April is Parkinson’s Awareness Month. Last year, I wrote a post about common issues faced by individuals affected by Parkinson’s disease. This year, I want to focus on new treatments that are already available or soon coming down the pipeline.
Given Parkinson’s disease is due to the depletion of dopaminergic neurons in the substantia nigra, the mainstay of therapy continues to focus on dopamine replacement therapy. We have seen a number of advances throughout the years. From the original DOPA therapy, to the synthesis of L-DOPA, and to the addition of decarboxylase inhibitor, these modifications all aim to optimize the steady delivery of L-DOPA to the brain and to minimize the breakdown of the peripheral concentration.
During the advanced stages of Parkinson’s disease, inadequate levodopa concentration in the brain may result in various motor complications such as: “wearing off”, “on-off” fluctuations, freezing and dyskinesia. Some of these complications can easily be managed by increasing the frequency of administration, changing the formulation or adding additional non-levodopa therapies such as amantadine. But overtime, many of these strategies will lose their efficacy.
Recently, Duodopa (an intestinal levodopa/carbidopa gel) has been made available in Canada. It is made as an intestinal gel containing 20mg/mL of Levodopa and 5mg/mL of Carbidopa in a 100mL cassette. It is designed to be given as a continuous intestinal infusion to achieve an optimal steady state concentration of plasma levodopa. It has been shown to significantly increase “on”time and decrease “off” time as well as significantly improving the control of the Parkinson’s symptoms.
In Ontario, it is covered under the Ontario Drug Benefits Program as an Exceptional Access Product in selected area. Below is the current reimbursement criteria as listed by ODB:
For the treatment of Parkinson’s disease in patients who meet the following criteria;
•Experiences at least 25% of the waking day in the off state; AND
•Has severe disability while in the off-state as assessed by a Movement Disorder Specialist; AND
•Has received an adequate trial of maximally tolerated doses of levodopa, with demonstrated clinical response; AND
•Has failed adequate trials of other adjunctive medications (entacapone, dopamine agonists, monoamine oxidase-B [MAO-B] inhibitors) if not contraindicated. Note that if a contraindication is deemed to be applicable to the patient, the requesting physician must state the contraindication and provide the rationale why it is considered a contraindication for the patient).
Clinical details pertaining to the severity of the patient’s disability while in the off-state as well as a complete history of all previous and current medications (e.g., name, start date and duration of therapy, doses used, side effects, and response) must be included.
Requests for treatment initiation will be limited to the physicians practicing in the following specialized movement disorder clinics:
Ottawa, London, Toronto Western, Kingston, Baycrest and Hamilton.
Given that many of the residents living in long term care facilities do have significant motor complications from years of Parkinson’s disease, I wonder why they are not made aware of this therapy. One of the challenges is that Duodopa must be prescribed by neurologists or specialists of movement disorders, very expensive, requires close follow up and likely need the individual to be cognitively intact.
Another exciting therapy is pimavanserin. It is not yet available in Canada but is marketed as Nuplazid in the United States and is approved for Parkinson’s disease psychosis. Currently, psychosis or other psychiatric or behavioural symptoms are not uncommon in individuals taking Levodopa. Managing these psychiatric complications can be challenging as the use of antipsychotics may also worsen Parkinson’s symptoms (as many are dopamine antagonists). Agents that have been shown to be safe are clozapine and quetiapine. But the mandatory blood work monitoring requirement for agranulocyotosis of Clozapine often discourages clinicians and patients from trying. In addition, quetiapine has not demonstrated strong efficacy results. Pimavanserin is a selective serontinin 2A receptor inverse agonist, which has been shown to treat Parkinson’s disease psychosis without worsening the motor functions. While it has received FDA approval, post marketing clinical trials have been made mandatory to demonstrate long term safety and efficacy. But this new agent will be a great addition and allow clinicians more treatment options for Parkinson’s induced psychosis.
There are many other molecules and treatment options currently in Phase 2-3 clinical trials. It is unlikely that I will hear about them in the next year or so. However, some ongoing studies are trying out off label use of marketed drugs. Here are some examples:
- Amantadine and topiramate are studied together for management of dyskinesia
- Varenicline which is marketed for smoking cessation is now studied for gait and balance in Parkinson’s disease.
- Donepezil which is a cognitive enhancer in dementia is being evaluated for its role in postural instability.
Clearly, the management of Parkinson’s disease continues to evolve and and there is still much to be learned in the years to come. But one thing for sure is that I hope we will find a cure soon!