At the Centre and on the Fringes"Fringe" medicine is often in the news but orthodox

medicine, at least in the U.K., has done little to get togrips with it. Patients with back pain, including somedoctors, will often take themselves to a chiropractor astheir first choice and more will do so whenconventional methods have failed. Homoeopathy iswell established and is practised by some doctors. Thefact that many people avail themselves of alternativemethods (a term which their practitioners rightlyprefer) suggests some kind of therapeutic value. Butimpressions are what we mostly have to go on atpresent. The report of the Commission for AlternativeSystems of Medicine in the Netherlands makes a usefulcontribution to clarifying some of the issues. The mainreport is in Dutch and is over 600 pages long but a 26page summary’ in English has also been prepared. TheCommission was instructed to concentrate on the social

significance of alternative medicine in the light of itswidespread usage in the Netherlands-despitelegislation in 1865 which allowed only one group ofprofessionals to practise every branch of medicine. Itobserved that not everything that orthodox

practitioners do is based on "conclusivelydemonstrated facts". Demands for alternative

practitioners to demonstrate the effectiveness of theirtreatments before they can be granted recognitionseemed to the Commission to be indefensible. TheCommission also recognised that placebo effects,through which alternative (as well as more

conventional) therapies may often operate, should notnecessarily be referred to disparagingly.About a fifth of the Dutch population has at one time

or another consulted a practitioner of alternativemedicine. Homoeopathy, acupuncture, naturopathy,manipulative medicine, and paranormal medicine arethe most favoured specialties. The number of

practitioners of acupuncture, to which theCommission devotes particular attention, apparentlyrose from 5 in 1970 to over 600 by 1977 and the latterfigure is expected to have doubled soon. The 1975congress of the Royal Dutch Medical Association wasdevoted to medicine and its fringe areas and oneuniversity (unnamed in the English summary)provides a special series of lectures on alternativemedicine.Not surprisingly, a powerful stimulus to moves for

the recognition of alternative practitioners is financial.Their regulation by law would help towards theinclusion of their services in public and private healthinsurance schemes. With an annual turnover in thealternative health care sector of somewhere between160 and 210 million guilders (about 35-45 million)there is a good deal at stake. Several appeals against thenon-refunding of costs of alternative medicine havemade it clear that patients feel their freedom of choice isbeing restricted.

1. Summary of the Report of the Commission for Alternative Systems of MedicineMinistry of Health and Environmental Protection, The Hague, 1981.

Despite its concern mainly with the social issues,the Commission does stray into the scientific area-andmuch less convincingly. It dismisses randomisedcontrolled trials out of hand and prefers to rely on themedical forum, "an abstract normative framework forassessment within which the truth ofcertain facts andtheories is weighed and decided upon in a specificallyscientific mode of discussion". The Commission

recognises that biases for and against different methodsmean the forum will work less than perfectly but, evenso, sees it as the method of choice. It is not hard to thinkof instances when other forums got it wrong. That doesnot mean that randomised controlled trials will alwaysget it right, but they surely stand a better chance. Ifhome and hospital care after myocardial infarction canbe studied this way, why not the orthodox andalternative treatments of sciatica? Orthodox

practitioners will have to ensure that patients in anytrials are under their general supervision. But, with thisproviso, there need be no prior conditions about whichsciatica treatment method has to come up to thestandards of the other. Let the best man win-and the

patient reap the benefit.

PENECILLAMINE — THE THERAPEUTIC PARADOX

IN addition to its original therapeutic role as a chelator ofcopper in the long-term management of Wilson’s disease,D-penicillamine has become established in the past ten yearsas one of a group of useful anti-rheumatoid drugs. 1

Therapeutic agents in rheumatoid arthritis can be usefullydivided into two basic types-those with anti-inflammatoryand/or analgesic properties and those which seem to act on therheumatoid process itself. Since penicillamine, like gold, fallsinto this latter group, there has been considerable interest inits mode of action: unlocking this door might allow a glimpseof at least part of the complex process which ultimately leadsto joint destruction.

Successful penicillamine therapy in rheumatoid arthritis isalmost always associated with a fall in rheumatoid factortitres2 and decreased levels of circulating immune

complexes3,4 and immunoglobulins.4 Although one cannotbe sure whether these changes are a direct result of primarydrug effects or simply a reflection of decreased disease

activity, these clinical observations suggest that

penicillamine may depress humoral immune responses.Direct supporting evidence includes the observation that theantibody response to immunisation with ovalbumin and cell-mediated immunity is lowered in rabbits given penicillaminefor long periods.5,6 However, a troublesome feature of

1. Multicentre Trial Group. Controlled trial of D-penicillamine in severe rheumatoidarthritis. Lancet 1973; i. 275-80.

2. Jaffe IA. The effects of penicillamine on the laboratory parameters in rheumatoidarthritis. Arthritis Rheum 1965; 8: 1064-79.

3. Jaffe IA. Penicillamine treatment of rheumatoid arthritis Effects of immune

complexes. Ann N Y Acad Sci 1975, 256: 330-37.4 Mohammed I, Barraclough D, Holborow EJ, Ansell BM. Effects of penicillamine

therapy on circulating immune complexes in rheumatoid arthritis. Ann RheumatDis 1976, 35: 458-62.

5 Hunneyball IM, Stewart GA, Stanworth DR. The effects of oral D-penicillaminetreatment on experimental arthritis and associated immune response in rabbits: IEffects on humoral parameters. Immunology 1978; 34: 1053-61

6. Hunneyball IM, Stewart GA, Stanworth DR The effects of oral D-penicillaminetreatment on experimental arthritis and associated immune response in rabbits: IIThe effects on cellular parameters. Immunology 1978; 35: 159-66.

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penicillamine therapy in rheumatoid arthritis is the highincidence of side-effects including a lupus erythematosus(SLE)-like syndrome in which a membranous nephropathy ofthe immune complex type is a prominent feature.7 Thus theparadox-on the one hand, immunosuppression, on theother, transformation to a more vigorous immune-mediateddisease. Can the same drug be both immunosuppressive andimmunopotentiating? One approach to this question,examination of the effects of penicillamine on lymphocyteand macrophage function in vitro, was discussed at a

workshop which reviewed the therapeutic role of

penicillamine and explored its mode of action. 8

Lipsky and Ziff have shown that lymphocytespreincubated with a mixture of penicillamine and coppersalts in serum-free medium, became hyporesponsive to

stimulation with both T-cell and B-cell mitogens, althoughincubation with either penicillamine or copper alone waswithout effect. 8,9 Lipsky has also shown, by exposingpreparations of monocytes, B-cells, or T-cells individually tothe penicillamine/copper mixture, that the effect was due to aspecific inhibition of helper-T-cell function.1O Since theconcentrations of penicillamine and copper in treated

patients often exceed the concentrations used in the studies(12-5 5 Ilg/ml and 2 pg/ml, respectively) it is tempting toconclude that these in-vitro observations reflect one of themechanisms leading to immunosuppressive effects in vivo.However, a major drawback is the use of serum-free mediumin the preincubation step. This may be one reason whyRoom and Maini" obtained rather different results. Theycultured peripheral blood mononuclear cells from normalsubjects or patients with rheumatoid arthritis with differentconcentrations of D-penicillamine for 72 h in mediumsupplemented with 10% human serum. A suppressive effectof the drug on the mitogenic response to

phytohaemagglutinin was consistently observed with bothnormal and rheumatoid cells at a penicillamine concentrationof 100 g/ml, but at the lower concentration of 10 1.4g/mlinhibitory effects were almost confined to the normal cells.When the same studies were done with purified T-cells, low-dose penicillamine did not affect the mitogenic response ofnormal cells while in the rheumatoids some cultures showed

penicillamine-induced enhancement of cell proliferation.These results are reminiscent of those obtained by Binderupand colleagues who, in penicillamine-treated rats with

adjuvant arthritis, found enhanced lymphocyte proliferativeresponses to the mitogen concanavalin A and increasec’

phagocytic activity of peritoneal and splenicmacrophages.12,13 3

7. Harpey JR Lupus like syndromes induced by drugs. Ann Allergy 1974, 33: 256.8. Modulation of autoimmunity and disease: The penicillamine experience. Edited by R.

N. Maini and H. Berry. Eastbourne and New York Praeger. Pp. 310. £129 Lipsky PE, Ziff M. The effect of D-penicillamine on mitogen-induced human

lymphocyte proliferation. Synergistic inhibition by D-penicillamine and coppersalts J Immunol 1978; 120: 1006-13

10. Lipsky PE. The effect of D-pecicillamine on human helper T cell function. In: MainiRN, Berry H, eds. Modulation of autoimmunity and disease. The penicillamineexperience. Eastbourne and New York. Praeger, 1981 79-88

11. Room G, Maini RN The in vitro effect of D-penicillamine on mitogen-inducedresponses of human mononuclear cell subpopulations In. Maini RN, Berry H, eds.Modulation of autoimmunity and disease. The penicillamine experience.Eastbourne and New York: Praeger, 1981 89-96

12. Arrigoni-Martelli E, Binderup L. Enhancement of macrophage phagocytic activityinduced by D-penicillamine in vitro and in vivo In: Maimi RN, Berry H, edsModulation of autoimmunity and disease. The penicillamine experience.Eastbourne and New York. Praeger, 1981: 104-10

13. Binderup L, Braram E, Arrigoni-Martelli E. Immunological effects of D-penicillamineduring experimentally induced inflammation in rats Scand J Immunol 1980 12:239-47

Thus penicillamine, in different circumstances, can eithersuppress or enhance the proliferation of lymphocytes; andRoom and Maini" have pointed to considerable individualvariation in the effect of the drug on the response ofrheumatoid lymphocytes. In view of the complexity of thefeedback network of immunological interactions determiningimmune reactivity, these results are not surprising, but manymore detailed studies of the effects on rheumatoid cells invitro and in vivo will be needed before we can say anythingdefinite about the relevance of these observations to thetherapeutic effects of penicillamine or to the drug-inducedSLE-like syndrome.

ANALGESIC POISONING

ALTHOUGH drug overdose is one of the commonest reasonsfor admission to hospital, few centres are engaged in researchinto its epidemiology and management. In the U.K., theNational Poisons Information Service has produced papersabout particular drugs but in almost all these projects thereporting of cases was entirely voluntary. The first issue of anew journal, Human Toxicology, is graced by the results ofa amulticentre prospective study of analgesic poisoning,coordinated from the Guy’s Hospital Poisons Unit.2 Thispaper is of interest not only because it provides a wider viewof the problems of analgesic overdosage than can be obtainedfrom a single-centre study but also because it shows that thissort of reporting system is applicable to the monitoring ofother aspects of poisoning.The study was undertaken in five hospitals and comprised

878 consecutive cases of analgesic poisoning treated in theaccident and emergency departments. Hospital staff

completed questionnaires on all patients and the results wereprocessed by computer. The commonest drugs taken wereaspirin (45%), paracetamol (acetaminophen) (29%), and

’Distalgesic’ (17%), which contains both dextro-propoxyphene and paracetamol. Almost half the patientstook more than one drug, the commonest being alcohol andbenzodiazepines. One-third of the analgesics were known tohave been extracted from child-resistant containers or unit-dose packages and half the drugs were known to have beenpurchased without prescription over the counter. Solublepreparations, mainly containing aspirin, accounted for only10% of the cases. Most of the patients presented within fourhours of the overdose and in very few cases did new

symptoms develop after arrival in hospital.The poisoning was not usually severe. In those taking

aspirin the plasma salicylate levels were often within thetherapeutic range and fewer than 1 in 10 patients ingestingparacetamol had biochemical evidence of liver damage(clinical features of hepatic necrosis were observed in only 4).Methionine by mouth was the most commonly used antidoteand its administration caused no problems. Both coma due tothe dextropropoxyphene component of distalgesic and liverdamage due to its paracetamol component were uncommon.

1. Volans GN, Mitchell GM, Proudfoot AT, Shanks RG, Woodcock JA. NationalPoisons Information Services: Report and comment 1980. Br Med J 1981; 282:1613-15.

2. The National Poisons Information Service Monitoring Group. Analgesic poisoning Amulti-centre, prospective study. Hum Toxicol 1981; 1: 7-23. Human Toxicology(editor, Prof. R. Goulding) will be published quarterly by Macmillan PublishersLtd (subscription dept, Brunel Road, Basingstoke, Hampshire RG21 2XS,U.K.), annual subscription £40, U.K. and Eire: $U.S. 95, U S A. and Canada;£45 elsewhere.