ReviewDISEASES AND DISORDERS

Current advances in research in treatment and recovery: Nicotine addiction

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Science Advances  16 Oct 2019:
Vol. 5, no. 10, eaay9763
DOI: 10.1126/sciadv.aay9763

Figures

  • Fig. 1 The nicotine addiction cycle.

Tables

  • Table 1 Diversity of tobacco products.

    ProductDefinitionTypespHNicotine levels
    CigaretteTobacco rolled in paper
    for smoking
    A typical cigarette weighs <1 g;
    regular length (70 mm long),
    king (84 mm), 100s (100 mm),
    and 120s (120 mm)
    Acidic, inhalable, pH 5.5–6Average in rod, 13.5 mg
    (range: 11.9–14.5 mg);
    nicotine yield to the
    smoker: 1–1.5 mg/cigarette
    CigarAir-cured, fermented tobacco
    wrapped in material made at
    least, in part, of tobacco leaf
    Small filtered cigars (0.9–1.3 g
    tobacco), cigarillos (1.3–2.5 g tobacco),
    and large (premium) cigars
    pH 6.5–8.0 inhalable and/or
    buccal depending on
    product pH
    Nicotine content ranges
    from 10 to 444 mg and
    dependent on weight of
    the cigar
    BluntCannabis filled in a
    hollowed-out cigarillo shell
    No pH data availableNicotine intake much lower
    than from cigarette or
    cigar smoking, but, based on
    animal studies, could
    enhance rewarding effects of
    delta 9-tetrahydrocannbinaol
    Smokeless tobaccoTobacco inserted between lip
    and gum or snorted into
    the nose rather than
    smoked by the user
    Snuff (ground tobacco), snus
    (ground tobacco in a tea bag–like
    pouch), chew (shredded
    tobacco)
    Products range from more
    acidic, pH 5.2–7.1, to more
    alkaline for greater buccal
    absorption, pH 7.6–8.6
    Nicotine concentrations vary,
    range of 0.2 to 34 mg/g,
    the more alkaline
    products are capable of
    delivering higher levels of
    nicotine
    Waterpipe/HookahCharcoal-heated flavored
    tobacco passed through a
    water-filled chamber that
    cools the smoke
    Water tobacco is a mixture of
    dried fruit, molasses and
    glycerin, and conventional
    tobacco leaf
    pH 3.8–5.8Average of 1.13 mg/g and
    high of 3.30 mg/g for
    product containing
    nicotine; nicotine-free for
    herbal (nontobacco) varieties
    Heated tobaccoElectronic devices that heat
    reconstituted tobacco
    sticks treated with a
    glycerin humectant to
    deliver an aerosol
    IQOS, Glo, and Ploom TechpH 5.5–6Nicotine delivery can match
    that of conventional cigarettes
    E-cigaretteElectric devices that produce
    an aerosol from a liquid
    that typically contains
    nicotine, propylene glycol,
    vegetable glycerin, and
    flavorings
    Cigalikes/e-pens, tank systems,
    pods/nicotine salts (e.g.,
    benzoate and lactate)
    Free base e-liquid: alkaline,
    pH 7–9; nicotine salts:
    acidic, inhalable, pH
    3.5–6.8
    E-liquid nicotine content
    from 0 to 100 mg/ml.
    Nicotine delivery can
    match that of
    conventional cigarette but
    varies by device design
    (heating temperature),
    e-liquid nicotine content,
    and user behavior
  • Table 2 FDA-approved medications for smoking cessation.

    Nicotine Replacement Therapy (NRT) FormulationsBupropion SRVarenicline
    GumLozengeTransdermal PatchNasal SprayOral Inhaler
    ProductNicorette1, Generic
    OTC 2 mg, 4 mg
    original, cinnamon,
    fruit, mint
    Nicorette1, Generic
    Nicorette1 Mini OTC
    2 mg, 4 mg;
    cherry, mint
    NicoDerm CQ1,
    Generic
    OTC (NicoDerm
    CQ, generic)
    7 mg, 14 mg, 21 mg
    (24-hr release)
    Nicotrol NS2 Rx
    Metered spray
    10 mg/mL nicotine
    solution
    Nicotrol Inhaler2 Rx
    10 mg cartridge
    delivers 4 mg
    inhaled vapor
    Zyban1, Generic Rx
    150 mg sustained-
    release tablet
    Chantix2
    Rx 0.5 mg, 1 mg
    tablet
    Precautions
    • Recent (≤ 2 weeks) myocardial infarction

    • Serious underlying arrhythmias

    • Serious or worsening angina pectoris

    • Temporomandibular joint disease

    • Pregnancy3 and breastfeeding

    • Adolescents (<18 years)

    • Recent (≤ 2 weeks) myocardial infarction

    • Serious underlying arrhythmias

    • Serious or worsening angina pectoris

    • Pregnancy3 and breastfeeding

    • Adolescents (<18 years)

    • Recent (≤ 2 weeks) myocardial infarction

    • Serious underlying arrhythmias

    • Serious or worsening angina pectoris

    • Pregnancy3 and breastfeeding

    • Adolescents (<18 years)

    • Recent (≤ 2 weeks) myocardial infarction

    • Serious underlying arrhythmias

    • Serious or worsening angina pectoris

    • Underlying chronic nasal disorders (rhinitis, nasal polyps, sinusitis)

    • Severe reactive airway disease

    • Pregnancy3 and breastfeeding

    • Adolescents (<18 years)

    • Recent (≤ 2 weeks) myocardial infarction

    • Serious underlying arrhythmias

    • Serious or worsening angina pectoris

    • Bronchospastic disease

    • Pregnancy3 and breastfeeding

    • Adolescents (<18 years)

    • Concomitant therapy with medications/conditions known to lower the seizure threshold

    • Hepatic impairment

    • Pregnancy3 and breastfeeding

    • Adolescents (<18 years)

    • Treatment-emergent neuropsychiatric symptoms4 Boxed warning removed 12/2016

    Contraindications:

    • Seizure disorder

    • Concomitant bupropion (e.g., Wellbutrin) therapy

    • Current or prior diagnosis of bulimia or anorexia nervosa

    • Simultaneous abrupt discontinuation of alcohol or sedatives/benzodiazepines

    • MAO inhibitors in preceding 14 days; concurrent use of reversible MAO inhibitors

    • Severe renal impairment (dosage adjustment is necessary)

    • Pregnancy3 and breastfeeding

    • Adolescents (<18 years)

    • Treatment-emergent neuropsychiatric symptoms4

      Boxed warning removed 12/2016

    Dosing1st cigarette ≤30
    minutes after
    waking: 4 mg
    1st cigarette >30
    minutes after
    waking: 2 mg
    Weeks 1–6:
    1 piece q 1–2 hours
    Weeks 7–9:
    1 piece q 2–4 hours
    Weeks 10–12:
    1 piece q 4–8 hours
    • Maximum, 24 pieces/day

    • Chew each piece slowly

    • Park between cheek and gum when peppery or tingling sensation appears (~15–30 chews)

    • Resume chewing when tingle fades

    • Repeat chew/park steps until most of the nicotine is gone (tingle does not return; generally 30 min)

    • Park in different areas of mouth

    • No food or beverages 15 minutes before or during use

    • Duration: up to 12 weeks

    1st cigarette ≤30
    minutes after
    waking: 4 mg
    1st cigarette >30
    minutes after
    waking: 2 mg
    Weeks 1–6:
    1 lozenge q 1–2 hours
    Weeks 7–9:
    1 lozenge q 2–4 hours
    Weeks 10–12:
    1 lozenge q 4–8 hours
    • Maximum, 20 lozenges/day

    • Allow to dissolve slowly (20–30 minutes)

    • Nicotine release may cause a warm, tingling sensation

    • Do not chew or swallow

    • Occasionally rotate to different areas of the mouth

    • No food or beverages 15 minutes before or during use

    • Duration: up to 12 weeks

    >10 cigarettes/day:
    21 mg/day x
    4–6 weeks
    14 mg/day x 2 weeks
    7 mg/day x 2 weeks
    ≤10 cigarettes/day:
    14 mg/day x 6 weeks
    7 mg/day x 2 weeks
    • Rotate patch application site daily; do not apply a new patch to the same skin site for at least one week

    • May wear patch for 16 hours if patient experiences sleep disturbances (remove at bedtime)

    • Duration: 8–10 weeks

    1–2 doses/hour
    (8–40 doses/day)
    One dose = 2 sprays
    (one in each nostril);
    each spray delivers
    0.5 mg of nicotine
    to the nasal mucosa
    • Maximum

      • 5 doses/hour or

      • 40 doses/day

    • For best results, initially use at least 8 doses/day

    • Do not sniff, swallow, or inhale through the nose as the spray is being administered

    • Duration: 3 months

    6–16 cartridges/day
    Individualize dosing;
    initially use 1
    cartridge q 1–2 hours
    • Best effects with continuous puffing for 20 minutes

    • Initially use at least 6 cartridges/day

    • Nicotine in cartridge is depleted after 20 minutes of active puffing

    • Inhale into back of throat or puff in short breaths

    • Do NOT inhale into the lungs (like a cigarette) but “puff” as if lighting a pipe

    • Open cartridge retains potency for 24 hours

    • No food or beverages 15 minutes before or during use

    • Duration: 3–6 months

    150 mg po q AM x 3 days,
    then 150 mg po bid
    • Do not exceed 300 mg/day

    • Begin therapy 1–2 weeks prior to quit date

    • Allow at least 8 hours between doses

    • Avoid bedtime dosing to minimize insomnia

    • Dose tapering is not necessary

    • Duration: 7–12 weeks, with maintenance up to 6 months in selected patients

    Days 1–3: 0.5 mg
    po q AM
    Days 4–7: 0.5 mg
    po bid
    Weeks 2–12: 1
    mg po bid
    • Begin therapy 1 week prior to quit date

    • Take dose after eating and with a full glass of water

    • Dose tapering is not necessary

    • Dosing adjustment is necessary for patients with severe renal impairment

    • Duration: 12 weeks; an additional 12-week course may be used in selected patients

    • May initiate up to 35 days before target quit date OR may reduce smoking over a 12-week period of treatment prior to quitting and continue treatment for an additional 12 weeks

    Adverse
    Effects
    • Mouth and throat irritation

    • Jaw muscle soreness

    • Hiccups

    • GI complaints (dyspepsia, nausea)

    • May stick to dental work

    • Mouth and throat irritation

    • Hiccups

    • GI complaints (dyspepsia, nausea)

    • Local skin reactions (erythema, pruritus, burning)

    • Sleep disturbances (abnormal or vivid dreams, insomnia); associated with nocturnal nicotine absorption

    • Nasal and/or throat irritation (hot, peppery, or burning sensation)

    • Ocular irritation/ tearing

    • Sneezing

    • Cough

    • Mouth and/or throat irritation

    • Cough

    • Hiccups

    • GI complaints (dyspepsia, nausea)

    • Insomnia

    • Dry mouth

    • Nausea

    • Anxiety/difficulty concentrating

    • Constipation

    • Tremor

    • Rash

    • Seizures (risk is 0.1%)

    • Neuropsychiatric symptoms (rare; see Precautions)

    • Nausea

    • Sleep disturbances (insomnia, abnormal/vivid dreams)

    • Headache

    • Flatulence

    • Constipation

    • Taste alteration

    • Neuropsychiatric symptoms (rare; see Precautions)

    • Adverse effects more commonly experienced when chewing the lozenge or using incorrect gum chewing technique (due to rapid nicotine release):

      • Lightheadedness/dizziness

      • Nausea/vomiting

      • Hiccups

      • Mouth and throat irritation

    Advantages
    • Might serve as an oral substitute for tobacco

    • Might delay weight gain

    • Can be titrated to manage withdrawal symptoms

    • Can be used in combination with other agents to manage situational urges

    • Relatively inexpensive

    • Might serve as an oral substitute for tobacco

    • Might delay weight gain

    • Can be titrated to manage withdrawal symptoms

    • Can be used in combination with other agents to manage situational urges

    • Relatively inexpensive

    • Once-daily dosing associated with fewer adherence problems

    • Of all NRT products, its use is least obvious to others

    • Can be used in combination with other agents; delivers consistent nicotine levels over 24 hours

    • Relatively inexpensive

    • Can be titrated to rapidly manage withdrawal symptoms

    • Can be used in combination with other agents to manage situational urges

    • Might serve as an oral substitute for tobacco

    • Can be titrated to manage withdrawal symptoms

    • Mimics hand-to-mouth ritual of smoking

    • Can be used in combination with other agents to manage situational urges

    • Twice-daily oral dosing is simple and associated with fewer adherence problems

    • Might delay weight gain

    • Might be beneficial in patients with depression

    • Can be used in combination with NRT agents

    • Relatively inexpensive (generic formulations)

    • Twice-daily oral dosing is simple and associated with fewer adherence problems

    • Offers a different mechanism of action for patients who have failed other agents

    • Most effective cessation agent when used as monotherapy

    Disadvantages
    • Need for frequent dosing can compromise adherence

    • Might be problematic for patients with significant dental work

    • Proper chewing technique is necessary for effectiveness and to minimize adverse effects

    • Gum chewing might not be acceptable or desirable for some patients

    • Need for frequent dosing can compromise adherence

    • Gastrointestinal side effects (nausea, hiccups, heartburn) might be bothersome

    • When used as monotherapy, cannot be titrated to acutely manage withdrawal symptoms

    • Not recommended for use by patients with dermatologic conditions (e.g., psoriasis, eczema, atopic dermatitis)

    • Need for frequent dosing can compromise adherence

    • Nasal administration might not be acceptable or desirable for some patients; nasal irritation often problematic

    • Not recommended for use by patients with chronic nasal disorders or severe reactive airway disease

    • Cost of treatment

    • Need for frequent dosing can compromise adherence

    • Cartridges might be less effective in cold environments (≤60°F)

    • Cost of treatment

    • Seizure risk is increased

    • Several contraindications and precautions preclude use in some patients (see Precautions)

    • Patients should be monitored for potential neuropsychiatric symptoms4 (see Precautions)

    • Patients should be monitored for potential neuropsychiatric symptoms4 (see Precautions)

    • Cost of treatment

    Cost/day52 mg or 4 mg:
    $1.90–$3.60
    (9 pieces)
    2 mg or 4 mg:
    $3.33–$3.60
    (9 pieces)
    $1.52–$2.90
    (1 patch)
    $8.72
    (8 doses)
    $14.88
    (6 cartridges)
    $2.58–$8.25
    (2 tablets)
    $15.14
    (2 tablets)

    Abbreviations: MAO, monoamine oxidase; NRT, nicotine replacement therapy; OTC, over-the-counter (nonprescription product); Rx, prescription product.

    For complete prescribing information and a comprehensive listing of warnings and precautions, please refer to the manufacturers’ package inserts.

    Copyright © 1999-2019 The Regents of the University of California. All rights reserved. Updated January 9, 2019.

    1Marketed by GlaxoSmithKline.

    2Marketed by Pfizer.

    3The U.S. Clinical Practice Guideline states that pregnant smokers should be encouraged to quit without medication based on insufficient evidence of effectiveness and theoretical concerns with safety. Pregnant smokers should be offered behavioral counseling interventions that exceed minimal advice to quit.

    4In July 2009, the FDA mandated that the prescribing information for all bupropion- and varenicline-containing products include a black-boxed warning highlighting the risk of serious neuropsychiatric symptoms, including changes in behavior, hostility, agitation, depressed mood, suicidal thoughts and behavior, and attempted suicide. Clinicians should advise patients to stop taking varenicline or bupropion SR and contact a health care provider immediately if they experience agitation, depressed mood, or any changes in behavior that are not typical of nicotine withdrawal, or if they experience suicidal thoughts or behavior. If treatment is stopped due to neuropsychiatric symptoms, patients should be monitored until the symptoms resolve. Based on results of a mandated clinical trial, the FDA removed this boxed warning in December 2016.

    5Approximate cost based on the recommended initial dosing for each agent and the wholesale acquisition cost from Red Book Online. Thomson Reuters, December 2018.

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