Varenicline tartrate—the first nicotine-free medication FDA-approved for smoking cessation in nearly a decade (Table 1)—has helped patients stop smoking and remain smoke-free for up to 1 year in clinical trials. Its selective action on the receptor subtype that makes tobacco enjoyable offers a novel approach to antismoking therapy.
Table 1
Varenicline: Fast facts
| Brand name: Chantix |
| Class: Partial nicotinic acetylcholine receptor agonist |
| Indication: Tobacco dependence |
| Approval date: May 10, 2006 |
| Manufacturer: Pfizer |
| Dosing forms: 0.5- and 1-mg tablets |
| Recommended dosage: 0.5 mg/d for 3 days, 0.5 mg bid for next 4 days, then 1 mg bid for 11 weeks. Patients who quit successfully should receive an additional 12-week course to reduce relapse risk. |
How it works
Unlike other FDA-approved smoking cessation treatments such as nicotine replacement therapy and sustained-release bupropion, varenicline selectively targets the α4β2 nicotinic acetylcholine receptor (nAChR),1 which helps mediate nicotine’s reinforcing effects.2-4 By targeting this receptor subtype, varenicline ultimately diminishes these effects in the mesocorticolimbic dopamine system—the brain’s “reward center.”
As a partial α4β2 nAChR agonist, varenicline offers a two-pronged approach to smoking cessation:1
- During abstinence, varenicline stimulates low-level dopamine release by binding to α4β2 receptors located on dopamine neurons. This action, which compensates for loss of exogenous nicotine after quitting, can help counteract craving and other signs and symptoms of nicotine withdrawal caused by dopamine depletion.
- If the patient resumes smoking, varenicline makes tobacco less pleasurable by competitively binding at the α4β2 receptor.1,5
Pharmacokinetics
Varenicline is rapidly absorbed across the gut mucosa and reaches maximum concentration in approximately 4 hours. After repeated dosing, the drug reaches steady-state concentrations within 4 days, and its elimination half-life is 17 to 24 hours.
Because varenicline’s simple benzazepine structure lacks bulky moieties that would promote hepatic biotransformation,5 90% of the drug is excreted through the kidneys. To date, no clinically relevant drug-drug interactions have been reported.6
Efficacy
Varenicline showed a dose-dependent effect in phase-2 clinical trials,7,8 with 1 mg bid providing optimal efficacy and tolerability. Compared with placebo, varenicline was significantly more effective in initiating:
- continuous abstinence for ≥4 weeks during active treatment, confirmed by measuring carbon monoxide (CO) in exhaled breath
- long-term abstinence, evidenced by self-report and exhaled CO ≤10 ppm at 24 and 52 weeks.7,8
Odds ratios calculated for patients who stayed smoke-free for ≥4 weeks during 7 to 12 weeks of active treatment suggest that smokers who use varenicline, 1 mg bid, are approximately 4 to 8 times more likely to achieve short-term abstinence during this active treatment period than those who received placebo.7,8
In phase-3 trials,9-11 patients were also followed for up to 1 year and received brief, standardized counseling along with medication or placebo—as recommended in the U.S. Department of Health and Human Services Clinical Practice Guideline, Treating Tobacco Use and Dependence.12
12-week treatment trials.9,10 A total of 2,052 adults in two randomized, double-blind trials received varenicline, sustained-release (SR) bupropion, or placebo for 12 weeks. Based on phase-2 trial results—which showed that varenicline was better tolerated after a 1-week dosage titration period—varenicline was given at:
- 0.5 mg/d for days 1 through 3
- 0.5 mg bid for days 4 through 7
- 1 mg bid through week 12.
Bupropion SR was given at 150 mg/d for days 1 through 3, then 150 mg bid through week 12.
Patients were then followed for up to 40 weeks after drug discontinuation. Patients had been smoking ≥10 cigarettes/day at baseline and were motivated to stop smoking.
Overall, varenicline was associated with higher short- and long-term abstinence rates compared with bupropion SR or placebo (Table 2), although the comparison with bupropion SR was not statistically significant (P=0.057) for weeks 9 through 52 in one study.9 As in the phase-2 studies, abstinence was confirmed by measuring CO in exhaled breath.
Compared with placebo, varenicline also reduced cravings and other signs and symptoms of tobacco withdrawal as measured with the Brief Questionnaire of Smoking Urges and Minnesota Nicotine Withdrawal Scale.9,10
Relapse prevention study. Tonstad et al11 investigated whether extended varenicline treatment prolongs smoking abstinence. A total of 1,210 patients who quit smoking after 12 weeks of open-label varenicline treatment continued taking varenicline at 1 mg bid or were switched to placebo during a 3-month, double-blind phase.
Compared with placebo, rates of continuous smoking abstinence were significantly higher among the varenicline group during the double-blind active treatment phase (70.5% vs. 49.6%) and for 6 months after drug discontinuation (43.6% vs. 36.9%).11 These data suggest that an extended varenicline regimen might promote long-term abstinence.6,13
Table 2
Smoking abstinence* rates among patients
during varenicline phase-3 clinical trials
| 4 weeks of continued abstinence, weeks 9 through 12 | Continued abstinence, weeks 9 through 24 | Continued abstinence, weeks 9 through 52 | |
|---|---|---|---|
| Gonzales et al 20069 | |||
| Varenicline, 1 mg bid | 44% | 29.5% | 21.9% |
| Bupropion SR, 150 mg bid | 29.5% | 20.7% | 16.1% |
| Placebo | 17.7% | 10.5% | 8.4% |
| Jorenby et al 200610 | |||
| Varenicline, 1 mg bid | 43.9% | 29.7% | 23% |
| Bupropion SR, 150 mg bid | 29.8% | 20.2% | 14.6% |
| Placebo | 17.6% | 13.2% | 10.3% |
| * Confirmed by self-report and exhaled carbon monoxide ≤10 ppm. | |||