Continuing Education Activity

Heroin toxicity is a life-threatening emergency caused by excessive activation of opioid receptors following the use of heroin, a powerful opioid derived from morphine. After administration, heroin is rapidly metabolized to morphine and 6-monoacetylmorphine, producing profound central nervous system and respiratory depression. Patients commonly present with slow or absent respirations, decreased consciousness, and pinpoint pupils, though findings may vary with coingestants such as alcohol, benzodiazepines, sympathomimetics, or anticholinergics. Management focuses on airway protection, ventilatory support, and administration of naloxone, an opioid antagonist that reverses respiratory depression. Ongoing care includes assessment for opioid use disorder, harm reduction interventions, and coordinated referral for addiction treatment and recovery support.

This activity for healthcare professionals is designed to enhance the learners' understanding of the pathophysiology, recognition, and management of heroin toxicity while fostering practical, patient-centered approaches to improve outcomes. Participants will strengthen their ability to identify key clinical features of heroin toxicity, such as respiratory depression, altered mental status, and miosis, and implement evidence-based interventions, including airway management, naloxone use, and post-reversal monitoring. Clinicians will also gain insight into effective harm reduction and relapse prevention strategies, such as naloxone distribution, initiation of medication-assisted treatment, and patient and family education on overdose prevention. By emphasizing interprofessional communication and coordinated care among physicians, advanced practitioners, nurses, pharmacists, and behavioral health professionals, this activity further enhances participants' ability to deliver compassionate, evidence-based treatment, improve team performance, reduce recurrent overdose, and promote long-term patient safety and recovery.

Objectives:

• Identify the signs and symptoms of acute heroin toxicity, including respiratory depression, altered mental status, and miosis.
• Differentiate heroin toxicity from other causes of central nervous system and respiratory depression, such as benzodiazepine or alcohol toxicity.
• Implement evidence-based emergency interventions, including airway management and timely administration of naloxone.
• Collaborate with emergency medicine, toxicology, addiction medicine, nursing, and pharmacy teams to optimize patient outcomes.

Access free multiple choice questions on this topic.

Introduction

Heroin toxicity is a life-threatening medical emergency caused by excessive activation of opioid receptors following heroin use. Heroin, or diacetylmorphine, is a potent opioid derived from morphine that exerts its toxic effects primarily through suppression of the central nervous and respiratory systems. Once administered, either through injection, nasal insufflation, or inhalation, heroin is rapidly metabolized to 6-monoacetylmorphine (6-MAM) and morphine, which bind to μ-opioid receptors in the brainstem and peripheral tissues, inhibiting respiratory drive leading to hypoventilation, hypoxia, and potentially death.[1] The unpredictability of heroin’s potency, contamination with synthetic opioids such as fentanyl, coingestion of alcohol or benzodiazepines, and reduced tolerance after periods of abstinence significantly increase overdose risk.[2][3][4] 

Clinically, patients with heroin toxicity may present with altered mental status, slow or shallow respirations, miosis, hypothermia, hypotension, or evidence of aspiration and pulmonary edema. Severe cases can progress to apnea, coma, and cardiac arrest within minutes if not promptly recognized and treated. Initial management focuses on airway stabilization, ventilatory support, and administration of naloxone, titrated to restore adequate respirations.[5] Equally as crucial is long-term management following acute treatment. Assessing patients for opioid use disorder (OUD), initiating medication-assisted treatment with agents such as buprenorphine or methadone, and implementing harm reduction measures, such as naloxone distribution and connection to recovery services, can significantly reduce the morbidity and mortality associated with OUD.[6] A coordinated, interprofessional approach that emphasizes compassion and avoids stigma enhances patient engagement, decreases the likelihood of recurrent overdose, and promotes long-term recovery and safety.

Etiology

The etiology of heroin toxicity is the binding of heroin and its metabolites to μ-opioid receptors in the brain, which suppresses the central nervous and respiratory systems. These effects, combined with factors such as unknown purity and the concomitant use of other substances, may result in life-threatening respiratory depression and overdose. Additional risk factors contributing to the toxicity and risk of heroin overdose are as follows:

• Unknown purity and the addition of unknown substances, including fentanyl, quinine, heavy metals, or possibly infectious agents.
• As an individual continues to use heroin, their tolerance increases, resulting in the need for continually increased doses. Following a period of abstinence, such as incarceration or sobriety, if they return to their previous dose, overdose can occur. 
• Coingestion of heroin with other CNS depressants such as benzodiazepines or alcohol increases the risk of respiratory depression.
• Injecting heroin allows the drug to reach the brain quickly, increasing the risk of respiratory depression.
• Concurrent medical conditions such as chronic obstructive pulmonary disease (COPD), sleep apnea, or liver and kidney disease can increase susceptibility to overdose.[7]

Epidemiology

According to the Substance Abuse and Mental Health Services Administration, nearly 2.3% of people in the United States, 12 or older, have used heroin at some point in their lives. In the United States, the prevalence of heroin use disorder doubled between 2002 and 2018.[8] However, the incidence of heroin related overdose deaths decreased from 15,000 in 2018 to 6000 in 2022. Heroin use disorder is most common in men, young adults 18 to 29, and non-Hispanic White individuals. The strongest risk factor is prior nonmedical use of prescription opioids.[9][10] Additional risk factors for heroin use disorder are psychiatric comorbidities such as depression, PTSD, and personality disorders, social disadvantage, and recent release from institutional settings such as incarceration or substance use treatment facilities.[11] 

Pathophysiology

The pathophysiology underlying heroin toxicity is primarily due to its rapid conversion to active metabolites that act as potent opioid receptor agonists, central nervous system, and respiratory depressants. After administration, heroin quickly metabolizes to 6-MAM and morphine, both of which bind to μ-opioid receptors in the periphery and the areas of the brain that control respiration, mood, and pain. When morphine binds to the opioid receptors on these GABAergic neurons, it inhibits them from releasing GABA. This receptor activation in the brainstem inhibits the medullary respiratory centers and peripheral chemoreceptors, resulting in decreased respiratory drive, hypoventilation, and hypoxia.[12][13] Secondary mechanisms involved in heroin toxicity involve a neuroinflammatory response, neuronal apoptosis, and organ toxicity.

Hypoxic-ischemic brain injury from respiratory depression triggers the release of cytokines and activation of microglia, contributing to further neuronal damage.[14] Additionally, heroin and its metabolites can induce mitochondrial dysfunction and apoptosis in neurons via caspase activation and the c-Jun N-terminal kinase (JNK/c-Jun) signaling pathway, an essential component of the cellular response to stress that helps regulate cell survival and apoptosis.[15] Chronic or high-dose exposure to heroin may also cause hepatotoxicity, rhabdomyolysis, renal failure, as well as rare complications like leukoencephalopathy and myelitis.[16] Coadministration with other CNS depressants, such as alcohol and benzodiazepines, can potentiate respiratory depression due to overlapping inhibitory effects on GABA and glutamate neurotransmission.

Toxicokinetics

Heroin has a short half-life, requiring dosing several times a day to maintain the effect. Additionally, tolerance usually develops over time, requiring patients who use heroin to increase their dosage to achieve the same impact continually. Patients may develop tolerance to respiratory depression more slowly than they develop tolerance to euphoric effects. The level of tolerance to opioids can have a significant impact on an individual's risk of opioid overdose. Because the dose of heroin is not controlled or clear in heroin, due to adulterants used to dilute the drug, the risk of overdose is high.[17] 

History and Physical

Classic physical examination findings of acute heroin intoxication are depressed mental status, respiratory rate, tidal volume, and bowel sounds, along with miosis. A respiratory rate below 12/breaths per minute is the best predictor of opioid toxicity.[18] The absence of miosis does not exclude heroin toxicity, as coingestion of sympathomimetics or anticholinergics may make the pupils appear normal or enlarged. Some potential additional findings are as follows:

• Hypothermia due to environmental exposure and impaired thermogenesis;
• Seizures due to hypoxia;
• Hyperthermia due to aspiration pneumonia or endocarditis;
• Hypoxia;
• Mild hypotension due to histamine release;
• Trauma and TBI (may be mistaken as obtundation due to heroin toxicity);
• Crackles on lung examination due to aspiration or ARDS;
• Medication patches on the skin;
• Chronic soft tissue infections; and
• Needle marks indicating chronic injection drug use.[19]

A severe overdose can progress to apnea with coma, which is followed within minutes by cardiac arrest and death unless immediate rescue measures are taken.[20] 

Evaluation

The initial evaluation begins with an immediate assessment of the patient's airway, breathing, and circulation. Clinicians should measure temperature, respiratory rate (including evaluating chest wall excursion), pulse oximetry, heart rate, and blood pressure. Capnography measures end-tidal CO2. The initial diagnosis is clinical, based on the presence of respiratory depression, miosis, and altered mental status, though not all features may be present. Clinicians should attempt to discover the specific drug or medication ingested, the possible presence of any coingestants, if the patient has a history of opioid or substance use disorder, and the reason for poisoning. Clinicians should also obtain a rapid blood glucose level, a serum acetaminophen level if coingestion or with suspicion of self-harm, and a serum creatine phosphokinase level to exclude rhabdomyolysis in the setting of prolonged immobilization.[21] Additional laboratory tests may include serum creatinine and electrolytes. A urine toxicology screen is unnecessary, as the management of acute heroin toxicity will not change based on the results. A positive test only indicates recent use and not acute intoxication, or it may be a false positive. Additionally, patients who ingest some synthetic opioids will have a false negative result. 

Patients with suspected coingestion of cyclic antidepressants or self-harm should undergo an ECG, and chest radiography is necessary in patients with suspected aspiration, ARDS, or those who continue to have hypoxia despite correction of hypoventilation. A plain abdominal radiograph or ultrasound, followed by abdominal computed tomography (CT) or barium-enhanced studies, may be necessary in patients suspected of body packing. 

On the secondary survey, clinicians should evaluate for trauma and traumatic brain injury, secondary skin infections, and any other potential complications such as endocarditis. Additionally, and only with the patient's permission, with suspected body packing, a rectal and vaginal examination may be necessary. In a comatose patient, consent is implied; however, the examination is solely for diagnostic and treatment purposes, not for evidence collection for law enforcement.  

Treatment / Management

Initial management centers around airway, breathing, and circulation. Pulse oximetry is a good measure of oxygenation, but not a valuable tool for monitoring a patient's ventilation while they receive supplemental oxygen. Naloxone is a mainstay of therapy to reverse the effects of heroin toxicity.[22] 

• Apnea or impending respiratory arrest:  Administer 0.2 to 1 mg of intravenous (IV) naloxone. Patients who experience cardiopulmonary arrest should receive 2 mg of naloxone. In patients who are apenic, have very shallow respirations, or very low respiratory rates, clinicians should establish oxygenation with a bag valve mask before administering naloxone to help prevent ARDS. 
• Patients with spontaneous respirations: Administer 0.04 or 0.08 mg of naloxone intravenously, and continue upward titration every few minutes until the respiratory rate exceeds 12 breaths per minute. The goal is adequate ventilation, not normal consciousness. 

If the patient does not have IV access, alternative routes of naloxone administration include nasal, subcutaneous, intramuscular, or intraosseous. Depending on the opioid causing toxicity, repeat dosing or an infusion of naloxone may be necessary. If the patient has not ingested any additional substances or other opioids, there is minimal risk of rebound opioid effects. After observing the patient for one hour, clinicians can safely discharge them if they can ambulate normally, maintain stable vital signs, and have a Glasgow Coma Score of 15.[23]

Clinicians are encountering increasingly variable intensity and duration of opioid effects due to the presence of potent synthetic analogs such as fentanyl and nitazenes in the illicit drug supply. This variability has made it more difficult to predict the effective naloxone dose or duration of monitoring required to prevent re-sedation after reversal. Concerns have also arisen about naloxone availability, as larger or repeated doses are often required to reverse these newer synthetic opioids. Some experts have proposed that, in some instances of prolonged toxicity, management should prioritize airway protection and mechanical ventilation until spontaneous respiration resumes, rather than relying solely on repeated naloxone administration. However, most toxicology and emergency medicine guidelines continue to emphasize that naloxone remains effective for all opioids, including fentanyl analogs, when given in adequate doses and with appropriate ongoing observation and supportive care.

Differential Diagnosis

The differential diagnoses for a patient who is unresponsive are extensive. Some potential diagnoses are as follows: 

• Multiple drug toxicities, including benzodiazepines, lithium, baclofen, and hypoglycemic agents
• Carbon monoxide toxicity
• Stroke
• Cyanide toxicity
• Hypoglycemia
• Hypoxia
• Hypercarbia
• Hypocalcemia
• Hypothyroidism
• Hypothermia
• Liver failure
• Renal failure
• Encephalitis
• Sepsis
• Status epilepticus
• Elevated intracranial pressure due to abscess, tumor, or edema
• Traumatic brain injury
• Systemic hypotension
• Cardiac arrest

Pertinent Studies and Ongoing Trials

The pharmacologic action of heroin on opioid receptors is well characterized. An ongoing area of forensic investigation involves identifying opioid contaminants that may be present in heroin shipments entering the United States. Many of these adulterants, such as carfentanil, are not detected on standard drug screens. Gas chromatography–mass spectrometry (GC–MS) is often required to determine the exact composition of a sample.[24] Some interest exists in evaluating whether cannabis could serve as a harm reduction alternative for patients with heroin use disorder, given its substantially lower risk of fatal overdose compared to heroin.[25] However, no current high-quality evidence from randomized controlled trials supports that cannabis is effective or safe as a harm reduction strategy for reducing opioid use or overdose risk in patients with heroin use disorder. Further studies are necessary.

The latest clinical trial data indicate that buprenorphine is as effective as naloxone for reversing opioid-induced respiratory depression in opioid-dependent patients, with a lower incidence of acute opioid withdrawal and reduced need for intubation or repeated antagonist dosing. Naloxone remains the first-line agent per current guidelines, as further studies are needed to define optimal dosing and the broader applicability of buprenorphine.[26][27]

Treatment Planning

Patients who survive an opioid overdose and present to the ED face a high risk of subsequent mortality, with a one-year death rate of 5.5% and nearly 1 in 5 deaths occurring within the first month. For patients with OUD, early initiation of opioid agonist therapy, such as buprenorphine, significantly reduces both all-cause and opioid-related mortality compared with no treatment. Initiation of medications for opioid use disorder (MOUD) in the ED has proven both feasible and cost-effective, improving engagement in treatment, decreasing illicit opioid use, and reducing the need for inpatient care.[28][29] Following the removal of the United States federal X-waiver in 2023, clinicians with appropriate DEA authorization can now prescribe buprenorphine more readily, facilitating broader implementation of ED-based MOUD programs.[30] 

The management of OUD should be guided by shared decision-making between the clinician and the patient.[31] Individuals with mild OUD typically lack physical dependence, while those who are physically dependent meet criteria for moderate or severe OUD. For these patients, experts recommend pharmacotherapy as first-line treatment, most often with an opioid agonist such as methadone or buprenorphine. Patients who decline agonist therapy may choose an opioid antagonist, such as naltrexone, following a medically supervised withdrawal period. Pharmacologic therapy supports sustained abstinence, improves treatment retention, and lowers mortality, including deaths from suicide. Extended-release naltrexone administered by monthly injection is an appropriate option for patients without physical dependence, as it does not produce opioid dependence like methadone or buprenorphine. Those who prefer not to receive injections may use daily oral naltrexone instead. Regardless of the medication selected, psychosocial interventions, such as counseling, behavioral therapy, or peer support, are recommended as adjuncts to pharmacotherapy for all patients undergoing treatment for OUD.[32][33][32]

Take-home naloxone distribution is another cornerstone of harm reduction, empowering patients, families, and community members to reverse overdoses and reduce mortality. Comprehensive programs that include education and naloxone distribution result in a significant decline in overdose deaths, and as of 2023, naloxone is available over the counter in the United States. Additional harm reduction measures include brief motivational interventions, peer recovery support, rapid linkage to addiction treatment within 1 to 2 days of discharge, and access to sterile injection supplies and fentanyl test strips, all of which help reduce morbidity and mortality associated with OUD.[34][35][36]

Prognosis

Heroin use disorder is a chronically relapsing disorder with a mortality rate 6 to 20 times higher than the general population, with overdose, infectious disease, and cardiovascular complications as the leading causes of death.[37][38] Less than 30% of patients maintain abstinence at 10 and 30 years.[37] However, continuous engagement in opioid substitution treatment, such as methadone, buprenorphine, or naltrexone, is associated with significant reductions in heroin use, criminality, risk-taking, and improvements in physical and mental health.[39][40][41][42] Major depressive disorder and lack of social support are predictors of poorer outcomes, while employment and psychosocial interventions improve overall prognosis.

Complications

The most immediate and life-threatening complication of heroin toxicity is respiratory depression, which can progress to hypoxic brain injury and death if not rapidly reversed. Additional complications are as follows:

• Noncardiogenic pulmonary edema;
• Aspiration pneumonia;
• Rhabdomyolysis;
• Compartment syndrome;
• Acute renal failure due to prolonged immobilization;
• Toxic leukoencephalopathy;
• Seizure;
• Stroke;
• Transverse myelitis;
• Peripheral neuropathy;
• Cellulitis;
• Abscesses;
• Endocarditis;
• Hepatitis B and C;
• HIV;
• Tuberculosis;
• Constipation;
• Venous sclerosis and chronic venous insufficiency; and
• Reproductive dysfunction.[43][44][45]

Deterrence and Patient Education

Clinicians play a vital role in reducing heroin-related morbidity and mortality through prevention, patient education, and linkage to ongoing care. After ingestion, heroin rapidly metabolizes to morphine, which binds to μ-opioid receptors, producing euphoria, analgesia, and marked central nervous system effects. Excessive receptor activation leads to profound respiratory and central nervous system depression, which may progress to hypoxia, coma, or death. Most heroin toxicity occurs among experienced users, often involving co-ingestion of alcohol, benzodiazepines, or other sedatives, or following a period of abstinence, such as after incarceration or discharge from a treatment program, when tolerance to opioids has diminished.The unpredictable potency of illicit heroin, largely due to contamination with synthetic opioids such as fentanyl and its analogs, significantly increases the risk of fatal toxicity. Patients experiencing heroin toxicity typically present with miosis, shallow or absent respirations, decreased level of consciousness, cyanosis, and cold, clammy skin. Prompt recognition of these signs and the immediate administration of naloxone are critical and often lifesaving. Clinicians should educate patients and their families about the warning signs of overdose, proper use of naloxone, and ensure access to take-home kits or prescriptions for emergency use.

Additional harm reduction interventions include referral to syringe service programs, medication-assisted treatment options such as buprenorphine or methadone, and counseling or peer support networks. Emphasizing that recovery is achievable and providing care in a confidential, nonjudgmental environment helps reduce stigma and promote engagement. Education should also address relapse prevention and trigger management, including strategies for coping with stress, pain, or environmental cues. Clinicians should encourage safe disposal of drug-use equipment and secure medication storage to prevent diversion. Through empathetic communication and interprofessional collaboration among addiction medicine and behavioral health specialists, pharmacists, nurses, and social workers, clinicians can empower patients to adopt safer practices, seek treatment early, and help break the cycle of overdose and reinjury.

Enhancing Healthcare Team Outcomes

Heroin is a potent opioid prodrug derived from morphine ingested by inhalation, smoking, or injection. Heroin is more lipid-soluble than morphine, allowing for rapid central nervous system penetration and potent euphoric effects. Once ingested, heroin is rapidly metabolized to 6-MAM and subsequently to morphine, both of which activate μ-opioid receptors. Toxicity results from excessive central nervous system and respiratory depression secondary to μ-opioid receptor activation. Overdoses often occur in experienced users, especially following periods of abstinence or co-ingestion with depressants such as alcohol or benzodiazepines. Patients typically present with depressed mental status, shallow or absent respirations, decreased bowel sounds, and pinpoint pupils, though pupil size may vary with coexposures. Complications include hypoxia, aspiration, pulmonary edema, and ARDS, the latter sometimes following rapid naloxone reversal. Management centers on airway protection, assisted ventilation, and administration of naloxone, titrated to restore adequate respiratory effort rather than full arousal. Continuous pulse oximetry and capnography help monitor ventilation and oxygenation. Supportive care includes managing hypothermia, hypoglycemia, and aspiration risk. Once stabilized, patients should be screened for OUD and linked to addiction treatment and harm reduction services to reduce the risk of recurrence.

Comprehensive care extends beyond the acute episode. Coordination across inpatient and outpatient settings ensures that patients are not only stabilized but also linked to harm reduction programs, MAT clinics, and psychosocial support networks. Physicians and advanced practitioners develop discharge plans that include naloxone distribution, overdose prevention education, and follow-up appointments. Nurses reinforce these instructions, assess readiness for change, and provide motivational support. Pharmacists review medication regimens to prevent dangerous drug combinations, while behavioral health specialists and social workers facilitate ongoing therapy, recovery resources, and community-based follow-up. When care teams operate cohesively, outcomes improve across multiple dimensions, including faster response times during overdose management, reduced incidence of complications, better treatment adherence, and lower rates of recurrent overdose. Interprofessional teamwork fosters trust, reduces stigma, and creates a supportive environment where patients feel respected and motivated to engage in treatment. Collaborative reflection and debriefing after overdose events also strengthen team performance, highlight opportunities for process improvement, and reinforce a culture of patient safety. Through shared expertise, coordinated communication, and unified commitment to compassionate care, healthcare teams can transform acute heroin toxicity encounters into opportunities for recovery, prevention, and long-term improvement in both patient health and system-level performance.

Review Questions

• Access free multiple choice questions on this topic.
• Click here for a simplified version.
• Comment on this article.

References

1.

Love SA, Lelinski J, Kloss J, Middleton O, Apple FS. Heroin-related Deaths from the Hennepin County Medical Examiner's Office from 2004 Through 2015. J Forensic Sci. 2018 Jan;63(1):191-194. [PubMed: 28422290]

2.

Darke S, Zador D. Fatal heroin 'overdose': a review. Addiction. 1996 Dec;91(12):1765-72. [PubMed: 8997759]

3.

Sporer KA. Strategies for preventing heroin overdose. BMJ. 2003 Feb 22;326(7386):442-4. [PMC free article: PMC1125320] [PubMed: 12595388]

4.

Binswanger IA, Blatchford PJ, Mueller SR, Stern MF. Mortality after prison release: opioid overdose and other causes of death, risk factors, and time trends from 1999 to 2009. Ann Intern Med. 2013 Nov 05;159(9):592-600. [PMC free article: PMC5242316] [PubMed: 24189594]

5.

Viglino D, Bourez D, Collomb-Muret R, Schwebel C, Tazarourte K, Dumanoir P, Paquier C, Danel V, Debaty G, Maignan M. Noninvasive End Tidal CO2 Is Unhelpful in the Prediction of Complications in Deliberate Drug Poisoning. Ann Emerg Med. 2016 Jul;68(1):62-70.e1. [PubMed: 26810758]

6.

Ingram T, Rubi S, Brown JL, Sprunger J, Shadwick A, Crago C, Lyons MS, Winhusen TJ. Increasing access: Making naloxone available at highway rest areas. Explor Res Clin Soc Pharm. 2025 Dec;20:100660. [PMC free article: PMC12513219] [PubMed: 41080420]

7.

Warner-Smith M, Darke S, Lynskey M, Hall W. Heroin overdose: causes and consequences. Addiction. 2001 Aug;96(8):1113-25. [PubMed: 11487418]

8.

Han B, Volkow ND, Compton WM, McCance-Katz EF. Reported Heroin Use, Use Disorder, and Injection Among Adults in the United States, 2002-2018. JAMA. 2020 Feb 11;323(6):568-571. [PMC free article: PMC7042840] [PubMed: 32044936]

9.

Jones CM, Logan J, Gladden RM, Bohm MK. Vital Signs: Demographic and Substance Use Trends Among Heroin Users - United States, 2002-2013. MMWR Morb Mortal Wkly Rep. 2015 Jul 10;64(26):719-25. [PMC free article: PMC4584844] [PubMed: 26158353]

10.

Compton WM, Jones CM, Baldwin GT. Relationship between Nonmedical Prescription-Opioid Use and Heroin Use. N Engl J Med. 2016 Jan 14;374(2):154-63. [PMC free article: PMC11784537] [PubMed: 26760086]

11.

Volkow ND, Jones EB, Einstein EB, Wargo EM. Prevention and Treatment of Opioid Misuse and Addiction: A Review. JAMA Psychiatry. 2019 Feb 01;76(2):208-216. [PubMed: 30516809]

12.

Perekopskiy D, Afzal A, Jackson SN, Muller L, Woods AS, Kiyatkin EA. The Role of Peripheral Opioid Receptors in Triggering Heroin-induced Brain Hypoxia. Sci Rep. 2020 Jan 21;10(1):833. [PMC free article: PMC6972941] [PubMed: 31964994]

13.

White JM, Irvine RJ. Mechanisms of fatal opioid overdose. Addiction. 1999 Jul;94(7):961-72. [PubMed: 10707430]

14.

Neri M, Panata L, Bacci M, Fiore C, Riezzo I, Turillazzi E, Fineschi V. Cytokines, chaperones and neuroinflammatory responses in heroin-related death: what can we learn from different patterns of cellular expression? Int J Mol Sci. 2013 Sep 30;14(10):19831-45. [PMC free article: PMC3821589] [PubMed: 24084728]

15.

Tan M, Li Z, Ma S, Luo J, Xu S, Lu A, Gan W, Su P, Lin H, Li S, Lai B. Heroin activates Bim via c-Jun N-terminal kinase/c-Jun pathway to mediate neuronal apoptosis. Neuroscience. 2013 Mar 13;233:1-8. [PubMed: 23262244]

16.

Cunha-Oliveira T, Rego AC, Garrido J, Borges F, Macedo T, Oliveira CR. Street heroin induces mitochondrial dysfunction and apoptosis in rat cortical neurons. J Neurochem. 2007 Apr;101(2):543-54. [PubMed: 17250679]

17.

Shover CL, Koncsol AJ, Godvin ME, Goodman-Meza D, Pardo B, Poimboeuf M, Molina CA, Romero R, Feng J, Friedman JR. High variation in purity of consumer-level illicit fentanyl samples in Los Angeles, September 2023-April 2025. Int J Drug Policy. 2025 Nov;145:104977. [PMC free article: PMC13159572] [PubMed: 40886524]

18.

Hoffman JR, Schriger DL, Luo JS. The empiric use of naloxone in patients with altered mental status: a reappraisal. Ann Emerg Med. 1991 Mar;20(3):246-52. [PubMed: 1996818]

19.

Stam NC, Cogger S, Schumann JL, Weeks A, Roxburgh A, Dietze PM, Clark N. The onset and severity of acute opioid toxicity in heroin overdose cases: a retrospective cohort study at a supervised injecting facility in Melbourne, Australia. Clin Toxicol (Phila). 2022 Nov;60(11):1227-1234. [PubMed: 36200988]

20.

Pavarin RM, Fioritti A, Sanchini S. Mortality trends among heroin users treated between 1975 and 2013 in Northern Italy: Results of a longitudinal study. J Subst Abuse Treat. 2017 Jun;77:166-173. [PubMed: 28237351]

21.

Ashbourne JF, Olson KR, Khayam-Bashi H. Value of rapid screening for acetaminophen in all patients with intentional drug overdose. Ann Emerg Med. 1989 Oct;18(10):1035-8. [PubMed: 2802276]

22.

Dahan A, Franko TS, Carroll JW, Craig DS, Crow C, Galinkin JL, Garrity JC, Peterson J, Rausch DB. Fact vs. fiction: naloxone in the treatment of opioid-induced respiratory depression in the current era of synthetic opioids. Front Public Health. 2024;12:1346109. [PMC free article: PMC10933112] [PubMed: 38481848]

23.

Willman MW, Liss DB, Schwarz ES, Mullins ME. Do heroin overdose patients require observation after receiving naloxone? Clin Toxicol (Phila). 2017 Feb;55(2):81-87. [PubMed: 27849133]

24.

Fiorentin TR, Krotulski AJ, Martin DM, Browne T, Triplett J, Conti T, Logan BK. Detection of Cutting Agents in Drug-Positive Seized Exhibits within the United States. J Forensic Sci. 2019 May;64(3):888-896. [PubMed: 30485426]

25.

Lucas P, Baron EP, Jikomes N. Medical cannabis patterns of use and substitution for opioids & other pharmaceutical drugs, alcohol, tobacco, and illicit substances; results from a cross-sectional survey of authorized patients. Harm Reduct J. 2019 Jan 28;16(1):9. [PMC free article: PMC6350348] [PubMed: 30691503]

26.

Zamani N, Buckley NA, Hassanian-Moghaddam H. Buprenorphine to reverse respiratory depression from methadone overdose in opioid-dependent patients: a prospective randomized trial. Crit Care. 2020 Feb 07;24(1):44. [PMC free article: PMC7006192] [PubMed: 32033582]

27.

Dezfulian C, Orkin AM, Maron BA, Elmer J, Girotra S, Gladwin MT, Merchant RM, Panchal AR, Perman SM, Starks MA, van Diepen S, Lavonas EJ., American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; Council on Quality of Care and Outcomes Research; and Council on Clinical Cardiology. Opioid-Associated Out-of-Hospital Cardiac Arrest: Distinctive Clinical Features and Implications for Health Care and Public Responses: A Scientific Statement From the American Heart Association. Circulation. 2021 Apr 20;143(16):e836-e870. [PubMed: 33682423]

28.

Lu T, Ryan D, Cadet T, Chawarski MC, Coupet E, Edelman EJ, Hawk KF, Huntley K, Jalali A, O'Connor PG, Owens PH, Martel SH, Fiellin DA, D'Onofrio G, Murphy SM. Cost-Effectiveness of Implementation Facilitation to Promote Emergency Department-Initiated Buprenorphine for Opioid Use Disorder. Ann Emerg Med. 2025 Mar;85(3):205-213. [PMC free article: PMC11845297] [PubMed: 39570250]

29.

Busch SH, Fiellin DA, Chawarski MC, Owens PH, Pantalon MV, Hawk K, Bernstein SL, O'Connor PG, D'Onofrio G. Cost-effectiveness of emergency department-initiated treatment for opioid dependence. Addiction. 2017 Nov;112(11):2002-2010. [PMC free article: PMC5657503] [PubMed: 28815789]

30.

Bansback N, Tam ACT, Palis H, Kanters S, Popoff E, Schechter MT, Anis AH, Marsh DC, Oviedo-Joekes E. Oral and injectable opioid agonist treatments for people who use street opioids: a systematic literature review and network meta-analysis. BMC Public Health. 2025 Aug 30;25(1):2974. [PMC free article: PMC12398115] [PubMed: 40885969]

31.

Smith A, Weslosky K, Haynes A, Crew D. Clinical strategies for low-dose overlap initiation of buprenorphine and potential barriers to use. Ment Health Clin. 2025 Oct;15(5):228-231. [PMC free article: PMC12510631] [PubMed: 41079526]

32.

McHugh RK, Bailey AJ, McConaghy BA, Weiss RD, Fiellin DA, Hillhouse M, Moore BA, Fitzmaurice GM. Behavioral Therapy as an Adjunct to Buprenorphine Treatment for Opioid Use Disorder: A Secondary Analysis of 4 Randomized Clinical Trials. JAMA Netw Open. 2025 Aug 01;8(8):e2528529. [PMC free article: PMC12368672] [PubMed: 40833692]

33.

Weiner SG, Venkatesh AK, Sharma PB, Rothenberg C, Shahid S, Sambell M, Goyal P, Hawk KF. Treatment of Opioid Use Disorder Across a National Emergency Department Practice Improvement Network. Ann Emerg Med. 2026 Mar;87(3):313-320. [PubMed: 41071133]

34.

Smith DE. Medicalizing the Opioid Epidemic in the U.S. in the Era of Health Care Reform. J Psychoactive Drugs. 2017 Apr-Jun;49(2):95-101. [PubMed: 28296623]

35.

Goldberg SA, Dworkis DA, Liao VT, Eyre AJ, Albert J, Fawcett MM, Narovec CM, DiClemente J, Weiner SG. Feasibility of Bystander Administration of Public-Access Naloxone for Opioid Overdose. Prehosp Emerg Care. 2018 Nov-Dec;22(6):788-794. [PubMed: 29723076]

36.

Stam NC, Gerostamoulos D, Smith K, Pilgrim JL, Drummer OH. Challenges with take-home naloxone in reducing heroin mortality: a review of fatal heroin overdose cases in Victoria, Australia. Clin Toxicol (Phila). 2019 May;57(5):325-330. [PubMed: 30451007]

37.

Hser YI, Evans E, Grella C, Ling W, Anglin D. Long-term course of opioid addiction. Harv Rev Psychiatry. 2015 Mar-Apr;23(2):76-89. [PubMed: 25747921]

38.

Darke S, Marel C, Mills KL, Ross J, Slade T, Tessson M. Years of potential life lost amongst heroin users in the Australian Treatment Outcome Study cohort, 2001-2015. Drug Alcohol Depend. 2016 May 01;162:206-10. [PubMed: 27021806]

39.

Saxon AJ, Akerman SC, Liu CC, Sullivan MA, Silverman BL, Vocci FJ. Extended-release naltrexone (XR-NTX) for opioid use disorder in clinical practice: Vivitrol's Cost and Treatment Outcomes Registry. Addiction. 2018 Aug;113(8):1477-1487. [PubMed: 29493836]

40.

Lee JD, Nunes EV, Novo P, Bachrach K, Bailey GL, Bhatt S, Farkas S, Fishman M, Gauthier P, Hodgkins CC, King J, Lindblad R, Liu D, Matthews AG, May J, Peavy KM, Ross S, Salazar D, Schkolnik P, Shmueli-Blumberg D, Stablein D, Subramaniam G, Rotrosen J. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet. 2018 Jan 27;391(10118):309-318. [PMC free article: PMC5806119] [PubMed: 29150198]

41.

Bell J. Pharmacological maintenance treatments of opiate addiction. Br J Clin Pharmacol. 2014 Feb;77(2):253-63. [PMC free article: PMC4014029] [PubMed: 23210630]

42.

Eastwood B, Strang J, Marsden J. Continuous opioid substitution treatment over five years: Heroin use trajectories and outcomes. Drug Alcohol Depend. 2018 Jul 01;188:200-208. [PubMed: 29778774]

43.

Moiseev VS, Kobalava ZD, Pisaryuk AS, Milto AS, Kotova EO, Karaulova YL, Kahktsyan PV, Chukalin AS, Balatskiy AV, Safarova AF, Ratchina SА, Merai IA, Povalyaev NM. [Not Available]. Kardiologiia. 2018 Dec 25;58(12):66-75. [PubMed: 30625099]

44.

Bandaru S, Manthri S, Sundareshan V, Prakash V. Empyema Necessitans in the Setting of Methicillin-Susceptible Staphylococcus aureus Causing Pneumonia and Bacteremia. Case Rep Infect Dis. 2018;2018:4906547. [PMC free article: PMC5907393] [PubMed: 29850305]

45.

Jiang Z, Xiu C, Yang J, Zhang X, Liu M, Chen X, Liu D. HIV test uptake and related factors amongst heterosexual drug users in Shandong province, China. PLoS One. 2018;13(10):e0204489. [PMC free article: PMC6193625] [PubMed: 30335766]

Disclosure: Robert Oelhaf declares no relevant financial relationships with ineligible companies.

Disclosure: Mohammadreza Azadfard declares no relevant financial relationships with ineligible companies.