Monday, September 26, 2022

Parkinson’s Disease Treatment Guidelines 2020

Exploring Seven Recently Approved Parkinsons Treatments

Parkinson’s Disease (Shaking Palsy) – Clinical Presentation and Pathophysiology

Remarkably, in the last five years, seven new medications have been approved for the treatment of the motor symptoms of Parkinsons disease , with two approved in 2020. Thats exciting progress! And while it is great to have so many choices, the various options can be confusing so today I will describe these new medications and their uses.

Monoamine Oxidase B Inhibitors

Other PD medications work by inhibiting the enzymes involved in dopamine metabolism, which preserves the levels of endogenous dopamine. One such class is the MAO-B inhibitors. As is discussed above, MAO-B is one of the main enzymes involved in the breakdown of dopamine, and reducing the activity of this enzyme therefore results in increased dopaminergic activity within the striatum, mediated by endogenous dopamine . Their use relieves motor symptoms in PD patients, and as with dopamine agonists they may be used as an initial treatment option, to delay the need for levodopa therapy, to reduce the risk of levodopa-induced motor complications . While they are sometimes sufficient for control of symptoms in early disease, most patients ultimately require levodopa-based treatment. MAO-B inhibitors may also be used in combination with levodopa-based preparations, to allow for a reduction in the levodopa dose.

Management Of Parkinsons Disease

Overall treatment is specific to the patient and the symptoms they experience. Symptoms can be variable from day to day or even hour to hour therefore, it is important that patients have a good understanding of their treatment, disease, coping mechanism, support system and regular reviews. Life expectancy can be normal however, more advanced symptoms can lead to increased disability and poor health, which may make someone more vulnerable to complications .

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Starting Treatment In Early Parkinson’s Disease

The optimal time to start treatment in PD has been the source of much debate. In an open-label study of 198 patients with untreated PD, quality of life as measured by the Parkinson’s Disease Questionnaire-39 worsened in those left untreated, but was stable or improved in patients receiving dopaminergic treatment. In an observational study comparing Italian patients with PD who started levodopa early with those in Ghana where therapy was delayed, motor fluctuations and dyskinesia occurred at similar disease duration. This showed that duration of disease rather than treatment is a key determinant of motor complications. Therefore, delaying dopaminergic therapy does not avoid the development of motor complications and may be associated with poorer QoL. The recent delayed-start LEAP study showed no disease-modifying effect of levodopa in patients diagnosed < 2 years prior, but PDQ-39 score was improved in the blinded phase in those receiving early vs delayed treatment.

Lifestyle And Other Protective Factors

Parkinsons Disease

Cigarette smoking and caffeine consumption are the two most consistent protective factors associated with a reduced risk of PD. Other reported associations include higher serum urate, ibuprofen use and exercise, among others. The negative association between cigarette smoking and PD is most intriguing. This inverse relationship is not easily explained, but some have suggested that PD-related cautious personality predisposes some individuals to quitting neuroprotective smoking as the biological mechanism involved in PD. The other hypothesis links nicotine to dopaminergic neuronal protection since it has been shown to stimulate the release of dopamine in the striatum and preserve dopaminergic function in experimental models. It is also possible that there are other unidentified neuroprotective components in cigarette smoke.

The relative risk reduction of PD among caffeine drinkers is between 0.5 and 0.8 and, similar to smoking, a dose-dependent effect has been consistently demonstrated in most studies. Caffeine, an antagonist of adenosine A2a receptor, has been postulated to exert neuroprotective role by blocking this receptor. In addition to caffeine, it is possible that antioxidants present in some beverages may contribute to a protective effect among black tea drinkers, independent of caffeine.

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Symptomatic And Neuroprotective Therapy

Pharmacologic treatment of Parkinson disease can be divided into symptomatic and neuroprotective therapy. At this time, there is no proven neuroprotective or disease-modifying therapy.

Levodopa, coupled with carbidopa, a peripheral decarboxylase inhibitor , remains the gold standard of symptomatic treatment for Parkinson disease. Carbidopa inhibits the decarboxylation of levodopa to dopamine in the systemic circulation, allowing for greater levodopa distribution into the central nervous system. Levodopa provides the greatest antiparkinsonian benefit for motor signs and symptoms, with the fewest adverse effects in the short term however, its long-term use is associated with the development of motor fluctuations and dyskinesias. Once fluctuations and dyskinesias become problematic, they are difficult to resolve.

Monoamine oxidase -B inhibitors can be considered for initial treatment of early disease. These drugs provide mild symptomatic benefit, have excellent adverse effect profiles, and, according to a Cochrane review, have improved long-term outcomes in quality-of-life indicators by 20-25%.

Neuroprotective therapy aims to slow, block, or reverse disease progression such therapies are defined as those that slow underlying loss of dopamine neurons. Although no therapy has been proven to be neuroprotective, there remains interest in the long-term effects of MAO-B inhibitors. Other agents currently under investigation include creatine and isradipine.

Drug And Medication Therapies

The purpose of treating Parkinsons is to reduce the effect of symptoms on your daily life. Without treatment, you will eventually find that the symptoms make it hard to perform daily activities. Symptoms, such as shaking and stiffness, may cause discomfort the risk of injury from falls may increase, and swallowing may become more difficult. People are encouraged to maintain open and ongoing discussions with their Parkinsons healthcare team when exploring treatment options.

Medication will help you function, but may cause side effects. It is important to find the right balance between the medications benefits and side effects. Everyone with Parkinsons is unique and will experience different symptoms, which means the treatment you receive will be geared to your specific needs. Drugs for Parkinsons work on the brains complex chemistry and may need to be taken several times a day. Use them as prescribed and do not alter your doses without consulting your doctor. Current treatment neither cures Parkinsons nor stops it from advancing.

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Progression Of Parkinson’s Disease

The disease progression of PD from diagnosis has been conceptualised into four stages . It is also important to recognise a prodromal phase in which non-motor symptoms, such as anosmia, constipation and rapid-eye-movement sleep behaviour disorder may predict the development of motor PD. Motor complications are more common as PD progresses, and typify transition to the complex phase. Many so-called axial symptoms of later stage PD, such as dysphagia, gait disturbance and falls, do not respond to levodopa, but may be helped by multidisciplinary team input. Dementia occurs in up to 80% of people with PD after 20 years disease duration. The rate of PD progression is heterogeneous and is generally more rapid in those with older age and more severe motor impairment at onset.

Stages of Parkinson’s disease. RBD = rapid eye movement sleep behaviour disorder.

Deep Brain Stimulation For The Treatment Of Pd Patients

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Current surgical indications for PD include reducing motor fluctuations, off time, dyskinesias, tremor, and improvement of levodopa-responsive symptoms. Deep brain stimulation is probably the most critical advance in treatment of PD since the introduction of levodopa. The beneficial effects of DBS on motor symptoms and quality of life in advanced PD have been shown in randomized, controlled studies6666. Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schäfer H, Bötzel K, et al. A randomized trial of deep-brain stimulation for Parkinsons disease. N Engl J Med. 2006 Aug 31 355:896-908. https://doi.org/10.1056/NEJMoa060281 ,6767. Williams A, Gill S, Varma T, Jenkinson C, Quinn N, Mitchell R, et al. Deep brain stimulation plus best medical therapy versus best medical therapy alone for advanced Parkinsons disease : a randomised, open-label trial. Lancet Neurol. 2010 Jun 1 9:P581-91. https://doi.org/10.1016/S1474-442270093-4 .

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Stay Safe With Your Medicines

Read all labels carefully.

  • Tell all your health care providers about all the medicines and supplements you take.
  • Know all the medicines and foods youâre allergic to.
  • Review any side effects your medicines can cause. Most reactions will happen when you start taking something, but thatâs not always the case. Some reactions may be delayed or may happen when you add a drug to your treatment. Call your doctor right away about anything unusual.
  • Use one pharmacy if possible. Try to fill all your prescriptions at the same location, so the pharmacist can watch for drugs that might interact with each other.
  • You can use online tools to see if any of your medicines wonât work well together.

You have the right and responsibility to know what medications your doctor prescribes. The more you know about them and how they work, the easier it will be for you to control your symptoms. You and your doctor can work together to create and change a medication plan. Make sure that you understand and share the same treatment goals. Talk about what you should expect from medications so that you can know if your treatment plan is working.

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When Should I Start Taking Medication

If you have been diagnosed with Parkinsons, you may be wondering when you should start treatment and with what medication. There is no single strategy that applies to everyone. The timing will differ from person to person. It depends on a variety of factors, such as:

  • the nature of your symptom
  • your lifestyle
  • your overall physical health
  • whether you experience balance problems with walking
  • changes in intellectual abilities, and
  • your own attitude toward taking medication

When to start taking medication can be decided in consultation with your neurologist or movement disorder specialist. The decision to delay taking medication requires close monitoring and evaluation for risks of falls and injuries, especially if you are older. The older you are, the more you are at risk for a fall, and Parkinsons medication, when used appropriately, may reduce this risk.

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A Review On Parkinsons Disease Treatment

Tori K. Lee Eva L. Yankee

Department of Biology, Angwin, CA 94508, USA .

Correspondence Address: Tori K. Lee, Department of Biology, Pacific Union College, 1 Angwin Ave, Angwin, CA 94508, USA. E-mail: tolee@puc.edu

Received:First Decision:Revised:Accepted:Available online:Academic Editors:Copy Editor:Production Editor:

© The Author 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License , which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Surgical Therapies With Transplantation And Gene Therapy

Parkinson

Cell transplantation is regarded as a potential future PD treatment. There have been trials using autologous and non-autologous cells. Human embryonic stem cells and induced pluripotent stem cells are few of the cells that have been included in these transplantation studies. One of the concerns with cell transplantation using stem cells is the ethical bounds that must be considered.

Since the first clinical trial in 1987 involving the transplantation of dopaminergic- neuron-rich human fetal mesencephalic tissue into PD patients striatums, more research has aimed to explore whether the grafted dopaminergic neurons will live and form connections in the brain, if the patients brain can harmonize and make use of the grafted neurons, and if the grafts can generate significant clinical improvement. Clinical trials with cell therapy intend to discover if there are long-lasting improvements following restoration of striatal DA transmission by grafted dopaminergic neurons. Experimental data from rodents and nonhuman primates show that fetal ventral mesencephalon intrastriatal grafted DA neurons demonstrate many morphological and functional characteristics of normal DA neurons. Significant improvements of PD-like symptoms in animal models have been demonstrated after successful reinnervation by the grafts. Dopaminergic grafts can reinnervate the striatum in the brain, restore regulated release of DA in the striatum, and can become functionally integrated into neural circuitries.

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American Academy Of Neurology

In 2010, the AAN released guidelines on the treatment of nonmotor symptoms of Parkinson disease. Recommendations included the following :

  • Sildenafil citrate may be considered to treat erectile dysfunction

  • Polyethylene glycol may be considered to treat constipation

  • Modafinil should be considered for patients who subjectively experience excessive daytime somnolence

  • For insomnia, evidence is insufficient to support or refute the use of levodopa to improve objective sleep parameters that are not affected by motor symptoms evidence is also insufficient to support or refute the use of melatonin for poor sleep quality

  • Levodopa/carbidopa should be considered to treat periodic limb movements of sleep in Parkinson disease, but there are insufficient data to support or refute the use of nonergot dopamine agonists to treat this condition or that of restless-legs syndrome

  • Methylphenidate may be considered for fatigue

  • Evidence is insufficient to support or refute specific treatments of orthostatic hypotension, urinary incontinence, anxiety, and RMD

References
  • Hauser RA, Grosset DG. FP-CIT SPECT Brain Imaging in Patients with Suspected Parkinsonian Syndromes. J Neuroimaging. 2011 Mar 16. .

  • Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J. Epidemiology and etiology of Parkinson’s disease: a review of the evidence. Eur J Epidemiol. 2011 Jun. 26 Suppl 1:S1-58. .

  • Bekris LM, Mata IF, Zabetian CP. The genetics of Parkinson disease. J Geriatr Psychiatry Neurol. 2010 Dec. 23:228-42. . .

  • Rapid Eye Movement Sleep Behaviour Disorder

    REM sleep behaviour is associated with PD and is a prodromal symptom in many cases. Patients with REM sleep disorder often physically act out vivid dreams during REM sleep, which can affect their quality of life and that of their family and carers. NICE recommends the off-label use of clonazepam or melatonin . Benzodiazepines are cautioned in the elderly population therefore, this patient cohort must be monitored closely by their care team if started on clonazepam.

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    What Medications Are Used To Treat Parkinson’s Symptoms

    Since many of the motor symptoms of Parkinsons are the result of a lack of dopamine in the brain, most drugs used to treat Parkinsons are aimed at temporarily replenishing or imitating dopamine. The following list is a guide to medications approved by Health Canada to treat symptoms of Parkinsons1. Speak to your doctor for detailed information regarding effectiveness and side effects of a particular drug.

    Levodopa

    • Converted into dopamine in the brain and stored in nerve cells to replace depleted dopamine
    • Combined with another drug, carbidopa or benzerazide, allows more levodopa to get to the brain and reduces side effects
    • Helps improve muscle rigidity and movement
    • Side effects include dyskinesias
    • Over years of use, may be associated with wearing off

    Dopamine Agonists

    • Mimics or imitates action of dopamine
    • Can be used as initial treatment or with levodopa in advanced stages
    • Side effects include sleepiness, hallucinations, leg swelling and obsessions with food, sex and activities such as shopping, gambling and Internet use Amantadine
    • Enhances dopamine release and blocks glutamate, a brain transmitter
    • Used to treat early symptoms
    • Can reduce dyskinesias and improve wearing off

    Dopamine Agonist

    COMT Inhibitors

    Symptomatic Treatment Of Motor Symptoms

    Myths and Misconceptions About Parkinson Disease Treatment

    Levodopa

    A majority of patients with PD require levodopa therapy within 2 years of symptom onset. Levodopa, the most effective drug in the treatment of PD, is almost always combined with carbidopa or benserazide, aromatic acid decarboxylase inhibitors that prevent its peripheral metabolism and markedly reduce the risk of nausea. Increasing the ratio of carbidopa:levodopa from the current standard 1:4 has been shown to increase on time without dyskinesia and reduce off time.

    The global antiparkinsonian efficacy of levodopa is so predictable that a positive therapeutic response is used to support the diagnosis of PD. Adverse effects of levodopa include nausea and vomiting, orthostatic hypotension, sedation, confusion, sleep disturbance, hallucinations and dyskinesias. There are many different types of dyskinesia but peak-dose chorea or stereotypy and wearing off dystonia are most common. About half of the patients experience wearing off, and a third experience dyskinesias within 2 years after initiation of levodopa therapy. Latency from ingestion of levodopa to observable therapeutic benefit can be shortened by taking levodopa on an empty stomach , avoiding or reducing protein intake, or by crushing the levodopa tablet and mixing it with a carbonated beverage.

    Other drugs

    Besides levodopa, there are many other types of medications available for the treatment of PD-related motor symptoms: anticholinergics, amantadine, MAOIs, COMTIs, dopamine agonists and istradefylline.

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    Opportunities For Input From Pharmacy Professionals

    As there is no cure for PD, medication management is crucial in managing the disease. Pharmacy professionals can play a significant role in both primary and secondary care. It is important that pharmacy professionals are familiar with PD symptoms and are aware of which referral pathway is most suitable for the patient. Many of the symptoms are straightforward to manage for example, constipation, and simple interventions can make a big difference to the patients quality of life.

    Pharmacy professionals should also be aware of local services that are available to both patients and themselves. The Parkinsons UK website provides support and resources for healthcare professionals, patients and their family or carers.

    Diagnosis Of Parkinson’s Disease

    The diagnosis of PD is clinical and requires bradykinesia, defined as slowness of movement and decrement in amplitude or speed, usually assessed using finger tapping, foot tapping or pronationsupination hand movements. In addition, rest tremor or rigidity is required to confirm a parkinsonian syndrome. Tremor was absent at presentation in 30% in one series of pathologically proven PD. Patients with suspected PD should be referred quickly and untreated to a specialist in movement disorders for evaluation. Key points for discussion at diagnosis include the need to inform vehicle licensing agencies and insurers, signposting to written or web-based information on newly diagnosed PD, and provision of contact details for the local PD nurse specialist .

    Current International Parkinson and Movement Disorder Society diagnostic criteria for Parkinson’s disease adapted from Postuma RB, Berg D, Stern M et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 2015 30:1591601. At least two supportive criteria and no red flags required for a diagnosis of clinically established Parkinson’s disease. Conditions in italics should be considered if the corresponding exclusion criteria or red flags are present.

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