Cardiovascular and Neuropsychiatric Events after Varenicline Use for Smoking Cessation.

RATIONALE: Varenicline aids in smoking cessation but has also been associated with serious adverse events. OBJECTIVES: The aim of this study was to determine the risks of cardiovascular and neuropsychiatric events after varenicline receipt in a real-world setting. METHODS: A population-based, self-controlled risk interval study using linked universal health administrative data from the diverse, multicultural population of Ontario, Canada, was conducted. In two separate analyses, new varenicline users between September 1, 2011 and February 15, 2014 were observed from 1 year before to 1 year after varenicline receipt. The relative incidences of cardiovascular and neuropsychiatric hospitalizations and emergency department visits in the 12 weeks after varenicline receipt (the risk interval) compared with the remaining observation period (the control interval) were estimated in two separate fixed-effect conditional Poisson regressions. Sensitivity analyses tested the robustness of the results. MEASUREMENTS AND MAIN RESULTS: Among 56,851 new users of varenicline, 6,317 cardiovascular and 10,041 neuropsychiatric hospitalizations and emergency department visits occurred from 1 year before to 1 year after receipt. The incidence of cardiovascular events was 34% higher in the risk compared with the control interval (relative incidence, 1.34; 95% confidence interval, 1.25-1.44). Findings were consistent in sensitivity analyses, most notably in those without any history of previous cardiovascular disease. The relative incidence of neuropsychiatric events was marginally significant in the primary (relative incidence, 1.06; 95% confidence interval, 1.00-1.13) but not all sensitivity analyses. CONCLUSIONS: Varenicline appears to be associated with an increased risk of cardiovascular but not neuropsychiatric events.

Impact of large-scale distribution and subsequent use of free nicotine patches on primary care physician interaction.

BACKGROUND: Large-scale distribution efforts of free nicotine replacement therapy (NRT) have been documented to be cost-effective interventions for increasing smoking quit rates. However, despite nearly a dozen studies evaluating their effectiveness, none have examined whether free NRT provision promotes further primary care help-seeking and the impact that it may have on cessation efforts. METHODS: In the context of a randomized controlled trial, a secondary analysis was conducted on 1000 adult regular smokers randomized to be mailed a 5-week supply of nicotine patches or to a no intervention control group. Recipients and users of free nicotine patches at an 8 week follow-up were successfully case matched to controls based on age, gender, baseline level of nicotine dependence and intent to quit (n = 201 per group). Differences in physician interaction between the two groups were evaluated at both 8 week and 6 month follow-ups. The impact of physician interaction on self-reported smoking abstinence at each follow-up was also examined. RESULTS: Although no differences in physician interaction were noted between groups at the 8 week follow-up, at the 6 month follow-up, nicotine patch users reported greater frequency of discussing smoking with their physician (43.9%), as compared to the control group (30.3%) (p = 0.011). Across both groups, over 90% of those that discussed smoking with a physician were encouraged to quit and approximately 70% were provided with additional support. Separate ANOVAs revealed no significant impact of physician interaction on cessation (p > 0.05), regardless of group or follow-up period, however, at the 6 month follow-up, nicotine patch users who discussed cessation with a physician had made serious quit attempts at significantly greater rates (72.6%), compared to controls (49.1%) (p = 0.007). CONCLUSIONS: Irrespective of group, the majority of smokers in the present study did not discuss cessation with their physician. Recipients and users of nicotine patches however, were more likely to discuss smoking with their physician, suggesting that the provision of free NRT particularly to those who are likely to use it may facilitate opportunities for benefits beyond the direct pharmacological effects of the medication. TRIAL REGISTRATION: clinicaltrials.gov , NCT01429129 . Registered: 2 September 2011.

Mailed distribution of free nicotine patches without behavioral support: Predictors of use and cessation.

INTRODUCTION: There is growing evidence that the mailed distribution of free nicotine replacement therapy (NRT), usually as part of smokers' helplines, can been effective in increasing the odds of cessation on a population level. However, limited information is available on the utilization of NRT when it is provided for free, and factors associated with regimen adherence have remained largely unexplored. METHODS: In the context of a randomized controlled trial, 500 adult smokers across Canada hypothetically interested in free NRT were mailed a 5week supply of nicotine patches, but no other support was offered. Analyses evaluated which a priori-defined demographic and smoking characteristics predicted nicotine patch use at 8week follow-up of 421 patch recipients, as well as examined the association between patch use and smoking cessation at 6months. RESULTS: At 8weeks, 10.9% had used all, 47.5% had used some but not all, and 41.6% had not used any of the provided nicotine patches. Lower age, unemployment, past NRT use and intent to quit in the next 30days at baseline (preparation stage of change) were all identified as independent predictors of some nicotine patch use. Only use of all patches was associated with greater odds of smoking cessation, compared to non-users (Adj. OR=2.96; 95%CI=1.06-8.27). CONCLUSIONS: The mailed distribution of free nicotine patches to smokers at large can be effective at promoting cessation, particularly among financially disadvantaged groups, those with previous NRT experience and among individuals with already advanced intent to quit.

Impact of self-reported lifetime depression or anxiety on effectiveness of mass distribution of nicotine patches.

BACKGROUND: Large-scale public health initiatives providing free nicotine replacement therapy have been shown to increase smoking cessation rates; however, their effectiveness among the highly prevalent population of smokers with depression and anxiety disorders has not been explored. The aim of this study was to investigate the influence of lifetime history of depression or anxiety on smoking cessation success following the free distribution of nicotine patches. METHOD: In the context of a randomised controlled trial, a secondary analysis was conducted on 1000 adult regular smokers randomised to be mailed a 5-week supply of nicotine patches or to a no intervention control group. Participants were divided into subgroups based on the presence of self-reported lifetime diagnosis of depression and anxiety. RESULTS: Irrespective of self-reported lifetime history of depression or anxiety, odds of self-reported cessation at 6 months were significantly greater among groups receiving nicotine patches compared to no intervention control (no history of depression or anxiety: OR 2.20; 95% CI 1.05 to 4.63; history of depression or anxiety present: OR 3.90; 95% CI 1.28 to 11.88). Among nicotine patch recipients only, quit outcomes did not differ between those with and without self-reported lifetime depression or anxiety in models unadjusted and adjusted for differences in demographic and smoking characteristics. CONCLUSIONS: The mass distribution of free nicotine patches (without behavioural support) is effective among smokers with or without lifetime history of depression or anxiety alike, providing further support for the adoption of similar initiatives as a means of promoting tobacco cessation on a population level. TRIAL REGISTRATION NUMBER: NCT01429129, Post-results.

Nonmedical use of opioid analgesics among Ontario students.

OBJECTIVE: To explore the prevalence and the demographic predictors of nonmedical use of opioid analgesics in the Canadian adolescent population. DESIGN: Data are based on self-reports derived from the 2007 Ontario Student Drug Use and Health Survey, which is an anonymous, in-school, cross-sectional survey. SETTING: Schools in Ontario. PARTICIPANTS: A total of 2914 students in grades 7 to 12. MAIN OUTCOME MEASURES: Demographic predictors of nonmedical use of opioid analgesics during the past year and the sources of opioid analgesics. RESULTS: Students ranged in age from 12 to 19 years (mean 15.0, SD 1.9) and 52% were male. Of the students surveyed, 20.6% (95% confidence interval [CI] 18.9% to 22.3%) reported using opioid analgesics at least once nonmedically during the past year, with 6.2% using exclusively nonmedically and 14.4% using nonmedically and medically. Female students (16.6%, CI 14.1% to 19.6%) were more likely than male students (12.0%, CI 10.0% to 14.2%) to have used opioid analgesics both nonmedically and medically in the past year, although exclusive nonmedical use was similar between female (6.7%, CI 5.3% to 8.5%) and male (5.8%, CI 4.5% to 7.3%) students. Among students who reported using opioid analgesics nonmedically, 72% reported obtaining them from home and only 6% reported obtaining them from friends. Nonmedical opioid analgesic users had higher past-year prevalences for alcohol use, daily smoking, and other illicit drug use compared with nonusers. CONCLUSION: Nonmedical use of opioids is common among Ontario students. The motivation for using these medications without prescriptions or without medical supervision is not known. Students might have used these medications recreationally or for pain relief. Regardless of motivation, these medications are being used without medical supervision. It is important to note that the home is the main source for opioid analgesics in the absence of a prescription. Parents should be vigilant and educate themselves and their children about these medications, ensuring that prescription opioids are stored properly and avoiding casual sharing of these medications among family members.

Methadone-nicotine interactions in methadone maintenance treatment patients.

Smoking is highly prevalent (85%-98%) in methadone maintenance treatment (MMT) patients. Methadone has been shown to increase cigarette smoking in a dose-dependent manner, whereas smoking/nicotine has been shown to increase methadone self-administration and reinforcing properties. The objective of this study was to evaluate methadone-nicotine interactions in MMT patients during trough and peak methadone effect conditions. Subjective effects of nicotine (administered by cigarette smoking, 4 mg of nicotine gum and placebo gum) and methadone and their combination were assessed in 40 regularly smoking, stabilized MMT patients using a randomized, placebo-controlled, within-subject study design. Subjects responded to a battery of subjective assessments before and after nicotine administration both before methadone administration (cycles 1 and 2) and 3 hours after methadone administration (cycles 3 and 4). There was a main effect of methadone on the decrease of opioid withdrawal scores (P < 0.001), and cigarette smoking enhanced this effect (day x methadone interaction, P = 0.031). Both nicotine and methadone had main effects on the decrease of nicotine withdrawal scores (P < 0.001 and P = 0.001, respectively); this was associated with the cigarette day (day x nicotine interaction, P = 0.003, and day x methadone interaction, P = 0.004). Nicotine plasma levels were highest on the cigarette smoking day (P < 0.001). Methadone and nicotine shared main effects on the increase of ratings of euphoria and drug liking and on the decrease of restlessness, irritability, and depression. The overall results may help to explain high smoking rates in the MMT population and may account for reports of increased positive effects of methadone when the drugs are taken together.

Desvenlafaxine succinate for major depressive disorder.

Desvenlafaxine (O-desmethylvenlafaxine) is the major active metabolite of venlafaxine. Desvenlafaxine succinate is now undergoing active evaluation for its therapeutic efficacy in a variety of disorders, including major depressive disorder, vasomotor symptoms associated with menopause, fibromyalgia and diabetic neuropathy. Desvenlafaxine is a serotonin and norepinephrine reuptake inhibitor (SNRI) with similar activity to its parent compound venlafaxine, and little affinity for other brain targets, including muscarinic, cholinergic, histamine H(1) and alpha-adrenergic receptors. Desvenlafaxine has linear pharmacokinetics, low protein binding, a half-life of approximately 10 hours and is metabolized primarily via glucuronidation, and to a minor extent through CYP3A4. The desvenlafaxine succinate formulation appears to have good oral bioavailability. Clearance rates are reduced in the elderly, those with severe renal dysfunction and those with moderate to severe hepatic dysfunction, which may require dosage adjustments. Three published clinical trials have shown supportive but mixed results for the efficacy of desvenlafaxine in the treatment of major depressive disorder with daily doses ranging from 100 mg to 400 mg. One published clinical trial has shown mixed results for the efficacy of desvenlafaxine in the treatment of vasomotor symptoms associated with menopause with daily doses ranging from 50 mg to 200 mg. In these four clinical trials, desvenlafaxine was associated with several mild adverse effects, with the most common effect being nausea. Less common, but more serious, adverse effects reported in these trials included hypertension, QTc interval prolongation, exacerbation of ischemic cardiac disease, elevated lipids and elevated liver enzymes. The exact nature of these serious adverse effects, including the prevalence, clinical significance and potential risk factors, still needs to be fully elucidated. Desvenlafaxine has a low propensity for pharmacokinetic-based drug interactions, although it has the same potential for pharmacodynamic interactions as other serotonin-norepinephrine reuptake inhibitors. Desvenlafaxine is currently another treatment option for major depressive disorder. The only identified potential advantage of desvenlafaxine over venlafaxine or other antidepressant agents at this time is the apparently reduced risk for pharmacokinetic drug interactions.