Affective Withdrawal Symptoms Research Articles

Effects of xylazine on naloxone-precipitated fentanyl withdrawal in male and female rats

PurposeThe combination of fentanyl and xylazine (i.e., “tranq-dope”) was recently declared an emerging national health threat in the United States. Given the recency of this development, very little is known regarding the behavioral pharmacology of fentanyl-xylazine combinations. The purpose of this study was to characterize the somatic and affective withdrawal symptoms of this drug combination. MethodsMale and female Long Evans rats were given twice daily (08:00 and 20:00) subcutaneous injections of fentanyl, xylazine, or combined fentanyl-xylazine for five days. On the sixth (testing) day, rats were given a final injection at 08:00. Four hours later, rats were injected intraperitoneally with either saline or a naloxone challenge before behavioral observation. Somatic withdrawal was examined using the Gellert-Holtzman scale and anxiety-like behavior was examined using the elevated plus maze. ResultsNaloxone administration did not induce somatic or affective symptoms in rats treated with fentanyl alone, a low dose of xylazine alone, or a high dose of xylazine alone. Naloxone induced somatic but not affective withdrawal symptoms in rats treated with both fentanyl and xylazine. ConclusionChronic co-exposure to fentanyl and xylazine produces an opioid-like somatic withdrawal syndrome at doses that are not apparent with either drug alone. These results corroborate clinical reports that xylazine worsens fentanyl withdrawal and suggest that novel interventions may be required to treat withdrawal from fentanyl-xylazine combinations in humans.

Sex Differences in Withdrawal-Induced Anxiety in Rats After Exposure to Tobacco Smoke

Nicotine, a component of cigarettes, possesses strong reinforcing properties and improves cognitive function, which can lead to dependence. Upon cigarette smoking cessation, withdrawal symptoms occur and may cause an individual to relapse. Affective withdrawal symptoms, such as anxiety, is of great concern as studies have shown its ability to cause relapse in men and women. In this in vivo study, anxiety resulting from smoking cessation after 2-day smoke-free intervals per week for the duration of 4 weeks was investigated in 8 male and 8 female rats after their exposure to cigarette smoke compared to unexposed control rats (8 males and 8 female rats). The anxiety in rats during smoke-free intervals was investigated using an elevated plus-maze (EPM), open-field (OF), and light/dark test (LD). In all tests male rats exhibited significantly higher anxiety symptoms compared to female rats during nicotine withdrawal, despite control rats showing no differences. In the EPM, male rats spent less time in open arm as well having as lower number of crossings than female rats. As for the OFT, the amount of time spent in the center of the open field was also lower in male rats than female rats. In the LD test, the time spent in the light chamber and the latency (delay) to enter the dark chamber was lower in male rats compared to female rats. Our study showed that male rats show greater nicotine withdrawal effects, in terms of anxiety-like behavior than female rats.

Children's Sugar-Sweetened Beverage Consumption: Striking Parallels With Substance Use Disorder Symptoms.

Sugar-sweetened beverage (SSB) intake contributes to obesity and cardiometabolic disease (1). Children's SSB consumption considerably exceeds public health recommendations (2), and efforts to reduce intake have had limited success (3). In addition to high sugar content, many SSBs also contain caffeine, and caffeinated SSBs are the predominant source of caffeine intakes among youth (4). Sugar activates central reward pathways, and similar to drugs of abuse, stimulates dopamine release (5), and meets several criteria for addiction (6). Chronic caffeine intake causes tolerance and withdrawal in children (7), which are core behavioral indicators of substance use disorders (SUDs) (6). Compelling evidence for addictive-like responses to excess sugar intake is emerging, with accumulating support in rodent models (5). Synergistic biopsychological effects of caffeine and sugar may reinforce unfavorable beverage consumption patterns (7). SSBs are a novel stimulus from an evolutionarily standpoint, yet products containing sugar and caffeine (e.g., energy drinks) are increasingly available (8) and heavily advertised to children (7). Children have developing brains and less inhibitory control compared to adults, and thus, are particularly vulnerable to addictive substances (9). Added caffeine in already highly palatable SSBs increases their hedonic and reinforcing properties (10) and may further promote excess added sugar intakes (11). Emerging evidence indicates that children's consumption of highly processed foods, typically high in added sugar and/or saturated fat, can lead to an addictive process reflected by core behavioral indicators of SUDs (12). These include craving, loss of control, tolerance, and withdrawal (12). Children who demonstrate more signs of addiction in their highly processed food consumption are more likely to have higher reward drive for food and higher body mass index (12). Signs of addiction have also been reported among children in response to frequent SSB consumption (13, 14). In our qualitative study (14), parents of children 8–17 years old reported that children experienced physical and affective withdrawal symptoms when caffeinated SSB intake was restricted. Similarly, Falbe et al. (13) reported that adolescents, who reported habitual SSB consumption, regardless of whether SSBs were caffeinated or caffeine-free indicated increased SSB cravings and headaches, and decreased motivation, contentment, concentration, and well-being during 72 h of SSB cessation. It is likely that other aspects of addiction (e.g., tolerance, craving, repeated unsuccessful efforts to reduce) represent important and overlooked obstacles to sustained SSB reduction. Herein, we propose that children's SSB consumption may reflect SUD symptomology and focus specifically on caffeinated SSBs, which are manufactured to contain a highly rewarding mixture of added sugar and caffeine, two ingredients that do not naturally occur in combination.

Activation of PPARγ Attenuates the Expression of Physical and Affective Nicotine Withdrawal Symptoms through Mechanisms Involving Amygdala and Hippocampus Neurotransmission.

An isoform of peroxisome proliferator-activated receptors (PPARs), PPARγ, is the receptor for the thiazolidinedione class of anti-diabetic medications including pioglitazone. Neuroanatomical data indicate PPARγ localization in brain areas involved in drug addiction. Preclinical and clinical data have shown that pioglitazone reduces alcohol and opioid self-administration, relapse to drug seeking, and plays a role in emotional responses. Here, we investigated the behavioral effect of PPARγ manipulation on nicotine withdrawal in male Wistar rats and in male mice with neuron-specific PPARγ deletion (PPARγ(-/-)) and their littermate wild-type (PPARγ(+/+)) controls. Real-time quantitative RT-PCR and RNAscope in situ hybridization assays were used for assessing the levels of expression and cell-type localization of PPARγ during nicotine withdrawal. Brain site-specific microinjections of the PPARγ agonist pioglitazone were performed to explore the role of this system on nicotine withdrawal at a neurocircuitry level. Results showed that activation of PPARγ by pioglitazone abolished the expression of somatic and affective nicotine withdrawal signs in rats and in (PPARγ(+/+)) mice. This effect was blocked by the PPARγ antagonist GW9662. During early withdrawal and protracted abstinence, the expression of PPARγ increased in GABAergic and glutamatergic cells of the amygdala and hippocampus, respectively. Hippocampal microinjections of pioglitazone reduced the expression of the physical signs of withdrawal, whereas excessive anxiety associated with protracted abstinence was prevented by pioglitazone microinjection into the amygdala. Our results demonstrate the implication of the neuronal PPARγ in nicotine withdrawal and indicates that activation of PPARγ may offer an interesting strategy for smoking cessation.SIGNIFICANCE STATEMENT Smoking cessation leads the occurrence of physical and affective withdrawal symptoms representing a major burden to quit tobacco use. Here, we show that activation of PPARγ prevents the expression of both somatic and affective signs of nicotine withdrawal. At molecular levels results show that PPARγ expression increases in GABAergic cells in the hippocampus and in GABA- and glutamate-positive cells in the basolateral amygdala. Hippocampal microinjections of pioglitazone reduce the insurgence of the physical withdrawal signs, whereas anxiety linked to protracted abstinence is attenuated by pioglitazone injected into the amygdala. Our results demonstrate the implication of neuronal PPARγ in nicotine withdrawal and suggest that PPARγ agonism may represent a promising treatment to aid smoking cessation.

Why are Antidepressant Drugs Effective Smoking Cessation Aids?

BackgroundBefore the advent of varenicline, antidepressant drugs were reported to exhibit better clinical efficacy than nicotine replacement therapy as smoking cessation aids. The most studied is bupropion, a clinically-effective antidepressant, the first to be marketed throughout Europe for smoking cessation. Since depression and tobacco smoking have a high incidence of co-occurrence, this would implicate an underlying link between these two conditions. If this correlation can be confirmed, then by treating one condition the related state would also be treated.ObjectivesThis review article will evaluate the various theories relating to the use of antidepressant drugs as smoking cessation aids and the underlying mechanisms link tobacco smoking and depression to explain the action of antidepressants in smoking cessation. One plausible theory of self-medication which proposes that people take nicotine to treat their own depressive symptoms and the affective withdrawal symptoms seen with abstinence from the drug. If the depression can instead be treated with antidepressants, then they may stop smoking altogether. Another theory is that the neurobiological pathways underlying smoking and depression may be similar. By targeting the pathways of depression in the brain, antidepressants would also treat the pathways affected by smoking and ease nicotine cravings and withdrawal. The role of genetic variation predisposing an individual to depression and initiation of tobacco smoking has also been discussed as a potential link between the two conditions. Such variation could either occur within the neurobiological pathways involved in both disorders or it could lead to an individual being depressed and self-medicating with nicotine.

An online survey of tobacco smoking cessation associated with naturalistic psychedelic use.

Data suggest psychedelics such as psilocybin and lysergic acid diethylamide (LSD) may hold therapeutic potential in the treatment of addictions, including tobacco dependence. This retrospective cross-sectional anonymous online survey characterized 358 individuals (52 females) who reported having quit or reduced smoking after ingesting a psychedelic in a non-laboratory setting ⩾1 year ago. On average, participants smoked 14 cigarettes/day for 8 years, and had five previous quit attempts before their psychedelic experience. Of the 358 participants, 38% reported continuous smoking cessation after psychedelic use (quitters). Among quitters, 74% reported >2 years' abstinence. Of the 358 participants, 28% reported a persisting reduction in smoking (reducers), from a mode of 300 cigarettes/month before, to a mode of 1 cigarette/month after the experience. Among reducers, 62% reported >2 years of reduced smoking. Finally, 34% of the 358 participants (relapsers) reported a temporary smoking reduction before returning to baseline smoking levels, with a mode time range to relapse of 3-6 months. Relapsers rated their psychedelic experience significantly lower in personal meaning and spiritual significance than both other groups. Participants across all groups reported less severe affective withdrawal symptoms (e.g. depression, craving) after psychedelic use compared with previous quit attempts, suggesting a potential mechanism of action for psychedelic-associated smoking cessation/reduction. Changes in life priorities/values were endorsed as the most important psychological factor associated with smoking cessation/reduction. Results suggest psychedelics may hold promise in treating tobacco addiction as potentially mediated by spiritual experience, changed priorities/values, and improved emotional regulation.

Behavioural and Neurochemical Assessment of Heantos 4 on Preclinical Models of Morphine-Dependence

Objective: Opiate addiction is characterized by compulsive drug use and severe withdrawal symptoms during abstinence. Heantos 4, an herbal pharmacotherapy recently approved for opiate withdrawal treatment in Vietnam, has shown anti-craving properties. The present study is the first preclinical assessment of the effects of Heantos 4 on opiate withdrawal and the rewarding properties of morphine, along with its action on a critical neural substrate of addiction, the mesolimbic dopamine (DA) system. Methods: Rats received morphine treatments (10 mg/kg, i.p.) for seven days. On Day 8, Heantos 4 (100, 250 or 500 mg/kg, p.o.) was administered prior to naloxone (1 or 10 mg/kg, i.p.). Affective withdrawal symptoms were measured using conditioned place aversion (CPA) and somatic withdrawal symptoms were scored separately. The effect of Heantos 4 on morphine-induced (5 mg/kg, i.p.) conditioned place preference (CPP) was assessed by administering it prior to conditioning, expression or morphine-induced reinstatement. Additionally, the effect of Heantos 4 on the long-term maintenance of morphine-induced CPP was assessed bi-weekly for 6 weeks. Microdialysis studies assessed DA efflux in the nucleus accumbens of rats receiving one or seven repeated treatments of Heantos 4 (500 mg/kg, p.o.) and morphine, or receiving Heantos 4 and naloxone (10 mg/kg, i.p.). Results: Heantos 4 reduced somatic but not affective components of naloxone-precipitated opiate withdrawal. It attenuated acquisition but not expression or reinstatement of morphine-induced CPP. Long-term maintenance of morphine-induced CPP was also reduced. Heantos 4 by itself enhanced DA efflux but blunted morphine-evoked DA release on Day 1 and 7. Heantos 4 attenuated naloxone-induced decrease in DA in morphine-dependent rats. Conclusion: These findings demonstrate that Heantos 4 alleviates symptoms of somatic opiate withdrawal and indicate potential effects on incentive motivation. Moreover, Heantos 4 may modulate DA transmission that limits or antagonizes non-physiological fluctuations in mesolimbic DA activity induced by morphine and naloxone.

Ultrasonic Vocalizations as a Measure of Affect in Preclinical Models of Drug Abuse: A Review of Current Findings.

The present review describes ways in which ultrasonic vocalizations (USVs) have been used in studies of substance abuse. Accordingly, studies are reviewed which demonstrate roles for affective processing in response to the presentation of drug-related cues, experimenter- and self-administered drug, drug withdrawal, and during tests of relapse/reinstatement. The review focuses on data collected from studies using cocaine and amphetamine, where a large body of evidence has been collected. Data suggest that USVs capture animals’ initial positive reactions to psychostimulant administration and are capable of identifying individual differences in affective responding. Moreover, USVs have been used to demonstrate that positive affect becomes sensitized to psychostimulants over acute exposure before eventually exhibiting signs of tolerance. In the drug-dependent animal, a mixture of USVs suggesting positive and negative affect is observed, illustrating mixed responses to psychostimulants. This mixture is predominantly characterized by an initial bout of positive affect followed by an opponent negative emotional state, mirroring affective responses observed in human addicts. During drug withdrawal, USVs demonstrate the presence of negative affective withdrawal symptoms. Finally, it has been shown that drug-paired cues produce a learned, positive anticipatory response during training, and that presentation of drug-paired cues following abstinence produces both positive affect and reinstatement behavior. Thus, USVs are a useful tool for obtaining an objective measurement of affective states in animal models of substance abuse and can increase the information extracted from drug administration studies. USVs enable detection of subtle differences in a behavioral response that might otherwise be missed using traditional measures.

Are tobacco dependence and withdrawal related amongst heavy smokers? Relevance to conceptualizations of dependence.

Measured tobacco dependence is typically only modestly related to tobacco withdrawal severity among regular smokers making a quit attempt. The weak association between dependence and withdrawal is notable because it conflicts with core theories of dependence and because both measures predict cessation outcomes, suggesting they both index a common dependence construct. This study used data from a smoking cessation comparative effectiveness trial (N = 1504) to characterize relations of tobacco dependence with craving and negative affect withdrawal symptoms using multiple dependence measures and analytic methods to detect both additive and interactive effects and to determine whether withdrawal meaningfully mediates the influence of dependence on smoking cessation. We conclude: (a) Although univariate analyses suggest dependence and withdrawal measures are only modestly interrelated, more powerful analytic techniques show they are, in fact, meaningfully related and their shared variance is associated with cessation likelihood; (b) there are clear differences between craving and negative affective withdrawal symptoms, with the former more related to smoking heaviness and the latter related to trait measures of negative affect; moreover, craving more strongly mediates dependence effects on cessation; and (c) both craving and negative affect withdrawal symptoms are strongly related to a pattern of regular smoking that is sensitive to the passage of time and powerfully affected by smoking cues. These findings support models that accord an important role for associative processes and withdrawal symptoms, especially craving, in drug dependence. The findings also support the use of withdrawal variables as criteria for the evaluation of dependence measures.

Nicotine vaccines for smoking cessation.

By reducing the amount of nicotine that reaches the brain when a person smokes a cigarette, nicotine vaccines may help people to stop smoking or to prevent recent quitters from relapsing. The aims of this review are to assess the efficacy of nicotine vaccines for smoking cessation and for relapse prevention, and to assess the frequency and type of adverse events associated with the use of nicotine vaccines. We searched the Cochrane Tobacco Addiction Review Group specialised register for trials, using the term 'vaccine' in the title or abstract, or in a keyword (date of most recent search April 2012). To identify any other material including reviews and papers potentially relevant to the background or discussion sections, we also searched MEDLINE, EMBASE, and PsycINFO, combining terms for nicotine vaccines with terms for smoking and tobacco use, without design limits or limits for human subjects. We searched the Annual Meeting abstracts of the Society for Research on Nicotine and Tobacco up to 2012, using the search string 'vaccin'. We searched Google Scholar for 'nicotine vaccine'. We also searched company websites and Google for information related to specific vaccines. We searched clinicaltrials.gov in March 2012 for 'nicotine vaccine' and for the trade names of known vaccine candidates. We included randomized controlled trials of nicotine vaccines, at Phase II and Phase III trial stage and beyond, in adult smokers or recent ex-smokers. We included studies of nicotine vaccines used as part of smoking cessation or relapse prevention interventions. We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, blinding of participants and personnel, reporting of outcomes, and completeness of follow-up.Our primary outcome measure was a minimum of six months abstinence from smoking. We used the most rigorous definition of abstinence, and preferred cessation rates at 12 months and biochemically validated rates where available. We have used the risk ratio (RR) to summarize individual trial outcomes. We have not pooled the current group of included studies as they cover different vaccines and variable regimens. There are no nicotine vaccines currently licensed for public use, but there are a number in development. We found four trials which met our inclusion criteria, three comparing NicVAX to placebo and one comparing NIC002 (formerly NicQbeta) to placebo. All were smoking cessation trials conducted by pharmaceutical companies as part of the drug development process, and all trials were judged to be at high or unclear risk of bias in at least one domain. Overall, 2642 smokers participated in the included studies in this review. None of the four included studies detected a statistically significant difference in long-term cessation between participants receiving vaccine and those receiving placebo. The RR for 12 month cessation in active and placebo groups was 1.35 (95% Confidence Interval (CI) 0.82 to 2.22) inthe trial of NIC002and 1.74 (95% CI 0.73 to 4.18) in one NicVAX trial. Two Phase III NicVAX trials, for which full results were not available, reported similar quit rates of approximately 11% in both groups. In the two studies with full results available, post hoc analyses detected higher cessation rates in participants with higher levels of nicotine antibodies, but these findings are not readily generalisable. The two studies with full resultsshowed nicotine vaccines to be well tolerated, with the majority of adverse events classified as mild or moderate. In the study of NIC002, participants receiving the vaccine were more likely to report mild to moderate adverse events, most commonly flu-like symptoms, whereas in the study of NicVAX there was no significant difference between the two arms. Information on adverse events was not available for the large Phase III trials of NicVAX.Vaccine candidates are likely to undergo significant changes before becoming available to the general public, and those included in this review may not be the first to reach market; this limits the external validity of the results reported in this review in terms of both effectiveness and tolerability. There is currently no evidence that nicotine vaccines enhance long-term smoking cessation. Rates of serious adverse events recorded in the two trials with full data available were low, and the majority of adverse events reported were at mild to moderate levels. The evidence available suggests nicotine vaccines do not induce compensatory smoking or affect withdrawal symptoms. No nicotine vaccines are currently licensed for use in any country but a number are under development.Further trials of nicotine vaccines are needed, comparing vaccines with placebo for smoking cessation. Further trials are also needed to explore the potential of nicotine vaccines to prevent relapse. Results from past, current and future research should be reported in full. Adverse events and serious adverse events should continue to be carefully monitored and thoroughly reported.

Acute effects of moderate intensity aerobic exercise on affective withdrawal symptoms and cravings among women smokers

A growing number of laboratory studies have shown that acute bouts of aerobic exercise favorably impact affect and cravings among smokers. However, randomized trials have generally shown exercise to have no favorable effect on smoking cessation or withdrawal symptoms during quit attempts. The purpose of the present study was to explore this apparent contradiction by assessing acute changes in affect and cravings immediately prior to and following each exercise and contact control session during an eight-week smoking cessation trial. Sixty previously low-active, healthy, female smokers were randomized to an eight-week program consisting of brief baseline smoking cessation counseling and the nicotine patch plus either three sessions/week of moderate intensity aerobic exercise or contact control. Findings revealed a favorable impact of exercise on acute changes in positive activated affect (i.e., energy), negative deactivated affect (i.e., tiredness), and cigarette cravings relative to contact control. However, effects dissipated from session to session. Results suggest that aerobic exercise has potential as a smoking cessation treatment, but that it must be engaged in frequently and consistently over time in order to derive benefits. Thus, it is not surprising that previous randomized controlled trials—in which adherence to exercise programs has generally been poor—have been unsuccessful in showing effects of aerobic exercise on smoking cessation outcomes.

The effect of a lyric analysis intervention on withdrawal symptoms and locus of control in patients on a detoxification unit: A randomized effectiveness study

Withdrawal symptoms are one of the primary reasons people enter a detoxification facility while internal locus of control has been associated with maintenance of sobriety and relapse prevention. The purpose of this study was to determine if a music therapy lyric analysis intervention could affect withdrawal symptoms and locus of control in patients who were in detoxification. Participants ( N = 118) were randomized into a music therapy lyric analysis condition or a verbal therapy condition by group. After the session, participants completed a posttest with established psychometric instruments measuring symptoms of withdrawal and locus of control. Although there were no significant differences between groups, results indicated that patients in detoxification facility tended to have slightly less severe withdrawal symptoms after a music therapy session than after a verbal psychotherapy session. Participants in the experimental group tended to have slightly higher mean external of control scores. A greater number of inpatients attended the music therapy sessions than the verbal therapy control sessions, potentially providing implications for funding and billing. Most participants indicated they thought the music therapy (experimental) or relapse prevention (control condition) was most helpful/therapeutic program in which they had participated on the unit. Concerning free response written comments on the posttest, participants in the experimental condition made more comments categorized into the “positive change” category than participants in the control condition. Limitations, implications for clinical practice, and suggestions for future research are provided.

DRD2 -related TaqIA polymorphism modulates motivation to smoke

TaqIA polymorphism, a genetic variant associated with the expression level of dopamine D2 receptors in the brain, has been linked to various aspects of smoking behavior, including smoking prevalence, affective withdrawal symptoms, and smoking cessation outcome. However, its involvement in motivation to smoke cigarettes has not been elucidated. The present study examined the possible differences in self-reported reasons to smoke and craving for smoking in 160 smokers participating in a clinical trial. Individuals with at least one A1 allele of the TaqIA polymorphism were more likely to report smoking for stimulating effects and to reduce negative affect compared with those lacking an A1 allele. The association of the A1 genotype with a higher probability and stronger motive to smoker to enhance cognitive functioning was evident in female but not in male smokers. Female A1 carriers also expected a greater likelihood of smoking for pleasure than those without an A1 allele. A1 subjects reported stronger craving for cigarettes during early days and the last phase of a 6-week abstinence period. These results support the idea that dopaminergic transmission plays an important role in the neurobiological basis of reasons for smoking and that the TaqIA variant is one of the genetic factors underlying individual differences in these aspects. These findings also have implications for improving treatment strategies to help individuals quit smoking by controlling their motivation to continue cigarette consumption.

Effect of nicotine lozenges on affective smoking withdrawal symptoms: Secondary analysis of a randomized, double-blind, placebo-controlled clinical trial

Background:The suggested mechanism for the effects of nicotine replacement medications such as nicotine lozenges on smoking abstinence is reduction in the withdrawal symptoms of emotional distress and craving (the subjective desire to smoke). Objectives:This study assessed the effect of nicotine lozenges on affective withdrawal symptoms (collectively termed emotional distress) and craving over 6 weeks of treatment and the role of emotional distress and craving in mediating the effect of the lozenges on smoking abstinence. Methods:This was a secondary analysis of data from a randomized, double-blind, placebo-controlled clinical trial of nicotine lozenges. High-dependence smokers (those who smoked their first cigarette of the day within 30 minutes of waking) were assigned to recieve the 4-mg lozenge; low-dependence smokers (those who smoked their first cigarette of the day >30 minutes after waking) were assigned to receive the 2-mg lozenge. Participants were randomized to receive active or placebo lozenges within these dose and dependence strata. Smokers were to rate their withdrawal symptoms daily during the baseline week (while still smoking) and for 6 weeks after starting treatment. Study analyses included the effect of the active lozenge on affective symptoms (ie, anxiety; anger, irritability, or frustration; difficulty concentrating; restlessness; and depressed mood) during weeks 1 through 6 in high- and low-dependence smokers; the prospective associations between these symptoms and craving and subsequent abstinence; and the mediating influence of these symptoms on the lozenge's effect on abstinence. The analyses included smokers who provided symptom data for the baseline period and for at least week after the initiation of treatment. Results:Of 1818 smokers enrolled in the original study, this analysis included data from 1144. The population was predominantly white, had a mean age ranging ranging from 40.65 to 46.01 years, and included slightly more women than men. The 2-mg lozenge did not have consistently significant effects on the withdrawal symptoms of emotional distress among low-dependence smokers; however, in high-dependence smokers, the 4-mg dose was associated with significant reductions versus placebo in overall emotional distress symptoms through week 4 ( P < 0.001− P = 0.025), all individual symptoms through week 3 ( P < 0.001− P = 0.035), and irritability and anxiety through week 4 ( P = 0.002− P = 0.049). In the low-dependence group, the 2-mg lozenge was associated with significant reductions versus placebo in craving through week 3 ( P = 0.012− P = 0.033), whereas in the high-dependence group, the 4-mg lozenge was associated with significant reductions in craving in each of the first 6 weeks ( P < 0.001− P = 0.028). Among high-dependence smokers, both week-1 and week-2 emotional distress scores were associated with a return to smoking by week 6 ( P < 0.001); among lowdependence smokers, the association applied only to week-2 symptoms ( P = 0.017). Week-1 and week-2 craving was associated with a return to smoking at week 6 in both groups ( P < 0.001− P = 0.001). Emotional distress modestly and inconsistently mediated the effects of the lozenges, accounting for 3% to 13% of the treatment effects, whereas craving more strongly (though incompletely) mediated the treatment effects, particularly among high-dependence smokers, in whom it accounted for 29% to 39% of the treatment effects. Conclusions: In high-dependence smokers, the 4-mg nicotine lozenge significantly reduced all affective withdrawal symptoms through the first 4 weeks of treatment. Lozenge-related decreases in craving partially mediated the effect of treatment on abstinence, particularly in high-dependence smokers.

Varenicline

Varenicline is an orally administered alpha4beta2 nicotinic acetylcholine (ACh) receptor partial agonist. It has been approved by the US FDA (Chantix) and the European Commission (Champix) for use as an aid to smoking cessation therapy. Varenicline is an effective and generally well tolerated treatment for use in smokers who want to quit. In two well designed, phase III trials, 12 weeks' treatment with varenicline was associated with significantly higher continuous abstinence rates at weeks 9-12 than placebo or bupropion sustained-release (SR). In the longer term, continuous abstinence rates for weeks 9 through 52 demonstrated that the odds of remaining abstinent were 2.7 to 3.1 times higher with 12 weeks of varenicline treatment than with placebo; the significant difference between varenicline and bupropion SR was also maintained in the longer term in one trial. Moreover, varenicline appeared to attenuate the urge to smoke, negative affect withdrawal symptoms and the reinforcing effects of smoking. Among those achieving abstinence, an additional 12 weeks of varenicline therapy helped increase the likelihood of long-term abstinence. Thus, varenicline is a valuable new agent for use as an aid to smoking cessation treatment.

Postoperative analgesia in patients with substance use disorders: Part II

Summary The specific problems related to postoperative analgesia in patients with substance use disorders (SUD) concerning opioids, alcohol, benzodiazepines, barbiturates (Part I), cocaine, crack, amphetamines, amphetamine-like designer drugs (MDMA, ecstasy), LSD, and marijuana (Part II) are described. Whereas SUD with only one substance rarely occurs, the number of polysubstance abusers is increasing. Patients with SUD may have multiple organic diseases, impaired immune response psychiatric and behavioural abnormalities, and substance-induced disorders (intoxication, withdrawal, delerium, psychotic disorders), often associated with low compliance and craving behaviour. The perioperative management should be focused on three problems: (1) on the prevention of physical withdrawal symptoms and stressful complications in patients with SUD using CNS-depressants, (2) on the symptomatic treatment of the predominant affective withdrawal symptoms in patients suffering from SUD with CNS-stimulants, and (3) on the effective pain treatment. The analgesic therapy is often difficult and required for longer periods of time than in other patients. However, the principles of multimodal analgesia are as valid as in non-addicts. To be effective, systemic analgesia with paracetamol, NSAIDs and opioids has to be adapted as usual, but regional analgesia techniques should be preferred for postoperative pain relief. Patients enrolled in preoperative maintenance programmes (methadone, buprenorphine) need their daily maintenance dosage as baseline. This baseline therapy does not, however, induce analgesia. Therefore, these patients need additional short-acting opioids which have to be administered at higher dosages than usual (which do not cause respiratory depression due to opioid tolerance). The additional opioid does not increase the risk of relapse into active SUD. On the other hand, regional analgesia in patients who are enrolled in a maintenance programme does not mean withdrawal prophylaxis. These patients have an excellent analgesia, but they need their previously used maintenance opioid to prevent withdrawal. Special considerations will have to be made in patients with naltrexone. Recovering patients with a history of SUD have both an intensive fear of relapsing into the active SUD as well as fear of suffering from postoperative pain. These patients require an equally effective analgesia as other patients. Depending on the type of surgery and pain intensity they need atypical opioids (eg tramadol) or strong opioids (eg buprenorphine or morphine) as a part of balanced analgesia to the same degree as other patients. Withholding effective analgesic treatment can paradoxically lead to relapses in recovering patients. The common opinion of healthcare providers to withhold strong opioids from recovering patients with SUD is obsolete. However, in order to avoid psychotropic side effects the dosages of opioids, as well as the analgesic efficacy, should be monitored closely.

Postoperative analgesia in patients with substance use disorders: Part I

The specific problems related to postoperative analgesia in patients with substance use disorders (SUD) concerning opioids, alcohol, benzodiazepines, barbiturates, cocaine, crack, amphetamines, amphetamine-like designer drugs (MDMA, ecstasy), LSD, and marijuana are described. Whereas SUD with only one substance rarely occurs, the number of polysubstance abusers is increasing. Patients with SUD may have multiple organic diseases, impaired immune response, psychiatric and behavioural abnormalities and substance-induced disorders (intoxication, withdrawal, delerium, psychotic disorders), often associated with low compliance and craving behaviour. The perioperative management should be focused on three problems: (1) on the prevention of physical withdrawal symptoms and stressful complications in patients with SUD using CNS-depressants, (2) on the symptomatic treatment of the predominant affective withdrawal symptoms in patients suffering from SUD with CNS-stimulants, and (3) on the effective pain treatment. The analgesic therapy is often difficult and required for longer periods of time than in other patients. However, the principles of multimodal analgesia are as valid as in non-addicts. To be effective, systemic analgesia with paracetamol, NSAIDs and opioids has to be adapted as usual, but regional analgesia techniques should be preferred for postoperative pain relief. Patients enrolled in preoperative maintenance programmes (methadone, buprenorphine) need their daily maintenance dose as baseline. Ths baseline therapy does not, however, induce analgesia. Therefore, these patients need additional short-acting opioids which have to be administered at higher doses than usual (which do not cause respiratory depression due to opioid tolerance). The additional opioid does not increase the risk of relapse into active SUD. On the other hand, regional analgesia in patients who are enrolled in a maintenance programme does not mean withdrawal prophylaxis. These patients have excellent analgesia, but they need their previously used maintenance opioid to prevent withdrawal. Special considerations will have to be made in patients with naltrexone. Recovering patients with a history of SUD have both an intensive fear of relapsing into the active SUD as well as fear of suffering from postoperative pain. These patients require an equally effective analgesia as other patients. Depending on the type of surgery and pain intensity they need atypical opioids (eg tramadol) or strong opioids (eg buprenorphine or morphine) as a part of balanced analgesia to the same degree as other patients. Withholding effective analgesic treatment can paradoxically lead to relapses in recovering patients. The common opinion of healthcare providers to withhold strong opioids from recovering patients with SUD is obsolete. However, in order to avoid psychotropic side effects the dosages of opioids, as well as the analgesic efficacy, should be monitored closely.

Alcohol dependence and cue reactivity.

A group of 35 severely dependent male alcoholic patients undergoing cue exposure treatment were studied. Thirty-one subjects had complete data and their physiological and subjective responses to drink cues on the first day of the cue exposure program were subjected to a principal components analysis. The principal component loadings were then used to construct a single measure of responsivity and this responsivity measure was found to correlate significantly with Severity of Alcohol Dependence Questionnaire (SADQ) scores. Further analysis of the relationship between responsivity and the subscales of the SADQ showed that the experience of affective withdrawal symptoms, craving for alcohol and drinking to relieve withdrawal symptoms were the most strongly correlated with responsivity.