Nicotine Withdrawal

Nicotine withdrawal is the symptom complex that follows abrupt reduction or cessation of regular nicotine use (cigarettes, other tobacco, e-cigarettes, nicotine pouches and chewing tobacco). It is the main reason that quit attempts fail and is treatable.

• Onset 4 to 24 hours after the last nicotine, peak at days 2 to 3, and resolution over 2 to 4 weeks; craving and mood symptoms may persist for months.
• Mechanism: chronic nicotine upregulates nicotinic acetylcholine receptors; abrupt withdrawal reduces dopamine release in the reward circuit and causes irritability and craving.
• Severity depends on the number of cigarettes per day, time to first cigarette in the morning (within 30 minutes signals high dependence), prior withdrawal severity, mental illness, and use of other substances.
• Smoking is the leading preventable cause of death; quitting at any age reduces mortality, and quitting before age 40 reduces excess risk by about 90 percent.

• Craving, irritability, anger, anxiety, restlessness, difficulty concentrating, low mood, insomnia, increased appetite and weight gain (average 3 to 5 kg), constipation, headache, cough and mouth ulcers, bradycardia.
• Depressed mood may unmask or worsen depression; look for suicidal thoughts.
• Smoking cessation changes the metabolism of certain drugs: clozapine and olanzapine levels rise (by about 50 percent and 30 to 50 percent respectively), as do levels of theophylline, caffeine, warfarin (sometimes), flecainide, and imipramine; monitoring and dose reduction may be required.
• Assess dependence: cigarettes per day, time to first cigarette, previous attempts, reasons for relapse, motivation, other tobacco and vaping use, mental health, alcohol and drug use, medical conditions, and pregnancy.

• Clinical, based on a history of regular nicotine use and the characteristic symptoms within 24 hours of stopping.
• Measure dependence with the Fagerstrom Test for Nicotine Dependence (score 6 or more is high dependence) or the Heaviness of Smoking Index.
• Exhaled carbon monoxide (over 10 ppm suggests smoking) or urine and salivary cotinine to verify abstinence.
• Screen for depression (PHQ-9), anxiety, alcohol use, and cardiovascular risk (blood pressure, lipids, glucose); spirometry in smokers over 35 with respiratory symptoms.
• Differentials: anxiety disorder, depression, caffeine withdrawal, alcohol or cannabis withdrawal, hyperthyroidism, and side effects of stop smoking medicines.

Behavioural support (all patients)

• Brief advice: ask, advise and offer help at every contact; agree a quit date; weekly or twice weekly support for the first 4 weeks (individual, group or telephone); coping plans for triggers; remove cigarettes; involve family; regular exercise.
• Combined behavioural support and medicine doubles to triples abstinence rates compared with willpower alone.

Nicotine replacement therapy (use combination for best effect)

• Combination therapy: a patch plus a short acting form (gum, lozenge, inhaler, mouth spray).
• 24-hour patch (more than 10 cigarettes/day): 21 mg daily for 6 weeks, then 14 mg for 2 weeks, then 7 mg for 2 weeks; for 10 or fewer cigarettes/day, start at 14 mg for 6 weeks, then 7 mg for 2 to 4 weeks. 16-hour patch: 25 mg, 15 mg, 10 mg in similar steps (remove at night if vivid dreams or insomnia).
• Gum or lozenge: 2 mg if first cigarette is more than 30 minutes after waking, 4 mg if within 30 minutes, one every 1 to 2 hours as needed (maximum 15 to 24 pieces daily); inhaler 15 mg cartridge (6 to 12 daily); mouth spray 1 mg per spray (1 to 2 sprays every 30 to 60 minutes, maximum 64 sprays daily). Continue 8 to 12 weeks, then taper.
• Side effects: skin irritation (rotate sites), vivid dreams, local mouth irritation, hiccups, nausea. Nicotine replacement is safe in stable cardiovascular disease.

Varenicline (the most effective single agent)

• 0.5 mg orally once daily on days 1 to 3, 0.5 mg twice daily on days 4 to 7, then 1 mg twice daily; set the quit date between days 8 and 35; treat for 12 weeks and extend for another 12 weeks if abstinent. Take after food with a full glass of water.
• Creatinine clearance below 30 mL/min: start 0.5 mg once daily, up to 0.5 mg twice daily maximum.
• Side effects: nausea (about 30 percent), abnormal dreams, insomnia, headache, constipation. Neuropsychiatric safety is acceptable in people with and without mental illness; stop if agitation, hostility, depressed mood or suicidal thoughts appear. Do not use in pregnancy.

Bupropion

• Bupropion sustained release 150 mg orally once daily for 6 days, then 150 mg twice daily (maximum 300 mg daily) for 7 to 9 weeks; quit date in the second week. Contraindicated with seizure disorder, eating disorder, bipolar disorder, alcohol or benzodiazepine withdrawal, brain tumour and severe liver disease; reduce the dose in renal or hepatic impairment; avoid with monoamine oxidase inhibitors and with tamoxifen; monitor blood pressure.

Cytisine

• Cytisine 1.5 mg orally six times daily for days 1 to 3 (one tablet every 2 hours while awake), then reducing the frequency over 25 days (five times daily on days 4 to 12, four times daily on days 13 to 16, three times daily on days 17 to 20, then 1 to 2 tablets daily on days 21 to 25); where available, it is a low cost alternative with efficacy similar to varenicline. Avoid in pregnancy and with unstable cardiovascular disease.

Relapse prevention and weight

• Review at 1 week, 4 weeks, 12 weeks and 6 months; check carbon monoxide; treat any slip as a lapse and reset the quit date; advise on diet and activity to limit weight gain; do not cut back on medicines too early.

Special groups

• Pregnancy: behavioural support first; if unsuccessful, nicotine replacement (intermittent forms or a patch removed at night) is safer than smoking; varenicline and bupropion are avoided unless specialist advice.
• Mental illness: offer the same medicines; coordinate with the mental health team to monitor and adjust clozapine, olanzapine and other drug doses (reduce clozapine by about 10 percent a day to 25 percent over a week, check levels at 1 and 2 weeks).
• Adolescents: behavioural support first; nicotine replacement for those who are heavily dependent, under specialist supervision.
• Cardiovascular disease: nicotine replacement and varenicline are safe after stabilisation.