SIR,-Aspirin is commonly prescribed as an antiplatelet agent. The work of Moncada and Korbut suggests that high dosage may enhance platelet aggregation.’ The probable mechanism is inhibition of platelet cyclo-oxygenase at low salicylate concentration, thus decreasing thromboxane A2 activity; but at higher concentrations there is inhibition of vessel-wall cyclooxygenase also, causing decreased prostacyclin production. The possible risk of high-dose aspirin in patients who already have increased platelet adhesiveness is illustrated by the following case. The patient is a 58-year-old male with a 20-year history of migraine. Attacks are stereotyped, with a right lower homonymous quadrantic scintillation followed by throbbing bifrontal headache associated with nausea and relieved by sleep. The frequency of attacks has been about two a month. There is a family history of migraine. 2 years ago he had an episode of right hemisensory disturbance and arch aortography was performed by a transfemoral (Seldinger) approach. This was negative, but soon afterwards arterial insufficiency in the right leg developed and this was attributed to the above investigation. Reconstructive arterial surgery was not thought necessary and aspirin 325 mg twice a day was prescribed. In July, 1978, during a typical migraine attack, a right lower homonymous quadrantic field defect developed, and this has persisted. The clinical diagnosis is cerebral infarction. The cerebral infarction may have been fortuitous-perhaps’ degenerative vascular disease was primarily responsible rather than any induced abnormality of platelet function-nevertheless an association between aspirin and the cerebral infarction be dismissed. Abnormal platelet aggregability is claimed in migraineboth chronically2 and during prodroma.3 Aspirin is freely available and self-medication with large amounts is common in çhronic pain including migraine. Large amounts may be prescribed, for example; for painful arthropathies, acute rheumatic fever, Paget’s disease of bone, and polymyositis. We suggest that migraine may be a contraindication to aspirin therapy, assuming that other treatment of equal worth is available. Attention has already been drawn to the aspirin dilemma.’4 After an unsuccessful trial of dipyridamole as prophylaxis for migraineS other antiplatelet agents will be evaluated, and there is some evidence that aspirin might be successful.6 We suggest that the dose of aspirin used in future trials be guided by the finding that a single aspirin tablet (325 mg) reduces platelet cyclo-oxygenase activity by 89% and the inhibition only starts to wear off after 2 days.’ cannot

Institute of Neurological Sciences, Southern General Hospital,

Glasgow Department of Ophthalmology, Stobhill General Hospital,





SIR,-You kindly published my letter (Aug. 25, p. 472) about the mystery of a boy who went into deep coma on many occasions without obvious explanation. I have received, as a result of that letter, many interesting and learned comments from colleagues, for which I thank them. The cause of Moncada, S., Korbut, R. Lancet, 1978, i, 1286. Couch, J. R., Hassanein, R. S. Neurology, 1976, 26, 348. Deshmukh, S. V., Meyer, J. S. ibid. 1976, 26, 347. Marcus, A. J. New Engl J. Med. 1977, 297, 1284. 5. Hawkes, C. H. Lancet, 1978, ii, 153 6. Deshmukh, S. V., Meyer, J. S. Thrombos. Hæmostas., 1976, 36, 319. 7. Burch, J. W., Stanford, N., Majerus, P. W J. clin. Invest. 1978, 61, 314. 1. 2. 3. 4.

boy’s coma is now clear. A poison (quinalbarbitone and amylobarbitone, ’Tuinal’) was administered to him both before he was admitted and while he was in hospital. I cannot give further information at this point because the matter is in the hands of the police. the

Children’s Hospital, Sheffield S10 2TH



SIR,-Your editorial drew attention to the growing evidence for the relevance of social factors in medical research.’ Brown has provided empirical evidence that life experiences can precipitate clinical depression. Similar studies have shown that comparable social factors—e.g., sedentary life-style, dietary preferences-are relevant to nonpsychiatric disorders. These parallels illustrate two important principles: that approaches to unravelling the "causes" of a psychiatric disorder are not different from approaches to other medical disorders ; and that there is increasing empirical evidence that social factors can cause illness. Brown’s work, while based on sociology, has a strong linkage with epidemiology. The social influences he termed "vulnerability" could also be considered "risk factors" in epidemiological terms2 and a relative risk could have been calculated for each (absence of close ties, lack of employment, presence of 3 or more children, and so on). However, the criticism that Brown’s research is potentially misleading because not all women with these social influences become depressed is incorrect. Risk factors only increase the probability that an illness will occur--e.g., not all cigarette smokers have lung cancer. Genetic factors have a role in depression but this should not detract from Brown’s findings. Ideally, future research will relate genetic to psychosocial and other risk factors and provide estimates of their relative weight in causing different forms of depression. Research on the relative contribution of various risk factors in psychiatric disorders is advancing and is not very much behind that of cardiovascular disease or diabetes.34 You have a biassed view of the relation of psychiatry to medicine. It is not true, as you state, that "the suggestion that social therapy is important is potentially dangerous" or that "social forms of treatment have not been systematically evaluated." There is increasing evidence, from randomised controlled trials that many forms of depression are improved by different types of psychotherapy. The value of psychotherapy alone, in comparison, and in combination with pharmacotherapy for depression is the subject of increasingly sophisticated investigation. A review of clinical trials in depressed patients5 pointed out that all nine studies comparing psychotherapy to a control group supported the efficacy of psychotherapy, five studies comparing psychotherapy to pharmacotherapy presented equivocal results, and four studies showed the efficacy of combined pharmacotherapy and psychotherapy over either treatment alone or various control groups. Finally, you confuse interventions directed at causes or risk factors (primary prevention) with interventions directed at the clinical disorder or its consequences (secondary prevention). You note that social factors may be responsible for cigarette smoking but that "this is irrelevant to the chest surgeon removing a carcinoma of the bronchus." In fact, the sequence of social factors in the case of cigarette smoking and cancersocial factors such as adolescent peer pressure, cigarette smok1. 2.

Lancet, 1978, i, 343. MacMahon, B., Pugh, T. Epidemiology. Principles and Methods; p. 268. Boston, 1970. 3. Kolata, G. B., Marz, J. L. Science, 1976, 194, 509.

4. Weissman, M. M., Klerman, G. L. Archs gen. Psychiat. 1978, 35, 705. 5. Weissman, M. M. Unpublished.

681 cancer risk-is reasonably well established. Given this sequence, a public health approach would demand intervention at all stages: public education to prevent people starting to smoke; pharmacological or behavioural treatment to help tobacco addicts to stop smoking; and surgical excision of lung carcinoma for those who become afflicted. Interventions at each stage require assessment as to efficacy, safety, and

ing, addiction,


These criticisms should not overshadow the importance of Brown’s work to the attention of physicians; depressions are the most prevalent of adult psychiatric disorders and are usually treated to non-psychiatrists.


Harvard Medical School, Boston, Massachusetts, U.S.A.


Depression Research Unit, Connecticut Mental Health Center, New Haven, Connecticut,


that the suspended crystals cannot easily pass through the narrow constriction between the needle bevel and the subcutaneous tissue. The probability of blockage appears to increase if the injection is given slowly but it is not clear what the injection-rate has to be to avoid blockage. Since most insulin syringes used in North America are disposable the problem is not due to inadequate cleaning of reusable needles. It has been reported that spontaneous blockage cannot be induced by storing filled syringes with the needle downward. In view of these findings, the reason for plugging during adjustment of the dosage as reported by Dr O’Mullane and Dr Robinson (July 15, p. 165) is difficult to explain.. Clinical Devices Division, Bureau of Medical Devices, Health and Welfare Canada, Tunney’s Pasture, Ottawa, Canada





SiR,—Needle plugging during injection of insulin has been reported to us on several occasions and has attracted notice in the United States and, lately, in your correspondence columns. In January, 1976, the U.S. Food and Drug Administration held a meeting with manufacturers, and the July, 1976 issue of Diabetes carried an F.D.A. appeal for information on this problem. Although the exact cause is not well understood, the reports share certain characteristics which suggest a possible mechanism. Most cases occur with crystalline insulin suspensions such as lente or ultralente, and in North America the problem reports seem to have begun with the widespread use of the U-100 (100 units/ml)concentration in 1973. We have simulated this plugging in glass micropipette tubing cemented to a needle hub attached to a 1 ml syringe filled with U-100 lente insulin. The bore of the tubing was roughly 0.38 mm, which corresponds to a 22 or 23 gauge needle, a fairly large size for insulin injection. The end of the tubing was held with moderate pressure against a wad of paper tissue or a. finger tip and the insulin was expressed slowly. Crystals rapidly accumulated at the tip of the tubing and the flow was sometimes blocked before 0-5ml had been ejected (see figure). This suggests that the plugging is caused simply by the fact

SiR,—There is evidence that the anti-tumour drug dacarba-

(D.T.I.C., dimethyltriazeno-imidazole carboxamide) is susceptible to photodegradation in solution’ and, as commonly administered, its breakdown products (including 5-diazoimidazole carboxamide and 2-azohypoxanthine) may be responsible for the troublesome local venous pain and other systemic sideeffects such as nausea, vomiting, and hepatic toxicity. Having regularly seen these side-effects we have lately tried reconstituting and rapidly injecting the drug at a concentration of 100 mg in 10 ml in a room lit by a red photographic lamp only. In a total of fourteen such injections in three patients pain was entirely eliminated or reduced to minor discomfort during the first few seconds. These patients had previously experienced moderate to severe pain along the vein throughout the injection. There also seemed to be less nausea and vomiting. The improved patient acceptability was striking. Evidence that the tumoricidal value of D.T.I.C. is enhanced by preventing photodegradation will be less easy to obtain. zine

Department of Hæmatology, Royal Hospital for Sick Children, Glasgow, G3 8SJ



Simulated needle plugging with U-100 lente insulin.

Upper. crvsta) blockade at end of microptpettc tubing. I.oBvcrr mat;mticaoun shwang plug of msutm crystals.

SIR,-It is worth reinforcing the hazards of prescribing psychotropic drugs to recovered alcoholics. A 42-year-old man was admitted to my alcohol treatment programme this year with a history of an alcohol-related divorce, two to three bottles of whisky per day from early morning onwards, black-outs, amnesias, and so on. He had been an inpatient at another hospital and had gone to Alcoholics Anonymous meetings in the hope of curing his addiction, but without success. His progress was satisfactory and he was discharged at the end of the six-week programme but things soon went badly. He had, before admission, been prescribed various tranquillisers, and he now became addicted to lorazepam, behaving with lorazepam precisely as he had with alcohol: he lied in order to obtain supplies, which he then hid surreptitiously around the house, and he took unknown quantities of the drug: "After the first three or four you don’t know how many you have taken". Calculations suggested that he took at least 80 2.5 mg capsules between 5 P.M. and 10 A.M. the next morning. Withdrawal symptoms of tremor, guilt, and remorse were precisely as they were with alcohol and his erratic behaviour was identicallying and illogical, hazardous conduct (e.g., putting an empty saucepan on the cooker). "You blank out the same as you do with alcohol." 1

Shealy, Y , Krauth,

C. A,

Montgomery, J. A. J.

org. Chem

1962, 27, 2150

Social causes of depression.

680 POSSIBLE DANGER OF ASPIRIN THERAPY IN PRESENCE OF MIGRAINE SIR,-Aspirin is commonly prescribed as an antiplatelet agent. The work of Moncada and...
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