Breakthrough Pain in the Management of Chronic Persistent Pain Syndromes

Supplements and Featured Publications, Breakthrough Pain in Chronic Persistent Pain Syndromes: Emerging Treatment Options and Implications , Volume 14, Issue 4 Suppl

Chronic pain results from tissue damage (nociceptive) or damage to the nerves or nervous system (neuropathic); it can stem from internal organs or cavity linings (visceral) or from the body’s tissues (somatic). Mixed pain results from any number or combination of these types. Breakthrough pain (BTP) is a transitory, and often excruciating, flare that occurs against a background of chronic pain otherwise controlled by opioids. BTP is highly prevalent in patients with chronic pain of both cancer and noncancer origin, with episodes typically occurring several times daily that tend to peak within 10 to 30 minutes. Patients with BTP also endure heightened chronic pain, worsened physical function, and psychological distress. Several subtypes of BTP have been identified, including idiopathic, incident, and end-of-dose failure. The BTP Questionnaire is available to identify and characterize BTP and help determine the best treatment strategy for individual patients. This article reviews the etiology, prevalence, and characteristics of BTP along with assessment of patients and therapeutic strategies available to treat this condition.

(Am J Manag Care. 2008;14:S116-S122)

Pain occurs most commonly when tissue is damaged or has the potential to become damaged.1 However, pain is a complicated mechanism that is modulated at many sites throughout the central nervous system2,3 and is further influenced by mood and cognitive processes.4-6 Because pain is multifactorial, its assessment and treatment must address various etiologies and mechanisms.

Breakthrough pain (BTP), which occurs against a background of otherwise controlled pain,7 is common and often debilitating for patients with cancer- and noncancer-related chronic pain.8,9 The management of BTP is a necessary component of pain care for approximately 70% of patients with chronic cancer pain7,8,10-12 and noncancer pain13,14 and is accomplished separately from treatment of the persistent background pain.

Origins of Chronic Pain

Nociceptive pain results from connective tissue injury.15 In acute pain, nociception is the direct cause of pain, but chronic pain does not always demonstrate such a clear link.16 When the nociceptors (sensory receptors) are activated, they can become sensitized, meaning their excitability is increased and they discharge more frequently. In peripheral sensitization, the state of heightened neuron excitability occurs at the site in which the pain impulse originated in the body; in central sensitization, it occurs in the spinal neurons. When certain spinal neurons are repeatedly stimulated, they begin to fire more frequently. The result: pain intensifies and lasts far longer than the stimulus applied.17

Sensitization can result in hyperalgesia, in which response to paincausing stimuli is intensified, and allodynia, a pain response to a stimulus that normally is not painful. When sensitization occurs, the resulting pain comes not just from the injury site but from neural messages or neural impulses. Nerve damage can result in neuropathic pain that long outlasts the injury and far exceeds what would be considered a normal response to a pain stimulus. The pain can even spread beyond the initial injury site (referred pain). The process just described plays an important part in the development of chronic pain and also, in theory, of BTP.17

The Cost of Chronic Pain

Pain of all types often goes uncontrolled. In a survey of almost 900 physicians treating cancer patients, only about half of the respondents thought that cancer patients received adequate pain relief.20 Barriers to treatment vary, but include legal and policy restrictions; clinician knowledge deficits regarding pain management; a preference by clinicians to treat disease rather than ease symptoms; fear of opioid use from both clinicians and patients; and geography and resource limitations, especially in developing countries.21

Management of chronic pain can be pharmaceutical or nonpharmaceutical; if pharmaceutical, it can be managed with nonopioids or opioids. Although no treatment is 100% effective, prescription pain medications are among the treatments most relied on for pain. In a US survey, 58% of chronic pain sufferers stated that prescription medication effectively controlled their pain. That figure compares with 41% of those who took over-the-counter medication, 54% who tried chiropractic treatments, 48% who attempted standard physical therapy, and 54% who tried surgery.22

The pain may not be eliminated entirely, but patients who can exercise a degree of control over their pain realize improved function and quality of life. These are the goals of treatment when removing the underlying cause of pain is not possible. The large variability in patient response to treatment modalities requires an ongoing commitment to clinical assessment and vigilance.

Prevalence and Etiologies of Cancer Pain

Chronic pain persists beyond the time presumed to be adequate for most healing—typically 3 months— and can be continuous or intermittent.1 One of 4 or approximately 76.5 million Americans report some type of persistent pain, and of those who report pain, 42% say it has lasted longer than 1 year.25 A similar prevalence was described in a World Health Organization (WHO) survey of 15 centers, which found that 22% of primary care patients reported persistent pain and were more likely to have an anxiety or depressive disorder than patients without persistent pain.26 Vulnerable populations suffer even more; in a chart review of a US veteran general medical population, 50% of 300 patients suffered from at least 1 type of chronic pain.27

The etiologies of chronic pain of noncancer origins are varied. According to a WHO survey, the 3 most commonly reported sites of noncancer pain are back pain (47.8%), headache (45.2%), and joint pain (41.7%), and more than two thirds (68%) of primary care patients with persistent pain report pain in at least 2 anatomical sites.26

In a United Kingdom survey of 3605 general practice patients, 1445 reported chronic pain.28 Of those, 48.7% graded their pain as least severe and 15.8% as most severe. Back pain and arthritis were by far the most common causes, accounting for about one third of all reported chronic pain.28

BTP: Definition, Prevalence, and Types Definition

Many patients with chronic cancer pain experience BTP; most studies put the prevalence in the range of 65% to 85%.7,8,10-12 One study by 58 clinicians in 24 countries reported the prevalence of BTP as 64.8% among 1095 patients with cancer pain.10 The prevalence of BTP in noncancer patients is similar. In a survey of 228 patients with diverse types of noncancer chronic pain, 74% experienced severe-to-excruciating BTP.13 Of 43 hospice patients with noncancer terminal disease who reported pain, 63% also experienced BTP.14

Figure 1

Characteristics of BTP. Because BTP usually occurs against a background of otherwise controlled pain, it often has the same etiology as background persistent pain; it may, however, be independent of it.31 Breakthrough episodes of moderate-to-severe pain typically occur several times daily; the worst pain can occur in mere seconds to more than an hour after onset, but the episodes tend to peak within 3 to 30 minutes ().8,13 Other data show that most BTP events peak in 3 to 5 minutes and disappear within 30 minutes.31 The pain of even the shortest lived events can be excruciating.

The Effect of BTP on Patients

. BTP, particularly when treatment is absent or inadequate, damages the patient’s quality of life and reduces his or her ability to work and participate in other daily activities. Even brief but excruciating episodes can cause lasting harm. Patients who experience BTP suffer heightened severe chronic pain, worsened physical function, and psychological distress.13 As fear of breakthrough events grows, patients tend to remain sedentary, thus exacerbating physical deconditioning and painrelated disability. Together, these circumstances make effective control of BTP a leading clinical priority.

Figure 2

Types of BTPConsensus has not been reached on precise definitions of terms related to BTP31; however, many clinicians consider BTP to comprise 3 subtypes ().17,31,32

BTP Etiology

Only appropriate assessment of BTP can lead to proper treatment. One must determine the type of BTP, the number of daily episodes, the pattern of onset, the severity, the duration, any precipitating or exacerbating factors, any alleviating factors, and the patient responses to all treatments.7,31,32 The clinician should assess whether the BTP is nociceptive, neuropathic, visceral, somatic, or mixed, and whether it mimics the persistent baseline pain or is distinct from it.7,13,31

At every clinic visit, the clinician should assess and document the degree of pain experienced by the patient over baseline. In addition, quality of life, physical function, and the patient’s satisfaction with treatment should be recorded.33,34

Patient self-reporting is the main form of assessment using tools such as the visual analog scale. The BTP Questionnaire assesses for the presence of controlled baseline pain and asks a series of questions to identify and characterize BTP.13 Patient reports may be supplemented by family members or caretakers. Imaging studies can sometimes find sources of BTP that can be surgically corrected.31 More multifactorial assessments can gather data on the patient’s progress, including the important assessment of appropriate medication use.

Assessment of Opioid Abuse

Because BTP is separate from persistent pain, it requires separate assessment and treatment.31 The etiology of BTP should be addressed to the extent possible, for example, by taking steps to minimize precipitating events. Nonpharmacologic strategies may be appropriate, depending on the physical and psychosocial status of the patient, and may be combined with pharmacotherapy. These may include heat, ice, massage, physical therapy, certain exercises, weight reduction, transcutaneous electrical nerve stimulation, and acupuncture.45,46

If opioid therapy is selected to treat breakthrough events, goals for therapy should be realistic and discussed with the patient. Around-the-clock medication is the usual treatment of chronic baseline pain. The clinical characteristics of BTP usually call for administration of rescue doses in addition to medications used to control baseline pain.47 However, BTP also may be treated using pharmacologic approaches:

• Increasing the quantity of a long-acting opioid;

• Replacing a short-acting opioid with a longacting opioid; or

BTP is a common, debilitating byproduct of persistent cancer and noncancer pain. A variety of strategies to combat BTP are available and should be tailored to each patient, whose pain may have unique causes and perpetuating factors. For analgesia to be meaningful to the patient, he or she should achieve improvements in daily functioning, psychosocial health, and quality of life. Patient response to treatment is highly variable, and ongoing assessment and adjustment of treatment modalities are essential to good outcomes.

AcknowledgmentThe author gratefully acknowledges the contribution of Beth Dove, BA, Medical Writer, in the development of this manuscript.

Author Affiliation: Medical Director, Lifetree Clinical Research and Pain Clinic, Salt Lake City, UT.

Author Disclosures: The author reports grant/research support: Advanced Bionics, CoMentis, DURECT, Elan Pharmaceuticals, Elite, Forest Laboratories, GlaxoSmithKline, Jazz Pharmaceuticals, Mallinckrodt, Medtronic, Merck & Co, Inc, NeurogesX, Predix, Purdue Pharma, Takeda Pharmaceuticals, TorreyPines Therapeutics, ZARS Pharma; consultant for: Advanced Bionics, Cephalon, Elan Pharmaceuticals, King Pharmaceuticals, Medtronics.

Authorship Information: Concept and design; acquisition of data; drafting of the manuscript.

Address Correspondence to: Lynn R. Webster, MD, FACPM, FASAM, Medical Director, Lifetree Clinical Research and Pain Clinic, 3838 South 700 East, Suite 200, Salt Lake City, UT 84106. E-mail:

1. International Association for the Study of Pain, Subcommittee on Taxonomy. Classification of chronic pain. Descriptions of chronic pain syndromes and definitions of pain terms. Pain Suppl. 1986;3:S1-S226.2. Melzack R,Wall PD. Pain mechanisms: a new theory. Science. 1965;150:971-979.

4. de Wied M,Verbaten MN. Affective pictures processing, attention, and pain tolerance. Pain. 2001;90:163-172.

6. Rhudy JL, Dubbert PM, Parker JD, Burke RS, Williams AE. Affective modulation of pain in substance-dependent veterans. Pain Med. 2006;7:483-500.

8. Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: characteristics and impact in patients with cancer pain. Pain. 1999;81:129-134.

10. Caraceni A, Martini C, Zecca E, et al; Working Group of an IASP Task Force on Cancer Pain. Breakthrough pain characteristics and syndromes in patients with cancer pain. An international survey. Palliat Med. 2004;18:177-183.

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

14. Zeppetella G, O’Doherty CA, Collins S. Prevalence and characteristics of breakthrough pain in patients with non-malignant terminal disease admitted to a hospice. Palliat Med. 2001;15:243-246.

16. Jayson MI. Why does acute back pain become chronic? BMJ. 1997;314:1639-1640.

18. Bowsher D, Rigge M, Sopp L. Prevalence of chronic pain in the British population: a telephone survey of 1037 households. Pain Clinic. 1991;4:223-230.

20. Von Roenn JH, Cleeland CS, Gonin R, Hatfield AK, Pandya KJ. Physician attitudes and practice in cancer pain management. A survey from the Eastern Cooperative Oncology Group. Ann Intern Med. 1993;119:121-126.

22. America Speaks: Pain in America. 2003 survey conducted by Peter D. Hart Research Associates for Research!America. American Pain Foundation Web site. Accessed October 12, 2007.

24. Brescia FJ, Portenoy RK, Ryan M, Krasnoff L, Gray G. Pain, opioid use, and survival in hospitalized patients with advanced cancer. J Clin Oncol. 1992;10:149-155.

26. Gureje O, Von Korff M, Simon GE, Gater R. Persistent pain and well-being: a World Health Organization study in primary care. JAMA. 1998;280:147-151.

28. Elliott AM, Smith BH, Penny KI, Smith WC, Chambers WA. The epidemiology of chronic pain in the community. Lancet. 1999;354:1248-1252.

30. Højsted J, Nielsen PR, Eriksen J, Hansen OB, Sjøgren P. Breakthrough pain in opioid-treated chronic non-malignant pain patients referred to a multidisciplinary pain centre: a preliminary study. Acta Anaesthesiol Scand. 2006;50:1290-1296.

32. Davies AN. Cancer-related breakthrough pain. Br J Hosp Med (Lond). 2006;67:414-416.

34. Passik SD, Kirsh KL, Whitcomb L, et al. Monitoring outcomes during long-term opioid therapy for noncancer pain: results with the Pain Assessment and Documentation Tool. J Opioid Manage. 2005;1:257-266.

36. Butler SF, Budman SH, Fernandez K, Jamison RN. Validation of a screener and opioid assessment measure for patients with chronic pain. Pain. 2004;112:65-75.

38. Brown RL, Rounds LA. Conjoint screening questionnaires for alcohol and other drug abuse: criterion validity in a primary care practice. Wis Med J. 1995;94:135-140.

40. Storgaard H, Nielsen SD, Gluud C. The validity of the Michigan Alcoholism Screening Test (MAST). Alcohol Alcohol. 1994;29:493-502.

42. Davis LJ Jr, Hurt RD, Morse RM, O’Brien PC. Discriminant analysis of the Self-Administered Alcoholism Screening Test. Alcohol Clin Exp Res. 1987;11:269-273.

44. Webster LR, Dove B. Avoiding Opioid Abuse While Managing Pain: A Guide for Practitioners. North Branch, MN: Sunrise River Press; 2007.

46. Abrahm JL. Nonpharmacologic strategies for pain and symptom management. In: Abrahm JL, ed. A Physician’s Guide to Pain and Symptom Management in Cancer Patients. 2nd ed. Baltimore, MD: Johns Hopkins University Press; 2005:279-316.

48. Fishbain DA. Pharmacotherapeutic management of breakthrough pain in patients with chronic persistent pain. Am J Manag Care. 2008;14:S123-S128.