Chemical formula: C₂₂H₂₈N₂O Molecular mass: 336.471 g/mol PubChem compound: 3345
Fentanyl is a potent µ-opioid analgesic with rapid onset of analgesia and short duration of action. Its primary therapeutic actions are analgesia and sedation and is approximately 100-fold more potent than morphine as an analgesic. Secondary effects of fentanyl on central nervous system (CNS), respiratory and gastro-intestinal function are typical of opioid analgesics and are considered to be class effects. These can include respiratory depression, bradycardia, hypothermia, constipation, miosis, physical dependence and euphoria.
Fentanyl can be used as an analgesic supplement to general anaesthesia or as the sole anaesthetic. Fentanyl preserves cardiac stability, and obtunds stress-related hormonal changes at higher doses. A dose of 100 micrograms (2.0 ml) is approximately equivalent in analgesic activity to 10 mg of morphine. The onset of action is rapid. However, the maximum analgesic and respiratory depressant effect may not be noted for several minutes. The usual duration of action of the analgesic effect is approximately 30 minutes after a single IV dose of up to 100 micrograms. Depth of analgesia is dose-related and can be adjusted to the pain level of the surgical procedure. Fentanyl has a broad safety margin. In rats, the ratio LD50/ED50 for the lowest level of analgesia is 277, as compared with 69.5 and 4.6 for morphine and pethidine respectively.
Like other opioid analgesics, fentanyl, depending upon the dose and speed of administration, can cause muscle rigidity, as well as euphoria, miosis and bradycardia.
Histamine assays and skin-wheal testing in man, as well as in vivo testing in dogs, have indicated that clinically significant histamine release is rare with fentanyl.
All actions of fentanyl are immediately and completely reversed by a specific opioid antagonist, such as naloxone.
Opioids may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical signs and symptoms may be manifest from these hormonal changes.
Fentanyl, in common with all µ-opioid receptor agonists, produces dose dependent respiratory depression. This risk is higher in opioid-naïve subjects than in patients experiencing severe pain or receiving chronic opioid therapy. Long-term treatment with opioids typically leads to development of tolerance to their secondary effects.
While opioids generally increase the tone of urinary tract smooth muscle, the net effect tends to be variable, in some cases producing urinary urgency, in others, difficulty in urination.
Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract leading to a prolongation in gastrointestinal transit time, which may be responsible for the constipating effect of fentanyl.
Fentanyl is a highly lipophilic drug absorbed very rapidly through the oral mucosa and more slowly through the gastrointestinal tract. Orally administered fentanyl undergoes pronounced hepatic and intestinal first pass effects. Abstral is a quick dissolving sublingual tablet formulation. Rapid absorption of fentanyl occurs over about 30 minutes following buccal administration. The absolute bioavailability has been calculated to be 54%. Mean maximal plasma concentrations of fentanyl range from 0.2 to 1.3 ng/ml (after administration of 100 to 800 µg fentanyl) and are reached within 22.5 to 240 minutes.
Following intravenous injection, there is a short distribution phase during which high concentrations of fentanyl are achieved quickly in well-perfused tissues such as the lungs, kidneys and brain.
The fentanyl transdermal patch provides continuous systemic delivery of fentanyl during the 72-hour application period. Following patch application, the skin under the system absorbs fentanyl, and a depot of fentanyl concentrates in the upper skin layers. Fentanyl then becomes available to the systemic circulation. The polymer matrix and the diffusion of fentanyl through the layers of the skin ensure that the release rate is relatively constant. The concentration gradient existing between the system and the lower concentration in the skin drives drug release. The average bioavailability of fentanyl after application of the transdermal patch is 92%.
After the first patch application, serum fentanyl concentrations increase gradually, generally leveling off between 12 and 24 hours and remaining relatively constant for the remainder of the 72-hour application period. By the end of the second 72-hour application, a steady-state serum concentration is reached and is maintained during subsequent applications of a patch of the same size. Due to accumulation, the AUC and Cmax values over a dosing interval at steady state are approximately 40% higher than after a single application. Patients reach and maintain a steady-state serum concentration that is determined by individual variation in skin permeability and body clearance of fentanyl. High inter-subject variability in plasma concentrations has been observed.
A pharmacokinetic model has suggested that serum fentanyl concentrations may increase by 14% (range 0-26%) if a new patch is applied after 24 hours rather than the recommended 72-hour application.
Skin temperature elevation may enhance the absorption of transdermally-applied fentanyl. An increase in skin temperature through the application of a heating pad on low setting over the Matrifen system during the first 10 hours of a single application increased the mean fentanyl AUC value by 2.2-fold and the mean concentration at the end of heat application by 61%.
Fentanyl after nasal use, utilises the nasal drug delivery system to modulate the delivery and absorption of fentanyl. The PecSys system allows the product to be sprayed into the front area of the nasal cavity as a fine mist of droplets, which gel on contact with the calcium ions present in the nasal mucosa. Fentanyl diffuses from the gel and is absorbed through the nasal mucosa; this gel-modulated absorption of fentanyl restrains the peak in plasma concentration (Cmax) whilst allowing the attainment of an early time to that peak (Tmax). In a pharmacokinetic study comparing fentanyl nasal spary, solution (100, 200, 400 and 800 micrograms) with oral transmucosal fentanyl citrate (OTFC, 200 micrograms), fentanyl was shown to be rapidly absorbed following single dose intranasal administration, with median Tmax ranging from 15 to 21 minutes (Tmax for OTFC was approximately 90 minutes).
The drug is redistributed to other tissues; it accumulates more slowly in skeletal muscle and yet more slowly in fat, from which it is gradually released into the blood.
About 80-85% of fentanyl is bound by plasma proteins, mainly α1-glycoprotein and to a lesser extent albumin and lipoprotein. The volume of distribution of fentanyl at steady state is about 3-6 l/kg.
Fentanyl accumulates in skeletal muscle and fat and is released slowly into blood. In a study in cancer patients treated with transdermal fentanyl, plasma protein binding was on average 95% (range 77-100%). Fentanyl crosses the blood-brain barrier easily. It also crosses the placenta and is excreted in breast milk.
Fentanyl is metabolised primarily via CYP3A4 to a number of pharmacologically inactive metabolites, including norfentanyl. Within 72 hours of intravenous fentanyl administration around 75% of the dose is excreted into the urine, mostly as metabolites, with less than 10% as unchanged drug. About 9% of the dose is recovered in the faeces, primarily as metabolites. Total plasma clearance of fentanyl is about 0.5 l/h/kg. The terminal half-life of fentanyl is 3.7 hours.
After buccal administration, the main elimination half-life of fentanyl is about 7 hours (range 3-12.5 hours) and the terminal half-life is about 20 hours (range 11.5-25 hours).
Following a 72-hour patch application, the mean fentanyl half-life ranges from 20 to 27 hours. As a result of continued absorption of fentanyl from the skin depot after removal of the patch, the half-life of fentanyl after transdermal administration is about 2- to 3-fold longer than intravenous administration.
Disposition of fentanyl following intranasal administration has not been characterised in a mass balance study. Less than 7% of an administered dose of fentanyl is excreted unchanged in the urine and only about 1% is excreted unchanged in the faeces. The metabolites are mainly excreted in the urine, while faecal excretion is less important.
The serum fentanyl concentrations attained are proportional to the fentanyl transdermal patch size. The pharmacokinetics of transdermal fentanyl do not change with repeated application.
There is a high inter-subject variability in fentanyl pharmacokinetics, in the relationships between fentanyl concentrations, therapeutic and adverse effects, and in opioid tolerance. The minimum effective fentanyl concentration depends on the pain intensity and the previous use of opioid therapy. Both the minimum effective concentration and the toxic concentration increase with tolerance. An optimal therapeutic concentration range of fentanyl can therefore not be established. Adjustment of the individual fentanyl dose must be based on the patient’s response and level of tolerance. A lag time of 12 to 24 hours after application of the first patch and after a dose increase must be taken into account.
Data from intravenous studies with fentanyl suggest that elderly patients may have reduced clearance, a prolonged half-life, and they may be more sensitive to the drug than younger patients. In a study conducted with transdermal fentanyl, healthy elderly subjects had fentanyl pharmacokinetics which did not differ significantly from healthy young subjects although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours. Elderly patients should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary.
The influence of renal impairment on the pharmacokinetics of fentanyl is expected to be limited because urinary excretion of unchanged fentanyl is less than 10% and there are no known active metabolites eliminated by the kidney. However, as the influence of renal impairment on the pharmacokinetics of fentanyl has not been evaluated, caution is advised.
Patients with hepatic impairment should be observed carefully for signs of fentanyl toxicity and the dose of transdermal fentanyl should be reduced if necessary. Data in subjects with cirrhosis and simulated data in subjects with different grades of impaired liver function treated with transdermal fentanyl suggest that fentanyl concentrations may be increased, and fentanyl clearance may be decreased compared to subjects with normal liver function. The simulations suggest that the steady-state AUC of patients with Child-Pugh Grade B liver disease (Child-Pugh Score = 8) would be approximately 1.36 times larger compared with that of patients with normal liver function (Grade A; Child-Pugh Score = 5.5). As for patients with Grade C liver disease (Child-Pugh Score = 12.5), the results indicate that fentanyl concentration accumulates with each administration, leading these patients to have an approximately 3.72 times larger AUC at steady state.
Fentanyl concentrations were measured in more than 250 children aged 2 to 17 years who were applied fentanyl patches in the dose range of 12.5 to 300 mcg/h. Adjusting for body weight, clearance (L/h/kg) appears to be approximately 80% higher in children 2 to 5 years old and 25% higher in children 6 to 10 years old when compared to children 11 to 16 years old, who are expected to have a similar clearance as adults. These findings have been taken into consideration in determining the dosing recommendations for paediatric patients.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity. In vitro fentanyl showed, like other opioid analgesics, mutagenic effects in a mammalian cell culture assay, only at cytotoxic concentrations and along with metabolic activation.
Embryo-foetal developmental toxicity studies conducted in rats and rabbits revealed no compound-induced malformations or developmental variations when administered during the period of organogenesis.
In a fertility and early embryonic development study in rats, a male-mediated effect was observed at high doses (300 mcg/kg/day, s.c.) and is consistent with the sedative effects of fentanyl in animal studies.
In studies on pre and postnatal development in rats the survival rate of offspring was significantly reduced at doses causing severe maternal toxicity. Further findings at maternally toxic doses in F1 pups were delayed physical development, sensory functions, reflexes and behaviour. These effects could either be indirect effects due to altered maternal care and/or decreased lactation rate or a direct effect of fentanyl on the pups.
Carcinogenicity studies (26-week dermal alternative bioassay in Tg.AC transgenic mice; two-year subcutaneous carcinogenicity study in rats) with fentanyl did not induce any findings indicative of oncogenic potential. Evaluation of brain slides from the carciogenicity study in rats revealed brain lesions in animals administered high doses of fentanyl citrate. The relevance of these findings to humans is unknown.
There are no long-term animal studies to investigate the tumor-forming potential of fentanyl.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
