What is documented for the use of Sinemet (levodopa/carbidopa) in patients with brain injury follow

Fråga: What is documented for the use of Sinemet (levodopa/carbidopa) in patients with brain injury following head trauma or stroke? Are there any risks with long-term treatment with Sinemet? These patients are sometimes treated with levodopa/carbidopa (12.5/50 mg three times daily or 37.5/150 mg three times daily) at the rehab-department. The physician has seen positive response to the treatment with increased activity, especially in one trauma patient.

Sammanfattning: A literature search revealed one controlled, randomised trial of the levodopa/carbidopa combination, used in the rehabilitation of patients with ischemic stroke. Single, daily doses of 100 mg levodopa during three weeks gave significant improvement in motor function. Neither long-term effects, nor dose-response relations, have been evaluated for this indication. Studies of long-term levodopa/carbidopa use in Parkinson´s disease have not revealed any increased risk of serious adverse effects.

Svar: Sinemet contains a combination of levodopa and carbidopa, and is used to treat parkinsonism. Levodopa is decarboxylated to dopamine in the brain. Carbidopa is a dopa-carboxylate inhibitor of levodopa metabolism. Carbidopa does not pass the blood-brain barrie and therefore prevents peripheral decarboxylated of levodopa and increases brain dopamine levels (1).

After brain damage a decrease of dopamine and serotonin metabolites have been shown. Alteration of the levels by administration of neurotransmitter altering agents might influence consciousness, motor and cognitive function (2). Several neurotransmitter altering agents have been studied in brain damaged patients. Treatment with neurotransmitters, or their precursors, might improve the clinical condition of patients following head trauma/stroke (3). One theory about the effect of levodopa is that damaged dopamine receptors are stimulated, which activates the production of monoamines and other neurotransmitters, leading to formation of new neural pathways (2). A small fraction of dopamine, about five per cent, is also converted to norepinephrine in the central nervous system, and thereby acts directly on norepinephrine receptors (8).

Several open studies have been published where L-dopa alone, or in combination with a dopa-decarboxylase inhibitor, have been used to treat patients following stroke or head trauma (2-4). The clinical status of the studied subjects varies greatly. Some patients are comatos, while other are conscious, but have problems with speech, motor function and/or cognitive function. As some degree of spontaneous recovery is to expected in many patients, it is hard to determine the contribution of L-dopa treatment in these open, non-randomised studies, which are briefly described below.

In a study of fifteen comatose patients, improvement of consciousness was seen following treatment with levodopa (50-400 mg/day). Improvement occurred within a few days after starting levodopa treatment, and seemed to be dose dependant. Also, symptoms became worse during temporary withdrawal of the treatment (4).

Forty-five head injury patients (aged 7-54), with a stable condition for at least four weeks, were treated with levodopa (200-800 mg/day) in combination with benzerazide (dopa-decarboxylase inhibitor, 50-200mg/day) and/or physostigmine (cholinesterase inhibitor, 1-1.5 mg iv or 3x1 mg im). Twenty-nine of the patients showed clinical improvement, especially during the first week of treatment. Patients with a long period without improvement after their accident, showed no or weak response to treatment (3).

Twelve patients, aged 17-54, with traumatic brain injury were treated with Sinemet (10/100mg x 3 or 25/250mg x 4). All subjects showed some degree of improvement and patients treated within 18 months after injury showed improvement in physical, cognitive and behavioural areas. No adverse drug reactions were seen during the three week study. Again, worsening during temporary drug withdrawal is reported (2).

We also found three case reports concerning head trauma patients. A 74-year-old woman, did not respond clinically to Sinemet treatment, started seven months after her accident (5), while a 9-year-old girl showed remarkable improvement of motor function following levodopa (100mg x 4/day) intake, started one and a half years after injury (6). A 24-year-old man, who had been unresponsive for 6 months following trauma, became conscious already a few days after administration of Sinemet (10/100 mg x 3 for 3 days and then 25/250 mg 4 times daily). After a few months with levodopa he was able to use a manual wheelchair and was independent in all day living (7).

We found only one randomised, placebo controlled, blinded study, in which a single, daily dose of a levodopa (100 mg) carbidopa combination, or placebo was administered to 53 thromboembolic stroke patients with decreased motor function. A three week treatment period, combined with physiotherapy, was started one to six months after the stroke. For a second three week period patients had only physiotherapy. Patients receiving levodopa were able to walk independently better and earlier than patients only receiving physiotherapy, and the advantage of the levodopa group was maintained at the end of the study (after three weeks of physiotherapy only). The study was designed not to give steady-state concentrations of levodopa, to avoid down regulation of norepinephrine receptors (8).

Long-term treatment with levodopa for indications, other than parkinsonism, has not been studied. In Parkinson patients, there seems to be no increase in adverse effect during long-term treatment. In a 36-months trial with Sinemet in Parkinson patients, no unexpected side effects were observed (9). In a 52 week trial, two thirds of adverse reactions following Sinemet where seen within the first three months (10). Drug related dream phenomena have been reported in patients on chronic levodopa/carbidopa therapy (11).