Epidural vs. intravenous fentanyl during colorectal surgery using a double-blind, double-dummy design.

BACKGROUND: The overall therapeutic effectiveness of epidural fentanyl vs. the intravenous route is controversial. The present work describes a randomized, controlled, double-blind, double-dummy study of the intraoperative requirements of fentanyl administered by the intravenous or epidural routes during open colon surgery. METHODS: Thirty patients were randomized to receive intraoperative analgesia with boluses of fentanyl administered by either the epidural or intravenous route (2 µg/kg). The first fentanyl bolus was administered 10 min before incision, and repeated boluses were given when mean arterial pressure or heart rate increased more than 20% over basal values. General anaesthesia was maintained with a propofol infusion. Intraoperative fentanyl and propofol requirements, time to awakening, time to analgesia request, and incidence of adverse effects were recorded. RESULTS: Median [interquartile range (range)] fentanyl requirements in the epidural and intravenous groups were 0.81 [0.65 (0.47-2.61)] and 2.5 [1.08 (1.07-4.85)] µg/kg/h, respectively (P < 0.001). The epidural group had a shorter time to awakening, with a median of 8 min [4.5 (3-18)] compared with 20 min [12.5 (7-34)] for the intravenous group (P < 0.001). There were no significant differences in propofol requirements. The time to analgesia request was also delayed in the epidural group, with a median of 5 h [5.5 (1-16)] vs. 2 h [1 (1-5)] when fentanyl was administered intravenously (P < 0.001). The incidence of adverse effects was similar in both groups. CONCLUSION: During major abdominal surgery, epidural administration requires lower doses of intraoperative fentanyl when compared with the intravenous route. Epidural fentanyl also facilitates early awakening and residual analgesia without increasing adverse events.

Endogenous opiate receptor ligand: electrically induced release in the guinea pig ileum.

Opiate receptors mediate the electrically evoked inhibition of the myenteric plexus-longitudinal muscle preparation of the guinea pig ileum. The electrically induced activation of the opiate receptor was produced by a prolonged simulation at 10 hertz and provides the first evidence that an endogenous opiate receptor ligand is released by nerve stimulation. The specificity of the phenomenon was demonstrated by the reversal obtained with the narcotic antagonists naloxone, naltrexone, and GPA 1843; GPA 1847, the (+)-isomer of 1843, did not cause reversal. The model system described should be useful for the study of the storage, synthesis, and release of endorphins.

A procedure-specific systematic review and consensus recommendations for postoperative analgesia following laparoscopic cholecystectomy.

BACKGROUND: Laparoscopic cholecystectomy has advantages over the open procedure for postoperative pain. However, a systematic review of postoperative pain management in this procedure has not been conducted. METHODS: A systematic review was conducted according to the guidelines of the Cochrane Collaboration. Randomized studies examining the effect of medical or surgical interventions on linear pain scores in patients undergoing laparoscopic cholecystectomy were included. Qualitative and quantitative analyses were performed. Recommendations for patient care were derived from review of these data, evidence from other relevant procedures, and clinical practice observations collated by the Delphi method among the authors. RESULTS: Sixty-nine randomized trials were included and 77 reports were excluded. Recommendations are provided for preoperative analgesia, anesthetic and operative techniques, and intraoperative and postoperative analgesia. CONCLUSIONS: A step-up approach to the management of postoperative pain following laparoscopic cholecystectomy is recommended. This approach has been designed to provide adequate analgesia while minimizing exposure to adverse events.

PAIN OUT: the making of an international acute pain registry.

BACKGROUND: About 240 million patients undergo surgery every year, worldwide. Roughly 50% of these patients report clinically significant pain. Numerous barriers impede provision of adequate management. Lack of evidence about appropriateness and effectiveness of interventions is one. A registry can provide such information, eventually facilitating better management. This paper reports the development and feasibility of PAIN OUT, the first international acute pain registry, established with funds from the European Commission, and presents preliminary analysis to illustrate the nature of investigations that registry data make possible. METHODS: On the first postoperative day, 6347 adult patients undergoing orthopaedic or general surgery, in 11 medical centres in Europe and Israel, provided Patient Reported Outcomes (PROs) using a validated questionnaire. Clinical data were abstracted from the patient's chart. RESULTS: Feasibility worked well. Over a period of 1 year, surveyors accrued targeted data sets and entered them into an online browser. Collaborators could receive online feedback comparing their findings about PROs against anonymized findings from other centres. Missing data for the majority of variables were low. Despite considerable variability between institutions, a large number of patients were treated according to the generic, evidence-based recommendations we assessed. However, this was not sufficient to result in acceptable outcomes for the majority of patients. CONCLUSION: The initial development of PAIN OUT has been achieved. From 2013, it continues as a not-for-profit academic project, open to clinicians and researchers worldwide. The International Association for Study of Pain and PAIN OUT will work together to maintain, disseminate and develop the registry.

Antinociceptive effects of azepexole (BHT 933) in mice.

Subcutaneous (s.c.) administration of azepexole (BHT 933) at doses between 4 and 40 mg/kg produced dose-dependent antinociceptive effects in mice as assessed by tail-immersion, tail-pinch and acetic acid writhing tests. The ED16s were 5.6 +/- 0.4, 6.7 +/- 1.2 and 2.96 +/- 0.2 mg/kg respectively. Similarly, morphine produced analgesia in the same tests with ED16s of 0.87 +/- 0.03, 0.47 +/- 0.1 and 0.45 +/- 0.01 mg/kg respectively. In all instances naloxone (0.1 mg/kg s.c.) shifted the dose-response curves to morphine to the right in a parallel manner. Naloxone (0.1 and 1 mg/kg s.c.) partially antagonized the effect of azepexole in the tail-immersion and tail-pinch tests but significantly decreased the slope of the dose-response curve suggesting that a competitive interaction at the level of the opioid receptors did not occur. Naloxone had no effect on the antinociceptive action of azepexole in the acetic acid writhing test.

Pharmacological evidence for the involvement of the endogenous opioid system in the response to local inflammation in the rat paw.

We have investigated the role of the endogenous opioid system (EOS) on the inflammatory response induced by subplantar (s.p.) injection of saline (SS) and carrageenan (CA) in the hindpaw of the rat. The administration of intraperitoneal (i.p.) naloxone was used in order to unmask the effects of endogenous opiates released during peripheral inflammation. Three groups of rats received one of the following s.p. treatments: SS, CA, or no injection (NI). Pain pressure threshold (PPT), paw volume (edema) and local temperature were evaluated in baseline conditions and 3 h after treatment. In each group, the effects of i.p. vehicle, naloxone and (+)-naloxone (0.1 mg/kg) were also investigated. Both SS and CA induced a significant inflammatory response with hyperalgesia, edema and local hyperthermia. The i.p. administration of naloxone but not that of (+)-naloxone 15 min prior to testing, significantly increased edema in all groups of treatment (P < 0.05), without altering PPT or local temperature. Two-way ANOVA revealed that treatment and drugs, as well as their interaction, had a significant impact on edema which was related to the effects of CA and naloxone. Our findings illustrate the involvement of the EOS in the physiological response to local injury, regulating microvascular leakage in the inflamed tissues.

Naloxone elicits an excitatory response in the morphine-tolerant mouse vas deferens.

The effects of naloxone on the electrically stimulated vas deferens from mice implanted with morphine (tolerant) or placebo (naive) pellets were studied. In tolerant vas deferens, naloxone produced an 86.6% increase of the twitch contractions when the preparations were stimulated with 15 V, while only a 12% increase was observed with supramaximal voltage (40 V). Naloxone had no effect at either voltage in preparations from naive animals. The effect of morphine in naive vas deferens stimulated with 15 V, was reversed by naloxone without further increase over baseline contractions. The results suggest that opioid receptors other than those located in the neuronal soma and/or coupled to adenylate cyclase may be involved in the development of dependence.

Reversal of tolerance to the antitransit effects of morphine during acute intestinal inflammation in mice.

1. The aim of investigation was to establish and compare the reversibility of tolerance to the antitransit effects of morphine by three different procedures: (a) acute inflammation of the gut, (b) lorglumide a cholecystokininA (CCKA) receptor antagonist, or (c) MK-801, an N-methyl-D-aspartate (NMDA) receptor ion channel blocker. The type of interaction between morphine and lorglumide or MK-801 on the inhibition of gastrointestinal transit (GIT) in naive animals was also evaluated. 2. Male Swiss CD-1 mice were implanted with 75 mg of morphine base or placebo pellets. Gastrointestinal transit was assessed with a charcoal meal and results expressed as % inhibition of GIT. Inflammation was induced by the intragastric (p.o.) administration of croton oil (CO), while controls received castor oil (CA) or saline (SS). Morphine was administered by subcutaneous (s.c.) or intracerebroventricular (i.c.v.) injection, to naive and tolerant animals treated with CO, CA or SS. Dose-response curves for s.c. morphine were also performed in naive and tolerant mice receiving 5.2 or 7.4 nmol (s.c.) lorglumide or MK-801, respectively. 3. The ED50 values for inhibition of GIT by s.c. morphine were: 45.9 +/- 2.7 and 250.1 +/- 3.1 nmol in naive and tolerant animals, respectively, demonstrating a five fold decrease in the potency of morphine. In naive animals, inflammation (CO) decreased the ED50 of morphine three times (14.4 +/- 2.2 nmol). However, no tolerance to s.c. morphine (ED50 16.4 +/- 2.6 nmol) was manifested during intestinal inflammation. After i.c.v. administration, a similar degree of tolerance to morphine was observed (4.8 fold decrease in potency). Intestinal inflammation had no effect on the ED50 values of i.c.v. morphine in naive and tolerant animals, showing that reversal of tolerance is related to local mechanism/s. Mean values for intestinal pH were 6.9 +/- 0.04 and 6.2 +/- 0.04 in SS and CO treated mice, respectively. In addition, morphine was 74 times more potent by the i.c.v. than by the s.c. route (naive-SS). 4. Morphine and lorglumide interacted synergistically in naive animals; in addition, the administration of lorglumide reversed tolerance to s.c. morphine. No interaction (additivity) was observed in naive animals when morphine and MK-801 were administered in combination. However, the drug completely reversed tolerance to the antitransit effects of morphine. 5. The present investigation shows that acute inflammation of the gut reverses tolerance to the antitransit effects of s.c. morphine by a peripheral mechanism. Qualitatively similar results were obtained after the administration of lorglumide or MK-801. Our results suggest that a local decrease in pH could play an important role during inflammation, while antagonism of endogenous compensatory systems would explain the reversal of tolerance induced by lorglumide or MK-801.

The inhibitory effects of alpha(2)-adrenoceptor agonists on gastrointestinal transit during croton oil-induced intestinal inflammation.

1. The peripheral effects of alpha(2)-adrenoceptor agonists were investigated in a model of intestinal inflammation induced by intragastric administration of croton oil (CO). Our hypothesis was that inflammation would 'sensitize' adrenoceptors in peripheral and/or central terminals of myenteric and submucous plexus neurones, and enhance systemic effects of alpha(2)-adrenoceptor agonists. 2. Male swiss CD-1 mice, received intragastrically CO (0.05 ml), castor oil (CA, 0.1 ml) or saline (SS) 3 h before the study: gastrointestinal transit (GIT) was evaluated 20 min afterwards with a charcoal meal. The presence of inflammation was assessed by electron microscopy. 3. The intragastric administration of CA or CO caused an increase in GIT and weight loss, but only CO induced an inflammatory response. Both clonidine (imidazoline1/alpha(2)-agonist) and UK-14304 (alpha(2)-agonist) produced dose-related inhibitions of GIT in all groups. During inflammatory diarrhoea (CO), potencies of systemic (s.c.) clonidine and UK-14304 were significantly increased 3.5 and 2.1 times, respectively, while potencies remained unaltered in the presence of diarrhoea without inflammation (CA). The effects were reversed by administration (s.c.) of receptor-specific adrenoceptor antagonists, but not by naloxone. 4. Clonidine was 8.3 (SS) and 2.8 (CO) times more potent when administered intracerebroventricularly (i.c.v.), than when administered s.c. Inflammation of the gut did not alter the potency of i.c.v. clonidine, demonstrating that enhanced effects of s.c. clonidine are mediated by peripheral receptors. During inflammation, i.c.v. efaroxan did not antagonize low doses of s.c. clonidine (ED20 and ED50S), but partially reversed ED80S, further supporting the peripheral effects of the agonists in CO treated animals. 5. The results demonstrate that inflammation of the gut enhances the potency of alpha(2)-adrenoceptor agonists by a peripheral mechanism. The results also suggest that the inflammatory response induces an up-regulation or sensitization of alpha(2)-adrenoceptors and/or imidazoline receptors.

Antibodies and antisense oligodeoxynucleotides to mu-opioid receptors, selectively block the effects of mu-opioid agonists on intestinal transit and permeability in mice.

1. We have studied the effects of mu and delta opioids on intestinal function (permeability, PER; gastrointestinal transit, GIT), and their antagonism after the intracerebroventricular (i.c.v.) administration of specific antibodies (ABs) or antisense oligodeoxynucleotides (ODN) to mu-receptors (OR). Central versus peripheral site/s of action of subcutaneous (s.c.) mu-opioids, were also assessed. 2. Male Swiss CD-1 mice were used. GIT was measured with charcoal and PER by the passage of 51Cr-EDTA from blood to lumen. 3. Morphine and fentanyl (i.c.v. and s.c.) inhibited GIT and PER in a dose-related manner; they were more potent by i.c.v. route, both on GIT and PER (70 and 17 times for morphine and fentanyl). They also had a greater effect on GIT than PER (4.3 and 1.6 times). DPDPE had a lower potency than mu-agonists in all experiments, and no dose-response could be obtained after s.c. administration on GIT. 4. Pretreatment with i.c.v. ABs (24 h) or antisense ODN (5 days), decreased the effects (GIT and PER) of i.c.v. morphine and fentanyl, while those of DPDPE remained unchanged. The ABs did not alter the peripheral effects of mu-opioids. 5. The results show that (i.c.v. or s.c.) mu opioids produce dose-related inhibitions of PER and GIT, being more potent by the i.c.v. route. Delta-opioids had a greater effect on PER than GIT, while the opposite occurred for mu-agonists. Pretreatment with ABs or ODN to mu-OR, blocked the central effects of mu (but not delta) agonists on GIT and PER.

The hyperalgesic effect of naloxone is attenuated in streptozotocin-diabetic mice.

In mice with streptozotocin-induced hyperglycemia, nociception was tested after naloxone administration in hot plate and tail immersion tests. The choice of these two tests was to include a supra-spinal nociceptive reflex indicative of higher cognitive process (hot-plate test) as well as a reflex which predominantly represents lower spinal motor mechanisms (tail immersion test). Naloxone-induced hyperalgesia was attenuated in both tests in mice with streptozotocin-induced diabetes. In mice with hyperglycemia induced by intraperitoneal dextrose administration, naloxone hyperalgesia was significantly enhanced in the hot plate test. The basal nociceptive threshold in streptozotocin-treated animals was decreased in the immersion but not in the hot plate test. These results indicate that hyperglycemia per se does not adequately explain the changes in naloxone hyperalgesia in experimental models of diabetes. They also suggest that acute hyperglycemia may modify the interaction of endogenous opioid peptides with their receptors only at supra-spinal sites. However, chronic hyperglycemia appears to affect endogenous opioid peptides both at spinal and supra-spinal levels and their interaction with the opiate receptors.

Influence of hypo and hyperthermia on disposition of morphine.

Using morphine as a prototype opiate anesthetic, the dispositional changes and cardiovascular effects during hypothermia (30 degrees C) and hyperthermia (40 degrees C) in dogs under isoflurane anesthesia was assessed. Single intravenous bolus injection of 1 mg/kg morphine resulted in a significant and sustained decrease in mean arterial pressure in hypothermic, but not in hyperthermic or normothermic (37 degrees C) conditions. Hypothermic dogs showed significantly higher levels of morphine both in plasma and in cerebrospinal fluid. In contrast, hyperthermia did not affect these levels. Body temperature did not affect the t1/2 alpha, however t1/2 beta and mean residence time were significantly increased while volume of distribution at steady state and total body clearance were decreased during hypothermia. The results provide evidence that hypothermia is likely to be associated with a sustained increase in opiate levels and might be associated with a enhanced side effects. The results suggests the need for a controlled clinical trial to assess the dose of opiate anesthetics during hypothermia.

Simultaneous changes in hypothalamic catecholamine levels and plasma corticosterone concentration in the rat after acute morphine and during tolerance.

The effects of morphine on plasma corticosterone and hypothalamic noradrenaline (NA) and dopamine (DA) content were studied in naive and in morphine-tolerant rats. Acutely administered morphine (30 mg/kg i.p.) significantly increased the plasma levels of corticosterone and significantly reduced the hypothalamic NA and DA content. In chronically morphine-treated rats (subcutaneously implanted with pellets for 7 days), a challenge dose of morphine (30 mg/kg intraperitoneally (i.p.)) did not modify the plasma corticosterone levels and inhibited the morphine-induced decreases in hypothalamic NA and DA content. These results suggest that: (1) In naive rats, the morphine-induced activation of hypothalamus-pituitary-adrenocortical (HPA) axis is mediated by catecholaminergic neurons in the hypothalamus; (2) In tolerant rats morphine did not modify the plasma corticosterone concentrations, presumably by attenuating hypothalamic noradrenergic and dopaminergic activity. (3) Hypothalamic catecholamines have a role in regulating the HPA axis during morphine tolerance.

Ondansetron facilitates neuromuscular transmission in the guinea-pig ileum.

The effects of ondansetron on the neuromuscular function of the guinea-pig ileum were investigated in vitro. Ondansetron, but not tropisetron or MDL 72222 (1alpha-H-3alpha-5alpha-H-tropan-3-yl-3,5-dichlo robenzoate), enhanced submaximal electrically induced contractions (EC50) = 1.3 x 10(-5) M). Desensitization with 5-hydroxytryptamine (1 x 10(-5) M) or 2-methyl-5-HT (1 x 10(-5) M) abolished this facilitatory response, which remained unaltered after desensitization with 5-methoxytryptamine (1 x 10(-5) M) or addition of tropisetron, MDL 72222, N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan, SB203186 (1-piperidinylethyl-1H-indole-3 carboxylate hydrochloride), pirenzepine or hexamethonium. At higher concentrations, ondansetron decreased the electrically induced contractions (EC50 = 1 x 10(-4) M); the inhibitory response was unaffected by (-)-naloxone (1 x 10(-6) M) or idazoxan (1 x 10(-6) M). We conclude that, in the guinea-pig ileum, ondansetron elicits a biphasic response: facilitation of neuromuscular transmission mediated by a serotonergic receptor distinct from the 5-HT3, 5-HT4 or putative 5-HT1P receptors, and an inhibitory response that does not involve opiate or alpha2-adrenoceptors.

Effects of mu-opioid receptor agonists on intestinal secretion and permeability during acute intestinal inflammation in mice.

We evaluated and compared the effects of mu-opioid receptor agonists on mucosal fluid transport and permeability, during acute intestinal inflammation. We hypothesized that inflammation would sensitize mu-opioid receptors in the submucosal plexus and/or enterocytes enhancing the effects of mu-opioid receptor agonists. Inflammation was induced by intragastric administration of croton oil, whereas controls received saline. Fluid transport was assessed by enteropooling, and intestinal permeability by blood-to-lumen passage of [51Cr] etylenediaminetetraacetate ([51Cr] EDTA). Intestinal inflammation induced a significant increase in enteropooling (1.9 times) and permeability (2.5 times). In saline- and croton oil-treated animals, mu-opioid receptor agonists produced dose-related inhibitions of enteropooling and intestinal permeability. During inflammation, the potency of morphine increased 4.8 and 3.7 times, inhibiting enteropooling and intestinal permeability, respectively; the potencies of fentanyl and PL017 similarly increased by approximately three (enteropooling) and two times (permeability) in croton oil animals. All effects were reversed by naloxone and naloxone methiodide. The results show that inflammation increases the inhibitory potency of mu-opioid receptor agonists on secretion and permeability, suggesting a sensitization of peripheral mu-opioid receptors.

Antisense oligodeoxynucleotides to mu- and delta-opioid receptor mRNA block the enhanced effects of opioids during intestinal inflammation.

Intestinal inflammation enhances the inhibitory effects of mu- and delta-opioids in the gut, possibly related to an increased receptor expression. We evaluated the effects of opioids after intraperitoneal administration of antisense oligodeoxynucleotides to mu- and/or delta-opioid receptor mRNA. Inflammation was induced in mice by intragastric administration of croton oil; gastrointestinal transit was assessed with charcoal and permeability with [51Cr]etylenediaminetetraacetate ([51Cr]EDTA). Baseline values were unaltered after antisense oligodeoxynucleotides. In controls, antisense oligodeoxynucleotides to mu-opioid receptor mRNA decreased the antitransit effects of morphine (27%) and [N-MePhe3D-Pro4]morphiceptin (PL017) (26%), and the reduction was significantly greater during inflammation (50% and 47%). A similar effect was observed on permeability (control: 41-21% decrease; inflamed: 66-45%). In both assays, antisense oligodeoxynucleotides to delta-opioid receptor mRNA also reduced the effects of [D-Pen2,5]enkephalin (DPDPE) in a higher percentage during inflammation (43-32% controls, 60-49% inflamed). We show that antisense oligodeoxynucleotides to mu- and/or delta-opioid receptor mRNA are efficiently blocking the intestinal effects of opioids during inflammation, suggesting that an increased transcription of these receptors in the gut mediates the enhanced effects of opioids during inflammation.

Stereospecific inhibition of gastrointestinal transit by kappa opioid agonists in mice.

Systemic administration of highly selective kappa opiate agonists, U-50488H and U-69593 (3, 10 and 30 mg/kg i.p.) produced significant inhibition of the gastrointestinal transit in mice as assessed by charcoal meal test. In contrast, the (+) stereoisomer of U-50488H, U-53455E did not inhibit the gastrointestinal motility. Furthermore, the kappa-selective antagonist, Mr 2266 (3 mg/kg) when administered along with the agonists, reversed the effects of the agonists. These results suggest that stereospecific kappa opiate receptors are involved in inhibition of gut motility in mice.

Interaction between halothane and morphine on isolated heart muscle.

The present study describes the effects of halothane on morphine activity in the isolated left atria of the rat. Concentration-response curves were obtained for the negative inotropic effects of morphine on electrically stimulated left atria. Morphine significantly decreased the contractile force, with an inhibitory concentration 16 (IC16) of 3.130.698 +/- 22.5 X 10(-9) M. The opiate agonist was more potent in reserpinized rats, causing a consistent negative inotropic action over a wide range (10(-8)-10(-4) M) or morphine concentrations. The IC16 of morphine was significantly (P less than 0.001) decreased in the presence of 1.5% v/v halothane. The administration of L-naloxone (3 X 10(-7)-10(-6) M) but not D-naloxone (10(-6) M) antagonized the inhibitory effects of morphine in the presence of halothane. These results demonstrate that halothane increases the potency of morphine on the isolated left atria and suggest that this effect is mediated by opioid receptors.

Effects of the benzomorphan kappa-opiate, MR 2266 and its (+) enantiomer MR 2267, on thermonociceptive reactions in different strains of mice.

The effects of the benzomorphan kappa opiate MR 2266 and its dextro enantiomer MR 2267 were assessed on thermonociception in Swiss Webster, C57BL/6, BALB/c and DBA/2 strains of mice. In the hot plate (60 +/- 0.5 degrees C, cut-off time 120 s and tail immersion tests, MR 2266 (10 mg/kg, s.c., 15 min before) decreased, while MR 2267 (10 mg/kg s.c., 15 min before) increased the reaction latencies. In the hot plate test, the sensitivities for the effects of MR 2266 and MR 2267 on jump latency in different strains of mice were as follows: MR 2266; BALB greater than Swiss greater than C57BL greater than DBA and MR 2267; DBA greater than BALB = Swiss greater than C57BL. In the immersion test, for the hyperalgesic response of MR 2266, the rank order of strains was; BALB greater than C57BL and DBA greater than or equal to Swiss while the rank order for the analgesic effect of MR 2267 was; Swiss greater than DBA and BALB. The results indicate the presence of tonic kappa-receptor-mediated regulation of the spinal and supra-spinal thermonociceptive reactions which is stereospecific and strain dependent.

Prevention of hyperthermia-induced seizures in immature rats by a hydantoin derivative of naloxone.

The non-specific opiate antagonist naloxone protects immature rats from hyperthermic seizures which occur when the animals are exposed to an environment of 40 degrees C and 55% humidity. Most of the currently used antiepileptic therapeutic agents can be said to contain either a hydantoin or a moiety stereochemically closely related to one. We have added a hydantoin group to naloxone and created a new combined chemical, naloxyl-6-alpha spirohydantoin. The new compound was ten times as effective as naloxone against hyperthermic seizures in 15-day old rat pups. Unlike naloxone, the new naloxone-hydantoin derivative retained a protective effect 24 hrs after injection.