MEDICAL TREATMENT OF PARKINSON'S DISEASE

Although it is a known fact the Parkinson’s disease has no cure, through the years, there have been various recommendations in the treatment of PD.  Some studies show promising results but others have unacceptable side effects, complications and even no therapeutic value. Thus, an international task force of the Movement Disorder Society conducted a systematic review of all articles and clinical reports published until September 2009 which has been the basis for the 2010 update.

An evidenced based scientific explanation is still the most reliable and acceptable standard for patient care. However, the physician is still expected to exercise his own clinical judgment as to the best treatment options for a PD patient based on the latter’s perception of his own impairment and disability

In the early stages of uncomplicated Parkinson’s disease, use of pharmacological agents is still the primary mode of treatment. The different drugs used in the therapy of PD will be discussed based on the mechanism of action (MOA), symptomatic treatment (monotherapy), adjunctive therapy, prevention of motor complications, symptomatic treatment of non-motor problems and safety.

These are the different pharmacological agents available in the market, namely:

     1. LEVODOPA

     2. ANTICHOLINERGICS

     3. AMANTADINE

     4. MAO-B INHIBITORS

     5. COMT INHIBITORS

     6. DOPAMINE AGONISTS



LEVODOPA

     Levodopa is the most effective treatment to improve the motor symptoms during the initial stages of PD. It is available in 2 formulations, namely (1) standard and (2) controlled-release (CR).

             Mechanism of Action:

           The standard levodopa formulation exerts its symptomatic benefits through conversion to dopamine, and is routinely administered in combination with a decarboxylase inhibitor (benserazide, carbidopa) to prevent its peripheral conversion to dopamine with the resultant nausea and vomiting. Levodopa passes the blood – brain barrier – in contrast to dopamine. It has a short half -   life, which eventually results in short - duration responses with a wearing - off (end- of- dose) effect. Controlled - release (CR) formulations aim to prolong the effect of a single dose of levodopa, and reduce the number of daily doses.
    
            Symptomatic Treatment of Parkinsonism ( monotherapy):

            The effiacy of levodopa is firmly established from more than 30 years of use in clinical practice. Sytematic reviews show that levodopa monotherapy, in general, produced lower UPDRS (Unified Parkinson’s Disease Rating Scale) scores than cabergoline, pramipexole, ropinirole, bromocriptine, lisuride, and pergolide. Standard and CR levodopa maintain a similar level of control in de novo PD after 5 years and also in more advanced PD with a duration of about 10 years and without motor fluctuations.

          Adjunctive Therapy:

            Supplementation of levodopa to other antiparkinsonian medications in stable PD is common clinical practice to improve symptomatic control.

            Prevention of Motor Complications:

            The motor complications like fluctuations and dyskinesia are actually caused by levodopa. Usually, levodopa is started three times daily, which offers symptomatic control throughout the day, but after several months or years of chronic treatment, these motor complications may arise. However, by   carefully shortening the dose interval to compensate for shortening of the duration of effect of each levodopa dose (wearing - off), and by reducing the dose of each levodopa intake to reduce the magnitude of the effect (peak dose dyskinesia), the clinical emergence of these motor problems may be  postponed. CR levodopa has no significant preventive effect on the incidence of motor fluctuations or dyskinesia, as compared with standard levodopa.

            Symptomatic Treatment of Non-motor Problems:

            Off - period psychiatric symptoms (anxiety, panic attacks, depression) and other non - motor symptoms (drenching sweats, pain, fatigue, and akathisia) may be alleviated by modifying the treatment schedule of levodopa.

            Safety:

            Peripheral side effects of levodopa include gastrointestinal and cardiovascular dysfunction. Central adverse effects include levodopa motor problems such as fluctuations, dyskinesia, and dystonia, and psychiatric side effects such as confusion, hallucinations, and sleep disorders. There is a 40 %  likelihood of developing motor fluctuations and dyskinesias after 4 – 6 years of levodopa therapy and up to 80-90% in later years. Neuropsychiatric complications occur in less than 5% of de novo patients on levodopa monotherapy.

ANTICHOLINERGICS (Bornaprine, Benzhexol, Benzotropine, Biperiden)

            Mechanism of Action:

            Anticholinergics are believed to act by correcting the disequilibrium between striatal dopamine and acetylcholine neurotransmission. Some anticholinergics, e.g. benzotropine, can also block dopamine uptake in central dopaminergic neurons. The anticholinergics used to treat PD specifically block muscarinic receptors.

            Symptomatic Treatment of Parkinsonism (monotherapy):

            The results are consistent with reviews concluding that anticholinergics have only a small effect on PD symptoms, and that evidence for a special effect on tremor is inconclusive.

            Adjunctive Therapy:

            The two reviews indicate that adjunctive anticholinergics have only a minor effect on PD symptoms in patients on levodopa therapy, and that the tremor - specific data are inconclusive.

            Prevention of Motor Complications:

            No studies are available.

            Symptomatic Treatment of Non- motor Problems:

            Because of the risk of side effects, centrally acting anticholinergics are usually not advised for the therapy of non - motor, i.e. autonomic, dysfunctions.

            Safety:

            The clinical use of anticholinergics has been limited by their side- effect profiles and contraindications. The most commonly reported side effects are blurred vision,urinary retention, nausea, constipation (rarely leading to paralytic ileus), and dry mouth. The incidence of reduced sweating, particularly in those patients on neuroleptics, can lead to fatal heat stroke.           Anticholinergics are contraindicatedin patients with narrow-angle glaucoma, tachycardia, hypertrophy of the prostate, gastrointestinal obstruction, and   megacolon. Impaired mental function (mainly immediate memory and  memory acquisition) and acute confusional state are a well documented central side effect that resolves after drug withdrawal. Therefore, if dementia is present, the use of anticholinergics is contraindicated. The abrupt withdrawal of anticholinergics may lead to a rebound effect with marked deterioration of parkinsonism. Consequently, anticholinergics should be discontinued gradually and with caution.

AMANTADINE

            Mechanism of Action:

            The mechanism of action of amantadine appears to be multiple. A blockade of NMDA glutamate receptors and an anticholinergic effect are proposed, whereas other evidence suggests an amphetamine - like action to release presynaptic dopamine stores.

            Symptomatic Treatment of Parkinsonism (monotherapy):

            Some studies and reviews show that amantadine induces symptomaticimprovement.

             Adjunctive Therapy:

            The addition of amantadine to anticholinergic agents is superior to placebo,  with the improvement more pronounced in severely affected patients. Over 9 weeks, amantadine was beneficial as an adjunctive treatment to levodopa with a more noticeable improvement in patients on low levodopa doses .Together with the results of low class evidence studies, data suggest that amantadine is probably effective as adjunct therapy, with an unproven long - term duration of effect.

            Prevention of Motor Complications:

            No studies available.

            Symptomatic Treatment of Non- motor Problems:

            Not applicable.

            Safety:

            Side effects are generally mild, most frequently including dizziness, anxiety, impaired coordination and insomnia ( > 5%), nausea and vomiting (5-10%), peripheral distal edema (unresponsive to diuretics), and headache, nightmares, ataxia, confusion/agitation, drowsiness, constipation/diarrhoea, anorexia, xerostomia, and livedo reticularis ( < 5%). Less common side effects include psychosis, abnormal thinking, amnesia, slurred speech, hyperkinesia, epileptic seizures (rarely, and at higher doses), hypertension, urinary retention, decreased libido, dyspnea, rash, and orthostatic hypotension (during chronic administration).

MAO-B INHIBITORS (Selegiline and Rasagiline)

            Mechanism of Action:

            Selegiline and rasagiline inhibit the action of monoamine oxidase isoenzyme type B (MAO - B). MAO - B inhibition prevents the breakdown of dopamine, producing greater dopamine availability. Mechanisms besides MAO-B inhibition may also contribute to the clinical effects. Unlike selegiline,      rasagiline is not metabolized to amphetamine, and has no sympathomimetic activity.

            Symptomatic Treatment of Parkinsonism (monotherapy):

            Five of six studies with a typical follow-up period of 3 - 12 months and a meta-analysis showed a small symptomatic effect of selegiline monotherapy. Two large scale placebo - controlled trials with rasagiline monotherapy in early PD with a follow-up of 6 – 9 months demonstrated consistent and significant results for a modest symptomatic benefit of early use of 1 mg and 2 mg/daily to early de novo PD patients.

            Adjunctive Therapy:

            The addition of selegiline to other antiparkinsonian therapies (mainly levodopa), showed no consistent beneficial effect on the core symptoms of PD in non-fluctuating patients. Rasagiline has not been studied in this context.

            Prevention of Motor Complications:

            Selegiline has shown no effect in preventing motor fluctuations including   wearing- off, ON– OFF fluctuations, and dyskinesia. Rasagiline has not been  studied in this context.

            Symptomatic Treatment of Non-motor Problems:

            A study detected no effect of selegiline on depression in PD. MAO - B inhibitors have not been investigated for the treatment of other non-motor problems.

            Safety:

            Like any dopaminergic drug, MAO - B inhibitors can induce a variety of dopaminergic adverse reactions. At the daily doses of selegiline currently recommended, the risk of tyramine - induced hypertension (the ‘ cheese effect ’ ) is low. The tyramine - effect does not need to be taken into          consideration when using rasagiline. Concerns that the selegiline/levodopa combination increased mortality rates have been allayed.

COMT INHIBITORS (Entacapone and Tolcapone)
    
            Mechanism of action:

            Catechol- O - methyltransferase (COMT) inhibitors reduce the metabolism of levodopa, extending its plasma half - life and prolonging the action of each   levodopa dose. Therapeutic dose of entacapone only acts peripherally and does not alter cerebral COMT activity. It is administered together with each dose of levodopa and is not approved for use in early (uncomplicated) and non- fluctuating PD patients. Tolcapone (a second-line drug) also acts peripherally but with a small central effect. Due to its stronger and longer action, tolcapone is recommended to be taken three times a day. Tolcapone is also not approved for use in early (uncomplicated) and non-fluctuating PD patients.

            Symptomatic Treatment of Parkinsonism (monotherapy):

            Not applicable (COMT inhibitors should always be given with levodopa).

            Adjunctive Therapy:

            All trials showed a small benefit in the control of the symptoms of parkinsonism, mostly reflected in the activities of daily living but the results  were not consistent. In two recent trials, levodopa/cerbidopa/entacapone showed only borderline significance when compared to levodopa/carbidopa alone in patients with no or minimal fluctuations. In a 39 - week, randomized,         double - blind, multicentre study, the efficacy, safety, and tolerability of  levodopa/carbidopa/entacapone (LCE, Stalevo ® ) was compared with levodopa/carbidopa (LC, Sinemet IR) in patients with early, de novo PD with note of a significant difference in the motor experiences of daily living and motor examinations combined.
           
            Prevention of Motor Complications:

            When the initiation of treatment with levodopa/carbidopa/entacapone was compared to that with levodopa/carbidopa, no difference was found  between the two treatment arms as to the prevention of motor fluctuations and dyskinesia.

            Symptomatic Treatment of Non-motor Problems:

            No studies available.
    
            Safety:

            COMT inhibitors increase levodopa bioavailability, so they can increase the incidence of dopaminergic adverse reactions, including nausea, and cardiovascular and neuropsychiatric complications. Diarrhea and urine discoloration are the most frequently reported non-dopaminergic adverse reactions. The combination with selective MAO-B inhibitors (selegiline) is allowed if the dose of MAO-B inhibitor does not exceed the recommended dose.

DOPAMINE AGONISTS

            Mechanism of Action:

            Of the ten dopamine agonists available in the market for treatment of PD,  five are ergot derivatives (bromocriptine, cabergoline, dihydroergocryptine, lisuride, and pergolide) and five are non-ergot derivatives (apomorphine, piribedil, pramipexole, ropinirole, and rotigotine).
            It is generally accepted that the shared D 2 - like receptor agonistic activity produces the symptomatic antiparkinsonian effect. This D 2 effect also explains peripheral (gastrointestinal – nausea and vomiting), cardiovascular (orthostatic hypotension), and neuropsychiatric (somnolence, psychosis, and hallucinations) side effects. In addition, dopamine agonists have other properties (e.g. anti - apoptotic effect) that have prompted their testing as putative neuroprotective agents. Apart from apomorphine or rotigotine, which are used via the subcutaneous (penject and pumps) or transdermal   (patch) routes respectively , all dopamine agonists are used orally. A once - daily controlled – release formulation of ropinirole has recently became available ,while one such formulation for pramipexole is currently under development .

            Symptomatic Treatment of Parkinsonism ( monotherapy):

            Based on some studies on dopamine agonists vs, placebo in the treatment of early PD, the following are found effective: dihydroergocryptine, pergolide, pramipexole, ropinirole, piribedil, and rotigotine; whereas bromocriptine and cabergoline are probably effective while lisuride is possibly effective.
            However, on studies on dopamine agonists vs. levodopa, it has been found that levodopa is more efficacious than any orally active dopamine agonist monotherapy. The number of patients able to remain on agonist monotherapy falls progressively over time after 5 years of treatment as in the          case of using any of these: bromocriptine, cabergoline, pergolide, pramipexole, and ropinirole.  After a few years of treatment, most patients who initially use a dopamine agonist monotherapy will receive levodopa as a replacement or adjunct treatment to control motor Parkinsonian signs. Over the past decade, a commonly tested strategy has been to start with an   agonist and to add levodopa later if worsening of symptoms cannot be controlled with the agonist alone. However, previously, it was common practice to combine an agonist like bromocriptine or lisuride with levodopa within the first months of treatment ( ‘ early combination strategy ’ ).

            Adjunctive Therapy:

            Most agonists have been shown to be effective in improving the cardinal    motor signs of parkinsonism in patients already treated with levodopa such as: apomorphine, bromocriptine, cabergoline, pergolide, piribedil, pramipexole, and ropinirole.

            Prevention of motor complications:

            Early use of an agonist can reduce the incidence of motor complications versus levodopa which has been observed in the studies on cabergoline, pramipexole, pergolide, ropinirole and bromocriptine. The risk of dyskinesia reappears once levodopa is adjunct to initial agonist monotherapy.

            Symptomatic Treatment of Non- motor Problems:

            Dopamine agonists like pramipexole may improve depression, as observed in clinical trials conducted in non – parkinsonian subjects with major or bipolar depression. 

            Safety:

            Dopamine agonists and all other active dopamine - mimetic medications share a common safety profile reflecting dopamine stimulation. Side effects such as nausea, vomiting, orthostatic hypotension, confusion, psychosis, and somnolence may occur with administration of any of these  agents. Peripheral leg edema, hallucinations and somnolence are more frequent with some  agonists than with levodopa, even in healthy subjects, in the case of somnolence. A recent meta – analysis suggested that while frequencies of somnolence, hallucination, or anxiety cases were higher with non - ergot DAs, incidence of vomiting, arterial hypotension, or depression was higher with   ergots. The rare but severe risks of pleuropulmonary/retroperitoneal fibrosis and valvular heart disorders are greater with ergot agonists than with non- ergot agonists. As pergolide and cabergoline have been the most frequently reported drugs at the present time, they are only used as a second - line alternative option, when other agonists have not provided an adequate response. If employed, regular monitoring of heart valves by ultrasound is mandatory.
            Impulse - control disorders have recently been identified as a common adverse drug reaction to dopamine agonists with prevalence rates ranging from 5-15% depending on the author. The principal risk factor is treatment with dopamine agonists, although they can occur on levodopa as well. Other risk factors    implicated are personal traits, disturbed decision-making abilities, younger age, comorbidities, cognitive impairment, disease severity, and polytherapy.