INTRODUCTION
The management of breakthrough pain usually involves the use of so-called rescue (“breakthrough”) medication, and invariably necessitates the use of a short-acting opioid formulation [1].

Traditionally, fixed doses of oral opioids have been used as rescue medication, i.e. the dose of rescue medication being proportional to the dose of the around the clock (“background”) medication.  However, the suggested proportion has varied from 5-50% [2-4]. The influential European Association for Palliative Care (EAPC) generic pain guidelines recommended that the dose of morphine given for breakthrough pain should be the same as the four hourly dose of morphine given for background pain (i.e. 17% of daily dose of morphine) [4].  

Nevertheless, other experts have recommended titration of rescue medication. For example, Portenoy and Hagen commented that “titration of the rescue dose should be viewed as a key principle in the management of breakthrough pain” [5]. Similarly, the EAPC breakthrough pain guidelines recommended that “titration of the rescue dose according to the characteristics of the event should be attempted in an individual way to identify the most appropriate dose” [6]. The following sections will discuss the evidence for / against titration of rescue medication.   

STUDIES SUPPORTING TITRATION OF OPIOID RESCUE MEDICATION
A number of novel transmucosal formulations have been developed for the management of breakthrough pain (i.e. oral transmucosal fentanyl preparations, intranasal fentanyl preparations). Most of the pivotal trials of these products have involved an initial dose titration phase, and most of the pivotal trials have reported no meaningful relationship between the “successful” dose of rescue medication and the dose of around the clock medication [7-14]. Moreover, data from one of the trials suggests that there may be no relationship between the most effective dose of oral morphine used for rescue medication and the dose of opioid used for around the clock medication [9]. As a result, it is recommended that these novel transmucosal formulations should be individually titrated to a dose that produces adequate analgesia and minimal adverse effects.
It should be noted that the titration schedules vary from one product to another, and so it is important that prescribers refer to the individual summary of product characteristics. Furthermore, patients that are switched to another transmucosal formulation require re-titration of the new transmucosal formulation (due to their differing pharmacological characteristics).

STUDIES SUPPORTING FIXED DOSAGE OF OPIOID RESCUE MEDICATION
Mercadante et al reported a comparative study of fixed doses of intravenous morphine and oral transmucosal fentanyl citrate in the management of breakthrough cancer pain [15]. The study involved 25 patients admitted to a pain and palliative care unit, and 53 “couples” (paired episodes) of breakthrough pain. The authors found that the use of these formulations in doses proportional to the daily dose of around the clock medication was safe, effective and generally well tolerated.

In contrast to similar studies (see above), one of the pivotal trials of a novel intranasal fentanyl formulation did report a weak correlation between the “successful” dose of rescue medication and the dose of around the clock medication [16]. Nevertheless, the manufacturers of the intranasal formulation recommend that the dose of this product should be titrated (rather than estimated).

Recently, Mercadante et al further reported on their experience of using fixed doses of various opioid formulations in the management of breakthrough cancer pain (most frequently intravenous morphine and oral transmucosal fentanyl citrate) [17]. The study involved 66 patients admitted to a pain and palliative care unit, and 624 individual episodes of breakthrough pain. The authors again found that the use of these different formulations in doses proportional to the daily dose of around the clock medication was safe, effective and generally well tolerated.

CONCLUSION
A Task Group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland after reviewing the literature recommended that “the dose of opioid rescue medication should be determined by individual titration” [1]. The Task Group also proposed a dose titration scheme where the dose of rescue medication is determined by reviewing both the efficacy and tolerability of the rescue medication (Figure 1).
Dose titration is undoubtedly more onerous than the use of a fixed dose of rescue medication, but dose titration should lead to improved outcomes as compared to the use of a fixed dose of rescue medication (i.e. improved efficacy, improved tolerability, improved adherence with rescue medication). It should be remembered that dose titration is the strategy used to determine the “correct dose” of the around the clock medication.

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Figure 1 – Dose titration scheme for opioid “rescue medication” [1].

References

[1]. Davies AN, Dickman A, Reid C, Stevens AM, Zeppetella G. The management of cancer-related breakthrough pain: recommendations of a task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland. European Journal of Pain 2009; 13: 331-8.

[2]. Glare PA, Walsh TD. Dose-ranging study of oxycodone for chronic pain in advanced cancer. Journal of Clinical Oncology 1993; 11: 973-8.

[3]. Librach SL, Squires BP. The Pain Manual. Principles and Issues in Cancer Pain Management, 2nd edition. Pegasus Health Care International: Montreal; 1997.

[4]. Hanks GW, de Conno F, Cherny N, Hanna M, Kalso E, McQuay HJ, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. British Journal of Cancer 2001; 84: 587-93.

[5]. Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain 1990; 41: 273-81.

[6]. Mercadante S, Radbruch L, Caraceni A, Cherny N, Kaasa S, Nauck F et al. Episodic (breakthrough) pain: consensus conference of an expert working group of the European Association for Palliative Care. Cancer 2002; 94: 832-9.

[7]. Christie JM, Simmonds M, Patt R, Coluzzi P, Busch MA, Nordbrock E et al. Dose-titration, multicenter study of oral transmucosal fentanyl citrate for the treatment of breakthrough pain in cancer patients using transdermal fentanyl for persistent pain. Journal of Clinical Oncology 1998; 16: 3238-45.

[8]. Farrar JT, Cleary J, Rauck R, Busch M, Nordbrock E. Oral transmucosal fentanyl citrate: randomized, double-blinded, placebo-controlled trial for treatment of breakthrough pain in cancer patients. Journal of National Cancer Institute 1998; 90: 611-6.

[9]. Coluzzi PH, Schwartzberg L, Conroy JD, Charapata S, Gay M, Busch MA et al. Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain 2001; 91: 123-30.

[10]. Portenoy RK, Payne R, Coluzzi P, Raschko JW, Lyss A, Busch MA 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.

[11]. Portenoy RK, Taylor D, Messina J, Tremmel L. A randomized, placebo-controlled study of fentanyl buccal tablet for breakthrough pain in opioid-treated patients with cancer. Clinical Journal of Pain 2006; 22: 805-11.

[12]. Slatkin NE, Xie F, Messina J, Segal TJ. Fentanyl buccal tablet for relief of breakthrough pain in opioid-tolerant patients with cancer-related chronic pain. Journal of Supportive Oncology 2007; 5: 327-34.

[13]. Kress HG, Orońska A, Kaczmarek Z, Kaasa S, Colberg T, Nolte T. Efficacy and tolerability of intranasal fentanyl spray 50 to 200 microg for breakthrough pain in patients with cancer: a phase III, multinational, randomized, double-blind, placebo-controlled, crossover trial with a 10-month, open-label extension treatment period. Clinical Therapeutics 2009; 31: 1177-91.

[14]. Rauck RL, Tark M, Reyes E, Hayes TG, Bartkowiak AJ, Hassman D et al. Efficacy and long-term tolerability of sublingual fentanyl orally disintegrating tablet in the treatment of breakthrough cancer pain. Current Medical Research and Opinion 2009; 25: 2877-85.

[15]. Mercadante S, Villari P, Ferrera P, Casuccio A, Mangione S, Intravaia G. Transmucosal fentanyl vs intravenous morphine in doses proportional to basal opioid regimen for episodic-breakthrough pain.  British Journal of Cancer 2007; 96: 1828-33.

[16]. Mercadante S, Radbruch L, Davies A, Poulain P, Sitte T, Perkins P et al. A comparison of intranasal fentanyl spray with oral transmucosal fentanyl citrate for the treatment of breakthrough cancer pain: an open-label, randomised, crossover trial. Current Medical Research and Opinion 2009; 25: 2805-15.

[17]. Mercadante S, Villari P, Ferrera P, Mangione S, Casuccio A. The use of opioids for breakthrough pain in acute palliative care unit by using doses proportional to opioid basal regimen. Clinical Journal of Pain 2010; 26: 306-9.

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