Intravenous Infusion Of Naloxone Research Articles

Characterizing the opioidergic mechanisms of repetitive transcranial magnetic stimulation-induced analgesia: a randomized controlled trial.

Repetitive transcranial magnetic stimulation (rTMS) is a promising technology to reduce chronic pain. Investigating the mechanisms of rTMS analgesia holds the potential to improve treatment efficacy. Using a double-blind and placebo-controlled design at both stimulation and pharmacologic ends, this study investigated the opioidergic mechanisms of rTMS analgesia by abolishing and recovering analgesia in 2 separate stages across brain regions and TMS doses. A group of 45 healthy participants were equally randomized to the primary motor cortex (M1), the dorsolateral prefrontal cortex (DLPFC), and the Sham group. In each session, participants received an intravenous infusion of naloxone or saline before the first rTMS session. Participants then received a second dose of rTMS session after the drugs were metabolized at 90 minutes. M1-rTMS-induced analgesia was abolished by naloxone compared with saline and was recovered by the second rTMS run when naloxone was metabolized. In the DLPFC, double but not the first TMS session induced significant pain reduction in the saline condition, resulting in less pain compared with the naloxone condition. In addition, TMS over the M1 or DLPFC selectively increased plasma concentrations of β-endorphin or encephalin, respectively. Overall, we present causal evidence that opioidergic mechanisms are involved in both M1-induced and DLPFC-rTMS-induced analgesia; however, these are shaped by rTMS dosage and the release of different endogenous opioids.

Accidental Methadone Poisoning in a Four-Year-Old Child Reversed With Continuous Intravenous Infusion of Naloxone

Reported case of methadone poisoning among children is infrequent in Malaysia. Since the implementation of methadone maintenance therapy (MMT) programme by Malaysian Ministry of Health in year 2006, there are only three case reports of methadone poisoning in children. Methadone toxicity in children can be deadly if antidote and supportive measures are not instituted in time. We report a case of accidental ingestion of about 25 mg of methadone in a 4-year-old boy. The methadone syrup belonged to his father, a former intravenous drug user (IVDU), who is currently a participant of the MMT detoxification programme under the supervision of a licensed general practitioner. The child presented with typical early signs and symptoms opioid toxicity. Upon examination, vital signs were normal, but he appeared lethargic and drowsy. Venous blood gas results noted mild respiratory acidosis and complete blood count revealed leukocytosis. He was treated with continuous intravenous infusion (CIVI) naloxone 10 µg/kg/h for approximately 78 h. He was hospitalized for 6 days and discharged well. Advice should be given to family who has patient under MMT programme with take-home doses to be more cautious in storage of methadone syrup at home, and to keep the bottle far from the reach of children. Methadone poisoning in children can be deadly and early administration of naloxone as CIVI can effectively reverse its toxicity. Int J Clin Pediatr. 2021;10(1):18-23 doi: https://doi.org/10.14740/ijcp386

High-dose naloxone: Effects by late administration on pain and hyperalgesia following a human heat injury model. A randomized, double-blind, placebo-controlled, crossover trial with an enriched enrollment design.

Severe chronic postsurgical pain has a prevalence of 4-10% in the surgical population. The underlying nociceptive mechanisms have not been well characterized. Following the late resolution phase of an inflammatory injury, high-dose μ-opioid-receptor inverse agonists reinstate hypersensitivity to nociceptive stimuli. This unmasking of latent pain sensitization has been a consistent finding in rodents while only observed in a limited number of human volunteers. Latent sensitization could be a potential triggering venue in chronic postsurgical pain. The objective of the present trial was in detail to examine the association between injury-induced secondary hyperalgesia and naloxone-induced unmasking of latent sensitization. Healthy volunteers (n = 80) received a cutaneous heat injury (47°C, 420 s, 12.5 cm2). Baseline secondary hyperalgesia areas were assessed 1 h post-injury. Utilizing an enriched enrollment design, subjects with a magnitude of secondary hyperalgesia areas in the upper quartile ('high-sensitizers' [n = 20]) and the lower quartile ('low-sensitizers' [n = 20]) were selected for further study. In four consecutive experimental sessions (Sessions 1 to 4), the subjects at two sessions (Sessions 1 and 3) received a cutaneous heat injury followed 168 h later (Sessions 2 and 4) by a three-step target-controlled intravenous infusion of naloxone (3.25 mg/kg), or normal saline. Assessments of secondary hyperalgesia areas were made immediately before and stepwise during the infusions. Simple univariate statistics revealed no significant differences in secondary hyperalgesia areas between naloxone and placebo treatments (P = 0.215), or between 'high-sensitizers' and 'low-sensitizers' (P = 0.757). In a mixed-effects model, secondary hyperalgesia areas were significantly larger following naloxone as compared to placebo for 'high-sensitizers' (P < 0.001), but not 'low-sensitizers' (P = 0.651). Although we could not unequivocally demonstrate naloxone-induced reinstatement of heat injury-induced hyperalgesia, further studies in clinical postsurgical pain models are warranted.

Comparison of the efficacy of an infusion pump or standard IV push injection to deliver naloxone in treatment of opioid toxicity

Background:The optimal goal of naloxone infusion in intensive care units is to ameliorate opioid-induced side effects in therapy or eliminate the symptoms of opioid toxicity in overdoses. Accurately monitoring and regulating the doses is critical to prevent adverse effects related to naloxone administration. The present study aimed to compare treatment outcomes when using two methods of intravenous naloxone infusion: an infusion pump or the standard method. Methods:This study involved 80 patients with signs and symptoms of opioid overdose. The patients were randomly assigned into two groups with respect to intravenous infusion of naloxone by either an infusion pump or the standard method. Results:Comparison of study parameters between the two groups at 12 and 24 hours after intervention showed significantly more compensatory acid-base imbalance in the naloxone infusion pump group. In the group that received naloxone by pump, only one patient experienced withdrawal symptoms, but withdrawal symptoms appeared in 12 patients (30.0%) in the standard intravenous infusion group within 12 hours and in seven additional patients (17.5%) within 24 hours of intervention. In the group receiving pump-based naloxone infusion therapy, no another complications were reported; however in the standard infusion group, the 12-hour and 24-hour complication rates were 55.0% and 32.5%, respectively. The length of hospital stay was 2.85±1.05 and 4.22±0.92 days for the pump and standard infusion groups, respectively (P<0.001). Conclusions:Naloxone infusion using an infusion pump may be safer with regard to hemodynamic stability, resulting in shorter hospitalization periods, and fewer posttreatment complications.

Comparative Study between Naloxone as an Additive to Lidocaine and Naloxone Infusion in Intravenous Regional Anaesthesia for Short Procedures of Upper Limb Surgeries

Background: intravenous regional anesthesia (IVRA) was first described by August Bier in 1908. IVRA is an anesthetic technique for surgical procedures on the body's extremities where a local anesthetic is injected intravenously. The local anesthetic diffuses from the peripheral vascular bed to nonvascular tissue such as axons and nerve endings. Objective: The aim of the present study was to compare the effect of adding ultra-low dose of naloxone to lidocaine for IVRA and the effect of using intravenous naloxone infusion with IVRA for elective short procedures in the upper limb. Patients and Methods: This is Prospective; randomized, controlled, multicenter, double blind study that done in Alazhar University hospitals. Each group contains 30 patients. The lidocaine in the study is 2% 3mg/kg in all groups. In all groups 0.9% NaCl is added to make up a total volume of 30 ml. Results: The result of our study showed that local intravenous adjuvant naloxone (100 or 50ng) with lidocaine 1 % shortens the onset of blocks and prolongs the recovery from anesthesia. Moreover, it reduces the amount of opioids consumption and intraoperative pain score in patient undergoing short upper limb surgeries. Conclusion: Naloxone IV infusion not improves the analgesic effect of intravenous anesthesia or prolongs the recovery from anesthesia. Regarding safety, adjuvant naloxone appears to be safe with no recorded side effects.

Comparative Study between Naloxone as an Additive to Lidocaine and Naloxone Infusion in Intravenous Regional Anaesthesia for Short Procedures of Upper Limb Surgeries

Background: intravenous regional anesthesia (IVRA) was first described by August Bier in 1908. IVRA is an anesthetic technique for surgical procedures on the body's extremities where a local anesthetic is injected intravenously. The local anesthetic diffuses from the peripheral vascular bed to nonvascular tissue such as axons and nerve endings. Objective: The aim of the present study was to compare the effect of adding ultra-low dose of naloxone to lidocaine for IVRA and the effect of using intravenous naloxone infusion with IVRA for elective short procedures in the upper limb. Patients and Methods: This is Prospective; randomized, controlled, multicenter, double blind study that done in Alazhar University hospitals. Each group contains 30 patients. The lidocaine in the study is 2% 3mg/kg in all groups. In all groups 0.9% NaCl is added to make up a total volume of 30 ml. Results: The result of our study showed that local intravenous adjuvant naloxone (100 or 50ng) with lidocaine 1 % shortens the onset of blocks and prolongs the recovery from anesthesia. Moreover, it reduces the amount of opioids consumption and intraoperative pain score in patient undergoing short upper limb surgeries. Conclusion: Naloxone IV infusion not improves the analgesic effect of intravenous anesthesia or prolongs the recovery from anesthesia. Regarding safety, adjuvant naloxone appears to be safe with no recorded side effects.

Influence of naloxone on quality and duration of analgesia produced by thoracic epidural morphine and bupivacaine

800x600 800x600 Introduction Controlled trials in children and adolescents have shown that, small-dose naloxone infusions (0.25µg/kg/hour) can significantly reduce opioid induced side effects without affecting opioid-induced analgesia. Material and methods 84 elective thoracotomy patients having combined thoracic epidural and general anesthesia for thoracotomy surgeries were randomly assigned to one of the two study groups. All patients of Group A (n=42) received continuous intravenous infusion of naloxone at a calculated dose of 0.25µgkg -1 hr -1 and patients of Group B (n=42) received continuous intravenous infusion of normal saline at a fixed rate. All patients were premedicated with fentanyl 1 µg/kg i.v. After placement of epidural catheter at T 6-8 interspaces, all patients were administered morphine 0.1mg/kg with 0.125% bupivacaine immediately before induction of general anaesthesia. VAS was assessed immediately after extubation and a bolus dose of 0.01mg/kg epidural morphine was administered when VAS exceeded 3 in postoperative follow up period of 72hrs in all patients. We measured the incidence of side effects like vomiting, nausea, pruritus and respiratory depression and number of times rescue analgesic was required. Results Small dose naloxone infusion significantly reduced the opioid induced side effects without antagonizing opioid induced analgesia. Conclusion N aloxone reduces epidural morphine-induced side effects without significant alteration of its analgesic effects. DOI: http://dx.doi.org/10.4038/slja.v22i2.6231 Normal 0 false false false EN-US X-NONE X-NONE MicrosoftInternetExplorer4

Hipoacusia en un paciente tras administración de morfina intratecal

The administration of intrathecal opioids is a common technique when treating patients with chronic pain. The chosen drug is morphine due to its pharmacokinetic characteristics that determine a good analgesic quality, still required monitoring of patients for the first 24 hours because of their fundamental risk of respiratory depression. We present a case of hearing loss associated with opioid intoxication after administration of morphine by intrathecal infusion pump in a patient with chronic pain with post-laminectomy syndrome. The patient was treated with respiratory support and continuous intravenous infusion of naloxone. The hearing loss reverted within one hour after gradual increase of the treatment. The different articles that we analyzed include nausea, vomiting, pruritus, urinary retention and respiratory depression as side effects of intrathecal morphine. There is no reference to the onset of hearing loss associated with intrathecal opioid intoxicaton in the literature we have reviewed so far.

Does Naloxone Reinstate Secondary Hyperalgesia in Humans after Resolution of a Burn Injury? A Placebo-Controlled, Double-Blind, Randomized, Cross-Over Study

IntroductionDevelopment of secondary hyperalgesia following a cutaneous injury is a centrally mediated, robust phenomenon. The pathophysiological role of endogenous opioid signalling to the development of hyperalgesia is unclear. Recent animal studies, carried out after the resolution of inflammatory pain, have demonstrated reinstatement of tactile hypersensitivity following administration of μ-opioid-receptor-antagonists. In the present study in humans, we analyzed the effect of naloxone when given after the resolution of secondary hyperalgesia following a first-degree burn injury.MethodsTwenty-two healthy volunteers were included in this placebo-controlled, randomized, double-blind, cross-over study. Following baseline assessment of thermal and mechanical thresholds, a first-degree burn injury (BI; 47°C, 7 minutes, thermode area 12.5 cm2) was induced on the lower leg. Secondary hyperalgesia areas around the BI-area, and separately produced by brief thermal sensitization on the contralateral thigh (BTS; 45°C, 3 minutes, area 12.5 cm2), were assessed using a polyamide monofilament at pre-BI and 1, 2, and 3 hours post-BI. At 72 hrs, BI and BTS secondary hyperalgesia areas were assessed prior to start of a 30 minutes intravenous infusion of naloxone (total dose 21 microg/kg) or placebo. Fifteen minutes after start of the infusion, BI and BTS secondary hyperalgesia areas were reassessed, along with mechanical and thermal thresholds.ResultsSecondary hyperalgesia areas were demonstrable in all volunteers 1–3 hrs post-BI, but were not demonstrable at 72 hrs post-burn in 73–86% of the subjects. Neither magnitude of secondary hyperalgesia areas nor the mechanical and thermal thresholds were associated with naloxone-treated compared to placebo-treated subjects.ConclusionNaloxone (21 microg/kg) did not reinstate secondary hyperalgesia when administered 72 hours after a first-degree burn injury and did not increase BTS-generated hyperalgesia. The negative results may be due to the low dose of naloxone or insufficient tissue injury to generate latent sensitization.

T NOVER MUTATION IN HMBS GENE PRESENTING WITH ‘BATHING SUIT’ SENSORY IMPAIRMENT AND RECURRENT NEUROLOGICAL DEFICIT

64-year old lady presented with sudden onset of flaccid tetraparesis and absent reflexes. Sensory deficit was non-dermatomal: affecting trunk, shoulders and buttocks. She was intolerant of multiple antibiotics and analgesics....

Management of an Oral Ingestion of Transdermal Fentanyl Patches: A Case Report and Literature Review

Purpose. Fentanyl is available as a transdermal system for the treatment of chronic pain in opioid-tolerant patients; however, it carries a black box warning due to both the potency of the product and the potential for abuse. In this report, we describe a case of transbuccal and gastrointestinal ingestion of fentanyl patches and the management of such ingestion. Summary. A 32-year-old man was brought to the emergency department (ED) via emergency medical services for toxic ingestion and suicide attempt. The patient chewed and ingested two illegally purchased transdermal fentanyl patches. In the ED, the patient was obtunded, dizzy and drowsy. Initial vital signs showed the patient to be afebrile and normotensive with a heart rate of 63, respiratory rate of 16, and oxygen saturation of 100% on 2 liters nasal cannula after administration of 2 milligrams of intravenous naloxone. The patient was treated with whole bowel irrigation and continuous intravenous naloxone infusion for approximately 48 hours without complications. Conclusion. Despite numerous case reports describing oral ingestion of fentanyl patches, information on the management of such intoxication is lacking. We report successful management of such a case utilizing whole bowel irrigation along with intravenous push and continuous infusion naloxone.

Case report: quantification of methadone-induced respiratory depression using toxicokinetic/toxicodynamic relationships

IntroductionMethadone, the most widely delivered maintenance therapy for heroin addicts, may be responsible for life-threatening poisonings with respiratory depression. The toxicokinetics and the toxicokinetic/toxicodynamic (TK/TD) relationships of methadone enantiomers have been poorly investigated in acute poisonings. The aim of this study was to describe the relationships between methadone-related respiratory effects and their corresponding concentrations.MethodsWe report a 44-year-old methadone-maintained patient who ingested a 240-mg dose of methadone. He was found comatose with pinpoint pupils and respiratory depression. He was successfully treated with intravenous naloxone infusion over the course of 31 hours at a rate adapted to maintain normal consciousness and respiratory rate. We performed a TK/TD analysis of the naloxone infusion rate needed to maintain his respiratory rate at more than 12 breaths per minute (as toxicodynamics parameter) versus plasma R,S- and R-methadone concentrations (as toxicokinetics parameter), determined using an enantioselective high-performance liquid chromatography assay.ResultsInitial plasma R,S-methadone concentration was 1,204 ng/ml. Decrease in plasma R- and S-methadone concentrations was linear and demonstrated a first-order pharmacokinetics (maximal observed concentrations 566 and 637 ng/ml, half-lives 16.1 and 13.2 hours, respectively). TK/TD correlation between naloxone infusion rate and R,S- and R-methadone concentrations fitted well a sigmoidal Emax model (concentration associated with a half-maximum effect [EC50] 334 and 173 ng/ml, Hill coefficient 10.0 and 7.8, respectively). In our chronically treated patient, EC50 values were in the range of previously reported values regarding methadone analgesic effects, suggesting that plasma methadone concentrations to prevent withdrawal are lower than those associated with methadone analgesic effects.ConclusionAfter the ingestion of a toxic dose of a racemic mixture, plasma R- and S-enantiomer concentrations decreased in parallel. Despite large inter-individual variability in methadone toxicokinetics and toxicodynamics, TK/TD relationships would be helpful for providing quantitative data regarding the respiratory response to methadone in poisonings. However, further confirmatory TK/TD data are needed.

Naloxone lowers cerebrospinal fluid levels of excitatory amino acids after thoracoabdominal aortic surgery

Although naloxone has been used to prevent ischemic spinal cord injury (SCI), its effect on excitatory amino acids (EAAs) has not been understood. We investigated the clinical significance of naloxone by measuring EAAs in the cerebrospinal fluid (CSF) in patients undergoing thoracoabdominal aortic surgery. Twenty-seven patients (15 men and 12 women; mean age, 66 +/- 12 years) undergoing prosthetic replacement of the thoracoabdominal aorta (n = 19) or the descending thoracic aorta (n = 8) from April 1997 to June 2003 under distal perfusion and mild hypothermia were enrolled in this cohort study with historical controls. Their etiology was 7 dissections and 20 nondissections. In 16 patients (naloxone group), intravenous infusion of naloxone (1 microg/kg/h) was continued until the patients became alert. In the remaining 11 patients (control group) naloxone was not given. CSF drainage was used in all patients. CSF levels of EAAs, glutamate, aspartate, and glycine were measured at 6 points in time until 72 hours postoperatively, using a high-performance liquid chromatography method. In 5 patients with SCI (2 patients in control group, 3 in naloxone group), CSF levels of glutamate and glycine continued to increase even at 72 hours postoperatively, and were significantly more elevated than those in patients without SCI ( P < .0001, glutamate; P = .0006, glycine). Postoperative maximum levels of CSF glutamate and glycine were also significantly higher in patients with postoperative SCI than in patients without SCI (glutamate: 215.3% +/- 158.6% vs 32.9% +/- 37.3% increase from baseline, P < .0001; glycine: 309.1% +/- 218.2% vs 89.2% +/- 103.1% increase from baseline, P = .0036). CSF levels of glutamate and aspartate in naloxone group were significantly lower than those in control group ( P = .0161, glutamate; P < .0001, aspartate). Postoperative maximum level of CSF aspartate was also significantly lower in the naloxone group than in the control group (8.3% +/- 75.5% vs 119.7% +/- 120.6% increase from baseline, P = .0077). In multivariate logistic regression analysis, postoperative maximum CSF glutamate >100% from baseline ( P < .001) and postoperative maximum level of CSF glycine ( P = .005)were identified as the independent risk factors for SCI. Both SCI ( P < .001) and postoperative maximum level of CSF glycine ( P = .005) were the independent predictors for postoperative maximum level of CSF glutamate >100% from baseline. CSF levels of EAAs are elevated in patients with SCI. CSF glutamate is the strongest independent predictor of SCI. Naloxone is effective in lowering CSF levels of EAAs.

Fos expression in gonadotropin-releasing hormone neurons by naloxone or bicuculline in intact male rats

Double immunocytochemistry for Fos and GnRH was performed after the intravenous infusion of naloxone or bicuculline. Either naloxone or bicuculline significantly increased serum LH concentrations. After the naloxone infusion, some Fos-positive GnRH neurons were found from the preoptic area to the basal hypothalamic area, whereas those were found from the diagonal band of Broca to the preoptic area after the bicuculline infusion. These results suggest the distribution of GnRH neurons activated by naloxone and bicuculline in intact male rats.

Effects of naloxone on myocardial ischemic preconditioning in humans

OBJECTIVESWe attempted to establish whether naloxone, an opioid receptor antagonist, abolishes the adaptation to ischemia observed in humans during coronary angioplasty after repeated balloon inflations.BACKGROUNDExperimental studies indicate that myocardial opioid receptors are involved in ischemic preconditioning.METHODSTwenty patients undergoing angioplasty for an isolated stenosis of a major epicardial coronary artery were randomized to receive intravenous infusion of naloxone or placebo during the procedure. Intracoronary electrocardiogram and cardiac pain (using a 100-mm visual analog scale) were determined at the end of the first two balloon inflations. Average peak velocity in the contralateral coronary artery during balloon occlusion, an index of collateral recruitment, was also assessed by using a Doppler guide wire in the six patients of each group with a stenosis on the left anterior descending coronary artery.RESULTSIn naloxone-treated patients, ST-segment changes and cardiac pain severity during the second inflation were similar to those observed during the first inflation (12 ± 6 vs. 11 ± 7 mm, p = 0.3, and 58 ± 13 vs. 56 ± 12 mm, p = 0.3, respectively), whereas in placebo-treated patients, they were significantly less (6 ± 3 vs. 13 ± 6 mm, p = 0.002 and 31 ± 21 vs. 55 ± 22 mm, p = 0.008, respectively). In both naloxone- and placebo-treated patients, average peak velocity significantly increased from baseline to the end of the first inflation (p = 0.04 and p = 0.02, respectively), but it did not show any further increase during the second inflation.CONCLUSIONSThe adaptation to ischemia observed in humans after two sequential coronary balloon inflations is abolished by naloxone and is independent of collateral recruitment. Thus, it is due to ischemic preconditioning and is, at least partially, mediated by opioid receptors, suggesting their presence in the human heart.

Comparison of intravenous nalbuphine infusion versus naloxone in the prevention of epidural morphine-related side effects

Background and Objectives. Epidural morphine is accepted as an efficient means of postoperative pain management. However, development of side effects such as nausea and vomiting and pruritus has been reported. This study compared the efficacy of intravenous infusions of nalbuphine or naloxone in the prevention of epidural morphine-related side effects. Methods. Seventy-five female patients undergoing epidural anesthesia for total hysterectomy were enrolled in a randomized, double-blind study. At the end of the surgery, all patients received epidural 3 mg morphine (every 12 hours) for postoperative pain. Meanwhile, patients in group 1 received an adjuvant intravenous infusion of nalbuphine 60 μg/kg/h, patients in group 2 received intravenous infusion of naloxone 2 μg/kg/h, and patients in group 3 received intravenous saline infusion only. A rescue analgesic of intramuscular 50 mg meperidine (every 4 hours) was available for each patient. Patients were observed for 24 hours. Results. All patients had adequate postoperative pain relief. However, the proportion of patients requiring rescue analgesia and the total consumption of rescue analgesic were higher in group 2 than in the other two groups. The incidence of nausea and vomiting and pruritus was higher in group 3 than in the other two groups. Conclusions. We found that coadministration of either nalbuphine or naloxone with epidural morphine reduces the incidence of morphine-related side effects. However, unlike naloxone, nalbuphine did not attenuate the analgesic effect of epidural morphine.

Continuous intravenous infusion of naloxone does not change behavioral, cardiovascular, or inflammatory responses to subcutaneous formalin in the rat

The opioid antagonist, naloxone, produces equivocal effects on the magnitude of nociceptive responses in several animal models of persistent pain, including the formalin test. Hindpaw injection of dilute formalin produces not only inflammation but also phasic (Phase 1) and persistent (Phase 2) behavioral and cardiovascular nociceptive responses in the rat. To test the hypothesis that endogenous opioid systems contribute to the magnitude of responses to intraplantar formalin injection, we evaluated the effects of continuous naloxone administration (0.01–100 mg/kg per h, i.v.) on formalin-evoked hindpaw inflammation, on behavioral indices of pain, flinching and licking pain behavior, and on changes in mean arterial pressure and heart rate. We report that naloxone, at doses less than 100 mg/kg per h, did not change any formalin-evoked response. Although the 100 mg/kg per h dose significantly decreased these responses, it also produced muscle rigidity and profound bradycardia. We conclude that endogenous opioids do not significantly modulate the nociceptive processing induced by subcutaneous formalin.

Insulin-induced hypoglycemia decreases luteinizing hormone secretion in the castrated male rat: involvement of opiate peptides.

Insulin-induced hypoglycemia (IIH) has been reported to inhibit luteinizing hormone (LH) secretion in ovariectomized ewes as well as in intact or gonadectomized female rhesus monkeys. An infusion of naloxone, a specific opiate receptor antagonist, while able to prevent this inhibitory effect in ewes, was ineffective in monkeys, suggesting a difference in the mechanisms involved in the response to IIH in these two species. The present study was designed to investigate the influence of this stimulus on the dynamics of LH release and the possible activation of an opioidergic pathway in the long-term castrated male rat. Blood samples were collected every 7 min, for several hours, in freely-moving rats bearing a jugular cannula. The intravenous injection of 0.4 IU of insulin triggered an acute hypoglycemia and reduced LH release. In contrast, during a continuous intravenous naloxone infusion (0.5 mg/kg/h), insulin, while still lowering the glycemia, failed to affect the LH secretory pattern. In a control experiment, naloxone infusion alone had no significant effect on mean LH concentration and pulse intervals. These experiments indicate that, in long-term gonadectomized male rats, IIH impairs the LH secretory pattern, and that endogenous opioid peptides are involved in this response.

Enhanced Nocturnal Melatonin Secretion in Women with Functional Secondary Amenorrhea: Relationship to Opioid System and Endogenous Estrogen Levels

The purpose of this study was to evaluate the role of the opioid system and the estrogen environment in the nocturnal secretion of melatonin in women with secondary amenorrhea (SA). Nocturnal melatonin concentrations in patients with SA were significantly higher than in normal women (p < 0.01 vs. women with normal menstrual cycles). There were significant negative correlations between cumulative melatonin levels (between 8 p.m. and 8 a.m.) and serum estradiol-17 beta (r = -0.561, p < 0.01) and between peak serum melatonin values and serum estradiol-17 beta concentrations (r = -0.608, p < 0.01) in SA. Intravenous administration of a conjugated estrogen (Premarin 20 mg) significantly suppressed nocturnal melatonin secretion (p < 0.05), but a continuous intravenous infusion of naloxone (1.6 mg/h from 8 p.m. to 6 a.m.), an opiate antagonist, did not affect nocturnal melatonin secretion in SA. Our findings suggest that elevated nocturnal melatonin secretion may be related to low estrogen levels, but that it is not mediated by the opioid system.

Treatment of high-dose intrathecal morphine overdose

The case is reported of a 45-year-old woman who was being treated for chronic back and right leg pain with intrathecal morphine administered via a subcutaneous continuous-infusion device. She received an accidental 450-mg bolus injection of morphine intrathecally and developed hypertension, status epilepticus, intracerebral hemorrhage, and respiratory failure. Treatment with continuous intravenous naloxone infusion, lumbar catheter drainage of cerebrospinal fluid, and control of hypertension and status epilepticus resulted in an excellent outcome with return to neurological baseline. Care providers who refill pump reservoirs with morphine must be knowledgeable about these devices and the life-threatening consequences associated with errors in refilling them. This case describes the complications and successful treatment of high-dose intrathecal morphine overdose.