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Assessing combined effects of varenicline and N-acetylcysteine on reducing nicotine seeking in rats.Addiction Biology Mar 2022Nicotine addiction is a chronic relapsing brain disorder, and cigarette smoking is the leading cause of preventable death in the United States. Currently, the most...
Nicotine addiction is a chronic relapsing brain disorder, and cigarette smoking is the leading cause of preventable death in the United States. Currently, the most effective pharmacotherapy for smoking cessation is Varenicline (VRN), which reduces both positive and negative reinforcement by nicotine. Clinically, VRN attenuates withdrawal symptoms and promotes abstinence, but >50% of smokers relapse within 3 months following a quit attempt. This may indicate that VRN fails to ameliorate components of nicotine-induced neuroplasticity that promote relapse vulnerability. Animal models reveal that glutamate dysregulation in the nucleus accumbens is associated with nicotine relapse. N-acetylcysteine (NAC) normalizes glutamate transmission and prolongs cocaine abstinence. Thus, combining VRN and NAC may promote and maintain, respectively, nicotine abstinence. In rats, we found that VRN effectively reduced nicotine self-administration and seeking in early abstinence, but not seeking later in abstinence. In contrast, NAC reduced seeking only later in abstinence. Because VRN and NAC are sometimes associated with mild adverse effects, we also evaluated a sequential approach combining subthreshold doses of VRN during self-administration and early abstinence with subthreshold doses of NAC during late abstinence. As expected, subthreshold VRN did not reduce nicotine intake. However, subthreshold VRN and NAC reduced seeking in late abstinence, suggesting a combined effect. Overall, our results suggest that combining subthreshold VRN and NAC is a viable and drug-specific approach to promote abstinence and reduce relapse while minimizing adverse effects. Our data also suggest that different components and time points in addiction engage the different neurocircuits targeted by VRN and NAC.
Topics: Acetylcysteine; Animals; Nicotine; Rats; Smoking Cessation; Tobacco Use Disorder; Varenicline
PubMed: 35229943
DOI: 10.1111/adb.13151 -
JAMA Network Open Sep 2023Adaptive pharmacotherapy, ie, starting a medication regimen and then modifying that regimen based on patient response, is common in many medical domains but is not... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Adaptive pharmacotherapy, ie, starting a medication regimen and then modifying that regimen based on patient response, is common in many medical domains but is not common in smoking cessation. Recently, studies have found that adaptive treatment using precessation nicotine patches is efficacious for smoking cessation; however, adaptive treatment using precessation varenicline and adaptive treatment in clinical practice settings have not been fully assessed.
OBJECTIVE
To determine whether adaptive pharmacotherapy leads to higher smoking abstinence rates than standard pharmacotherapy in a clinical practice setting.
DESIGN, SETTING, AND PARTICIPANTS
This double-blinded stratified placebo-controlled randomized clinical trial compared adaptive treatment with standard treatment for smoking cessation. The study was conducted at a university health system in Durham, North Carolina, from February 2018 to May 2020 and was stopped early due to COVID-19. Data were analyzed as intent-to-treat from May 24, 2021, to February 27, 2022.
INTERVENTIONS
Participants were allowed to choose varenicline or nicotine patches and were then randomized to adaptive or nonadaptive (standard) treatment. Participants started on their chosen medication (adaptive) or placebo (standard) 4 weeks before their target quit day. Two weeks later, participants were assessed for treatment response. Adaptive participants who did not decrease daily cigarettes smoked by at least 50% (nonresponders) received bupropion in addition to their chosen medication. Participants in the adaptative treatment group who did decrease daily cigarettes smoked by at least 50% (responders) and participants in the standard treatment group received additional placebo bupropion. Participants in the standard treatment group received varenicline starting 1 week before the target quit date or nicotine patches starting on the target quit day. All participants received brief behavioral support.
MAIN OUTCOME AND MEASURES
The main outcome was biochemically verified 30-day continuous smoking abstinence 12 weeks after their target quit smoking day. Other measures included demographic characteristics, smoking history, and repeated smoking assessments.
RESULTS
Of the planned 300 participants, a total of 188 participants (mean [SD] age, 49.1 [12.5] years; 102 [54%] female) were enrolled before the trial was stopped because of the COVID-19 pandemic. A total of 127 participants chose to use varenicline, including 64 randomized to adaptive treatment and 63 randomized to standard treatment, and 61 participants chose to use nicotine patches, including 31 randomized to adaptive treatment and 30 randomized to standard treatment. At baseline, participants smoked a mean (SD) of 15.4 (7.3) cigarettes per day. At 12 weeks after the target quit day, biochemically verified 30-day continuous smoking abstinence was observed in 23 of 95 participants (24%) in the adaptive treatment group and 8 of 93 participants (9%) in the standard treatment (odds ratio [OR], 3.38; 95% CI, 1.43-7.99; P = .004); among participants who used varenicline, 30-day continuous abstinence was 18 participants (28%) in the adaptive treatment group, and 5 participants (8%) in the standard treatment group (OR, 4.54; 95% CI, 1.57-13.15); among participants who used nicotine patches, 30-day continuous abstinence was 5 participants (16%) in the adaptive treatment group and 3 participants (10%) in the standard treatment group (OR, 1.73; 95% CI, 0.38-7.99). Sleep problems were more common for participants in the varenicline adaptive treatment group than in the varenicline standard treatment group (rate ratio, 1.74; 95% CI, 1.18-2.58; P = .03).
CONCLUSIONS AND RELEVANCE
This randomized clinical trial found that adaptive pharmacotherapy was efficacious for smoking cessation treatment in a practice setting.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02501265.
Topics: Female; Humans; Middle Aged; Male; Smoking Cessation; Varenicline; Bupropion; Nicotine; Pandemics; COVID-19; Tobacco Use Cessation Devices
PubMed: 37682573
DOI: 10.1001/jamanetworkopen.2023.32214 -
BMC Public Health Jul 2015Smoking is a major preventable cause of morbidity and premature death worldwide. Both varenicline and nicotine replacement therapy (NRT) help achieve smoking cessation.... (Meta-Analysis)
Meta-Analysis Review
Combination therapy of varenicline with nicotine replacement therapy is better than varenicline alone: a systematic review and meta-analysis of randomized controlled trials.
BACKGROUND
Smoking is a major preventable cause of morbidity and premature death worldwide. Both varenicline and nicotine replacement therapy (NRT) help achieve smoking cessation. However, limited evidence exists regarding whether combination of varenicline and NRT is more effective than either alone. The aim of this research was to investigate the efficacy and safety of varenicline combined with NRT.
METHODS
A systematic search of MEDLINE, EMBASE, ClinicalTrial.gov, and Cochrane Library was conducted in November 2014. Two authors independently reviewed and selected randomized controlled trials. The quality of the studies was evaluated by the Jadad score. We carried out meta-analysis of both early (abstinence rate assessed before or at the end of treatment) and late (assessed after the end of the treatment) outcomes.
RESULTS
Three randomized controlled trials with 904 participants were included in this meta-analysis. All three were comparing combination therapy with varenicline therapy alone. The late outcomes were assessed in 2 of the 3 trials. Both the early and late outcomes were favorable for combination therapy (OR = 1.50, 95 % CI 1.14 to 1.97; OR = 1.62, 95 % CI 1.18 to 2.23, respectively). However, this significance diminished after eliminating a study with pre-cessation treatment using nicotine patch. The most common adverse events were nausea, insomnia, abnormal dreams, and headache. One study reported more skin reactions (14.4 % vs 7.8 %; p = 0.03) associated with combination therapy.
CONCLUSIONS
Combination therapy is more effective than varenicline alone, especially if pre-cessation treatment of nicotine patch is administrated. Adverse events of combination therapy are similar to mono-therapy except for skin reactions.
Topics: Drug Therapy, Combination; Humans; Randomized Controlled Trials as Topic; Smoking Cessation; Tobacco Use Cessation Devices; Varenicline
PubMed: 26198192
DOI: 10.1186/s12889-015-2055-0 -
Addiction (Abingdon, England) Jun 2021Varenicline and nicotine replacement therapy (NRT) are the most commonly used medications to quit smoking. Given their widespread use, monitoring adverse risks remains...
Risk of neuropsychiatric and cardiovascular adverse events following treatment with varenicline and nicotine replacement therapy in the UK Clinical Practice Research Datalink: a case-cross-over study.
BACKGROUND AND AIMS
Varenicline and nicotine replacement therapy (NRT) are the most commonly used medications to quit smoking. Given their widespread use, monitoring adverse risks remains important. This study aimed to estimate the neuropsychiatric and cardiovascular risks associated with varenicline and NRT as used in routine UK care.
DESIGN
Case-cross-over study.
SETTING
UK-based electronic primary care records in the Clinical Practice Research Datalink from 2006 to 2015 linked to hospital and mortality data sets.
PARTICIPANTS
Adult smokers (n =282,429) observed during periods when exposed and not exposed to either varenicline or NRT.
MEASUREMENTS
Main outcomes included suicide, self-harm, myocardial infarction (MI), all-cause death and cause-specific death [MI, chronic obstructive pulmonary disease (COPD)]. In primary analyses, conditional logistic regression was used to compare the chance of varenicline or NRT exposure during the risk period (90 days prior to the event) with the chance of exposure during an earlier single reference period (91-180 days prior to the event) or multiple 90-day reference periods to increase statistical power.
FINDINGS
In the primary analyses, findings were inconclusive for the associations between varenicline and the main outcomes using a single reference period, while NRT was associated with MI [odds ratio (OR) = 1.40, 95% confidence interval (CI) = 1.18-1.67]. Using multiple reference periods, varenicline was associated with an increased risk of self-harm (OR = 1.32, 95% CI = 1.12-1.56) and suicide (OR = 3.56, 95% CI = 1.32-9.60) but a reduction in all-cause death (OR = 0.75, 95% CI = 0.61-0.93). NRT was associated with MI (OR = 1.54, 95% CI = 1.36-1.74), self-harm (OR = 1.30, 95% CI = 1.18-1.44) and deaths from MI (OR = 1.53, 95% CI = 1.11-2.10), COPD (OR = 1.33, 95% CI = 1.14-1.56) and all causes (OR = 1.28, 95% CI = 1.18-1.40) when using multiple reference periods.
CONCLUSIONS
There appear to be positive associations between (1) nicotine replacement therapy (NRT) and myocardial infarction, death and risk of self-harm and (2) varenicline and increased risk of self-harm and suicide, as well as a negative association between varenicline and all-cause death. The associations may not be causal. They may reflect health changes at the time of smoking cessation (nicotine replacement therapy is prescribed for people with cardiac problems) or be associated with quit attempts (exposure to both medicines was associated with self-harm).
Topics: Adult; Aged; Benzazepines; Bupropion; Cross-Over Studies; Female; Humans; Male; Middle Aged; Myocardial Infarction; Self-Injurious Behavior; Smoking Cessation; Suicide; Tobacco Use Cessation Devices; United Kingdom; Varenicline
PubMed: 33197082
DOI: 10.1111/add.15338 -
Therapeutic Advances in Respiratory... 2019Smoking causes various diseases and is a major public health threat worldwide. Therefore, promoting smoking cessation is the most important intervention contributing to... (Review)
Review
Smoking causes various diseases and is a major public health threat worldwide. Therefore, promoting smoking cessation is the most important intervention contributing to maintaining the health of smokers and nonsmokers and saving enormous financial expense. We reviewed existing and emerging smoking-cessation pharmacotherapies from the Cochrane Database of Systemic Reviews, PubMed, Ovid, and ClinicalTrials.gov databases. A literature review revealed that bupropion may be appropriate for patients interested in reducing smoking who dislike, or who have failed, nicotine-replacement therapy (NRT). Additionally, varenicline and NRT are efficacious first-line smoking cessation treatments and should be given to all individuals unless contraindicated.
Topics: Bupropion; Cigarette Smoking; Humans; Nicotinic Agonists; Recurrence; Smoking Cessation; Smoking Cessation Agents; Tobacco Use Cessation Devices; Tobacco Use Disorder; Treatment Outcome; Varenicline
PubMed: 31533544
DOI: 10.1177/1753466619875925 -
Jornal Brasileiro de Pneumologia :... 2020This study aimed to investigate acute and chronic effects of varenicline on lung tissue in an experimental study.
OBJECTIVE
This study aimed to investigate acute and chronic effects of varenicline on lung tissue in an experimental study.
METHODS
A total of 34 rats were randomly allocated into study (varenicline) and control groups. The rats were divided into two groups (i) control group, (ii) varenicline group. Then, the rats in the each group were sub-divided equally in turn as acute (C1; V1) and chronic (C2; V2) ; all rats of acute and chronic groups were sacrificed under the anesthesia on the 45th day for acute group [C1 (n=5) and V1 (n=12)] and the 90th day for chronic group [C2 (n=5) and V2 (n=12)], respectively. Thus, biochemical and histopathological analysis were carried out.
RESULTS
Thirty four rats completed the study, 24 were in varenicline group and 10 were in control group. In chronic exposure to varenicline, oxidant levels comprising of malondialdehyde (MDA), and myeloperoxidase (MPO) increased and superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and glutathione peroxidase (GPx) levels, named as antioxidants, decreased significantly when compared to the control group. MDA and MPO levels were also significantly higher and SOD, CAT, GPx, GSH levels were also significantly lower in chronic varenicline group when compared to acute varenicline group. These findings were also supported by histopathological observations.
CONCLUSION
This is the first study, which evaluated pulmonary effects of varenicline experimentally on an animal model. It was observed that chronic varenicline treatments cause inflammation and lung cell injury.
Topics: Animals; Catalase; Glutathione; Glutathione Peroxidase; Lung; Malondialdehyde; Oxidative Stress; Rats; Superoxide Dismutase; Varenicline
PubMed: 32130342
DOI: 10.36416/1806-3756/e20180406 -
Addictive Behaviors Dec 2017While adherence to medication in smoking cessation clinical trials is strongly associated with clinical outcome, very few studies have evaluated the validity of pill...
INTRODUCTION
While adherence to medication in smoking cessation clinical trials is strongly associated with clinical outcome, very few studies have evaluated the validity of pill count as a measure of adherence relative to a biological assay, and evaluated a broad range of correlates of adherence.
METHODS
In a smoking cessation clinical trial of varenicline, we compared pill counts collected over 4 different time periods to varenicline salivary levels taken after 2weeks of treatment, as well as evaluated predictors of adherence to varenicline.
RESULTS
Using a binary measure of adherence based on salivary varenicline levels, adherence was higher among older, white, and more educated participants. Relative to 3, 7, and 14-day pill count, 12-week pill count was the only significant measure able to discriminate adherence as defined by salivary varenicline levels (assessed by area under the receiver operating characteristic curve; AUC=0.59, p=0.004). Seventy-two percent of participants who indicated adherence on 12-week pill count were classified as adherent based on varenicline saliva levels (sensitivity=0.80; specificity=0.40). There was modest variability in the relationship between 12-week pill count and varenicline levels across race and rate of nicotine metabolism. Lastly, General Estimating Equation models demonstrated that longitudinal changes in withdrawal, craving, negative and positive affect, and side effect count and severity were not related to adherence based on salivary varenicline levels.
CONCLUSIONS
These results indicate that 12-week pill count was the best, albeit a relatively weak, measure of varenicline adherence; additional factors associated with treatment adherence need to be identified.
Topics: Adult; Affect; Craving; Female; Humans; Logistic Models; Male; Medication Adherence; Middle Aged; Nicotine; Nicotinic Agonists; Randomized Controlled Trials as Topic; Saliva; Self Report; Smoking Cessation; Substance Withdrawal Syndrome; Tobacco Use Disorder; Varenicline
PubMed: 28728040
DOI: 10.1016/j.addbeh.2017.07.006 -
JAMA Network Open Jun 2022Evidence of effective smoking cessation interventions in patients with diabetes is limited. The unique behavioral and metabolic characteristics of smokers with type 2... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Evidence of effective smoking cessation interventions in patients with diabetes is limited. The unique behavioral and metabolic characteristics of smokers with type 2 diabetes warrants a randomized clinical trial of the smoking cessation drug varenicline.
OBJECTIVE
To evaluate the efficacy and safety of varenicline in patients with type 2 diabetes with an intention to quit smoking.
DESIGN, SETTING, AND PARTICIPANTS
This multicenter, double-blind, placebo-controlled randomized clinical trial recruited patients from 6 outpatient clinics in 5 hospitals in Catania, Italy. Patients with type 2 diabetes, who were smoking at least 10 cigarettes a day, and who intended to quit smoking were screened for eligibility. Eligible patients were randomized to either varenicline or placebo treatment. The trial consisted of a 12-week treatment phase followed by a 40-week follow-up, nontreatment phase. Intention-to-treat data analysis was performed from December 2020 to April 2021.
INTERVENTIONS
Varenicline, 1 mg, twice daily or matched placebo administered for 12 weeks. Patients in both treatment groups also received smoking cessation counseling.
MAIN OUTCOMES AND MEASURES
The primary efficacy end point of the study was the continuous abstinence rate (CAR) at weeks 9 to 24. Secondary efficacy end points were the CAR at weeks 9 to 12 and weeks 9 to 52 as well as 7-day point prevalence of abstinence at weeks 12, 24, and 52.
RESULTS
A total of 300 patients (mean [SD] age, 57.4 [0.8] years; 117 men [78.0%] in varenicline group and 119 men [79.3%] in placebo group) were randomized to receive varenicline (n = 150) or placebo (n = 150). The CAR at weeks 9 to 24 was significantly higher for the varenicline than placebo group (24.0% vs 6.0%; odds ratio [OR], 4.95; 95% CI, 2.29-10.70; P < .001). The CARs at weeks 9 to 12 (31.3% vs 7.3%; OR, 5.77; 95% CI, 2.85-11.66; P < .001) and weeks 9 to 52 (18.7% vs 5.3%; OR, 4.07; 95% CI, 1.79-9.27; P < .001) as well as the 7-day point prevalence of abstinence at weeks 12, 24, and 52 were also significantly higher for the varenicline vs placebo group. The most frequent adverse events occurring in the varenicline group compared with the placebo group were nausea (41 [27.3%] vs 17 [11.4%]), insomnia (29 [19.4%] vs 19 [12.7%]), abnormal dreams (19 [12.7%] vs 5 [3.4%]), anxiety (17 [11.4%] vs 11 [7.3%]), and irritability (14 [9.4%] vs 8 [5.4%]). Serious adverse events were infrequent in both groups and not treatment-related.
CONCLUSIONS AND RELEVANCE
Results of this trial showed that inclusion of varenicline in a smoking cessation program is efficacious in achieving long-term abstinence without serious adverse events. Varenicline should be routinely used in diabetes education programs to help patients with type 2 diabetes stop smoking.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01387425.
Topics: Benzazepines; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Nicotinic Agonists; Quinoxalines; Smoking Cessation; Varenicline
PubMed: 35727580
DOI: 10.1001/jamanetworkopen.2022.17709 -
Nicotine & Tobacco Research : Official... Feb 2022Varenicline is the most efficacious drug for smoking cessation; saliva varenicline concentrations can be useful for the evaluation of adherence in smoking cessation...
INTRODUCTION
Varenicline is the most efficacious drug for smoking cessation; saliva varenicline concentrations can be useful for the evaluation of adherence in smoking cessation trials. Saliva is a useful noninvasive matrix for mail-in specimen collection, if stable. We investigated the stability of varenicline in saliva at different storage temperatures simulating the time it takes to mail in a sample.
METHODS
We evaluated the concentrations of varenicline, nicotine, cotinine, 3'-hydroxycotinine, and 3'-hydroxycotinine/cotinine (3HC/COT) ratio in quality control saliva samples (and after repeated freezing and thawing), and in smokers' saliva samples, stored for up to 21 days at room temperature (~25°C), 4°C, and -80°C.
RESULTS
In saliva quality control samples, concentrations of varenicline, nicotine, cotinine, 3'-hydroxycotinine, and 3HC/COT remained unchanged and showed little within-sample variation (CV ≤ 5.5%) for up to 21 days at the three storage temperatures; they were also not altered after three thaw-freeze cycles. In smokers' saliva, a significant main effect of storage duration, but not temperature, was observed for varenicline, cotinine, and 3'-hydroxycotinine, but not for nicotine or the 3HC/COT ratio. However, these changes were within analytical (i.e., equipment) variation resulting in little within-sample variation (CV ≤ 5.8%) for all analytes in smokers' saliva.
CONCLUSIONS
Varenicline, the other analytes, and the 3HC/COT ratio remained stable in saliva during storage for 21 days at all temperatures tested and after repeated freezing and thawing with only minor changes in concentration over time. These findings support the potential use of mail-in approach for saliva samples in varenicline smoking cessation clinical trials.
IMPLICATIONS
Assessing saliva varenicline concentrations can be useful for the evaluation of adherence in smoking cessation trials. Saliva is a noninvasive matrix suitable for mail-in specimen collection. This is the first investigation of stability of varenicline in saliva. Varenicline, nicotine, cotinine, 3'-hydroxycotinine, and 3HC/COT were stable in saliva for up to 21 days at room temperature (~25°C), 4°C, and -80°C, supporting the use of a mail-in approach for saliva specimen in smoking cessation trials.
Topics: Cotinine; Humans; Nicotine; Saliva; Smoking Cessation; Temperature; Varenicline
PubMed: 34460924
DOI: 10.1093/ntr/ntab173 -
Addiction (Abingdon, England) Oct 2022In Australia, patterns of use of smoking cessation medications and factors associated with their dispensing are currently not known. This study aimed to measure the...
BACKGROUND AND AIMS
In Australia, patterns of use of smoking cessation medications and factors associated with their dispensing are currently not known. This study aimed to measure the demographic and clinical factors associated with varenicline dispensing compared with nicotine replacement therapy (NRT) and bupropion among first-time users of Pharmaceutical Benefits Scheme (PBS) subsidised smoking cessation medicines in Australia and to characterise those who discontinued varenicline treatment prematurely.
DESIGN
Retrospective, population-based study. Logistic regression was used to identify factors associated with varenicline dispensing compared with NRT and bupropion. Sensitivity analyses estimated the proportion of individuals who completed the recommended 12 weeks of varenicline treatment.
SETTING AND PARTICIPANTS
First-time users of PBS subsidised smoking cessation medicines in Australia. Individuals first dispensed a smoking cessation medicine between 2011 and 2019 were identified from a 10% random sample of the national dispensing claims data.
MEASUREMENTS
The outcome for the regression analysis was the dispensing of varenicline compared with NRT and bupropion. The dispensing of a smoking cessation medicine was identified using the World Health Organization Anatomical Therapeutic Chemical Classification System and PBS item codes. Independent variables included demographic and clinical characteristics such as sex, age, concessional status, year of treatment initiation and comorbidities identified using the Rx-Risk index. The proportion of people who discontinued varenicline treatment after the initiation pack was determined using prescription refill data.
FINDINGS
A total of 94 532 people had their first PBS subsidised smoking cessation medicine. Of these, 62 367 (66.0%) were dispensed varenicline, 29 949 (31.7%) NRT and 2216 (2.3%) bupropion. The odds of varenicline dispensing were higher in males (OR, 1.18; 95% CI, 1.14-1.21), but lower in older adults (0.86 [0.82-0.90] in above 30 years to 0.49 [0.47-0.52] in 61 years and above), among concession beneficiaries (0.44; 0.43-0.46), and those with congestive heart failure (0.60; 0.53-0.68), depression (0.61; 0.54-0.69), anxiety (0.70; 0.66-0.73), psychotic illness (0.39; 0.37-0.42), and chronic obstructive pulmonary disease (0.87; 0.82-0.92). The majority (37 670; 60.4%) of those dispensed varenicline discontinued treatment after the initiation pack. Anxiety and psychotic illnesses were significantly more prevalent in those who discontinued treatment. Only 2804 (4.5%) of those dispensed varenicline completed 12 weeks of treatment.
CONCLUSION
Individuals dispensed varenicline in Australia appear to be healthier compared with those who are dispensed nicotine replacement therapy or bupropion.
Topics: Aged; Australia; Benzazepines; Bupropion; Humans; Male; Nicotine; Nicotinic Agonists; Quinoxalines; Retrospective Studies; Smoking; Smoking Cessation; Tobacco Use Cessation Devices; Varenicline
PubMed: 35603915
DOI: 10.1111/add.15949