It is striking how often medical advances occur as a result of the recognition of something that, in retrospect, is obvious. Pain has always been a feared consequence of disease, particularly cancer. Only in the past decade, however, has the widespread undertreatment of pain and its impact on the quality of life of patient and family gained the attention of mainstream medical research. Rapid, simultaneous advances in basic neurobiology and clinical investigation have dramatically improved the clinician’s ability to diagnose and treat pain.
As the field of pain medicine ("analgesiology") has evolved, a number of specific, previously overlooked or undifferentiated problems have come into focus and are now being vigorously attacked. Efforts to define the optimal approaches for neuropathic and other opioid-resistant pains, procedure-related pain, and pain in subpopulations, such as children, the elderly, and the demented, are all now taking place.
The review of breakthrough pain by Patt and Ellison highlights a key challenge that oncologists and pain specialists must overcome if they are to provide optimal analgesic therapy in the future. As clinicians who help care for patients with cancer-related pain, we applaud their timely, comprehensive survey.
All of us have personally encountered many patients whose pain is well-controlled much of the time and yet emerges during daily self-care or other activities, during rehabilitation after an illness episode, or upon reentering the home or workplace. These episodes of uncontrolled or poorly controlled pain--even if brief--render the most carefully crafted pain control plan inadequate, and foster patient and family frustration with the patient’s care and those providing it.
Given the high incidence of breakthrough pain in patients with cancer, documented in the eight published series summarized in the authors’ Table 3, it is clear that improvements in the practical assessment and treatment of breakthrough pain can offer substantial benefit for patients with cancer and their families. Perhaps the greatest contribution of the review by Patt and Ellison is the demonstration of how little has been done to clarify the incidence, prevalence, and clinical spectrum of breakthrough pain in patients with cancer--and therefore what a rich area for research and study this relatively unexplored topic is.
Role of Currently Available Therapies
Their survey--and, in particular, their discussion and presentation in Table 2 of data from Portenoy and Hagen--suggest several practical means for reducing the incidence of breakthrough pain that can be accomplished using currently available therapies. Just over half of the episodes of breakthrough pain occur just before the next scheduled dose of an around-the-clock opioid. Yet, it is recognized that opioid tolerance is manifested not only by a lessening of analgesic benefit from successive, fixed doses of drug but also by a shortening of duration of such benefit. Therefore, a readiness to increase dosing frequency, as well as dosage amount, during ongoing opioid theapy should avert or at least diminish the incidence of breakthrough pain episodes.
Likewise, slightly more than half of breakthrough pain episodes are precipitated by physical activity, and the majority of these occur with purposeful movement. Although Patt and Ellison focus on opioid therapy, we have found that physical measures (ie, nondrug therapies, such as splints and positioning) and cognitive-behavioral approaches are valuable supplements to pharmacotherapy in such instances. Also, adjuvant nonopioid medications, such as anxiolytics or nonsteroidal drugs, often provide temporary augmentation of analgesia when given above a baseline opioid regimen ] and/or together with short-acting opioids, ideally in advance of anticipated breakthrough pain.
Patients Receiving Neuraxial Drug Infusions
A particular problem not covered by Patt and Ellison is how to approach breakthrough pain in the patient receiving neuraxial drug infusions. Intrathecal or other central drug delivery is becoming more common, and yet supplemental brief increases in the infusion rate of opioids, such as morphine(Drug information on morphine), may require 20 to 30 minutes to achieve an increment in analgesia. Concomitant central infusion of opioids, together with nonopioids, such as bupivacaine(Drug information on bupivacaine) and clonidine(Drug information on clonidine), is now also daily clinical
practice in the unfortunate minority of patients whose pain cannot be controlled by lesser measures. This has occurred despite the fact that the safety of sudden additional bolus infusions of such mixtures into the central nervous system has not been proven.
It is our clinical impression that oral or parenteral opioids may be safely given to patients receiving such long-term continuous neuraxial infusions of drugs with vasodepressor potential, and that they often provide a worthwhile approach to the control of occasional breakthrough pain. On the other hand, a placebo effect may be responsible for some of this benefit. In any case, it is no longer acceptable to practice medicine according to clinical impressions.
Importance of Randomized, Controlled Trials
Therefore, randomized, controlled trials of analgesic approaches for the treatment of breakthrough pain are urgently required. We hasten to point out that the "controls" in such trials should not be given a placebo. Standard analgesic therapies are perfectly acceptable controls, just as standard chemotherapy is a suitable yardstick against which to measure a novel antitumor regimen.
Naysayers may decry subjecting patients with cancer pain to any form of randomized, controlled analgesic trial. Nevertheless, only through such means can clinical practice be systematically advanced. Such testing is particularly important to define the benefits, costs, and risks of a number of novel drugs and delivery systems that hold great promise for cancer pain relief, whether stable or incident. For example, the authors mention oral transmucosal fentanyl(Drug information on fentanyl) citrate (Actiq), a novel means to deliver drug promptly across the oral mucosa. To this will soon be added on-demand, transdermal electrophoretic delivery of bolus doses of fentanyl by means of a small patch. Randomized, controlled trials of these and other emerging technologies are necessary to define which patients may benefit from which new (and old!) analgesic measures. Patt and Ellison point out that such trials are often difficult to conduct in patients with cancer pain, in part, because they require a new level of rigor in characterizing the patients studied, their episodes of pain, and related outcomes, such as functionality, quality of life, and cost of care. However, randomized, controlled trials--and their aggregation and synthesis into widely accessible registries--are the foundation of contemporary clinical medicine, including oncology. Therefore, as analgesiology joins the ranks of other mainstream medical specialties, we should only expect that its research methods and credibility will converge with theirs.
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