Differences In Withdrawal Severity Research Articles

An empirical study of the use of Chewing Gum by Youth as a replacement to Cigarette addiction

The current study aimed to add to this of knowledge by examining the effect of chewing gum on smoking withdrawal severity over a long period, as well as identifying the specific characteristics of chewing gum that may be responsible for the reported reductions in withdrawal. Chewing, flavour, and the combination of the two were all investigated separately. The study is based on quantitative research. The data has been classified on basis of smoker and non-smoker. Participants reported a significant difference in withdrawal severity across conditions using repeated measures Chi square, F(3, 69)=2.89, p.05. The flavoured gum condition had considerably lower withdrawal scores than the flavourless gum base and no product control conditions, according to follow-up analyses. These data suggest that chewing gum is effective in reducing the severity of nicotine withdrawal symptoms over a 24-hour period of nicotine abstinence, and that the impact is due to a combination of flavour and chewing. These findings, together with findings from previous laboratory studies, show that chewing gum could be a useful coping mechanism for those who are trying to quit smoking.

An alcohol withdrawal test battery measuring multiple behavioral symptoms in mice.

Despite acceptance that risk for alcohol-use disorder (AUD) has a large genetic component, the identification of genes underlying various components of risk for AUD has been hampered in humans, in part by the heterogeneity of expression of the phenotype. One aspect of AUD is physical dependence. Alcohol withdrawal is a serious consequence of alcohol dependence with multiple symptoms, many of which are seen in multiple species, and can be experienced over a wide-ranging time course. In the present three studies, we developed a battery of withdrawal tests in mice, examining behavioral symptoms from multiple domains that could be measured over time. To permit eventual use of the battery in different strains of mice, we used male and female mice of a genetically heterogeneous stock developed from intercrossing eight inbred strains. Withdrawal symptoms were assessed using commonly used tests after administration of ethanol in vapor for 72 continuous hours. We found significant effects of ethanol withdrawal versus air-breathing controls on nearly all symptoms, spanning 4 days following ethanol vapor inhalation. Withdrawal produced hypothermia, greater neurohyperexcitability (seizures and tremor), anxiety-like behaviors using an apparatus (such as reduced transitions between light and dark compartments), anhedonia (reduced sucrose preference), Straub tail, backward walking, and reductions in activity; however, there were no changes in thermal pain sensitivity, hyper-reactivity to handling, or anxiety-like emergence behaviors in other apparatus. Using these data, we constructed a refined battery of withdrawal tests. Individual differences in severity of withdrawal among different tests were weakly correlated at best. This battery should be useful for identifying genetic influences on particular withdrawal behaviors, which should reflect the influences of different constellations of genes.

Ondansetron Does Not Reduce Withdrawal in Patients With Physical Dependence on Chronic Opioid Therapy.

Individuals taking opioids for an extended period of time may become physically dependent, and will therefore experience opioid withdrawal should they stop taking the medication. Previous work in animal and human models has shown that the serotonin (5-HT3) receptor may be implicated in opioid withdrawal. In this study, we investigated if ondansetron, a 5-HT3-receptor antagonist, could reduce the symptoms of opioid withdrawal after chronic opioid exposure in humans. In this double-blinded, randomized, crossover study, 33 chronic back pain patients (N = 33) were titrated onto sustained-release oral morphine for 30 days. After titration, participants attended 2 study sessions, 1 week apart, in which opioid withdrawal was induced with intravenous naloxone, with or without 8 mg intravenous ondansetron pretreatment. Opioid withdrawal symptoms were assessed by a blinded research assistant (objective opioid withdrawal score [OOWS]) and by the research participant (subjective opioid withdrawal score [SOWS]). Clinically significant signs of withdrawal were observed during both the ondansetron (ΔOOWS = 3.58 ± 2.22, P < 0.0001; ΔSOWS = 12.48 ± 11.18, P < 0.0001) and placebo sessions (ΔOOWS = 3.55 ± 2.39, P < 0.0001; ΔSOWS = 12.21 ± 10.72, P < 0.0001), but no significant differences were seen between the treatment sessions in either the OOWS or SOWS scores. We hypothesized that ondansetron would reduce opioid withdrawal symptoms in human subjects, but found no difference in withdrawal severity between ondansetron and placebo sessions. These findings suggest that more investigation may be necessary to determine if 5-HT3-receptor antagonists are suitable treatment options for opioid withdrawal.

Withdrawal Severity After Chronic Intermittent Ethanol in Inbred Mouse Strains

To study withdrawal, ethanol is usually administered chronically without interruption. However, interest has recurred in models of episodic exposure. Increasing evidence suggests that chronic intermittent exposure to ethanol leads to a sensitization effect in both withdrawal severity and ethanol consumption. The goal of the present study was to examine mouse inbred strain differences in withdrawal severity following chronic intermittent exposure using the handling-induced convulsion as the behavioral endpoint. We also sought to compare the withdrawal responses of inbred strains across acute, chronic continuous, and chronic intermittent exposure regimens. Male mice from 15 standard inbred strains were exposed to ethanol vapor for 16 hours each day for 3 days and removed to an air chamber during the intervening 8 hours. Mice in the control groups were handled the same, except that they were exposed only to air. Daily blood ethanol concentrations were averaged for each mouse to estimate total dose of ethanol experienced. Across strains, mice had an average daily blood ethanol concentration (BEC) of 1.45 +/- 0.02 mg/ml and we restricted the range of this value to 1.00-2.00 mg/ml. To evaluate strain differences, we divided data into two dose groups based on BEC, low dose (1.29 +/- 0.1 mg/ml) and high dose (1.71 +/- 0.02 mg/ml). After the third inhalation exposure, ethanol-exposed and air-exposed groups were tested hourly for handling-induced convulsions for 10 hour and at hour 24 and 25. Strains differed markedly in the severity of withdrawal (after subtraction of air control values) in both dose groups. The chronic intermittent exposure paradigm is sufficient to elicit differential withdrawal responses across nearly all strains. Data from the high-dose groups correlated well with withdrawal data derived from prior acute (single high dose) and chronic continuous (for 72 hours) ethanol withdrawal studies, supporting the influence of common genes on all three responses.

The effect of chewing gum on self-reported nicotine withdrawal: Is it the flavor, the act of chewing, or both?

A healthy alternative that has been shown to lessen the severity of nicotine withdrawal symptoms during brief periods of nicotine abstinence (e.g., 3–4 h) is confectionary chewing gum (Cohen and colleagues, 1997, 1999, & 2001). The current study sought to build upon this line of research by examining the impact of chewing gum on nicotine withdrawal severity over an extended period of nicotine abstinence (e.g., 24 h) while also identifying the specific attributes of chewing gum that may be responsible for the reported decreases in withdrawal. Specifically, the acts of chewing, flavor, as well as the combination of the two, were independently examined. Twenty-four dependent cigarette smokers participated in three experimental conditions (e.g., a flavorless gum base, flavor strips, and flavored chewing gum) as well as a no product control across four weeks while abstaining from smoking for 24 h each week. Using repeated measures ANOVAs, a significant difference in withdrawal severity was reported by participants across conditions, F(3, 69) = 2.89, p < .05. Follow-up analyses revealed that the flavored gum condition yielded significantly lower withdrawal scores than the flavorless gum base and no product control conditions. These findings indicate that chewing gum appears useful in lessening the severity of nicotine withdrawal symptoms over a 24-hour period of nicotine abstinence and that it is a combination of flavor and chewing that appears to lead to this effect.

Differential activation of limbic circuitry associated with chronic ethanol withdrawal in DBA/2J and C57BL/6J mice

Although no animal model exactly duplicates clinically defined alcoholism, models for specific factors, such as the withdrawal syndrome, are useful for identifying potential neural determinants of liability in humans. The well-documented difference in withdrawal severity following chronic ethanol exposure, between the DBA/2J and C57BL/6J mouse strains, provides an excellent starting point for dissecting the neural circuitry affecting predisposition to physical dependence on ethanol. To induce physical dependence, we used a paradigm in which mice were continuously exposed to ethanol vapor for 72 h. Ethanol-exposed and air-exposed (control) mice received daily injections of pyrazole hydrochloride, an alcohol dehydrogenase inhibitor, to stabilize blood ethanol levels. Ethanol-dependent and air-exposed mice were killed 7 h after removal from the inhalation chambers. This time point corresponds to the time of peak ethanol withdrawal severity. The brains were processed to assess neural activation associated with ethanol withdrawal indexed by c-Fos immunostaining. Ethanol-withdrawn DBA/2J mice showed significantly ( P < .05) greater neural activation than ethanol-withdrawn C57BL/6J mice in the dentate gyrus, hippocampus CA3, lateral septum, basolateral and central nuclei of the amygdala, and prelimbic cortex. Taken together with results using an acute model, our data suggest that progression from acute ethanol withdrawal to the more severe withdrawal associated with physical dependence following chronic ethanol exposure involves recruitment of neurons in the hippocampal formation, amygdala, and prelimbic cortex. To our knowledge, these are the first studies to use c-Fos to identify the brain regions and neurocircuitry that distinguish between chronic and acute ethanol withdrawal severity using informative animal models.

Sex differences in acute ethanol withdrawal severity after adrenalectomy and gonadectomy in Withdrawal Seizure-Prone and Withdrawal Seizure-Resistant mice

Recent findings suggest that the ability of ethanol (EtOH) to increase the levels of neurosteroids with potent γ-aminobutyric acid (GABA)ergic properties can influence measures of EtOH sensitivity. Earlier studies determined that removal of the adrenals and gonads diminished the steroidogenic effect of EtOH and significantly increased acute EtOH withdrawal severity in two inbred mouse strains that differed in withdrawal severity, suggesting the contribution of anticonvulsant GABAergic steroids to acute withdrawal in intact animals. Thus, the goal of the present study was to investigate the consequence of steroid removal on acute EtOH withdrawal through excision of the adrenals and gonads, in another genetic animal model of EtOH withdrawal differences, the Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) selected lines. Male and female WSP and WSR mice underwent surgical removal of the adrenals and gonads or no organ removal (SHAM). One to 2 weeks later, baseline handling-induced convulsions (HICs) were assessed, mice were given a 4 g/kg dose of EtOH, and HICs were measured hourly for 12 h and then at 24 h. The combination surgery significantly increased EtOH withdrawal in WSP and WSR female mice, as measured by area under the curve (AUC) and peak HIC scores. The AUC was significantly positively correlated with plasma corticosterone levels and significantly negatively correlated with progesterone levels. In contrast, surgical status did not alter withdrawal severity in male WSP and WSR mice. Overall, the increase in acute EtOH withdrawal severity in female WSP and WSR mice after adrenalectomy and gonadectomy corroborate our recent evidence that withdrawal from a high dose of EtOH can be modulated by anticonvulsant steroids produced in the periphery.

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.

Double dissociation in the neural substrates of acute opiate dependence as measured by withdrawal-potentiated startle

The basolateral amygdala and portions of the “extended” amygdala (i.e. central nucleus of the amygdala, bed nucleus of the stria terminalis and shell of the nucleus accumbens) have been implicated in the aversive aspects of withdrawal from chronic opiate administration. Given that similar withdrawal signs are observed following a single opiate exposure, these structures may also play a role in “acute opiate dependence.” In the current study, drug-naïve rats underwent naloxone-precipitated withdrawal from acute morphine (10 mg/kg) exposure on two successive days. On either the first or second day of testing, the basolateral amygdala, central nucleus of the amygdala, bed nucleus of the stria terminalis, or nucleus accumbens was temporarily inactivated immediately prior to naloxone injection by microinfusion of the glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo{f}quinoxaline-7-sulfonamide (3 μg/0.5 μl). On the first day, inactivation of the basolateral amygdala, central nucleus of the amygdala, or bed nucleus of the stria terminalis, but not the nucleus accumbens blocked withdrawal-potentiated startle, a behavioral measure of the anxiogenic effects of withdrawal. On the second day, inactivation of the nucleus accumbens, but not the basolateral amygdala, central nucleus of the amygdala, or bed nucleus of the stria terminalis disrupted the withdrawal effect. Effects of structural inactivations on withdrawal-potentiated startle were not influenced by differences in withdrawal severity on the two days of testing. A fear-potentiated startle procedure provided functional confirmation of correct cannulae placement in basolateral amygdale– and central nucleus of the amygdala–implanted animals. Our findings indicate a double dissociation in the neural substrates of withdrawal-potentiated startle following a first versus second morphine exposure, and may reflect a reorganization of the neural circuitry underlying the expression of withdrawal-induced negative affect during the earliest stages of opiate dependence.

Chromosomal loci influencing chronic alcohol withdrawal severity.

Ethanol (alcohol) withdrawal-induced convulsions are a key index of physical dependence on ethanol and a clinically important consequence of alcohol abuse in humans. In rodent models, severity of withdrawal is strongly influenced by genotype. For example, many studies have reported marked differences in withdrawal severity between the WSR (Withdrawal Seizure Resistant) and WSP (Withdrawal Seizure Prone) mouse strains selectively bred for over 25 generations to differ in chronic withdrawal severity. Therefore, we used an F(2) intercross between the inbred WSP and WSR strains for a genome-wide search for quantitative trait loci (QTLs), which are chromosomal sites containing genes influencing the magnitude of withdrawal. We also used the recently developed HW, RHW (high withdrawal) and LW, RLW (low withdrawal) lines selectively bred for the same trait and in the same manner as the WSP, WSR lines. QTL analysis was then used to dissect the continuous trait distribution of withdrawal severity into component loci, and to map them to broad chromosomal regions by using the Pseudomarker 0.9 and Map Manager QT29b programs. This genome-wide search identified five significant QTLs influencing chronic withdrawal severity on Chromosomes (Chrs) 1 (proximal), 4 (mid), 8 (mid), 11 (proximal), and 14 (mid), plus significant interactions (epistasis) between loci on Chr 11 with 13, 4 with 8, and 8 with 14.

Reduced ethanol withdrawal severity and altered withdrawal-induced c-fos expression in various brain regions of mice lacking protein kinase C-epsilon.

Withdrawal from chronic ethanol consumption can be accompanied by motor seizures, which may be a result of altered GABA(A) receptor function. Recently, we have generated and characterized mice lacking the epsilon isoform of protein kinase C as being supersensitive to the behavioral and biochemical effects of positive GABA(A) receptor allosteric modulators, including ethanol. The aim of the present study was to determine whether protein kinase C-epsilon null mutant mice display altered seizure severity during alcohol withdrawal. In addition, we used c-fos immunohistochemistry immediately following seizure assessment to identify potential brain regions involved in any observed differences in withdrawal severity. Mice were allowed to consume an ethanol-containing or control liquid diet as the sole source of food for 14 days. During the 7-h period following removal of the diet, both ethanol-fed wild-type and protein kinase C-epsilon null mutant mice displayed an overall increase in Handling-Induced Convulsion score versus control-fed mice. However, at 6 and 7h following diet removal, the Handling-Induced Convulsion score was reduced in ethanol-fed protein kinase C-epsilon null mutant mice compared to ethanol-fed wild-type mice. Ethanol-fed protein kinase C-epsilon null mutant mice also exhibited a decrease in the number of Fos-positive cells in the lateral septum, and an increase in the number of Fos-positive cells in the dentate gyrus, mediodorsal thalamus, paraventricular nuclei of the thalamus and hypothalamus, and substantia nigra compared to ethanol-fed wild-type mice. These data demonstrate that deletion of protein kinase C-epsilon results in diminished progression of ethanol withdrawal-associated seizure severity, suggesting that selective pharmacological inhibitors of protein kinase C-epsilon may be useful in the treatment of seizures during alcohol withdrawal. These data also provide insight into potential brain regions involved in generation or suppression of ethanol withdrawal seizures.

Positive relationship between the number of prior ethanol withdrawal episodes and the severity of subsequent withdrawal seizures

One factor that has been shown to influence the severity of an ethanol withdrawal syndrome is a history of prior experience with episodes of ethanol withdrawal. It has been hypothesized that the progressive intensification of withdrawal symptoms following repeated bouts of ethanol intoxication and withdrawal may represent the manifestations of a "kindling-like" process. In mice, repeated episodes of ethanol withdrawal potentiate the severity of subsequent withdrawal seizures, even when the total amount of ethanol intoxication is equated across groups. In the current experiments, mice received 16-h bouts of continuous exposure to ethanol vapor in inhalation chambers separated by 8-h periods of abstinence. The withdrawal response was assessed by scoring handling-induced convulsions. The results demonstrated that a positive relationship exists between the number of prior episodes of ethanol withdrawal and the severity of subsequent withdrawal seizures. This conclusion was supported by both between-subject and within-subject comparisons. The difference in withdrawal severity does not appear to be related to differences in the level of intoxication, since blood ethanol levels immediately preceding withdrawal testing were similar for all groups. Further, the differential withdrawal response exhibited by multiple and single withdrawal groups cannot be explained by a difference in the rate of ethanol elimination. Although the mechanism(s) remain to be determined, taken together, these results provide support for the "kindling" hypothesis of ethanol withdrawal.

Common genetic determinants of severity of acute withdrawal from ethanol, pentobarbital and diazepam in inbred mice.

Severity of drug withdrawal is in part genetically mediated, and can be indexed by exacerbation of the handling-induced convulsion in mice. Acute withdrawal has been reported following single injections of hypnotic doses of ethanol and pento-barbital, and can be precipitated by injection of flumazenil following a single dose of diazepam. Results with Swiss-Webster mice indicate that the magnitude of ethanol and diazepam withdrawal severity did not differ across a range of doses in the acute paradigm. We characterized 15 inbred mouse strains for handling-induced convulsion severity following administration of standard doses of each of these drugs. Significant strain differences in withdrawal severity were found for each drug. Two of the strains showed a tendency toward more pronounced withdrawal from all drugs, while six strains showed low withdrawal from all drugs. The correlations among strain mean withdrawal responses were analyzed to estimate common genetic influences. Ethanol and pentobarbital withdrawal severities were positively genetically correlated, indicating influence of some genes on both responses. A positive genetic correlation was also found between the severity of the withdrawal from pentobarbital and diazepam; however, diazepam and ethanol withdrawal severities were not found to be genetically related. These experiments suggest that some genes influence severity of withdrawal from more than one subclass of depressant drugs.

Signs and symptoms from nicotine gum abstinence

This study examined and compared withdrawal signs and symptoms from cessation of 0, 2 and 4 mg nicotine gum. In addition, a comparison was made between nicotine gum versus cigarette withdrawal symptoms. Smokers first underwent cigarette deprivation for 4 days and then were randomly assigned to 0 (N = 16), 2 (N = 25), and 4 (N = 21) mg gum. They were asked to chew the gum for 1 month and then to undergo a 4-day nicotine gum deprivation period. The results showed a number of significant changes occurring after deprivation from 4 mg gum, one change from 2 mg gum, and no changes from 0 mg gum. There were no significant differences in severity of withdrawal among the various doses of nicotine gum. There were more severe symptoms of withdrawal from cigarette as opposed to 4 mg nicotine gum deprivation.

Carbamazepine Treatment in Patients Discontinuing Long-term Benzodiazepine Therapy

Forty patients with a history of difficulty discontinuing long-term, daily benzodiazepine therapy were randomly assigned, under double-blind conditions, to treatment with carbamazepine (200 to 800 mg/d) or placebo. A gradual taper (25% per week reduction) off benzodiazepine therapy was then attempted. Five weeks after taper, significantly more patients who had received carbamazepine than placebo remained benzodiazepine free, this despite the fact that no statistically significant differences in withdrawal severity could be demonstrated. Patients receiving carbamazepine reported a larger reduction in withdrawal severity than patients receiving placebo, but only at a trend level, and only on the daily patient-rated withdrawal checklist. Eleven patients (28%) required antidepressant therapy for depression or panic when assessed at 12-weeks follow-up. The results of this pilot investigation suggest that carbamazepine might have promise as an adjunctive drug therapy for the benzodiazepine withdrawal syndrome, particularly in patients receiving benzodiazepines in daily dosages of 20 mg/d or greater of diazepam equivalents.

255 PRENATAL METHADONE EXPOSURE: FACTORS AFFECT- ING SEVERITY OF WITHDRAWAL

There is conflicting evidence in the literature concerning the relation between maternal methadone dose during pregnancy and the severity of the withdrawal reaction experienced by the newborn. As part of an ongoing longitudinal study of children born to methadone-maintained mothers, 38 children exposed to methadone in utero were observed and their withdrawal evaluated and coded on a scale of one(mild) to 3(severe) by a trained observer. The relation between severity of withdrawal and the maternal methadone dose(MMD) prior to delivery was not significant. The relation between birth weight (BW) and severity of withdrawal was also not significant. The data indicated clear sex differences in severity of withdrawal (see above Table), with significantly more males having moderate to severe withdrawal reactions than females (x2=3.69, p<.07). This finding confirms developmental data indicating that males are more vulnerable than females to adverse environmental factors .

983 POLYDRUG VS. METHADONE USE IN PREGNANCY: STUDIES ON OFFSPRING

Twenty-one neonates of drug-dependent mothers were studied prospectively. Of 19 mothers on methadone (M), 13 were polydrug abusers (PD); 2 mothers were heroin-dependent. Mean birth weight was 2675 grams ± 580 (SD); mean gestational age was 38.0 weeks ± 2.7 (SD). Eighteen of 21 had birth weights appropriate for dates; 3 were small for dates. All lengths were between 10th and 90th percentile. Eighteen of 21 head circumferences were between the 10th and 90th percentile; 3 fell below the 10th percentile. Mean maximal weight loss in the first postnatal week was 7.25% of body weight ± 3.67% (SD). From 7 to 30 days of age, 16 infants gained weight normally, 3 subnormally and 2 excessively. Weight gain corrected for caloric intake was inversely related to severity of withdrawal on day 14 (p<.05), but not on days 7 or 21. Drug withdrawal was assessed twice daily by standardized score. Mean time of symptom onset was 13.5 hours ± 0.7 (SD). No difference in withdrawal severity was seen between the M and PD groups. No correlation was found between withdrawal severity and maternal M dosage late in pregnancy or at delivery. Term infants showed more severe withdrawal than preterm infants. Infants randomly treated for moderate to severe symptoms with paregoric or phenobarbital showed no difference in modification of withdrawal severity or treatment time required.