Sufentanil

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Abstract
Sufentanil, an opioid analgesic, is an analogue of fentanyl, and has been used for the induction and maintenance of anaesthesia, and for postsurgical analgesia. It has shorter distribution and elimination half-lives, and is a more potent analgesic than fentanyl. In clinical practice, however, intravenously administered sufentanil produces essentially equivalent anaesthesia to fentanyl and is a better anaesthetic than morphine or pethidine (meperidine) for major surgery. It would appear to maintain haemodynamic stability during surgery better than other opioids or inhalational anaesthetics. Postoperative respiratory depression has been reported in a few patients. For outpatient surgery, intravenous sufentanil produces equivalent anaesthesia to isoflurane or fentanyl. Recovery tends to be more rapid after sufentanil and the requirement for postoperative analgesia is less. Initial clinical trials with sufentanil administered epidurally to relieve pain during labour have produced encouraging results, but further studies are required to establish the drug’s role in this indication. Epidural sufentanil produces a more rapid onset and better initial quality of analgesia than morphine, buprenorphine or hydromorphine when administered postoperatively, but the duration of analgesia is shorter. Thus, sufentanil’s primary place in therapy at this time would appear to be as high dose anaesthesia for major surgery such as cardiac surgery, and as low dose supplement to balanced anaesthesia in general surgery. In addition, low doses administered epidurally seem to have a potential role for analgesia during labour or after surgery although further studies are required to clarify this situation. Sufentanil, an analogue of fentanyl, is an opioid analgesic which is highly selective for the μ-receptor site. It is a very potent analgesic; in animals it is 625 to 4,000 times more potent than morphine and 5 to 15 times more potent than fentanyl. It is also more potent than morphine in man but produces a shorter duration of analgesia. Sufentanil has a better cardiovascular safety margin in dogs undergoing deep surgical analgesia relative to morphine or fentanyl. Like other opioids, sufentanil increases the amplitude and reduces the frequency of the EEG. Unlike many other opioids, sufentanil produces very little haemodynamic instability. It may produce a reduction in heart rate and blood pressure shortly after induction, but the cardiovascular instability usually associated with surgery is largely avoided. Some studies indicate that sufentanil maintains better haemodynamic stability than fentanyl. Plasma catecholamine concentrations and concentrations of other ‘stress hormones’ tend to remain stable following sufentanil administration, but still increase during surgery. Sufentanil reduces mean minute volume and respiratory rate, and may produce respiratory depression during or after surgery. This may be managed by the concomitant use of muscle relaxants or reversed by the subsequent administration of naloxone. Following intravenous administration, sufentanil disappears from the plasma in a triexponential fashion. Sufentanil is highly lipophilic and is rapidly distributed into brain and other tissues with an initial distribution phase (half-life 1.4 minutes) and a slower distribution phase (half-life 18 minutes). It is highly protein-bound (92.5%) and has a large apparent volume of distribution, in the range 1.74 to 5.17 L/kg and is extensively taken up by tissues. The metabolic pathways of sufentanil in man have not yet been determined, but in animals N-dealkylation and O-demethylation are involved. At least 1 metabolite retains some of the activity of the parent molecule, although it appears at such low concentrations as to be of questionable clinical significance. Sufentanil metabolites are eliminated in urine and faeces. The reported elimination half-life has ranged from about 2 hours in non-cardiac surgery patients to about 10 hours in patients undergoing cardiac surgery. There is some evidence that the pharmacokinetics of sufentanil may be altered in patients with reduced renal or hepatic function, although limited data are available in such subjects, and the pharmacokinetics of sufentanil would seem to be more variable in neonates compared with children or adults. Following epidural administration to women following caesarean section the plasma concentration of sufentanil reached a peak after about 10 minutes which was about 25% of the peak reached after intravenous administration. The concentration then declined gradually over a period of 1 to 2 hours. Early clinical trials involving medium or high doses of sufentanil (up to 50 μg/kg) focussed on its use as a supplement to balanced anaesthesia in patients undergoing general surgery or as the sole anaesthetic in cardiac or neurological surgery. Many of these were controlled studies comparing sufentanil with other opioid analgesics or with an inhalational anaesthetic agent. Sufentanil proved superior to morphine or pethidine in its anaesthetic activity, and its haemodynamic and postoperative effects. However, little difference was demonstrated between sufentanil and fentanyl anaesthesia, although sufentanil maintained better haemodynamic stability and has been associated with a faster recovery. Low doses of sufentanil (<1 μg/kg) have been employed in outpatient surgery as premedication or for anaesthetic induction, allowing reduction of the amount of inhalational anaesthetic and postoperative analgesic required. Initial recovery from anaesthesia was quicker after sufentanil than after isoflurane or fentanyl. Epidural administration of sufentanil (10 to 100μg) has proven effective for pain relief during labour or after surgery. When administered with bupivacaine during labour, sufentanil reduced the time to onset of analgesia and improved the quality of epidural block compared with bupivacaine alone. Following abdominal, thoracic, orthopaedic, urologic or general surgery, or after caesarean section, sufentanil induced rapid analgesia, but the duration of analgesia was shorter than that after morphine, hydromorphine or buprenorphine. The most frequently reported disturbing side effects following medium or high dose intravenous sufentanil administration are hypotension, chest wall rigidity, tachycardia and bradycardia, which occurred at incidences of 6%, 2.9%, 1.3% and 3.4%, respectively, in 1 large multicentre trial. Nausea and/or vomiting, pruritus and sedation also occur, and are the most frequently reported events after epidural administration of sufentanil. Other events reported in clinical trials included hypertension, dizziness, urinary retention and headache. There have been some reports of myoclonus (which would not appear to involve cortical seizure activity) and severe respiratory depression. For use in anaesthesia sufentanil may be given in low, moderate or high doses. Low doses (⩽2 μg/kg) are used in minor surgery, moderate doses (2 to 8 μg/kg) in more complex surgery and high doses (8 to 50 μg/kg) in cardiac and neuro-surgery. The dose should be determined for each patient according to age, weight, general condition, other medication and surgical procedure to be undertaken. For postsurgical epidural analgesia optimal doses would appear to be 30 to 50μg administered at the first onset of pain and repeated as necessary.