28 May 2007


Opiate Agonists

Opiate Agonists

NOTE: Fentanyl is a schedule C-II controlled substance.

Description: Fentanyl is a potent synthetic opiate agonist. Fentanyl is a phenylpiperidine derivative and is structurally similar to meperidine, alfentanil, and sufentanil. Fentanyl is very lipid soluble. A 100 mcg dose of fentanyl is approximately equipotent to 10 mg of morphine. As compared with morphine or meperidine, fentanyl has a shorter duration of action and half-life. Fentanyl is used to aid induction and maintenance of general anesthesia and to supplement regional and spinal analgesia. Fentanyl is preferred to morphine in anesthesia due to its ability to attenuate hemodynamic responses and maintain cardiac stability. Fentanyl may be administered alone or in combination with inhaled anesthetics, local anesthetics such as bupivacaine, or benzodiazepines. The FDA approved fentanyl for intravenous administration in February 1968. Transdermal and transmucosal fentanyl are available for the treatment of severe pain in patients requiring opioid analgesia. The FDA approved the transdermal preparation, Duragesic®, in August 1990 and a transmucosal preparation, Actiq®, in November 1998. A sugar-free formulation of Actiq® is FDA-approved; the date of commercial availability in the U.S. is uncertain. In September 2006, the FDA approved a buccal tablet called Fentora™, which is only for breakthrough pain in opioid-tolerant patients with cancer; a 300 mcg buccal tablet is expected to be available in late 2007. IONSYS™ (fentanyl iontophoretic transdermal system) is a self-contained, needle-free, pre-programmed system that delivers 40 mcg of fentanyl over 10 minutes to the skin when the patient pushes a button. IONSYS™ was FDA approved in May of 2006 for the short-term management of acute, post-operative pain in adults requiring opioid analgesia during hospitalization, but commercial availability is not expected until 2007. The system uses iontophoresis technology; iontophoresis (electrotransport) is a pain-free process that delivers fentanyl, an ionizable drug, into the skin by application of an external electrical field. Fentanyl lozenges (Oralet®, FDA-approval October 1993) were indicated for use in a hospital setting as an anesthetic premedication or to induce conscious sedation prior to a diagnostic or therapeutic procedure; however, Oralet® is no longer commercially available in the United States.

Mechanism of Action: Similar to morphine, fentanyl is a strong agonist at µ- and kappa- opiate receptors. Opiate receptors are coupled with G-protein (guanine-nucleotide-binding protein) receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins. Opioid-G-protein systems include adenylyl cyclase-cyclic adenosine monophosphate (cAMP) and phospholipase3 C (PLC)-intositol 1,4,5 triphosphate (Ins(1,4,5)P3)-Ca2).[1937] Opiates do not alter the pain threshold of afferent nerve endings to noxious stimuli, nor do they affect the conductance of impulses along peripheral nerves. Analgesia is mediated through changes in the perception of pain at the spinal cord (µ2-, delta-, kappa-receptors) and higher levels in the CNS (µ1- and kappa3 receptors). There is no ceiling effect of analgesia for opiates. The emotional response to pain is also altered. Opioids close N-type voltage-operated calcium channels (kappa-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (µ and delta receptor agonist) resulting in hyperpolarization and reduced neuronal excitability. Binding of the opiate stimulates the exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the G-protein complex. Binding of GTP leads to a release of the G-protein subunit, which acts on the effector system. In this case of opioid-induced analgesia, the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane.[1938] Thus, opioids decrease intracellular cAMP by inhibiting adenylate cyclase that modulates the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and norepinephrine. Opioids also modulate the endocrine and immune systems. Opioids inhibit the release of vasopressin, somatostatin, insulin and glucagon.[1939]

The stimulatory effects of opioids are the result of 'disinhibition' as the release of inhibitory neurotransmitters such as GABA and acetylcholine is blocked. The exact mechanism how opioid agonists cause both inhibitory and stimulatory processes is not well understood. Possible mechanisms including differential susceptibility of the opioid receptor to desensitization or activation of more than one G-protein system or subunit (one excitatory and one inhibitory) by an opioid receptor.

The actions of fentanyl are similar to those of morphine, although fentanyl is much more lipophilic as compared to morphine (580:1) and has a more rapid onset of action. Clinically, stimulation of µ-receptors produces analgesia, euphoria, respiratory depression, miosis, decreased gastrointestinal motility, and physical dependence. Kappa-receptor stimulation also produces analgesia, miosis, respiratory depression, as well as, dysphoria and some psychomimetic effects (i.e., disorientation and/or depersonalization). Miosis is produced by an excitatory action on the autonomic segment of the nucleus of the oculomotor nerve. Opiate-induced respiratory depression is caused by direct action on respiratory centers in the brain stem. Opiate agonists increase smooth muscle tone in the antral portion of the stomach, the small intestine (especially the duodenum), the large intestine, and the sphincters. Opiate agonists also decrease secretions from the stomach, pancreas, and biliary tract. The combination of effects of opiate agonists on the GI tract results in constipation and delayed digestion. Urinary smooth muscle tone is also increased by opiate agonists. The tone of the bladder detrusor muscle, ureters, and vesical sphincter is increased, which sometimes causes urinary retention. Fentanyl exhibits little hypnotic activity and rarely stimulates histamine release. Bradycardia is due to medullary vasomotor center depression and vagal nucleus stimulation and may lead to decreased cardiac output. Myocardial contractility is not affected by fentanyl. Muscle rigidity of the chest and abdominal muscles is often seen with opiate agonist anesthesia. This effect may be due to opiate stimulation of spinal reflexes or interference with basal ganglia integration. When used as part of anesthesia, opiate agonists provide analgesic protection against hemodynamic responses to surgical stress by attenuating the catecholamine response.

Pharmacokinetics: Fentanyl is administered parenterally and via transmucosal or transdermal systems. Analgesic effects are related to the fentanyl blood concentration.
•Transdermal Administration: When applied topically on the upper torso, the drug is well absorbed, with the average rate of absorption being designed to occur at 25 mcg/hour per 10 cm2. Serum fentanyl concentrations increase gradually after topical application. Peak concentrations occur 24—72 hours after the initial patch application. A small amount of ethanol is also released, but this enhances the rate of drug flow through the membrane and increases skin permeability. Once a steady state is achieved, serum concentrations remain relatively constant over the 72 hours that a patch is worn. After removal, serum concentrations of fentanyl decrease slowly due to absorption of residual drug concentrations in the skin. The average half-life during transdermal application is 17 hours. Not surprisingly, this can vary considerably among individual patients.
•Transmucosal Administration (Actiq®): Following transmucosal administration, peak effects usually occur within 20—30 minutes after the beginning of administration. If Actiq® is administered as directed (see Administration), approximately 25% of the total dose becomes systemically available via absorption from the buccal mucosa. The remaining 75% is swallowed with the saliva and is slowly absorbed from the GI tract. About one-third of this amount (25% of the total dose) avoids hepatic first-pass elimination and becomes systemically available. Thus, absolute bioavailability is approximately 50% the value obtained after intravenous administration of fentanyl. Dose proportionality exists for four available dosage strengths of Actiq®: 200 mcg, 400 mcg, 800 mcg, and 1600 mcg. The mean maximum fentanyl concentration after administration of each dosage strength was 0.39 ng/ml, 0.75 ng/ml, 1.55 ng/ml, and 2.51 ng/ml, respectively.
•Transmucosal Administration (Fentora™): Fentanyl is readily absorbed after buccal administration with an absolute bioavailability of 65%. Peak plasma concentrations of fentanyl are generally attained within an hour of buccal administration. Tablet disintegration usually takes 14—25 minutes, and the amount of time needed for the tablet to fully disintegrate does not appear to affect early systemic exposure to fentanyl. Approximately 50% of the total dose administered is absorbed transmucosally and becomes systemically available. The remaining half of the total dose is swallowed and undergoes more prolonged absorption from the gastrointestinal tract. Systemic exposure to fentanyl increases linearly in an approximate dose-proportional manner over the 100 mcg to 800 mcg dose range. The mean maximum fentanyl concentration after administration of each dosage strength was 0.25 ng/ml, 0.4 ng/ml, 0.97 ng/ml, and 1.59 ng/ml, respectively. A 400 mcg tablet is not bioequivalent to four 100 mcg tablets, as the maximum serum concentration was 12% higher, and the systemic exposure was 13% higher with the four 100 mcg tablets. Consequently, patients converting from four 100 mcg tablets to one 400 mcg tablet would be expected to experience a decrease in fentanyl plasma concentration.
NOTE: Actiq® and Fentora™ are not equivalent from a dosing perspective, although both are given by transmucosal administration (see Dosage). In a comparative study, the rate and extent of fentanyl absorption were approximately 30% greater with Fentora™, and exposure to fentanyl was approximately 50% greater with Fentora™ in another study. Further, the median time to maximum serum concentration with Fentora™ 400 mcg was 46.8 minutes (range, 20—240 minutes) as compared with 90.8 minutes (range, 35—240 minutes) with Actiq®.
•Intravenous Administration: Following IV administration, peak analgesia occurs within minutes and lasts for 30—60 minutes after a single dose. Following the IM route, onset of analgesia is within 7—15 minutes and lasts for 1—2 hours. In both cases, duration is directly dose-related. Respiratory depressant effects persist longer than analgesic actions, and residual fentanyl from one dose can potentiate the effect of subsequent doses. Serum fentanyl concentrations appear to fall rapidly, within 5 minutes, from a peak level after IV dosage, but residual drug can be detected for at least 6 hours.
•Epidural Administration: Following epidural administration, the onset of analgesia occurs within 10—15 minutes and lasts 2—3 hours. The high lipid solubility of fentanyl leads to rapid clearance from the CSF and less rotral or 'hook-like' spread than hydrophilic agents such as morphine. Fentanyl does not provide analgesia at distant sites from where it was administered; thus, epidural catheter placement is of great importance. Epidural administration of fentanyl is more effective than IM administration in producing lower spontaneous and provoked pain scores. The transfer of fentanyl to the placenta occurs rapidly. Eight pregnant women at term received epidural administration of 2 ml of 0.05 mg/ml fentanyl citrate along with 15 ml of 0.5% bupivacaine hydrochloride with 1:200,000 epinephrine, and 10 ml 2% lidocaine hydrochloride without a vasoconstrictor. Babies were born by Cesarean section a median of 28.5 minutes after epidural drug administration, and the median fetal/maternal plasma concentration ratio was 0.892 at birth. The median fetal plasma fentanyl concentration was 0.25 ng/ml as compared with the median maternal plasma fentanyl concentration of 0.31 ng/ml. All babies had an Apgar score of 10 at the 5 minute time point.[8283]

Fentanyl is 80—85% protein bound mainly to alpha-1-acid glycoprotein, but free fractions increase with acidosis. Fentanyl does not appear to be metabolized in the skin, as 92% of a transdermal dose can be found unchanged in systemic circulation. However, fentanyl does undergo liver and intestinal mucosa metabolism via cytochrome P450 (CYP) 3A4 to norfentanyl then hydrolysis to 4-N-anilinopiperidine and propionic acid. Norfentanyl and other fentanyl metabolites are inactive and do not contribute to the activity of the drug. As fentanyl is extensively metabolized by CYP3A4, significant drug interactions may occur if inhibitors or inducers of this enzyme are administered concurrently (see Drug Interactions). The metabolites and unchanged drug (<7% of the administered dose) are excreted in the urine, which can take several days.

•Special Populations: Pharmacokinetic data are limited regarding the use of fentanyl in patients with either hepatic or renal impairment. An inverse relationship between the degree of azotemia and fentanyl clearance was noted in 8 patients with end-stage renal failure who got intravenous fentanyl 25 mcg/kg before skin incision for renal transplantation. The 2 patients with the highest blood urea nitrogen concentrations (108 mg/dl and 111 mg/dl) were the only patients to require postoperative mechanical ventilation; the BUN concentrations for the other patients ranged from 35—80 mg/dl.[9596] Use lowest possible fentanyl dose in patients with either hepatic or renal impairment (see Contraindications).

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Moises EC, de Barros Duarte L, de Carvalho Cavalli R, et al. Pharmacokinetics and transplacental distribution of fentanyl in epidural anesthesia for normal pregnant women. Eur J Clin Pharmacol 2005;61:517—22.

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