Dopamine Agonists

Author: Dr. Sarah Richards

20 February 2015

What data underpin the use of these drugs?

The availability of data obtained through clinical trial analyses of l-dopa and the dopamine agonists is restricted to those trials which pharmaceutical companies have made available on their websites. Even where clinical trials have been published on company websites, it is virtually impossible to determine the details of the trials.

Clinical trial details reported on a company’s website and those submitted to the Regulators are often significantly different.

Has anyone access to all the data?

As far as the author is aware, no one has had access to all the data.

What publications are there on the use of these drugs?

Most clinical studies, whether run by pharmaceutical companies or academic centres, have examined the efficacy of dopamine supplements and receptor agonists on improving the motor dysfunction associated with Parkinson’s disease. Their primary focus has been to extend the period of efficacy provided by dopamine agonists, and the development of adjuncts in order to delay for as long as possible the introduction of l-dopa.

Each pharmaceutical company has a strong imperative to promote its own product over that of its competitors. Academic departments often strapped for cash will undertake clinical trial studies on a contract basis, but then publishing the data as if it was an independent study. The financial support academics receive for a study is only sometimes declared. In view of this, we should be skeptical about the advantage conveyed by one drug over another, and even the efficacy of drug over placebo needs careful scrutiny of the trial design.

Cochrane systematic reviews

These adopt a highly conservative approach to inclusion criteria, often to such an extent that most scientific reports are excluded from consideration. This leaves few published papers meeting the strict Cochrane criteria for review, thereby ignoring a large amount of relevant data. In adopting this approach, Cochrane reviews are particularly unsuitable for identifying serious side effects of drugs.

Nineteen Cochrane systematic reviews have been identified to date concerning pharmaceutical interventions in Parkinson’s disease and not one has reported data concerning dopamine dysregulation syndrome or impulse control disorder associated with l-dopa/dopamine agonist treatment in spite of publications appearing in the peer-reviewed academic literature for more than 20 years.

What studies have been done on these drugs?

It is impossible to know how many studies have been undertaken on this class of drug or the origins of these studies. If a study produces negative results, it is less likely to be published. Conversely, a single phase III clinical trial (101468/054) conducted by GlaxoSmithKline plc (GSK) between 1992 – 1994 resulted in 14 publications by different authors over the period 1996 – 2002. This makes it difficult to determine whether a new treatment is effective and whether it is associated with more side effects than other available treatments.

As a part of licensing and post marketing surveillance, dopamine agonists undergo clinical Phase I – III safety and efficacy evaluation. Only a selection of these studies is submitted to the regulator in support of Marketing Authorisation Applications and subsequent Periodic Safety Update Reports (PSURs). Not all studies are published and not all are submitted for scrutiny.

Throughout the 1990s and 2000s, the assessments commonly used by the industry to assess safety and efficacy of dopamine agonists were the Unified Parkinson’s Disease Rating Scale (UPDRS), Clinical Global Impression scale (CGI) and modified Hoehn & Yahr scale. None of these tests identify Impulse Control Disorder or the extent of the problem.

The first appropriately designed study reported on the Boehringer Ingelheim website for its drug pramipexole (Mirapexin) (the DOMINION study) was not conducted until 2006 and reported by Lang and Weintraub in 2010. A second study was undertaken in 2008 and reported in 2011. Yet by 2003 patients’ were blogging about their medication linked disinhibitory behaviours and several peer-reviewed reports of this iatrogenic problem had been published in the academic literature. This was a slow response to a serious adverse event which, by Boehringer’s own studies, was experienced by 17% of patients.

GSK has similarly posted approximately 26 phase III and IV clinical trials relating to its dopamine agonist, ropinirole (Requip) as a treatment for Parkinson’s disease during the period 1992-2010. None of these is designed to identify impulse control disorder as an adverse event and in spite of many thousands of patients being enrolled on the company’s dopamine agonist trials there is no mention of disinhibitory behaviour.

Both companies are vulnerable to lawsuits in the USA, UK and elsewhere. Based on the clinical trials available to the public and possibly without access to all clinical trials conducted, it does seem astonishing to conclude that the industry was ignorant of these adverse events until 2006, especially as it is a dopamine agonists class effect.

In 2007 the European Pharmacovigilance Working Party announced the outcome of its review of impulse control disorder and dopamine agonists. Manufacturers were required to add a note to their Patient Information Leaflets warning of drug induced pathological gambling, increased libido and hypersexuality.

Are there any problems with recognized guidelines?

Current guidelines are confusing and out of date.

Physicians’ Desk References are regularly updated but the information is often out of date and inconsistent. In the case of dopamine dysregulation syndrome and impulse control disorders warnings were issued in a piecemeal manner for the different dopamine agonists and across several years.

There remains a lack of systematic approach to warnings. For many years dopamine agonists have been recorded in Formularies as a treatment for Parkinson’s disease yet some of these same drugs, are also listed for their endocrine effects. One in particular was marketed as a sexual enhancer. This information did not appear alongside the information provided under Parkinson’s disease treatments. If the information had been consistent, prescribers might have been alerted years earlier to the sexual disinhibitory effects associated with this particular drug, and extrapolated this to the class in general.

Physician’s Desk References mainly receive information from the Regulator and the pharmaceutical companies. The regulator is financed by industry, and this may contribute to the slow communication of adverse effects to prescribers.

Clinicians plead lack of time to keep themselves informed and lack of time to complete reports of problems to the regulator. For all these reasons, adverse effects are slow to be recognized, reported and warnings issued with the result that guidelines often fall behind the awareness raised through patients’ blogs or investigative reporting in the media.

As of 2012, the main independent Guidelines for Parkinson’s disease (NICE) had been last updated in 2006 and did not properly recognize the disinhibitory behaviours associated with l-dopa and dopamine agonists.

The British Medical Association refers physicians to the BNF. Something similar happens with the American Medical Association. The World Health Organization, the Royal Pharmaceutical Society and the General Medical Council all issue guidelines and advisory notices from time to time but none has been identified for these serious issues.

The benefits of dopaminergic treatments

Do dopaminergic system based therapies work?

There is a consensus across the literature which supports the use of l-dopa, either as a monotherapy or in association with an adjunct for the treatment of Parkinson’s disease. However, as the disease progresses, drawbacks and side effects emerge. The most significant of which is that the window of efficacy declines – both in terms of between dose interval and before the drug becomes ineffective – and the patient fluctuates between “On” and “Off” states.

Dopamine agonists have a different mode of action and are either prescribed as a monotherapy or as an adjunct to other therapies for the preservation of motor function in Parkinson’s disease, and to delay the onset of the fluctuations and other side effects associated with long-term l-dopa treatment.

What do dopamine agonists do?

While l-dopa provides a supplementary source of dopamine to the brain, dopamine agonists stimulate post-synaptic receptors. Although each has a different mode of action both are non-selective and can increase dopamine or stimulate the dopaminergic receptors in parts of the brain other than the caudate putamen associated with motor function.

What overall impact will dopamine agonists have on function?

Both l-dopa and dopamine agonists will improve motor function including walking, gait, balance and co-ordination while suppressing the tremor and rigidity associated with the disease. Side effects occur, at least in part, due to the stimulation of dopamine receptors in non-motor regions of the brain (e.g. the cortex and limbic system). This is believed to be the cause of some patients experiencing the unwanted disinhibitory behaviours of gambling, binge eating, shopping and hypersexuality, and psychiatric difficulties the most commonly reported one being that of hallucination.

Are the effects of dopamine agonists down to placebo?

Clinical trials report significant improvement of treatment over placebo effects. This is predicted by the neurodegenerative processes underlying the disease.

Acute trials and chronic treatment

One reason suggested for the tardiness of dopamine dysregulation syndrome being noted during clinical trial is that the average duration of drug trials is 6 weeks whereas the emergence of disinhibition often starts 4 weeks after initiation of treatment.

A further explanation for these symptoms being slow to emerge at trial was that assessment scales included within the trial design related to improvement in motor function. The first clinical study to include a questionnaire explicitly assessing impulse control disorder was conducted by Weintraub et al. in 2006.

When should I take treatment?

Dopamine agonists are reported in the academic literature as conveying a neuroprotective effect early in the progression of the disease. This would predict an advantage of early diagnosis and treatment. However, as with l-dopa, dopamine agonists deliver reduced efficacy over time and will eventually provide little benefit for motor function.

The decision for the prescriber regarding the commencement of treatment is a balance between preserving neural integrity and maximizing treatment efficacy.

Are there any problems with treatment combinations?

The challenge for the prescriber is that of increasing the daily prescription to maximize movement control without reaching the threshold where unwanted side effects emerge such as dyskinesia, disinhibitory behaviours, hallucinations, sleep disorder or mood swings. Adjuncts may be used to extend the period of efficacy but these too may introduce adverse effects. Feedback from the patient is essential and support provided by a Specialist Parkinson’s Disease Nurse is vital in some cases for drug regime management.

What can be done to help in addition to drug treatment?

Medical advice, including that provided by Parkinson’s groups, indicates the importance of physiotherapy, speech and occupational therapies. Depression may emerge upon diagnosis and as the disease develops with the commensurate dysfunction in neural circuitry. Psychiatric referral may be necessary in additional to counseling. Marital relations come under pressure as dependency increases.

Patient-specific questions

How do I know which dopamine receptor agonist to take?

There are currently 6 different agonists available for prescription in the UK.

Ergot-derived dopamine-receptor agonists, bromocriptine and cabergoline have been associated with pulmonary, retroperitoneal, and pericardial fibrotic reactions. A warning was put in place in 2004 and prescribers advised that patients given these drugs should be regularly monitored for cardiac fibrosis by echocardiography commencing 3–6 months of initiating treatment and at 6 monthly intervals thereafter.

Pramipexole, marketed as Mirapexin in the UK by Boehringer Ingelheim, has been reported in the scientific literature as being worst of all the dopamine agonists for causing disinhibitory behaviours. However, as more investigations are conducted and publications emerge, this picture may change with no worst in class being apparent.

The dopamine agonist pergolide mesylate marketed as Celance in the UK by Eli Lilly was voluntarily withdrawn from the U.S. market in 2007. This followed the publication of 2 independent reports one of which indicated a 17% increase in incidence of cardio- valvulopathy over non-dopamine treated patients. Pergolide was subsequently withdrawn from the UK market for the same reasons in August 2011.

How long do I have to be on treatment?

There is no cure for Parkinson’s disease and the likelihood is that the patient will receive long-term, dopaminergic intervention.

What are the risks?

The warnings for dopamine drugs comprise fibrotic reactions, hypotension, sudden onset of sleep and disinhibitory behaviours.

Other side effects listed are: nausea, vomiting, drowsiness, confusion, injection site reactions, rash, difficulty breathing, dyskinesias during ‘on’ periods, haemolytic anaemia with levodopa, eosinophilia and disinhibitory behaviours of pathological gambling, increased libido and hypersexuality.

How likely are the listed side effects of dopaminergic drugs to happen?

It is difficult to assess the frequency of any of these side effects as they may occur transiently upon treatment initiation or when titration either upwards or downwards occurs. Some symptoms such as the psychiatric and disinhibitory effects may not occur until the treatment regime has been established over several weeks.

In the absence of reliable empirical data predictive of incidence and time of onset, it is important for the prescriber to alert the patient and his/her carer to such reactions. Drug-related side effects should be identified by questioning the patient or carer during clinic or surgery attendance and they should be carefully monitored.

Do dopaminergic treatments actually cause problems?

There is a body of literature that suggests l-dopa could be neurotoxic and exacerbate neuronal death of those cells producing dopamine. The evidence is not clear-cut while the advantages for treatment are well founded.

Could my drug have caused this, doctor?

The long running failure to link serious problems of anti-social and impulsive behaviour with treatment with the dopamine agonist class of drug is shameful. Current figures reported from clinical studies indicate that as many as 23% of patients prescribed dopamine agonists suffer from dopamine dysregulation syndrome or impulse control disorder. In some cases the behaviours have resulted in bankruptcy, criminal convictions and loss of family support at a time when the patient is experiencing a disintegration of neural integrity and commensurate losses of motor function and cognitive skills.

The fact that such adverse effects occurred and were massively under-reported for a period of more than 20 years reflected the patients’ shame and attempts to hide such anti-social behaviours. Also, patients attributed these changes in personality to the disease itself rather than the medication they were being prescribed.

Over this 20-year period, few doctors submitted reports to the regulators or companies. Patients became aware of the issues through patient blogs and legal cases being reported in the press.

What kind of doctor have I got?

An astute doctor will keep up-to-date with their patients’ disorder through websites, conferences, journals and recurrent training. Importantly, patients should be asked about the onset of any new behaviour or symptom in response to a change in medication or increase or decrease in dose.

There should never be a complete reliance upon the Patient Information Leaflet, BNF, or e- compendiums as these rely heavily upon data provided by the pharmaceutical company. In specific cases the pharmaceutical companies have been shown to place profit before patient safety through selective clinical trial design and the under-reporting of negative results.