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

- Rogue Medic

Narcan Solves Riddle – Part III


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.


[1] naloxone hydrochloride (Naloxone Hydrochloride) injection, solution

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]

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

[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]

[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]

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

[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]

[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.

[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

[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