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Summary Table

Domain	High-Yield Detail
Risk Factors	Heavy daily smoker (greater than 10 cigarettes/day), high score on the Fagerstrom Test for Nicotine Dependence, prior failed quit attempts, comorbid psychiatric illness (depression, anxiety, schizophrenia), low socioeconomic status
Etiology	Abrupt cessation or marked reduction of prolonged, regular nicotine use leading to a state of relative dopaminergic deficit in the mesolimbic reward pathway
Patient Presentation	A patient who recently quit smoking now presents with irritability, anxiety, difficulty concentrating, insomnia, and increased appetite within hours to days of cessation
Classic Physical Exam	No pathognomonic physical signs; the patient appears restless, agitated, and may demonstrate weight gain on follow-up. Vital signs are generally unremarkable, though a mild decrease in heart rate compared to baseline smoking state may be observed
Key Diagnostic Results	Clinical diagnosis based on DSM-5 criteria (no confirmatory lab required). Urine cotinine or serum cotinine can verify recent tobacco use or abstinence but are not required for diagnosis
Management	First-line pharmacotherapy: Varenicline, Bupropion SR, or Nicotine Replacement Therapy (NRT). All patients should also receive behavioral counseling (the "5 A's" framework). Combination therapy (e.g., NRT patch + short-acting NRT) is superior to monotherapy
Keywords	"Recently quit smoking," "irritable and anxious after stopping cigarettes," "craving cigarettes," "restless with increased appetite," "difficulty concentrating after smoking cessation"

1. Pathophysiology

Nicotine exerts its central effects by binding to nicotinic acetylcholine receptors (nAChRs), most importantly the alpha-4/beta-2 (α4β2) subtype located on dopaminergic neurons in the ventral tegmental area (VTA). When nicotine activates these receptors, it triggers a surge of dopamine release into the nucleus accumbens, the brain's core reward center. This dopamine surge is what produces the pleasurable, calming, and concentration-enhancing effects of smoking.

With chronic, repeated nicotine exposure, the brain undergoes a compensatory upregulation of nAChRs. The total number of receptors on the neuronal surface increases substantially because the brain is attempting to maintain homeostasis in the face of constant receptor stimulation. As long as the patient continues to smoke, these extra receptors remain occupied and the system stays in balance.

The moment nicotine is abruptly removed, the problem becomes clear: there are now far more receptors than there is endogenous acetylcholine to stimulate them. This creates a functional state of cholinergic and dopaminergic underactivity in the mesolimbic pathway. The result is the classic withdrawal syndrome: irritability and frustration (loss of reward signaling), anxiety and restlessness (unopposed stress-circuit activation), depressed mood (dopamine deficit), difficulty concentrating (loss of nicotine's pro-cognitive cholinergic effect), increased appetite and weight gain (nicotine normally suppresses appetite via hypothalamic pathways and increases basal metabolic rate), and insomnia (disruption of sleep-wake neurotransmitter balance).

The timeline of withdrawal is predictable and often tested. Symptoms begin within 2 to 12 hours of the last cigarette, peak at 24 to 72 hours, and gradually improve over 2 to 4 weeks. However, cravings can persist for months to years, driven by conditioned environmental cues that reactivate reward-associated memory circuits.

2. Classification and Clinical Manifestation

Symptom	Clinical Correlation	Onset / Duration
Irritability, frustration, or anger	Most commonly reported symptom; dopamine deficit in the reward circuit	Peaks at 24 to 48 hours; lasts 2 to 4 weeks
Anxiety	Unopposed noradrenergic and CRF (corticotropin-releasing factor) activity	Peaks within the first week
Difficulty concentrating	Loss of nicotine's cholinergic enhancement of prefrontal attention circuits	Peaks at 24 to 72 hours; lasts up to 2 weeks
Increased appetite / weight gain	Removal of nicotine's anorexigenic and metabolic effects; average gain of 4 to 5 kg	Begins within days; appetite normalizes over weeks, but weight gain may persist
Restlessness	General CNS hyperexcitability from receptor upregulation without ligand	Peaks at 48 to 72 hours
Depressed mood	Reduced dopaminergic tone in the nucleus accumbens	Peaks within the first week; monitor closely in patients with psychiatric history
Insomnia	Disruption of nicotine's modulatory role on sleep-wake neurotransmitters (ACh, serotonin)	Peaks at 48 to 72 hours; improves within 1 to 2 weeks
Decreased heart rate	Loss of nicotine's sympathomimetic effect on the cardiovascular system	Measurable within 24 hours

3. Diagnostic Workup

Test	Role	Key Detail
Clinical history and DSM-5 criteria	Best initial and confirmatory "test"	Diagnosis is entirely clinical; no lab test is required
Fagerstrom Test for Nicotine Dependence (FTND)	Severity assessment tool	6-item questionnaire; score 0 to 10. A score of 6 or higher indicates high dependence and predicts more severe withdrawal
Urine cotinine	Objective biomarker of tobacco use/abstinence	Cotinine (nicotine metabolite) has a half-life of approximately 16 hours. A level above 200 ng/mL suggests active smoking. Useful for verification, not diagnosis
Exhaled carbon monoxide (CO)	Point-of-care confirmation of smoking status	CO level above 8 to 10 ppm suggests recent smoking; useful in cessation programs for monitoring

Nicotine withdrawal is a clinical diagnosis. When a vignette describes a patient who has recently quit or significantly reduced cigarette use and develops at least four of the cardinal symptoms listed above within 24 hours, the answer is nicotine withdrawal. You do not need to order labs to make this diagnosis.

The Fagerstrom Test for Nicotine Dependence is the most commonly referenced screening instrument in the exam context. Two questions from this tool are particularly high-yield: (1) "How soon after waking do you smoke your first cigarette?" and (2) "How many cigarettes per day do you smoke?" A patient who smokes within 5 minutes of waking and consumes more than 30 cigarettes per day is at the highest tier of dependence and is expected to have the most severe withdrawal.

Cotinine testing and exhaled CO are adjunctive tools used primarily in cessation clinics and research settings. They are not part of the diagnostic criteria but may appear in a question stem to confirm or refute active tobacco use.

4. Management and Treatment

Intervention	Category	Dosing / Protocol	Duration
Varenicline	First-line pharmacotherapy (partial agonist at α4β2 nAChR)	Days 1 to 3: 0.5 mg once daily. Days 4 to 7: 0.5 mg twice daily. Day 8 onward: 1 mg twice daily. Start 1 week before the target quit date	12 weeks (may extend to 24 weeks to prevent relapse)
Bupropion SR	First-line pharmacotherapy (norepinephrine-dopamine reuptake inhibitor)	Days 1 to 3: 150 mg once daily. Day 4 onward: 150 mg twice daily. Start 1 to 2 weeks before the target quit date	7 to 12 weeks (may continue up to 6 months)
NRT Patch	First-line pharmacotherapy (long-acting NRT)	Greater than 10 cigarettes/day: 21 mg/day for 6 weeks, then 14 mg/day for 2 weeks, then 7 mg/day for 2 weeks	8 to 10 weeks total taper
NRT Gum / Lozenge	First-line pharmacotherapy (short-acting NRT)	First cigarette within 30 minutes of waking: use 4 mg. Otherwise: use 2 mg. Dose: 1 piece every 1 to 2 hours for weeks 1 to 6, then taper	12 weeks
NRT Inhaler / Nasal Spray	First-line pharmacotherapy (short-acting NRT, prescription only)	Inhaler: 6 to 16 cartridges/day. Nasal spray: 1 to 2 doses/hour (max 40 doses/day)	Up to 6 months with taper
Behavioral counseling (5 A's)	Nonpharmacologic, recommended for ALL patients	Ask, Advise, Assess, Assist, Arrange follow-up	Ongoing
Combination NRT	Superior to monotherapy	Long-acting (patch) + short-acting (gum or lozenge) for breakthrough cravings	As above

Step 1: Behavioral Counseling for Every Patient. The 5 A's framework is the recommended approach and should be offered universally, regardless of whether pharmacotherapy is also used. (1) Ask about tobacco use at every visit. (2) Advise the patient to quit in a clear, personalized manner. (3) Assess willingness to make a quit attempt. (4) Assist by providing a quit plan, pharmacotherapy, and resources. (5) Arrange a follow-up contact within the first week after the quit date.

Step 2: Select Pharmacotherapy Based on Patient Profile. For most patients ready to quit, varenicline is the preferred first-line agent based on evidence of superior efficacy compared to NRT monotherapy or bupropion alone. Varenicline works by partially stimulating the α4β2 receptor (providing a low level of dopamine release to reduce cravings and withdrawal) while simultaneously blocking nicotine from fully activating the receptor if the patient relapses. This dual mechanism is why it is the highest-yield drug to know.

Bupropion SR is an excellent alternative, particularly in patients with comorbid depression, as it has independent antidepressant properties. It is contraindicated in patients with a seizure disorder, current or prior eating disorder (anorexia nervosa or bulimia nervosa), or concurrent use of MAO inhibitors, as bupropion lowers the seizure threshold.

NRT is appropriate for patients who prefer an over-the-counter option or have contraindications to varenicline or bupropion. Combination NRT (patch for baseline control plus gum or lozenge for breakthrough cravings) has been shown to be more effective than a single NRT product and is recommended by current guidelines.

Step 3: Timing Matters. Both varenicline and bupropion must be started before the quit date (1 week for varenicline, 1 to 2 weeks for bupropion) to allow steady-state drug levels to build up before the patient stops smoking. NRT, by contrast, is started on the quit date itself. Patients should not smoke while using NRT, as the additive nicotine can cause toxicity (nausea, tachycardia, hypertension).

Step 4: Manage Relapse. If a patient relapses, the appropriate response is to re-engage them in counseling, reassess pharmacotherapy, and set a new quit date. Relapse is common (most smokers require multiple quit attempts) and should not be treated as failure.

Contraindications and Cautions

Drug	Contraindication / Caution
Varenicline	Previously carried an FDA black box warning for neuropsychiatric events (suicidal ideation, behavioral changes); this was removed in 2016 after large trial data showed no increased risk. Still monitor patients with pre-existing psychiatric conditions
Bupropion	Seizure disorder, eating disorder (anorexia/bulimia), concurrent MAOIs, abrupt discontinuation of alcohol or sedatives
NRT	Caution within 2 weeks of an acute myocardial infarction, serious arrhythmia, or unstable angina (though NRT is still safer than continued smoking)
All agents in pregnancy	Behavioral counseling alone is first-line in pregnant patients. If pharmacotherapy is needed, NRT (intermittent dosing forms like gum or lozenge) is preferred over systemic agents

5. Differential Diagnosis and Distractors

Differential	Why It Is Similar	Key Discriminator
Generalized Anxiety Disorder (GAD)	Both present with anxiety, restlessness, difficulty concentrating, insomnia	GAD is chronic (present for at least 6 months) with excessive worry across multiple domains. Nicotine withdrawal has a clear temporal link to smoking cessation and resolves within 2 to 4 weeks
Major Depressive Disorder (MDD)	Depressed mood, insomnia, poor concentration, appetite changes overlap	MDD requires symptoms lasting at least 2 weeks and typically includes anhedonia, guilt, and psychomotor changes. In withdrawal, depressed mood is temporally tied to cessation and is accompanied by cravings and irritability rather than guilt or worthlessness
Caffeine Withdrawal	Irritability, difficulty concentrating, depressed mood, and headache	Caffeine withdrawal prominently features a diffuse headache, which is not characteristic of nicotine withdrawal. The history will reveal recent cessation of coffee or caffeinated beverages rather than tobacco
Adjustment Disorder	Anxiety, depressed mood, and behavioral disturbance after a stressor	The stressor in adjustment disorder is psychosocial (job loss, divorce). In the vignette, the "stressor" is physiologic (nicotine cessation), and the symptom profile matches the DSM-5 withdrawal criteria
Hyperthyroidism	Anxiety, restlessness, insomnia, weight loss, irritability	Hyperthyroidism presents with heat intolerance, tremor, tachycardia, and elevated free T4/low TSH. Nicotine withdrawal causes weight gain, not weight loss, and has no thyroid-related findings
Substance withdrawal (alcohol, benzodiazepines)	Anxiety, insomnia, restlessness, autonomic instability	Alcohol and benzodiazepine withdrawal can produce tremor, seizures, and delirium, which are not features of nicotine withdrawal. Nicotine withdrawal is uncomfortable but not life-threatening

6. Traps and High-Yield Pearls

The most common way students lose points on nicotine withdrawal questions is by overthinking the diagnosis. The vignette will describe a patient who recently quit smoking and now presents with a constellation of mood and behavioral symptoms. Students often jump to a primary psychiatric diagnosis (GAD, MDD, adjustment disorder) because the symptoms overlap. The key to getting the question right is recognizing the temporal relationship: the symptoms began within hours to days of smoking cessation. If the timeline fits, the answer is nicotine withdrawal, not a new psychiatric disorder.

A second major trap involves pharmacotherapy selection. Students frequently confuse the mechanisms and contraindications of varenicline and bupropion. Remember: Varenicline is a partial agonist (stimulates the receptor just enough to ease withdrawal while blocking nicotine's full effect if the patient smokes). Bupropion is a norepinephrine-dopamine reuptake inhibitor with a seizure risk profile. If the vignette includes a history of seizures or an eating disorder, bupropion is the wrong answer.

A third testing point is the timing of drug initiation. Both varenicline and bupropion are started before the quit date, not on the day of cessation. NRT is started on the quit date. This distinction is a favorite "next best step" question format.

Finally, for pregnant patients, the tested answer is almost always behavioral counseling first. Pharmacotherapy in pregnancy is reserved for patients who cannot quit with counseling alone, and when used, short-acting NRT (gum or lozenge) is preferred to minimize sustained fetal nicotine exposure.

The core competency being tested is the ability to recognize a substance withdrawal syndrome based on its temporal pattern, select appropriate pharmacotherapy while respecting contraindications, and apply the correct sequencing of behavioral and pharmacologic interventions.

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