User login
Smoking cessation: Varenicline and the risk of neuropsychiatric adverse events
Mr. T, age 34, is a veteran who recently returned to civilian life. He presents to his local Veteran Affairs facility for transition of care. During active duty, he had been diagnosed with obstructive sleep apnea, tobacco use disorder, posttraumatic stress disorder (PTSD) secondary to combat exposure, and insomnia. Mr. T says he wants to quit smoking; currently, he smokes 2 packs of cigarettes per day. The primary care clinician notes that Mr. T has uncontrolled PTSD symptoms and poor sleep, and refers him for an outpatient mental health appointment.
At the mental health appointment 3 weeks later, Mr. T asks about medications to quit smoking, specifically varenicline (Table 11). Mr. T’s PTSD Checklist for DSM-5 score is 52, which indicates severe PTSD symptomatology. He says he sees shadowy figures in his periphery every day, and worries they are spying on him. His wife reports Mr. T has had these symptoms for most of their 10-year marriage but has never been treated for them. After a discussion with the outpatient team, Mr. T says he is willing to engage in exposure therapy for PTSD, but he does not want to take any medications other than varenicline for smoking cessation.
Cigarette smoke is a known carcinogen and risk factor for the development of cardiovascular and respiratory diseases and other comorbidities. People with severe mental illness (SMI) are 3 to 5 times more likely to smoke, and they often face multiple barriers to cessation, including low socioeconomic status and lack of support.2 Even when patients with SMI are provided appropriate behavioral and pharmacologic interventions, they often require more frequent monitoring and counseling, receive a longer duration of drug therapy, and experience lower smoking cessation rates than the general population.2
Current guidelines recommend nicotine replacement therapy (NRT), bupropion, varenicline, and behavioral support as first-line therapies for smoking cessation in patients with and without SMI.2 Evidence suggests that varenicline is more effective than other pharmacologic options; however, in 2009 a black-box warning was added to both varenicline and bupropion to highlight an increased risk of neuropsychiatric events in individuals with SMI.2 This led some clinicians to hesitate to prescribe varenicline or bupropion to patients with psychiatric illness. However, in 2016, the EAGLES trial evaluated the safety of varenicline, bupropion, and NRT in smokers with and without psychiatric disorders, and based on the findings, the black-box warning was removed.2
This article reviews the evidence regarding the use of varenicline and the risk of neuropsychiatric adverse events in patients with psychiatric illness. Table 23-6 provides a summary of each varenicline trial we discuss.
The EAGLES trial
EAGLES was a multicenter, multinational, randomized, double-blind, triple-dummy, placebo- and active-controlled trial of 8,144 individuals who received treatment for smoking cessation.3 The primary endpoint was the incidence of a composite measure of moderate to severe neuropsychiatric events (NPSAEs).3 Participants were split into psychiatric (N = 4,116) and nonpsychiatric (N = 4,028) cohorts and randomized into 4 treatment arms: varenicline 1 mg twice a day, bupropion 150 mg twice a day, nicotine patch 21 mg/d with taper, or placebo, all for 12 weeks with an additional 12 weeks of follow-up. All participants smoked ≥10 cigarettes per day. Individuals in the psychiatric cohort had to be psychiatrically stable (no exacerbations for 6 months and stable treatment for 3 months). Exclusionary diagnoses included psychotic disorders (except schizophrenia and schizoaffective disorder), dementia, substance use (except nicotine), and personality disorders (except borderline personality disorder).2
The rates of moderate to severe NPSAEs in the varenicline groups were 1.25% (95% CI, 0.60 to 1.90) in the nonpsychiatric cohort and 6.42% (95% CI, 4.91 to 7.93) in the psychiatric cohort.3 However, when comparing the varenicline group of the psychiatric cohort to the other arms of the psychiatric cohort, there were no differences (bupropion 6.62% [95% CI, 5.09 to 8.15], nicotine patch 5.20% [95% CI, 3.84 to 6.56], placebo 4.83% [95% CI, 3.51 to 6.16], respectively). The primary efficacy endpoint was continuous abstinence rates (CAR) for Week 9 through Week 12. In the psychiatric cohort, varenicline was superior compared to placebo (odds ratio [OR] 3.24; 95% CI, 2.56 to 4.11), bupropion (OR 1.74; 95% CI, 1.41 to 2.14), and nicotine patch (OR 1.62; 95% CI, 1.32 to 1.99).3
Continue to: Further analysis of EAGLES
Further analysis of EAGLES
Beard et al4 used Bayes factor testing for additional analysis of EAGLES data to determine whether the data were insensitive to neuropsychiatric effects secondary to a lack of statistical power. In the psychiatric cohort, the varenicline and bupropion groups exhibited suggestive but not conclusive data that there was no increase in NPSAEs compared to placebo (Bayes factor 0.52 and 0.71, respectively).4
Another EAGLES analysis by Ayers et al5 evaluated participants with anxiety disorders (N = 712), including PTSD (N = 192), generalized anxiety disorder (GAD) (N = 243), and panic disorder (N = 277).Of those with PTSD who received varenicline, there were no statistically significant differences in CAR from Week 9 to Week 12 vs placebo.5 However, there was a significant difference in individuals with GAD (OR 4.53; 95% CI, 1.20 to 17.10), and panic disorder (OR 8.49; 95% CI, 1.57 to 45.78).5 In contrast to CAR from Week 9 to Week 12, 7-day point prevalence abstinence at Week 12 for participants with PTSD was significant (OR 4.04; 95% CI, 1.39 to 11.74) when comparing varenicline to placebo. Within the anxiety disorder cohort, there were no significant differences in moderate to severe NPSAE rates based on treatment group. Calculated risk differences comparing varenicline to placebo were: PTSD group -7.73 (95% CI, -21.95 to 6.49), GAD group 2.80 (95% CI, -6.63 to 12.23), and panic disorder group -0.18 (95% CI, -9.57 to 9.21).5
Other studies
Evins et al6 conducted a randomized controlled trial to evaluate the safety of varenicline maintenance therapy in patients with schizophrenia or bipolar disorder. To be deemed clinically stable, participants in this study needed to be taking a stable dose of an antipsychotic or mood-stabilizing agent(s) for ≥30 days, compared to the 3-month requirement of the EAGLES trial.3,6 Participants received 12 weeks of open-label varenicline; those who achieved abstinence (N = 87) entered the relapse-prevention phase and were randomized to varenicline 1 mg twice a day or placebo for 40 weeks. Of those who entered relapse-prevention, 5 in the placebo group and 2 in the varenicline group were psychiatrically hospitalized (risk ratio 0.45; 95% CI, 0.04 to 2.9).6 These researchers concluded that varenicline maintenance therapy prolonged abstinence rates with no significant increase in neuropsychiatric events.6
Although treatment options for smoking cessation have advanced, individuals with SMI are still disproportionately affected by the negative outcomes of cigarette smoking. Current literature suggests that varenicline does not confer an appreciable risk of neuropsychiatric events in otherwise stable patients and is the preferred first-line treatment. However, there is a gap in understanding the impact of this medication on individuals with unstable psychiatric illness. Health care professionals should be encouraged to use varenicline with careful monitoring for appropriate patients with psychiatric disorders as a standard of care to help them quit smoking.
CASE CONTINUED
After consulting with the psychiatric pharmacist and discussing the risks and benefits of varenicline, Mr. T is started on the appropriate titration schedule (Table 11). A pharmacist provides varenicline education, including the possibility of psychiatric adverse effects, and tells Mr. T to report any worsening psychiatric symptoms. Mr. T is scheduled for frequent follow-up visits to monitor possible adverse effects and his tobacco use. He says he understands the potential adverse effects of varenicline and agrees to frequent follow-up appointments while taking it.
Related Resources
- Leone FT, Zhang Y, Evers-Casey S, et al. Initiating pharmacologic treatment in tobacco-dependent adults. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;202(2):e5-e31. doi:10.1164/rccm.202005.1982ST
- Cieslak K, Freudenreich O. 4 Ways to help your patients with schizophrenia quit smoking. Current Psychiatry. 2018; 17(2):28,33.
Drug Brand Names
Bupropion • Wellbutrin
Varenicline • Chantix
[embed:render:related:node:157276]
1. Chantix [package insert]. New York, NY: Pfizer Inc; 2019.
2. Sharma R, Alla K, Pfeffer D, et al. An appraisal of practice guidelines for smoking cessation in people with severe mental illness. Aust N Z J Psychiatry. 2017;51(11):1106-1120. doi:10.1177/0004867417726176
3. Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet. 2016;387(10037):2507-2520. doi:10.1016/s0140-6736(16)30272-0
4. Beard E, Jackson SE, Anthenelli RM, et al. Estimation of risk of neuropsychiatric adverse events from varenicline, bupropion and nicotine patch versus placebo: secondary analysis of results from the EAGLES trial using Bayes factors. Addiction. 2021;116(10):2816-2824. doi:10.1111/add.15440
5. Ayers CR, Heffner JL, Russ C, et al. Efficacy and safety of pharmacotherapies for smoking cessation in anxiety disorders: subgroup analysis of the randomized, active- and placebo-controlled EAGLES trial. Depress Anxiety. 2020;37(3)247-260. doi:10.1002/da.22982
6. Evins AE, Cather C, Pratt SA, et al. Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder: a randomized clinical trial. JAMA. 2014;311(2):145-154. doi:10.1001/jama.2013.285113
Mr. T, age 34, is a veteran who recently returned to civilian life. He presents to his local Veteran Affairs facility for transition of care. During active duty, he had been diagnosed with obstructive sleep apnea, tobacco use disorder, posttraumatic stress disorder (PTSD) secondary to combat exposure, and insomnia. Mr. T says he wants to quit smoking; currently, he smokes 2 packs of cigarettes per day. The primary care clinician notes that Mr. T has uncontrolled PTSD symptoms and poor sleep, and refers him for an outpatient mental health appointment.
At the mental health appointment 3 weeks later, Mr. T asks about medications to quit smoking, specifically varenicline (Table 11). Mr. T’s PTSD Checklist for DSM-5 score is 52, which indicates severe PTSD symptomatology. He says he sees shadowy figures in his periphery every day, and worries they are spying on him. His wife reports Mr. T has had these symptoms for most of their 10-year marriage but has never been treated for them. After a discussion with the outpatient team, Mr. T says he is willing to engage in exposure therapy for PTSD, but he does not want to take any medications other than varenicline for smoking cessation.
Cigarette smoke is a known carcinogen and risk factor for the development of cardiovascular and respiratory diseases and other comorbidities. People with severe mental illness (SMI) are 3 to 5 times more likely to smoke, and they often face multiple barriers to cessation, including low socioeconomic status and lack of support.2 Even when patients with SMI are provided appropriate behavioral and pharmacologic interventions, they often require more frequent monitoring and counseling, receive a longer duration of drug therapy, and experience lower smoking cessation rates than the general population.2
Current guidelines recommend nicotine replacement therapy (NRT), bupropion, varenicline, and behavioral support as first-line therapies for smoking cessation in patients with and without SMI.2 Evidence suggests that varenicline is more effective than other pharmacologic options; however, in 2009 a black-box warning was added to both varenicline and bupropion to highlight an increased risk of neuropsychiatric events in individuals with SMI.2 This led some clinicians to hesitate to prescribe varenicline or bupropion to patients with psychiatric illness. However, in 2016, the EAGLES trial evaluated the safety of varenicline, bupropion, and NRT in smokers with and without psychiatric disorders, and based on the findings, the black-box warning was removed.2
This article reviews the evidence regarding the use of varenicline and the risk of neuropsychiatric adverse events in patients with psychiatric illness. Table 23-6 provides a summary of each varenicline trial we discuss.
The EAGLES trial
EAGLES was a multicenter, multinational, randomized, double-blind, triple-dummy, placebo- and active-controlled trial of 8,144 individuals who received treatment for smoking cessation.3 The primary endpoint was the incidence of a composite measure of moderate to severe neuropsychiatric events (NPSAEs).3 Participants were split into psychiatric (N = 4,116) and nonpsychiatric (N = 4,028) cohorts and randomized into 4 treatment arms: varenicline 1 mg twice a day, bupropion 150 mg twice a day, nicotine patch 21 mg/d with taper, or placebo, all for 12 weeks with an additional 12 weeks of follow-up. All participants smoked ≥10 cigarettes per day. Individuals in the psychiatric cohort had to be psychiatrically stable (no exacerbations for 6 months and stable treatment for 3 months). Exclusionary diagnoses included psychotic disorders (except schizophrenia and schizoaffective disorder), dementia, substance use (except nicotine), and personality disorders (except borderline personality disorder).2
The rates of moderate to severe NPSAEs in the varenicline groups were 1.25% (95% CI, 0.60 to 1.90) in the nonpsychiatric cohort and 6.42% (95% CI, 4.91 to 7.93) in the psychiatric cohort.3 However, when comparing the varenicline group of the psychiatric cohort to the other arms of the psychiatric cohort, there were no differences (bupropion 6.62% [95% CI, 5.09 to 8.15], nicotine patch 5.20% [95% CI, 3.84 to 6.56], placebo 4.83% [95% CI, 3.51 to 6.16], respectively). The primary efficacy endpoint was continuous abstinence rates (CAR) for Week 9 through Week 12. In the psychiatric cohort, varenicline was superior compared to placebo (odds ratio [OR] 3.24; 95% CI, 2.56 to 4.11), bupropion (OR 1.74; 95% CI, 1.41 to 2.14), and nicotine patch (OR 1.62; 95% CI, 1.32 to 1.99).3
Continue to: Further analysis of EAGLES
Further analysis of EAGLES
Beard et al4 used Bayes factor testing for additional analysis of EAGLES data to determine whether the data were insensitive to neuropsychiatric effects secondary to a lack of statistical power. In the psychiatric cohort, the varenicline and bupropion groups exhibited suggestive but not conclusive data that there was no increase in NPSAEs compared to placebo (Bayes factor 0.52 and 0.71, respectively).4
Another EAGLES analysis by Ayers et al5 evaluated participants with anxiety disorders (N = 712), including PTSD (N = 192), generalized anxiety disorder (GAD) (N = 243), and panic disorder (N = 277).Of those with PTSD who received varenicline, there were no statistically significant differences in CAR from Week 9 to Week 12 vs placebo.5 However, there was a significant difference in individuals with GAD (OR 4.53; 95% CI, 1.20 to 17.10), and panic disorder (OR 8.49; 95% CI, 1.57 to 45.78).5 In contrast to CAR from Week 9 to Week 12, 7-day point prevalence abstinence at Week 12 for participants with PTSD was significant (OR 4.04; 95% CI, 1.39 to 11.74) when comparing varenicline to placebo. Within the anxiety disorder cohort, there were no significant differences in moderate to severe NPSAE rates based on treatment group. Calculated risk differences comparing varenicline to placebo were: PTSD group -7.73 (95% CI, -21.95 to 6.49), GAD group 2.80 (95% CI, -6.63 to 12.23), and panic disorder group -0.18 (95% CI, -9.57 to 9.21).5
Other studies
Evins et al6 conducted a randomized controlled trial to evaluate the safety of varenicline maintenance therapy in patients with schizophrenia or bipolar disorder. To be deemed clinically stable, participants in this study needed to be taking a stable dose of an antipsychotic or mood-stabilizing agent(s) for ≥30 days, compared to the 3-month requirement of the EAGLES trial.3,6 Participants received 12 weeks of open-label varenicline; those who achieved abstinence (N = 87) entered the relapse-prevention phase and were randomized to varenicline 1 mg twice a day or placebo for 40 weeks. Of those who entered relapse-prevention, 5 in the placebo group and 2 in the varenicline group were psychiatrically hospitalized (risk ratio 0.45; 95% CI, 0.04 to 2.9).6 These researchers concluded that varenicline maintenance therapy prolonged abstinence rates with no significant increase in neuropsychiatric events.6
Although treatment options for smoking cessation have advanced, individuals with SMI are still disproportionately affected by the negative outcomes of cigarette smoking. Current literature suggests that varenicline does not confer an appreciable risk of neuropsychiatric events in otherwise stable patients and is the preferred first-line treatment. However, there is a gap in understanding the impact of this medication on individuals with unstable psychiatric illness. Health care professionals should be encouraged to use varenicline with careful monitoring for appropriate patients with psychiatric disorders as a standard of care to help them quit smoking.
CASE CONTINUED
After consulting with the psychiatric pharmacist and discussing the risks and benefits of varenicline, Mr. T is started on the appropriate titration schedule (Table 11). A pharmacist provides varenicline education, including the possibility of psychiatric adverse effects, and tells Mr. T to report any worsening psychiatric symptoms. Mr. T is scheduled for frequent follow-up visits to monitor possible adverse effects and his tobacco use. He says he understands the potential adverse effects of varenicline and agrees to frequent follow-up appointments while taking it.
Related Resources
- Leone FT, Zhang Y, Evers-Casey S, et al. Initiating pharmacologic treatment in tobacco-dependent adults. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;202(2):e5-e31. doi:10.1164/rccm.202005.1982ST
- Cieslak K, Freudenreich O. 4 Ways to help your patients with schizophrenia quit smoking. Current Psychiatry. 2018; 17(2):28,33.
Drug Brand Names
Bupropion • Wellbutrin
Varenicline • Chantix
[embed:render:related:node:157276]
Mr. T, age 34, is a veteran who recently returned to civilian life. He presents to his local Veteran Affairs facility for transition of care. During active duty, he had been diagnosed with obstructive sleep apnea, tobacco use disorder, posttraumatic stress disorder (PTSD) secondary to combat exposure, and insomnia. Mr. T says he wants to quit smoking; currently, he smokes 2 packs of cigarettes per day. The primary care clinician notes that Mr. T has uncontrolled PTSD symptoms and poor sleep, and refers him for an outpatient mental health appointment.
At the mental health appointment 3 weeks later, Mr. T asks about medications to quit smoking, specifically varenicline (Table 11). Mr. T’s PTSD Checklist for DSM-5 score is 52, which indicates severe PTSD symptomatology. He says he sees shadowy figures in his periphery every day, and worries they are spying on him. His wife reports Mr. T has had these symptoms for most of their 10-year marriage but has never been treated for them. After a discussion with the outpatient team, Mr. T says he is willing to engage in exposure therapy for PTSD, but he does not want to take any medications other than varenicline for smoking cessation.
Cigarette smoke is a known carcinogen and risk factor for the development of cardiovascular and respiratory diseases and other comorbidities. People with severe mental illness (SMI) are 3 to 5 times more likely to smoke, and they often face multiple barriers to cessation, including low socioeconomic status and lack of support.2 Even when patients with SMI are provided appropriate behavioral and pharmacologic interventions, they often require more frequent monitoring and counseling, receive a longer duration of drug therapy, and experience lower smoking cessation rates than the general population.2
Current guidelines recommend nicotine replacement therapy (NRT), bupropion, varenicline, and behavioral support as first-line therapies for smoking cessation in patients with and without SMI.2 Evidence suggests that varenicline is more effective than other pharmacologic options; however, in 2009 a black-box warning was added to both varenicline and bupropion to highlight an increased risk of neuropsychiatric events in individuals with SMI.2 This led some clinicians to hesitate to prescribe varenicline or bupropion to patients with psychiatric illness. However, in 2016, the EAGLES trial evaluated the safety of varenicline, bupropion, and NRT in smokers with and without psychiatric disorders, and based on the findings, the black-box warning was removed.2
This article reviews the evidence regarding the use of varenicline and the risk of neuropsychiatric adverse events in patients with psychiatric illness. Table 23-6 provides a summary of each varenicline trial we discuss.
The EAGLES trial
EAGLES was a multicenter, multinational, randomized, double-blind, triple-dummy, placebo- and active-controlled trial of 8,144 individuals who received treatment for smoking cessation.3 The primary endpoint was the incidence of a composite measure of moderate to severe neuropsychiatric events (NPSAEs).3 Participants were split into psychiatric (N = 4,116) and nonpsychiatric (N = 4,028) cohorts and randomized into 4 treatment arms: varenicline 1 mg twice a day, bupropion 150 mg twice a day, nicotine patch 21 mg/d with taper, or placebo, all for 12 weeks with an additional 12 weeks of follow-up. All participants smoked ≥10 cigarettes per day. Individuals in the psychiatric cohort had to be psychiatrically stable (no exacerbations for 6 months and stable treatment for 3 months). Exclusionary diagnoses included psychotic disorders (except schizophrenia and schizoaffective disorder), dementia, substance use (except nicotine), and personality disorders (except borderline personality disorder).2
The rates of moderate to severe NPSAEs in the varenicline groups were 1.25% (95% CI, 0.60 to 1.90) in the nonpsychiatric cohort and 6.42% (95% CI, 4.91 to 7.93) in the psychiatric cohort.3 However, when comparing the varenicline group of the psychiatric cohort to the other arms of the psychiatric cohort, there were no differences (bupropion 6.62% [95% CI, 5.09 to 8.15], nicotine patch 5.20% [95% CI, 3.84 to 6.56], placebo 4.83% [95% CI, 3.51 to 6.16], respectively). The primary efficacy endpoint was continuous abstinence rates (CAR) for Week 9 through Week 12. In the psychiatric cohort, varenicline was superior compared to placebo (odds ratio [OR] 3.24; 95% CI, 2.56 to 4.11), bupropion (OR 1.74; 95% CI, 1.41 to 2.14), and nicotine patch (OR 1.62; 95% CI, 1.32 to 1.99).3
Continue to: Further analysis of EAGLES
Further analysis of EAGLES
Beard et al4 used Bayes factor testing for additional analysis of EAGLES data to determine whether the data were insensitive to neuropsychiatric effects secondary to a lack of statistical power. In the psychiatric cohort, the varenicline and bupropion groups exhibited suggestive but not conclusive data that there was no increase in NPSAEs compared to placebo (Bayes factor 0.52 and 0.71, respectively).4
Another EAGLES analysis by Ayers et al5 evaluated participants with anxiety disorders (N = 712), including PTSD (N = 192), generalized anxiety disorder (GAD) (N = 243), and panic disorder (N = 277).Of those with PTSD who received varenicline, there were no statistically significant differences in CAR from Week 9 to Week 12 vs placebo.5 However, there was a significant difference in individuals with GAD (OR 4.53; 95% CI, 1.20 to 17.10), and panic disorder (OR 8.49; 95% CI, 1.57 to 45.78).5 In contrast to CAR from Week 9 to Week 12, 7-day point prevalence abstinence at Week 12 for participants with PTSD was significant (OR 4.04; 95% CI, 1.39 to 11.74) when comparing varenicline to placebo. Within the anxiety disorder cohort, there were no significant differences in moderate to severe NPSAE rates based on treatment group. Calculated risk differences comparing varenicline to placebo were: PTSD group -7.73 (95% CI, -21.95 to 6.49), GAD group 2.80 (95% CI, -6.63 to 12.23), and panic disorder group -0.18 (95% CI, -9.57 to 9.21).5
Other studies
Evins et al6 conducted a randomized controlled trial to evaluate the safety of varenicline maintenance therapy in patients with schizophrenia or bipolar disorder. To be deemed clinically stable, participants in this study needed to be taking a stable dose of an antipsychotic or mood-stabilizing agent(s) for ≥30 days, compared to the 3-month requirement of the EAGLES trial.3,6 Participants received 12 weeks of open-label varenicline; those who achieved abstinence (N = 87) entered the relapse-prevention phase and were randomized to varenicline 1 mg twice a day or placebo for 40 weeks. Of those who entered relapse-prevention, 5 in the placebo group and 2 in the varenicline group were psychiatrically hospitalized (risk ratio 0.45; 95% CI, 0.04 to 2.9).6 These researchers concluded that varenicline maintenance therapy prolonged abstinence rates with no significant increase in neuropsychiatric events.6
Although treatment options for smoking cessation have advanced, individuals with SMI are still disproportionately affected by the negative outcomes of cigarette smoking. Current literature suggests that varenicline does not confer an appreciable risk of neuropsychiatric events in otherwise stable patients and is the preferred first-line treatment. However, there is a gap in understanding the impact of this medication on individuals with unstable psychiatric illness. Health care professionals should be encouraged to use varenicline with careful monitoring for appropriate patients with psychiatric disorders as a standard of care to help them quit smoking.
CASE CONTINUED
After consulting with the psychiatric pharmacist and discussing the risks and benefits of varenicline, Mr. T is started on the appropriate titration schedule (Table 11). A pharmacist provides varenicline education, including the possibility of psychiatric adverse effects, and tells Mr. T to report any worsening psychiatric symptoms. Mr. T is scheduled for frequent follow-up visits to monitor possible adverse effects and his tobacco use. He says he understands the potential adverse effects of varenicline and agrees to frequent follow-up appointments while taking it.
Related Resources
- Leone FT, Zhang Y, Evers-Casey S, et al. Initiating pharmacologic treatment in tobacco-dependent adults. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;202(2):e5-e31. doi:10.1164/rccm.202005.1982ST
- Cieslak K, Freudenreich O. 4 Ways to help your patients with schizophrenia quit smoking. Current Psychiatry. 2018; 17(2):28,33.
Drug Brand Names
Bupropion • Wellbutrin
Varenicline • Chantix
[embed:render:related:node:157276]
1. Chantix [package insert]. New York, NY: Pfizer Inc; 2019.
2. Sharma R, Alla K, Pfeffer D, et al. An appraisal of practice guidelines for smoking cessation in people with severe mental illness. Aust N Z J Psychiatry. 2017;51(11):1106-1120. doi:10.1177/0004867417726176
3. Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet. 2016;387(10037):2507-2520. doi:10.1016/s0140-6736(16)30272-0
4. Beard E, Jackson SE, Anthenelli RM, et al. Estimation of risk of neuropsychiatric adverse events from varenicline, bupropion and nicotine patch versus placebo: secondary analysis of results from the EAGLES trial using Bayes factors. Addiction. 2021;116(10):2816-2824. doi:10.1111/add.15440
5. Ayers CR, Heffner JL, Russ C, et al. Efficacy and safety of pharmacotherapies for smoking cessation in anxiety disorders: subgroup analysis of the randomized, active- and placebo-controlled EAGLES trial. Depress Anxiety. 2020;37(3)247-260. doi:10.1002/da.22982
6. Evins AE, Cather C, Pratt SA, et al. Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder: a randomized clinical trial. JAMA. 2014;311(2):145-154. doi:10.1001/jama.2013.285113
1. Chantix [package insert]. New York, NY: Pfizer Inc; 2019.
2. Sharma R, Alla K, Pfeffer D, et al. An appraisal of practice guidelines for smoking cessation in people with severe mental illness. Aust N Z J Psychiatry. 2017;51(11):1106-1120. doi:10.1177/0004867417726176
3. Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet. 2016;387(10037):2507-2520. doi:10.1016/s0140-6736(16)30272-0
4. Beard E, Jackson SE, Anthenelli RM, et al. Estimation of risk of neuropsychiatric adverse events from varenicline, bupropion and nicotine patch versus placebo: secondary analysis of results from the EAGLES trial using Bayes factors. Addiction. 2021;116(10):2816-2824. doi:10.1111/add.15440
5. Ayers CR, Heffner JL, Russ C, et al. Efficacy and safety of pharmacotherapies for smoking cessation in anxiety disorders: subgroup analysis of the randomized, active- and placebo-controlled EAGLES trial. Depress Anxiety. 2020;37(3)247-260. doi:10.1002/da.22982
6. Evins AE, Cather C, Pratt SA, et al. Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder: a randomized clinical trial. JAMA. 2014;311(2):145-154. doi:10.1001/jama.2013.285113
<!--$RCSfile: InCopy_agile.xsl,v $ $Revision: 1.35 $-->
<!--$RCSfile: drupal.xsl,v $ $Revision: 1.7 $-->
<root generator="drupal.xsl" gversion="1.7"> <header> <fileName>Savvy 0722</fileName> <TBEID>0C0299FA.SIG</TBEID> <TBUniqueIdentifier>NJ_0C0299FA</TBUniqueIdentifier> <newsOrJournal>Journal</newsOrJournal> <publisherName>Frontline Medical Communications Inc.</publisherName> <storyname>Smoking cessation: Varenicline a</storyname> <articleType>1</articleType> <TBLocation>Copyfitting-CP</TBLocation> <QCDate/> <firstPublished>20220630T085556</firstPublished> <LastPublished>20220630T085556</LastPublished> <pubStatus qcode="stat:"/> <embargoDate/> <killDate/> <CMSDate>20220630T085556</CMSDate> <articleSource/> <facebookInfo/> <meetingNumber/> <byline>Danielle Murray, PharmD, Emily Montgomery, PharmD</byline> <bylineText/> <bylineFull>Danielle Murray, PharmD, Emily Montgomery, PharmD</bylineFull> <bylineTitleText/> <USOrGlobal/> <wireDocType/> <newsDocType/> <journalDocType/> <linkLabel/> <pageRange>41-45</pageRange> <citation/> <quizID/> <indexIssueDate/> <itemClass qcode="ninat:text"/> <provider qcode="provider:"> <name/> <rightsInfo> <copyrightHolder> <name/> </copyrightHolder> <copyrightNotice/> </rightsInfo> </provider> <abstract/> <metaDescription>Mr. T, age 34, is a veteran who recently returned to civilian life. He presents to his local Veteran Affairs facility for transition of care. During active duty</metaDescription> <articlePDF>287347</articlePDF> <teaserImage/> <title>Smoking cessation: Varenicline and the risk of neuropsychiatric adverse events</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear>2022</pubPubdateYear> <pubPubdateMonth>July</pubPubdateMonth> <pubPubdateDay/> <pubVolume>21</pubVolume> <pubNumber>7</pubNumber> <wireChannels/> <primaryCMSID/> <CMSIDs> <CMSID>1985</CMSID> </CMSIDs> <keywords> <keyword>addiction medicine</keyword> <keyword> smoking cessation</keyword> <keyword> varenicline</keyword> <keyword> neuropsychiatric</keyword> </keywords> <seeAlsos/> <publications_g> <publicationData> <publicationCode>CP</publicationCode> <pubIssueName>July 2022</pubIssueName> <pubArticleType>Audio | 1985</pubArticleType> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle>Current Psychiatry</journalTitle> <journalFullTitle>Current Psychiatry</journalFullTitle> <copyrightStatement>Copyright 2015 Frontline Medical Communications Inc., Parsippany, NJ, USA. All rights reserved.</copyrightStatement> </publicationData> </publications_g> <publications> <term canonical="true">11</term> </publications> <sections> <term canonical="true">36771</term> </sections> <topics> <term canonical="true">174</term> </topics> <links> <link> <itemClass qcode="ninat:composite"/> <altRep contenttype="application/pdf">images/1800215a.PDF</altRep> <description role="drol:caption"/> <description role="drol:credit"/> </link> </links> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Smoking cessation: Varenicline and the risk of neuropsychiatric adverse events</title> <deck/> </itemMeta> <itemContent> <p> <strong>Danielle Murray, PharmD, Emily Montgomery, PharmD, Ellie Nazzoli, PharmD, and Melissa C. Palmer, PharmD, BCPS, BCPP</strong> </p> <p>Mr. T, age 34, is a veteran who recently returned to civilian life. He presents to his local Veteran Affairs facility for transition of care. During active duty, he had been diagnosed with obstructive sleep apnea, tobacco use disorder, posttraumatic stress disorder (PTSD) secondary to combat exposure, and insomnia. Mr. T says he wants to quit smoking; currently, he smokes 2 packs of cigarettes per day. The primary care clinician notes that Mr. T has uncontrolled PTSD symptoms and poor sleep, and refers him for an outpatient mental health appointment.</p> <p>At the mental health appointment 3 weeks later, Mr. T asks about medications to quit smoking, specifically varenicline (<b><i>Table 1</i></b>,<sup>1</sup> <b><i>page 42</i></b>). Mr. T’s PTSD Checklist for DSM-5 score is 52, which indicates severe PTSD symptomatology. He says he sees shadowy figures in his periphery every day, and worries they are spying on him. His wife reports Mr. T has had these symptoms for most of their 10-year marriage but has never been treated for them. After a discussion with the outpatient team, Mr. T says he is willing to engage in exposure therapy for PTSD, but he does not want to take any medications other than varenicline for smoking cessation.</p> <p>Cigarette smoke is a known carcinogen and risk factor for the development of cardiovascular and respiratory diseases and other comorbidities. People with severe mental illness (SMI) are 3 to 5 times more likely to smoke, and they often face multiple barriers to cessation, including low socioeconomic status and lack of support.<sup>2</sup> Even when patients with SMI are provided appropriate behavioral and pharmacologic interventions, they often require more frequent monitoring and counseling, receive a longer duration of drug therapy, and experience lower smoking cessation rates than the general population.<sup>2</sup></p> <p>Current guidelines recommend nicotine replacement therapy (NRT), bupropion, varenicline, and behavioral support as first-line therapies for smoking cessation in patients with and without SMI.<sup>2</sup> Evidence suggests that varenicline is more effective than other pharmacologic options; however, in 2009 a black-box warning was added to both varenicline and bupropion to highlight an increased risk of neuropsychiatric events in individuals with SMI.<sup>2 </sup>This led some clinicians to hesitate to prescribe varenicline or bupropion to patients with psychiatric illness. However, in 2016, the EAGLES trial evaluated the safety of varenicline, bupropion, and NRT in smokers with and without psychiatric disorders, and based on the findings, the black-box warning was removed.<sup>2 <br/><br/></sup>This article reviews the evidence regarding the use of varenicline and the risk of neuropsychiatric adverse events in patients with psychiatric illness. <b><i>Table 2</i></b><sup>3-6</sup> provides a summary of each varenicline trial we discuss.</p> <h3>The EAGLES trial</h3> <p>EAGLES was a multicenter, multinational, randomized, double-blind, triple-dummy, placebo- and active-controlled trial of 8,144 individuals who received treatment for smoking cessation.<sup>3</sup> The primary endpoint was the incidence of a composite measure of moderate to severe neuropsychiatric events (NPSAEs).<sup>3</sup> Participants were split into psychiatric (N = 4,116) and nonpsychiatric (N = 4,028) cohorts and randomized into 4 treatment arms: varenicline 1 mg twice a day, bupropion 150 mg twice a day, nicotine patch 21 mg/d with taper, or placebo, all for 12 weeks with an additional 12 weeks of follow-up. All participants smoked ≥10 cigarettes per day. Individuals in the psychiatric cohort had to be psychiatrically stable (no exacerbations for 6 months and stable treatment for 3 months). Exclusionary diagnoses included psychotic disorders (except schizophrenia and schizoaffective disorder), dementia, substance use (except nicotine), and personality disorders (except borderline personality disorder).<sup>2</sup></p> <p>The rates of moderate to severe NPSAEs in the varenicline groups were 1.25% (95% CI, 0.60 to 1.90) in the nonpsychiatric cohort and 6.42% (95% CI, 4.91 to 7.93) in the psychiatric cohort.<sup>3</sup> However, when comparing the varenicline group of the psychiatric cohort to the other arms of the psychiatric cohort, there were no differences (bupropion 6.62% [95% CI, 5.09 to 8.15], nicotine patch 5.20% [95% CI, 3.84 to 6.56], placebo 4.83% [95% CI, 3.51 to 6.16], respectively). The primary efficacy endpoint was continuous abstinence rates (CAR) for Week 9 through Week 12. In the psychiatric cohort, varenicline was superior compared to placebo (odds ratio [OR] 3.24; 95% CI, 2.56 to 4.11), bupropion (OR 1.74; 95% CI, 1.41 to 2.14), and nicotine patch (OR 1.62; 95% CI, 1.32 to 1.99).<sup>3</sup></p> <h3>Further analysis of EAGLES</h3> <p>Beard et al<sup>4</sup> used Bayes factor testing for additional analysis of EAGLES data to determine whether the data were insensitive to neuropsychiatric effects secondary to a lack of statistical power. In the psychiatric cohort, the varenicline and bupropion groups exhibited suggestive but not conclusive data that there was no increase in NPSAEs compared to placebo (Bayes factor 0.52 and 0.71, respectively).<sup>4</sup></p> <p> Another EAGLES analysis by Ayers et al<sup>5</sup> evaluated participants with anxiety disorders (N = 712), including PTSD (N = 192), generalized anxiety disorder (GAD) (N = 243), and panic disorder (N = 277).<sup> </sup>Of those with PTSD who received varenicline, there were no statistically significant differences in CAR from Week 9 to Week 12 vs placebo.<sup>5</sup> However, there was a significant difference in individuals with GAD (OR 4.53; 95% CI, 1.20 to 17.10), and panic disorder (OR 8.49; 95% CI, 1.57 to 45.78).<sup>5</sup> In contrast to CAR from Week 9 to Week 12, 7-day point prevalence abstinence at Week 12 for participants with PTSD was significant (OR 4.04; 95% CI, 1.39 to 11.74) when comparing varenicline to placebo. Within the anxiety disorder cohort, there were no significant differences in moderate to severe NPSAE rates based on treatment group. Calculated risk differences comparing varenicline to placebo were: PTSD group -7.73 (95% CI, -21.95 to 6.49), GAD group 2.80 (95% CI, -6.63 to 12.23), and panic disorder group -0.18 (95% CI, -9.57 to 9.21).<sup>5</sup></p> <h3>Other studies</h3> <p>Evins et al<sup>6</sup> conducted a randomized controlled trial to evaluate the safety of varenicline maintenance therapy in patients with schizophrenia or bipolar disorder. To be deemed clinically stable, participants in this study needed to be taking a stable dose of an antipsychotic or mood-stabilizing agent(s) for ≥30 days, compared to the 3-month requirement of the EAGLES trial.<sup>3,6 </sup>Participants received 12 weeks of open-label varenicline; those who achieved abstinence (N = 87) entered the relapse-prevention phase and were randomized to varenicline 1 mg twice a day or placebo for 40 weeks. Of those who entered relapse-prevention, 5 in the placebo group and 2 in the varenicline group were psychiatrically hospitalized (risk ratio 0.45; 95% CI, 0.04 to 2.9).<sup>6</sup> These researchers concluded that varenicline maintenance therapy prolonged abstinence rates with no significant increase in neuropsychiatric events.<sup>6</sup></p> <p>Although treatment options for smoking cessation have advanced, individuals with SMI are still disproportionately affected by the negative outcomes of cigarette smoking. Current literature suggests that varenicline does not confer an appreciable risk of neuropsychiatric events in otherwise stable patients and is the preferred first-line treatment. However, there is a gap in understanding the impact of this medication on individuals with unstable psychiatric illness. Health care professionals should be encouraged to use varenicline with careful monitoring for appropriate patients with psychiatric disorders as a standard of care to help them quit smoking.</p> <h3> <span class="dingbat"> </span> <span class="box">CASE CONTINUED</span> <span class="dingbat"> </span> </h3> <p>After consulting with the psychiatric pharmacist and discussing the risks and benefits of varenicline, Mr. T is started on the appropriate titration schedule (<b><i>Table 1,</i></b><sup>1</sup><b><i> page 42</i></b>). A pharmacist provides varenicline education, including the possibility of psychiatric adverse effects, and tells Mr. T to report any worsening psychiatric symptoms. Mr. T is scheduled for frequent follow-up visits to monitor possible adverse effects and his tobacco use. He says he understands the potential adverse effects of varenicline and agrees to frequent follow-up appointments while taking it.</p> <p> <strong>References</strong> </p> <p class="reference"> 1. Chantix [package insert]. New York, NY: Pfizer Inc; 2019.<br/><br/> 2. Sharma R, Alla K, Pfeffer D, et al. An appraisal of practice guidelines for smoking cessation in people with severe mental illness. Aust N Z J Psychiatry. 2017;51(11):1106-1120. doi:10.1177/0004867417726176<br/><br/> 3. Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet. 2016;387(10037):2507-2520. doi:10.1016/s0140-6736(16)30272-0<br/><br/> 4. Beard E, Jackson SE, Anthenelli RM, et al. Estimation of risk of neuropsychiatric adverse events from varenicline, bupropion and nicotine patch versus placebo: secondary analysis of results from the EAGLES trial using Bayes factors. Addiction. 2021;116(10):2816-2824. doi:10.1111/add.15440<br/><br/> 5. Ayers CR, Heffner JL, Russ C, et al. Efficacy and safety of pharmacotherapies for smoking cessation in anxiety disorders: subgroup analysis of the randomized, active- and placebo-controlled EAGLES trial. Depress Anxiety. 2020;37(3)247-260. doi:10.1002/da.22982<br/><br/> 6. Evins AE, Cather C, Pratt SA, et al. Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder: a randomized clinical trial. JAMA. 2014;311(2):145-154. doi:10.1001/jama.2013.285113</p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>bio</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> <p>Dr. Murray is a PGY-1 Pharmacy Resident, Wesley Medical Center, Wichita, Kansas. Dr. Montgomery is a PGY-1 Pharmacy Resident, Nebraska Medical Center, Omaha, Nebraska. Dr. Nazzoli is a PGY-1 Pharmacy Resident, Missouri Baptist Medical Center, St. Louis, Missouri. Dr. Palmer is Clinical Pharmacist Practitioner, Mental Health, Alaska VA Healthcare System, Anchorage, Alaska.</p> </itemContent> </newsItem> </itemSet></root>
