Management of Breakthrough Pain Due to Cancer

Introduction

Cancer pain is experienced by 30% to 45% of patients at the time of diagnosis[1] and by about 75% of patients with advanced disease.[2] Good pain control can be achieved in most patients with cancer pain but commonly requires the use of “rescue” or supplemental doses of analgesic.[3] Standard practice in palliative care is to prescribe both scheduled doses of an analgesic (around-the-clock dosing) for persistent pain and supplemental doses as needed for breakthrough pain.

Defined as a “transitory exacerbation of pain that occurs on a background of otherwise stable persistent pain,”[4] breakthrough pain has been associated with a reduced likelihood for adequate pain control in some groups of cancer patients.[5] Breakthrough pains characteristically have a rapid onset and severe intensity but brief duration (range, 1 to 240 minutes; median, 30 minutes). Pain of such an intense severity but short duration is particularly difficult to treat because currently available oral agents administered at the onset of a breakthrough pain episode may require 30 to 45 minutes to be absorbed and produce an analgesic effect.[6-9] Because breakthrough pain, like other types of cancer pain, may limit patient mobility, adversely affect a patient’s mood, and inhibit social interactions,[10] skill in managing breakthrough pain may significantly affect a patient’s quality of life.

Characteristics and Classification

Breakthrough pain may be caused by somatic, visceral, or neuropathic pathophysiology, and it is most often related to the same mechanism that causes the persistent pain. By definition, breakthrough pain is of moderate or severe intensity. Although the onset of breakthrough pain is often paroxysmal (peaking in intensity within 3 minutes), it may develop gradually. Like persistent cancer pain, breakthrough pain may be related directly to the location of the neoplasm, treatment effects, or other etiologies.[4]

Breakthrough pain may be classified according to precipitating events. Breakthrough pain related to movement is generally termed incident pain. Incident pain may be caused by volitional movements, such as walking or sitting, or nonvolitional movements, such as bowel or ureter distention.[4] Breakthrough pain that is not linked to scheduled analgesic dosing and that cannot be linked to bodily movement or function is called spontaneous or idiopathic breakthrough pain. Pain exacerbations that typically occur at the end of the dosing interval of an around-the-clock opioid are termed end-of-dose failures.

Treatment

Breakthrough pain is managed primarily with supplemental opioid analgesics, but multiple modalities may be used. One study that asked patients to report palliative measures that lessened breakthrough pain listed numerous measures, in addition to the use of supplemental analgesic doses; these included a change in position or movement and suppression of a pain-inducing movement (eg, cough).[4]

Because breakthrough pain (like persistent pain) is often related to neoplastic growth, primary treatment measures, including antineoplastic therapy, should be considered. Increasing the around-the-clock medication dosage may also be considered but may be associated with unacceptable side effects. The goals of cancer pain therapy are to find the right dose of around-the-clock medications to control persistent pain and the right dose of supplemental medication to relieve breakthrough pain. Pharmacologic therapy combined with non-pharmacologic measures should control pain in most patients.

Primary Therapies

In the past, many physicians considered palliative care only after all active antineoplastic treatments had failed.[11] Failure to attempt to relieve pain and other symptoms, however, is unacceptable at any phase of the cancer treatment process. Recent issues (such as assisted suicide requested by patients suffering pain related to terminal illness) have underscored the importance of pain relief to patients.[12] Appropriate analgesia should therefore be used alone or in combination with active antineoplastic therapy as part of standard treatment.

This discussion of primary therapies does not mean to imply that palliative care should be instituted only after primary therapy has been terminated. Indeed, analgesics should be offered as soon as they are required, since patients who are in less pain experience improvements in sleep, mental attitude, appetite, and general quality of life.[10]

Primary therapy and pain management should be used together, although the need to increase pain management strategies typically arises when active neoplastic therapy becomes less effective, often during the later stages of disease.[11] Sometimes, however, a primary neoplastic therapy may not be curative but may substantially alleviate pain. Thus, irradiation of a metastatic tumor on or near nerves or weight-bearing bones could potentially relieve a patient’s pain.

Chemotherapy used to treat particularly painful conditions, such as pancreatic or prostate cancer, may also lessen pain. For this reason, agents such as gemcitabine(Drug information on gemcitabine) (Gemzar) and mitoxantrone(Drug information on mitoxantrone) (Novantrone) have been approved for palliative care, even though they are traditionally considered to be antineoplastic agents.[13,14]

Primary therapies need not treat the neoplasm directly. Breakthrough pain due to coughing, for instance, may be managed with an antitussive agent. Similarly, stool softeners may lessen pain associated with defecation. Movement-related pain may sometimes be ameliorated by orthotic devices. Finally, surgical means of pain relief, such as denervation or joint replacement, are generally reserved for highly specific situations or severe, intractable pain.

Increase in Dosage of Around-the-Clock Analgesics

Pain cannot always be managed by removing its direct cause. Most primary interventions are associated with risks, complications, and side effects that may make strict analgesic treatment of pain preferable.

Traditionally, frequent episodes of breakthrough pain have been treated with increased dosages of regularly scheduled analgesics. This practice developed, in part, because of the appropriate goal of trying to prevent as much pain as possible. In addition, due to their pharmacokinetics, the available oral analgesics often take longer (30 to 45 minutes) to provide relief than is acceptable to patients. Increased dosages of around-the-clock analgesia may mask some of the less severe exacerbations of pain.

Increasing the dosage of around-the-clock medications, however, increases the opioid levels present in the blood at all times, thereby increasing the likelihood of opioid side effects. In patients with few side effects from opioid therapy, increasing the around-the-clock dosage may not be problematic. In patients with constipation, sedation, confusion, or similar side effects, however, increasing the around-the-clock dosage may disturb the balance between analgesic effectiveness and side effects. Thus, the likelihood of increasing analgesic side effects should be weighed against the need for around-the-clock analgesia before around-the-clock dosage is altered.

Supplemental Analgesics

Supplemental analgesic agents, sometimes referred to as “rescue” analgesics, are crucially important in the management of breakthrough pain. Historically, supplemental analgesics have been dosed as a percentage of the around-the-clock analgesic dose. The rule of thumb has been to use a short-acting formulation of the long-acting around-the-clock analgesic, whenever possible; in general, the supplemental dose has been 5% to 15% of the daily around-the-clock dose, administered every 1 to 2 hours.[15]

As more analgesic agents have been used more widely to treat cancer pain, it has become acceptable to prescribe different opioids for around-the-clock and breakthrough pain, provided that the combination does not unacceptably increase side effects. Indeed, around-the-clock analgesics, such as transdermal fentanyl(Drug information on fentanyl) (Duragesic) and methadone(Drug information on methadone), have commonly been combined with another opioid for breakthrough pain. (Note, however, that methadone is not commonly considered for initial therapy of cancer pain due to its long and unpredictable half-life.) Like the around-the-clock medication, the supplemental analgesic should be titrated to manage persistent pain and to provide adequate analgesia with acceptable side effects.

In theory, the use of supplemental analgesic agents in combination with around-the-clock medications should provide more effective analgesia with fewer side effects than long-term scheduled analgesics used alone because higher levels of analgesic are present in the bloodstream only when pain relief is needed (Figure 1a). In reality, however, the delay between the administration of supplemental analgesics and their absorption and the achievement of pain relief can leave a patient suffering from excruciating pain during the interim (Figure 1b). Thus, many physicians treat breakthrough pain prophylactically, maintaining higher dosages of around-the-clock analgesic at all times. In some patients, however, this strategy may result in unbearable side effects, such as sedation, nausea, or constipation (Figure 1c).

When oral supplemental analgesics are used, the patient must often be asked to accept a balance between the side effects associated with long-acting opioids and the pain experienced between the time a breakthrough pain begins and the time when analgesics take effect. New supplemental analgesics that are rapidly absorbed via novel routes of administration may allow clinicians to approach the ideal of breakthrough pain relief by providing active drug that circulates systemically more quickly to bring relief as soon as the pain occurs.