Tobacco Cessation and Substance Use Management

Which receptor does nicotine bind to?

a4B2 nicotinic receptor, the most abundant receptor in the brain.

What determines high dependence of nicotine?

Time to first cigarette

What are the therapeutic targets of nicotine management?

NRT: occupies receptors, blunts withdrawal

Varenicline: partial a4B2 agonist, relieves and blocks

Bupropion: boosts dopamine/NE; blocks nAChR

Behavioral therapy: retrains conditioned cues

Which medications should be started before the quit date for cigarettes?

Bupropion (start 1 week before) or Varenicline.

What is the MOA of nicotine replacement therapy?

Delivers nicotine without combustion toxins; partially occupies a4B2 nACHRs to blunt withdrawal, long-acting patch gives steady levels, short-acting forms treat breakthrough craving.

Describe the class and typical US dosing of the patch NRT

Class: Long-acting

Dosing: > 10 cig/day: 21mg/24h x 6 weeks then 14mg x 2 weeks then 7 mg x 2 weeks. ≤10 cig/day: start at 14mg. Can start on quit date

Describe the class and typical US dosing of the gum NRT

Class: Short-acting

Dosing: First cigarette > 30 minutes after waking: 2mg. ≤30 min after waking: 4mg. One piece q1-2h; max 24/day.

What are the cautions and CI to NRT?

No absolute CI in most adults

Caution: MI within 2 weeks, unstable angina, although continued smoking is worse!

Caution: serious or worsening arrhythmias

Gum/lozenge: TMJ disease, dentures, ulcers

What are the local ADE of NRT?

Patch: erythema and itching, rotate sites

Gum/lozenge: jaw ache, hiccups, dyspepsia

Inhaler: mouth and throat irritation, cough

Spray: nasal burning, sneezing, watery eyes

What are the systemic ADE of NRT?

HA, D/N, palpitations

Vivid dreams or insomnia with the 24 hour patch

Remove patch at bedtime if sleep is disrupted

Excess: nausea, tachycardia, cold sweat

What are the counseling pearls of NRT?

Gum: chew until peppery, then park in cheek

Repeat park-and-chew for about 30 minutes

Lozenge: let dissolve, never chew or swallow

No acidic drinks 15 minutes before or during use - completely blocks nicotine absorption.

What is the MOA of Bupropion?

Inhibits reuptake of NE and DA by blocking their transporters.

What are the key ADE of Bupropion?

Seizures

Insomnia

Anxiety, agitation (may occur early in treatment)

Nausea, dry mouth, HA

Weight loss

What is the success rate of Bupropion after 12 weeks of therapy for nicotine?

35%

What is the dosing for Bupropion SR?

150 mg PO once daily x 3 days

Then 150 mg PO BID, ≥8 hours apart

Start 1-2 weeks before the quit date

Continue: 7-12 weeks; may extend to 6 months

What is the MOA of Varenicline?

Partial agonist at a4B2 nicotinic Ach receptors. Stimulates these receptors, blocks nicotine and leads to partial activation which reduces dopamine release.

How should you dose Varenicline in renal impairment?

Halve the dose

What is the success rate of Varenicline at 12 weeks?

40%

What are the key ADE of Varenicline?

Nausea

Vivid/abnormal dreams

Headache

Insomnia

What is the main therapeutic use of Varenicline?

Smoking cessation. It reduces cravings and withdrawal symptoms.

When should you start Varenicline and how is it renally dosed?

Start 1 week before the quit date, but can quit any time during weeks 2-5.

CrCl < 30: maximum 0.5 mg BID

ESRD on hemodialysis: maximum 0.5 QD

How do you titrate Vareniciline?

Days 1-3: 0.5 mg PO QD

Days 4-7: 0.5 mg PO BID

Day 8 onward: 1mg PO BID x 12 weeks

Take after food with a full glass of water

What are the ADE and monitoring points for Varenicline?

Nausea is most common, dose related

Vivid or abnormal dreams, insomnia, headache

Neuropsychiatric boxed warning removed in 2016

Still monitor mood in pyschiatric illness

Describe NRT

MOA: nicotine agonist at nAchR; no combustion toxins

Forms: patch, gum, lozenge, inhaler, nasal spray

Dosing: patch 21/14/7 mg taper; gum and lozenge 2 or 4 mg

Key CIs: none absolute; caution recent MI or unstable angina

Key ADEs: local irritation; vivid dreams with 24hr patch

Efficacy: roughly doubles quit rates; combination NRT is best

Describe Bupropion SR

MOA: DA/NE reuptake inhibitor; nAChR antagonist

Forms: oral SR tablet

Dosing: 150 mg daily x 3 d, then 150 mg BID

Key CIs: seizure or eating disorder; MAOI ≤14 days

Key ADEs: insomnia, dry mouth, seizure risk

Efficacy: roughly doubles quit rates

Describe Varenicline

MOA: a4B2 nAChR partial agonist

Forms: oral tablet

Dosing: 0.5 mg daily x 3 d, 0.5 mg BID x 4 d, then 1 mg BID

Key CIs: none absolute; reduce dose if CrCl

What is the standard NRT combination?

Patch plus a short acting form is the standard

Patch gives basal levels; gum or lozenge rescues

More effective than any single NRT product

Recommended as 1st line by USPHS guideline

What is the most effective single agent in most trials?

Varenicline

EAGLES: superior to bupropion and to patch

Varenicline plus patch may add further benefit

Reasonable first choice absent CI

What is the duration of nicotine cessation therapy?

Standard course is 12 weeks

Extend to 24 weeks in select patients

Long term NRT is safer than resuming smoking

Taper is optional for NRT, not mandatory

What are the relapse and re-treatment pearls?

Most successful quitters need several attempts

A slip is not a relapse, resume the plan

Re-treat: switch, combine or extend therapy

Reassess adherence and technique first

What is the counseling dose-response pearls?

More contact time yields higher quit rates

Even advice under 3 minutes improves outcomes

≥4 sessions and >90 total minutes is optimal

How do comorbidities affect nicotine cessation treatment?

Depression favors bupropion

Seizure or eating disorder excludes it

Renal impairment: adjust Varenicline

What are the DDI with nicotine?

Smoking induces CYP1A2

Affects clozapine, olanzapine, theophylline

Levels rise after quitting, monitor.

What are the adherence pearls of nicotine cessation?

Use short-acting NRT on a schedule, not only PRN

Under-dosing is the most common failure

Complete the full 12 week course

Do not stop the medication after a slip

When does withdrawal peak in tobacco cessation?

2-3 days. Most symptoms fade within 2-4 weeks. Individual cravings last only minutes.

When should a patient on tobacco cessation treatment seek medical help?

Seizure, chest pain or fainting

New agitation, depression, or suicidal thoughts.

Rash, facial swelling, or trouble breathing.

Routine f/u: week 1 then monthly.

What is the first line approach for tobacco cessation in pregnant patients?

Behavioral counseling. NRT only after shared risk-benefit discussion: bupropion and varenicline not routinely recommended.

What is the first line approach for tobacco cessation in CVD patients?

Behavioral plus pharm. NRT safe outside recent MI, unstable angina, or serious arrhythmia; quitting benefit is large

What is the first line approach for tobacco cessation in

Behavioral intervention. No FDA approved pharm; NRT case by case with specialist input.

Which synthetic opioid does not respond to naloxone?

Xylazine

Describe Xylazine

It is an alpha 2 agonist but with different pharmacokinetics and binding capacities.

It prolongs the duration of the sedative effect of fentanyl, mimicking a longer-lasting high.

Causes severe necrotizing wounds: with chronic use, peripheral blood vessels are chronically constricted, leading to gangrene/necrotizing wounds.

What is part of the CDC 2022 principles?

Non Opioid therapy preferred for most pain

Start low; immediate-release first.

What is tolerance?

Reduced effect from the same dose

Expected physiologic adaptation

Develops for analgesia and sedation

What is physical dependence?

Withdrawal on abrupt cessation

Expected with chronic opioid therapy (and non opioid drugs)

Managed by tapering, not dismissal

What is addiction?

Compulsive use despite clear harm.

Loss of control and craving

Behavioral, not merely physiologic

What classifies a mild/moderate/severe substance use disorder?

Mild: 2-3 criteria of DSM-5

Moderate: 4-5

Severe: ≥6

What is the full agonist medication for opioid use disorder (MOUD)?

Methadone

Prevents withdrawal and craving

Highest retention in treatment

OTP dispensing required for OUD

What is the partial agonist MOUD?

Buprenorphine

Ceiling on respiratory depression

Office-based prescribing

Risk of precipitated withdrawal

What is the antagonist MOUD?

Naltrexone

Blocks euphoria; no withdrawal relief

Requires 7-10 opioid free days

Monthly extended release IM option

What are the goals of MOUD therapy?

Reduce overdose mortality

Reduce craving and illicit use

Retain patients in care

MOUD is standard of care

What is the MOA of Methadone?

Full mu-opioid receptor agonist, suppression of withdrawal, reduction of cravings, and opioid blockade.

Long half-life, roughly 24-60 hours

Cross-tolerance prevents withdrawal, standard doses block euphoric effect of other opioids

What is the therapeutic role of methadone?

Strongest evidence for treatment reduction

Reduces overdose death and illicit use

Useful with high tolerance or prior failure

Daily observed dosing early in treatmetn

What are the key safety concerns with methadone?

QTc prolongation and torsades risk: baseline ECG

Respiratory depression during induction, no ceiling effect on respiratory depression

Accumulates for days, start low go slow

CYP3A4 interactions; additive sedation

What are the regulatory requirements for methadone?

For OUD, dispensed only by a certified OTP; strict

Clinic delivery and supervision initially

Take-home doses earned over time

May be prescribed for pain in any setting

Both federal and state rules apply

What is the MOA of Buprenorphine?

Partial mu agonist with high receptor affinity and slow dissociation: abruptly displaces full agonists, such as fentanyl, leading to withdrawal

Produces less euphoria (lower abuse liability)

Ceiling effect on respiratory depression, safer

Long duration allows daily dosing

What is the therapeutic role and formulations of Buprenorphine?

First line maintenance treatment for OUD (alongside methadone)

Combined with naloxone to deter injection

Naloxone is poorly absorbed SL

Monthly ER injection available

What is the induction with Buprenorphine?

Start in moderate withdrawal (COWS ≥8, usually wait for around 13)

Too early causes precipitated withdrawal

Longer wait after fentanyl exposure

Low-dose initiation is an alternative

No QTc prolongation

What is the access and prescribing with Buprenorphine?

Any DEA-registered prescriber may prescribe

Enables treatment in primary care

Rx to be taken home unlike methadone

What are the key safety concerns with Buprenorphine?

Precipitated withdrawal at induction

What COWS score is indicated for medication initiation?

13-24. Moderate withdrawal

What is the MOA of Naltrexone?

Competitive mu-opioid receptor antagonist

Long-acting maintenance medication

Blocks euphoria if opioids are used

No relief in craving or withdrawal

Reduces reward in alcohol withdrawal too

What are the forms and dosing in Naltrexone?

Oral 50mg daily

ER IM 380 mg every 4 weeks

Injection markedly improves adherence

Approved for both OUD and AUD

What should be done before starting Naltrexone?

Requires 7-10 opioid free days

Starting too early precipitates withdrawal

Naloxone challenge if timing is unclear

Check baseline liver function tests, safe in fatty liver disease and compensated cirrhosis, not acute hepatitis or severely elevated LFTs

What are the cautions with Naltrexone?

Tolerance falls, overdose risk if use resumes

Blocks opioid analgesia in emergencies

Avoid in acute hepatitis or liver failure

Lower retention than agonist therapy

What is the MOA for Naloxone in opioid overdose reversal?

Competitive mu-opioid receptor antagonist

Short-acting rescue agent for acute overdose

Rapidly displaces opioid from receptors

Onset 2-3 minutes; duration 30-90 minutes

No effect if no opioid is present

What are the community formulations of Naloxone?

Intranasal 4 mg spray (OTC)

IM vial or auto-injector

Repeat every 2-3 minute if no response

Fentanyl often needs repeat dosing

What happens after opioid reversal with Naloxone?

Precipitated withdrawal is expected

Naloxone outlasted by most opioids

Observe for re-sedation

Offer buprenorphine and follow up

Describe Naloxone

Primary indication: emergency reversal of opioid overdose

Duration of action: short-term (minutes to hours)

Half-life: 30-90 minutes

Routes: IV, IM, SC, intranasal, auto-injector

Bioavailability: varies by route, IV 100%, IM/SC 90%, IN 50-80%

Onset relative to need: rapid onset, use immediately during overdose

Opioid free req. before use: none

Describe Naltrexone

Primary indication: relapse prevention in opioid use disorder (maintenance therapy)

Duration of action: long-term (days to weeks)

Half-life: 4 hours (PO), 5-10 days (injectable ER)

Routes: PO, IM (ER)

Bioavailability: oral 5-40%; IM ER 100%

Onset relative to need: not for acute use, requires planning, not effective for overdose

Opioid free req. before use: required! patient should be opioid free for 7-10 days (PO) or 7-14 days (IM) to avoid precipitated withdrawal

What medication class is used as withdrawal adjuncts?

A-2 adrenergic agonists

What is the MOA of A-2 adrenergic agonists?

Central A-2 adrenergic agonists

Blunt the noradrenergic withdrawal surge

Reduce autonomic symptoms

No activity at opioid receptors

What are the A-2 adrenergic agonists agents?

Lofexidine: the ONLY FDA approved drug for withdrawal sx, but its expensive

Clonidine: widely used off label

PO dosing over roughly 7-14 days

Taper rather than stop abruptly

What is the clincal role of A-2 adrenergic agonists?

Management of opioid withdrawal

Bridge when MOUD is not yet available

Adjunct before naltrexone induction

Does not reduce overdose mortality

Adjunctive therapy in alcohol withdrawal

What are the cautions of A-2 adrenergic agonists?

Hypotension and bradycardia

Sedation, dizziness, dry mouth

Rebound HTN if stopped abruptly

Lofexidine can prolong the QT interval!

When/why should you choose Buprenorphine/naloxone over Methadone?

Ceiling effect on respiratory depression: safer in patients who have overdosed

Lower overdose mortality risk, especially at induction, which is the first month of treatment

QT and cardiac safety, methadone associated with higher rates of arrhythmias and long QT syndrome

Long, variable methadone half-life: delayed respiratory depression during titration

Office-based prescribing; more flexible

Lower diversion risk with naloxone combination

When/why should you choose Methadone over Buprenorphine/naloxone?

Severe/high physiologic dependence or high-dose opioid use, especially fentanyl

Prior failure with or intolerance to buprenorphine/naloxone induction

When maximizing retention is priority

Persistent cravings or continued illicit use of buprenorphine

Patient preference or prior positive experience with methadone

Pregnancy: has the longest track record

What are the management pearls for stimulants use?

Benzos are first-line for agitation

Aggressive cooling for hyperthermia

Avoid B-blocker alone in cocaine toxicity

No FDA approved drug for stimulant use disorder

What is the opioid toxidrome signs?

Triad: Coma, miosis, respiratory depression

Bradycardia and hypothermia

Diminished bowel sounds

Naloxone is diagnostic and therapeutic

What are the opioid adverse effects?

Constipation

Pruritus, nausea, urinary retention

Noncardiogenic pulmonary edema

Hypogonadism with chronic use, called opioid induced androgen deficiency (OPIAD), stops hypothalamus from releasing GnRH

What are the classic hallucinogens?

Serotonin 5-HT2A receptor agonsits.

What class is THC in?

Partial CB1 receptor agonist: ceiling effect.

Describe stimulants

Agents: cocaine, meth

Expected effects: euphoria, alertness, anorexia

Dangerous ADE: MI, stroke, hyperthermia, seizure

Toxidrome clues: dilated pupils, hot, diaphoretic

Describe opioids

Agents: fentanyl, heroin, oxy

Expected effects: analgesia, sedation, euphoria

Dangerous ADE: respiratory arrest, aspiration

Toxidrome clues: pinpoint pupils, slow breathing

Describe hallucinogens

Agents: LSD, psilocybin, PCP, ketamine

Expected effects: perceptual distortion, dissociation

Dangerous ADE: panic, trauma, PCP, hyperthermia

Toxidrome clues: nystagmus suggest PCP/ketamine

Describe cannabinoids

Agents: cannabis

Expected effects: euphoria, appetite, slowed time

Dangerous ADE: psychosis, hyperemesis, ingestions

Toxidrome clues: conjunctival injection, tachycardia

Describe synthetics

Agents: K2/spice, bath salts

Expected effects: unpredictable stimulant effects

Dangerous ADE: seizure, psychosis, hyperthermia

Toxidrome clues: severe agitation, negative screen

What is the pathophysiology of alcohol withdrawal syndrome?

Alcohol potentiates GABA-A inhibition. Chronic use down-regulates GABA-A. NMDA glutamate receptors up-regulate. Cessation leaves unopposed excitation.

What is the timeline with alcohol withdrawal syndrome?

Minor sx at 6-24 hours

Withdrawal seizures and alcoholic hallucinosis at 12-24 hours

Delirium tremens at 48-96 hours

What is the CIWA-AR?

Assessment for alcohol withdrawal

10 items; max score 67

Under 8 is mild, 8-18 is moderate, over 18 is severe

When should symptom triggered dosing be used?

Dose only when score crosses threshold

Less total drug and shorter treatment

Preferred when monitoring is reliable

Unsuitable if patient cannot report

When should fixed-schedule dosing be used?

Standing doses plus PRN coverage

Use in high-risk or critically ill patients

Use when CIWA scoring is unreliable

Taper over several days

What is the first line pharm treat for AW?

Benzos!

Reduce seizures, DT, and mortality

Cross tolerant with alcohol at GABA-A

Diazepam, chlordiazepoxide: long acting

Lorazepam, oxazepam: no active metabolites

How should you choose which benzo to use?

Long-acting gives a smoother self taper

Lorazepam or oxazepam in liver disease

Shorter-acting agents in older adults

Watch for oversedation and hypoventilation

When should you use phenobarbital in AW?

Option in benzo-refractory cases

Acts at GABA-A and reduces glutamate

Long half-life provides a built in taper

Requires close respiratory monitoring

What are the adjuncts used for AW?

A-2 agonists for autonomic hyperactivity

B-blockers for persistent HTN/tachycardia

Carbamazepine to reduce seizures in mild/moderate AWS

Thiamine to prevent Wernicke's

What are the first-line meds to use for AUD?

Naltrexone and Acamprosate

What is the MOA of Naltrexone in AUD?

Mu-opioid antagonist blunts alcohol reward (possibly by blocking dopamine release)

Reduces heavy drinking days and craving

Oral 50 mg daily or monthly 380 mg IM

Reasonable first choice for most patients

What are the cautions with Naltrexone use in AUD?

Avoid in current opioid use or MOUD

Precipitates withdrawal if opioid-dependent

Check LFTs; avoid in acute hepatitis

Can be started while still drinking

What is the MOA of Acamprosate?

Modulates glutamate and NMDA signaling

Supports abstinence after detoxication

Reduces unpleasant feelings brought on by abstinence

666 mg 3 times daily

Safe to use in liver disease

What are the cautions with Acamprosate use in AUD?

Renally cleared, reduce dose if CrCl 30-50

CI if CrCl