Substance use concerns

Substance use concerns cover any presentation in which substance use is the problem, or is suspected as the cause of a physical, psychiatric or social complaint. The substances include alcohol, tobacco, cannabis, opioids, stimulants, sedatives, hallucinogens, inhalants, khat and new synthetic substances.

Patients present with intoxication, overdose, withdrawal, complications of use (infection, injury, psychosis, cardiovascular events), concern from family, legal or work problems, or a request for help.

Definitions.

• A substance use disorder is a problematic pattern of use with clinically significant impairment or distress, shown by 2 or more of 11 features within 12 months.
• The features are: larger amounts or longer use than intended, unsuccessful efforts to cut down, much time spent obtaining or recovering, craving, failure to fulfil roles, continued use despite social or interpersonal problems, reduced activities, use in hazardous situations, continued use despite physical or psychological harm, tolerance, and withdrawal.
• Severity is mild (2 to 3 features), moderate (4 to 5) or severe (6 or more).
• Hazardous use is a pattern that raises risk of harm. Harmful use is a pattern that has already caused harm.
• Dependence is the syndrome of tolerance, withdrawal, craving and loss of control.
• In alcohol, low risk drinking is up to 14 units weekly spread over 3 or more days (1 unit is 10 mL or 8 g of pure alcohol). A binge is 5 or more drinks for men or 4 or more for women in about 2 hours.

Classification by substance

• Alcohol: hazardous use, harmful use, dependence, intoxication, withdrawal, Wernicke encephalopathy and Korsakoff syndrome, alcohol related liver disease, pancreatitis, cardiomyopathy, and neuropathy.
• Opioids: heroin, morphine, codeine, tramadol, oxycodone, fentanyl and analogues, and nitazenes.
• Stimulants: cocaine, amphetamines, methamphetamine, methylphenidate misuse, khat (cathinone), and synthetic cathinones.
• Cannabis and synthetic cannabinoids.
• Sedative hypnotics: benzodiazepines, Z drugs, barbiturates, gamma-hydroxybutyrate, gabapentinoids.
• Tobacco and nicotine, including vaping.
• Hallucinogens and dissociatives: lysergic acid diethylamide, psilocybin, ketamine, phencyclidine, MDMA.
• Inhalants (solvents, nitrites, nitrous oxide).
• Anabolic steroids and performance enhancing drugs, caffeine, and over the counter drugs (codeine, dextromethorphan, loperamide, antihistamines).
• Behavioural addictions with similar mechanisms: gambling disorder.

Epidemiology.

• About 5% of the adult population has an alcohol use disorder, and alcohol causes about 5% of the global burden of disease.
• About 1.3 billion people use tobacco.
• Cannabis is the commonest illicit drug, with dependence in about 10% of users (higher with adolescent onset or daily use).
• About 60 million people use opioids and about 20 million have dependence. Overdose deaths are mainly opioid related, and rising with potent synthetic opioids.
• Use often starts in adolescence, and mental illness coexists in 30% to 50% of patients (dual diagnosis).
• In many regions khat, alcohol, cannabis and tobacco are the commonest substances, and injecting use drives HIV, hepatitis B and C.

Mechanisms. Substances act on the mesolimbic dopamine reward system and related circuits. Repeated use causes tolerance and neuroadaptation. This leads to withdrawal on stopping, craving through conditioned cues, and impaired prefrontal control. Genetic vulnerability, early exposure, trauma, mental illness, social context and availability all contribute.

Key distinctions.

• Pinpoint pupils, slow breathing and reduced consciousness point to opioid toxicity.
• Dilated pupils, agitation, tachycardia, hyperthermia and sweating point to stimulant or hallucinogen toxicity or to serotonin syndrome.
• Slurred speech, ataxia and smell of alcohol point to alcohol intoxication.
• Tremor, sweating and agitation 6 to 48 hours after the last drink point to alcohol withdrawal.
• Yawning, rhinorrhoea, lacrimation, piloerection, myalgia and diarrhoea point to opioid withdrawal.
• New psychosis after stimulant or cannabis use may persist beyond intoxication.

History

• Ask about all substances in a nonjudgemental way, including prescribed and over the counter drugs: type, route (oral, smoked, snorted, injected, rectal), amount, frequency, age at first use, pattern in the last 4 weeks, last use, and time to first use each day.
• Screening tools:
  • AUDIT-C (3 questions, score of 4 or more in men and 3 or more in women is positive)
  • full AUDIT (8 or more indicates hazardous use, 20 or more suggests dependence)
  • single question screening ("How many times in the past year have you used an illegal drug or used a prescription medication for non medical reasons?", 1 or more is positive)
  • DAST-10 for drugs, CRAFFT in adolescents, Fagerstrom test for nicotine dependence, and the Severity of Dependence Scale
• Dependence features: tolerance, withdrawal history (seizures, delirium tremens), craving, and previous attempts to stop and relapse triggers.
• Complications: injuries, overdoses, infections (skin abscess, endocarditis, HIV, hepatitis, tuberculosis), cardiac symptoms, chest pain, liver disease, cognitive change, psychosis, mood and anxiety, suicidal thoughts, sleep, weight, and sexual problems.
• Injecting practice: sharing equipment, sites, supply, and safe disposal.
• Social and legal: work, school, relationships, children at home, driving, violence, debt, and legal problems.
• Mental illness and trauma, and family history of addiction.
• Medical history and medicines: liver and kidney disease, pregnancy, HIV and hepatitis status, interacting drugs.
• Motivation and readiness to change (precontemplation, contemplation, preparation, action, maintenance), previous treatment, and goals (abstinence or reduced use).
• Collateral history from family with consent.

Examination

• Vital signs: temperature, pulse, blood pressure, respiratory rate, oxygen saturation, and glucose.
• General: level of consciousness, hygiene, nutrition, signs of intoxication or withdrawal, pupil size and reactivity, tremor, sweating, nystagmus, and track marks, abscesses, cellulitis and phlebitis.
• Alcohol related: jaundice, spider naevi, palmar erythema, gynaecomastia, ascites, hepatomegaly, parotid enlargement, Dupuytren contracture, peripheral neuropathy, cerebellar signs, ophthalmoplegia and confusion (Wernicke encephalopathy).
• Cardiorespiratory: murmurs (endocarditis), arrhythmia, wheeze, crackles, and chest signs after smoking or inhalation.
• Nasal septum (cocaine), dental disease, and skin changes (methamphetamine sores).
• Mental state: orientation, mood, perception, thought content, insight, suicide risk, and cognition.
• Withdrawal scales:
  • Clinical Institute Withdrawal Assessment for Alcohol revised (CIWA-Ar, 0 to 67; under 10 mild, 10 to 18 moderate, over 18 severe)
  • Clinical Opiate Withdrawal Scale (COWS; 5 to 12 mild, 13 to 24 moderate, 25 to 36 moderately severe, over 36 severe)

Red flags

• Reduced consciousness, respiratory rate under 10 breaths/min, oxygen saturation under 92%, or pinpoint pupils (opioid toxicity).
• Hyperthermia (over 39 degrees Celsius), rigidity, clonus, seizures, or rhabdomyolysis (stimulant toxicity, serotonin syndrome).
• Alcohol or benzodiazepine withdrawal with hallucinations, seizures, fever or confusion (delirium tremens).
• Wernicke encephalopathy: confusion, ataxia, ophthalmoplegia, or nystagmus.
• Chest pain, arrhythmia, severe hypertension, or stroke symptoms with cocaine, amphetamines or cannabis.
• Suicidal intent, self harm, or psychosis.
• Intoxication with head injury, or a hidden co-ingestion (paracetamol, tricyclic antidepressants).
• Fever with injecting drug use (endocarditis, abscess, epidural abscess, osteomyelitis).
• Pregnancy, child at risk at home, or inability to care for dependants.
• Gamma-hydroxybutyrate or inhalant use with sudden collapse.
• Use of synthetic opioids (nitazenes, fentanyl) with high overdose risk.
• Liver failure, variceal bleeding, or alcohol related hepatitis.

Special groups

• Adolescents: confidential interview, family involvement within safety limits, and high risk of dependence with early use. Screen with CRAFFT.
• Pregnancy: alcohol, tobacco and opioids affect the foetus (foetal alcohol spectrum disorder, neonatal abstinence syndrome). Offer early, nonpunitive specialist care.
• Older adults: lower tolerance, falls, cognitive impairment, drug interactions and misuse of sedatives and opioids.
• People who inject drugs: test for HIV, hepatitis B and C, offer vaccination, sterile equipment, and treatment.
• Health workers and professionals: confidential specialist services.
• Mental illness: integrated treatment of both problems.
• Region specific: khat, home brewed and unrecorded alcohol (methanol poisoning), tramadol misuse, and injecting use in coastal and urban regions.

Acute intoxication and toxicity

• Opioid toxicity versus hypoglycaemia, head injury, stroke, sedative or alcohol toxicity, sepsis, and hepatic encephalopathy.
• Stimulant toxicity versus thyrotoxicosis, phaeochromocytoma, serotonin syndrome, neuroleptic malignant syndrome, anticholinergic toxicity, sepsis, and mania.
• Alcohol intoxication versus head injury, hypoglycaemia, diabetic ketoacidosis, methanol or ethylene glycol poisoning, stroke, and postictal state.
• Hallucinogen intoxication versus primary psychosis and delirium.

Withdrawal

• Alcohol and benzodiazepine withdrawal versus delirium of other cause, thyrotoxicosis, sepsis, hypoglycaemia, and meningitis.
• Opioid withdrawal versus gastroenteritis and influenza.
• Stimulant crash versus depression.

Psychiatric disorders (primary or coexisting)

• Depression, bipolar disorder, anxiety, posttraumatic stress disorder, psychosis, attention deficit hyperactivity disorder, personality disorder, and eating disorders.
• Substance induced mood, anxiety or psychotic disorder, which resolve within weeks of abstinence, compared with persistent primary illness.
• Gambling and other behavioural addictions.

Medical and neurological conditions presenting as substance concerns

• Hyperthyroidism, diabetes, hepatic encephalopathy, Wilson disease.
• Epilepsy, head injury, dementia, and frontotemporal dementia.
• Chronic pain with prescription opioid dependence.
• Insomnia with benzodiazepine dependence.

Complications of use

• Alcohol related liver disease, pancreatitis, cardiomyopathy, gastritis, and neuropathy.
• Infectious: HIV, hepatitis B and C, endocarditis, skin and soft tissue infection, tuberculosis, and sexually transmitted infections.
• Cardiovascular: myocardial infarction, arrhythmia, stroke, and aortic dissection with stimulants.
• Respiratory: chronic obstructive pulmonary disease, lung cancer, and vaping associated lung injury.
• Neuropsychiatric: Wernicke encephalopathy, Korsakoff syndrome, substance induced psychosis, and cognitive decline.

Step 1. Triage. Check airway, breathing, circulation, consciousness, temperature and glucose. Treat life threatening intoxication or withdrawal first. Ask about co-ingestants.

Step 2. Screen and diagnose. Use AUDIT-C or AUDIT, DAST-10 or single question screening, CRAFFT in adolescents, and tobacco status in everyone. Apply criteria for substance use disorder and grade severity. Assess readiness to change and risk (suicide, violence, driving, children).

Step 3. First line tests

• Capillary glucose, full blood count (macrocytosis, thrombocytopenia), urea, creatinine, electrolytes, calcium, magnesium, phosphate, liver tests (gamma-glutamyl transferase, aspartate and alanine aminotransferase, bilirubin, albumin), coagulation, and creatine kinase.
• Blood alcohol level in acute presentations.
• Paracetamol and salicylate levels in any overdose or unclear ingestion.
• Urine drug screen (immunoassay) as supportive evidence, understanding limits: opioids (many synthetic opioids and tramadol are missed), benzodiazepines (clonazepam and lorazepam may be missed), amphetamines (false positives), cannabinoids (long detection), and cocaine metabolites (2 to 4 days).
• ECG (QTc, arrhythmia, ischaemia) for stimulant, opioid and methadone related presentations.
• Pregnancy test in women of reproductive age.

Step 4. Targeted tests

• HIV, hepatitis B surface antigen and core antibody, hepatitis C antibody (with polymerase chain reaction), syphilis, tuberculosis screening, and sexually transmitted infection tests in those at risk.
• Troponin for chest pain, CT head for head injury or focal signs or unexplained coma.
• Blood cultures, echocardiography, and imaging for fever in people who inject drugs.
• Liver ultrasound and elastography or FIB-4 score (age, aspartate and alanine aminotransferase, platelets) for suspected alcohol related liver disease.
• Carbohydrate deficient transferrin, phosphatidylethanol (alcohol use over past 2 to 4 weeks), and urine ethyl glucuronide for monitoring.
• Serum osmolality and osmolar gap, blood gas and lactate in suspected toxic alcohol ingestion.
• Cognitive testing (Montreal Cognitive Assessment) after 4 weeks of abstinence if cognitive impairment is suspected.
• Mental health assessment for mood, psychosis, attention deficit hyperactivity disorder and trauma.

Step 5. Interpretation. Treat positive screens as the start of an assessment. Urine screens show recent use, not pattern or impairment. Substance induced psychiatric symptoms that persist beyond 4 weeks of abstinence suggest a primary disorder. Raised gamma-glutamyl transferase with macrocytosis and aspartate to alanine aminotransferase ratio over 2 supports heavy alcohol use.

Limits. Patients under report use, and screening tools have lower sensitivity in adolescents and older adults. Toxicology does not detect many new synthetic drugs. Biomarkers are affected by liver disease and drugs.

Immediate: opioid overdose

• Airway positioning and bag valve mask ventilation with oxygen for respiratory rate under 10 breaths/min or oxygen saturation under 92%.
• Naloxone 0.4 to 2 mg intravenously (or 0.4 to 0.8 mg intramuscularly or subcutaneously, or 4 mg intranasally), repeated every 2 to 3 minutes up to 10 mg total, aiming for adequate breathing and not full arousal. Avoid precipitating severe withdrawal with higher doses than needed.
• The effect of naloxone lasts 30 to 90 minutes (shorter than most opioids), so observe for at least 4 to 6 hours. For long acting opioids (methadone) and extended release or synthetic opioids, give an infusion of two thirds of the effective bolus dose hourly (typically 0.4 to 0.8 mg/hour).
• Check for co-ingestants, hypoglycaemia (glucose 5 mg/kg or 50 mL of 50% dextrose), aspiration, rhabdomyolysis, and compartment syndrome.

Immediate: stimulant toxicity

• Cooling and fluids for hyperthermia (target under 38.5 degrees Celsius).
• Benzodiazepines are first line for agitation, seizures, hypertension and tachycardia: diazepam 5 to 10 mg intravenously or lorazepam 1 to 2 mg intravenously, repeated every 5 to 10 minutes to effect, or midazolam 5 to 10 mg intramuscularly.
• Chest pain: aspirin 300 mg, glyceryl trinitrate 0.4 mg sublingually, benzodiazepines, and avoid beta blockers acutely in cocaine toxicity.
• Hypertensive emergency: glyceryl trinitrate infusion 10 to 200 micrograms/minute or phentolamine 5 mg intravenously.
• Agitation with psychosis not controlled: olanzapine 5 to 10 mg orally or intramuscularly (not within 1 hour of a parenteral benzodiazepine), or haloperidol 5 mg intramuscularly (maximum 12 mg in 24 hours) after ECG.
• Rhabdomyolysis: isotonic fluids 200 to 500 mL/hour targeting urine output over 200 mL/hour (potassium monitoring).

Immediate: alcohol and sedative intoxication and withdrawal

• Intoxication: protect airway, recovery position, glucose, thiamine, and observation. Exclude head injury and toxic alcohols.
• Withdrawal: chlordiazepoxide 15 to 30 mg orally every 6 hours reducing over 5 to 7 days (or symptom triggered diazepam 10 to 20 mg orally every hour when CIWA-Ar is 10 or over).
• Give thiamine 200 to 500 mg intravenously three times daily for 3 days if Wernicke encephalopathy is suspected, then 100 mg orally three times daily.
• Use lorazepam 1 to 2 mg orally every 6 hours in significant liver disease or older adults.
• Benzodiazepine dependence: convert to diazepam (diazepam 10 mg is equal to lorazepam 1 mg, alprazolam 0.5 mg and clonazepam 0.5 mg), stabilise, and reduce by 5% to 10% of the daily dose every 1 to 2 weeks (slower near the end).

Immediate: other

• Cannabinoid hyperemesis: supportive, fluids, haloperidol 5 mg or topical capsaicin; stop cannabis.
• Gamma-hydroxybutyrate toxicity: supportive airway care; observe until recovery; withdrawal severe and requires inpatient benzodiazepines.
• Hallucinogen or dissociative toxicity: quiet environment, reassurance, lorazepam 1 to 2 mg if agitated.
• Serotonin syndrome: stop serotonergic agents, diazepam 5 to 10 mg, cooling, and cyproheptadine 12 mg orally then 2 mg every 2 hours while symptoms continue.
• Toxic alcohol (methanol, ethylene glycol): fomepizole 15 mg/kg intravenously then 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours. Haemodialysis for acidosis, visual symptoms or renal failure; ethanol infusion if fomepizole is not available.

Brief intervention and referral (all positive screens)

• Feedback, advice, and goal setting in 5 to 15 minutes (FRAMES approach: feedback, responsibility, advice, menu of options, empathy, self efficacy), with motivational interviewing.
• Harm reduction: do not drive, do not use alone, avoid mixing substances, safe injecting, sterile equipment, naloxone supply and training, safer sex, vaccination, and hydration.

Treatment of alcohol use disorder (after withdrawal; lasts at least 6 to 12 months)

• Psychological: motivational enhancement, cognitive behavioural therapy, relapse prevention, mutual help groups, family and social support.
• Naltrexone 25 mg orally once daily for 1 to 3 days, then 50 mg once daily (check liver tests; avoid with any opioid use or acute hepatitis).
• Or acamprosate 666 mg orally three times daily, started as soon as abstinence is reached and continued for 6 to 12 months. Use 333 mg three times daily if weight is under 60 kg, 333 mg twice daily at creatinine clearance 30 to 50 mL/min, and avoid it under 30 mL/min.
• Or disulfiram 200 mg once daily (range 100 to 250 mg) with supervised administration and counselling, for informed, motivated patients (avoid in heart disease, psychosis, and severe liver disease).
• Second line:
  • baclofen 5 mg three times daily increased weekly to 10 mg three times daily (up to 30 mg three times daily under specialist care; the only option with proof in cirrhosis)
  • gabapentin 300 mg increased to 900 to 1800 mg daily
  • topiramate 25 mg at night increased by 25 mg weekly to 100 to 150 mg twice daily
• Thiamine 100 mg orally three times daily and a multivitamin, folic acid 5 mg daily when deficient.

Treatment of opioid use disorder

• Opioid agonist treatment (methadone or buprenorphine) reduces mortality by about half and is first line.
• Buprenorphine: start when COWS is 12 or over (at least 8 to 12 hours after short acting opioid, 24 to 72 hours after methadone) with 2 to 4 mg sublingually, repeated every 1 to 2 hours up to 8 mg on day 1. Then increase to 16 mg daily by day 2 to 3 (usual range 8 to 24 mg daily, maximum 32 mg).
• Buprenorphine with naloxone combination is used to limit injection. Extended release injections: 100 mg or 300 mg monthly after stabilisation.
• Methadone: 20 to 30 mg orally on day 1 (maximum 40 mg on the first day), increased by 5 to 10 mg every 3 to 5 days to 60 to 120 mg daily. Check ECG for QTc (over 450 ms caution, over 500 ms avoid or switch), monitor sedation, and avoid interacting drugs (benzodiazepines, rifampicin, carbamazepine, azoles, macrolides).
• Naltrexone 50 mg daily or 380 mg intramuscular monthly after 7 to 10 days opioid free (relapse prevention).
• Withdrawal without agonist treatment: lofexidine 0.4 mg orally increased to 0.8 mg every 6 to 8 hours (maximum 2.4 mg daily), or clonidine 0.1 to 0.2 mg every 6 hours (monitor blood pressure), loperamide 4 mg then 2 mg after each loose stool (maximum 16 mg), metoclopramide, paracetamol and ibuprofen. This approach has high relapse and overdose risk after detoxification and is not preferred.
• Supply naloxone to patients and contacts. Treat infections, and offer vaccination.

Treatment of stimulant, cannabis and other use disorders

• Psychological treatment is first line: cognitive behavioural therapy and contingency management (the best evidence for stimulants), motivational interviewing, and community reinforcement.
• Stimulants: no approved drug. Bupropion 150 mg twice daily with naltrexone 50 mg daily (mixed evidence) or lisdexamfetamine under specialist care may help in methamphetamine and amphetamine disorders. Treat psychosis with olanzapine 5 to 10 mg or risperidone 1 to 2 mg daily.
• Cannabis: cognitive behavioural therapy and motivational therapy. For withdrawal (irritability, insomnia, anxiety, reduced appetite for 1 to 2 weeks) give sleep advice and short term symptomatic treatment; avoid long term benzodiazepines.
• Benzodiazepine and Z drug dependence: slow supervised taper (convert to diazepam and reduce by 5% to 10% of the daily dose every 1 to 2 weeks), with cognitive behavioural therapy and sleep treatment.
• Khat: psychological and social intervention, and treatment of psychosis, hypertension and insomnia.
• Inhalants: psychological therapy, nutritional support, and treatment of organ damage.

Tobacco and nicotine dependence

• Brief advice for every smoker (ask, advise, assist), followed by behavioural support and medication, which together double or triple quit rates.
• Nicotine replacement: patch 21 mg every 24 hours for 6 weeks (people smoking over 10 cigarettes daily; 14 mg if fewer), then 14 mg for 2 weeks and 7 mg for 2 weeks. Add short acting gum or lozenge (2 mg if first cigarette after 30 minutes, 4 mg if within 30 minutes of waking) up to 15 to 20 pieces daily.
• Varenicline 0.5 mg once daily for 3 days, 0.5 mg twice daily for 4 days, then 1 mg twice daily for 12 weeks (reduce to 0.5 mg twice daily at creatinine clearance under 30 mL/min). Set quit date in week 2. Nausea is the commonest effect.
• Bupropion extended release 150 mg once daily for 3 days, then 150 mg twice daily for 7 to 12 weeks (avoid in seizure disorders, eating disorders, and with alcohol withdrawal).
• Combining patch with a short acting product or varenicline improves outcomes.

Treatment of coexisting problems

• Treat depression, anxiety, psychosis, bipolar disorder, post-traumatic stress disorder, and attention deficit hyperactivity disorder alongside, using usual doses (sertraline 50 to 200 mg, for example), taking care with drug interactions and misuse potential.
• Infection:
  • abscess: drainage and flucloxacillin 1 g every 6 hours (or doxycycline 100 mg twice daily in penicillin allergy)
  • endocarditis: specialist antibiotic courses
  • hepatitis C: direct acting antivirals
  • HIV: antiretroviral therapy
  • hepatitis B vaccination in non immune patients
• Pain: nonopioid and nondrug approaches; coordinate with the opioid agonist prescriber.

Special populations

• Pregnancy: stop alcohol, tobacco and other drugs. Opioid agonist treatment (methadone or buprenorphine) is preferred over detoxification. Nicotine replacement can be used when behavioural support fails. Specialist antenatal and neonatal care for neonatal abstinence syndrome.
• Adolescents: family based therapy, motivational interviewing, and treatment of mental illness; avoid long term benzodiazepines.
• Older adults: lower doses, falls prevention, and review of sedatives and opioids.
• Liver and kidney impairment: avoid naltrexone in acute hepatitis, adjust acamprosate, avoid disulfiram in liver disease, and use lorazepam or oxazepam for withdrawal.
• People who inject drugs: needle and syringe services, hepatitis and HIV treatment, and wound care.

Monitoring. Substance use (self report with urine or breath testing in agreed settings), AUDIT or other scales, withdrawal scores, vital signs and consciousness, liver tests (every 3 to 6 months), QTc on methadone, mental state and suicide risk, adherence, weight, blood pressure, infections, and social function.

Referral and escalation. Addiction services for moderate to severe disorder, injecting use, polysubstance use, previous complicated withdrawal, or failure of primary care treatment. Psychiatry for dual diagnosis and psychosis. Hepatology, infectious diseases, cardiology and obstetrics as indicated. Social services and child protection when children are at risk. Mutual help organisations.

Admission criteria. Reduced consciousness or respiratory depression, moderate to severe alcohol or sedative withdrawal, history of withdrawal seizures or delirium tremens, Wernicke encephalopathy, severe liver disease, suicidal intent, psychosis, pregnancy needing detoxification, unsafe home, and serious medical complications such as endocarditis.

Discharge and follow up. Written plan with the next appointment within 1 week, naloxone supply, harm reduction advice, medication with limited supply, and contact for crisis.

Safety net advice: return for drowsiness, slow breathing, chest pain, seizure, hallucinations, vomiting blood, black stools, jaundice, fever, suicidal thoughts, or relapse with unsafe use.