Side Effects

Table 28.2 shows the frequency of the adverse reactions described in association with the use of thalidomide. Side effects are common during thalidomide treatment. Its original therapeutic use was as a sedative, and, accordingly, it is the cause of somnolence and drowsiness reported in a high percentage of patients. Although this adverse reaction improves with reduction in dose and is minimized if the drug is taken at night, sometimes it is severe enough to discontinue the treatment (Atra and Sato 1993, Kyriakis et al. 2000, Stevens et al. 1997).

The two most worrying side effects of thalidomide use are teratogenicity and neuropathy. The current availability of contraceptive methods has dramatically reduced the frequency of congenital malformation to almost zero. Nevertheless, a pregnancy test before treatment and the use of strict contraceptive measures during treatment for at least 3 months after taking the last dose are mandatory. Even the slightest doubt

Table 28.2. Side effects associated with thalidomide use

Table 28.2. Side effects associated with thalidomide use

Dizziness Insomnia Depression

Drowsiness

60 41 8 13 0 25 50 24 35.7 4.3 18 31.6 11.6 6.6 3.3

Knop et al. 1983 Kyriakis et al. 2000

Atra et al. 1993 Atra et al. 1993 Sato et al. 1998 Knop et al. 1983

Dizziness Insomnia Depression

Drowsiness

60 41 8 13 0 25 50 24 35.7 4.3 18 31.6 11.6 6.6 3.3

Knop et al. 1983 Kyriakis et al. 2000

Neuropathy

Atra et al. 1993 Atra et al. 1993 Sato et al. 1998 Knop et al. 1983

Amenorrhea

Ochonisky et al. 1994 Frances et al. 2002

Edema Xerostomia

Galactorrhea Weight gain Constipation Rash

Ordi et al. 2000 Atra et al. 1993 Ordi et al. 2000 Knop et al. 1983 Knop et al. 1983 Knop et al. 1983 Knop et al. 1983

Up to 12,000 cases of teratogenicity have been reported (Mellin and Katzenstein 1962). There is a series of four lupus patients who developed thrombosis (Flageul et al. 2000). Mood alterations other than depression have been described in most series, but the percentage is not available.

about comprehension or compliance of safe contraception should be an absolute contraindication to treatment with thalidomide in women of fertile age.

Peripheral neuropathy is described in all trials with thalidomide, affecting a variable number of patients. Thalidomide mainly produces an axonal sensory neuropathy that typically manifests as painful, symmetrical paresthesia of the hands and feet, frequently accompanied by lower-limb sensory loss. Muscle weakness, muscle cramps, signs of pyramidal tract involvement, and carpal tunnel syndrome have been reported in many patients (Tseng et al. 1996).

The true incidence of thalidomide-induced neuropathy and its relationship to the cumulative dose is still controversial and varies between the conditions and the series. The incidence in prurigo nodularis is near 100%, whereas in Behcet's disease it is 25%-50%. In leprosy, despite neurologic involvement by the disease itself, the incidence seems to be quite low. In cutaneous LE, different series report peripheral neuropathy affecting 0% (Sato et al. 1998) to 25% (Knop et al. 1983). A study by Ochonisky et al. (Ochonisky et al. 1994) including 42 patients with different skin diseases found that 21% of patients had definite thalidomide-induced neuropathy and as many as 50% had clinical and/or electrophysiologic features of nerve damage. The discrepancies between the different studies might be due to the methods used to diagnose neuropathy, the frequency with which neurophysiologic studies were performed, and individual idiosyncrasy. Some reports have suggested that the development of neuropathy is related to the cumulative dose and the duration of the treatment (Clemmensen et al. 1984, De Iongh 1990), but most studies did not find any quantitative or qualitative correlation between neuropathy and total dose of thalidomide or duration of the therapy (Kyriakis et al. 2000, Ochonisky et al. 1994, Rovelli et al. 1998, Stevens et al. 1997). Patient-related factors such as female sex and older age seem to predispose to the development of neuropathy in the first few months of treatment (Fullerton and O'Sullivan 1968, Ochonisky et al. 1994). In the 1980s, a possible relationship between slow acetylation and the development of thalidomide-induced neuropathy was found (Hess et al. 1986), but a more recent study could not confirm this finding (Harland et al. 1995). The study included 16 patients with severe orogen-ital ulceration who were treated with thalidomide and 16 healthy controls. Forty percent of the patients and 35.7% of the controls were slow acetylators; 28.6% of the patients with neuropathy were slow acetylators compared with 50% without neuropathy.

Several electrophysiologic measures have been suggested for monitoring thalidomide toxicity. Use of the peripheral sensory nerve action potential (SNAP) index has been recommended based on a retrospective study of 59 patients treated with thalidomide (Gardner-Medwin et al. 1994). All patients were routinely assessed with three sensory potentials (medial, radial, and sural nerves). A baseline SNAP was calculated, giving each individual nerve an equal weighting of 100% and the three summated. A decrease of approximately 50% from this baseline total percentage SNAP was prospectively considered as an indication of subclinical neuropathy, and thalidomide therapy was discontinued. In the United Kingdom, the guidelines for the use of thalidomide (Powell and Gardner-Medwin, 1994) propose that electrophysiologic tests should be performed at baseline and should include at least three SNAPs and that thalidomide administration should be stopped immediately if either paresthe-siae are developed or the SNAP index declines by more than 40%. They recommend electrophysiologic monitoring every 6 months. Recently, measures of F-wave chrono-dispersion have been proposed to monitor thalidomide-induced neuropathy (Rao et al. 2000). Further studies should be performed to establish the correlation of F-wave chronodispersion with the SNAP index.

The outcome of thalidomide-induced peripheral neuropathy is uncertain. Early reports of this side effect described 50% of cases with irreversible neuropathy after a long follow-up of 4-6 years (Fullerton et al. 1968). In all patients, recovery was very slow. Other studies have reported similar rates of poor recovery (Aronson et al. 1984, Mellin et al. 1962, Ochonisky et al. 1994). In some patients, recovery did not begin for years. Sural nerve biopsy samples showed severe degeneration of large axons with few signs of regeneration (Lagueny et al. 1986). Education of patients about the earliest symptoms of neuropathy and instructions to stop the drug and contact their physician may reduce the risk of permanent neuropathy. Careful examination for signs of neuropathy and electrophysiologic tests performed every 3 or 6 months should also help detect neuropathy early.

A poorly investigated side effect of thalidomide is amenorrhea. Although the first report was in 1989 in a small group of patients with rheumatoid arthritis treated with thalidomide (Gutierrez-Rodriguez et al. 1989), its importance has only recently been emphasized. Ordi-Ros et al. (Ordi-Ros et al. 1998) described 4 cases of amenorrhea in a series of 18 patients. Amenorrhea appeared 4-5 months after the drug was first administered and resolved 2-3 months after withdrawal. Reintroduction of the drug in two patients was again associated with amenorrhea. Ovarian biopsy performed in one patient showed severe ovarian atrophy. No patients had antiovarian antibodies. Three more cases more have been described in patients with aphthosis (Gompel et al.

1999) and in another two patients with DLE (Passeron et al. 2001). The most recent report (Frances et al. 2002) aimed to establish the prevalence of thalidomide-related amenorrhea retrospectively by studying a group of 21 patients treated with thalidomide. Five patients (24%) with cutaneous LE and one patient with aphthosis developed amenorrhea. All had high serum levels of pituitary gonadotropins (follicule-stimulating hormone and luteinizing hormone). Amenorrhea as a side effect of thalidomide use might be underrecognized in diseases other than lupus since the combined oral contraceptive pill is a widely used contraceptive measure. Usually, patients with SLE use the progesterone-only pill, depot progestogens, or nonhormonal contraceptive measures. When the combined oral contraceptive pill is used, menstruation may continue even when endocrine abnormalities are present.

Thrombotic events have been described as occurring shortly after the onset of thalidomide treatment (Flageul et al. 2000). Four of five patients who developed thrombosis had SLE and were antiphospholipid antibody positive. Thrombosis has also been described in patients with multiple myeloma treated with thalidomide, dexamethasone, and chemotherapy (Osman et al. 2001). The possible underlying thrombogenic mechanism of thalidomide is still unknown and might only be exerted when other risk factors for thrombosis are present, such as antiphospholipid antibodies or malignancy. Although the role of thalidomide as a trigger factor to develop thrombosis has to be confirmed in larger series of patients, thalidomide should be used with caution in patients who are antiphospholipid antibody positive or who have other known risk factors for thrombosis.

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