CONTENTS

• Overview
• Varenicline
• Nicotine replacement therapy
• Bupropion
• Clonidine
• Questions & discussion

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overview

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basics

• Nicotine and other substances in tobacco are extremely addictive. As such, tobacco addiction is a chronic relapsing disorder which requires aggressive and ongoing therapy.
• Patients frequently require several attempts before successfully quitting. Cravings can persist long after smoking cessation, making this a major driver of relapse.
• The most effective therapies are combination strategies involving counseling as well as pharmacological support.

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assessment

• Intensity of smoking:
  • Cigarettes per day?
  • How early is their first cigarette (<30 or >30 min after waking)?
• Readiness/interest in quitting?
• Prior quitting attempts?
  • Success with any particular therapy?
  • Adverse effects from any therapies?
• Barriers or concerns regarding quitting?
• Explore motivations to quit (financial, health-related).

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selection of pharmacotherapy

most effective overall

• (#1) Varenicline ⚡️ +/- nicotine patch is generally preferred as front-line therapy (based on superiority in head-to-head trials as compared to bupropion or nicotine replacement). (35939580)
  • Varenicline has additionally been shown to be effective for inpatient initiation. (EVITA trial, 26553744)
• (#2) Nicotine patch + PRN short-acting nicotine products ⚡️ is another front-line strategy.
• (#3) Bupropion ⚡️ +/- nicotine patch.
  • Nicotine replacement plus bupropion seems to provide synergistic activity. (Fishman 2023)

patient-centered selection

• If a patient was previously successful with one drug, it's generally best to use the same medication again. (35233133)
• Helpful with weight loss: bupropion, nicotine replacement therapy.
• For patients with depression, bupropion may be especially beneficial.
• 🤰Pregnancy: Nicotine replacement is generally the safest form of pharmacotherapy (there are risks, but it's preferable to ongoing tobacco use). The American College of Obstetricians and Gynecologists recommends that nicotine replacement therapy be considered for pregnant women. (34210714) Varenicline is contraindicated. 

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nonpharmacologic therapies

counseling & follow-up

• 1-800-QUIT-NOW (1-800-784-8669) provides free counseling and support.
• Follow-up should be arranged with the patient's primary care physician.

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varenicline

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mechanism & pharmacology

• Varenicline is a partial agonist of the alpha-4 beta-2 nicotinic receptor (which is the target of nicotine in the brain). As a partial agonist it may prevent withdrawal, but also block the effect of full agonism if the patient does relapse (it's essentially the suboxone of nicotine addiction).
• Half-life is 24 hours.
• Varenicline may be combined with a nicotine patch to achieve higher success rates. (25005652, 26198192)

precautions/contraindications

• ⚠️ Renal dysfunction (cleared by the kidneys, so dose must be adjusted accordingly).
• ⚠️ Acute kidney injury (varenicline has demonstrated nephrotoxicity in rats; it's unclear whether it is also nephrotoxic in humans). (25812822) 
• ⚠️ OCT2 inhibitors (human organic cation transport) will increase the drug level of varenicline; these include:
  • Erdafitinib.
  • Histamine type 2 receptor blockers (aka H2-blockers).
  • Quinolones.
  • Trimethoprim.
  • Vandetanib.

adverse effects

• Severe nausea (this is usually self-limiting, and may also be reduced with gradual dose titration), xerostomia.
• Insomnia, vivid dreams.
• Headache.
• Increased effects from alcohol co-administration. (34210714)
• Neuropsychiatric symptoms (rare; generally felt to be safe among people with stable mental illness; neuropsychiatric symptoms weren't observed in randomized trials or meta-analyses). (35233133, 34210714)

dose & duration

• Dose escalation:
  • 0.5 mg/day for three days.
  • 0.5 mg BID for 4 days.
  • 1 mg BID.
  • If adverse effects occur, the dose may be reduced back to 0.5 mg BID. (34210714)
  • Instructions: Take medication with food and a full glass of water (to avoid nausea).
• Timing:
  • Ideally start treatment 1 week before quit date.
  • The EVITA trial demonstrated that varenicline can be effectively initiated during hospitalization. (26553744)
• Duration: continue for 3-6 months.

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nicotine replacement therapy

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mechanism & pharmacokinetics

• A 21-mg nicotine patch delivers about the same concentration of nicotine as one half pack of cigarettes per day (10/day). For many patients, this is an inadequate dose to prevent withdrawal and cravings (by itself). (35939580) Nicotine therapy is safe but often suffers from inadequate dosing. Two approaches to this include either: 
  • (i) Oral nicotine may be used as a supplement to the patch.
  • (ii) Two patches may be needed for patients with greater dependency. (35233133)
• At least ten weeks of treatment is recommended. However, extending the course for 12-18 months may help reduce relapse. (35233133) Some people may need to use nicotine replacement indefinitely (which should be viewed as a treatment success, if it achieves durable smoking cessation). (34210714)

selection of modality

• Gum, lozenges, and patches are widely available (including over the counter).
• Adherence may be best with the patch.
• Combination therapy may be the most effective (patch + PRN gum/lozenge). PRN gum/lozenge is more rapid-acting, to manage breakthrough cravings.

nicotine gum

• Dose is based on the patient's prior pattern of smoking:
  • First cigarette >30 minutes after waking: 2-mg dose of nicotine gum.
  • First cigarette <30 minutes after waking: 4-mg dose of nicotine gum.
  • Q1hr PRN, up to 24 pieces of gum/day.
• Instructions: Gum must be chewed very slowly and frequently parked in different parts of the mouth, over ~30 minutes.
• Potential side effects: dyspepsia, nausea/vomiting, throat irritation, headache, palpitations.

nicotine lozenge

• Dose:
  • First cigarette >30 minutes after waking: 2 mg
  • First cigarette <30 minutes after waking: 4 mg
  • Q1hr PRN, up to 20 lozenges per day.
• Instructions: Allow to dissolve on its own, rotate between different areas of the mouth.
• Potential side effects: dyspepsia, nausea/vomiting, throat irritation, headache, palpitations.

nicotine patch

• Advantages: Easy to use, high compliance.
• Dose:
  • >10 cigarettes/day (>half-pack/day):
    • 21 mg for 4 weeks
    • 14 mg for 2 weeks
    • 7 mg for two weeks
  • <10 cigarettes/day (<half-pack/day):
    • 14 mg for 6 weeks.
    • 7 mg for 2 weeks.
  • Apply daily in the morning. If insomnia or disturbing dreams occur, remove the patch at bedtime.
  • Rotate sites, avoiding use of the same site for a week.
• Potential side effects: insomnia, vivid dreams, skin irritation.

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bupropion

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mechanism of action

• Bupropion is a dopamine-norepinephrine reuptake inhibitor.
• The mechanism of action for bupropion in tobacco cessation isn't entirely clear. However, it's possible that effects on dopamine and noradrenaline receptors may mimic the effect of nicotine. (34210714)
• (Chapter on bupropion intoxication: 📖)

advantages

• Additionally functions as an antidepressant.
• May prevent weight gain.
• Can be safely utilized in combination with a nicotine patch.

precautions/contraindications

• ⚠️ Seizure disorder, or high risk for seizures (e.g., known stroke, brain tumor, CNS infection, severe head injury, acute alcohol withdrawal). (34210714)
• ⚠️ Risk of serotonin syndrome:
  • Multiple other serotonergic medications. 📖
  • Use of monoamine oxidase (MAO) inhibitor within the last two weeks.
• ⚠️ Current or prior eating disorder (bulimia or anorexia), since bupropion could exacerbate malnutrition.
• ⚠️ Bupropion is a strong inhibitor of CYP2D6, which may increase the concentration of drugs cleared by this enzyme. (34210714)
• ⚠️ Bupropion increases dopamine levels, which may be problematic in patients on medications for Parkinson disease. (34210714)
• ⚠️ Bupropion may decrease digoxin levels. (34210714)

adverse effects

• Insomnia (avoid dosing before sleep; space doses at least 8 hours apart).
• Weight loss.
• Xerostomia (dry mouth), pharyngitis.
• Nausea/vomiting.
• Headache.
• Seizure (risk of 1/1,000). (35233133)
• (Neuropsychiatric symptoms don't seem to be more common with bupropion as compared to placebo). (34210714)

dosage & duration

• Dosing regimes:
  • Standard: 150 mg bupropion XR qAM for three days, then 150 mg BID.
  • A fixed dose of 150 mg bupropion XR qAM is nearly as effective as BID dosing, so this may also be utilized. (Fishman 2023)
• Start 1-2 weeks before quit date.
• Duration of therapy:
  • Initiation: 7-12 weeks.
  • Maintenance: may be used long term (e.g., >1 year).

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clonidine

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• Clonidine is not a preferred, front-line therapy for smoking cessation.
• Clonidine may be used to treat withdrawal symptoms. (34210714)
• (Further discussion of clonidine here: 💉)

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questions & discussion

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