HABITUAL USE OF BARBITURIC ACID DERIVATIVES IN INDIA

By R. N. CHOPRA, C.I.E., m.a., m.d. (Cantab.) LIEUTENANT-COLONEL, I.M.S. and

G. S. CHOPRA, m.b., b.s. {Drug Addiction Enquiry, Indian Research Fund Association. Series No. 22)

Introduction.?During recent years a large number of barbituric acid derivatives have been introduced into therapeutics; the follow- ing are some of the important compounds known to the profession in this country :? (1) Barbitone, or veronal (di-ethyl-barbituric acid), (2) sodium barbitone, or medinal (sodium salt of barbitone), (3) proponal (di-propyl-barbituric acid), (4) neonal, or soneryl (N. butyl-etliyl-barbituric acid), (5) dial (di-allyl-barbituric acid), (6) phenobarbitone, or luminal (di-phenyl-barbiturie acid), (7) sodium luminal, (8) phanodorn (cyclo-hexenyl-ethyl-barbituric acid), (9) evipan (N. methyl-cyclo-hexenyl-methyl- barbituric acid), (10) sodium evipan, (11) pento- barbitone (ethyl-methyl-butyl-barbituric acid) and (12) its sodium salt, nembutal, (13) ipral (calcium ethyl iso-propyl-barbituric acid), (14) allonal (a com- bination of allyl-iso-propyl-barbituric acid with amido- pyrin), (15) veramon (a combination of veronal with amidopyrin), (16) somnifain> (a combination of dial and amidopyrin), (17) cibalgin (a combination of dial and amidopyrin), (these last four all produce a reddish- brown colour in urine on account of the presence of amidopyrin), (18) gardenal (phenyl-ethyl-barbituric acid), (19) sodium hebaral (sodium salt of hexyl- barbituric acid), (20) beatol (a proprietary preparation said to be a mixture of veronal with extracts of valerian and jusquiame), (21) quadronox (a propri- etary preparation said to contain 80 per cent veronal with phenacetin, phenazone, etc.; urine may be coloured reddish-brown from the phenazone present), (23) amytal (iso-amyl-ethyl-barbiUiric acid), (24) pernocton (2 butyl-brom-ethyl-barbituric acid), (the sodium salts of both these are used by the intravenous route to produce anaesthesia), (25) nastal (iso-propyl-brom- allyl-barbituric acid), and (26) sandoptal (iso-butyl- allyl-barbituric acid). The addition of alkyl or aryl radicles of higher mole- cular weight than ethyl adds to the toxicity of the substance, thus luminal, dial, proponal, gardenal, soneryl and nembutal are all more toxic than veronal. Launoy and Contiere, taking veronal as unity, have found that the relative toxicity for dial is 3.1, for soneryl 4.7, and for both amytal and nembutal 10.1. It is therefore safer to use for hypnotic purposes barbitone or its sodium salt than the more complex derivatives. Although these drugs as a rule are not very toxic and the average minimum fatal dose for barbitone (veronal) is 3 to 4 grammes (45 to 60 grains) deaths have occurred from much smaller doses, e.g., 1 gramme or 15 grains given in one dose. On account of their easy availability they have been used for suicidal purposes. The combination of a barbituric acid compound with an analgesic drug, such as amidopyrin, phenacetin, etc., occurs in veramon, allonal, cibalgin, ^Omnifaine and quadronox. Such combinations are likely to have more toxic effects on the organism and frequent repetition of therapeutic doses may produce serioua effects. Wagner (1933) has divided the barbituric acid com- pounds into two groups, (1) the shorter-acting drugs, which are eliminated rapidly and whose cumulative effects are not marked; to this category belong pento- barbital sodium, amytal and secondary butyl beta ABUSE OF BARBITURIC ACID DERIVATIVES: R. N. & G. S. CHOPRA 189

brom-allyl-barbituric acid sodium salt, and (2) the without unpleasant after-effects. There is more longer-acting drugs, which are eliminated slowly, have certainty of action than with most of the other marked cumulative effects and lead to delirious re- hypnotics, with the exception of opiates, and action or other toxic to this symptoms: category belong this is the reason for the of this phenobarbital, neonal, ipral, a barbital derivative with popularity of of the men- amidopyrin, dial and barbital. It may be generally group hypnotics. Many drugs said that combination with sodium makes the com- tioned have been used for basal anaesthesia, pounds more rapid in their action. The degree of those which are most commonly used at the toxicity of these compounds according to this author present time being nembutal, starting from the highest is as follows : pernocton, amytal secondary and On account of their effective butyl beta brom-allyl-barbituric acid sodium salt, evipan. barbital, phenobarbital, amytal, neonal, a barbital sedative properties, they are used in the treat- derivative with amidopyrin, dial and pentobarbital ment of chorea and sodium. hysteria, neurasthenia, epilepsy. Action and use.?The physiological effects of Toxic effects and habit formation.?In a these compounds comprise not only a specific paper in the Lancet, Sir James Purves-Stewart hypnotic action on the brain, but also on the and Sir William Willcox (1934) have described lungs, heart and kidneys. The heart rate is a series of cases of poisoning by barbitone and quickened, vasodilatation is produced and the allied drugs. Besides the toxic effects produced blood pressure falls partly owing to vasodilata- by massive doses of these compounds they also tion and partly to the toxic action of the drugs produce dangerous cumulative effects when on the myocardium; the pulse may become inter- repeated in therapeutic doses and there is a mittent. In severe cases death may occur from tendency to habit formation. These facts have heart failure. In certain patients, such as those not been sufficiently appreciated by the medical suffering from hyperthyroidism, exophthalmic profession in India. During recent years the goitre or severe toxaemia, sepsis, etc., the toxic use of barbituric acid derivatives has consid- effects of barbituric acid compounds are greatly erably increased in India and a number of com- enhanced so that even an ordinary therapeutic pounds, particularly luminal, veronal, medinal, dose veramon are may produce dangerous symptoms or even and adaline, being largely used fatal results. by medical practitioners. On account of their marked hypnotic and analgesic properties, less a tem- They produce slight fall in the body disagreeable taste and irritant effects, they are the basic metabolic rate is little perature; preferred to the chloral and sulphonal group affected; they have no appreciable effect on of drugs. The lay public have also begun to blood the calcium content of the blood sugar; use them, without medical advice, for the pur- is of this definitely decreased. All members poses of producing sleep or relieving pain, with series the and depress respiratory system pro- the result that in quite a number of cases habit duce physical signs of broncho-pneumonia. The J formation have occurred. output is diminished but urinary appreciably The of habit formation with these the flow returns to normal within about 24 question drugs has been discussed by (1934) hours; drugs like nembutal are said to Gillespie produce and he has forward certain a suppression of urine. Some workers have brought priori considerations against the likelihood of the found a slight but transient to the liver, damage | frequent occurrence of this. others consider very little action on the hepatic function. The tone of the gastro-intestinal While engaged in the study of drug habits muscle is decreased. So far as the nervous in India we have been making enquiries is system concerned the threshold for painful regarding the use of these drugs by the public stimuli is decidedly increased and during deep and have found that habit formation does narcosis no response to painful stimuli can be sometimes follow the use of members of this obtained. The pain has been controlled in group of drugs. Our enquiries show that addic- patients with or tabetic crises. Large doses, tion is still uncommon, as there are no in J but, susceptible individuals even small doses, may restrictions to the sale of these drugs, there is cause a drowsy condition accompanied by fever likelihood of the extension of this practice. and rapid development of coma. The psycho- Instances of abuse of these drugs are at present logical effects of these compounds have been confined to large towns only. We have been forked out; after administration of these drugs informed that certain members of this group there a is striking change in the emotional are being employed by young licentious individ- of attitude the subjects and a definite uals and for their sexual of feeling by prostitutes effects, euphoria is said to be obtained. and it has been alleged that they have been for im- The barbituric acid derivatives are perhaps employed for stupefying young girls We not the most commonly used hypnotics at the moral purposes. have, however, been case of this use Present day. When taken by the mouth they able to trace any nature. The are is at to the quickly absorbed and within an hour or so of barbiturates present confined a educated because have after clinical dose sleep usually ensues. After classes, probably they a of notices in the medical single therapeutic dose a period of sleep opportunities reading and the the and lasting from six to twelve hours usually occurs. lay press extolling hypnotic 190 THE INDIAN MEDICAL GAZETTE [April, 1935 analgesic properties and alleged freedom from only partly overcome by other measures for a few toxic and harmful effects of these drugs, and weeks. The patient then secretly bought a bottle of and started in doses of thus start self-medication. sodium barbitone taking it they 7$ grains daily. One pill was enough to produce The following cases which have come to our sound sleep in the beginning, but after some time he notice are typical examples of the abuse of had to resort to 2 pills to obtain the desired effect. for about 6 weeks which these drugs :? This continued during period the patient became extremely pale and listless, suffered hands and of (1) S. L., a Hindu male, aged 22, an intelligent and from tremors of the feet, dimness vision, tinnitus and thickness of The was com- healthy-looking young man, was working as a com- speech. drug and the was pounder with a medical practitioner in Gujranwala. pletely withdrawn patient carefully In April 1928 he suffered from acute bronchitis and watched. He was given a nourishing diet and a tonic arsenic These could not sleep for four nights. He prescribed him- mixture containing iron, and strychnine. measures to a certain extent self two tablets (7? grains each) of sodium barbitone succeeded in the begin- on it was to which procured him good sleep. This dose was ning, but later thought necessary administer in \ doses with repeated every alternate night before going to bed, opium grain daily along measures. Within 3 weeks' time the for a period of a fortnight, after which it was dis- general patient continued. Although his cough was alleviated, the gained in weight, started taking an interest in life, patient could not sleep and again resorted to the drug. and became mentally normal. Later, opium also was On being warned he stopped the drug for a few successfully withdrawn. months but was so much troubled with insomnia and Case 3.?F., an Anglo-Indian female, aged 25, un- irritability of temper that he secretly continued the married, had much worry on account of family affairs, drug off and on for a period of 3 years, sometimes and suffered from sleeplessness. Under the advice of taking as much as 4 tablets (30 grains) in 24 hours. a doctor she started to take sodium barbitone occa- During this time the patient suffered from progressive sionally. One to two pills were enough to procure anaemia and loss of weight, but carried on his work. her sound sleep and this was continued for some In January 1932 he showed signs of exhaustion, in- months. The patient then began to suffer from dull- ability to concentrate and was compelled to abandon ness and heaviness in the head, irritability of temper, his work. He suffered from palpitation, marked breathlessness on exertion and listlessness. The drug asthenia, unsteady gait, tremors of the hands and feet, was discontinued at once and the dangers of this form and a sinking feeling in the chest. He looked very of self-medication were explained to the patient. There pale and anaemic; his total red cell count was 3,500,000 were no untoward symptoms and the patient regained in a month as and haemoglobin 75 per cent. The upper eye-lids were her normal health and so far is known puffy and slightly swollen; the urine was scanty, high- has not gone back to the drug. coloured and showed traces of albumin; he had of tachycardia, and hsemic murmurs were present. There Discussion.?An analysis of the cases was severe headache and slow cerebration. This condi- poisoning and of abuse of these drugs in this tion lasted 3 months, the patient still continuing to country for the last five years occurring in the take two tablets of this drug daily. reports of chemical examiners of different now came under The patient treatment, the drug provinces shows that most of the cases were was withdrawn without and any difficulty general addicted to the use of some other at the measures, such as hot foot-baths, sponging, massage, drug same In some or one etc., were adopted to combat insomnia. An alkaline time. cases, barbitone, mixture containing 10 grains each of bromides of of its derivatives, was used by itself, but, ammonium and potassium with 10 minims of tincture in others the drug was taken by those using of was After a week's treatment digitalis prescribed. alcohol and cocaine to overcome insomnia little or no improvement was observed in the mental their excessive use. condition, although the general condition was better. produced by Persons with Insomnia however was so troublesome that he secretly unstable nervous systems under worry and arranged to buy a phial of sodium barbitone. On the strain may resort to these drugs. We have seen 20th he took two tablets at 6-30 January p.m. without cases where death of some near losses getting sleep; at 8-30 p.m. two more were taken. relative,, in or the of domestic Half an hour after the second dose he became dysp- business, maladjustment nceic and sleepy, and went to bed at 9-15 p.m. Coma affairs have induced their use, either under the supervened and the patient became cyanosed; the tem- advice of the family physician or independently, rose to 103 ?F. and perature the pulse rate to 130 per in order to allay the uneasiness of mind from the became stertorous and minute; breathing laboured; which suffered. there were physical signs of broncho-pneumonia in they both lungs. The stomach was immediately washed out In a number of instances we have observed with a weak solution of potassium permanganate, that although these drugs were continuously and were digitalin strychnine administered hypoder- used for weeks together did not lead to and inhalations were started. they mically, oxygen About the intense of addiction 3 pints of normal saline with glucose were given sub- type usually produced cutaneously, but the patient expired in a comatose by opiates. Although the abstinence symptoms condition on the 23rd of January. on withholding the drugs are absent and the an can be Case 2.?X., educated Hindu male, aged 28 years, drugs suddenly stopped without any of highly neurotic temperament, had been a morphine difficulty, there is a distinct desire for repeat- addict since 1928. The drug was administered to him ing the dose for control of symptoms for which after an attack of biliary colic and the habit was the is taken. We have on record cases thus started. His father consulted the writers and, drug of individuals who in under their advice in December 1933, morphine was certain the first instance completely withdrawn with the help of insulin injec- took these drugs in order to overcome the without tions any untoward effects. The patient, feelings of fatigue, worry and as they suffered from insomnia and to combat this insomnia, however, could not afford the use of condition a pill containing grains of sodium bar- expensive euphorics or were afraid on bitone was administered for 4 consecutive nights by like alcohol, of using opium the doctor in charge. This procured sleep but when account of the risk of habit formation. These the drug was stopped insomnia returned. This was persons exhibited a strong desire to repeat the April, 1935] ABUSE OF BARBITURIC ACID DERIVATIVES: R. N. & G. S. CHOPRA 191

dose dose for relief of some rather than towards the evening. The feeling dis- symptom for the euphoric effects of the as is the appeared rapidly after taking the dose and drug, before case with opium, hemp and alcohol. the drug was actually absorbed into the drugs In this connection it be system, indicating that there was a strong may pointed out that psychic factor. there is no control whatever in this country It over the sale of these drugs, anyone can buy is believed by some in practitioners this them in any quantity and their use by the lay country that of this cure drugs series drug public is increasing. In Great Britain all the addiction. medinal and Luminal, pronocton barbituric acid derivatives are placed in part II are not to uncommonly prescribed combat of the Poisons Schedule, 1918, i.e., they cannot insomnia from of resulting withdrawal drugs without the of a like be dispensed prescription opium, morphine, cocaine and alcohol. In man. In a qualified medical India, however, number of cases were these addictions over- are not classed as and are there- come they poisons and beneficial results were produced, but fore not included in any of the schedules of in a few instances the individuals became habit- the Poisons Act of 1919 (amended in 1931). uated to the in addition to drug the original The need for bringing the sale of this group of drugs of addiction. drugs, as well as of the hypnotics of chloral and The usual sequence of events is to start with sulphonal series, under control in this country a therapeutic dose of 5 to 10 grains for a few is very urgent. "weeks in the form of a pill at bedtime, but soon the ordinary dose becomes ineffective and and conclusions it Summary becomes necessary to increase the dose to The use of barbituric acid derivatives achieve the desired effect. As little or no (1) has increased in India the tolerance is toxic set in greatly during last developed, symptoms few These have Quite early after a small increase years. compounds powerful in comparatively and dosage. The average toxic dose in Indians hypnotic pain-relieving properties being only second to opiates in this respect. ranges between 60 to 80 grains, though un- toward effects .have been produced with thera- (2) The fact that this group may produce peutic toxic effects even in doses and are doses, especially in persons with damaged therapeutic hearts, lungs and kidneys. The excretion of cumulative in their action has not been suffi- the medical these drugs appears to be slow and may extend ciently appreciated by profession. over a period of 5 to 7 days, and probably this (3) Their repeated use is harmful and accounts for certain instances of fatal poison- dangerous, definite pathological changes being ing after repeated therapeutic doses. produced in vital organs. No tolerance is and any increase of dose may give We have not come across case where the developed any rise to dangerous symptoms and even fatal habit had lasted for more than five years. Most of results. The margin between toxic and thera- the patients were compelled to give up peutic doses is very narrow and certain individ- the habit or, if succumbed to they persisted, uals are to the action some intercurrent disease. Persons between particularly susceptible of these Caution is therefore recom- the ages of 30 to 50 are more to their drugs. prone mended in their use. Use, as at this age they are more active and subject to greater mental strains. (4) Habit formation has occurred with these drugs in Indian subjects, but the desire for the According to in the majority of the dose is more for relief of ?f Gillespie (1934), repetition instances barbiturates produce nothing symptoms than anything else. They do not the euphoria of alcohol or morphine. appear to like opiates, hemp ResemblingUn produce euphoria the contrary, patients sometimes complain and alcohol. Abstinence are of drugs symptoms discomfort following their use. Lindemann not produced and habit can be easily broken. ?1932) studied the effects induced psychological (5) The need for bringing this group of .}y small doses of sodium amytal. In healthy drugs under control, similar to that exercised in he a individuals found there was striking Great Britain, is emphasized. change in the emotional attitude of the A subjects. here was a of and a feeling well-being serenity, References feeling of warmth and towards friendship R. N. (1935). Drug addiction in India and he world in and and Chopra, general, gratitude appre- its treatment. Indian Med. Gaz., Vol. LXX, p. 121. ciation for the kindness and goodness of friends R. D. (1934). On alleged dangers of the and Gillespie, associates. There was thus a distinct pro- barbiturates. Lancet, Vol. I, p. 337. duction of euphoria. In patients also Lindemann, E. (1932). Amer. Journ. Psychiat., psychotic Vol. 1083. snnilar in the emotional reaction were XI, p. changes Purves-Stewart, J., and Willcox, W. H. (1934). pbserved. Our own experience in this respect Poisoning by barbitone and allied drugs. Ibid., s but limited, in the cases that have come under Vol. I, p. 6. 0llr observation among Indians the symptoms of Wagner, C. P. (1933). Pharmacological action of barbiturates. Journ. Amer. Med. Vol. CI, euphoria, such as those were not Assoc., described, 1773. Present. The patients wanted to repeat the p.