Breakthrough Pain in Cancer Patients: Characteristics, Prevalence, and Treatment

Introduction

Breakthrough pain is currently recognized as an important clinical phenomenon. It is referred to with increasing frequency in the cancer pain literature despite a lack of consensus on a formal definition and despite limited data from controlled research. Contemporary guidelines for the management of cancer pain uniformly recommend the provision of supplemental "rescue" or "escape" doses of short-acting analgesics to manage breakthrough pain, and most recommend monitoring the frequency of breakthrough pain as a gauge of the adequacy of treatment with regularly scheduled analgesics.[1-4] In addition, Bruera and others cite the presence of incident pain, a specific type of breakthrough pain, as one of the few indicators that reliably predict a poor response to treatment with routine pharmacotherapy.[5-8]

Widespread acceptance of empiric treatment and emerging evidence of the utility of breakthrough pain as a prognostic marker demonstrate the importance of breakthrough pain as a key component of cancer pain. Unfortunately, data on breakthrough pain are limited and remain difficult to interpret, presumably due to variations in how the phenomenon is defined, assessed, and treated. Although breakthrough pain occurs in conjunction with baseline pain that is under stable control, the criteria for what constitutes controlled baseline pain vary from investigator to investigator. In addition, investigators differ in their working definitions of breakthrough pain and its subsets, and a number of studies measure only specific types of breakthrough pain. All of these factors contribute to the widely disparate published figures for breakthrough pain prevalence, which range from 19%[9] to 93%.[10]

The clinical significance of breakthrough pain is also controversial. Studies intended to evaluate the adequacy of long-acting analgesics often utilize the incidence of breakthrough pain as a surrogate outcome measure, and imply that the presence of even modest breakthrough pain reflects an inappropriately low dosage of regularly scheduled, around-the-clock (ATC) analgesic.[11-12]Investigators who are concerned with the identification of factors that predict the success or failure of pain therapy associate breakthrough pain with intractability.[5] Still others recommend titration of scheduled and prn (pro re nata, or as needed) analgesics to balance the adequacy of overall and breakthrough pain relief against the intensity of associated side effects and functional impairment.[1,13]

Treatment recommendations for patients with breakthrough pain also vary considerably. All treatment regimens are empiric, and usually involve estimating the dose of breakthrough pain medication as a proportion of the scheduled ATC dosage. Some authorities recommend the use of prn doses equivalent to a scheduled dose at specific intervals.[1,14] Others provide breakthrough pain medication doses every 1 to 2 hours in a dose that is a proportion (usually 5% to 15%) of the total daily scheduled dose.[15]

Rather than being just an artifact of ATC dosing, breakthrough pain appears to represent a distinct heterogeneous clinical entity that warrants careful assessment and an individualized management approach. With the recognition that breakthrough pain comprises a key component of chronic cancer pain, it has become increasingly apparent that there is a critical need for standardization of terminology, carefully designed epidemiologic studies, and controlled trials of various treatment approaches.

Temporal Characteristics of Pain

Various schemata for characterizing cancer pain have been advanced that, when applied, may aid in diagnosis and the determination of initial and subsequent therapies. These include classifications based on pain chronicity, intensity, pathophysiology, syndromal presentation, disease stage, patient characteristics, and temporal features (Table 1). An appreciation of the temporal characteristics of pain, including the presence and nature of breakthrough pain, is a fundamental requisite to a better understanding of the pain syndrome and the institution of effective treatment.

The temporal characteristics of pain consist of: (1) the presence or absence of pain at a given moment in time; (2) its intensity or severity at a given moment in time; and (3) the rate and pattern of change in intensity or severity over short or long intervals of time (ie, its tempo). Both acute and chronic pain consist of a series of related events that can be broadly classified as constant or intermittent. Chronic pain is usually a relatively constant phenomenon punctuated by intermittent exacerbations. The constant, unrelenting component of chronic pain has been variously referred to as baseline or basal pain. Superimposed intermittent exacerbations of pain (changes in tempo from baseline) have come to be known generically as breakthrough pain and have recently become a focus of intense clinical interest.

The International Association for the Study of Pain (IASP) has established a taxonomy for painful disorders, which uses an alphanumeric coding system aimed at assisting clinicians and investigators in comprehensively classifying painful disorders.[16,17] This system classified pain along the following five axes: region, system, temporal characteristics, intensity, and etiology. Although the temporal classifications suggested by the IASP may have important implications for researchers, they are expansive and unwieldy for the clinician managing cancer pain.

Defining Breakthrough Pain

First, breakthrough pain needs to be distinguished from poorly controlled baseline pain, the pain emergency, and "crescendo pain." The main feature that distinguishes breakthrough pain from these other conditions is that, when breakthrough pain occurs, baseline (basal) pain is, by definition, under relatively stable control.

Although ill-defined and heterogeneous, the pain emergency is best viewed as an acute condition of mounting pain that occurs either de novo or in the context of a history of well-controlled pain.[18,19] In contrast to breakthrough pain, for which the cause is usually known and symptomatic treatment can thus be implemented, a pain emergency mandates a diagnostic evaluation aimed at identifying the etiology of the pain. Pinpointing the cause of the pain may suggest an appropriate treatment strategy to limit morbidity and even mortality. Examples of pain emergencies include pain due to bowel obstruction, pathologic fractures, and epidural spinal cord compression.

Crescendo pain[20] is probably best regarded as a subacute pain emergency characterized by progressive, unrelenting increases in pain severity. It is usually described in the context of a history of stable pain due to cancer and has been reported most often in dying patients. The presence of crescendo pain implies the need to treat mounting basal pain, usually with rapidly titrated doses of parenteral opioids administered by continuous infusion and supplemental nurse- or patient-administered boluses.

In contrast to breakthrough pain, treatment of crescendo pain is directed at the entirety of the pain experience, rather than the exacerbations. Crescendo pain in a dying patient is associated with special management considerations that may include the use of various alternate routes, anesthetic or neurosurgical interventions, and even terminal sedation.[20]

Portenoy and Hagen were the first investigators to propose a standardized definition of breakthrough pain. They defined breakthrough pain as a transitory increase in pain to greater than moderate intensity occurring on a baseline of pain of moderate intensity or less.[21] Using this definition, Portenoy and Hagen characterized breakthrough pain in a group of 63 patients. Prior to this seminal observational study, breakthrough pain had usually been described only as a secondary outcome measure.[6-10,22,23] Portenoy and Hagen also identified six characteristics that are relevant to understanding breakthrough pain: the relationship of breakthrough pain to a fixed opioid dose, temporal characteristics, precipitating events, predictability, pathophysiology, and etiology (Table 2).[21]

Relationship to Fixed Opioid Dose

Chronic cancer pain is typically composed of variable components of basal pain and breakthrough pain and, in this respect, differs from acute cancer pain syndromes, such as postoperative and procedure-related pain, which have more predictable, unidimensional temporal courses.[24] Most guidelines recommend that chronic cancer pain warranting the use of opioid analgesics be treated with the concomitant use of two pharmacokinetically distinct preparations of opioid analgesics. Oncepain is stabilized (usually with short-acting opioids), baseline pain is typically treated with a relatively long-acting agent, such as oral controlled-release morphine(Drug information on morphine), oral controlled-release oxycodone(Drug information on oxycodone), or transdermal fentanyl(Drug information on fentanyl)

(Duragesic), prescribed on a time-contingent or ATC basis. A short-acting agent with a relatively rapid onset (eg, immediate-release morphine, hydromorphone(Drug information on hydromorphone), and oxycodone) is prescribed on a symptom-contingent or prn basis. In this context, the frequency with which prn doses are required is used to gauge the need to adjust the dose of basal analgesic.

End-of-Dose Failure--Breakthrough pain that bears a consistent relationship to the ATC dosing regimen usually occurs with greater frequency near the end of a dosing interval and is referred to as end-of-dose failure. This form of breakthrough pain typically has a relatively gradual onset and generally lasts longer than pain that is unrelated to the dosing interval.[25]

The incidence and severity of end-of-dose failure usually correlate with the adequacy of ATC dosing regimens prescribed for the management of basal pain. End-of-dose failure is typically more prevalent and more severe when either basal (ATC) analgesics are prescribed in inadequate doses or the interval between administrations is excessive. In contrast to other types of breakthrough pain, end-of-dose failure is best managed by modifying the dose or schedule of long-acting ATC opioids.[25]

Other types of breakthrough pain include incident pain (sometimes referred to as precipitated pain or movement-related pain) and so-called spontaneous or idiopathic breakthrough pain. Incident pain has a relatively consistent temporal relationship to specific events or activities. Breakthrough pain that is unrelated to either activity or scheduled doses of analgesics is typically referred to as either spontaneous or idiopathic breakthrough pain. It is worth noting that McQuay and Jadad advocate an alternate classification from the one presented here; this system regards breakthrough pain as a subset of incident pain, rather than the reverse.[26]