Nausea and Vomiting Side Effects with Opioid Analgesics during Treatment of Chronic Pain: Mechanisms, Implications, and Management Options
Frank Porreca PhD,
Michael H. Ossipov PhD,
Frank Porreca PhD
Department of Pharmacology, University of Arizona, Tuscon, Arizona, USA
Search for more papers by this authorMichael H. Ossipov PhD
Department of Pharmacology, University of Arizona, Tuscon, Arizona, USA
Search for more papers by this authorFrank Porreca PhD,
Michael H. Ossipov PhD,
Frank Porreca PhD
Department of Pharmacology, University of Arizona, Tuscon, Arizona, USA
Search for more papers by this authorMichael H. Ossipov PhD
Department of Pharmacology, University of Arizona, Tuscon, Arizona, USA
Search for more papers by this authorFrank Porreca, PhD, Department of Pharmacology, LSN 562, University of Arizona, Tucson, AZ 85724, USA. Tel: 520-626-7421; Fax: 520-626-4182; E-mail: [email protected].
ABSTRACT
Objectives. Gastrointestinal (GI) side effects such as nausea and vomiting are common following opioid analgesia and represent a significant cause of patient discomfort and treatment dissatisfaction. This review examines the mechanisms that produce these side effects, their impact on treatment outcomes in chronic pain patients, and counteractive strategies.
Results. A number of mechanisms by which opioids produce nausea and vomiting have been identified. These involve both central and peripheral sites including the vomiting center, chemoreceptor trigger zones, cerebral cortex, and the vestibular apparatus of the brain, as well as the GI tract itself. Nausea and vomiting have a negative impact on treatment efficacy and successful patient management because they limit the effective analgesic dosage that can be achieved and are frequently reported as the reason for discontinuation of opioid pain medication or missed doses. While various strategies such as antiemetic agents or opioid switching can be employed to control these side effects, neither option is ideal because they are not always effective and incur additional costs and inconvenience. Opioid-sparing analgesic agents may provide a further alternative to avoid nausea and vomiting due to their reduced reliance on mu-opioid signalling pathways to induce analgesia.
Conclusions. Nausea and vomiting side effects limit the analgesic efficiency of current opioid therapies. There is a clear need for the development of improved opioid-based analgesics that mitigate these intolerable effects.
References
- 1 Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D. Survey of chronic pain in Europe: Prevalence, impact on daily life, and treatment. Eur J Pain 2006; 10: 287–333.
- 2 Blyth FM, March LM, Brnabic AJ, et al. Chronic pain in Australia: A prevalence study. Pain 2001; 89: 127–34.
- 3 Eriksen J, Jensen MK, Sjogren P, Ekholm O, Rasmussen NK. Epidemiology of chronic non-malignant pain in Denmark. Pain 2003; 106: 221–8.
- 4 Jensen TS, Backonja MM, Hernandez Jimenez S, et al. New perspectives on the management of diabetic peripheral neuropathic pain. Diab Vasc Dis Res 2006; 3: 108–19.
- 5 Catala E, Reig E, Artes M, et al. Prevalence of pain in the Spanish population: Telephone survey in 5000 homes. Eur J Pain 2002; 6: 133–40.
- 6 McDermott AM, Toelle TR, Rowbotham DJ, Schaefer CP, Dukes EM. The burden of neuropathic pain: Results from a cross-sectional survey. Eur J Pain 2006; 10: 127–35.
- 7 Eriksen J, Sjogren P, Bruera E, Ekholm O, Rasmussen NK. Critical issues on opioids in chronic non-cancer pain: An epidemiological study. Pain 2006; 125: 172–9.
- 8 OPEN Minds. The white paper on opioids and pain: a pan-European challenge; 2005. Available at: http://www.openmindsonline.org/english/pdf/White_Paper.pdf (accessed April 9, 2008).
- 9 Rowbotham MC, Lindsey CD. How effective is long-term opioid therapy for chronic noncancer pain? Clin J Pain 2007; 23: 300–2.
- 10 Portenoy RK. Opioid therapy for chronic nonmalignant pain: A review of the critical issues. J Pain Symptom Manage 1996; 11: 203–17.
- 11 Nicholson B. Responsible prescribing of opioids for the management of chronic pain. Drugs 2003; 63: 17–32.
- 12 Harris J-D. Management of expected and unexpected opioid-related side effects. Clin J Pain 2008; 24: S8–13.
- 13 Cherny NI. Opioid analgesics: Comparative features and prescribing guidelines. Drugs 1996; 51: 713–37.
- 14 Chou R, Clark E, Helfand M. Comparative efficacy and safety of long-acting oral opioids for chronic non-cancer pain: A systematic review. J Pain Symptom Manage 2003; 26: 1026–48.
- 15 Villars P, Dodd M, West C, et al. Differences in the prevalence and severity of side effects based on type of analgesic prescription in patients with chronic cancer pain. J Pain Symptom Manage 2007; 33: 67–77.
- 16 Moore RA, McQuay HJ. Prevalence of opioid adverse events in chronic non-malignant pain: Systematic review of randomised trials of oral opioids. Arthritis Res Ther 2005; 7: R1046–51.
- 17 Sussman G, Shurman J, Creed MR, et al. Intravenous ondansetron for the control of opioid-induced nausea and vomiting. International S3AA3013 Study Group. Clin Ther 1999; 21: 1216–27.
- 18 Hornby PJ. Central neurocircuitry associated with emesis. Am J Med 2001; 111(suppl 8A): 106S–12S.
- 19 Rousseau P. Nonpain symptom management in terminal care. Clin Geriatr Med 1996; 12: 313–27.
- 20 Herndon CM, Jackson KC, 2nd, Hallin PA. Management of opioid-induced gastrointestinal effects in patients receiving palliative care. Pharmacotherapy 2002; 22: 240–50.
- 21 Guyton AC, Hall JE. Textbook Of Medical Physiology, 11th edition. Philadelphia: Elsevier Saunders; 2006.
- 22 Holden JE, Jeong Y, Forrest JM. The endogenous opioid system and clinical pain management. AACN Clin Issues 2005; 16: 291–301.
- 23 Raynor K, Kong H, Chen Y, et al. Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors. Mol Pharmacol 1994; 45: 330–4.
- 24 Iasnetsov VV, Drozd Iu V, Shashkov VS. Emetic and antiemetic properties of regulatory peptides. Biull Eksp Biol Med 1987; 103: 586–8.
- 25 Breitfeld C, Peters J, Vockel T, Lorenz C, Eikermann M. Emetic effects of morphine and piritramide. Br J Anaesth 2003; 91: 218–23.
- 26 Costello DJ, Borison HL. Naloxone antagonizes narcotic self blockade of emesis in the cat. J Pharmacol Exp Ther 1977; 203: 222–30.
- 27 Freye E, Latasch L. Development of opioid tolerance—molecular mechanisms and clinical consequences. Anasthesiol Intensivmed Notfallmed Schmerzther 2003; 38: 14–26.
- 28 Kurz A, Sessler DI. Opioid-induced bowel dysfunction: Pathophysiology and potential new therapies. Drugs 2003; 63: 649–71.
- 29 Shukla VK, Turndorf H, Bansinath M. Pertussis and cholera toxins modulate kappa-opioid receptor agonists-induced hypothermia and gut inhibition. Eur J Pharmacol 1995; 292: 293–9.
- 30 Popper P, Cristobal R, Wackym PA. Expression and distribution of mu opioid receptors in the inner ear of the rat. Neuroscience 2004; 129: 225–33.
- 31 Jongkamonwiwat N, Phansuwan-Pujito P, Sarapoke P, et al. The presence of opioid receptors in rat inner ear. Hear Res 2003; 181: 85–93.
- 32 Eisenach JC, Carpenter R, Curry R. Analgesia from a peripherally active kappa-opioid receptor agonist in patients with chronic pancreatitis. Pain 2003; 101: 89–95.
- 33 Portenoy RK, Farrar JT, Backonja MM, et al. Long-term use of controlled-release oxycodone for noncancer pain: Results of a 3-year registry study. Clin J Pain 2007; 23: 287–99.
- 34 Mao J. Opioid tolerance and neuroplasticity. Novartis Found Symp 2004; 261: 181–6, discussion 87–93.
- 35 Ossipov MH, Lai J, King T, et al. Antinociceptive and nociceptive actions of opioids. J Neurobiol 2004; 61: 126–48.
- 36 Ossipov MH, Lai J, King T, Vanderah TW, Porreca F. Underlying mechanisms of pronociceptive consequences of prolonged morphine exposure. Biopolymers 2005; 80: 319–24.
- 37 Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med 2003; 349: 1943–53.
- 38 Barnes NM, Bunce KT, Naylor RJ, Rudd JA. The actions of fentanyl to inhibit drug-induced emesis. Neuropharmacology 1991; 30: 1073–83.
- 39 Scotto di Fazano C, Vergne P, Grilo RM, et al. Preventive therapy for nausea and vomiting in patients on opioid therapy for non-malignant pain in rheumatology. Therapie 2002; 57: 446–9.
- 40 Campora E, Merlini L, Pace M, et al. The incidence of narcotic-induced emesis. J Pain Symptom Manage 1991; 6: 428–30.
- 41 Kalso E, Vainio A. Morphine and oxycodone hydrochloride in the management of cancer pain. Clin Pharmacol Ther 1990; 47: 639–46.
- 42 Aldrete JA. Reduction of nausea and vomiting from epidural opioids by adding droperidol to the infusate in home-bound patients. J Pain Symptom Manage 1995; 10: 544–7.
- 43 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 2003; 4: 231–56.
- 44 Bruera E, Seifert L, Watanabe S, et al. Chronic nausea in advanced cancer patients: A retrospective assessment of a metoclopramide-based antiemetic regimen. J Pain Symptom Manage 1996; 11: 147–53.
- 45 Dundee JW, Jones PO. The prevention of analgesic-induced nausea and vomiting by cyclizine. Br J Clin Pract 1968; 22: 379–82.
- 46 Ferris FD, Kerr IG, Sone M, Marcuzzi M. Transdermal scopolamine use in the control of narcotic-induced nausea. J Pain Symptom Manage 1991; 6: 389–93.
- 47 Cole RM, Robinson F, Harvey L, Trethowan K, Murdoch V. Successful control of intractable nausea and vomiting requiring combined ondansetron and haloperidol in a patient with advanced cancer. J Pain Symptom Manage 1994; 9: 48–50.
- 48 Coluzzi F, Pappagallo M. Opioid therapy for chronic noncancer pain: Practice guidelines for initiation and maintenance of therapy. Minerva Anestesiol 2005; 71: 425–33.
- 49 Maxwell LG, Kaufmann SC, Bitzer S, et al. The effects of a small-dose naloxone infusion on opioid-induced side effects and analgesia in children and adolescents treated with intravenous patient-controlled analgesia: A double-blind, prospective, randomized, controlled study. Anesth Analg 2005; 100: 953–8.
- 50 Hardy J, Daly S, McQuade B, et al. A double-blind, randomised, parallel group, multinational, multicentre study comparing a single dose of ondansetron 24 mg p.o. with placebo and metoclopramide 10 mg t.d.s. p.o. in the treatment of opioid-induced nausea and emesis in cancer patients. Support Care Cancer 2002; 10: 231–6.
- 51 Okamoto Y, Tsuneto S, Matsuda Y, et al. A retrospective chart review of the antiemetic effectiveness of risperidone in refractory opioid-induced nausea and vomiting in advanced cancer patients. J Pain Symptom Manage 2007; 34: 217–22.
- 52 Stannard C, Johnson M. Chronic pain management—can we do better? An interview-based survey in primary care. Curr Med Res Opin 2003; 19: 703–6.
- 53
Dunlop GM.
A study of the relative frequency and importance of gastrointestinal symptoms and weakness in patients with far advanced cancer.
Palliative Med
1989; 4: 37–43.
10.1177/026921639000400108 Google Scholar
- 54 Aparasu R, McCoy RA, Weber C, Mair D, Parasuraman TV. Opioid-induced emesis among hospitalized nonsurgical patients: Effect on pain and quality of life. J Pain Symptom Manage 1999; 18: 280–8.
- 55
Sabatowski R,
Tark M,
Frank L, et al.
Effect of Alvimopan on health-related quality of life (HRQOL) in subjects with opioid-induced gastrointestinal (GI) side effects: The PAC-QOL Questionnaire.
Eur J Pain
2006; 10: S181–2.
10.1016/S1090-3801(06)60699-X Google Scholar
- 56 Neighbors DM, Bell TJ, Wilson J, Dodd SL. Economic evaluation of the fentanyl transdermal system for the treatment of chronic moderate to severe pain. J Pain Symptom Manage 2001; 21: 129–43.
- 57 Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic non-cancer pain: Systematic review of efficacy and safety. Pain 2004; 112: 372–80.
- 58 Anonymous. Chronic pain in America: Roadblocks to relief, a study conducted by Roper Starch Worldwide for American Academy of Pain Medicine, American Pain Society and Janssen Pharmaceutica, 1999. Available at: http://www.ampainsoc.org/links/roadblocks/ (accessed October 16, 2008).
- 59 Salzman RT, Roberts MS, Wild J, et al. Can a controlled-release oral dose form of oxycodone be used as readily as an immediate-release form for the purpose of titrating to stable pain control? J Pain Symptom Manage 1999; 18: 271–9.
- 60 Bloor K, Leese B, Maynard A. The costs of managing severe cancer pain and potential savings from transdermal administration. Eur J Cancer 1994; 30A: 463–8.
- 61 Frei A, Andersen S, Hole P, Jensen NH. A one year health economic model comparing transdermal fentanyl with sustained-release morphine in the treatment of chronic noncancer pain. J Pain Palliat Care Pharmacother 2003; 17: 5–26.
- 62 Greiner W, Lehmann K, Earnshaw S, Bug C, Sabatowski R. Economic evaluation of Durogesic in moderate to severe, nonmalignant, chronic pain in Germany. Eur J Health Econ 2006; 7: 290–6.
- 63
Lehmann K,
Radbruch L,
Gockel HH,
Neighbors D,
Nuyts G.
Costs of opioid therapy for chronic nonmalignant pain in Germany: An economic model comparing transdermal fentanyl (Durogesic) with controlled-release morphine.
Eur J Health Econ
2002; 3: 111–9.
10.1007/s10198-002-0097-6 Google Scholar
- 64 Davis MP, Walsh D, Lagman R, LeGrand SB. Controversies in pharmacotherapy of pain management. Lancet Oncol 2005; 6: 696–704.
- 65 Moss-Morris R, Humphrey K, Johnson MH, Petrie KJ. Patients' perceptions of their pain condition across a multidisciplinary pain management program: Do they change and if so does it matter? Clin J Pain 2007; 23: 558–64.
- 66 Allan L, Hays H, Jensen NH, et al. Randomised crossover trial of transdermal fentanyl and sustained release oral morphine for treating chronic non-cancer pain. BMJ 2001; 322: 1154–8.
- 67 Radbruch L, Sabatowski R, Loick G, et al. Constipation and the use of laxatives: A comparison between transdermal fentanyl and oral morphine. Palliat Med 2000; 14: 111–9.
- 68 Ahmedzai S, Brooks D. Transdermal fentanyl versus sustained-release oral morphine in cancer pain: Preference, efficacy, and quality of life. The TTS-Fentanyl Comparative Trial Group. J Pain Symptom Manage 1997; 13: 254–61.
- 69 Donner B, Zenz M, Tryba M, Strumpf M. Direct conversion from oral morphine to transdermal fentanyl: A multicenter study in patients with cancer pain. Pain 1996; 64: 527–34.
- 70 Muijsers RB, Wagstaff AJ. Transdermal fentanyl: An updated review of its pharmacological properties and therapeutic efficacy in chronic cancer pain control. Drugs 2001; 61: 2289–307.
- 71 Wong JO, Chiu GL, Tsao CJ, Chang CL. Comparison of oral controlled-release morphine with transdermal fentanyl in terminal cancer pain. Acta Anaesthesiol Sin 1997; 35: 25–32.
- 72 Noble M, Tregear SJ, Treadwell JR, Schoelles K. Long-term opioid therapy for chronic noncancer pain: A systematic review and meta-analysis of efficacy and safety. J Pain Symptom Manage 2008; 35: 214–28.
- 73 DeHaven-Hudkins DL, DeHaven RN, Little PJ, Techner LM. The involvement of the mu-opioid receptor in gastrointestinal pathophysiology: Therapeutic opportunities for antagonism at this receptor. Pharmacol Ther 2008; 117: 162–87.
- 74 Webster L, Jansen JP, Peppin J, et al. Alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist for the treatment of opioid-induced bowel dysfunction: Results from a randomized, double-blind, placebo-controlled, dose-finding study in subjects taking opioids for chronic non-cancer pain. Pain 2008; 137(2): 428–40.
- 75 Becker G, Galandi D, Blum HE. Peripherally acting opioid antagonists in the treatment of opiate-related constipation: A systematic review. J Pain Symptom Manage 2007; 34: 547–65.
- 76
Müller-Lissner S,
Leyendecker P,
Hopp M, et al.
Oral prolonged release (PR) oxycodone/naloxone combination reduces opioid-induced bowel dysfunction (OIBD) in patients with severe chronic pain.
Eur J Pain
2007; 11(Suppl 1): 82.
10.1016/j.ejpain.2007.03.204 Google Scholar
- 77 Webster LR, Butera PG, Moran LV, et al. Oxytrex minimizes physical dependence while providing effective analgesia: A randomized controlled trial in low back pain. J Pain 2006; 7: 937–46.
- 78 Mundipharma International Limited. New phase III data demonstrate oxycodone/naloxone combination tablet reduces opioid-induced bowel dysfunction in patients with severe chronic pain; 2007. Available at: http://www.mundipharma.co.uk (accessed April 9, 2008).
- 79 Liu M, Wittbrodt E. Low-dose oral naloxone reverses opioid-induced constipation and analgesia. J Pain Symptom Manage 2002; 23: 48–53.
- 80 King GL. Animal models in the study of vomiting. Can J Physiol Pharmacol 1990; 68: 260–8.
- 81 Tzschentke TM, Christoph T, Kogel B, et al. (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): A novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther 2007; 323: 265–76.
