Nicotine replacement therapy: what are the options?

NICOTINE REPLACEMENT THERAPY

Nicotine replacement therapy (NRT) aims to reduce the withdrawal symptoms associated with smoking cessation by providing some of the nicotine that would normally be obtained from cigarettes, without providing the harmful components of tobacco smoke.¹

Previous concerns about NRT (e.g. concomitant smoking, use in clients with stable cardiovascular disease) are no longer considered valid, as decades of research and use have shown that NRT products do not appear to have significant potential for abuse or dependence and are also safe in challenging situations such as post-myocardial infarction.²

NRT can increase the rate of quitting, regardless of the setting. Various product forms are available, all of which can help people who make a quit attempt increase their chances of successfully stopping smoking. The effectiveness of NRT is largely dependent on the dose and the intensity of additional support provided to the individual.¹

A combination of short- and long-acting forms of NRT should be considered, e.g. the long-acting nicotine patch may be used, together with the shorter-acting nicotine gum, inhaler or lozenge to manage sudden nicotine cravings.³ Dosing guidelines for these therapies are provided in Table 1.^1,4,5

Table 1. Pharmacotherapy for smoking cessation, based on product monographs* ^1,4,5

Product	Client group	Approved Dosage	Remarks
Nicotine patch	>10 cigarettes per day and weight >45 kg	· 21 mg/24 hours or 25 mg/16 hours**	· Duration 8–12 weeks* · May cause local skin reaction, headache, sleep problems and abnormal dreams, cold/flu‐like symptoms, dizziness
	<10 cigarettes per day or weight <45 kg	· 14 mg/24 hours or 10 mg/16 hours
Gum***	First cigarette >30 minutes after waking	· 2 mg, 8–12/day · Duration: up to 12 weeks* · Reduce to quit strategy may also be used	· May cause mouth, throat, or gum irritation, nausea and stomach upset, jaw ache, hiccups, headache
	First cigarette <30 minutes after waking	· 4 mg, 6–10/day · Maximum, 24 pieces/day · Duration: up to 12 weeks* · Park between cheek and gum when peppery or tingling sensation appears; resume chewing when tingle fades · No food or beverages 15 minutes before or during use · Reduce to quit strategy may also be used
Inhaler***	>10 cigarettes per day	· 6–12 cartridges/day · Duration: 3–6 months	· May cause nausea, headache, mouth or throat Irritation, stomach upset
Lozenge***	First cigarette >30 minutes after waking	· 1.5 mg or 2 mg, 1 lozenge every 1–2 hours · Duration: up to 12 weeks*	· May cause mouth, throat or tongue irritation, nausea and stomach upset, hiccups, headache, taste change
	First cigarette <30 minutes after waking	· 4 mg, 1 lozenge every 1–2 hours · Duration: up to 12 weeks*
Nicotine oral spray***	First cigarette >30 minutes after waking	· Up to 4 sprays/hour · Duration: up to 12 weeks*	· May cause tingling lips, hiccups, taste change
Bupropion SR	Smokers who have been offered NRT and would prefer to use bupropion	· Days 1–3: 150 mg q am · Day 4–end: 150 mg twice daily (at least 8 hours between doses) · Start 1–2 weeks before quit date · Duration: 7–12 weeks; maintenance up to 6 months in selected clients	· May cause dry mouth, insomnia, headache, nervousness, weight loss · Contraindications: seizure disorder, concomitant bupropion therapy, bulimia/anorexia nervosa, MAO inhibitor therapy in previous 14 days
Varenicline	Smokers who have been offered NRT and would prefer to use varenicline	· Days 1–3: 0.5 mg daily · Days 4–7: 0.5 mg twice daily · Day 8–end: 1 mg twice daily (0.5 mg twice daily for severe renal impairment) · Start 1–2 weeks before quit date so that receptors are saturated well · Duration: 12 weeks; additional 12–weeks in selected clients	· May cause nausea/vomiting, flatulence, constipation, insomnia, abnormal dreams, headache, mood/behaviour change, suicidal ideation; monitor changes in mood

*Extending treatment beyond 12 weeks may help prevent relapse with any of the medications
**Higher dosages are endorsed by treatment guidelines for those who are highly nicotine dependent and experience severe withdrawal symptoms
***Can be used in combination with nicotine patches to relieve breakthrough cravings for nicotine

Nicotine patch: The nicotine patch is long-acting form of NRT that is applied on the skin, from where nicotine is absorbed into the blood stream. The patch should be changed every 24 hours. Minor skin irritation at the patch site is reported by 30–50% of users, and can be relieved by moving the patch to another site and ensuring proper rotation (at least 1 week should elapse before the same area of the skin is used again). Other side effects include headache and nausea. Sleep disruption is usually resolved by removing the patch at bedtime.^3,6 If the client removes the patch prior to bedtime, consider recommending a short-acting NRT (inhaler, gum, lozenge) to use in the morning as their blood nicotine levels may be very low and they could experience withdrawal symptoms.

Nicotine inhaler: With the inhaler, nicotine is absorbed primarily through the oral cavity (36%), esophagus and stomach (36%), rather than through the lungs (4%). It acts quickly and has a short duration of action; thus, it is useful for coping with nicotine cravings. Side effects may include irritation of the throat and mouth, which can be caused by incorrect administration technique. Incorrect administration technique may also reduce efficacy of the inhaler. This highlights the need for teaching in this regard.^3,7

• Line up markers and pull each end in opposite directions.
• Insert cartridge into mouthpiece. Twist to close securely.
• Inhale deeply into the back of your throat or puff in short breaths. (Each cartridge lasts for approximately 20 minutes of frequent puffing.)

Nicotine gum: Absorption of nicotine from the gum formulation occurs through the buccal mucosa. It is a short-acting preparation, and can be used to ease cravings for a brief period. The gum should be kept in the buccal area and chewed once or twice every few minutes. If chewed too quickly, nicotine will be swallowed with the saliva, and patients may experience nausea or dyspepsia. Other possible side effects include sore mouth or throat, throat irritation, increased salivation and headache. Nicotine gum can also be used according to a reduce to quit regimen, proposed as part of the Canadian Action Network for the Advancement, Dissemination and Adoption of Practice-informed Tobacco Treatment (CAN-ADAPTT) guidelines.⁸ Ideally, quit plans will include setting a target quit date and complete abstinence from smoking after that date. However, some smokers, while motivated to quit, may not be willing to adopt this approach and prefer a ‘reduce to quit’ strategy. CAN-ADAPTT offers guidance in the form of a stepwise algorithm for operationalizing this approach (Table 2).⁸

Table 2. CAN-ADAPTT stepwise algorithm for smoking cessation ⁸

Step	Action
Step 1: (0 to 6 weeks)	· Smoker sets a target for the number of cigarettes per day to cut down and a date by which to achieve it (a reduction of at least 50% is recommended) · Smoker uses nicotine gum to manage cravings
Step 2: (6 weeks up to 6 months)	· Smoker continues to cut down cigarettes by using nicotine gum · The goal should be complete abstinence from smoking by 6 months · Smoker should seek advice from a healthcare provider if smoking has not stopped within 9 months
Step 3: (within 9 months)	· Smoker stops all cigarettes and continues to use nicotine gum to relieve cravings
Step 4: (within 12 months)	· Smoker cuts down the amount of nicotine gum used · Smoker stops nicotine gum use completely within 3 months of stopping smoking

Nicotine lozenge: This formulation releases nicotine as the lozenge slowly dissolves in the mouth. It is also short-acting, with a duration of 20–30 minutes. Side effects may include soreness of the teeth and gums, throat irritation, and indigestion.^3,7

The correct usage of nicotine lozenges is as follows:

1. Purchase the appropriate strength for your amount smoked per day (either 2 or 4 mg strengths).
2. Place lozenge in your mouth; it will soon begin to melt. Keep moving it from one side of your mouth to the other, until the lozenge has completely dissolved; this usually takes about 10 minutes.

Nicotine mouth spray: This system provides a faster nicotine delivery than nicotine lozenges. Nasal and throat irritation, rhinorrhea, and nausea are common side effects.^9,10

The correct usage of nicotine mouth spray is as follows:

1. Prime the dispenser: point the nozzle away and press the dispenser several times until a fine mist appears. If the spray is not used for 2 or more days, this may be repeated.
2. Hold dispenser as close to the open mouth as possible; avoid the lips.
3. Press the top of the dispenser to release one spray into the mouth.
4. Do not inhale while spraying. Spray into the mouth not the throat.
5. For best results, do not swallow for a few seconds after spraying.
6. If, after a few minutes, cravings are still present, spray once more.

Nicotine-containing e-cigarettes: Nicotine-containing electronic cigarettes (e-cigarettes) deliver a nicotine-containing vapour with lower levels of some of the toxins delivered in traditional cigarette smoke. These products are not authorized for sale in Canada and clinical trials of their safety and efficacy have not been reviewed by Health Canada to gain market approval here. Unanswered questions about e-cigarettes include their safety, efficacy for harm reduction and cessation, and total impact on public health. Dual use of e-cigarettes with cigarettes results in delayed or deferred quitting.¹¹ Another concern with e-cigarettes is that their use may undo some of the ‘denormalization’ of smoking achieved by smoke-free legislation and other measures, and create new smoking role models for children. An additional issue with the use of nicotine containing e-cigarettes relates to the observation that nicotine may be a ‘gateway drug.’

According to the gateway hypothesis, there is a well-defined developmental sequence of drug use that begins with legal drugs (e.g., nicotine and alcohol), which leads to illicit drug use (e.g., marijuana and cocaine).^4,8 Thus, with the uptake of e-cigarettes in the younger population, there is a possibility that this may create a new generation addicted to nicotine, which may be the precursor to the use of other drugs as well.

OTHER MEDICATIONS USED FOR SMOKING CESSATION

Bupropion is an antidepressant that inhibits the neuronal reuptake of dopamine and may act by maintaining dopamine levels. Bupropion suppresses nicotine withdrawal symptoms, and has demonstrated efficacy for smoking cessation in a number of clinical trials. Bupropion therapy increases the odds of smoking cessation approximately twofold.¹²

Bupropion should be started 1–2 weeks before the quit date and continued for 12 weeks. Seizures are the most serious adverse effect, occurring in an estimated 1 in 1000 users. Other adverse effects include insomnia, dry mouth, nervousness, difficulty concentrating, rash, and constipation.^12-14

Varenicline is a partial agonist that binds to the α4β2 nicotinic acetylcholine receptor, which is thought to mediate the rewarding properties of nicotine by modulating the release of dopamine in the nucleus accumbens. Varenicline is the most efficacious monotherapy for smoking cessation.^15,16 There have been concerns about the neuropsychiatric safety of varenicline, but a recent meta-analysis¹⁷ of randomized controlled trials found no evidence of an increased risk of suicide or attempted suicide, suicidal ideation, depression or death with varenicline.

Varenicline therapy should be started 1 week before the quit date, the dose should be titrated up and continued for at least 12 weeks. Adverse effects include nausea, sleep disturbances, constipation, flatulence and vomiting.^5,14

Conclusions

The most successful smoking cessation technique involves a combination of medication and behavioural support. Effective pharmacotherapy options include NRT (i.e. patch, inhaler, gum, lozenges) and the prescription medications bupropion and varenicline.

References

1. Stead LF, Perera R, Bullen C, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2012;11:CD000146.
2. Nicotine Replacement Therapy Labels May Change. Available at: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm345087.htm. Accessed September 19, 2016.
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4. Supporting Smoking Cessation: A Guide for Health Professionals. Melbourne: The Royal Australian College of General Practitioners; 2011. [Updated July 2014]. Available at: http://www.racgp.org.au/your-practice/guidelines/smoking-cessation/. Accessed September 19, 2016.
5. Pharmacologic Product Guide: FDA-approved Medications for Smoking Cessation. Available at: http://www.aafp.org/dam/AAFP/documents/client_care/tobacco/pharmacologic-guide.pdf. Accessed September 19, 2016.
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8. Algorithm for Tailoring Pharmacotherapy in Primary Care Setting. Available at: https://www.nicotinedependenceclinic.com/English/CANADAPTT/Pages/Home.aspx. Accessed September 19, 2016.
9. Mallin R. Smoking cessation: integration of behavioral and drug therapies. Am Fam Physician. 2002;65(6):1107-1114.
10. Hansson A, Hajek P, Perfekt R, et al. Effects of nicotine mouth spray on urges to smoke, a randomised clinical trial. BMJ Open. 2012;2(5).
11. Grana R, Benowitz N, Glantz SA. E-Cigarettes: A Scientific Review. Circulation. 2014;129(19):1972-1986.
12. Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: US Department of Health and Human Services. Public Health Service; 2008.
13. Roddy E. Bupropion and other non-nicotine pharmacotherapies. BMJ. 2004;328(7438):509-511.
14. Effective Pharmacological Aids to Smoking Cessation. Available at: https://www.health.gov.bc.ca/pharmacare/pdf/sc-prod-info.pdf. Accessed September 19, 2016.
15. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev. 2012;4:CD006103.
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17. Thomas KH, Martin RM, Knipe DW, et al. Risk of neuropsychiatric adverse events associated with varenicline: systematic review and meta-analysis. BMJ. 2015;350.