Nicotine Addiction

Article Author:
Allen Widysanto
Article Editor:
Abdolreza Saadabadi
1/25/2019 11:03:03 PM
PubMed Link:
Nicotine Addiction


Habitual use of tobacco and tobacco products continues to be a significant contributor to health problems worldwide. The increasing affordability of tobacco and nicotine products has been a contributing factor as well as marketing strategies that increasingly use social media to reach consumers globally.[1][2][3]


Major causes of nicotine addiction include lack of motivation to quit smoking, lack of enforcement of smoking bans, inadequate training among mental health professionals, and inadequate treatments.[4]


Tobacco use accounts for more than 5 million deaths worldwide each year. The deaths due to tobacco consumption are reported to be twice the number of deaths due to alcohol and narcotic drugs combined. Most of the deaths due to tobacco use occur in low or middle-income countries.[5][6]


Nicotine is an amine found in tobacco and tobacco products. It is the addictive agent which confers a much lower risk than other elements of tobacco, but it is not completely benign. When tobacco smoke is inhaled, nicotine rapidly enters the bloodstream through the pulmonary circulation. Inhaled nicotine escapes the first pass intestinal and liver metabolism. Nicotine readily crosses the blood-brain barrier which then promptly diffuses into the brain tissue. The process is said to take only 2 to 8 seconds from the time of inhalation. Nicotine is a selective binder to nicotinic cholinergic receptors (nAChRs) in the brain and other tissues. The half-life of nicotine in the human body is estimated to be around 2 hours from the time of consumption.

Brain imaging studies have demonstrated that nicotine acutely increases activity in the prefrontal cortex, thalamus, and visual system consistent with activation of corticobasal ganglia and thalamic brain circuits. Nicotine which stimulates nAChRs produces the release of neurotransmitters, predominantly dopamine but also norepinephrine, acetylcholine, serotonin, GABA, glutamate, and endorphins. These neurotransmitters cause the various responses and behaviors after nicotine intake. When there is repeated exposure to nicotine, tolerance develops to some of the physiological effects of nicotine. Nicotine is a sympathomimetic drug that causes the release of catecholamines and increases heart rate, cardiac contractility, constricts cutaneous and coronary blood vessels and increases blood pressure. 

Nicotine undergoes metabolism in the liver, primarily by the liver enzyme CYP2A6, and converts nicotine to cotinine. Cotinine is a metabolite that can be used as a marker for exposure to nicotine. There are broad individual and racial variations in the rate of nicotine metabolism due to genetic polymorphism in CYP2A6. Thus the metabolism of nicotine is faster in Caucasians than Asians and Africans. Sex hormones also significantly affect CYP2A6 activity, and females metabolize nicotine faster than males.[7][8]


In animals, nicotine can inhibit apoptosis, resulting in the impaired killing of malignant cells. Nicotine also has promoted angiogenesis in animals, which could lead to more significant tumor invasion and metastases.


Animal studies have found nicotine exposure to increase behavioral control of conditioned stimuli, which may contribute to the compulsive smoking behavior. Although conditioning is an important element of nicotine addiction, conditioning primarily develops because of the pharmacological actions of the drug with behaviors.

History and Physical

Intake of nicotine from tobacco smoke or products produces stimulation and a decrease in a feeling of stress and anxiety. Thus smokers modulate their consumption to experience arousal and mood control day. Smoking may improve concentration, reaction time, and performance in specific areas. But when there is a cessation of smoking, there is the appearance of nicotine withdrawal symptoms. Withdrawal symptoms may manifest as irritability, mood depression, anxiety, inability to socialize, increased appetite or desire to eat, and sleeplessness. If nicotine withdrawal is left untreated in habitual tobacco users, it may produce symptoms with similar intensity as psychiatric disorders.

The relative decrease in dopamine release following longstanding nicotine exposure is a possible explanation for many of the mood disturbances as well as tobacco craving experienced by smokers for a long time even after they have stopped smoking. The habituation to cigarette smoking is partly maintained because of conditioning. People habitually smoke cigarettes in specific situations such as after a meal, with a cup of coffee or an alcoholic drink, or in the company of friends who smoke.


Nicotine is metabolized to cotinine and then to trans-3'-hydroxycotinine or nornicotine and other chemicals such as anabasine. Both of these metabolites can be detected in urine and blood. With a long half-life of 16 hours. These tests can be used to test compliance with withdrawal therapy or nicotine toxicity. Another method to assess nicotine is COa level. This method is related to cotinine. Some questionnaires can measure nicotine dependence such as the Fagerstrom Test for Nicotine Dependence, Wisconsin Inventory of Smoking Dependence and Motives, and Smokeless Tobacco Dependence Scale. [9][10][11]

Treatment / Management

The three types of medication are used for smoking cessation are as follows:

Nicotine Replacement Products

These include products such skin patches or gum. Often nicotine replacement products are not used correctly. It has been recommended that the bite and park technique is used rather than chewing the gum.[2][6][12]

Nicotine Replacement Medications 

Bupropion and, most recently, varenicline has been shown to be effective for smoking cessation. Nortriptyline and Clonidine are considered as the second-line drugs. Nicotine replacement medications are believed to facilitate smoking cessation in several ways: (1) Their primary action is by the relief of withdrawal symptoms when a person stops tobacco use. (2) The second mechanism of benefit is positive reinforcement particularly for the arousal and stress-relieving effect. (3) The third possible mechanism of benefit is related to the ability of nicotine medication to desensitize nicotine receptors.

Bupropion: initially marketed as an antidepressant; increases brain levels of dopamine and norepinephrine, simulating the effect of nicotine on these neurotransmitters. 

Varenicline: an analog of cysteine, a naturally occurring plant alkaloid; has a strong binding affinity for nAChR.

Rimonabant: a cannabinoid receptor antagonist which is effective as an aid for smoking cessation.It is believed to contribute to reinforcing effects of nicotine action.

Two other medications of interest: 

Mecamylamine: a noncompetitive antagonist of nicotinic cholinergic receptors; blocks nicotinic effect as well as reinforcement 

lobeline: an alkaloid which is a nicotine receptor agonist; satisfies the nicotine receptor.

Phase 1 and phase 2 clinical trials are studying the effect of a nicotine vaccine that produces antibodies that bind to nicotine to prevent it from acting on nicotine receptors.

Genome-wide association studies that are exploring the possibility of using gene clusters such as the CHNRA5 and CYP2A6 genes that are involved with nicotine metabolism and its conversion continue as a surrogate marker for response to therapy of nicotine replacement.


The adverse reproductive effects of nicotine are predominantly fetal neuroteratogenic effect. Smoking has been associated with retardation of fetal growth. Evidence shows that smoking is causative for premature births, stillbirths, placental abruption, and sudden infant death syndrome. The incidence of spontaneous abortions, ectopic pregnancies, and placenta previa in women smokers is increasing. Behavioral disorders have been observed among infants born to mothers who smoke during pregnancy. Smoking is recognized as a significant risk factor for poor maternal-fetal outcomes.


  • Lung cancer
  • Peripheral vascular disease
  • Bronchitis
  • COPD/Emphysema
  • Halitosis
  • Head and neck cancer
  • Stained teeth

Deterrence and Patient Education

Clinicians have an opportunity to impact treatment outcomes significantly by incorporating patient education on the critical issues of nicotine addiction. Individualized psychosocial or community-based interventions can help to reduce the use of medications.

Pearls and Other Issues

Substantial evidence supports combining both psychosocial and pharmacological interventions for the best results.The best outcomes are when medications are combined with behavioral therapy and community-based interventions.

Enhancing Healthcare Team Outcomes

Nicotine addiction is a complex disorder with no easy cure. Millions of people throughout the globe would like to discontinue smoking but cannot. Many people try to quit smoking and are successful for a few weeks or months but relapse rates are very high. There is no one magical treatment to curing nicotine addiction but evidence suggests that a multidisciplinary approach that encourages changes in lifestyle may have better outcomes. The nurse is in the prime position to educate the patient at discharge. The pharmacist can educate outpatients on the adverse effects of smoking. The social worker should encourage the patient to change lifestyle, join a support group and keep away from people who smoke. The pharmacist may recommend nicotine substitutes but at the same time should encourage a healthy diet, starting a new hobby and participating in an exercise program.  Some individuals may benefit from cognitive behavior therapy. Finally physicians should continually enforce the importance of nicotine cessation and remind the patient that it adversely affects health.[13][14][15] (Level V)


Nicotine addiction affects millions of people all over the globe and has a very high morbidity and mortality. Besides causing cancers, increasing the risk of adverse cardiac events and stroke, it also results in premature birth, spontaneous abortions and peripheral vascular disease. The costs to healthcare from the adverse health affects as a result of nicotine are enormous. Stopping nicotine addiction is another industry that has evolved over the past decade with very poor success rates. Most nicotine addicts cease smoking more to good luck rather than any bona fide remedy. All healthcare workers should try and educate the patients on the harm of nicotine; until then the healthcare costs will continue to increase.[16][17][18] (Level V)