Addiction Medicine

01 Neurobiology of Addiction

Addiction is a chronic, relapsing brain disorder characterized by compulsive substance seeking and use despite harmful consequences. The neurobiology centers on the mesolimbic dopamine pathway — a circuit linking the ventral tegmental area (VTA) in the midbrain to the nucleus accumbens (NAc) in the ventral striatum, with projections to the prefrontal cortex (PFC), amygdala, and hippocampus. Natural rewards (food, sex, social bonding) increase dopamine release in the NAc by 50–100%; drugs of abuse hijack this system with supraphysiologic dopamine surges — cocaine increases synaptic dopamine 300–400%, methamphetamine up to 1,200%.

Reward Circuitry & Key Structures

The VTA contains dopaminergic neurons that project to the NAc (mesolimbic pathway) and PFC (mesocortical pathway). The nucleus accumbens integrates motivational salience — it assigns "wanting" (incentive salience) to stimuli, distinct from "liking" (hedonic pleasure). The prefrontal cortex mediates executive function, impulse control, and decision-making; chronic substance use produces PFC hypofrontality, impairing the ability to inhibit compulsive drug-seeking. The amygdala (extended amygdala including the bed nucleus of the stria terminalis) encodes negative emotional states during withdrawal, driving the "dark side" of addiction. The hippocampus consolidates contextual memories linking environmental cues to drug reward, forming the neurobiological basis of triggers and cue-induced craving.

Neurotransmitter Systems

Dopamine is central but not the only neurotransmitter involved. GABA (the principal inhibitory neurotransmitter) is the target of alcohol, benzodiazepines, and barbiturates — they enhance GABA-A receptor chloride conductance, producing sedation and anxiolysis. Glutamate (the principal excitatory neurotransmitter, acting on NMDA and AMPA receptors) is suppressed by alcohol and upregulated during chronic use — withdrawal unmasks excitotoxicity, producing seizures and delirium tremens. Endogenous opioids (endorphins, enkephalins, dynorphins acting on mu, kappa, and delta receptors) modulate pain, reward, and stress. Endocannabinoids (anandamide, 2-AG) act as retrograde messengers at CB1 receptors throughout the reward circuitry. Serotonin (5-HT) modulates mood, impulsivity, and the subjective effects of MDMA, psychedelics, and alcohol.

Neuroadaptation: Tolerance, Sensitization & Kindling

Tolerance is the need for increasing doses to achieve the same effect, resulting from receptor downregulation (pharmacodynamic tolerance) and increased hepatic metabolism (pharmacokinetic tolerance). Cross-tolerance occurs between drugs acting on the same receptor system (e.g., alcohol and benzodiazepines at GABA-A). Sensitization (reverse tolerance) is the progressive amplification of a drug response with repeated exposure — particularly relevant to stimulants, where repeated administration produces escalating locomotor activation and stereotyped behaviors. Kindling describes the phenomenon where repeated withdrawal episodes become progressively more severe; each alcohol withdrawal episode lowers the seizure threshold for subsequent episodes, making untreated withdrawal increasingly dangerous. This is mediated by NMDA receptor upregulation and glutamatergic excitotoxicity.

Genetic Factors

Heritability of substance use disorders is estimated at 40–60%. Key genetic variants include: OPRM1 A118G (mu-opioid receptor polymorphism) — the G allele is associated with greater opioid binding affinity, increased alcohol reward, and better response to naltrexone treatment. ADH1B*2 and ALDH2*2 — the ALDH2*2 variant (common in East Asian populations, ~30–50% prevalence) produces a nonfunctional aldehyde dehydrogenase, causing acetaldehyde accumulation after alcohol ingestion (flushing, nausea, tachycardia) and conferring a strong protective effect against AUD. CHRNA5-A3-B4 gene cluster on chromosome 15q25 encodes nicotinic acetylcholine receptor subunits and influences nicotine dependence severity and lung cancer risk. GABRA2 polymorphisms are associated with alcohol dependence and altered neural response to alcohol cues. DRD2 Taq1A (dopamine D2 receptor) — the A1 allele reduces D2 receptor density and has been inconsistently associated with SUD vulnerability.

02 Screening & Assessment

Universal screening for substance use disorders is recommended by USPSTF (Grade B for alcohol in adults; Grade I for drugs). The SBIRT framework (Screening, Brief Intervention, Referral to Treatment) is the evidence-based model for integrating screening into primary care, emergency departments, and hospital settings.

CAGE Questionnaire

A 4-item screening tool for alcohol use disorder. Each "yes" scores 1 point. Score ≥2 is considered positive (sensitivity 60–95%, specificity 40–95% depending on population). Limitations: poor sensitivity in women, minorities, and binge drinkers; does not quantify consumption.

AUDIT (Alcohol Use Disorders Identification Test)

A 10-item WHO-developed instrument covering consumption (items 1–3), dependence (items 4–6), and consequences (items 7–10). Each item scored 0–4 (total range 0–40). Scoring thresholds: 0–7 = low risk; 8–15 = hazardous use (brief intervention); 16–19 = harmful use (brief intervention + continued monitoring); ≥20 = possible dependence (referral for specialist evaluation). Sensitivity 80–97%, specificity 78–95% for AUD at the ≥8 threshold.

AUDIT — All 10 Items

AUDIT-C (Abbreviated)

First 3 items of the AUDIT (consumption questions only). Score range 0–12. Positive screen: ≥4 for men, ≥3 for women. Widely used in primary care for rapid screening; comparable sensitivity to full AUDIT for identifying hazardous drinking.

DAST-10 (Drug Abuse Screening Test)

A 10-item yes/no questionnaire assessing drug use (excluding alcohol and tobacco) over the past 12 months. Scoring: 0 = no problems; 1–2 = low level; 3–5 = moderate level; 6–8 = substantial level; 9–10 = severe level. A score ≥3 warrants further assessment.

CRAFFT (Adolescent Screening)

A 6-item screening tool for substance use in adolescents aged 12–21 years. Part A asks about alcohol, cannabis, and other drug use in the past 12 months. Part B (the CRAFFT questions) is administered if any Part A answers are positive:

NIDA Quick Screen

Single-question prescreening: "In the past year, how many times have you used [alcohol/tobacco/prescription drugs for non-medical reasons/illegal drugs]?" Any use triggers the NIDA-Modified ASSIST for substance-specific risk assessment.

DSM-5 Substance Use Disorder Criteria

The DSM-5 eliminated the distinction between "abuse" and "dependence," replacing them with a single substance use disorder diagnosis graded by severity. The diagnosis requires ≥2 of 11 criteria within a 12-month period:

03 Motivational Interviewing & Stages of Change

Transtheoretical Model (Prochaska & DiClemente)

The Stages of Change model describes readiness for behavior change as a dynamic, non-linear process. Patients may cycle through stages multiple times before achieving sustained change. Relapse is considered a normal part of the change process, not a failure.

Motivational Interviewing (MI)

Motivational interviewing is a collaborative, person-centered counseling method developed by Miller and Rollnick that strengthens a person's own motivation and commitment to change. MI is not a technique to "get people to change" but a way of communicating that evokes the patient's own reasons for change. The spirit of MI rests on four elements: partnership (collaboration, not authority), acceptance (absolute worth, autonomy, affirmation, accurate empathy), compassion (prioritizing the patient's welfare), and evocation (drawing out the patient's own ideas and motivations).

OARS — Core MI Skills

Key MI Principles

Express empathy: Use reflective listening to convey understanding. Ambivalence is normal, not pathological. Develop discrepancy: Help the patient see the gap between current behavior and stated values or goals. "You've said being a good father is the most important thing to you — how does your drinking fit with that?" Roll with resistance: Avoid arguing or confronting directly. Resistance is a signal to change approach, not to push harder. Reframe statements, emphasize autonomy. Support self-efficacy: Belief in one's ability to change is a key predictor of outcome. Highlight past successes and strengths.

Brief Interventions

Brief interventions are time-limited (5–30 minutes), structured counseling sessions typically delivered in primary care or ED settings. The FRAMES model summarizes effective elements: Feedback (personalized information about risk), Responsibility (emphasize that change is the patient's choice), Advice (clear, specific recommendation to reduce or stop use), Menu (offer a range of options), Empathy (warm, reflective, non-judgmental style), Self-efficacy (support confidence in ability to change). Evidence shows that a single brief intervention in primary care can reduce heavy drinking by 10–30% over 6–12 months.

Change Talk & Sustain Talk

Change talk is any patient speech that favors movement toward change. It can be categorized using the mnemonic DARN-CAT: Desire ("I want to quit"), Ability ("I could cut back"), Reasons ("My health would improve"), Need ("I have to stop before I lose my job"), Commitment ("I will call the program tomorrow"), Activation ("I'm ready to make a change"), Taking steps ("I poured out the bottles last night"). Preparatory change talk (DARN) signals readiness; mobilizing change talk (CAT) predicts actual behavior change. The clinician's goal is to evoke and reinforce change talk while not amplifying sustain talk (arguments against change). When the patient makes a change talk statement, the clinician should reflect it, affirm it, and ask for elaboration.

Assessing Readiness: Readiness Rulers

A practical MI tool: ask the patient to rate on a scale of 1–10 "How important is it for you to make this change?" and "How confident are you that you could make this change if you decided to?" Then ask: "Why did you choose a [number] and not a lower number?" This evokes change talk by asking the patient to argue for the side of change. If the patient scores low (≤3), the focus is on importance building; if importance is high but confidence is low, the focus shifts to self-efficacy enhancement and practical planning.

04 Key Terminology & Abbreviations

Core definitions used throughout addiction medicine. These terms have specific clinical meanings that differ from colloquial usage.

05 AUD — Diagnosis & Medical Complications

Alcohol use disorder affects approximately 29 million Americans (10.5% of adults). It is the third leading preventable cause of death in the United States (~95,000 deaths/year). The DSM-5 SUD criteria (Section 2) are applied specifically to alcohol. Standard drink definition: 14 g pure ethanol = 12 oz beer (5%), 5 oz wine (12%), or 1.5 oz spirits (40%).

NIAAA Drinking Thresholds

Biomarkers for Alcohol Use

GGT (gamma-glutamyl transferase): Elevated in 75% of heavy drinkers; non-specific (also elevated with hepatobiliary disease, medications, obesity). Half-life ~26 days; normalizes in 2–4 weeks of abstinence. CDT (carbohydrate-deficient transferrin): More specific than GGT for heavy alcohol use (≥60 g/day for ≥2 weeks); sensitivity 60–80%, specificity 80–95%. MCV (mean corpuscular volume): Macrocytosis (MCV >100 fL) is common in chronic AUD due to direct toxic effect of ethanol on erythropoiesis and folate deficiency; non-specific. AST:ALT ratio >2:1 is suggestive of alcoholic liver disease (alcohol induces AST via mitochondrial damage and depletes pyridoxal phosphate needed for ALT synthesis). EtG (ethyl glucuronide) and EtS (ethyl sulfate) are direct ethanol metabolites detectable in urine for 2–3 days after consumption; highly sensitive but can be positive from incidental alcohol exposure (hand sanitizer, mouthwash).

Medical Complications of Chronic Alcohol Use

Wernicke encephalopathy: Acute thiamine (B1) deficiency — classic triad of confusion, ophthalmoplegia (typically lateral rectus palsy/nystagmus), and ataxia. Only 10–16% of patients present with all three findings. Treat emergently with IV thiamine 500 mg TID for 3–5 days before giving glucose (glucose metabolism consumes thiamine and can precipitate or worsen Wernicke). Korsakoff syndrome: Chronic/irreversible sequela of untreated Wernicke — anterograde amnesia, confabulation, apathy. Only ~20% fully recover with treatment.

Alcoholic hepatitis: Presents with jaundice, hepatomegaly, fever, leukocytosis, AST >ALT (both typically <300). Maddrey discriminant function (MDF) = 4.6 × (patient PT − control PT) + total bilirubin; MDF ≥32 indicates severe disease (28-day mortality ~35%) and is an indication for prednisolone 40 mg/day × 28 days (if no contraindications: GI bleeding, sepsis, hepatorenal syndrome). MELD score ≥21 is an alternative severity threshold. Alcoholic cirrhosis: End-stage liver disease; portal hypertension leading to varices, ascites, hepatic encephalopathy, hepatorenal and hepatopulmonary syndromes. Abstinence is the single most important intervention and can reverse fibrosis if pre-cirrhotic.

Alcoholic cardiomyopathy: Dilated cardiomyopathy with reduced EF from chronic heavy drinking (typically >7–8 drinks/day for ≥5 years); can improve significantly with abstinence. Cerebellar degeneration: Truncal ataxia, wide-based gait from Purkinje cell loss (superior vermis most affected). Peripheral neuropathy: Symmetric, distal, sensory-predominant "stocking-glove" pattern from direct toxic effect and thiamine/B12/folate deficiency. Pancreatitis: Alcohol is the most common cause of chronic pancreatitis and the second most common cause of acute pancreatitis (after gallstones). Macrocytosis: Direct toxic effect on erythroid precursors even without folate/B12 deficiency. Increased cancer risk: Oropharyngeal, esophageal (squamous), hepatocellular, breast, colorectal — alcohol is classified as a Group 1 carcinogen by IARC.

06 Alcohol Withdrawal — CIWA Protocol & Management

Alcohol withdrawal results from abrupt cessation or reduction of heavy, prolonged alcohol use. Chronic alcohol exposure upregulates excitatory NMDA glutamate receptors and downregulates inhibitory GABA-A receptors. Upon cessation, unopposed glutamatergic excitation produces the withdrawal syndrome. Onset is typically 6–24 hours after last drink, with peak severity at 24–72 hours.

Timeline of Alcohol Withdrawal

CIWA-Ar Scale (Clinical Institute Withdrawal Assessment for Alcohol, Revised)

The CIWA-Ar is a 10-item assessment tool used to quantify the severity of alcohol withdrawal and guide pharmacotherapy. Each item is scored by the clinician based on observation and patient interview. Maximum score = 67.

CIWA-Ar Scoring Interpretation & Management

Benzodiazepine Protocols

Symptom-triggered dosing (preferred): Administer benzodiazepine only when CIWA-Ar ≥10. Results in lower total benzodiazepine dose and shorter treatment duration compared to fixed-schedule dosing. Fixed-schedule dosing (for patients unable to participate in CIWA assessment, e.g., intubated, severe cognitive impairment): Chlordiazepoxide 50–100 mg q6h with taper over 3–5 days.

Phenobarbital Protocol

Phenobarbital is increasingly used as a first-line or adjunctive agent for alcohol withdrawal, particularly in severe cases or benzodiazepine-refractory withdrawal. Protocol: Loading dose 10 mg/kg IV (typical: 650–1300 mg over 30 minutes, max rate 60 mg/min), then 130–260 mg IV q15–30 min PRN for ongoing severe symptoms. Phenobarbital has a very long half-life (80–120 hours), providing a built-in taper. Monitor respiratory status closely. Advantages: effective in benzodiazepine-resistant withdrawal, acts at a different site on the GABA-A receptor (prolongs chloride channel opening vs. benzodiazepine-mediated increased frequency), can directly open the channel at high doses without requiring endogenous GABA.

Delirium Tremens (DT)

DT occurs in ~5% of patients undergoing alcohol withdrawal, typically 48–96 hours after last drink. Risk factors: prior DT or withdrawal seizures, age >65, concurrent illness, CIWA >15 on admission, heart rate >100, heavy prolonged drinking, kindling from multiple prior withdrawals. Management requires ICU-level care with IV benzodiazepines (diazepam 10–20 mg IV q5–10 min or lorazepam 2–4 mg IV q15 min until calm but arousable), aggressive fluid and electrolyte replacement (hypomagnesemia and hypokalemia are common), thiamine, glucose monitoring, and hemodynamic monitoring. Refractory DT may require propofol or dexmedetomidine infusion.

Seizure Prophylaxis

Benzodiazepines are effective for seizure prevention. Phenytoin is NOT effective for alcohol withdrawal seizures and should not be used. If seizures occur, treat with lorazepam 2 mg IV; if recurrent, load with phenobarbital. Status epilepticus protocol applies if seizures are prolonged (>5 minutes).

07 Pharmacotherapy for AUD

Three medications have FDA approval for AUD: naltrexone, acamprosate, and disulfiram. Several off-label agents have supporting evidence. Despite strong efficacy data, fewer than 10% of patients with AUD receive any pharmacotherapy.

08 Alcohol-Related Emergencies

Acute Alcohol Intoxication

BAC (blood alcohol concentration) correlates with clinical effects: 50–100 mg/dL = impaired coordination and judgment; 100–200 mg/dL = ataxia, slurred speech, nystagmus; 200–300 mg/dL = marked ataxia, vomiting, obtundation; 300–400 mg/dL = stupor, hypothermia, respiratory depression; >400 mg/dL = coma and risk of death (though chronic users may tolerate much higher levels). Management is supportive: airway protection, IV fluids, glucose check, thiamine, electrolyte monitoring, aspiration precautions. Consider co-ingestants in any intoxicated patient (acetaminophen, opioids).

Toxic Alcohols — Methanol & Ethylene Glycol

Both methanol (windshield washer fluid, moonshine) and ethylene glycol (antifreeze) are metabolized by alcohol dehydrogenase (ADH) to toxic metabolites. Methanol → formaldehyde → formic acid (causes retinal toxicity and blindness, basal ganglia hemorrhagic necrosis). Ethylene glycol → glycolaldehyde → glycolic acid → oxalic acid (causes renal tubular damage, calcium oxalate crystalluria, acute kidney injury).

Wernicke Encephalopathy Prophylaxis & Treatment

Prophylaxis for at-risk patients (malnourished, chronic AUD, prolonged vomiting): thiamine 250–500 mg IV daily for 3–5 days. Always give before or concurrent with glucose-containing fluids. Treatment of established Wernicke: thiamine 500 mg IV TID for 2–3 days, then 250 mg IV daily for 3–5 days, then oral thiamine 100 mg TID indefinitely. Oral thiamine alone is inadequate for treatment — gut absorption is saturated at ~4.5 mg and is further impaired in alcoholism.

Alcoholic Ketoacidosis (AKA)

AKA develops in chronic alcohol users after a binge followed by cessation of intake (often with vomiting and poor oral intake). The combination of alcohol metabolism (high NADH:NAD+ ratio), glycogen depletion, volume depletion, and starvation shifts hepatic metabolism toward ketogenesis. Presentation: anion gap metabolic acidosis, ketonemia/ketonuria, nausea, vomiting, abdominal pain, and typically a low or normal blood glucose (distinguishes from DKA). Ethanol level is often low or undetectable by the time of presentation. Treatment: IV normal saline with dextrose (D5NS) — dextrose stimulates insulin release, which suppresses ketogenesis, and volume repletion restores renal acid excretion. Thiamine before glucose. Electrolyte repletion (K+, Mg2+, phosphate). Resolves rapidly with fluids and dextrose, typically within 12–24 hours.

Mallory-Weiss & Boerhaave Syndrome

Forceful vomiting or retching (common in alcohol intoxication) can cause a Mallory-Weiss tear (partial-thickness mucosal laceration at the gastroesophageal junction, presenting as hematemesis; usually self-limited, treat with PPI and endoscopy if persistent). Rarely, complete transmural esophageal rupture occurs (Boerhaave syndrome), a surgical emergency presenting with severe chest pain, subcutaneous emphysema, and pneumomediastinum.

09 OUD — Epidemiology, Pharmacology & Diagnosis

Opioid use disorder (OUD) affects approximately 2.7 million Americans. Opioid-involved overdose deaths reached ~82,000 in 2022, driven primarily by illicitly manufactured fentanyl. The opioid epidemic evolved through three waves: (1) prescription opioid deaths rising from the late 1990s; (2) heroin deaths increasing from 2010; (3) synthetic opioid (fentanyl) deaths surging from 2013.

Opioid Receptor Pharmacology

Opioid Drug Classification

Fentanyl Potency & Equivalency Comparisons

10 Opioid Withdrawal — COWS Protocol

Opioid withdrawal is intensely uncomfortable but, unlike alcohol or benzodiazepine withdrawal, is not life-threatening in otherwise healthy adults. Symptoms resemble a severe flu: rhinorrhea, lacrimation, yawning, myalgias, diarrhea, abdominal cramps, piloerection ("gooseflesh" / "cold turkey"), anxiety, insomnia, restlessness, and dilated pupils. The timeline varies by drug half-life.

Withdrawal Timeline by Opioid

COWS (Clinical Opiate Withdrawal Scale) — Fully Enumerated

The COWS is an 11-item clinician-rated instrument used to assess opioid withdrawal severity and guide buprenorphine induction. Score range: 0–48.

COWS Scoring Interpretation

Symptomatic Management of Opioid Withdrawal

11 Buprenorphine — Induction, Stabilization & Maintenance

Buprenorphine is a partial mu-opioid agonist with very high receptor binding affinity (Ki ~1 nM, higher than morphine, methadone, or fentanyl). Its partial agonism produces a ceiling effect on respiratory depression (maximal at ~24–32 mg SL), making it significantly safer than full agonists in overdose. It also has kappa-opioid antagonist activity, which may contribute to antidepressant effects.

Regulatory History

The Drug Addiction Treatment Act (DATA) of 2000 allowed office-based buprenorphine prescribing via the "X-waiver." This requirement was eliminated in January 2023 by the Consolidated Appropriations Act — any DEA-licensed prescriber with a Schedule III authority can now prescribe buprenorphine for OUD without additional waiver, training, or patient caps.

Formulations

Standard Induction Protocol

Because buprenorphine has higher receptor affinity but lower intrinsic activity than full agonists, it can displace full agonists from receptors and cause precipitated withdrawal if administered too early. Standard induction requires the patient to be in moderate withdrawal (COWS ≥8–12) before first dose.

Micro-dosing / Bernese Method

The Bernese method involves gradual initiation of buprenorphine while the patient continues their full agonist opioid, avoiding the need for a withdrawal period. The rationale: very low doses of buprenorphine gradually accumulate on mu receptors over days, eventually displacing the full agonist without precipitating withdrawal. This approach is particularly useful for patients using fentanyl (which has unpredictable tissue depot effects making standard induction difficult) or patients unable to tolerate withdrawal.

Precipitated Withdrawal

Precipitated withdrawal occurs when buprenorphine displaces a full agonist from mu receptors, producing acute, severe withdrawal within 30–60 minutes of administration. It is more intense than spontaneous withdrawal and can last 2–4 hours. Management: additional buprenorphine (paradoxically, providing more buprenorphine increases receptor occupancy and resolves symptoms), clonidine 0.1–0.3 mg, ondansetron, benzodiazepines for severe agitation. Prevention: ensure adequate COWS score before induction, use micro-dosing protocol for fentanyl users, wait longer for long-acting opioids (methadone: wait ≥72 hours).

12 Methadone Maintenance

Methadone is a full mu-opioid agonist with additional NMDA receptor antagonist activity and serotonin/norepinephrine reuptake inhibition. It has strong evidence for reducing illicit opioid use, criminal activity, HIV transmission, and all-cause mortality. However, its unique pharmacokinetics require careful management.

Regulatory Framework

In the US, methadone for OUD can only be dispensed through federally certified Opioid Treatment Programs (OTPs), regulated by SAMHSA, DEA, and state authorities. Patients must attend the OTP for observed daily dosing until they earn take-home privileges. Methadone for pain can be prescribed by any DEA-licensed practitioner, but methadone for OUD cannot be prescribed in an office setting (unlike buprenorphine). Take-home criteria are based on time in treatment, negative drug screens, attendance, and clinical stability.

Dosing & Titration

QTc Monitoring

Methadone prolongs the QTc interval in a dose-dependent manner by blocking the hERG (human ether-a-go-go-related gene) potassium channel. This creates a risk of torsades de pointes. Recommendations: obtain baseline ECG; repeat at 30 days and annually. If QTc >450 ms, discuss risks, monitor more frequently. If QTc >500 ms, consider dose reduction, switching to buprenorphine, or elimination of other QTc-prolonging medications. If patient develops syncope, palpitations, or seizure — obtain urgent ECG.

Drug Interactions — CYP3A4 Considerations

Methadone is primarily metabolized by CYP3A4, with contributions from CYP2B6, CYP2D6, and CYP2C19. CYP3A4 inducers decrease methadone levels and can precipitate withdrawal; CYP3A4 inhibitors increase levels and risk toxicity.

Take-Home Criteria (Abridged)

SAMHSA regulations define a phased approach: Phase 1 (first 90 days) = no take-homes, daily observed dosing. After 90 days with demonstrated stability (negative UDS, regular attendance, no criminal activity, absence of recent substance use): 1 take-home per week. Gradually increasing to 2/week after 6 months, 3/week after 1 year, 6/week after 2 years, and up to 27 days of take-homes after 3 years of continuous demonstrated stability. COVID-era blanket exceptions (2020) expanded take-home access significantly.

13 Naloxone & Overdose Reversal

Naloxone is a competitive mu-opioid receptor antagonist that rapidly reverses opioid-induced respiratory depression. It is the cornerstone of opioid overdose emergency response and has been designated an over-the-counter (OTC) medication (Narcan nasal spray) since 2023.

Dosing & Routes

Renarcotization

Naloxone's duration of action (30–90 minutes) is shorter than most opioids, especially long-acting agents (methadone: half-life 8–59 hours) and fentanyl (which, when used in large quantities or as tissue depots, can outlast naloxone by hours). Renarcotization occurs when naloxone wears off and residual opioid re-activates receptors, causing recurrent respiratory depression. Any patient receiving naloxone should be observed for a minimum of 2 hours after the last naloxone dose (4 hours or more for long-acting opioids or large fentanyl exposures). If repeated naloxone doses are required, consider a continuous naloxone infusion (two-thirds of the initial effective bolus dose per hour).

Community Distribution Programs

Naloxone distribution programs provide take-home naloxone kits to people who use opioids, their family members, and community organizations. Evidence shows these programs are associated with reduced opioid overdose mortality at the community level. All 50 US states have enacted naloxone access laws, and most allow pharmacist dispensing without a prescription. Training focuses on recognizing overdose (unresponsiveness, shallow/absent breathing, cyanosis, pinpoint pupils) and administering naloxone with rescue breathing.

Good Samaritan Laws

Most US states have enacted Good Samaritan laws that provide limited legal immunity to individuals who call 911 to report an overdose. These laws aim to reduce overdose deaths by removing the fear of criminal prosecution (for drug possession) that may otherwise deter bystanders from seeking emergency assistance. Coverage varies by state — some only protect the caller, others protect the overdose victim as well.

14 Stimulant Use Disorder — Cocaine & Methamphetamine

Stimulant use disorder encompasses cocaine and amphetamine-type stimulants (methamphetamine, prescription amphetamines). There are no FDA-approved pharmacotherapies for stimulant use disorder; contingency management is the most effective evidence-based behavioral treatment.

Pharmacology

Cocaine blocks the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT), preventing reuptake and increasing synaptic monoamine concentrations. It also blocks voltage-gated sodium channels (local anesthetic effect). Half-life: ~1 hour (intranasal); onset varies by route — smoked/IV: seconds, intranasal: 3–5 minutes. Methamphetamine enters the presynaptic terminal via DAT, reverses the vesicular monoamine transporter (VMAT2), and causes massive release of dopamine (and norepinephrine/serotonin) into the synapse. It also inhibits monoamine oxidase (MAO). The result is a much longer and more intense dopamine surge than cocaine (half-life 10–12 hours).

Intoxication — Sympathomimetic Toxidrome

Stimulant intoxication produces the sympathomimetic toxidrome: tachycardia, hypertension, hyperthermia, diaphoresis, mydriasis (dilated pupils), agitation, paranoia, psychosis, seizures, and potentially life-threatening cardiovascular events. Specific complications include: acute coronary syndrome (cocaine causes coronary vasospasm and thrombosis — treat with benzodiazepines, nitrates, aspirin; AVOID beta-blockers due to unopposed alpha stimulation), aortic dissection, stroke (hemorrhagic > ischemic), rhabdomyolysis, and hyperthermia (can be fatal; treat aggressively with external cooling and benzodiazepines).

Withdrawal / "Crash"

Stimulant withdrawal is characterized by the "crash" phase: profound fatigue, hypersomnia, increased appetite, dysphoria, anhedonia, vivid unpleasant dreams, psychomotor retardation, and intense craving. Withdrawal is not medically dangerous (no seizures, no autonomic instability) but the severe dysphoria and craving drive relapse. Symptoms peak at 2–4 days and may last 1–3 weeks, with protracted anhedonia for months.

Contingency Management

Contingency management (CM) provides tangible incentives (typically escalating monetary-value vouchers or prize draws) contingent on verified abstinence (negative UDS). CM produces the largest effect sizes of any behavioral treatment for stimulant use disorder (d = 0.42–0.62). The VA and some state Medicaid programs have implemented CM programs. Limitations: sustainability after incentives end, funding, and perceived ethical concerns about "paying people not to use drugs."

Cardiovascular Complications of Chronic Use

Cocaine cardiovascular effects: Accelerated atherosclerosis (even in young patients without traditional risk factors), coronary artery aneurysms, coronary artery dissection, dilated cardiomyopathy, aortic dissection, and infective endocarditis (particularly right-sided tricuspid valve endocarditis in IV cocaine users — often caused by Staphylococcus aureus). Cocaine-associated MI should be treated with benzodiazepines, aspirin, nitroglycerin, and cardiac catheterization if indicated; avoid beta-blockers acutely.

Methamphetamine cardiovascular effects: Dilated cardiomyopathy is the most common cardiovascular complication, often presenting in patients aged 30–50 with no other risk factors; may partially reverse with abstinence and standard HF therapy. Pulmonary arterial hypertension (associated with methamphetamine more than cocaine), accelerated hypertension, and aortic dissection. Methamphetamine-associated dental disease ("meth mouth"): Results from xerostomia (decreased salivary flow), bruxism, poor oral hygiene, high sugar intake, and direct vasoconstriction of oral blood supply; manifests as rampant caries, tooth fractures, and periodontal disease.

Dermatologic Complications

Methamphetamine use is associated with formication (tactile hallucination of insects crawling on or under the skin), leading to compulsive skin-picking and excoriations ("meth sores" or "crank bugs"). Cocaine use via nasal insufflation causes nasal septal perforation from chronic vasoconstriction-mediated ischemic necrosis of the septal cartilage. IV stimulant use carries the same injection-related complications as IV opioid use: abscess, cellulitis, endocarditis, HIV, HCV.

15 Cannabis Use Disorder

Cannabis is the most widely used illicit substance globally. Approximately 16 million Americans meet DSM-5 criteria for cannabis use disorder. The primary psychoactive compound is delta-9-tetrahydrocannabinol (THC), which acts as a partial agonist at CB1 receptors (densely expressed in the hippocampus, cerebellum, basal ganglia, and cortex) and CB2 receptors (primarily immune cells). Cannabidiol (CBD) is a non-intoxicating cannabinoid with complex pharmacology including 5-HT1A agonism, GPR55 antagonism, and allosteric modulation of mu-opioid receptors.

Intoxication

Acute effects of cannabis include euphoria, relaxation, altered time perception, impaired short-term memory, increased appetite, conjunctival injection, dry mouth, tachycardia, and impaired psychomotor coordination. High doses or high-potency products can produce anxiety, paranoia, and acute psychosis (especially in predisposed individuals). THC concentration in commercial cannabis products has increased from ~4% in 1995 to >15–20% currently, with concentrates reaching 60–90%.

Cannabis Withdrawal

Withdrawal is a recognized DSM-5 diagnosis: onset within 1 week of cessation, peak at 1–2 weeks, duration up to 4 weeks. Symptoms include irritability, anger, anxiety, insomnia, decreased appetite, restlessness, depressed mood, and at least one physical symptom (abdominal pain, tremor, sweating, fever, chills, headache). Withdrawal is not medically dangerous but can drive relapse.

Cannabinoid Hyperemesis Syndrome (CHS)

CHS is a paradoxical condition in chronic, heavy cannabis users characterized by cyclic episodes of severe nausea, intractable vomiting, and diffuse abdominal pain. The pathophysiology is poorly understood but may relate to CB1 receptor desensitization in the enteric nervous system or hypothalamic thermoregulation. Diagnostic features: history of regular cannabis use for ≥1 year, ≥3 stereotypical episodes, and resolution with cannabis cessation.

Synthetic Cannabinoids (K2/Spice)

Synthetic cannabinoids are full CB1 agonists (unlike THC, which is a partial agonist), producing more intense and unpredictable effects: severe agitation, psychosis, seizures, tachycardia, hypertension, acute kidney injury, coagulopathy (some batches have been contaminated with brodifacoum, a long-acting anticoagulant). Not detected on standard urine drug screens. Management is supportive; benzodiazepines for agitation and seizures.

Medical Consequences of Chronic Cannabis Use

Pulmonary: Regular cannabis smoking is associated with chronic bronchitis symptoms (cough, sputum, wheeze); evidence for COPD and lung cancer is less clear than with tobacco due to confounding (most cannabis smokers also smoke tobacco). Cannabis smoke contains many of the same carcinogens as tobacco smoke. Psychiatric: Cannabis use during adolescence (especially heavy use of high-potency products) is associated with a 2–4 fold increased risk of developing psychotic disorders, including schizophrenia, particularly in individuals with genetic predisposition (COMT Val158Met polymorphism). Cognitive: Acute THC impairs attention, working memory, and executive function; chronic heavy use during adolescence may produce persistent cognitive deficits even after cessation, though evidence for permanent structural brain changes is debated. Reproductive: THC reduces sperm count and motility; cannabis use during pregnancy is associated with lower birth weight.

Treatment

No FDA-approved pharmacotherapy exists for cannabis use disorder. Motivational Enhancement Therapy (MET) combined with CBT is the most studied behavioral approach (MET/CBT-5 and MET/CBT-12 are manualized protocols). N-acetylcysteine (NAC) 1200 mg BID showed modest benefit in adolescents (but not adults) in one RCT. Gabapentin has shown preliminary evidence for reducing withdrawal symptoms and cannabis use. Abstinence-based contingency management also shows efficacy. Brief interventions using MI principles are effective for reducing cannabis use in young adults.

16 Sedative-Hypnotic Use Disorder — Benzodiazepines & Z-drugs

Benzodiazepines and Z-drugs (zolpidem, zaleplon, eszopiclone) act on the GABA-A receptor complex. Benzodiazepines bind the alpha subunit at the benzodiazepine binding site, increasing the frequency of chloride channel opening (requiring endogenous GABA). Physiologic dependence develops rapidly, often within 2–4 weeks of daily use, and withdrawal can be life-threatening (seizures, delirium).

Diazepam Equivalency Table

Converting all benzodiazepines to a diazepam equivalent facilitates standardized tapering. Diazepam is preferred for tapering because of its long half-life and availability in small-dose increments.

Ashton Taper Method

The Ashton Manual (Professor C. Heather Ashton) provides detailed, individualized benzodiazepine tapering protocols. Key principles: (1) Convert to an equivalent dose of diazepam (long half-life, smoother plasma levels); (2) Taper by approximately 10% of the current dose every 1–2 weeks (some patients require slower reductions of 5% every 2–4 weeks); (3) Final stages of taper are the hardest — slow down further below 5 mg diazepam equivalent; (4) Total taper duration: 6 weeks to 12+ months depending on the dose, duration of use, and patient tolerance. Withdrawal symptoms: insomnia, anxiety, irritability, tremor, diaphoresis, perceptual disturbances, seizures (most dangerous), depersonalization, and rarely psychosis.

Benzodiazepine Withdrawal Symptom Phases

Barbiturate Withdrawal

Barbiturate withdrawal is similar to but potentially more severe than benzodiazepine withdrawal. Barbiturates directly open GABA-A chloride channels (do not require endogenous GABA at high doses), and withdrawal produces severe autonomic instability, seizures, and delirium. Phenobarbital taper is the standard treatment: convert to phenobarbital equivalents, stabilize for 2–3 days, then taper by 30 mg/day. The pentobarbital tolerance test can help estimate the degree of barbiturate dependence: administer 200 mg pentobarbital orally and observe after 1 hour — if the patient is asleep, minimal dependence; if awake and comfortable, moderate dependence; if no effect, severe dependence requiring higher stabilization doses.

Z-Drug Considerations

Zolpidem, zaleplon, and eszopiclone bind selectively to the alpha-1 subunit of the GABA-A receptor (unlike benzodiazepines, which are non-selective). Despite initial marketing as non-addictive, physical dependence and withdrawal occur with chronic use, and the withdrawal syndrome is similar to benzodiazepine withdrawal (though typically less severe). Cross-tolerance with benzodiazepines is partial. Zolpidem is associated with complex sleep-related behaviors (sleep-driving, sleep-eating) and is a controlled substance (Schedule IV). Taper by converting to an equivalent diazepam dose (zolpidem 10 mg ≈ diazepam 10 mg) and following the Ashton protocol.

17 Tobacco Use Disorder

Tobacco use is the leading preventable cause of death in the United States (~480,000 deaths/year, including ~41,000 from secondhand smoke). Nicotine acts on nicotinic acetylcholine receptors (nAChRs), particularly the alpha-4-beta-2 subtype in the VTA, stimulating dopamine release in the nucleus accumbens. Nicotine is one of the most addictive substances known, with a relapse rate of ~95% without treatment.

Fagerstrom Test for Nicotine Dependence (FTND)

Score range 0–10: 0–2 = very low dependence; 3–4 = low; 5 = medium; 6–7 = high; 8–10 = very high dependence.

Pharmacotherapy — Nicotine Replacement Therapy (NRT)

Varenicline

Varenicline (Chantix) is a partial agonist at the alpha-4-beta-2 nAChR. It provides moderate dopaminergic stimulation (reducing craving and withdrawal) while blocking the rewarding effects of nicotine from cigarettes. Dosing: 0.5 mg daily × 3 days, then 0.5 mg BID × 4 days, then 1 mg BID for 12 weeks (may extend to 24 weeks). Set a quit date during the second week of treatment. Most effective single agent for smoking cessation (OR ~2.2–2.9 vs. placebo). The earlier FDA black box warning for neuropsychiatric events was removed in 2016 based on the EAGLES trial (no significant increase in neuropsychiatric adverse events vs. NRT or placebo). Common side effects: nausea (30%, mitigate by taking with food), vivid dreams, insomnia.

Bupropion

Bupropion SR (Zyban) is a norepinephrine-dopamine reuptake inhibitor (NDRI) that reduces craving and withdrawal symptoms. Dosing: 150 mg daily × 3 days, then 150 mg BID for 7–12 weeks. Start 1–2 weeks before quit date. Contraindicated in seizure disorders, eating disorders (bulimia/anorexia), and concurrent MAOIs. Lowers the seizure threshold. Also used for depression (Wellbutrin), providing dual benefit in patients with comorbid depression.

Combination Therapy

Combination NRT (patch + short-acting form such as gum or lozenge) is more effective than single NRT (OR ~1.9 vs. monotherapy). Varenicline + NRT patch may provide additional benefit. Combination pharmacotherapy + behavioral counseling is the most effective overall strategy, with 6-month quit rates of 25–35% (vs. ~5% for unaided quit attempts).

18 Hallucinogens, Inhalants & Novel Psychoactive Substances

Classic Serotonergic Hallucinogens

LSD (lysergic acid diethylamide) and psilocybin (from Psilocybe mushrooms) are 5-HT2A receptor agonists that produce altered perception, visual hallucinations, synesthesia, mystical experiences, and altered sense of time. Duration: LSD 8–12 hours; psilocybin 4–6 hours. There is no physiologic dependence or withdrawal syndrome with classic psychedelics. Tolerance develops rapidly (tachyphylaxis within 1–3 days) and cross-tolerance exists between LSD and psilocybin. Acute adverse effects: "bad trip" (anxiety, paranoia, panic), rare persistent perceptual changes (HPPD — hallucinogen persisting perception disorder). Psilocybin has shown promising results in clinical trials for treatment-resistant depression and end-of-life distress; FDA granted "breakthrough therapy" designation in 2018.

MDMA (3,4-methylenedioxymethamphetamine)

MDMA is an amphetamine derivative ("entactogen") that causes massive serotonin release (with dopamine and norepinephrine release). Effects: empathy, emotional openness, euphoria, heightened sensory perception. Risks: hyperthermia, hyponatremia (SIADH from serotonin release + excessive water intake), serotonin syndrome (especially with SSRIs or MAOIs), hepatotoxicity, neurotoxicity (serotonergic axon damage with chronic use). MDMA-assisted psychotherapy received FDA review for PTSD treatment; initial results showed significant efficacy but the NDA was not approved in 2024 due to study design concerns.

Dissociative Agents — PCP & Ketamine

PCP (phencyclidine) is an NMDA receptor antagonist that also affects dopamine, sigma, and opioid receptors. Intoxication: violent agitation, vertical and horizontal nystagmus (unique to PCP), analgesia, psychosis, hyperthermia, rhabdomyolysis, seizures. Management: benzodiazepines for agitation (avoid antipsychotics if hyperthermia is present, as they impair thermoregulation); dark quiet room; monitor for rhabdomyolysis (CK, renal function). Ketamine is a shorter-acting NMDA antagonist; intoxication produces dissociative anesthesia, "K-hole" (deep dissociation at high doses). Esketamine (Spravato) nasal spray is FDA-approved for treatment-resistant depression. Chronic ketamine use causes ulcerative cystitis ("ketamine bladder").

Inhalants

Inhalants include volatile solvents (toluene, gasoline, paint thinner), aerosols, gases (nitrous oxide), and nitrites (amyl nitrite/"poppers"). Most prevalent in early adolescence (12–14 years). Mechanism: most are CNS depressants enhancing GABA and inhibiting glutamate. Sudden sniffing death syndrome is the leading cause of inhalant-related death — volatile hydrocarbons sensitize the myocardium to catecholamines, causing fatal ventricular fibrillation, often triggered by startle or exertion during or immediately after inhalant use. Chronic toluene exposure causes renal tubular acidosis (non-anion gap metabolic acidosis), cerebellar ataxia, and cognitive impairment. Chronic nitrous oxide use depletes vitamin B12, causing subacute combined degeneration of the spinal cord (posterior columns + lateral corticospinal tracts).

Novel Psychoactive Substances

Synthetic cathinones ("bath salts" — mephedrone, MDPV, alpha-PVP/"flakka") are synthetic analogs of cathinone (from the khat plant). They inhibit catecholamine reuptake and/or promote catecholamine release. Effects resemble methamphetamine or MDMA: severe sympathomimetic toxidrome with agitation, psychosis, hyperthermia, and rhabdomyolysis. MDPV is a particularly potent DAT inhibitor with high abuse potential. Treatment is supportive with benzodiazepines for agitation. Kratom (Mitragyna speciosa) contains mitragynine, a partial mu-opioid agonist; used for self-treatment of pain and opioid withdrawal, but carries risks of dependence, seizures, and hepatotoxicity.

19 Harm Reduction Principles & Programs

Harm reduction is a public health approach that aims to minimize the negative health, social, and economic consequences of substance use without necessarily requiring abstinence. It is grounded in the pragmatic recognition that some people cannot or will not stop using substances, and that reducing harm while maintaining engagement is preferable to an all-or-nothing approach.

Core Principles

(1) Pragmatism: Accept that drug use is part of the human experience and work to minimize harm rather than ignore or condemn use. (2) Spectrum of use: Understand drug use as a spectrum from abstinence to severe dependence — some use is clearly safer than other use, and any movement toward reduced harm is valuable. (3) Quality of life focus: Establish quality of individual and community life as criteria for evaluating interventions, not simply reduction in drug use. (4) Non-judgmental services: Provide services without judgment and without requiring abstinence as a precondition for receiving help. (5) Meaningful participation: Ensure people who use drugs have a voice in creating and evaluating programs that serve them. (6) Social determinants: Recognize that the root causes of problematic drug use — poverty, racism, trauma, adverse childhood experiences, social isolation, incarceration, homelessness — must be addressed alongside individual substance use.

Key Programs & Interventions

20 Co-Occurring Disorders — Dual Diagnosis

Approximately 50% of individuals with a severe mental illness and 30–40% with any mental illness also have a substance use disorder. Conversely, people with SUD have high rates of comorbid depression (20–40%), anxiety disorders (20–30%), PTSD (30–60% in women with SUD), bipolar disorder, ADHD, and personality disorders (particularly antisocial and borderline).

Treatment Models

Medication Considerations

Avoid benzodiazepines whenever possible in patients with SUD (high abuse potential; cross-tolerance with alcohol; risk of respiratory depression with opioids). Preferred anxiolytics: SSRIs, SNRIs, buspirone, hydroxyzine, gabapentin (with caution regarding misuse potential). Antidepressants: SSRIs are first-line for comorbid depression/anxiety; bupropion is useful if comorbid tobacco dependence. Mood stabilizers: Valproate may reduce both alcohol and cannabis use in bipolar disorder. Lithium remains first-line for bipolar disorder but does not independently reduce substance use. Antipsychotics: Clozapine has the best evidence for reducing substance use in schizophrenia. Avoid prescribing medications with high abuse potential (stimulants for ADHD in active SUD — use extended-release formulations or non-stimulants like atomoxetine if needed).

21 Special Populations

Pregnancy — Opioid Use Disorder

MOUD is the standard of care for pregnant patients with OUD. Both methadone and buprenorphine are safe and recommended; medically supervised withdrawal (detoxification) during pregnancy is associated with high relapse rates and increased risk of fetal distress. Methadone has been used longest; buprenorphine is associated with shorter NICU stays and less severe neonatal withdrawal in the MOTHER trial (2012). Buprenorphine monoproduct (without naloxone) has traditionally been preferred in pregnancy, though evidence suggests the combination product is likely safe as naloxone has poor sublingual bioavailability. Dose requirements often increase during pregnancy (expanded volume of distribution, increased hepatic metabolism, especially in the third trimester).

Neonatal Abstinence Syndrome (NAS) / Neonatal Opioid Withdrawal Syndrome (NOWS)

NAS/NOWS occurs in 30–80% of neonates exposed to opioids in utero. Onset is typically 24–72 hours after birth (may be delayed up to 5–7 days with methadone or buprenorphine). Symptoms include high-pitched cry, tremors, irritability, poor feeding, vomiting, diarrhea, sneezing, yawning, nasal congestion, fever, and seizures (rare).

Breastfeeding Guidelines

Breastfeeding is encouraged for mothers on methadone or buprenorphine who are: (1) stable in treatment, (2) not using illicit drugs, (3) HIV-negative, and (4) not using other contraindicated medications. The small amount of methadone/buprenorphine transferred in breast milk is insufficient to treat NAS but may ease symptoms slightly. Breastfeeding should be discontinued if the mother resumes illicit drug use.

Adolescents

Screen with CRAFFT (Section 2). Adolescent brains are particularly vulnerable to substances due to ongoing prefrontal cortex development (not complete until age ~25). Earlier onset of use is associated with higher lifetime risk of SUD. Family-based therapies (Multidimensional Family Therapy, Functional Family Therapy) are first-line behavioral treatments. Buprenorphine is approved for adolescents ≥16 years with OUD; younger adolescents may receive it off-label with specialist consultation.

Older Adults

Prescription opioid and benzodiazepine misuse is the most common form of SUD in older adults. Screening is often missed due to atypical presentations (confusion attributed to dementia, falls attributed to aging). Lower doses of medications are needed due to decreased hepatic/renal function, reduced lean body mass, and increased sensitivity. AUDIT thresholds may need to be lower (≥5 instead of ≥8) in older adults.

Healthcare Professionals

Physician Health Programs (PHPs) provide confidential monitoring, treatment referral, and advocacy for healthcare professionals with SUD. PHPs have excellent outcomes: 5-year sobriety rates of 70–80%, far exceeding general population outcomes. This is attributed to high motivation (licensure at stake), structured monitoring (random drug testing, group meetings), and professional accountability. Anesthesiologists have the highest rate of opioid use disorder among physician specialties due to occupational exposure.

Healthcare Professionals — PHP Programs in Detail

Physician Health Programs operate in all 50 states and monitor healthcare professionals with SUD or psychiatric illness. The typical PHP contract includes: random urine drug testing (80–100+ tests/year for 5 years), mandatory 12-step or mutual support group attendance (typically 3–5 meetings/week), facilitated peer support groups, workplace monitoring by a colleague, complete abstinence from all intoxicants (including alcohol), restriction of prescribing controlled substances for a defined period, and regular reports to the licensing board. Non-compliance results in license suspension. The PHP model achieves 70–80% long-term sobriety rates because it combines high-intensity monitoring with significant consequences (loss of medical license and career). Anesthesiologists with fentanyl OUD pose a unique challenge: they have the highest relapse rates among physician specialties, and relapse is often fatal due to IV fentanyl access. Many programs recommend career change away from operating room environments for anesthesiologists with fentanyl OUD.

Criminal Justice System

Incarcerated individuals have SUD rates of 50–65%. MOUD should be offered in correctional settings — the first 2 weeks after release from incarceration is the highest-risk period for fatal overdose (tolerance loss during incarceration with return to prior use levels). Multiple court decisions (including Pesce v. Coppinger and Smith v. Aroostook County) have affirmed the right of incarcerated individuals to receive MOUD. Evidence shows that in-jail MOUD initiation reduces post-release overdose mortality by ~60%. Drug courts are specialized court programs that divert non-violent drug offenders from incarceration into supervised treatment; participants have lower recidivism rates (8–14%) compared to traditional adjudication (25–50%). The drug court model combines judicial supervision, mandatory treatment, graduated sanctions and incentives, and frequent drug testing.

Indigenous & Racial/Ethnic Minority Populations

American Indian/Alaska Native populations have the highest rates of SUD and substance-related deaths of any racial/ethnic group in the US, driven by historical trauma, poverty, limited treatment access on reservations, and inadequate IHS funding. Culturally adapted treatments (incorporating traditional healing practices, sweat lodge ceremonies, talking circles, and Indigenous identity strengthening) show improved engagement and outcomes. Black Americans with OUD are significantly less likely to receive buprenorphine compared to White Americans despite similar prevalence of OUD, reflecting structural racism in healthcare access. Hispanic/Latino populations face barriers including language, immigration-related fears, and cultural stigma around addiction treatment.

22 Urine Drug Screens & Confirmatory Testing

Immunoassay (Screening) vs. Confirmatory Testing

Standard urine drug screens (UDS) use immunoassay technology: antibodies recognize drug class metabolites. Advantages: rapid (results in minutes), inexpensive, broad panels available. Limitations: cross-reactivity produces false positives; cannot distinguish specific drugs within a class; cannot quantify levels; certain synthetic opioids are not detected by standard assays.

Confirmatory testing uses gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-tandem mass spectrometry (LC-MS/MS). These identify specific drugs and metabolites with very high sensitivity and specificity. Confirmatory testing should be ordered when clinical decisions depend on the result, when a result is unexpected, or when a patient disputes a positive result.

Standard Panel & Detection Windows

Common False Positives

EtG/EtS Testing for Alcohol

Ethyl glucuronide (EtG) and ethyl sulfate (EtS) are direct, non-oxidative metabolites of ethanol detectable in urine for 2–3 days after consumption. EtG is highly sensitive but can be positive from incidental alcohol exposure: hand sanitizer (transdermally absorbed ethanol), mouthwash (Listerine), fermented foods, communion wine, or even overripe fruit. Cutoff recommendations: ≥500 ng/mL = recent intentional drinking (within 24 hours); 100–500 ng/mL = possible incidental exposure; <100 ng/mL = negative. EtS is less susceptible to bacterial production artifacts in vitro and is often tested alongside EtG for confirmation. Phosphatidylethanol (PEth) in whole blood is a newer biomarker with a detection window of 2–4 weeks, reflecting cumulative alcohol exposure.

Observed vs. Unobserved Collection

Observed collection (direct visual observation of voiding) is required in federal workplace testing following a positive test and in some treatment/legal settings. Temperature strips on collection cups (90–100°F within 4 minutes) detect substitution. Specimen validity testing includes creatinine (<2 mg/dL = substituted; <20 = dilute), specific gravity (<1.001 or >1.020 = abnormal), pH (normal 4.5–9.0; outside range suggests adulteration), and oxidant assays (detect bleach, nitrites, chromate additives).

Alternative Matrices for Drug Testing

23 Prescription Drug Monitoring & Safe Prescribing

Prescription Drug Monitoring Programs (PDMPs)

PDMPs are state-run electronic databases that track controlled substance prescriptions. All 50 US states have operational PDMPs. Most states mandate PDMP check before prescribing opioids or benzodiazepines. PDMPs help identify: patients receiving controlled substances from multiple prescribers ("doctor shopping"), escalating doses, dangerous combinations (opioids + benzodiazepines), and prescribers with aberrant patterns.

CDC Clinical Practice Guideline for Prescribing Opioids (2022 Update)

Opioid Risk Assessment Tools

Naloxone Co-Prescribing

Co-prescribe naloxone when: opioid dose ≥50 MME/day, concurrent benzodiazepine prescribing, history of SUD or overdose, patient request, or other high-risk factors (sleep apnea, renal/hepatic impairment, elderly). Evidence from VA studies shows naloxone co-prescribing is associated with a 47% reduction in opioid-related ED visits.

Opioid Prescribing for Acute Pain — Best Practices

For acute pain (post-surgical, injury, dental), the CDC recommends the lowest effective dose of immediate-release opioids for the shortest expected duration. Specific guidance by condition: Dental pain: NSAIDs ± acetaminophen are first-line; opioids rarely indicated beyond 3 days. Post-surgical: Multimodal analgesia (acetaminophen + NSAID + regional anesthesia) reduces opioid requirements; most patients need ≤3–5 days of opioids after major surgery. Fracture/trauma: Short-acting opioids for 3–7 days with reassessment. Chronic non-cancer pain: Opioids should only be considered after failure of non-opioid pharmacotherapy (NSAIDs, duloxetine, gabapentin, physical therapy, cognitive behavioral therapy for chronic pain). Starting opioids for chronic pain commits the patient to a long-term medication that is difficult to discontinue and may not improve function.

Tapering Patients Off Chronic Opioids

The CDC emphasizes that abrupt discontinuation or rapid taper of opioids in physically dependent patients is dangerous and can lead to withdrawal, psychological crisis, illicit opioid use, and suicide. Recommended approach: reduce by 5–10% of the original dose per month. Slower tapers (5% per month) are better tolerated. Pause the taper if the patient reports increased pain, decreased function, or psychological distress. Adjunctive strategies: start or optimize non-opioid analgesics, initiate CBT for chronic pain, consider buprenorphine transition if the patient has OUD features, provide frequent follow-up and psychosocial support throughout the taper.

24 Levels of Care — ASAM Criteria

The ASAM Criteria (American Society of Addiction Medicine), formerly known as the "ASAM Patient Placement Criteria," is the most widely used and comprehensive set of guidelines for matching patients to appropriate levels and types of addiction treatment. Placement decisions are based on a multidimensional assessment across six dimensions.

Six Assessment Dimensions

ASAM Levels of Care

25 Evidence-Based Psychotherapies

Family-Based Therapies

Multidimensional Family Therapy (MDFT): Evidence-based for adolescent SUD; addresses individual, family, peer, and community systems simultaneously over 4–6 months. Functional Family Therapy (FFT): Short-term (12–14 sessions) for youth with behavioral problems and SUD; focuses on improving family communication and reducing negative interaction patterns. CRAFT (Community Reinforcement and Family Training): Trains concerned family members of treatment-resistant individuals in behavioral strategies to encourage their loved one to enter treatment; 64–74% treatment entry rate vs. 30% with Al-Anon and 13% with Johnson intervention. Behavioral Couples Therapy (BCT): For patients with SUD and a committed partner; incorporates a recovery contract with partner-observed medication taking and couples communication skills; strong evidence for reducing substance use and improving relationship functioning simultaneously.

26 Classification Systems & Scoring Tools

This section consolidates all clinical scoring instruments referenced throughout the page with scoring thresholds and clinical application. Each tool is validated for specific populations and clinical contexts; using the correct tool in the correct setting improves diagnostic accuracy and treatment decisions.

27 Medications Master Table

Medications for Alcohol Use Disorder

Medications for Opioid Use Disorder

Medications for Tobacco Use Disorder

Adjunctive Medications for Withdrawal

28 MME Conversion Table

The morphine milligram equivalent (MME) is a standardized measure used to compare potency across different opioid medications. It represents the dose of a given opioid that is approximately equivalent to 1 mg of oral morphine. The 2022 CDC guideline uses MME thresholds for risk assessment: use caution at ≥50 MME/day and avoid or carefully justify ≥90 MME/day.

29 Drug Interaction Reference

Methadone Drug Interactions

Buprenorphine Drug Interactions

Disulfiram-Ethanol Reaction

Serotonin Syndrome Risk Combinations

Several substances encountered in addiction medicine carry serotonin syndrome risk when combined with serotonergic medications:

Recognition: The Hunter Serotonin Toxicity Criteria require a serotonergic agent plus any of: spontaneous clonus, inducible clonus + agitation/diaphoresis, ocular clonus + agitation/diaphoresis, tremor + hyperreflexia, or hypertonia + temperature >38°C + clonus. The classic triad is altered mental status, autonomic instability, and neuromuscular hyperactivity (clonus > rigidity, hyperreflexia). Treatment: Discontinue all serotonergic agents; benzodiazepines for agitation; cyproheptadine (5-HT2A antagonist) 12 mg PO loading, then 2 mg q2h PRN (max 32 mg/day); active cooling for hyperthermia; IV fluids; severe cases may require intubation, paralysis, and ICU-level care. Avoid dantrolene (only for NMS, not serotonin syndrome).

30 Abbreviations Master List