The type of treatment depends on the disease stage. The drugs used in the first stage are safer and easier to administer than those for second stage. Also, the earlier the disease is identified, the better the prospect of a cure. The assessment of treatment outcome requires follow up of the patient up to 24 months and entails laboratory exams of body fluids including cerebrospinal fluid obtained by lumbar puncture, as parasites may remain viable for long periods and reproduce the disease months after treatment.

Treatment success in the second stage depends on drugs that cross the blood-brain barrier to reach the parasite. Such drugs are toxic and complicated to administer.

In total five different drugs are used for the treatment of sleeping sickness. These drugs are donated to WHO by manufacturers and distributed free of charge to disease endemic countries.

Drugs used in first stage treatment:
1)Pentamidine: discovered in 1940, used for the treatment of the first stage of T.b. gambiense sleeping sickness. Despite non-negligible undesirable effects, it is in general well tolerated by patients.

2)Suramin: discovered in 1920, used for the treatment of the first stage of T.b. rhodesiense. It provokes certain undesirable effects, including urinary tract and allergic reactions.

Drugs used in second stage treatment:
1)Melarsoprol: discovered in 1949, it is used for the treatment of both gambiense and rhodesiense infections. It is derived from arsenic and has many undesirable side effects, the most dramatic of which is reactive encephalopathy (encephalopathic syndrome) which can be fatal (3% to 10%). An increase in resistance to the drug has been observed in several foci, particularly in central Africa. It is currently recommended as first-line treatment for the rhodesiense form, and as second-line for the gambiense form.

2)Eflornithine: this molecule, less toxic than melarsoprol, was registered in 1990. It is only effective against T.b. gambiense. The regimen is complex and difficult to apply.

3)Nifurtimox: A combination treatment of nifurtimox and eflornithine was introduced in 2009. It simplifies the use of eflornithine by reducing the duration of treatment and the number of IV perfusions, but unfortunately it has not been studied for T.b. rhodesiense. Nifurtimox is registered for the treatment of American trypanosomiasis but not for human African trypanosomiasis. Nevertheless, after safety and efficacy data provided by clinical trials, its use in combination with eflornithine has been included in the "WHO List of Essential Medicines" and is currently recommended as first-line treatment for the gambiense form. Both drugs are provided free of charge by WHO to endemic countries with a kit containing all the material needed for its administration.