Exploring Approaches for Breakthrough Cancer Pain

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Exploring Approaches for Breakthrough Cancer Pain ll

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YVONNE D’ARCY, MS, CRNP, CNS

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Nurse Practitioner Pain Management & Palliative Care Suburban Hospital-Johns Hopkins Medicine Bethesda, Maryland

Ms. Darcy reported that she is on the speakers’ bureau for Pfizer and is a consultant for Pfizer, Archimedes, Zogenix, and Oridion.

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reakthrough cancer pain (BTCP) often

remains unidentified

until the problem becomes so severe that it limits patients’ activities. Patients may report severe pain coming on unexpectedly with no identified stimulus. Patients may identify this pain, also known as incident pain, when certain

activities are performed, such as changing positions, standing, or bathing.

When pain occurs in direct relations to an identified pain stimulus, such as an activity, it may cause the patient to avoid those activities to prevent the pain.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

spontaneous exacerbation of a stable level of pain for nonspecific reasons.”2 The definition from the American Pain Society (APS) Cancer Pain Guidelines also includes end-of-dose failure and pain flares.3 BTP is common in cancer patients, who frequently have a background level of pain that is controlled by medications but periodically breaks through. Most experts agree that BTCP has a sudden onset and high intensity levels, and that it occurs when pain has an established level with stable medication use. The fact that the current definition includes end-of-dose failure is controversial. Some argue that end-of-dose failure signals a need for dose titration of the baseline medication. The 2010 TIME report indicated that aroundthe-clock (ATC) use of immediate-release (IR) morphine resulted in fewer intense episodic pain breakouts in patients with cancer- or non–cancer-related pain and that pain could be managed with rescue doses

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The definition of breakthrough pain (BTP) has changed over time. Originally, it was defined as sudden exacerbations of pain, and the medications designed to treat it were termed rescue doses.1 Patients were prescribed a baseline regimen for relieving pain and then given a certain number of rescue doses to use if pain levels increased. The current definition of BTP, as described by Turk and Okifuji, is more comprehensive and includes endof-dose failure as an important element. BTP is defined as “a transient increase in pain to greater than moderate intensity superimposed on an otherwise stable pattern or level of pain of mild-to-moderate intensity. By definition, breakthrough pain includes: 1) incident pain that may arise from activity or physical function (eg, coughing or standing up); 2) pain that routinely increases as the duration of analgesic medication is reaching its limit (end-of-dose failure); and 3)

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of IR morphine.4 The broader definition also highlights the idea that BTPis greater than the normal intensity level of a stable presentation of pain that can be controlled with baseline medications (Table 1).5

Impact of Breakthrough Pain

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From the patient’s perspective, BTP is particularly distressing because the pain occurs spontaneously, has a high intensity, and makes the individual feel out of control. This effect can be magnified when medications used to treat the condition are not effective in time to offset the pain, or the adverse effects associated with the medication last beyond the pain. For most patients, quality of life is adversely affected by uncontrolled BTP. Once the patient identifies a trigger for BTP—either an activity or a sensation that leads to an increase in pain—the patient often may become fearful of each potential new event. Patients with BTCP experience 4 episodes per day, on average.6 The pain has an acute onset that reaches maximum intensity within 5 minutes and gradually decreases over a period of 30 minutes.6 The severity of the pain and uncertainty about pain control can be destructive to the patient, as well as to those around the patient. BTP can be frightening, leading to upsetting thoughts about the progression of the disease in many patients. Because BTP is difficult to treat, the patient may imagine the increasing severity of future episodes. This may lead the patient to become apprehensive and depressed at the prospect of dealing with pain that is so difficult to control. Caregivers, family members, and health care professionals also can be adversely affected by continued BTP episodes. Family members may feel helpless and concerned about how to help control their loved one’s pain. Health care providers may feel defeated when the usual medications they use for pain do not provide adequate pain relief. Mental well-being, health-related quality of life (HRQoL), and psychological distress also are adversely affected by BTCP. Patients with cancer and BTP

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have more functional impairment, higher anxiety, and depressed mood compared with patients with cancer who do not have BTP.7 Disparities in patient populations based on race and gender also have been identified. In a study of 96 patients with cancer who were experiencing BTP episodes, all exhibited higher levels of depression compared with cancer patients who did not have BTCP; this conclusion supports the current literature on the psychological effects of BTP.7 Minorities in the study reported significantly greater severity of baseline pain (P=0.04) and BTP at its most (P=0.009) or least (P≤0.001) severe. Minorities also consistently reported poorer outcomes on HRQoL, which included physical, role, emotional, cognitive, and social functioning. Thus, although BTP is a problem for all patients who experience it, the pain can have more adverse effects on overall well-being in some patient populations. Overall, there are several ways to help control some types of BTP. Some of these methods are listed in Table 2.6

Table 1. Prevalence of BTP and BTCP Incident pain occurrence ranges from 32% to 94% of patients with cancer

Pharmacotherapy

For the patient with BTCP, it is important that medications have a rapid onset and offset. Opioids of all types are commonly used to treat BTCP. The usual dose is 10% to 20% of the total daily dose of opioids.7 Research shows, however, that the actual doses needed to control BTCP have a much larger range, varying from 1% to 71% of the total daily dose. Moreover, the recommended doses of opioids were sufficient for pain relief in only one-third of cases.8 One of the problems BTP patients face is the use of short-acting combination medications and/or IR opioids, the effects of which can last well beyond the current episode of pain and can have a time to onset of 30 minutes.8 Some practitioners, hoping to decrease the time to onset, use faster-acting compounds. One example is an effervescent morphine compound, which provides faster pain relief than IR morphine.9 However, most oral analgesics with onset times that range from 30 to 60 minutes will not provide analgesia when

Table 2. Methods for Controlling BTCP Lifestyle changes, such as use of assistive devices or exercises that limit joint movement

Palliative chemotherapy, radiation therapy, or surgery

Overall prevalence rates for all types of BTP are reported to be about 65% BTCP, breakthrough cancer pain; BTP, breakthrough pain Based on reference 5.

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Spontaneous pain occurrence ranges from 28% to 45% of patients with cancer

Nonpharmacologic therapies for adjunct pain relief, such as relaxation or distraction Use of medications, such as ATC opioid therapy or rapid-onset opioids ATC, around the clock Based on reference 6.

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needed and will last well beyond the episode of BTP. For BTP that results from incident pain, oral opioids are most useful when BTP can be anticipated, such as when a patient knows he or she is going to physical therapy at a specified time. The IV route can be used for opioid administration in acute settings but it is not feasible for the average patient to use at home. The end effects of extended opioid action also can be problematic for the patient, potentially resulting in unwanted sedation after the BTCP episode subsides. The most commonly used opioid for BTP is fentanyl, a lipophilic medication with a rapid onset of between 10 and 15 minutes.9 It is available in a number of formulations, such as oralets for buccal absorption, fentanyl buccal tablets or film, intranasal spray, and sublingual compounds. Because of the rapid onset of fentanyl, fentanyl-based medications are recommended only for opioid-tolerant patients receiving daily doses of least 60 mg oral morphine for at least 2 weeks. This standard qualifies the patients to be considered opioid-tolerant.

Table 3. Management of Cancer Pain With Opioids Begin a bowel regimen to prevent constipation when the patient is started on an opioid analgesic. Evidence strength: B Administer a long-acting opioid on an around-theclock basis, along with an immediate-release opioid to be used on an as-needed basis, for BTP once the patient’s pain intensity and dose are stabilized. Evidence strength: A

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Adjust opioid doses for each patient to achieve pain relief with an acceptable level of side effects. Evidence strength: A Use optimally titrated doses of opioids and maximal safe and tolerable doses of coanalgesics through other routes of administration before considering spinal analgesics. Empirical evidence only: Panel consensus Monitor for and prophylactically treat opioid-induced side effects. Evidence strength: B

Types of Rapid-Onset Opioids

Titrate naloxone, in the rare instance when it is indicated for the reversal of opioid-induced respiratory depression, by giving incremental doses that improve respiratory function but do not reverse analgesia. Evidence strength: B

A, strongest evidence; B, less evidence but possibly effective Based on reference 3.

delivery method easy to use and preferable to some of the other forms of medication delivery. The nasal option for fentanyl uses a pectin-based spray delivery system. This allows the fentanyl droplets to adhere to the nasal membranes and decreases the potential for any swallowing of medication, which can be seen with buccal administration routes. When delivered nasally, fentanyl is absorbed rapidly (starting within 10-15 minutes) and is more effective than oral transmucosal fentanyl citrate.9,11 Effective doses for patients ranged from 50 to 200 mcg.9 This formulation of fentanyl shows a significantly faster onset of meaningful pain relief, and there is a higher patient preference for this route of administration. Sublingual fentanyl (Abstral, ProStrakan). Sublingual fentanyl is a viable option for BTP. A study comparing doses of sublingual fentanyl (100, 200, and 400 mcg) with placebo showed good pain relief with the 400mcg dose but only slight pain decreases with the lower doses.9 The oral cavity is well suited to absorbing medication placed sublingually. Fentanyl buccal soluble film (Onsolis, Meda). This drug has 2 layers of water-soluble film, one with fentanyl that adheres to the buccal mucosa.12 The second layer of film isolates the fentanyl and limits the

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Oral transmucosal fentanyl citrate (Actiq, Cephalon). Commonly called the fentanyl oralet, oral transmucosal fentanyl citrate is a lozenge containing fentanyl that is rubbed along the buccal mucosa until it dissolves. It is available in a variety of strengths—200, 400, 600, 800, 1,200, and 1,600 mcg. The buccal tissue is vascular and allows for rapid absorption within approximately 15 minutes. For BTCP, studies show that fentanyl oralets reduce pain levels more and provide better pain relief than oral IR opioids.8,9 Effective doses for BTCP range from 200 to 1,600 mcg when patients are on baseline opioid therapy for cancer pain. The actual percentage of fentanyl absorbed by the mouth is about 25% of the dose.9 Fentanyl buccal tablets (Fentora, Cephalon). Fentanyl buccal tablets are an effervescent formulation that can alter the pH in the oral cavity, increasing the rate and extent of absorption.9 Adequate saliva is required for the tablet to dissolve. The fentanyl buccal tablet is placed along the upper gum and cheek; the patient then rubs the outside of the cheek until the tablet dissolves. Analgesia action can take place as soon as 5 to 15 minutes post-dose, and in some studies meaningful pain relief was achieved in approximately 70% of pain episodes with doses of 400 mcg.10 With this formulation, there also is some effect from the amount of the medication that is swallowed and absorbed from the gastrointestinal tract. In patients with cancer who developed mild mucositis, the ability to absorb the dose was not affected.9 Intranasal fentanyl (Lazanda, Archimedes). Nasal fentanyl, which has been used successfully in Europe to treat BTCP, recently received FDA approval and is available in the United States. Patients tend to find the

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3. American Pain Society. Cancer Pain in Adults and Children. Glenview, IL: The American Pain Society; 2005. 4. Lo Presti C, Roscetti A, Muriess D, Mammucari M. Time to pain relief after immediate-release morphine in episodic pain: the TIME study. Clin Drug Investig. 2010;30(suppl 2):49-55, PMID: 20670049. 5. Swanwich M, Haworth M, Lennard RF. The prevalence of episodic pain in cancer: a survey of hospice patients on admission. Palliat Med. 2001;15(1):9-18, PMID: 11212475. 6. Zeppetella G. Impact and management of breakthrough pain in cancer. Curr Opin Support Palliat Care. 2009;3(1):1-6, PMID: 19365156.

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amount of fentanyl that can be swallowed. The film dissolves within 15 to 30 minutes, allowing about 50% of the dose to be absorbed. The total bioavailability of the fentanyl is approximately 71%.12 The recommended starting dose is 200 mcg, and subsequent doses should be separated by at least 2 hours. More than 4 doses per day and doses higher than 1,200 mcg per day are not recommended. Management recommendations from the APS treatment guidelines for the cancer pain patient receiving opioid therapy can be found in Table 3.


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Conclusion

7. Montague B, Green CR. Cancer and breakthrough pain’s impact on a diverse population. Pain Med. 2009;10(3):549-561, PMID: 19254338. 8. Hagen NA, Biondo P, Stiles C. Assessment and management of breakthrough pain in cancer patients: current approaches and emerging research. Curr Pain Headache Rep. 2008;12(4): 241-248, PMID: 18625100.

References

11. Portenoy RK, Burton AW, Gabrail N, Taylor D. A multicenter, placebo-controlled, double blind, multiple-crossover study of Fentanyl Pectin Nasal Spray (FPNS) in the treatment of breakthrough cancer pain. Pain. 2010;151(3):617-624, PMID: 208000358.

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No matter which type of medication patients use to treat BTP, it is important that they are on a stable medication regimen and that they are classed as opioid-tolerant before they use fentanyl-based drugs. Managing BTP can be challenging, but rapid-onset opioids provide hope that patients can treat their pain effectively and avoid oversedation. Focusing more attention on the problem of treating BTP will help increase quality of life for patients with this difficult-to-treat pain syndrome.

1.

Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain. 1990;41(3):273-281, PMID: 1697056.

2. Turk D, Okifuji A. Pain terms and taxonomies of pain. In: Bonica’s Management of Pain. Philadelphia, PA: Lippincott Williams and Wilkins; 2010:15.

9. Mercadante S. The use of rapid onset opioids for breakthrough cancer pain: the challenge of its dosing. Crit Rev Oncol Hematol. 2011 Jan 5. [Epub ahead of print], PMID: 21215653. 10. 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, PMID: 20634985.

12. Delgado-Guay MO. Efficacy and safety of fentanyl buccal for cancer pain management by administration through a soluble film: an update. Cancer Manag Res. 2010;2:303-306, PMID: 21301590.

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