[Treatment Principles
I. Comprehensive treatment
A comprehensive and integrated treatment should be adopted for motor and non-motor symptoms of Parkinson’s disease. Treatment methods and means include medication, surgery, exercise therapy, psychological guidance and care. Drug therapy is preferred and is the main treatment throughout the treatment process, while surgery is an effective complement to drug therapy. The currently applied treatments, whether pharmacological or surgical, can only improve the patient’s symptoms, but cannot stop the development of the disease, let alone cure it. Therefore, treatment should not only be based on the present, but also requires long-term management to achieve long-term benefits.
Second, the principle of medication
The principle of medication should be aimed at achieving effective improvement of symptoms, work ability and quality of life. Early diagnosis and early treatment can not only improve the symptoms but also slow down the disease progression. Dose titration” should be adhered to in order to avoid acute side effects of drugs and to achieve the principle of “achieving satisfactory clinical effects with as small a dose as possible”, so as to avoid or reduce the incidence of motor complications, especially ochronosis.
Treatment should follow the evidence of evidence-based medicine, and should also emphasize the characteristics of individualization. The selection of medication for different patients should take into account the characteristics of the patient’s disease (whether it is predominantly tremor or tonic hypokinesia) and the severity of the disease, the presence of cognitive impairment, age of onset, employment status, the presence of co-morbidities, possible side effects of medication, the patient’s willingness, affordability and other factors, in order to avoid, delay or reduce as much as possible side effects and motor complications of medications. When performing anti-Parkinson’s disease drug therapy, especially when using levodopa, the drug should not be stopped suddenly to avoid withdrawal malignant syndrome.
Drug therapy]
According to the severity of clinical symptoms, the course of Parkinson’s disease can be divided into early and intermediate and late stages, i.e. Hoehn-Yahr grade l-2.5 is defined as early stage, and Hoehn-Yahr grade 3-5 is defined as intermediate and late stage. Below we present specific treatment advice for early and mid to late stage Parkinson’s disease, respectively.
I. Treatment of early Parkinson’s disease
Once early diagnosis is made, treatment should be started as early as possible to grasp the timing of disease modification, which plays a key role in the success or failure of the entire treatment of Parkinson’s disease in the future. Early treatment can be divided into non-pharmacological treatment (including awareness and understanding of the disease, supplemental nutrition, strengthening exercise, firm confidence in overcoming the disease, as well as social and family understanding, care and support for patients) and pharmacological treatment. Generally, monotherapy is given in the early stage of the disease, but the combination of multiple drugs (embodying multiple targets) in optimized small doses can also be used to achieve the goal of optimal efficacy, longer maintenance time and lowest incidence of exercise complications.
Pharmacological treatments include disease-modifying therapeutic agents and symptomatic therapeutic agents. In addition to their potential disease-modifying effects, disease-modifying drugs also have a symptom-modifying effect; symptomatic drugs, in addition to significantly improving disease symptoms, also have some disease-modifying effects.
The goal of disease-modifying therapy is to delay the progression of the disease. Currently, the main drugs that may have disease-modifying effects in clinical practice include monoamine oxidase type B (MAO-B) inhibitors and dopamine receptor (DR) agonists.
Among MAO-B inhibitors, sregiline + vitamin E (DATATOP) and resagiline (ADAGIO) clinical trials may have a delaying effect on disease progression; among DR agonists, the pramipexole CALM-PD study and the ropinirole REAL-PET study suggest a possible disease-modifying effect. Clinical trials of coenzyme Q10 at high doses (1200 mg/d) also suggest a possible disease-modifying effect.
(A) Preferred drug principles (Figure 1)
1. Patients with early onset of the disease, in the absence of concomitant hypo-intelligence, may have the following options.
①Non-ergot DR agonists;
②MAO-B inhibitors;
③Amantadine;
④Compound levodopa;
⑤ compound levodopa + catechol-0-methyltransferase (COMT) inhibitors. The preferred drugs are not in the above order, and different regimens should be chosen according to the specific conditions of different patients.
2. In patients with late onset of the disease or with associated hypo-intelligence, compound levodopa therapy is generally preferred. As symptoms worsen, DR agonists, MAO-B inhibitors or COMT inhibitors can be added to the treatment when the efficacy decreases. Try not to apply anticholinergic drugs, especially for elderly male patients, because they have more side effects.
(B) Therapeutic drugs
1.Anticholinergic drugs: At present, benzhexol is mainly applied in China at a dose of 1-2 mg, 3 times/d. It is mainly applied to patients with tremor, while it is not recommended for patients without tremor. For patients <60 years old, it is important to inform that long-term application of this class of drugs may cause their cognitive function to decline, so the cognitive function should be reviewed regularly and discontinued as soon as the patient's cognitive function is found to decline; for patients ≥60 years old, it is best not to apply anticholinergic drugs. Narrow-angle glaucoma and prostatic hypertrophy patients are prohibited.
2, amantadine: the dose is 50-100mg, 2-3 times / d, the last time should be taken before 4 pm. It has an ameliorative effect on hypokinesia, tonicity, tremor and is helpful in improving heterokinesia (Class C evidence). Use with caution in patients with renal insufficiency, epilepsy, severe gastric ulcer, liver disease, and contraindicated in lactating women.
3.Compound levodopa (benserazide levodopa, carbidopa levodopa): the initial dosage is 62.5~125.0 mg, 2~3 times/d, gradually increase the dosage to the appropriate dose for maintenance with satisfactory efficacy and no side effects according to the condition, and take the drug l h before or 1.5 h after meal. Previously, it was advocated to postpone the application as much as possible because the early application induced xerostomia; available evidence suggests that the early application of small doses (≤400 mg/d) does not increase the occurrence of xerostomia.
The rapid onset of action of compounded levodopa in regular release and the relatively long maintenance time of controlled release, but the slow onset of action and low bioavailability, require attention when using, especially when switching between the 2 different dosage forms. Active peptic ulcers, narrow-angle glaucoma, psychiatric patients are prohibited.
4, DR agonists: most of the current push for non-ergot DR agonists as the drug of choice, especially for early-onset Parkinson’s disease patients in the early stages of the disease. Because, these long half-life agents can avoid the DR of the striatal postsynaptic membrane “pulse” like stimulation, thus preventing or reducing the occurrence of motor complications. Agonists should be started at small doses and gradually increased until satisfactory efficacy is achieved without side effects.
The side effects of DR agonists are similar to those of compounded levodopa, except that they have a low incidence of symptom fluctuations and allodynia and a high incidence of postural hypotension, ankle edema, and psychiatric abnormalities (hallucinations, hyperphagia, hypersexuality, etc.).
There are 2 types of DR agonists, the ergot class including bromocriptine, pergolide, d-dihydroergotocriptine, ergometrine, and ergometrine; and the non-ergot class including pramipexole, ropinirole, piribedil, rotigotine, and apomorphine. Ergot DR agonists can lead to heart valve lesions and pulmonary pleural fibrosis, therefore, their use is no longer advocated, of which Pergolide has been discontinued in China.
Non-ergot DR agonists that have been on the market for many years in China are.
①Piberidil extended-release: the initial dose is 50 mg once daily, which can be changed to 25 mg twice daily for patients prone to side effects, and increased to 50 mg twice daily in the second week, with an effective dose of 150 mg/d, divided into 3 oral doses, with the maximum dose not exceeding 250 mg/d;
②Praxol: there are 2 dosage forms: normal release and extended release. The use of normal release: the initial dose is 0.125 mg 3 times a day (1 or 2 times for individual patients prone to side effects), increasing by 0.125 mg 3 times a day every week, with a general effective dose of 0.50-0.75 mg 3 times a day and a maximum dose of no more than 4.5 mg/d. The use of extended release: the daily dose is the same as normal release, but is taken once a day.
Upcoming non-ergot DR agonists are.
① Ropinirole: initial dose of 0.25 mg 3 times daily, increasing by 0. 75 mg weekly to 3 mg daily, generally effective dose of 3-9 mg daily, divided into 3 doses, maximum daily dose of 24 mg;
②Rotigotine: initial dose of 2 mg once daily, increasing by 2 mg per week, the general effective dose is 6-8 mg per day for early stage patients and 8-16 mg per day for patients with intermediate to late stage.
Ergot DR agonists that have been marketed in China for many years are.
①bromocriptine: 0. 625 mg once daily, increasing by 0. 625 mg every 5 days, effective dose 3.75-15. 00 mg/d, divided into 3 oral doses;
②a-dihydroergotocryptine: 2.5 mg twice daily, increased by 2.5 mg every 5 days, effective dose 30～50 mg/d in 3 oral doses. The dose conversion between the above 5 drugs is: piribedil: pramipexole: ropinirole: bromocriptine: d-dihydroergotocryptine = 100:1:5:10:60), due to individual differences only as a reference.
5, MAO-B inhibitors: mainly sellegran and resagiline, of which sellegran has normal release and oral mucosal disintegration agent.
The usage of Silegiline (normal release) is 2.5-5.0 mg twice daily, taken in the morning and noon, not in the evening or at night to avoid insomnia, or combined with vitamin E 2000 U (DATATOP program); oral mucosal disintegration agent absorption, action, safety are better than Silegiline normal release, the dosage is 1. 25-2.50 mg/d. Raisagiline’s The dosage is 1 mg once a day, taken in the morning. Gastric ulcer patients are cautiously used, and the combination with 5-hydroxytryptamine reuptake inhibitors (SSRI) is prohibited.
6, COMT inhibitors: In the early stage of the disease, compound levodopa + COMT inhibitors such as entacapone bidopa tablets (a combination of entacapone/levodopa/carbidopa, divided into four dosage forms according to the dose of levodopa, can not only improve the patient’s symptoms, but also may prevent or delay the occurrence of motor complications, but FIRST-STEP and STRIDE-PD However, FIRST-STEP and STRIDE-PD studies suggest that the early application of entacapone bidopa does not delay motor complications and increases the chance of atopic disorders, which is controversial and needs to be further verified; in the middle and late stages of the disease;
The addition of entacapone or tolcapone may be used to further improve symptoms when the efficacy of compounded levodopa is diminished. The dosage of entocapone is 100-200 mg per dose, and the number of doses is the same as that of levodopa, or less than the number of doses of levodopa if the number of doses of levodopa per day is higher, and it should be taken together with levodopa. Tolcapone is 100 mg per dose, 3 times a day, the first dose is taken with compounded levodopa, thereafter it is taken at 6h interval, and can be used alone, the maximum daily dose is 600 mg.
Its drug side effects include diarrhea, headache, excessive sweating, dry mouth, elevated transaminases, abdominal pain, and yellowing of the urine. Tolcapone may cause liver function impairment and close monitoring of liver function is required, especially during the first 3 months after the drug is administered.
II. Treatment of mid- to late-stage Parkinson’s disease
The clinical manifestations of mid- to late-stage Parkinson’s disease, especially advanced Parkinson’s disease, are extremely complex, with the progression of the disease itself, as well as the involvement of drug side effects or motor complications. The treatment of patients with mid- to late-stage Parkinson’s disease should, on the one hand, continue to strive to improve the patients’ motor symptoms; on the other hand, some motor complications and non-motor symptoms should be properly managed.
(A) Treatment of motor complications
Motor complications (symptom fluctuations and dyskinesia) are common symptoms in the middle and late stages of Parkinson’s disease. Adjusting the type, dose and number of medications can improve symptoms, and surgical treatment such as deep brain electrical stimulation (DBS) is also effective.
1. Treatment of symptom fluctuations: Symptom fluctuations mainly include end-dose deterioration and on/off phenomenon.
The treatment of end-of-dose worsening is as follows
(1) Do not increase the total daily dose of compounded levodopa, but increase the number of doses per day and reduce the dose per dose (provided that it is still effective in improving motor symptoms), or increase the total daily dose (if the original dose is not large), and increase the number of doses per dose;
② Switching from regular release to controlled release to prolong the duration of action of levodopa is more appropriate for early onset of end-of-dose deterioration, especially at night, and the dose should be increased by 20%-30% (US guidelines consider that it cannot shorten the “off” period, which is level C evidence, while UK NICE guidelines recommend it for use in patients with advanced disease, but not as a first choice, as level B evidence);
③Add DR agonists with long half-life, including pramipexole and ropinirole as level B evidence, carte blanche and apomorphine as level C evidence, bromocriptine cannot shorten the “off” period, as level C evidence, if the DR agonist has been used and the efficacy is reduced, try to switch to another DR agonist;
④Add a COMT inhibitor that produces sustained DAergic stimulation of the striatum, of which entocapone is level A evidence and tolcapone is level B evidence;
⑤ Add MAO-B inhibitors, of which resagiline is level A evidence and sellegrin is level C evidence;
⑥Avoid the effect of diet (containing protein) on the absorption of levodopa and its passage through the blood-brain barrier; it is advisable to take the drug 1h before or 1.5h after meals; adjustment of protein diet may be effective;
(7) Surgical treatment mainly for the thalamic floor nucleus (STN) may be beneficial with DBS, which is level C evidence. The management of the on-off phenomenon is more difficult, oral DR agonists can be used, or micro-pump continuous infusion of levodopa methyl or ethyl ester or DR agonists (such as ergocalciferol, etc.) can be used.
2, treatment of isokinetic disorders (Figure 3): isokinetic disorders (AIMs), also known as movement disorders, include agent-peak isokinetic disorder, biphasic isokinetic disorder and dystonia.
The management of agent-peak isokinetic disorder is.
(i) Reduce the dose of compounded levodopa for each dose;
②If the patient is using compound levodopa alone, the dose can be reduced appropriately and DR agonist can be added at the same time or COMT inhibitor can be added;
③Add amantadine (level C evidence);
④Add atypical antipsychotics such as clozapine;
⑤ If a compounded levodopa controlled-release agent is used, it should be replaced with a regular-release agent to avoid the cumulative effect of the controlled-release agent.
The treatment of biphasic heteronegativity (including early and late dose heteronegativity) is as follows.
①If compounded levodopa controlled-release agent is used, it should be replaced with normal-release agent, preferably with water solvent, which can effectively alleviate the first-dose anomaly;
②Adding a DR agonist with a long half-life or a COMT inhibitor with an extended levodopa plasma clearance half-life can alleviate end-dose anisotropy and may also help to improve first-dose anisotropy. Continuous infusion of DR agonists or levodopa methyl or ethyl ester by micropump can improve both isokinetic disorder and symptom fluctuations, and oral formulations are being tested to see if the same effect can be achieved.
Clinical trials related to the therapeutic efficacy of other drugs for the treatment of athetoid disorder such as adenosine A2A receptor antagonists acting on non-DAergic aspects of the basal ganglia are underway. The management of morning dystonia is based on the addition of a combination of levodopa controlled-release tablets or a long-acting DR agonist at bedtime, or a combination of levodopa regular-release or aqueous solution before waking up; the management of “open” dystonia is based on the same dose of peak anisokinesia. Surgical treatment is mainly DBS, which can be beneficial.
(B) Treatment of postural balance disorder
Postural balance disorder is the most common cause of falls in patients with Parkinson’s disease, and it occurs easily when changing positions such as turning, rising and bending. Active body weight adjustment, stepping, striding, listening to commands, walking to music or clapping, or crossing objects (real or imaginary) may be beneficial. Use a walker or even a wheelchair if necessary and be well protected.
Summary]
There is no absolute fixed pattern of treatment for Parkinson’s disease, as symptoms may differ between patients and sensitivity to treatment varies somewhat. The need for treatment varies from patient to patient, and the same patient may have different needs for treatment at different stages of the disease.
Therefore, this guideline may apply to the general rule, but in clinical practice, care should be taken to understand in detail the patient’s condition (severity of disease, type of symptoms, etc.), response to treatment (whether it is effective, duration of onset of action, duration of maintenance of action, prolongation of the “on” period and “off” period When applying the drug, we should pay attention to the patient’s condition (severity of disease, type of symptoms, etc.), treatment response (whether it is effective, onset of action, duration of maintenance of action, prolongation of “on” and “off” period, and whether there are side effects or complications), and combine with your own treatment experience to follow the guidelines and reflect the principle of individualization in order to achieve more ideal treatment results.