Review Article

Nicotine replacement therapy for smoking cessation

Priyanka Chauhan*, Asish Dev, Seema Desai, Varsha Andhale

Department of Pharmaceutics, Oriental College of Pharmacy, Sanpada, Navi Mumbai, Maharashtra 400705, India

*For correspondence

Priyanka Chauhan,

Department of Pharmaceutics, Oriental College of Pharmacy, Sanpada, Navi Mumbai, Maharashtra 400705, India.

Email: c.priyanka175@gmail. com


Received: 12 April 2016

Accepted: 30 May 2016


Smoking is a process that involves inhaling smoke of burning tobacco. The inhaled tobacco smoke consists of over four thousand chemicals mainly nicotine, tar, carbon monoxide, which is responsible for death causing diseases. Every year 6 million people die because of tobacco consumption. To overcome the risk of death, various smoking cessation therapies are followed which include cold turkey, non-NRT, e-cigarette and NRT. This review focuses on NRT which basically provides nicotine in order to relieve craving and withdrawal symptoms. NRT consists of various types of formulations gum, patch, lozenge, inhaler, and spray. This strategy is also proved to be effective in combination but the selection of dosage form varies from patient to patient.

Keywords: Nicotine, Nicotine mouth spray, E-cigarette, Nicotine nasal spray, Tobacco smoking


Inhalation of the smoke of burning tobacco encased in cigarettes, pipes, and cigars is known as smoking. Radioactive materials are found in the tobacco leaves which is used to make cigarettes and cigars the amount of which depends on type of soil the plants were grown in and fertilizers used.1

Tobacco consumption is one of the major causes of preventable disease and death in India. Unfortunately, very few people in India give up tobacco use.2


Tobacco kills up to half of its users. 60 lacs people die each year because of tobacco consumption. Tobacco consumption is the sixth leading cause of disease causing death worldwide. More than 50 lacs deaths are due to direct tobacco use while more than 6, 00,000 are from exposure to second hand smoke.3

Over one in two people in India are exposed to second hand smoke at home and 29% at open spaces.4

In India, 47% of males and 14% of females make use of tobacco, and there are about 194 million users of both smokeless and smoking forms. Annual oral cancer occurrence in the Indian subcontinent has been expected to be as high as 10 per 100,000 among males and oral cancer rates are progressively increasing among adolescent tobacco users. Smoking increases the possibility of Mycobacterium tuberculosis infection, the risk of progression from infection to disease, and the risk of death among tuberculosis patients.2,4

Smoking cessation

There are basically four methods of smoking cessation:

  1. Cold turkey method
  2. Non NRT
  3. Electronic cigarette
  4. Nicotine replacement therapy (NRT)

Cold turkey method: "Cut to quit" is when a person stops smoking without using any quit smoking products and occasionally without any particular plan or support. Willpower is a very important element of making the initial decision to quit smoking and then staying quit for excellent.5

Non-NRT therapies: The commonly used agents for management include varenicline, bupropion and nortryptiline.2,6 Varenicline is a novel orally administered alpha 4 beta 2-nicotinic acetylcholine (ACh) receptor partial agonist used particularly for smoking cessation. Varenicline shows both short-term and long-term efficacy compared with placebo in a randomized controlled trial. Varenicline has been reported to be well tolerated and appears to satisfy the urge to smoke.6 Bupropion is an antidepressant drug. It is act as an antagonist by blocking nicotine receptors in the brain and affecting the brain's reward/bliss system. Bupropion approximately doubles the chances of accomplishment in quitting.6 Nortryptiline, a second-generation tricyclic antidepressant and clonidine, an alpha-agonist antihypertensive are suggested as second-line medications. These drugs have not been evaluated as widely as the other drugs, but their lower costs make them probable pharmacotherapies in low-income countries.2,6

An electronic cigarette (also called e-cigarettes or electronic nicotine delivery systems) are battery-operated devices intended to deliver nicotine with flavorings and other chemicals to users in vapor as a replacement for smoke. They can be manufactured to be similar to traditional tobacco cigarettes, cigars or pipes, or even everyday objects like pens or USB memory sticks.7

Clinic-based tobacco cessation

In the first 5 years of the clinics, 34,741 cases were registered at these clinics and baseline information recorded for 23,320 cases. Only behavioral strategies were engaged in 69% of the cases, and pharmacotherapy, primarily bupropion, and nicotine gums were used in 31% along with behavioral psychotherapy.2,3


Figure 1: Tobacco use is a risk factor for six of the eight leading causes of death in the world.


Figure 2: Method of cessation.

Nicotine replacement therapy

Nicotine replacement therapy (NRT) is extensively used therapy for smoking cessation and comprises a series of products with passive (transdermal patch) and instantaneous nicotine delivery (gum, lozenge, spray, inhaler) which provide a slow and steady supply of nicotine to attain constant concentration levels of nicotine in order to relieve craving and withdrawal symptoms.2,6

NRT is the most accepted and cost-effective pharmacotherapy currently available and should be made easily available and subsidized. on the other hand, the range of pharmacotherapy must be offered so that the public that can afford out-of-pocket expenses has the choice of evidence-based pharmacotherapy.9,10


Nicotine is a tertiary amine with following structure.

Figure 3: Nicotine (3-[(2S)-1-methylpyrrolidin-2-yl]pyridine).11

Nicotine binds to nicotinic acetylcholine receptors on dopaminergic neurons in the cortico-limbic pathways. This causes the channel to open and allow conductance of multiple cations including sodium, calcium, and potassium. This leads to depolarization, which activates voltage-gated calcium channels and allows more calcium to enter the axon terminal. Calcium stimulates vesicle trafficking towards the plasma membrane and the release of dopamine into the synapse. Dopamine binding to its receptors is responsible the euphoric and addictive properties of nicotine.12

Nicotine replacement therapy6

The US Food and Drug Administration (FDA) have approved 5 forms of nicotine replacement therapy:

  • Gum
  • Patch
  • Lozenges
  • Inhalers
  • Spray

Mechanism of action

The main mode of action of NRT is thought to be the stimulation of nicotinic receptors in the ventral tegmental area of the brain and the consequent release of dopamine in the nucleus accumbens. This and other peripheral actions of nicotine lead to a reduction in nicotine withdrawal symptoms in regular smokers who abstain from smoking.13

A second possible mechanism of benefit has been the potential to inactivate nAchRs. Such inactivation would result in a reduced effect of nicotine from cigarettes, if a person relapses to smoking while taking NRT. Hence NRT also provide a coping mechanism, making cigarettes less satisfying to smoke.14

Nicotine gum

Nicotine gum is one of several nicotine replacement therapies (NRTs) recognized as a safe and effective treatment for tobacco dependence and withdrawal.15

Chewing gums permit release of the active over time as the gum product is masticated, or chewed. The actions of saliva on the gum further encourage release of the active and consequent absorption by the mucous membranes lining the mouth, throat, larynx and esophagus. Gum brings at least about 40-50% of its nicotine content within about 3-5-minute or even less time. As result loaded nicotine content in the bloodstream of about 2-5 ngm of nicotine per milliliter of blood can be achieved within 10 minutes.16

Nicotine free base is labile to oxidation through an electrophilic attack; therefore all ingredients used in formulation of nicotine gum should be free of non-bonded electron pairs and hydrophilic liquid to prevent degradation of nicotine.17

Ingredients used in formulation

Various nicotine salts that can be used are nicotine hydrogen tartrate, nicotine bitartrate, nicotine hydrochloride, and nicotine zinc chloride monohydrate and nicotine salicylate. The preferred form of nicotine is a nicotine cation ion exchange complex such as the nicotine-AMBERLITE 164 complex which is commonly known as nicotine polacrilex. Each chewing gum unit should contain 2mg to 5mg of nicotine.17

Examples of natural gum bases include Chicle-, Jelutong-, Lechi di Caspi-, Soh-, Siak-, Katiau, and Percha-gums, Sheets and natural resins such as Dammer and Mastix.16Plasticizers may include softeners and emulsifiers reduce the viscosity of the gum base to a favorable or desirable consistency. Examples include lecithin, lanolin, glycerides (mono-and di-), stearic acid, sodium stearate, potassium stearate etc.17 Buffering agents that can be used include calcium hydroxide, magnesium hydroxide, aluminum hydroxide sodium bicarbonate, potassium bicarbonate trisodium phosphate and calcium hydroxide. Buffering agent present in the chewing gum enough to increase the pH of the saliva to about 8-10 for about 5-10 minutes from the time the chewing gum unit is placed in the mouth and the chewing process begins which reduces the throat irritation caused by the release of the nicotine sweeteners saccharide materials such as mono-, di-, tri- and polysaccharides as well as oligosaccharides. Sugars such as sucrose, glucose (corn syrup), dextrose, invert sugar, fructose etc .17 Peppermints, spearmint, wintergreen, cinnamon, coconut, coffee, chocolate, vanilla, menthol, liquirice, anise, mint can be used as flavoring agent mixture can also be employed. Examples of probable Fillers include calcium carbonate, talc, sodium sulfate etc.16 Coloring agents are used to improve the color and appearance of the final composition. Examples of coloring agents include FD&C-type dyes and lakes, fruit and vegetable extracts, titanium dioxide.17

Nicotine transdermal patch

Patches give a measured dose of nicotine through the skin. Patches are available as OTC. The 16-hour patches which works well for light-to-average smokers. It's less expected to cause side effects like skin irritation, racing heartbeat, sleep problems, and headache. But it doesn't deliver nicotine throughout the night, so it may not be right for those with early morning withdrawal symptoms. The 24-hour patch provides a steady dose of nicotine, avoiding peaks and valleys. It helps with early morning withdrawal. But there may be more side effects like disrupted sleep patterns and skin irritation.8,18

Figure 4: Transdermal patch.

The patch is present in the form of a reservoir system in which a depot of nicotine is separated from the skin by means of a non porous polymeric membrane, through which the nicotine diffuses at a controlled rate. It can also be in the form of monolithic matrix, consisting of a single phase solution on mixture of nicotine in a polymeric material.19

The concentration of nicotine in the patch generally ranges from about 10 to about 20%. Examples of topical antipruritics effective in reducing itching during transdermal nicotine delivery are bisabolol, oil of chamomile etc.20

Ingredients used in patch formulation

Solvents useful for affecting the transdermal delivery of nicotine include aqueous and organic solvents. [16] Water is a typical solvent used in the transdermal nicotine patch. Polar organic solvents, such as ethanol, may also be useful. Butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfate, a tocopherol, maleic acid, ethylene diamine tetra acetic acid (EDTA), and cysteine hydrochloride are preservative, antioxidant and chelating agents used in formulation.19 The thickener can be an acrylic polymer thickener such as methyl cellulose and hydroxyl propyl methyl cellulose. Plasticizers may be added to impart softness and flexibility to the adhesive, a typical plasticizer being glycerin. Stabilizers, added to prevent degradation by heat and light.20

Nicotine lozenges

Nicotine lozenges are hard candy-like tablet that contains a small dose of nicotine. The nicotine is absorbed through the lining of the mouth and goes into the blood. This helps stop nicotine cravings and relieves symptoms that occur when a individual is trying to quit smoking Side effects include Trouble sleeping, Nausea, Hiccups, Coughing, Heartburn, Headache, Gas.21

Both nicotine gum and transdermal nicotine compete with each other as products providing steady-state nicotine blood levels, but do not satisfy craving symptoms for cigarettes in some smokers. A lozenge contains 0.1 to 5 mg nicotine as a base for quitting smoking. The nicotine lozenges are intended to be held in the patient's mouth and sucked, as they dissolve slowly and discharge nicotine gradually in the buccal cavity.22

Ingredients used in formulation of nicotine lozenge

The lozenge contains quite low doses of nicotine, from 0.5 to 2.0 mg, to prevent accidental over dosage by swallowing the lozenge intact. Suitable absorbent excipients comprise of, mannitol, cyclodextrins, α, β and γ-cyclodextrin.22

Icing sugar can be used in formulation. The lozenge is a buffered formulation in order to aid in buccal absorption of nicotine. Additives such as sodium bicarbonate, sodium carbonate or potassium hydroxide or aluminium hydroxide can be added.23

Suitable flavorant include menthol, peppermint, wintergreen, sweet mint, spearmint, vanillin, chocolate, coffee, cinnamon, clove, citrus and fruit flavors. Other additives that are incorporated within the lozenges include preservatives, antimicrobial agents, and antioxidants.24

Nicotine inhaler

A nicotine replacement tool used for smoking cessation is comprised of a mouthpiece and a cartridge containing a nicotine-imbibed plug. Every puff from the inhaler contains ± 10 times less nicotine than a puff of a cigarette. The inhaler also helps to manage smokers' physcological cravings, as it mimics the "actions" of smoking and thereby shows major behavioral component. Unlike cigarettes, inhalers do not deliver a 'hit', but they can help with cravings by releasing nicotine which is absorbed through the lining of the mouth.25

Nicotine inhalers are the FDA-approved nicotine replacement method that is mostly like smoking a cigarette, which some smokers find cooperative. Inhaler contains a nicotine formulation, in a pharmaceutical grade sugar and liquid carrier. The nicotine is combined with the carrier such that it will be conveyed to the alveoli and lower airways of a person with the carrier. Upon inhalation by the user, by having a dimpled surface, the aerodynamics of the medicament particles are improved where the particles may by more easily entrained in the air inhaled by the addict.26

Nicotine spray

There are two types of nicotine sprays are available as NRT for smoking cessation.

  • Nicotine nasal spray
  • Nicotine mouth spray

Nicotine nasal spray

A nasal spray that contains a small dose of nicotine enters the blood by being absorbed through the lining of the nose. This prevents nicotine cravings and relieves symptoms that arise when a person is trying to quit smoking. A prescription is required for nicotine nasal spray.21

The nasal spray delivers nicotine to the bloodstream rapidly because it is absorbed through the nose. It also reduces the nasal symptoms related with administration of higher concentrations of nicotine to the nasal mucosa. Smokers usually like the nasal spray because it is easy to use. The FDA recommends that the spray be prescribed for 3-month periods and that it not to be used for longer than 6 months. 6

When the nasal spray is used nicotine is not drawn only in the nose, thus avoiding respiratory irritation and allowing the use of higher nicotine concentrations, permitting bloods nicotine levels to be boosted into the range which reduces nicotine Withdrawal symptoms without associated irritation.27

Nicotine or a nicotine salt is dissolved in a solvent, such as phosphate buffered saline, and is adjusted to pH in the range of about 7.0. The composition is delivered to the nose by a spray device which delivers about 0.05 ml of the composition per activation of a pump-type nasal spray atomizer in the form of a spray having droplets of about 10 microns or more in diameter.28

Nicotine mouth spray

This acts like the nasal spray, providing a rapid increase in nicotine level.9

The pump sprays a fine mist onto the inside of cheek or under tongue. The nicotine absorb from the lining of mouth. Use of the mouth spray can help to reduce withdrawal symptoms, such as cravings, irritability, restlessness and poor concentration. The mouth spray relieves cravings faster than other nicotine replacement formulation, and it starts to act within five minutes of use. Mouth spray users may absorb about one-third to one-half of the dose of nicotine than one cigarette.29

Table 1: Marketed formulations of NRT.

S. no.

Types of NRT

Brand name



Nicotine gum






Niclonz pastilles




German Remedies




Nicotine patch

2Baconil TTS10

Nicorderm CQ


Clear NicotineTDS

Rusan health care

Johnson & Johnson




Nicotine Lozenges



Commit Lozenge







Nicotine Inhaler






Nicotine nasal spray


Nicotine Mouth spray






EZ Quit


Boots phceuticals




Combination therapy

In combination therapy two forms of Nicotine Replacement Therapy (NRT) are used together. The common combination therapy is the nicotine patch combined with oral nicotine replacement products.5

Combination therapy is suitable for those smokers who are still experiencing considerable cravings and nicotine withdrawal symptoms while using one form of NRT, or for those who are unable to quit altogether using one form of NRT alone. Combination therapy may be mainly useful for heavy smokers with a higher nicotine addiction.29

Using any NRT products or in combination is more successful when combined with psychotherapy A clinical trial were conducted for helpfulness of combination of nicotine mouth spray and nicotine patch Smokers were randomized to a nicotine or placebo spray for 6 months, and all received nicotine patches daily for the period of 5 months. They were followed at regular intervals for 12 months. It is seen that a total of 1,423 subjects were randomized to nicotine oral spray (1mg of nicotine free base per spray) plus nicotine patch or a placebo spray and nicotine patch. The nicotine mouth spray plus nicotine patch showed considerable improvements in prolonged abstinence for all measures to 6 months (7 consecutive days at each visit for 6 months: 15.5% vs. 10.6%; p = 0.006) for the combination versus placebo and nicotine patch.30


All the commercially available NRT forms are efficient strategy to promote smoking cessation. The choice of NRT depends on various factors that vary from patients to patients these include tolerability, other risk factors and cost considerations. It is estimate that a steady increase in the proportion of NRT-aided quit attempts to 100% by 2025 would lead to 40 000 premature deaths avoided over a 20-year period. Most avoided deaths would be attributable to lung cancer and cardiovascular disease. Even after we assumed some harm from long-term NRT use, the benefits from increased cessation accomplishment far outweigh the risks.

Funding: No funding sources

Conflict of interest: None declared


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