Table 2.

Non-nicotine replacement therapies and their combinations

Formulation	Population	Comments	Refs.
Varenicline	Asian	Helps patients achieve smoking cessation by reducing cravings/withdrawal symptoms and smoking satisfaction. The most commonly reported adverse effects for varenicline, bupropion sustained release, and placebo in the pooled analysis were nausea (28.8%, 9.9%, and 9.1%, respectively), insomnia (14.2%, 21.5%, and 12.6%), and headache (14.2%, 11.1%, and 12.4%). Particular attention with patients with comorbid conditions such as those with psychiatric disorders and cardiovascular disease. There is no consistent evidence that varenicline reduces weight gain compared with placebo.	78–85
Bupropion sustained release	African-American	Smokers abstain at a significantly greater rate (P < 0.05) when using bupropion sustained release versus placebo.	86
Bupropion sustained release	American	The efficacy of bupropion has been confirmed in several large studies. Its most common side effects (occurrence >1:100) are dry mouth, headache, nausea and insomnia and its most rare side effects (occurrence > 1:10,000 and <1:1000) are seizure, severe hypersensitivity reaction. Moreover, bupropion has been reported more effective than the nicotine patch. Bupropion advantage is that it reduces post-cessation weight gain (0.8 kg), compared with nicotine replacement therapies by 0.5 kg.	87–91
Nortriptyline	American, Brazilian	In controlled clinical trials nortriptyline alone has shown to be effective with odds ratios ranging from 1.2 to 5.5, for smoking cessation in four studies, with only one study lacking a statistically significant benefit. The smoking cessation rates achieved with nortriptyline appear to be comparable to those achieved with bupropion. Common side effects reported are dry mouth, light-headedness, shakiness, and blurred vision, although urinary retention, constipation, sexual difficulties, and risk of seizures.	92–96
Clonidine (can be taken orally or through a transdermal patch)	American, Chinese, French	Placebo-controlled clinical trials indicate that clonidine is superior to placebo (2.4 and 2.0 ratios). This is comparable with the efficacy of nicotine replacement therapies and bupropion. It may be beneficial in female smokers. Significant side effects, such as dry mouth, dizziness and postural hypotension make its use less desirable. Patients with a history of depression or occlusive peripheral vascular disease should avoid using clonidine.	97–99
Endogenous Opioids (EOPs) – naltrexone	American	There is conflicting evidence for the effectiveness of naltrexone monotherapy for smoking cessation.	100
Naltrexone and Transdermal nicotine patch	84.3% of white American	Treatment with low-dose naltrexone does not significantly reduce weight gain or improve smoking cessation in highly weight-concerned smokers. Given that this population gained relatively little weight even on placebo, cognitive interventions to reduce weight concerns in combination with approved smoking cessation pharmacotherapy are preferable. Nevertheless, there may be other sub-populations of smokers at risk of substantial weight gain following smoking cessation for whom the weight suppressing effects of naltrexone might be of benefit.	101
Naltrexone and bupropion	White American, American, non-obese adults, overweight and obese adults	Smoking cessation rates are similar to bupropion, but there was a significant trend for less weight gain with the combination than with placebo and monotherapy.	102,103
Naltrexone and bupropion both sustained release formulations, plus behavioral counseling	93.3% white American with overweight or obese adults	Combination decreased nicotine use, limited nicotine withdrawal symptoms, and no significant weight gain. The most common adverse events were nausea, insomnia, and constipation.	104
Selective serotonin reuptake inhibitors (SSRIs)	British, American	Significant short-term effect (6 months). None demonstrated any long-term benefit.	105,106
– fluoxetine and paroxetine		An analysis of fluoxetine trials with negative results indicated some benefit in the subgroup of smokers who had a history of major depression.
Selective serotonin reuptake inhibitors (SSRIs) Anxiolytics: – buspirone – diazepam – meprobamate – propanolol – metoprolol – oxprenolol – ondansetron	American, British	Buspirone does not cause physical dependence. However, a placebo-controlled trial failed to support its efficacy in smoking cessation. Anxiolytics have been examined to aid smoking cessation, finding no or unclear effects on abstinence or withdrawal symptoms.	107,108
Mecamylamine	American and Canadian	Mecamylamine reduces cholinergic activity, so it was hypothesized that it may reduce urges to smoke by blocking the rewarding effect of nicotine, and be most effective when combined with nicotine replacement therapies. Mecamylamine, compared to placebo, increased the number of cigarettes smoked and plasma nicotine levels. Moreover, it increased smoking intensity and resulted in greater plasma nicotine levels in smokers with schizophrenia compared to controls.	109–111
Monoamine oxidase (MAO) inhibitors: – moclobemide – selegiline hydrochloride	American and Canadian	In one long term trial, moclobemide was found to have a significant effect on smoking cessation at 6 months, but not at 1 year, compared with placebo. Selegiline hydrochloride was safe and well-tolerated by adult cigarette smokers, but did not improve smoking abstinence rates compared to placebo. A common adverse effect reported for selegiline hydrochloride was dry mouth.	112,113