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Abstracts & Commentary
Sources: Rammohan KW, et al. J Neurol Neurosurg Psychiatry. 2002;72:179-183; Willoughby E. J Neurol Neurosurg Psychiatry. 2002;72:150.
With all their functional neurological impairments, patients with multiple sclerosis (MS) suffer from a potentially enormous, steadily rising risk of the vulnerable inflammatory and degenerative myelin of the brain. Many experienced observers say that 75-90% of MS patients are destined to suffer serious fatigue periods at one time or another during their lifetime. Experienced observers also state that 45-64% of all chronic MS patients will at least briefly express disabling fatigue at almost any given time or place. A number of drugs have attempted to relieve these sufferings. At present, however, neither the pharmaceutical industry nor experienced clinical neurologists have found effective ways to help MS patients overcome their progressive fatigue. However, a great deal of effort and, possibly, some success to the problem has now been applied recently. This relates to giving particular attention to a drug called modafinil and how it works for narcolepsy.
In 1998, 18 US narcolepsy centers reported on the efficacy and safety of modafinil, a promising new drug promoting daytime wakefulness (Ann Neurol. 1998;43: 88-97). The study analyzed 283 patients who all suffered from genetically engendered, pathological narcolepsy. Prior to treatment, innate narcolepsy had forced the onset of irresistible sleep and cataplexy at random intervals throughout the day. Treatment with modafinil, however, has measurably and rapidly improved the daily, wakeful functions of active narcolepsy. For example, in a recent additional trial of 151 patients with genetic-based narcolepsy, modafinil significantly increased daytime wakefulness and improved individuals’ states of fatigue at night. Because of the benefits of this narcolepsy program, the next step for modafinil is to bring patients with MS out of their fatigued state.
Modafinil is a drug somewhat like amphetamine, which stimulates wakefulness, but the 2 are not functionally identical to that sympathomimetic amine. Modafinil also does not bind to relevant receptors for sleep/wake regulation such as do the norephinephrins, serotinin, dopamine, GABA, benzodiazepam, or others. Modafinil does not reduce cataplexy, but if as noted, it could possibly reduce fatigue in patients with MS and in a single-blind study it would bring a great response.
In hoping to reduce fatigue in patients with MS, a single-blind study was conducted as follows. The following protocol lasted 9 weeks without omissions, infections, or temporary absences.
• Phase 1. The first 2 weeks took only blinded placebos to test patients who might confound the protocol’s excess of emotional improvement. Thenceforth:
• Phase 2. Gave 200 mg/d of modafinil for 2 weeks followed by placebos for 2 weeks;
• Phase 3. Gave 400 mg/d modafinil during subsequent 2 weeks followed by placebos for 2 weeks;
• Phase 4. Four matching subsequent daily placebos of pretended 200 or 400 modafinil for 2 weeks.
In this protocol, treatment with Phase 2 brought 200 mg/d of modafinil for 2 weeks and attained a modest, but significant, improvement in all 3 fatigue scales. This compares more favorably than to the parallel placebo as well as amantadine and pemoline. Later, however, this test slipped back to neutral and lost its favorable effect.
Phase 3 raised the dose to 400 mg of modafinil per day for 14 days. This time, however, another question test indicated that greater fatigue followed the modafinil, particularly when taking the 400-mg dose.
The most general adverse symptoms included headache, nausea, and asthenia. Modafinil by and large was well tolerated in these patients.
Seventy-six percent of patients were taking interferons or glatiramer acetate with no interference. Rammohan and colleagues suggest that 200 mg/d modafinil significantly improves fatigue and is well tolerated in patients with MS. Sixty five (90%) patients completed the study.
Neurologists will appreciate the excellent up-to-minute essay about MS in a recent issue of Lancet (Compston A, Coles A. Lancet. 2002;359:1221-1231). —Fred Plum
Dr. Plum is Editor of Neurology Alert.