Abstract
As was the case in the era before us, in the new millennium we will continue to see an abundance of patients experiencing cancer-related pain for different reasons. Although much needless pain and suffering still affects many of those with cancer, we are presented with a medical dichotomy. With the analgesic drugs available today, and the relatively simple and effective guidelines to treat cancer pain published and disseminated by the World Health Organization, why do people with cancer continue to experience pain?
As we search for the answer, the horizon may hold promising new drugs, ‘old drugs’ with new interest and applications, and new strategies for the field of pain therapy. Possibilities include the isolation and development of analgesics or analgesic combinations that may minimise the adverse effects which are often associated with the current therapeutic class of opioid analgesics. In addition, current research points to promising results identifying the N-methyl D-aspartate non-opioid receptor as a likely component of neuropathic pain.
Drugs such as gabapentin, the mechanism of action of which is not well known, have found favour within the clinical community for their analgesic properties and good tolerability. Methadone, in a phase of resurgence, has garnered the attention of the clinical community because of its unique receptor activity and pharmacoeconomic benefits. A number of clinical studies have demonstrated that methadone has a valuable role in treating cancer pain. Perhaps, an unbalanced focus on the risks of inappropriate use, rather than the benefits, should not compromise or distract from the use of methadone as an alternative to morphine. Studies are on going to assess the potential role of methadone in treating neuropathic pain. Drugs such as cannabinoids, although currently applicable for patients with anorexia, nausea and/or vomiting, may offer benefits to patients experiencing pain. Other opportunities exist with such compounds as (X2-adrenergic agonists, nicotine, lidocaine and ketamine.
New strategies such as the switching opioids and/or their route of administration may offer improved analgesia with fewer adverse effects, thus providing therapeutic alternatives for the clinical community. In addition, there is interest in the co-administration of opioids that act on different receptors. For instance, oxycodone appears to be a κ opioid receptor agonist and may offer enhanced analgesia when combined with morphine.
Similar content being viewed by others
References
Bonica JJ. Cancer pain. In: Bonica JJ, editor. The management of pain. 2nd ed. Vol. 1. Philadelphia: Lea and Febiger, 1990: 400–60
Daut RL, Cleeland CS. The prevalence and severity of pain in cancer. Cancer 1982; 50: 1913–8
Elliot SC, Miser AW, Dose AM, et al. Epidemiologic features of pain in pediatric cancer patients. A cooperative community-based study. Clin J Pain 1991; 7: 263–8
Von Roenn JH, Cleeland CS, Gonin R, et al. Physicians attitudes and practice in cancer pain management. Ann Intern Med 1993; 119: 121–6
World Health Organization: cancer pain relief. Geneva: WHO Office of Publication, 1986
World Health Organization: cancer pain relief. 2nd ed. Geneva: WHO Office of Publication, 1996
Ventafridda V, Tamburini M, Caraceni A, et al. A validation study of the WHO method for cancer pain relief. Cancer 1987; 59: 851–6
Zech DFJ, Grond S, Lynch J, et al. Validation of the World Health Organisation guidelines for cancer pain relief. A 10-year prospective study. Pain 1995; 63: 65–76
Mercadante S. Pain treatment and outcomes for patients with advanced cancer who receive follow-up care at home. Cancer 1999; 85: 1849–58
Cleeland CS, Gonin R, Hatfield AK, et al. Pain and its treatment in outpatients with metastatic cancer. N Engl J Med 1994; 330: 592–6
Larue F, Colleau SM, Brasseur L, et al. Multicentre study of cancer pain and its treatment in France. BMJ 1995; 310: 1034–7
Grossman SA, Sheidler VR, Sweeden K, et al. Correlation of patient and care giver ratings of cancer pain. J Pain Symptom Manage 1991; 6: 53–7
Foley KM. Pain relief into practice: rhetoric without reform. J Clin Oncol 1995; 13(9): 2149–51
Wilson JF, Brockopp GW, Kryst S, et al. Medical students’ attitudes toward pain before and after a brief course on pain. Pain 1992; 50: 251–6
Larue F, Colleau SM, Fontaine AL, et al. Oncologists and primary care physicians’ attitudes toward pain control and morphine prescribing in France. Cancer 1995; 76: 2375–82
Zenz M, Willweber-Strumpf A. Opiophobia and cancer pain in Europe. Lancet 1993; 341: 1075–6
Porter J, Jick H. Addiction rare in patients treated with narcotics. N Engl J Med 1980; 302(2): 123
Joranson DE, Cleeland CS, Weissman DE, et al. Opioids for chronic cancer and non-cancer pain: a survey of state medical board members. Federation Bulletin: J Med Licensure Discipline 1992; 79(4): 15–49
Portenoy RK. Opioid and adjuvant analgesics. In: Max M, editor. Pain 1999-an updated review. Seattle: IASP Press, 1999: 3–18
Hanks GW, De Conno F, Ripamonti C, et al. Morphine in cancer pain: modes of administration. BMJ 1996; 312: 823–6
Ripamonti C, Zecca E, De Conno F. Pharmacological treatment of cancer pain: alternative routes of opioid administration. Tumori 1998; 84: 289–300
Hanks GW, Forbes K. Opioid responsiveness. Acta Anaesthesiol Scand 1997; 41: 154–8
Ripamonti C, Bruera E. CNS adverse effects of opioids in cancer patients. Guidelines for treatment. CNS Drugs 1997; 8(1): 21–37
Bruera E, Fainsinger RL, Schoeller T, et al. Rapid discontinuation of hypnotics in terminal cancer patients: a prospective study. Ann Oncol 1996; 7: 855–6
deWit R, van Dam P, Vielroye-Kerkmeer A, et al. The treatment of chronic cancer pain in a cancer hospital in the Netherlands. J Pain Symptom Manage 1999; 17(5): 333–50
Cherny N, Ripamonti C, Pereira J, et al. Strategies to manage the adverse effects of oral morphine. J Clin Oncol 2001; 19: 2542–54
Ventafridda V, Ripamonti C, De Conno F, et al. Antidepressants increase bioavailability of morphine in cancer patients. Lancet 1987; 1: 1204
McQuay HJ, Carroll D, Faura CC, et al. Oral morphine in cancer pain: influences on morphine and metabolite concentration. Clin Pharmacol Ther 1990; 48: 236–44
Potter JM, Reid DB, Shaw RJ, et al. Myoclonus associated with treatment with high doses of morphine: the role of supplemental drugs. BMJ 1989; 299: 150–3
Bruera E, Chadwick S, Weinlick A, et al. Delirium and severe sedation in patients with terminal cancer. Cancer Treat Rep 1987; 71: (7/8): 87–8
O’Neil WM, Hanks GW, White L, et al. The cognitive and psychomotor effects of opioid analgesics. I. A randomized controlled trial of single doses of dextropropoxyphene, lorazepam and placebo in healthy subjects. Eur J Clin Pharmacol 1995; 48: 447–53
Hanks GW, O’Neill WM, Simpson P, et al. The cognitive and psychomotor effects of opioid analgesics. II. A randomized controlled trial of single doses of morphine, lorazepam and placebo in healty subjects. Eur J Clin Pharmacol 1995; 48: 455–60
Caraceni A, Martini C, De Conno F, et al. Organic brain syndromes and opioid administration for cancer pain. JPSM 1994; 9: 527–33
Glare PA, Walsh TD, Pippenger CE. Normorphine, a neurotoxic metabolite? (letter]. Lancet 1990; 335(8691): 725–6
Hagen NA, Foley KM, Cerbone DJ, et al. Chronic nausea and morphine-6-glucuronide. J Pain Symptom Manage 1991; 6(3): 125–8
Sear JW, Hand CW, Moore RA, et al. Studies on morphine disposition: influence on renal failure on the kinetics of morphine and its metabolites. Br J Anaesth 1989; 62: 28–32
Peterson GM, Randall CT, Paterson J. Plasma levels of morphine and morphine-glucuronides in the treatment of cancer pain: relationship to renal function and route of administration. Eur J Clin Pharmacol 1990; 38: 121–4
Faura CC, Collins SL, Moore RA, et al. Systemic review of factors affecting the ratios of morphine and its major metabolites. Pain 1998; 74: 43–53
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 opioid rotation? JPSM 1995; 10(4): 287–91
Yan E, Bruera E. Case report: parenteral hydration of terminally ill cancer patients. J Palliat Care 1991; 7: 40–3
Fainsinger RL, MacEachern T, Miller MJ, et al. The use of hypodermoclysis for rehydration in terminally ill cancer patients. JPSM 1994; 9: 298–302
MacDonald N, Fainsinger R. Indications and ethical considerations in the hydration of patients with advanced cancer. In: Bruera E, Higginson I, editors. Cachexia-anorexia in cancer patients. New York: Oxford University Press, 1996; 7: 94–109
Hanks GW, De Conno F, Cherny N, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendatios. Br J Cancer 2001; 84(5): 587–93
Gupta SK, Bernstein KJ, Noorduin H, et al. Fentanyl delivery from an electrotransport system: delivery is a function of total current, not duration of current. J Clin Pharmacol 1998; 38(10): 951–8
Cherny NJ, Chang V, Frager G, et al. Opioid pharmacotherapy in the management of cancer pain: a survey of strategies used by pain physicians for the selection of analgesic drugs and routes of administration. Cancer 1995; 76: 1283–93
Bruera E, MacMillan K, Hanson J. Palliative care in a cancer center: results in 1984 versus 1987. J Pain Symptom Manage 1990; 5(1): 1–5
Coyle N, Adelhart J, Foley KM, et al. Character of terminal illness in the advanced cancer patient: pain and other symptoms during the last four weeks of life. J Pain Symptom Manage 1990; 5: 83–93
Kalso E, Heiskanen T, Rantio M, et al. Epidural and subcutaneous morphine in the management of cancer pain: a double-blind cross-over study. Pain 1996; 67: 443–9
Morley JS, Watt JWG, Wells JC, et al. Methadone in pain uncontrolled by morphine. Lancet 1993; 342: 1243
Galer BS, Coyle N, Pasternak GW, et al. Individual variability in the response to different opioids: report of five cases. Pain 1992; 49: 87–91
Drexel H, Dzien A, Spiegel RW, et al. Treatment of severe cancer pain by low-dose continuous subcutaneous morphine. Pain 1989; 36: 169–76
McDonald P, Graham P, Clayton M, et al. Regular subcutaneous bolus morphine via an indwelling cannula for pain from advanced cancer. Palliat Med 1991; 5: 323–9
Bruera E, Fainsinger R, Spachinsky K, et al. Clinical efficacy and safety of a novel controlled-release morphine suppository and subcutaneous morphine in cancer pain: a randomized evaluation. J Clin Oncol 1995; 13: 1520–7
Babul N, Provencher L, Laberge F, et al. Comparative efficacy and safety of controlled-release morphine suppositories and tablets in cancer pain. J Clin Pharmacol 1998; 38: 74–81
De Conno F, Ripamonti C, Saita L, et al. Role of rectal route in treating cancer pain: a randomized cross-over clinical trial of oral vs rectal morphine administration in opioid-naive cancer patients with pain. J Clin Oncol 1995; 13: 1004–8
Bruera E, Belzile M, Neumann CM, et al. Twice-daily versus once-daily morphine sulphate controlled-release suppositories for the treatment of cancer pain. A randomized controlled trial. Support Care Cancer 1999; 7: 280–3
Du Pen SL, Du Pen AR. Intraspinal analgesic therapy in palliative care: evolving perspective. In: Topics in palliative care. Vol. 4. Portenoy RK, Bruera E, editors. New York: Oxford University Press, 2000; 12: 217–35
Hogan Q, Haddox JD, Abram S, et al. Epidural opiates and local anesthetics for the management of cancer pain. Pain 1984; 46: 271–9
Mercadante S. Problems of long term spinal opioid treatment in advanced cancer patients. Pain 1999; 79: 1–13
Eisenach JC, Du Pen S, Dubois M, et al. Epidural clonidine analgesia for intractable cancer pain. Pain 1995; 61: 391–9
Vainio A, Tigersted I. Opioid treatment for radiating cancer pain: oral administration vs epidural techniques. Acta Anaesthesiol Scand 1988; 32: 179–80
Gong Q-L, Hedner J, Bjorkman R, et al. Morphine-3-glucuronide may functionally antagonize morphine-è-glucuronide induced antinociception and ventilatory depression in the rat. Pain 1992; 48: 249–55
Ekblom M, Gardmark M, Hannarlund-Udenaes M. Pharmacokinetics and pharmacodynamics of morphine-3-glucuronide in rats and its influence on the antinociceptive effect of morphine. Biopharm Drug Dispos 1993; 14: 1–11
Pasternak GW, Bodnar RJ, Clark JA, et al. Morphine-6-glucuronide, a potent mu agonist. Life Sci 1987; 41: 2845–9
Smith MT, Watt JA, Cramond T. Morphine-3-glucuronide: a potent antagonist of morphine analgesia. Life Sci 1990; 47: 579–85
Yaksh TL, Harty LG, Onofrio BM. High doses of spinal morphine produced a nonopiate receptor-mediated hyperesthesia: clinical and theoretic implications. Anesthesiology 1989; 71: 936–40
Dale AP, Riegler FX, Albrecht RF. Ventilatory effects of fourth cerebroventricular infusions of morphine-6- or morphine-3-glucuronide in the awake dog. Anesthesiology 1989; 71: 936–40
Bruera E, Belzile M, Pituskin E, et al. Randomized, double-blind, cross-over trial comparing safety and efficacy of oral controlled-release oxycodone with controlled-release morphine in patients with cancer pain. J Clin Oncol 1998; 16: 3222–9
Katcher J, Walsh D. Opioid-induced itching: morphine sulfate and hydromorphone hydrochloride. JPSM 1999; 17: 70–2
Paix A, Coleman A, Lees J, et al. Subcutaneous fentanyl and sufentanil infusion substitution for morphine intolerance in cancer pain management. Pain 1995; 63: 263–9
de Stoutz ND, Bruera E, Suarez-Almazor M. Opioid rotation for toxicity reduction in terminal cancer patients. JPSM 1995; 10: 378–84
Sjogren P, Jensen N-H, Jensen T-S. Disappearance of morphine-induced hyperalgesia after discontinuation or substituting morphine with other opioid agonists. Pain 1990; 59: 315–6
Maddocks I, Somogyi A, Abbott F, et al. Attenuation of morphine-induced delirium in palliative care by substitution with infusion of oxycodone. JPSM 1996; 12: 182–9
Lawlor P, Walker P, Bruera E, et al. Severe opioid toxicity and somatization of psychological distress in a cancer patient with a background of chemical dependence. JPSM 1997; 13: 356–61
Eisendrath SJ, Goldman B, Douglas J, et al. Meperidine -induced delirium. Am J Psychol 1987; 144: 1062–5
Steinberg RB, Gilman DE, Johnson III Fet. Acute toxic delirium in a patient using transdermal fentanyl. Anesth Analg 1992; 75: 1014–6
Szeto HH, Inturrisi CE, Houde R, et al. Accumulation of normeperidine, an active metabolite of meperidine, in patients with renal failure or cancer. Ann Intern Med 1977; 86: 738–41
Kaiko RF, Foley KM, Grabinski PY, et al. Central nervous system excitatory effects of meperidine in cancer patients. Ann Neurol 1983; 13: 180–5
Parkinson SK, Bailey SL, Little WL, et al. Myoclonic seizure activity with chronic high-dose spinal opioid administration. Anesthesiology 1990; 72: 743–5
MacDonald N, Der L, Allan S, et al. Opioid hyperexcitability: the application of alternate opioid therapy. Pain 1993; 53: 353–5
Ahmedzai S, Brooks D. Transdermal fentanyl versus sustained-release oral morphine in cancer pain: preference, efficacy, and quality of life. JPSM 1997; 13: 254–61
Grond S, Zech D, Lehmann KA, et al. Transdermal fentanyl in the long-term treatment of cancer pain: a prospective study of 50 patients with advanced cancer of the gastrointestinal tract or the head and neck region. Pain 1997; 69: 191–8
Korte W, de Stoutz N, Morant R. Day-to-day titration to initiate transdermal fentanyl in patients with cancer pain: short-and long-term experiences in a prospective study on 39 patients. JPSM 1996; 11: 139–46
Payne R, Mathias SD, Pasta DJ, et al. Quality of life and cancer pain: satisfaction and side effects with transdermal fentanyl versus oral morphine. J Clin Oncol 1998; 16: 1588–93
Zenz M, Donner B, Strumpf M. Withdrawal symptoms during therapy with transdermal fentanyl (fentanyl TTS)? JPSM 1994; 9: 54–5
Higgs C, Vella-Brincat J. Withdrawal with transdermal fentanyl. JPSM 1995; 10: 4–5
Davies A, Bond C. Transdermal fentanyl and the opioid withdrawal syndrome. Palliat Med 1996; 10: 348
Hunt R. Transdermal fentanyl and the opioid withdrawal syndrome. Palliat Med 1996; 10: 347–8
Megens A, Artois K, Vezmeize J, et al. Comparison of the analgesic and intestinal effects of fentanyl and morphine in rats. JPSM 1998; 15: 253–8
Daeninck PJ, Bruera E. Reduction in constipation and laxative requirements following opioid rotation to methadone: a report of four cases. JPSM 1999; 18: 303–9
Mercadante S, Sapio M, Serretta R. Treatment of pain in chronic bowel subobstruction with self-administration of Methadone. Support Care Cancer 1997; 5: 1–3
Mancini IL, Hanson J, Neumann CM, et al. Opioid type and other clinical predictors of laxative dose in advanced cancer patients. J Palliat Med 2000; 3: 49–56
Gorman AL, Elliot KJ, Juturrisi CE, et al. The d- and 1-isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate receptor in rat forebrain and spinal cord. Neurosci Lett 1997; 223: 5–8
Egbert B, Andersen S, Krogsgaard-Larsen P. Ketobemidone, methadone and pethidine are non-competitive N-methyl-D-aspartate (NMDA. antagonists in the rat cortex and spinal cord. Neurosci Lett 1995; 187: 165–8
Denton JE, Beecher HK. New analgesics. JAMA 1949 Dec; 17: 1146–53
Mercandante S, Casuccio A, Agnello A, et al. Morphine versus methadone in the pain treatment of advanced-cancer patients followed up at home. J Clin Oncol 1998; 16(11): 3656–61
Mercadante S, Casuccio A, Agnello A, et al. Methadone response in advanced cancer patients with pain followed at home. JPSM 1999; 18: 188–92
Ventafridda V, Ripamonti C, Bianchi M, et al. A randomized study on oral administration of morphine and methadone in the treatment of cancer pain. JPSM 1986; 1: 203–7
De Conno F, Groff L, Brunelli C, et al. Clinical experience with oral methadone administration in the treatment of pain in 196 advanced cancer patients. J Clin Oncol 1996; 14: 2836–42
Mercadante S, Sapio M, Serretta R, et al. Patient-controlled analgesia with oral methadone in cancer pain. Ann Oncol 1996; 7: 613–7
Ripamonti C, Zecca E, Bruera E. An update on the clinical use of methadone for cancer pain. Pain 1997; 70: 109–15
Mancini I, Lossignol DA, Body JJ. Opioid switching to oral methadone in cancer pain. Curr Opin Oncol 2000; 12: 308–13
Fitzgibbon DR, Ready LB. Intravenous high-dose methadone administered by patient controlled analgesia and continuous infusion for the treatment of cancer pain refractory to high-dose morphine. Pain 1997; 73: 259–61
Manfredi PL, Borsook D, Chandler SW, et al. Intravenous methadone for cancer pain unrelieved by morphine and hydromorphone: clinical observations. Pain 1997; 70: 99–101
Morley JS, Makin MK. The use of methadone in cancer pain poorly responsive to other opioids. Pain Rev 1998; 5: 51–8
Crews JC, Sweeney NJ, Denson DD. Clinical efficacy of methadone in patients refractory to other mu-opioid receotor agonist analgesics for management of terminal cancer pain. Cancer 1993; 72: 2266–72
Bennett GJ. Update on the neurophysiology of pain transmission and modulation: focus on the NMDA-Receptor. J Pain Symptom Manage 2000; 19: S2–S6
Price DD, Mayer DJ, Mao J, et al. NMDA-Receptor antagonists and opioid receptor interactions as related to analgesia and tolerance. J Pain Symptom Manage 2000; 19: S7–S11
Portenoy RK. Current pharmacotherapy of chronic pain. J Pain Symptom Manage 2000; 19: S16–S20
Sang CN. NMDA-Receptor antagonists in neuropathic pain: experimental methods to clinical trials. J Pain Symptom Manage 2000; 19: S21–S25
Gagnon B, Bruera E. Differences in the ratios of morphine to methadone in patients with neuropathic pain versus non-neuropathic pain. JPSM 1999; 18: 120–5
Makin MK, O’Donnell V, Skinner JM, et al. Methadone in the management of cancer related neuropathic pain: report of five cases. Pain Clin 1998; 4: 275–9
Faisinger R, Schoeller T, Bruera E. et al. Methadone in the management of cancer pain: a review. Pain 1993; 52: 137–47
Wheeler WL, Dickerson ED. Clinical applications of methadone. Am J Hosp Palliat Care 2000; 17(3): 1–8
Health and Welfare Canada, Cancer pain: a monograph on the management of cancer pain. Ottawa: Health & Welfare Canada: Minister of Supply and Services, Canada: H42-2/5, 1984E
Levy MH. Pharmacological treatment of cancer pain. N Engl J Med 1996; 335(15): 1124–32
Agency for Health Care Policy Research. Management of cancer pain. Clinical Practice Guidelines. Rockville, M.D. U.S. Department of Health and Human Services. AHCPR Publications N. 94-0592, 1994 Mar: 52
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: 852–7
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 1998; 16(10): 3216–21
Lawlor PG, Turner K, Hanson J, et al. Dose ratio between morphine and methadone in patients with cancer pain: a retrospective study. Cancer 1998; 82: 1167–73
Ripamonti C, De Conno F, Groff L, et al. Equianalgesic dose/ratio between methadone and other opioid agonists in cancer pain: comparison of two clinical experiences. Ann Oncol 1998; 9: 79–83
Mercadante S, Casuccio A, Calderone L. Rapid switching from morphine to methadone in cancer patients with poor response to morphine. J Clin Oncology 1999; 17(10): 3307–12
Lawlor PG, Turner K, Hanson J, et al. Dose ratio between morphine and hydromorphone in patients with cancer pain: a retrospective study. Pain 1997; 72: 79–85
Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain 1990; 41: 273–81
Petzke F, Radbruch L, Zech D, et al. Temporal presentation of chronic cancer pain: transitory pains on admission to a multidisciplinary pain clinic. JPSM 1999; 17: 391–41
Banning A, Sjogren P, HenriKsen H. Treatment outcome in a multidisciplinary cancer pain clinic. Pain 1991; 47: 129–34
Bruera E, Schoeller T, Wenk R, et al. A prospective multi-center assessment of the Edmonton staging system for cancer pain. JPSM 1995; 10: 348–55
Mercadante S, Maddaloni S, Roccella S, et al. Predictive factors in advanced cancer pain treated only by analgesics. Pain 1992; 50: 151–5
Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: characteristics and impact in patients with cancer pain. Pain 1999; 81: 129–34
Ripamonti C, Fulfaro F. Malignant bone pain: pathophysiology and treatments. Curr Rev Pain 2000; 4: 187–96
Bloomfield DJ. Should bisphosphonates be part of the standard therapy of patients with multiple myeloma or bone metastases from other cancers? An evidence-based review. J Clin Oncol 1998; 16: 1218–25
Hillner BE, Ingle JN, Berenson JR, et al. American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. J Clin Oncol 2000; 18: 1378–91
Fulfaro F, Casuccio A, Ticozzi C, et al. The role of bisphopshonates in the treatment of painful metastatic bone disease: a review of phase III trials. Pain 1998; 78: 157–69
Ripamonti C, Bruera E. Current status of patient-controlled analgesia in cancer patients. Oncology 1997; 11: 373–80
Streisand JB, Varvel JR, Stanski DR, et al. Absorption and bioavailability of oral and transmucosal fentanyl citrate. Anesthesiology 1991; 75: 223–9
Fine PG, Marcus M, De Boer AJ, et al. An open label study of oral transmucosal fentanyl citrate (OTFC. for the treatment of breakthrough cancer pain. Pain 1991; 45: 149
Fine PG. Fentanyl in the treatment of cancer pain. Semin Oncol 1997; 24(5) Suppl. 16: 20–7
Streisand JB, Busch MA, Egan TD, et al. Dose proportionality and pharmacokinetics of oral transmucosal fentanyl citrate. Anesthesiology 1998; 88: 305–9
Christie JM, Simmonds M, Patt R, et al. Dose titration: a multicenter study of oral transmucosal fentanyl citrate for the treatment of breakthrough pain in cancer patients using transdermal fentanyl for persistent pain. J Clin Oncol 1998; 16: 3238–45
Farrar JT, Clearly J, Rauck R, et al. Oral transmucosal fentanyl citrate: randomized, double-blinded, placebo-controlled trial for treatment of breakthrough pain in cancer patients. J Natl Cancer Inst 1998; 90(8): 611–6
Portenoy RK, Payne R, Coluzzi P, et al. Oral transmucosal fentanyl citrate (OTFC. for the treatment of breakthrough pain in cancer patients: a controlled dose titration study. Pain 1999; 79: 303–12
Chandler S. Oral transmucosal fentanyl citrate: a new treatment for breakthrough pain. Am J Hosp Palliat Care 1999; 16(2): 489–91
Lipman AG. New and alternative noninvasive opioid dosage forms and routes of administration. Support Oncol Updates 2000; 3(1): 1–8
Nimmo W. Novel delivery systems: electrotransport. J Pain Symptom Manage 1992; 7: 160–2
Ashburn M, Streisand J, Zhang J. The iontophoresis of fentanyl citrate in humans. Anesthesiology 1995; 83: 1146–53
Vanbever R, LeBoulenge E, Preat V. Transdermal delivery of fentanyl by electroporation.I. Influence of electrical factors. Pharm Res 1996; 13(4): 559–65
Cherny NI. Cancer pain: principles of assessment and syndromes. In: Principles and practice of supportive oncology. Berger A, Portenoy RK, Weissman, DE, et al. editors. Philadelphia: Lippincott-Raven Publishers, 1998; 1: 3–42
Caraceni A, Portenoy RK, and a Working Group of the IASP Task Force on Cancer Pain. An international survey of cancer pain characteristics and syndromes. Pain 1999; 82: 263–74
Cherny NI, Thaler HT, Friedlander-Klar H, et al. Opioid responsiveness of cancer pain syndromes caused by neuropathic or nociceptive mechanisms: a combained analysis of controlled single dose studies. Neurology 1994; 44: 857–61
Arner S, Meyerson BA. Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain. Pain 1988; 33: 11–23
Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 1999; 83: 389–400
Grond S, Radbruch L, Meuser T, et al. Assessment and treatment of neuropathic cancer pain following WHO guidelines. Pain 1999; 79: 15–20
Dellemijn P. Are opioids effective in relieving neuropathic pain? Pain 1999; 80: 453–62
Portenoy RK, Foley KM, Inturrisi CE. The nature of opioid responsiveness and its implications for neuropathic pain: new hypotheses derived from studies of opioid infusion. Pain 1990; 43: 273–86
Rowbotham MC, Reisner-Keller LA, Fields HL. Both intravenous lidocaine and morphine reduce the pain of postherpetic neuralgia. Neurology 1991; 41: 1024–8
Sindrup S, Andersen G, Madsen C, et al. Tramadol relieves pain and allodynia in polyneuropathy: a randomised, double-blind, controlled trial. Pain 1999; 83: 85–90
Harati Y, Gooch C, Swenson M, et al. Double-blind randomized trial of tramadol for the treatment of pain of diabetic neuropathy. Neurology 1998; 50: 1842–6
Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain. A randomized trial in postherpetic neuralgia. Neurology 1998; 50: 1837–41
Dellemijn PLI, Vanneste JAL. Randomised double-blind active-controlled crossover trial intravenous fentanyl in neuropathic pain. Lancet 1997; 349: 753–8
McQuay HJ, Carroll D, Jadad AR, et al. Dextromethorphan for the treatment of neuropathic pain: a double-blind randomised controlled crossover trial with integral n-of-1 design. Pain 1994; 59: 127–33
Mercadante S, Casuccio A, Genovese G. Ineffectiveness of dextromethorphan in cancer pain. JPSM 1998; 16: 317–22
Nelson KA, Park KM, Robinovitz E, et al. High-dose dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia. Neurology 1997; 48: 1212–8
Mao J, Price DD, Caruso F, et al. Oral administration of dextromethorphan prevents the development of morphine tolerance and dependence in rats. Pain 1996; 67: 361–8
Grass S, Hoffman O, Xu X-J, et al. N-Methyl-D-aspartate receptor antagonists potenjtiate morphine’s anti-nociceptive effect in the rat. Acta Physiol Scand 1996; 158: 269–73
Katz NP. MorphiDex (MS:DM. double-blind, multiple-dose studies in chronic pain patients. JPSM 2000; 19: S37–S41
Caruso FS. MorphiDex pharmacokinetic studies and single-dose analgesic efficacy studies in patients with postoperative pain. JPSM 2000; 19: S31–S36
Goldblum R. Long-term safety of Morphi-Dex. JPSM 2000; 19(18): S50–S56
Mercadante S. Ketamine in cancer pain: an update. Palliat Med 1996; 10(3): 225–30
Mercadante S, Lodi F, Sapio M, et al. Long-term ketamine subcutaneous infusion in neuropathic cancer pain. J Pain Symptom Manage 1995; 10(7): 564–8
Clark JL, Kalan GE. Effective treatment of severe cancer pain of the head using low-dose ketamine in an opioid-tolerant patient. J Pain Symptom Manage 1995; 10(4): 310–4
Sosnowski M. Pain management: physiopathology, future research and endpoints. Support Care Cancer 1993; 1(2): 79–88
Felsby S, Nielsen J, Arendt-Nielsen L, et al. NMDA receptor blockade in chronic neuropathic pain: a comparison of ketamine and magnesium chloride. Pain 1996; 64: 283–91
Max MB, Byas-Smith MG, Gracely RH, et al. Intravenous infusion of the NMDA antagonist ketamine, in chronic post-traumatic pain and allodynia: a double-blind comparison to alfentanil and placebo. Clin Neuropharmacol 1995; 18: 360–8
Yang CY, Wong CS, Chang JY, et al. Intrathecal ketamine reduces morphine requirements in patients with terminal cancer. Can J Anaesth 1996; 43(4): 379–83
Muller A, Lemos D. Cancer pain: beneficial effect of ketamine addition to spinal administration of morphine-clonidine-lidocaine mixture. Ann Fr Anesth Reanim 1996; 15(3): 271–6
Warncke T, Stubhaug A, Jorum E. Ketamine, an NMDA receptor antagonist, suppresses spatial and temporal properties of burn-induced secondary hyperalgesia in man: a double-blind, cross-over comparison with morphine and placebo. Pain 1997; 72: 99–106
Kastrup J, Peterson P, Dejgard A, et al. Intravenous lidocaine infusion -a new treatment of chronic painful neuropathy? Pain 1987; 28: 69–75
Bach FW, Jensen TS, Kastrup J, et al. The effect of intravenous lidocaine on nociceptive processing in diabetic neuropathy. Pain 1990; 40: 29–34
Petersen P, Kastrup J. Dercum’s disease (adiposis dolorosa.. Treatment of the severe pain with intravenous lidocaine. Pain 1987; 28: 77–80
Rowlingson JC, DiFazio CA, Foster J, et al. Lidocaine as an analgesic for experimental pain. Anesthesiology 1980; 52: 20–2
Elleman K, Sjogren P, Banning AM, et al. Trial of intravenous lidocaine on painful neuropathy in cancer patients. Clin J Pain 1989; 5: 291–4
Bruera E, Ripamonti C, Brenneis C, et al. A randomized double-blind crossover trial of intravenous lidocaine in the treatment of neuropathic cancer pain. J Pain Symptom Manage 1992; 7: 138–40
Koppert W, Zeck S, Sittl R, et al. Low-dose lidocaine suppresses experimentally induced hyperalgesia in humans. Anesthesiology 1998; 89(6): 1345–53
Ferrante FM, Paggioli J, Cherukuri S, et al. The analgesic response to intravenous lidocaine in the treatment of neuropathic pain. Anesth Analg 1996; 82(1): 91–7
Koscielniak-Nielsen Z, Hesselbjerg L, Brushoj J, et al. EMLA patch for spinal puncture. A comparison of EMLA patch with lignocaine infiltration and placebo patch. Anaesthesia 1998; 53(12): 1218–22
Fuchs PN, Pappagallo M, Meyer RA. Topical EMLA pre-treatment fails to decrease the pain induced by 1 % topical capsaicin. Pain 1999; 80(3): 637–42
Rowbotham MC, Davies PS, Verkempinck C, et al. Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain 1996; 65(1): 39–44
Portenoy RK, Kanner RM. Nonopioid and adjuvant analgesics. In: Portenoy RK, Kanner RM, editors. Pain management: theory and practice, contemporary neurology series. Philadelphia: FA Davis, 1996: 219–47
Max MB, Schafer SC, Culnane M, et al. Association of pain relief with drug side effects in posttherpetic neuralgia: a single-dose study of clonidine, codeine, iburprofen and placebo. Clin Pharmacol Ther 1988; 43: 363–71
Pappagallo M. Aggressive pharmacologic treatment of pain. Pain Manage Rheum Dis 1999; 25(1): 193–213
Glynn C, Dawson D, Sanders RA. A double-blind comparison between epidural morphine and epidural clonidine in patients with chronic non-cancer pain. Pain 1988; 34: 123–8
Glynn C, Jamous MA, Teddy PJ, et al. Role of spinal noradrenergic system in transmission of pain in patients with spinal cord injury. Lancet 1986; 2: 1249–50
Byas-Smith MG, Max MB, Muir J, et al. Transdermal clonidine compared to placebo in painful diabetic neuropathy using a two-stage ‘enriched enrollment’ design. Pain 1995; 60(3): 267–74
Abadir AR, Kraynack BJ, Maida J, et al. Postherpetic neuralgia: response to topical clonidine. Proc West Pharmacol Soc 1996; 39: 47–8
Cherny N, Portenoy RK. Practical issues in the management of cancer pain. In: Wall PD, Melzack R, editors. Textbook of pain. Edinburgh: Churchill Livingstone, 1994: 1437–67
Payne R. Pharmacological management of pain. In: Berger AM, Portenoy RK, Weissman DE. editors. Principles and practice of supportive oncology. Philadelphia: Lippincott-Raven Publishers, 1998: 3: 61–76
Portenoy RK. Adjuvant analgesics in pain management. In: Doyle D, Hanks GWC, MacDonald N, editors. Oxford textbook of palliative medicine. 2nd ed. Oxford: Oxford University Press, 1998: 361–90
McQuay H, Carroll D, Jadad AR, et al. Anticonvulsant drugs for management of pain: a systemic review. BMJ 1995; 311: 1047–52
MacDonald RL, Kelly KM. Mechanisms of action of currently prescribed and newly developed antiepileptic drugs. Epilepsia 1994; S41-S50
Attal N, Brasseur L, Parker F, et al. Effects of gabapentin on the different components of peripheral and central neuropathic pain syndromes: a pilot study. Eur Neurol 1998; 40: 191–200
Field MJ, Oles RJ, Lewis AS, et al. Gabapentin and S- (+. -3-isobutylgaba represent a novel class of selective anti-hyperalgesic agents. BrJPharmacol 1997; 121: 1513–22
Field MJ, Holloman EF, McCleary S, et al. Evaluation of gabapentin and S- (+. -3-isobutylgaba in a rat model of postoperative pain. J Pharmacol Exp Ther 1997; 282: 1242–6
Hun Jun J, Yaksh TL. Effect of intrathecal gabapentin and 3-isobutyl GABA on the hyperalgesia observed after thermal injury in the rat. Anesthesiology 1997; 87: A720
Partridge B, Chaplan SR, Sakamoto E, et al. Characterization of the effects of gabapentin and 3-isobutyl-gamma-aminobutyric acid and substance P-induced thermal hyperalgesia. Anesthesiology 1998; 88: 196–205
Shimoyama M, Shimoyama N, Inturrisi CE, et al. Gabapentin enhances the antinociceptive effects of spinal morphine in the rat tail-flick test. Pain 1997; 72: 375–82
Segal A, Rordorf G. Gabapentin as a novel treatment for postherpetic neuralgia. Neurology 1996: 46(4): 1175–6
Sist TC, Filadora V, Miner M, et al. Gabapentin for idiopathic trigeminal neuralgia. Report of two cases. Neurology 1997; 48(5): 1467
Sist TC, Filadora V, Miner M, et al. Experience with gabapentin for neuropathic pain in the head and neck: report of ten cases. Reg Anesth 1997; 22: 473–8
Rosner H, Rubin L, Kestenbaum A. Gabapentin adjunctive therapy in neuropathic pain states. Clin J Pain 1996; 12: 56–8
Stacey BR, Tipton KD, Owen GT, et al. Gabapentin and neuropathic pain states: a case series report. Reg Anesth 1996: 21 Suppl. 2: 65
Rosenberg JM, Harrell C, Ristic H, et al. The effect of gabapentin on neuropathic pain. Clin J Pain 1997; 13: 251–5
Kathri A, Pearlstein L, Bensalem PA. Pain in Guillain-Barre’ syndrome. Neurology 1997; 49: 1474
Samkoff LM, Daras M, Tuchman AT, et al. Amelioration of refractory dysesthesic limb pain in multiple sclerosis by gabapentin. Neurology 1997; 49: 304–5
Backonja M, Beydoun A, Edwards KR, et al. for the Gabapentin Diabetic Neuropathy Study Group. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus. A randomized controlled trial. JAMA 1998; 280: 1831–6
Rowbotham M, Harden N, Stacey B, et al., for the Gabapentin Postherpetic Neuralgia Study Group. Gabapentin for the treatment of Postherpetic Neuralgia. A randomized controlled trial. JAMA 1998; 280: 1837–42
Caraceni A, Zecca E, Martini C, et al. Gabapentin as an adjuvant to opioid analgesia for neuropathic cancer pain. JPSM 1999; 17: 441–5
Minotti V, Patoia L, Roila F, et al. Double-blind evaluation of analgesic efficacy of orally administered diclofenac, nefopam and acetylsalicylic acid plus codeina in chronic cancer pain. Pain 1989; 36: 177–9
Moore A, Collins S, Carroll D, et al. paracetamol with and without codeine in acute pain: a quantitative systematic review. Pain 1997; 70: 193–201
Crain SM, Shen K-F. Antagonists of excitatory opioid receptor functions enhance morphine’s analgesic potency and attenuate opioid tolerance/dependence liability. Pain 2000; 84: 121–31
Levine JD, Gordon NC, Taiwo YO, et al. Potentiation of pentazocine analgesia by low-dose naloxone. J Clin Invest 1988; 82: 1574–7
Gan TJ, Ginsberg B, Glass PSA, et al. Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulphate. Anesthesiology 1997; 87: 1075–81
O’Brien CP. A range of research-based pharmacotherapies for addiction. Science 1997; 278: 66–70
Shen K-F, Crain SM. Ultra-low doses of naltrexone or etorphine increase morphine’s antinociceptive potency and attenuate tolerance/dependence in mice. Brain Res 1997; 757: 176–90
Joshi GP, Duffy J, Chehade J, et al. Effects of prophylactic nalmefene on the incidence of morphine-related side effects in patients receiving intravenous patient-controlled analgesia. Anesthesiology 1999; 90: 1007–11
Miaskowski C, Sutters KA, Taiwo YO, et al. Antinociceptive and motor effects of delta/mu and kappa/mu combinations of intrathecal opioid agonist. Pain 1992; 49: 137–44
Miaskowski C, Taiwo YO, Levine JD. Antinociception produced by receptor selective opioids. Modulation of supraspinal antinociceptive effects by spinal opioids. Brain Res 1993; 608: 87–94
Ross FB, Smith MT. The intrinsic antinociceptive effects of oxycodone appear to be kappa opioid receptor mediated. Pain 1997; 73: 151–7
Ross FB, Wallis SC, Smith MT. Co-administration of sub-antinociceptive doses of oxycodone and morphine produces marked antinociceptive synergy with reduced CNS side-effects in rats. Pain 2000; 84: 421–8
Sharpe P, Smith G. Cannabis: time for scientific evaluation of this ancient remedy? Anesth Analg 2000; 90: 237–40
Mannix KA. Palliation of nausea and vomiting. In: Doyle D, Hanks GWC, MacDonald N, editorss. Oxford textbook of palliative medicine. 2nd ed. Oxford: Oxford University Press, 1997: 489–99
Pugh G, Smith PB, Dombrowski DS, et al. The role of endogenous opioids in enhancing the antinociception produced by the combination of Delta-9-tetrahydrocannabinol and morphine in the spinal cord. J Pharmacol Exp Ther 1996; 279: 608–16
Fuentes JA, Ruiz-Gayo M, Manzanares J, et al. Cannabinoids as potential new analgesics. Life Sci 1999; 65: 675–85
Holdcroft A, Pertwee MA, Rice AS, et al. Development of Analgesics from Cannabinoid Receptor Ligands Proceedings. Abstracts, International Association for the Study of Pain, 9th World Congress, Vienna, 1999: 108
Fride E, Mechoulam R. Pharmacological activity of the can-nabinoid receptor agonist, anandamide, a brain constituent. Eur J Pharmacol 1993; 231: 313–4
Smith PB, Comptom DR, Welch SP, et al. The pharmacological activity of anandamide, a putative endogenous cannabinoid, in mice. J Pharmacol Exp Ther 1994; 270: 219–27
Richardson JD, Aanonsen L, Hargreaves KM. SR 141716A, a cannabinoid receptor antagonist, produces hyperalgesia in untreated mice. Eur J Pharmacol 1997; 319: R3–R4
Calignano A, La Rana G, Giuffrida A, et al. Control of pain initiation by endogenous cannabinoids. Nature 1998; 394: 277–81
Richardson JD, Aanonsen L, Hargreaves KM. Antihyperalgesic effects of spinal cannabinoids. Eur J Pharmacol 1998; 345: 145–53
Martin WJ, Loo CM, Basbaum AI. Spinal cannabinoids are anti-allodynic in rats with persistent inflammation. Pain 1999; 82: 199–205
Herzberg U, Eliav E, Bennett GJ, et al. The analgesic effects of R (+. -WIN 55.212-2 mesylate, a high affinity cannabinoid agonist, in a rat model of neuropathic pain. Neurosci Lett 1997; 221: 157–60
Richardson JD, Kilo S, Hargreaves KM. Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheal CB1 receptors. Pain 1998; 75: 111–9
Gilbert PE. A comparison of THC, nantradol, nabilone and morphine in the chronic spinal dog. J Clin Pharmacol 1981; 21: 311S–319S
Noyes R, Brunk ST, Avery DH, et al. The analgesic properties of delta-9-tetrahydrocannibinol and codeine. Clin Pharmacol Ther 1975; 18: 84–9
Li J, Daughters RS, Bullis C, et al. The cannabinoid receptor agonist WIN 55,212-2 mesylate blocks the development of hyperalgesia produced by capsaicin in rats. Pain 1999; 81: 25–33
McKay DB, Trent-Sanchez P. Effect of noncompetitive nicotinic receptor blockers on catecholamine release from cultured adrenal chromaffin cells. Pharmacology 1990; 40: 224–30
Miao FJ, Benowitz N, Basbaum AI, et al. Sympathoadrenal contribution to nicotinic and muscarinic modulation of bradykinin plasma extravasation in the knee joint of the rat. J Pharmacol Exp Ther 1992; 95: 105–7
Decker MW, Meyer MD. Therapeutic potential of neuronal nicotinic acetylcholine receptor agonists as novel analgesics. Biochem Pharmacol 1999; 58(6): 917–23
Heller PH, Green PG, Tanner KD, et al. Peripheral neural contributions to inflammation. In: Fields HL, Liebeskind JC, editors. Pharmacological approaches to the treatment of chronic pain: new concepts and critical issues. Seattle: IASP Press, 1994: 32
Acknowledgements
The Fellowship at the Oxford International Centre for Palliative Care held by ED Dickerson is funded by Boehringer Ingelheim, Ingelheim, Germany.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ripamonti, C., Dickerson, E.D. Strategies for the Treatment of Cancer Pain in the New Millennium. Drugs 61, 955–977 (2001). https://doi.org/10.2165/00003495-200161070-00005
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003495-200161070-00005