The Effects on the Cat of Addictive Morphine Derivatives and Synthetic Drugs (Mayor's Law)

Abstract

Dr. Sermet Akad, of the Medical Faculty of the Institute of Pharmacology, Istanbul University, explores in this article a method for determning in advance whether any narcotic is habit-producing. On the bases of Mayor's Law, he proposes to demonstrate that any narcotic inducing madness in the cat is also liable to cause drug addiction in man.

Details

Author: Sermet Akad
Pages: 10 to 14
Creation Date: 1952/01/01

TECHNICAL

The Effects on the Cat of Addictive Morphine Derivatives and Synthetic Drugs (Mayor's Law)

M.D. Sermet Akad

Dr. Sermet Akad, of the Medical Faculty of the Institute of Pharmacology, Istanbul University, explores in this article a method for determning in advance whether any narcotic is habit-producing. On the bases of Mayor's Law, he proposes to demonstrate that any narcotic inducing madness in the cat is also liable to cause drug addiction in man.

The habit-forming effects of opium, the oldest of all pain-relieving drugs, and of its main alkaloid, have been known for a long time. It is on account of this drawback that these substances cannot be freely used in medical practice. The harmful effects produced by the continual use of morphine can be summed up as follows:

  1. Morphine confers on the patient a euphoria which arouses the desire for continual use of this drug. Thus habituation and addiction are the results.

  2. The continued use of the drug makes it necessary for the subject to increase the doses in order to obtain the same effect (tolerance). When a person has arrived at that state he can, without any danger, absorb quantities of this drug far in excess of the dose which would be lethal to a person not habituated.

  3. After a certain time, the patient reaches a condition where he must use the drug in order to carry on his normal daily activities (physical dependence).

  4. The sudden suppression of the drug at this period causes severe symptoms (withdrawal symptoms).

  5. Continued use of the drug causes psychic as well as physical troubles.

One of the principal aims of research in new synthetic analgesics is to produce a substance capable of being used continually without causing addiction. The need for a practical method for the study of every new drug from that point of view is obvious It is beyond doubt that the most reliable method for such a purpose is extensive clinical application. Nevertheless, the first tests must certainly be limited to animals.

Many authors believe that the addiction liability of a drug can be determined by studying the development of tolerance, to some of the effects of the drug in animals. Joel and Ettinger, for example, have studied the development of tolerance to the analgesic and the narcotic effects of morphine. A rat that is tolerant to the narcotic effect of morphine is also tolerant to the narcotic effect of eucodal, dicodid and codein (cross-tolerance).

Seevers, Collins and Tatum have shown that rats become tolerant to the narcotic effect of morphine, but not to its exciting effect, and that tolerance to two different actions of morphine, such as the narcotic and analgesic effects, occurred at different speeds.

Lewis has shown that after daily injections of 1 mg. Win 1539, rats developed tolerance to its narcotic, sedative and hyperglycemic effects, but not to its hyperthermic and bradycardic effects.

Lewis has also shown that cross-tolerance to analgesic effects, against given thermal stimuli did not develop in dogs, between morphine and ketobemidon. But later on, Isbell proved ketobemidon to be far more effective than morphine in the treatment of morphine withdrawal symptoms.

These, as well as Ettinger's experiments, where codein is found to have properties similar to morphine, show that the development of tolerance to some effects, such as the narcotic or analgesic effects, are not sufficient to prove that a drug is habit-forming. Further-more, it is known that drugs such as atropin given continually in large quantities produce tolerance but not addiction when the development of withdrawal symptoms has been studied for the purpose of detect-10 ing the habit-forming capacity of a drug. Lewis Himmelsbach, Gerlach and Stanton, Isbell, Scott, have in their experiments on various animals observed various degrees and forms of withdrawal symptoms But Wood, Wyngaarden and Seevers state that withdrawal symptoms were not seen in Rhesus monkeys after methadon. Gross and Meier have found that ketobemidon produces withdrawal symptoms in dogs less severe than morphine, this being the reverse of what Isbell had observed in men.

As evidenced by all these experiments, the withdrawal symptoms in animals are too uncertain and irregular, and as proved by Isbell, too closely related to the dosage and duration of the administration of the drug, and to the number of times per day the drug is given. This too, shows that this method requires a rather long time, and that its results are not altogether reliable.

In this respect, the most trustworthy results are obtained from clinical experiments. Lately, Isbell experimented with a series of new synthetic drugs derived from meperidin, namely, bemidon, ketobemidon, NU-1196, NU-1179, and NU-1932. These drugs produced euphoria and relieved withdrawal symptoms of morphine. The most potent of these drugs has been found to be ketobemidon, which is even more potent than morphine and can, at the same time, produce tolerance and addiction, causing the severest forms of withdrawal symptoms.

Lewis in his experiments on animals, found isomethadon less potent in developing tolerance or addiction than methadon or morphine, whereas Finniger has proved that methadon develops tolerance to its hyperglycemic effect in rats, and Weckler and Frank, to its sedative, analgesic and hypothermic effects in dogs. Schwaiger and Boeck, through their clinical observations, claim that methadon does not develop tolerance and addiction, and that no withdrawal symptoms are seen when the drug is withheld.

Troxill, also relying on clinical observation, claims that methadon could produce tolerance, and could be given instead of morphine to morphine addicts. Hewer and Keele state that methadon can produce euphoria to the same degree as morphine. Isbell has shown that methadon can relieve the withdrawal symptoms of morphine addicts, and also if given long enough, produce weak withdrawal symptoms, once it has been withheld. Later on, Isbell and Windler have shown the development of tolerance in men to its sedative action, as well as its effects upon the pupils and respiration. They have also noted full withdrawal symptoms by discontinuing the drug in men, as well as in animals. Morphine or methadon were found to relieve those symptoms. Leufeld too, observed tolerance formation to the analgesic effect of methadon.

Today, with chemists hard at work to produce new synthetic analgesics, the need for a quick and sure method to detect a probable habit-forming potential in these new products is obvious.

The mad-cat, method discovered by Mayor, nearly forty years ago, for the purpose of detecting the habit-forming capacity of analgesics in men, has not been mentioned in the medical literature of this last decade. This method, which gives in a very short time results completely in accordance with clinical observation, seems to be nearly forgotten. Mayor used this method to detect addiction liability in opium alkaloids and their derivatives. Thus, an alkaloid which, when injected subcutaneously in a cat, makes it mad, is known to have addiction liability for men, whereas the alkaloids that do not act thus are known to have no such liability. Thus morphine, heroine, dicodid, dilaudid and eucodal make a cat mad, and codein and dionin do not.

Following a subcutaneous injection of 0.0008 gr. per kg. of morphine, a cat shows a maximum dilatation of its pupils and quickening of its respiration; it moans without interruption, climbs the walls of its cage, throws itself down, heedless to pain. It shows no interest in its surroundings; a mouse, a dog or another cat awake no interest. It neither eats nor drinks. It may jump and fall down from high places. It appears to be suffering from hallucinations. A few hours later, these symptoms disappear and it becomes normal again. If during this madness, large doses such as 15-20 mg./kg. are given from time to time, the cat deveolps tonic and clonic convulsions. Morphine never puts a cat to sleep.

Joel and Fritz Arndt have shown that in a cat the cortex of whose brain has been removed, morphine only causes tonic and clonic convulsions. They also state that morphine injected in cats at the dose of 0.1-02 mg./kg. will induce sleep. We have never been able to induce sleep in cats with these doses; they were only calmed. In 1942, Akil Muhtar Ozden used this test with dolantin and found that it induced madness in the cat. This caused him to think that dolantin could be habit-forming. This was subsequently proved by extensive clinical observations.

In our experiments with this method, we first investigated the actions of the opium alkaloids. The results are given below.

Morphine: The injection of 8 mg/kg. always produces the picture described above. With smaller doses such as 0.05/kg., the animal was seen to pass successively through states of consciousness and unconsciousness, so that it became mad at times and then was conscious again, during which period, it looked up when called and enjoyed being caressed. When 15-20 mg./kg. were used, it sometimes fell and showed tonic and clonic convulsions. With still higher doses such as 30 mg./kg., these convulsions became continuous, and in this state the cat usually died. With small doses such as 0.1-0.2 mg./kg., the cat was quiet and depressed, showing at times clumsiness in scratching itself with its hindlegs.

Dilaudid: Usually, 1 mg./kg. is enough to produce madness, though this becomes a rule when 3 mg/kg. are used.

Dicodid: 1 mg./kg. produced madness in a cat in every case.

Eucodal 4 mg./kg. produced madness, but often of shorter duration. The results of these experiments are summarized in the table below:

Weight of the cat (grammes)

Sex

Drug used

Dose mg / kg.

Total dose

Pupils

Observations

1,300
F
Morphine
0.2 0.66
Moderate mydriasis
Cat sat calmly, was rather sluggish and perfectly conscious.
1,500
M
"
0.1 0.15
"
Sluggish and calm Showed clumsiness in the use of its hindlegs, but was awake and conscious.
2,000
M
"
0.2 0.4
"
"
2,500
M
"
0.2 0.5
"
"
2,000
F
"
1 2
"
Seemed calm but presented exaggerated reflexes.
2,200
M
"
2 4.4
"
"
2,650
M
"
5 13.25
Pronounced mydriasis
Became mad but showed periods of consciousness.
3,000
F
"
5 15
"
"
1,700
M
"
8 13.6
"
Complete madness
2,200
M
"
8 17.6
"
"
2,400
M
"
12 20.8
"
Complete madness with periods of convulsion.
2,200
M
"
15 33
"
"
2,400
F
"
20 48
"
"
3,300
M
"
30 99
"
Half an hour's madness followed by a fall with tonic and clonic convulsions Was normal the next morning
2,000
M
"
30 60
"
Half an hour's madness followed by convulsions. Died an hour later
1,800
F
Heroin
1 1.8
Moderate mydriasis
Cat showed hyper-irritability but no madness
2,100
F
"
1 2.1
Pronounced mydriasis
Showed a few periods of madness from time to time.
1,800
M
"
2 3.6
"
Slight periods of madness from time to time.
1,750
F
"
2 3.5
"
Madness.
2,200
F
"
3 6.6
"
"
2,000
F
"
4 8
"
3,100
F
Dilaudid
1 3.1
Moderate mydriasis
The cat was irritable but not mad
2,500
M
"
1 2.5
Pronounced mydriasis
Slight periods of madness from time to time.
2,200
F
"
2 4.4
"
"
2,200
M
"
2 4.4
"
Madness
2,400
F
"
3 7.2
"
"
1,500
M
Eucodal
1 1.5
Moderate mydriasis
Nothing important seen
2,200
F
"
2 4.4
"
Showed hyper-irritability.
2,100
F
"
4 8.4
"
Alternate periods of madness and consciousness.
2,200
M
"
5 11
Pronounced mydriasis
Complete madness.
2,000
M
"
5 10
"
"
2,800
M
Dicodid
5 14
"
Alternate periods of madness and consciousness.
2,200
M
"
10 22
"
Complete madness.
2,100
F
"
10 21
"
"
2,000
F
"
5 10
"
"

One may see from our experiments that these drugs, long known for their habit-forming capacity, all cause madness in cats. Likewise, experiments with dionin and codeinum phosphate never caused madness in the cat. Smaller doses produced hyper-irritability, exaggerated reflexes and mydriasis, whereas higher doses caused convulsions which were mostly tonic, opisthotonos and death.

Weight of the cat (grammes)

Sex

Drugused

Dose mg /kg

Total dose

Pupils

Observations

2,100
M
Dionin
20 42
Moderate mydriasis
Cat was fretful, enjoyed being caressed, and presented exaggerated reflexes
2,000
M
"
30 60
"
Highly irritable Showed tremor of ears and body when frightened Exaggerated reflexes
1,800
F
"
40 72
Pronounced mydriasis
Generalized tonic convulsions and opisthotonos; showed periods of relaxation followed again by convulsions Unconscious even in these periods Died in four hours
1,700
M
Dionin
80 136
Pronounced mydriasis
Same as above Died in two hours
1,650
M
"
80 120
"
Opisthotonos, tonic and rarely clonic convulsions followed a short period of irritability Showed periods of relaxation during which it tried unsuccessfully to get up Died in three hours during convulsions.
2,000
F
Codeinum phosphate
40 80
Moderate mydriasis
The cat was irritable, easily frightened, and presented exaggerated reflexes
2,100
M
"
60 126
"
 
1,800
M
"
80 144
Pronounced mydriasis
Irritated, frightened, showing exaggerated reflexes Showed periods of opisthotonos and convulsions between which it was conscious
2,000
M
"
120 240
"
Same as above Died in four hours
2,200
F
"
150 330
"
Half an hour's irritability followed by opisthotonos, tonic and rarely clonic convulsions. Recovered the next morning
2,600
M
"
200 520
"
Same as above, but died in three hours
3,000
M
"
300 900
"
Died in two hours during tonic convulsions and opisthotonos

These results are concordant with the clinical observations. It is generally recognized that codein and dionin are not habit-forming for humans.

We performed another series of experiments in which the drug used was dolantin. Dolantin injected subcutaneously in a cat in quantities of 5-10 mg./kg. produces torpor. The use of 20-25 mg./kg. induces sleep in cats, but madness and periods of tonic convulsions and opisthotonos are seen with the use of 40 mg./kg.

The results of our experiments with dolantin are given below:

Weight of the cat (grammes)

Sex

Drugused

Dose mg /kg

Total dose

Pupils

Observations

2,700
M
Dolantin
5 13 5
Moderate mydriasis
The cat was calm and sluggish
2,000
M
"
10 22
"
 
1,800
F
"
20 36
Pronounced mydriasis
First fretful, then stunned, then slept.
2,200
F
"
25 50
"
 
2,100
M
"
40 84
"
Became mad in half an hour Showed periods of opisthotonos and clonic and tonic convulsions during which it breathed haltingly and was unconscious Started reacting when called, one hour later Four hours later, all the symptoms except mydriasis had disappeared
1,650
M
"
20 32
"
Seemed stunned Became mad with a second dose of 20 mg given half a hour later Returned to normal in three hours
1,500
M
"
35 52
"
Became mad, showing periods of opisthotonos and convulsions

The madness produced is the same as in the case of morphine. The cat moves about incessantly in an unconscious way. It climbs the walls of its cage, hitting and even injuring itself. It shows no interest for its surroundings and seems to be suffering hallucinations as if it had visions. Respiration is rapid. The cat neither eats nor drinks. It is not frightened by anything. Its pupils are mydriatic. These experiments show that dolantin can induce madness in a cat, which is in accordance with its habit-forming potential in humans.

We experimented finally with methadon. When 5-10 mg. of methadon is injected into a cat, it produces madness as in the case of morphine. This shows that methadon may produce addiction in men, this is in accordance with the experiments on animals described before, and with numerous clinical observations. The results of our experiments are given below:

Weight of the cat (grammes)

Sex

Drugused

Dose mg /kg

Total dose

Pupils

Observations

1,750
M
Polamidon
3 5 25
Moderate mydriasis
The cat showed some excitement after lying quietly for an hour
3,400
F
"
1 3 4
"
Was quieter
3,400
M
Polamidon
5 17
Pronounced mydriasis
Showed alternate periods of madness and quietness during which it was conscious
1,800
M
"
7 12 6
"
 
1,750
M
"
12 5 22
"
Became completely mad, showing periods of opisthotonos and convulsions Later on, it spread itself out on its belly paralysed, with its fore and hind legs lying flat apart Respiration was very rapid. It had recovered by the next morning
1,600
M
"
6 9.6
"
Became completely mad and recovered slowly in four to five hours
2,000
F
"
8 16
"
 

Experiments with pethidin and methadon on rabbits showed that smaller doses produced sluggishness in some, and sleep in others. Larger doses were seen to cause death with convulsions. On dogs, these drugs caused sluggishness. Therefore, not only were the effects of these drugs on cats similar to those of morphine, but also their effects on other animals were the same.

In another series of experiments which we, performed with amphetamin, we never succeeded in causing madness. Large doses resulted in tonic and clonic convulsions, while still larger doses caused death. This proves that the cat experiment can only be used to discover the habit-forming capacities of morphinelike analgesics.

Experiments with persedon, a new hypnotic, never resulted in madness. The action of persedon on the cat can be seen below:

Weight of the cat (grammes)

Sex

Drugused

Dose mg /kg

Total dose

Pupils

Observations

1,750
M
Persedon
30 52.5
Mydriasis
The cat showed little movement, was sluggish, had difficulties in scratching itself, ate when given food.
2,700
M
"
50 135
Pronounced
Sat quietly
3,250
M
"
50 172.5
-
"
1,500
M
"
60 60
-
Showed quarrelsome temper, clumsiness, ate when given food
2,650
M
"
75 198
Moderate
Showed exaggerated reflexes, staggered about clumsily
1,750
F
"
100 175
Pronounced
Slept.
1,900
F
"
100 190
Moderate
Slept; showed exaggerated reflexes.
1,600
M
"
150 240
-
Slept after half an hour. Exaggerated reflexes.
1,700
M
"
200 340
Pronounced
Slept after half an hour; exaggerated reflexes Had slight clonic convulsions that lasted for hours. Woke up the next day.

It can be seen from these experiments that the cat test first proposed by Mayor for opium alkaloids, helps to detect the habit-forming potential not only in opium alkaloids, but also in synthetic analgesic substances showing morphine-like actions as well.

This method is simple to use and gives in a few hours wholly reliable results.

In view of the considerable work done by chemists in producing new synthetic analgesics of different types and formulae, we think it very important to have a method that would show rapidly the habit-forming possibilities of these new drugs. We believe that the cat method is very useful for this purpose and hope that it may be of some advantage in helping chemists and pharmacologists in the search for analgesics free of such harmful effects.