Effect of promedol on the bioelectric activity of the cortex of the brain

Sections

Method
Results
Conclusion
Bibliography

Details

Author: V. V. Vasilyeva, K. M. Lakin, P. V. Sergeev
Pages: 13 to 19
Creation Date: 1958/01/01

Effect of promedol on the bioelectric activity of the cortex of the brain

(Experimental study)

V. V. Vasilyeva
K. M. Lakin
P. V. Sergeev
(Department of Pharmacology, Second Moscow State Medical Institute)

Pain-killers are an important means of pathogenetic therapy in many diseases. The pain impulses accompanying various pathogenetic processes cause excessive irritation to the central nervous system, exhaust the cortex of the brain and help to perpetuate and aggravate the disease. By weakening or eliminating the reception of pain impulses, analgesics prevent over-irritation of the central nervous system and help medically protective inhibitions to develop and the higher regulative mechanisms to resume their functions.

Of the pain-killing substances, promedol- a synthetic substitute for morphine - is of considerable interest. It is a new analgesic, synthetized in 1951 by Academician I. N. Nazarov. In chemical parlance, it consists of hydrochloride of 1,2,5-trimethyl-4-phenyl-4-propionoxypiperidine.

Full size image: 5 kB

It is a white crystalline powder with a bitter taste. It is soluble in water, alcohol and chloroform, and insoluble in ether and benzol. Promedol solutions have an almost neutral reaction, remain stable when stored and are sterilized by heating to 100o for thirty minutes or to 120o for fifteen minutes. Its pharmacological properties have been studied by M. D. Mashkovsky, V. I. Ishchenko, V. I. Legostev, Siu Bin, L. I. Grebennik, E. N. Guseva and others.

The pain-killing effect of promedol resembles that of morphine and its synthetic substitutes. The organism usually supports it better than morphine or pantopon; it does not cause vomiting or constipation, and has an anti-spasmodic action.

Promedol is used as an analgesic for pains of various origins: ulcer pains, cholecystitis, stenocardia, infarct of the myocardium, colics of the intestines and kidneys, and other diseases accompanied by a pain syndrome.

In surgery, promedol is indicated for various traumata for administering before operations and for post-operative pains.

An analgesic effect is also observed in cases of malignant tumours.

In midwifery, promedol is valuable as an analgesic and for hastening the birth. It has no toxic effect on the mother or child (G. A. Tonkikh, A. M. Foy, V. M. Karatygin, Z.I. Roshnova, S.V. Bazanova and others). Despite this relatively wide range of uses, the effect of promedol on the higher nervous activity after one or (and this is particularly important) more doses has not been adequately studied.

In the research test described below, we observed the effect of one or more doses of promedol on the bioelectric activity of the brain cortex in animals.

Method

The experiments were performed on rabbits of both sexes weighing 2,000-3,220 g.

The bioelectric potentials of the animal’s brain cortex were recorded by a six-channel electroencephalographic machine. During the test the rabbits were tied down to a special bench and placed in a sound-proof chamber insulated from interference.

In most cases the electroencephalogram was made with unipolar right and left frontal and occipital localization after the animal had been left for fifteen minutes to adapt itself to the dark inside the chamber. The animal’s bio-potentials were first recorded at normal and then at 5, 15 and 30 minutes and 1, 11/2, 2 and 3 hours after administration of the promedol in the form of varying doses of a 1% aqueous solution.

Results

In experiments with a single subcutaneous injection of promedol in doses of 0.25, 0.5 and 1 mg/kg, no marked changes in the brain cortex potentials were observed.

With doses of 3 to 5 mg/kg, marked changes developed. The number of slow waves (1 to 6.5 c/s) and alpha waves (7.5 to 12 c/s) increased and the number of beta waves (15 to 30 c/s) and faster ones (30 c/s and over) decreased. The amplitude of the bio-electrical waves increased. These deviations were particularly marked 30 and 60 minutes after injection but became more moderate after 21/2to 3 hours, when the waves more or less returned to their original pattern.

In the case of rabbit No. 12 before injection; for example, irregular slow waves predominated on the EEG as the background to a large number of fast waves (photograph No. 1). In particular, on a section of the left frontal recording showing the bio-potentials for five seconds there were 10 slow, 14 alpha and 80 beta waves, out of a total of 107 waves in all. The average voltage of the bio-potentials, calculated with a planimeter, was 5.13 microvolts.

Photograph No. 1. - Original condition. Rabbit No. 12, weight 2,400 g

Full size image: 14 kB, Photograph No. 1.  -  Original condition. Rabbit No. 12, weight 2,400 g

Photograph No. 2. - 30 minutes after a 5 mg/kg subcutaneous injection of promedol

Full size image: 14 kB, Photograph No. 2.  -  30 minutes after a 5 mg/kg subcutaneous injection of promedol

On the right, occipital recording there were 12 slow, 20 alpha and 30 beta waves, while the total number of waves was 72. The average voltage was about 3.4 microvolts.

Thirty minutes after a 5 mg/kg subcutaneous injection of promedol, the EEG showed high slow waves as the background to a large number of fast waves of very small amplitude (photograph No. 2). On the left frontal recording the number of alpha waves increased from 14 to 19 and the number of slow waves from 10 to 14. The frequency of the slow waves dropped from 5-6 to 1-3 c/s, the number of beta waves from 80 to 29 and the total number of waves from 107 to 70. The average voltage rose from 5.13 to 11.33 microvolts.

On the right occipital recording the slow waves increased in number from 12 to 19 and were very long. The number of beta waves dropped from 30 to 9 and the total number of waves from 72 to 55. The average voltage rose from 3.4 to 7.2 microvolts.

After 3 hours the brain cortex potentials were almost back to their original pattern (photograph No. 4).

Papers by various writers (S. A. Sarkisov, V. S. Rusinov, M. N. Livanov, P. I. Spilberg, P. I. Gulyaev and others) have shown that a decrease in the number of fast waves and an increase in the number of slow waves indicate an increase in the inhibiting processes in the brain cortex. It would appear from the EEG changes shown above that the doses of promedol studied cause the inhibiting processes in the brain cortex to predominate. This tallies with the data obtained by N. D. Mashkovsky, V. I. Ishchenko, V. I. Legostev, O. N. Voevodina, Siu Bin and others, who found, by the conditioned reflex and the impulse aggregation methods, that promedol in these doses reduces the excitability of the cortex of the cerebral hemispheres.

In clinical pratice, a highly important criterion for determining the value of analgesics is habituation and addiction to them by the patient. Much attention has been given to this question in experimental and clinical tests of analgesics (articles by H. Isbell, H. F. Fraser, A. Wikler and others), but an adequate study of habituation to promedol has yet to be made. Whereas B. I. Legostev, Sin Bin and E. N. Guseva say that habituation occurs, M.D. Mashkovsky and V.I. Ishchenko state that none was observed in rats and dogs after testing with repeated promedol injections.

Photograph No. 3, - 60 minutes after a 5 mg/kg subcutaneous injection of promedol

Full size image: 15 kB, Photograph No. 3, - 60 minutes after a 5 mg/kg subcutaneous injection of promedol

Photograph No. 4. - 3 hours after promedol injection

Full size image: 14 kB, Photograph No. 4.  -  3 hours after promedol injection

Photograph No. 5. - After two weeks of daily 5 mg/kg promedol injections. Original condition before regular injection

Full size image: 15 kB, Photograph No. 5. - After two weeks of daily 5 mg/kg promedol injections. Original condition before regular injection

The next stage of our research was to observe the changes in the brain cortex potentials after the rabbits had been given promedol injections over a period of two weeks.

Photograph No. 6. - 30 minutes after a 5 mg/kg subcutaneous injection of promedol

Full size image: 16 kB, Photograph No. 6.  -  30 minutes after a 5 mg/kg subcutaneous injection of promedol

Photograph No. 7 - 60 minutes after injection

Full size image: 16 kB, Photograph No. 7  -  60 minutes after injection

Photograph No. 8. - 3 hours after injection

Full size image: 16 kB, Photograph No. 8. - 3 hours after injection

The animals were given a 3-5 mg/kg subcutaneous injection twice a day. Every three days the changes in the bio-electric potentials due to regular promedol injections were ascertained.

The experiments showed that after promedol had been taken for a week the succeeding injection always produced the changes in the electrical waves described above - i.e., an increase in the number of slow and alpha waves, a larger number of fast waves and an increase in the amplitude of the bio-electrical waves. But these changes lasted a shorter time, and after 1-1? hours the EEG wave pattern resembled the original one.

Photograph No. 9 . - Two weeks from the commencement of daily 5 mg/kg injections of promedol. Original condition

Full size image: 18 kB, Photograph No. 9.  -  Two weeks from the commencement of daily 5 mg/kg injections of promedol. Original condition

Photograph No. 10. - Same rabbit, 30 minutes after a 15 mg/kg subcutaneous injection of promedol

Full size image: 14 kB, Photograph No. 10.  -  Same rabbit, 30 minutes after a 15 mg/kg subcutaneous injection of promedol

By the end of the second week it was found that the regular promedol injection no longer produced this effect (photographs Nos. 6, 7 and 8).

From the data obtained it may be concluded that habituation develops in the rabbits after a long series of promedol injections. Habituation was expressed in our experiments by the reaction of the bio-electrical waves to the regular injection becoming weaker and finally disappearing.

In rabbits which had been injected over a period of two weeks these changes in the bioelectrical waves occurred only when the dose was increased to 10-15 mg/kg.

Prior to the regular promedol injection the rabbits’ EEG (photograph No. 9) showed irregular slow waves forming the background to fast waves. In the left frontal recording there were 10 slow and 16 alpha waves, 56 beta waves and 97 waves in all. The average voltage was 7.13 microvolts.

In the right occipital recording there were 14 slow, 19 alpha and 34 beta waves, and 71 waves in all. The average voltage was 10.33 microvolts.

After the rabbit had received a 15 mg/kg injection the EEG showed high slow waves (photograph No. 10). The number of fast waves decreased.

Photograph No. 11. - 60 minutes after a 15 mg/kg subcutaneous promedol injection

Full size image: 15 kB, Photograph No. 11.  -  60 minutes after a 15 mg/kg subcutaneous promedol injection

Photograph No. 12. - Three hours after a 15 mg/kg subcutaneous promedol injection

Full size image: 17 kB, Photograph No. 12.  -  Three hours after a 15 mg/kg subcutaneous promedol injection

In the left frontal recording the slow waves increased in number from 10 to 15 and sharply decreased in frequency. The number of beta waves dropped from 56 to 24 and the total number of waves from 97 to 70. The average voltage rose from 7.13 to 9.4 microvolts.

Although in the right occipital recording the slow waves showed practically no change in number (15), their frequency decreased from 5-6 to 1-3 c/s. The number of beta waves dropped from 34 to 21 and the total number of waves from 71 to 60. The average voltage rose from 10.33 to 12.2 microvolts.

In this case, however, the pattern of the bioelectrical potentials approximated to the original one three hours after the prome-dol injection (photograph No. 12).

Conclusion

It may be conclued from our experiments that in rabbits given subcutaneous injections of 0.25-0.5-1 mg/kg of prome- dol, no discernible changes in the brain cortex potentials occur.

When the dose was increased to 3-5 mg/kg the number of alpha waves and slow waves increased. Their frequency decreased considerably and their amplitude increased. The number of fast waves invariably fell. This may indicate the predominance of inhibiting processes in the central nervous system.

With repeated injections, the animals develop an habituation to promedol, as was indicated by the disappearance of the normal reaction of the bioelectrical brain-waves to regular injection.

An intensification of the inhibiting process in these animals can be brought about only by increasing the dose to 10-15 mg/kg. This is evidence of a decrease in the sensitivity of the central nervous system to promedol and the occurrence of habituation to it.

Bibliography

BAZANOVA, S. V.: Clinical Medicine, 1954, Vol. 32, No. 6, pp. 80-81.

BAZANOVA, S.V.: Soviet Medicine, 1954, No. 10, pp. 39-40.

BAZANOVA, S.V. & KLIMENTYEV, F.V. : Clinical Medicine, 1954, Vol. 32, No. 6, pp. 77-79.

VOEVODINA, O.N.: Pharmacology and Toxicology, 1954, Vol. 17, No. 1, pp. 8-12.

GEFTER, A.I. & MATUSOVA, A. F .: Soviet Medicine, 1955, No. 8, pp. 22-25.

GOROBETZ, E. F. & NASONOV, B. A.: Medical Matters (Vrachebnoe delo), 1956, No. 4, pp. 425-428.

GRASCHENKOVA, Z.P. & KHOKHLOVA, G.P.: Midwifery and Gynaecology, 1954, No. 6, pp. 36-38.

GREBENNIK, L. I.: Pharmacology and Toxicology, 1954, No. 4, Vol. 17, pp. 48-51.

GULYAEV, P.I.: Papers read at the First Conference on Physical Research Methods in Biology, Moscow, 1954, p. 19.

DICHESKUL, S.V.: Grekov Bulletin of Surgery, 1955, No. 9, Vol. 76, pp. 81-84.

IZOSIMOV, V.V.: Clinical Medicine, 1954, No. 8, pp. 63-65.

KARATYGIN, V.M. & ROZHNOVA, Z. I.: Clinical Medicine, 1953, No. 3, Vol. 31, pp. 64-67.

KRUGLIKOVA-LVOVA, R.P.: Pharmacology and Toxicology, 1953, Vol. 16, No. 3, pp. 8-11.

KRUPKO, A. Ya.: Midwifery and Gynaecology, 1955. No. 1, pp. 8-13.

LEGOSTEV, V.I.: Pharmacology and Toxicology, 1952, No. 4, pp. 20-23.

LIVANOV, M. N.: Soviet Neuropathology, Psychiatry and Mental Health, 1945, Vol. 3, No. 11-12, p. 98.

LIVANOV, M. N.: Transactions of the Brain Institute, 1938, 3-4, p. 483.

LIVANOV, M.N. : Papers read at the Eighth All-Union Congress of Physiologists, Biochemists and Pharmacologists, 1955, p. 384.

MASHKOVSKY, M. D. & ISHCHENKO, V. I.: Pharmacology and Toxicology, 1952, No. 4, pp. 11-19.

NAZAROV, I. N., MASHKOVSKY, M. D., RUDENKO, V. A., PROSTAKOV, N. S. & ISHCHENKO, V. I.: Clinical Medicine, No. 8, pp. 60-63.

RADUGIN, K.B.: Bulletin of Oto-rhino-laryngology, 1954, No. 2, pp. 68-70.

RUSINOV, V. S.: Bulletin of Experimental and Biological Medicine, 1944, Vol. 17, No. 6, p. 18.

RUSINOV, V.S.: Transactions of the Seventh All-Union Congress of Physiologists, Biochemists and Pharmacologists, 1947, p. 201.

RUSINOV, V. S.: Papers for the First Conference on Physical Methods in Biology, Moscow, 1954, p. 57.

SARKISOV, S. A.: Soviet Neuropathology, Psychiatry and Mental Health, 1935, Vol. 4, No. 6, p. 1.

SARKISOV, S.A. & LIVANOV, M.N.: Soviet Neuropathology, Psychiatry and Mental Health, 1933, Vol. 2, No. 10, p. 1.

SARKISOV, S.A. & LIVANOV, M.N.: First Session of the Neuro-surgical Council, 1937, p. 67.

SIGIDIN, Ya. A.: Soviet Medicine, 1953, No. 10, pp. 25-27.

SOKOLOV, I.V.: Soviet Medicine, 1955, No. 8, pp. 26-28.

SIU BIN.: Pharmacology and Toxicology, 1955, Vol. 18, No. 4, pp. 8-12.

SIU BIN: Papers read at the Eighth All-Union Congress of Physiologists, Biochemists and Pharmacologists, Moscow, 1955, pp. 596-597.

SIU BIN: Pharmacology and Toxicology, 1956, Vol. 19, No. 3, pp. 33-36.

TESALOVA, O.T.: Socialist Care of Public Health in Uzbekistan, 1955, 4, pp. 80-81.

TONKIKH, V. A.: Pharmacology and Toxicology, 1952, No. 4, pp. 24-25.

FOY, A. M.: Pharmacology and Toxicology, 1952, No. 4, pp. 25-26.

KHODASEVICH, A. P.: Chemical Matters (Aptechnoe delo), Vol. 4, No. 5, p. 38.

TZOBKALLO, G. I., SAFRONOV, N. S., & FEDOROV, V. K.: Papers read at the Eighth All-Union Congress of Physiologists, Biochemists and Pharmacolagists, Moscow, 1955, pp. 663-664.

SHCHARTZ, S.E. & KOTOVA, E. S.: Soviet Medicine, 1955, No. 2, pp. 75-77.

SHPILBERG, P.I.: Transactions of the Seventh All-Union Congress of Physiologists, Biochemists and Pharmacologists, 1947, p. 131.

EIDINOVA, M.B.: Soviet Medicine, 1954, No. 11, pp. 12-14.

** *

ISBELL, H. & FRASER, H. F. : Journal of Pharmacology and Experimental Therapy, 1950, Vol. 99, pp. 355-397.

WIKLER, A.: Journal of Pharmacology and Experimental Therapy, 1950, Vol. 100, pp. 435-506.