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Fentanyl Effervescent Buccal Tablets in Patients With Chronic Pain

Posted 03/18/2006 Lynn R. Webster, MD, FACPM, FASAM 

Introduction

Most patients with chronic pain experience breakthrough pain (BTP), a sudden, temporary flare-up that occurs against a background of otherwise controlled pain.[1] These episodes peak within an average of 5 minutes and usually last no longer than 20 minutes. Although the event is short-lived, the impact can be excruciating or even incapacitating.[2-4]

The special characteristics of BTP call for medications with unique pharmacologic properties. The list of desired qualities in an ideal medication for BTP include rapid onset, a short duration of action, and quick elimination with no active metabolites left behind to cause adverse side effects. Because medication to treat BTP is taken after the pain event has already started, it should be readily available and simple to use. The drug should also be easy to titrate to an analgesic level that matches the degree of pain experienced, whether neuropathic or nociceptive.

In short, the perfect medication would be a "designer drug," whose analgesic action lasts for the duration of the pain event and then quickly dissipates without side effects. Although a "perfect" medication is not yet available, compared with other medications, fentanyl delivered via the oral mucosa route is particularly well suited to treat BTP. Fentanyl, which is highly lipophilic, rapidly crosses the blood-brain barrier following intravenous (IV) or oral transmucosal administration and is eliminated quickly. In contrast, hydrophilic medications such as morphine are absorbed and eliminated much slower. Oxycodone and other short-acting opioids are not optimal for treating BTP because their peak blood levels usually occur when the pain has already begun to wane.

Presently, only oral transmucosal fentanyl citrate (OTFC) is available as a rapid-onset, non-IV medication for BTP. However, a new formulation of a fentanyl effervescent buccal tablet (FEBT) is now in development and, although not a perfect drug, it promises to meet several of the desired specifications for a BTP medication. FEBT is placed between the cheek and gum adjacent to an upper molar and allowed to dissolve for 10-15 minutes. This delivery system features characteristics that differentiate it from OTFC. One is the effervescent action, which facilitates the rate and efficiency of absorption through shifts in the pH balance.[5] An additional feature is the lack of stigma offered by the discreet dosing method -- no stick betrays the presence of the medication as with the OTFC lollipop.

Bioavailability of FEBT

In clinical studies, FEBT delivered more fentanyl across the oral mucosa than did a comparable dose of OTFC. Part of the reason for this lies in the delivery system. The buccal delivery route allows for avoidance of the gastrointestinal tract and first-pass liver metabolism. With OTFC, a portion of the medication is swallowed, diluting and delaying its absorption far beyond the duration of the breakthrough event. OTFC takes an average of 10 minutes to achieve analgesia.[6] Along with greater bioavailability, FEBT is expected to have a quicker onset of analgesia.

In one trial, the absorption rates of 2 separate formulations of fentanyl buccal tablets (200 mg) were compared with absorption rates of OTFC.[7] The 2 formulations of buccal tablets were prepared to test whether effervescence and variation in pH enhance delivery. When blood serum levels for the first 30 minutes were assessed, faster absorption of fentanyl compared with the effervescent buccal tablet was clearly evident. The enhanced absorption helps FEBT deliver analgesia with a lower dose than that needed with OTFC.

Safety and Tolerability of FEBT

FEBT has performed well in phase 3 safety studies. One trial with 360 subjects showed it to be well tolerated. Another double-blind, placebo-controlled trial of 123 cancer patients treated with FEBT showed a statistically significant improvement on the primary endpoint, a measure of the Sum of Pain Intensity Difference scale (P < .01).[8]

This author was a principal investigator in a recent 4-month interim analysis of safety and tolerability data in 94 opioid-tolerant patients with chronic noncancer pain.[9] The patients, who experienced 1-4 episodes of BTP per day, reported low-back pain as the most frequent complaint (61 out of 94, or 65% of patients). They were using at least 60 mg/day of oral morphine (or the equivalent) as around-the-clock therapy or at least 50 micrograms (mcg)/hour of transdermal fentanyl for 7 days prior to the administration of FEBT.

Patients were titrated to an effective dose, and safety and tolerability were assessed by evaluating vital signs (heart rate, respiration, and systolic and diastolic blood pressure), weight, and adverse events. Forty-five patients (48%) identified ≤ 600 mcg as an effective dose of FEBT, 41 (44%) were managed at the 800-mcg dose, and 8 patients (9%) did not find an effective FEBT dose (Figure).

Figure.  (click image to zoom) Proportion of patients at each dose of FEBT for the effective doses of FEBT. The effective dose of FEBT is defined as the single dose strength of FEBT used consistently for episodes of BTP during the titration period. n = number of patients at each dose of FEBT. Proportions of patients do not total 100% because 9% of patients were unable to find an effective dose of FEBT. Source: Hale ME, Webster LR, Peppin JF, Messina J. Open-label study of fentanyl effervescent buccal tablets in patients with chronic pain and breakthrough pain: interim safety and tolerability results. Program and abstracts of the annual meeting of the American Academy of Pain Medicine; February 22-25, 2006; San Diego, California. Abstract 120. Published with permission of Lynn R. Webster, MD.

The data suggest that FEBT is safe and well tolerated in opioid-tolerant patients with chronic noncancer pain. There was no respiratory depression, and a low incidence of treatment-related adverse events was reported. Thirty-five patients (37%) reported having at least 1 adverse event, the most common of which were nausea (7%) and dizziness (5%).

Potential Applications for FEBT and Important Considerations for Appropriate and Safe Use

Several different types of patients could benefit from the targeted pain relief offered by FEBT. The first and most obvious benefactors are sufferers of BTP, which is of 2 varieties. The first is spontaneous pain, which comes on without warning and is marked by a sudden, often disabling crescendo. Spontaneous pain is common in neuropathic pain conditions. An example is the sharp, lancinating pain suffered during attacks of acute shingles or postherpetic neuralgia. The second type of BTP is incident pain, which is anticipated pain. A patient who is nonambulatory following hip or knee surgery but who is planning to move, perhaps to participate in a social event, is anticipating an episode of incident pain. This patient could take FEBT 5 minutes before the anticipated painful move.

FEBT could be useful as a rescue medication in other instances as well. In addition to supplementing around-the-clock opioids, it could be administered as a sole medication for isolated pain incidents. This need would arise when short episodes of moderate-to-severe pain require only brief periods of analgesia. Procedures such as biopsies or painful events such as physical therapy are examples. A medication such as FEBT would be a less invasive, cheaper alternative to an IV and would eliminate concerns about exposure to blood-product contamination, which is a risk with a difficult IV access. FEBT could deliver "abortive therapy" for severe pain events such as migraines recalcitrant to other treatments. An advantage is the medication's ability to deliver targeted pain relief only for the duration of the pain.

It should be noted that FEBT is not a perfect solution for brief pain events. Like any potent opioid, fentanyl carries the disadvantage of being liable to abuse. FEBT is highly lipophilic and thus prone to delivering the "binge" effect sought by abusers under certain conditions. In addition, as with any opioid delivered outside a hospital setting, it has a potential for diversion to black-market sales. Some consider the introduction of rapid-onset analgesics somewhat risky outside of the cancer population, which traditionally has low rates of abuse. The potential for the abuse of fentanyl delivered through the oral mucosa is not yet known, and no risk-management studies to determine the potential have been performed with FEBT. Although the manufacturer has said that it considers OTFC to be an ineffective route for would-be abusers of fentanyl, there have been some reports of abuse of the lozenge.

Until more is known, care should be observed in prescribing any rapid-onset, lipophilic opioid, including FEBT, to persons with serious current or lifetime substance-use disorders. One could go further and say that FEBT should be prescribed only to patients who have proven themselves compliant and reliable. Recent evidence, however, bolsters a growing view that drug properties contribute less to the development of drug abuse and addiction than previously thought. In a study of 72 frequent users of heroin -- a highly lipophilic, rapid-onset opiate -- the subjects took an average of 9 months to become addicted.[10] Thus it appears -- as many experts believe already -- that the drug properties constitute a less important risk factor for abuse than the individual's genetics and environmental influences.

In a further caution, as with any opioid, respiratory depression is a risk. To target the incident pain in an opioid-naive patient, including one about to undergo a painful procedure, one would need to titrate carefully. This, however, should not be a clinical problem because the available dosages (100, 200, 400, 600, and 800 mcg) are easy to titrate, and a low starting dose can be introduced.

Conclusion

In summary, FEBT is a new rapid-onset opioid analgesic for BTP that has been shown to be effective for both cancer and noncancer pain. The onset and duration of analgesia appear to match many types of BTP with a quicker demonstrated absorption than is achieved with OTFC. Over time, clinical use will determine its appropriate place in the armamentarium of pain therapy.

Funding Information
Supported by an independent educational grant from Cephalon.