Author: Dr. Sarah Richards
20 February 2015
- Rationale for levodopa and dopamine agonists
- Dopamine agonists
- Therapeutic benefits of dopamine agonists
- Benefits of dopamine agonists as a frontline treatment
- Limitations to dopamine agonists
- Current dopamine agonists
- Adverse effects common to all dopamine-receptor agonists
- Delayed recognition of DDS
- Non-clinical sources of information
- A quarter of a century
- Physicians’ desk reference or BNF and prescription safety?
Rationale for levodopa and dopamine agonists
The recognition that Parkinson’s disease is caused by a depletion of the neurotransmitter dopamine came from post mortem studies reported by Oleh Hornykiewicz in 1960. His studies concluded that the caudate and putamen of patients suffering from Parkinson’s disease showed a marked depletion of dopamine. He later showed a link between striatal dopamine deficiency and most of the motor symptoms now associated with Parkinson’s disease. Subsequent studies implicated a nigrostriatal pathway which extends between the cell bodies of the substantia nigra to their nerve terminals within the striatum. Experimentally induced damage to this pathway in laboratory rodents produced a movement disorder comparable to Parkinson’s disease.
These findings signaled a role for l-dopa in re-establishing neurochemical levels of dopamine within this neurodegenerative disease. Intravenous injection of l-dopa to a Parkinson’s disease patient produced dramatic benefit and from this, the era of dopamine and levodopa therapy was born (Birkmayer and Hornykiewicz, 1961). Subsequent trials reported benefits for the akinesia, rigidity and tremor associated with Parkinson’s disease in ~75% of cases, although full remission was never achieved.
First reports of levodopa adverse events
The initial paper by Cotzias et al. (1967) on the first proper drug trial of l-dopa gave little attention to any motor adverse effects associated with this new form of therapy although they mentioned anorexia, nausea, vomiting, faintness and hematologic changes. However, in their 1969 paper, these authors described l-dopa induced dyskinesias as well as the mental symptoms of irritability, anger, hostility, paranoia, insomnia and awakening effect.
Therapeutic benefits of levodopa with adjuncts
L-dopa is rapidly metabolized leading to ‘off’ periods as it expires. These ‘off’ periods are associated with the emergence of dyskinesia, dystonia and choreic type movements. L-dopa is converted to dopamine by the enzyme dopa-decarboxylase in both the peripheral and central nervous system. This led to the clever strategy of developing carboxylase inhibitors and blocking their transit across the blood brain barrier prevented the conversion of l-dopa to dopamine in the peripheral system, thereby maximally preserving l-dopa for enzymatic processing to dopamine in the brain. This not only extended central therapeutic effect of each dose but also reduced the peripheral adverse cardiovascular and gastrointestinal effects.
Carbidopa (Lodosyn) and benserazide are peripherally acting decarboxylase inhibitors which when given with l-dopa produce a 4-fold increase in available dose for conversion to dopamine.
Sinemet and Madopar combine decarboxylase inhibitors and l-dopa into a single tablet usually in ratios of 1:10 e.g. 10/100 and 25/250 mg strength tablets although the most common strength prescribed is 25/100mg.
The next class of drugs developed were the inhibitors of monoamine oxidase-B (MAO-B). These potentiate l-dopa by approximately one third, by inhibiting the brain metabolism of both endogenous and therapeutically-derived dopamine. Selegiline and rasagiline do this.
The third adjunct of l-dopa to be developed exploited inhibition of the enzyme COMT, which disrupts the 3-0-methylation breakdown route for both dopamine and l-dopa. COMT inhibitors such as tolcapone and entacapone are given as adjuncts to l-dopa in the early stages of the disease to prevent the development of motor complications.
Limitations to levodopa
Debates exist concerning the therapeutic effect of l-dopa given early in the diagnosis as a means of delaying the onset of motor symptoms. This exogenous dopamine is considered to alleviate the pressure placed upon dying dopamine cells to produce dopamine. However, an opposing view is that l-dopa, in the absence of sufficient oxidative mechanisms in the degenerating brain, becomes toxic to dying dopamine neurons and promotes their death rather than prolongs their life.
A consistent finding is that l-dopa whether given alone or in conjunction with an adjunct has diminished efficacy over time. Patients report a decrease in response to l-dopa therapy within 5 years after initiation of treatment. As the disease progresses 3 main types of problem emerge to limit the effectiveness of l-dopa to suppress the motor symptoms of the disease:
- Wearing off — the period for which each dose of l-dopa remains effective becomes progressively shorter;
- On-off fluctuations — the patients oscillate between a good alleviation of symptoms and periods when the drug is ineffective; and
- Peak dose dyskinesias — when the drug reaches its peak dose in the system and is at its most effective for alleviating bradykinesia the patients can exhibit an opposite response uncontrollable dyskinetic movements.
These problems interact so that as the disease progresses the window of effective dose narrows progressively, between doses without effect and doses inducing abnormal dyskinetic movements, and the level of response fluctuates more erratically over time.
Such difficulties emerge with prolonged l-dopa treatment, not just with the duration of the disease. Consequently, since l-dopa remains the most effective treatment for advanced disease, some doctors delay starting treatment so that the drug will be available to assist at more advanced stages. In parallel, other drugs are sought which, although less effective, can be used earlier in the disease when the symptoms are less severe, in order to delay starting treatment with l-dopa itself until it is finally needed.
The need to spare l-dopa use led to the development of dopamine agonists. In 2002, the American Academy of Neurology concluded that dopamine agonists, a class of drugs developed in the 1970’s, may be preferred as the first-line treatment of patients. As a monotherapy, dopamine agonists have the potential to delay the need to use l-dopa and are considered to convey neuroprotective effects.
Various lines of evidence indicate that agonists act via a different mechanism to l-dopa and their use early in the disease does not compromise the later use of l-dopa. As an adjunct to l-dopa, dopamine agonists can be used in a lower dose and decrease the involuntary movements which occur in response to the higher doses. They can therefore extend the time before a patient requires high and approximating toxic levels of l-dopa in order to receive benefit.
Therapeutic benefits of dopamine agonists
Dopamine agonists directly stimulate central and peripheral dopamine receptors. Their efficacy in Parkinson’s disease reflects stimulation of receptors in the nigrostriatal pathway. They may also exert neuroprotective effects as a result of reducing levels of free-radical metabolites of dopamine thereby reducing oxidative stress.
Dopamine agonists are either ergot-derived or synthetic compounds, the majority of which primarily activate dopamine 2 (D2) receptors and to a lesser extent, dopamine 1 (D1) and dopamine 3 (D3) receptors. There are 5 known types of dopamine receptor each variously associated with neurological functions of cognition, memory, learning, motivation, pleasure, fine motor control and neuro-endocrine function. The precise role of each receptor is still unclear although as a general rule, loss of receptor stimulation to the D1 receptor has neuropsychiatric ramifications while loss of stimulation to the D2 receptor is causative of the movement disorder synonymous with Parkinson’s disease. The D3 receptor has been linked to the pleasure/reward centre of the brain while the dopamine 4 (D4) receptor is associated with attention deficit hyperactivity disorder (ADHD).
Dopamine receptors are associated with 5 different anatomical pathways in the brain. The nigrostriatal pathway is associated with motor control while the meso-limbic and meso-cortical pathways regulate mood, reward, motivation, euphoria and compulsiveness. Overstimulation of dopamine receptors in the meso-cortical pathway can result in psychiatric disorders, mood changes, euphoria and impulsive behavior referred to as dopamine dysregulation syndrome or impulse control disorder.
Additional separate dopamine neuron networks occur in the hypothalamus and the amacrine cells of the retina. Receptors are also located in the cardio-pulmonary and renal systems which account for the adverse effects of direct dopamine agonist receptor activity in the peripheral nervous system. In addition, dopamine is a precursor to endogenous noradrenaline synthesis in the adrenergic and noradrenergic neurons of the sympathetic system and adrenal pituitary axis, so drugs that enhance dopamine production (such as l-dopa) or modify its metabolism (such as MAO Inhibitors) will also have effects of peripheral sympathetic activation, blood flow and cardio vascular responses throughout the body.
Benefits of dopamine agonists as a frontline treatment
The advantages of dopamine agonists over l-dopa are several. They are not dependent upon a transporter for entry or absorption into the brain; therefore, their effects are not influenced by food; they do not require metabolic conversion for their therapeutic effects; several dopamine agonists have long plasma half lines and unlike l-dopa, they do not produce free radicals upon metabolism; and some dopamine agonists can be given by injection. Some specific dopamine receptors exist only in the central nervous system, allowing in principle the design of drugs to target specific brain neurons without peripheral side effects. Apomorphine is an injectable dopamine agonist with a broad receptor profile of activity that produces an acute anti-Parkinsonian effect, but is too rapidly metabolized and short acting for general use.
Limitations to dopamine agonists
The limitation of dopamine agonists as monotherapy is that efficacy is not sustained. Treatment with bromocriptine monotherapy revealed that although 75% of patients remained well controlled at 1 year more than 50% of patients required a supplement of l-dopa after 2 years.
Current dopamine agonists
There are 6 dopamine agonist drugs currently licenced. All are required to be titrated for determination of efficacy at the lowest possible dose. While some dopamine agonists are unselective and stimulate both D1 and D2 receptors e.g. apomorphine and pergolide, others such as bromocriptine, cabergoline, pramipexole, ropinirole and rotigotine target the D2 receptor with varying degrees of specificity. Thus, D2 receptor dopamine agonists are predominantly prescribed for the movement disorder found in Parkinson’s disease and also Restless Leg Syndrome.
Ergot derived bromocriptine and cabergoline have less receptor specificity than the synthetically produced dopamine agonists and because of this and complications of fibrotic reactions they are nowadays not widely prescribed.
Adverse effects common to all dopamine-receptor agonists
As a monotherapy for Parkinson’s disease, dopamine agonists are reported as causing fewer motor complications in long-term treatment compared with l-dopa but they are associated with more psychiatric side-effects. The explanation for this is that the neurodegeneration underlying Parkinson’s disease lies in the nigrostriatal pathway and spares cortical dopamine receptors so that they are vulnerable to over-stimulation in response to dopamine agonists. Over stimulation of cortical D2 and D3 receptors are considered to cause the neuropsychiatric side effects of treatment. In contrast, the excess of cortical dopamine produced by the metabolism of l-dopa appears to be harmlessly processed by a relatively well preserved cortical processing machine.
Ergot-derived dopamine-receptor agonists, bromocriptine and cabergoline have been associated with pulmonary, retroperitoneal, and pericardial fibrotic reactions. Patients given these drugs should be regularly monitored for cardiac fibrosis by echocardiography within 3–6 months of initiating treatment and at 6 monthly intervals thereafter. The dopamine agonist pergolide marketed as Celance in the UK and Permax in the USA by Eli Lilly was voluntarily withdrawn from the U.S. market in 2007, following 2 independent reports one of which indicated a 17% increase in the incidence of cardio-valvulopathy over non-dopamine treated patients. Pergolide was withdrawn from the UK market for the same reasons in 2011.
Sudden onset of sleep
Prominent warnings have been in place for daytime drowsiness since 2001 when sudden onset of sleep was reported as an adverse effect associated with dopamine receptor agonists. Patients were to be advised that they should avoid driving or operating machinery until any sudden drowsiness problem experienced was resolved.
Hypotensive reactions, especially during the early days of treatment with dopamine agonists are also subject of a boxed warning.
Dopamine dysregulation syndrome
The major problem to emerge with dopamine receptor agonists has been uncontrollable gambling, hypersexuality, shopping, binge eating and other activities collectively referred to as impulse control disorders (ICD) or dopamine dysregulation syndrome (DDS). Failure to advise patients of this possible outcome of dopamine receptor agonist treatment in a timely manner has resulted in bankruptcy, broken marriages and serious criminal prosecution.
Since the 1980’s academic literature has reported the involvement of the mesocorticolimbic dopamine pathway in pleasure and reward. Neuroimaging studies have revealed that patients with DDS have enhanced dopamine release in the ventral striatum further implicating the mesolimbic pathway and including the anatomical region of the nucleus accumbens — the reward seeking centre. Irrespective of the extent to which the underlying mechanism is understood, the fact remains that while these behaviours were associated with dopamine receptor stimulation within the experimental systems of the laboratory, correlating these effects with observations in the clinic were tardy. Only recently has ICD and DDS been widely acknowledged by specialists and in clinical practice.
Delayed recognition of DDS
Guidance such as the National Institute for Health and Clinical Excellence (NICE) guidance on the Diagnosis and Management in Primary and Secondary Care for Parkinson’s Disease, in June 2006 warned clinicians “to be aware of dopamine disregulation syndrome (an uncommon disorder in which misuse of dopaminergic medication is associated with behaviours such as hypersexuality, pathological gambling and stereotypic motor acts). This syndrome may be difficult to manage”.
This advice is out of date. Weintraub et al. (2010) reported 13.6% of patients on dopamine agonists suffer ICD. Hassan et al. (2011) reported ICD in 23% of Parkinson’s disease patients receiving dopamine agonists. Reports confirm that such behaviour is more prevalent at high doses but that it is not only found in medication misuse. Ensuring optimal drug efficacy whilst avoiding ICD is the responsibility of the GP, specialist and specialist nurse. By 2005 knowledge about these serious disorders were known to lawyers, the media and patient online groups, yet at each point of medical contact there was systematic denial that the problems were linked to medication. The suspicion prevailed that patients were reaping the whirlwind of their own medication misuse.
Guidelines should warn patients fully and encourage questions about any new behaviours. The process of communicating sensitive behavioural difficulties and special needs may be time consuming and require a trusting relationship, perhaps with a specialist nurse. It is essential that information about treatment safety is effectively communicated to all those involved including patients and their carers.
- Patients are reluctant to admit to behaviours that are anti-social, degrading and in some cases illegal.
- They attributed their new found pre-occupations to the disease rather the treatment.
- As patients knew the drugs had been used for years they thought any warnings would have been explained to them.
- The impulsive behaviours were pleasurable — it was the consequences that were the problem.
- Few if any patients are asked by anyone whether they were experiencing thoughts of, or engaging in, any unusual behaviours since treatment started.
- Patients who mention problems found they embarrassed their clinicians and were referred to the psychiatric services or elsewhere.
- Most patients found out what is going on online or from family members faced with obvious financial/criminal predicaments.
Non-clinical sources of information
From 2003 onwards, patients reported that they had gained insight into their conditions through national and local press articles in which other sufferers had revealed similar problems.
Patients’ blogs were another source of information exchange often linked through the website Love and Casino War — an internet site where patients provided information on published academic studies and personal experiences. From 2003, this website posted 100s of blogs referring to the devastating effects of dopamine agonists for sufferers and their families.
In August 2003, David Derbyshire, Science correspondent for the Daily Telegraph highlighted the results of the Driver-Dunkley (2003) paper in his article Gambling Risk to Parkinson’s Drug.
In 2005, a case was filed in the Ontario Superior Court of Justice against Eli Lilly for damages concerning the financial losses suffered through impulsive gambling following dopamine agonist treatment for Parkinson’s disease. Other legal cases followed and have been reported.
In 2005, the Parkinson’s Disease Society (UK) through its Q&A forum adopted the line that pathological gambling and obsessive sexual behaviours were most likely associated with medication misuse.
In contrast, health services did not ask patients about behavioural side effects and company trials were not designed to detect these problems. This has added to the plight of many Parkinson’s disease patients.
The emerging literature on ICD since the late 1980’s did not initially appear in mainstream journals. Novel findings that challenge dogma rarely are.
Insurance companies and healthcare providers in this case provided a quicker system of notification to medical staff than information from academic journals.
A quarter of a century
The first paper on this issue was Vogel and Schiffter (1983) in the journal Pharmacopsychiatria entitled Hypersexuality — a complication of dopaminergic therapy in Parkinson’s disease.
Publications describing incidences of pathological gambling appeared in the peer reviewed academic literature in 2000 (Molina et al 2000). This reported that 5% of patients treated with l-dopa suffered from pathological gambling. Many neurologists reading this dismissed the data on the basis that this behaviour would have been noticed in the 20 years or more that l-dopa had been used as the mainstay of treatment for Parkinson’s disease.
In 2000, Seedat et al. published Pathological gambling behaviour: emergence secondary to treatment of Parkinson’s disease with dopaminergic agents in Depression and Anxiety.
Gschwandtner et al. (2001) published Pathologic gambling in patients with Parkinson’s disease which reported gambling occurring in response to 2 patients becoming addicted to their dopaminergic medication. Two further articles were published in 2002 in little known journals with one paper suggesting that the patients’ pre-morbid personality may have been a risk factor for treatment to amplify sexual compulsions and gambling.
The seminal report was by Driver-Dunkley, Samangta and Stacy in 2003 in Neurology. The overall incidence of gambling irrespective of dopamine agonist therapy was 0.05% with a 1.5% incidence for pramipexole and 0.3% for pergolide. The incidence of gambling in the normal population of 0.3–1.3% was exceeded for pramipexole. Symptoms emerged within 4 weeks of increasing the dose of dopamine agonist.
Several papers published in 2004 reporting impulse control disorders being experienced in response to Parkinsonian treatment but none appeared in mainstream journals.
In 2005, 3 reports were published including ‘Betting on Dopamine’ by Stein and Grant published in CNS Spectrums. Another paper reported similar disinhibitory behaviours occurring following dopamine treatment in Parkinson’s disease but that symptoms resolved upon the patients receiving deep brain stimulation or lesions to the subthalamic nucleus. Surprisingly this article assumes that symptoms of DDS are commonly known and discusses their amelioration.
Dodd et al. (2005) published Pathological gambling caused by drugs used to treat Parkinson’s disease in Archives of Neurology. Eleven patients with idiopathic Parkinson’s disease treated with therapeutic levels of dopamine agonists developed pathological gambling. The authors reported pramipexole (Mirapexin) was the worst for causing this effect.
Stocchi published Pathological gambling in Parkinson’s disease in Lancet Neurology and by the end of 2005 a further paper was published entitled Hypersexuality due to dopaminergic drugs.
But any prescriber checking drug safety as of September 2005 in the Physician’s Desk Reference (US) or British National Formulary (UK) would not have found these adverse effects.
In March 2006, the BNF reported an increase in libido as a side effect of pramipexole.
In April, June and July 2006, further papers were published reporting compulsive eating, pathological gambling and obsessive sexual behaviour associated with dopamine agonist treatment in Parkinson’s disease.
In July 2006, Weintraub and colleagues in Archives of Neurology confirmed that >6% of Parkinson’s patients treated with dopamine agonists had ICD. The authors found no significant differences between dopamine agonists in their ability to cause compulsive behaviours of gambling, buying or sexual behaviour. They concluded “Patients with Parkinson’s disease treated with a dopamine agonist should be made aware of the risk of developing an impulse control disorder and monitored clinically”.
Many publications have subsequently reported the impulsive behaviours of hypersexuality, binge eating, compulsive shopping and internet gambling.
In November 2006, British and European regulators finally recommended that all dopamine agonists warn that pathological gambling, increased libido and hypersexuality were potential class effects of treatment with dopamine agonists within Parkinson’s disease.
Physicians’ desk reference or BNF and prescription safety?
This is exactly what most clinicians rely on. But in the case of dopamine agonists, the BNF still reveals omissions and inconsistencies. Dopamine agonists are listed under 2 different sections, Dopaminergic drugs for the treatment of parkinsonism; and Endocrine Drugs. The information reported for the same drugs differs between sections. For instance, bromocriptine is noted for hypersexuality and increased libido in the Endocrine Drugs section but not in the Parkinsonian Treatment section. The Parkinson’ section has a for ICD whereas the Endocrine section does not.
Cabergoline is marketed as Cabaser and Dostinex by Pharmacia/Pfizer. As a Parkinson’s treatment Cabaser is listed. In the Endocrine section both Dostinex and Cabaser are noted. Since 2004, Dostinex has been marketed online as a sex enhancing drug. On the website Buy-Dostinex.com, it is marketed as ‘The Sex Drug’. The advert states ’Dostinex, also known as cabergoline can make sex better, much better for almost anyone, that’s the reason some refer to it as ‘The pleasure drug’ or the ‘Miracle drug’.’
Throughout this period, cabergoline was not listed as associated with the side effects of hypersexuality or increased libido. In fact by 2008, after the regulator asked for warnings for the entire class of dopamine agonists, cabergoline was still the only dopaminergic drug which did not report increased libido and hypersexuality!
The BNF and Physicians’ Desk Reference rely for Adverse Drug Reactions on summaries of the Specific Product Characteristics reported by the drug manufacturers, clinical literature and safety warnings issued by regulators and pharmaceutical companies. However, adverse events are massively under-reported by clinicians and are rarely the subject of academic research grant proposals. The primary source of adverse effects comes from the manufacturers’ own pre-clinical and clinical trial data. None of the phase 3 or phase 4 trials of these drugs incorporated questions relating to ICD.
- Dopamine agonists are the frontline treatment for Parkinson’s disease but their efficacy is counterbalanced by adverse effects of fibrotic reactions, sudden onset of sleep, hypertensive reactions and impulse control disorders (ICD).
- Titrating the dose is essential and regular treatment review is important.
- All dopamine agonists have the potential to cause adverse effects of ICD or dopamine dysregulation syndrome (DDS). Current studies are investigating whether or not age, gender and personality traits determine which patients will suffer from such behaviours. Where the dose can be reduced, ICD usually improves.
- Medical teams should enquire about symptoms of pathological gambling, impulse buying, obsessive sexual behaviour and increases in libido and not rely on the patients’ spontaneous feedback.
- All adverse effects reported by the patient to the medical team should be notified to regulators.