Quinacrine method of family planning Science unblinded SiR-In his news report Malcolm Potts (March 12, p 662) reviews our 46-month field trial of ne...

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Quinacrine method of family planning

Science unblinded

SiR-In his news report Malcolm Potts (March 12, p 662) reviews our 46-month field trial of nearly 32 000 women who chose non-surgical sterilisation with quinacrine pellets. It is true that we abruptly halted our quinacrine programme in December. By then the programme had reached 33 provinces and was proceeding smoothly. Stopping of the programme was prompted by a letter from Dr F T G Webb of WHO to United Nations Population Fund director Linda Demers in Hanoi. Webb stated: "WHO experts and FDA [US Food, and Drug Administration] officials have said that they would be very surprised if quinacrine did not turn out to be carcinogenic". Although we were not aware of any scientific evidence that this drug causes cancer in man, and none was brought to our attention at that time, the government felt that we had to terminate this programme in view of the authority of WHO. Potts notes that the FDA approved phase I clinical trials in US volunteers. FDA approval followed the completion of the required toxicology work at Johns Hopkins University and this work has been published. This phase I clinical trial took place in San Antonio, Texas, and the results were satisfactory. If there were objections to these toxicology studies or to the results of this phase I clinical trial, these objections were not expressed in publications. These facts weighed heavily in our decision to move forward with this method. Webb did not explain the inconsistency between FDA approval of the quinacrine toxicology work, the approval of the clinical trial, and the statements of the unidentified FDA officials that they "would be very surprised if quinacrine did not turn out to be

SIR-In your March 5 editorial you provide arguments why blinding in randomised clinical trials is not always possible or desirable. We draw attention to a clinical trial of drug treatment in which we deliberately abstained from double blinding. In patients with transient ischaemic attack (TIA) or nondisabling ischaemic stroke aspirin reduces the risk of important vascular events (vascular death, stroke, or myocardial infarction) by 18%;’ in recent trials in patients after myocardial infarction oral anticoagulants show a risk reduction of as much as

35% for these events.2.3 Hence,


group of Dutch

neurologists embarked on SPIRIT (the Stroke Prevention In Reversible Ischemia Trial), which compares the efficacy of oral anticoagulants with that of aspirin in patients after cerebral ischaemia. Patients randomised to anticoagulants are referred to the local thrombosis service for dose titration at regular intervals, and those randomised to aspirin receive an open prescription for 30 mg of aspirin daily.4 Outcome events are classified blindly. In this way the two treatment strategies reflect future practice. Double blinding would mean the use of double dummies and all patients would have to visit a local thombosis service; also, co-medication would have to be adapted to the use of anticoagulants in all patients. In that situation the study addresses the pharmacological question of whether tablets containing anticoagulants or aspirin are better in the prevention of vascular events. We, however, wish to know which strategy is best; this also allows a cost-effectiveness analysis, which would have been of limited value in the setting of a double-blind trial.

carcinogenic". No scientific evidence that this drug causes cancer in man has yet been presented to us. Our position has been the one stated by the panel of toxicologists asked by Family Health International (FHI) in 1990 to evaluate the carcinogenicity of quinacrine. Their conclusion was "the lack of positive in vivo data and, considering the extent of medicinal use, the lack of relevant human data, suggests that the risk for cancer may be quite small" (Tice RR, unpublished). This conclusion led us to undertake our investigation in 1990. In a collaborative study by FHI and Dr Jaime Zipper of Chile, the conclusion reads, "no evidence was found of excess cancer risk associated with quinacrine pellet transcervical sterilization" (Sokel D, unpublished). WHO did not mention this work. We have not been given an opportunity to respond by either WHO or the Association for Voluntary Surgical Contraception (AVSC) to their criticisms of our paper; instead they distributed their criticims widely on their own. These methods stifle proper scientific debate. At the AVSC (Dec 3, 1993) meeting in New York, which was attended by WHO, our Lancet paper (July 24, 1993, p 213) was the major topic of discussion and was criticised extensively. This meeting was attended by representatives of about 15 organisations, but the co-authors of our paper were not invited to the meeting. There have been a few warranted criticisms of our paper, but they are minor and we can justifiably say that both the methods and conclusions remain fundamentally sound. We were both surprised and disappointed by the treatment given by the scientific community with respect to our Lancet report. Scientific debate should be out in the open. Unsubstantiated opinions of unidentified WHO experts and FDA officials should not be accepted by the scientific community in this attempt to undermine our decision to proceed with this method; nor should these opinions be allowed to obstruct the international evaluation of this most promising family planning method. Do

Trong Hieu

Maternal and Child Vietnam


Health/Family Planning Department, Ministry of Health, Hanoi,

A Algra, J van Gijn University Department of Neurology and Clinical Epidemiology Unit, Utrecht University, 3508 Utrecht, Netherlands



Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308: 81-106. Smith P, Arnesen H, Holme I. The effect of warfarin on mortality and reinfarction after myocardial infarction. N Engl J Med 1990; 323: 147-52.



Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) Research Group. Effect of long-term oral anticoagulant treatment on mortality and cardiovascular morbidity after myocardial infarction. Lancet 1994; 343: 499-503. The Dutch TIA Trial Study Group. A comparison of two doses of aspirin (30 mg vs 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. N Engl J Med 1991; 325: 1261-66.

Munchausen’s-by-proxy SIR-In your Feb 19 news item Clare Thompson (p 471) outlines recommendations by the inquiry into the Beverley Allitt case. Apropos the four recommendations made by Sir Cecil Clothier QC, we were alarmed by the one about candidates with "major personality disorders" not being hired as nurses.

First, what does "major" imply? DSM III-R makes no such distinction in its classification of personality disorders (major vs minor) (DSM III-R). Second, personality traits show a continuous distribution without a single discrete cutoff (which would divide them) from disorders.1 DSM III-R defines "disorder" using the notion of significant impairment. "Significant" is left undefined. Third, the patient’s crosssectional presentation is not necessarily an accurate reflection of long-standing patterns. Moreover, the patient’s description of previous functioning may be retrospectively distorted by his current mood and/or the circumstances of the moment.2 In any specific evaluation of personality the consultant has to judge whether the patient’s behaviour is deeply ingrained or a

current environment; this leads to difficulty in trait from state and role factors. Fourth, there is distinguishing considerable overlap between the diagnostic categories and criteria that define the personality disorders. Few patients show all the required characteristics of one personality disorder and many show features of several.’ These difficulties lead to poor reliability of diagnoses. Spitzerin his field trials for DSM-III inter-rater reliability notes a kappa of 0 54 for personality disorders (test re-test). A kappa of 0-7 and above generally indicates agreement as to whether or not a patient has a disorder within a diagnostic class. Finally, there are several fairly distinct methods available for establishing the validity of a clinical syndrome.These have not been successful in defining personality disorders as entities. Identification and description of these disorders are so far done only by clinical intuition. There have been no controlled follow-up studies establishing a distinctive course or outcome, and no controlled therapeutic trials establishing a distinctive treatment response. No family studies prove that these disorders breed true. There is as yet no association with some fundamental abnormality, histological, biochemical, or molecular. Serious doubt about the validity of these diagnoses are therefore in order. Sanctioning a largely unvalidated diagnostic scheme and labelling someone unfit to perform certain duties on that basis is dangerous. There are no controlled studies to indicate that people with personality disorders are less suited for one or other employment. The present day taxonomy of personality disorders distorts clinical realities and is a poor predictor of future behaviour.




A Chatterjee, M C

1 van Praag HM. Make believes in psychiatry or the perils of progress. New York: Brunner and Mazel, 1993: 209-14. 2 Frances A. Categorical and dimensional systems of personality diagnoses: a comparison. Comp Psychiatry 1982; 23: 516-27. 3 Frances A. The DSM-III personality disorders section: a commentary. Am J Psychiatry 1980; 137: 1050-54. 4 Spitzer RL, Forman JBW, Nee J. DSM-III Field Trials: I. Initial interrater diagnostic reliability. Am J Psychiatry 1979; 139: 815-17. 5 Kendell RE. Clinical validity. Psychol Med 1989; 19: 45-55.

Thalidomide: 35 years


and still


SiR-As Jakeman and Smith point out in their Feb 19 commentary, the two main limitations on the use of thalidomide in the treatment of lepra reaction (ENL) remain

drug-induced neuropathy (TIN) and teratogenicity. First, despite its use for almost three decades, whether or not thalidomide causes neuropathy in patients undergoing for ENL remains unresolved. Certain evidencel the absence of TIN in ENL patients given thalidomide is too brief and insubstantial to support the weight of authority accorded by Jakeman and Smith. The primary target of peripheral TIN is sensory rather than motor function,2 and then more in the legs than in the arms.2 Damage in TIN was revealed in patients treated for prurigo nodularis by measurements of sensory action potentials in the sural nerve; by contrast, motor and sensory conduction were normal along the ulnar nerve in all patients investigated.2 Not surprisingly, no thalidomide-induced abnormalities in motor conduction velocity along the cubital nerve were reported after thalidomide treatment of ENL.3 Because sensitivity to thalidomide in utero extends from the twentieth to the thirty-fifth day of pregnancy, a woman can easily be unaware of her condition for much of this time. Most authorities are therefore insistent that women of childbearing age are not given thalidomide for ENL. Nonetheless, in Brazil,


non-steroidal anti-inflammatory drugs (NSAID) as candidates for the management of ENL. NSAIDs are not teratogenic, and obviate the necessity of developing novel analogues. A new and aggressive investigation of the potential of NSAIDs would be welcome. Last, it is difficult to bring to mind another chemical similar to thalidomide with such severe side-effects, yet for which new applications have been so persistently sought. One wonders how much longer innocent lives must remain hostage to the myth that from under all the horrors and nightmares of the past there lies a wonder drug with a golden future bursting to get out.

G R N Jones 30

Poplar Walk, London SE24 OBU, UK

1 2

Sagher J. Thalidomide neuropathy. Lepr Rev 1969; 40: 126-27. Wulff CH, Hoyer H, Astsoe-Hansen G, Brodthagen H. Development of polyneuropathy during thalidomide therapy. Br J Dermatol 1985; 112: 475-80. Sheskin J, Yaar I. Motorische Leitungsgeschwindigkeit der Kubitalnerven bei Patienten mit Leprareaktion. Hautarzt 1979; 30: 376-79. Gollop TR, Eigier A, Guiduglio Neto J. Prenatal diagnosis of thalidomide syndrome. Prenat Diagn 1987; 7: 295-98. Thiers H, Rousset J, Coudert J, Battesti MR, Than LH. Indométhacine dans les états réactionnels lépreux. Bull Soc Franc Dermatol Syph 1966; 73: 347-49.


Aftercare Department, Hillside Hospital, Glen Oaks, NY 11004, USA


where thalidomide remains freely available, one case of an aborted fetus with phocomelia of the upper limbs together with other major deformities has been described.’ The existence of twenty-nine thalidomide children born between 1968 and 1988 of mothers who received thalidomide for ENL has been confirmed by Cutler (March 26, p 795). The exclusion of all pre-menopausal women with ENL from thalidomide treatment should stimulate the quest for safer drugs, but the search for alternatives need not be restricted to thalidomide analogues. Like thalidomide, indomethacin is not the drug of first choice for ENL treatment, though early successes were impressive. This early work opened up the entire field of


4 5

Living wills SiR-Taranta (March 5, p 602) points out some of the negative aspects of a living will. We too had a very trying experience that interfered with proper medical care of a patient because of a living will. An elderly woman with advanced metastatic colon cancer was admitted for intestinal obstruction. Upper and lower gastrointestinal tubes failed to decompress the patient who was in severe pain and distress. The patient’s suffering was not relieved even by continuous infusion of narcotics. The patient’s daughters presented a living will that their mother had executed several years earlier directing "no heroic measures in the terminal phases of an incurable illness". Decompressive colostomy was refused on that basis. After several days of pleading and begging by the medical and other support staff, the daughters relented and, with tremendous guilt feelings, allowed a colostomy under local anaesthesia for palliative purposes. Immediate relief of pain and suffering was seen on the patient’s face. She died peacefully two days later. Living wills are as much a help as they are a hindrance.1,2 Appointing a health-care proxy may be a better method of having one’s wishes carried out. Fred Rosner Mt Sinai Services at

1 2

Queens Hospital Center, Jamaica, New York 11432, USA

Rosner F. The living will. Chest 1986; 90: 441-42. Eisendrath SJ, Jonson AR. The living will: help or hindrance. JAMA 1983; 249: 2054-58.