Thalidomide
Authors: B.R. Allen
Journal: British Journal of Dermatology (2001)

No other drug has a name that evokes such emotions as that of thalidomide. Its infamous and unexpected teratogenicity has, more than any other single factor, been responsible for the current stringent regulations concerning drug development and use. Thalidomide was first synthesized in 1954 and marketed as a hypnotic in 1956. It rapidly became popular because it was effective and lacked acute toxicity, but it was withdrawn from general use throughout the world between late 1961 and early 1962, having been linked with irreversible neuropathy and limb deformities in the children of mothers who had taken the drug during the first trimester of pregnancy. Initially thalidomide appeared to be the ideal hypnotic with negligible acute toxicity. The early animal work was encouraging, clinical trials were favourable and neither the animal nor the clinical studies uncovered the risks which were subsequently to become only too clear. The story of the disaster is fully described by Mellin.1 The frequency of phocomelia in Germany rose from four cases in 1958 to eight in 1959, 70 in 1960 and 222 in 1961, paralleling the increased use of thalidomide before the link was recognised. Even small doses can be devastating and anecdotal reports of 50 mg daily for 1 week starting 7 days after the last menstrual period and 100 mg taken for 3 nights followed by 50 mg for 2 nights during the second week have been recorded as causing deformities. Phocomelia is more common in the upper limbs. In 65–75% of cases only the arms are affected; in 10–25% both upper and lower limbs are involved and in 2–5% only the legs are deformed. The embryotoxic effects of thalidomide vary between species. Thalidomide is teratogenic in humans, monkey, rabbit, rat, mouse, and chicken but not in the hamster;2 despite the fact that it does cross the placental barrier. The critical period for embryopathy occurs in the period between 20 and 40 days of gestation. The exact risk is not known. The intact phthalimide or phthalimidine groups appear to be responsible for the teratogenic activity but the mechanism has not been conclusively demonstrated. Hypothetical bases for thalidomide's teratogenicity include vitamin or amino acid antagonism, acylation of biogenic amines, interaction with various enzymes or nucleic acids, interference with energy metabolism, and interference with hydroxyproline biosynthesis.3 The possibilities have been reviewed by Stephens.4 Thalidomide is also known to cause an axonal neuropathy that predominantly affects sensory nerves although there is some evidence to suggest more widespread effects on the nervous system.5 The clinical symptoms reported and reviewed by Gunzler6 include hypo- and hyper-aesthesia, impaired temperature sensitivity and impaired autonomic function. Reports of motor disturbances are rare. It has been claimed that symptoms may occur some time after thalidomide has been stopped. They may resolve slowly but usually persist. The most useful objective measurement of thalidomide-induced peripheral neuropathy is decreased sensory nerve action potential amplitude as measured in the sural and median nerves.7 Conflicting estimates of the incidence of thalidomide-induced neurological disturbances have been given ranging from less than 1% to 50%. It may be related to the total dose but this is far from clear with cases having been reported with cumulative doses of 15 g whereas other patients have been treated continuously for years without overt problems. It has been suggested that the risk of neuropathy is unpredictable and cannot be correlated to the total dose of thalidomide.8 Symptoms in the original 13 patients developed 2–18 months after starting regular medication on 50–400 mg nightly.5 It is recommended that sensory nerve conduction studies are performed, using standard techniques and surface electrodes at regular intervals throughout therapy, which will permit an early detection of reduced amplitudes before symptoms occur. Thalidomide has two distinct pharmacological actions: a potent depressant effect on the CNS, and a less clearly understood immunomodulatory effect in inflammatory disease. The efficacy of thalidomide as a hypnotic and sedative was the reason for its introduction and popularity in the 1950s. These effects are probably a result of the glutarimide moiety substituted in the 3 position with a nonspecific space-filling group. This configuration exists in a number of sedative and hypnotic drugs such as glutethimide.3 Interest in thalidomide has been rekindled by its effect in type II reactions in leprosy and its potent anti-inflammatory and immunomodulatory properties in a number of different diseases. Most of the reports on the efficacy of thalidomide in all of its indications, none of which are licensed in this country, are anecdotal and most of the information has been acquired by uncontrolled clinical observations over the past 30 years. There is nevertheless ample clinical evidence that thalidomide has anti-inflammatory properties in certain specific diseases such as erythema nodosum leprosum (ENL) reactions, severe aphthous stomatitis, Behçet's disease and graft-vs.-host disease (GVHD), but it remains open to question how these are effected and whether they are the result of a single activity. Attention has recently focused on the ability of thalidomide to selectively inhibit the inflammatory cytokine tissue necrosis factor (TNF-α). This is achieved by accelerating the degradation of mRNA encoding the protein. Serum levels of TNF-α are elevated in ENL9 and lowered with thalidomide therapy.10In vitro, thalidomide in concentrations up to 1 µg mL−1 has been reported to inhibit TNF-α production by 40% in peripheral blood mononuclear cells.11 The number of publications on thalidomide is rising, with over 1000 in the last decade but its increasing popularity should not make us complacent about its use and its potential to cause harm. In this issue Chave et al. look at the way thalidomide is being used in Wales, a small (2·93 million) but clearly defined population served by 19 dermatologists.12 They draw attention to the wide variation between the United Kingdom and the United States in the requirements before thalidomide is prescribed. In the U.K., there are voluntary guidelines and recommendations whereas in the U.S. registration of patients is mandatory and their supervision arduous. They also draw attention to the haphazard and potentially dangerous way in which thalidomide is sometimes being used. The purpose of any guidelines or regulations is to ensure that a drug is used safely and effectively. There have been several attempts to have thalidomide prohibited worldwide and there are still some who are understandably bitter about the damage it caused and would wish, even now, to have it banned. Conversely, there are patients whose lives have been transformed by its use. It is essential that those who do prescribe it do so responsibly and are fully conversant with all the precautions surrounding its use in order to minimise the risks of any further disasters that could result in the loss of an invaluable drug.