Canadian Journal of Anesthesia, Vol 11, 354-381, Copyright © 1964 by Canadian Anesthesiologists' Society

Effects of Alcoholism, Morphinism, and Barbiturate Resistance on Induction and Maintenance of General Anaesthesia

¹ Postdoctoral Research Fellow Presently Associate Professor of Anesthesiology, University Hospital, Taiper, Taiwan (Formosa)

The responses of over 250 rodents made tolerant in groups to ethanol, dihydro-morphinone HC1, and methohexital were evaluated during the administration of approximately 2000 individual general anaesthetics in order to identify the effects of the interaction of addicting sedatrve-type drugs and the general anaesthetics at various stages in the development of toleranee

Rats were made ethanol-tolerant m two ways by daily intraperitoneal injections with weekly increases in the dose, and by adding ethanol to the drinking water, which was rendered progressively more alcoholic The addition of ethanol to the drinking water was found to be the more satisfactory way of producing ethanol tolerance in rats because oral intake more closely simulates clinical conditions for developing ethanol tolerance, and it is attended by a lower mortality

During the development of ethanol tolerance, rats have a stormy and somewhat prolonged induction time with diethyl ether and methoxyflurane anaesthesia, whereas the duration of anaesthesia with these two agents does not appear to be affected After ethanol tolerance is established, the induction time with the inhalation anaesthetics is no longer affected

Ethanol-tolerant rats seem to be slightly resistant to the onset of anaesthesia after intraperitoneal administiation of methohexital or thiopental This response is not evident when methohexital is combined with Innovar Rats then appear to be rather more sensitive than resistant during the maintenance of thiopental anaesthesia, whereas they tend to recover a little faster when they are given methohexital Howevei, the biological variation is so great that it is impossible to predict an individual response to the very short-acting barbiturates from these experiments, and it is likely that established ethanol tolerance has m flact no appreciable influence on the induction or maintenance response to thiopental, methohexital, and Innovar

"Morphinism" in mice is produced satisfactorily by adding the narcotic analgesic to the milk provided for oral feeding Dihydromorphinone HC1 addiction in mice causes slight resistance to induction of anaesthesia with diethyl ether, whereas they seem to be somewhat more sensitive to methoxyflurane and much more sensitive to methohexital anaesthesia The altered response to general anaesthesia by mice tolerant to dihydromorphinone HC1 as compared with normal mice disappears when the narcotic is withdrawn

Prolonged methohexital pretreatment of rats causes no appreciable change in their response to general anaesthesia with diethyl ether or melthoxyflurane even though the rats become quite resistant to this oxybarbiturate

In this study, we paid special attention to the effect of tolerance to there chemically different kinds of sedative-type drugs on the speed and duration of depression by general anaesthetics Although some degree of antagonism and synergism with anaesthesia was observed during the development of tolerance and habituation, as noted above, we have little unequivocal knowledge concerning the mechanism by which these interaction were brought about

The simple explanation of the interaction of ethanol and diethyl ether being merely an additive synergism applies only before ethanol tolerance develops because progressive acute intake of ethanel by itself usually mimics the signs of a slow induction of general anaesthesia, as described by Guedel for diethyl ether The first effect with ether in the unpremedicated subject is observed as a change in the cortical control of behaiviour. There is then a gradual descent of the depression to envelop the entire brain, including the medulla When the medullary effects set in, respiratory, cardiovascular, and vasomotor functions are characteristically depressed. The general effect of deep ethanol coma is then vutually the same as that of diethyl ether anaesthesia and both undoubtedly have a marked depressant effect on synaptiC transmission in the cortex of the brain, the reticular system, and the peripheral nervous system. The metabolic effects of ethanol depression and diethy ether anaesthesia are also rather similar Both cause a deciease in the alkali binding power of the blood and the accumulation of lactic acid, and both show manifestations of a similar metabolic disturbance during recovery, marked by hangover, nausea, emesis, and thirst One would expect, therefore, that if these two agents were given to a patient at the same time, the manifestation of an additive synergism would be apparent, and this is actually what is seen However, once ethanol tolerance is developing, only the initial excitement stage with diethyl ether is exaggerated while the maintenance of anaesthesia is not obviously affected The response to methoxyflurane appears to be similarly affected, while the response to barbiturate anaesthesia is virtually unaffected

Much work is still in progress in an attempt to explain the basic mechanism of addiction to narcotic analgesics The development of tissue immunity is the favoured explanation It appears that the reaction of the narcotics addict to general anaesthesia with diethyl ether and methoxyflurane would be much the same as that for the alcoholic On the other hand, there seems to be some uncertainty as to whether the narcotics addict is more sensitive or more resistant to barbiturate anaesthesia From these experiments it seems that increased sensitivity should be expected with oxybarbitiurates

It may remain difficult to explain changes that might occur after resistance or tolerance develops to a barbiturate until we can define in detail the changes in rate of absorption, distribution, and metabolic degradation characteristic for each of the many chemical arrangements these drugs take New work in the past few years seems to indicate that rapid metabolic breakdown to inactive compounds is part of the mechanism for the apparent development of resistance with the oxybarbiturates For the present, one has little to fear from interactions between barbiturates to which tolerance has developed and inhalation anaesthetics, since the occurrence of barbiturate resistance does not appear to have any appreciable effect on the course of an inhalation anaesthetic

"If a drop of water falls on the surface of the sea just over the flower-like disc of a sea-anemone, the whole animal contracts vigorously If then, a second drop falls within a few minutes of the first there is less contraction, and finally, on the third and fourth drop, the response disappears altogether Here, in this marine polyp, is clearly exhibited one of the most persuasive phenomena of the animal kingdom-decrement of response with repeated stimulation" This observation by Sharpless and Jasper⁴¹ is fundamental to the broad understanding of habituation and drug tolerance In almost every case where the corticoreticular system is subjected to monotonous stimulation or is subjected to recurring sensory deprivation, the initial response is eventually suppressed and then disappears, while new types of stimulation or stress are handled in the usual way, because the oiganism has not as yet developed a feedback control of input for the new stimulus. This is perhaps an oversimplified explanation of all the responses we observed above in drug-tolerant rodents that were subjected to general anaesthesia, but it seems to explain most of the effects that were observed

Note:

From the Anesthesiology Research Laboratory State University of New York, Upstate Medical Center, Syracuse, New York Supported by U S Public Health Service Grant No NB-03809-02 and a grant-in-aid from Abbott Laboratories, Chicago, Illinois