Commentary (Hewitt): An Alternative Algorithm for Dosing Transdermal Fentanyl for Cancer-Related Pain

The inadequate treatment of pain associated with malignancy remains a significant clinical problem.[1-4] Despite published guidelines on the appropriate management of cancer pain, 50% of dying patients experience moderate to severe pain.[1,5-8] One of the greatest barriers to the proper treatment of cancer pain remains health care professionals’ lack of knowledge regarding the appropriate use of analgesic medications.[9-11] The failure to refer to and limited availability of knowledgeable specialists in pain and palliative care also contribute to this pervasive problem.[12]

In order to treat cancer pain appropriately, the clinician must possess a facility with the use of opioid analgesics and the management of their often-troubling accompanying side effects. Although treating side effects by adding another drug is a useful strategy, it can result in adverse effects associated with polypharmacy. One solution to this problem is switching the patient to a different analgesic, since one opioid may be tolerated better than another.

Opioid Rotation

It is commonly recognized in the field of pain and palliative care that opioid analgesic therapy requires sequential trials until the drug that is most effective and has the least side effects is found.[13-19] Sequential trials should be considered routine. This practice of switching among the various opioid analgesics, referred to as opioid rotation, enables the clinician to pinpoint the right drug for the individual patient and balance side effects with optimal analgesic effect. Studies have shown that opioid substitution can effectively manage pain and reduce side effects associated with opioid therapy.[20]

Opioid switching is a common practice among pain and palliative care specialists.[21] However, the majority of patients with cancer do not have access to palliative care specialists, and it is unclear how commonly opioid rotation is employed by health professionals involved in the care of patients with cancer-related pain, or in outpatient, hospital, and hospice settings.

Opioid rotation, which includes switching the patient to a new opioid, as well as changing the route of administration of a drug already in use, can significantly improve a patient’s quality of life. Patients often gain better analgesia with fewer side effects. Changing to a nonoral route of administration can ameliorate distressing gastrointestinal side effects and can be used in patients with significant gastrointestinal involvement from obstruction, infiltration, or compression by tumor.

More Than a Just a Barrier to Good Pain Management

Lack of recognition of the importance of opioid switching not only is a barrier to good pain management but also may lead to increased morbidity and mortality. Patients with significant side effects, such as sedation, may be bedridden, which increases morbidity and hastens death. Oversedation may also lead to aspiration pneumonia. Constipation and nausea may decrease oral and nutritional intake, leading to weight loss and a catabolic state, which, in turn, may result in tissue breakdown, infection, and increased mortality. Inadequate pain control in combination with confinement to bed may lead to splinting, as well as inadequate ventilation of the lungs and pneumonia.

Switching to Transdermal Fentanyl

Breitbart et al have done a masterful job describing the benefits and challenges of changing from another opioid to transdermal fentanyl (Duragesic). They correctly point out that the manufacturer’s recommendations for equianalgesic dosing can result in initial transdermal fentanyl doses that are too low in some patients. The authors’ proposed algorithm for dosing transdermal fentanyl is a valuable contribution to the literature on pain and palliative care, providing a safe and effective way to change from an orally or intravenously administered opioid analgesic to transdermal fentanyl. Although the conversion process suggested in this review is both reasonable and well thought out, this algorithm requires adoption by other practitioners in order to clarify and confirm the doses calculated.

Compared with oral morphine, transdermal fentanyl has been shown to be associated with improved patient satisfaction[22] and better quality of life, with less constipation, less daytime drowsiness, and less disruption to daily life.[23] Constipation also is less of an issue with transdermal fentanyl than with parenteral approaches.[22,24]

A comparison of transdermal fentanyl vs sustained-release oral forms of morphine performed in 504 cancer patients demonstrated that patients who were treated with transdermal fentanyl were more satisfied overall with their pain medication than those who received sustained-release oral morphine (P = .035). Pain intensity, sleep adequacy, and symptoms did not differ significantly between the two groups.[22]

A basic tenet of pain management is that analgesia should be administered in the safest, least invasive route possible; consequently, the oral route is commonly endorsed as the preferred method of administration. Since studies have shown that the patch system is often preferred by patients and is potentially associated with fewer adverse effects,[22,24] it could be argued that the transdermal route is equal to or better than the oral route. With the help of the dosing guidelines presented in this article, it is reasonable to consider using the transdermal system as a first-line therapy for moderate to severe pain.

Determining Equianalgesia in a World of Incomplete Cross-Tolerance

Published equianalgesic dose tables for converting from one opioid to another are derived from single-dose studies and should provide a rough guide when selecting a starting dose of a new drug or when changing the route of administration of a drug already in use. When switching, it is important to determine the total amount of opioid given during the previous 24 hours, calculate the equianalgesic dose, and then, for most opioids, divide by 30% to 50% (or by > 90% if the new drug is methadone).[13] Decreasing the dose is necessary, since there is incomplete cross-tolerance among the opioid analgesics.[21]

Since, unfortunately, direct comparisons of the efficacy of opioids are rare, the expert consensus algorithm described in the article by Breitbart et al and the multicenter study conducted by Donner et al[24] are very helpful in determining the appropriate dose of transdermal fentanyl. Previous studies have shown significant problems with underestimating the dose when converting from oral morphine to transdermal fentanyl and overestimating the dose when reverting to oral morphine from the patch.[25] This algorithm will remedy those problems. When an inadequate dose is selected, the patient and caregiver can quickly become disillusioned and reject the use of a potentially beneficial drug just because the initial dose was too low.

Points Worthy of Further Discussion

Although the algorithm developed by Breitbart et al is excellent, some points made in the article are worthy of further discussion. The choice of 60 mg/d of oral morphine as equivalent to 25 µg/h of transdermal fentanyl in cancer patients with chronic pain is reasonable. The conversion ratio for oral morphine to transdermal fentanyl of approximately 2:1 is easily remembered. Since available patch strengths are limited, it is necessary to round up or down to the nearest available patch strength. Whatever method is employed, liberal use of a short-acting rescue medication will prevent escalation of pain or withdrawal-type symptoms.

Confirmation of the proposed conversion ratio in a randomized, placebo-controlled study would support the conclusions reached by Breitbart and colleagues, since the study by Donner et al[24] was open labeled and nonrandomized. It is also important to determine whether the conversion ratios hold for higher doses. A number of studies have demonstrated that conversion ratios may vary as the dose of the opioid that is to be changed increases. The incompleteness of analgesic cross-tolerance also may be affected by the length of time that a patient has been taking an opioid analgesic.

Other studies have attempted to remedy the inadequate existing information on more effective and appropriate opioid conversion. In one study, controlled-release formulations of oxy-codone and morphine, at a ratio of 2:3, provided comparable analgesia,[26] while in another study, the effective methadone dose was only 3% of the equianalgesic hydromorphone dose calculated from the standard tables.[27]

Other studies support the need for caution when converting to methadone from another opioid and also demonstrate that incomplete cross-tolerance may increase when higher doses of an opioid are being converted to methadone.[13,28] Further investigation is needed to determine whether opioid conversion ratios change at higher opioid doses and whether the dose ratios are strongly dependent on the previous opioid dose.

Perhaps most importantly, successful conversion from one opioid to another, when performed in the outpatient setting, requires close follow-up through phone contact. Significant input from the physician’s staff is needed to carry out the recommendations outlined by the authors; this is usually done over the phone. Patients or caregivers must feel comfortable about making these changes in the absence of an office visit.

Recommendation 3 of Breitbart et al, which focuses on the treatment of breakthrough pain during the initial phase of conversion to transdermal fentanyl, is therefore very important. Patients must be made aware that transdermal fentanyl does not reach a steady-state level for 72 hours, and that a supplemental opioid will be needed until steady state is attained. Furthermore, it is important to clarify that this supplemental medication is different from the additional medication that can be used for breakthrough pain. The authors’ use of the phrase “treating breakthrough pain during titration” to describe recommendation 3 confuses these separate issues of continuing the previously used opioid until steady state is achieved and using another opioid for breakthrough pain.

Another important point related to recommendation 4-the long-term treatment of breakthrough pain-should be stressed. As the dose of the transdermal system is increased and once steady state is achieved, further escalations of the fentanyl dose should be accompanied by an increase in the dose of the rescue medication for breakthrough pain so that it remains at 5% to 15% of the total 24-hour dose.

Although frequent use of medications for breakthrough pain may be an indication to increase the dose of the longer-acting opioid, it is unclear why the authors selected more than three doses of a breakthrough medication as an indication to increase the strength of the patch. In my view, this number needs to be individualized to the patient. Breakthrough pain can vary from day to day. Increasing patch strength without recognizing this variability could lead to an increase in unwanted side effects.

Unanswered Questions

An important question to consider when using transdermal fentanyl is the role of the new oral transmucosal fentanyl (Actiq, Oralet) as a rescue medication. The fast onset of action of the transmucosal fentanyl seems ideal for breakthrough pain. Use of long- and short-acting preparations of the same analgesic is often recommended (eg, sustained- and immediate-release morphine). Should the same recommendation be routine for fentanyl?

Another key question that needs to be addressed is, how many fentanyl patches can be used as the need arises to escalate the dose? The pure mu-opioid agonists have no maximum or ceiling dose. The dose of these agents can be increased until an adequate level of analgesia is obtained or until analgesia reaches a balance with side effects.

A related question to consider is, what happens to patient satisfaction as the number of patches needs to be increased, as compared with increasing the number of pills? In the study by Donner et al,[24] the highest dose of transdermal fentanyl reached was 500 µg/h.

Conclusions

There is a major impetus within the pharmaceutical industry to develop long-acting opioid analgesics. Several 24-hour preparations will soon be available in pill form, and other transdermal systems are being investigated. Novel approaches for the delivery of medication through the skin include the iontophoretic devices that are currently under development.[29]

The transdermal fentanyl system is the only currently available opioid that provides analgesic effects lasting 3 days and that is both well tolerated and, in some studies, preferred to oral regimens. The recommendations made by Breitbart et al provide a useful algorithm for dosing transdermal fentanyl in the management of cancer-related pain and are an important contribution to the pain and palliative care literature.

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