Commentary (Carr/Goudas): An Alternative Algorithm for Dosing Transdermal Fentanyl for Cancer-Related Pain

To assist in converting patients from one opioid agent to another in their daily practice, many oncologists carry pocket dosage conversion guides based on package inserts approved by the US Food and Drug Administration (FDA). One such guide issued by the manufacturer of transdermal fentanyl (Duragesic), reproduced in Table 3 of the expert consensus article written by Breitbart et al, presents the equivalent of 25 µg/h of transdermal fentanyl as 45 to 134 mg/d of oral morphine. In another guide, distributed by one of the manufacturers of controlled-release morphine, the 25 µg/h strength of transdermal fentanyl is said to be equianalgesic to 15 mg of controlled-release morphine administered every 12 hours (and both are deemed equivalent to 10 mg of controlled-release oxycodone every 12 hours). Faced with such a wide range of conversion factors, it is of little surprise-as Breitbart et al point out-that clinicians often fail to achieve equianalgesia when converting patients from one opioid to another.

Simple Rules of Thumb

The recommendations offered by Breitbart and his expert coauthors distill a vast amount of experience into several simple rules of thumb: Simply put, they first recommend a conversion ratio of about 2:1 when changing patients from oral morphine (dose expressed in mg/d) to transdermal fentanyl (dose expressed in µg/h). According to this recommendation, a total daily dose of 120 mg of morphine should be changed, when clinically indicated, to a transdermal fentanyl dose of about 60 µg/h. In practice, because transdermal fentanyl doses are limited, one would choose the 50-µg/h strength. In the future, if a 12.5-µg/h dose of transdermal fentanyl becomes available, one might possibly apply this “patch” in addition to the 50-mg/h strength, so as to commence therapy with 62.5 µg/h.

Not every patient receives oral morphine, but like the US dollar or the Euro, doses of whatever opioid the patient is receiving are converted to and from this common “currency” because it is a well-understood benchmark. Yet, despite this theoretical equivalence, not all currencies (or all opioids) are equivalent in the “real” world, as each one cannot be used interchangeably for all purposes in every setting. (Try, for example, to pay for a meal in Rome using Russian rubles!)

>Clinical Insights Inform Basic Science-and Vice Versa

In recent years, basic scientists have clarified the insights of clinicians who observed that opioid rotation may restore analgesia in the patient who has become tolerant to one opioid, or may achieve analgesia in the first place in a patient whose pain has been poorly controlled despite maximal doses of one opioid. Clinicians (ourselves included) were taught that all morphine-like opioids were equivalent, provided that one adjusted the dose accordingly. Only with reluctance did practitioners grasp the subtle, and sometimes not-so-subtle, differences between different individual responses to the same opioid, or one individual’s responses to different mu-opioids. This heterogeneity of individual responsiveness reflects the variability in pharmacokinetics (yielding a spectrum of active and inactive metabolites) and pharmacodynamics evident across genetically distinct “strains”[1] or genders.[2] Mu-opioids in daily use, such as methadone, are now recognized as having significant nonopioid effects that range from inhibition of synaptic reuptake of amines[3] to antagonism of glutamate action on the N-methyl-d-aspartate (NMDA) receptor.[4,5] Interestingly, the partial nonselectivity of many mu-opioids that also act on non–mu-opioid receptors raises the possibility of analgesic synergy resulting from concurrent mu- and non–mu-opioid receptor occupancy after a single opioid dose.[6] Support for this idea comes from the finding by Ventafridda et al[7] of a slower rate of dosage escalation during treatment of cancer pain with methadone than with morphine, consistent with methadone’s capacity to concurrently activate the mu-opioid receptor and block the NMDA receptor. A clinical implication of deliberately prescribing opioid regimens that activate diverse receptors might be to select a mu-opioid molecule for breakthrough pain that is different from the mu-opioid administered around the clock for continuous pain control.

Aggressive Treatment of Breakthrough Pain

Based on their clinical experience, Breitbart et al advocate aggressive treatment of breakthrough pain, both early during titration of the transdermal fentanyl dose and after a steady state of fentanyl has been achieved. Their corresponding recommendations are easily remembered as two “25% rules.” For each episode of breakthrough pain that occurs during the initial titration of transdermal fentanyl dose, 25% of the prior total daily dose of opioid should be administered. When a stable fentanyl dose has been achieved, frequent episodes of breakthrough pain (four or more per day) should be treated by increasing the baseline dose of transdermal fentanyl by at least 25%.

The availability of exciting, new methods to treat as well as study (through innovative clinical trial designs) the phenomenon of breakthrough pain should advance the care of this often overlooked and undertreated problem.

Importance of Dosage Frequency

Finally, the authors observe that “when dose selection and titration are too conservative, patient care is adversely affected.” They reiterate information on dosage frequency that, while available in the package insert, is still too often overlooked by practitioners. Some patients observe that their pain control is less than adequate during the third day of transdermal fentanyl dosing; this problem may be solved simply by changing from a 72-hour to a 48-hour dosing schedule.

Conclusions

The simple set of consensus recommendations advanced by Breitbart et al reflect nearly 15 years of worldwide experience with this valuable modality and millions of patient-years of exposure. If widely followed, they should help ease the transition when converting patients from another opioid agent, dose, and route to transdermal fentanyl.

Although, unfortunately, Breitbart et al do not address conversion from transdermal fentanyl to other analgesic agents, the principles that they advocate-aggressive dosing and early, sufficient treatment of breakthrough pain-are equally applicable in this circumstance as well.

References:

1. Mogil JS: The genetic mediation of individual differences in sensitivity to pain and its inhibition. Proc Natl Acad Sci USA 96:7744-7751, 1999.

2. Miaskowski C, Levine JD: Does opioid analgesia show a gender preference for females? Pain Forum, 8:34-44,.1999.

3. Codd EE, Shank RP, Schupsky JJ, et al: Serotonin and norepinephrine inhibiting activity of centrally acting analgesics: Structural determinants and role in antinociception. J Pharmacol Exp Ther 274:1263-1270, 1995.

4. Inturrisi CE: Old dogs, new tricks. Pain Forum 8:210-212, 1999.

5. Morley JS: New perspectives in our use of opioids. Pain Forum 8:200-205, 1999.

6. Yaksh TL, Malmberg AB: Interactions of spinal modulatory receptor systems, in Fields HL, Liebeskind JC (eds): Pharmacological Approaches to the Treatment of Chronic Pain, pp 151-171. Seattle, Washington, IASP Press, 1994.

7. Ventafridda V, Ripamonti C, Bianchi M, et al: A randomized study on oral administration of morphine and methadone in the treatment of cancer pain. J Pain Symptom Management 1:203-207, 1986.