Impact of age on the severity, course, and complications of alcohol withdrawal

BACKGROUND: Early identification of alcohol-dependent patients at increased risk for severe or complicated alcohol withdrawal would improve triage and treatment. However, the role of age in predicting alcohol withdrawal outcomes has not been well studied. OBJECTIVE: To assess the impact of age on the severity, course, and complications of alcohol withdrawal. METHODS: We performed a retrospective cohort study of 284 inpatients admitted for alcohol withdrawal between September 1992 and August 1994. Outcomes included alcohol withdrawal severity measured by the revised Clinical Institute Withdrawal Assessment for Alcohol scale, quantity and duration of benzodiazepine therapy, and complications during withdrawal. RESULTS: Initial and maximal withdrawal severity scores, amount of benzodiazepine administered, and duration of benzodiazepine treatment for elevated withdrawal severity scores did not change significantly with age. However, patients aged 60 years and older had increased risk for delirium (adjusted odds ratio [OR], 4.7; 95% confidence interval [CI], 1.5-15.0; P = .008), falls (OR, 3.1; 95% CI, 0.9-11.2; P = .08), and transient dependency in 2 or more activities of daily living (OR, 5.8; 95% CI, 2.9-11.7; P < .001). As age increased, there were significant increases in length of stay (P < .001) and frequency of discharge to an extended care facility (P < .001). CONCLUSIONS: Although alcohol withdrawal severity scores and benzodiazepine requirements were similar across age groups, patients aged 60 years and older were at increased risk for cognitive and functional impairment during withdrawal. These findings support recommendations that older patients with alcohol withdrawal are best treated in closely supervised settings.     

Dexmedetomidine alleviates ethanol withdrawal symptoms in the rat

The effect of dexmedetomidine, a selective alpha 2-adrenoceptor agonist, on ethanol withdrawal symptoms was studied in chronically ethanol-fed rats. After a 4-day ethanol intoxication period the rats were given s.c. injections of dexmedetomidine (3, 10, or 30 micrograms/kg) or saline (control group) at 10, 16, 22, and 39 h after the last dose of ethanol. The severity of ethanol withdrawal symptoms (rigidity, tremor, irritability, hypoactivity) was rated up to 58 h, blind to the treatments. The results showed that dexmedetomidine at doses 10 and 30 micrograms/kg significantly diminished the severity of the ethanol withdrawal reaction as measured by the sum score of the three most specific withdrawal signs (rigidity, tremor, and irritability). Dexmedetomidine at 10 micrograms/kg was the most effective dose, especially in the latter half of the withdrawal period (23-58 h after last dose of ethanol). The results suggest that dexmedetomidine in the treatment of ethanol withdrawal symptoms should be further studied.     

Effects of halothane on mucociliary activity in vivo

The effect of halothane on mucociliary activity in the rabbit maxillary sinus in vivo was recorded photoelectrically. Administration of halothane (1%, 2% or 4%) into the maxillary sinus induced a temporary acceleration of mucociliary activity. The peak increase (39.1% +/- 9.1%, p < 0.05, n = 5) was seen after the 4% concentration. Long-term exposure (60 minutes) of the maxillary sinus to halothane (2%) first induced an increase of 28.4% +/- 4.6% (p < 0.05, n = 6), lasting approximately four minutes, and followed after about 15 minutes by a decrease of mucociliary activity. The maximum decrease during the 60-minute period was 19.6% +/- 2.8% (p < 0.05, n = 6). Mucociliary activity returned to its baseline level approximately 25 minutes after withdrawal of halothane. Halothane delivered to the rabbit through a tracheal cannula at 1.1% for 60 minutes did not impair mucociliary activity in the maxillary sinus. On the contrary, it initially stimulated mucociliary activity, 19.9% +/- 2.7% (p < 0.05, n = 5). There was also an initial increase in respiratory rate from 62 +/- 7.3 to 89 +/- 12.9 breaths per minute (p < 0.05), which was noticeable after approximately 10 seconds and lasted 4 to 5 minutes. The dose-dependent increase in mucociliary activity seen after short-term exposure to halothane is probably due to stimulation of afferent C fibers, because halothane may be considered an airway irritant. The reversible depressant effect seen after 15 minutes of exposure is in accordance with findings in previous studies in vitro. The mechanism by which halothane impairs mucociliary activity is at present not known. However, halothane administered to the lower airways does not impair mucociliary activity in the maxillary sinus, indicating that halothane affects the ciliated epithelium directly and that the state of anesthesia itself has no effect on mucociliary activity.     

The acceptability, safety, and tolerability of methadone/naloxone in a 50:1 ratio.

Methadone is an effective therapy for heroin addiction, but the public health benefits are compromised by diversion and injection of prescribed methadone. Combination with naloxone is one way to reduce the risk of diversion and injection. Two studies were conducted. The first ascertained the safety, tolerability, pharmacokinetics, and pharmacodynamics of oral methadone-naloxone in a 50:1 ratio compared with methadone. The second study investigated the effectiveness of intramuscularly injected methadone-naloxone in precipitating withdrawal in methadone-maintained subjects. The first double-blind, crossover study randomized 10 stable methadone-maintained subjects equally to receive either methadone-naloxone or methadone over two alternate 14 day periods. In the second study, 5 subjects received intramuscular injections of methadone-naloxone before their scheduled methadone dose. Oral methadone-naloxone in a 50:1 ratio appeared to be well tolerated, although a taste difference between the preparations may have compromised blinding. There were no significant differences between methadone and methadone-naloxone in objective and subjective opioid withdrawal signs, and trough and peak plasma concentrations. Methadone-naloxone in a 50:1 ratio intramuscularly precipitated mild to moderate signs of opioid withdrawal in 4 out of 5 subjects whereas a 5th subject who did not experience withdrawal at a lower dose refused higher dose challenges. Withdrawal symptoms peaked 15 to 30 minutes postchallenge and returned to baseline levels at 60 minutes. Methadone-naloxone in 50:1 ratio has the pharmacological properties to be a useful combination product for treatment of heroin addiction with reduced risk of injection. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Alcohol withdrawal severity in inbred mouse (Mus musculus) strains.

Male mice (Mus musculus) from 15 standard inbred strains were exposed to a nearly constant concentration of ethanol (EtOH) vapor for 72 hr, averaging 1.59 ± 0.03 mg EtOH/mL blood at withdrawal. EtOH- and air-exposed groups were tested hourly for handling-induced convulsions for 10 hr and at Hours 24 and 25. Strains differed markedly in the severity of withdrawal (after subtraction of control values), and by design these differences were independent of strain differences in EtOH metabolism. Correlation of strain mean withdrawal severity with other responses to EtOH supported previously reported genetic relationships of high EtOH withdrawal with low drinking, high conditioned taste aversion, low tolerance to EtOH-induced hypothermia, and high stimulated activity after low-dose EtOH. Also supported were the positive genetic correlations among EtOH, barbiturate, and benzodiazepine withdrawal. Sensitivity of naive mice to several chemical convulsant-induced seizures was also correlated with EtOH withdrawal. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Smoking withdrawal dynamics in unaided quitters.

Considerable research shows that withdrawal severity is inconsistently related to smoking cessation outcomes. This may result from measurement problems or failure to scrutinize important dimensions of the withdrawal experience. Two recent studies demonstrated that withdrawal elevation and variations in the time course of withdrawal were related to relapse in smokers treated with the nicotine patch (T. M. Piasecki, M. C. Fiore, & T. B. Baker, 1998). This article reports a conceptual replication and extension of those findings in unaided quitters. Evidence for temporal heterogeneity was found across different types of withdrawal symptoms. Patterns or slopes of affect and urge reports over time predicted smoking status at follow-up, as did mean elevation in withdrawal symptoms. These results suggest that affect and urge withdrawal symptoms make independent contributions to relapse and that relapse is related to both symptom severity and trajectory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Corticosterone increases severity of acute withdrawal from ethanol, pentobarbital, and diazepam in mice

It has been suggested that withdrawal from several subclasses of central nervous system (CNS) depressants involves common underlying mechanisms. For example, mice genetically selected for severe ethanol withdrawal convulsions (Withdrawal Seizure Prone or WSP) have also been found to express severe withdrawal following treatment with barbiturates and benzodiazepines. Corticosteroids appear to modulate severity of withdrawal from CNS depressants. Therefore, it was hypothesized that corticosterone would enhance withdrawal convulsions following acute ethanol, pentobarbital, and diazepam in WSP mice. Corticosterone (20 mg/kg) administered following each of these drugs significantly increased severity of handling-induced convulsions during withdrawal. Corticosterone did not affect pre-withdrawal convulsion scores or handling-induced convulsions of drug-naive mice. These results suggest that withdrawal convulsions following acute ethanol, pentobarbital, and diazepam are sensitive to modulation by corticosterone and they support the hypothesis that stress may increase drug withdrawal severity.     

Autonomic control of asystolic vasovagal syncope

A 30 year old woman with a lifelong history of severe, recurrent, vasovagal syncope became asystolic for 30 seconds after 37 minutes of 60 degrees head-up tilt. During early tilt, sympathetic activity, heart rate, left ventricular contractility, and cardiac output increased. Mean blood pressure was initially maintained. Presyncope was associated with maximal contractility and bradycardia despite sustained sympathetic activity. Subsequently, asystole occurred associated with complete withdrawal of muscle nerve sympathetic activity. In asystolic vasovagal reactions, presyncope may be triggered by increased left ventricular contractility and is associated with increased levels of parasympathetic and sympathetic activity. Asystole and peripheral vasodilatation may be caused by sudden and complete withdrawal of the increased sympathetic activity.     

Does reducing withdrawal severity mediate nicotine patch efficacy? A randomized clinical trial.

Nicotine replacement therapy (NRT) repeatedly has been shown to improve smoking treatment outcome. The major mechanism posited for this improvement in outcome is that NRT reduces nicotine craving and withdrawal. The authors tested this hypothesized mechanism of action using real-time data on craving and withdrawal, collected by ecological momentary assessments administered on a palm-top computer. Smokers (N = 324) were randomized to receive either active high-dose (35 mg) 24-hr patches or placebo. Increases in positive affect and decreases in craving, negative affect, and attention disturbance severity were related to lower risk of lapsing. Although NRT treatment did significantly decrease withdrawal and craving severity, these reductions only partially accounted for NRT's impact on time to first lapse: The results from a mediation analysis showed that the hazard ratio for NRT, when controlling for withdrawal and craving severity, was only a third to a half lower than the uncontrolled hazard ratio for NRT alone. This suggests that other mechanisms for the effectiveness of NRT need to be examined. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Postischemic hyperglycemia worsens neurologic outcome after spinal cord ischemia

PURPOSE: The neurologic effect of induced hyperglycemia in the postischemic period was investigated with a rat aortic occlusion model. METHODS: Sprague-Dawley rats weighing 200 to 350 gm were anesthetized, intubated, and ventilated with 1% to 1.5% halothane. Temperature was continuously monitored and maintained at 37 degrees +/- 0.5 degrees C. The chest was opened, the thymus excised, and the aortic arch exposed. Snares were placed around the aorta distal to the left subclavian artery and the right and left subclavian arteries. The three vessels thus isolated were occluded for 8 minutes. With snare release and withdrawal, the rats received an intraperitoneal injection of 5% dextrose in water (2 gm/kg) or an equivalent volume of 0.9% saline solution. In a second group of rats the administration of glucose or saline solution was delayed until 30 minutes after snare release. Blood samples for blood glucose determination were obtained before operation, before occlusion, immediately after occlusion, and 15, 30, 45, 60, and 240 minutes after occlusion. A neurologic deficit score was assigned at 1, 4, 18, and 24 hours after occlusion to quantify hindlimb neurologic deficit based on 15-point scale (0 = normal, 15 = severe deficit). Sham-operated rats received the same operation and injection, but the snares were only manipulated and not made occlusive. RESULTS: The rats that were administered glucose immediately after snare release showed a statistically significant exacerbation of lower extremity neurologic deficit at 24 hours after occlusion (p < or = 0.05, Mann-Whitney U test). The sham-operated rats were normal (0 score) at 24 hours. Significant elevation of blood glucose (321 +/- 33 mg/dl) was seen in the glucose-injected rats at 15 minutes and continued for up to 4 hours after occlusion (p = 0.040 and 0.014, respectively; Student's t test). CONCLUSION: Postischemic hyperglycemia immediately after a standard spinal cord ischemic stress worsens neurologic outcome.     

Sex differences in physical dependence on orally self-administered phencyclidine (PCP) in rhesus monkeys (Macaca mulatta).

Withdrawal from orally self-administered phencyclidine (PCP) has been shown to alter operant baselines of food-maintained responding. The goal of the present study was to determine whether there are sex differences in these alterations. Seven female and 7 male rhesus monkeys (Macaca mulatta) were given concurrent access to PCP and water under fixed ratio (FR) 8 schedules during 2 daily sessions that alternated with 2 sessions during which pellet deliveries were contingent on lever presses under an FR 64 schedule. After operant responding stabilized, PCP was replaced by water for 10 days, and food access remained under the same schedule. Subsequently, concurrent PCP and water access was reintroduced for 10 days. This procedure was repeated with 3 PCP concentrations (0.125, 0.25, and 0.50 mg/ml) and 3 FR requirements for food-reinforced responding (64, 128, and 256). Disruptions in operant responding for food served as a quantitative measure of withdrawal severity. During PCP withdrawal, males showed a greater suppression of food-maintained behavior than females at the 2 highest PCP concentrations and the lowest FR requirement tested. Males responded more than females for PCP; however, when weight was taken into consideration, PCP intake (milligrams per kilogram) in males and females was equal. The data suggest that males may experience more severe withdrawal effects than females, and the duration of the adverse effects of withdrawal lasts longer in males than in females. This study is the 1st to use nonhuman primates to document sex differences in withdrawal severity as measured by a quantifiable baseline. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Renal ACE immunohistochemical localization in NIDDM patients with nephropathy

PURPOSE: A new protective method against the spinal cord ischemia that occurs during aortic clamping was investigated in dogs. Oxygenated blood containing prostaglandin E1 (PGE1) was administered at the clamped aortic segment, and the effect was evaluated by measurement of the sensory evoked spinal potential (SESP). METHODS: In 30 dogs, a thoracotomy was made with dissection of the thoracic aorta. After intravenous heparin (100 units/kg) was administered, the proximal and distal descending thoracic aortas were cross-clamped for 60 minutes. Group A (n=10) received oxygenated blood at the rate of 1.0 ml/kg/min. Groups B (n=10) and C (n=10) received oxygenated blood at the same rate, with PGE1 at the dosage of 25 and 50 ng/kg/min, respectively. The infusion was continuously administered throughout the entire period of ischemia. SESP was measured with epidural electrodes before clamping, 10 and 60 minutes after clamping, and 10 and 60 minutes after declamping. Neurologic outcome was assessed at 24 hours after the operation and graded according to the method of Tarlov. RESULTS: There was no significant hemodynamic change in any group. At 60 minutes after damping and at 10 and 60 minutes after declamping, the amplitude of SESP was lower than that at preclamping in groups A and B (p < 0.05). At 60 minutes after damping and at 10 and 60 minutes after declamping, the SESP was more markedly decreased in group A compared with groups B and C. Regarding postoperative neurologic outcome, the dogs with SESP amplitude of more than 50% of the preclamping control value at 60 minutes after clamping showed neither paralysis nor paraplegia. Seven of nine dogs with less than 50% SESP amplitude showed neurogenic deficit. In a comparison of groups A, B, and C, the Tarlov score for group A dogs was significantly lower than that for group C dogs (p < 0.05). CONCLUSION: In this model, PGE1 administration at the rate of 50 ng/kg/min showed sufficient spinal cord protection against ischemia without a decrease in the blood pressure. Further studies are needed to determine the dose that will provide the maximal protective effect and to determine the maximum duration of ischemia against which PGE1 shows protective effects.     

Rebound pulmonary hypertension after inhalation of nitric oxide

BACKGROUND: We describe the hemodynamic response to initiation and withdrawal of inhaled nitric oxide (NO) in infants with pulmonary hypertension after surgical repair of total anomalous pulmonary venous connection. METHODS: Between January 1, 1992, and January 1, 1995, 20 patients underwent repair of total anomalous pulmonary venous connection. Nine patients had postoperative pulmonary hypertension and received a 15-minute trial of inhaled NO at 80 parts per million. Five of these patients received prolonged treatment with NO at 20 parts per million or less. RESULTS: Mean pulmonary artery pressure decreased from 35.6 +/- 2.4 to 23.7 +/- 2.0 mm Hg (mean +/- standard error of the mean) (p = 0.008), and pulmonary vascular resistance decreased from 11.5 +/- 2.0 to 6.4 +/- 1.0 U.m2 (p = 0.03). After prolonged treatment with NO, pulmonary artery pressure increased transiently in all patients when NO was discontinued. CONCLUSIONS: After operative repair of total anomalous pulmonary venous connection, inhaled NO selectively vasodilated all patients with pulmonary hypertension. Withdrawal of NO after prolonged inhalation was associated with transient rebound pulmonary hypertension that dissipated within 60 minutes. Appreciation of rebound pulmonary hypertension may have important implications for patients with pulmonary hypertensive disorders when interruption of NO inhalation is necessary or when withdrawal of NO is planned.     

Prophylactic nefopam administration for post-anesthetic shivering

PURPOSE: Shivering is a frequent postanaesthetic complication. Its definite reason is unknown. Patients with cardiovascular or pulmonary diseases are endangered by postanaesthetic shivering. The aim of this study was to assess the efficacy of nefopam in prophylaxis of shivering. Additionally we investigated the influence of nefopam on haemodynamic parameters and on the time until extubation. METHODS: 30 patients (ASA I-II) were randomly allocated in a double-blind fashion to one of two groups to receive directly after the end of isoflurane application either nefopam (0.15 mg/kg) or placebo (0.9% saline). The period of anaesthesia had to be longer than 60 minutes. All patients received a premedication with lorazepam (0.02 mg/kg) 30-45 minutes prior to surgery. Induction of anaesthesia was standardised: fentanyl (3 micrograms/kg), thiopentone (5 mg/kg), atracurium (0.4 mg/kg). Intraoperatively a mixture of isoflurane, nitrous oxide (60%) and oxygen was used to maintain anaesthesia. The following parameters were evaluated: Age, sex, duration of operation and anaesthesia and the time between the end of application of volatiles and extubation. Heart rate (HR), mean arterial blood pressure (MAP), rectal temperature and O2-saturation were measured at predefined data points. Postoperatively the consumption of analgesic was documented. The severity of shivering was classified in five grades. RESULTS: In the control-group nine patients shivered (60%), whereas in the nefopam group only one patient (6.6%) shivered (p < 0.05). In comparison to the placebo group we observed in the nefopam group a significantly decreased HR 30 and 60 minutes postoperatively (p < or = 0.007 and p < or = 0.002). We did not observe prolonged awakening in the nefopam-treated patients. MAP and O2-saturation showed similar reactions in both groups. CONCLUSION: The data indicate that prophylactic administration of nefopam can suppress postanaesthetic shivering. Prolonged awakening was not observed.     

Body temperature in mice: a quantitative measure of alcohol tolerance and physical dependence

Mice undergoing withdrawal after chronic ethanol consumption were found to be hypothermic if kept at room temperature. The extent of the hypothermia correlated well with the behavioral withdrawal symptoms and could be used as a quantitative measure of the severity and time course of the withdrawal syndrome. Placing mice in a cold environment (4 degrees C) exacerbated the hypothermia whereas placing animals at 34 degrees C reversed the hypothermia and produced hyperthermia. It was concluded that the temperature set point mechanism and the ability to regulate around this set point was disturbed in animals physically dependent on alcohol. During consumption of the ethanol-containing diets, mice exhibited tolerance to the hypothermic effects of an acutely administered dose od ethanol. Tolerance to the hypothermic effects of ethanol mirrored the development of behavioral tolerance as measured by performance on a tilting plane. Temperature and behavioral tolerance were both shown to extend well beyond the period of the withdrawal syndrome. Ethanol-treated mice were found to be cross-tolerant to the hypothermic effects of barbiturates but not to the hypothermia produced by the monoamine oxidase inhibitor, pargyline.     

Plasma cortisol responses after intramuscular corticotropin 1-24 in healthy men

Intravenous infusion of corticotropin 1-24 (ACTH 1-24) followed by a plasma cortisol measurement after 60 minutes of less than 20 microg/dL indicates clinically important glucocorticoid deficiency. In this study, we evaluated the morning plasma cortisol response to an intramuscular (IM) injection of ACTH 1-24 (250 microg) in 64 healthy men. Plasma cortisol increased significantly 30 and 60 minutes after IM ACTH 1-24 (P < .0001). In most subjects, a maximal response was obtained at 60 minutes. The cortisol response correlated positively with the morning basal cortisol concentration. The lowest cortisol peak and the lowest increment observed after IM ACTH 1-24 were, respectively, 12.6 and 3.5 microg/dL after 30 minutes and 16.3 and 5.3 microg/dL after 60 minutes. We conclude that a plasma cortisol level less than 16.0 microg/dL 60 minutes after IM ACTH 1-24 can be used as an index of glucocorticoid deficiency.     

Effect of polymerization mode of a dual-cured resin cement on time-dependent shear bond strength to porcelain

PURPOSE: To evaluate the shear bond strengths to porcelain and setting times of a dual-cured resin cement with light/chemical curing (dual) or chemical only curing versus time. MATERIALS AND METHODS: Variolink resin cement was bonded to specimens of etched, silanated porcelain. Groups of specimens were cured by dual cured or by chemical curing only. Shear bond strengths were recorded at 2, 3, 5, 60 minutes and 24 hours for dual cured and at 10, 20, 40, 50, 60 minutes and 24 hours for chemical-cured only after mixing. Kinetic-temperature profiles of dual and chemical curing modes of cement were calculated. RESULTS: Maximum bond strengths and time to attainment were 17.5 +/- 2.7 MPa at 60 minutes for chemical-cured and 26.1 +/- 2.3 MPa at 5 minutes for dual-cured. The peak in the kinetic-temperature setting profiles were 14.1 +/- 0.9 minutes for chemical curing and 52.2 +/- 5.2 seconds for dual curing. Dual curing provided significantly higher shear bond strengths versus chemical curing at both the 60-minute and 24-hour time periods.     

Helicopter use in the Swiss air rescue service for children. Inland transport in 1992

In 1992, the Swiss helicopter rescue service (REGA) transported 515 injured and 141 sick children (total n = 656). More than 60% of the children were boys; the age group from 10 to 16 years dominated. Primary care was provided in 415 of the flights, whereas the remaining cases were interhospital transfers to institutions with pediatric intensive care units. The main reason for primary interventions was sports accidents, followed by medical disease and traffic accidents. The majority of the sick children (70%) were severely ill with life-threatening diseases according to National Advisory Committee for Aeronautics (NACA) indices IV to VII. On the other hand, only 47% of the injured children had NACA indices of IV to VII. Most of these children had minor injuries suffered during sports activities; they were rescued mainly because of the site of the accident and not the severity of the injury. The remaining trauma victims had had traffic or home accidents and were usually severely injured. Head injuries were the most common reason for intervention due to accidents, and central nervous disorders and respiratory problems were the main reason for interventions in children suffering from serious illnesses. For primary REGA rescue interventions, the mean time from accident to arrival at the hospital was 64 minutes: 18 minutes from injury to alarm, 17 minutes from alarm to arrival at the scene, and 29 minutes for scene time and flight to the hospital. Costs for helicopter rescue are twice as high as for ground-based rescue (ambulance). However, considering the relatively high percentage of severely injured or life-threatened sick children involved, air rescue and its higher costs appear to be justified.     

The changing effector pattern of tardive dyskinesia during the course of neuroleptic withdrawal.

Tardive dyskinesia (TD) is a movement disorder that can be expressed at various body effector points, including the face, neck, arms, fingers, legs, and torso. In this prospective longitudinal study researchers examined whether the effector pattern of TD changed during the course of neuroleptic medication withdrawal in adults with mental retardation. Results indicated that the effector pattern of TD changed over the course of neuroleptic withdrawal. Peak dyskinesia was associated with the involvement of more body areas relative to baseline. Although dyskinesia decreased at follow-up and fewer body areas showed signs of dyskinesia, there were still differences in the effector pattern of dyskinesia relative to baseline at periods of 1 to 2 years following neuroleptic withdrawal. These findings suggest that TD is a dynamic disorder associated with changes in both severity and effector pattern over time. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The severity of naloxone-precipitated opiate withdrawal is attenuated by felbamate, a possible glycine antagonist

Recent studies indicate that an N-methyl-D-aspartate (NMDA) receptor system in the rostral medulla is involved in opiate withdrawal. Although NMDA antagonists attenuate naloxone-precipitated opiate withdrawal, they can cause phencyclidine (PCP)like effects that contraindicate clinical use. Because NMDA channels contain sites for the glutamate coagonist, glycine, we assessed the effects of glycinergic agents on naloxone-precipitated opiate withdrawal in rats. The putative antagonist, felbamate (100, 300 mg/kg), attenuated overall withdrawal severity in a dose-related manner and reduced occurrences of chews, teeth chatters, and penile grooming. The partial agonist, D-cycloserine (3, 10 mg/kg), attenuated withdrawal severity, but not in a dose-related manner. Conversely, the low dose of the partial agonist, (+/-)-HA-966 (3, 10 mg/kg), heightened the occurrences of some withdrawal signs. These results support a role for glycine in opiate withdrawal and suggest that these agents, which do not cause PCPlike effects, may be potential treatment for agents for opiate detoxification.