Opioid delivery in the treatment of cancer breakthrough pain: A review of routes of administration

Bruce Nicholson, MD; Sanjiv S. Agarwala, MD

doi:10.5055/jom.2011.0050

Authors

Bruce Nicholson, MD
Sanjiv S. Agarwala, MD

DOI:

https://doi.org/10.5055/jom.2011.0050

Keywords:

breakthrough pain, delivery systems, opioids

Abstract

Analgesics delivered via the oral route of administration (capsules, tablets, or solutions) are most commonly used to treat cancer breakthrough pain (BTP); however, the effectiveness of oral opioids may be limited by slow gastrointestinal absorption and first-pass metabolic effects. Although the limitations presented by oral opioid delivery are acknowledged and formulations and delivery systems that mirror the temporal characteristics of the majority of cancer BTP episodes are available, short-acting oral opioids are the accepted standard of care. The purpose of this review is to provide an overview of the different routes of opioid administration used in the treatment of cancer BTP and briefly discuss the characteristics of different delivery systems.

Author Biographies

Bruce Nicholson, MD

Director, Division of Pain Medicine, Pain Specialists of Greater Lehigh Valley and Clinical Associate Professor, Anesthesia Penn State School of Medicine, Allentown, Pennsylvania.

Sanjiv S. Agarwala, MD

Chief, Oncology and Hematology, St. Luke’s Cancer Center, Bethlehem, Pennsylvania.

References

Caraceni A, Martini C, Zecca E, et al.: Breakthrough pain characteristics and syndromes in patients with cancer pain. An international survey. Palliat Med. 2004; 18(3): 177-183.

Hwang SS, Chang VT, Kasimis B: Cancer breakthrough pain characteristics and responses to treatment at a VA medical center. Pain. 2003; 101(1-2): 55-64.

Portenoy RK, Payne D, Jacobsen P: Breakthrough pain: Characteristics and impact in patients with cancer pain. Pain. 1999; 81(1-2): 129-134.

Fishbain DA: Pharmacotherapeutic management of breakthrough pain in patients with chronic persistent pain. Am J Manag Care. 2008; 14(5, Suppl 1): S123-S128.

Portenoy RK, Hagen NA: Breakthrough pain: Definition, prevalence and characteristics. Pain. 1990; 41(3): 273-281.

Shoemaker S, Bruns D, Portenoy RK: Characteristics and impact of breakthrough pain (BTP) in noncancer and cancerrelated chronic pain managed by clinicians who are not pain specialists. Presented at the 25th Annual Meeting of the American Academy of Pain Medicine, Honolulu, HI, 2009.

Fortner BV, Okon TA, Portenoy RK: A survey of pain-related hospitalizations, emergency department visits, and physician office visits reported by cancer patients with and without history of breakthrough pain. J Pain. 2002; 3(1): 38-44.

Taylor DR, Webster LR, Chun SY, et al.: Impact of breakthrough pain on quality of life in patients with chronic, noncancer pain: Patient perceptions and effect of treatment with oral transmucosal fentanyl citrate (OTFC, ACTIQ). Pain Med. 2007; 8(3): 281-288.

Abernethy AP, Wheeler JL, Fortner BV: A health economic model of breakthrough pain. Am J Manag Care. 2008; 14(5, Suppl 1): S129-S140.

National Comprehensive Cancer Network (NCCN): National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology, Adult Cancer Pain. Available at http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed May 22, 2009.

McCarberg BH: The treatment of breakthrough pain. Pain Med. 2007; 8 (Suppl 1): S8-S13.

National Cancer Institute: Pain (PDQ®) Health Professional Version. Available at http://www.cancer.gov/cancertopics/pdq/supportivecare/pain/HealthProfessional. Accessed January 29, 2010.

Payne R: Recognition and diagnosis of breakthrough pain. Pain Med. 2007; 8 (Suppl 1): S3-S7.

Gallagher R, Hawley P, Yeomans W: A survey of cancer pain management knowledge and attitudes of British Columbian physicians. Pain Res Manag. 2004; 9(4): 188-194.

Davis MP, Walsh D: Epidemiology of cancer pain and factors influencing poor pain control. Am J Hosp Palliat Care. 2004; 21(2): 137-142.

Forbes K: Opioids: Beliefs and myths. J Pain Palliat Care Pharmacother. 2006; 20(3): 33-35.

Patt RB, Ellison NM: Breakthrough pain in cancer patients: Characteristics, prevalence, and treatment. Oncology (Williston Park). 1998; 12(7): 1035-1046; discussion 1049-1052.

Mercadante S, Radbruch L, Caraceni A, et al.: Episodic (breakthrough) pain: Consensus conference of an expert working group of the European Association for Palliative Care. Cancer. 2002; 94(3): 832-839.

Mercadante S, Villari P, Ferrera P, et al.: Safety and effectiveness of intravenous morphine for episodic (breakthrough) pain using a fixed ratio with the oral daily morphine dose. J Pain Symptom Manage. 2004; 27(4): 352-359.

Walker G, Wilcock A, Manderson C, et al.: The acceptability of different routes of administration of analgesia for breakthrough pain. Palliat Med. 2003; 17(2): 219-221.

Flogegard H, Ljungman G: Characteristics and adequacy of intravenous morphine infusions in children in a paediatric oncology setting. Med Pediatr Oncol. 2003; 40(4): 233-238.

Enting RH, Mucchiano C, Oldenmenger WH, et al.: The “pain pen” for breakthrough cancer pain: A promising treatment. J Pain Symptom Manage. 2005; 29(2): 213-217.

Shargel L, Yu ABC: Applied Biopharmaceutics and Pharmacokinetics. 3rd ed. Norwalk, CT: Appleton & Lange, 1993.

Davies A: Cancer-Related Breakthrough Pain. Oxford, New York: Oxford University Press, 2006.

Stuart-Harris R, Joel SP, McDonald P, et al.: The pharmacokinetics of morphine and morphine glucuronide metabolites after subcutaneous bolus injection and subcutaneous infusion of morphine. Br J Clin Pharmacol. 2000; 49(3): 207-214.

Zhang H, Zhang J, Streisand JB: Oral mucosal drug delivery: Clinical pharmacokinetics and therapeutic applications. Clin Pharmacokinet. 2002; 41(9): 661-680.

Senel S, Hincal AA: Drug permeation enhancement via buccal route: Possibilities and limitations. J Control Release. 2001; 72(1-3): 133-144.

Hussain AA: Intranasal drug delivery. Adv Drug Deliv Rev. 1998; 29(1-2): 39-49.

Coda BA, Rudy AC, Archer SM, et al.: Pharmacokinetics and bioavailability of single-dose intranasal hydromorphone hydrochloride in healthy volunteers. Anesth Analg. 2003; 97(1): 117-123 (Table of Contents).

Zeppetella G: An assessment of the safety, efficacy, and acceptability of intranasal fentanyl citrate in the management of cancer-related breakthrough pain: A pilot study. J Pain Symptom Manage. 2000; 20(4): 253-258.

Zeppetella G: Nebulized and intranasal fentanyl in the management of cancer-related breakthrough pain. Palliat Med. 2000; 14(1): 57-58.

Scheuch G, Kohlhaeufl MJ, Brand P, et al.: Clinical perspectives on pulmonary systemic and macromolecular delivery. Adv Drug Deliv Rev. 2006; 58(9-10): 996-1008.

Shoyele SA, Slowey A: Prospects of formulating proteins/peptides as aerosols for pulmonary drug delivery. Int J Pharm. 2006; 314(1): 1-8.

Farr SJ, Otulana BA: Pulmonary delivery of opioids as pain therapeutics. Adv Drug Deliv Rev. 2006; 58(9-10): 1076-1088.

Dolor RJ, Witsell DL, Hellkamp AS, et al.: Comparison of cefuroxime with or without intranasal fluticasone for the treatment of rhinosinusitis. The CAFFS Trial: A randomized controlled trial. JAMA. 2001; 286(24): 3097-3105.

Gosepath J, Ecke U, Kozlov VS, et al.: Yamik sinus catheter in the topical treatment of patients with acute rhinosinusitis after previous sinus surgery. Am J Rhinol. 2002; 16(6): 297-302.

Marks SC, Kissner DG: Management of sinusitis in adult cystic fibrosis. Am J Rhinol. 1997; 11(1): 11-14.

Stankiewicz JA, Musgrave BK, Scianna JM: Nasal amphotericin irrigation in chronic rhinosinusitis. Curr Opin Otolaryngol Head Neck Surg. 2008; 16(1): 44-46.

Wood CC, Fireman P, Grossman J, et al.: Product characteristics and pharmacokinetics of intranasal ipratropium bromide. J Allergy Clin Immunol. 1995; 95(5, Part 2): 1111-1116.

Enkhbaatar P, Herndon DN, Traber DL: Use of nebulized heparin in the treatment of smoke inhalation injury. J Burn Care Res. 2009; 30(1): 159-162.

Graff GR, Stark JM, Grueber R: Nebulized fentanyl for palliation of dyspnea in a cystic fibrosis patient. Respiration. 2004; 71(6): 646-649.

Miller WC, Awe R: Effect of nebulized lidocaine on reactive airways. Am Rev Respir Dis. 1975; 111(6): 739-741.

Spektor M, Kaplan J, Kelley J, et al.: Nebulized or sprayed lidocaine as anesthesia for nasogastric intubations. Acad Emerg Med. 2000; 7(4): 406-408.

Lam CF, van Heerden PV, Sviri S, et al.: The effects of inhalation of a novel nitric oxide donor, DETA/NO, in a patient with severe hypoxaemia due to acute respiratory distress syndrome. Anaesth Intensive Care. 2002; 30(4): 472-476.

Reutershan J, Schmitt A, Dietz K, et al.: Non-invasive measurement of pulmonary blood flow during prone positioning in patients with early acute respiratory distress syndrome. Clin Sci (Lond). 2004; 106(1): 3-10.

Sheridan RL, Zapol WM, Ritz RH, et al.: Low-dose inhaled nitric oxide in acutely burned children with profound respiratory failure. Surgery. 1999; 126(5): 856-862.

Welling PG: Pharmacokinetics: Processes, Mathematics, and Applications. 2nd ed. Washington, DC: American Chemical Society, 1997.

World Health Organization: Cancer Pain Relief. 2nd ed. Geneva: World Health Organization, 1996.

Deschamps M, Band PR, Hislop TG, et al.: The evaluation of analgesic effects in cancer patients as exemplified by a doubleblind, crossover study of immediate-release versus controlledrelease morphine. J Pain Symptom Manage. 1992; 7(7): 384-392.

Finn JW, Walsh TD, MacDonald N, et al.: Placebo-blinded study of morphine sulfate sustained-release tablets and immediate-release morphine sulfate solution in outpatients with chronic pain due to advanced cancer. J Clin Oncol. 1993; 11(5): 967-972.

Citron ML, Kaplan R, Parris WC, et al.: Long-term administration of controlled-release oxycodone tablets for the treatment of cancer pain. Cancer Invest. 1998; 16(8): 562-571.

Palangio M, Northfelt DW, Portenoy RK, et al.: Dose conversion and titration with a novel, once-daily, OROS osmotic technology, extended-release hydromorphone formulation in the treatment of chronic malignant or nonmalignant pain. J Pain Symptom Manage. 2002; 23(5): 355-368.

Wolff K: Characterization of methadone overdose: Clinical considerations and the scientific evidence. Ther Drug Monit. 2002; 24(4): 457-470.

Frolich MA, Giannotti A, Modell JH: Opioid overdose in a patient using a fentanyl patch during treatment with a warming blanket. Anesth Analg. 2001; 93(3): 647-648.

Dale O, Sheffels P, Kharasch ED: Bioavailabilities of rectal and oral methadone in healthy subjects. Br J Clin Pharmacol. 2004; 58(2): 156-162.

De Conno F, Ripamonti C, Saita L, et al.: Role of rectal route in treating cancer pain: A randomized crossover clinical trial of oral versus rectal morphine administration in opioid-naive cancer patients with pain. J Clin Oncol. 1995; 13(4): 1004-1008.

Wilkinson TJ, Robinson BA, Begg EJ, et al.: Pharmacokinetics and efficacy of rectal versus oral sustained-release morphine in cancer patients. Cancer Chemother Pharmacol. 1992; 31(3): 251-254.

Mercadante S, Villari P, Ferrera P, et al.: Safety and effectiveness of intravenous morphine for episodic breakthrough pain in patients receiving transdermal buprenorphine. J Pain Symptom Manage. 2006; 32(2): 175-179.

Mercadante S, Villari P, Ferrera P, et al.: Transmucosal fentanyl vs intravenous morphine in doses proportional to basal opioid regimen for episodic-breakthrough pain. Br J Cancer. 2007; 96(12): 1828-1833.

Moulin DE, Kreeft JH, Murray-Parsons N, et al.: Comparison of continuous subcutaneous and intravenous hydromorphone infusions for management of cancer pain. Lancet. 1991; 337(8739): 465-468.

Burton AW, Driver LC, Mendoza TR, et al.: Oral transmucosal fentanyl citrate in the outpatient management of severe cancer pain crises: A retrospective case series. Clin J Pain. 2004; 20(3): 195-197.

Watanabe S, Pereira J, Tarumi Y, et al.: A randomized double-blind crossover comparison of continuous and intermittent subcutaneous administration of opioid for cancer pain. J Palliat Med. 2008; 11(4): 570-574.

Weinberg DS, Inturrisi CE, Reidenberg B, et al.: Sublingual absorption of selected opioid analgesics. Clin Pharmacol Ther. 1988; 44(3): 335-342.

Kunz KM, Theisen JA, Schroeder ME: Severe episodic pain: Management with sublingual sufentanil. J Pain Symptom Manage. 1993; 8(4): 189-190.

Mercadante S, Arcuri E, Ferrera P, et al.: Alternative treatments of breakthrough pain in patients receiving spinal analgesics for cancer pain. J Pain Symptom Manage. 2005; 30(5): 485-491.

Lennernas B, Hedner T, Holmberg M, et al.: Pharmacokinetics and tolerability of different doses of fentanyl following sublingual administration of a rapidly dissolving tablet to cancer patients: A new approach to treatment of incident pain. Br J Clin Pharmacol. 2005; 59(2): 249-253.

Hagen NA, Fisher K, Stiles C: Sublingual methadone for the management of cancer-related breakthrough pain: A pilot study. J Palliat Med. 2007; 10(2): 331-337.

Coluzzi PH, Schwartzberg L, Conroy JD, et al.: Breakthrough cancer pain: A randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain. 2001; 91(1-2): 123-130.

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(2-3): 303-312.

Farrar JT, Cleary 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): 611-616.

Slatkin NE, Xie F, Messina J, et al.: Fentanyl buccal tablet for relief of breakthrough pain in opioid-tolerant patients with cancer-related chronic pain. J Support Oncol. 2007; 5(7): 327-334.

Portenoy RK, Taylor D, Messina J, et al.: A randomized, placebo-controlled study of fentanyl buccal tablet for breakthrough pain in opioid-treated patients with cancer. Clin J Pain. 2006; 22(9): 805-811.

Rauck R, North J, Gever LN, et al.: Fentanyl buccal soluble film (FBSF) for breakthrough pain in patients with cancer: A randomized, double-blind, placebo-controlled study. Ann Oncol. 2010; 21(6): 1308-1314.

Streisand JB, Varvel JR, Stanski DR, et al.: Absorption and bioavailability of oral transmucosal fentanyl citrate. Anesthesiology. 1991; 75(2): 223-229.

Vasisht N, Gever LN, Tagarro I, et al.: Evaluation of the single-and multiple-dose pharmacokinetics of fentanyl buccal soluble film in normal healthy volunteers. J Clin Pharmacol. 2010; 50(7): 785-791.

Darwish M, Kirby M, Robertson P, et al.: Absorption of fentanyl from fentanyl buccal tablet in cancer patients with or without oral mucositis: A pilot study. Clin Drug Investig. 2007; 27(9): 605-611.

Vasisht N, Gever L, Tagarro I, et al.: Single-dose pharmacokinetics of fentanyl buccal soluble film. Pain Med. 2010; 11(7): 1017-1023.

Meda Inc.: Onsolis (Fentanyl Buccal Soluble Film). Prescribing Information. Dulles, VA: Meda Inc. 2009.

Dale O, Hjortkjaer R, Kharasch ED: Nasal administration of opioids for pain management in adults. Acta Anaesthesiol Scand. 2002; 46(7): 759-770.

Zeppetella G, O’Doherty CA, Collins S: Prevalence and characteristics of breakthrough pain in cancer patients admitted to a hospice. J Pain Symptom Manage. 2000; 20(2): 87-92.

Lang E, Jedeikin R: Acute respiratory depression as a complication of nebulised morphine. Can J Anaesth. 1998; 45(1): 60-62.

Masood AR, Thomas SH: Systemic absorption of nebulized morphine compared with oral morphine in healthy subjects. Br J Clin Pharmacol. 1996; 41(3): 250-252.