Promedol: technical characteristics, use and addiction liability

Sections

I.-Technical characteristics
II. - Use of promedol
III. - Addiction liability of promedol
Discussion of results
Conclusions
BIBLIOGRAPHY

Details

Pages: 27 to 35
Creation Date: 1957/01/01

Promedol: technical characteristics, use and addiction liability

Promedol is a synthetic analgesic of the pethidine group which was developed in the Union of Soviet Socialist Republics in the early ' fifties '; was first reported as not producing addiction; but was later found to create addiction. It is usually more easily borne than morphine, and is used in the U.S.S.R. as a substitute for it, especially in obstetrics.

Promedol has been authorized by the Pharmacological Committee of the Scientific Council of the Ministry of Health of the U.S.S.R., 2 June 1955. Its supply and use are subject to the same restrictions as the supply and use of morphine.

The following documents transmitted by the Government of the U.S.S.R. give the technical characteristics of the drug, its action and instructions for its use.

I.-Technical characteristics

Chemical name : 1,2,5-trimethyl-4-phenyl-4-propionoxypi-peridine hydrochloride.

Formula:

Full size image: 6 kB

Mol. Wt.: 311.84.

Physical properties : A white, crystalline powder with a bitter taste, soluble in water, in alcohol and in chloroform; insoluble in ether and benzene. Solutions of the compound are almost neutral, are stable when stored, and are rendered sterile by exposure to a temperature of 100°C for 30 minutes, or to a temperature of 120°C for 15 minutes.

Pharmacological properties : Promedol is a potent analgesic. In its analgesic action it resembles morphine and the latter's synthetic substitutes (pethidine (lidol) and methadone).

The compound has spasmolytic properties.

Promedol is usually more easily borne than morphine Or pantopon. It does not cause vomiting or constipation. When the drug is taken over a prolonged period, symptoms of tolerance and addiction may develop.

Identification tests : When 0.5 ml of dilute nitric acid and a few drops of silver nitrate solution are added to 3 ml of a 2% aqueous solution of the compound, a white, flocculent precipitate is produced. When 5 drops of a saturated solution of picric acid are added to 3 ml of an identical solution of the compound, a yellow precipitate is produced.

Tests for purity : 0.4 g of the compound are dissolved in 20 ml of water. 10 ml of this solution must not contain more sulphates than 10 ml of the standard solution-i.e., the compound must not contain more than 0.05% of sulphates.

The addition of one drop of a solution of methyl orange to 5 ml of the same solution produces a yellow colouration which changes to red when two drops of a 0.1 N solution of hydrochloric acid are added (limit test for alkalinity).

About 0.5 g of the compound are weighed out accurately into a tared crucible moistened with 0.5 ml of concentrated sulphuric acid, carefully warmed on the hot-plate until all the sulphuric acid fumes have been expelled, and ignited to constant weight. The weight of the residue must not exceed 0.1% of that of the original compound, and must not contain more heavy metals than l0 ml of the standard solution i.e., the compound must not contain more than 0.001% of heavy metals.

Assay : 0.25-0.30 g of the compound (accurately weighed) are placed in a 50-ml Kjeldahl flask, and 20 ml of a 10% solution of sulphuric acid added. The flask is connected to a source of steam (apparatus for determining nitrogen content-cf. Gosud. Pharmokopeia [State Pharmacopeia], eighth edition, 1952, p. 637) and the propionic acid distilled over into a receiver containing 50 ml of distilled water. When 250-300 ml of the distillate have been collected, the receiver is changed (200 ml are collected for each subsequent batch). To remove the carbon dioxide from each batch of distillate, air from which the carbon dioxide has been removed-by passing it through a washing bottle containing a 10% solution of alkali - is bubbled through the distillate for 30 minutes. Each batch of distillate is then titrated against a 0.1 N solution of caustic soda, using phenophthalein as an indicator. Distillation is stopped when the same number (not more than 0.1-0.15) of mi of the 0.1 N solution of caustic soda is consumed in titrating two successive batches of distillate. This number of ml, multiplied by the number of batches titrated, is subtracted from the total volume of the 0.1 N solution of caustic soda consumed in titrating all the batches.

1 ml of the 0.1 N solution of caustic soda corresponds to 0.03118 g of promedol, of which there must be not less than 98. 0% in the compound.

Solutions:There are 1% and 2% solutions of promedol in ampoules. Their composition is : 1% solution : 10g of promedol up to 1 l of water; 2% solution : 20 g of promedol up to 1 l of water.

Method of preparation : The solution is filtered and poured into inert glass ampoules, 1.1 ml per ampoule. The ampoules are sealed and sterilized in a current of steam at 100°C for 30 minutes, or in an autoclave at 120°C for 15 minutes.

Properties: A transparent, colourless liquid which does not readily wet glass. pH: 4.5-6.0.

Identification tests: When 0.5 ml of a 10% solution of nitric acid and 0.5 ml of a 0.1 N solution of silver nitrate are added to 1 ml of the preparation, a white, flocculent precipitate is produced.

When three drops of a saturated solution of picric acid are added to 1 ml of the preparation, a yellow precipitate is produced.

Assay: 5 ml of a 10% solution of nitric acid and 10 ml of a 0.1 N solution of silver nitrate are added to 10 ml of the preparation. The flask is shaken for two to three minutes. The excess silver nitrate is titrated against a 0.1 N solution of ammonium thiocyanate. Indicator: ferric-ammonium alum.

One millilitre of a 0.1 N solution of silver nitrate corresponds to 0.031184 g of promedol, of which there must be, in 1 ml of the promedol solution, 0.0097-0.0103 g in the case of the 1% solution, and 0.0194-0.0206 g in the case of the 2% solution.

Packing: The ampoules containing the preparation are packed in cardboard boxes on which labels are pasted. On the top of each box is a banderole of the prescribed type, the ends of which are secured by the seal of the producing factory·

Storage:Under lock and key (schedule A) in well-stoppered jars or in sealed ampoules. Period for which the preparation can be stored (solution) one year.

II. - Use of promedol

Indications for use: Promedol is used as an analgesic for relieving pain of various origins. In clinics for internal diseases, it may be used in cases of ulcer, cholecustitis, angina pectoris, infarct of the myocardium, intestinal and nephritic colic, and in other illnesses accompanied by painful syndromes.

In surgery, promedol is used in various traumatic conditions, to relieve post-operational pain, and in preparing the patient for operation.

The drug is an effective analgesic for patients suffering from malignant tumours.

In obstetrics, promedol is used to relieve pain and to accelerate labour.

Administration and dosage: Promedol is administered per os or subcutaneously.

Doses of 0.025-0·05 g are used for administration per os,and 1 ml of a 1% or 2% solution for subcutaneous injection.

Doses of 1 ml of a 1% solution administered subcutaneously, or of 0.025-0.05 g administered per os,produce a well marked analgesic effect on pain of various origins. Where the pain is severe, however, and particularly in cases of malignant tumour, severe injuries, etc., it is preferable to administer 1 ml of the 2% solution subcutaneously.

The drug is usually administered once or twice per 24 hours.

Promedol usually takes effect within 10-20 minutes of being administered, its action continuing for 4-6 hours or more after a single dose.

As with other analgesics, the degree and duration of the analgesic action may vary, depending on the special features of the case. Besides being relieved of pain, the patient often becomes drowsy or goes to sleep.

To produce painless childbirth, promedol is administered subcutaneously in doses of 2-3 ml of a 1% solution. The drug is administered after the contractions have become regular, when the os uteri is dilated to a diameter of not less than 1?-2 inches, and where the condition of the foetus is satisfactory (normal rhythm and frequency of heartbeats).

Promedol not only has an analgesic action but also, by reason of its spasmolytic properties, accelerates the dilatation of the os uteri and shortens labour.

The following maximum doses have been temporarily laid down : maximum single dose administered per os, 0.075; subcutaneously, 0.04, maximum 24-hr dose administered per os, 0.15; subcutaneously, 0.08.

Contra-indications:Promedol is contra-indicated in old age and in cases of depression of the respiratory centre.

Possible complications: In rare cases, slight nausea is observed, and sometimes slight dizziness. These symptoms disappear by themselves. If side-effects are observed when the drug is administered for the second time, the dose must be reduced.

III. - Addiction liability of promedol

Statement by T. Kovalyukh, principal physician at the Lvov Psycho-Neurological Hospital

The treatment of promedol addicts was begun in the Narcotics Department of the Lvov Psycho-Neurological Hospital in 1955. Addiction to promedol may arise where the drug is taken as an analgesic, prescribed as a substitute for morphine by doctors at hospitals in cases of ulcer, angina pectoris, hepatic colic, bronchial asthma and other diseases. Observation of the development of the abstinence syndrome in promedol addicts indicates that, in the majority of cases, the sensations of discomfort, distress and sickness are more intense than in the case of morphine addicts.

It has been observed that emaciation sets in much more quickly in promedol addicts than in morphine addicts.

According to statements made by patients, the largest dose of promedol taken was 120 ml of a 2% solution. Some patients buy promedol in powder form and prepare a more concentrated solution themselves.

In all, sixteen promedol addicts underwent treatment in our hospital. Ten of them had previously taken morphine and had then changed to promedol, and six had become addicted to promedol during treatment for angina pectoris, ulcer, bronchial asthma or hepatic colic.

The question of addiction to promedol was discussed in the Psychiatric Section of the Lvov Psycho-Neurological Hospital in the presence of the eminent scientist, Professor E.V. Maslov. Reports of addiction to promedol are also coming in from specialists in other branches of medicine.

Statement by Professor Popov, Director of the "S.S. Korsakov" Psychiatric Clinic at the First Moscow Medical Institute

There was a patient in our clinic whose condition was diagnosed as drug addiction: misuse of promedol.

The patient began using injections of promedol in the summer of 1954 to relieve phantom limb pains after the amputation of a leg. Addiction to promedol quickly developed, and the patient gave himself injections of promedol of up to 75 ml of a 1% solution. He experienced sensations of distress in the absence of the drug.

During his first days in the clinic, pronounced abstinence phenomena were observed, similar to those which accompany abstinence from morphine.

Conclusions of an article by E.N. Guseva 1 entitled "Comparison between the analgesic action of Promedol, Phenadone 2,Tecodine 3 and Morphine"

The action of promedol, phenadone, tecodine and morphine were investigated in experiments carried out on dogs, cats, rabbits, rats and frogs. In the experiment on rats, the relation between the potency of the analgesic action and the size of the dose administered was investigated.

  1. The action of promedol, tecodine and phenadone resembles that of morphine. This is shown by the visible signs of reaction to these drugs.

  2. A comparison of the therapeutic potency of all three drugs and the corresponding data for morphine showed that morphine has the most potent analgesic and the strongest therapeutic action, and that phenadone and tecodine are the least effective in these respects. In a series of investigations of these drugs, promedol took an intermediate place.

  3. When promedol, phenadone, tecodine and morphine were administered daily to rats over a period of 10 to 15 days, symptoms of addiction appeared, and when the drugs were suddenly withdrawn, the animals displayed symptoms which could be described as abstinence phenomena (temporary loss of weight, fever and increased motor activity). These phenomena gradually subsided over 5 to 7 days, after which the animals' sensitivity to the drugs was found to have been restored.

The Influence of Promedol on the Processes of Excitation and Inhibition of the Cerebral Cortex 4by Prof. Sin Bin 5

Promedol is a new analgesic agent, synthesised in the Soviet Union by Academician I. N. Nazarov. This compound has already been used in surgical, obstetric and other clinics (Tonkikh, Foy & others, 1952).

The influence of promedol on the fundamental processes, which take place in the cerebral cortex, has hitherto been insufficiently studied. In 1954, O. N. Voyevodina established the fact that promedol has a specific action only on the process of excitation of the cerebral cortex. These findings agree with the results of our observations of mice in experiments carried out using the motor-defence method of investigating conditioned reflexes (Siu Bin, 1954).

1 See Pharmakologiya i Toxikologiya, 6, 1956.

2Phenadone = Methadone (proposed international non-proprietary name of 4,4-diphenyl-6-dimethylamino-heptanone-3).

3 Tecodine = Oxycodone (recommended international non-proprietary name of dihydrohydroxycodeinone).

4See Pharmakologiya i Toxicologiya, 4, 1956.

5Chair of Pharmacology (Director: Professor V. V. Zakusov, Active Member of the Academy of Medical Sciences of the U.S.S.R.) of the First Leningrad Medical Institute, named after Academician I. P. Pavlov, and Department of Physiology, named after Academician I. P. Pavlov (Director : Professor P. S. Kupalov, active member of the Academy of Medical Sciences of the U.S.S.R.), of the Institute of Experimental Medicine of the Academy of Medical Sciences of the U.S.S.R.

To elucidate the influence of promedol on higher nervous activity, we carried out investigations on dogs.

The experiments were carried out on three animals by the conditioned reflex method. On two dogs (Inga and Palma), the experiments were made in a soundproof room by Pavlov's classical method. In these dogs, positive conditioned reflexes were established to the following conditioned stimuli : the sound of a metronome with a frequency of 120 beats a minute; the light of a 40-watt electric lamp, the ringing of an electric bell; and a change in the frequency of the metronome to 60 beats a minute (discrimination). The conditioned stimuli were applied in a definite order, and were maintained for thirty seconds before the unconditioned reinforcement, consisting of a meal of 20 g of a meat-sugar powder, mixed with water in the proportions of 2: 1, was supplied. The stimuli were applied at intervals of four minutes.

The conditioned and unconditioned secretion from the parotid gland was recorded by means of a scale, one division of which corresponded to 0.01 ml of liquid. Conditioned reflex salivation was measured for thirty seconds, and unconditioned-reflex salivation for each thirty seconds of the first minute from the moment when the dog started eating.

With the third dog, Buyan, we worked by Kupalov's method, the animal being allowed freedom of movement within the experiment room (1948). The following complex conditioned motor reflexes were established in Buyan: (1) a conditioned reflex to a particular spot in the experiment room; and (2) a conditioned reflex to the sound of a bell or metronome, by discriminating between which the dog was able to tell the position of the unconditioned reinforcement.

To the sound of the metronome (M 120), the unconditioned reinforcement was placed on a table facing the dog; to the sound of the bell, the food reinforcement was placed on a table to the left of the animal. On the day on which the experiments were carried out, the conditioned stimuli - the bell and the metronome - were applied six times in random order, to avoid building up a stereotyped pattern of behaviour. The conditioned stimuli (the bell and metronome) were reinforced by the meat-sugar powder mixed with water (2 : 1). In the experimental report we noted: (1) the time taken to run to the table; (2) the duration of the act of eating; (3) the period for which the dog stayed on the table after he had eaten the food; and (4) the elapsed time up to the moment of the animal's return to the conditioned spot in the experiment room.

We started experimenting on the three dogs with promedol after a definite background of conditioned reflexes had been established.

The drug, prepared in an isotomic solution of NaCl, was administered to the dogs subcutaneously twenty minutes before the start of each experiment. We studied the change in the animals' higher nervous activity following the administration of promedol in doses of 0.005, 0.01, 0.1, 0.25, 0.5 and 1mg/kg.

The experiments showed that in small doses (0.005 mg/kg was given to Palma, and 0.01 mg/kg to Inga) promedol increases the excitability of the cerebral cortex. Reports Nos. 250, 251 and 252 show that, under the influence of an 0.01 mg/kg dose of promedol, the strength of the secretory conditioned reflexes increased considerably. Thus in Inga's case the level of the positive conditioned reflexes increased as follows (average figures based on three experiments) : in response to the bell, by 78%; in response to the metronome, by 97%; and in response to light, by 50%. The latent period of the conditioned secretory reflex was shortened by one to four seconds. At the same time, the power of discrimination was not impaired, and the relative strengths of the conditioned reflexes were unaffected. The reports also show that the volume of unconditioned saliva was substantially unchanged. The strength of the conditioned reflexes reverted to normal the day following the administration of a single dose of 0.01 mg/kg of promedol.

Records of experiments carried out on the dog Inga with a dose of 0.01 mg/kg of promedol

 

Volume of secretion from the parotid salivary gland (in divisions of the scale)

   

Unconditioned

Serial No.

Conditioned stimulus

Interval between conditioned stimuli in minutes

Duration of the isolated action of the conditioned stimulus (in seconds)

Latent period of conditioned secretory stimulus (in seconds)

Conditioned for 30 seconds

First 30 seconds

Second 30 seconds

Experiment No. 250

Started at 3.30 p.m. on 24 April 1954 (before administration of promedol)

 
Food supplied at once
 
 
 
 
100 42
615
Bell
4 30 5 22 91 41
629
M 120
4 30 6 34 101 25
165
M 60
4 30 7 4
Not reinforced
 
630
M 120
4 30 5 37 100 47
475
Light
4 30 8 10 103 40

Experiment No. 251

Started at 3.30 p.m. on 25 April 1954. (A dose of 0.01 mg/kg of promedol was administered 20 minutes before the start of the experiment.)

 
Food supplied at once
 
 
 
 
110 51
616
Bell
4 30 4 45 101 52
631
M 120
4 30 5 84 90 55
166
M 60
4 30 5 6
Not reinforced
 
632
M 120
4 30 5 74 99 52
476
Light
4 30 4 15 93 50

Experiment No. 252

Started at 3.30 p.m. on 26 April 1954 (day following administration of promedol)

 
Food supplied at once
 
 
 
 
105 58
617
Bell
4 30 7 17 103 41
633
M 120
4 30 5 32 110 50
167
M 60
4 30 8 3
Not reinforced
 
634
M 120
4 30 6 28 111 50
477
Light
4 30 8 8 99 60

Similar results were obtained with Palma. But an increase in the strength of the positive conditioned reflexes was observed with a smaller dose (0.005 mg/kg).

TABLE 1

The influence of promedol on the reflex motor activity of dogs in response to conditioned stimuli

 

Average quantities

 
 

Time taken to run to table (Seconds)

Duration of act eating (Seconds)

Period for which dog stayed on table (Seconds)

Time spent moving about room (Seconds)

Duration of experiment

Before administration of promedol
3.0 13.5 3.0 23 15
After administration of 0.01 mg/kg of promedol
2.2 13.0 2.3 9 13
On day following administration of promedol
3.1 13.2 3.2 20 14?

TABLE 2

The influence of promedol on the reflex motor activity of dogs in response to conditioned stimuli

 

Average quantities

 
 

Time taken to run to table (Seconds)

Duration of act eating (Seconds)

Period for which dog stayed on table (Seconds)

Time spent moving about room (Seconds)

Duration of experiment

Before administration of promedol
3.4 13.1 2.9 21
18' 30"
After administration of 0.5 mg/kg of promedol
3.3 13.3 2.8 22
17' 37"
On day following administration of promedol
3.4 12.9 3.1 20
18' 3"

The following changes were observed in Buyan under the influence of a dose of 0.01 mg/kg of promedol, the dog being allowed freedom of movement (Table 1) : (1) The time taken to run to the table in response to the conditioned stimuli (metronome or bell) was reduced; (2) the dog did not stay so long on the table after the meal; and (3) the dog returned more quickly to the conditioned spot in the experiment room. These facts show that, on administration of the dose of promedol mentioned, the excitability of the cerebral cortex is increased, and the animal’s reflex motor activity in response to conditioned stimuli consequently improved.

The experiments justify the conclusion that in small doses promedol causes an increase in the excitability of the cerebral cortex. This heightened excitability, however, does not affect the areas of the cortex to which the differential stimulus is addressed. This is proved by the fact that the animals' power of discrimination is not weakened.

When the doses of promedol were increased to 0.25 and 0.5 mg/kg, a decline was observed in the strength of the conditioned reflexes in Inga and Palma (reports Nos. 273, 274, 275, 279, 280 and 281). Thus, after a 0.25 mg/kg dose of the drug, the strength of the positive conditioned reflexes in response to positive conditioned stimuli decreased on an average by 20% in the case of the bell, by 15% in the case of the metronome, and by 40% in the case of light. The latent period of the conditioned reflexes was not noticeably affected. Moreover, the power of discrimination was unimpaired. On the day following the administration of the drug, reflex motor activity in response to conditioned stimuli was fully restored to normal.

Reports of experiments carried out on the dog Inga with a dose of 0.25 mg/kg of promedol

 

Volume of secretion from the parotid salivary gland (in divisions of the scale)

   

Unconditioned

Serial No.

Conditioned stimulus

Interval between conditioned stimuli in minutes

Duration of the isolated action of the conditioned stimulus (in seconds)

Latent period of conditioned secretory stimulus (in seconds)

Conditioned for 30 seconds

First 30 seconds

Second 30 seconds

Experiment No. 273

Started at 3.30 p.m. on 20 April 1954 (before administration of promedol)

 
Food supplied at once
 
 
 
 
107 60
638
Bell
4 30 5 20 110 50
675
M 120
4 30 5 32 113 42
188
M 60
4 30 6 4
Not reinforced
 
676
M 120
4 30 5 30 115 43
498
Light
4 30 6 10 101 51

Experiment No. 274

Started at 3.30 p.m. on 21 April 1954. (A dose of 0.25 mg/kg of promedol was administered 20 minutes before the start of the experiment.)

 
Food supplied at once
 
 
 
 
107 63
639
Bell
4 30 5 15 112 53
677
M 120
4 30 6 25 120 40
189
M 60
4 30 6 4
Not reinforced
 
678
M 120
4 30 5 26 120 38
499
Light
4 30 8 5 101 49

Experiment No. 275

Started at 3.30 p.m. on 22 April 1954 (day following administration of promedol)

 
Food supplied at once
 
 
 
 
110 62
640
Bell
4 30 5 21 115 48
679
M 120
4 30 5 30 114 41
190
M 60
4 30 6 3
Not reinforced
 
680
M 120
4 30 4 32 120 48
500
Light
4 30 6 9 108 44

Under the influence of a dose of 0.5 mg/kg of promedol, the strength of the positive conditioned reflexes was still further reduced : by 48% when the bell was used as a conditioned stimulus, by 40% when the metronome was used, and by 81% when light was used. The latent period was lengthened by three to five seconds. Salivation in response to the differential stimulus (M 60) was reduced by one division of the scale, and hence it may be taken that the inhibitory process was unaffected. The conditioned reflexes regained their former strength on the first or second day following the administration of the drug.

Reports of experiments on the dog Inga, with a dose of 0.5 mg/kg of promedol

 

Volume of secretion from the parotid salivary gland (in divisions of the scale)

   

Unconditioned

Serial No.

Conditioned stimulus

Interval between conditioned stimuli in minutes

Duration of the isolated action of the conditioned stimulus (in seconds)

Latent period of conditioned secretory stimulus (in seconds)

Conditioned for 30 seconds

First 30 seconds

Second 30 seconds

Experiment No. 279

Started at 3.30 p.m. on 27 April 1954 (before administration of promedol)

 
Food supplied at once
 
 
 
 
100 580
644
Bell
4 30 5 25 118 51
687
M 120
4 30 5 37 110 50
194
M 60
4 30 8 3
Not reinforced
 
688
M 120
4 30 5 35 115 43
504
Light
4 30 6 11 108 53

Experiment No. 280

Started at 3.30 p.m. on 28 April 1954. (A dose of 0.5 mg/kg of promedol was administered 20 minutes before the start of the experiment.)

 
Food supplied at once
 
 
 
 
96 72
645
Bell
4 30 8 13 121 33
689
M 120
4 30 7 17 97 70
195
M 60
4 30 8 2
Not reinforced
 
690
M 120
4 30 9 19 103 61
505
Light
4 30 11 2 101 59

Experiment No. 281

Started at 3.30 p.m. on 29 April 1954 (day following administration of promedol)

 
Food supplied at once
 
 
 
 
99 74
646
Bell
4 30 4 26 110 56
691
M 120
4 30 4 39 120 43
196
M 60
4 30 6 4
Not reinforced
 
692
M 120
4 30 5 37 119 50
506
Light
4 30 5 12 106 50

These figures show that in medium doses (0.25 and 0.5 mg/kg) promedol depresses the excitatory process. This is reflected in the diminished strength of the positive conditioned reflexes, the weakening of the conditioned reflex in response to a weak stimulus (light) being particularly marked and in the prolongation of the latent period of the conditioned reflexes. The power of discrimination is not impaired. Unconditioned salivation is not substantially affected by administration of promedol in the doses mentioned.

In experiments carried out on Buyan with freedom of movement within the experiment room, the administration of such doses of promedol (0.25 and 0.5 mg/kg) caused no substantial changes in reflex activity in response to conditioned stimuli (cf. Table 2).

Under the influence of larger doses of the drug (1 mg/kg), a sharp fall in conditioned salivation was observed in Inga and Palma, and the animals in all cases refused food (reports Nos. 257, 258, 259 and 260). The strength of the conditioned reflexes reverted to normal within one to two days of administration of this dose of the drug.

We also twice tested the influence of a large dose of promedol on Buyan's reflex motor activity in response to conditioned stimuli. During the first test, the dog refused food, whined, wandered around the room, showing signs of shortness of breath, scratched at the door and tried to get out of the experiment room. He did not stop at his usual place, which is for him a conditioned stimulus. The experiment of starting the metronome was therefore made in response to which the dog usually jumps on to the table, at the moment at which the animal was passing the place where he usually stands. The use of the metronome in these conditions evoked a negative motor reaction: Buyan ran to the door and tried to get out of the experiment room. We therefore stopped the experiments sooner than usual. Within three days of administration of this dose, reflex motor activity in response to conditioned stimuli regained normality. Two weeks after this experiment, we again administered a large dose (1 mg/kg) of promedol to the animal. This time, the following changes in higher nervous activity were observed in Buyan: he took longer to run to the table, and there was a sharp increase in the time during which he wandered around the room. In response to conditioned stimuli (metronome and bell), Buyan jumped on to the table, began to eat from the dish put before him, but stopped eating before he had half finished the meal.

Reports of experiments on the dog Inga, with a dose of l mg/ kg of promedol

 

Volume of secretion from the parotid salivary gland (in divisions of the scale)

   

Unconditioned

Serial No.

Conditioned stimulus

Interval between conditioned stimuli in minutes

Duration of the isolated action of the conditioned stimulus(in seconds)

Latent period of conditioned secretory stimulus(in seconds)

Conditioned for 30 seconds

First 30 seconds

Second 30 seconds

Experiment No. 257

Started at 3.30 p.m. on 1 April 1954 (before administration of promedol)

 
Food supplied
       
105
55
622
Bell
4
30
5
15
108
51
643
M 120
4
30
5
30
103
60
172
M 60
4
30
7
3
Not reinforced
 
644
M 120
4
30
6
36
115
50
482
Light
4
30
8
9
100
51

Experiment No. 258

Started at 3.30 p.m. on 2 April 1954. (A dose of 1 mg/kg of promedol was administered 20 minutes before the start of the experiment.)

 
Food supplied
       
Refused food
623
Bell
4
30
5
6
"
645
M 120
4
30
7
12
"
173
M 60
4
30
8
2
Not reinforced
646
M 12o
4
30
8
11
Refused food
483
Light
4
30
15
1
"

Experiment No. 259

Started at 3.30 p.m. on 3 April 1954 (day following administration of promedol)

 
Food supplied
       
108
50
624
Bell
4
30
5
18
91
49
647
M 120
4
30
5
27
118
27
174
M 60
4
30
9
3
Not reinforced
 
648
M 120
4
30
6
30
118
41
484
Light
4
30
8
6
113
37

Experiment No. 260

Started at 3.30 p.m. on 5 April 1954 (third day following administration of promedol)

 
Food supplied
       
105
38
625
Bell
4
30
5
20
107
45
649
M 120
4
30
4
33
112
40
175
M 60
4
30
7
3
Not reinforced
 
650
M 120
4
30
4
36
113
52
485
Light
4
30
6
11
103
50

Thus, in large doses (1 mg/kg), promedol not only lowers the level of the conditioned reflexes - a phenomenon typical of diminished excitability of the cerebral cortex - but also affects the alimentary centre.

INFLUENCE OF PROMEDOL ON THE EXTINCTION OF CONDITIONED REFLEXES

Vertical axis - volume of conditioned secretion, in scale divisions; horizontal axis - number of unreinforced conditioned stimuli

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To explain the influence of the drug on the course of the inhibitory process in the cerebral cortex, experiments were carried out on the extinction of conditioned reflexes. In Inga, the positive conditioned reflex to a metronome with a frequency of 120 beats per minute, applied at intervals of two minutes, was intermittently extinguished.

The experiments showed that, as a rule, in this animal the extinction of the conditioned reflex set in when the metronome, beating at a frequency of 120, was applied for the thirteenth time without reinforcement. After the administration of an 0.01 mg/kg dose of promedol, the extinction of the reflex was considerably delayed: it occurred at the twenty-first application of the conditioned stimulus. Under the influence of medium doses of the drug (0.5 mg/kg), the animal began to behave less excitedly than usual, extinction of the conditioned reflex occurring when the metronome, beating at 120, was applied for the sixth time without reinforcement. One week after the drug had been tested in this way, we carried out experiments on the extinction of the conditioned reflex without the administration of promedol. In this case, extinction set in at the twelfth application of the unreinforced stimulus (see graphic above).

These experiments justify the conclusion that promedol has some effect on the inhibitory process as well. When a small dose (0.01 mg/kg) is administered, promedol prolongs the development of the internal extinguishing inhibition; and in medium doses (0.5mg/kg) it strengthens this process, with the result that the extinguishing inhibition develops more rapidly. However, the increase or decrease in the speed at which the extinguishing inhibition develops is obviously the result of a change in the balance between the processes of excitation and inhibition in the cerebral cortex. Thus, in small doses promedol, by increasing the excitability of the cortex, encourages the predominance of the excitatory process. Consequently, to promote the extinguishing inhibition, the unreinforced conditioned stimulus must be applied a greater number of times than before administration of the drug. With medium doses of promedol, the excitability of the cerebral cortex is lowered. Hence the extinguishing inhibition develops considerably more quickly than when the drug is not administered.

Discussion of results

It is known from the literature that varying doses of drugs similar to promedol - morphine and phenadone - have different effects on the higher nervous activity of dogs. Thus, even during Pavlov's lifetime, I.V. Zavadsky (1908) established the fact that, when 0.01 g of morphine is administered sub-cutaneously, the natural and artificial reflexes in dogs are extinguished for a prolonged period. Restoration of the reflexes did not set in at the same time in all cases. The natural reflexes recovered their original strength in thirty minutes to one hour, and the artificial reflexes in seven to eight hours. Later, S.I.Potekhin (1911) thoroughly investigated the influence of morphine on higher nervous activity. He administered morphine to the animal in considerably smaller doses - 0.25 to 1.25 mg. He established that, after subcutaneous administration of such doses, the strength of the conditioned reflexes, both artificial and natural, is diminished. Potekhin then analysed this phenomenon in detail, and proved that the lowering of the level of the conditioned reflexes is connected with the action of the drug on the vomiting centre. This action is more strongly marked with larger doses of morphine.

In 1952, when studying the influence of phenadone on higher nervous activity in dogs, M.M.Lenkevich showed that the administration of small doses of the drug (0.001 to 0.004 mg/kg) causes an increase in the excitability of the cerebral cortex and impairs the power of discrimination. A therapeutic dose of phenadone (0.1 mg/kg) causes a reduction in the strength of the conditioned reflexes and an improvement in the power of discrimination.

A comparison of these data and the results obtained by us justify the conclusion that in its action on higher nervous activity promedol has certain special features not possessed by the analgesics mentioned above. In the first place, when administered in small doses, this drug increases the excitability of the cerebral cortex without impairing the power of discrimination. In the second place, medium (analgesic) doses of the drug somewhat reduce the strength of conditioned positive reflexes without affecting discrimination. While it may therefore be considered that, like morphine and phenadone, promedol influences higher nervous activity, it possesses the advantage of not producing the negative effects of these other drugs (the excitatory effect of morphine on the vomiting centre, and impairment of the power of discrimination caused by small doses of phenadone). There is reason to believe that these advantages will lead to the wider use of promedol in clinical practice.

Conclusions

  1. Promedol affects the course of the fundamental nervous processes which take place in the cerebral cortex in animals.

  2. Small doses of the drugs enhance the excitability of the cerebral cortex in animals; this increase is reflected in the greater strength of the positive conditioned reflexes, in conformity with the law of energy, and in retardation of the development of extinguishing inhibition.

  3. Medium doses of promedol (0.25 to 0.5 mg/kg) reduce the excitability of the cerebral cortex. This action is accom-panied by a reduction in the strength of the positive conditioned reflexes in accordance with the law of energy for conditioned stimuli, and in a reduction in the time required for internal inhibition to develop (in experiments with intermittent extinction of the conditioned reflex).

  4. Under the influence of large doses of promedol, a sharp drop (by 88% when a weak stimulus is applied) is observed in the strength of the positive conditioned reflexes. This indicates a reduction in the excitability of the cerebral cortex.

BIBLIOGRAPHY

Voevodina, O.M., Pharmakol. i Toksikol., 1954, vol. VIII, No. 1, p. 8; Zavadsky, I. V., Trudi Obshchesteva Russkikh Vrachei, 1908, p. 75; Kupalov, P.S., Obyedinennaya sessia, posvyashch desyatiletiu so dnya smerti I. P.Pavlova, 1948, p. 67; Lenkevich, M. M., Pharmakol. i Toksikol., 1952, vol. XV, No. 6, p. 22; Potekhin, S. I., Trudi Obshchesteva Russkikh Vrachei, 1911, p.78; Siu Bin, 5th nauchnaya konferentsiya aspirantov i klinicheskikh ordinatorov l-go Leningradskogo Med. (Instituta imeni akad. I. P. Pavlova, 1954, p. 95; Tonkikh, G. A ., Pharmakol. i Toksikol., 1952, vol. XV, No. 4, p. 24; Foy, A.M., ibid., 1952, vol. XV, No. 4, p. 25.