Without evidence of benefit, an intervention should not be presumed to be beneficial or safe.

- Rogue Medic

Narcan Solves Riddle – Part II

Here is another late Normal Sinus Rhythm post. This week, again, there is not a theme in sight. Read the rest of the NSR Blog posts at NSR Week 13.

Part I of this is Narcan Solves Riddle – Part I.

I used clonidine as an example of a drug that is not an opioid, yet responds to naloxone. Another way to look at this is by looking at naltrexone.

Naltrexone is a longer acting opioid antagonist, but it is also used in treatment of alcoholism. Are we supposed to believe that alcohol and opioids are the same?

No, but the reason people seem to die from HOD (Heroin OverDose) is from respiratory depression. Opioids have a significant effect on the respiratory drive. The mu (μ) receptor appears to be the major cause of respiratory depression. With large doses of opioids, the brain stem’s respiratory centers become much more tolerant of high concentrations of CO2.

Alcohol seems to have some respiratory depressant effect. Benzodiazepines can have a powerful respiratory depressant effect, as well. Combining either of these with an opioid is more likely to result in significant respiratory depression, or apnea. Naltrexone is expected to have an effect on alcohol use, but not benzodiazepine use. Naloxone also seems to have an effect on alcohol use, but not benzodiazepine use. Still, we are supposed to believe that naloxone does not work on anything that is not an opioid.

Is alcohol an opioid? No. Alcohol may cause stimulation of opioid receptors, but other addictive drugs might be expected to interact with these receptors. Benzodiazepines are addictive, but do not seem to respond to naloxone or naltrexone. So, why alcohol?

The mechanism of action of naltrexone in alcoholism is not understood; however, involvement of the endogenous opioid system is suggested by preclinical data. Naltrexone, an opioid receptor antagonist, competitively binds to such receptors and may block the effects of endogenous opioids. Opioid antagonists have been shown to reduce alcohol consumption by animals, and naltrexone has been shown to reduce alcohol consumption in clinical studies.

Naltrexone is not aversive therapy and does not cause a disulfiram-like reaction either as a result of opiate use or ethanol ingestion.

Pharmacokinetics: Naltrexone is a pure opioid receptor antagonist.[1]

Naltrexone is a pure opioid receptor antagonist, yet is used for the treatment of alcoholism. Naloxone is also a pure opioid receptor antagonist, yet many claim it has no effect on alcohol.

Way back in 1999, Dr. Karl Sporer wrote a review of HOD. In order to be mysterious, he hid it under the title Acute Heroin Overdose. Here is some of what he wrote. –

The heroin overdose syndrome (sensitivity for diagnosing heroin overdose, 92%; specificity, 76%) consists of abnormal mental status, substantially decreased respiration, and miotic pupils. The response of naloxone does not improve the sensitivity of this diagnosis.[2]

In many heroin-related deaths, morphine levels alone do not account for the fatal outcome.[2]

Multiple drug use is common in heroin-related deaths. Most patients who die of heroin-related causes have significant alcohol (29% to 75%) or benzodiazepine (5% to 12%) levels.[2]

What about responses to naloxone when no opioid is found in the body?

Another series of patients with presumed heroin overdose who responded to naloxone underwent extensive serum quantitative drug testing (58). The clinical variables used to diagnose heroin overdose in this study were not well defined. Of the 53 patients, 45 had clinically significant serum drug levels that were consistent with heroin intoxication, 6 had detectable levels of other opiates, and 2 had no detectable levels of serum opiates.[2]

One study by Hoffman, referred to frequently in the previous paper, looked at 730 patients treated with naloxone. This was back in the dark ages of EMS, in Los Angeles (home of Emergency!), and they apparently gave naloxone to everyone with AMS (Altered Mental Status). Not that things are very different in some places, today. They were trying to find out if the routine administration of naloxone to every AMS patient was necessary. They found that their diagnostic criteria were better than response to naloxone.

AMS with any of the following criteria – respirations less than 13, pinpoint pupils, or circumstantial evidence of drug abuse were compared with response to naloxone.

Six of the 25 complete responders to naloxone (24%) ultimately were proven to have had false-positive responses, as they were not ultimately given a diagnosis of opiate overdose. In four of these patients, the acute episode of AMS was related to a seizure, whereas in two, it was due to head trauma; in none of these cases did the ultimate diagnosis include opiates or any other class of drug overdose (which might have responded directly to naloxone). Thus, what was apparently misinterpreted as a response to naloxone in these cases appears in retrospect to have been due to the natural lightening that occurs with time during the postictal period or after head trauma.[3]

Almost one quarter of the complete responders to naloxone did not have opioids on board. Maybe a bit of this is poor assessment, but what do you expect from people who are trained to believe that response to naloxone indicates opioid overdose?

Easily determined clinical indicators detected 22 of the 24 patients in our study diagnosed as having an opiate overdose, whereas only 21 of them had any response to naloxone (and only 19 had a complete response). The two patients with opiate overdose who were not identified by these clinical findings did not respond to naloxone, suggesting that serial administration of these tests fails to improve sensitivity over that achieved through the use of the clinical findings alone. The study indicates that there is no diagnostic benefit derived from the administration of naloxone to all AMS patients.

In addition, response to naloxone created a substantial amount of diagnostic confusion, as not only were there several false-positives among the complete responders (who fortuitously awoke around the time the naloxone was administered) but also the number of equivocal responders to naloxone was greater than either the number of complete responders or even the total number of patients with opiate overdose. If the clinician interprets these equivocal responses as evidence of opiate overdose, he will be misclassifying most of these patients; interpreting partial response as evidence against opiate overdose further decreases the sensitivity of response to naloxone. Finally, treating partial response as “indeterminate” excludes naloxone response as a potential tool in a group even larger than the small group of opiate overdoses for whom this diagnostic challenge with naloxone is supposed to provide potential benefit.[3]

Apparently the diagnostic value of naloxone response tells you nothing that you didn’t already know about the patient.

Naloxone may mislead you to conclude that you know something about the patient that is not true.

Naloxone is not diagnostic.

naloxone’s value as a possible diagnostic tool for clinicians can be estimated only according to whether it actually helps clinicians in their diagnostic decision making.[3]

Telling someone that you know they took an opioid, because they responded to naloxone, is not using naloxone as they suggest and it may lead to an incorrect diagnosis. In other words, it is an example of misinformation and bad logic. If the police use your statement to charge someone with a crime, but it later turns out that you were not correct, are they going to think that you are so smart? What is the purpose of making this incorrect statement, except to appear to be smart. It might be slander. Fortunately, nobody would ever sue anyone in EMS.

Reciting bad information, to show off how smart you are, is not smart.

We should not be encouraging misinformation in EMS. We have too much of that already. We need to eliminate bad teachings, and this is one.

It seems that naloxone and naltrexone have an effect on non-opioid respiratory depression OR other drugs that cause respiratory depression may be activating the opioid receptors, even in the absence of opioids. Neither of these would encourage me to make the unsupportable statement –

Narcan woke you up, so we know you took heroin (or another opioid).

Part III will be next week.

Footnotes:

[1] Vivitrol (naltrexone)
[Alkermes, Inc.]

DailyMed
FDA label from DailyMed

naltrexone hyrdochloride (Naltrexone Hydrochloride) tablet, film coated
[Mallinckrodt Inc.]
FDA label from DailyMed

naltrexone hydrochloride (Naltrexone Hydrochloride) tablet
[BARR LABORATORIES, INC.]
FDA label from DailyMed

[2] Acute heroin overdose.
Sporer KA.
Ann Intern Med. 1999 Apr 6; 130 (7): 584-90. Review.
PMID: 10189329 [PubMed – indexed for MEDLINE]

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

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Comments

  1. A simple assessment does a better job of diagnosing heroin, or related drugs, use than Narcan response?Why do people still choose the mediocre way and ignore even a little use of skill?

  2. first rule of fireThey are afraid of people thinking. If people think, they can make a mistake. For some reason they think that a committee is smarter than an individual.I prefer the despair.com slogan – None of Us is as Dumb as All of Us.And for all who love the election politics, the celebration of those who protect us from what ifs, If You Think the Problems We Create Are Bad, Just Wait Until You See Our Solutions.

  3. Whatever the scientific explanations may be, one thing is certain. Alcohol can cause many illnesses and addiction to it would be the worst thing a person might get.

  4. drug addiction treatment,There are many bad things a person might get, choosing alcoholism as the worst is misleading. I am not suggesting that alcoholism is not a problem. Picking the worst is completely subjective.

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