Elsevier Logo

ThisiscontentfromClinicalKey

Want even more answers?

Sign up for your free ClinicalKey trial today!  Your first step in getting the right answers when you need them. ClinicalKey is a clinical knowledge solution designed to help healthcare professionals and students find the right answers by providing in-depth, evidence-based knowledge – all from one resource.

Aug.11.2020View related content

Opioid toxicity

Synopsis

Key Points

  • Opioid toxicity results in severe—sometimes fatal—effects that most commonly occur after overdose, which can be intentional or accidental
  • Opioid toxicity causes respiratory depression, generally accompanied by depressed consciousness and miosis
    • Diagnosis is made based on these 3 primary symptoms, which may not always present together, paired with a positive response to naloxone
  • Opioid toxicity is often coupled with ingestion of other substances, such as acetaminophen or ethanol
  • Restore respiration using a bag-valve mask until naloxone can be administered
  • IV naloxone, a competitive opioid antagonist, is the gold standard reversal agent
  • Continuously observe patients receiving naloxone because it has a short half-life
    • Observation must last longer than the expected elimination time for naloxone. Minimum observation time for naloxone is 1 to 2 hours, but observe patient 4 to 6 hours in case there are coingestants
  • Naloxone, although necessary, can cause withdrawal symptoms, which can be stressful to patients and caregivers; cautious titration to desired effect (reversal of respiratory suppression) is recommended
  • Recurrence is likely in patients with opioid misuse history

Urgent Action

  • First priority is to restore respiration
  • If symptoms are present, begin treating with naloxone to reverse opioid toxicity; do not wait for drug screen or immunoassay results to confirm diagnosis
  • Admit to ICU if patient is intoxicated by long-lasting opioids, has recurrent respiratory depression, requires naloxone infusion, or requires intubation

Pitfalls

  • Naloxone can precipitate opioid withdrawal and is titrated for best effect
  • Do not attribute altered mental status to opioid toxicity solely based on positive drug screen results; the screen is qualitative, not quantitative
    • May present along with head trauma, which can hinder restoration of consciousness

Terminology

Clinical Clarification

  • Opioid toxicity results in severe—sometimes fatal—effects that most commonly occur after overdose, which can be intentional or accidental r1
  • Primary toxic effect of opioid overdose is decreased rate and depth of respiration leading to pulmonary edema r1
    • May result in death from hypoxia and respiratory arrest before pulmonary edema develops
  • Effects on other organs include hypotension, bradycardia, and decreased body temperature r1

Classification

  • Toxicity caused by short-acting opioids, such as:
    • Morphine sulfate
    • Fentanyl
      • Fentanyl analogues
        • Carfentanyl is the most potent analogue (ie, potency 100 times that of fentanyl) and is used as an anesthetic for large animals
        • Analogues with no licensed medical use include acetylfentanyl and butyrylfentanyl
    • Oxycodone
    • Hydrocodone
    • Codeine
    • Heroin
  • Toxicity caused by longer-acting and delayed-release opioids, including:
    • Extended-release morphine sulfate
    • Methadone
    • Oxymorphone
  • Toxicity caused by opioid receptor agonist-antagonist drugs, such as:
    • Agonist at one opioid receptor, antagonist at a different opioid receptor
      • Pentazocine
      • Butorphanol
      • Nalbuphine
      • Dezocine
    • Partial agonist at a single opioid receptor
      • Buprenorphine
      • Meptazinol

Diagnosis

Clinical Presentation

History

  • History of nonprescribed opioid use or misuse r2c1
    • Medical records may indicate previous use
    • Family or friends may confirm opioid use
    • Needles or other paraphernalia found near patient
  • History of prescribed opioid use r2c2
    • Pills, pill bottles, or drug paraphernalia found near patient
  • Common symptoms even without any available history r2
    • Apnea c3
    • Depressed consciousness c4
      • Can range from drowsiness to coma c5c6

Physical examination

  • Common signs r3
    • Depressed respiratory rate is the most specific sign c7
      • Respiratory rate of 12 breaths or fewer per minute, with stupor, is highly suggestive of acute opioid toxicity, especially when accompanied by miosis and/or depressed consciousness c8c9c10
    • Reduced size and reactivity of pupils c11
      • Pupil constriction to less than 2-mm diameter r4
      • Not always present, particularly if opioids were ingested along with other substances
    • Hypotension, bradycardia, and hypothermia are usually present r3c12c13c14
  • Other examination findings r3
    • Skin
      • Evidence of fentanyl patches r1c15
      • Needle track marks c16
        • Recent injection marks are small, red, inflamed, or surrounded by slight bruising c17c18
        • Old injection sites show pigmentation change and atrophied skin c19c20
    • Neurologic
      • Seizures often are associated with overdose of tramadol, propoxyphene, and meperidine, particularly if used concomitantly with medicines that lower seizure thresholds r1c21c22c23
    • Mucous membrane r3c24c25
      • Mucous membrane cyanosis is a late sign of hypoxia and hypotension
    • Pulmonary
      • Pulmonary edema in patients with apnea or severe bradypnea c26c27
        • Rales and frothy sputum are a late sign of severe opioid toxicity r1c28c29
    • Cardiac
      • QTc prolongation may occur in some patients receiving methadone, increasing chance of developing a ventricular arrhythmia, particularly torsades de pointes r5c30

Causes and Risk Factors

Causes

  • Overdose of opioid drugs r2c31
    • Opioid drugs are substances that bind to 1 or more of the 4 opioid receptors (δ, κ, μ, and nociceptin receptors) c32
    • Toxicity is not necessarily dependent on dose of opioid used, but instead depends on individual tolerance at time of exposure
      • Tolerance may be dramatically different in patient subpopulations
    • More overdose deaths are due to prescription opioids than nonprescription forms r6
      • Commonly prescribed opioids r7
      • Commonly prescribed opioid receptor agonist/antagonist or partial-agonist drugs
      • Most common nonprescription opioids
        • Heroin c50
        • Fentanyl (diverted or illicitly produced; typically added to heroin) c51
        • Carfentanyl (diverted from veterinary sources; typically added to heroin) c52
        • Loperamide (in supratherapeutic doses) c53
  • Overdose of buprenorphine usually does not cause lethal respiratory depression in adults unless administered intravenously or combined with another respiratory depressant, but lethal respiratory depression can occur in elderly or weak patients r8
    • Death from buprenorphine in children results from respiratory depression, usually following unintentional exposure secondary to medication being stored in sight, accessed from a bag or purse, or not being stored in its original packaging r9
  • Effects of toxic metabolites r10
    • Normeperidine from meperidine: lowers seizure threshold and accumulates with repeated dosing
    • Morphine-3-glucuronide from morphine: lowers seizure threshold and may be responsible for myoclonus and allodynia

Risk factors and/or associations

Age
  • Higher incidence of opioid poisoning deaths in those aged 25 to 64 years, with highest incidence among those aged 45 to 54 years r11c54c55
  • Advanced age is associated with reduced clearance of morphine, fentanyl, codeine, and oxymorphone, which increases risk of overdose (and requires more caution with prescribing) r10
  • Children are more likely than adults to experience respiratory depression and death after unintentional exposure to agonist/antagonists such as buprenorphine r9r12c56c57
  • Children may be more sensitive to codeine dosing and can be accidentally overdosed owing to existence of rapid metabolizers of the prodrug codeine to the active drug morphine r13
    • Avoid giving codeine to breastfeeding mothers
Sex
  • Incidence is higher in men r2c58
Ethnicity/race
  • Death rates in non-Hispanic White populations are 4 times higher than in Hispanic or Black populations r11c59
Other risk factors/associations
  • Opioid toxicity is most highly associated with people who are prescribed high doses of opioid analgesics (more than 100 mg of morphine or equivalent per day) r14c60
  • Also associated with people who seek care from multiple physicians or receive early refills r2c61c62
    • Risk of distribution to others
  • Prescription opioid death rates are highest in rural populations r2r11c63
  • Heroin death rates are highest in large central metropolitan areas r2c64
  • Populations at greatest risk for opioid toxicity r2
    • People with mental illness c65
    • People who report long-term medical use of opioids c66
    • People who report nonmedical use of opioids in the past month (ie, use without a prescription or medical need) c67
  • Hepatic impairment r10c68
    • Especially important to consider when using oxycodone, morphine, or oxymorphone c69c70c71
    • Lower risk of toxicity with fentanyl and methadone c72c73
  • Renal impairment r10c74
    • Particularly important when using morphine, hydromorphone, and other opioids with active metabolites c75c76
    • Less risk with fentanyl and methadone c77c78

Diagnostic Procedures

Primary diagnostic tools

  • Primary diagnosis is based on: r15
    • Classic symptoms of opioid overdose c79
      • Respiratory depression, often accompanied by central nervous system depression and miosis
    • Responsiveness to naloxone c80

Laboratory

  • Urine toxicology tests r15c81
    • Screen for acetaminophen levels
    • Do not rely on toxicology screens for the initial diagnosis or management of suspected opioid overdose
    • Positive screen for opioids does not confirm toxicity
    • Although positive toxicology results can indicate presence of opioids, negative results do not necessarily mean absence of opioids
      • Some opioids, such as fentanyl, may not be detectable using typical toxicology screening methods

Imaging

  • Obtain chest radiographs in patients with opioid toxicity who have rales or hypoxia (to evaluate for pulmonary edema or aspiration pneumonia) c82c83

Functional testing

  • Can use ECG to monitor bradycardia r15c84
  • QTc prolongation may occur in some patients receiving methadone, increasing the chance of developing a ventricular arrhythmia, particularly torsades de pointes r5
    • Doses above 100 mg daily produce a dose-dependent QTc prolongation
      • Regular monitoring of the QTc is recommended for patients receiving therapy who have baseline prolonged QT intervals greater than 501 milliseconds
    • QTc prolongation also may occur with loperamide toxicity r16

Differential Diagnosis

Most common

  • Clonidine and oxymetazoline toxicity (particularly in pediatric patients) c85c86c87c88
    • Both drugs are centrally acting α₁-blockers that cause depressed mental status, bradycardia, hypotension, and miosis
    • Partial response to naloxone is common
      • No easy or consistent way to differentiate from opioid toxicity
      • Urine test for these drugs is typically available only at reference laboratories
        • Results will not change patient management
    • Most children with clonidine or oxymetazoline toxicity will be treated as if they had opioid toxicity, and vice versa
    • Nonresponse to naloxone is the best way to determine that the diagnosis is likely something other than opioid toxicity, but eliciting a response in patients with opioid toxicity may require large doses of naloxone
  • Acute subdural hematoma r15c89
    • Common presentation is depressed mental status
    • CT scan results differentiate pure opioid toxicity from subdural hematoma
  • Other central nervous system depressant toxicity (eg, alcohol, barbiturate, benzodiazepine, cannabinoid) r17c90c91c92c93c94
    • Cannot differentiate easily by symptoms alone
    • Differentiate by ineffectiveness of naloxone
      • Combined with quantitative alcohol serum levels, narrows diagnostic considerations
  • Meningitis and encephalitis c95c96d1
    • Both present with confusion and depressed mental status
      • Additional symptoms include headache, vomiting, and fever
    • Both do not respond to naloxone
    • Differentiate by using CT scan to reveal meningeal inflammation and using lumbar puncture to show evidence of infection
  • Hypoglycemia c97d2
    • Presents with confusion and depressed mental status
    • Differentiate using a bedside blood glucose test and response to glucose administration

Treatment

Goals

  • Reverse opioid toxicity
    • Treat with reversal agent
    • Secure airway
    • Restore respiratory status
    • Reverse central nervous system depression
  • Avoid precipitating withdrawal

Disposition

Admission criteria

Admit children aged 3 years or younger who were exposed to opioids other than immediate-release formulations for 24-hour observation if ingestion of agents is suspected from history but cannot be confirmed r18

Respiratory depression

  • Occurs after nonresponse to naloxone or during resedation after naloxone wears off and continued observation in the emergency department is unavailable
Criteria for ICU admission r1r19
  • Patients whose toxicity is due to long-lasting and extended-release opioids
    • Long-lasting and extended-release opioids cause resedation after naloxone wears off
    • Require prolonged observation for respiratory depression and airway compromise
  • Patients who require a naloxone infusion
  • Patients who require orotracheal intubation

Recommendations for specialist referral

  • Refer to medical toxicologist for specialty management of opioid toxicity
  • Refer to pain or addiction specialist to prevent recurrence and treat addiction

Treatment Options

First priority is to restore respiration using a bag-valve mask until naloxone can be administered r1

Advanced airway intervention is rarely required unless there are coingestants or other illnesses or injuries

Observe for and remove any fentanyl patches

Drug treatment is the same regardless of causative opioid

  • Naloxone therapy is the standard treatment of opioid toxicity r1
    • Empiric administration to unresponsive patients with suspected opioid overdose is recommended to reverse respiratory depression; however, only small doses may be required. Larger doses may precipitate withdrawal unnecessarily
    • Small doses also may be used for diagnostic purposes for patients with decreased level of consciousness of unknown cause
  • Naloxone prescription or access to OTC naloxone is an important treatment option for people at high risk (eg, those with history of misuse)

Drug therapy

  • Naloxone r1c98
    • Dose is empiric and depends on the amount of opioid that the patient received or has taken
    • IV administration is the most common and preferable method of delivery c99
      • IV naloxone continuous infusion is difficult and has several drawbacks
        • Difficult to titrate adequate dose to maintain adequate respiration while avoiding precipitating withdrawal
          • Recommended infusion strategy of hourly dose to match dose required to reverse apnea has not been validated
        • Relying on an IV infusion of drug to maintain ventilation
          • IV catheters can become kinked, be pulled out, or become otherwise dysfunctional
        • Patients still require ICU admission for monitoring
    • Use intramuscular, intranasal, or pulmonary administration when IV is not an option c100c101c102
    • Do not administer orally because it has high first-pass metabolism rate
    • Observation must last longer than the expected elimination time for naloxone. Minimum observation time for naloxone is 1 to 2 hours, but observe patient 4 to 6 hours in case there are coingestants r20r21
    • Toxic effects often reappear within 30 minutes of naloxone dosing, requiring further naloxone because it has a short half-life
    • Gradual titration of naloxone dose is preferred over isolated larger doses to avoid precipitating withdrawal
    • Opioids that require larger doses of naloxone r20
      • Natural opium derivatives
      • Synthetic opiates
      • Mixed opioid agonist-antagonists
      • Partial agonist
        • Buprenorphine
    • Intermittent IV, intramuscular, subcutaneous, or intraosseous dosage (standard syringe)
      • Naloxone Hydrochloride Solution for injection; Neonates: 0.1 mg/kg/dose IV/IM; may require repeated doses. FDA-approved labeling recommends 0.01 mg/kg/dose IV, IM, or subcutaneously every 2 to 3 minutes as needed.
      • Naloxone Hydrochloride Solution for injection; Infants and Children younger than 5 years or weighing 20 kg or less: 0.1 mg/kg/dose IV/IO; may require repeated doses. FDA-approved labeling recommends 0.01 mg/kg/dose IV, IM, or subcutaneously every 2 to 3 minutes as needed.
      • Naloxone Hydrochloride Solution for injection; Children and Adolescents 5 to 17 years or weighing more than 20 kg: 2 mg IV/IO; may require repeated doses. FDA-approved labeling recommends 0.01 mg/kg/dose IV, IM, or subcutaneously every 2 to 3 minutes as needed.
      • Naloxone Hydrochloride Solution for injection; Adults: 0.4 to 2 mg IV, IM, or subcutaneously every 2 to 3 minutes as needed up to a total dose of 10 mg.
        • High doses (eg, 5-10 mg) of naloxone have been required to reverse buprenorphine-induced respiratory depression; it may take up to 3 hours before maximum reversal is observed r22r23
          • Prompt consultation with a medical toxicologist is prudent
        • Giving bolus doses of naloxone, followed by an IV infusion (eg, 4 mg/hour) has been described to treat buprenorphine overdose r22
    • Endotracheal dosage
      • Naloxone Hydrochloride Solution for injection; Infants and Children younger than 5 years or weighing 20 kg or less: Optimal ET dosage has not been determined; a dose of 2 to 3 times the IV dose has been recommended (equivalent to 0.2 to 0.3 mg/kg/dose ET).
      • Naloxone Hydrochloride Solution for injection; Children and Adolescents 5 to 17 years or weighing more than 20 kg: Optimal ET dosage has not been determined; a dose of 2 to 3 times the IV dose has been recommended (equivalent to 4 to 6 mg/dose ET).
      • Naloxone Hydrochloride Solution for injection; Adults: Optimal ET dosage has not been determined; a dose of 0.4 to 2 mg ET has been recommended.
    • Intranasal dosage (Narcan nasal spray)
      • Naloxone Hydrochloride Nasal spray, solution; Neonates: 1 spray (2 mg or 4 mg of naloxone) intranasally; repeat dose every 2 to 3 minutes in alternating nostrils as needed.
      • Naloxone Hydrochloride Nasal spray, solution; Infants, Children, and Adolescents: 1 spray (2 mg or 4 mg of naloxone) intranasally; repeat dose every 2 to 3 minutes in alternating nostrils as needed.
      • Naloxone Hydrochloride Nasal spray, solution; Adults: 1 spray (2 mg or 4 mg of naloxone) intranasally; repeat dose every 2 to 3 minutes in alternating nostrils as needed.
    • Continuous IV or intraosseous infusion dosage
      • Naloxone Hydrochloride Solution for injection; Infants, Children, and Adolescents: Limited data available. If repeated intermittent doses are required, calculate initial infusion rate based on effective intermittent dose; use two-thirds up to the full intermittent dose as initial hourly infusion rate and titrate as needed. A continuous infusion rate of 0.002 to 0.16 mg/kg/hour IV/IO has been suggested; however, most reports have utilized 0.024 to 0.044 mg/kg/hour IV. When appropriate, wean in 25% increments while closely monitoring patient.
      • Naloxone Hydrochloride Solution for injection; Adults: 0.005 mg/kg IV load followed by 0.0025 mg/kg/hour IV.
  • Naloxone can precipitate withdrawal symptoms, including: r24
    • Anxiety, irritability, and restlessness
    • Patients can become violent and uncooperative
    • Goose flesh
    • Hot and cold sweats
    • Muscle, bone, and joint aches
    • Tremor
    • Nausea, vomiting, and diarrhea
    • Increased resting pulse rate

Nondrug and supportive care

For apnea of fewer than 12 breaths per minute r1

  • Provide ventilation with a bag-valve mask c110
  • Perform chin-lift and jaw-thrust maneuvers to diminish hypercapnia c111c112
Procedures
Orotracheal intubation r1c113
General explanation
  • Insertion of a tube into the trachea to restore respiration
  • Safely ensures oxygenation and ventilation while providing protection against aspiration
Indication
  • To gain definitive control of the airway to restore respiration

Special populations

  • Children
    • Overdose is characterized by: r1
      • Unexpectedly severe poisoning based on dose received
      • Prolonged toxic effects
    • Admit children aged 3 years or younger who were exposed to opioids other than immediate-release formulations for 24-hour observation if ingestion of agents is suspected from history but cannot be confirmed r18
    • Children who ingest opioids may require larger doses of naloxone because they often ingest a higher dose than adults per kilogram of body weight r1
  • Older adults (eg, those aged 65 years or older)
    • Age-related changes in physiology and body composition may cause persistent intoxication r1

Monitoring

  • For patients with opioid toxicity, it is mandatory to monitor respiratory adequacy and cardiovascular stability
    • Use pulse oximetry or end-tidal CO₂ to monitor respiration
    • Use periodic blood pressure monitoring (every 15 minutes) to assess for hypotension

Complications and Prognosis

Complications

  • Respiratory depression and apnea c114c115c116c117c118c119c120c121c122c123c124c125c126
    • Apneic patients who receive naloxone frequently develop noncardiogenic pulmonary edema r1
  • Central nervous system depression with airway compromise
    • Vomiting can result in aspiration of gastric contents into the lungs
  • Head trauma or brain injury due to falls related to loss of consciousness c127c128
  • Multiple complications can occur secondary to prolonged hypotension, bradycardia, and hypothermia
  • Death may occur in severe situations c129
    • Accidental overdose can occur when nonpharmaceutical agents contain unexpected substances such as fentanyl or its analogues c130

Prognosis

  • Recurrence is likely in patients with opioid misuse history r2
  • In one study, about 1% of patients with nonfatal opioid overdoses went on to have fatal overdoses within 1 year r25
  • Mortality rate is 5.1 per 100,000 with opioid analgesics r26

Screening and Prevention

Screening c131

Prevention

  • Provider education and implementation of prescription drug monitoring programs assist in avoiding the following: r27r28c132
    • Inappropriate prescription of opioid analgesics c133
    • Chronic prescription of opioids for acute pain c134
    • Prescription of high-dose opioid analgesics c135
  • Use prescription and insurance data to screen and reduce opioid prescription for: r27r28c136
    • Patients seeking care from multiple physicians c137
    • Patients obtaining early refills c138
      • At risk for providing opioids to others
  • Increase availability of opioid-dependence treatment, especially office-based medication-assisted treatment with buprenorphine-naloxone r27r28c139
  • To decrease risk of opioid toxicity death, distribute naloxone and promote education about its use in communities where opioid toxicity is likely r27r28c140c141
  • Provide naloxone to patients receiving chronic opioid therapy, particularly those requiring higher doses, and train patient and family members how to administer intranasally when overdose is suspected r27r28c142c143
  • Refer opioid-misusing or opioid-dependent patients to Narcotics Anonymous or similar support programs r27r28c144
    • Inpatient and outpatient rehabilitation counseling is an important aspect of prevention c145
Boyer EW: Management of opioid analgesic overdose. N Engl J Med. 367(2):146-55, 201222784117CDC: CDC grand rounds: prescription drug overdoses--a U.S. epidemic. MMWR Morb Mortal Wkly Rep. 61(1):10-3, 201222237030Fareed A et al: Illicit opioid intoxication: diagnosis and treatment. Subst Abuse. 5:17-25, 201122879747Weinhold LL et al: Opioid miosis: effects of lighting intensity and monocular and binocular exposure. Drug Alcohol Depend. 31(2):177-81, 19938436062Alinejad S et al: A systematic review of the cardiotoxicity of methadone. EXCLI J. 14:577-600, 201526869865Warner M et al: Drugs most frequently involved in drug overdose deaths: United States, 2010-2014. Natl Vital Stat Rep. 65(10):1-15, 201627996932Dunn KM et al: Opioid prescriptions for chronic pain and overdose: a cohort study. Ann Intern Med. 152(2):85-92, 201020083827Häkkinen M et al: Parenteral buprenorphine-naloxone abuse is a major cause of fatal buprenorphine-related poisoning. Forensic Sci Int. 232(1-3):11-5, 201324053859Lavonas EJ et al: Root causes, clinical effects, and outcomes of unintentional exposures to buprenorphine by young children. J Pediatr. 163(5):1377-83.e1-3, 201323993129Smith HS: Opioid metabolism. Mayo Clin Proc. 84(7):613-24, 200919567715Chen LH et al: Drug-poisoning deaths involving opioid analgesics: United States, 1999-2011. NCHS Data Brief. 1-8, 201425228059Pedapati EV et al: Toddlers requiring pediatric intensive care unit admission following at-home exposure to buprenorphine/naloxone. Pediatr Crit Care Med. 12(2):e102-7, 201120921918Andrzejowski P et al: Codeine in paediatrics: pharmacology, prescribing and controversies. Arch Dis Child Educ Pract Ed. 101(3):148-51, 201626984558WHO: Information Sheet on Opioid Overdose. WHO website. Updated August 2018. Accessed July 31, 2020. https://www.who.int/substance_abuse/information-sheet/en/https://www.who.int/substance_abuse/information-sheet/en/Williams RH et al: Emergency diagnosis of opioid intoxication. Lab Med. 31(6):334-42, 2000https://doi.org/10.1309/QY8T-KGBN-BVA6-H706Miller H et al: Loperamide misuse and abuse. J Am Pharm Assoc (2003). 57(2S):S45-50, 201728189538Erickson TB et al: The approach to the patient with an unknown overdose. Emerg Med Clin North Am. 25(2):249-81; abstract vii, 200717482020Boyer EW et al: Methadone and buprenorphine toxicity in children. Am J Addict. 19(1):89-95, 201020132125Nelsen JL et al: Management considerations following overdoses of modified-release morphine preparations. World J Emerg Med. 1(1):75-6, 201025214946Bickell WH et al: Life-threatening opioid toxicity. In: Dellinger RP, ed: The Substance Abuser: Problems in Critical Care. Lippincott; 1987:106Clarke SF et al: Naloxone in opioid poisoning: walking the tightrope. Emerg Med J. 22(9):612-6, 200516113176van Dorp E et al: Naloxone reversal of buprenorphine-induced respiratory depression. Anesthesiology. 105(1):51-7, 200616809994Gal TJ: Naloxone reversal of buprenorphine-induced respiratory depression. Clin Pharmacol Ther. 45(1):66-71, 19892491980Berna C et al: Tapering long-term opioid therapy in chronic noncancer pain: evidence and recommendations for everyday practice. Mayo Clin Proc. 90(6):828-42, 201526046416Olfson M et al: Risks of fatal opioid overdose during the first year following nonfatal overdose. Drug Alcohol Depend. 190:112-9, 201830005310CDC: QuickStats: Rates of Deaths From Drug Poisoning and Drug Poisoning Involving Opioid Analgesics--United States, 1999-2013. CDC website. Published January 16, 2015. Accessed July 31, 2020. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6401a10.htmhttps://www.cdc.gov/mmwr/preview/mmwrhtml/mm6401a10.htmCDC: Community-based opioid overdose prevention programs providing naloxone--United States, 2010. MMWR Morb Mortal Wkly Rep. 61(6):101-5, 201222337174Beletsky L et al: Prevention of fatal opioid overdose. JAMA. 308(18):1863-4, 201223150005