Clenbuterol

Heroin use typically produces a well-recognized syndrome of euphoria, miosis, and respiratory and central nervous system depression; cardiovascular effects are not a common finding. In January 2005, a man aged 21 years in New Jersey was hospitalized with an atypical reaction (e.g., tachycardia and palpitations) after reported heroin use. During the next 3 months, 25 additional persons in five states were reported to poison control centers (PCCs) and local public health agencies with a similar reaction after reported heroin use; in all, 24 of 26 patients were hospitalized. Analysis of drug specimens or testing of urine was performed in certain cases; in eight patients, the veterinary pharmaceutical clenbuterol was detected. This report describes four representative cases and summarizes the investigation by state and local health and law enforcement authorities and CDC into the 26 cases of atypical reactions after heroin use reported in five states (Connecticut, New Jersey, New York, North Carolina, and South Carolina) during January 28-April 17, 2005 (Figure). Unintentional or intentional adulteration of illicit drugs such as cocaine or heroin is an additional potential hazard associated with their use.

New Jersey

During January 28-February 2, 2005, nine cases of atypical reactions after heroin use were reported to the New Jersey poison Information and Education System (NJPIES). The reports originated from hospitals in four New Jersey counties. The reported route of exposure was intranasal in six patients, intravenous in two, and unknown in one. Tachycardia (89%), hyperglycemia (78%), palpitations (78%), and hypokalemia (78%) were the most common signs, symptoms, and laboratory findings; six patients (67%) had all four. In addition, multiple patients had nausea, hypotension, chest pain, venous hyperoxia, lactic acidosis, agitation, and anxiety.

Early in the investigation, cyanide was suspected as the adulterant responsible for the atypical reactions because several patients had venous hyperoxia and lactic acidosis. However, the uncharacteristic responses of the patients to antidotal therapy (i.e., sodium thiosulfate and sodium nitrite) for cyanide, presence of signs not typically associated with cyanide poisoning (e.g., hypokalemia), and negative cyanide levels made cyanide an unlikely etiology. Law enforcement personnel with the New Jersey State Police responded to the outbreak and tested samples of the heroin involved; the presence of clenbuterol, a [[beta].sub.2] adrenergic receptor agonist, was reported.

Information regarding the atypical reactions to heroin use was disseminated by NJPIES and local public health agencies to the general public, public health agencies in neighboring states, national toxicology organizations, and federal agencies. One patient reported atypical symptoms on multiple occasions after using heroin but only sought medical attention after seeing a flyer informing heroin users of suspected drug adulteration.

Case 1. The first reported patient was a man aged 21 years who went to the emergency department (ED) of a New Jersey hospital January 28, 2005, complaining of chest pain, palpitations, and shortness of breath, which had begun soon after intranasal exposure to what he believed was heroin. While in the ED, his highest recorded heart rate was 137 beats per minute (bpm), and his lowest recorded systolic blood pressure was 69 mmHg. On physical examination, the patient had tachycardia, tachypnea, pale skin, and mydriasis (dilated pupils). Laboratory studies revealed the following serum values: potassium, 2.2 mmol/L (reference range: 3.5-5.3 mmol/ L); glucose, 243 mg/dL (reference range: 65-115 mg/dL); C[O.sub.2], 13 mmol/L (reference range: 22-32 retool/L); an elevated anion gap; and an elevated lactate level (1). An electrocardiogram (ECG) revealed ischemic changes. The patient required intravenous fluid replacement, potassium supplementation, and an intravenous calcium channel blocker for persistent tachycardia. His laboratory, ECG, and vital sign abnormalities resolved during his 4 days in the intensive care unit. The patient left against medical advice on the fifth day of hospitalization with no apparent remaining impairments.

Case 2. A man aged 23 years visited the ED at the same New Jersey hospital on January 29, 2005, a day after the patient in case 1. The man had headache, nausea, palpitations, chest pain, and anxiety after intranasal exposure to heroin the night before. He had no known connection to the patient in case 1. While in the ED, he was tachypneic and hypotensive; he had a widened pulse pressure (120/48 mmHg) and was persistently tachycardic (120-122 bpm). He was noted to have agitation and mydriasis on physical examination. Laboratory serum values included potassium, 2.9 mmol/L, and blood glucose, 157 mg/dL. The patient was admitted to the intensive care unit and discharged from the hospital on the fifth day with no known impairments.

New York

Nine cases of atypical reactions to intranasally insufflated heroin were reported to the New York City Poison Control Center during February 5-March 14, 2005. Tachycardia (89%), palpitations (78%), chest pain (67%), and hypotension (56%) were the most common abnormal findings. Of the seven patients for whom potassium and glucose measurements were available, seven (100%) were hypokalemic, and five (71%) were hyperglycemic. Clenbuterol was detected in the urine by liquid chromatography mass spectrometry in four of the patients and ranged from 1.7 to 969 ng/mL. Testing for clenbuterol was not conducted on the other five patients.

Cases 3 and 4. A man aged 43 years and a man aged 29 years visited an ED on February 8, 2005, after intranasally insufflating heroin together. Both patients noted the heroin "smelled like vanilla." Within 15 minutes of exposure, both complained of palpitations, chest pain, and shortness of breath. After arrival in the ED, both patients were noted to be tachycardic, hypotensive, and tremulous. One patient complained of tinnitus, and the other complained of "ear throbbing." A mild leukocytosis, hypokalemia, and hyperglycemia were noted on the initial laboratory results for both men. Both patients were admitted to the hospital but left against medical advice.

North Carolina, South Carolina, and Connecticut

During February 19-22, 2005, two cases of suspected adulterated heroin exposure were reported to Carolinas Poison Center in North Carolina and two cases were reported to Palmetto Poison Center in South Carolina. In April, the Connecticut Poison Control Center received information on four more patients who had developed atypical reactions after using heroin. Five patients had intranasally insufflated the heroin, and three had injected it. All eight patients complained of palpitations with maximum heart rates of 120-141 bpm in the ED and were hypokalemic with serum potassium values ranging from 1.9-2.8 mmol/L. Six of the eight patients were noted as hypotensive in the ED. Seven patients had serum glucose testing performed, and all had results higher than 150 mg/dL. Urine from all four Connecticut patients tested positive for clenbuterol. A drug sample involved in one of the Connecticut cases was tested and was found to contain heroin, procaine, and clenbuterol.

Provisional Case Definition for Future Cases

To facilitate uniform reporting of future cases of heroin adulterated with clenbuterol, a provisional case definition (Box) was created by CDC, in coordination with PCCs and public health agencies involved with this investigation. Because the assay for clenbuterol is not available in the majority of laboratories, only eight of the 26 cases described in this report were confirmed; 16 cases were classified as probable and two as suspected.

Reported by: RS Hoffman, MD, LS Nelson, MD, GM Chan, MD, SE Halcomb, MD, NC Bouchard, MD, B Y Ginsburg, MD, New York City Poison Control Center; J Cone, MD, Y Jean-Francois, MD, S Voit, MSPH, New York City Dept of Health and Mental Hygiene. S Marcus, MD, New Jersey Poison Information and Education System, Newark. M Ford, MD, Carolinas Poison Center, Charlotte; C San ford, MSPH, North Carolina Dept of Health and Human Svcs. JE Michels, PharmD, WH Richardson, MD, Palmetto Poison Center, Columbia; LM Bretous, MD, South Carolina Dept of Health and Environmental Control. K Johnson-Arbor, MD, Connecticut Poison Control Center, Farmington. J Thomas, MD, Div of Laboratory Sciences, C Barthold, MD, M Belson, MD, M Patel, MD, J Schier, MD, A Wolkin, MSPH, C Rubin, DVM, Div of Environmental Hazards and Health Effects, National Center for Environmental Health; Z Duprey, DVM, EIS Officer, CDC

Editorial Note: Clenbuterol is a [[beta].sub.2] adrenergic receptor agonist with a rapid onset and long duration of action approved for limited veterinary use in the United States (2,3). Clenbuterol is also used illicitly as an alternative to anabolic steroids in humans and livestock because it can increase muscle mass (4,5). Most adverse health effects are related to its stimulation of [[beta].sub.2] adrenergic receptors and clinical manifestations, including hypokalemia, hyperglycemia, hyperlactemia, agitation, tachycardia, and hypotension (6). Adverse human health effects have been reported previously in a case of clenbuterol ingestion (7) and from ingestion of meat from livestock fed clenbuterol (3). However, the 26 cases described in this report are the first published accounts of poisoning from clenbuterol associated with reported heroin use.

Whether these cases represent adulteration of a single source of heroin before widespread distribution or adulteration of multiple sources is unknown. Also unclear is whether the substance used by each patient was heroin contaminated with clenbuterol or pure clenbuterol sold as heroin. The presence of adulterants in heroin is common. In some years, substances such as caffeine were detected in more than half of samples tested (8). Widespread poisoning secondary to adulterated heroin has occurred before as in the case of scopolamine-adulterated heroin reported in four states during the mid-1990s (9).

For various reasons, the 26 cases described in this report likely represent a fraction of actual cases of clenbuterol poisoning. Patients might not have medical evaluation for fear of legal repercussions. Passive reporting to public health agencies or PCCs might not have occurred because ED physicians, hospital intensivists, and the patients themselves might have presumed that the effects were related to a known coingestant. The identification of potential cases during the PCC record review process might have been limited by each center's database classification. The etiologic agent in suspicious cases might have been coded by using words other than "heroin" or "clenbuterol," such as "unknown drug" or "presumed coingestant."

Communication and cooperation among PCCs, EDs, CDC, and local public health agencies allowed for coordination of an appropriate response to the clenbuterol incidents. Local public health agencies and PCCs (available 24 hours a day at telephone 800-222-1222) should be notified of any case of suspected or known human exposure to an adulterated product. Early and rapid collaboration among local, state, and federal public health and law enforcement agencies might be necessary to identify, respond to, and minimize the effects of unintentional or intentional adulteration of substances used by the public.

Acknowledgments

This report is based, in part, on contributions from the New Jersey State Police, West Trenton; B Ruck, PharmD, Z Vassilev, MD, New Jersey Poison and Education System, Newark; E Bresnitz, MD, New Jersey Dept of Health and Senior Svcs. N Kim, PhD, P Smith, MD, New York State Dept of Health. D Drociuk, MSPH, South Carolina Dept of Health and Environmental Control. E Tan, MBBS, EIS Officer, CDC.

References

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(2.) Center for Veterinary Medicine, Food and Drug Administration. Update on illegal compounding of clenbuterol veterinary drug products. Rockville, MD: Food and Drug Administration; 2002. Available at http://www.fda.gov/cvm/cvm_updates/clenbut.htm.

(3.) Brambilla G, Cenci T, Franconi E et al. Clinical and pharmacological profile in a clenbuterol epidemic poisoning of contaminated beef meat in Italy. Toxicol Left 2000;114:47-53.

(4.) Prather ID, Brown DE, North P, Wilson JR. Clenbuterol: a substitute for anabolic steroids? Med Sci Sports Exerc 1995;27:1118-21.

(5.) Mitchell GA, Dunnavan G. Illegal use of [beta]-adrenergic agonists in the United States. J Anim Sci 1998;76:208-11.

(6.) Hoffman BB. Catecholamines, sympathomimetic drugs, and adrenergic receptor antagonists. In: Gilman AG, Hardman JG, Limbird LE, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 10th ed. New York, NY: McGraw Hill; 2002:215-68.

(7.) Hoffman RJ, Hoffman RS, Freyberg CL, Poppenga RH, Nelson LS. Clenbuterol ingestion causing prolonged tachycardia, hypokalemia, and hypophosphatemia with confirmation by quantitative levels. J Toxicol Clin Toxicol 2001 ;39:339-44.

(8.) Kaa E. Impurities, adulterants and diluents of illicit heroin. Changes during a 12-year period. Forensic Sci Int 1994;64:171-9.

(9.) CDC. Scopolamine poisoning among heroin users--New York City, Newark, Philadelphia, and Baltimore, 1995 and 1996. MMWR 1996;45:457-60.

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