This article on the management of breakthrough pain by Simmonds is one of a number of excellent reviews on the palliative aspects of cancer care published in ONCOLOGY over the last 2 years. Breakthrough pain is a frequent, poorly understood cancer pain syndrome. It has a number of unique characteristics with regard to its pathophysiology, assessment, and management. In view of recent research with transmucosal opioid analgesics, it is quite appropriate to review this difficult pain syndrome.
Simmonds succinctly describes the characteristics of breakthrough pain. It is important to stress that a number of studies have found breakthrough pain to be an independent poor prognostic factor for pain control in cancer patients.[1,2]
Simmonds appropriately starts her discussion of primary analgesic interventions by emphasizing the importance of nonpharmacologic measures, such as changes in body position and movement, consideration of orthotics or orthopedic procedures, and the impeccable management of cough and constipation. Not discussed by the author, but also important, bisphosphonates have been found, in at least one study, to be effective for both continuous and incidental pain due to bone metastases. Since these drugs have relatively low toxicity and can prevent osteolysis, there is strong justification for considering their possible use in the treatment of incidental bone pain.
Titrating Dose and Selecting Analgesics for Breakthrough Pain
With regard to opioid analgesics, the main problem posed by breakthrough pain is the difficulty in titrating dose. The dose of regular opioid analgesic that can achieve good pain control for most of the day is ineffective during the episode of breakthrough pain. On the other hand, the dose of opioid that can control pain during the breakthrough episode would result in intolerable sedation during the rest of the day. Therefore, patients with breakthrough pain usually undergo multiple trials of opioid titration. Since the relationship between analgesia and sedation can change in individual patients, it is always appropriate to consider changing the type of opioid in those patients in whom analgesia can be achieved only when accompanied by severe side effects.
Although, in some cases, it may be necessary to use different opioids to treat stable and breakthrough pain, this is usually unacceptable because of unpredictable binding to the different opioid receptors and unpredictable toxicity. Ideally, the same opioid should be used to manage breakthrough and background pain, whenever possible. There is no evidence that any combination of opioids is superior to a single agent in controlling breakthrough pain. The decreased cost, increased simplicity, and easy identification of side effects are obvious advantages to opioid monotherapy in these very ill, frequently polymedicated patients.
With some agents, such as transdermal fentanyl(Drug information on fentanyl) (Duragesic), a different opioid needs to be used for breakthrough pain because of the lack of an available oral preparation. In the case of methadone(Drug information on methadone), extra oral doses can be safely used for breakthrough pain.
In breakthrough pain, titration of opioid dose is limited by severe sedation. A pilot study has found that the addition of methylphenidate(Drug information on methylphenidate) allowed patients to significantly increase their daily opioid dose and decrease pain intensity after they had reached their highest tolerated opioid dose because of sedation. The majority of these patients had breakthrough pain. Therefore, the use of psychostimulants, such as methylphenidate, can improve pain control in at least some of these patients.
An interesting finding in this study was that patients only took an average of two extra opioid doses for breakthrough pain per day. This observation confirms statements made by Simmonds and others about the relative uselessness of traditional rescue opioid doses: Patients soon become aware that their breakthrough pain episode will be gone long before the rescue analgesic dose starts to work.
The rectal route is used infrequently for the management of pain in general and breakthrough pain in particular. However, a recent, double-blind, crossover study found that a rectal preparation of liquid morphine(Drug information on morphine) resulted in significant analgesia within approximately 10 minutes, as compared to approximately 30 minutes for an oral preparation.
Unfortunately, there have been no large studies of rectal liquid opioids, at least in part because pharmaceutical companies have limited interest in these older analgesics. However, rectal injections of morphine might be a useful rescue analgesic in low-income populations, rural areas, or developing countries where the access to health care professionals and the maintenance of parenteral routes may be difficult.
Oral Transmucosal Route
The oral transmucosal route appears to be a potentially exciting approach to breakthrough pain in many patients. More clinical trials involving larger numbers of patients and a wider variety of doses are required to establish the safety and effectiveness of this route.
In the meantime, studies of transmucosal fentanyl (Actiq) have already made one major contribution to our understanding of breakthrough pain and its management: As discussed by Simmonds, the range of effective breakthrough pain doses was found in those studies to be between 5% to 15% of the daily regular analgesic dose. This differs from the previous recommendation that one should always keep the same ratio (usually 10%) between the regular and breakthrough dose. These studies suggest that clinicians should titrate not only the optimal regular analgesic dose in their patients but also the optimal rescue dose, as the latter may be three times higher in some patients than in others.
In summary, this review provides important, practical information for cancer specialists and generalists regarding the management of this frequent, frustrating pain syndrome.