Pharmacokinetics after a single dose of naloxone administered as a nasal spray in healthy volunteers.

BACKGROUND: There is increasing interest in the use of intranasal naloxone to reverse adverse opioid effects during management of procedural pain in children and in adults after overdose. There are limited data on the pharmacokinetics of intranasal naloxone so in this study we aimed to detail the pharmacokinetic profile of the commercially marketed injectable solution of naloxone 0.4 mg/ml when administered as an intranasal spray. METHODS: Twenty healthy volunteers received naloxone as an intranasal spray at a dose of 10 µg/kg. Venous blood sampling was carried out for 90 min after administration to determine the time profile of the plasma concentrations of using tandem mass spectrometry. Pharmacokinetic parameters were calculated using a one-compartment model. RESULTS: Median time to maximum naloxone concentration (Tmax) was 14.5 (95% CI: 9.0-16.5) min, mean maximum naloxone concentration (Cmax) was 1.09 ± 0.56 ng/ml and mean AUC0-90 min was 37.1 ± 15.0 ng*min/ml. Elimination half-life estimated from the median concentration data was 28.2 min. CONCLUSION: Our results show a faster uptake of intranasal naloxone to maximum concentration compared with previous studies although with a marked variation in maximum concentration. The findings are consistent with our clinical experience of the time profile for reversing the effects of sufentanil sedation in children.

Intranasal flumazenil and naloxone to reverse over-sedation in a child undergoing dental restorations.

We describe a 3-year-old child who became over-sedated after receiving intranasal (IN) midazolam (0.53 mg.kg(-1)) and IN sufentanil (1 mcg.kg(-1)) for dental restorations in the dental office. Desaturation was attributed to laryngospasm, which was managed with positive pressure ventilation and oxygen. The sedation was reversed with a combination of IN flumazenil and naloxone.

Accidental intrathecal sufentanil overdose during combined spinal-epidural analgesia for labor.

A laboring woman was accidentally given 45 microg of sufentanil intrathecally in the course of combined spinal-epidural analgesia. She experienced intense pruritus and transient swallowing difficulty without respiratory depression, but still had incomplete pain relief, with delivery and episiotomy repair requiring additional analgesia. This case highlights the importance of adding local anesthetic to intrathecal opioids to facilitate effective analgesia during the second stage of labor. The contributory systems issues and multiple factors that allowed this error to occur are examined.

Sufentanil and medetomidine anaesthesia in the rat and its reversal with atipamezole and butorphanol.

Injectable anaesthetics are widely used to anaesthetize rats, but recovery times are often prolonged. Reversible anaesthetic regimens have the advantage that animals may be recovered quickly, thus reducing the incidence of postoperative complications such as hypothermia, and also providing a means of treating inadvertent anaesthetic overdose. This study assessed and compared the characteristics of anaesthesia induced with combinations of sufentanil and medetomidine administered as a single subcutaneous or intraperitoneal dose, and reversal with butorphanol and atipamezole. Combinations of sufentanil/medetomidine at 40 microg/150 microg and 50 microg/150 microg/kg administered subcutaneously, and 80 microg/300 microg/kg by intraperitoneal injection were found to produce surgical anaesthesia for 101+/-49, 124+/-45 and 76+/-23 min (means +/- SD) respectively. All three combinations produced marked respiratory depression 30 min after injection (< 50% of resting respiratory rate). Oxygen saturation, measured by pulse oximetry, was < 50% in all groups 30 min following drug administration. Subcutaneous administration is recommended since it resulted in a more reliable and more rapid induction of anaesthesia than intraperitoneal administration. The administration of butorphanol and atipamezole (0.2/0.5 mg/kg s.c.) resulted in a rapid (< 7 min) reversal of anaesthesia and an associated respiratory depression. The induction of anaesthesia with sufentanil/medetomidine and its reversal with a combination of atipamezole and butorphanol is an effective technique for anaesthetizing rats. However, due to the marked respiratory depression and the resulting hypoxia, we recommend that this regimen should only be used in animals which are free from respiratory disease and that oxygen should be provided during anaesthesia.

14-methoxymetopon, a potent opioid, induces no respiratory depression, less sedation, and less bradycardia than sufentanil in the dog.

UNLABELLED: Opioids of the mu-receptor type depress respiration and induce addiction. At 10-min intervals 14-methoxymetopon (HS-198), which is 20,000 times more potent than morphine in the acethylcholine-writhing test, was given in graded IV doses (3, 6, and 12 microg/kg) to awake, trained canines (n = 7). The following variables were derived: PaO(2), PaCO(2), heart rate (lead II of the electrocardiogram), mean arterial blood pressure, relative changes in the delta domain and the beta domain of the electroencephalogram, the somatosensory evoked potential, and the skin-twitch reflex to electrical stimuli. Thereafter, 20 microg/kg naltrexone was given for reversal. After a washout period, the same animals were exposed to similar doses of sufentanil (SUF) followed by naltrexone. Both opioids induced a dose-related bradycardia and hypotension. The maximal bradycardic effect was 19% after HS-198 and 42% after SUF (P < 0.005). The maximal hypotension was 6% after HS-198 and 20% after SUF (P < 0.01). In the electroencephalogram, power in the delta band increased by 288% after HS-198 and by 439% after SUF (P < 0.01); simultaneously, power in the beta band decreased by 71% and by 95.7%, respectively (P < 0.01). PaO(2) decreased by 41% after SUF and by 4% after HS-198, and PaCO(2) increased by 56.8% and 6.6% in SUF and HS-198, respectively (P < 0.001). Both opioids induced a dose-related depression in the somatosensory evoked potential and increased tolerance to skin-twitch. The maximal effect was 92.7% after SUF and 81.3% after HS-198 was not significant. Naltrexone reversed all changes back to control. Compared with SUF, HS-198 does not induce hypoxia and hypercarbia, induces less hypotension and bradycardia, and induces less sedative effects. IMPLICATIONS: Compared with sufentanil, 14-methoxymetopone does not induce hypoxia and hypercarbia, induces less hypotension and bradycardia, and induces less sedative effects (electroencephalogram). Antinociception is similar to sufentanil (skin-twitch method, amplitude depression in the evoked potential). All effects are reversed by naltrexone. Interaction of kappa-receptor is suggested.

The effects of intravenous naltrindole and naltrindole 5'-isothiocyanate on sufentanil-induced respiratory depression and antinociception in rats.

Although the interactions between the mu- and the delta-opiate receptor subtypes are well documented with regard to supraspinal analgesia, less is known about the mutual interactions on respiratory depression. To clarify the functional interactions between both opiate receptor subtypes with regard to antinociception and respiratory depression, male Wistar rats were intravenously injected with 2.5 microg/kg of the mu-opiate agonist sufentanil and subsequently intravenously challenged with the delta antagonist naltrindole (NTI) or naltrindole 5'-isothiocyanate (5'-NTII), a delta-2 antagonist. Antinociception was measured by means of the tail-flick latency, and respiratory depression was evaluated by means of analysis of PaCO2, PaO2, and oxygen saturation. To quantify the antagonistic properties of NTI and 5'-NTII, mean areas under the curve were calculated for groups treated with sufentanil, control vehicle, and sufentanil plus a dose of the antagonists. NTI, but not 5'-NTII, antagonized the sufentanil-induced antinociception at 10 mg/kg NTI. Below this dose the effects were inconsistent. The sufentanil-induced hypercapnia and hypoxia were diminished with 10 mg/kg NTI or 5'-NTII. These data indicate that NTI antagonizes the sufentanil-induced antinociception and respiratory depression in rats. A dissociation between the antinociception and respiratory depression following intravenous sufentanil could be obtained with 10 mg/kg 5'-NTII pointing to different regulatory effects of opiate delta receptor subtypes on mu-opiate agonist-induced behavioral effects.

Respiratory arrest following intrathecal injection of sufentanil and bupivacaine in a parturient.

PURPOSE: To present a case of respiratory arrest following the use of intrathecal sufentanil and bupivacaine for combined spinal-epidural anaesthesia in a healthy labouring parturient. CLINICAL FEATURES: A 20-yr-old term parturient received 10 micrograms sufentanil and 2.5 mg bupivacaine intrathecally as part of a combined spinal-epidural technique for labour analgesia. She had received no previous analgesics. Twenty-three minutes after the intrathecal injection she became unresponsive and suffered a respiratory arrest. Resuscitation included manual bag/mask ventilation with oxygen and intravenous naloxone. CONCLUSION: Respiratory arrest is a rare but potentially life-threatening complication associated with the use of intrathecal opioids for labour analgesia. Vigilance in post-procedure patient monitoring is imperative.

The delta receptor is involved in sufentanil-induced respiratory depression--opioid subreceptors mediate different effects.

It is generally accepted that analgesia induced by central analgesics is mediated through the mu-receptor. However, it still remains open to question as to whether or not the mu- and/or the delta-receptor site is mainly involved in the mediation of opioid-related respiratory impairment. Using a highly selective antagonist, naltrindole (NTI), or its benzofuran analogue naltriben (NTB), the hypothesis that competitive antagonism at the delta-receptor is able to attenuate sufentanil-related respiratory depression was tested in the dog. High dose (20 micrograms kg-1) sufentanil-induced respiratory impairment could be reversed by selective NTI-antagonism in a dose-related fashion (40-80-160 micrograms kg-1) increasing PaO2 from 57 to 81 mmHg and lowering PaCO2 from 52.1 to 49.2 mmHg. NTB-antagonism (40-80-160 micrograms kg-1) increased PaO2 from 48.4 to 91.2 mmHg and reduced PaCO2 from 46.9 to 37.6 mmHg. Simultaneously, somatosensory-evoked potentials (SEP) were used to quantify the opioid-induced attenuation and the reversal of afferent sensory input to pain modulating centres in the CNS. Sufentanil induced a significant depression (P < 0.01) of amplitude height of the SEP (13.9 to 0.9 microV in the NTI- and 8.8 microV to 1.3 microV in the NTB-group) which was only partially reversed by NTI (2.6 microV) and NTB (2.3 microV) respectively. The results suggest that delta-receptors are involved in sufentanil-related respiratory impairment. These receptors play a minor role in opioid-induced attenuation of sensory input to the brain. Highly selective delta-antagonists may be of clinical interest in reversing the respiratory depressant effect of potent opioids while maintaining analgesia.