Behavioral Health

Opioid use disorder: medication-assisted treatment

Clinical Overview and When to Suspect Opioid Use Disorder

— Severity: Mild 2–3 criteria; moderate 4–5; severe ≥6. Moderate-to-severe OUD is the threshold most board questions use to justify medication for OUD (MOUD).

— Tolerance and withdrawal alone (in patients taking prescribed opioids as directed) do not count toward diagnosis.

— Requests for early refills, "lost" prescriptions, multiple prescribers (check state PDMP)

— Track marks, recurrent cellulitis/abscesses, endocarditis, hepatitis C seroconversion

— Unexplained constipation, miosis, sedation; unexplained mydriasis + yawning/rhinorrhea (withdrawal)

— Patients on chronic opioids escalating dose, using non-oral routes, or combining with benzodiazepines

— Pregnancy with no prenatal care, neonatal abstinence syndrome history

Definition: Opioid use disorder (OUD) is a DSM-5 diagnosis requiring ≥2 of 11 criteria over 12 months (tolerance, withdrawal, craving, use despite harm, failed cutdown, social/occupational impairment, hazardous use, time consumed, larger amounts than intended, role failure, continued use despite interpersonal problems).

Epidemiology: >80,000 US overdose deaths/year, predominantly fentanyl-driven. OUD is undertreated — <20% of affected adults receive MOUD despite 50% mortality reduction with buprenorphine or methadone.

When to suspect OUD in primary care:

Screening: USPSTF (2020) recommends screening all adults for illicit drug use, including opioids, when services for accurate diagnosis and treatment can be offered. Tools: TAPS, NIDA Quick Screen, single-item screen ("How many times in the past year have you used an illegal drug or prescription medication for nonmedical reasons?").

Board pearl: OUD is a chronic, relapsing brain disease, not a moral failing. Step 3 stems that frame OUD as willpower or that withhold MOUD pending "proof of sobriety" are wrong — MOUD is first-line, evidence-based, and should be offered at the point of diagnosis, including in the ED after a nonfatal overdose.

Presentation Patterns and Key History

— Patient in acute intoxication: pinpoint pupils, depressed respirations, somnolence, decreased bowel sounds

— Patient in withdrawal: yawning, lacrimation, rhinorrhea, piloerection, mydriasis, myalgias, diarrhea, abdominal cramping, anxiety, dysphoria — uncomfortable but not life-threatening in adults (contrast alcohol/benzo withdrawal)

— Patient seeking treatment/MOUD initiation in clinic, ED, or postpartum

— Drug(s) used: heroin, fentanyl (now dominant US supply), oxycodone, hydrocodone, methadone, tramadol

— Route: oral, intranasal, smoked, IV — IV use raises HIV/HCV/endocarditis risk

— Quantity, frequency, time of last use (critical for buprenorphine induction timing)

— Prior overdoses, naloxone reversals

— Prior treatment attempts: detox-only, residential, methadone clinic, buprenorphine, naltrexone — and what worked/failed

— Co-use: benzodiazepines, alcohol, stimulants (cocaine/methamphetamine), xylazine ("tranq")

— Psychiatric comorbidity: depression, PTSD, ADHD, bipolar — present in >50%

— Social: housing, employment, legal involvement, custody, partner with OUD

— 11 items, scored 0–4 each; 5–12 mild, 13–24 moderate, 25–36 moderately severe, >36 severe

— Buprenorphine induction generally requires COWS ≥8–12 to avoid precipitated withdrawal

— With fentanyl, COWS-based induction is unreliable — fentanyl's lipophilicity and tissue redistribution prolong the window before safe induction (often 24–72 hours of abstinence needed, or use low-dose/micro-dosing induction)

Three classic Step 3 stems:

Key history elements (the "opioid history"):

Clinical Opiate Withdrawal Scale (COWS):

Step 3 management: When a patient presents requesting MOUD, do not delay for labs, urine tox, or psychiatry consultation. Same-day initiation of buprenorphine in primary care, ED, or hospital is the standard of care and improves retention and reduces mortality. Treat OUD like you would treat new-onset diabetes — start the medication, arrange follow-up.

Physical Exam Findings and Hemodynamic Assessment

— Miosis (pinpoint pupils) — though fentanyl/meperidine/co-ingestants can produce normal or dilated pupils

— Respiratory depression — RR <12, shallow, eventually apnea; the cause of death

— Depressed mental status — somnolence to coma

— Other: bradycardia, hypotension, hypothermia, decreased bowel sounds, cyanosis, pulmonary edema (especially after naloxone reversal)

— Mydriasis, lacrimation, rhinorrhea, yawning, piloerection ("cold turkey"), diaphoresis

— Tachycardia, hypertension, low-grade fever

— Hyperactive bowel sounds, vomiting, diarrhea

— Restlessness, tremor, anxiety, dysphoria, myalgias, arthralgias

— Pupils are the most useful single sign distinguishing intoxication (miosis) from withdrawal (mydriasis)

— Track marks, sclerosed veins, skin popping scars, abscesses, cellulitis

— Endocarditis findings: new murmur (tricuspid regurgitation most common), Janeway lesions, Osler nodes, splinter hemorrhages, septic pulmonary emboli

— Xylazine-associated wounds: necrotic skin ulcers at non-injection sites, can be limb-threatening

— Hepatomegaly (HCV), lymphadenopathy (HIV)

— Airway and breathing first — bag-valve-mask ventilation before IV access

— Naloxone 0.04–0.4 mg IV/IM/IN, repeat q2–3 min, titrate to respirations not consciousness (avoid precipitating severe withdrawal)

— With fentanyl-era overdoses, higher cumulative doses (4–10 mg) and naloxone infusions (2/3 of waking dose per hour) may be needed

— Monitor for renarcotization — naloxone t½ 30–90 min vs fentanyl/methadone much longer; observe minimum 2–4 hours, longer for long-acting opioids

Acute opioid intoxication/overdose (the lethal triad):

Opioid withdrawal exam (sympathetic + GI overdrive):

Stigmata of chronic IV use:

Hemodynamic priorities in overdose:

CCS pearl: After naloxone reversal in the ED, the next CCS orders are pulse oximetry, continuous cardiac monitoring, ECG (QTc for methadone), and offer buprenorphine before discharge plus a naloxone kit prescription with overdose education.

Diagnostic Workup — Initial Labs, Tox Screen, and ECG

— Standard immunoassay opiate panel detects morphine and codeine (heroin metabolizes to morphine → positive)

— Does NOT reliably detect: fentanyl, methadone, buprenorphine, oxycodone, tramadol — each requires a specific assay

— False positives for opiates: poppy seeds, quinolones, rifampin

— Confirmatory GC-MS or LC-MS for legal/custody questions

— UDS results should not gatekeep MOUD initiation — a negative screen does not exclude OUD, and a positive screen for other substances is not a contraindication

— LFTs (AST/ALT) — buprenorphine and methadone metabolized hepatically; check at baseline and periodically

— HIV, HCV antibody (with reflex RNA), HBV serologies — offer/vaccinate

— Pregnancy test in patients of reproductive age — affects choice (methadone or buprenorphine preferred over naltrexone in pregnancy)

— CBC, BMP, syphilis (RPR) in IV users

— TB screening if entering methadone program (regulatory requirement)

— Mandatory before and during methadone — QTc prolongation, torsades risk

— Baseline ECG, then at 30 days and annually; obtain ECG at doses >100 mg/day or with QT-prolonging co-meds

— QTc >450 ms warrants caution; QTc >500 ms → reduce dose, switch agent, or address contributors

— Buprenorphine has minimal QT effect — preferred when QT is a concern

OUD is a clinical, DSM-5 diagnosis. No lab confirms it. Workup targets comorbidities, complications, and pre-MOUD safety.

Urine drug screen (UDS) — know the limitations cold:

Baseline labs before starting MOUD:

ECG:

Imaging/echo: Indicated only for complications — chest imaging for septic emboli, TTE/TEE for suspected endocarditis in IV users with fever or murmur.

Board pearl: A patient asking for MOUD who has a UDS positive for cocaine or benzodiazepines is still a candidate — co-occurring substance use is the rule, not an exclusion. Tighten monitoring, address polysubstance use, but do not withhold buprenorphine.

Diagnostic Workup — Confirmatory and Comorbidity Studies

— Send LC-MS/MS confirmatory testing with explicit request for fentanyl, norfentanyl, methadone (EDDP metabolite), oxycodone, buprenorphine (norbuprenorphine), and 6-MAM (the unique heroin metabolite, detection window 2–8 hours)

— Hair testing extends detection to ~90 days; useful in forensic contexts

— Document chain of custody when results may have legal consequences

— PHQ-9 (depression), GAD-7 (anxiety), PC-PTSD-5 (PTSD), AUDIT-C (alcohol), DAST-10 (other drugs)

— Suicidality assessment — OUD carries 6–10× general population suicide risk

— ADHD screening — untreated ADHD predicts relapse; treat with non-stimulants or carefully monitored stimulants

— HIV with viral load if positive; link to ART (do not delay for sobriety)

— HCV RNA, genotype if antibody positive; DAA therapy is offered regardless of active use — sustained virologic response is achievable on MOUD

— HBV vaccination if non-immune

— Annual STI screening (syphilis, gonorrhea, chlamydia)

— PrEP discussion for HIV-negative patients who inject or have high-risk sexual exposure

— 3 sets of blood cultures before antibiotics if stable

— TTE first; TEE if TTE non-diagnostic, prosthetic valve, or persistent bacteremia (Step 3 favorite)

— Modified Duke criteria; ID and CT surgery consults early

— Naltrexone (oral or extended-release IM) requires 7–10 days opioid-free (10–14 days for methadone) to avoid precipitated withdrawal

— Confirm with naloxone challenge (0.4–0.8 mg SC) and observe — no withdrawal → safe to dose

Confirming opioid exposure when stakes are high (custody, parole, employment, transplant):

Mental health comorbidity screening (do at intake):

Infectious disease workup in IV users or high-risk partners:

Endocarditis evaluation in febrile IV users:

Pre-naltrexone confirmation of opioid abstinence:

Key distinction: Buprenorphine induction needs the patient to be in mild-to-moderate withdrawal (COWS ≥8); naltrexone induction needs the patient to be fully abstinent and out of withdrawal. Confusing the two precipitates severe iatrogenic withdrawal.

Risk Stratification and First-Line Management Logic

— Buprenorphine (partial μ-agonist) — office-based, first-line in most outpatient settings

— Methadone (full μ-agonist) — opioid treatment program (OTP) only in US for OUD

— Naltrexone XR (μ-antagonist) — for patients past withdrawal, motivated, not pregnant

— Buprenorphine and methadone each cut all-cause mortality by ~50%

— Naltrexone XR is non-inferior to buprenorphine only if successfully inducted — but ~30% never get on it due to required abstinence window

— Detox alone (taper without maintenance MOUD) is harmful — relapse rates >90% and overdose death risk rises post-detox due to lost tolerance. Boards penalize "refer to detox and discharge."

— Pregnancy → buprenorphine or methadone (not naltrexone)

— Severe OUD, high-dose fentanyl, prior buprenorphine failure → methadone often more effective

— Unstable housing, no transport → buprenorphine (less daily-clinic dependence) or methadone with take-homes once stable

— Patient prefers no opioid agonist, criminal-justice-involved, alcohol co-use → naltrexone XR reasonable

— Chronic pain + OUD → buprenorphine (analgesic at split dosing q6–8h)

— QT prolongation, methadone-induced torsades risk → buprenorphine

— Hepatic failure → caution with all; methadone preferred to high-dose buprenorphine

— Office/clinic, ED, inpatient, telehealth (permanent post-COVID flexibilities), home induction with daily check-ins all acceptable

— X-waiver requirement was eliminated by MAT Act 2023 — any clinician with a standard DEA registration can prescribe buprenorphine for OUD

All patients with moderate-to-severe OUD should be offered MOUD. Three FDA-approved options:

Mortality data driving choice:

Patient-factor matching:

Setting of induction:

Step 3 management: The single best answer when a Step 3 stem describes a patient with OUD ready for treatment is almost always "initiate buprenorphine-naloxone." "Refer to inpatient detox," "psychotherapy alone," and "wait until next visit" are distractors.

Pharmacotherapy — Buprenorphine, Methadone, Naltrexone Detail

— Partial μ-agonist with ceiling effect on respiratory depression → favorable safety

— High receptor affinity → can displace full agonists → precipitated withdrawal if given too early

— Standard induction: Wait for COWS ≥8 (typically 12–24h after short-acting opioid, 24–72h after methadone/fentanyl). Give 2–4 mg SL, reassess at 1–2h, give additional 2–4 mg as needed. Day 1 total typically 8–12 mg; day 2 titrate to 16 mg; usual maintenance 16–24 mg/day (max 32 mg).

— Low-dose ("micro-dose," Bernese method) induction: for fentanyl-using patients — start 0.5 mg daily, titrate over 5–7 days while patient continues full agonist, no withdrawal required

— Naloxone component is poorly absorbed sublingually; deters IV misuse (precipitates withdrawal if injected)

— Long-acting injectable: Sublocade monthly SC, after ≥7 days of SL stabilization

— Full μ-agonist, OTP-only for OUD in US (any physician can prescribe for pain)

— Start 20–30 mg/day, increase by 5–10 mg every several days; effective dose typically 60–120 mg/day

— Long half-life (15–60h) → steady-state takes 5 days → deaths cluster in first 2 weeks of induction from accumulation

— Drug interactions via CYP3A4, 2B6, 2D6 — rifampin, phenytoin, efavirenz lower levels (precipitate withdrawal); fluconazole, ciprofloxacin raise levels

— QTc monitoring as above

— μ-antagonist; XR-naltrexone 380 mg IM monthly is the OUD formulation (oral naltrexone has poor adherence)

— Requires 7–10 days opioid-free; confirm with naloxone challenge

— Blocks analgesia from opioids — patients need medical alert ID; in trauma, use non-opioid analgesia, regional anesthesia, or high-dose opioid under monitoring

— Hepatotoxicity at high oral doses — avoid in acute hepatitis or liver failure

Buprenorphine-naloxone (Suboxone, sublingual film/tablet):

Methadone:

Naltrexone:

Board pearl: Buprenorphine + benzodiazepine is not an absolute contraindication — the FDA explicitly states the benefits of buprenorphine outweigh the risk of co-prescription, and withholding MOUD is more dangerous. Counsel on overdose risk, taper benzos when possible, prescribe naloxone.

Adjunctive Pharmacology, Overdose Reversal, and Behavioral Treatment

— IN spray 4 mg (most common), IM 0.4 mg, autoinjector 2 mg

— Now OTC in US (Narcan nasal spray, March 2023)

— Counsel: call 911, give naloxone, rescue breathing, repeat q2–3 min, recovery position

— Good Samaritan laws in most states protect bystanders and the overdose victim from drug-possession prosecution

— Clonidine 0.1–0.2 mg q6h for autonomic symptoms (monitor BP); lofexidine (FDA-approved for opioid withdrawal) is similar with less hypotension

— Loperamide for diarrhea (but warn against misuse — high-dose loperamide causes QT prolongation/torsades)

— Ondansetron for nausea (mind QT with methadone)

— Dicyclomine for cramping

— NSAIDs or acetaminophen for myalgias

— Hydroxyzine or trazodone for insomnia (avoid benzodiazepines)

— Contingency management — strongest evidence, financial/voucher incentives for negative UDS

— Cognitive behavioral therapy, motivational interviewing

— 12-step facilitation, peer recovery coaches

— Harm reduction: syringe service programs, fentanyl test strips, supervised consumption sites (where legal), HIV/HCV testing, wound care

— Continue MOUD through surgery — do not stop buprenorphine perioperatively per current ASA/ASAM consensus

— Add full agonists on top for acute pain; higher doses often needed due to receptor occupancy

— Multimodal: acetaminophen, NSAIDs, gabapentinoids (caution — overdose synergy), regional anesthesia, ketamine

Naloxone — prescribe to every OUD patient and family:

Symptomatic management of withdrawal (adjuncts during induction or taper):

Behavioral interventions (combine with MOUD, do not substitute):

Treating concurrent pain in OUD patients:

CCS pearl: On every CCS case involving OUD, your orders should include: buprenorphine induction or continuation, intranasal naloxone Rx with overdose education, HCV/HIV/HBV testing, vaccinations (HBV, pneumococcal if indicated), and behavioral health referral. Missing any of these costs points.

Special Populations — Elderly, Renal, and Hepatic Impairment

— Rising OUD prevalence — driven by long-term prescription opioid use, chronic pain

— Higher baseline risk of falls, cognitive impairment, polypharmacy, constipation

— Buprenorphine preferred — safer respiratory profile, fewer drug interactions, no QT issue

— Start low: 2 mg SL induction doses; titrate slowly

— Screen for cognitive impairment that may affect adherence; consider XR injectable buprenorphine for adherence support

— Address constipation prophylactically (osmotic laxative ± stimulant); avoid PRN opioids for breakthrough pain when possible

— Buprenorphine: no dose adjustment — minimal renal clearance; safe in dialysis (not dialyzed off)

— Methadone: minimal renal clearance, generally safe but accumulation possible in severe CKD; monitor for sedation, prolong dosing interval

— Naltrexone: caution if CrCl <50; limited data

— Avoid morphine (active metabolite M6G accumulates); use hydromorphone, fentanyl, or buprenorphine for any required analgesia in ESRD

— Mild-moderate (Child-Pugh A–B): both buprenorphine and methadone usable; start lower

— Severe (Child-Pugh C): buprenorphine plasma levels rise — consider buprenorphine monoproduct (no naloxone) since naloxone clearance falls disproportionately; some experts favor methadone in severe cirrhosis given more predictable kinetics

— Naltrexone contraindicated in acute hepatitis or liver failure; check LFTs at baseline and periodically

— HCV treatment with DAAs is fully compatible with MOUD — treat both

— Baseline ALT/AST, repeat at 1, 3, 6 months then yearly

— ALT >3× ULN or symptoms → evaluate; usually not MOUD-attributable

Older adults (≥65):

Renal impairment:

Hepatic impairment:

Hepatitis-related monitoring on MOUD:

Key distinction: In ESRD on hemodialysis, buprenorphine is the safest opioid agonist for OUD and for analgesia — no dose adjustment needed and it is not dialyzed. Methadone is also acceptable; morphine and codeine should be avoided due to neurotoxic metabolite accumulation.

Special Populations — Pregnancy, Adolescents, and Postpartum

— MOUD is standard of care. Medically supervised withdrawal/detox is not recommended — high relapse, fetal stress, no improved outcomes

— Buprenorphine or methadone are both first-line. ACOG/SAMHSA endorse either; choice individualized

— Historically buprenorphine monoproduct (without naloxone) was preferred in pregnancy, but recent data support buprenorphine-naloxone as also safe; either is acceptable

— Methadone dose typically increases in third trimester due to volume of distribution and increased metabolism — split BID dosing helps

— Naltrexone in pregnancy: insufficient data; generally continue if already stable on it before pregnancy and patient prefers, after counseling

— Occurs in 30–80% of opioid-exposed neonates regardless of MOUD agent

— Onset: 24–72h for short-acting opioids and buprenorphine; up to 5–7 days for methadone

— Management: Eat-Sleep-Console (ESC) model — non-pharmacologic first (swaddling, rooming-in, breastfeeding, low stimulation); morphine or methadone if needed

— Breastfeeding is encouraged on buprenorphine or methadone (low milk transfer); contraindicated only if HIV+ untreated or active illicit use

— Highest overdose risk window — relapse in months 7–12 postpartum is leading cause of maternal death in many US states

— Maintain MOUD; do not taper after delivery without explicit patient request and stable circumstances

— Ensure naloxone, contraception counseling, mental health support, custody/CPS navigation

— Buprenorphine FDA-approved ≥16 years; off-label younger with specialist input

— Naltrexone XR studied in young adults; oral can be considered

— Family-based therapy, school engagement, parental naloxone training

Pregnancy:

Neonatal opioid withdrawal syndrome (NOWS / NAS):

Postpartum period:

Adolescents:

Step 3 management: A pregnant patient with OUD presenting to clinic should be started on (or continued on) buprenorphine or methadone the same day, referred to high-risk OB and addiction-specialist co-management, screened for HIV/HCV/STIs, and counseled that breastfeeding and rooming-in reduce NAS severity.

Complications and Adverse Outcomes

— Fatal overdose — respiratory depression; risk ↑ with fentanyl, polysubstance (benzos, alcohol), post-incarceration, post-detox, post-hospitalization (lost tolerance)

— Anoxic brain injury from prolonged hypoxia even after reversal

— Aspiration pneumonia, rhabdomyolysis, compartment syndrome from prolonged immobility

— Noncardiogenic pulmonary edema post-naloxone reversal

— Right-sided endocarditis (S. aureus most common, including MRSA), tricuspid valve, septic pulmonary emboli

— Skin/soft tissue: cellulitis, abscess, necrotizing fasciitis

— Xylazine wounds — necrotic ulcers, often at non-injection sites

— Osteomyelitis, septic arthritis, epidural abscess (back pain + fever + IVDU = MRI urgently)

— HIV, HCV, HBV transmission; clusters in communities with limited syringe access

— Mycotic aneurysms

— Buprenorphine: constipation, headache, sweating, precipitated withdrawal at induction, dental caries with sublingual films (FDA warning 2022 — rinse mouth after dissolution), hepatotoxicity (rare)

— Methadone: QT prolongation/torsades, sedation, constipation, hypogonadism, weight gain, drug interactions, induction overdose deaths

— Naltrexone: injection site reactions, hepatotoxicity at high doses, precipitated withdrawal if not abstinent, loss of tolerance → fatal overdose risk if relapse occurs after stopping

— Hypogonadism, osteoporosis, opioid-induced hyperalgesia, sleep-disordered breathing/central apnea (especially methadone)

— Cognitive effects, depression

— Cardiovascular: methadone QT, IE-related valve damage

Acute complications of opioid use:

Infectious complications of IV use:

MOUD-specific adverse effects:

Chronic sequelae:

Social/legal: incarceration, child welfare involvement, employment loss, housing instability — addressing these is part of recovery, not separate from it

Board pearl: The single deadliest moment in OUD is the week after release from controlled settings (jail, hospital, detox, residential). Tolerance falls; patients return to prior doses; overdose mortality is 40–130× baseline. Boards reward initiating MOUD before discharge and providing naloxone.

When to Escalate — ICU, Consult, Inpatient Triage

— Persistent respiratory depression or apnea despite naloxone; need for naloxone infusion (typically two-thirds of waking dose per hour)

— Anoxic brain injury, post-cardiac arrest care

— Massive fentanyl/carfentanil overdose — often requires intubation and prolonged observation due to long tissue redistribution

— Severe co-ingestion (benzodiazepine, alcohol, methamphetamine with hyperthermia)

— Cardiogenic instability from endocarditis, sepsis from injection-related infection

— Endocarditis, osteomyelitis, epidural abscess, septic arthritis — IV antibiotics, often surgical consult

— Complicated withdrawal in patients with cardiac, pulmonary, or pregnancy comorbidities

— Complex MOUD induction: methadone-to-buprenorphine transitions, high-dose fentanyl users requiring micro-dose induction with close monitoring

— Acute psychiatric crisis (suicidality), severe co-occurring substance withdrawal (alcohol, benzodiazepine)

— Nonfatal overdose: observe minimum 2–4h after last naloxone dose (longer for methadone, long-acting opioids, sustained-release oxycodone); offer buprenorphine in ED (ED-initiated buprenorphine doubles 30-day engagement vs referral alone — D'Onofrio 2015)

— Discharge with naloxone kit, warm handoff to outpatient MOUD clinic within 72h

— Addiction medicine — complex induction, polysubstance, treatment-resistant OUD

— Infectious disease — endocarditis, HIV, HCV

— Cardiothoracic surgery — valve repair/replacement in endocarditis (recurrent IE in active use is an ethical and clinical challenge but not an absolute contraindication)

— Maternal-fetal medicine — pregnancy with OUD

— Pain medicine — perioperative buprenorphine management

— Psychiatry — co-occurring disorders, suicidality

ICU-level care indications:

Inpatient admission (non-ICU) — strong indications:

ED disposition pearls:

Consultations to consider:

CCS pearl: In a hospitalized OUD patient, your standing orders should include scheduled COWS assessments, PRN buprenorphine or methadone for withdrawal, DVT prophylaxis, screening labs, vaccinations, and addiction medicine consult — and you must explicitly document an MOUD plan before discharge or the case loses points.

Key Differentials — Same-Category (Substance-Related) Causes

— Alcohol withdrawal: also features autonomic hyperactivity, tremor, anxiety — but risk of seizures, hallucinations, delirium tremens distinguishes; CIWA-Ar guides treatment; benzodiazepine-managed, not clonidine

— Benzodiazepine withdrawal: seizures, psychosis, can be fatal; tapered with long-acting benzodiazepines

— Stimulant "crash" (cocaine, methamphetamine): hypersomnia, hyperphagia, dysphoria — but no autonomic surge, no myalgias, no GI hyperactivity

— SSRI discontinuation syndrome: dizziness, "brain zaps," flu-like — milder; resolves with reinstitution

— Cannabis withdrawal: irritability, sleep disturbance, anorexia — much milder autonomic features

— Benzodiazepine, alcohol, GHB intoxication: sedation without miosis (pupils variable/normal); naloxone won't reverse

— Clonidine, antipsychotic overdose: can produce miosis, sedation, hypotension — clonidine especially in children; respond minimally to naloxone

— Pontine stroke: pinpoint pupils, coma — but focal findings, no respiratory pattern reversal with naloxone, neuroimaging diagnostic

— Organophosphate poisoning: miosis, but with SLUDGE/DUMBELS, fasciculations, bradycardia — treat with atropine and pralidoxime

— Stimulant use disorder (no FDA-approved pharmacotherapy; contingency management is best evidence)

— Sedative-hypnotic use disorder

— Alcohol use disorder (naltrexone, acamprosate, disulfiram)

— Polysubstance use is common — treat the most dangerous first, but treat all

— Physical dependence ≠ OUD. A patient on chronic opioids for cancer pain who has tolerance and withdrawal but no loss of control, no craving, no use despite harm, no functional impairment does not have OUD. Step 3 stems test this distinction.

— Iatrogenic dependence — taper carefully if discontinuing, but do not label the patient with OUD

Opioid withdrawal mimics:

Opioid intoxication mimics:

OUD vs. other substance use disorders:

Opioid use without OUD:

Key distinction: The presence of withdrawal and tolerance in a patient using opioids exactly as prescribed for a legitimate indication does not establish OUD. Look for loss of control, compulsion, craving, and continued use despite harm — the behavioral hallmarks.

Key Differentials — Other-Category Causes of Altered Mental Status

— Hypoglycemia — check fingerstick on every AMS; diaphoresis, focal deficits possible; D50 reverses

— Hypercapnic respiratory failure (COPD, OHS, neuromuscular) — CO2 narcosis; ABG diagnostic; BiPAP, not naloxone

— CNS infection: meningitis, encephalitis — fever, neck stiffness, leukocytosis

— Intracranial hemorrhage / ischemic stroke — focal findings, imaging

— Hypothyroid (myxedema) coma — bradycardia, hypothermia, hyponatremia

— Hepatic encephalopathy — asterixis, elevated ammonia, cirrhosis stigmata

— Uremic encephalopathy — elevated BUN, dialysis indication

— Wernicke encephalopathy — ataxia, ophthalmoplegia, confusion in malnourished; thiamine

— Cholinergic (organophosphates, nerve agents): miosis but with bradycardia, salivation, fasciculations — atropine and pralidoxime

— Sympatholytic (clonidine, beta-blocker): miosis, bradycardia, hypotension; may transiently respond to naloxone at high doses

— Sedative-hypnotic: usually mydriasis (or normal); flumazenil reverses benzos in selected cases

— Adrenal crisis: hypotension, hypoglycemia, hyponatremia

— DKA/HHS in altered diabetic patients

— Severe hyponatremia → seizure, coma

— Opioid-induced (especially post-naloxone)

— Endocarditis with valvular dysfunction

— Talc granulomatosis from IV crushed pills

— Pseudoaddiction — pain-driven aberrant behavior that resolves with adequate analgesia; controversial term, but the principle (undertreated pain mimics OUD) remains valid clinically

— Step 3 stems may show a patient with cancer pain "drug-seeking" — answer is improve analgesia, not labeling OUD

Altered mental status + respiratory depression — beyond opioids:

Toxidromes mimicking opioid presentation:

Endocrine/metabolic causes of overdose-like picture:

Pulmonary edema in IVDU:

Chronic pain mistaken for OUD:

Board pearl: In any patient presenting with coma and respiratory depression, the DON'T (Dextrose, Oxygen, Naloxone, Thiamine) sequence is the empirical resuscitation cocktail — and the diagnostic workup (glucose, ABG, CT head, labs) runs in parallel rather than waiting for response to naloxone.

Secondary Prevention, Discharge Medications, and Long-Term Plan

— Initiate or continue MOUD — buprenorphine, methadone (via OTP), or naltrexone XR

— Naloxone prescription (intranasal 4 mg, 2 doses minimum) with overdose education for patient and household

— Warm handoff appointment within 72 hours; phone confirmation

— Address transportation barriers, insurance enrollment, prior authorization

— Hepatitis B vaccine series if non-immune

— Hepatitis A vaccine for people who inject drugs (PWID)

— Tdap, influenza, COVID, pneumococcal per ACIP for PWID and risk groups

— HPV through age 45 with shared decision-making

— HCV DAA therapy for chronic HCV — do not delay for sobriety

— HIV ART or PrEP as indicated

— Multimodal: PT, CBT for chronic pain, non-opioid analgesics

— If opioid pain medication required, coordinate with single prescriber, PDMP, written agreement, monthly visits

— Fentanyl test strips, syringe service programs, never use alone (988, Never Use Alone hotline 1-800-484-3731)

— Counsel about lost tolerance after any abstinence period

— Safer-use education, wound care, vein care

— Relapse is part of the disease; build re-engagement plan into care

— Adjust MOUD dose, intensify behavioral support, reassess setting

— Do not discharge from MOUD for a positive UDS alone — punitive discharge increases mortality

— Annual: lipid screen per USPSTF, BP, BMI, depression screen, IPV screen

— Cancer screening per age/sex guidelines (cervical, breast, colorectal, lung)

— Contraception counseling — OUD does not contraindicate any method; LARCs ideal

At discharge from ED, hospital, or after any acute encounter:

Co-prescriptions and vaccinations:

Pain management long-term:

Risk-reduction harm reduction:

Relapse planning:

Health maintenance to not forget:

Step 3 management: "Continue buprenorphine indefinitely" is the correct answer when a stable patient asks how long they need to stay on MOUD. There is no time-limited course; tapering is patient-driven, gradual, and only after sustained stability with strong support — and relapse rates after taper are high.

Follow-Up, Monitoring Parameters, and Counseling

— Induction phase (week 1–2): see in 3–7 days; phone/telehealth check at 24–48h

— Stabilization (weeks 2–8): every 1–2 weeks

— Maintenance (stable >3 months): monthly, then every 1–3 months once highly stable

— Telehealth fully acceptable (post-COVID DEA flexibilities, currently extended)

— Cravings, use of non-prescribed substances, mood, sleep, function, side effects

— Urine drug screen — periodic, non-punitive; used to refine treatment, not to dismiss

— Medication adherence and storage (safe storage from children, others in household)

— Pregnancy intentions, contraception

— PDMP review at initiation and periodically (state-dependent frequency)

— Daily observed dosing initially; take-homes earned per federal/SAMHSA criteria (recently liberalized — up to 28-day take-homes for stable patients)

— ECG baseline, 30 days, annually, and with dose >100 mg or co-meds

— LFTs periodically

— Monthly injection; LFTs every 6–12 months

— Reassess motivation, address barriers to injection adherence

— Ask about use, cravings, triggers

— Advise on continued treatment, harm reduction

— Assess readiness for goal changes

— Assist with referrals, mutual help (NA, SMART Recovery, Refuge Recovery)

— Arrange follow-up

— Peer recovery coaches improve retention

— Vocational rehab, housing first programs

— Family/couples therapy where appropriate

— Avoid 12-step-only programs that reject MOUD; refer to MOUD-friendly meetings

Follow-up cadence on buprenorphine:

Monitoring at each visit:

Methadone-specific monitoring:

Naltrexone monitoring:

Behavioral counseling at every visit (the "5 A's" adapted):

Rehabilitation and recovery supports:

Board pearl: A positive urine for marijuana, cocaine, or methamphetamine in a patient otherwise stable on buprenorphine is not an indication to stop MOUD. Address the additional substance use within the treatment plan; stopping buprenorphine increases overdose death.

Ethical, Legal, and Patient Safety Considerations

— OUD remains under-treated, with documented racial disparities — Black and Hispanic patients are less likely to receive buprenorphine and more likely to be funneled into methadone clinics

— Clinicians must examine bias; offer MOUD universally to all eligible patients

— Avoid stigmatizing language: "person with OUD," not "addict" or "abuser"; "positive/negative UDS," not "clean/dirty"

— Federal law gives substance use treatment records stricter confidentiality than HIPAA

— Disclosure requires specific written consent even for routine care coordination (recent revisions allow more HIPAA-aligned sharing with consent, but the heightened protection persists)

— Implications: discharge summaries, EHR notes, family communication — verify consent

— State laws vary: some mandate reporting of prenatal substance use; some treat in-utero exposure as child abuse

— Counsel patients about reporting requirements before UDS in pregnancy

— MOUD use itself is not child abuse — but documentation should be explicit

— Stable patients on MOUD can drive, work, operate machinery — no per-se restriction

— Counsel against driving during induction, after dose changes, with sedating co-meds

— Discuss benefits (mortality reduction), risks (overdose if combined with sedatives, precipitated withdrawal at induction, neonatal withdrawal in pregnancy), alternatives (other MOUD, no treatment), and uncertainty about duration

— Document shared decision-making

— Hospital discharge is a critical handoff — buprenorphine bridge prescription, naloxone kit, scheduled follow-up within 72h

— Incarceration dramatically raises post-release overdose risk; advocate for MOUD continuation in jails/prisons

— Pharmacy refusals, prior auth delays — have a workflow

— Most states have Good Samaritan overdose laws protecting callers and victims from minor drug-possession charges

— Counsel patients and families to always call 911 during an overdose

Stigma and equitable access:

Confidentiality — 42 CFR Part 2:

Pregnancy and CPS reporting:

Driving and occupational safety:

Informed consent for MOUD:

Patient safety/transitions of care:

Mandatory reporting and Good Samaritan laws:

Step 3 management: When a Step 3 stem describes a pregnant patient with OUD reluctant to disclose for fear of CPS, the answer involves transparent counseling about state law, continued offering of MOUD, and addressing fear with empathy — not threats and not withholding treatment.

High-Yield Associations and Rapid-Fire Clinical Facts

— Buprenorphine and methadone each ↓ all-cause mortality ~50%

— ED-initiated buprenorphine doubles 30-day treatment engagement

— Post-incarceration overdose death is 40–130× baseline in first 2 weeks

— Buprenorphine: partial μ-agonist, ceiling effect on respiration, κ-antagonist (potential mood benefit)

— Methadone: full μ-agonist + NMDA antagonist + SNRI activity (relevant in neuropathic pain; QTc risk)

— Naloxone: pure μ-antagonist, t½ 30–90 min

— Naltrexone: long-acting μ-antagonist, oral t½ ~4h, XR-IM lasts ~28 days

— Tramadol: weak μ-agonist + SNRI — seizure risk, serotonin syndrome with SSRIs

— Methadone + rifampin, phenytoin, carbamazepine, efavirenz → withdrawal (CYP induction)

— Methadone + fluconazole, ciprofloxacin, fluvoxamine → toxicity (CYP inhibition)

— Buprenorphine has minimal clinically significant CYP interactions

— MOUD + benzodiazepine/alcohol → respiratory depression, but not absolute contraindication

— Heroin → 6-MAM (unique, 2–8h window) → morphine

— Codeine → morphine, hydrocodone

— Methadone tested specifically (EDDP metabolite)

— Fentanyl and buprenorphine require dedicated assays

— Quinolones, rifampin → false-positive opiate immunoassay

— MOUD, naloxone Rx, HIV/HCV/HBV testing, HBV vaccination, contraception counseling, mental health screening, harm reduction education, follow-up scheduled

Mortality and treatment effect sizes:

Pharmacology quick recall:

Drug interactions worth memorizing:

UDS pearls:

The "always include" Step 3 bundle for OUD encounters:

CCS pearl: When a CCS case patient overdoses on the wards, the order sequence is stop offending agent → BVM ventilation → naloxone → continuous monitoring → naloxone infusion if needed → ICU transfer → addiction medicine consult → buprenorphine initiation prior to discharge → naloxone Rx and outpatient follow-up. Missing the buprenorphine and naloxone Rx tanks the score.

Board Question Stem Patterns

— A 32-year-old presents to clinic requesting help for heroin use. Last use 16 hours ago, COWS 12. Next step?

— Answer: Induce buprenorphine-naloxone 4 mg SL, not "refer to detox," not "obtain confirmatory testing first."

— Patient revived with naloxone in ED, alert, requests to leave. Next step?

— Answer: Offer buprenorphine in ED, prescribe naloxone kit, arrange 72h follow-up — not "discharge with referral to AA."

— Pregnant patient with active heroin use presents at 14 weeks. Best management?

— Answer: Initiate buprenorphine (or methadone), not "medically supervised withdrawal," not "naltrexone."

— Patient on methadone 140 mg presents with syncope; ECG QTc 530 ms. Action?

— Answer: Reduce methadone dose / address contributors / consider switch to buprenorphine.

— Patient receives buprenorphine 4 hours after last fentanyl use; develops severe withdrawal. Next step?

— Answer: Continue buprenorphine with higher doses (16+ mg "rescue") plus symptomatic care — not "stop and try again tomorrow." (Counterintuitive but evidence-supported.)

— Patient on buprenorphine 16 mg admitted with appendicitis. Postoperative pain management?

— Answer: Continue buprenorphine, add full agonists at higher doses for acute pain, multimodal analgesia.

— Patient sober 5 days post-detox; want naltrexone XR. Next step?

— Answer: Wait until 7–10 days opioid-free, perform naloxone challenge, then dose.

— Patient on alprazolam wants buprenorphine. Answer: Initiate buprenorphine with overdose counseling and naloxone; plan benzo taper — not "withhold MOUD."

— IVDU with second episode of tricuspid IE asking for valve replacement. Answer: Offer surgery with concurrent MOUD initiation and addiction medicine consult — not "deny surgery."

Pattern 1 — Same-day MOUD initiation:

Pattern 2 — Post-overdose disposition:

Pattern 3 — Pregnancy:

Pattern 4 — Methadone QT:

Pattern 5 — Precipitated withdrawal:

Pattern 6 — Pain in OUD:

Pattern 7 — Naltrexone induction:

Pattern 8 — Co-occurring benzodiazepine use:

Pattern 9 — Endocarditis recurrence:

Board pearl: When in doubt on a Step 3 OUD question, the answer is "start or continue MOUD." Detox-only, abstinence-only, and gatekeeping answers are wrong.

One-Line Recap

Moderate-to-severe opioid use disorder is a chronic, relapsing brain disease whose single most life-saving intervention is same-day initiation of medication for OUD — buprenorphine or methadone (each cutting mortality ~50%), or naltrexone XR in fully abstinent motivated patients — combined with naloxone co-prescription, harm reduction, infectious disease screening, and longitudinal behavioral support.

— MOUD over detox, every time. Medically supervised withdrawal without maintenance increases overdose death; never the right Step 3 answer. Buprenorphine and methadone are first-line; naltrexone XR is an alternative after 7–10 days abstinence.

— Induction timing is the trap. Buprenorphine needs COWS ≥8 (mild-moderate withdrawal); naltrexone needs complete abstinence (10+ days, naloxone challenge). With fentanyl, consider low-dose/micro-dose induction to avoid precipitated withdrawal.

— The OUD discharge bundle is non-negotiable: MOUD prescription, intranasal naloxone with overdose education, HIV/HCV/HBV screening, HAV/HBV vaccination, contraception/pregnancy counseling, mental health screen, warm-handoff follow-up within 72h, and harm reduction resources.

— Special populations: pregnancy → buprenorphine or methadone (never naltrexone-first, never withdrawal); ESRD → buprenorphine preferred; chronic pain + OUD → buprenorphine with split dosing; perioperative → continue buprenorphine through surgery and add full agonists for acute pain.

Top 4 high-yield recap bullets:

Step 3 management: Treat OUD like diabetes — chronic, biological, medication-managed, longitudinal. Document shared decision-making, never punitively discharge for a positive UDS, and remember that the highest-risk windows for overdose death are post-detox, post-hospitalization, post-incarceration, and postpartum — exactly when MOUD continuity matters most.