The Treatment of Breakthrough Pain

Transcription

1 Blackwell Publishing IncMalden, USAPMEPain Medicine American Academy of Pain Medicine? 20078S1813Original ArticleTreatment of Breakthrough PainMcCarberg PAIN MEDICINE Volume 8 Number S The Treatment of Breakthrough Pain Bill H. McCarberg, MD Kaiser Permanente, Escondido, California, USA ABSTRACT ABSTRACT Objective. To review strategies for treating patients with breakthrough pain (BTP). Design. This review is based on expert consensus recommendations for treating BTP and is supplemented by recent clinical studies and the author s clinical experience. Results. Breakthrough pain is severe or excruciating pain of rapid onset that can disable or even immobilize the patient. Patients with BTP should be assessed after baseline persistent pain has been stabilized with around-the-clock (ATC) analgesics. Clues about the cause and pattern of BTP may be identified from a patient history, preferably including a pain diary. Effective treatment can greatly improve the patient s quality of life and should be tailored for each patient, taking into consideration the cause and type of the BTP episodes. Short-acting opioid analgesics are the primary treatment. The absorption characteristics, onset of action, and duration of effect vary among the available opioid compounds based on their lipophilicity. The dose and/or dosing frequency of the ATC analgesic should be adjusted for patients with end-of-dose BTP. Short-acting oral opioids are useful when given preemptively in patients with predictable incident BTP, while rapid-onset transmucosal lipophilic opioids are most effective for patients with unpredictable incident or idiopathic BTP. Regardless of the subtype of BTP, nonpharmacologic strategies are often helpful in alleviating pain and anxiety and should be used to supplement pharmacologic intervention for BTP. Conclusion. Breakthrough pain can often be successfully treated by tailoring opioid therapy based on the subtype of BTP. These characteristics of BTP will determine the most appropriate opioid compound (i.e., hydrophilic vs lipophilic) and most effective mode of drug delivery. Key Words. Breakthrough Pain; Cancer-Related Pain; Chronic Pain; Immediate-Release Opioids; Transmucosal Fentanyl Introduction B reakthrough pain (BTP) refers to a transitory increase in pain to greater than moderate intensity, which occurs on a baseline pain of moderate intensity or less in a patient receiving chronic opioid therapy [1]. These pain flares typically Reprint requests to: Bill H. McCarberg, MD, Founder, Chronic Pain Management Program, Kaiser Permanente, 732 N Broadway, Escondido, CA 92025, USA. Tel: ; Fax: ; bill.h.mccarberg@ kp.org. This manuscript is based on the content of the CME symposium The Scope of Breakthrough Pain in Clinical Practice held on February 24, 2006, in San Diego, CA, at the Annual Meeting of the American Academy of Pain Medicine. occur in patients with persistent chronic pain due to cancer or various noncancer chronic conditions such as low back pain, arthritis, or diabetic neuropathy, but they may or may not be similar to that of the patient s chronic pain. Episodes of BTP typically reach peak severity within 3 5 minutes after onset and last approximately 30 minutes [2]. Most patients with BTP can be managed successfully in the community by their primary care physician. Initial evaluation and assessment of the patient are aimed at determining if there are identifiable and treatable causes for the baseline persistent pain or if the onset of pain episodes is in some way predictable. A detailed medical history is obtained, with attention to physical or other factors temporally associated with the onset of BTP. Often, a diary completed by the patient is a American Academy of Pain Medicine /07/$15.00/S8 S8 S13

2 Treatment of Breakthrough Pain useful tool [3]. Based on this information, BTP is then categorized as incident, idiopathic, or end-ofdose pain [2]. For those patients with particularly severe or frequent episodes of BTP, consultation with a pain specialist can be invaluable. In addition, treatment strategies for particularly difficult to manage BTP patients may include input from physical and occupational therapists, psychiatrists or psychologists, and anesthesiologists, as well as the primary care provider [4]. The best treatment approach is then determined based on feedback from these specialists and from the evaluation and conclusions of the pain specialist. Realistic goals are defined with a particular focus on outcomes that are meaningful to the patient. Nonpharmacologic Treatment of BTP For many patients, and especially those with predictable incident BTP, physical, behavioral, or psychological approaches to pain reduction or avoidance should be considered [5]. Physical therapy techniques such as warming up and stretching, or correcting poor posture or poor lifting techniques can help avoid or minimize BTP associated with failed back syndrome and some types of metastatic bone cancer. Another effective strategy is educating patients to recognize their limitations and modify their behavior and activity level accordingly: for instance, recommending that a patient reduce the duration of his or her engagement in an activity known to eventually precipitate BTP. In some cases, a necessary activity can be better tolerated when it is undertaken in short segments rather than all at once, such as cleaning one room each day rather than the whole house at once, or shopping for 1 hour at a time instead of spending the entire day. While at work, backrelated BTP often can be minimized (for those with sedentary jobs) by routinely standing and walking several times a day [6,7]. Physicians should provide patients with realistic expectations about their activity level. One approach is to bracket the patients expectations by identifying the high end as well as the low end of what can be expected. The ability to return to full-time work as a roofer or to carry heavy objects or to run a marathon may not be realistic, and the patient is best counseled to look for alternative and less physically demanding employment or recreational activities. Likewise, complete pain relief is usually not a realistic expectation, but the ability to shave or get out of bed without crippling BTP may be a more appropriate goal, one that may still significantly improve the patient s quality of life. Patient counseling may be helpful for reducing anxiety and avoiding defeatist thinking. Physicians need to recognize that pain treatment strategies will not be successful unless they account for underlying psychosocial issues [8]. Pharmacologic Therapy In order to effectively manage patients BTP, it is important to clearly understand the nature of the pain in terms of its predictability, duration, and relationship to dosing of long-acting around-theclock (ATC) medications. For this reason, several subtypes of BTP have been defined (Figure 1) [2]. End-of-dose BTP is defined as BTP episodes that occur soon before the next scheduled dose of an ATC analgesic; these episodes typically have a more gradual onset and longer duration than other BTP subtypes [9]. Management of end-ofdose BTP typically consists of carefully tailoring the ATC analgesia regimen by increasing the dose and/or shortening the dosing interval to better control the patient s baseline persistent pain. Adjustments of the type and dose of baseline pain medication can minimize the number and severity of BTP episodes, though an increase in the total daily dose of medication increases the risk of developing adverse events such as sleepiness or fatigue [10]. Incident BTP is caused by activity or movement, and in most cases is predictable. Management usually consists of preemptive use of a short-acting opioid given 30 minutes before the scheduled activity. Oral dosing is the most common route of administration for short-acting opioids in the United States, although rectal formulations have been successfully used in Italy [11]. Several oral short-acting opioid formulations are available, mostly in combination with acetaminophen, including hydrocodone, codeine, morphine, oxycodone, and hydromorphone. Despite their short-acting characteristics, these agents must still be absorbed from the gastrointestinal tract, and consequently their onset of action is about 30 minutes [10]. Because of the delayed onset of analgesia, and a duration of effect of approximately 4 hours, the oral short-acting opioids are most effective for predictable incident BTP, for which they can be given minutes before a known triggering activity. In some cases, incident BTP may occur unpredictably as a consequence of visceral activity, in which case preemptive treatment is not possible. Another BTP subtype, idiopathic BTP, also is not S9

3 S10 McCarberg Figure 1 Management of breakthrough pain subtypes. ATC = aroundthe-clock; IR = immediate-release. associated with any known causes and occurs unpredictably. Safely and effectively treating patients with either idiopathic BTP or unpredictable incident BTP is a challenge for the pain specialist. Peak intensity of these subtypes of BTP typically occurs within 3 5 minutes following pain onset, and the episode generally lasts for about 30 minutes [10]. As shown in Figure 2, a mismatch between BTP and pain relief occurs when an analgesic with a delayed onset is used. In the case illustrated in this schematic, persistent baseline pain is adequately controlled by ATC medication. With the first episode of BTP, the patient is prescribed an oral short-acting agent, such as hydrocodone/acetaminophen, which has a 30-minute onset and a duration of 3 4 hours. Because this agent s onset and duration of action do not match the profile of the BTP, the analgesia provided by Figure 2 Schematic showing mismatch between patient s pain profile and the current medication used to treat BTP. The peaks represent BTP that is not controlled by the current medication. This profile is expected for an analgesic with a 30-minute onset of action, which is taken at the start of one episode of BTP and then again at the start of the next episode. Figure courtesy of Cephalon, Inc. Frazer, PA. BTP = breakthrough pain. the hydrocodone compound occurs after the BTP has spontaneously subsided. If several episodes of BTP occur over a 24-hour period, the patient may require multiple doses of the hydrocodone/ acetaminophen compound, with the undesirable result that the peak intensity of BTP is never effectively treated, but toxicity of the drug (i.e., sleepiness, fatigue) becomes problematic. Clearly, an analgesic medication with a more rapid onset and a shorter duration of effect would be more appropriate for unpredictable episodes of BTP, because its analgesic activity would better coincide with the time profile of the BTP (Figure 3). Lipophilic fentanyl derivatives have been shown to be rapidly absorbed across mucosal membranes, therefore providing a rapid onset and shorter duration of effect that may be better matched to episodes of unpredictable BTP (Figure 4). Oral transmucosal fentanyl citrate (OTFC) is currently the only fentanyl formulation approved by the Food and Drug Administration for use in cancer-related BTP. A comprehensive search of all major medical databases, performed as part of a Cochrane collaboration, found only four clinical studies of the treatment of cancerrelated BTP that compared a study analgesic with placebo and included outcome measures [12]. All four reports were of OTFC, and all four found that OTFC was effective for the treatment of BTP. In one clinical trial, the median time to maximum plasma concentration of the drug was minutes, though patients reported significant improvement in their pain (compared with immediately before dosing) within 15 minutes after taking the medication [13]. Presumably because of these characteristics, OTFC was shown to be more effective than short-acting morphine sulfate

4 Treatment of Breakthrough Pain Figure 3 Schematic showing the match between patient s pain profile and an ideal agent for BTP, which has a rapid onset and short duration of effect. When taken at the start of each episode, the ideal agent covers the peak intensity of BTP. Figure courtesy of Cephalon, Inc. Frazer, PA. BTP = breakthrough pain. in treating cancer-related BTP in a multicenter, double-blind, randomized, crossover study of 134 ambulatory patients with cancer [14]. Before entering the study, the patients were experiencing one to four episodes of BTP per day while being managed with a fixed opioid schedule. OTFC produced significantly greater reductions in pain intensity (P 0.033) and significantly better pain relief (P 0.009) than short-acting morphine sulfate when assessed 15, 30, 45, and 60 minutes after administration. Other studies have found that OTFC is also more effective than conventional analgesics for treating neuropathic and nociceptive BTP [15] and for treating BTP associated with sickle-cell disease [16]. Investigational fentanyl formulations are in clinical development for the treatment of BTP and may soon be available for patients in the United States: a fentanyl sublingual tablet has been shown to dissolve rapidly and produce plasma drug levels that are detectable within 8 11 minutes [17]. In addition, a fentanyl buccal tablet (FBT) has been developed, which when administered by placement between the gum and cheek appears to be S11 absorbed more quickly than other fentanyl formulations [18]. In healthy volunteers, FBT produced dose-proportional increases in plasma fentanyl concentrations over the dose range of µg [19]. FBT has also been evaluated in a clinical study involving opioid-treated adult cancer patients with one to four episodes of BTP per day [20]. In that study, an open-label titration phase was used to establish an effective dose of FBT, from 100 to 800 µg, for relieving the patient s BTP. The open-label study was followed by a doubleblind study in which the effective dose of the FBT had to provide relief of BTP within 30 minutes, without unacceptable adverse events, during two consecutive BTP episodes, for patients to be eligible. In the double-blind phase, patients were randomized to one of 18 predefined dose sequences of 10 tablets (seven FBT tablets at the effective dose, and three placebo tablets). All 10 doses were to be taken within a 21-day period, with a maximum of four episodes of BTP treated per day. Among the 72 patients available for efficacy analyses following the double-blind study, FBT significantly reduced pain intensity (P < 0.003) and provided effective relief of BTP (P < 0.001) as compared with placebo at each assessment time (15, 30, 45, and 60 minutes). In another open-label study, long-term treatment with FBT at doses of µg was safe and generally well tolerated in patients with cancer-related BTP [21]. Overall, 68% of patients in this study identified an effective dose of FBT during dose titration, and that dose remained the same in 84% of the patients for up to 1 year of treatment. Similarly, in an open-label study of 94 patients with noncancer-related BTP, most patients (91%) were able to find an effective dose during dose titration, and FBT treatment was safe and well tolerated [22]. Oral mucosal adverse events, including pain, irritation, ulceration, or vesicular lesions, were reported by four patients, and few patients discontinued FBT treatment because of adverse events. Figure 4 Characteristics of immediate-release opioids for BTP. BTP = breakthrough pain; T max = time to maximum plasma level. Data source: morphine [27]; oxycodone [28]; hydromorphone [29]; methadone [30]; fentanyl [31].

5 S12 Summary Effective management of BTP requires matching the treatment to each patient s pain profile, after baseline persistent pain has been stabilized. To achieve this goal, it is important to understand the cause and pattern of BTP by obtaining a detailed medical history, preferably including a patient diary. An effective regimen should be tailored to each individual by monitoring outcomes relevant to that patient and then adjusting treatment as appropriate. Short-acting opioid analgesics are the primary treatment modality for BTP [23], but nonpharmacologic strategies and other classes of analgesics may also be helpful, particularly when used in an adjunctive role [24]. Opioids differ in terms of their lipophilicity, which in turn impacts their absorption characteristics and onset of action [11,25]. Fentanyl, a lipophilic opioid that is rapidly absorbed through the oral mucosa, has a more rapid onset than orally administered short-acting opioid formulations, and consequently it may be better suited for treating unpredictable incident BTP and idiopathic BPT [26]. New fentanyl formulations in development may offer a faster onset of action than currently available opioids [19]. Acknowledgments Sponsored by Boston University School of Medicine Office of Continuing Medical Education. Supported by an educational grant from Cephalon, Inc. References 1 Portenoy RK, Hagen NA. Breakthrough pain: Definition, prevalence and characteristics. Pain 1990;41: Bennett D, Burton A, Fishman S, et al. Consensus panel recommendations for the assessment and management of breakthrough pain. Part 1 Assessment. Pharmacy & Therapeutics 2005;30: Abrahm JL. Assessing the patient in pain. In: Abrahm JL, ed. A Physician s Guide to Pain and Symptom Management in Cancer Patients, 2nd edition. Baltimore, MD: Johns Hopkins University Press; 2005: Gordon DB, Dahl JL, Miaskowski C, et al. American pain society recommendations for improving the quality of acute and cancer pain management: American Pain Society Quality of Care Task Force. Arch Intern Med 2005;165: Hanks GWC, Portenoy RK, MacDonald N, O Neill WM. Difficult pain problems. In: Doyle D, Hanks GWC, MacDonald N, eds. Oxford Textbook of Palliative Medicine, 2nd edition. New York: Oxford University Press; 1998: McCarberg 6 Malmivaara A, Hakkinen U, Aro T, et al. The treatment of acute low back pain Bed rest, exercises, or ordinary activity? N Engl J Med 1995;332: Waddell G, Feder G, Lewis M. Systematic reviews of bed rest and advice to stay active for acute low back pain. Br J Gen Pract 1997;47: Ohayon MM, Schatzberg AF. Using chronic pain to predict depressive morbidity in the general population. Arch Gen Psychiatry 2003;60: Rhiner M, Palos G, Termini M. Managing breakthrough pain: A clinical review with three case studies using oral transmucosal fentanyl citrate. Clin J Oncol Nurs 2004;8: Bennett D, Burton A, Fishman S, et al. Consensus panel recommendations for the assessment and management of breakthrough pain. Part 2 Management. Pharmacy & Therapeutics 2005;30: Ripamonti C, Bruera E. Rectal, buccal, and sublingual narcotics for the management of cancer pain. J Palliat Care 1991;7: Zeppetella G, Ribeiro MD. Opioids for the management of breakthrough (episodic) pain in cancer patients. Cochrane Database Syst Rev 2006 Jan 25;(1):CD Mystakidou K, Katsouda E, Parpa E, Tsiatas ML, Vlahos L. Oral transmucosal fentanyl citrate for the treatment of breakthrough pain in cancer patients: An overview of its pharmacological and clinical characteristics. Am J Hosp Palliat Care 2005; 22: 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: Farrar J, Thompson C. Oral Transmucosal Fentanyl Citrate: Efficacy in Neuropathic Pain Patients. Presented at: 24th Annual American Pain Society Scientific Meeting, Boston, MA, March 30 April 2, Shaiova L, Wallenstein D. Outpatient management of sickle cell pain with chronic opioid pharmacotherapy. J Natl Med Assoc 2004;96: Lennernäs 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: Durfee S, Messina J, Khankari R. Fentanyl effervescent buccal tablets. Am J Drug Deliv 2006;4: Darwish M, Tempero K, Kirby M, Thompson J. Relative bioavailability of the fentanyl effervescent buccal tablet (FEBT) 1,080 pg versus oral transmucosal fentanyl citrate 1,600 pg and dose proportionality of FEBT 270 to 1,300 microg: A single-dose, randomized, open-label, three-period study in healthy adult volunteers. Clin Ther 2006;28:

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