Tobacco and Nicotine Dependence 1/7/2021

The good news is that the past 50 years have seen a tremendous decrease in the incidence of Americans who are smoking, with rates of prevalence dropping from over 40% in 1965 to roughly 15% in 2017.   This said, 16 million Americans have a smoking-related health condition and smoking remains the #1 preventable cause of death responsible with 20% of deaths, with a ten year average reduction in life expectancy from cancers (lung, bladder, oral, GI), cardiovascular illness, diabetes, along with other quality of life detractors: osteoporosis, erectile dysfunction, GI ulcers, skin aging, etc.    Men are at somewhat higher risk to be smokers (16%) compared to woman (12%).

For individuals with mental health conditions, smoking is a particular concern.  The following statistics show smoking prevalence by disorder:                                                          % of smokers

Alcohol Use Disorder                              > 60 %

Other Substance Use Disorder               < 60 %

Affective Disorder                                      45 %

Anxiety Disorders                                      40 %

No Mental Health Diagnosis                   < 15 %

While tobacco smoke has numerous toxic compounds (carbon monoxide, hydro-cyanide, benzene, formaldehyde, nitrosamines, lead, cadmium, polonium) of course, the active addictive agent is nicotine which is not per se a toxin.  Nicotine is a naturally occurring alkaloid, which is an agonist that binds to nicotinic receptors in the body leading to release of dopamine which is strongly reinforcing and thus, in conjunction with its very rapid absorption into the blood stream, accounts for nicotine’s highly addictive properties.    Nicotine has stimulant impacts on the brain and many help focus and briefly reduce anxiety.

The half-life of nicotine is 2 hours, with elimination through hepatic metabolism via the cytochrome P450 system.   Physiological withdrawal thus occurs within hours of the last cigarette smoked, with withdrawal symptoms that may include depressed mood, insomnia, irritability, frustration, anger, anxiety, reduced concentration, restlessness, hunger.  As withdrawal symptoms arise, there is natural pressure to grab for another cigarette and the addiction cycle continues.

Efforts to encourage smokers to quit smoking in primary care settings can be effective but success does require persistence and a willingness to provide significant support and to treat aggressively with appropriate medications.

The AAR strategy:  Ask, Advise, Refer

ASK:  Do you use tobacco? How much? How do you feel about quitting?  Can I give you some info about resources to help you quit?

ADVISE:  Tobacco is addictive, costly, and a health risk.  People who quit feel better and live longer.  Free voluntary support is available at 1 800 QUIT-NOW (toll free tele-counseling with screening and assessment, referrals to telephone specialists, with multiple language options).  Supplementing counseling and support with medically assisted treatment can help.

REFER FOR (or provide) TREATMENT:   Medication Assisted Treatment (MAT) strategies are established interventions that work for many.   Nicotine Replacement Therapy (NRT), bupropion and Varenicline are first line agents with evidence-based efficacy at rates approaching 2-3 times of placebo.   Each success in helping a patient stop smoking has multiplier impact on improving their health throughout their lifetime.

Use of MAT would clearly be most appropriate when the degree of nicotine dependence is most intense and would of course also require a full exploration of both benefits and risks.

The severity of dependence on the nicotine is strongly correlated both with the amount of tobacco use and can also be assessed by identifying the time of latency before smoking upon awakening in the morning—severe dependence is characterized by having the first cigarette within five minutes of awakening, and moderate dependence with a first cigarette within 30 minutes of awakening.  Individuals with these profiles are most likely to require medically assisted treatment (MAT), typically with higher dosing strategies, but MAT should also be recommended to all smokers.

Nicotine Replacement Therapy (NRT) is a convenient and safe treatment option with both non-prescription over-the-counter (OTC) products (gum, lozenges, patches) as well as prescription delivery systems (nasal spray and inhalers).   Strategies for effective use include assuring that the recommended (or prescribed) dose is high enough to substitute for the nicotine ‘high’ and scheduled to be routinely self-administered throughout the entire day—remember that a one pack per day smoker is already administering nicotine 20 times per day and that drug clearance (half-life) is 2 hours.  For comparative reference the newly FDA approved nicotine spray can be used up to 4 times per hour and up to 64 times per day. Optimizing dosing and frequency at the outset is thus most important.  Combining NRT delivery systems is a useful strategy to achieve this goal with combined use of a patch with concurrent use of gum/lozenge/spray being twice as successful of either delivery system alone.    Also of note, nicotine does not have any drug-drug interaction and it can be used in conjunction with other prescribed agents that reduce the urge to smoke (bupropion, varenicline).

An important consideration for managing the patient who is stopping smoking is to remember that the non-nicotine chemicals in tobacco smoke do have drug-drug interactions that increase metabolism of the following:  caffeine, theophylline, antipsychotics (clozapine, olanzapine, haloperidol, chlorpromazine, fluvoxamine)– discontinuing smoking can lead to increased blood levels of these chemicals and potential untoward side effects.  Caffeine drinkers should be guided to reduce intake and others taking prescribed medications should discuss potential health concerns with their prescribing providers.

Bupropion (Wellbutrin) is as effective as NRT and may be a particularly good choice for individuals with co-morbid issues of depression and/or attentional challenges.  Dosing can be titrated as needed from 100mg upward of 450mg per day with use of extended release preparations, with care given for individuals with seizure disorder conditions.  Drug-drug interactions can occur with impact with increased activation of CYP2B6 and inhibition of CYP2D6 hepatic metabolic systems.  Bupropion can be used successfully as an adjunct to NRT interventions.

Varenicline is a newer part of the armamentarium which has close to three times efficacy over placebo.  It is a selective partial agonist of 4B2 nicotinic receptors that competes with in vivo nicotine so that it increases dopamine release and can help reduce nicotine withdrawal.  Varenicline is reportedly of somewhat greater benefit for females than males.   Typical side effects can include insomnia, changes in dreams and headaches, with rare incidents of more significant psychological symptoms.   Combined use of Varenicline and NRT is a recommended strategy.  Varenicline is not metabolized in the liver but rather is excreted by the kidney. Recommended duration of treatment is 6 months though shorter courses of treatment may be helpful.

Special Populations: 

Pregnant Women: Problematically, nicotine crosses the placenta and is present in breast milk.  10% of pregnant woman are smokers with multiple medical consequences with increased:   pregnancy loss, ectopic pregnancies, placenta previa, premature rupture, lower birth weights, SIDS and decreased: milk production and lactation rates.   Second hand smoke is also a concern following the neonatal period and guiding a smoking mother away from the addictive habit helps preserve the health of two or more persons.    Early intervention with education about impacts on children and recommendations for supportive counseling (800 QUIT NOW) are to be strongly encouraged for pregnant smokers.   When medication might be considered, the first line Rx would be NRT or NRT with bupropion; no clear guidance and only limited data is available on use of Varenicline in the pregnant or breast-feeding population.  This said, there are indicators that Varenicline, as a partial agonist agent, may be more helpful for woman for whom withdrawal from nicotine can exacerbate other hormonal mood sensitivities.

Adolescents & Vaping:  Current recommendations are to screen for tobacco and e-cigarette use along with more general screening for other substance use concerns.   The advent of e-cigarettes in the past two decade is a particular issue for teens and young adults, with rates of use in older teens and young adults are of great concern, with rates of exposure as high as 30% for seniors in high school.  The use of flavorings is yet another inducement for the younger population to vape nicotine.    Youth who begin to vape are four times as likely to become cigarette smokers than those who don’t vape, and a percentage of youth who do vape, do so in excess with both behavioral and physiological problems.

Finally, the use of e-cigarettes as a nicotine replacement medication remains a research question with FDA approval as yet not authorized.   This said, it is being promoted in the U.K. and may become part of the armamentarium of MAT for smoking cessation in the future.


“Tobacco”; Jill M Williams, MD; Professor of Psychiatry and Director of Division of Addiction Psychiatry, Rutgers University—Robert Wood Johnson Medical Center; ASAM Board Exam Study Course 2020;




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