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Mechanism of Action
Fentanyl is a pure opioid agonist whose principal therapeutic action is analgesia. Other members of the class known as opioid agonists include substances such as morphine, oxycodone, hydromorphone, codeine, and hydrocodone.
Pharmacological effects of opioid agonists include anxiolysis, euphoria, feelings of relaxation, respiratory depression, constipation, miosis, cough suppression, and analgesia. Like all pure opioid agonist analgesics, with increasing doses there is increasing analgesia, unlike with mixed agonist/antagonists or non-opioid analgesics, where there is a limit to the analgesic effect with increasing doses. With pure opioid agonist analgesics, there is no defined maximum dose; the ceiling to analgesic effectiveness is imposed only by side effects, the more serious of which may include somnolence and respiratory depression.
In general, the effective concentration and the concentration at which toxicity occurs increase with increasing tolerance with any and all opioids. The rate of development of tolerance varies widely among individuals. As a result, individually titrate the dose of ABSTRAL to achieve the desired effect [see DOSAGE AND ADMINISTRATION].
Central Nervous System
The precise mechanism of the analgesic action is unknown although fentanyl is known to be a μ-opioid receptor agonist. Specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug.
Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves both a reduction in the responsiveness of the brain stem to increases in carbon dioxide and to electrical stimulation.
Fentanyl causes miosis even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings).
Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and in the duodenum. Digestion of food is delayed in the small intestine and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid induced-effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.
Fentanyl may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.
Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin secretion, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon in humans and other species (e.g., rats and dogs). Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids.
All opioid mu-receptor agonists, including fentanyl, produce dose-dependent respiratory depression. The risk of respiratory depression is less in patients receiving chronic opioid therapy who develop tolerance to these effects. Peak respiratory depressive effects may be seen as early as 15 to 30 minutes from the start of oral transmucosal fentanyl citrate administration and may persist for several hours.
Serious or fatal respiratory depression can occur even at recommended doses. Fentanyl depresses the cough reflex as a result of its CNS activity. Although not observed with oral transmucosal fentanyl products in clinical trials, fentanyl given rapidly by intravenous injection in large doses may cause rigidity in the muscles of respiration resulting in respiratory difficulties. Therefore, be aware of this potential complication [see BOXED WARNING - WARNINGS: Importance Of Proper Patient Selection and Potential for Abuse, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, and OVERDOSAGE].
Fentanyl is a highly lipophilic drug. Orally administered fentanyl undergoes pronounced hepatic and intestinal first pass effects. Absorption of fentanyl from ABSTRAL sublingual tablets is mainly through the oral mucosa.
The bioavailability of ABSTRAL sublingual tablets has been calculated to be 54%.
Dose proportionality across the 100 mcg to 800 mcg ABSTRAL dose range has been demonstrated (Table 3). Mean plasma fentanyl levels following single doses of ABSTRAL are shown in Figure 1. The median time to maximum plasma concentration (Tmax) across these four doses of ABSTRAL varied from 30 to 60 minutes (range of 15 – 240 minutes).
1: Mean (+/- SD) Plasma Fentanyl Concentration versus Time after Administration
of Single Doses of 100 mcg, 200 mcg, 400 mcg and 800 mcg ABSTRAL to Healthy
Pharmacokinetic parameters are presented in Table 3.
Table 3: Mean (CV%) Fentanyl Pharmacokinetic Parameters after
Single-Dose Administration of 100, 200, 400 and 800 mcg Doses of ABSTRAL to
Healthy Subjects (n=12 per Dose Level)
|100 mcg||200 mcg||400 mcg||800 mcg|
|Cmax||(ng/mL)||0.187 (33)||0.302 (31)||0.765 (38)||1.42 (33)|
|Tmaxa||(min)||30 [19-120]||52 [16-240]||60 [30-120]||30 [15-60]|
|AUC0-inf||(ng•h/mL)||0.974 (34)||1.92 (27)||5.49 (35)||8.95 (33)|
|T½||(h)||5.02 (51)||6.67 (30)||13.5 (37)||10.1 (34)|
|a median (range)|
In another study, dose proportionality between 800 mcg and 1600 mcg in Cmax and AUC has also been demonstrated.
Pharmacokinetic studies have shown that multiple tablets are bioequivalent to single tablets of the equivalent dose.
Fentanyl is highly lipophilic. Animal data showed that following absorption, fentanyl is rapidly distributed to the brain, heart, lungs, kidneys and spleen followed by a slower redistribution to muscles and fat. The plasma protein binding of fentanyl is 80-85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The free fraction of fentanyl increases with acidosis. The mean volume of distribution at steady state (Vss) was 4 L/kg.
Fentanyl is metabolized in the liver and in the intestinal mucosa to norfentanyl by cytochrome P450 3A4 isoform. Norfentanyl was not found to be pharmacologically active in animal studies [see DRUG INTERACTIONS].
Fentanyl is more than 90% eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites. Less than 7% of the dose is excreted unchanged in the urine, and only about 1% is excreted unchanged in the feces. The metabolites are mainly excreted in the urine, while fecal excretion is less important. The total plasma clearance of fentanyl was 0.5 L/hr/kg (range 0.3 - 0.7 L/hr/kg).
The efficacy of ABSTRAL was investigated in a clinical trial in opioid tolerant adult patients experiencing breakthrough cancer pain. Breakthrough cancer pain was defined as a transient flare of moderate-to-severe pain occurring in patients with cancer experiencing persistent cancer pain otherwise controlled with maintenance doses of opioid medications including at least 60 mg morphine/day, 50 mcg transdermal fentanyl/hour, or an equianalgesic dose of another opioid for 1 week or longer. All patients were on stable doses of either long-acting oral opioids or transdermal fentanyl for their persistent cancer pain.
A double-blind, placebo-controlled, crossover study was performed in patients with cancer to evaluate the effectiveness of ABSTRAL for the treatment of breakthrough cancer pain. Open-label titration identified a dose of ABSTRAL in which a patient obtained adequate analgesia with tolerable side effects, within the range of 100 mcg to 800 mcg. In the double-blind efficacy study, patients who identified a successful dose were randomized to a sequence of 10 treatments; seven with ABSTRAL and three with placebo.
Of the 131 patients who entered the titration phase of the study, 78 (60%) achieved a successful dose during the titration phase. Sixty-six patients entered the double-blind phase and 60 completed the study. The dose of ABSTRAL was determined by titration starting at 100 mcg. The final titrated dose of ABSTRAL for breakthrough cancer pain was not predicted from the daily maintenance dose of opioid used to manage the persistent cancer pain. In a second open-label safety study using an identical titration regimen, 96 of 139 patients (69%) who entered the study titrated to a dose in which the patient obtained adequate analgesia with tolerable side effects during the titration phase. Table 4 presents the final titrated dose for both the double-blind efficacy and open-label safety studies.
Table 4: Final dose of ABSTRAL following initial titration in all
clinical efficacy and safety studies
|100 mcg||11 (6)|
|200 mcg||15 (9)|
|300 mcg||35 (20)|
|400 mcg||25 (14)|
|600 mcg||40 (23)|
|800 mcg||48 (28)|
The primary outcome measure, the mean sum of pain intensity difference at 30 minutes (SPID30) for ABSTRAL-treated episodes was statistically significantly higher than for placebo-treated episodes.
Figure 2: Mean Pain Intensity Difference (±SE) for ABSTRAL
Compared to Placebo
Last reviewed on RxList: 6/13/2012
This monograph has been modified to include the generic and brand name in many instances.
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