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mise à jour du
29 août 2002
Arch neurol
A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events
Dewey RB, Hutton T, Lewitt PA, SA Factor
Drugs affecting dopamine neurons and yawning behavior Mogilnicka E
Motor fluctations are common in patients with advanced Parkinson discase (PD) whose symptoms are managed with oral levodopa and represent some of the most disabling complications of the disorder. The transition from good motor (on-state) function to that of poor motor (off-state) function occurs when brain levodopa levels fall below the threshold needed to adequately stimulate striatal dopamine receptors. Since the progression of PD is typically accompanied by progressive shortening of the clinical effect from each dose of levodopa, off states often occur unless strategies are used that can provide a more contirmous stimulation of dopamine receptors. A number of such strategies have been developed including the use of dopamine agonists, catechol O-methyl transferase inhibitors, and controlled-release formulations of levodopa. While these strategies are often helpful, some patients continue to suffer from episodic, often unpredictable, off states.

There are no agents available in the United States that can provide a rapid reversal of an individual off state, This "rescue" property is highly desirable since off states can be very disabling to some patients precipitating immobility, panicattacks, pain, screaming, or drenching sweats.

Apomorphine is a direct-acting dopamine agonist with strong D1 and D2 dopamine receptor-stiniulating properties that is administered by a parenteral route (intravenously, rectally, subcutaneously, sublingually, or intranasally). It has similar efficacy to levodopa with a substantially more rapid time to onset. While an extensive literature exists for apomorphine therapy for PD, only a few studies have been conducted as randomized, placebo-controlled trials using subcutaneous injections of apomorphine to abort offstate events.To our knowledge, only a single study has been previously published evaluating the drug in both inpatient and outpatient settings; in the outpatient setting, all patients received active drug without a placebo comparator. To date there have been no publislied studies attempting to correlate inpatient efficacy incasures with outpatient results. The present study was perforined to establish the efficacy and safety of subcutancous apomorphine injections in a therapeutic setting and establish wheter inpatient efficacy measures accurately predict outpatient responses when both assements are perfromed in a placebo-controlled, double-blind fashion. [...]

Adverse effects : Adverse events (mostly mild in severity) occurred in 85% of apomorphine-treated patients and in 89% of placebo-treated patients. A single serious adverse event (chest pain, myocardial infarction ruled out) occurred in a patient assigned to the placebo study drug. Similar events, without hospitalization, occurred in 3 apomorphine-treated patients. Injection site complaints (including bruising, pain, skin reaction, and nodule development) were common.

Yawning was reported by 40% of the apomorphine-treated group but none of the placebo-treated group (P=.03). Thirty-five percent of the apomorphine-treated patients (and no placebotreated patients) experienced drowsiness or somnolence (P=.07). Dyskinesias were reported as an adverse event by 35% of the apomorphine-treated group and 11% of the placebo-treated group. Nausea or vomiting occurred in 30% of the apomorphine-treated patients and 11% of the placebo-treated patients. In 1 apomorphine-treated patient, nausea with vomiting at the 6-mg dose (given during the inpatient phase) was severe and resulted in discontinuation from the study. Outpatient nausea was usually mild to moderate in severity and was generally reported as an isolated event (nausea was not seen in 96% of all apomorphine-treated patients who reccived outpatient injections).

Uric acid demonstrated statistically significant change from the mean baseline value (+0. 27 mg/dl for apomorphine, -0.34 mg/dL for placebo, P=.02) but was never outside the normal range. There were no statistically significant changes in other safety measures (blood test results, electrocardiograms, or physical examination findings).

Comment : This study was conducted in patients with significant residual off time despite aggressive attempts to control symptoms using both levodopa and oral dopamine agonists. In this setting, outpatient subcutaneous injections represent a reasonable therapeutic option for acutely reversing individual off events. This is the first clinical trial to evaluate both inpatient and outpatient use under placebo-controlled conditions, and it established the predictive nature of inpatient test responses on outpatient therapeutic responses to injected apomorphine.

Our study showed that subcutaneous apomorphine injections effectively reverse off-state events that occur in advanced PD. Outpatients or caregivers demonstrated the capacity to prepare apomorphine from glass ampules and inject it. While we did not use formal quality of life measures, most patients assigned to active drug were pleased with the effects. Patients randomized to apomorphine treatment had reduced total off time that was not derived from lessening the number of offstate events, but from shortening the duration of individual off states. Although within-day tolerance has been previously demonstrated following intravenous infusions of apomorphine, this phenomenon was not observed with the subcutaneous injections used in our study.

Since levodopa dosage was not predictive of apomorphine dose requirements, individual titration is required to establish the correct dose. Under inpatient observation, the average dose required to produce effects equivalent in magnitude to oral levodopa was 5.4 mg, while the average final outpatient dose was 5.8 mg. At levodopa-equivalent doses, dyskinesias were equal in magnitude to those produced by levodopa, but these were mild and generally nondisabling. The only adverse event that was significantly more common in the apornorphine-treated group was yawning. This adverse effect has been reported in patients treated with apomorphine in other studies but is rare with levodopa and the oral dopamine agonists. A review of the Physicians Desk Reference revealed that of the oral dopamine agonists and levodopa preparations available in the United States, yawning is a listed adverse effect only for ropinirole hydrochloride occurring in 3% of patients. The 40% incidence of yawning associated with apomorphine in our study represents more than a 10-fold increase compared with ropinirole. Studies of apomorphine induced yawning in rats have indicated that stimulation of D2 dopamine receptors on paraventricular neurons of the hypothalamus leads to increased nitric oxide synthase activity and yawning behavior. Why levodopa, which produces a similar degree of antiparkinsonian efficacy, is associated with a much lower incidence of yawning is unknown.

Our data show that domperidone is not needed to support the use of apomorphine in patients selected and treated according to our protocol. Clinically significant nausea and vomiting was as rare in our study (only 4% of injections of active drug caused nausea) as has been previously reported in European studies of apomorphine combined with domperidone. Our data suggest that trimethobenzamide is an adequate replacement for domperidone therapy. Alternatively, it is possible that down-regulation of dopamine receptors in the area postrema had already occurred because of chronic exposure to long-acting oral dopamine agonists and that this patient group actually does net require an antinauseant.

We conclude that subcutaneously injected apomorphine rapidly and reliably reversed off-state events in patients with advanced PD in whom conventional antiparkinsonian medications had been optimized. We believe that this study confirms previous work and serves as proof of the clinical effectiveness of subcutaneous apomorphine injections when used to reverse off events.