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

- Rogue Medic

Narcan Solves Riddle – Part I

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.

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

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

[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.

[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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Comments

  1. Well written and very interesting!

  2. ERP,Thank you. I hope that Part II (next Sunday) will be more persuasive.

  3. Narcan woke you up, so we know you took heroin (or another opioid).This is not based on any researchResearch has shown that giving narcan to opioid ODs makes them breathe again. Even reinvented, the wheel is still round.Many, many, many drug mechanisms of action are not fully understood.If you want only drugs around that “are fully understood”, you will have a VERY empty pharmacy.Hell, I don’t really care if the mech of action is an old wartnosed, pot stirring witch being channeled by the syringe. As long as it works…and it does.After all, some of naloxone’s effect on opioid overdose last about the same amount of time with standard IV doses.Not in my experience. IV narcan can’t hold a candle to a shitload of heroin as far as lasting effects go. Mu Kappa Sigma – I think I partied at their frat house once!

  4. 30 yr ff/pm,

    Giving naloxone to someone who took an opioid OD and having the person start breathing again is expected.

    Giving naloxone to someone, having them wake up, and concluding that they took an opioid is a mistake.

    We know that it works on opioids. We should also know that it works on other stuff. I will go over other things that naloxone works on, but that will be Part II.

    It does work on opioid ODs, but that does not mean that if it works, you took opioids is a logical conclusion. A response after giving naloxone to a patient, in an environment that makes you suspicious of opioid use, who has pinpoint pupils, respiratory depression, and altered mental status provides you with what information that you did not have before?

    Nothing.

    A response after giving naloxone to someone, who does not meet the above criteria, provides you with what information that you did not have before?

    Again, nothing.

    It may raise suspicions about a mixed OD, but that is raising further questions – not answering questions. Naloxone is not diagnostic.

    Some of the effects of naloxone last longer than the complete reversal of the opioid.

    Metabolism and EliminationNaloxone is metabolized in the liver primarily by glucuronide conjugation with naloxone-3-glucuronide as the major metabolite. In one study, the serum half-life in adults ranged from 30 to 81 minutes (mean 64 ± 12 minutes).

    http://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?id=4001&type=display

    That is the half life, so only about half of the drug is eliminated in that time. About half of what is left is eliminated over the next 30 to 81 minutes, if the reference is to be trusted. Some of the effects last the same amount of time as the effects on septic shock. I did not mean to suggest that IV naloxone will outlast an opioid that might have been taken. If these effects on septic shock last about as long as some effects of naloxone last, then it is not unreasonable to believe that they might be due to the naloxone.

    To conclude, as the author(s) of the label apparently did, that these effects can’t be drug effects from naloxone, because naloxone only works on opioids, would be a mistake.

    There is still a lot that we do not know about naloxone.

  5. very interesting, as always. I was watching an old episode of cops earlier in the week and they responded to an unresponsive, possible suicide. Anyway, the paramedics show up (start an EJ!!!) and push some narcan. the paramedic keeps asking “how much heroin did you do?”the suspect/patient, of course, denies using (go figure). then the paramedic says:”well thats interesting, because i just gave you a drug that reverses heroin and only heroin”and I laughed and thought of your post. either way, though, narcan is a great drug for us provders. if you think about ACLS guidelines, there are several drugs that are indicated as Class II or III yet we still give them…just because we can. Narcan, as you know, actually works, and is effective also on prescription overdoses, which I am starting to see more and more of (I run more opioid prescription OD’s than I do heroin OD’s)PS: why is my blog not one thats worth reading according to you?!? 😉

  6. VA FireMedic,I added you, but you are using logic similar to the logic concluding that since naloxone affects opioids dramatically – if naloxone affects something, the something must be an opioid.When a blog is in my list of blogs worth reading, that does mean that I think it is worth reading. If a blog is not on my list of blogs worth reading, that does not mean that the blog is not worth reading.Of course, the wink at the end suggests that you are aware of this and only kidding. 🙂

  7. Always giving us things to ponder…great post.

  8. Albinoblackbear,Thank you.

  9. Naloxone is not diagnosticNor does it need to be.When the pt is given narcan, and their condition improves, everything else from there on out is merely curiosity – not treatment IMO.This doesn’t mean I don’t try to get as much info as possible for the ED, but the hosp IS going to do a drug panel and they will find stuff that we couldn’t come up with no matter how much time we waste.ETOH OD’s can come up a little with narcan. The effect isn’t dramatic. Dextromethorphan responds to narcan but usually the effects of all the other shit in the cough/cold preps have screwed the pt up so bad, the DM isn’t a big deal. (poor mans PCP)

  10. 30 yr ff/pm said… “‘Naloxone is not diagnostic'” “Nor does it need to be.”I agree. I use it when appropriate, but I don’t claim that it is diagnostic. My posts are directed at those who do claim it is diagnostic. “ETOH OD’s can come up a little with narcan. The effect isn’t dramatic. Dextromethorphan responds to narcan but usually the effects of all the other shit in the cough/cold preps have screwed the pt up so bad, the DM isn’t a big deal. (poor mans PCP)”Thank you for supporting my point that other things do respond to naloxone. I have had one dramatic response to naloxone that may have been just alcohol. He refused, so the hospital refused to test the blood. He did not present as a typical opioid overdose, but medical command insisted he receive naloxone.

  11. Why does anyone think that Narcan is diagnostic? Do you get a syringe pin, just like a stork pin or a helicopter pin? A handcuffs pin for the ones who can’t get cop jobs? What about teaching medics to be smart? That would make too much sense.Narcan does work. When Narcan works that does not mean that heroin, or something similar, was taken. How hard is that to understand?

  12. first rule of fire,Nicely put. You should make some of those pins before Ambulance Driver corners the market on EMS apparel.

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  1. […] continues from Part I, Part II, and Part III. One of the problems with people claiming that naloxone is diagnostic, or […]

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