Sufentanil

Sufentanil citrate, introduced into human anaesthesia in the 1970s, is a pure, synthetic opioid agonist and a thienyl analogue of fentanyl (Fig. 1). It is more potent than morphine and is characterized by a relatively short duration of action.

PHARMACODYNAMICS AND PHARMACOKINETICS

Several studies, conducted both in vivo and in vitro, have shown that the μ receptor selectivity of sufentanil is considerably higher than that of fentanyl, methadone, morphine or pethidine._¹ Sufentanil is a potent analgesic: studies have shown that the analgesic potency of sufentanil in dogs is 625 higher than that of morphine and 5 times higher than that of fentanyl. The margin of safety for surgical analgesia (i.e. the ratio between the intravenous dose that produces severe cardiovascular side effects and the dose that produces deep analgesia) is 24, i.e. 6 times greater than that of fentanyl._²

Sufentanil is a highly lipid-soluble agent that quickly crosses the blood-brain barrier. This is reflected in the time required to reach the distribution equilibrium between plasma and cerebrospinal fluid, which is around 5 minutes. Sufentanil is characterized by significant first-pass pulmonary retention which causes the temporary sequestration of 50% of the active ingredient in this compartment, already 10 minutes after intravenous administration._³ The plasma protein binding of sufentanil is very high, reaching around 92.5% in humans, and mainly involves the α1-glycoprotein; in this aspect, it differs markedly from fentanyl, of which about 54% binds to plasma proteins._¹ As regards metabolism, this mainly occurs in the liver and includes N-dealkylation, oxidative O-demethylation and aromatic hydroxylation reactions. In dogs, the majority of the metabolites are eliminated in the urine (around 60%) and faeces (40%), in contrast to what occurs in rats, which eliminate around 62% in the faeces._¹

CLINICAL PROPERTIES

Unlike other opioids, sufentanil does not appear to cause significant haemodynamic changes such as reducing cardiac output, peripheral resistance and blood pressure. In dogs it has been shown that high doses of this drug cause only minimal haemodynamic changes; from a clinical point of view the most important aspect is vagally mediated bradycardia (Video 1).

Although sufentanil is associated with good cardiovascular stability when used alone, in combination with propofol and/or halogenated drugs, the haemodynamic effects typical of these two classes of anaesthetics may appear (reduction of cardiac output and/or peripheral vascular resistance);_⁴  the advantage comes from the fact that sufentanil can be used at high doses, in total cardiocirculatory safety, in order to keep the doses of the two hypnotics low.

Like fentanyl, its analogue, sufentanil does not cause the release of significant amounts of histamine, which might explain the lesser tendency shown by these opioids to cause vasodilatation and hypotension compared to other narcotic agents. As regards effects on the respiratory system, sufentanil causes dose-dependent respiratory depression, characterized by a reduction in respiratory rate and tidal volume and by an increase in end-tidal CO₂ (ETCO2), which may evolve into temporary apnoea, making it necessary to intubate the patient in order to provide intermittent positive pressure ventilation.

Compared to fentanyl, sufentanil appears to produce less respiratory depression in human patients._⁵ Muscle stiffness, especially of the chest, or tonic-clonic movements are commonly found in humans after the administration of fentanyl and its derivatives. This occurs more rarely in animals, probably because of the lower doses used._⁶ Sufentanil causes miosis in dogs and mydriasis in cats. Sufentanil and fentanyl both increase intracranial pressure in humans._⁷

CLINICAL USE

The intravenous route is the route of choice for administering sufentanil in humans and animals._⁶ The rapid onset and short duration of this drug enables its use not only in repeated boluses, but also as a continuous infusion in order to guarantee optimal stability of the level of anaesthesia and a rapid and adequate response to individual painful stimuli.

The commonly used dosages in the dog and cat are: 0.5 µg/kg, i.v. or 1 µg/kg, i.m. as a loading dose, followed by a continuous infusion of 0.2-2 µg/kg, i.v., depending on the analgesic requirements and on the phase of anaesthesia. The sedative effects after intravenous administration are obvious within a few minutes and are generally characterized by lethargy, ataxia, recumbency and panting (Videos 2 and 3). As for the majority of opioids, sudden noises interrupt the sedation (Video 3) and sometimes cause dysphoria. Sedative drugs may be used in combination to increase the level of sedation.

Sufentanil may also be used in combination with sedative drugs (acepromazine or alpha-2 agonists), with a considerable increase in the degree of lethargy. If sufentanil or other opioids are used together with benzodiazepines (midazolam or diazepam), the typical lethargy is usually not present (Video 2); however, abnormal behaviour and dysphoria may be exacerbated (Video 4). Thus, when using benzodiazepines, it is preferable to administer them only after the opioid has taken full effect, and just before the induction drug, in order to prevent the appearance of dysphoria.

Sufentanil at doses of 0.5 and 1 μg/kg reduces the need for thiopental by 50-68%, ensuring good haemodynamic stability during laryngoscopy and intubation of healthy patients.

This drug is not used as often as fentanyl in veterinary medicine, but it should be considered a drug of choice to obtain anaesthesia with optimal haemodynamic stability,_² or when perioperative pain is very intense and not easily manageable with the more common opioids. In a clinical study comparing sufentanil with fentanyl in dogs, sufentanil in continuous infusion proved much more effective in controlling acute orthopaedic pain, without producing significant side effects._⁸ Other routes of administration have also been described, such as the epidural and intrathecal routes, for controlling pain during delivery, but also for orthopaedic operations or abdominal surgery. In dogs, the peak concentration following spinal administration was reached after 6.5 minutes, thus producing a rapid onset of action._⁹

In another study comparing morphine and sufentanil administered by the epidural route in two groups of dogs, a dose of 5 μg/kg of sufentanil in 0.1 ml/kg of NaCl provided optimal analgesia for the perioperative management of animals undergoing orthopaedic surgery. In this study it was noted that sufentanil has a shorter latency of action than morphine, which can facilitate the anaesthetist’s task of rapidly achieving a suitable level of analgesia, allowing surgical procedures to start sooner. The analgesic efficacy of sufentanil was greater than that of morphine because of the significant reduction in the doses of isoflurane required to maintain anaesthesia. Pronounced bradycardia was found as a side effect, just a few minutes after the epidural administration of sufentanil. As regards postoperative analgesia, both drugs were able to control pain effectively both in the immediate period of recovering consciousness and in the 6 hours following the operation. Animals in the sufentanil group were already lively and interactive just a few hours after surgery, and this could be considered an additional advantage because it implies a shorter time spent in hospital and greater satisfaction by the owner._¹⁰

According to Savoia,_¹¹ there were no real advantages of epidural administration of sufentanil over intravenous administration in humans. However, a single intravenous bolus of sufentanil was insufficient to produce surgical analgesia, in contrast to what occurred with the same dose administered by the epidural route._¹² Furthermore, the high lipid solubility of sufentanil considerably limits the rostral spread of the drug in the spinal cord, thus making it safer than morphine with regards to perioperative respiratory depression, which can appear in humans given morphine even several hours after the end of the operation._⁹ Sufentanil (1 µg/kg) has been combined with 0.5% bupivacaine (1mg/kg) by the epidural route, again showing a rapid onset of analgesic effect, a short duration of motor block, limited side effects and analgesia for 360 minutes after the end of the surgery._¹³

References

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7. Sperry RJ, Bailey PL, Reichman MV, Peterson JC, Petersen PB, Pace NL. Fentanyl and sufentanil increase intracranial pressure in head trauma patients. Anesthesiology. 1992 Sep;77(3):416-20.
8. Bufalari A, Nannarone S, Adami C. Di Meo A. Fentanyl or sufentanil continuous infusion during isoflurane anesthesia in dogs: clinical experiences. In: AVA Spring Meeting. RIMINI, 20-23 aprile 2005
9. Bufalari A, Nannarone S, Maggio C, Bordoni T, Arcelli R, Di Meo A (2008). Sufentanil vs Morfine for epidural analgesia in the dog. In: Proceedings AVA Autumn Meeting. Barcellona, 2008.
10. Stevens R.A., Petty R.H., Hill H.F., Kao T.C., Schaffer R., Hahn M.B., Harris P., “Redistribution of sufentanil to cerebrospinal fluid and systemic circulation after epidural administration in dogs”. Anesth Analg. 1993;76:323-7
11. Savoia G, Loreto M, Gravino E., “Sufentanil: an overview of its use for acute pain management”. Minerva Anestesiol. 2001, 67(9 Suppl 1):206-16. Review.
12. Taverne R.H.T., Ionescu T.I., Nuyten S.T.M., “Comparative absorption and distribution pharmacokinetics of intravenous and epidural sufentanil for mayor abdominal surgery”. Clin Pharmacokinet, 1992, 23(3): 231-237
13. Almeida T.F., Fantoni D.T., Mastrocinque S., Tatarunas A.C., Imagawa V.H. “Epidural anesthesia with bupivacaine, bupivacaine and fentanyl, or bupivacaina and sufentanil during intravenous administration of propofol for ovariohysterectomy in dogs”. J Am Vet Med Assoc. 2007 Jan 1;230(1):45-51.