• Embed Doc
  • Copy Link
  • Readcast
  • Collections
  • CommentGo Back
Download
 
Psychiatry Research, 1, 249-254
(1979)
@ElsevieriNorth-Holland Biomedical Press249
Chronic Parkinsonism Secondary to Intravenous Injectionof Meperidine Analogues
Glenn C. Davis, Adrian C. Williams, Sanford P. Markey, Michael H. Ebert,Eric D. Caine, Cheryl M. Reichert, and Irwin J. Kopin
Received October 1, 1979; accepted October 16. 1979.
Abstract.
Abuse of 4-propyloxy-4-phenyl-N-methylpiperidine, a meperidine con-gener, produced parkinsonism in a 23-year-old man. Unlike other drug-inducedmotor disturbances, the syndrome perisited for 18 months and responded to drugsthat stimulate dopamine receptors. Biogenic amines and metabolites in the cere-brospinal fluid and microscopic evaluation of the brain at necropsy were consistentwith damage to aminergic neurons in the substantia nigra.Key
Words.
Parkinsonism, drug-induced, biogenic amines, substantia nigra.Parkinsonism is a well-recognized common side effect of drugs that either depletecentral catecholamines (e.g., reserpine, tetrabenazine) or block dopamine receptors(e.g., phenothiazines, butyrophenones). Drug-induced parkinsonism usually is rever-sible and abates over several weeks when the offending drug is discontinued.In this case report, we describe the acute development of parkinsonism in a youngman, subsequent to the parenteral abuse of a congener of meperidine. His symptomspersisted for I8 months, although they were controlled successfully with bromocrip-tine, a potent dopamine receptor agonist.
Case Report
A previously healthy 23-year-old white male was referred to the National Institute ofMental Health (NIMH) for evaluation of a persistent parkinsonian syndrome of 3months’ duration.He had abused a wide assortment of drugs during the 9 years before his admission.From 1968 to 1976, he had rarely experienced a drug-free interval greater than severalweeks. During this period he had experimented with marijuana, amphetamines,barbiturates, and other sedative-hypnotics; he finally chose opiate derivatives (meper-idine and codeine) as his preferred drugs. While in college, the patient unsuccessfullyGlenn C. Davis,
M.D., is
Associate
Professor of Psychiatry, University of Tennessee Center for the HealthSciences; Adrian C. Williams, M.B., MRCP, is Visiting Scientist, Experimental Therapeutics Branch,National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health(NIH); Sanford P. Markey, Ph.D., is Chief, Unit on Pharmacological Applications of Mass Spectrometry,Laboratory of Clinical Science (LCS), National Institute of Mental Health (NIMH); Michael H. Ebert,M.D., is Chief, Section on Experimental Therapeutics, LCS, NIMH; Eric D. Caine, M.D., was formerly inthe LCS, NIMH, and is now Assistant Professor, Department of Psychiatry, University of RochesterSchool of Medicine and Dentistry;
Cheryl M. Reichert,
M.D., Ph.D., is Resident, Department of Pathol-ogy, National Cancer Institute, NIH: Irwin J. Kopin, M.D., isChief, LCS, NIMH. (Reprint requests to Dr.Davis at Department of Psychiatry, University of Tennessee Center for the Health Sciences, M.M.H.I.,4-East, 865 Poplar Ave., Memphis, TN 38104.)
 
250attempted to synthesize several opiate derivatives. In the summer of 1976, he attemp-ted and apparently succeeded in the synthesis of 4-propyloxy-4-phenyl-N-methylpiperidine, a meperidine congener. This compound was reported by the patientto have produced an opiate-like “high” and other subjective effects similar to those ofmeperidine. After several months of intravenous and intramuscular self-administration of the home-synthesized compound, the patient prepared additionalbatches, but took synthetic shortcuts. In November 1976, after several days of inject-ing this “sloppy batch,” he developed a state of muteness, severe rigidity, weakness,tremor, flat facial expression, and altered sensorium. He was admitted to the psychiat-ric ward of a general hospital with an initial diagnosis of catatonic schizophrenia. Onexamination he was gaunt, lying motionless in bed unable to speak. He was unrespon-sive to most verbal stimuli, but responded slowly to simple instructions. His upperextremities showed waxy flexibility and lead-pipe rigidity. Thick saliva had accumu-lated in his mouth. The remainder of the physical examination was negative, androutine laboratory tests were normal. A short course of haloperidol failed to bringabout improvement although electroconvulsive therapy did result in reduced motorretardation. After consultation with a neurologist, the patient was treated withlevodopa/carbidopa, benztropine, and diazepam. He improved markedly.In February 1977, the patient was referred to NIMH for further investigation of hisparkinsonism. At that time he was taking levodopa/ carbidopa (25 mg and 250 mg) sixtimes a day and benztropine, 0.5 mg t.i.d. He complained of slowed thoughts. Mildblepharospasm and bradykinesia were the only neurological signs noted. There wereno abnormalities of speech, hallucinations, delusions, ideas of reference, or otherevidence of a thought disorder. His mood was depressed, and his affect was flat.Although complaining of slowed thoughts, the patient showed few signs of intellectualimpairment. Cognitive evaluation revealed no abnormalities suggestive of focalimpairment. His scores on the Wechsler Adult Intelligence Scale were 109 on theverbal scale and 100 on the performance scale. Significantly, he was most deficient onthose subtests that were timed (e.g., arithmetic, block design), with a “loss” of 21points from his performance score due to slow execution. The patient could performconsistently well on serial learning memory tests, which are impaired in most individu-als with idiopathic parkinsonism (Caine et al., 1977). Neither he nor his family recalleda gradual development of symptoms, and handwriting samples from the year preced-ing his sudden deterioration showed no change.The patient had no family history of neurological disease. Routine laboratory testswere normal. Serum copper, ceruloplasmin, slit lamp examination, cerebrospinalfluid (CSF) protein, glucose, immunoglobulins and cell count, electroencephalogram,skull films, brain scan, and computerized tomography (CT scan) of the head were alsonormal.When therapeutic agents were discontinued, severe bradykinesia, generalized rigid-ity, and a mild tremor progressively developed over a 3-day period. Speech andswallowing were severely impaired, and urinary retention developed. There were nopyramidal or cerebellar signs. Resumption of treatment with levodopa/ carbidopa(Sinemet) brought about rapid improvement. Bromocriptine (100 mg/day) wasequally effective and was continuted as the drug of choice because of its longerduration of action and because the patient tended to abuse levodopa.
 
251After maintenance on bromocriptine for 6 months, the patient was readmitted. Hismedication was discontinued for 3 days, whereupon his symptoms reappeared butwere milder than during the previous admission. At this point his CSF levels ofhomovanillic acid (HVA), 5-hydroxyindoleacetic acid (SHIAA), and norepinephrine(NE) were all well below values seen in 15 patients with idiopathic Parkinson’s diseaseand 25 normal controls (Table 1).
Table 1. Biogenic amines in the cerebrospinal fluid of the patientand controlsParkinson’s disease NormalPatient
(n =
15)
(n =
25)
HVA
(ng/mlk
SD) 5.017.5 f 11.643.0? 32.55HIAA
(ng/ml+
SD) 5.013.7 k 11.618.3 2 10.0NE
(pg/ml+
SD)105.0215.0 k 135.0374.0? 180.0
Fifteen months after the onset of illness, the patient required only 20 mg/day ofbromocriptine but continuted to have mild bradykinesia which became more promi-nent when the dose was reduced further. At 18 months, bromocriptine was discon-tinued; the patient exhibited no extrapyramidal signs but still complained of slowedthoughts.The patient continued to abuse many drugs including cocaine, codeine, dihydro-morphinone and L-dopa, and in September 1978 he was found dead of an overdose. Ablood level of 0.23 mg/ 1 of cocaine and < 0.05 mg/ 1 of codeine was found on autopsy.On gross examination of the brain, irregular patches of tan discoloration were seenwithin the ventricular lining, and microscopic examination disclosed destructionwithin the substantia nigra (Fig. I). Much of the neuromelanin pigment was extracel-lular and within microglial cells. A rounded eosinophilic intracytoplasmic “Lewy”body, characteristic of Parkinson’s disease, was noted (Fig. 2). The pigmented cells ofthe locus ceruleus were intact. The ependymal lining was focally disrupted by numer-ous partially fibrotic plaques, suggestive of a prior ependymitis. Other autopsyfindings included: pulmonary vascular crystalline material, pulmonary microgranulo-mata, pulmonary and hepatic intracellular crystalline material, hepatic triaditis, andthe presence of scars at injection sites on the arms.
Compound Identification and Synthesis
The patient chose to synthesize 4-propyloxy-4-phenyl-N-methylpiperidine (PPMP)because it was known to be a more potent analgesic than pethidine (Janssen and Eddy,1960) and could be readily produced from the commercially available, unrestrictedchemical L-methyl+piperidine (MP) (Berger et al., 1947; Ziering et al., 1974).Over a period of 5 to 6 months, the patient repeated the synthesis (Fig, 3) but withreduced reaction times and higher reaction temperatures; finally he neglected toisolate and crystallize the product properly. Duplication of the patient’s reactionconditions, however, yielded relatively pure 4-hydroxy-4-phenyl-N-methyl piperidine(HPMP) (Fig. 3) identical to traces of material found on the patient’s laboratoryglassware.
of 00

Leave a Comment

You must be to leave a comment.
Submit
Characters: ...
You must be to leave a comment.
Submit
Characters: ...