Ropinirole

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 10.07.2021
Released 07.06.1999
Expires For CME 10.07.2024

Ropinirole

Author: K K Jain MD†

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Ropinirole

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Introduction

Historical note and terminology

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.

Pharmacology

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).

Clinical trials

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.

Table 1. Randomized, Double-Blind, Placebo-Controlled Trials of Ropinirole

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.

Indications

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.

Off-label uses

	• 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).

Adverse effects

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).

References

01: Andrabi SS, Tabassum H, Parveen S, Parvez S. Ropinirole induces neuroprotection following reperfusion-promoted mitochondrial dysfunction after focal cerebral ischemia in Wistar rats. Neurotoxicology 2020;77:94-104. PMID 31816341
02: Bogan RK. Ropinirole treatment for restless legs syndrome. Expert Opin Pharmacother 2008;9(4):611-23. PMID 18312162
03: Dudhipala N, Gorre T. Neuroprotective effect of ropinirole lipid nanoparticles enriched hydrogel for Parkinson's disease: in vitro, ex vivo, pharmacokinetic and pharmacodynamic evaluation. Pharmaceutics 2020;12(5):448. PMID 32414195
04: Eden RJ, Costall B, Domeney AM, et al. Preclinical pharmacology of ropinirole (SK&F 101468-A) a novel dopamine D2 agonist. Pharmacol Biochem Behav 1991;38:147-54. PMID 1673248
05: Etminan M, Sodhi M, Samii A, Procyshyn RM, Guo M, Carleton BC. Risk of gambling disorder and impulse control disorder with aripiprazole, pramipexole, and ropinirole: a pharmacoepidemiologic study. J Clin Psychopharmacol 2017;37(1):102-4. PMID 27930495
06: Galati S, Möller JC, Städler C. Ropinirole-induced Pisa syndrome in Parkinson disease. Clin Neuropharmacol 2014;37(2):58-9. PMID 24614668
07: Garcia-Borreguero D, Högl B, Ferini-Strambi L, et al. Systematic evaluation of augmentation during treatment with ropinirole in restless legs syndrome (Willis-Ekbom disease): results from a prospective, multicenter study over 66 weeks. Mov Disord 2012;27(2):277-83. PMID 22328464
08: Garcia-Ruiz PJ, Martinez Castrillo JC, Alonso-Canovas A, et al. Impulse control disorder in patients with Parkinson's disease under dopamine agonist therapy: a multicentre study. J Neurol Neurosurg Psychiatry 2014;85(8):840-4. PMID 24434037
09: Giorgi L, Asgharian A, Hunter B. Ropinirole in patients with restless legs syndrome and baseline IRLS total scores ≥ 24: efficacy and tolerability in a 26-week, double-blind, parallel-group, placebo-controlled study followed by a 40-week open-label extension. Clin Ther 2013;35(9):1321-36.** PMID 23938061
10: Hansen RA, Song L, Moore CG, et al. Effect of ropinirole on sleep outcomes in patients with restless legs syndrome: meta-analysis of pooled individual patient data from randomized controlled trials. Pharmacotherapy 2009;29(3):255-62. PMID 19249945
11: Hattori N, Hasegawa K, Sakamoto T. Pharmacokinetics and effect of food after oral administration of prolonged-release tablets of ropinirole hydrochloride in Japanese patients with Parkinson's disease. J Clin Pharm Ther 2012;37(5):571-7. PMID 22390368
12: Hattori N, Hasegawa K, Sato K, Mitsuyama E, Numachi Y. Clinical evaluation of ropinirole controlled-release formulation at 18-24 mg/day in Japanese patients with Parkinson's disease. Parkinsonism Relat Disord 2017;40:33-9. PMID 28442303
13: Hussein N, Omer H, Ismael A, Albed Alhnan M, Elhissi A, Ahmed W. Spray-dried alginate microparticles for potential intranasal delivery of ropinirole hydrochloride: development, characterization and histopathological evaluation. Pharm Dev Technol 2019;1-36. PMID 30626225
14: Kohno N, Nabika Y, Toyoda G, Bokura H, Nagata T, Yamaguchi S. The effect of ropinirole on apathy and depression after herpes encephalitis. Cogn Behav Neurol 2012;25(2):98-102. PMID 22596109
15: Kurin M, Bielefeldt K, Levinthal DJ. Prevalence of nausea and vomiting in adults using ropinirole: a systematic review and meta-analysis. Dig Dis Sci 2018;63(3):687-93.** PMID 29383607
16: Liu S, Hu C, Peters J, et al. Pharmacokinetics and pharmacodynamics of ropinirole in patients with prolactinomas. Br J Clin Pharmacol 2019;85(2):366-76. PMID 30362146
17: MacDonald HJ, Stinear CM, Ren A, et al. Dopamine gene profiling to predict impulse control and effects of dopamine agonist ropinirole. J Cogn Neurosci 2016;28(7):909-19. PMID 26942320
18: Makumi CW, Asgharian A, Ellis J, Shaikh S, Jimenez T, VanMeter S. Long-term, open-label, safety study of once-daily ropinirole extended/prolonged release in early and advanced Parkinson's disease. Int J Neurosci 2016;126(1):30-8.** PMID 25495896
19: Mizuno Y, Abe T, Hasegawa K, et aI; STRONG Study Group. Ropinirole is effective on motor function when used as an adjunct to levodopa in Parkinson's disease: STRONG study. Mov Disord 2007;22(13):1860-5. PMID 17618525
20: Mustafa G, Ahuja A, Al Rohaimi AH, et al. Nano-ropinirole for the management of Parkinsonism: blood-brain pharmacokinetics and carrier localization. Expert Rev Neurother 2015;15(6):695-710. PMID 25955028
21: Nehal N, Nabi B, Rehman S, et al. Chitosan coated synergistically engineered nanoemulsion of ropinirole and nigella oil in the management of Parkinson's disease: formulation perspective and in vitro and in vivo assessment. Int J Biol Macromol 2021;167:605-19. PMID 33278450
22: Pahwa R, Stacy MA, Factor SA, et al; EASE-PD Adjunct Study Investigators. Ropinirole 24-hour prolonged release: randomized, controlled study in advanced Parkinson disease. Neurology 2007;68(14):1108-15. PMID 17404192
23: Ray Chaudhuri K, Martinez-Martin P, Rolfe KA, et al. Improvements in nocturnal symptoms with ropinirole prolonged release in patients with advanced Parkinson's disease. Eur J Neurol 2012;19(1):105-13. PMID 21699627
24: Rektorova I, Balaz M, Svatova J, et al. Effects of ropinirole on nonmotor symptoms of Parkinson disease: a prospective multicenter study. Clin Neuropharmacol 2008;31(5):261-6. PMID 18836343
25: Schmitz JM, Suchting R, Green CE, et al. The effects of combination levodopa-ropinirole on cognitive improvement and treatment outcome in individuals with cocaine use disorder: a bayesian mediation analysis. Drug Alcohol Depend 2021;225:108800.** PMID 34102508
26: Valldeoriola F, Cobaleda S, Lahuerta J. A multicentre retrospective study of the clinical use of ropinirole in the treatment of Parkinson's disease: the ROPI-PARK study. Clin Neurol Neurosurg 2009;111(9):742-7. PMID 19733003
27: Yun JY, Kim HJ, Lee JY, et al. Comparison of once-daily versus twice-daily combination of ropinirole prolonged release in Parkinson's disease. BMC Neurol 2013;13:113. PMID 24004540
28: Zesiewicz TA, Chriscoe S, Jimenez T, Upward J, Davy M, VanMeter S. A randomized, fixed-dose, dose-response study of ropinirole prolonged release in advanced Parkinson's disease. Neurodegener Dis Manag 2017;7(1):61-72. PMID 28120630
29: Zhao H, Ning Y, Cooper J, et al. Indirect comparison of ropinirole and pramipexole as levodopa adjunctive therapy in advanced Parkinson's disease: a systematic review and network meta-analysis. Adv Ther 2019;36(6):1252-65.** PMID 30963514

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Ropinirole

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levodopa
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Drug-induced insomnia and excessive daytime sleepiness
Drug-induced parasonmias, sleep apnea, and restless legs syndrome
Drug-induced sleep disorders
Neuropharmacology
Parkinson disease
- Periodic limb movements
- Restless legs syndrome
- Sleep disorders

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Clinical Trials

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Ropinirole

Ropinirole

Ropinirole

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Randomized, Double-Blind, Placebo-Controlled Trials of Ropinirole

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview.
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Ropinirole

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Randomized, Double-Blind, Placebo-Controlled Trials of Ropinirole

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Acupuncture

Dementia in Parkinson disease

ALS-like disorders of the Western Pacific

Illicit drug use: neurologic complications

Sleep and cerebral degenerative disorders

Progressive supranuclear palsy: cognitive and behavioral changes

Imaging of movement disorders

Movement disorders in chromosomal aneuploidies

This is an article preview.
Start a Free Account
to access the full version.