Consensus Panel Recommendations: PHARMACOLOGICAL TREATMENTS

27 Apr
2010

A primary goal of pharmacological treatment of BTP is to ensure that baseline persistent pain is treated effectively with around-the-clock (ATC) doses of an analgesic. If an immediate-release (IR) opioid is being used to treat the baseline persistent pain, the dose should be slowly tapered during conversion and titration of the ATC analgesic (opioid) dose. After this conversion to an ATC opioid is complete and an effective, tolerated dose of the ATC opioid is established, the use of the IR opioid should not be continued for the management of baseline persistent pain.

Baseline persistent pain should be assessed at regular intervals to ensure effective control with ATC doses of the analgesic. If end-of-dose BTP is identified, two treatment options are available:

1. increasing the total daily dose of the ATC opioid by 25% to 50% and then re-evaluating for a response. This approach may result in the development of intolerable side effects, such as drowsiness.
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2. shortening the dosing interval if the patient is already taking the maximally tolerated dose.

Finally, because of unpredictable variability among patients, some may require the dosing interval to be shorter than generally recommended. For example, a transdermal fentanyl patch (Duragesic®, Janssen) would be replaced every 48 hours instead of every 72 hours, or controlled-release oxycodone (e.g., OxyContin®, Purdue) might be prescribed every eight hours instead of every 12 hours.

Case Study: T. G.

T. G. is a 62-year-old woman with stage IV breast cancer (see Part 1 of this series in the May 2005 issue of P&T). She reports that she had been tolerating opioid therapy without any side effects except for constipation. Because of the frequent disturbance in T. G.’s sleep resulting from pain, the choice was made to increase her evening dose of sustained-release morphine and to increase her dose of her stimulant laxative, which was used to treat opioid-induced constipation.

After control of the baseline persistent pain has been achieved, the management goal is to decrease the frequency and intensity of BTP (Figure 2). This latter goal is particularly important, because it may reduce the patient’s level of discomfort or disability.
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Figure 2 Common difficulties

Figure 2 Common difficulties with around-the-clock and breakthrough pain medication regimens. Orange peaks represent persistent pain that is uncontrolled with the around-the-clock medication as well as with the current breakthrough pain medication. (Reproduced with permis­sion from Cephalon, Inc.)

The ideal treatment of BTP would match its onset and duration and would therefore typically have a rapid onset (within minutes) and a short duration of action (approximately 30 minutes in most cases) (Figure 3). Because no currently available pharmacological agent is ideal, management should be adjusted according to the following: (1) the chemical class, (2) the route of administration, (3) the dosage, (4) the setting (inpatient or outpatient), and (5) the subtype of BTP.

Figure 3 The ideal agent

Figure 3 The ideal agent will have a rapid onset and a short duration of action to cover the peak breakthrough pain. (Reproduced with permission from Cephalon, Inc.)

Chemical Class

Although a variety of drugs are used to treat chronic baseline persistent pain, most published and clinical experiences with BTP, regardless of etiology, involve opioids. Oral trans-mucosal fentanyl citrate (Actiq®, Cephalon) is the only opioid approved by the Food and Drug Administration (FDA) that is specifically indicated for cancer-related BTP, but the use of many other opioids, although they are “off-label,” is supported by extensive research. The wide experience with opioids is a using the same opioid for the treatment of baseline persistent pain and BTP is not unusual, but it is not clear whether this affords any benefit in terms of efficacy, compared with using a different opioid. However, using the same opioid does have some advantages, such as easier titration of the ATC opioid, as well as management of opioid-related side effects. On the other hand, any IR opioid can be used with longer-acting agents, such as methadone and levorphanol (e.g., Dolophine® or Levo-Dromoran®, Roxane) to avoid possible accumulation with repetitive doses of these agents. Similarly, a different IR opioid might be used for BTP in patients who have been treated with transdermal fentanyl.
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Non-opioid analgesics, such as acetaminophen (e.g., Tylenol®, Ortho-McNeil) and cyclooxygenase type 2 (COX-2) consequence, in part, of the lack of a “ceiling effect” (similar to insulin in the treatment of hyperglycemia); that is, analgesia is related to the dose with no upper limit, even though the dose may be limited by side effects.

Using the same opioid for the treatment of baseline persistent pain and BTP is not unusual, but it is not clear whether this affords any benefit in terms of efficacy, compared with using a different opioid. However, using the same opioid does have some advantages, such as easier titration of the ATC opioid, as well as management of opioid-related side effects. On the other hand, any IR opioid can be used with longer-acting agents, such as methadone and levorphanol (e.g., Dolophine® or Levo-Dromoran®, Roxane) to avoid possible accumulation with repetitive doses of these agents. Similarly, a different IR opioid might be used for BTP in patients who have been treated with transdermal fentanyl.

Non-opioid analgesics, such as acetaminophen (e.g., Tylenol®, Ortho-McNeil) and cyclooxygenase type 2 (COX-2) selective and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), should be efficacious in treating BTP because of their nociceptive mechanisms. However, the use of these agents is complicated by dose-limiting toxicities, an onset of a half-hour or more, a duration of action of several hours, and recent concerns about cardiovascular morbidity. In addition, no published evidence exists to support their use in BTP.

A similar situation exists with bisphosphonates for bone pain and with antidepressants, anticonvulsants, and other adjuvant analgesics for neuropathic BTP. Some evidence exists that subcutaneous midazolam (Versed®, Roche) and intra-nasal ketamine are efficacious in BTP, but the results are preliminary. Consequently, the Consensus Panel’s treatment recommendations focus on the use of opioids.
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An approach for selecting an IR opioid to treat BTP should be based on the sustained-release or ATC opioid that is used for baseline persistent pain. In addition, a careful review of the patient diary by the clinician can suggest when to administer the IR opioid. Finally, cost differences exist among opioids— a fact that clinicians need to consider when choosing an opioid for BTP.

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