Affiliations: Pfizer Global Research and Development, Neuroscience
Biology, Groton, CT 06340, USA | Clinical Pharmacology, Primary Care Unit, New London,
CT 06320, USA
Note: [] Correspondence: Hans Rollema, Pfizer Global Research and
Development, Neuroscience Biology, Eastern Point Road, Groton, CT 06340 USA.
Tel.: +1 860 441 6374; Fax: +1 860 715 5382; E-mail: [email protected]
Abstract: This review describes the role of α4β2 containing nicotinic acetylcholine
receptors in the mesolimbic reward pathway in the neurobiology of nicotine
addiction and discusses the rationale for targeting this receptor with partial
agonists as novel smoking cessation agents. Varenicline is a α4β2 nicotinic acetylcholine receptor partial
agonist that is a smoking cessation aid with a dual mechanism of action: relief
of craving and withdrawal symptoms, as well as attenuation of nicotine
reinforcement. The pharmacological profile of varenicline is consistent with
that of a potent and selective partial agonist at the target receptor, both in
in vitro and in vivo neurochemical and behavioral models.
Varenicline was nominated for full clinical development in 1997, and later
approved in the US and Europe as a smoking cessation aid in 2006. The
recommended dose of varenicline is 1 mg BID for 12 weeks after an initial
titration week in adult smokers motivated to stop smoking. The pharmacokinetics
of varenicline is linear and consistent regardless of smoking status, age,
gender or ethnic background. Varenicline is largely eliminated unchanged in the
urine, and consequently a dose adjustment is warranted for patients with severe
renal insufficiency. Although varenicline is currently not approved for use in
smokers under age 18, its pharmacokinetic and tolerability profile in
adolescents appeared generally similar to adults. Several large clinical trials
have consistently shown the efficacy, tolerability and safety of varenicline in
various ethnic smoking populations and in adult smokers with co-morbid chronic
pulmonary or cardiovascular disease. Additional clinical studies in special
patient populations are currently ongoing.
