Source: Web Search Revision Year: 2019 Publisher: Medochemie Ltd, 1-10 Constantinoupoleos Street, 3011, Limassol, Cyprus
Pharmacotherapeutic group: Opioid Anesthetics
ATC Code: N01AH03
Sufentanil is a potent synthetic opioid with μ-agonist pharmacological effect. Sufentanil is a very potent opioid (7-10 times more potent than fentanyl in humans) with a high safety index (LD50/ED50 for the lowest analgesia grade) in the rat; at 25, 211, the index is higher than that for fentanyl (277) or morphine (69.5). Intravenous sufentanil has a rapid onset effect. The limited accumulation in and rapid elimination from storage compartments allows rapid recovery. The depth of analgesia is dose-dependent, and can be adjusted, as appropriate, to the level of pain during surgery. As in the case of other opioids, sufentanil (depending on the dose and administration rate) may cause muscle rigidity, as well as euphoria, miosis and bradycardia.
Histamine assays have not shown any histamine release potential in patients receiving sufentanil. Sufentanil’s effect is immediately and completely reversed by a specific opiate antagonist. In epidural use, sufentanil gives spinal analgesia with rapid onset of action (5-10 min) of moderate duration (usually 4-6 hours).
The mean onset and duration of analgesia were 3.0 ± 0.3 and 198 ± 19 minutes, respectively after epidural administration of 0.75 micrograms/kg sufentanil in 15 children aged 4 to 12 years.
Epidural sufentanil has been administered in only a limited number of children aged 3 months to 1 year as a single bolus dose of 0.25-0.75 micrograms/kg for postoperative pain control.
In children older than 3 months, an epidural bolus dose of 0.1 micrograms/kg sufentanil followed by an epidural infusion of 0.03-0.3 micrograms/kg/h combined with an amide local anaesthetic of the amide type provided effective postoperative analgesia for up to 72 hours in patients after subumbilical surgery.
In epidural use, the maximum plasma concentration is reached within 10 minutes and is 4-6 times lower than the plasma concentration after intravenous administration. Concomitant administration of ephedrine (50-75 micrograms) further reduces initial rapid absorption by 25-50%.
In studies where sufentanil doses of 250-1500 micrograms were administered intravenously over a long period, the half-lives in the distribution phase were 2.3-4.5 minutes and 35-73 minutes, the distribution volume in the central compartment 14.2 litres, the distribution volume in steady state 344 litres.
The half-life in the distribution phase, rather than the elimination half-life (ranging from 4.1 h after 250 micrograms for 10-16 hours after 500-1500 micrograms) is the determinant of the rate of fall in plasma concentrations from the therapeutic to the subtherapeutic range. Sufentanil’s pharmacokinetics are linear in dose-range studies.
The plasma protein binding of sufentanil is 92.5%.
Biotransformation of the substance occurs primarily in the liver and small intestine. Sufentanil is metabolised mainly via the human cytochrome P450 3A4 enzyme.
The mean (range) terminal elimination half-life was 784 (656-938) minutes. As a result of the methodological detection limit, the elimination half-life after the 250 micrograms dose was significantly shorter (240 minutes) than that after the 1500 micrograms dose. The clearance rate was 917 ml/minute. Nearly 80% of the dose administered is eliminated within 24 hours, with only 2% in the form of the unchanged substance.
The volume of distribution is slightly increased, and overall clearance is slightly lower in patients with cirrhosis than in control patients. This results in a significant prolongation of half-life by about 30%, which often requires a longer post-operative monitoring period (see section 4.4).
The distribution volume at steady state, total clearance and terminal elimination half-life in patients on dialysis or undergoing renal transplantation is not different from healthy controls. The free fraction of sufentanil in this population is not different from healthy patients.
Pharmacokinetic information in children is limited.
Intravenous administration:
Plasma protein binding is lower in children compared to adults and increases with age. In newborns sufentanil is about 80.5% bound to proteins compared to 88.5% in infants, 91.9% in children and 92.5% in adults.
After administration of an intravenous sufentanil bolus dose of 10-15micrograms/kg in paediatric patients undergoing cardiac surgery, the pharmacokinetics of sufentanil can be described by a triexponential curve as in adults. Clearance normalised to body weight was shown to be higher in infants and children compared to adolescents, whose clearance rates were comparable to that of adults. In neonates clearance was significantly reduced and exhibited high variability (range 1.2 to 8.8 mL/min/kg and one outlying value of 21.4 mL/min/kg). Neonates were shown to have a greater distribution volume at steady state and a prolonged elimination half-life. Pharmacodynamic differences due to differences in the pharmacokinetic parameters may be greater if taking into account the unbound fraction.
Table 2. Mean sufentanil pharmacokinetic parameters in children following administration of 10-15 micrograms/kg sufentanil single intravenous bolus (N=28):
| Age Group | N | Vdss (L/kg) Mean (± SD) | T1/2β (min) Mean (± SD) | Clearance (ml/kg/min) Mean (± SD) |
|---|---|---|---|---|
| Neonates (0 to 30 d) | 9 | 4.15 (1.01) | 737 (346) | 6.7 (6.1) |
| Infants (1 to 23 mo) | 7 | 3.09 (0.95) | 214 (41) | 18.1 (2.8) |
| Children (3 to 11 y) | 7 | 2.73 (0.50) | 140 (30) | 16.9 (3.2) |
| Adolescents (13 to 18 y) | 5 | 2.75 (0.53) | 209 (23) | 13.1 (3.6) |
Cl = clearance, normalised to body weight; N=number of patients included in analysis; SD = standard deviation; T1/2β = elimination half-life; Vdss = volume of distribution at steady state. Age ranges stated are those of the children studied.
Epidural administration:
Following epidural administration of 0.75 micrograms/kg sufentanil in 15 children aged 4 to 12 years, plasma levels taken 30, 60, 120, and 240 min after injection ranged from 0.08 ± 0.01 to 0.10 + 0.01 nanograms/mL.
In 6 children aged between 5 and 12 years receiving a 0.6 micrograms/kg sufentanil bolus injection followed by continuous epidural infusion containing 0.08 micrograms/kg/h sufentanil and bupivacaine 0.2 mg/kg/h for 48 h, maximum concentrations were reached at approximately 20 min after bolus injection and ranged from below the limit of quantification (<0.02 nanograms/ml) to 0.074 nanograms/ml.
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