In the management of Parkinson's disease, due to the chronic nature of Parkinson's disease (PD), a broad-based program is needed that includes patient and family education, support-group services, general wellness maintenance, exercise, and nutrition. At present, no cure for the disease is known, but medications or surgery can provide relief from the symptoms.
While many medications treat Parkinson's, none actually reverses the effects of the disease. Furthermore, the gold-standard treatment varies with the disease state. People with Parkinson's, therefore, often must take a variety of medications to manage the disease's symptoms. Several medications currently in development seek to better address motor fluctuations and nonmotor symptoms of PD. However, none is yet on the market with specific approval to treat Parkinson's.
Medication
The main families of drugs useful for treating motor symptoms are levodopa, dopamine agonists, and MAO-B inhibitors. The most commonly used treatment approach varies depending on the disease stage. Two phases are usually distinguished: an initial phase in which the individual with PD has already developed some disability which requires pharmacological treatment, and a second stage in which the patient develops motor complications related to levodopa usage. Guidance was reviewed in 2011 and no changes were made. According to NICE as of July 2014 a revised guidance was under development with anticipated publication in 2017. Treatment in the initial state aims to attain an optimal tradeoff between good management of symptoms and side effects resulting from enhancement of dopaminergic function. The start of L-DOPA treatment may be delayed by using other medications such as MAO-B inhibitors and dopamine agonists, in the hope of delaying the onset of dyskinesias. In the second stage, the aim is to reduce symptoms while controlling fluctuations of the response to medication. Sudden withdrawals from medication, and overuse by some patients, also must be controlled. When medications are not enough to control symptoms, surgical techniques such as deep brain stimulation can relieve the associated movement disorders.
Levodopa
Levodopa (or L-DOPA) has been the most widely used treatment for over 30 years. L-DOPA is transformed into dopamine in the dopaminergic neurons by dopa-decarboxylase. Since motor symptoms are produced by a lack of dopamine in the substantia nigra, the administration of L-DOPA temporarily diminishes the motor symptoms.
Only 5–10% of L-DOPA crosses the blood–brain barrier. The remainder is often metabolised to dopamine elsewhere, causing a wide variety of side effects including nausea, dyskinesias, and stiffness. Carbidopa and benserazide are peripheral dopa decarboxylase inhibitors. They inhibit the metabolism of L-DOPA in the periphery, thereby increasing levodopa delivery to the central nervous system. They are generally given as combination preparations with levodopa. Existing preparations are carbidopa/levodopa (co-careldopa, trade names Sinemet, Pharmacopa, Atamet) and benserazide/levodopa (co-beneldopa, trade name Madopar). Levodopa has also been related to a dopamine dysregulation syndrome, which is a compulsive overuse of the medication, and punding.
Controlled, slow-release versions of Sinemet and Madopar spread out the effect of the levodopa. Duodopa is a combination of levodopa and carbidopa. Slow-release levodopa preparations have not shown an increased control of motor symptoms or motor complications when compared to immediate-release preparations.
Tolcapone inhibits the catechol-O-methyltransferase (COMT) enzyme, which degrades dopamine and levadopa, thereby prolonging the therapeutic effects of levodopa. It, alongside inhibitors of peripheral dopa decarboxylase, have been used to complement levodopa. However, due to its possible side effects such as liver failure, it is limited in its availability. A similar drug, entacapone, has not been shown to cause significant alterations of liver function and maintains adequate inhibition of COMT over time. Entacapone is available for treatment alone (COMTan) or combined with carbidopa and levodopa (Stalevo).
Long term usage of levodopa treatment is associated with the development of motor complications. The complications usually appear first as wearing-off, in which the dose effect fades before the next dose assumption is scheduled, and later by less predictable on-off phenomenon in which patients develop an ON-state with dyskinesia and an OFF state with akinesia. Roughly half of the patients with Parkinson's disease treated with levodopa develop motor fluctuations within the first 5 years of the treatment. Both pharmacokinetic and pharmacodynamic mechanism are the reason why the complications arise: decreasing dopamine storage capacity due to progressive loss of nigrostriatal terminals causes a pulsatile rather than steady stimulation. Risk can also be increased by a younger age disease onset, longer disease duration and higher levodopa dose.
For this reason, levodopa doses are kept as low as possible while maintaining functionality. Delaying the initiation of dopatherapy, using instead alternatives for some time, is also common practice. A former strategy to reduce motor complications was to withdraw patients from L-DOPA for some time. It is discouraged now since it can bring dangerous side effects such as neuroleptic malignant syndrome. Most people eventually need levodopa and later develop motor complications.
Redistribution of levodopa dosage which may mean smaller, more frequent doses, or larger less frequent increments, may be helpful in controlling oscillations in some patients. Dietary protein restriction and the use of selegiline and bromocriptine may also temporarily improve motor fluctuations. New approaches to management include:
Continuous subcutaneous apomorphine infusion delivered via a portable pump Duodopa or Levodopa-carbidopa intestinal gel (LCIG), a methylcellulose-based suspension of levodopa and carbidopa delivered in a continuous way into the duodenum or jejunum through a portable pump and PEG-J tube system. Produodopa, a soluble prodrug formulation of fosfolevodopa/foscarbidopa developed for a 24 hour subcutaneous infusion. After the infusion, the prodrug is converted by phosphatases into active levodopa and carbidopa that manage to stabilize their concentration in the blood. Levodopa-carbidopa microtablets (LC-5), marketed as Flexilev, are small dispersible low-dose tablets consisting of 5 mg levodopa and 1.25 carbidopa per tablet. The tablets are designed for frequent oral dosing throughout the day in order to maintain stable levodopa concentrations in the blood via fine granularity. Deep brain stimulation, often of the subthalamic nucleus, for eligible patients with fluctuations not responsive to the medications. It can substantially reduce off-time and dyskinesia, though it carries surgical risks.
In animal models it was shown that the intake of adenosine receptor antagonists together with levodopa can amplify its therapeutic effects.
Dopamine agonists Dopamine agonists in the brain have a similar effect to levodopa since they bind to dopaminergic postsynaptic receptors. Dopamine agonists were initially used for patients experiencing on-off fluctuations and dyskinesias as a complementary therapy to levodopa, but they are now mainly used on their own as an initial therapy for motor symptoms with the aim of delaying motor complications. When used in late PD, they are useful at reducing the off periods. Dopamine agonists include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, and lisuride.
Agonists produce significant, although mild, side effects including somnolence, hallucinations, insomnia, nausea, and constipation. Sometimes, side effects appear even at the minimal clinically efficacious dose, leading the physician to search for a different agonist or kind of drug. When compared with levodopa, while they delay motor complications, they control worse symptoms. Nevertheless, they are usually effective enough to manage symptoms in the initial years. They are also more expensive. Dyskinesias with dopamine agonists are rare in younger patients, but along other side effects, more common in older patients. All this has led to agonists being the preferential initial treatment for the former as opposed to levodopa in the latter. Agonists at higher doses have also been related to a wide variety of impulse-control disorders.
Apomorphine, which is a dopamine agonist not orally administered, may be used to reduce off periods and dyskinesia in late PD. Since secondary effects such as confusion and hallucinations are not rare, patients under apomorphine treatment should be closely monitored. Apomorphine can be administered by subcutaneous injection using a small pump which is carried by the patient. A low dose is automatically administered throughout the day, reducing the fluctuations of motor symptoms by providing a steady dose of dopaminergic stimulation. After an initial "apomorphine challenge" in hospital to test its effectiveness and brief patient and primary caregiver (often a spouse or partner), the latter of whom takes over maintenance of the pump. The injection site must be changed daily and rotated around the body to avoid the formation of nodules. Apomorphine is also available in a more acute dose as an autoinjector pen for emergency doses such as after a fall or first thing in the morning. Nausea and vomiting are common, and may require domperidone (an antiemetic).
In a study evaluating the efficacy of dopamine agonists compared to levodopa, the results showed patients who took dopamine agonists were less likely to develop dyskinesia, dystonia, and motor fluctuations, although were more likely to discontinue therapy due to negative side effects such as nausea, edema, constipation, etc.
MAO-B inhibitors Monoamine oxidase inhibitors (selegiline and rasagiline) increase the level of dopamine in the basal ganglia by blocking its metabolization. They inhibit monoamine oxidase-B (MAO-B) which breaks down dopamine secreted by the dopaminergic neurons. Therefore, reducing MAO-B results in higher quantities of L-DOPA in the striatum. Similarly to dopamine agonists, MAO-B inhibitors improve motor symptoms and delay the need of taking levodopa when used as monotherapy in the first stages of the disease, but produce more adverse effects and are less effective than levodopa. Evidence on their efficacy in the advanced stage is reduced, although it points towards them being useful to reduce fluctuations between on and off periods. Although an initial study indicated selegiline in combination with levodopa increased the risk of death, this has been later disproven.
Metabolites of selegiline include L-amphetamine and L-methamphetamine (not to be confused with the more potent dextrorotary isomers). This might result in side effects such as insomnia. Another side effect of the combination can be stomatitis. Unlike other nonselective monoamine oxidase inhibitors, tyramine-containing foods do not cause a hypertensive crisis.
Other drugs Some evidence indicates other drugs such as amantadine and anticholinergics may be useful as treatment of motor symptoms in early and late PD, but since the quality of evidence on efficacy is reduced, they are not first-choice treatments. In addition to motor symptoms, PD is accompanied by a range of different symptoms. Different compounds are used to improve some of these problems. Examples are the use of clozapine for psychosis, cholinesterase inhibitors for dementia, modafinil for day somnolence, and atomoxetine for executive dysfunction.