Chemical formula: C₂₂H₃₀N₂O₂S Molecular mass: 386.551 g/mol PubChem compound: 41693
Sufentanil is a synthetic, potent opioid with highly selective binding to µ-opioid receptors. Sufentanil acts as a full agonist in µ-opioid receptors. Sufentanil does not induce histamine release. All effects of sufentanil can immediately and completely be blocked by administration of a specific antagonist such as naloxone.
Analgesia induced by sufentanil is thought to be mediated via activation of µ-opioid receptors primarily within the CNS to alter processes affecting both the perception of and the response to pain. In humans the potency is 7 to 10-fold higher than fentanyl and 500 to 1,000-fold higher than morphine (per oral). The high lipophilicity of sufentanil allows it to be administered sublingually and achieve a rapid onset of analgesic effect.
Sufentanil may cause respiratory depression and also suppresses the cough reflex
High doses of intravenously administered sufentanil are known to cause muscle rigidity, probably as a result of an effect on the substantia nigra and the striate nucleus. Hypnotic activity can be demonstrated by EEG alterations.
Analgesic plasma concentrations of sufentanil may provoke nausea and vomiting by irritation of the chemoreceptor trigger zone. Gastrointestinal effects of sufentanil comprise decreased propulsive motility, reduced secretion and increased muscle tone (up to spasms) of the sphincters of the gastrointestinal tract.
Low doses of intravenous sufentanil associated with likely vagal (cholinergic) activity cause mild bradycardia and mildly reduced systemic vascular resistance without significantly lowering blood pressure. Cardiovascular stability is also the result of minimal effects on cardiac preload, cardiac flow rate and myocardial oxygen consumption. Direct effects of sufentanil on myocardial function were not observed.
The pharmacokinetics of sufentanil after sublingual administration can be described as a threecompartment model with first-order absorption. This route of administration results in higher absolute bioavailability by avoiding intestinal and first-pass liver 3A4 enzyme metabolism. Mean absolute bioavailability after a single sublingual administration of sufentanil relative to a oneminute intravenous sufentanil infusion of 15 micrograms was 59%. This compares to a substantially lower bioavailability of 9% after oral intake (swallowed). In clinical trials during repeated administrations the bioavailability decreased to 37.6%.
Buccal administration study showed an increased bioavailability of 78% when the tablets were placed in front of the front lower teeth.
Maximum concentrations of sufentanil are achieved approximately 50 minutes after a single dose; this is shortened to approximately 20 minutes following repeat dosing. When sufentanil was administered every 20 minutes, steady state plasma concentrations were achieved after 13 doses.
The central volume of distribution after intravenous application of sufentanil is approximately 14 litres and the volume of distribution at steady state is approximately 350 litres.
Biotransformation takes place primarily in the liver and the small intestine. Sufentanil is mainly metabolised in humans by the cytochrome P450-3A4 enzyme system. Sufentanil is rapidly metabolised to a number of inactive metabolites, with oxidative N- and O-dealkylation being the major routes of elimination.
The total plasma clearance after single intravenous administration is about 917 l/min. Approximately 80% of the intravenously administered dose of sufentanil is excreted within 24 hours. Only 2% of the dose is excreted in unchanged form. Clearance is not affected by race, sex, renal parameters, hepatic parameters, or concomitant CYP3A4 substrates.
Clinically relevant plasma levels are largely determined by the time for the sufentanil plasma concentration to drop from Cmax to 50% of Cmax after discontinuation of dosing (context sensitive halftime or CST½) rather than by the terminal half-life. After a single dose, the median CST½ was 2.2 hours, increasing to a median value of 2.5 h after multiple dosing: the sublingual delivery route thus substantially extends the duration of action associated with intravenous sufentanil administration (CST½ of 0.14 hours). Similar CST½ values were observed following both single and repeated administration demonstrating that there is a predictable and consistent duration of action after multiple dosing of the sublingual tablet.
After single administration of a 15 micrograms sufentanil sublingual tablet, mean terminal phase halflives in the range of 6 to 10 hours have been observed. After multiple administrations, a longer mean terminal half-life of up to 18 hours was determined, owing to the higher plasma concentrations of sufentanil achieved after repeated dosing and due to the possibility to quantify these concentrations over a longer time period.
A population pharmacokinetic analysis of plasma sufentanil concentrations following usage of sufentanil in patients and healthy volunteers (N=700), which included 75 patients with moderate and 7 patients with severe renal impairment, did not identify renal function as a significant covariate for clearance. However, due to the limited number of patients with severe renal impairment studied, sufentanil should be used with caution in such patients.
Based on the population pharmacokinetic analysis for sufentanil in patients and healthy volunteers (N=700), which included 13 patients with moderate and 6 patients with severe hepatic impairment, hepatic function was not identified as a significant covariate for clearance. Due to the limited number of patients with moderate to severe hepatic impairment, a potential effect of hepatic dysfunction as covariate on clearance may not have been detected. Therefore, sufentanil should be used with caution in such patients.
No pharmacokinetic data exist for the sufentanil in paediatric patients. There is limited pharmacokinetic data available in children after intravenous sufentanil administration.
No special population studies were performed using sufentanil in the elderly. Pharmacokinetic data from intravenous sufentanil administration did not reveal age related differences. In the placebo-controlled Phase 3 trials, approximately 20% of enrolled patients were elderly (≥75 years of age) and approximately 30% of enrolled patients were 65 to 75 years of age. The population pharmacokinetic analysis showed an effect of age with a 27% decrease in clearance in the elderly people (above 65 years of age). Since this decrease related to age is smaller than the observed inter-subject variability of 30-40% in exposure parameters for sufentanil, this effect is not considered to be of clinical relevance, particularly given that sufentanil is only used on an ‘as-needed’ basis.
When patients titrated themselves to analgesic effect with sufentanil, plasma sufentanil concentrations averaged 60-100 pg/ml over two days of use, with no effect based on age or body mass index (BMI), or mild to moderate renal or liver impairment.
Population pharmacokinetic analysis with a BMI as covariate showed that patients with a BMI >30 kg/m² dosed more frequently.
Sufentanil has been shown to induce opioid-like effects in a variety of laboratory animals (dogs, rats, guinea pigs, hamsters) at doses above those inducing analgesia and in two repeat-dose studies with sufentanil sublingual tablets administered buccally in Golden Syrian hamster.
Sufentanil was not teratogenic in rats and rabbits. Sufentanil caused embryolethality in rats and rabbits who were treated for 10-30 days during pregnancy with 2.5 times the maximum human dose by intravenous administration. The embryolethal effect was considered secondary to the toxicity for the mother animal.
No negative effects were observed in another study in rats that were treated with 20times the maximum human dose in the period of organogenesis. The preclinical effects were only observed following administrations of levels significantly above the maximum human dose, which are therefore of little relevance for clinical use.
The Ames test revealed no mutagenic activity of sufentanil. In the micronucleus test in female rats, single intravenous doses of sufentanil as high as 80 µg/kg (approximately 2.5 times the upper human intravenous dose) produced no structural chromosome mutations.
Carcinogenicity studies have not been conducted on sufentanil.
Two local tolerance studies were conducted in the hamster cheek pouch with the sufentanil sublingual tablets. It was concluded from these studies that sufentanil sublingual tablets have no or minimal potential for local irritation.
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