Dopaminergics and impulse control disorders

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Impulse control disorders (ICDs) are among pharmacology’s most unusual side-effects. People taking dopamine agonists (DAs) for restless legs syndrome (RLS) or Parkinson’s disease (PD) can feel an irresistible hypersexuality or a compulsion to gamble, binge eat or shop. Nevertheless, ICDs in RLS remain mysterious adverse events wrapped in an enigmatic disease. So what do we actually know?

Enigmatic disease

“About 25 years ago, I was asked to write an article on RLS. I thought: hang on, that’s what I’ve had for the last 10 years,” says Dr Julian Spinks, a GP and chairperson of patient group RLS UK.

“People with RLS have an irresistible urge to move their legs. It is like trying to eat a doughnut without licking your lips: you’ve got to do it. RLS can be painful, but often people experience tickling or itching that they describe as having insects under their skin or Coca-Cola in their veins,” he explains.

“Initially, RLS begins in the evening, stays overnight and disappears in the morning. It is worse when you are resting and eases for a short time if you move around. The ‘day-and-night’ pattern is not typical for other conditions, such as peripheral neuropathy. More severe RLS can, however, persist into the day and some people develop restless arm or trunk syndrome. Why RLS starts in the legs is a mystery,” Dr Spinks says.

About 10% of people develop RLS at some point. Perhaps 2-3% need medical help. “RLS is much more common than multiple sclerosis,” says Dr Spinks. “But RLS doesn’t get the publicity, partly because it is not life threatening. Nevertheless, RLS can be life destroying.”

Dopaminergic dangers

Dopamine agonists alleviate RLS. “DAs appear to be miracle drugs when first taken. The RLS just goes. It is so quick,” Dr Spinks says. “You can use DAs as a therapeutic trial. If the symptoms don’t come back after two days of treatment with DAs, then the person probably has RLS.”

However, according to NICE, 6-17% of people with RLS who take DAs develop ICDs. Clinicians recognised the risk of ICDs in Parkinson’s disease several years ago. “In PD, the risk of ICDs may be more worth taking than in RLS,” Dr Spinks suggests. “Initially, because the DA dose was lower than in PD, neurologists did not expect ICDs in RLS. Unfortunately, ICDs in RLS are not necessarily dose dependent.”

Unravelling the details…

Researchers are still trying to unravel this physiological mystery. However, essentially, a brain region called the ventral tegmental area (VTA) releases dopamine. By reinforcing pleasurable actions, dopamine influences learning, habits and goal-directed behaviours.

The mesolimbic and mesocortical pathways connect the VTA with brain regions involved in pleasure, emotion, motivation, reward, memory, and decision-making. DAs over-stimulate these pathways resulting in ICDs.

Common ICDs in people taking DAs include hypersexuality, which can end relationships, or a compulsion to gamble, binge eat or shop. Occasionally, RLS drives patients to commit suicide, which may partly be an ICD manifestation. “Suicidality is multifactorial, although it tends to affect people with very severe RLS on high doses of drugs that cause ICDs. But people who aren’t on dopamine agonists can also develop suicidality,” says Dr Spinks.

Tackling ICDs

Despite the efficacy of DAs, people with RLS can find that their symptoms gradually worsen. For example, the effects begin earlier in the day, are more intense or affect the arms or trunk. This is called augmentation.

“Augmentation is like getting hooked on opioids. The effect declines. So you increase the dose. You need to get people with ICDs off DAs as soon as possible before they’ve done major damage to their lives. But stopping DAs suddenly can be like an opioid addict going cold turkey – it is that bad,” says Dr Spinks.

Doctors usually manage ICDs by switching treatment. “However, pregabalin and gabapentin, the current first-line RLS treatments, can also cause intolerable side-effects. And RLS is not a single disease and, therefore, there is no single treatment. You’ve got to tailor treatment to the person,” says Dr Spinks.

For example, low iron levels increase RLS risk. So patients may need treatment with, ideally, intravenous iron. Oral iron can take months to restore ferritin levels. “Pharmacists could suggest a patient with suspected RLS asks their GP to measure their ferritin level,” says Dr Spinks, who takes an iron supplement to prevent his ferritin levels from falling.

Pharmacists could also suggest checking renal function. “There is a definite association with chronic kidney disease, especially with more severe RLS,” he says.

Warn patients

“Community pharmacists should warn patients receiving DAs, and their friends and family, to look out for changes in behaviour, especially if the impulse is hard to resist, such as suddenly starting drinking heavily, piling on weight or seeming to be addicted to gambling or sex. I tell patients to seek medical advice as soon as possible but they may need to spell their concerns out. A GP may not know very much about ICDs,” Dr Spinks says.

“If you warn patients, they stand a better chance of spotting ICDs. However, ICDs may not emerge soon after starting DAs. After a few months, they suddenly realise their behaviour has changed. Other people should watch for ICDs. But some changes, like gambling and excessive drinking, are often hidden,” Dr Spinks warns.

Further studies need to explore the link between DAs and ICDs, and identify those who are especially vulnerable. “Some people have a greater risk of addiction. Maybe there is a predisposition that doesn’t come to the fore until a patient takes a DA. Perhaps people with a history of addictive behaviour should avoid DAs, but there is no proof for that,” he says.

Much about ICDs and RLS treatment with DAs remains enigmatic. The MHRA is carrying out an assessment to determine whether any regulatory action is required to help raise further awareness of these risks with patients and healthcare professionals in the UK. “We encourage the reporting of any suspected side-effects experienced with these medicines to the Yellow Card scheme,” says Dr Alison Cave, MHRA chief safety officer.

“Patient safety is our top priority. No medicine is risk-free and impulse control disorders are a known risk for patients prescribed dopamine agonists. Our sympathies are with those affected by any side-effects from their use,” she says.

“These medicines have improved the lives of many patients but ultimately [healthcare professionals], together with their patients, must weigh up the pros and cons of the medicine when deciding on the most appropriate treatment.”