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Fatal intracranial hemorrhage associated with phenylpropanolamine, pentazocine, and tripelennamine overdose
The Joumai of Emergency Medune,
Vol 3, pp 127-I 32. 1985 PrInted m the USA ??CopyrIght
:
1985 Pergaman PressLtd
FATAL INTRACRANIAL HEMORRHAGE ASSOCIATED WITH PHENYLPROPANOLAMINE, PENTAZOCINE, AND TRIPELENNAMINE OVERDOSE Cary Jackson,
MD,*
Avery Hart, MD,t
and Mel D. Robinson,
MD*
‘Captain, MedIcal Corps, Department of Internal Medicine, Holloman Au Force Base Hospital, Alamogordo, New Mexico; tcaptaln, Department of Internal Medlclne, Torrejon Air Force Base Hospital. Madrld, Spaln and $Captaln, MedIcal Corps, Department of Emergency Medlclne. Madigan Army Medical Center, Tacoma, Washington Reprint address, Cary Jackson, MD, Holloman AFB Hospital, Holloman AFB. NM 88330
0 Abstract-Hemorrhagic cerebrovascular accident is an uncommon but serious complication of drug overdose. A case of fatal intracranial hemorrhage following overdose with phenylpropanolamine, pentazocine, and tripelennamine is presented. The pharmacology, pathophysiology, clinical presentation, and management of poisoning by these agents are discussed. 0 Keywords-intracranial hemorrhage; phenylpropanolamine; pentazocine; tripelennamine; amphetamine
Introduction Changing patterns of drug abuse present new clinical problems to physicians. Neurologic complications from the abuse of phenylpropanolamine and of the combination of pentazocine and tripelennamine are now being recognized more frequently. We report a case of fatal intracranial hemorrhage associated with abuse of these drugs in combination.
~ xzxz==
Case Report A 30-year-old man, brought to the emergency department (ED) in a coma, had been in good health until the night of admission. History obtained from his wife revealed that he had regularly abused a variety of drugs. These included pentazotine and tripelennamine (“T’s and Blues”), over-the-counter diet pills, cocaine, and marijuana. He had not used cocaine during the past four days. His last diet pill, an extended-release capsule of phenylpropanolamine (PPA) 75 mg and caffeine 200 mg, (Dexatrim Extra-Strength) was reported 20 hours before onset of neurologic symptoms. Over the six hours before admission, the patient and his wife split a total of five sets of “T’s and Blues,” each set consisting of one 50 mg pentazocine tablet and one 50 mg tripelennamine tablet crushed and injected intravenously. About 30 minutes after the last set, the patient vomited and complained of right-hand pain
Toxicology -one of the most critical and challenging areas confronting the emergency department staff-is coordinated by Kenneth Kulig, MD, of the Rocky Mountain Poison Center.
RECEIVED:27 November 1984; ACCEPTED:15 February 1985 0736-4679/85 $3.00 + .OO 127
128
Cary Jackson, Avery Hart, and Mel D. Robinson
and numbness. Shortly thereafter, he became unresponsive. On arrival at the ED, the patient was opisthotonic and profusely diaphoretic, with blood pressure of 200/120 mm Hg. Supraventricular tachycardia at 200 beats per minute, respiratory rate of 40 breaths per minute, and rectal temperature of 103.3”F were noted. The pupils were dilated and reactive to light. Fundoscopic exam revealed no hemorrhages, exudates, or papilledema. Cornea1 and oculovestibular reflexes were intact. While in the ED, he displayed opisthotonic, decorticate, and decerebrate posturing. Deep tendon reflexes were markedly hyperactive, with upgoing Babinski reflex bilaterally. The physical examination was otherwise unremarkable except for needle tracts on the upper limbs. Arterial pH was 7.22; pCO*, 20; and pOZ, 180 on supplemental oxygen. Serum glucose was 530 mg/dL (after administration of dextrose 50070, 50 mL). Serum creatinine was 1.8 mg/dL. Serum electrolytes were sodium 133, potassium 4.7, chloride 100, bicarbonate 14 mEq/L, calcium 7.7 mg/dL, magnesium 2.2 mg/dL, and phosphorus 3.3 mg/dL. The WBC was 28,000/~, with 43% hematocrit. Specimens were sent for toxicology analysis. Immediate nasotracheal intubation was accomplished. Initial intravenous medications included 50 cc of 50% dextrose, 2 mg naloxone, 1 mg propanolol, and 5 mg diazepam. The opisthotonic posturing ceased, pulse rate decreased to 110 beats per minute, and blood pressure fell to 160/90 mm Hg. Gastric lavage revealed no pill fragments. Charcoal and magnesium citrate were given per lavage tube. An emergency computed tomography (CT) scan of the head without contrast showed no abnormalities. The patient was admitted to the intensive care unit, where recurrent opisthotonus was treated with diazepam. His blood pressure remained stable at 160/90. The following morning the patient’s neurologic status acutely deteriorated. Repeat neurologic exam revealed the pupils to be mid-position and nonreactive. Pupillary,
cornea& oculocephalic, and oculovestibular reflexes were all absent, as were deep tendon reflexes. A second CT scan of the head revealed hyperdense areas in the left frontal and temporal areas consistent with intraparenchymal hemorrhage (Figure 1). Serial neurologic examinations over 48 hours showed no change. Spontaneous respirations were absent and a radionuclide brain scan revealed no flow. The patient was declared brain dead. Autopsy revealed intracranial hemorrhage from several sites. Intraparenchyma1 blood was found in the left frontal and temporal lobes, in both hypocampi, both internal capsules, in the putamina and pallidum, and also in the pons, midbrain, and medulla. There was also blood in the subarachnoid space and cisterna magna. The left uncus was herniated with a 2.0-cm acute hemorrhagic infarct. Results of toxicologic analysis of specimens taken at autopsy were normal. Urine (from admission) analyzed by the enzyme-multiplied immunoabsorbent technique (EMIT, Syva) revealed amphetamines. This method does not distinguish between several sympathomimetics including phenylpropanolamine, pseudoephedrine, ephedrine, and amphetamines. The EMIT test finding for opiates was negative. However, this method detects only natural and semisynthetic opiates and meperedine; it does not detect pentazocine. Gastric aspirate from admission contained pentazocine 8.2 pg/mL, tripelennamine 2.0 pg/mL, salicylate 13Opg/mL, and lidocaine 96 kg/mL (after intubation using a lubricant containing lidocaine). No other drugs were detected.
Discussion When pentazocine was released in 1969, it was promoted as an opiate analgesic with low potential for addiction because of its mixed agonist-antagonist properties. By 1978 heroin addicts in Chicago and other midwestern cities had discovered that pentazocine could serve as an acceptable substitute for heroin when injected with tripel-
Overdose
with Intracranial
Hemorrhage
Figure 1. CT scan without contrast reveals hyperdense with intracerebral hemorrhage.
ennamine. This combination is known on the street as “T’s and Blues.” “T” stands for Talwin. “Blues” stands for the blue Pyrenzamine (tripelennamine) tablet. These drugs are cheaper and more available than heroin. Parenteral abuse of pentazocine has dramatically increased since 1974.’ The most common side effect of pentazocine is sedation, followed by sweating and dizziness. Psychologic side effects include hallucinations, depression, and psychosis. In contrast to many opiates, pentazocine causes increases in blood pressure and heart rate, associated with rises in plasma epinephrine and norepinephrine. Pentazocine is primarily metabolized in the liver. Products of oxidation of terminal methyl groups and glucuronide conjugation are then excreted in the urine. These glucuronide conjugates will often be missed in routine urine drug screens unless a glucuronide enzyme is added to the specimen.2.3 The antihistamine tripelennamine has been previously known as “blue velvet” on the streets. When crushed and injected in-
left frontal and temporal areas consistent
travenously, it prolongs and intensifies the euphoria of pentazocine. Tripelennamine can depress or stimulate the central nervous system. In patients with focal neurologic lesions, even small doses can precipitate seizures. In overdose, there is usually a phase of CNS depression followed by excitement and culminating in seizures. The simultaneous injection of tripelennamine with pentazocine greatly increases the frequency of this complication, although seizures have been reported with pentazocine alone. Use of a one-to-one ratio of pentazocine and tripelennamine, rather than the usual twoto-one ratio, further increases the risk of seizures.3m5 Caplan reported a series of 13 patients with CNS complications resulting from “T’s and Blues” addiction.” Seizures, CNS infections, and stroke were identified, with one patient having multiple areas of cerebral infarction and intracranial hemorrhage. Microcrystalline cellulose and talc are the insoluble binders in pentazocine and tripelennamine tablets. Intravenous injec-
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Cary Jackson, Avery Hart, and Mel D. Robinson
tion of these binders can cause extensive embolic damage to vessels in the lung, liver, kidneys, endocardium, and brain. Complications of embolization include angiothrombosis of pulmonary arterioles leading to pulmonary infiltrates. Severe skin and muscle damage may occur if “T’s and Blues” are injected subcutaneously or intramuscularly.7-9 The treatment of “T’s and Blues” overdose is primarily supportive. Large doses of naloxone may be required to reverse the sedation of pentazocine overdose, approximately 1 mg for every 350 mg of pentazocine.‘O Signs of neurologic toxicity persisting after naloxone administration may be secondary to anticholinergic effects of tripelennamine.” Tripelennamine-induced seizures are best treated with phenytoin and by avoiding other anticonvulsants which may cause CNS depression.4 Physostigmine in doses of 0.5 mg to 2.0 mg may be used as a last resort, but is associated with a significant incidence of seizures and cardiac dysrhythmia. I2 Phenylpropanolamine (PPA) is a sympathomimetic amine structurally resembling amphetamine and ephedrine. First sold over the counter as a decongestant and then as an appetite suppressant, PPA is now widely used by a certain segment of the population as a stimulant. Reflecting these trends, the frequency of PPA involvement in poison control case reports rose tenfold from 1975 to 1980.13 Hypertensive crisis can result from even a single therapeutic dose of PPA.14 The hypertensive effect may be potentiated by a variety of other drugs including monoamine oxidase inhibitors, ephedrine, caffeine, anticholinergic drugs, antihistamines, nonsteroidal anti-inflammatory drugs, and antihypertensives.‘5-23 Hemorrhagic stroke associated with PPA has been reported in four cases. In two cases, neither of which was fatal, PPA was ingested a10ne.24,25In two fatal cases, PPA was ingested with caffeine and ephedrine.ls Nonhemorrhagic stroke and transient ischemic neurologic deficit have been reported.26 Other complications of PPA poison-
ing include arrhythmias, psychosis, seizures, and myocardial infarction.27-36 Intracranial hemorrhage has also been reported with oral and intravenous amphetamines and with pseudoephedrine.37-39 All of these sympathomimetic drugs in overdose can cause hypertension, tachycardia, tremor, arrhythmias, seizures, and coma. Sympathomimetic poisoning is treated with gastric emptying, charcoal ingestion and catharsis followed by supportive care. Intravenous propranolol has been found to be effective in controlling the tachycardia and hypertension of acute overdose, although nitroprusside may be necessary. Seizures are treated with diazepam. Acidification of urine will accelerate clearance, but entails additional risks such as precipitation of myoglobin in the kidneys with minimal clinical benefit. Dialysis is not effective owing to the large volume of distribution of these drugs. To our knowledge, there is no data on hemoperfusion.40-42 Stroke as a complication of drug abuse can occur from ischemic infarction, intracerebral hemorrhage, or subarachnoid hemorrhage.43 Proposed mechanisms of injury include (1) direct toxic injury, (2) pharmacologic alteration of vascular function, e.g., vasospasm or severe hypertension (3) embolization of foreign material and adulterants such as the microcrystalline cellulose of “T’s and Blues,” (4) immunogenic vasculitis, and (5) endocarditis with secondary embolization. Although the mechanism in our particular patient may have been multifactorial, his severe hypertension following the injection of “T’s and Blues” and the ingestion of PPA and caffeine probably played a major role. And although the patient’s last ingestion of PPA was the night before admission, it was reportedly an extended-release preparation. The patient had sympathomimetic drugs in his urine on admission. As previously mentioned, the hypertensive effect of PPA appears to be potentiated by a variety of drugs. In this patient the combination proved to be fatal. The drugs taken by this young man have become widely available, popular drugs of
Overdose
with Intracranial
131
Hemorrhage
abuse. In an attempt to decrease pentazotine abuse, Winthrop Laboratories reformulated its Talwin-50 tablets by adding 0.5 mg of naloxone to each tablet.44 Naloxone is fully metabolized on the first pass through the liver, so tablets taken orally remain efficacious. When crushed and injected, the tablet should, in principle, have little or no opiate effect owing to antagonism between the naloxone and the pentazocine. Repeated requests from toxicologists for withdrawal of phenylpropanolamine from overthe-counter diet aids have not met with success.45-48 We add to the reports of neurologic complications of drug abuse, this case of fatal intracranial hemorrhage in a young man
who had taken phenylpropanolamine and caffeine followed by pentazocine and tripelennamine. Toxic effects of these groups of drugs may present with similar clinical features, including fever, tachycardia, hypertension, diaphoresis, and mydriasis. Serious neurologic complications resulting from abuse of these drugs include seizures, coma, CNS infections, and stroke. Cerebrovascular accidents may occur from infarction, intraparenchymal hemorrhage, or subarachnoid hemorrhage. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the Department of Defense.
REFERENCES I Lahmeyer HW, Steingold RG: Pentazocine and tripelennamine: Drug abuse epidemic? Int .I Addict 1980; 14:1219-1232. 2. Bragden RN, Speight TM, Avery GS: Pentazocine: A review of its pharmacologic properties, therapeutic efficacy, and dependence liability. Drugs 1973; 5:6-91. 3. Lahmeyer HW, Steingold RG: Medical and psychiatric complications of pentazocine and tripelennamine abuse. JClin Psvchiafrv _ _ 1980: 41:275278. 4. Iserson KV, Hackney HU: Antihistamines, in Haddad LM, Winchester JF (ed): Clinical Management of Poisoning and Drug Overdose. Philadelphia, WB Saunders, 1983, pp 504-507. 5. Showalter CV: T’s and blues. JAMA 1980; 244: 1224-1225. 6. Caplan LR, Chanamma T, Banks G: Central nervous system complications of addiction to “T’s and blues”. Neurology (NY) 1982; 32:623-628. 7. Jomashefski JF, Hirsch CS, Jolly ON: Microcrystalline cellulose pulmonary embolism and granulomatosis. Arch P&ho/ Lab Med 1981; 105:8993. 8. Houck RJ, Bailey G, Garoca P, et al: Pentazotine abuse. Chest 1980; 77:227-230. 9. Butch AJ, Yokel R, Siegel1 L, et al: Abuse and pulmonary complications of injecting pentazocine and tripelennamine tablets. C/in Toxicol 1979; 14: 301-306. 10. Hatano S, Keane DM, Wade MA, et al: Naloxone reversal for anesthetic doses of pentazocine. Anesrh Rev 1975; 2~1 l-60. Il. Kulig K, Rumack B: Amphetamines, in Haddad LM, Winchester JF (ed): ClinicalManagemenf of Poisoning and Drug Overdose. Philadelphia, WB Saunders, 1983, pp 504-507. 12. Easom JM, Lovejoy FH: Opiates, in Haddad LM, Winchester JF (ed): ClinicalManagement of Poi-
13.
14.
15.
16.
17.
18. 19.
20. 21. 22.
23.
24.
Toning and Drug Overdose. Philadelphia, WB Saunders, 1983, pp 504-507. PPA and weight control products. Na// Clearing House for Poisoning Control Centers Bulletin 1981; 25:16-20. Horowitz JD, Howes LG, Christophidis N, et al: Hypertensive responses induced by phenylpropanolamine in anorectic and decongestant preparations. Lancer 1980; 1:60-61. Cathbert MF, Greenberg MP, Morley SW: Cough and cold remedies: A potential danger to patients on monoamine oxidase inhibitors. Br Med J 1969; 1:404-406. D’Mallo A: Interaction between phenylpropanolamine and MAO inhibitors. J Pharm Pharmacol 1969; 21:577-580. Smookler S, Bermerdez AJ: Hypertensive crisis resulting from an MAO inhibitor and an over the counter appetite suppressant. Ann Onerg Med 1982; 11:482--484. Bernstein E, Distant BM: PPA: A potentially hazardousdrug.AnnEmergMed1982; 11:311-315. Pentel P, Mike11 F: Reaction to phenylpropanolamine/chlorpheniramine/belladonna compound in a woman with unrecognized autonomic dysfunction. Lancer 1982; 1:274. Ostern S, Dodson WH: Hypertension following ornade ingestion. JAMA 1965; 194:472. Salmon PR: Hypertensive crisis with estornadel. Br J Med 1965; 1: 193. Lee KY, Beilin LJ, Vandougen R: Severe hypertension after ingestion of an appetite suppressant (phenylpropanolamine) with indomethacine. Lancet 1979; 2:1110-1111. McLaren EH: Severe hypertension produced by interaction of phenylpropanolamine with methyl dopa and oxprenolol. Br JMed 1976; 2:283-284. King J: Hypertension and cerebral hemorrhage after trimolets ingestion. Med J Aust 1979; 2:258.
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25. Elliot CF, Whyste JC: Phenylpropanolamine hypertension. Med J Aust 1981; 1:715.
and
26. Johnson DA, Etter RC, Reeves PM: Stroke and phenylpropanolamine use. Lancer 1983; 2:970. 27. Kane FJ, Green BQ: Psychotic episodes associated with the use of common proprietary decongestants. Am J Psych 1966; 123:484-487. 28. Wharton BK: Nasal decongestants and paranoid psychosis. Br J Psych 1970; 117:539-540. 29. Nouvenias 0, Widerlov E, Lennerholm G: PPA and mental disturbances. Lancet 1979; 2:13671368.
30. Reocamp P: Convulsive seizures due to phenylpropanolamine. JMed Sot NJ 1979; 76:591-592. 31. Merdler SM, Solon EB: Seizures associated with a combination “pick-me-up” pill. Ann Neural 1982; 10:322.
32. Howie DL, Wolfson JH: PPA induced hypertensive seizures. J Peds 1983; 102:143-145. 33. Peterson RB, Vasques LA: Phenylpropanolamine induced arrhythmias. JAMA 1973; 223:324. 34. Rumack BH, Anderson BH, Wolf JH, et al: Ornade and anticholinergic toxicity: Hypertension, hallucinations, and arrhythmias. C/in Tax 1984; 7:573-581. 35. Chouinard 0, Ghadirim AM, Towere BD: Death attributed to ventricular arrhythmia induced by thioridazine in combination with a single Contact capsule. Can Med Assoc J 1978; 119:729-731. 36. Pentel PR, Mike11FL, Zavoie JH: Myocardial injury after phenylpropanolamine ingestion. Br Heart J 1982; 47:51-54.
37. Olsen ER: Intracranial hemorrhage and amphetamine usage. Angiology 1977; 28:464-471.
38. Delaney P, Estes M: Intracranial hemorrhage with amphetamine abuse. Neural 1980; 30: 1125-l 128. 39. Loizov LA, Hamilton JG, Jsementzis SA: Intracranial hemorrhage in association with pseudoephedrine overdose. J Neurol Neurosurg Psychiatry 1982; 451471-472. 40. Keaton BF: Sympathomimetic
medication and phenylpropanolamine, in Haddad LM, Winchester LF (ed): Clinical Management of Poisoning and Drug Overdose. Philadelphia, WB Saunders, 1983, pp 868-875. 41. Goldfrank LR, Kirstein R: Amphetamines, in Goldfrank LR, Flomenbaum NE, Lewin NA, Weisman RS (ed): Toxicologic Emergencies (2nd Ed). New York, Appleton-Century-Crofts, 1982, pp 117-123. 42. Litovitz T: Amphetamines, in Haddad LM, Winchester JF (ed): Clinical Management of Poisoning and Drug Overdose. Philadelphia, WB Saunders, 1983, pp 469-474. 43. Caplan LR, Hier PB, Banks G: Current concepts of cerebrovascular disease: Stroke and drug abuse. Stroke 1982; 13:869-872. 44. Carlson C: Talwin-50 reformulated to overt “T’s and blues” abuse. JAMA 1983; 249:1689. 45. Blum A: PPA-an over-the-counter amphetamine. JAMA 1981; 245:1346-1347. 46. PPA over the counter (editorial). Lancet 1982;
1:839. 47. Rumack BH: Phenylpropanolamine: A potentially hazardous drug. Ann Emerg Med 1982; 11:332. 48. Mueller SM: phenylpropanolamine, a nonprescription drug with potentially fatal side-effects. N Engl J Med 1983; 308:653.
Vol 3, pp 127-I 32. 1985 PrInted m the USA ??CopyrIght
:
1985 Pergaman PressLtd
FATAL INTRACRANIAL HEMORRHAGE ASSOCIATED WITH PHENYLPROPANOLAMINE, PENTAZOCINE, AND TRIPELENNAMINE OVERDOSE Cary Jackson,
MD,*
Avery Hart, MD,t
and Mel D. Robinson,
MD*
‘Captain, MedIcal Corps, Department of Internal Medicine, Holloman Au Force Base Hospital, Alamogordo, New Mexico; tcaptaln, Department of Internal Medlclne, Torrejon Air Force Base Hospital. Madrld, Spaln and $Captaln, MedIcal Corps, Department of Emergency Medlclne. Madigan Army Medical Center, Tacoma, Washington Reprint address, Cary Jackson, MD, Holloman AFB Hospital, Holloman AFB. NM 88330
0 Abstract-Hemorrhagic cerebrovascular accident is an uncommon but serious complication of drug overdose. A case of fatal intracranial hemorrhage following overdose with phenylpropanolamine, pentazocine, and tripelennamine is presented. The pharmacology, pathophysiology, clinical presentation, and management of poisoning by these agents are discussed. 0 Keywords-intracranial hemorrhage; phenylpropanolamine; pentazocine; tripelennamine; amphetamine
Introduction Changing patterns of drug abuse present new clinical problems to physicians. Neurologic complications from the abuse of phenylpropanolamine and of the combination of pentazocine and tripelennamine are now being recognized more frequently. We report a case of fatal intracranial hemorrhage associated with abuse of these drugs in combination.
~ xzxz==
Case Report A 30-year-old man, brought to the emergency department (ED) in a coma, had been in good health until the night of admission. History obtained from his wife revealed that he had regularly abused a variety of drugs. These included pentazotine and tripelennamine (“T’s and Blues”), over-the-counter diet pills, cocaine, and marijuana. He had not used cocaine during the past four days. His last diet pill, an extended-release capsule of phenylpropanolamine (PPA) 75 mg and caffeine 200 mg, (Dexatrim Extra-Strength) was reported 20 hours before onset of neurologic symptoms. Over the six hours before admission, the patient and his wife split a total of five sets of “T’s and Blues,” each set consisting of one 50 mg pentazocine tablet and one 50 mg tripelennamine tablet crushed and injected intravenously. About 30 minutes after the last set, the patient vomited and complained of right-hand pain
Toxicology -one of the most critical and challenging areas confronting the emergency department staff-is coordinated by Kenneth Kulig, MD, of the Rocky Mountain Poison Center.
RECEIVED:27 November 1984; ACCEPTED:15 February 1985 0736-4679/85 $3.00 + .OO 127
128
Cary Jackson, Avery Hart, and Mel D. Robinson
and numbness. Shortly thereafter, he became unresponsive. On arrival at the ED, the patient was opisthotonic and profusely diaphoretic, with blood pressure of 200/120 mm Hg. Supraventricular tachycardia at 200 beats per minute, respiratory rate of 40 breaths per minute, and rectal temperature of 103.3”F were noted. The pupils were dilated and reactive to light. Fundoscopic exam revealed no hemorrhages, exudates, or papilledema. Cornea1 and oculovestibular reflexes were intact. While in the ED, he displayed opisthotonic, decorticate, and decerebrate posturing. Deep tendon reflexes were markedly hyperactive, with upgoing Babinski reflex bilaterally. The physical examination was otherwise unremarkable except for needle tracts on the upper limbs. Arterial pH was 7.22; pCO*, 20; and pOZ, 180 on supplemental oxygen. Serum glucose was 530 mg/dL (after administration of dextrose 50070, 50 mL). Serum creatinine was 1.8 mg/dL. Serum electrolytes were sodium 133, potassium 4.7, chloride 100, bicarbonate 14 mEq/L, calcium 7.7 mg/dL, magnesium 2.2 mg/dL, and phosphorus 3.3 mg/dL. The WBC was 28,000/~, with 43% hematocrit. Specimens were sent for toxicology analysis. Immediate nasotracheal intubation was accomplished. Initial intravenous medications included 50 cc of 50% dextrose, 2 mg naloxone, 1 mg propanolol, and 5 mg diazepam. The opisthotonic posturing ceased, pulse rate decreased to 110 beats per minute, and blood pressure fell to 160/90 mm Hg. Gastric lavage revealed no pill fragments. Charcoal and magnesium citrate were given per lavage tube. An emergency computed tomography (CT) scan of the head without contrast showed no abnormalities. The patient was admitted to the intensive care unit, where recurrent opisthotonus was treated with diazepam. His blood pressure remained stable at 160/90. The following morning the patient’s neurologic status acutely deteriorated. Repeat neurologic exam revealed the pupils to be mid-position and nonreactive. Pupillary,
cornea& oculocephalic, and oculovestibular reflexes were all absent, as were deep tendon reflexes. A second CT scan of the head revealed hyperdense areas in the left frontal and temporal areas consistent with intraparenchymal hemorrhage (Figure 1). Serial neurologic examinations over 48 hours showed no change. Spontaneous respirations were absent and a radionuclide brain scan revealed no flow. The patient was declared brain dead. Autopsy revealed intracranial hemorrhage from several sites. Intraparenchyma1 blood was found in the left frontal and temporal lobes, in both hypocampi, both internal capsules, in the putamina and pallidum, and also in the pons, midbrain, and medulla. There was also blood in the subarachnoid space and cisterna magna. The left uncus was herniated with a 2.0-cm acute hemorrhagic infarct. Results of toxicologic analysis of specimens taken at autopsy were normal. Urine (from admission) analyzed by the enzyme-multiplied immunoabsorbent technique (EMIT, Syva) revealed amphetamines. This method does not distinguish between several sympathomimetics including phenylpropanolamine, pseudoephedrine, ephedrine, and amphetamines. The EMIT test finding for opiates was negative. However, this method detects only natural and semisynthetic opiates and meperedine; it does not detect pentazocine. Gastric aspirate from admission contained pentazocine 8.2 pg/mL, tripelennamine 2.0 pg/mL, salicylate 13Opg/mL, and lidocaine 96 kg/mL (after intubation using a lubricant containing lidocaine). No other drugs were detected.
Discussion When pentazocine was released in 1969, it was promoted as an opiate analgesic with low potential for addiction because of its mixed agonist-antagonist properties. By 1978 heroin addicts in Chicago and other midwestern cities had discovered that pentazocine could serve as an acceptable substitute for heroin when injected with tripel-
Overdose
with Intracranial
Hemorrhage
Figure 1. CT scan without contrast reveals hyperdense with intracerebral hemorrhage.
ennamine. This combination is known on the street as “T’s and Blues.” “T” stands for Talwin. “Blues” stands for the blue Pyrenzamine (tripelennamine) tablet. These drugs are cheaper and more available than heroin. Parenteral abuse of pentazocine has dramatically increased since 1974.’ The most common side effect of pentazocine is sedation, followed by sweating and dizziness. Psychologic side effects include hallucinations, depression, and psychosis. In contrast to many opiates, pentazocine causes increases in blood pressure and heart rate, associated with rises in plasma epinephrine and norepinephrine. Pentazocine is primarily metabolized in the liver. Products of oxidation of terminal methyl groups and glucuronide conjugation are then excreted in the urine. These glucuronide conjugates will often be missed in routine urine drug screens unless a glucuronide enzyme is added to the specimen.2.3 The antihistamine tripelennamine has been previously known as “blue velvet” on the streets. When crushed and injected in-
left frontal and temporal areas consistent
travenously, it prolongs and intensifies the euphoria of pentazocine. Tripelennamine can depress or stimulate the central nervous system. In patients with focal neurologic lesions, even small doses can precipitate seizures. In overdose, there is usually a phase of CNS depression followed by excitement and culminating in seizures. The simultaneous injection of tripelennamine with pentazocine greatly increases the frequency of this complication, although seizures have been reported with pentazocine alone. Use of a one-to-one ratio of pentazocine and tripelennamine, rather than the usual twoto-one ratio, further increases the risk of seizures.3m5 Caplan reported a series of 13 patients with CNS complications resulting from “T’s and Blues” addiction.” Seizures, CNS infections, and stroke were identified, with one patient having multiple areas of cerebral infarction and intracranial hemorrhage. Microcrystalline cellulose and talc are the insoluble binders in pentazocine and tripelennamine tablets. Intravenous injec-
130
Cary Jackson, Avery Hart, and Mel D. Robinson
tion of these binders can cause extensive embolic damage to vessels in the lung, liver, kidneys, endocardium, and brain. Complications of embolization include angiothrombosis of pulmonary arterioles leading to pulmonary infiltrates. Severe skin and muscle damage may occur if “T’s and Blues” are injected subcutaneously or intramuscularly.7-9 The treatment of “T’s and Blues” overdose is primarily supportive. Large doses of naloxone may be required to reverse the sedation of pentazocine overdose, approximately 1 mg for every 350 mg of pentazocine.‘O Signs of neurologic toxicity persisting after naloxone administration may be secondary to anticholinergic effects of tripelennamine.” Tripelennamine-induced seizures are best treated with phenytoin and by avoiding other anticonvulsants which may cause CNS depression.4 Physostigmine in doses of 0.5 mg to 2.0 mg may be used as a last resort, but is associated with a significant incidence of seizures and cardiac dysrhythmia. I2 Phenylpropanolamine (PPA) is a sympathomimetic amine structurally resembling amphetamine and ephedrine. First sold over the counter as a decongestant and then as an appetite suppressant, PPA is now widely used by a certain segment of the population as a stimulant. Reflecting these trends, the frequency of PPA involvement in poison control case reports rose tenfold from 1975 to 1980.13 Hypertensive crisis can result from even a single therapeutic dose of PPA.14 The hypertensive effect may be potentiated by a variety of other drugs including monoamine oxidase inhibitors, ephedrine, caffeine, anticholinergic drugs, antihistamines, nonsteroidal anti-inflammatory drugs, and antihypertensives.‘5-23 Hemorrhagic stroke associated with PPA has been reported in four cases. In two cases, neither of which was fatal, PPA was ingested a10ne.24,25In two fatal cases, PPA was ingested with caffeine and ephedrine.ls Nonhemorrhagic stroke and transient ischemic neurologic deficit have been reported.26 Other complications of PPA poison-
ing include arrhythmias, psychosis, seizures, and myocardial infarction.27-36 Intracranial hemorrhage has also been reported with oral and intravenous amphetamines and with pseudoephedrine.37-39 All of these sympathomimetic drugs in overdose can cause hypertension, tachycardia, tremor, arrhythmias, seizures, and coma. Sympathomimetic poisoning is treated with gastric emptying, charcoal ingestion and catharsis followed by supportive care. Intravenous propranolol has been found to be effective in controlling the tachycardia and hypertension of acute overdose, although nitroprusside may be necessary. Seizures are treated with diazepam. Acidification of urine will accelerate clearance, but entails additional risks such as precipitation of myoglobin in the kidneys with minimal clinical benefit. Dialysis is not effective owing to the large volume of distribution of these drugs. To our knowledge, there is no data on hemoperfusion.40-42 Stroke as a complication of drug abuse can occur from ischemic infarction, intracerebral hemorrhage, or subarachnoid hemorrhage.43 Proposed mechanisms of injury include (1) direct toxic injury, (2) pharmacologic alteration of vascular function, e.g., vasospasm or severe hypertension (3) embolization of foreign material and adulterants such as the microcrystalline cellulose of “T’s and Blues,” (4) immunogenic vasculitis, and (5) endocarditis with secondary embolization. Although the mechanism in our particular patient may have been multifactorial, his severe hypertension following the injection of “T’s and Blues” and the ingestion of PPA and caffeine probably played a major role. And although the patient’s last ingestion of PPA was the night before admission, it was reportedly an extended-release preparation. The patient had sympathomimetic drugs in his urine on admission. As previously mentioned, the hypertensive effect of PPA appears to be potentiated by a variety of drugs. In this patient the combination proved to be fatal. The drugs taken by this young man have become widely available, popular drugs of
Overdose
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abuse. In an attempt to decrease pentazotine abuse, Winthrop Laboratories reformulated its Talwin-50 tablets by adding 0.5 mg of naloxone to each tablet.44 Naloxone is fully metabolized on the first pass through the liver, so tablets taken orally remain efficacious. When crushed and injected, the tablet should, in principle, have little or no opiate effect owing to antagonism between the naloxone and the pentazocine. Repeated requests from toxicologists for withdrawal of phenylpropanolamine from overthe-counter diet aids have not met with success.45-48 We add to the reports of neurologic complications of drug abuse, this case of fatal intracranial hemorrhage in a young man
who had taken phenylpropanolamine and caffeine followed by pentazocine and tripelennamine. Toxic effects of these groups of drugs may present with similar clinical features, including fever, tachycardia, hypertension, diaphoresis, and mydriasis. Serious neurologic complications resulting from abuse of these drugs include seizures, coma, CNS infections, and stroke. Cerebrovascular accidents may occur from infarction, intraparenchymal hemorrhage, or subarachnoid hemorrhage. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the Department of Defense.
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