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A review of rapid-onset opioids for breakthrough pain in patients with cancer

Steven M. Simon, RPh, MD, Lee S. Schwartzberg, MD, FACP


Pain management in patients with cancer remains suboptimal. Breakthrough pain (BTP) is characterized by abrupt onset of severe pain in a background of otherwise stable managed pain and presents a substantial burden to patients, as it disrupts activities and quality of life. Rapid-onset opioids (ROOs), with an appropriate onset and duration of effect, provide new options for effective and well-tolerated management of BTP. All currently available ROOs are various formulations of transmucosal immediate-release fentanyl (TIRF) and, although they were originally developed and approved for use in children before painful procedures, are only approved for use in opioid-tolerant adult patients with cancer and BTP. The formulation options include oral lozenge, buccal tablet, buccal film, sublingual tablet, nasal spray, and a sublingual spray; each has practical considerations that vary with the product and route of administration. All have the common advantage of rapid entry into the systemic circulation via transmucosal absorption, avoiding hepatic and intestinal first-pass metabolism and allowing a rapid onset of action that rivals intravenous injections. Rapid onset and short duration of action allow good patient control of analgesia. The pharmacokinetic and analgesic properties of ROOs may allow reduction of the total opioid burden and associated adverse effects, while still providing effective pain relief. The shared TIRF risk evaluation and mitigation strategy program implemented in March 2012 has simplified enrollment and administration of these products to help mitigate the risks of abuse and misuse and to help ensure safe use in patients with cancer suffering from BTP.


fentanyl, rapid onset, immediate release, transmucosal, breakthrough pain

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Deandrea S, Montanari M, Moja L, et al.: Prevalence of undertreatment in cancer pain. A review of published literature. Ann Oncol. 2008; 19 (12): 1985 - 1991.

Breivik H, Cherny N, Collett B, et al.: Cancer-related pain: A pan-European survey of prevalence, treatment, and patient attitudes . Ann Oncol. 2009; 20 (8): 1420 - 1433.

Portenoy RK: Treatment of cancer pain. Lancet. 2011; 377 (9784): 2236 - 2247.

Breuer B, Fleishman SB, Cruciani RA, et al.: Medical oncologists' attitudes and practice in cancer pain management: A national survey. J Clin Oncol. 2011; 29 (36): 4769 - 4775.

Paice JA, Ferrell B: The management of cancer pain. CA Cancer J Clin. 2011; 61 (3): 157 - 182.

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

Goudas LC, Bloch R, Gialeli-Goudas M, et al.: The epidemiology of cancer pain. Cancer Invest. 2005; 23 (2): 182 - 190.

Davies A, Zeppetella G, Andersen S, et al.: Multi-centre European study of breakthrough cancer pain: Pain characteristics and patient perceptions of current and potential management strategies. Eur J Pain. 2011; 15 (7): 756 - 763.

Bennett D, Burton AW, Fishman S, et al.: Consensus panel recommendations for the assessment and management of breakthrough pain. Part 1: Assessment. P&T. 2005; 30 (5): 296 - 301.

Zeppetella G: Breakthrough pain in cancer patients. Clin Oncol (R Coll Radiol). 2011; 23 (6): 393 - 398.

National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology. Adult Cancer Pain. Version 2.2011. Available at Accessed October 28, 2011.

Mercadante S: Pharmacotherapy for breakthrough cancer pain. Drugs. 2012; 72 (2): 181 - 190.

Zeppetella G: Opioids for the management of breakthrough cancer pain in adults: A systematic review undertaken as part of an EPCRC opioid guidelines project. Palliat Med. 2011; 25 (5): 516 - 524.

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.

Hagen NA, Moulin DE, Brasher PM, et al.: A formal feasibility study of sublingual methadone for breakthrough cancer pain. Palliat Med. 2010; 24 (7): 696 - 706.

Dolophine® Hydrochloride (methadone hydrochloride tablets). Full Prescribing Information. Columbus, OH: Roxane Laboratories, Inc., 2006.

Narita M, Imai S, Itou Y, et al.: Possible involvement of mu1- opioid receptors in the fentanyl- or morphine-induced antinociception at supraspinal and spinal sites. Life Sci. 2002; 70 (20): 2341 - 2354.

Chwieduk CM, McKeage K: Fentanyl sublingual: In breakthrough pain in opioid-tolerant adults with cancer. Drugs. 2010; 70 (17): 2281 - 2288.

Stanley TH, Egan TD, Van Aken H: A tribute to Dr. Paul A. J. Janssen: Entrepreneur extraordinaire, innovative scientist, and significant contributor to anesthesiology. Anesth Analg. 2008; 106 (2): 451 - 462, table of contents.

The Pink Sheet: Anesta/Abbott Oralet Oral Transmucosal Fentanyl Approved Oct. 4. The Pink Sheet. 1993; 55 (41).

Food and Drug Administration Center for Drug Evaluation and Research: Application Number NDA 20-195/S-002. Rockville, MD. May 20, 1996.

Food and Drug Administration Center for Drug Evaluation and Research: Application Number NDA 20747. Rockville, MD. November 4, 1998.

Zeppetella G, Ribeiro MD: Opioids for the management of breakthrough (episodic) pain in cancer patients. Cochrane Database Syst Rev. 2006; (1): CD004311.

Onsolis® (fentanyl buccal soluble film). Full Prescribing Information. Somerset, NJ: Meda Pharmaceuticals, Inc., 2011.

Abstral® (fentanyl sublingual tablet). Full Prescribing Information. Bridgewater, NJ: ProStrakan Inc., 2012.

Actiq® (fentanyl citrate oral mucosal lozenge). Full Prescribing Information. Salt Lake City, UT: Cephalon Inc., 2011.

Fentora® (fentanyl buccal tablet). Full Prescribing Information. Salt Lake City, UT: Cephalon, Inc., 2011.

Lazanda® (fentanyl nasal spray CII). Full Prescribing Information. Bedminster, NJ: Archimedes Pharma US Inc., 2011.

Subsys® (fentanyl sublingual spray). Full Prescribing Information. Phoenix, AZ: INSYS Therapeutics, Inc., 2012.

Bredenberg S, Duberg M, Lennernas B, et al.: In vitro and in vivo evaluation of a new sublingual tablet system for rapid oromucosal absorption using fentanyl citrate as the active substance. Eur J Pharm Sci. 2003; 20 (3): 327 - 334.

US Food and Drug Administration: FDA approves shared system REMS for TIRF products. Available at Accessed January 18, 2012.

Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program. Available at Accessed April 20, 2012.

Darwish M, Hamed E, Messina J: Fentanyl buccal tablet for the treatment of breakthrough pain: Pharmacokinetics of buccal mucosa delivery and clinical efficacy. Perspect Medicin Chem. 2010; 4: 11 - 21.

Abstral(fentanyl sublingual tablets for breakthrough cancer pain). P&T. 2011; 36 (2): 2 - 28.

Uberall MA, Muller-Schwefe GH: Sublingual fentanyl orally disintegrating tablet in daily practice: Efficacy, safety and tolerability in patients with breakthrough cancer pain. Curr Med Res Opin. 2011; 27 (7): 1385 - 1394.

England R, Maddocks M, Manderson C, et al.: How practical are transmucosal fentanyl products for breakthrough cancer pain?. Novel use of placebo formulations to survey user opinion. BMJ Support Palliat Care. 2011; 1 (3): 349 - 351.

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.

Nalamachu S, Hassman D, Wallace MS, et al.: Long-term effectiveness and tolerability of sublingual fentanyl orally disintegrating tablet for the treatment of breakthrough cancer pain. Curr Med Res Opin. 2011; 27 (3): 519 - 530.



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