A novel neuromuscular syndrome associated with clenbuterol-tainted heroin

Abstract

Background. Clenbuterol is a potent, long-acting β-adrenergic agonist that has been reported as an adulterant of heroin. We describe an atypical syndrome in five users of clenbuterol-tainted heroin. Methods. All cases were referred to a regional Poison Control Center. Urine and blood were analyzed using gas and liquid chromatography as well as mass spectrometry. Case Series. Five heroin users presented with a syndrome characterized by muscular spasm, tremor, hyperreflexia, and elevated serum creatine phosphokinase concentrations. All patients lacked findings of acute clenbuterol toxicity but tested positive for clenbuterol and negative for strychnine and a battery of common potential adulterants. Conclusions. We report five cases of a novel neuromuscular syndrome in users of clenbuterol-adulterated heroin. It is unclear whether these reactions represent an atypical response to clenbuterol or another unidentified contaminant.

Keywords:

• Disease outbreaks
• Toxins
• Opioids
• GC/MS
• Adverse effects

Introduction

Clenbuterol is a potent, long-acting β-adrenergic agonist used outside of the United States for the treatment of reactive airway disease in humans (1) and animals (2). Because of its unique β₃-adrenergic agonist effects, it is also used illegally by ranchers to increase the lean muscle mass of cattle (3). In addition, body builders use clenbuterol illicitly for its sympathomimetic, lipolytic, and anabolic effects (4–5). The oral dose of clenbuterol in human clinical trials has ranged from 0.75 to 1.0 mcg/kg, with effects on the bronchial smooth muscle persisting up to 8 h post-ingestion (6,7). By comparison, clenbuterol is about 100 times more potent than albuterol (6–8).

Clenbuterol toxicity is clinically similar to toxicity from other β-adrenergic agonists, and patients typically develop tachycardia, palpitations, hypotension, vomiting, hyperglycemia, and hypokalemia (9–14). Clenbuterol toxicity has been reported from ingesting the meat of clenbuterol-treated animals (9–11), intentional overuse in bodybuilders (5), and from adulterated heroin (12).

We describe a small epidemic of an atypical syndrome in five heroin users. Four of the patients presented to the same hospital on the same day and were likely exposed to the drug at approximately the same time. All patients' urine tested positive for clenbuterol and negative for strychnine and a battery of common adulterants.

Case reports

Case 1

A 47-year-old man injected heroin he had purchased from a new dealer. He subsequently developed diffuse muscle cramping that progressed in severity over 16 h prompting an ED visit. He had severe pain, agitation, and diaphoresis and appeared to have opisthotonos. Upon arrival, his vital signs were blood pressure, 140/84 mmHg; pulse, 105/min; respirations, 28/min; and temperature, 99.1°F. His head, neck, chest, and abdominal examinations were unremarkable. A neurological examination was limited because of agitation, but his mental status was clear and no focal motor deficits were noted. Initial laboratories were notable for potassium, 3.3 mEq/L; glucose, 129 mg/dL; and creatine phosphokinase, 5539 U/L. Troponin, serum electrolytes, and lumbar puncture were otherwise normal. To achieve adequate sedation, he required endotracheal intubation after receiving benzodiazepines and propofol. After sedation was achieved, the patient had intermittent spasms of his lower extremities, hyperreflexia, and clonus. Because of the presentation of muscle spasms after heroin use, both strychnine poisoning and tetanus were strongly suspected, and presumptive treatment for tetanus was begun with tetanus immune globulin and metronidazole. He remained intubated for 8 days secondary to concerns over tetanus and persistent muscle spasm, but he made a complete recovery. His urine and blood were negative for strychnine. Testing for clenbuterol revealed urine 206 ng/mL, blood 3.5 ng/mL, and cerebrospinal fluid (CSF) 1.9 ng/mL.

Case 2

A 40-year-old man with a history of opioid dependence on methadone maintenance therapy presented with nausea, vomiting, and bilateral spasmodic leg pain. He insufflated heroin 3 days prior to presentation. He reported that within 2 h of use, he noted the onset of these effects, and thereafter he developed crampy, diffuse muscle aches, and right-sided flank pain. The flank pain resolved prior to presentation. He stated that friends using the same sample had similar symptoms. On arrival, his vital signs were blood pressure, 128/77 mmHg; pulse, 96/min; respirations, 18/min; temperature, 97.8°F; and 98% oxygen saturation on room air. Physical examination was notable for moderate distress, akathisia, normal mental status, muscular spasms of both hamstrings, 4+ reflexes throughout, and clonus present in the knees and ankles. Laboratory studies were notable for potassium, 4.3 mEq/L; glucose, 113 mg/dL; calcium, 8.8 mg/dL; and creatine phosphokinase, 9734 U/mL. In the ED, there were two episodes of hamstring tetany and one episode of vomiting. He received intravenous midazolam (2 mg), ketorolac (30 mg), lorazepam (2 mg), and ondansetron (4 mg) and was subsequently admitted to the Medical Intensive Care Unit. Over the next 24 h, his creatine phosphokinase improved to 2398 U/mL and he was discharged home approximately 36 h after presentation. Results available subsequent to his discharge revealed that his urine assay sent on the date of admission was negative for strychnine. Testing for clenbuterol revealed a urine concentration of 234 ng/mL. Notably, heroin metabolites (morphine and 6-MAM) were absent.

Case 3

A 35-year-old woman with a history of mild asthma and substance abuse presented on the same day and to the same hospital as cases 2, 4, and 5. She insufflated heroin 2 days earlier and rapidly developed diffuse muscular pain and “spasms” involving the face, neck, arms, and chest. She stated that friends using the same sample had the same symptoms. In the ED, her vital signs were blood pressure, 144/75 mm/Hg; pulse, 80/min; respirations, 17/min; and temperature 98.5°F. Physical examination was notable for mild distress and anxiety, and 3+ reflexes without clonus. Laboratory studies were notable for potassium, 3.6 mEq/L; glucose, 111 mg/dL; calcium, 9.1 mg/dL; and creatine phosphokinase, 395 U/mL. In the ED, she received 1 L of normal saline and intravenous lorazepam (2 mg) with symptomatic improvement. She was discharged home with a prescription for oral benzodiazepines and scheduled outpatient follow-up. Subsequent urine testing was negative for strychnine, but positive for clenbuterol at 38 ng/mL, morphine, 6-MAM, and codeine. No further follow-up information is available.

Case 4

Following personal consultation with the poison center, this patient was asked to present to the ED but would not have sought medical care otherwise. He was a 33-year-old man who both sold and was known to have used the same heroin as patients 2 and 3. He complained of the onset of palpitations, “shaking,” and muscle tightness involving the face, neck, and shoulders within minutes after insufflating heroin. In the ED, his vital signs were blood pressure, 128/66 mm/Hg; pulse, 84/min; respirations, 18/min; temperature 100.1°F; and 97% oxygen saturation on room air. Physical examination was normal except for mild upper extremity resting tremor, and 3+ reflexes without clonus. He refused serum laboratory studies but was willing to submit his urine for testing. In the ED, he received oral lorazepam (0.5 mg) and left against medical advice. Subsequent urine testing was negative for strychnine, but positive for morphine, 6-MAM, and clenbuterol at 351.4 ng/mL.

Case 5

A 45-year-old man complained of the onset of nausea, vomiting, and leg shaking that began within 5 min of insufflating one bag of heroin 2 days previously. He presented to the same hospital on the same day as cases 2–4 but did not have any knowledge of their presentation with respect to his own. His complaints were still present at the time he sought medical attention. In the ED, his vital signs were blood pressure, 102/72 mm/Hg; pulse, 89/min; respirations, 18/min; temperature 97.9°F; and 96% oxygen saturation on room air. Physical examination was notable for mild distress and anxiety, and 4+ reflexes with ankle clonus. Laboratory studies were notable for potassium, 5.8 mEq/L; glucose, 133 mg/dL; calcium, 8.5 mg/dL; and creatine phosphokinase, 296 U/mL. He left against medical advice prior to receiving any treatment. Subsequent urine testing was negative for strychnine but positive for clenbuterol at 25.9 ng/mL, as well as for morphine, 6-MAM, and codeine.

Analytical methods

Urine, blood and CSF were sent for additional analysis to the Medical Examiner. Urine was screened by enzyme immunoassay (EI) for benzodiazepines, opiates, cannabinoids, amphetamines, barbiturates, and benzoylecgonine. Urine was tested quantitatively for strychnine using gas chromatography–mass spectrometry (GC/MS). Blood and urine were tested quantitatively for clenbuterol and heroin metabolites using liquid chromatography–mass spectrometry (LC/MS). Using a comprehensive GC/MS urine screen, we excluded 84 potential adulterants and metabolites including (but not limited to) amphetamines, benzoylecgonine, caffeine, chloroquine, cocaine, dextromethorphan, nicotine, phencyclidine, phenothiazines, pseudoephedrine, strychnine, and tricyclics.

Discussion

The patients in the present case series suffered from a previously undescribed neuromuscular syndrome characterized by muscle spasm and hyperreflexia which lasted from two or three to possibly up to 8 days. All were associated with urine clenbuterol concentrations ranging from 25.9 to 351.4 ng/mL. Although clenbuterol was previously associated with muscle tremor and myalgia in outbreaks of contaminated beef (9–11), tetany, muscle spasm, and hyperreflexia were not previously reported. The differential diagnosis of muscular spasms in heroin users includes tetanus, adulterant toxicity (such as strychnine, caffeine, amphetamines, and phencyclidine), extrapyramidal side effects from concomitant medication use or adulterants (e.g., dystonic reaction from an adulterant), opioid withdrawal, electrolyte abnormalities (e.g., hypocalcemia), and serotonin syndrome.

Strychnine causes muscle spasm and opisthotonos (15), and has been identified as an adulterant of heroin (16). Strychnine acts via competitive antagonism of the inhibitory neurotransmitter glycine on the post-synaptic spinal cord motor neuron (17). The absence of strychnine in any of the urine specimens excludes strychnine toxicity. However, a structurally related, strychnine-like toxin such as brucine cannot be excluded as a cause.

Tetanus is a complication of injection drug use, particularly “skin-popping” or intramuscular injection, and is due to clostridial infection (18–19). The clostridial organism typically becomes established in a wound (e.g., “skin-popping” site), where it elaborates a toxin that is transported retrogradely along motor nerves into the spinal cord or brainstem. The toxin is also disseminated through the bloodstream to skeletal muscle, where it gains additional access to motor nerves. The tetanus toxin itself interferes with the release of the inhibitory neurotransmitter glycine, resulting in motor nerve hyperactivity and autonomic disinhibition (20–21). The syndrome of heroin-associated tetanus is clinically similar to conventional tetanus, and masseter spasm is the most common initial symptom with a median onset of 7 days (22). The lack of an appropriate incubation period, combined with the variable routes of exposure (intranasal in 4 out of 5 cases), absence of masseter spasm, and short clinical course, makes tetanus a highly unlikely explanation for the clinical syndrome of the present case series.

Dystonia is also an unlikely explanation for the patients' clinical presentation. The onset of symptoms after exposure was too rapid (within minutes), and the duration of symptoms was too long (up to 8 days). Additionally, the comprehensive drug screen using GC/MS excluded many drugs that typically cause dystonia, such as antipsychotics and phenothiazines.

The neuromuscular effects of clenbuterol poisoning are likely mediated via either direct β-adrenergic stimulation or an indirect sequela of β-adrenergic agonism (e.g., hypokalemia). The neuromuscular syndrome in the present case series may simply represent a severe or exaggerated manifestation of clenbuterol poisoning. Clenbuterol is extremely potent (8), and when added to heroin as an adulterant, the dose is uncontrolled. In the setting of β₂-agonist therapy, reversible myopathy (23) and elevations of plasma creatine phosphokinase (24) have previously been reported. Alternatively, the effects described may be the results of massive β₃-adrenoceptor agonism. However, the lack of significant electrolyte abnormalities in the present cases is a surprising finding in light of previous reports of clenbuterol poisoning that demonstrate clinically significant hypokalemia (5,9–11), hypomagnesemia (13), and hypophosphatemia (13). Although the syndrome described in the present case series has never been reported, our data suggest that either the above explanation for clenbuterol-associated myalgia is incorrect or that the neuromuscular syndrome described here was actually caused by another occult adulterant.

Previously, Brambilla and colleagues (10) measured urine clenbuterol concentrations from an Italian outbreak of clenbuterol poisoning due to contaminated meat. In their epidemiologic study, the median urine concentration was 13 ng/mL in nine hospitalized patients, and all but one patient had a urine concentration below 25 ng/mL. There was no statistically significant difference in the median urine concentration after 48 h (10). In contrast, all patients in the present case series had urine clenbuterol concentrations greater than 25 ng/mL. While a dose–response analogy using urine concentration is tempting to consider, it is difficult to equate urine concentration to dose of exposure. Nevertheless, relevant clinical characteristics of all five patients in descending order of urine clenbuterol concentrations are summarized in Table 1.

Table 1.  Clinical characteristics of five heroin users in descending order of urine clenbuterol concentration

Urine clenbuterol concentration (ng/mL)	Age	Sex	TRGS	Symptom duration (days)	CPK (U/mL)	Case no.
351	33	M	3+	Unknown	Refused	4
234	40	M	4+	3	9,734	2
206	47	M	4+	8^a	5,539	1
38	35	F	3+	2	395	3
26	45	M	4+	2	296	5

CPK, plasma creatine phosphokinase; TRGS, tendon reflex grading scale.

^aCase 1 remained endotracheally intubated for 8 days secondary to concerns over tetanus and persistent muscle spasm.

Unfortunately, the etiology of the neuromuscular syndrome associated with clenbuterol-tainted heroin described in the present case series remains unclear. We excluded 84 other common adulterants (25–26) found in heroin that conceivably may cause muscle spasms (such as strychnine, cocaine, amphetamines, and phencyclidine), by comprehensive GC/MS and LC/MS. Clinically significant serotonin syndrome was not apparent due to the absence of hyperthermia or autonomic instability. It also seems to be a less likely explanation for the constellation of symptoms given the lack of serotonergic drugs detected in the comprehensive urine screens [dextromethorphan and metabolites, selective serotin uptake inhibitors (SSRIs), meperidine, etc.]. Furthermore, a dystonic reaction is unlikely given the negative comprehensive drug screen which excluded many drugs that typically cause dystonia.

Limitations

Some limitations of our data set must be considered. The lack of serum clenbuterol concentrations in all but one case limits the ability to draw more direct conclusions about a potential causal relationship between clenbuterol exposure and severity of symptoms. The absence of morphine, a heroin metabolite, in the urine of case 2 calls into question the history of exposure to heroin, but the product used may have been pure clenbuterol. Furthermore, since there was no product available for primary analysis, we cannot definitively identify adulterated heroin as the source of clenbuterol. Despite these limitations, the presence of clenbuterol in the urine of all subjects is proof of exposure, and onset of symptoms for all subjects was temporally associated with illicit use of a substance presumed (incorrectly) to be pure heroin.

Conclusion

We reported five cases of a novel neuromuscular syndrome in users of clenbuterol-adulterated heroin. All patients tested positive for clenbuterol and negative for strychnine and a battery of common adulterants. It is unclear whether these reactions represented an atypical response to clenbuterol or were due to another unidentified toxin.