Mu, delta, and kappa opioid receptors are widely distributed throughout the body, particularly in the central nervous system. The mu receptor is responsible for the majority of clinical effects caused by opioids. Opioid tolerance involves the progressive inability of the mu receptor to propagate its normal signal after opioid binding, resulting in receptor desensitization. The prolonged use of opioids results in tolerance of the analgesic and respiratory depressive effects of all opioids. Once absorbed, opioids undergo first order elimination pharmacokinetics, defined as a constant fraction of the drug being converted over a given period of time. This results in a half-life elimination profile. The system can be saturated with an overdose, however, producing zero kinetics where only a small given proportion of the drug is eliminated per time.
Clinical manifestations of opioid overdose produce a so-called opioid toxidrome. This includes respiratory depression leading to apnea, decreased mental status resulting in stupor or coma, and miosis (pinpoint pupils). The pupillary response may vary because of the presence of other substances, and not all opioids produce pinpoint pupils, but meperidine, propoxyphene, and tramadol, for example, produce dilated pupils. The diagnosis is relatively straightforward, and a variety of other specifics must be considered. Opioids can produce pulmonary edema, clandestine-retained fentanyl patches can result in continued opioid release, acetaminophen can cause concomitant liver damage, and some opioids can cause seizures (propoxyphene and meperidine most commonly). Prolonged immobilization can result in a rhabdomyolysis, myoglobinuric renal failure, or compartment syndrome. A persistent nonresponsive state in a cold environment may produce hypothermia. The use of many opioids results in a positive urine drug screen, but commonly used hospital tests do not routinely identify methadone, fentanyl, and even oxycodone. A routine urine drug screen should not be used to determine treatment or to confirm or rule out opioid toxicity.
The standard opioid antidote, naloxone, is a competitive mu opioid receptor antagonist. It reverses all signs of opioid intoxication and can be administered IM, IV, intranasally, or via the lung. It has minimal bioavailability after oral administration, which prompted its addition to pills to deter grinding and subsequent intravenous injection. The author states that the initial dose of naloxone is 0.04 mg, with increasing doses every two minutes for a last dose of 15 mg before concluding that naloxone will not be effective. It is not explained in the paper, but that dose is for a patient still breathing, not apneic. The duration of the effect of naloxone is transient, and recurrent respiratory depression or the return of other signs of toxicity indicates the need for repeat doses or a continuous naloxone infusion.
Naloxone will produce withdrawal in patients who are opioid-dependent. Opioid withdrawal is very unpleasant, consisting of yawning, lacrimation, diaphoresis, myalgia, vomiting, and diarrhea, but these symptoms are not life-threatening. Seizures do not occur from opioid withdrawal. The use of low-dose naloxone can lessen opioid toxicity without provoking withdrawal. The author said patients should be observed for four to six hours following improvement with naloxone before considering discharge.
Opioid overdose in children may be characterized by the delayed onset of toxicity and prolonged toxic effects. This author suggests that any young child who is exposed to opioids other than an immediate-release formulation should be routinely admitted to the hospital for 24 hours of observation even if the specific ingestion cannot be confirmed. This includes exposure to buprenorphine-naloxone products (Suboxone).
Comment: The term opiate refers to drugs that are derived from opium, such as morphine. Drugs that are semisynthetic or synthetic (methadone, oxycodone, fentanyl) but not directly derived from opium are called opioids. Most clinicians use the term opioids to refer to any drug that acts on opioid receptors and produces morphine-like effects.
Diagnosing Opioid Toxicity: Opioid toxicity is obvious in patients who have ingested or otherwise used heroin or oral opioids in the absence of other substances. The toxidrome consists of decreased mental status leading to coma, decreased respirations leading to apnea, and pinpoint pupils. But life is not that simple in the ED these days. It's actually unusual to obtain pure heroin on the street. The majority of street heroin is either fentanyl, contains fentanyl derivatives, or is heroin mixed with fentanyl or a number of other substances added for more pronounced effects for the user.
A user who injects heroin will experience well-known effects if they are, in fact, receiving the same drug and the same dose that he has been sold in the past, but death from respiratory depression can rapidly ensue if the concentration of heroin is higher, it has been increasing over the years, or if it is mixed with a heroin substitute for an added kick. An opioid overdose patient dying in the hospital is quite unusual, and most deaths occur before medical assistance arrives. This has been why police, EMS, and even patients and their relatives are being increasingly offered nasally administered naloxone to carry with them. Death is usually averted if the patient can be kept alive until he reaches the hospital.
Simply intubating patients with opioid overdose will usually be all that is needed because opioids cause death by respiratory depression, followed by cardiac arrest. Occasionally hypotension and pulmonary edema will require additional interventions. The patient may have opioid toxicity, but the concomitant use of ethanol or sedative-hypnotics, particularly benzodiazepines, will cause additional CNS depression and often negate the expected response to naloxone.
Opioid use can predispose patients to head trauma, which can simulate an opioid-like state, so concomitant head trauma in someone with an actual opioid overdose is always a consideration. The serum glucose should also be routinely checked early in the course. Opioids usually spare direct cardiac effects, but recent overdose of massive amounts of loperamide (Imodium) used as an opioid substitute has been reported to cause wide complex tachycardia. Loperamide abuse is likely underappreciated. (Read “Opioid Abusers Using Loperamide to Get High or Alleviate Withdrawal, with Fatal Consequences” by EMN columnist Leon Gussow, MD, at http://bit.ly/EMN-ToxJuly16.)
Ordering a routine urine drug screen is second nature to the emergency clinician, but acute opioid poisoning is a clinical diagnosis whose management will not change based on its result. A positive test can indicate use but not intoxication, and many of the synthetic opioids will produce a negative screen. Many clinicians do not know exactly what is detected by their hospital's urine drug screen, and laboratories vary widely. Simply stated, the urine drug screen is of minimal value in the acute clinical management of most overdose patients, but it is a universal test.
I recommend using it liberally, not to dictate initial management but to garner other useful information. No absolute indications for a urine drug screen exist in the ED, but it will generally detect even small amounts of morphine (the metabolite of heroin) and codeine, and perhaps or perhaps not, hydrocodone and hydromorphone. Oxycodone require a supplemental test. None will detect methadone, fentanyl, fentanyl derivatives, tramadol, propoxyphene, or meperidine, but these can be ordered as separate tests not available in the ED.
The Use of Naloxone: Naloxone will reverse all opioids, but the effective dose is wide ranging in today's opioid epidemic. This author's recommendation of 0.04 mg as an initial dose is quite small and unlikely to reverse a significant opioid overdose totally. This minimal dose is suggested for those who still have respirations (are not apneic) to ameliorate toxicity but to avoid opioid withdrawal. It now appears to be medically incorrect to induce withdrawal in an unconscious opioid addict; go figure. The author's goal is to produce adequate ventilations but not necessarily a normal mental status. Nice effect if you can get it.
I am uncomfortable with that goal in the ED. I would rather have an awake patient than one still obtunded. It's appropriate to increase the dose if the prior dose is ineffective, but I see no reason not to begin with a larger dose in someone who is significantly intoxicated. The old standard doses of naloxone just don't cut it with the current use of fentanyl and acetyl fentanyl. The recently available naloxone nasal spray delivers 4 mg per dose. The self-administered naloxone injection (Evzio) delivers 0.4 mg per dose. Injectable naloxone is available in a concentration of 0.4 mg/ml and 1 mg/ml. I may be old-school, but I still believe that one should administer at least 0.4 mg of naloxone IV in the ED as your initial dose.
If this is not effective, I would then go directly to a 2 mg, then a 5 mg, then a 10 mg dose before giving up. A patient who stays awake or stable after your initial reversal with naloxone does not need continued doses of this antidote. Naloxone in doses of up to 2 mg will lose its effect in about two hours, so prolonged observation after initial reversal is required. I would go right to a small-dose, continuous naloxone intravenous infusion if a patient responds to naloxone initially and then sedates again and requires more naloxone. The easiest way to provide this is to mix 10 mg of naloxone in a liter of saline and administer 40-50 ml an hour (0.04-0.5 mg), adjusting dosages upward or downward. This will usually keep the patient stable without producing severe withdrawal.
It is true that complete naloxone reversal will produce withdrawal in many patients, but not all are addicted. Attempting to treat serious intoxication and prevent withdrawal is a tightrope that is not easily walked in a busy ED. This requires continuous monitoring, a luxury not always available. I would much rather have an awake person in mild withdrawal than one who must be monitored closely because I was afraid to reverse the opioid overdose fully for fear of producing withdrawal. Opioid toxicity recurs unpredictably.
One can treat withdrawal with 0.2 to 0.3 mg of clonidine, a small amount of benzodiazepines, or both, but producing withdrawal will often prompt many patients to attempt to sign out against medical advice. Some will just up and leave. I would not allow someone to leave the ED in less than two hours if he were significantly intoxicated by opioids and responded to naloxone. That often causes significant strife and arguments. One can clearly finesse the approach or otherwise negotiate with such patients, but attempting to predict the subsequent course of someone whose naloxone has only been partially metabolized is impossible. The patient put into withdrawal by your efforts will often leave the ED and reuse the opioid, occasionally with a fatal outcome. Most heroin overdoses will not require more than one dose of naloxone because of the short half-life of heroin. All bets are off with prescription opioid overdoses or today's street heroin, scenarios that often put the emergency clinician in a no-win situation.
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Prescription Opioid Overdose Data
Overdose deaths involving prescription opioids have quadrupled since 1999, and so have sales of these prescription drugs. More than 165,000 people died in the United States from overdoses related to prescription opioids from 1999 to 2014.
Opioid prescribing continues to fuel the epidemic. Today, at least half of all U.S. opioid overdose deaths involve a prescription opioid. More than 14,000 people died from overdoses involving prescription opioids in 2014.
Most Commonly Overdosed Opioids
The most common drugs involved in prescription opioid overdose deaths are:
- Oxycodone (such as Oxycontin)
- Hydrocodone (such as Vicodin)
Among those who died from prescription opioid overdose between 1999 and 2014:
- Overdose rates were highest among people ages 25 to 54.
- Overdose rates were higher among non-Latino whites and American Indian or Alaskan Natives compared with non-Latino blacks and Latinos.
- Men were more likely to die from overdose, but the mortality gap between men and women is closing.
Source: Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, Division of Unintentional Injury Prevention, June 21, 2016; http://bit.ly/CDCOpioids.
Clinical Findings after Opioid Use
- Respiratory depression leading to apnea
- Hepatic injury from acetaminophen
- Myoglobinuric renal failure
- Absent or decreased bowel sounds
- Compartment syndrome
- Possible clandestine use of fentanyl patches
Adapted from New Engl J Med 2012;367:146.
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