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OK a double Normal Sinus Rhythm post this week. 🙂

This week, again, there is no theme. Read the rest of the NSR Blog posts at NSR Week 14.

This continues from Part I, Part II, and Part III. One of the problems with people claiming that naloxone is diagnostic, or that there is something to be gained by drawing conclusions from a response to naloxone, is that it is just bad logic.

Nassim Nicholas Taleb wrote about this in his book Fooled by Randomness: The Hidden Role of Chance in Life and in the Markets and in his latest book The Black Swan: The Impact of the Highly Improbable. He paraphrases the conclusion –

How many white swans does one need to observe before inferring that all swans are white and that there are no black swans? Hundreds? Thousands? The problem is that we do not know where to start^[1]

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While we do not care that much about swans in EMS, the occasional dying swan act is just something we occasionally need to deal with. The problem of drawing inappropriate conclusions may be our biggest problem. Claiming that naloxone is diagnostic is not any different from claiming that all swans are white.

I have seen many swans.

OK.

They were all white.

Still OK.

Therefore all swans are white.

That may be true, but there is no way that we can prove this.

How many swans do we need to see to be able to draw this conclusion?

All of them.

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Not 51%.

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Not 90%.

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Not 99%.

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Not 99 and 44/100^ths%.

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Not 99.999%.

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We need to see all of them.

So we round up all of the swans in the world and observe that they are all white. Then we are sure.

No.

Still not OK.

We also have to examine all past swans and all future swans.

There may have been a species of non-white swans that became extinct.

There may be a genetic mutation, or there may be genetic manipulation, that would lead to a non-white swan.

Therefore, how many administrations of naloxone to opioid-free people do you need to observe – without response – to be able to state that naloxone is diagnostic for opioids?

All of them.

All in the past.

All in the future.

We can conclude that it seems that naloxone is a way of identifying opioid consumers, but that we reserve judgment on something that cannot be proven.

So there is no way to prove this?

That’s right.

But there is a way to disprove this.

Why disprove it?

Because bad logic leads us to make mistakes.

In EMS, it is fortunate that we are only playing with patients’ lives. So why worry about making bad decisions? Especially, since this is not a decision likely to kill anyone?

Even though this is not likely to kill anyone, similar logic is not so benign.

So, how do we disprove something like this?

How many non-white swans would it take to prove that not all swans are white?

At least one.

It is such a fragile and useless conclusion, that to disprove it requires one and only one example of failure of the supposed rule.

An exception does not confirm a rule. An exception demonstrates that the rule is faulty.^[2]

Farther down in the same paragraph, Dr. Taleb provides the answer –

Note that the Black Swan is not just a metaphor: until the discovery of Australia common belief held that all swans were white; such belief was shattered with the sighting of the first cygnus atratus.^[1]

–

–

How many ways do I need to demonstrate that it is foolish to conclude what a person may have consumed based on their apparent response to a medication – a medication that has a long history of being wrong?

Well the patients who were postictal (recovering from a seizure) were clearly not patients who should have received naloxone.

Is that because a competent assessment is better at diagnosing the presence of opioids?

That eliminates any reason for using naloxone diagnostically, doesn’t it?

Seizures can occur secondary to opioid use. Stroke/TIA (Transient Ischemic Attack) can also appear to respond to naloxone without any opioid consumption. Alcohol can respond to naloxone. Clonidine can respond to naloxone. These are not opioids.

Squirting naloxone in the veins, muscles, nares, tongue, . . . of every unconscious person does not diagnose the cause of unconsciousness.

This drug abuse (abuse of naloxone by EMS) may mislead us.

If we give naloxone to a person who had a seizure, the patient appears to respond, and we then decide to treat the patient as a drug addict, is there a possibility for harm to the patient? Aren’t we supposed to treat seizure patients for seizure, rather than for an imaginary drug overdose?

If we give naloxone to a person who had a stroke, the patient appears to respond, and we then decide to treat the patient as a drug addict, is there a possibility for harm to the patient?

All this is doing is teaching us, or reinforcing, bad diagnostic skills.

Aren’t we supposed to be doing just the opposite?

Science is only valid if there is a way of disproving the hypothesis. Anything that cannot be disproved is not science. This use of naloxone to diagnose is not science. This use of naloxone to diagnose is pseudoscience and needs to be opposed.

Pseudoscience kills.

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Footnotes:

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^[1] The Roots of Unfairness: the Black Swan in Arts and Literature
Nassim Nicholas Taleb
FooledByRandomness.com
Free PDF

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^[2] What’s the meaning of the expression, “That’s the exception that proves the rule?”
A Straight Dope Classic from Cecil’s Storehouse of Human Knowledge
Article

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Here is another 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 14.

Part I and Part II are Narcan Solves Riddle – Part I and Narcan Solves Riddle – Part II.

Heroin overdoses can be reversed with naloxone.^[1] This much is understood.

A reason for being aware of the effects of naloxone is that HOD (Heroin OverDose) is not always simple. Often the user does not know what he took. The mystery drug may have been sold to him as heroin, but there is not much quality oversight in the illegal drug trade. Many of the health problems related to heroin use actually come from adulterants mixed with what they inject as heroin. So the user may have injected what he thought was heroin. You may be told that he injected heroin. Although the patient may present with pinpoint pupils, respiratory depression, and altered mental status, the heroin might be a cocktail that only contains a little heroin, contains no heroin at all, or contains an opioid that does not respond to naloxone the way that heroin responds to naloxone.

At our poison control center, xylazine, an alpha-2 adrenergic agonist which may produce pupil constriction and somnolence mimicking heroin effects, has also been found as an occasional contaminant of heroin. Most recently, clenbuterol, a long-acting beta-2 adrenergic agonist, has again surfaced in an epidemic of unusual heroin overdoses with symptoms and signs including tachycardia, tremor, diaphoresis, and laboratory findings of hyperglycemia, hypokalemia, and lactic acidosis.[3] and [4] Additionally, quinine has been detected in the urine of heroin abusers presenting with tinnitus.^[2]

Heroin is readily available and relatively inexpensive; law enforcement officials and treatment providers believe that heroin may eventually overtake cocaine as the region’s greatest drug threat. The purity level of South American (SA) heroin, the predominant type available in the region, is relatively high but has been gradually decreasing over the past several years. Declining heroin purity has contributed to local abusers’ alternative methods of abuse, including injecting larger doses, injecting more frequently, or abusing heroin along with other drugs, such as fentanyl—practices that pose a greater risk of overdose and death.^[3]

Some of the other drugs that have been mixed with heroin, or substituted for heroin, are xylazine, clenbuterol, scopolamine, and fentanyl.

Naloxone has not been effective in reversing the sedation caused by xylazine in several reported cases.^[4]

The patient, a 27-year-old farmer, attempted to commit suicide by self-administration of about 75 mL 2% aqueous solution xylazine (Proxylaz/Atarost) by intramuscular injection as a consequence of a conflict situation in his family. He was found to be comatose with narrow pupils and no response to light and pain stimuli.

Naloxone was administered without effect.^[5]

Clenbuterol is a beta-2 agonist only for use in non-food animals. Xylazine is also not supposed to be used in animals that might be eaten by humans. It appears to have a narrow therapeutic window (the effective dose and toxic dose are very close together), since some of the reports to the FDA are for ineffectiveness, while many of the others are for death. These are reports of veterinary use.^[6]<

The examination of 12 morgue cases positive for clenbuterol (11% of the total number of drugrelated deaths during a 3 month period) showed that there were many other drugs in their systems.

Heroin use was confirmed in postmortem specimens from eight of the cases by the presence of 6-acetylmorphine. In each of the other four cases (cases 3, 4, 7, and 11), heroin use by the decedent is strongly supported by the presence of morphine with a documented history of heroin abuse. Multi-drug use was predominant with cocaine present in four cases, fentany present in three cases, ethanol and a benzodiazepine present in two cases, and methadone present in one case. With illicit drug users, many of whom use multiple drugs, it is often not possible to determine the contribution of each individual drug to the cause of death.^[7]

Clenbuterol is a a used for weight loss, muscle building, and performance enhancement – not that kind of performance enhancement. It is used to stimulate muscle growth and several athletes have admitted to using it to improve competitiveness. Probably not the goal of heroin addicts.

Clenbuterol is a drug that has a rapid onset, yet lasts several times longer than heroin. Patients in several states came to the hospital after the heroin wore off. Almost all had hypokalemia, hyperglycemia, palpitations, and tachycardia. Most were also hypotensive.^[8]

Other adulterants may be opioids that are much less responsive to naloxone. I prefer to give much smaller than standard doses of naloxone. Just enough for the patient to be breathing adequately and somewhat responsive to stimuli. I have no hope to engage in fascinating conversations, take long walks on the beach, or travel with them. I just intend to keep them from deteriorating, clinically.

The possibility of an overdose that requires more than the standard dose of naloxone is real. This is where some judgment has to be applied. If initial small doses of naloxone are ineffective, perhaps larger doses are indicated. The recent fentanyl/heroin overdoses have led to some patients receiving much higher doses of naloxone and still having significant respiratory depression. At that point, maybe even much earlier, you may want to just work on your airway management, any other symptoms (such as hypotension), consider that it might be something more than an overdose, and make him somebody else’s problem transport.

An epidemic of naloxone-resistant heroin overdoses due to fentanyl adulteration has led to significant morbidity and mortality throughout the central and eastern United States. According to records of the Philadelphia County Medical Examiner’s office, at least 250 overdose deaths have been associated with fentanyl between April 1, 2006, and March 1, 2007.^[9]

The DEA claims to have shut down production of nonpharmaceutical fentanyl, which may have been a large factor in these overdoses.^[10]

These were some cases where the adulterant was only a problem for the user. There are cases where the adulterant is a significant risk for the person administering naloxone. Part of the problem is the increase in the use of opioids that are not responsive to standard doses of naloxone. Not that putting a junkie into withdrawal is safe, but with adulterants there can be a toxic effect covered up by the sedating effects of a heroin overdose.

On March 16, 1995, eight persons were treated in the emergency department (ED) of a Bronx hospital for acute onset of agitation and hallucinations approximately 1 hour after “snorting” heroin. On physical examination, all these persons had clinical manifestations of anticholinergic toxicity (i.e., tachycardia, mild hypertension, dilated pupils, dry skin and mucous membranes, and diminished or absent bowel sounds); five had urinary retention. All were initially lethargic and became agitated and combative after emergency medical service (EMS) personnel treated them with parenteral naloxone, which is routinely used for suspected heroin overdose to reverse the toxic effects of opioids (e.g., coma and respiratory depression). All patients received diazepam or lorazepam for sedation, and signs and symptoms resolved during the next 12-24 hours.^[11]

Going from a nice coma to the agitated delirium of scopolamine overdose, in a matter of about a minute, is not my idea of fun. Even if it were, it might not be a popular idea with my partner, the police, or any other person on scene. While a lot of these were taking heroin nasally, not all of them were. Wrestling with someone who has a good chance of sharing hepatitis+ and HIV+ blood is not good risk management. Starting an IV to sedate that person, after wrestling with the person, is also something to be avoided. Sedating the person with a respiratory depressant that powerfully interacts with opioids only complicates matters. It is so much easier to just manage the airway.

–

Continued in Narcan Solves Riddle – Part IV.

–

Footnotes:

–

^[1] naloxone hydrochloride (Naloxone Hydrochloride) injection, solution
[HOSPIRA, INC.]
DailyMed
FDA label from DailyMed

–

^[2] Heroin: what’s in the mix?
Muller AA, Osterhoudt KC, Wingert W.
Ann Emerg Med. 2007 Sep;50(3):352-3.
PMID: 17709054 [PubMed – indexed for MEDLINE]

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^[3] Philadelphia/Camden High Intensity Drug Trafficking Area
Drug Market Analysis
DOJ (Department Of Justice)
Free PDF

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^[4] Systemic toxicity after an ocular exposure to xylazine hydrochloride.
Velez LI, Shepherd G, Mills LD, Rivera W.J
Emerg Med. 2006 May;30(4):407-10.
PMID: 16740450 [PubMed – indexed for MEDLINE]

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^[5] Severe intoxication with the veterinary tranquilizer xylazine in humans.
Hoffmann U, Meister CM, Golle K, Zschiesche M.J
Anal Toxicol. 2001 May-Jun;25(4):245-9. Review.
PMID: 11386637 [PubMed – indexed for MEDLINE]

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^[6] Adverse Drug Experience (ADE) Reports (SZ)
FDA Report on All drugs for July 7, 2008
Free PDF

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^[7] Detection of clenbuterol in heroin users in twelve postmortem cases at the Philadelphia medical examiner’s office.
Wingert WE, Mundy LA, Nelson L, Wong SC, Curtis J.
J Anal Toxicol. 2008 Sep;32(7):522-8.
PMID: 18713522 [PubMed – in process]

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^[8] Atypical Reactions Associated With Heroin Use — Five States, January–April 2005
MMWR (Morbidity and Mortality Weekly Report).
Vol 54, No 32;793;
Free Full Text . . . . Free PDF

The erratum link (near the top of the page, when you open either of these) works on the full text, but the PDF does not take you straight to the information.
This is the erratum information:

Erratum: Vol. 54, No. 32
In the report, "Atypical Reactions Associated With Heroin Use — Five States, January–April 2005,” an error occurred in the Figure. Among the 26 suspected, probable, or confirmed cases of heroin-related clenbuterol poisoning, the case with a date of exposure of March 14, 2005, occurred in New York, not in North Carolina.

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^[9] Heroin: what’s in the mix?
Muller AA, Osterhoudt KC, Wingert W.
Ann Emerg Med. 2007 Sep;50(3):352-3.
PMID: 17709054 [PubMed – indexed for MEDLINE]

This is the same footnote as footnote number 2.

–

^[10] Nonpharmaceutical Fentanyl-Related Deaths — Multiple States, April 2005–March 2007
MMWR (Morbidity and Mortality Weekly Report).
Vol 57, No 29;793;
Free Full Text . . . . Free PDF

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^[11] Scopolamine Poisoning among Heroin Users — New York City, Newark, Philadelphia, and Baltimore, 1995 and 1996
MMWR (Morbidity and Mortality Weekly Report).
Vol 45, No 22;457;
Free Full Text . . . . Free PDF

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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).

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Part III will be next week.

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Footnotes:

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^[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

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

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^[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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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 12.

So, why do we so often hear people say –

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

This is not based on any research, otherwise we would have some indication of the specificity, selectivity, or sensitivity of naloxone for the reversal of opioid drugs. Perhaps we should look at the information provided on the FDA label.

There are these sentences, but nothing to support their claim –

Naloxone is an essentially pure opioid antagonist, i.e., it does not possess the “agonistic” or morphine-like properties characteristic of other opioid antagonists. When administered in usual doses and in the absence of opioids or agonistic effects of other opioid antagonists, it exhibits essentially no pharmacologic activity.^[1]

A paragraph down from there and they admit –

While the mechanism of action of naloxone is not fully understood, in vitro evidence suggests that naloxone antagonizes opioid effects by competing for the mu, kappa, and sigma opiate receptor sites in the CNS, with the greatest affinity for the mu receptor.^[1]

The “mechanism of action of naloxone is not fully understood,” but they are willing to state that “When administered in usual doses and in the absence of opioids or agonistic effects of other opioid antagonists, it exhibits essentially no pharmacologic activity.”

Then they go on to describe its Adjunctive Use in Septic Shock.

Naloxone has been shown in some cases of septic shock to produce a rise in blood pressure that may last up to several hours;^[1]

Hmmm. I guess more than one person is responsible for the compilation of the drug label – and they are not allowed to communicate. To me, “exhibits essentially no pharmacologic activity,” would rule out any activity in septic shock, since septic shock is not a sequela of opioid intoxication. A “rise in blood pressure that may last up to several hours,” is not insignificant, regardless of its effect on survival. After all, some of naloxone’s effect on opioid overdose last about the same amount of time with standard IV doses. It would not surprise me to learn that this rise in blood pressure, a rise that last about as long as the expected pharmacologic activity, is an indication of pharmacologic activity.

Let’s go back and look at what they wrote about how it works –

While the mechanism of action of naloxone is not fully understood, in vitro evidence suggests that naloxone antagonizes opioid effects by competing for the mu, kappa, and sigma opiate receptor sites in the CNS, with the greatest affinity for the mu receptor.^[1]

After claiming that naloxone works exclusively to reverse the effects of opioids, they demonstrate that this is an illogical and ridiculous thing to assume. The words not fully understood and in vitro evidence suggests do not make a good case for certainty about the effects of naloxone. Then stating that it works, not on one, not on two, but on three different receptor sites in the CNS (Central Nervous System) – the mu (μ) receptor, the kappa (κ) receptor, and the sigma (σ) receptor.

the mu, kappa, and sigma opiate receptor sites in the CNS, with the greatest affinity for the mu receptor.^[1]

To suggest that a drug that has such broad effects does nothing other than reverse opioids, well that is just silly. We do not know all of the effects of naloxone. We do not know all of the effects of these receptors

Elsewhere they state, on the topic of Respiratory Depression Due to Other Drugs –

Naloxone is not effective against respiratory depression due to non-opioid drugs and in the management of acute toxicity caused by levopropoxyphene. Reversal of respiratory depression by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete or require higher doses of naloxone. If an incomplete response occurs, respirations should be mechanically assisted as clinically indicated.^[1]

If the FDA is consistent, no other drug should describe reversal of respiratory depression by means of naloxone. I did not wander this far, just to describe one case of the FDA being consistent. One of the well known uses of naloxone is to reverse respiratory depression and other effects of overdose with clonidine (Catapres, Durapres, and others).^[2]

Under Overdosage –

Naloxone may be a useful adjunct for the management of clonidine-induced respiratory depression, hypotension and/or coma; blood pressure should be monitored since the administration of naloxone has occasionally resulted in paradoxical hypertension.^[2]

Maybe they describe clonidine as an opiod?

Clonidine stimulates alpha-adrenoreceptors in the brain stem. This action results in reduced sympathetic outflow from the central nervous system and in decreases in peripheral resistance, renal vascular resistance, heart rate, and blood pressure.^[2]

No mention of mu, kappa, or sigma receptors appears anywhere – just alpha (α) adrenergic receptors in the brain stem to convince the body that it is already overstimulated adrenergically.

Naloxone 2.0 mg intravenously was administered with a rapid and dramatic improvement in the patient’s respiratory effort and rate to 16 breaths/min, regular without apnea. Assisted ventilation and oxygen were discontinued. There was a modest improvement in the patient’s level of consciousness, and an intact gag reflex was present after naloxone administration.^[3]

The largest known clonidine overdose and the most effective drug appears to be one that could not work, because clonidine is not an opioid. There is more to write about this, but it is now over 14 hours late for the NSR blog and there is already a lot here.

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Continued in Narcan Solves Riddle – Part II, Narcan Solves Riddle – Part III, and Narcan Solves Riddle – Part IV.

Some other naloxone posts I have written:

Needle Stick Regrets

The Joy of Naloxone (Narcan)

Ambulance Driver writes about naloxone in:

Naloxone: The Most Abused Drug in EMS

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Footnotes:

^[1] naloxone hydrochloride (Naloxone Hydrochloride) injection, solution
[HOSPIRA, INC.]
FDA label from DailyMed

There are 3 other FDA labels for naloxone.

The others are (the third one below appears to be identical to the one above, but links to a different page):

narcan (naloxone hydrochloride) injection
[Endo Pharmaceuticals Inc.] FDA label from DailyMed

naloxone hydrochloride (Naloxone Hydrochloride) injection
[INTERNATIONAL MEDICATION SYSTEMS, LIMITED] FDA label from DailyMed

naloxone hydrochloride (Naloxone Hydrochloride) injection, solution
[HOSPIRA, INC.] FDA label from DailyMed

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^[2] clonidine hydrochloride (clonidine hydrochloride) tablet
[Mutual Pharmaceutical Co., Inc.]
FDA label from DailyMed

A bunch of other formulations of clonidine are listed on this page from DailyMed.

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^[3] A 1000-fold overdose of clonidine caused by a compounding error in a 5-year-old child with attention-deficit/hyperactivity disorder.
Romano MJ, Dinh A.
Pediatrics. 2001 Aug;108(2):471-2.
PMID: 11483818 [PubMed – indexed for MEDLINE]

Free Full Text from Pediatrics

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