996, 312:823–826.
Bruera E, Lawlor P: Cancer pain management. Acta Anaesthesiol Scand 1997, 41:146–153.
Arner S, Meyerson BA: Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain. Pain 1988, 33:11–23.
Portenoy RK, Foley KM, Inturrisi CE: The nature of opioid responsiveness and its implications for neuropathic pain: new hypotheses derived from studies of opioid infusions. Pain 1990, 43:273–286.
Mao J, Price D, Mayer DJ: Experimental mononeuropathy reduces the antinoceceptive effects of morphine: implications for common intracellular mechanisms involved in morphine tolerance and neuropathic pain. Pain 1995, 61:353–364.
Jaffe JH, Martin WR: Opioid analgesics and antagonists. In Goodman and Gilman’s Pharmacological Basis of Therapeutics, edn 8. New York: Pergamon; 1990:485–521.
Portenoy PK, Payne R: Acute and chronic pain. In Substance Abuse: A Comprehensive Textbook, edn 3. Edited by Lowinson JH et al. Baltimore, MD: Williams and Wilkins; 1997:563–589.
Yaksh TL: Pharmacology and mechanisms of opioid analgesic activity. Acta Anaesthesiol Scand 1997, 41:94–111.
Budd K: Monoamine function and analgesia. Pain Rev 1994, 1:3–8.
Chapman V, Dickenson AH: The combination of NMDA antagonism and morphine produces profound antinociception in the rat dorsal horn. Brain Res 1992, 573:321–323.
Codd EE, Shank RP, Schupsky JJ, Raffa RB: Serotonin and norepinephrine inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. J Pharmacol Exp Ther 1995, 274:1263–1270.
Eide PK, Jorum E, Stubhaug A, et al.: Relief of post-herpetic neuralgia with the N-methyl-d-aspartic acid receptor antagonist ketamine: a double blind, cross-over comparison with morphine and placebo. Pain 1994, 58:347–354.
Fallon M: Opioid rotation: does it have a role? Palliat Med 1997, 11:177–178.
Kristensen JD, Svensson B, Gordh T: The NMDA receptor antagonist antagonist CPP abolishes neurogenic "wind-up" pain after intrathecal administration in humans. Pain 1992, 51:249–253.
Luczak J, Dickenson AH, Kotlinska-Lemieszok A: The role of ketamine, an NMDA receptor antagonist, in the management of pain. Prog Palliat Care 1995, 3:127–134.
Caruso FS, Mehlisch DR, Minn FL, et al.: Synergistic analgesic interaction of morphine with dextromethorphan, an NMDA receptor antagonist, in oral surgery pain. Clin Pharmacol Ther 1998, 63:139.
Davis AM, Inturrisi CE: d-Methadone blocks morphine tolerance and N-Methyl-d-aspartate (NMDA)-induced hyperalgesia. J Pharmacol Exp Ther 1999, 289:1048–1053.
Elliot K, Kest B, Man A, et al.: N-methyl-d-aspartate (NMDA) receptors, mu and kappa opioid tolerance, and perspectives on new analgesic drug development. Neuropsychopharmacology 1995, 13:347–356.
Ebert B, Anderson S, Krogsgaardlarsen P: Ketobemidone, methadone and pethidine are noncompetitive N-methyl-daspartate (NMDA) antagonists in the rat cortex and spinal cord. Neurosci Lett 1995, 187:165–168.
Lang G, Finnegan MJ: Successful use of methadone in nociceptive cancer pain unresponsive to morphine. Palliat Med 1994, 8:153–155.
Bruera E, Pereira J, Watanabe S, et al.: Opioid rotation in patients with cancer pain: a retrospective comparison of dose ratios between methadone, hydromorphone and morphine. Cancer 1996, 78:852–857.
MacDonald N, Der L, Allan S, et al.: Opioid hyperexcitability: the application of alternate opioid therapy. Pain 1993, 53:353–355.
Bartlett SE, Dodd PR, Smith MT: Pharmacology of morphine and morphine-3-glucuronide at opioid, excitatory amino acid, GABA and glycine binding sites. Pharmacol Toxicol 1994, 75:73–81.
Bruera E, Franco JJ, Maltoni M, et al.: Changing pattern of agitated impaired mental status in patients with advanced cancer: association with cognitive monitoring, hydration and opiate rotation. J Pain Symptom Manage 1995, 10:287–291.
Crain SM, Shen K-F: Antagonists of excitatory opioid receptor functions enhance morphine’s analgesic potency and attenuate opioid tolerance/dependence liability. Pain 1999, 82:1–11. The most important comprehensive review concerned with opioid excitatory versus inhibitory receptor functions. The authors offer an excellent presentation of molecular, cellular, and clinical aspects of selective antagonism of opioid excitatory actions.
Crain SM, Shen K-F: Ultra-low concentrations of naloxone selectively antagonize excitatory effects of morphine on sensory neurons, thereby increasing its antinociceptive potency and attenuating tolerance/dependence during chronic co-treatment. Proc Natl Acad Sci U S A 1995, 92:10540–10544.
Crain SM, Shen K-F: GMI ganglioside-induced modulation of opioid receptor-mediated functions. Ann N Y Acad Sci 1998, 845:106–125.
Mercadente S: Malignant bone pain: pathophysiology and treatment. Pain 1997, 69:1–18.
Percherstorfer M, Vesely M: Diagnosis and monitoring of bone metastases. In Tumor Bone Diseases and Osteoporosis in Cancer Patients: Pathophysiology, Diagnosis, and Therapy. Edited by Body J-J. New York: Marcel Dekker; 1999.
Ripamonti C, Fulfaro F, Ticozzi, et al.: Role of pamidronate disodium in the treatment of metastatic bone disease. Tumori 1998, 84:442–455.
Theriault RL, Lipton A, Hortobagyi M, et al.: Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebocontrolled trial. J Clin Oncol 1999, 17:846–854.
Hortobagyi GN, Theriault RL, Lipton A, et al.: Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. J Clin Oncol 1998, 16:2038–2044.
Hortobagyi GN, Theriault RL, Porter L, et al.: Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. N Engl J Med 1998, 335:1785–1791.
Fulfaro F, Cassucio A, Ticozzi C, Ripamonti C: The role of bisphosphonates in the treatment of painful metastatic bone disease: a review of phase III trials. Pain 1998, 78:157–169.
Body JJ: Bisphosphonates for metastatic bone pain. Support Care Cancer 1999, 7:1–3. This editorial provides a good overview for the use and value of bisphosphonates.
Koeberle D, Bacchus L, Thuerlimann B, et al.: Pamidronate treatment in patients with malignant osteolytic bone disease and pain. Support Care Cancer 1999, 7:21–27. See annotation below.
Cascinu S, Graziano F, Ligi M, et al.: Different doses of pamidronate in patients with painful osteolytic bone metastases. Support Care Cancer 1998, 6:139–143. These two reports from prospective, randomized studies are both useful in justifying and planning treatment strategies with pamidronate.
Coleman RE, Houston S, Purohit OP, et al.: A randomized phase II study of oral pamidronate for the treatment of bone metastases from breast cancer. Eur J Cancer 1998, 34:820–824.
Purohit OP, Anthony C, Radstone CR, et al.: High-dose intravenous pamidronate for metastatic bone pain. Br J Cancer 1994, 70:554–558.
Dranitsaris G, Hsu T: Cost utility analysis of prophylactic pamidronate for the prevention of skeletal related events in patients with advanced breast cancer. Support Care Cancer 1999, 17:271–279. Report on an excellent study using an economic model that justifies the routine use of bisphosphonates in patients with metastatic bone disease.
Grant IS, Nimmo WS, McNicol LR, Clements JA: Ketamine disposition in children and adults. Br J Anaesth 1981, 53:27–30.
Lauretti GR, Lima IC, Reis MP, et al.: Oral ketamine and transdermal nitroglycerin as analgesic adjuvants to oral morphine therapy for cancer pain management. Anesthesiology 1999, 90:1528–1533. Report on a prospective, randomized study evaluating the effectiveness of ketamine and nitric oxide on pain management and the development of tolerance.
Fine PG: Low dose ketamine in the management of opioid nonresponsive terminal cancer pain. J Pain Symptom Manage 1999, 17:296–300.
Miyamoto H, Saito Y, Kirihara Y, et al.: Spinal co-administration of ketamine reduces the development of tolerance to visceral as well as somatic antinociception during spinal morphine infusion. Anesth Analg 2000, 90:136–141.
Enarson MC, Hays H, Woodroffe MA: Clinical experience with oral ketamine. J Pain Symptom Manage 1999, 17:384–386.
Fisher K, Hagen NA: Analgesic effect of oral ketamine in chronic neuropathic pain of spinal origin: a case report. J Pain Symptom Manage 1999, 18:61–66.
Lawlor PG, Tarumi Y: The need for ketamine [letter]. J Pain Symptom Manage 2000, 19:1–4. This letter reflects the current controversy regarding the use of ketamine.
Mercadante S, Lodi F, Sapio M: Long term ketamine subcutaneous continuous infusion in neuropathic cancer pain. J Pain Symptom Manage 1995, 10:564–568.
Woolf CJ, Thompson SW: The induction and maintenance of central sensitisation is dependant on N-methyl-d-aspartic acid receptor activation: implications for the treatment of post injury hypersensitivity states. Pain 1991, 44:293–299.
Shimoyama M, Shimoyama N, Gorman AL, et al.: Oral ketamine is antinociceptive in the rat formalin test: role of the metabolite norketamine. Pain 1999, 81:285–293.
Reeves JG, Glass PA: Non-barbiturate intravenous anesthetics. In Anesthesia, vol 1. edn 4. Edited by Miller R. London: Churchill Livingstone; 1994:254–259.
Staats PS, Hekmat H, Sauter P, Lillimoe K: The effects of alcohol, negative mood, and postoperative pain on life expectancy in patients with pancreatic cancer. American Pain Society, October 1997.
Lillimoe KD: Chemical splanchnicectomy in patients with unresectable pancreatic cancer: a prospective randomized trial. Ann Surg 1993, 217:447–457.
Kawamata MH, Ishitani K, et al.: Comparison between celiac plexus block and morphine treatment on quality of life in patients with pancreatic cancer. Pain 1996, 64:597–604.
Staats PS: The pain-mortality link: unravelling the mysteries. In Progress in Pain Research and Management, vol 12. Edited by Payne R et al. Seattle, WA: IASP Press; 1998:145–156. Excellent chapter on the effect of inadequate pain management on survival in cancer patients.
Rykowski JJ, Hilgier M: Efficacy of neurolytic celiac plexus block in varying locations of pancreatic cancer: influence on pain relief. Anesthesiology 2000, 92:347–354.
Zech D, Grond S, Lynch J, et al.: Validation of World Health Organization guidelines for cancer pain relief: 10-year prospective study. Pain 1995, 63:65–76.
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McDonnell, F.J., Sloan, J.W. & Hamann, S.R. Advances in cancer pain management. Current Science Inc 5, 265–271 (2001). https://doi.org/10.1007/s11916-001-0041-y
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DOI: https://doi.org/10.1007/s11916-001-0041-y