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 administration of sufentanil can be described as a twocompartment model with first-order absorption. This route of administration results in higher absolute bioavailability than oral (swallowed) administration by avoiding intestinal and first-pass liver 3A4 enzyme metabolism. Mean absolute bioavailability after a single sublingual administration of the sufentanil tablet relative to a one-minute intravenous sufentanil infusion of the same dose was 53%.
In a study of a sufentanil 15 microgram sublingual tablet (with the same formulation as the 30 microgram tablet), a substantially lower bioavailability of 9% after oral intake (swallowed) was observed. Buccal administration 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 60 minutes after a single dose; this is shortened to approximately 40 minutes following repeated hourly dosing. When sufentanil is administered every hour, steady-state plasma concentrations are achieved by 7 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.
With sufentanil, first dose clearance in the typical patient of weight 78.5 kg and age 47 years is 84.2 L/hr. Steady-state clearance is 129.3 L/hr. Patient weight and age are key covariates on clearance.
After single administration of sufentanil, mean terminal phase half-live of 13.4 hours (range of 2.5 to 34.4 hours) was observed. After multiple administrations, a longer mean terminal half-life of 12.68 hours (range 5.30 to 26.91 hours) was observed, 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.
With administration of sufentanil, clinical duration of analgesia is largely determined by the time for the sufentanil plasma concentration to drop from Cmax to 50% of Cmax after discontinuation of dosing (context sensitive half-time or CST½) rather than by the terminal half-life. Following either a single dose or multiple doses hourly over 12 hours, the median CST½ remained 2.3 hours: the sublingual delivery route thus substantially extends the duration of action associated with intravenous sufentanil administration (CST½ of 0.1 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.
Patients requested dosing with sufentanil to maintain plasma sufentanil concentrations averaging 40-50 pg/ml at 12 hours, with no effect based on age or body mass index (BMI), or mild to moderate renal or liver impairment.
A population pharmacokinetic analysis of plasma sufentanil concentrations following usage of sufentanil 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, 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 sufentanil in paediatric patients.
No special population studies were performed using sufentanil in the elderly. For sufentanil, population pharmacokinetic analysis showed an effect of age, with an 18% decrease in clearance in the elderly (above 65 years of age).
Population pharmacokinetic analysis with weight as a covariate showed that patients with a higher BMI dosed more frequently.
Fertility and early embryonic development studies were conducted in male and female rats. Increased mortality was noted in all treatment groups.
Lower pregnancy rates were noted following treatment of males suggesting the potential for an adverse effect on fertility in males. Increased resorption of foetuses and reduced litter size was noted in the high dose females suggesting the potential for foetotoxicity, likely due to maternal toxicity.
The Ames test revealed no mutagenic activity of sufentanil.
Carcinogenicity studies have not been conducted with 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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