Withdrawal Intensity Research Articles

Combined bulk and wall reactions in turbulent pipe flow: decay coefficients and concentration profiles

This study discusses the effect of combined first-order, bulk and wall reactions on the overall intensity of mass withdrawal in smooth pipes. A one-dimensional model for the transport of high Schmidt number compounds (where the Schmidt number is the ratio of the fluid viscosity to the solute diffusivity) is extended with the effect of a first-order bulk reaction. Profiles of velocity and eddy diffusivity are obtained with a standard high Reynolds number k–∊ closure in combination with a modified Van Driest wall function. By comparing the results of the 1D model to an analytical asymptotic high Sc approximation, it is shown that the interaction between bulk and wall reactions is very weak. In terms of the decay coefficient, a maximum deviation of 4% is observed for very high bulk demand due to the attenuation of the streamwise solute mass flux. The parameter range for which the concentration profiles can be safely assumed to be uniform, both in the viscous sublayer and in the bulk, is established.

Physical dependence potential of daily tramadol dosing in humans.

Tramadol is an atypical, mixed-mechanism analgesic involving both opioid and catecholamine processes that appears to have low abuse potential and may be useful as a treatment for opioid dependence. The current study assessed the level of physical dependence and opioid blockade efficacy produced by daily maintenance on oral tramadol. Nine residential opioid-dependent adults were maintained on two doses of daily oral tramadol (200 and 800 mg) for approximately 4-week intervals in a randomized, double-blind, crossover design. The acute effects of intramuscular placebo, naloxone (0.25, 0.5, and 1.0 mg), and hydromorphone (1.5, 3.0, and 6.0 mg) were tested under double-blind, randomized conditions. Outcomes included observer- and subject-rated measures and physiologic indices. Challenge doses of naloxone resulted in significantly higher mean peak withdrawal scores compared to placebo. Withdrawal intensity from naloxone was generally greater during 800 versus 200 mg/day tramadol maintenance. Mean peak ratings of agonist effects were elevated at higher hydromorphone challenge doses, but did not differ significantly between tramadol doses. Physiologic measures were generally affected by challenge conditions in a dose-dependent manner, with few differences between tramadol maintenance dose conditions. Chronic tramadol administration produces dose-related opioid physical dependence, without producing dose-related attenuation of agonist challenge effects. Tramadol may be a useful treatment for patients with low levels of opioid dependence or as a treatment for withdrawal during opioid detoxification, but does not appear to be effective as a maintenance medication due to a lack of opioid cross-tolerance.

Caffeine Withdrawal and High Intensity Endurance Cycling Performance.

PURPOSE: This study investigated the impact of a controlled four-day caffeine withdrawal period on the effect of an acute caffeine dose on endurance exercise performance. METHOD: 12 trained and familiarised male cyclists [28.3±5.8 y, 80.2±6.6 kg BW, 182.5±4.2 cm, VO2 peak 63.7±7.4 mL[[Unsupported Character - Symbol Font ž]]kg-1[[Unsupported Character - Symbol Font ž]]min-1; values are mean±SD] who were regular caffeine consumers, were recruited for the study. A double-blind placebo-controlled cross-over design was employed in which all subjects participated in four experimental trials. For 4 days prior to each trial subjects abstained from dietary caffeine sources and ingested caspulses containing either placebo (P) or caffeine (C) [1.5 mg[[Unsupported Character - Symbol Font ž]]kg-1 BW[[Unsupported Character - Symbol Font ž]]day-1]. Following this subjects then ingested capsules containing placebo (P) or caffeine (C) [3 mg[[Unsupported Character - Symbol Font ž]]kg-1 BW] 90 minutes prior to completing a time trial (TT), equivalent to 1 hour cycling at 75% peak sustainable power output (PPO). Hence the study was designed to incorporate conditions PP, PC, CP and CC. RESULTS: Performance time was significantly improved after acute caffeine ingestion by 1:49 ± 1:41 min (3.0%) following a withdrawal period (PP vs. PC), and 2:07 ± 1:28 min (3.6%) following the non-withdrawal period (CP vs. CC). No significant difference was detetcted between the two acute caffeine trials (PC vs. CC). Average HR throughout exercise was significantly higher following acute caffeine administration compared to placebo. No differences were observed in RPE between trials. CONCLUSION: 3 mg[[Unsupported Character - Symbol Font ž]]kg-1 BW of caffeine significantly improves exercise performance irrespective of whether a four-day withdrawal period is imposed on habitual caffeine users.

Opioid antagonists under heavy sedation or anaesthesia for opioid withdrawal

Withdrawal (detoxification) is necessary prior to drug-free treatment or as the end point of long-term substitution treatment. To assess the effectiveness of opioid antagonists to induce opioid withdrawal with concomitant heavy sedation or anaesthesia, in terms of withdrawal signs and symptoms, completion of treatment and adverse effects. We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2009), Medline (January 1966 to 11 August 2009), Embase (January 1985 to 2009 Week 32), PsycINFO (1967 to July 2009), and reference lists of articles. Controlled studies of antagonist-induced withdrawal under heavy sedation or anaesthesia in opioid-dependent participants compared with other approaches, or a different regime of anaesthesia-based antagonist-induced withdrawal. One reviewer assessed studies for inclusion, undertook data extraction and assessed quality. Inclusion decisions and the overall process were confirmed by consultation between all authors. Nine studies (eight randomised controlled trials) involving 1109 participants met the inclusion criteria for the review.Antagonist-induced withdrawal is more intense but less prolonged than withdrawal managed with reducing doses of methadone, and doses of naltrexone sufficient for blockade of opioid effects can be established significantly more quickly with antagonist-induced withdrawal than withdrawal managed with clonidine and symptomatic medications. The level of sedation does not affect the intensity and duration of withdrawal, although the duration of anaesthesia may influence withdrawal severity. There is a significantly greater risk of adverse events with heavy, compared to light, sedation (RR 3.21, 95% CI 1.13 to 9.12, P = 0.03) and probably with this approach compared to other forms of detoxification. Heavy sedation compared to light sedation does not confer additional benefits in terms of less severe withdrawal or increased rates of commencement on naltrexone maintenance treatment. Given that the adverse events are potentially life-threatening, the value of antagonist-induced withdrawal under heavy sedation or anaesthesia is not supported. The high cost of anaesthesia-based approaches, both in monetary terms and use of scarce intensive care resources, suggest that this form of treatment should not be pursued.

Intensity of opiate withdrawal in relation to the 825C>T polymorphism of the G-protein beta 3 subunit gene

Objectives The intensity of withdrawal in opiate dependence shows a high inter-individual variability. The 825C>T polymorphism (rs5443) of the G-protein beta 3 ( GNB3) subunit gene has a strong influence on clinical signs of sympathetic activity in cardiac research. This study was carried out in order to test the hypothesis that carriers of the T allele have an increased sympathetic activity in opiate withdrawal. Methods Thirty-nine monovalent opiate addicted patients consecutively admitted to a detoxification ward were investigated. The main parameter for sympathetic activity was the pulse rate in the first 3 days after the regular end of gradual methadone reduction. Results Thirty-three out of 39 patients achieved a drug-free state: 22 carried a T allele (TT, CT), 11 belonged to the CC genotype group. The pulse rate was significantly ( p < 0.05) raised in the T allele group compared to the CC genotype group on the first 2 days after stopping methadone administration. In addition, about a third of the T allele carriers needed clonidine treatment on the respective days, but only one patient among the 11 CC homozygotes. There was no significant difference between groups in systolic and diastolic blood pressures as well as in subjective withdrawal ratings. Conclusion A group difference regarding pulse rate could be observed in a small sample and despite a higher degree of concomitant clonidine medication in T allele carriers. The failure to detect group differences in blood pressure and self-rated withdrawal symptoms may be attributed to the more complex regulation of blood pressure and the known weak correlation between objective and subjective withdrawal symptoms.

Early Outcomes Following Low Dose Naltrexone Enhancement of Opioid Detoxification

Although withdrawal severity and treatment completion are the initial focus of opioid detoxification, post-detoxification outcome better defines effective interventions. Very low dose naltrexone (VLNTX) in addition to methadone taper was recently associated with attenuated withdrawal intensity during detoxification. We describe the results of a seven-day follow-up evaluation of 96 subjects who completed inpatient detoxification consisting of the addition of VLNTX (0.125 or 0.250 mg per day) or placebo to methadone taper in a double blind, randomized investigation. Individuals receiving VLNTX during detoxification reported reduced withdrawal and drug use during the first 24 hours after discharge. VLNTX addition was also associated with higher rates of negative drug tests for opioids and cannabis and increased engagement in outpatient treatment after one week. Further studies are needed to test the utility of this approach in easing the transition from detoxification to various follow-up treatment modalities designed to address opioid dependence.

Benzodiazepin-Abhängigkeit: Ursachen und Behandlungsmöglichkeiten

Benzodiazepines are very often prescribed because of their anxiolytic, sedative and hypnotic properties. However, long term treatment is associated with development of benzodiazepine dependence. Besides development of physical dependence, which is linked to a typical benzodiazepine withdrawal syndrome when drug intake is discontinued, also behavioural addiction to benzodiazepines has been described. Benzodiazepines are known to enhance GABAergic neurotransmission. Counter regulation of enhanced GABAergic neurotransmission by enhancement of glutamatergic neurotransmission is thought to be one reason underlying the typical symptoms of benzodiazepine withdrawal. Also alterations in the expression of neuropeptides like Corticotropin Releasing Hormone and Neuropeptide Y are thought to be involved in the development of benzodiazepine dependence. However, until today the knowledge of neural mechanisms underlying the development of benzodiazepine dependence remains incomplete. Because even long term treatment with small doses of benzodiazepines is associated with adverse reactions like cognitive dysfunctions withdrawal from benzodiazepines should be aimed. Anticonvulsants and antidepressants seem to reduce the intensity of benzodiazepine withdrawal and to enhance long term prognosis of dependence.

The Withdrawal Assessment Tool–1 (WAT–1): An assessment instrument for monitoring opioid and benzodiazepine withdrawal symptoms in pediatric patients*

To develop and test the validity and reliability of the Withdrawal Assessment Tool-1 for monitoring opioid and benzodiazepine withdrawal symptoms in pediatric patients. Prospective psychometric evaluation. Pediatric critical care nurses assessed eligible at-risk pediatric patients for the presence of 19 withdrawal symptoms and rated the patient's overall withdrawal intensity using a Numeric Rating Scale where zero indicated no withdrawal and 10 indicated worst possible withdrawal. The 19 symptoms were derived from the Opioid and Benzodiazepine Withdrawal Score, the literature and expert opinion. Two pediatric intensive care units in university-affiliated academic children's hospitals. Eighty-three pediatric patients, median age 35 mos (interquartile range: 7 mos-10 yrs), recovering from acute respiratory failure who were being weaned from more than 5 days of continuous infusion or round-the-clock opioid and benzodiazepine administration. Repeated observations during analgesia and sedative weaning. A total of 1040 withdrawal symptom assessments were completed, with a median (interquartile range) of 11 (6-16) per patient over 6.6 (4.8-11) days. Generalized linear modeling was used to analyze each symptom in relation to withdrawal intensity ratings, adjusted for site, subject, and age group. Symptoms with high redundancy or low levels of association with withdrawal intensity ratings were dropped, resulting in an 11-item (12-point) scale. Concurrent validity was indicated by high sensitivity (0.872) and specificity (0.880) for Withdrawal Assessment Tool-1 > 3 predicting Numeric Rating Scale > 4. Construct validity was supported by significant differences in drug exposure, length of treatment and weaning from sedation, length of mechanical ventilation and intensive care unit stay for patients with Withdrawal Assessment Tool-1 scores > 3 compared with those with lower scores. The Withdrawal Assessment Tool-1 shows excellent preliminary psychometric performance when used to assess clinically important withdrawal symptoms in the pediatric intensive care unit setting. Further psychometric evaluation in diverse at-risk groups is needed.

Attenuation of morphine withdrawal signs by muscimol in the locus coeruleus of rats

This study examined the effects of intra-locus coeruleus injection of a gamma-amino-butyric acid type A (GABAA) receptor agonist on naloxone-induced withdrawal signs of morphine-dependent rats. Twenty different withdrawal signs were assessed. The total withdrawal score was calculated and used as an index of withdrawal intensity. The gamma-amino-butyric acid agonist and antagonists were injected 15 and 30 min before naloxone injection, respectively. Muscimol, a GABAA agonist (25, 50, and 100 ng/site), decreased the total withdrawal score in a dose-independent manner, whereas bicuculline (0.367, 3.67, and 36.7 ng/site), a GABAA antagonist, and CGP35348 (48.6 ng/site), a gamma-amino-butyric acid type B antagonist, alone had no effects. On the other hand, muscimol effects were reversed by CGP35348 (48.6 ng/site) but not by bicuculline (36.7 ng/site). It may be concluded that the effects of muscimol were antagonized by gamma-amino-butyric acid type B but not by GABAA receptor antagonists. The mechanism involved seems to be intricate and needs further study.

Opioid Antagonists, Partial Agonists, and Agonists/Antagonists: The Role of OfficeBased Detoxification

Background: The opioid receptor antagonists naloxone and naltrexone are competitive antagonists at the mu, kappa, and sigma receptors with a higher affinity for the mu receptor and lacking any mu receptor efficacy. Buprenorphine is classified as a partial agonist. It has a high affinity, but low efficacy at the mu receptor where it yields a partial effect upon binding. It also, however, possesses kappa receptor antagonist activity making it useful not only as an analgesic, but also in opioid abuse deterrence, detoxification, and maintenance therapies. Naloxone is added to sublingual buprenorphine (Suboxone®) to prevent the intravenous abuse of buprenorphine. The same product (sublingual buprenorphine) when used alone (i.e. without naloxone) is marketed as Subutex®. Objective: To evaluate and update the available evidence regarding the use of agonist/antagonists to provide office-based opioid treatment for addiction. Methods: A review using databases of EMBASE and MEDLINE (1992 to December 2007). These included systematic reviews, narrative reviews, prospective and retrospective studies, as well as cross-references from other articles. Outcome Measures: The primary outcome measure was treatment retention. Other outcome measures included opioid-free urine drug testing, opioid craving, intensity of withdrawal, pain reduction, adverse effects, addiction severity index, and HIV risk behavior. Results: The results found 17 studies, 1 systematic review, 12 RCTs, and 4 observational series, which document the efficacy and safety of buprenorphine alone and in combination with naloxone in detoxifying and maintaining abstinence from illicit drugs in patients with opioid addiction. Conclusion: Based on the present evaluation, it appears that opioid antagonists, partial agonists, and antagonists are useful in office-based opioid treatment for addiction. Key words: Opioid, antagonist, partial agonist, tolerance, dependence, detoxification, withdrawal, hyperalgesia, buprenorphine, naloxone, naltrexone, methylnaltrexone, butorphanol, nalbuphine, pentazocine

Brain levels of dextromethorphan and the intensity of opioid withdrawal in mice

Consistent with their antagonistic actions at N-methyl- d-aspartate type glutamate receptors, dextromethorphan (DXM) and its metabolite, dextrorphan (DXT) decrease the intensity of opioid withdrawal syndrome. Since quinidine (QND) affects CYP2D6-mediated metabolism and P-glycoprotein governed transport, we sought to determine whether co-treatment with QND would affect brain levels of DXM and DXT as well as the effect of these compounds on opioid withdrawal syndrome in mice. We found that DXM dose dependently inhibited the intensity of opioid withdrawal syndrome and that there was a tendency for a further decrease when QND was co-administered with DXM. Administration of 30 mg/kg of DXM resulted in higher brain levels of DXM and DXT than administration of 10 mg/kg of DXM, but much lower DXT levels than that produced by 30 mg/kg of DXT. Co-treatment with QND resulted in higher brain levels of DXM (but not DXT) suggesting that QND produces an increase in the brain availability of DXM. In summary, brain levels of DXM were inversely correlated with the intensity of opioid withdrawal syndrome. QND induced increased brain levels of DXM tend to attenuate the intensity of opioid withdrawal syndrome. We suggest that it is DXM, rather than DXT, that is responsible for the attenuating effect on the intensity of opioid withdrawal syndrome, and that the beneficial action of QND on the effect of DXM should be more pronounced in humans.

Physiological and psychological symptoms and predictors in early nicotine withdrawal

The present study assessed the structure and intensity of the nicotine withdrawal syndrome in 30 (22 male, 8 female) heavy smokers across three experimental conditions: smoking, brief abstinence (3.5 h), and extended abstinence (18 h). Physiological variables (heart rate and blood pressure) and psychological variables (anxious and depressed mood) were examined in terms of symptom validity and as predictors of nicotine withdrawal intensity. As length of abstinence increased, heart rate and blood pressure decreased, and anxious and depressed mood increased. Only anxious and depressed mood were significant individual predictors of withdrawal intensity. The symptom structure of withdrawal did not change over time as abstinence levels increased; each symptom's contribution to nicotine withdrawal intensity remained stable throughout the first 18 h of abstinence.

Impact de la personnalité sur l’intensité du syndrome de sevrage alcoolique : une étude préliminaire avec le modèle de Cloninger

The personality of alcohol dependant patients as a factor influencing the intensity of the alcohol withdrawal syndrome has been seldom examined. Cloninger's biosocial model of personality describes four temperaments (novelty seeking, harm avoidance, reward dependence, persistence) which, except for persistence, are admittedly linked to specific central neurotransmitters, and three characters. Novelty seeking is linked with low levels of mesencephalic dopamine, harm avoidance with high levels of serotonin in the septo-hippocampic system and reward dependence with low levels of noradrenaline in the ascending pathways from the locus coeruleus to the limbic system. The same neurotransmitters pathways are known to be involved in alcohol withdrawal, with a decrease of dopaminergic activity in the mesolimbic system, a decrease of serotonergic activity in the nucleus accumbens and an increase of the noradrenergic system. In view of the similarities between the neurobiological systems involved in Cloninger's model and in the neurobiological changes occurring during the withdrawal period, one would expect to observe severe withdrawal symptoms more frequently for patients with high novelty seeking, low harm avoidance and low reward dependence. To test this hypothesis, alcohol dependent patients according to DSM IV classification criteria who have drunk in the last twenty four hours were included in the study and received a standardized withdrawal treatment. The withdrawal syndrome intensity was examined with repeated measures of CIWA-Ar, the scores of which were correlated with TCI-R. Twenty eight patients, between 30 et 65 years old and drinking 22,2 +/- 12 standard drinks per day were included. Antidepressant drugs, benzodiazepines and neuroleptics treatment introduced before hospitalisation were stopped or decreased as much as possible. A correlation matrix was carried out between all the variables which could influence withdrawal intensity (age at the hospitalisation, age at the begining of the dependance, ratio between the time of the dependance and the patients' age, the number of alcohol withdrawals carried out and the number of standard drinks per day), and showed a positive correlation between the number of standard drinks per day and withdrawal intensity at day 3 (r=0.7, p<0.000), at day 4 (r=0.52, p<0.005), at day 7 (r=0.41, p<0.036) and at day 8 (r=0.44, p<0.02); as between the ratio between the time of the dependance and the patients' age and withdrawal intensity at day 2 (r=0.43, p<0.03) and at day 5 (r=0.5, p<0.01). Therefore, partial correlations were calculated between the dimensions of personality and withdrawal intensity. The study showed a positive correlation between withdrawal intensity and harm avoidance from day 5 onwards (r=0.6 and P<0.003 at day 5, r=0.59 and P<0.004 at day 6, r=0.56 and P<0.006 at day 7, r=0.66 and P<0.001 at day 8), a negative correlation between withdrawal intensity and reward dependence at day 7 and 8 (r=- 0.45 and P<0.037 at day 7, r=- 0.49 and P<0.02 at day 8) and a negative correlation between withdrawal intensity and persistence from day 6 onwards (r=- 0.5 and P<0.017 at day 6, r=- 0.5 and P<0.019 at day 7, r=- 0.51 and P<0.014 at day 8). No correlation was found between withdrawal intensity and novelty seeking. The same relevant results were found again with the 22 patients without anti-depressant drugs' population. Personality dimensions seem to influence alcohol withdrawal intensity once the severe symptomatology is over, while high doses of anti withdrawal treatment in the first days of abstinence may decrease the influence of personality on withdrawal symptoms. The positive correlation between harm avoidance and withdrawal intensity seems to invalidate our neurobiological hypotheses, but can be explained by clinical observations and corroborate studies assessing the influence of personality in benzodiazepine withdrawal intensity and in pain perception. This result encourages the introduction of support therapy during withdrawal and a cognitive-behavioural therapy before withdrawal in order to decrease patients' sensitivity to anxiety. The negative correlation between reward dependence and withdrawal intensity confirms the neurobiological hypotheses, but the weak correlation demands to be cautious in the interpretation of the results. The negative correlation between persistence and withdrawal intensity was expected. The characteristics associated with persistence seem to act as protective factors during alcohol withdrawal, whereas those associated with harm avoidance appear to increase the symptoms of alcohol withdrawal. In contrast, the neurobiological hypotheses are only partially confirmed.

P.6.a.007 Risks and pattern of alcohol withdrawal delirium

P.6.a.007 Risks and pattern of alcohol withdrawal delirium

Attenuation of morphine withdrawal signs by a D1 receptor agonist in the locus coeruleus of rats

In the present study, the effects of intra-locus coeruleus injection of a dopamine D(1) receptor agonist (SKF38393) on naloxone-induced withdrawal signs of morphine-dependent rats were examined. Twenty different withdrawal signs were assessed. The total withdrawal score was calculated and used as an index of withdrawal intensity for comparison. The D(1) agonist and antagonist were injected 15 and 30 min prior to expression of naloxone-induced withdrawal signs, respectively. SKF38393 (2 and 4 microg/site) decreased while SCH23390 (a D(1) antagonist) had no effect on the total withdrawal score. On the other hand, SCH23390 (25 ng/site) reversed the SKF38393 effect. It may be concluded that activation of dopamine D(1) receptors in the locus coeruleus attenuates naloxone-induced withdrawal.

A pharmacological modulation of opiate withdrawal using an up-/down-regulation of the noradrenergic system in opiate-dependent rats

Chronic opioid exposure induces neuroadaptative changes in several brain systems. Amongst others the alpha adrenergic system appears to be extremely sensitive to opioid exposure and has, therefore, been proposed to play a key role in opiate withdrawal symptoms. In order to better understand the influence of the noradrenergic system in opioid withdrawal and be able to develop new therapeutic strategies, we studied the effect of pre-treatment with the alpha2 agonist (clonidine) and alpha2 antagonist (yohimbine) on naloxone-precipitated withdrawal in opiate-dependent rats. As is already known clonidine pre-treatment significantly enhances autonomic and behavioural signs of opioid withdrawal whereas yohimbine significantly attenuates them with dose-related effect. We also tested the effect of clonidine (0.1 mg/kg) during naloxone-precipitated opiate withdrawal in rats pre-treated with yohimbine (5 mg/kg) and we observed that yohimbine pre-treatment potentiates clonidine efficiency in decreasing opiate withdrawal signs. This study supports the possibility of using a noradrenergic antagonist in order to regulate adrenoreceptors chronically exposed to opioids, therefore interfering with the intensity of naloxone-precipitated opiate withdrawal and potentiating later effectiveness of noradrenergic agonists like clonidine. These results may have various applications in clinical opiate detoxification protocols and are discussed through an up-/down- regulation of adrenoreceptors.

Withdrawal following sufentanil/propofol and sufentanil/midazolam

Patients in the ICU after long-term administration of an opioid/hypnotic often develop delirium. To assess the nature of this phenomenon, patients in a surgical ICU following ventilatory support and sedation with an opioid/hypnotic/sedative were studied. Following sufentanil/midazolam (group 1; n =14) or sufentanil/propofol (group 2; n =15) sedation, patients were evaluated for changes in mean arterial blood pressure and heart rate, the activity of the central nervous system (sensory evoked potentials, spectral edge frequency of EEG), and the endogenous opioids plasma concentrations (beta-endorphin, met-enkephalin). Data obtained were correlated with the individual intensities of withdrawal symptoms 6-, 12-, and 24 h following sedation. Following a mean duration of ventilation of 7.7 days (+/-3.6 SD) in groups 1 and 3.5 (+/-1.7 SD) in group 2, withdrawal intensities peaked within the 6th hour after cessation. Plasma beta-endorphin and met-enkephalin levels were low during sedation, and only the sufentanil/midazolam group demonstrated a postinhibitory overshoot. Withdrawal symptom intensities demonstrated an inverse correlation with beta-endorphin and met-enkephalin levels, a direct linear correlation with amplitude height of the evoked potential, and blood pressure and heart rate changes. Withdrawal intensities did not correlate with EEG power spectral edge frequency. The endorphinergic system is suppressed when a potent exogenous opioid like sufentanil is given over a long period of time. Following sedation, abstinence symptoms seem to be related to postinhibitory increased endorphin synthesis. This is mostly seen in the combination of sufentanil/midazolam. In addition, an increase in the amplitude of the sensory-evoked potential suggests a postinhibitory excitatory state within the nociceptive system.

Mapping of a quantitative trait locus for morphine withdrawal severity.

Chronic morphine exposure results in physical dependence, manifested by physical symptoms during naloxone-precipitated withdrawal. Jumping frequency is widely considered the most sensitive and reliable index of withdrawal intensity in mice. Inbred mouse strains surveyed for naloxone-precipitated withdrawal display large and significant strain differences in jumping frequency, including an approximately tenfold difference between C57BL/6 and 129P3 mice. In the present study, (B6 x 129)F2 hybrid mice were given daily morphine injections for four days using an escalating dosing schedule, and naloxone-precipitated withdrawal on day 5 was measured. A full-genome scan for linkage to phenotypic data was performed using polymorphic microsatellite markers. Significant linkage was observed between withdrawal jumping frequencies and a 28 cM-wide region of Chromosome 1 (32-60 cM; peak at 51 cM), accounting for 20% of the overall phenotypic variance. Two other suggestive QTLs were found, on Chromosomes 5 and 10, and an additive model fitting all three loci accounted for 43% of the total variance. F2 mice were also assessed for changes in morphine analgesic potency using the tail-withdrawal test in dose-response studies on days 1 and 4. No linkage was observed between Chromosomes 1, 5, and 10 and morphine analgesic tolerance, suggestive of genetic dissociation of naloxone-precipitated withdrawal from morphine and chronic morphine intake per se. The significant quantitative trait locus for naloxone-precipitated withdrawal severity in morphine-dependent mice, which we name Depmq1, may prove to be of considerable heuristic value once the underlying gene or genes are identified.

Blockade of ionotropic glutamatergic transmission in the ventral tegmental area attenuates the physical signs of morphine withdrawal in rats

The present study sought to assess whether the blockade of ionotropic glutamate receptors in the ventral tegmental area (VTA) could modulate the morphine withdrawal in male Sprague–Dawley rats. The effects of dizocilpine (MK-801) or 6,7-dinitroquinnoxaline-2,3-dione (DNQX), ionotropic glutamate receptor antagonists, microinjected unilaterally into the VTA 30 min before naloxone [2 mg/kg, intraperitoneally (i.p.)] administration on the morphine withdrawal were assessed. Morphine dependence was developed with increasing morphine injection (i.p.), and morphine withdrawal was induced by injection of naloxone (2 mg/kg, i.p.). Jumping, wet-dog shakes, writhing posture, wall clamber, weight loss and Gellert–Holtzman scale were used as the indices to evaluate the intensity of morphine withdrawal. The results showed that unilateral microinjection of MK-801 or DNQX into the VTA significantly increased the incidence of wall clamber, had no effect on weight loss, and reduced all other symptoms of morphine withdrawal. These data suggest that the ionotropic glutamate receptors in the VTA are involved in mediating naloxone-precipitated opiate withdrawal.

The Clinical Opiate Withdrawal Scale (COWS)

The clinical opiate withdrawal scale (COWS) is a clinician-administered, pen and paper instrument that rates eleven common opiate withdrawal signs or symptoms. The summed score of the eleven items can be used to assess a patient's level of opiate withdrawal and to make inferences about their level of physical dependence on opioids. With increasing use of opioids for treatment of pain and the availability of sublingual buprenorphine in the United States for treatment of opioid dependence, clinical assessment of opiate withdrawal intensity has received renewed interest. Buprenorphine, a partial opiate agonist at the mu receptor, can precipitate opiate withdrawal in patients with a high level of opioid dependence who are not experiencing opioid withdrawal. Since development of the first opiate withdrawal scale in the mid-1930s, many different opioid withdrawal scales have been used in clinical and research settings. This article reviews the history of opiate withdrawal scales and the context of their initial use. A template version of the COWS that can be copied and used clinically is appended. PDF formatted versions of the COWS are also available from the websites of the American Society of Addiction Medicine, the California Society of Addiction Medicine, the UCLA Integrated Substance Abuse Programs, and AlcoholMD.com.