Restless Legs and Requip

What is Requip?

Requip is an oral formulation of ropinirole manufactured by GlaxoSmithKline. It is available as tablets in two formulations: normal release and extended-release.

Requip contains the hydrochloride salt of ropinirole. It is available as film-coated pentagonal tablets containing 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg or 5 mg of ropinirole monohydrochloride. The rest of each tablet is packed with inactive ingredients such as iron oxide, lactose, cellulose, titanium dioxide, polysorbate, glycol, and colorants.

Requip is a dopamine agonist commonly prescribed for treating Parkinson’s disease and Restless Leg Syndrome.

It is recommended for treating moderate to severe restless leg syndrome.

Requip can be taken with or without food although the manufacturer claims taking Requip with food reduces nausea, one of the major side effects of the drugs.

Other side effects of Requip include daytime sleepiness and drowsiness (this may occur suddenly while talking, eating, driving, or any other normal daytime activity), syncope, low blood pressure (more specifically postural hypotension), sweating, and hallucination.

Requip and drugs in its class are known to increase the urge of compulsive behaviors by reducing the control and inhibition of such behaviors. These intense urges include increased sexual urges and compulsive gambling. Although this side effect is rare for Requip, it has inspired a few damage claims.

Requip may also cause the symptoms of restless leg syndrome to occur earlier in the evening or worsen the morning after. These shifts in symptoms are referred to as augmentation and rebound. Their occurrence, cause, and management are not well studied yet.

Requip should not be taken by patients who are hypersensitive to ropinirole or any of the inactive ingredients used in the tablets.

Because of its side effects, Requip should not be taken with alcohol or sedatives. Other central nervous system depressants such as benzodiazepines and anti-depressants should also be avoided.

Since Requip contains a dopamine agonist, dopamine antagonists such as neuroleptics can reduce its efficacy.

Furthermore, some drugs interfere with the metabolism of ropinirole in the body.

Therefore, Requip should be used with care (and with the knowledge of a prescribing physician) when drugs such as cimetidine, omeprazole, ciprofloxacin, and estrogens are also being used.

Requip should not be withdrawn suddenly. It is advised that withdrawal should be done by tapering the dose of the drug over 7 days.

Requip XR (extended-release Requip) has a similar pharmaceutical profile to immediate-release Requip.

However, it is available in the following strengths: 2 mg, 4 mg, 6 mg, 8 mg, and 12 mg. It is also prescribed for once-daily administration.

What is Ropinirole?

Ropinirole is a non-ergoline dopamine agonist initially intended for only treating Parkinson’s disease. Currently, it is also used for treating restless leg syndrome, a use for which ropinirole is even more popular.

Since the patent on ropinirole expired in 2008, it has become available under different brand names and in many generic formulations. The most common brands under which ropinirole is sold are Requip, Ropark, and Adartel.

Ropinirole is one of the 3 drugs approved by the FDA for the treatment of restless leg syndrome. The others are pramipexole and gabapentin enacarbil.

Ropinirole is a dopamine receptor agonist. It is a full agonist on dopamine, D2 receptors. It also acts on D3 and D4 dopamine receptors although its highest affinity is for the D1 receptor.

Ropinirole has a weak affinity for serotonin, 5-HT2 receptor as well as alpha-2 receptors. It has no affinity for 5-HT1, alpha-1, beta-adrenoreceptors, and GABA receptors.

Most of the ropinirole’s activities including therapeutic and side effects are due to its binding to dopamine receptors including D3 and D4 receptors. For example, the unusual side effects which show as hypersexuality and compulsive gambling are due to binding with the D3 receptors.

At the doses at which ropinirole is administered to restless leg syndrome patients, the major enzyme metabolizing the drug is cytochrome P450 CYP1A2. This enzyme converts ropinirole to metabolites which are then excreted with urine.

After oral administration, about half of ropinirole is absorbed and made bioavailable. It is widely distributed in the body with 40% of the dose found bound to plasma proteins.

Ropinirole is metabolized in the liver and eliminated in the urine. Less than 10% of the ingested drug is eliminated unchanged while most of the eliminated compounds are metabolites of ropinirole.

Studies on Requip and Restless Leg Syndrome

Several studies have been done to access the efficacy of Requip in the treatment of Restless Leg Syndrome.

Examples of these studies include the three quoted studies on the drug information brochure of Requip. One study was done in the US, another outside the US and the third was a multinational study including US patients.

These randomized, double-blind, placebo-controlled studies recruited patients with at least 15 episodes of restless leg syndrome during the previous months. Evaluation of symptoms was done on the International RLS Rating Scale (IRLS) and by Clinical Global Impression-Global Improvement (CGI-I) scores.

380 patients were involved in the US study (with 187 placed on Requip and 193 given placebo); 284 patients were involved in the multinational study excluding the US (with 146 given Requip and 138 placed on placebo), and 267 patients were recruited for the multinational study including the US (with 131 placed on Requip and 136 given placebo).

The result after 12 weeks of treatment was taken as the primary efficacy of Requip.

In each study, patients were started on 0.25 mg of Requip and allowed to go up to a maximum of 4 mg. The mean dose of Requip used in all 3 trials was 2 mg.

In all 3 studies, Requip outperformed the placebo by statistically significant margins. The Requip groups also showed a greater reduction in the symptoms of restless leg syndrome than the placebo groups.

After 36 weeks of treatment, Requip was shown to produce long-term efficacy and prevent the relapse of symptoms.

During the period of these clinical trials, the most common side effects were nausea, vomiting, dizziness, fatigue, and somnolence.

A 52-Week Safety and Efficacy Study of Ropinirole

The long-term safety of ropinirole was investigated and detailed in a 2007 paper published in the journal, Sleep Medicine.

This study specifically studied the safety of ropinirole in restless leg syndrome patients. The study took 52 weeks and is currently the longest clinical trial involving the use of ropinirole in the treatment of this syndrome.

The mean dose of ropinirole given to the patients recruited for this trial is 1.9 mg although the actual range of doses is 0.25 – 4 mg. Each patient received ropinirole once daily, 1 – 3 hours before going to bed.

Of the 310 who were recruited for the study, 251 patients completed it and 282 reported at least one side effect during the trial.

The results showed that most side effects were mild to moderate. The most common side effect was nausea.

However, some of the side effects seen during the trial were enough to cause 8.7% of patients to discontinue treatment.

These results show that ropinirole is safe and well-tolerated in most patients even when used for long-term therapy. Most of the side effects of the drug, especially nausea, may be improved by taking the extended-release, once-daily formulation of ropinirole with food.

Of efficacy, the 52-week clinical trial showed that ropinirole was effective for most of the patients. 82.7% of the patients who partook in the trial experienced significant improvements in symptoms. At the end of the trial, the average patient improved by 12 points on the IRLS scale.

The results also showed that ropinirole improved sleep and general quality of life in the patients.