521 Adult male Wistar rats were made dependent on morphine hydrochloride by twice daily intraperitoneal injections, the doses being increased progressively from 10 mg/kg on the first day to 200 mg/kg on day 21. The 200 mg/kg dose was then maintained until day 35, when it was discontinued. Thus on day 35 the animals entered a state of "spontaneous abstinence syndrome", before being given clonidine. The rat is less susceptible to the effects of clonidine than is man, and previous experiments had indicated that a dose of 800 fig/kg was suitable for use in this interaction evaluation. This dose of clonidine was administered to spontaneously abstinent animals 17 h after their last dose of morphine, the animals exhibiting clear withdrawal signs with distress and physical pain. An equal volume of normal saline vehicle was administered to a parallel series of spontaneously abstinent animals acting as controls. For 7 h after clonidine or saline administration, the animals were observed continuously and the intensity of twenty signs of the withdrawal syndrome known to occur in the rat were noted and recorded on closed-circuit television for later reviewing and confirmation of the behavioural scores obtained.
findings confirm those of Gold et al. in that clonidine suppressed all the major signs of morphine withdrawal; and Our
Effect of naloxone in congenital insensitivity to pain. Each trace is an average of 50 trials presented at a rate of 1 toothpulp stimulation/3 sec at 15mA. Negativity up. Top: without naloxone ; middle: 10 min after 2-0 mg of naloxone; bottom: 10 min after 10 mg of naloxone. Initial downward deflection indicates stimulating artifact. no T.P.E.P. were observed during stimuli of 2.0 mA 6-0 mA, but some T.P.E.P. were observed during stimuli of 15.0 mA. (see figure), in particular, after stimuli of 15.0 mA and 10 mg of naloxone. The patient could recognise these stimuli as pressure sensations without apparent distress. These findings were exactly reproducible, and strongly suggested that naloxone may be a possible treatment of congenital insensi-
venously), or
tivity to pain. Although the terms "congenital insensitivity" and "congenital indifference" to pain are often used interchangeably, they imply different mechanisms of defective pain sensation. Many questions about the mechanism of congenital insensitivity to pain remain unanswered but the overproduction of brain endorphins may be one contributing factor. of Anæsthesia and Yokohama Teishin Hospital,
Department
EEG,
3-59, Nishikanagawa-cho, Kanagawa-ku, Yokohama, Japan
Gold,
M.
Boehringer Ingelheim for financial
assistance.
Pharmacology Laboratories, School of Pharmacy, University of Wales Institute of Science and Technology,
J. J. LIPMAN
P. S. J. SPENCER
HISASHI YANAGIDA
al.’ used clonidine successfully to withdraw five male patients from a state of chronic opiate addiction. These workers found that clonidine antagonised the objectively assessed withdrawal symptoms and that the patients themselves reported great relief of distress. The condition of the patients after discontinuation of clonidine therapy was not described. We are investigating the neuropharmacological mechanisms that subserve opiate actions-particularly, the effects of direct interaction of x-adrenoceptor activation with opiate analgesic effects in the laboratory rat. Our experiments with clonidine in the opiate-dependent rat undergoing withdrawal prompt us to write this cautionary note; complete technical details will be published elsewhere. 1.
We thank
Cardiff CF1 3NU
CLONIDINE AND OPIATE WITHDRAWAL
SIR,-Gold
the behavioural correlates associated with distress in this laboratory model were abolished. Clonidine, however, also produced certain novel effects not seen in non-opiate-dependent animals given clonidine alone, or in spontaneously abstinent animals given saline. These effects included some very bizarre stereotypies which in animal models are considered to be related to clinically psychotic symptoms. On attenuation of clonidine’s action (i.e., after 4-5 h) certain morphine-withdrawal signs remained suppressed whilst others, notably those associated with clinical irritability and hypersesthesia, rebounded to levels more intense than they had been before clonidine administration. We have long believed that clonidine and drugs based on the clonidine structure might ameliorate the symptoms of opiate withdrawal. Clonidine’s sedative and analgesic properties, its ability to render postganglionic nerves less reactive, and its reductive effects upon sympathetic tone and hence upon the withdrawal symptoms of autonomic storm are all desirable properties for a drug used to treat opiate dependence. We hope to demonstrate that derivatives of the parent imidazoline drug (or thiazine drugs, with which we are also working) avoid both’ the psychotomimetic interaction and the rebound exacerbation of certain symptoms. If clonidine is to be used clinically in opiate withdrawal the dose may need to be controlled. Preliminary experiments in mice suggest that very low doses administered directly into the brain ventricles may exacerbate the withdrawal rather than mask or ameliorate the symptoms.
et
S., Redmond Jr., D. G., Kleber, H. D. Lancet, 1978,
1, 929.
NON-OCCUPATIONAL EXPOSURE TO ASBESTOS AND MALIGNANT MESOTHELIOMA
SIR,-Vianna and Polan’
say that "For statistical purposes, and their matched controls were subdivided according as to whether their occupations were asbestos related (as defined by Hamilton and Hardy)2 or not." Our understanding of the epidemiology of mesothelioma would be much facilitated if, indeed, there was an accepted definition of what constitutes an asbestos exposure. Hamilton and Hardy provide no such definition: they offer no more than a very incomplete, and somewhat haphazard, list of the uses to which asbestos is put. Vianna and Polan regard six of their patients as having had an occupational exposure to asbestos, one as a milliner and another as a shoemaker. The remaining four were textile workers but unless they were asbestos textile workers-and no
patients
1. Vianna, N. J., Polan, A. Lancet, 1978, i, 1061. 2. Hamilton, A., Hardy, H. L. in Industrial Toxicology,
chusetts, 1974.
p. 421. Acton,
Massa-
findings confirm those of Gold et al. in that clonidine suppressed all the major signs of morphine withdrawal; and Our
Effect of naloxone in congenital insensitivity to pain. Each trace is an average of 50 trials presented at a rate of 1 toothpulp stimulation/3 sec at 15mA. Negativity up. Top: without naloxone ; middle: 10 min after 2-0 mg of naloxone; bottom: 10 min after 10 mg of naloxone. Initial downward deflection indicates stimulating artifact. no T.P.E.P. were observed during stimuli of 2.0 mA 6-0 mA, but some T.P.E.P. were observed during stimuli of 15.0 mA. (see figure), in particular, after stimuli of 15.0 mA and 10 mg of naloxone. The patient could recognise these stimuli as pressure sensations without apparent distress. These findings were exactly reproducible, and strongly suggested that naloxone may be a possible treatment of congenital insensi-
venously), or
tivity to pain. Although the terms "congenital insensitivity" and "congenital indifference" to pain are often used interchangeably, they imply different mechanisms of defective pain sensation. Many questions about the mechanism of congenital insensitivity to pain remain unanswered but the overproduction of brain endorphins may be one contributing factor. of Anæsthesia and Yokohama Teishin Hospital,
Department
EEG,
3-59, Nishikanagawa-cho, Kanagawa-ku, Yokohama, Japan
Gold,
M.
Boehringer Ingelheim for financial
assistance.
Pharmacology Laboratories, School of Pharmacy, University of Wales Institute of Science and Technology,
J. J. LIPMAN
P. S. J. SPENCER
HISASHI YANAGIDA
al.’ used clonidine successfully to withdraw five male patients from a state of chronic opiate addiction. These workers found that clonidine antagonised the objectively assessed withdrawal symptoms and that the patients themselves reported great relief of distress. The condition of the patients after discontinuation of clonidine therapy was not described. We are investigating the neuropharmacological mechanisms that subserve opiate actions-particularly, the effects of direct interaction of x-adrenoceptor activation with opiate analgesic effects in the laboratory rat. Our experiments with clonidine in the opiate-dependent rat undergoing withdrawal prompt us to write this cautionary note; complete technical details will be published elsewhere. 1.
We thank
Cardiff CF1 3NU
CLONIDINE AND OPIATE WITHDRAWAL
SIR,-Gold
the behavioural correlates associated with distress in this laboratory model were abolished. Clonidine, however, also produced certain novel effects not seen in non-opiate-dependent animals given clonidine alone, or in spontaneously abstinent animals given saline. These effects included some very bizarre stereotypies which in animal models are considered to be related to clinically psychotic symptoms. On attenuation of clonidine’s action (i.e., after 4-5 h) certain morphine-withdrawal signs remained suppressed whilst others, notably those associated with clinical irritability and hypersesthesia, rebounded to levels more intense than they had been before clonidine administration. We have long believed that clonidine and drugs based on the clonidine structure might ameliorate the symptoms of opiate withdrawal. Clonidine’s sedative and analgesic properties, its ability to render postganglionic nerves less reactive, and its reductive effects upon sympathetic tone and hence upon the withdrawal symptoms of autonomic storm are all desirable properties for a drug used to treat opiate dependence. We hope to demonstrate that derivatives of the parent imidazoline drug (or thiazine drugs, with which we are also working) avoid both’ the psychotomimetic interaction and the rebound exacerbation of certain symptoms. If clonidine is to be used clinically in opiate withdrawal the dose may need to be controlled. Preliminary experiments in mice suggest that very low doses administered directly into the brain ventricles may exacerbate the withdrawal rather than mask or ameliorate the symptoms.
et
S., Redmond Jr., D. G., Kleber, H. D. Lancet, 1978,
1, 929.
NON-OCCUPATIONAL EXPOSURE TO ASBESTOS AND MALIGNANT MESOTHELIOMA
SIR,-Vianna and Polan’
say that "For statistical purposes, and their matched controls were subdivided according as to whether their occupations were asbestos related (as defined by Hamilton and Hardy)2 or not." Our understanding of the epidemiology of mesothelioma would be much facilitated if, indeed, there was an accepted definition of what constitutes an asbestos exposure. Hamilton and Hardy provide no such definition: they offer no more than a very incomplete, and somewhat haphazard, list of the uses to which asbestos is put. Vianna and Polan regard six of their patients as having had an occupational exposure to asbestos, one as a milliner and another as a shoemaker. The remaining four were textile workers but unless they were asbestos textile workers-and no
patients
1. Vianna, N. J., Polan, A. Lancet, 1978, i, 1061. 2. Hamilton, A., Hardy, H. L. in Industrial Toxicology,
chusetts, 1974.
p. 421. Acton,
Massa-
