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Republished: Nicotine and health

BMJ 2014; 349 doi: https://doi.org/10.1136/bmj.2014.7.0264rep (Published 26 November 2014) Cite this as: BMJ 2014;349:2014.7.0264rep
  1. Drug and Therapeutics Bulletin
  1. 1Drug and Therapeutics Bulletin Editorial Office, London WC1H 9JR, UK
  1. dtb{at}bmjgroup.com

Abstract

Nicotine, an alkaloid derived from the leaves of tobacco plants (Nicotiana tabacum and Nicotiana rustica) is the primary addictive agent in tobacco products.1,2 There are different ways of administering the various products including smoking cigarettes, chewing tobacco, holding moist snuff in the mouth, inhaling dry snuff through the nose, inhaling smoke from a waterpipe and inhaling vapour from an electronic cigarette.3–6 It can be difficult differentiating the effects of nicotine from the many other toxic substances these products also contain. Here we review the pharmacological effects of nicotine but we will not review the well-known harmful effects of cigarettes, where it is primarily the toxins and carcinogens in tobacco smoke rather than the nicotine that cause illness and death.7 A future article will consider the use of electronic cigarettes.

Nicotine and its pharmacology

What's in nicotine-containing products?

Different products deliver varying doses of nicotine and other toxic substances (see Table). In considering the dose of nicotine from tobacco and other products, it is important to understand the difference between the nicotine content of the product (how much nicotine is contained in the product either by weight of tobacco or in a unit of use, e.g. a cigarette) and the systemic dose of nicotine delivered to the user (the absolute amount of nicotine absorbed by the user).6

Table:

Examples of nicotine content and systemic dose of products36,813

View this table:

Absorption, distribution and excretion

The distribution and elimination of nicotine vary according to the delivery method.13 When tobacco smoke reaches the small airways and alveoli of the lungs, nicotine is absorbed rapidly; about 25% of nicotine inhaled during smoking reaches the bloodstream, and it reaches the brain within 15 seconds.14,15 Concentrations of nicotine in the blood rise gradually with the use of smokeless tobacco and tend to reach a plateau after about 30 minutes.14 While the elimination half-life of nicotine is around 2–3 hours, it has a very long terminal half-life of 20 hours or more, reflecting the slow release of nicotine from body tissues.14

If nicotine is swallowed, it undergoes first pass metabolism in the liver, reducing the overall bioavailability, so nicotine replacement products are formulated for absorption through the oral or nasal mucosa (chewing gum, lozenges, sublingual tablets, inhaler/inhalator, spray) or the skin (transdermal patches).8

Receptor activity

Nicotine is a tertiary amine consisting of a pyridine and a pyrrolidine ring, which binds to nicotinic cholinergic receptors (nAChRs), resulting in the release of dopamine and other neurotransmitters, including noradrenaline (norepinephrine), acetylcholine, serotonin, gamma-aminobutyric acid, glutamate and endorphins.13 Habitual cigarette smoking (but not nicotine administration) reduces brain monoamine oxidase A and B (MAOA and MAOB) activity, which increases monoaminergic neurotransmitters such as dopamine and noradrenaline in synapses, augmenting the effects of nicotine and contributing to addiction.13 With repeated exposure to nicotine, tolerance develops to some of the effects, with an increase in the number of nAChR binding sites in the brain, believed to represent up-regulation in response to nicotine-mediated desensitisation of receptors.13 Nicotine also activates nAChRs in the adrenal medulla leading to the release of adrenaline (epinephrine) and beta endorphin, which may contribute to the systemic effects of nicotine.16

Negative effects of nicotine

Dependence

Addiction to nicotine arises from a combination of genetic, environmental and pharmacological factors, but the characteristics of the nicotine delivery system are also crucially important; for example, cigarettes are the most addictive tobacco product.6 A report published by the Royal College of Physicians notes that “cigarettes and many other tobacco products have been specifically designed, engineered and marketed to enhance both development and maintenance of addiction”, while “medicinal nicotine products are designed and marketed to minimise their addiction potential”.6 Nicotine withdrawal removes the ‘reward’ of the drug and leads to irritability, depressed mood, restlessness, anxiety, difficulty concentrating, increased hunger and eating, insomnia and craving, which may lead to relapse.13

Success rates in attempts to quit nicotine-containing products vary, being generally lower for cigarettes (around 10–11% when using nicotine gum, nicotine patch, ▼varenicline or bupropion to assist quit attempts), and higher for smokeless tobacco (around 19% using bupropion, 21% using nicotine lozenge, 26% using nicotine patch, 27% using nicotine gum or 33% using varenicline).3 This may be due to differences in pharmacokinetics (e.g. cigarette smoking produces significant peaks and troughs in concentrations), presence of non-nicotine substances in tobacco with dependence potential, and the behavioural and sensory aspects of product use (e.g. the social elements of product use, the taste and the smell).3

Concerns have been raised about the possibility of addiction to nicotine replacement therapy (NRT), especially nasal sprays which have the fastest absorption, and so are likely to be the most addictive of the medicinal formulations.6 Nicotine gum, inhaler and lozenge have similar pharmacokinetic profiles and also provide some degree of positive reinforcement, although much less than a cigarette. Nicotine gum does have some dependence liability and some people have difficulty stopping gum use.6 Clinical trials of nicotine gum show prolonged use at 12 months after smoking cessation in 9–22% of users, and for nicotine nasal spray in 32–43% of individuals, although sustained use from self-purchased products is much lower.6 Nicotine patches release nicotine slowly, producing little or no positive reinforcement, so dependence does not appear to be a problem with the use of these products.

Cancer

Nicotine is not a direct carcinogen; animal studies suggest that it may be a tumour promoter, but this has not been established in humans.13 There is no evidence that medicinal nicotine is carcinogenic.6

Cardiovascular disease

Nicotine is a sympathomimetic drug that releases catecholamines, increases heart rate and cardiac contractility, constricts cutaneous and coronary blood vessels, transiently increases blood pressure, reduces sensitivity to insulin, may aggravate or precipitate diabetes, and may contribute to endothelial dysfunction.13 It has been suggested that such effects on the cardiovascular system could promote atherogenesis and precipitate acute ischaemic events in people with coronary artery disease.13 In a systematic review (15 trials, 11,074 participants), palpitations or chest pains occurred more frequently with NRT than with placebo (odds ratio [OR] 1.88, 95% CI 1.37 to 2.57).8 However, a meta-analysis of 35 clinical trials involving more than 9,000 participants found no evidence of an increase in the incidence of acute cardiovascular events with the use of nicotine patches.17

Problems in pregnancy

Suspected adverse reproductive effects of nicotine include fetal neuro-teratogenicity.13 If abstinence from nicotine is not possible in pregnancy, NRT is considered to be less hazardous than cigarette smoking.6,13 However, the available data on the safety of NRT during pregnancy are limited, and more clinical trials and post-marketing surveillance studies are needed.6

Other unwanted effects of NRT

Unwanted effects of NRT include:

  • hiccoughs, gastrointestinal disturbances, jaw pain and orodental problems with nicotine gum;

  • throat irritation, coughing and oral burning with inhalers;

  • nasal irritation and runny nose with nasal sprays;

  • hiccoughs and throat irritation with oral sprays;

  • skin sensitivity and irritation with patches;

  • hiccoughs, burning and smarting sensation in the mouth, sore throat, coughing, dry lips and mouth ulcers with sublingual tablets.8

However, in general, the local effects of NRT tend to be mild and transient.6

Poisoning

Poisoning, which may be fatal, with nicotine has occurred either by deliberate suicidal intent or by accident, related to nicotine-containing pesticides or young children eating cigarettes.18,19 Poisoning related to electronic cigarettes involves the nicotine-containing liquid used in the devices and can occur by ingestion, inhalation or absorption through the skin or eyes.9,19

Symptoms of overdose of NRT are those of acute nicotine poisoning and include nausea, vomiting, increased salivation, abdominal pain, diarrhoea, respiratory failure, pallor, sweating, headache, dizziness, tremor, mental confusion, disturbed hearing or vision and marked weakness; at high doses, these symptoms may be followed by hypotension, rapid or weak or irregular pulse, breathing difficulties, prostration, circulatory collapse and general convulsions, and may be fatal, especially in small children.20,21

Harm reduction with NRT

When nicotine is provided via NRT, the user avoids roughly 4,000 other toxic substances that are inhaled with nicotine in tobacco smoke.10 Nicotine levels in licensed nicotine-containing products are much lower than in tobacco, and the way these products deliver nicotine makes them less addictive than smoking tobacco.7 People can use one product on its own or a combination of different ones; for example, fast acting products (e.g. gum, lozenge) deal better with immediate cravings, whereas long-acting products (e.g. patch) provide a steadier supply of nicotine.7 Although nicotine itself has the potential to cause harm, it is very much less harmful than tobacco smoke, so while complete abstinence from nicotine is preferred, the risk to health from NRT use is smaller than the risk from continued smoking.8 Nicotine medications act on nAChRs to mimic or replace the effects of nicotine from tobacco, facilitating smoking cessation by relief of withdrawal symptoms, positive reinforcement (particularly for rapid-delivery formulations such as nasal spray and to a lesser extent gum, inhaler and lozenge; less so for patches, which deliver nicotine gradually and produce sustained nicotine levels throughout the day), and desensitising nicotinic receptors, so if a person lapses to smoking while on NRT, the cigarette is less satisfying and the person is less likely to resume smoking.13

Licensed nicotine-containing products have marketing authorisation for use as a smoking cessation aid and for tobacco harm-reduction from a regulatory body (Medicines and Healthcare products Regulatory Agency [MHRA] or European Medicines Agency [EMA]). Such authorisation, provides assurance that they have been assessed for efficacy and safety and that they are manufactured to a consistent quality.7 NRT products have been demonstrated in trials to be safe to use for at least 5 years, and even lifetime use of licensed nicotine-containing products will be considerably less harmful than smoking.7 The commercially available forms of NRT (gum, transdermal patch, nasal spray, inhaler and sublingual tablets/lozenges) can help people who make a quit attempt to increase their chances of successfully stopping smoking. A systematic review (117 trials, 51,265 participants) assessed the outcome of smoking cessation at ≥6 months follow-up with NRT compared with placebo and showed greater abstinence for any form of NRT relative to control (4,704/27,258 [17%] vs. 2,466/24,007 [10%]; pooled risk ratio [RR] 1.60, 95% CI 1.53 to 1.68).8 When cutting down, using NRT products also helps avoid compensatory smoking (inhaling more deeply or smoking more of each cigarette to compensate for smoking fewer cigarettes).7 In another systematic review (9 trials, 3,429 participants), there was a statistically significant effect of NRT on the likelihood of reducing cigarette use by 50% or more at least 6 months from baseline compared with placebo or unassisted reduction (226/1,767 [13%] vs. 119/1,662 [7%]; RR 1.72, 95% CI 1.41 to 2.10).11

Postulated positive effects of nicotine

People who smoke claim positive effects such as pleasure, arousal, relaxation and improved cognitive performance, as well as relief of negative affect, tension and anxiety.14,16 To what extent these ‘rewards’ of smoking are caused by the relief of symptoms of abstinence or by an intrinsic enhancement effect of nicotine are unclear.14 Objective tests assessing choice reaction time, verbal memory and spatial processing show no difference between smokers, non-smokers and ex-smokers, so it can be concluded that nicotine has no clear performance enhancing effect.22 Psychological well-being, measured using the General Health Questionnaire, is worse among smokers than never- or ex-smokers and a clear dose response effect was demonstrated, with heavy smokers feeling worst of all.22 Similarly, the malaise questionnaire showed progressively increasing unhappiness with the number of cigarettes smoked; malaise scores fell among those who gave up smoking, remained high in those who continued to smoke and were highest of all in those taking up smoking.22 These findings do not support the idea that smoking enhances mood or performance.22

Although systematic reviews have assessed nicotine as a treatment for Alzheimer's disease,1 Parkinson's disease23 or schizophrenia,15 trials have been small and the results inconclusive.

Ulcerative colitis is a chronic inflammatory disorder of the colon and is largely a disease of non- and ex-smokers.24 Anecdotal reports note that intermittent smokers may experience improvement in symptoms while smoking, and non-smokers with ulcerative colitis who begin smoking may go into remission.24 In a systematic review, after 4–6 weeks of treatment, more people remitted with transdermal nicotine than with placebo (OR 2.56, 95% CI 1.02 to 6.45, 2 trials, 141 participants) but not when compared with standard therapy (oral prednisone or mesalamine: OR 0.90, 95% CI 0.12 to 6.94, 3 trials, 129 participants).24 Patients treated with nicotine were significantly more likely to withdraw due to adverse events, including light-headedness, nausea and contact dermatitis (OR 5.82, 95% CI 1.66 to 20.47).24

Conclusion

Nicotine is an addictive substance contained in cigarettes, smokeless tobacco, waterpipe, electronic cigarettes and nicotine replacement therapy (NRT). The harmful effects of smoking are well known, but the specific effects of the nicotine are hard to disentangle from the effects of the many other harmful components of cigarette smoke. Nicotine's sympathomimetic activity affects heart rate and cardiac contractility, constricts cutaneous and coronary blood vessels, transiently increases blood pressure, reduces sensitivity to insulin, may aggravate or precipitate diabetes and may contribute to endothelial dysfunction. Poisonings and deaths have been reported among people eating cigarettes; by ingestion, inhalation or absorption through the skin or eyes of liquid from electronic cigarettes; or from overdosing on NRT. Licensed nicotine-containing products are a safe and effective way of reducing the amount people smoke or helping them to quit smoking. Positive effects have been suggested for nicotine in ulcerative colitis when compared with placebo but not when compared with standard therapy, and more adverse effects were reported by those using nicotine. The evidence is insufficient to endorse any positive health effects of nicotine.

  • This article was originally published with the title Nicotine and health in Drug and Therapeutics Bulletin (DTB 2014;52:78-81, doi:10.1136/dtb.2014.7.0264).

  • DTB is a highly regarded source of unbiased, evidence based information and practical advice for healthcare professionals. It is independent of the pharmaceutical industry, government, and regulatory authorities, and is free of advertising.

  • DTB is available online at http://dtb.bmj.com.

References

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