ABSTRACT: Many cancer patients are undermedicated and inappropriately managed for pain, leading to a diminished quality of life. Patients with moderate to severe pain often require opioid analgesics. Recently published guidelines emphasize individualization of opioid treatment to provide the drug and route of administration that meet the needs of the particular patient. Intolerable side effects, ineffective pain relief, or a change in the patient’s clinical status can dictate the need for a new pain management regimen. Physicians must be able to readily quantify relative analgesic potency when converting from one opioid to another or from one route of administration to another. Transdermal fentanyl (Duragesic) is an opioid agonist that has been shown to be safe and effective for the treatment of cancer pain. However, clinicians should realize that the manufacturer’s recommendations for equianalgesic dosing of transdermal fentanyl may result in initial doses that are too low in some patients, and in a titration period that is too long. Under these circumstances, the patient is likely to experience unrelieved pain. An alternative dosing algorithm that considers both a review of the literature and our combined clinical experience with transdermal fentanyl should help clinicians individualize the treatment of pain. [ONCOLOGY 14(5):695-705, 2000]
Pain associated with malignancy is a critical problem in cancer patients. The majority of patients (65% to 85%) with advanced disease and at least one-third of newly diagnosed patients report pain.[1-4] Although approximately 90% of patients with cancer pain can be effectively treated with an integrated program of non-pharmacologic, pharmacologic, and anticancer therapies, a significant number of cancer patients are undermedicated and inappropriately managed, resulting in suboptimal pain control.[4-6]
Appropriate pain management requires proper pain assessment followed by a targeted approach to pain control.[4,7] A thorough assessment of an individual cancer patient’s etiology of pain, age, extent of disease, previously effective and ineffective therapies, concurrent medical problems, and psychosocial status is required to select the best approach. Each patient’s plan of care must be individualized, reassessed, and, if necessary, altered regularly to maximize pain control, functionality, and ultimately, quality of life. The patient’s self-report of pain should be the basis of pain management, since both caregivers and health care workers tend to underestimate pain severity.
According to guidelines published by the World Health Organization, the choice of analgesic should be based on the intensity of pain reported by the patient, rather than its specific etiology. Patients with mild pain may benefit from nonopioid agents, including aspirin, acetaminophen, ibuprofen, or other nonsteroidal anti-inflammatory drugs.
If mild to moderate pain is not adequately relieved with optimally used nonopioid analgesics, or if nonsteroidal medications are contraindicated, opioid analgesics should be considered. At this point, opioids can be used alone or in combination with nonopioid therapies. Adjuvant agents, such as corticosteroids, tricyclic antidepressants, and anticonvulsants, can be used concurrently to enhance analgesic efficacy, treat opioid-induced symptoms or to alleviate specific types of pain.
Persistent or recurrent pain requires treatment with a regularly scheduled regimen. However, even patients whose pain is generally well managed with around-the-clock dosing experience episodes of “breakthrough” pain resulting from activity, stress, or disease progression. When this occurs, patients require agents that provide a rapid onset of action and short duration of effect to complement the pain-control regimen. When breakthrough pain occurs regularly, an increase in the dose of the currently prescribed medication or the use of a different analgesic or a different delivery system may be needed.[4,9,10]
Uncontrolled pain diminishes the quality of life of cancer patients. Cancer pain and its treatment may exacerbate other symptoms of cancer, including fatigue, weakness, dyspnea, nausea, constipation, and impaired cognition.[1,2] Patients with pain hesitate to participate in normal daily activities for fear of worsening the pain. Social and family relationships may suffer as patients avoid interpersonal interaction or experience personality changes as a result of persistent pain.
Recently, a number of experts and organizations have developed guidelines for the treatment of pain. Although initially the “step” approach was recommended, more recent guidelines emphasize individualization of therapy, advocating selection of the appropriate drug and route of administration for each patient.[11-14]
During the course of cancer pain management, patients frequently require a change from one opioid to another. A different opioid may be necessary as a result of intolerable side effects, cost considerations, or the need for an alternative route of administration as the patient’s disease progresses.
In an attempt to quantify the frequency with which experienced clinicians make treatment changes in response to the changing clinical status of cancer patients, Cherny et al conducted a prospective survey of 100 patients referred to the Pain Service at Memorial Sloan-Kettering Cancer Center over a 14-week period. Of the 100 patients, 99 had received therapy with a median of 2 different opioids (range, 1 to 8) administered by a median of two different routes (range, 1 to 8).
After initial evaluation, the Pain Service physicians changed the opioid or route of administration in 58 patients. Of the 42 patients whose medication was unchanged at initial evaluation, 22 required subsequent changes in either drug or route of administration. Thus, 80 patients required changes in drug or route of administration prior to death or discharge. These 80 patients experienced a total of 182 changes in drug and/or route of administration.
Frequent changes between different drugs and different routes of administration require physicians to readily quantify relative analgesic potency when changing from one opioid to another or one route of administration to another, so that pain control can be maintained and side effects minimized.[16,17]
When a change in opioids is required, physicians often refer to conversion tables published in textbooks or guidelines. Conversion tables are often based on the results of single-dose studies in patients receiving low opioid doses for postoperative pain. Although relative analgesic potency is conventionally expressed in comparison with 10 mg of parenteral morphine or 60 mg of oral morphine (Table 1),[11,18] many recent studies have reported that the standard conversion tables underestimate the potency of opioids in patients who are receiving repeated doses.[19,20]
Based on their interactions with the various receptor subtypes, opioid agents can be divided into four classes: pure agonists, partial agonists, agonist-antagonists, and pure antagonists. Pure agonists are used most commonly in the treatment of cancer pain.
Agents in this class include codeine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol (Levo-Dromoran), meperidine, methadone, morphine, oxycodone, and oxymorphone (Numorphan). Pure agonists bind completely to mu receptors and usually do not have a ceiling dose. The dose is increased as necessary to allow for adequate analgesia unless intolerable or unmanageable side effects occur.
Fentanyl, like other opioids, exerts its principal pharmacologic effects on the central nervous system. Fentanyl is approximately 75 times more potent than morphine on a molar basis.
Transdermal fentanyl (Duragesic) is a system that provides continuous systemic delivery of fentanyl. In the transdermal system, fentanyl is released from a cutaneously applied reservoir at a nearly constant amount per unit of time. The amount of fentanyl released per hour is directly proportional to the surface area of the patch in contact with the skin. Commercially available patch sizes provide delivery rates of 25, 50, 75, and 100 µg/h.
Following patch application, fentanyl initially concentrates in the upper skin layers before it becomes available to the systemic circulation. Serum fentanyl concentrations level off between 12 and 24 hours after the first application. With continuous use, serum fentanyl levels reach and maintain a steady state after the second dose, and fluctuations of serum levels are minimal after the first 72 hours. This allows for a constant level of analgesia.
Although about 40% of the fentanyl remains in the gel matrix in the patch after 72 hours, the gradient across the skin is too low to maintain adequate diffusion of fentanyl after this time. After removal, serum fentanyl levels decrease gradually, about 50% in 17 hours (range, 13 to 22 hours).
Studies in Cancer Pain—The transdermal route has been the most extensively studied method of administration of fentanyl in cancer patients. Several nonblinded clinical studies have shown that transdermal fentanyl effectively controls chronic pain associated with cancer. Therapy was converted from stabilized morphine doses to transdermal fentanyl generally without loss of pain relief. Table 2 summarizes the results of these trials.[26-32]
In addition, two studies have assessed quality of life and patient preference. In one study of 202 cancer patients who required strong opioids for pain, significantly more patients preferred transdermal fentanyl to sustained-release oral morphine (P = .037). This preference may have been related to the fact that transdermal fentanyl was associated with less constipation (P < .001), less daytime drowsiness (P = .015), and less disruption to daily life (55% in fentanyl-treated patients vs 20% in morphine recipients).
These data were recently confirmed in a trial assessing quality of life and satisfaction with transdermal fentanyl vs oral morphine. Again, patients receiving transdermal fentanyl were more satisfied overall with their pain medication than were patients receiving sustained-release oral morphine. This may have resulted from the significantly lower frequency (P < .002) and severity (P < .001) of side effects. There were no significant differences between treatment groups with respect to measures of pain intensity, sleep adequacy, or symptoms.
Although these studies were not randomized, controlled trials and the interpretation of the data is confounded by the concomitant use of rescue doses of opioids, they nonetheless provide consistent data on pain relief and side effects in large numbers of patients managed with oral morphine or transdermal fentanyl.
Patient Acceptance and Side Effects—In general, transdermal fentanyl is well accepted by cancer patients, leading to excellent compliance with the prescribed regimen. Transdermal fentanyl is noninvasive, and analgesia is sustained for long durations. This therapy can be administered to patients who cannot take oral analgesic medications because of such cancer-related side effects as nausea, vomiting, and dysphagia.
Like other opioids, transdermal fentanyl has been reported to produce adverse reactions during both clinical trials and postmarketing studies. The most serious reactions were deaths due to hypoventilation resulting from inappropriate use. Specifically, use of a patch size greater than 25 µg/h in opioid-nave patients or those with acute self-limited pain (eg, acute dental pain) is contraindicated. Hypotension and hypertension were observed in opioid-nave patients.
The most common side effects seen with transdermal fentanyl include sedation, nausea, vomiting, and constipation. However, an open multicenter study of 40 cancer patients requiring opioid analgesia suggested that transdermal fentanyl may result in less nausea, vomiting, and constipation than does morphine.
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