Opioid Toxicity


Article Author:
Robert Oelhaf


Article Editor:
Mohammadreza Azadfard


Editors In Chief:
Paul DiCesare


Managing Editors:
Frank Smeeks
Scott Dulebohn
Erin Hughes
Pritesh Sheth
Mark Pellegrini
James Hughes
Richard Ciresi
Phillip Hynes


Updated:
11/8/2018 8:23:07 PM

Introduction

Opioids and opiates together comprise a class of medications that are widely used primarily to control severe pain. Conventionally, the term opiates refer to natural compounds usually obtained from the poppy flower base. Opioids are synthesized by chemical processes. Opiates and opioids are among the most commonly abused substances throughout the world. Addiction to opioids and opiates has become a major health problem in the developed world since the 2000s, particularly in the United States. [1][2][3]

Etiology

Opioids are derived synthetically from generally unrelated compounds. Opiates are derived from the liquid of the opium poppy either by direct refinement or by relatively minor chemical modifications. Both opioids and opiates act on five opioid receptors: mu, kappa, delta, nociceptin, and zeta. Simplifying significantly, the mu receptors are thought to provide analgesia, respiratory suppression, and euphoria. The kappa agonism can yield hallucinations and dysphoria. The delta receptor likely has pain control and mood modulation effects, but some have suggested that mu agonism is necessary for the delta receptor to function strongly for analgesia. The nociceptin receptor modulates brain dopamine levels. The zeta receptor, also known as the opioid growth factor receptor, can modulate certain types of cell proliferation, such as skin growths, and is not thought to have many functions in the modulation of pain or emotion. [4][5]

Epidemiology

Deaths from overdoses of opioids and opiates had very large increases in the United States between 2000 and 2014, a pattern not seen before in history. In the early 2010s, many states in the US enacted new regulations either enhancing scrutiny of consumers, restricting prescribers, or both. As of 2014, a trend toward a decrease in prescription opioid deaths was seen. However, a marked jump in deaths from opiates, particularly heroin, was seen concurrently. [6][7]

Pathophysiology

Opioids can be administered through a variety of routes. In the healthcare setting, the method of administration is usually intravenous, intramuscular, or oral. Different routes of administration can provide different onsets and offsets of action. In the setting of abuse, complications of problematic injection are common, diverse, and covered elsewhere (cellulitis, abscess, thrombophlebitis, endocarditis, compartment syndrome, foreign body, human immunodeficiency virus, hepatitis). [8]

Toxicokinetics

Opioids have an extremely wide diversity of durations and intensities of effect. Alfentanil, for example, has a half-life of around 1.5 hours; whereas, Methadone has a half-life of between 8 to 60 hours. Opioid uptake and effect can also vary by route of administration, some examples being fentanyl patches or long-acting oral formulations of oxycodone and morphine. Some, such as diphenoxylate and loperamide, have almost no effect other than suppression of bowel motility. Opioids such as methadone can significantly prolong the QT interval. Opioids can sometimes precipitate serotonin syndrome, especially when given to patients already taking a variety of psychoactive medications. There is an evolving body of knowledge that the intensity and quality of response to opioids can vary significantly between patients which can be unrelated to tolerance. This is likely related to genetics, but this is not well characterized at this time. 

History and Physical

Patients with opioid overdose typically have decreased responsiveness, hypopnea (abnormally slow respirations), slow speech, and constricted pupils. Constricted pupils may be seen in opioid tolerized individuals during active use even without the associated sedation and decreased respiratory drive issues. Constipation is common, particularly in chronic consumers and the elderly. Opioids are thought to decrease bowel motility, but on occasion, bowel spasms can be produced such as with "codeine cramps." Naloxone is the treatment of choice for opioid-induced bowel spasms. If there is intravenous use, there can be "track marks." These are very small abrasion-type skin changes overlying veins, usually in the extremities but occasionally in the neck and other anatomic locations. 

Evaluation

Diagnosis of acute opioid poisoning is primarily clinical. In the overdose setting, hypopnea can progress to apnea. Naloxone is a mainstay of therapy, but the practitioner is warned that first-line treatment is control of the airway and rescue breathing. Bag valve mask ventilation or similar intervention should be initiated immediately by the primary rescuer to restore oxygen supply to vital organs while other rescuers evaluate available methods of naloxone administration. Basic Life Support and Advanced Cardiac Life Support principles should be followed during the resuscitation of the opioid poisoned patient. Laboratory testing can include drug screening, but there is a widespread opinion that drug screening in this setting is not useful in making a timely diagnosis of opioid poisoning. Drug screening is much more useful in screening for occult opioid use in settings such as pre-employment testing. When there is disagreement between the patient and the provider regarding a drug screen result, gas chromatography and mass spectroscopy (GCMS) can provide a definitive answer regarding what was in the patient sample. In the United States, Medical Review Officers manage the data produced by employment drug testing. [9][10]

Treatment / Management

Traditional treatment of opioid/opiate addiction focuses on self-help in the setting of counseling and mentorship by addicts already successfully in recovery, with a focus on drug-free living. "Drug-free" in the minds of many in both recovery and treatment involves an absence of any chemicals including those prescribed by a medical provider. In the 2010s the concept of harm reduction became increasingly accepted by the mainstream of addiction treatment providers, which allowed for ingested medications to be taken, with an increased focus on objective patient outcome optimization. Chronic treatment of addicts with methadone, buprenorphine, and similar medications became more accepted. Increasing numbers of studies comparing various strategies of recovery and relapse suppression were seen in the literature. Concurrently, naltrexone injection for enhancement of complete opioid avoidance became available. Each naltrexone injection lasts approximately 30 days. During that time opioids are rendered ineffective by the effect of the naltrexone on the target receptors. Disadvantages of naltrexone include difficulties in controlling acute pain in the setting of trauma and other acute medical issues. It is also contraindicated in the setting of chronic pain. Oral naltrexone is taken daily but is just about always ineffective if the patient controls their dosing schedule. Observed oral naltrexone administration controlled by a significant other may have promise given recent literature regarding disulfiram in the treatment of alcoholism. [11][12][2]

Pearls and Other Issues

It is important for a provider to carefully evaluate for chronic pain in any patient under consideration for referral to opioid recovery services. Improper referral of chronic pain patients without proper pain control contingency can result in severe patient distress and at times lead to a variety of medical complications. In the 2000s and 2010s, there was a dramatic increase in population-level opioid consumption in the United States, leading to a national discussion on how to better control distribution and use. Interdiction with control of physician behavior had some modest effects in reduction of street availability of opioids with the following results (1) a concurrent rise in consumption of heroin, and (2) no improvement in the number of overall deaths from opioids from all sources combined. Also noted was the risk of theft of medications prescribed to the elderly and disabled, and steps were taken to educate these populations regarding those risks.

Portugal had a severe problem with people addicted to these drugs and overdose deaths in the 2000s and early 2010s. Shortly after regulatory changes emphasizing drug decriminalization and referral to heavily government-subsidized treatment, Portugal documented a rapid and significant drop in addiction deaths. Portugal's example may provide a way forward for the United States with similar policy changes.

Enhancing Healthcare Team Outcomes

The opioids have created a major crisis in the US with reports of dozens of people dying almost every day. To ensure patient safety numerous guidelines have been developed to help healthcare workers mitigate the risks associated with opioid therapy. All healthcare workers who prescribe and dispense opiates are important partners in preventing the opioid overdose epidemic from getting worse. The guidelines all agree that the doses of opioids greater than 90 -200 mg of morphine equivalents per days should be avoided. Further, when starting or switching fentanyl patches to oral opioids, the doses should be reduced by 25-50%. The guidelines also recommend the use of opioid risk assessment tools, written agreements and urine drug testing to mitigate the risks. [13][14] (Level III)

The pharmacist is perhaps in the ideal position to fight the opioid overdose epidemic. He or she should be the first to detect high prescription doses of opioids and speak to the healthcare provider before dispensing the drug. In addition, the pharmacist can check the drug database to determine if the patient is a drug abuser.  Thirdly the pharmacist should inform the authorities if he or she deems that a healthcare worker is overprescribing narcotics each month.[14][15] (level III)

Outcomes

There is good evidence to support the use of an opioid for chronic pain but only with careful monitoring and education of the patient. For all in patients, nurses are in the prime position to educate patients about the potential toxicity of opioids and the risk of addiction. Data show that in the short term, education and restriction of opioid prescriptions may be helping to avert the crises but the long-term data on whether it solves the addiction and physical dependence remain unknown. [16][17][18] (Level V)[17]


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Opioid Toxicity - Questions

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A postoperative patient has been medicated for pain with a long-acting opioid. The patient's respiratory rate is 6 breaths/min, and she is lethargic. Her oxygen saturation begins to decrease into the 80s. Which medication should be administered?



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A patient was brought to the emergency department unconscious as a result of heroin overdose. What medication is used?



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A patient recovering from a cholecystectomy received morphine sulfate in the postanesthesia care unit. The patient returns to the surgical unit, with vital signs of blood pressure 124/64 mmHg, pulse 64 beats/min, respirations 8 per minute, and temperature 97.4 F. Which of the following medications should be given?



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A 52-year-old male is found by a friend. The friend called 911 because he could not wake him up. He told the 911 operator that his friend was still breathing but barely. The patient is found to be very lethargic, bradycardic, apneic, hypotensive, and has pinpoint pupils. His point of care glucose is 72 mg/dL. What is the best treatment for him?



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A patient has taken excess buprenorphine and failed to respond to naloxone. What medication should be used?



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Which of the following is not seen with postoperative morphine overdose?



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In a post-open-heart surgery patient, excessive morphine has been administered. What is the most sensitive indicator of opioid-induced respiratory depression?



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A patient was found to be hypotensive, lethargic, and diaphoretic due to morphine overdose. Breathing rate was 4-6/min and pulse oximetry showed oxygen saturation of 87%. What should be the initial treatment?



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A patient ingested an unknown substance and presented to the emergency department with evidence of respiratory depression. Which of the following drugs would not cause this symptom?



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A young drug user is found to be very lethargic, bradycardic, apneic, hypotensive, and has pinpoint pupils. Which of the listed interventions is most likely to help this patient?



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A post-operative cardiac patient is receiving IV morphine for pain control. The nurse notices that his respiratory rate has decreased with labored respirations, oximeter reading of 65 percent, and an obtunded mental state. What antidote should be given in this setting?



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Overdose with which medication can cause bradycardia and hypotension?



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A patient presents with decreased consciousness and pinpoint pupils. Which of the following is the best pharmacotherapy?



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How should respiratory depression caused by morphine overdose be treated?



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A 22-year-old male overdosed on heroin is obtunded and has a respiratory rate of 8. Blood pressure is 80/60 mmHg, heart rate is 85, and oxygen saturation is 72 percent on room air. Arterial blood gas shows pH=7.10, PCO2=78, and PO2=45. Select the best interpretation.



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A drug user is found to be very lethargic, bradycardic, apneic, hypotensive, and with pinpoint pupils. What medication should be given?



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Which of the following would reverse the effects of a morphine overdose?



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A 4-year-old male presents with miosis, respiratory depression, and a depressed mental status. What ingestion is most likely?



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The sedation nurse mishears the order for "2 and 50" and instead gives 250 mcg of fentanyl. Two minutes later the oxygen saturation is 80 percent. Which should be administered first?



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A patient is taking Anaprox DS, Lomotil, Verapamil, and Vicodin. What combination is concerning?



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Which of the following drugs is given in cases of hydromorphone overdose?



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A 17-year-old male patient is brought to the emergency department after being found unresponsive in his home. The patient was recently diagnosed with pancreatic cancer and started on oxycodone for pain management. Vital signs show a heart rate of 90 bpm, respiratory rate of 10/min, and blood pressure of 99/63 mmHg. Physical exam reveals miotic pupils, shallow respirations and a Glasgow coma scale of 9. Which of the following medications should be given immediately.



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A patient is brought by emergency medical services to the emergency department with a possible opioid overdose. Which of the following signs and symptoms may be present? Select all that apply.



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Opioid Toxicity - References

References

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Pergolizzi J,Böger RH,Budd K,Dahan A,Erdine S,Hans G,Kress HG,Langford R,Likar R,Raffa RB,Sacerdote P, Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone). Pain practice : the official journal of World Institute of Pain. 2008 Jul-Aug     [PubMed]
Chou R,Korthuis PT,McCarty D,Coffin PO,Griffin JC,Davis-O'Reilly C,Grusing S,Daya M, Management of Suspected Opioid Overdose With Naloxone in Out-of-Hospital Settings: A Systematic Review. Annals of internal medicine. 2017 Dec 19     [PubMed]
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