Book Review

Dark Remedy: The Impact of Thalidomide and Its Revival as a Vital Medicine

N Engl J Med 2001; 345:226-227July 19, 2001

Article

Dark Remedy: The Impact of Thalidomide and Its Revival as a Vital Medicine
By Trent Stephens and Rock Brynner. 228 pp. Cambridge, Mass., Perseus, 2001. $26. ISBN: 0-7382-0404-8

Some drugs have become household names — penicillin, insulin, aspirin. Most are known — indeed, revered — as lifesavers. Thalidomide, too, falls into the category of well-known drugs, but for an entirely different reason. As a medicine that maimed rather than saved, it had atrocious effects on the unborn child that make it an object of terror and horror.

Thalidomide appeared in the late 1950s — a decade of optimism about therapies, fueled largely by the success of penicillin during the Second World War. Postwar Western society was essentially at peace with the great infectious diseases, thanks to vaccines and antisera, and the new antibiotics had dramatically reduced the dangers of everyday life. Drugs were being developed for heart disease, kidney conditions, neurologic problems, and skin ailments, among other problems. The appearance of chlorpromazine in the early 1950s revolutionized the treatment of psychiatric disorders, and by the 1960s every facet of life was becoming “pharmaceuticalized,” as the Rolling Stones recognized so acutely in “Mother's Little Helper.”

Pills for the ill led to pills for the well; about 1 million people in Great Britain were believed to be taking sedatives daily in the mid-1950s, and 1 in 7 people in the United States was believed to be taking barbiturates. Into this highly charged and lucrative medical marketplace came a new sedative in 1956. Originally manufactured by and distributed in continental Europe by Chemie Grünenthal of Germany, thalidomide was licensed to and marketed in Britain and the British Commonwealth by Distillers Company.

Laboratory tests had shown that the drug was astonishingly “safe” because it was impossible to find a dose high enough to kill a rat. Clinical testing in Germany had been scanty — packets of pills distributed to employees, samples given to local doctors — a consequence, Stephens and Brynner conclude, of the medical callousness exhibited by the Third Reich and the distorted view that still prevailed about the acceptability of various testing practices. Because of its low toxicity, the drug was sold openly, over the counter, and was heavily promoted as the safest sedative on the market.

The first baby with malformations was born on Christmas Day, 1956, before the drug went on the market; she was the daughter of an employee of Chemie Grünenthal who had given his pregnant wife some of the free tablets. During the next few years, obstetricians in Germany noted more rare abnormalities in newborn infants, especially the condition of tetra-phocomelia (literally, “four seal's limbs”) — a condition in which the baby's arms and legs were shortened to such an extent that the hands and feet were often attached directly to the trunk. At the same time, physicians and neurologists reported an increased incidence of peripheral neuritis in adult patients who were taking the sedative. The connection between these cases and the use of thalidomide, however, was not yet clear.

It was in Australia in 1960 that the obstetrician William McBride prescribed the drug for women suffering from morning sickness and then, months later, as he delivered the first Australian babies with malformations, suspected a causal link. The rest of the tragedy is well known — McBride's growing conviction that thalidomide was responsible, the difficulties of replicating the teratogenic effects in laboratory animals, the initial intransigence of the drug companies that were involved, and the important role of journalists, especially the “Insight Team” of the London Sunday Times, in uncovering the scandal and securing proper compensation for the victims. One estimate is that thalidomide caused peripheral neuritis in 40,000 people and malformations in between 8000 and 12,000 infants, 5000 of whom lived to adulthood.

A major issue of immediate concern in countries affected by the tragedy was the safety of other drugs. Regulatory bodies were quickly established to create guidelines for the appropriate, adequate, and effective testing of new remedies, both in the laboratory and in the clinic. Astonishingly, this was the first comprehensive drug-safety legislation in many Western countries. The United States already had a monitoring body, the Food and Drug Administration (FDA), although its working methods and its habit of fraternizing with the pharmaceutical industry made it a less effective agency than it might have been or was to become. Richardson–Merrell of Cincinnati had 10 million tablets waiting to hit the U.S. market in March 1961 when the company confidently applied for FDA approval to market thalidomide. A newly appointed FDA medical officer, Dr. Frances Kelsey (Figure 1Figure 1Dr. Frances Kelsey receiving an award from President John F. Kennedy.), expressed her dissatisfaction with the medical data and returned it for amplification. At the time, this was the only delaying tactic open to her. Immediately put under immense pressure from the company, its lawyers, and even some of her own colleagues, Kelsey forced the company to resubmit its application half a dozen times. It was while the company was still awaiting approval from the resolute Kelsey that the drug was withdrawn from the German market. The FDA application was soon withdrawn. The United States did not entirely escape the thalidomide tragedy, since some infants and adults were adversely affected as a result of Richardson–Merrell's testing procedures, but by and large Kelsey's vigilance protected the world's largest market from the horrifying effects of the drug.

Thus might the story of thalidomide have ended. A dangerous drug was removed from the market, and important questions were raised and addressed about the practice and ethics of developing, testing, and marketing drugs and about the relationships among industry, medical professionals, and legislators. But in 1964, Dr. Jacob Sheskin was treating patients with leprosy in Marseilles, France. While in despair at his inability to lessen the pain and misery of his patients, he found some packs of thalidomide on the dispensary shelves. Deciding that this sedative might be worth a try in patients in whom other sedatives had failed, he gave two tablets to one of his patients. The man slept, got out of bed the following morning, and after two more pills, his lesions started to heal.

Sheskin's unexpected discovery led to further research on the discredited drug: could it be useful in other inflammatory conditions? For the first time, scientists began studying its mechanisms of action, and they gradually revealed that thalidomide could modify some types of immune reactions and could be effective not only for patients with leprosy but also for those infected with the human immunodeficiency virus and those with a wide variety of autoimmune conditions, such as multiple sclerosis and inflammatory bowel disease. Research on the possibility that thalidomide might act on cancer cells revealed that it could inhibit the proliferation of blood vessels associated with the development of tumors, thus effectively stopping or slowing tumor growth. And here, finally, was a clue to the devastating effects of the drug in utero, for it was shown to interfere with the blood supply to the developing limbs of the fetus.

One of the authors of this book, Trent Stephens, is an embryologist who has been working on thalidomide for nearly a quarter of a century, and much of his own work has focused on unraveling the cellular effects of the drug. His coauthor, Rock Brynner, is a historian and novelist, and together, contributing their different skills and knowledge, they have told a compelling story decisively, with style and clarity. Dark Remedy deserves to be widely read.

E.M. Tansey, Ph.D.
University College London, London NW1 1AD, United Kingdom
t.tansey@ucl.ac.uk

Citing Articles (3)

Citing Articles

1. 1

   M. Rosenbach, Victoria P. Werth. (2007) Dermatologic therapeutics: thalidomide. A practical guide. Dermatologic Therapy 20:4, 175-186
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2. 2

   Ramón García-Sanz. (2006) Thalidomide in multiple myeloma. Expert Opinion on Pharmacotherapy 7:2, 195-213
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3. 3

   S.James Matthews, Christopher McCoy. (2003) Thalidomide: A review of approved and investigational uses. Clinical Therapeutics 25:2, 342-395
   CrossRef