Off spells and dyskinesias: Pharmacologic management of motor complications

TREATMENT OF DYSKINESIAS

Reduction of levodopa doses will reduce the frequency of dyskinesias, but at a cost of worsened parkinsonism and increased numbers of off periods. An alternative is to spread out the doses of levodopa (more frequent smaller doses), but this practice has not achieved good results. Replacing levodopa with dopamine agonists can also reduce the frequency of dyskinesias, but control of PD symptoms is less optimal than with levodopa. Amantadine and clozapine both have been shown to reduce dyskinesias.

Amantadine

Amantadine is an N-methyl-d-aspartate antagonist with antidyskinesia effects. Metman et al¹² demonstrated that amantadine reduced dyskinesia severity by 60%, without exacerbation of motor function, in a randomized placebo-controlled crossover study. Dose-response studies with amantadine have not been conducted, but 100 mg two or three times daily is used in practice. In some studies, a short duration of benefit has been a concern. Side effects of amantadine include leg edema, hallucinations, confusion, and rash.

Clozapine

Clozapine is an atypical antipsychotic that has been shown in open-label trials and a randomized, double-blind, placebo-controlled trial to reduce the duration and severity of levodopa-induced dyskinesias without worsening of parkinsonian features and with no change in motor fluctuation.¹³ No benefit of clozapine was observed during activation dyskinesia, however. Cloza pine carries the inconvenience of weekly blood draws to monitor for the development of agranulocytosis, which occurs rarely.

GAIT FREEZING

Gait freezing, most commonly a manifestation of off states, causes substantial disability. It has been thought to occur as a result of a loss of noradrenaline due to locus ceruleus degeneration. Improvement in gait freezing has been shown with apomorphine and methylphenidate.

CONCEPT OF CONTINUOUS DOPAMINE STIMULATION

Short-acting dopaminergic drugs have the potential for nonphysiologic pulsatile stimulation of postsynaptic receptors, leading to motor complications. Continuous dopaminergic stimulation to prevent this pulsatile stimulation would theoretically avoid motor complications.¹⁴ Continuous dopaminergic stimulation can be achieved by using the extended-release formulation of ropinirole or pramipexole or by continuous delivery of levodopa or dopamine agonists. Several double-blind controlled trials have shown that treatment with long-acting dopamine agonists lowers the risk of motor complications compared with short-acting levodopa treatment.

In 2005, Stocchi concluded that in patients with advanced PD, a continuous infusion of levodopa was more effective in reducing motor complications than standard oral formulations.¹⁵ The reduction in motor complications was attributed to avoidance of low plasma levodopa trough levels; motor complications were not affected by relatively high plasma levodopa concentrations. The authors of this study speculated that if oral levodopa could be given “in a manner that mirrors the pharmacokinetic pattern of infusion,” it might be able to reduce motor complications.

This hypothesis led to an interest in treatment with levodopa plus entacapone. A regimen of levodopa-carbidopa-entacapone, four times daily at 3.5-hour intervals, was compared with levodopa-carbidopa in 747 patients with early PD over 134 weeks.¹⁶ Initiating levodopa therapy with levodopa-carbidopa in combination with entacapone did not delay the induction of dyskinesia compared with levodopa-carbidopa alone. In fact, levodopa-carbidopa-entacapone was associated with a shorter time to onset and an increased frequency of dyskinesia compared with levodopa-carbidopa.

Potential future treatment options

An intrajejunal pump system delivers a constant-rate infusion of levodopa. A double-blind study of this system is being conducted in the United States. Implantation of the system is an invasive procedure with the potential for infection, kinking dislocation, and occlusion and reposition of the catheter.

Miniature pumps for continuous subcutaneous delivery of apomorphine, currently available only in Europe, have been shown to reverse dyskinesias and motor fluctuations. Limitations of the minipumps are the development of red itchy nodules, ulcerations, and abscesses at infusion sites.

Extended-release dopamine agonists

Extended-release formulations of the dopamine agonists ropinirole and pramipexole are easy to administer, and they maintain therapeutic plasma levels for up to 24 hours. They are unlikely to replace stronger continuous dopamine stimulation with levodopa and apomorphine.

SUMMARY

Motor complications in PD result from progression of the disease and limitations of levodopa. Although the effects of levodopa on PD eventually wane, leaving patients vulnerable to motor complications, clinicians should not undertreat patients.

Effective options for the management of motor complications include prolonging the efficacy of levodopa through the use of selective MAO-B inhibitors and COMT inhibitors as adjuncts to levodopa or continuous dopaminergic stimulation achieved by the use of long-acting dopamine agonists or continuous intraduodenal levodopa.

Emerging therapies will be more efficient for continuous delivery of dopaminergic drugs. Pump delivery systems and extended-release formulations have shown promise.