Neuropharmacology & Neurotherapeutics
Drug-induced aseptic meningitis
May. 19, 2023
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Ropinirole is a second-generation dopamine agonist. Dopamine agonists were first used in patients with moderate or advanced Parkinson disease. There is now a tendency to introduce dopamine agonists in the first stages of the disease as an attempt to delay motor fluctuations. Although many dopamine agonists were developed, only four were marketed and are used extensively for the treatment of Parkinson disease: apomorphine, bromocriptine, lisuride, and pergolide. Ropinirole is one of three newer dopamine agonists; the other two are cabergoline and pramipexole. Ropinirole hydrochloride was developed as SKF-101468A and was shown to have antiparkinsonian effects in primate MPTP models of parkinsonism (04). The United States Food and Drug Administration approved it in 1997 for the treatment of Parkinson disease.
Pharmacodynamics. Ropinirole is a selective D2-type dopamine agonist with a low affinity for D1-type, 5-HT, benzodiazepine, and GABA receptors. It has a direct and selective stimulant effect on postsynaptic D2 receptors. It likely has a neuroprotective effect in the early as well as late phase of Parkinson disease.
Pharmacokinetics. The important points are as follows:
• Most of the orally administered dose is rapidly absorbed from the gastrointestinal tract following administration. The bioavailability is approximately 50%. | |
• Ropinirole shows approximately linear steady-state pharmacokinetics and a good safety profile when administered with L-dopa. | |
• The compound crosses the blood-brain barrier. | |
• Elimination half-life for the compound is about 6 hours. | |
• Plasma concentrations of ropinirole are below the lower limit of quantification in humans at the doses used in various studies. | |
• Ropinirole is extensively metabolized; the major metabolic pathway is via N-despropylation. The N-despropyl metabolite is metabolized further to form 7-hydroxy and carboxylic acid derivatives. 7-Hydroxy ropinirole is the only metabolite of ropinirole previously shown to possess significant dopamine agonist activity in vivo. The principal metabolic enzyme is the cytochrome P450 (CYP) isoenzyme CYP1A2. | |
• The major route of excretion of ropinirole-related material after oral or intravenous administration of the compound is renal (60% to 90% of dose). | |
• Gender, mild or moderate renal impairment, Parkinson disease stage, concomitant illness, and the use of several common concomitant medications have no significant effect on the pharmacokinetics of ropinirole. | |
• A 24-hour prolonged-release formulation of ropinirole provides continuous delivery of the drug over 24 hours, reducing fluctuations in plasma concentration. The titration regime of prolonged-release ropinirole is faster with significant efficacy versus placebo. Prolonged-release ropinirole prolonged-release is a once-daily formulation, but multiple dosing is preferred in some cases if once-daily dosing is unsatisfactory because of individual pharmacokinetic differences (27). In a phase 4 study on patients with advanced Parkinson disease to test different doses of once daily prolonged-release ropinirole, the 16 mg dose reduced “off-time,” with 8 mg as the lowest maximally effective dose, and the safety profile was consistent with previous studies (28). | |
• In Japanese patients with Parkinson disease, the plasma pharmacokinetics of ropinirole and its metabolites are like those described in studies on Western patients and are not affected by food (11). Prolonged-release ropinirole tablets can be administered to Japanese patients at a lower daily dose frequency than the immediate-release tablets and can be adjusted to the maintenance dose after fewer dose changes with a smaller diurnal variation in the plasma ropinirole concentration. In a multicenter, randomized, double-blind study followed by an open-label, long-term study on Japanese patients with Parkinson disease, high-dose (18 to 24 mg/day) controlled-release ropinirole did not significantly increase its efficacy or plasma level in a dose-dependent manner (12). |
Alternative formulations. Limited oral bioavailability and frequent dosing limits the use of ropinirole, and efforts are being made to improve formulations and route of delivery. Spray drying of ropinirole hydrochloride using sodium alginate polymer has produced microparticles of suitable characteristics for potential intranasal administration to overcome relativity low oral bioavailability because of its extensive hepatic first-pass metabolism (13). Pharmacokinetic and pharmacodynamic activity of ropinirole loaded solid lipid nanoparticles (RP-SLNs) and nanostructured lipid carriers (RP-NLCs) and containing hydrogel (RP-SLN-C and RP-NLC-C) formulations for improved oral and topical delivery have been evaluated. Results show that lipid nanoparticles and corresponding hydrogel formulations can be considered an alternative delivery approach for the improved oral and topical delivery of ropinirole for neuroprotection and effective treatment of Parkinson disease (03).
Ropinirole hydrochloride nanoemulsion with nigella oil for Parkinson disease in silico study was done to explore interactions of ropinirole and thymoquinone at receptor site TNF-alpha and NFK-beta (21). In vitro release and permeation studies exhibited 2-fold and 3.4-fold enhancement when compared with the drug suspension. Neurobehavioral activity and biochemical parameters corroborated well with the pharmacokinetic results. Thus, nanoemulsion is a promising synergistic approach yielding enticing outcomes for better management of Parkinson disease-related symptoms.
Pharmacogenetics. Profiling of five genes that control dopamine transmission (catechol-O-methyltransferase, dopamine transporter, and those encoding receptors D1, D2, and D3) can be used to predict impulse control and whether it will improve or worsen with the administration of ropinirole dopamine agonists (17).
Randomized, double-blind, placebo-controlled trials are shown in Table 1. Long-term trials (3 to 5 years) to determine if postponement of L-dopa therapy with ropinirole administration influences the outcome of Parkinson disease are in progress.
Study design | Results |
A double-blind, placebo-controlled study of adjunct ropinirole (24-hour prolonged release) in patients with advanced Parkinson disease not optimally controlled with levodopa | Ropinirole 24-hour demonstrated an improvement in both motor and nonmotor symptoms of Parkinson disease while permitting a reduction in adjunctive levodopa dose (22). |
A randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of ropinirole as an adjunct to levodopa in patients with advanced Parkinson disease | Ropinirole was more effective than placebo in improving motor function and activities of daily life (19). |
A 6-month prospective study to evaluate the effects of ropinirole on nonmotor symptoms of Parkinson disease, including anxiety, depressive symptoms, sleep disturbances/excessive daytime sleepiness, and sexual functions | In addition to controlling motor symptoms, ropinirole improved both anxiety and depressive symptoms in patients with motor fluctuations and/or dyskinesias (24). |
A multicenter retrospective study of the clinical use of ropinirole in the treatment of Parkinson disease | Ropinirole showed a low incidence of adverse reactions and low rate of treatment withdrawal (26). |
The 24-week, double-blind Efficacy and Safety Evaluation in PD-Adjunct (EASE-PD Adjunct) study randomized patients with advanced Parkinson disease suboptimally controlled with levodopa to once-daily placebo or adjunctive prolonged-release ropinirole | Once-daily prolonged-release ropinirole improves nocturnal symptoms in patients with advanced Parkinson disease not optimally controlled with levodopa who suffer troublesome nocturnal disturbance (23). |
A systematic review and network metaanalysis of double-blind randomized controlled trials of patients with advanced Parkinson disease with motor fluctuations receiving levodopa shows that adjunctive therapy with slow release ropinirole or pramipexole offers similar efficacy and tolerability based on this indirect comparison (29).
Restless legs syndrome. Several controlled clinical trials have shown the effectiveness of ropinirole in restless legs syndrome on objective measures of motor symptoms and subjective measures of sleep (02).
Pooled data from clinical trials show that ropinirole improves sleep and lessens daytime somnolence in patients with primary restless legs syndrome (10). In a 66-week controlled trial, the incidence of augmentation was approximately 3% higher with ropinirole than with placebo (07).
Results of a randomized, double-blind, placebo-controlled, parallel-group trial on a subset of patients with restless legs syndrome and a baseline International Restless Legs Scale (IRLS) total score equal to or greater than 24 showed that ropinirole was effective as compared with placebo (09).
As of October 2020, 87 clinical trials of ropinirole are listed, including those that have been terminated or are still ongoing or have been completed. These include use of prolonged-release and controlled-release preparations. Some are for the indication of restless legs syndrome. Further information on clinical trials is available at https://clinicaltrials.gov/ct2/results?cond=&term=ropinirole.
Ropinirole is used for the treatment of signs and symptoms of idiopathic Parkinson disease. Ropinirole is used as a monotherapy in early cases and as an adjunct to L-dopa in advanced cases. Ropinirole is also used for the treatment of restless legs syndrome.
• A randomized, placebo-controlled, double-blind study of ropinirole in chronic stroke did not show any improvement beyond the effect of physical therapy although the drug was well tolerated. Preclinical studies in rat models of reversible cerebral ischemia have shown that ropinirole induces neuroprotection following reperfusion by preventing mitochondrial dysfunction (01). | |
• Cocaine dependence. Chronic cocaine use impairs cognitive processes associated with dopamine circuitry. A clinical trial of bayesian mediation hypothesized the effect was strongest for levodopa plus 2 mg ropinirole, indicating that this dopamine combination predicted improvement in attention and impulsivity with reduction in cocaine use (25). | |
• Treatment for patients who develop apathy and depression after encephalitis (14). | |
• A pharmacokinetic study of chitosan-coated oil in water nanoemulsion of ropinirole delivered intranasally in haloperidol-induced Parkinson disease rat models showed successful delivery of the drug to bypass the blood-brain barrier to show effective concentration in the brain (20). This has the potential for development for clinical use. | |
• A pharmacokinetic-pharmacodynamic model of ropinirole may facilitate the identification of optimal dose regimens of ropinirole for the treatment of prolactinomas as a nonergot dopamine agonist alternative to ergoline dopamine agonists, which can be complicated by intolerance and resistance (16). |
Patients with known hypersensitivity to ropinirole should not take the drug.
The aim is control of the symptoms of Parkinson disease as well as slowing the progression of the disease. As an adjunct to L-dopa in late cases, the aim is to reduce the dose of L-dopa to lessen dyskinesias. Ropinirole seems to be an effective treatment for early Parkinson disease. Although levodopa remains the optimal treatment for Parkinson disease, ropinirole provides similar improvements in functional abilities as it minimizes abnormal involuntary movements. Postmarketing surveillance studies have shown that ropinirole may not only improve motor symptoms, the activity of daily living, and complications of the treatment (dystonia, dyskinesia), but may also alleviate symptoms of depression and anxiety. An open-label multicenter extension study has shown that long-term treatment (up to 73 months) with extended- or prolonged-release ropinirole was not associated with any new or unexpected adverse events in patients with early or advanced Parkinson disease, and the most patients preferred the once-daily dose (18).
The dose is increased gradually to achieve maximum therapeutic effect with minimal side effects. The starting dose is 0.25 mg three times a day, and the dose is increased by 0.25 mg weekly to a total daily dose of 3 mg. It is further increased by 1.5 mg per day weekly to a dose of 9 mg per day. Further increase is 3 mg per day weekly to a total dose of 24 mg per day.
Pediatric. Safety and efficacy in the pediatric population has not been demonstrated.
Geriatric. Most of the experience with this drug is in geriatric patients.
Pregnancy. Ropinirole causes adverse effects on embryo-fetal development in experimental animals, including teratogenicity. There are no studies of the use of ropinirole in pregnant women. It should be used during pregnancy only if potential benefits outweigh potential risks.
Anesthesia. Dopaminergic drugs should be stopped 8 to 12 hours prior to anesthesia and surgery and resumed as soon as possible following the procedure.
Dopamine antagonists. Because ropinirole is a dopamine agonist, dopamine antagonists such as neuroleptics (phenothiazines, metoclopramide) may diminish its efficacy.
Nausea and vomiting. A systematic review of clinical trials shows that nausea and vomiting represented approximately 50% of all adverse events reported (15). With increase in use of ropinirole, it should be considered a cause of chronic nausea and vomiting.
Syncope. This is more likely to occur during the dose escalation phase and is usually associated with postural hypotension. Patients normally recover spontaneously without any therapeutic intervention. Syncope has been reported due to ropinirole-induced sinus node dysfunction, and this problem can be resolved by discontinuation of the drug.
Sudden episodes of daytime sleepiness. Sleep attacks have been reported with all dopamine agonists currently used in practice. It can be ameliorated by changing the dosing schedule or discontinuing the agonist.
Dyskinesias. The risk of developing dyskinesias during maintained initial ropinirole monotherapy is low. Early use of ropinirole postpones the onset of dyskinesias, but these benefits decline when levodopa therapy is started.
Pisa syndrome. This is also referred to as "pleurothotonus,” and the characteristic feature is an abnormal lateral flexion of the trunk to the right or left. Reports of ropinirole-induced Pisa syndrome have appeared in the literature, and it occurred after about 1 year on the medication among the cases described (06). The posture usually disappears approximately 3 months after discontinuing the medication, but Pisa syndrome may be irreversible despite discontinuing this medication.
Hallucinations. These are usually dose-related and may occur in 5% to 17% of patients on ropinirole monotherapy. Dosage reduction may be required.
Psychoses. Psychoses have been reported during treatment of Parkinson disease and restless legs syndrome with ropinirole. These may not respond to anti-psychotic therapy and require discontinuation of ropinirole. Ropinirole should be used with caution in patients with affective disorders.
Impulse control disorders. These encompass a wide spectrum of abnormal behavior found in patients with Parkinson disease treated with dopamine agonists. Impulse control disorders are significantly associated with the use of ropinirole as compared with transdermal rotigotine (08). An epidemiologic study has confirmed the association of ropinirole with impulse control disorder and gambling disorder (05).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
K K Jain MD†
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.
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3525 Del Mar Heights Rd, Ste 304
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Editor: editor@medlink.com
ISSN: 2831-9125
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