Treating PD with medications
Treatment with medications (i.e., pharmacological treatment) is central to the management of Parkinson’s disease (PD). Unfortunately, no treatment has yet been proven to cure the disease, but there are many efficient medications that are able to treat the symptoms of PD and reduce their effects on everyday living.
In addition, some medications have been shown to protect brain cells in the laboratory, and researchers are investigating whether these medications can help to slow down the progression of the disease in people with PD.
Maintaining the right balance of medications is often difficult in PD. People with PD need a treatment schedule that is tailored for their particular symptoms and that takes into account their personal preferences. When beginning treatment with most anti-Parkinsonian medication, the dose level may be slowly increased until the most effective dose is found. This process is called titration. The chosen dose needs to be strong enough to control symptoms, but not so strong that it causes troublesome side effects.
As PD progresses, different combinations and dosages of medication will be needed from time to time.
Dopaminergic therapies
The movement-related symptoms of PD are caused by the lack of a chemical called dopamine in the brain. At present, PD is mostly treated with medications that replace, or maintain, the amount of dopamine in the brain. Medications that are used to restore dopamine levels in this way are called dopaminergic medications.
There are several types of dopaminergic medication. They all aim to increase dopamine levels, but they work in different ways. Each medication is better at treating some symptoms than others, and will also produce different patterns of side effects. In addition, different forms of medication delivery (e.g., fast-dissolving wafers or slow-release tablets) are continually being developed to improve treatment convenience and compliance with the ultimate goal of optimizing treatment outcomes.
The different dopaminergic medications and the ways in which they work are described in the ‘Medication options’ section, but a summary of available therapies is given below.
Levodopa
Levodopa is most commonly prescribed under the brand names Prolopa® and Sinemet®.
These tablets contain levodopa together with another substance to help it reach the brain (e.g., Sinemet®contains levodopa with carbidopa, and Prolopa® contains levodopa with benserazide). The tablets come in many colors and strengths to help with different dose schedules. They are also available as slow-release tablets (such as Sinemet® CR), or as a gel via the ‘Duodopa® pump’, which may be helpful for some people.
MAO-B inhibitors
Currently, there are two MAO-B inhibitors on the market, rasagiline (Azilect®) and selegiline (Eldepryl®).
Dopamine agonists
There are many dopamine agonists on the market, and these include ropinirole (ReQuip®), bromocriptine , pramipexole (Mirapex®).
COMT inhibitors
Entacapone (Comtan®).
COMT inhibitors are only effective when taken together with levodopa, and entacapone is also available as Stalevo® – a combination tablet that also contains levodopa and carbidopa (available without entacapone as Sinemet®, see above).
Early treatment
When the first symptoms of Parkinson’s disease appear, a medication may or may not be prescribed. This decision depends on many factors such as whether disease symptoms are having a negative effect on life at work or at home, and whether the PD patient has other medical conditions to be considered. The treatment decision should therefore be discussed in detail between the PD patient and their doctor/PD nurse. The aim of this discussion is to ensure that each person receives the treatment best suited to their individual needs.
In addition, there is considerable debate regarding whether starting treatment early (i.e., soon after the disease has been diagnosed) has a long-term advantage over delaying the start of treatment.
Those who support early treatment argue that the use of a suitable medication will improve control of symptoms. Those who support delayed treatment initiation feel that, in the early stages of PD, any small treatment benefits on mild symptoms are outweighed by the risk of short-term and long-term side effects of medication. However, if medications are approved for modifying the course of PD and slowing its progression, then starting treatment as early as possible is likely to become a more relevant treatment strategy.
Whenever treatment is started, a single medication will usually be given, with the doctor and PD patient working together to establish the most effective dose. This medication is most commonly an MAO-B inhibitor, a dopamine agonist, or levodopa – although the use of levodopa may be delayed for use later on in the disease. As PD progresses, doses may need to be altered and medications switched or added to provide the best control for the particular symptoms experienced. However, throughout the disease, the PD patient will always have the final say on their treatment regimen.
Timing of medication
When treatment is given for Parkinson’s disease (PD), there are several reasons why different medications may be given at different times.
- PD is a neurological disorder with a wide range of symptoms, so an individualized treatment approach is needed to treat particular symptoms.
- PD is a progressive disease and symptoms change over time. A combination of medications may be needed – especially in the later stages of PD – as some medications treat certain symptoms better than others.
- Some of the medications used in PD may cause unpleasant side effects and, if this happens, the doctor may change the medication or prescribe extra medication to treat the side effects.
- Most people with PD will receive levodopa at some point during their treatment. This is an effective medication that provides the brain with extra dopamine. However, when the disease progresses, there may be periods of the day when the effects of the medication appear to ‘wear off’. At this point, other medications can be added to reduce the wearing off phenomenon, and the dose of levodopa adjusted accordingly.
- Chronic levodopa treatment is frequently associated with the development of motor complications, some doctors have tended to delay the use of levodopa for as long as possible. Consequently, a person may begin treatment on another medication (such as an MAO-B inhibitor or dopamine agonist) to control the symptoms of early disease, and to delay the use of levodopa until it is really needed. However, it has recently been suggested that it is the disease becoming more severe over time, rather than long-term levodopa use, that causes the effects of levodopa to wear off. Therefore, early treatment with levodopa may be considered for some people with PD – particularly the elderly, due to levodopa’s effectiveness against movement-related (motor) symptoms. Starting treatment with a dopamine agonist is preferred in younger people, as they are prone to developing long-term complications (see sections on ‘What are motor fluctuations?’ and ‘What is wearing off?’).
What are motor fluctuations?
In Parkinson’s disease (PD), there are times when control over movement is good and the medication seems to be working well – this is called ‘ON time’. At other times, motor control may be poor with symptoms not appearing to respond to medication – this is called ‘OFF time’. ‘Motor’ is the scientific word that is used to refer to anything to do with movement, and the term ‘motor fluctuations’ (or ‘ON–OFF fluctuations’) refers to a state where a person with PD changes between ON time and OFF time. This situation is common in people who have been receiving levodopa treatment for many years.
Another change in symptom control can be seen during the peak of levodopa absorption from the digestive system, when a person may experience restless movements known as dyskinesias (‘peak-dose’ dyskinesias) – almost as if there was ‘too much’ movement. On the other hand, when levodopa levels are at their lowest (usually before the next scheduled dose of levodopa), abnormal and painful posture may occur, which is known as dystonia (usually ‘OFF dystonia’).
What is wearing off?
‘Wearing off’ is a common phrase used in PD. It describes the period of time between the end of the effect of one dose of medication, and the beginning of the next one. That is, the beneficial effects of the previous dose appear to be ‘wearing off’.
Why does wearing off occur?
There is no definite explanation for what causes wearing off. Levodopa works by supplying dopamine to the nerve cells of people with PD. However, as PD progresses, it is possible that the levodopa medication is less able to compensate for the increasing loss of dopamine-producing nerve cells. Another possibility is based on the theory that, in early PD, the extra dopamine supplied by each levodopa dose is stored and then released when needed. In more advanced PD, the dopamine can no longer be stored and so it is released all at once, beginning by working well (ON time), progressing to working too well (ON with dyskinesias), returning to working well again (ON time), and then wearing off (OFF time). These variations are examples of motor fluctuations.
What are the symptoms of wearing off?
The symptoms of wearing off vary from person to person, and may not occur after every dose of levodopa. Wearing off tends to produce a mild and gradual increase in symptoms, with some people noticing an increase in tremor or slowness. In contrast, other types of motor fluctuations associated with more advanced PD, such as those known as ON–OFF fluctuations, have more rapid and sometimes unpredictable switches between periods of good function and periods of poor function. People may experience a return of symptoms including tremor, stiffness, anxiety, depression, and pain.
Treating wearing off
As might be expected, wearing off is relieved by taking the next dose of levodopa – although there is often a delay of up to 1 hour before the medication takes effect. A doctor may be able to reduce the effects of wearing off by recommending:
- smaller, but more frequent, levodopa doses
- a different form of levodopa that releases the medication more gradually (i.e., a slow/controlled/extended-release tablet)
- chewing the levodopa tablets or taking them with carbonated drinks to increase the speed of their effect
- not taking levodopa with meals (food slows its action)
- treating constipation (levodopa is absorbed just beyond the stomach and, if a person is constipated, the dose may stay in the stomach for several hours, unable to work)
- an alternative option is to add another medication (MAO-B inhibitor, dopamine agonist, or COMT inhibitor) to minimise the wearing off symptoms. The addition of this second medication is known as adjunct or combination therapy.
It is clear that treatment of motor fluctuations is a complicated process, and therefore doctors tailor the treatments for each individual. For this reason, it is sometimes helpful if the person with PD keeps a daily diary of their symptoms and the effects of medication, noting any variations during the day. This gives the doctor extra information when recommending a therapy, and saves the person from having to remember these details from visit to visit.
Long-term treatment
Parkinson’s disease (PD) is a long-term neurological condition involving mild symptoms that progress, over a period of years, to more severe symptoms. Therefore, treatment plans must take into consideration the fact that people are likely to be treated for PD for many years.
In the early stages of PD, a single dopaminergic medication (most commonly levodopa, an MAO-B inhibitor, or a dopamine agonist) is usually a sufficient treatment. As PD progresses, most people will need a combination of various medications, including levodopa. When an MAO-B inhibitor is initiated as the first therapy, it does not need to be discontinued when a second anti-Parkinsonian medication is started although this decision rests with the physician and the patient.
In later disease, once the effects of levodopa start to wear off, become unpredictable, or produce dyskinesias (restless movements), MAO-B inhibitors, dopamine agonists, or COMT inhibitors can be added to the treatment schedule to control these complications. If the person with PD experiences problems with thought and memory, depression, or hallucinations/psychosis, then cholinesterase inhibitors, antidepressants, or antipsychotic medications may be prescribed, respectively.
In addition to therapy with medications, there are other ways in which people with PD can manage the condition, and improve their overall well-being in the long term. Consequently, it is often difficult to determine the precise effects of any long-term treatment for PD, as the person may also be receiving other types of therapy.