Optimizing Pain Control With Fentanyl Patches

Meredith McLean, PharmD; Jeffrey Fudin, BS, PharmD


July 15, 2008

How often can fentanyl patches be replaced to optimize pain control? That question and its answer might seem straightforward, but when we published a column on the topic earlier this year,[1] readers flooded us with more questions related to the appropriate use of fentanyl transdermal patches (FTPs). This column seeks to address some of the most pressing issues that clinicians face today when using this important agent in the management of pain.

Q: What is the maximum dose of fentanyl for in-hospital use?

A: The only dosage limit on fentanyl occurs when side effects or toxicity overcome the therapeutic benefit; otherwise, there is no set quantity assigned as a maximum dosage. The package insert provides conservative estimates of morphine to fentanyl conversions for fentanyl doses as high as 300 mcg per hour.[2] A brief case report published in the Journal of the American Board of Family Medicine described an elderly gentleman with rectal carcinoma, whose fentanyl dosage was titrated to 1000 mcg/hr (10 100-mcg patches) with good pain control.[3] Another case, published in the European Journal of Pain in 2001, reported a woman with a tumor of the left lung receiving 3400 mcg/hr (thirty-four 100-mcg patches) for uncontrolled neuropathic pain.[4]

Opioid-experienced patients generally can tolerate higher doses due to opiate receptor down-regulation. FTP doses may be adjusted 3 days after initiation of therapy and at 6-day intervals thereafter, with the goal of achieving adequate analgesia.[5] Tolerability typically will be the dose-limiting factor. In patients receiving high transdermal doses (multiple patches), body surface area may also play an important role in absorption.[3]

Q: What is the half-life of fentanyl in the body? How long would one have to stop using FTP before switching to extended-release morphine?

A: The pharmacokinetics of FTP shows broad interpatient and intrapatient variability. Elimination of fentanyl after discontinuation is slow, with an elimination half-life after patch removal of about 17 hours, ranging from 13 to 22 hours.[5] This is due to the slow release of drug from the skin depot commensurate with transdermal delivery. However, the elimination half-life in the elderly may be prolonged.[5] Careful consideration should be taken transitioning from FTP to an extended-release morphine product, particularly if the patient is on high-dose opioids.

Once the fentanyl patch is removed, the patient may be transitioned to morphine by administering half of the morphine-equivalent dose in immediate release (IR) formulation every 4 hours for 2 to 4 days, until the lowest possible pain level is maintained. Afterward, the IR formulation may be converted to a sustained-release (SR) formulation given at appropriate dosing intervals.[6] Due to prolonged pharmacokinetics associated with FTP, the dose titration phase may be extended as fentanyl is slowly released from the depot and ultimately metabolized. After patch removal, the analgesic effects of fentanyl may continue for 12 to 24 hours.[5]

Q: How can you get Medicare and private insurers to pay for a shorter FTP dosing schedule because the patches generally are restricted to replacement every 72 hours?

A: The decision to approve or deny a prescription claim rests with the individual insurer. Some third-party payers allow clinicians to present information for a "prior authorization." In this instance, clinicians provide documentation to the insurer stating that a specific medication and/or medication schedule is medically necessary and that the care plan is evidence based. This information purportedly is evaluated by a committee at the insurer, and a ruling is based on financially and medically sound criteria. Patients also may provide this information to their insurer. Numerous published cases have established the appropriateness of a shortened dosing interval.[1]

Q: Have researchers studied "end-of-dose failure" for other sustained-release opioid medications?

A: Several studies have evaluated end-of-dose failure with sustained-release morphine, oxymorphone, and oxycodone. A survey of patients with chronic pain using SR oxycodone identified end-of-dose failure as the primary reason for patients increasing the dose frequency above the manufacturer's recommendations. Another study evaluated usage patterns in patients taking controlled-release (CR) oxycodone; 17.5% reported a dosing interval of 12 hours or longer, even though 1.9% said their pain relief lasted that long.[8] Gallagher and colleagues studied patients using oxycodone CR, methadone, and morphine CR; they found that many patients using opioids for chronic nonmalignant pain needed more frequent doses than that recommended by product labeling, and many patients were taking 3-4 extra doses of rescue opioid per day,[9] still without achieving adequate pain relief.

Q: If a fentanyl patch comes off or becomes loosened before a scheduled patch change, can it be replaced with a new one?

A: In the authors' experience, it may be prudent to apply a new patch to the same location on the skin as the prior patch. The reason for this is that the skin depot of fentanyl that accumulates during patch adherence is already available and will be less likely to result in decreased serum concentrations from a break in therapy. The newly applied patch should remain on for the full 72 hours or as otherwise directed by the prescription. If patch adherence becomes a chronic problem, occlusive dressings may be applied over the patch to improve skin adhesion.

Q: Is there any way to keep fentanyl from getting into the system too fast?

A: Case reports have indicated that extraneous heat application to a fentanyl patch has increased systemic absorption of the drug.[5] Heating pads, tanning beds, electric blankets, hot tubs, saunas, and heated water beds should be avoided while using FTPs. Hot baths and sunbathing also should be discouraged.[2] Fentanyl absorption is thought to increase by about 30% with a rise in body temperature to 104ºF (40ºC).[2] Therefore, patients using FTPs who develop fevers should be monitored for increased toxicity. There are no approved methods of slowing the FTP absorption rate.

Q: Is it true that fentanyl patches infuse more quickly in patients with very little subcutaneous fat?

A: No. The amount of fentanyl absorbed is proportional to the surface area of the patch. The absorption rate does not vary to any clinically significant extent between the chest, abdomen, and thigh.[5] Fentanyl is released from the patch into top layers of the skin (stratum corneum and epidermis), and it accumulates within these layers to form a depot. The drug is released slowly into the systemic circulation via small blood vessels within the dermis. Fat tissue should not impair release, as the drug is released directly from the skin into the blood supply.[2,5]

Furthermore, fentanyl exhibits wide tissue distribution to the lungs, kidneys, heart, spleen, brain, muscles, and body fat -- indicating a high extravascular volume of distribution (3-8 L/kg). It takes about 6 days to reach steady-state plasma concentrations after initiating fentanyl patch therapy.[5]

Q: What is the recommended method of weaning patients from a 25-mcg/hr fentanyl patch if he or she is allergic or intolerant to other opioids?

A: One method would be to leave the patch on the skin beyond the indicated 72 hours, thereby slowly draining the patch of fentanyl into the skin until both the patch and the skin are depleted of active fentanyl. IR breakthrough medication may be needed during this titration.

A second option is switching to another class of opioids, assuming there is no history of allergy. (Note that true opioid allergies are very rare, < 1%.)[10] If a patient is intolerant or allergic to 1 opioid (eg, meperidine, a phenylpiperidine), an opioid from another chemical class (eg, phenanthrenes, diphenylheptanes) may be tried. A low-dose IR oral preparation from a different chemical class may be used for 2 to 4 days.[11]

Adjunctive therapy with clonidine may be beneficial during the "weaning" period. Clonidine can reduce autonomic manifestations of withdrawal such as sweating, tremor, anxiety, agitation, headache, or nausea. A dose of 0.2 mg administered orally 3 times daily may be appropriate,[12] or a clonidine transdermal patch may be considered.

Q: How long does it take for the fentanyl patch to reach a steady rate of absorption?

A: Upon initial application, the patch is designed to release drug at a constant rate for up to 72 hours.[2] Data suggest that neither the local blood supply nor the anatomical site of patch application significantly affect this rate or extend drug absorption. Plasma concentrations are typically proportional to patch delivery rates.[5] It may take 34 to 38 hours to reach a maximum serum concentration of fentanyl after patch application. This is secondary to the formation of a fentanyl depot within the skin, before the drug is allowed to pass into the systemic circulation.[5] Steady-state serum concentrations are typically reached by day 6 and can be maintained with regularly scheduled FTP changes.[5]

Q: Is there any potential advantage to overlapping patches on a rotating schedule?

A: This practice is definitely not evidence-based. It has not been studied, and it can result in unpredictable pharmacokinetics and cause significant morbidity or even death. If multiple patches are needed for pain control, prudent practice is to apply them on the same day and remove all of them at the same time before applying the next scheduled patch(es).

Q: Does the fentanyl patch cause addiction?

A: Narcotics do not "cause" addiction, but chronic use of any habit-forming medication could lead to addiction in a patient who is vulnerable. FTPs are no more or less likely to result in addiction than any other opioid narcotic; however, it is generally more cumbersome to abuse this dosage form compared with oral or injectable narcotics. The fentanyl patch contains a highly concentrated, potent schedule II opioid agonist. Schedule II opioids have a high potential for abuse and accidental overdose. Fentanyl can be abused and is subject to criminal diversion.[2] Many factors may predispose an individual to addiction, including a history of substance abuse, the psychosocial environment, and genetics.[13] These factors should be considered when prescribing, dispensing, or administering any schedule II substance.

Q: Can a patient on warfarin use the fentanyl patch for pain control? If not, which pain control medications can such patients can use?

A: Warfarin is a medication that has the potential for interacting with many other drugs. Many of these interactions are mediated via its hepatic metabolism. Cytochrome (CYP) P450 enzymes are responsible for the metabolism of many drugs. The CYP isoenzymes involved with warfarin metabolism include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4, with 2C9 being primarily responsible for the metabolism of S-warfarin, the active isomer of warfarin. Drugs that induce or inhibit these isomers -- particularly CYP 2C9 -- may interact with the metabolism of warfarin.[14]

Fentanyl is predominantly metabolized via CYP 3A4 by N-dealkylation to norfentanyl,[15] an inactive metabolite, and although this enzyme also metabolizes some warfarin, it is much less likely to cause a significant alteration in warfarin metabolism. Importantly, those medications that are potent inhibitors or inducers of the CYP 3A4 isoenzyme may significantly affect the metabolism of fentanyl. Therefore, potent inhibitors such as azole antifungals, protease inhibitors, diltiazem, and macrolide antibiotics should be used cautiously in patients concomitantly receiving fentanyl because those other drugs may elevate the serum plasma levels of fentanyl and prolong or increase adverse drug events.[2] Conversely, caution must be used if abruptly discontinuing an enzyme inhibitor, because the serum levels of fentanyl could drop precipitously, resulting in increased pain or withdrawal.

In summary, fentanyl is a safe alternative for pain control in a patient concomitantly using warfarin. Still, despite the lack of a significant interaction between these 2 drugs, it is always wise to inform clinicians managing a patient's warfarin therapy of any other new, discontinued, or dose-adjusted medication.

This commentary is the sole opinion of the authors and does not reflect the opinion of, nor was it reviewed by, any government agency. It was not prepared as a part of the authors' official government duties in their respective capacities as a Pharmacy Resident or Clinical Pharmacy Specialist.


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