Varenicline: mode of action, efficacy, safety and accumulated experience salient for clinical populations

Figures & data

Figure 1. Concentration-dependent functional effects of a partial nAChR agonist. Short exposures to high concentrations (μM) of a partial agonist cause activation of nAChRs (dotted line). A partial agonist like varenicline causes only partial activation (here 20%) versus the full agonist ACh that causes maximal nAChR activation (100%). Prolonged exposures to low partial agonist concentrations (nM) causes receptor desensitization, shown by the decrease in the ACh response in the presence of increasing concentrations of the partial agonist (solid line). In the sustained presence of low agonist concentrations present in human brain (nM range, gray bar), only a small fraction of the nAChRs that are not desensitized can be activated, resulting in extensive nAChR desensitization and low-level activation at steady state. Abbreviations. Ach, acetylcholine; nAChRs, nicotinic acetylcholine receptors.

Figure 2. Comparison of agonist and antagonist activities of NRT, cytisine and varenicline. (A) The degree of activation and desensitization (agonist activity) of α4β2 and α6β2* nAChRs by clinical doses of each agonist relative to the effects of nicotine from smoking (= 100%). (B) The decrease in nicotine receptor occupancy of α4β2 and α6β2* nAChRs (antagonist activity) by clinical doses of each agonist relative to the decrease in nicotine receptor occupancy when smoking without nAChR agonist treatment (= 0%). Bars represent the magnitude of activities expressed as a percentage of the corresponding effects of nicotine from smoking. Smoking activation and desensitization = 100%, decrease in nicotine receptor occupancy = 0%, indicated by dotted lines. Abbreviations. nAChRs, nicotinic acetylcholine receptors; NRT, nicotine replacement therapy; RO, receptor occupancy.

Figure 3. Comparison of continuous abstinence rates in randomized trials that were included in the clinical program: 12 weeks’ varenicline treatment for smoking cessation at weeks 9‒12. Pfizer-sponsored studies by (A) General populations, (B) Comorbid populations or (C) Alternative treatment paradigms. *Varenicline 1 mg BID vs. placebo or active treatment comparator: difference significant at week 12; N, intention-to-treat population (varenicline plus placebo or active treatment comparator). ORs (95% CI) are varenicline vs. placebo or active treatment comparator. Abbreviations. BID, twice daily; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular disease; NPS, neuropsychiatric; NRT, nicotine replacement therapy; OR, odds ratio.

Table 1. Extended use and other alternative treatment paradigms.

Treatment paradigm	Study	Objective	Participants and intervention	Study outcomes	Clinical implications
Maintenance of abstinence	Tonstad et al. 2006^47; Hajek et al. 2009^48	To determine whether smokers who quit after 12 weeks of treatment with varenicline maintain greater abstinence if the treatment is extended to 24 weeks	12 weeks of open-label varenicline treatment, 1.0 mg BID, plus those who succeed quitting during week 12 randomized to an additional 12 weeks of varenicline (N = 603) or placebo (N = 607), with non-treatment follow-up through week 52	CARs varenicline vs. placebo: Weeks 13 − 24: 70.5% vs. 49.6%* Weeks 13 − 52: 43.6% vs. 36.9%*	Smokers who successfully quit after standard 12 weeks of treatment can be offered an additional 12 weeks of varenicline to help maintain their abstinence; smokers who do not quit by their TQD, but attain abstinence later on in the 12-week period, are most likely to benefit from the extended treatment
Varenicline pre-loading	Hajek et al. 2011^50	To determine whether increasing the time from start of treatment until quit attempt facilitates quitting	Varenicline 1.0 mg BID for 4 weeks prior to TQD (N = 53) or placebo for 3 weeks then varenicline for 1 week prior to TQD (N = 48). All smokers then received varenicline for a further 12 weeks	Varenicline preload vs. placebo preload, CARs: Week 4: 49.1% vs. 33.3% Weeks 12: 35.8% vs. 14.6%*	Preliminary evidence of some benefit to initiating the treatment period prior to the TQD particularly if the smoker reduces their smoking during that period. Effects may be more pronounced in women
	Hawk et al. 2012^51	To determine whether a longer pre-treatment with varenicline would reduce smoking prior to TQD and increase abstinence	4 weeks of pre-TQD varenicline (extended run-in) (N = 32), or 3 weeks of placebo and 1 week of pre-TQD varenicline (standard run-in) (N = 28). All followed by 11 weeks post-TQD varenicline	Pre-quit run-in: reduction in smoking rates was greater in the extended run-in group vs. the standard run-in group (42.0% vs. 24.0%*). CARs during the final 4 weeks of treatment were higher among women in the extended group vs. women in the standard run-in group (67.0% vs. 35.0%).
	Ashare et al. 2012^105	To examine the effect of extended pre-treatment with varenicline on smoking behavior	Crossover design: participants received standard varenicline 1.0 mg BID for 21 days, followed by a 14-day washout period then 21 days of placebo	Reduction in self-reported number of cigarettes smoked per day (days 10 − 21), urge to smoke and nicotine metabolites during varenicline phase
Flexible quit date	Rennard et al. 2012^52	To determine whether treatment with varenicline improves abstinence rates vs. placebo when smokers are permitted to choose their own quit date within 1 month after the first week of treatment titration (between day 8 and 35)^a	Varenicline 1.0 mg BID (N = 493) or placebo (N = 166) for 12 weeks with follow-up through week 24	CARs varenicline vs. placebo: Weeks 9 − 12: 53.1% vs. 19.3%* Weeks 9 − 24: 34.7% vs. 12.7%*	Treatment can be personalized by advising smokers that they can set their own quit date from 1 to 5 weeks after starting treatment, when they feel they are ready
Reduce to quit	Ebbert et al. 2015^53	To determine the efficacy of varenicline in smokers not willing/able to quit abruptly but willing to reduce smoking and make a quit attempt within 3 months^a	Varenicline 1.0 mg BID (N = 760) or placebo (N = 750) for 24 weeks (reduction target of ≥50% in number of cigarettes smoked by 4 weeks, ≥75% by 8 weeks and a quit attempt by 12 weeks) with follow-up through week 52	CARs varenicline vs. placebo: Weeks 15 − 24: 32.1% vs. 6.9%* Weeks 21 − 24: 37.8% vs. 12.5%* Weeks 21 − 52: 27.0% vs. 9.9%*	Smokers who cannot or do not want to quit abruptly can be given the option to start treatment and reduce their smoking before quitting completely after 12 weeks and should continue treatment for another 12 weeks (a total of 24 weeks)
Low-dose varenicline	Oncken et al. 2006^55	To evaluate the efficacy and safety of 0.5 mg and 1.0 mg BID varenicline; with and without titration	N = 647 smokers: 0.5 mg BID, N = 259^b; 1.0 mg BID, N = 259^b; Placebo, N = 129; 12 weeks treatment with follow-up at weeks 24 and 52	CO-validated CARs, 0.5 mg BID varenicline vs. placebo: Weeks 9 − 12: 44.0% vs. 11.6%* Weeks 9 − 52: 18.5% vs. 3.9%*	Low doses of varenicline show better abstinence rates than placebo particularly at end of treatment, but generally at lower rates than 1.0 mg BID. Low doses may be beneficial to subjects who do not tolerate 1 mg BID
	Nakamura et al. 2007^29	To compare the efficacy of 3 doses of varenicline with placebo after 12 weeks of treatment	N = 619 smokers: Varenicline 0.25 mg BID, N = 153; Varenicline 0.5 mg BID, N = 156; Varenicline 1.0 mg BID, N = 156; Placebo, N = 154	CO-validated CARs, varenicline vs. placebo: Weeks 9 − 12: 0.25 mg BID, 54.7% vs. 39.5%*; 0.5 mg BID, 55.5% vs. 39.5%*; 1.0 mg BID, 65.4% vs. 39.5%* Weeks 9 − 52: 0.25 mg BID, 27.3% vs. 23.3%; 0.5 mg BID, 28.9% vs. 23.3%; 1.0 mg BID, 34.6% vs. 23.3%*
	Nides et al. 2006^56	To assess the efficacy, tolerability and safety of 3 doses of varenicline administered for 6 weeks vs. placebo and bupropion	N = 638 smokers: Varenicline 0.3 mg QD, N = 128; Varenicline 1.0 mg QD, N = 128; Varenicline 1.0 mg BID, N = 127; Bupropion 150 mg BID, N = 128; Placebo, N = 127	CO-validated CARs Weeks 4 − 7: Varenicline vs. placebo: 0.3 mg QD, 25.4% vs. 13.8%*; 1.0 mg QD, 31.0 vs. 13.8%*; 1.0 mg BID, 40.8 vs. 13.8%*; Bupropion vs. placebo: 28.6% vs. 13.8%* Weeks 4 − 52: Varenicline vs. placebo: 0.3 mg QD, 7.9% vs. 4.9%; 1.0 mg QD, 5.6% vs. 4.9%; 1.0 mg BID, 14.4% vs. 4.9%*; Bupropion vs. placebo: 6.3% vs. 4.9%
High-dose varenicline	Jimenez-Ruiz et al. 2013^60	Open-label cohort study investigating increased varenicline dose in smokers struggling to quit after 8 weeks of standard treatment^a	73 patients (varenicline, 3 mg/day): 52 patients had continued to smoke at 8 weeks; 21 had stopped smoking, but reported severe withdrawal discomfort	CO-validated CARs for Weeks 9 − 24: 40.0% and 48.0% in the smoking and quit subgroups, respectively	The benefit of increasing the varenicline dose above the recommended 1 mg BID in smokers having difficulty quitting is unclear, although no serious safety concerns were apparent with higher doses
	Hajek et al. 2015^59	To determine whether increasing varenicline dose in patients showing no response to the standard dosage improves efficacy	N = 503 smokers. All began taking varenicline 1 mg BID, gradually increasing to 5 mg/day (N = 200 patients who reported no strong nausea, no clear reduction in smoking enjoyment and <50% reduction in their baseline smoking on day 12)	CARs for higher-dose varenicline vs. placebo at 12 weeks post-TQD: 26.0% vs. 23.0%
	Karam-Hage et al. 2018^61	To investigate the effect of varenicline 3 mg/day on smoking abstinence among smokers who had reduced their smoking by ≥50% in response to 2 mg/day for ≥6 weeks, but had not quit smoking^c	2833 patients treated with varenicline 2 mg/day. In a subset of 73 smokers, dosage was increased to 3 mg/day after 6 weeks. Propensity score analysis involving multiple baseline covariates used to create a comparative sample of 356 smokers who remained on standard dose	7-day point prevalence abstinence rate, 3 mg/day vs. 2 mg/day at 3 months: 26.0% vs. 11.5%.* Differences in abstinence rates remained at 6- and 9-month follow-ups

Abbreviations. BID, twice daily; CAR, continuous abstinence rate; CI, confidence interval; CO, carbon monoxide; QD, once daily; RD, risk difference; RR, risk ratio; TQD, target quit date.

* Statistically significant treatment difference (p < .05).

^a Study did not include a comparison with standard varenicline treatment.

^b Titrated and non-titrated pooled.

^c <10% of the sample accepted the varenicline 3-mg dosing. ∼30% of the 3-mg cohort were excluded because they did not attend further sessions, while such early treatment failures were retained in the 2-mg cohort.

Table 2. Neuropsychiatric adverse events reported in the EAGLES randomized controlled safety trial: incidence of the primary composite endpoint and selected components.

Treatment, cohort	Study	Number of participants (AST)	Primary composite neuropsychiatric endpoint^a N (%)	Anxiety N (%)	Depression N (%)	Suicidal behavior N (%)	Suicidal ideation N (%)
Placebo
Non-psychiatric	Anthenelli et al. 2016^33	999	24 (2.4)	3 (0.3)	0	0	3 (0.3)
Psychiatric^b		1015	50 (4.9)	2 (0.2)	6 (0.6)	1 (0.1)	2 (0.2)
Psychotic disorders	Evins et al. 2019^110	96	6 (6.3)	0	1 (1.0)	0	0
Anxiety disorders		194	11 (5.7)	0	1 (0.5)	0	0
Mood disorders		722	33 (4.6)	2 (0.3)	4 (0.6)	1 (0.1)	2 (0.3)
NRT
Non-psychiatric	Anthenelli et al. 2016^33	1006	25 (2.5)	0	0	1 (0.1)	2 (0.2)
Psychiatric^b		1016	53 (5.2)	6 (0.6)	7 (0.7)	0	3 (0.3)
Psychotic disorders	Evins et al. 2019^110	99	5 (5.1)	1 (1.0)	0	0	1 (0.1)
Anxiety disorders		195	9 (4.6)	2 (1.0)	1 (0.5)	0	1 (0.5)
Mood disorders		713	40 (5.6)	3 (0.4)	6 (0.8)	0	2 (0.3)
Bupropion
Non-psychiatric	Anthenelli et al. 2016^33	989	22 (2.2)	1 (0.1)	0	1 (0.1)	1 (0.1)
Psychiatric^b		1017	68 (6.7)	4 (0.4)	4 (0.4)	1 (0.1)	2 (0.2)
Psychotic disorders	Evins et al. 2019^110	96	6 (6.3)	0	0	0	1 (0.1)
Anxiety disorders		200	16 (8.0)	3 (1.5)	1 (0.5)	0	1 (0.5)
Mood disorders		716	46 (6.4)	1 (0.1)	3 (0.4)	1 (0.1)	0
Varenicline
Non-psychiatric	Anthenelli et al. 2016^33	990	13 (1.3)	0	1 (0.1)	0	0
Psychiatric^b		1026	67 (6.5)	5 (0.5)	6 (0.6)	1 (0.1)	5 (0.5)
Psychotic disorders	Evins et al. 2019^110	95	6 (6.3)	0	1 (1.1)	0	0
Anxiety disorders		193	11 (5.7)	1 (0.5)	1 (0.5)	0	2 (1.0)
Mood disorders		731	50 (6.8)	4 (0.5)	4 (0.5)	1 (0.1)	3 (0.4)

Abbreviations. AST, as-treated; NRT, nicotine replacement therapy.

^a Primary composite endpoint comprised 16 neuropsychiatric symptom categories that included 261 Medical Dictionary for Regulatory Activities version 18.1-derived preferred terms [33].

^b Includes subjects with borderline personality disorder.

Table 3. Meta-analyses of randomized controlled trials examining neuropsychiatric adverse events related to varenicline.

Study	Data source	Number of participants	NPS AEs	Varenicline, % NPS AEs	Placebo, % NPS AEs	Varenicline vs. placebo comparison
Wu et al. (2016)^89	8 RCTs (patients with severe mental illness)	398	Suicidal ideation Depressed mood Anxiety	Not reported	Not reported	Relative risk (95% CI) 1.06 (0.40 − 2.82) 1.45 (0.45 − 4.64) 0.77 (0.28 − 2.17)
Roberts et al. (2016)^90	14 RCTs (patients with mental illness)	423	Discontinuations due to AEs	No differences in dropouts due to AEs, including changes in mental state and suicidal ideation		No significant differences in tolerability
Kishi et al. (2015)^91	7 RCTs^a (patients with schizophrenia)	439	Abnormal dreams/nightmare Anxiety Depression Insomnia Irritability Suicidal ideation	Not reported	Not reported	Risk ratio (95% CI) 0.47 (0.22 − 0.99) 0.86 (0.47 − 1.59) 0.75 (0.22 − 2.63) 1.15 (0.72 − 1.85) 0.68 (0.37 − 1.26) 0.96 (0.35 − 2.67)
Thomas et al. (2015)^92	39 RCTs (patients with and without psychiatric disorders)	10,761	Risk of suicide or attempted suicide Suicidal ideation Depression Irritability Aggression Sleep disorders Insomnia Abnormal dreams Fatigue Anxiety	Not reported	Not reported	Odds ratio (95% CI) 1.67 (0.33 − 8.57) 0.58 (0.28 − 1.20) 0.96 (0.75 − 1.22) 0.98 (0.81 − 1.17) 0.91 (0.52 − 1.59) 1.63 (1.29−2.07) 1.56 (1.36 − 1.78) 2.38 (2.05 − 2.77) 1.28 (1.06 − 1.55) 0.75 (0.61 − 0.93)
Gibbons et al. (2013)^93	17 RCTs (patients with and without psychiatric disorders)	8027	Suicidal thoughts and behavior Depression Aggression/agitation	0.05^b 2.3^b 1.0^b	0.15^b 2.0^b 0.7^b	Odds ratio (95% CI) 0.57 (0.23 − 1.38) 1.01 (0.68 − 1.52) 1.27 (0.85 − 1.92)
Huang et al. (2012)^94	10 RCTs (patients without psychiatric disorders)	6375	Any NPS AE	Not reported	Not reported	Risk ratio (95% CI) 1.45 (0.90 − 2.32)
Tonstad et al. (2010)^95	10 RCTs (patients without psychiatric disorders)	5096	Depression Suicidality Anxiety	2.8 0.0 4.5	1.9 0.1 5.0	Relative risk (95% CI) 1.42 (0.96 − 2.08) N/A 0.86 (0.67 − 1.12)

Abbreviations. AEs, adverse events; CI, confidence interval; N/A, not applicable; NPS, neuropsychiatric; RCT, randomized controlled trial.

^a Two trials conducted in patients with schizophrenia with no intention to quit smoking may have been inappropriately included.

^b Participants without a current psychiatric disorder.

Table

Recommendations for practitioners

For patients willing to use varenicline for an immediate quit attempt, a TQD should be set and varenicline prescribed for standard administration in accordance with the product label (1 week of dose titration prior to the TQD followed by 11 weeks of 1 mg BID treatment).

Varenicline should be considered for generally healthy smokers as well as smokers with comorbid conditions including CVD, COPD and stable psychiatric disorders.

Consider individualized prescription of pharmacotherapy depending on the smoking history and preference of the patient. Smokers may achieve better outcomes with any of the following treatment modifications recommended in varenicline prescribing information: Smokers who achieve abstinence at the end of varenicline dosing at 3 months, particularly those who did not achieve continuous abstinence from their TQD, may be offered a treatment extension of an additional 12 weeks to help maintain abstinence. Rather than being required to quit at the end of the first week, smokers can follow the standard dosing regimen, but can quit smoking when they feel ready later in the treatment period. Smokers who are unwilling or unable to quit abruptly should be encouraged to gradually reduce the number of cigarettes smoked per day to zero during the first 12 weeks of the standard varenicline dosing regimen and then to continue with varenicline 1 mg BID for an additional 12 weeks. For smokers who have tried varenicline previously and either failed to quit or succeeded in quitting, but subsequently relapsed, another trial of varenicline should be considered.

Additional treatment modifications reported in the literature that have been shown to have some success in improving efficacy include: Pre-loading varenicline for at least 4 weeks prior to the TQD in highly dependent smokers. Clinicians should emphasize that the recommendation is based on preliminary data and strong theoretical rationale, but that definitive trials have not yet been conducted. Combination therapy with NRT or bupropion, although clinicians should note that mixed results have been reported when varenicline has been combined with these other pharmacotherapies.

Clinicians should provide follow-up and monitor treatment adherence.

Clinicians should advise patients on how to manage potential AEs. Mild-to-moderate nausea is the only AE consistently associated with varenicline use, and certain sleep disorders such as insomnia and abnormal dreams have been noted marginally more frequently versus placebo. Neuropsychiatric events have been reported, generally at low frequencies, in smokers attempting to quit, regardless of therapy. Patients should be advised that stopping smoking itself may cause some of the symptoms, but to always notify their healthcare provider should they experience neuropsychiatric events.

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