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Q12 How could you monitor and assess Mr. LN’s response to these changes?
- By charting his mobility regularly.
- Some neurology wards use mobility charts
on which an indication of a patient’s
mobility can be recorded at suitable
intervals.
- Such charts can be a valuable aid to the
manipulation of drug administration in
order to optimize therapy.
Mobility Chart
Q13 Can you suggest any non-drug management that might benefit Mr. LN?
Non-pharmacological Management
Exercise.
Nutritional counseling.
Psychological and social support.
Occupational therapy.
Speech therapy and swallow evaluations.
Surgical therapy: Deep brain stimulation (DBS):
DBS: battery-powered neurostimulation device that is
surgically implanted under the clavicle with electrical wires
projecting to brain area of interest.
Proposed action mechanisms of DBS include depolarization
blockade, synaptic inhibition, synaptic depression,
stimulation-induced disruption of pathological network, and
stimulation of afferent axons projecting to the subthalamic
nucleus.
Generally, DBS is considered adjunct to pharmacotherapy for
patients whose symptoms are not adequately controlled with
optimal medication therapy and requires routine monitoring and adjustments.
• Mr. LN’s drug therapy was changed to one Madopar dispersible 62.5 mg tablet (L-dopa 50 mg + benserazide 12.5 mg) on waking around 7 am,
• and one Sinemet Plus tablet (Carbidopa 25 mg+L-dopa 100 mg) at 10 am, 1 pm, 4 pm and 7 pm.
• In addition, he was prescribed
one Sinemet CR tablet at 10 pm.
• The nursing staff were asked to complete an hourly ‘on–off’ chart. Parts of the chart for days 1 and 5 are shown in the
Table here under.
Month 66, Day 6: Mr. LN’s mobility and dyskinesias were improved; however, he remained depressed about his condition.
Q14 Would Mr. LN benefit from an antidepressant?
- Probably. Depression is very common in Parkinson’s disease,
approximately 40–50% of patients suffer from depression at
least once during the course of their disease.
- Depression in Parkinson’s disease is characterized by feelings
of guilt, helplessness, remorse and sadness. It is independent of
age, disease duration, severity of symptoms or cognitive
impairment.
- Ensuring adequate treatment for Parkinson’s disease should be
the first step before considering more specific antidepressant
therapy.
- This has been achieved in Mr LN, so a trial of an
antidepressant would be reasonable.
Q15 If so, which would you choose?
- A tricyclic antidepressant (TCA) or
selective serotonin reuptake inhibitor
(SSRI) could be prescribed for Mr. LN.
- At present, there is insufficient evidence
to recommend one
antidepressant/antidepressant class over
another. This lack of data is also
highlighted in the NICE guidance.
- Clinical practice, as well as trial data, supports
the use of some TCAs (e.g. amitriptyline,
nortriptyline) in Parkinson’s disease; however,
they are often associated with anticholinergic
effects and orthostatic hypotension, which may
limit their usefulness.
- The SSRIs (e.g. fluoxetine, sertraline,
citalopram) have also been shown to be
effective in Parkinson’s disease. They are free
of the anticholinergic effects associated with
the tricyclics, and theoretical concerns that
they may worsen parkinsonian symptoms have
not been borne out by recent studies.
Month 66, Day 8
• Mr. LN had noticed a significant reduction in the shaking of his arms following his recent regimen change;
• however, he was still becoming considerably immobile about 1 hour before his dose of Sinemet.
• His sleep had improved so that he was getting at least 6 continuous hours’ sleep and no longer woke in pain from cramps.
• The consultant neurologist recommended commencing entacapone.
Q16 Why has the consultant neurologist recommended entacapone, and does this necessitate the adjustment of Mr. LN’s other PD therapy?
- Mr. LN is still displaying signs of end-of-
dose akinesia, despite appropriate
adjustment to his levodopa therapy.
- Entacapone therapy may improve these
symptoms, but his other IPD therapies will
need to be adjusted as the drug is
introduced.
Clinical Pearls Entacapone is licensed for use as an adjunct to
levodopa in Parkinson’s disease.
Studies have shown that its use can significantly reduce
‘off’ time and increase ‘on’ time in patients with
‘wearing-off’ episodes.
It should be given at a dose of 200 mg with each dose of
levodopa, up to 10 times daily.
The introduction of entacapone to a regimen can cause
a new-onset or worsening of existing dyskinesias.
In order to minimize this, the daily dose of levodopa
should be reduced by about 10–30% by extending the
dosing intervals and/or by reducing the amount of
levodopa per dose.
In practice, the choice varies from
patient to patient.
Tolcapone, the only other commercially
available COMT inhibitor, differs from
entacapone in that it also blocks
central COMT.
Tolcapone was withdrawn in 1998 after
a number of cases of hepatitis, but has
since been relaunched with strict
monitoring parameters and guidance
on use.
Q17 What counselling points would you highlight to a patient commencing entacapone?
- Entacapone can discolor the urine reddish
brown.
- Patients should also be advised that nausea
and vomiting can occur due to
augmentation of levodopa, and that
diarrhea is a common adverse effect.
- The large size of the tablets may cause
problems for patients with swallowing
difficulties.
Month 66, Day 11:
• During the ward round, you noted that Mr. LN’s morning medication was still on his bedside table.
• His medication now comprised one Madopar dispersible 62.5 mg tablet on waking around 7 am, one Sinemet Plus tablet at 10 am, 1 pm, 4 pm and 7 pm, and a Sinemet CR tablet at 10 pm. In addition, he was taking one entacapone tablet alongside each dose of Sinemet Plus and 3 mg ropinirole three times a day (made up of a 1 mg and a 2 mg tablet for each dose).
• His regimen thus comprised a total of 16 tablets per day. On questioning, Mr. LN informed you that although he was feeling better, he was concerned at the number of tablets he was taking and feared that he would have problems remembering to take them all when he returned home.
• He also found the new tablet quite hard to swallow because of its size.
Q18 In view of MR. LN’s concerns, what options are there for rationalizing his medications?
- The use of combination products and
alternative formulations could be considered.
- In the literature it has been noted that
approximately 20% of patients with IPD are
non-adherent with their medication.
• The transdermal patch rotigotine and the oral formulation ropinirole XL are both designed for once-daily administration.
- Stalevo is a combined preparation of levodopa, carbidopa and entacapone formulated into one tablet.
- A Stalevo tablet is smaller than a tablet of entacapone alone and is thus also helpful in patients with swallowing difficulties who require therapy.
- Stalevo is available in a number of strengths, although dose titration is more limited than with the individual components.
- Mr LN could be started on Stalevo in place of Sinemet and entacapone.
Month 75:
• Mr. LN was admitted as an emergency by his GP, having developed visual and auditory hallucinations over the previous week.
• He was hearing voices talking about him, threatening to kill him.
• He was also seeing insects crawling up the walls and burrowing into his skin.
• On examination he was clearly distressed and very frightened.
• His medication on admission was one Madopar dispersible tablet on waking, one Stalevo 100/25/200 tablet four times daily, one Sinemet CR tablet at night and one ropinirole XL tablet 8 mg daily
Q19 Which drugs might have contributed to Mr. LN’s symptoms?
- All the drugs prescribed for Mr. LN can cause the
psychiatric complications described.
- Levodopa causes a variety of psychiatric
symptoms, including hallucinations.
- Dopamine agonists such as ropinirole can cause
central nervous system effects such as
hallucinations and confusion. These psychiatric
complications are especially common in elderly
patients. In addition, progression of the disease
itself may contribute to these symptoms.
Q20 What adjustments would you recommend be made to Mr. LN’s medication?
- Gradually reduce his dose of
ropinirole XL and stop if
necessary.
Q21 What course of action would you suggest to improve Mr. LN’s symptoms?
- Add a low dose of an ‘atypical’
antipsychotic drug, or consider
acholinesterase inhibitor.
• Mr. LN was started on rivastigmine 1.5 mg twice daily.
• The dose was increased over the next 10 days to 4.5 mg twice daily.
• His dopaminergic therapy was adjusted to one Stalevo 100/25/200 tablet five times daily,
• one Sinemet CR tablet at night and one Madopar 62.5 mg dispersible tablet upon waking.
• His ropinirole XL therapy was discontinued.
• His hallucinations resolved and acceptable control of his Parkinson’s symptoms was achieved. He was discharged on this regimen.
Q22 What is the long-term outlook for Mr. LN?
- It is likely that Mr. LN’s condition will
continue to deteriorate with time, and
that he will experience more ‘off’ time
and increasing dyskinesias. His
cognitive function may also decline
further.
Clinical Pearl
Amantadine has been used for the management of
dyskinesias based on its antiglutamate activity;
however, its side-effects (confusion, hallucinations)
would preclude its use in Mr. LN. Other side-
effects of amantadine include ankle swelling and
livedo reticularis.
A small number of other therapies can be used at
this stage in patients with Parkinson’s disease, but
their risks and financial implications are
considerable.
The use of apomorphine, a potent dopamine agonist licensed for the treatment of refractory motor fluctuations (‘off’ periods) in IPD, is a possibility in patients who deteriorate despite maximum tolerated oral therapy. The drug cannot be given orally and must be administered subcutaneously. It may be given as a continuous subcutaneous infusion or as single injections. It causes severe nausea and vomiting, so 3 days’ pretreatment with domperidone (20 mg three times daily) is used to minimize this. Domperidone therapy may be continued until tolerance to this side-effect develops.
Apomorphine is effective within 5–10 minutes, and
patients may remain in the ‘on’ state for up to 60
minutes. During this time an oral dose of medication
should have taken effect. Many patients are helped by up
to five injections a day, although up to 10 may be needed
in some patients. If the number of injections needed is
high, then continuous infusions of apomorphine should
be considered. If the nausea and vomiting can be
overcome, apomorphine therapy is generally well
tolerated. Bruising, nodules or abscesses may form at the
site of an infusion, so the site should be changed daily. As
Mr. LN has had psychotic features in the past that
resolved following discontinuation of his dopamine
agonist, the use of apomorphine may not be appropriate
and may further exacerbate this symptom.
The use of surgical techniques such as subthalamic deep brain stimulation (STN-DBS) may also be precluded in Mr. LN by his previous psychotic symptomatology. The relatively high morbidity and mortality rate associated with lesioning operations such as thalamotomy and pallidotomy has recently made STN-DBS more favorable. STN-DBS involves the placement of tiny wires into the subthalamic nucleus (STN). These emit continuous electrical impulses from a neurostimulator, which is similar to a heart pacemaker. This stimulation can have a positive effect on the brain activity involved in controlling movement, and can improve tremor, stiffness, slowness and dyskinesia. In addition, with improvement in these symptoms medication can be reduced, thereby further reducing dyskinesias.
Mr. LN may, however, be an appropriate candidate for Duodopa, a gel formulation of levodopa/carbidopa that is infused directly into the duodenum. Duodopa is designed to mimic the pharmacokinetic profile of endogenous dopamine release. The technique, albeit initiated using a nasogastric tube, requires a percutaneous gastrostomy tube for long-term administration. Such a procedure in patients with advanced Parkinson’s disease can be hazardous.
Although there have been many recent advances in the management of IPD, there is still no cure. Ongoing research is targeted at neuroprotection strategies: interventions to protect or rescue vulnerable dopaminergic neurons, and to slow down or stop disease progression. Gene therapy trials are also currently under way.