Professionals' Q+A: Parkinson's medicine management 2013
Dr Janine Barnes joined us in October 2013 to answer questions from health and social care professionals on available drug treatments for Parkinson's.
Thank you to everyone who submitted a question. See Janine's answers to your questions below.
About Dr Janine Barnes
Janine is a neurology specialist pharmacist at Dudley Clinical Commissioning Group.
She was awarded the Royal Pharmaceutical Society's clinical pharmacist of the year in 2012 for her work in developing a pharmacy-led clinic for people with Parkinson's that has led to reduced waiting times.
She has a PhD in neurosciences and qualiﬁed as an independent prescriber in 2007. Janine was accredited as a pharmacist with a special interest in neurology in 2011.
Janine says: "Professional understanding of how to best manage Parkinson's symptoms with medication is central to improving patient outcomes."
Questions and answers
ARE THERE ALTERNATIVES TO DOMPERIDONE FOR NAUSEA?
Joanne: We used to use domperidone suppositories when:
- patients are nil by mouth and cannot tolerate a naso-gastric tube
- patients are starting a transdermal dopamine agonist replacement
However we are no longer able to prescribe this - do you have any advice?
Gina: When domperidone can't be used or doesn't help with drug-induced nausea, what else can be used?
An alternative anti-emetic would be cyclizine, which is available as a tablet or injection. There is no reason why cyclizine should not be used, therefore if this is not tolerated you could consider a 5-HT3 receptor antagonist such as ondansetron which is available as a tablet, oral solution or injection.
Metoclopramide and prochlorperazine should definitely be avoided as these can worsen Parkinson's symptoms.
DOES ENTERAL FEEDING AFFECT MEDICATION?
Pauline: Does enteral feeding affect the absorption of medication and therefore should be given at night?
Khaled: What Parkinson's drugs can't be given through a PEG or a nasogastric tube?
The protein content of a typical feed is 4-6g/100ml, so when designing a regime our dietitians try to commence the feed 40 minutes after medication and the regimes tend to be given overnight. However depending upon the nutritional requirements of the patient and other considerations, it can be difficult to design an ideal regime.
For instance, if a patient required just 1000ml of a feed and tolerated a rate of 125ml/hr, this will only take 8 hours to go through and providing the patient can maintain an angle of 30 degrees (minimum) to reduce the risk of aspiration, then an overnight regime would be fairly easy.
Some patients however require a larger volume (eg 1500ml of a 1.5kcal/ml feed would be 2250kal/day and so this would take 12 hours). Also some patients are prone to delayed gastric emptying/nausea/reflux and so need a slower rate, therefore a discussion would then be needed with the patient's GP regarding suitable medication.
In the past, the dietitians have used regimes where the feed has stopped before and after the Parkinson's medication but this can make the regime more complicated. In general they try to avoid feed coinciding with medication but it is not always possible in patients with complex needs.
Apart from dispersible and liquid preparations, most Parkinson's medication are not licensed for use in enteral feeding systems. However many, such as co-careldopa, ropinirole and immediate release pramipexole will disperse and so can be given via a tube, ensuring it is flushed completely afterwards. The exception is modified-release preparations (labelled CR, MR, XL or PR) which should never be split open.
IS THERE A DIFFERENCE BETWEEN RASAGILINE AND SELEGILINE?
Richard: In the US, rasagiline is more than 10 times more costly than selegiline. Do you think there is any significant difference between them?
Rasagiline is a lot more expensive than selegiline in the UK too. However rasagiline is 10 times more potent in its inhibition of monoamine oxidase type B (MAO-B) than selegiline with less contraindications and side effects.
In addition, the 1mg OD one-off daily dose of rasagiline tends to aid compliance.
IS A DIARY USEFUL AT THE LATER STAGES OF PARKINSON'S?
Ceri-Lynne: When responses to medication worsen in the latter stages of Parkinson's, is it important or useful for people to fill in a diary?
I think it is extremely useful, once symptoms become problematic, for a patient to fill in a daily diary so that the severity of their symptoms can be tracked throughout the day. This way, medication can be increased in line with when 'off' periods are occurring.
ARE THERE ANY NEUROPROTECTIVE SUPPLEMENTS?
Richard: Do you recommend any supplements for people with Parkinson's for potential neuroprotection?
There is no evidence to suggest that any food supplement is neuroprotective in Parkinson's.
Food supplements are normally only indicated if a patient is underweight or struggling to eat with symptoms of nausea, loss of appetite, taste changes or increased movement.
More generally, there are still no neuroprotective drugs for the treatment of Parkinson's and so management is purely symptomatic. Levodopa remains the gold standard of drug treatment along with non-pharmacological measures such as physiotherapy delivered by a multi-disciplinary team.
CAN SUB-CUTANEOUS APOMORPHINE PREVENT DYSKINESIA?
Linda: Is continuous subcutaneous apomorphine effective in preventing dyskinesias given that it acts more closely to levodopa than other agonists?
How does it compare to Duodopa intestinal gel?
What are the most troubling side effects of both drugs?
Apomorphine is effective in reducing or preventing dyskinesias particularly when administered by continuous infusion via a pump. Apomorphine works much quicker than oral medication (within 5-10 minutes) and so it is effective as a rescue treatment when oral medications are not working so well. The effects last about 45 minutes but this is usually long enough to allow the oral medication to kick in and so it is useful to treat a sudden 'off' period. This allows many patients to lead more normal lives with a better quality of life.
The advantage of the apomorphine continuous infusion is that far fewer 'off' periods are experienced and so over a period of time, the 'on'-'off' swings become less obvious. The main side effects include short-term nausea and vomiting.
Injection sites may become sore and irritated with nodule formation occurring at the point of needle insertion and so rotation of the daily injection site and skin massage at the point of needle removal is necessary. As with other Parkinson's medication, hallucinations, delusions and impulsive or compulsive behaviour may become a problem.
Duodopa is licensed in the UK for the treatment of advanced levodopa-responsive Parkinson's with severe motor fluctuations and dyskinesia when available combinations of Parkinson medication have not given satisfactory results.
It is a combination of levodopa and carbidopa in the form of a gel that is administered directly into the small intestine through a surgically placed tube. As the site of its administration is more invasive than apomorphine, there can be side-effects related to this.
As a continuous infusion, it is very effective at reducing severe motor fluctuations and dyskinesia but it is rarely commissioned via health authorities in the UK in view of its high cost.
ARE SOME DRUGS BETTER FOR THOSE ON HAEMODIALYSIS?
Maire: Are there any drug treatments for Parkinson's that are better for patients on haemodialysis?
There seems to be a large variation in patient response to levodopa treatment while on haemodialysis, dependent on the level of renal failure.
Of the dopamine agonists, the rotigotine patch seems best tolerated as its dose does not need altering even in severe renal impairment. This is because while plasma levels of conjugates of rotigotine and its desalkyl metabolites increase with impaired renal function, a contribution of these metabolites to clinical status is unlikely.
This is in contrast to ropinirole and pramipexole where dose reductions are necessary as renal function declines.
HOW MUCH DOPA DECARBOXYLASE INHIBITOR IS TOO MUCH?
Mick: If one chooses to increase co-careldopa and co-beneldopa doses up to 800mg and beyond, the DOPA decarboxylase inhibitors are also increased to 200mg and beyond. Considering the side effects of benserazide and carbidopa, how much DOPA decarboxylase inhibitor is considered too much?
By reducing the peripheral conversion of levodopa to dopamine, the DOPA decarboxylase inhibitors are particularly important in allowing effective brain-dopamine concentrations to be achieved with lower doses of levodopa.
To be effective, the total daily dose of carbidopa in co-careldopa should be at least 70mg. With co-beneldopa, it is necessary to have 1 part benserazide to 4 parts levodopa. Below these, full inhibition of extracerebral DOPA-decarboxylase may not be achieved with a resultant increase in side effects.
I think that it is important to keep the overall daily dose of levodopa as low as possible to minimise side effects but within the levodopa/DOPA-decarboxylase mix, it is equally important to have the necessary proportion of DOPA-decarboxylase inhibitor in order to limit overall side effects.
CAN PHARMACIES SUPPORT TELECARE MEDICATION DISPENSERS?
Wendy: Currently, telecare medication dispensers, which use an alarm system to dispense the medication at the correct time, are only used if someone has family support to fill the dispensers. Could pharmacies do this?
They already do in my local authority! A device that is widely available in Dudley is the Pivotell® device which allows 4 doses of medication to be dispensed each day. When pills are due, the internal pill tray will rotate, the alarm will sound and the red light on the lid will flash. As it might be difficult for a carer to fill the dispenser themselves with a potentially complicated medication regime, we have a number of local pharmacies who fill the device on their behalf.
The company have advised that they supply their systems to many health authorities all over the UK. You can find out more at www.pivotell.co.uk. (They also have a device called 'Minitell' which looks quite good for patients with sufficient dexterity or support from a carer.)
If you have a patient in need of an alarm system to dispense their medication at the correct time, you should contact the local CCG, social services department or local pharmacy to check what is available. If the response is negative, suggest to the local CCG that the service should be commissioned as a necessary aid for patients with Parkinson's.
Parkinson's UK: Other devices can be found in our online shop.
WHAT ANTIDEPRESSANTS ARE RECOMMENDED FOR PEOPLE WITH PARKINSON'S?
Jane: Which antidepressants do you recommend for people with Parkinson's, especially if they are on rasagiline?
Tracey: How common is serotonin syndrome when using an selective serotonin reuptake inhibitor (SSRI) with rasagiline or selegiline? What can be used to manage depression if the MAO-B inhibitor can't be stopped?
We tend to prescribe one of the SSRIs or mirtazepine for patients with Parkinson's.
Serious adverse reactions are known to occur with concomitant use of SSRIs, SNRIs, tricyclic, tetracyclic antidepressants and MAO-B inhibitors. In the post-marketing period, cases of serotonin syndrome associated with agitation, confusion, rigidity, pyrexia and myoclonus have been reported by patients treated with antidepressants/SNRI concomitantly with rasagiline.
Rasagiline clinical trials did not allow concomitant use of fluoxetine or fluvoxamine with rasagiline, but the following antidepressants and doses were allowed in the rasagiline trials: amitriptyline ≤ 50 mg/daily, trazodone ≤ 100 mg/daily, citalopram ≤ 20 mg/daily, sertraline ≤ 100 mg/daily and paroxetine ≤ 30 mg/daily. There were no cases of serotonin syndrome in the rasagiline clinical programme in which 115 patients were exposed concomitantly to rasagiline and tricyclics and 141 patients were exposed to rasagiline and SSRIs/SNRIs.
If an antidepressant is needed for a patient on rasagiline, it is important to keep the dose of antidepressant as low as possible, while maintaining its therapeutic effect. We have prescribed citalopram at maximally 20mg OD with careful monitoring and no adverse effects became apparent.
CAN A CHOLINESTERASE INHIBITOR BE CONTINUED IF ECG ABNORMALITIES EXIST?
Shankar: What is the accepted evidence to support a decision to continue or stop (for safety reasons) a cholinesterase inhibitor in a patient who develops new conduction abnormalities on the ECG while on treatment?
There is very little concrete evidence to aid such a decision so it would have to be made on an individual patient basis through careful monitoring and taking into account their previous cardiac history and their potential risk of developing bradycardia.
COULD YOU TELL ME ABOUT RECENT ADVANCES IN THE TREATMENT OF PARKINSON'S?
Posa Mahesh: Have there been any recent advances in treatments available, including surgical treatments, to improve the lives of people with Parkinson's? Are there any new medicines that aren't based on levodopa?
Deep brain stimulation (DBS) uses a surgically implanted neurostimulator, similar to a cardiac pacemaker, to deliver electrical stimulation to precisely targeted areas within the brain. It is thought that high frequency stimulation of cells in these areas blocks the abnormal outputs that cause movement disorders. Sites chosen include the thalamus (which can reduce or completely suppress around 80% of cases of drug resistant tremors) and the globus pallidus (used to treat dyskinesias, dystonia, rigidity and pain related to Parkinson's). Other sites include the subthalamic nucleus and caudal zona incerta.
This surgical technique is extremely effective when used in the right patients. However, the selection criteria for eligible patients is very stringent with exclusion criteria including patients with an unsure diagnosis, poor dopamine response, cognitive impairment or dementia, psychiatric disturbances and unstable medical problems.
Lesioning techniques can also be used. This involves making selective damage to cells in a target area of the brain found using a scan. An electrode is then inserted into the site and an electric current is passed through the tip. This causes damage to some of the cells that control movement. This may reduce movement symptoms, such as tremor or dyskinesias.
The most commonly lesioned areas are the globus pallidus, the thalamus and the subthalamic nucleus. It can be an effective treatment for Parkinson's but is often not recommended as lesioning can cause irreversible side effects.
Other surgical treatments for Parkinson's include the infusion of chemicals into the basal ganglia, implantation of foetal brain tissue and the non-invasive technique of gamma knife surgery.
A lot of research is also ongoing into the study of adenosine receptor sub-types, as non-dopaminergic medications that improve symptoms such as motor fluctuations are in demand. Adenosine A2A receptors are abundantly expressed within the basal ganglia and offer a unique target to modify abnormal striatal signalling associated with Parkinson's.
Preclinical animal models have shown the ability of adenosine A2A receptor antagonists to improve motor symptoms, reducing motor fluctuations and dyskinesia as well as protecting against toxin-induced neuronal degeneration. Both istradefylline and preladenant have demonstrated moderate efficacy in reducing 'off' periods in patients with motor fluctuations. The safety and efficacy of this class of compounds continues to be defined and future studies should focus on non-motor symptoms, dyskinesias and neuroprotection.
HOW DO YOU CALCULATE EQUIVALENT DOSES FOR ROTIGOTINE PATCHES?
Lajju: I have a patient with Parkinson's on Requip XL who is soon to undergo surgery and we need to switch him to an equivalent dose of the rotigotine patch. Could you advise on the dose ratio that I should be using for conversion?
Emma: If a patient is acutely unwell and oral or gastric access is impossible, what conversion ratio should we use for short term change from levodopa to rotigotine patch. Is there a better alternative than this?
We have done this switch between ropinirole and rotigotine in a couple of patients but found that it is best to go cautiously with the patch dose due to patient variability in their tolerance to the dopamine agonists.
The two references below show that an overnight switch is usually well tolerated but it is important to remember that the patch can take 24-48 hours to take effect which may be too long for adequate motor symptom control. So I would aim to start the patch 24 hours before discontinuing the ropinirole.
The dose equivalence is cited as 1:1 dose equivalence or 1:1.5 dose equivalence but I would err on the side of caution using the lower strength patch initially with a view to increasing in steps of 2mg/24 hours at weekly intervals as required.
Useful articles include:
- LeWitt et al. Overnight switch from oral dopaminergic agonists to transdermal rotigotine patch in subjects with Parkinson's disease. Clinical Neuropharmacology; 2007.30 (5) 256-65(suggesting 1:1 dose equivalence)
- Kim et al. Overnight switch from ropinirole to transdermal rotigotine patch in patients with Parkinson's disease. BMC Neurology 2011; 11:100 (suggesting 1:1.5 dose equivalence).
If oral and gastric access for levodopa is impossible then the patch seems the next most appropriate option. The conversion ratio for levodopa to rotigotine can be calculated from: Brennan and Genever. Managing Parkinson's disease during surgery. British Medical Journal 2010; 341; 990-993
Parkinson's UK: We will be publishing a new Emergency management of patients with Parkinson's booklet in November 2013 that will contain details of how to calculate estimated equivalent levodopa/dopamine agonist dosages for rotigotine patches.
HOW DOES LEVODOPA WORK?
Andrea: Can you explain the pharmacokinetics and pharmacodynamics of levodopa preparations? I'm particularly interested in absorption, excretion and half-life.
Co-careldopa (levodopa and carbidopa) are well absorbed, reaching maximum plasma concentrations after 1 to 3 hours. The terminal half-life of levodopa is about 2 hours in the presence of carbidopa (which reduces the plasma clearance of levodopa to about 50%). In the presence of carbidopa, levodopa is mainly metabolised to amino acids and, to a lesser extent, to catecholamine derivatives. All the metabolites of carbidopa and levodopa are excreted renally.
After oral administration of co-beneldopa, levodopa and benserazide are rapidly absorbed, mainly in the upper regions of the small intestine. Interaction studies indicate that a higher proportion of levodopa is absorbed when administered in combination with benserazide, compared with levodopa administered alone. Maximum plasma concentrations of levodopa are reached approximately 1 hour after ingestion of co-beneldopa.
Food intake generally reduces the extent of levodopa absorption by 15% but this can be variable.
Levodopa crosses the blood-brain barrier by a saturable transport system. It is not bound to plasma proteins. Benserazide does not cross the blood-brain barrier at therapeutic doses. Benserazide is concentrated mainly in the kidneys, lungs, small intestine and liver.
In the presence of the peripheral DOPA decarboxylase inhibitor, benserazide, the elimination half-life of levodopa is approximately 1.5 hours. In elderly patients the elimination half-life is slightly (25%) longer. Clearance of levodopa is 430ml/min.
Benserazide is almost entirely eliminated by metabolism. The metabolites are mainly excreted in the urine (64%) and to a small extent in faeces (24%).
WHAT IS THE BEST DRUG REGIME FOR TREMOR?
Sally: What have you found to be the best drug regime for tremor?
Our local guidelines only list the antimuscarinic trihexyphenidyl which we use at very low doses for tremor associated with Parkinson's. We tend to restrict this to younger patients but have found it very effective if side effects are minimal. If intention tremor is also apparent, we use propranolol if this is not contraindicated.
CAN ANTICHOLINERGICS OR ANTIMUSCARINICS WORK FOR SIALORRHOEA?
Tarun: What is the evidence for the use of topical agents such as hyoscine or anticholinergics for sialorrhoea (excessive drooling) in Parkinson's?
The evidence is not very robust regarding the use of these agents. We find a few drops of atropine eye drops sublingually equally effective but again this is an unlicensed use.
CAN CO-CARELDOPA AND CO-BENELDOPA BE USED AT THE SAME TIME?
Majella: Is there a rationale for using both co-careldopa and co-beneldopa in the same patient? Also what is the minimum effective dose of carbidopa?
I think it is good clinical practice to prescribe the same DOPA decarboxylase inhibitor to a patient when giving separate doses of levodopa. Obviously if there are supply issues or a dispersible formulation is required, then a switch from carbidopa to benserazide may be unavoidable.
Studies show that peripheral enzyme DOPA decarboxylase is fully inhibited (saturated) by carbidopa at doses between 70 and 100mg a day. Patients receiving less than this are more likely to experience nausea and vomiting.
DOES SINEMET WORK IN ASYMMETRICAL PARKINSONIAN SYNDROME?
Rhian: How does Sinemet work in a patient with asymmetrical parkinsonian syndrome who has no signs of neurodegeneration but exhibits symptoms akin to Parkinson's?
Most people with forms of parkinsonism other than Parkinson's usually do not respond, or respond less well, to Parkinson's drugs such as Sinemet. However paradoxically some will show a good response and the reason for this is unknown.
COULD INDERAL LA WORK WHERE MADOPAR HASN'T?
Khaled: I have a 77-year-old patient who is currently taking Madopar but is still having disabling tremors and is not tolerating the side effects of anticholinergic drugs. Could Inderal LA be considered?
Inderal LA can be very effective if a beta blocker is not contraindicated, particularly if there is a combination of essential tremor with anxiety as well as a Parkinson's tremor.
HOW SHOULD DOPAMINE AGONISTS BE WITHDRAWN?
Deb: When withdrawing dopamine agonists in response to impulsive and compulsive behaviour, is it best to withdraw it completely or continue the patient on a small dose?
I would slowly reduce the dose of dopamine agonist with a view to discontinuing it as soon as is feasible.
IS QUETIAPINE OR RIVASTIGMINE PREFERABLE FOR MENTAL HEALTH PROBLEMS?
Lee: Would you recommend quetiapine or rivastigmine for controlling confusion, hallucinations and paranoia?
I have found low doses of quetiapine very effective in controlling these symptoms.
WHAT CAN BE DONE ABOUT DROWSINESS FROM STALEVO?
Elinor: Is there anything that can be done about significant drowsiness as a side effect of Stalevo?
The problem with adding entacapone to levodopa is that it enhances the therapeutic effects as well as the side effects of the levodopa.
As Parkinson's progresses and the medications are increased, daytime sleepiness can become a difficult problem to manage. Entacapone can exacerbate this problem and so the risk/benefit of using the combination tablet of Stalevo has to be assessed on an individual patient basis.