Neurology Update

Dr. Prithika Chary*

Senior Consultant, Neurology, Neurosurgery amd Epileptology, Kauvery Hospital, Chennai, Tamilnadu, Trichy, India

*Correspondence: [email protected]

Introduction

Any one who treats Parkinson Disease is familiar with the on/off syndrome which is a distressing complication of levodopa therapy in these patients. In addition to the progressive nature of the disease, as the disease advances the chances of the on/off syndrome increase. In this article which is a summary of a Medscape CME activity we discuss the modern management of this complication with newer treatment options

“ON DEMAND” Therapies for Parkinson’s Disease

 

Motor fluctuations in PD

Many patients on medications for PD often do very well with their tremors, stiffness and motor symptoms on dopaminergic therapy. But as time goes on this therapy can suddenly fail and bring on the symptoms again sub acutely. This is called the “Off” period.

This can show up as motor slowness but sometimes even as depression. It is estimated that about 40% of patients with PD will experience Off episodes within 4-6 years of starting levodopa therapy. About 70% experience this after 9 years. It is therefore very important for clinicians to be aware of this and diagnose them accurately.

“OFF” symptoms

Motor Symptoms

  1. Tremor
  2. Stiffness
  3. Slowing
  4. Shuffling
  5. Muscle Cramping
  6. Reduced dexterity
  7. Balance problems
  8. Speech difficulties

Nonmotor symptoms

  1. Mood changes
  2. Slowness of thinking
  3. Anxiety
  4. Pain
  5. Abdominal discomfort
  6. Sweating

The off symptoms may be motor slowness, wane offs, delayed “Ons”, Dose failure, and a random pattern where things come on and off and there is no expectation when to anticipate these episodes or any reason why this happens.

Those more prone to off symptoms

  1. Younger people
  2. Longer duration of disease
  3. Those who have been on antiPD therapies for a longer period
  4. Those with more severe disability to start with

This impairs quality of life. As PD progresses there is a loss of dopamine terminals and as a result, the striatum fails to store dopamine in synaptic terminal vesicles. This is aggravated by a loss of DAT, the dopamine transporter. This can result in abnormal pulsatile swings in dopamine levels. This can make the dopamine receptors temporarily unavailable contributing to this failed treatment response.

Other considerations include the fact that Levodopa has a very short half-life about 90 minutes.

The tendency for gastrointestinal symptoms like poor gastric emptying, constipation, bacterial overgrowth, H. Pylori etc., can diminish absorption of levodopa. There is a competitive absorption with neutral amino acids and this is why proteins in the diet can interfere with levodopa absorption. We should also remember that when levodopa is crushed and put in orange juice or something acidic it works faster.

When to consider “ON DEMAND” therapies

We need to accept that off symptoms occur commonly and understand what leads to off symptoms to consider what therapies can treat these symptoms.

When to review treatment in PD patients is very important

  1. When in the disease course?
  2. When in the day?
  3. When during an “off” episode?
  4. When in the treatment paradigm?

When in the course of the disease – At the end of the 1st year to optimize levodopa dosage, after 4-5 years when we have a drug dose adjustment and again after 10 years later in the disease course may all be times when on demand therapy may be useful.

When in the course of the day – in some it is at the end of the day, postprandial off symptoms especially after a protein meal, after exercise or physical therapy

When do we use on demand therapy – early on when symptoms occur, when symptoms are more severe, or later on when they are fully off?

When in the course of treatment do, we use on demand therapies – later in the disease when on/off is more frequent, and they are on polypharmacy or early on before they are put on polypharmacy.

Ideally, we should be able to optimize therapy so off does not occur instead of trying to find ways to treat off symptoms.

There are many ways to deal with this – the combination of the cocktail could be changed, the doses of medicines can be changed – we can change the timing of the levodopa, we can adjust the dopamine agonists, or increase the dose of levodopa, add a MAO inhibitor or COMT inhibitor, etc before resorting to on demand therapy.

Available on demand therapy and their selection

These therapies are important not just to improve quality of life in people with PD, but also to reduce the considerable caregiver burden that off periods cause.

Options available

  1. Apomorphine subcutaneous
  2. Apomorphine sublingual film
  3. Levodopa inhalation powder

Apomorphine subcutaneous was the first on demand therapy to be approved by the FDA in 2004. Apomorphine hydrochloride is a dopamine agonist that can be administered subcutaneously and is given for acute, end of dose off symptoms but is also useful for unpredictable on/off episodes.

The subcutaneous route bypasses the problems of absorption which occur with GI symptoms of PD. It is supplied in cartridges which can be administered easily by the caregiver with relief as quickly as 10 minutes of the symptoms. 30 mg in 3 ml or 10 mg in 1 ml for single patient use is available with a pen injector.

3 RCTs conducted between 2001 and 2007 led to the approval of the drug in 2004. An open label, phase IV multicenter study showed that subcutaneous apomorphine was very useful for prolonged periods of morning akinesia. The time to on was also pretty quick.

Adverse events included yawning, dyskinesias, dizziness, drowsiness, somnolence, rhinorrhea, postural hypotension, nausea, vomiting, hallucinations, confusion, oedema of extremities. These usually occur at initiation of therapy till the patient gets used to it.

Management of adverse events.

Nausea and vomiting – antiemetics started 3 days prior to the first dose.

Contraindicated with 5HT3 antagonists including antiemetics like ondanstetron and similar group of drugs.

The patient or caregiver must be able to administer the injection and needs to be trained and initial dose has to be titrated by the physician.

Apomorphine sublingual

Approved by the FDA in May 2020. It is available in 5 dosage strengths. 10,15,20,25, 30 mg of apomorphine hydrochloride.

It was found to work better predose and enabled full on by 30 minutes post dose, sometimes even as early as 15 minutes. Side effects were local soft tissue changes of swelling and pain, and dizziness and somnolence, nausea and vomiting, postural hypotension, paraesthesiae.

It can be an alternative in those with needle phobia or motor impairment which interferes with the ability to use a subcutaneous injection.

Dosing can be completed at home as the initiation kit contains 2 strips of all 5 doses to allow patients to find the optimal dose.

Levodopa inhalation powder

Approved in 2018 as an on-demand therapy which has the advantage of bypassing the delay and variable absorption of swallowed levodopa due to the GI disturbances seen in patients with PD. It is a dry powder inhaled through the mouth. It was approved for the intermittent treatment of off episodes in patients taking Carbidopa/Levodopa.

It uses a technology called Acuform technology which opens up the levodopa molecule which enters the lungs and alveoli and enter the blood stream quickly and reliably. The usual dose is 84 mg (2 capsules of 42 mg) which is approximately equivalent to 50 mg of levodopa and can be used up to 5 times a day.

The PanPD double blind study in about 300 patients of younger and older patients, showed the UPDRS scores improved as early as 10 minutes and maximized at 30 minutes and this improvement was maintained even at 60 minutes.

Side effects were cough, upper respiratory infection, an after taste in the mouth (which can be managed by rinsing the mouth with water after the inhalation).

It is contraindicated with selective MAO inhibitors. Non selective MAOB inhibitors are okay. When levodopa dose is increased it is important to watch for hypotension. It is also not recommended for patients with underlying lung disease like childhood asthma, COPD and other chronic lung disease. Using inhaled levodopa for 12 months does not affect the lung function as seen on CT chest.

When do we advise inhalation levodopa over apomorphine which has robust evidence of efficacy?

It can be used with apomorphine to go from a full off to a full on, on the first symptoms of off.

In conclusion we have a lot of options of on demand therapy today which is good for chronic PD patients. Many patients find one or more of these options work for them and some patients also use them in combination.

Subcutaneous apomorphine has a 95% reliability of efficacy. The other therapies are less reliable but still are effective.

Reference

Factor SA, Isaacson S, Okun M. Expert Exchange: The Why, When, and How of “On-Demand” Therapies for Parkinson Disease. 2021. https://www.medscape.org/viewarticle/949587.

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