Levodopa is a precursor of dopamine. It was the first breakthrough in the treatment of Parkinson's and is still the most widely used treatment. Almost everyone requires levodopa at some point during the course of their Parkinson’s.

During the first few years of levodopa use in the clinic, large amounts of the drug were needed to be effective due to the rapid breakdown of levodopa in the body by enzymes. These were associated with side-effects such as nausea and vomiting.

One of the main enzymes involved in this breakdown of levodopa is peripheral dopa-decarboxylase (DDC). It was quickly realised that by blocking the action of this enzyme using a compound termed a DDC inhibitor, it was possible to reduce the levodopa dose required by 70%, thereby reducing the severity of side-effects, while still maintaining its anti-Parkinson’s activity. This combination is so effective that, today, levodopa is almost always given with a DDC inhibitor, either carbidopa or benserazide. However, another enzyme, catechol-O-methyl transferase (COMT), can also break down levodopa. Consequently, COMT inhibitors were also developed as a way of further improving the delivery of levodopa to the brain.

How levodopa works

Levodopa is taken up by the remaining nerve cells where it is converted to dopamine. This then helps to overcome the deficit associated with the Parkinson’s-related nerve cell death.

Levodopa can be used at all stages of Parkinson’s. However, it can have side effects that build up over time. One side effect of levodopa is ‘off ’ periods, when your body becomes so stiff and slow that you are unable to move. Another side effect that can happen with long-term use of levodopa is involuntary movements (dyskinesia).

There is no specific time to start taking medication that is right for everyone. You and your specialist, or Parkinson’s nurse if you have one, will need to discuss this and agree what is the best choice for you at this time.

Treatment will usually start with a low dose and this is gradually increased until you and your specialist, or Parkinson’s nurse, agree that your symptoms are under control.

If you have problems with swallowing tablets, there may be other options available. These include formulations which release the active ingredients slowly (controlled or prolonged release capsules or tablets). These allow you to take fewer tablets daily. However, these will not be suitable for everyone who has been prescribed levodopa.

Available forms of levodopa

Several different forms are available:

1. Tablets

These come in different strengths, depending on the dose your specialist or Parkinson’s nurse thinks you need.

Controlled release (CR) or prolonged release (PR) capsules or tablets

These allow the levodopa enter your body slowly instead of all at once. Involuntary movements (dyskinesia) can be a side effect of taking high doses of levodopa. Controlled release options can sometimes reduce the number of times you experience dyskinesia or its severity. They can also be taken before going to bed to reduce stiffness during the night.

Dispersible tablets

This form can be mixed with water to make a drink. It takes effect more quickly than capsules because it doesn’t need to be broken down in your stomach to release the active ingredient. It can also be used if you have trouble swallowing tablets or capsules. If you are prescribed non-dispersible tablets or capsules, these should not be crushed or put into water.

2. Intestinal gel

This option is only suitable for a very small number of people, whose symptoms cannot be controlled with the more common forms of treatment. The medication is pumped continuously through a tube that is surgically inserted in the intestine. If you are prescribed this option you are less likely to experience involuntary movements. You might also have fewer ‘off’ periods. It may also help to control your symptoms at night.

Advantages

Levodopa is seen as the most effective treatment for Parkinson’s symptoms. When taking it, you may experience a big improvement in your symptoms, especially with stiffness and slowness of movement. It can also improve non-motor symptoms such as speech, swallowing, sleep and depression and so can enhance wellbeing.

Disadvantages

1. Becomes less effective after time

After a while, you may have a less predictable response to levodopa. You may get ‘off’ periods, when you feel weak and cannot move well. The effect of the dose may wear off more quickly, maybe even before your next one is due or has begun to work. When this happens, your specialist or Parkinson’s nurse will sometimes change or increase your dose, change the form of medication or how often you take it. They may add other Parkinson’s medications to take alongside levodopa. This will help it to be more effective in treating your Parkinson’s symptoms.

2. Movement problems

One of the main problems with levodopa is a side effect called dyskinesia. These are spasms or muscle movements that happen when you don’t want them to. Dyskinesia can increase over time, although not everyone will have this side effect.

See also Dyskinesia.

Over time you may also find your symptoms re-emerge or become noticeably worse before it is time to take your next dose of levodopa. This is known as 'wearing-off' with periods of time when certain symptoms such as tremor, rigidity and bradykinesia (slow movement) are no longer effectively controlled.

See also ‘wearing off’.

3. Sleepiness and fainting

Levodopa treatment can make you feel very sleepy. Sometimes this happens quite suddenly and without warning. Levodopa can also make you faint or feel dizzy.

4. Other side effects

We cannot list all of the side effects of the drug. Some common side effects of levodopa include: nausea and vomiting, hypotension (low blood pressure), loss of appetite, psychological problems, hallucinations (seeing, hearing, feeling and smelling things that aren’t there), and sleep problems.

Levodopa and diet

Taking levodopa with food can sometimes help to reduce feelings of sickness. However, for some people, protein (which is found mainly in meat, fish, eggs, cheese and beans) seems to interfere with the way levodopa works, by affecting how well the medication is absorbed by the body.

Protein is needed by the body so it is important not to stop eating protein. However, some people may benefit from taking their medication at least 30 minutes before eating. Your specialist or Parkinson’s nurse can advise you on timing your doses and this should be discussed with them when you are first prescribed the medication. They may also refer you to a dietician for advice.

See also Eating well.

Impulsive and compulsive behaviour

A small number of people taking levodopa have problems with impulsive or compulsive behaviour. This can also be called impulse control disorder. It affects a much smaller percentage of people taking levodopa than those taking dopamine agonists, but it is still a possible side effect. Further information is available at Compulsive and impulsive behaviour.

Another potential problem is dopamine dysregulation syndrome, where someone with Parkinson’s might be tempted to take more of their Parkinson’s medication than they are prescribed. If you think this is happening to you or the person you are caring for, tell your GP, specialist or Parkinson’s nurse right away.

It is important that all people with Parkinson’s are monitored for any potential risk of impulsive and compulsive behaviour while being treated with levodopa.

People with Parkinson’s, their carers, friends and family members should work with healthcare professionals to monitor any changes in behaviour. If you start to experience these symptoms, you should discuss it with your specialist or Parkinson’s nurse immediately. You should not stop taking the medication.

Withdrawal syndrome with levodopa

Research has shown that withdrawal symptoms can happen when someone very suddenly stops taking levodopa, perhaps because they are experiencing impulsive and compulsive behaviour. It can lead to symptoms such as depression, anxiety and pain. Any withdrawal from Parkinson’s medications needs to be done gradually, under the supervision of a health professional, to avoid the risk of developing this syndrome.

Dopamine is a chemical messenger made in the brain. The symptoms of Parkinson’s are caused by a decrease in the levels of dopamine, due to the death of the nerve cells in the brain that make it. Catechol-O-methyl transferase (COMT) is an enzyme in the brain that breaks down dopamine. So, one approach to treat Parkinson’s is to block the action of COMT.

Three COMT inhibitors have been developed to date: entacapone, opicapone and tolcapone. These medications are used alongside levodopa to help it work more smoothly – they are not used on their own. They can be tried if your dose of levodopa is not working for long enough or it ‘wears off’. They can also be used if high doses of levodopa are causing severe side effects.

COMT inhibitors come as tablets. There is also a combined tablet that includes levodopa, carbidopa (one of the ‘helper’ medications that are always given alongside levodopa) and the COMT inhibitor entacapone.

Advantages

1. Helping levodopa work more smoothly

COMT inhibitors can help when levodopa is not working long enough and starts to wear off between your doses. It can help to reduce the ‘off’ time when you have more trouble with your Parkinson’s symptoms and it can increase the amount of ‘on‘ time when your symptoms are better controlled.

2. Taking less levodopa (in some cases)

In many cases, levodopa can be taken less often and at a lower dose and this could overcome side effects being experienced.

Disadvantages

1. Liver damage

With tolcapone, there is a risk of liver damage that can be fatal. It is rare, but for this reason, it is a second choice, only used if you can’t take another COMT inhibitor such as entacapone or opicapone. If you take this medication, you will need regular blood tests to check the health of your liver. Regular liver monitoring is not required with opicapone in patients with normal liver function¹, and entacapone therapy has shown no risk of liver damage².

2. Worse levodopa side effects

Because COMT inhibitors strengthen levodopa, the side effects of levodopa, including unwanted movements and sickness, can get worse, too. If this happens, your specialist or Parkinson’s nurse can help you reduce the dose of levodopa.

3. Other side effects

We can’t list all the possible side effects. However, some of the most common side effects that can happen with COMT inhibitors include: sleeping problems, loss of appetite, diarrhoea, dizziness, fainting, falls, hallucinations (seeing, hearing, feeling and smelling things that aren’t there), headache, confusion, dry mouth, chest pain, sleepiness and getting flu or having flu-like symptoms. These medications can also discolour your urine.

References

1. Scott LJ, Opicapone: A review in Parkinson’s disease. Drugs 2016 Sep. Vol. 76(13); 1293-1300 – read article
2. Watkins P., COMT inhibitors and liver toxicity. Neurology 2000. Vol. 55(11 Suppl 4); S51-2; discussion S53-6 – read article

Dopamine agonists may be given on their own or prescribed alongside levodopa or other drugs. They act to mimic the actions of dopamine within the brain.

Unlike other dopamine agonists, apomorphine is usually reserved for late stage Parkinson’s when symptoms are severe and levodopa is not working well all of the time.

How dopamine agonists are used

Dopamine agonists are used at all stages of Parkinson’s. You might take them alone when treatment is being started, or alongside levodopa to provide a more effective treatment with fewer side effects.

Treatment with dopamine agonists has to be started carefully to minimise the risk of side effects, with the dose gradually increasing until you and your specialist or Parkinson’s nurse are happy that your symptoms are under control. Some dopamine agonists are available as ‘one a day’ tablets. These can be a better option for the body and may help both movement and other symptoms of Parkinson’s.

Available forms

Several different forms are available:

1. Tablets and capsules

These come in different strengths, depending on the dose your specialist or Parkinson’s nurse thinks you need.

2. Prolonged release tablets

These can be taken less frequently and they work longer in the body, compared to normal capsules and tablets.

3. Skin patch

A skin patch containing the dopamine agonist rotigotine is also available. This may be helpful if you have trouble swallowing tablets, as well as for those who have problems with drooling and gastritis. It might also reduce stomach upsets. The patch should be held in place for 30 seconds. Once in place it lasts for 24 hours. The patch may cause a skin reaction, such as reddening or itching, but this is usually mild or moderate, will only affect the area the patch has been and will normally disappear after a few hours when you remove the patch. Moving the patch to a different site every day will help to avoid irritation. The patch should be stored in a refrigerator.

4. Injection or infusion

Apomorphine is a dopamine agonist that is given by injection or infusion pump. It is the strongest known dopamine agonist. It is reserved for more advanced Parkinson’s that does not respond as well to oral (taken through the mouth) medication or when most oral Parkinson’s drugs become less effective or do not work. If you continue to have sudden and unpredictable changes in your symptoms that aren’t controlled by other Parkinson’s medications, apomorphine may help.

You may need to have injections of apomorphine between doses of your usual tablets, or you may need apomorphine more often. In this case, you can use a portable, battery-driven pump, which gives the medication through a needle under the skin. However, this is not commonly used, and is only suitable in certain cases.

Ideally, apomorphine will be started in hospital, under the guidance of a specialist or Parkinson’s nurse. Once you are settled on this treatment, you and your carers (if relevant) can be trained in how to use it or, depending on where you live, community nurses may be able to visit your home.

Advantages

Delaying levodopa treatment

Dopamine agonists may be effective treatments for several years when used alone. However, this will not be the case for everyone.

Fewer movement problems

Your symptoms may be controlled during the day for a longer period than is usually the case with levodopa. When happening, you may be less prone to long-term side effects such as the ‘on/off' effect’ and dyskinesia (movements that you can’t control).

Helping levodopa work better

Dopamine agonists can also be taken in conjunction with levodopa, at all stages of Parkinson’s. They can help when the effect of levodopa wears off or doesn’t always work so well. Dopamine agonists may help to smooth out the ‘on/off’ effect that you may have with levodopa.

Fewer tablets to take (in some cases)

There are now some once-daily preparations that could make a big difference by reducing the number of tablets you take. But this option may not suit everyone.

Positive effects on non-motor symptoms

Dopamine agonists have recently been shown to have a good effect on the symptoms of Parkinson’s not related to movement, including sleep problems, pain and mood.

Disadvantages

1. Heart problems

Some of the older dopamine agonists increase the risk of heart problems. As a group, these are known as the ‘ergot’ types and they include: bromocriptine, pergolide and cabergoline. Because of this risk, these Parkinson’s medications are only used when other dopamine agonists do not work well. All newer dopamine agonists are non-ergot in type. These are apomorphine, pramipexole, ropinirole and rotigotine. They have not been associated with an increased risk of heart damage. Doctors prefer to use these if possible.

2. Sleepiness and fainting

Dopamine agonists can make you feel very sleepy, faint or dizzy. This is most likely to happen when you start taking the medication. Once a stable dose is reached, this effect often wears off. In a few people, sleepiness happens quite suddenly. Sudden sleep onset, without any warning, has been reported. If this happens, it’s important that you tell your specialist or Parkinson’s nurse.

3. Other side effects

We cannott list all the possible side effects. However, some of the most common side effects that can happen with dopamine agonists include: nausea, constipation, low blood pressure, headaches, psychological problems, hallucinations (seeing, hearing, feeling and smelling things that aren’t there), movement problems, swollen limbs, a stuffy nose and a dry mouth. Sight problems can include blurred vision, so it’s important to have regular eye checks.

Apomorphine can cause severe short-term nausea and sickness, so an anti-sickness medication called domperidone (Motilium) will also be given two to three days before this treatment is started and continued for at least two weeks or more, once your treatment is underway.

Impulsive and compulsive behaviour

Some people taking dopamine agonists have problems controlling compulsive or impulsive behaviour. It can also affect people taking levodopa, but it more frequently affects people taking dopamine agonists.

Impulsive behaviour is when a person can’t resist the temptation to carry out certain activities that could lead them to harm themselves or others. In many cases, this behaviour is out of character. For further information, see Compulsive and impulsive behaviour.

If you think this is happening to you or the person you are caring for, tell your GP, specialist or Parkinson’s nurse right away so they can help.

It is important that all people with Parkinson’s are assessed for any potential risk of impulsive and compulsive behaviour before they start taking their medication.

There are certain factors that may mean you’re more likely to experience this behaviour: a family history of gambling or alcohol abuse, a personal history of addictive behaviour, being male, being a younger person with Parkinson’s, being a smoker, or single and living alone.

Even if you do not fit any of these categories, treatment should be monitored over time. People with Parkinson’s, their carers, friends and family members should work with healthcare professionals to monitor any changes in behaviour.

Dopamine agonist withdrawal syndrome

Recent research has discovered dopamine agonist withdrawal syndrome, which can happen when someone very suddenly stops taking dopamine agonists, perhaps because they are experiencing impulsive and compulsive behaviour. It can lead to symptoms including depression, anxiety or pain . Any withdrawal from Parkinson’s medications needs to be gradual, under the supervision of a health professional, to avoid the risk of this syndrome.

Injections of apomorphine are taken in a similar way to insulin for diabetes. There is a ready-to-use injection pen that works within 10 minutes and is often used as a ‘rescue’ measure. This is very useful if you have a sudden ‘off’ period.

Soreness or nodules can develop where the needle enters your skin. If this happens, do not stop the treatment and quickly seek advice from your specialist or Parkinson’s nurse. It is important to change injection site to minimise scarring or infection. Simple massage, silicone gel patches or ultrasound can help to reduce any nodules that form.

How MAO-B inhibitors work

Unfortunately, taking dopamine as a drug treatment for Parkinson’s would not help.

Dopamine is a chemical messenger made in the brain. The symptoms of Parkinson’s are caused by a decrease in the levels of dopamine, due to the death of the nerve cells in the brain that make it.

MAO-B inhibitors can help your nerve cells to make better use of the dopamine that it does have. They do this by blocking an enzyme called monoamine oxidase type B (MAO-B), which breaks down dopamine in your brain. This helps to increase the amount of dopamine that the brain can use, which helps to relieve the symptoms of Parkinson’s.

Three main MAO-B  inhibitors have been developed to date: rasagiline, selegeline and safinamide.

How MAO-B inhibitors are used

A MAO-B inhibitor can be used on its own in early Parkinson’s, especially in the early stages of the condition, or in combination with other medications at all stages of Parkinson’s. These medications are mainly available as tablets. There is also a form that dissolves on the tongue and a liquid preparation. These may help if you have trouble swallowing.

Advantages

1. Improving Parkinson's symptoms

On its own, a MAO-B inhibitor can help with some Parkinson’s symptoms, but it can become less effective over time.

2. Not all have to be increased gradually

Many medications for Parkinson’s have to be started gradually, with the dose slowly being increased over time. Rasagiline can be started on the full dose, but selegiline cannot.

3. Helping levodopa work better

When you have been taking levodopa for a while, you may find that its effects wear off too quickly.

A MAO-B inhibitor can help with this. Taking a MAO-B inhibitor may also reduce the dose of levodopa you need and lengthen the time between your doses of levodopa

Disadvantages

1. Combination with antidepressants

If you are taking some types of antidepressant, you might not be able to take MAO-B inhibitors, as these medications can interact with each other to raise blood pressure to a dangerous level.

2. Combination with decongestants

Decongestants or cold remedies can affect some types of MAO-B inhibitor. If you need to use one of these products, check with your pharmacist which one is safest to use.

3. Worse levodopa side effects

Because MAO-B inhibitors strengthen levodopa, the side effects of levodopa, including unwanted movements and sickness, can get worse, too. If this happens, your specialist or Parkinson’s nurse can help you reduce the dose of levodopa.

Dietary precautions

Your specialist or Parkinson’s nurse may advise you to avoid certain foods, such as cheese, broad beans, yeast extracts or fermented soya bean (tofu).

Other side effects

We cannot list all the possible side effects. However, some of the most common side effects that can happen with MAO-B inhibitors include headache, aching joints, indigestion, flu-like symptoms and depression.

Amantadine is usually used with other Parkinson’s medication and has an effect on tremor and stiff muscles.

How Amantadine works

Exactly how this medication works for Parkinson’s isn’t known yet. It may modify levels of certain chemicals in the brain.

How Amantadine is used

Amantadine can be used to treat tremor and stiff muscles. It isn’t used very often and it is unlikely to be prescribed alone. It is usually given with other medications for Parkinson’s and can be used at all stages of Parkinson’s. It is available as both capsules and syrup.

Advantages

Fewer movement side effects

It is generally agreed that there is not enough scientific evidence to support amantadine as a first choice in early Parkinson’s. But for some people, amantadine may reduce dyskinesia (involuntary movements) caused by your other Parkinson’s medications, without making your Parkinson’s symptoms worse.

Disadvantages

1. Limited effects on Parkinson's

Amantadine is not a first choice for the treatment of Parkinson’s and it may have only a mild effect. Over time, amantadine can become less effective.

2. Other side effects

These can include blurred vision, fainting, confusion or dizziness. If you have these side effects, it is not safe to drive or use machinery. Some other common side effects that can happen with a glutamate antagonist include: feeling nervous, anxious or overexcited, poor concentration, headache, hallucinations (seeing, hearing, feeling and smelling things that aren’t there), movement problems, sleep problems such as insomnia, fast or irregular heartbeat, loss of appetite, nausea and vomiting, constipation, sweating, swollen hands and ankles, and skin reactions.

Anticholinergics are not used very often for Parkinson’s but sometimes they are used for reducing tremor and stiff muscles.

How anticholinergics work

These medications block the action of acetylcholine, a chemical messenger (neurotransmitter) that is found in your body. Acetylcholine helps to send messages from your nerves to your muscles.

In the brain, there is normally a balance between the activity of dopamine and the activity of acetylcholine. But in Parkinson’s a deficiency in the brain of the neurotransmitter dopamine causes over-activity of acetylcholine. Anticholinergics work by blocking acetylcholine’s activity to restore this balance and help reduce your Parkinson’s symptoms.

How anticholinergics are used

These medications are older and are not used very often for Parkinson’s today. Sometimes they are prescribed for reducing tremor and muscle stiffness. They can be used on their own, especially in the early stages of your Parkinson’s when symptoms are mild, before levodopa is prescribed.

Anticholinergics can also be used with levodopa or a glutamate antagonist. They are taken as tablets or as a liquid.

Advantages

1. Possible effect on mild movement symptoms

Older medical studies found some benefit with Parkinson’s symptoms. Anticholinergics can be effective for younger people in the early stages of Parkinson’s when symptoms are mild.

2. Possible effect on other Parkinson's symptoms

Anticholinergics may also be used to reduce saliva production if you have a problem with drooling.

Oxybutynin is an anticholinergic that is used in people without Parkinson’s to reduce bladder contractions that can cause a strong, frequent urge to urinate. It is only used very cautiously in people with Parkinson’s.

Disadvantages

1. Limited effect on movement symptoms

It is generally agreed that the limited improvement in movement symptoms do not outweigh the disadvantages of using anticholinergics.

2. Memory problems

Anticholinergics are not very often given to people with Parkinson’s because they can cause memory problems or make them worse. If you’re taking anticholinergics, your specialist or Parkinson’s nurse must closely monitor your situation.

3. Side effects

Another reason these drugs are not seen as a first choice is their side effects. We can’t list all the possible side effects. However, some of the most common side effects that can happen with anticholinergics include: dry mouth, blurred vision, upset stomach, constipation, dizziness and trouble urinating. Confusion, hallucinations (seeing, hearing, feeling and smelling things that aren’t there), forgetfulness and psychological problems are less common, but they can also happen with these medications. Anticholinergics are not recommended for older people because of the increased risk of confusion.

Content last reviewed: August 2020

We would like to thank Dr Kieran Breen, PhD (St. Andrews Healthcare, UK) for his help in reviewing this information.

Our thanks to Parkinson's UK for permission to use the following source(s) in compiling this information:

• Drug Treatments for Parkinson's.

• Pagonabarraga J, Garraux G, Henriksen T. Optimising Dopamine Treatment Strategies in Progressive Parkinson's Disease. European Neurological Review. 2019;14(Suppl. 4):2–8 – read article
• VIDEO: Recognition and management of wearing off utilisation of catechol-O-methyltransferase (COMT) inhibitors – Olivier Rascol in Oruen platform

Articles from Parkinson's Life online magazine

• Dopamine agonists for Parkinson’s: a simple introduction