Recently, the Chinese Parkinson’s Disease Treatment Guidelines (Third Edition), developed by the Parkinson’s Disease and Movement Disorders Group of the Chinese Medical Association’s Neurology Branch, was officially released, authored by Professor Chen Shengdi of Ruijin Hospital, Shanghai Jiaotong University.
The first and second editions of the Chinese Parkinson’s Disease Treatment Guidelines were developed by the group in 2006 and 2009 respectively, which have played an important role in standardizing and optimizing the treatment behavior of Parkinson’s disease and improving treatment outcomes in China. In the past 5 years, there have been some more updates of treatment concepts and advances in treatment methods in this treatment area both domestically and externally. In order to better accommodate these developments and to better guide clinical practice, the guideline development group has made the necessary changes and updates to the second edition of the Chinese Parkinson’s disease treatment guidelines.
The new version of the guideline clearly puts forward the concept of comprehensive treatment for motor and non-motor symptoms of Parkinson’s disease, and emphasizes the principle of “early diagnosis and early treatment”. Professor Chen Shengdi called on “neurologists to refer to the new guidelines in clinical practice, with the goal of controlling Parkinson’s disease symptoms and delaying disease progression, so that patients can obtain long-term benefits in terms of improved quality of life.”
1.Treatment principles
(1) Comprehensive treatment
A comprehensive and integrated treatment should be adopted for both motor and non-motor symptoms of Parkinson’s disease. Treatment methods and tools include medication, surgery, exercise therapy, psychological guidance and care nursing, etc. 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.
(2) Medication principles
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 symptoms, but also delay disease progression. Dose titration” should be adhered to in order to avoid acute side effects 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 be based on evidence-based medicine and should emphasize individualized characteristics. The selection of medication for different patients should take into account the patient’s disease characteristics (whether tremor or tonic hypokinesia is the main cause), disease severity, cognitive impairment, age of onset, employment status, co-morbidity, possible side effects of medication, patient’s willingness and affordability, etc., in order to avoid, delay or reduce as much as possible side effects and motor complications of medications. When conducting anti-Parkinson’s disease drug therapy, especially when using levodopa, the drug should not be stopped suddenly to avoid withdrawal malignant syndrome.
2. 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. In the following, we provide specific treatment advice for early and intermediate to late stage Parkinson’s disease, respectively.
(1) Treatment of early Parkinson’s disease
Once diagnosed early, 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, nutritional supplementation, 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. Among the MAO-B inhibitors, selagiline + vitamin E (DATATOP) and resagiline (ADAGIO) have been clinically tested for their potential to delay disease progression; among the DR agonists, pramipexole CALM- PD study and the ropinirole REAL-PET study suggest a possible disease-modifying effect. Clinical trials of high-dose (1200 mg/d) coenzyme Q10 also suggest a possible disease-modifying effect.
Preferred drug principles.
a. Patients with early onset of the disease, without associated hypo-intelligence, may have the following choices: ① non-ergot DR agonists; ② MAO-B inhibitors; ③ amantadine; ④ compounded levodopa; ⑤ compounded levodopa + catechol-0-methyltransferase (COMT) inhibitors. The preferred drugs are not in the above order, and different regimens are chosen according to the specific conditions of each patient. If the patient cannot afford the high price of the drug for financial reasons, then regimen ③ may be preferred; if the patient has a special job, seeks to significantly improve motor symptoms, or has cognitive impairment, then regimen ④ or ⑤ may be preferred; or regimen ④ may be used in combination with a low dose of regimen ①, ②, or ③. In cases where tremor is obvious and other anti-Parkinsonian drugs are ineffective, anticholinergic drugs, such as benzodiazepines, may be used.
b. In patients with late onset disease or with concomitant mental retardation, compound levodopa therapy is generally preferred. DR agonists, MAO-B inhibitors or COMT inhibitors can be added to the treatment as the symptoms worsen and the efficacy decreases. Anticholinergic drugs should be avoided as much as possible, especially for elderly male patients, because they have more side effects.
Treatment drugs
a. 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 immediately once the patient's cognitive function is found to decline; for patients ≥60 years old, it is best not to apply anticholinergic drugs. Patients with narrow-angle glaucoma and prostatic hypertrophy are prohibited.
b. Amantadine: The dose is 50-100mg, 2-3 times/d, the last time should be taken before 4pm. It has an ameliorative effect on hypokinesia, tonicity, tremor, and is helpful in improving isokinesia (Class C evidence). Use with caution in patients with renal insufficiency, epilepsy, severe gastric ulcer, liver disease, and contraindicated in lactating women.
c. Compound levodopa (benserazide levodopa, carbidopa levodopa): The initial dosage is 62.5-125.0 mg, 2-3 times/d, and the dosage is gradually increased to a suitable dose for maintenance with satisfactory efficacy and no side effects according to the condition, taken l h before or 1.5 h after meals. Previously, it was advocated to postpone the application as much as possible because early application could induce xerostomia; available evidence suggests that 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.
d. DR agonists: Currently, most of the non-ergot DR agonists are promoted as the drug of choice, especially for patients with early-onset Parkinson’s disease at the beginning of the disease course. Because, this kind of long half-life agents can avoid the striatal postsynaptic membrane of DR “pulse” stimulation, so as to prevent or reduce the occurrence of motor complications. 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 higher 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, among which pergolide has been discontinued in China.
At present, the non-ergot DR agonists that have been marketed in China for many years are: ①Pirabedil extended-release agent: 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, and the maximum dose not exceeding 250 mg/d; ②Praxol: there are 2 types of dosage forms: normal-release agent and extended release. The use of normal release: the initial dose is 0.125 mg 3 times a day (1 to 2 times for individual patients prone to side effects), increasing by 0.125 mg 3 times a day every week, and the effective dose is generally 0.50 to 0.75 mg 3 times a day, with the maximum dose not exceeding 4.5 mg/d. The use of extended release: the daily dose is the same as normal release, but is taken once a day.
The upcoming non-ergot DR agonists are: ① Ropinirole: initial dose of 0.25 mg, 3 times daily, increasing by 0. 75 mg per week to 3 mg per day, the general effective dose is 3-9 mg per day, divided into 3 doses, the maximum daily dose is 24 mg; ② Rotigotine: initial dose of 2 mg, 1 time daily, increasing by 2 mg per week, the general effective dose is 6-8 mg per day for early stage patients, and 6-8 mg per day for patients with intermediate to late stage. The effective dose is generally 6 to 8 mg daily for early stage patients and 8 to 16 mg for patients in the middle and late stages.
Ergot DR agonists that have been marketed in China for many years include: ①bromocriptine: 0.625 mg once daily, increasing by 0.625 mg every 5 days, effective dose 3.75-15.00 mg/d in 3 oral doses; ②a-dihydroergotocriptine: 2.5 mg twice daily, increasing 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.
e. MAO-B inhibitors: The main ones are silegiline and resagiline, of which silegiline is available as a normal-release agent and an oral mucosal disintegrant. The usage of sellegran (normal release) is 2.5-5.0 mg twice daily in the morning and noon, do not apply in the evening or night to avoid insomnia, or combine with vitamin E 2000 U (DATATOP program); the absorption, action and safety of oral mucosal disintegration agent are better than sellegran normal release, the dosage is 1. 25-2.50 mg/d. The dosage of resagiline The dosage is 1 mg once a day, taken in the morning. Use with caution in patients with gastric ulcer. Combination with 5-hydroxytryptamine reuptake inhibitors (SSRI) is prohibited.
f. 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 4 dosage forms according to the levodopa dose) are preferred, not only to improve the patient’s symptoms, but also to potentially 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 disorder, which is still controversial and needs to be further verified; in the middle and late stages of the disease, entacapone or tolcapone can be added to the treatment to further improve the symptoms when the efficacy of compound levodopa is reduced. 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. Side effects include diarrhea, headache, excessive sweating, dry mouth, elevated transaminases, abdominal pain, and yellowing of urine. Tolcapone may cause hepatic impairment and requires close monitoring of liver function, especially during the first 3 months after administration.
(2) 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 continue to strive to improve the motor symptoms of patients on the one hand; on the other hand, some motor complications and non-motor symptoms should be properly managed.
Treatment of motor complications
Motor complications (symptom fluctuations and dyskinesia) are common 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.
a. Treatment of symptom fluctuations: Symptom fluctuations mainly include end-dose deterioration and on/off phenomenon.
The treatment of end-of-dose deterioration is as follows
(1) not increasing the total daily dose of compounded levodopa, but appropriately increasing the number of daily doses and decreasing the dose per dose (provided that it is still effective in improving motor symptoms), or appropriately increasing the total daily dose (if the original dose is not large), with the same dose per dose and increasing the number of doses.
② Switching from regular release to controlled release to prolong the duration of action of levodopa is preferable to early end-of-dose deterioration, especially at night, and the dose should be increased by 20%-30% (US guidelines consider that the “off” period cannot be shortened, which is level C evidence, while UK NICE guidelines recommend it for late stage patients, but not as a first choice, level B evidence).
(iii) Add DR agonists with long half-lives, of which pramipexole and ropinirole are level B evidence, carte blanche and apomorphine are level C evidence, and bromocriptine does not shorten the “off” period and is level C. If a DR agonist has been used and the efficacy is reduced, try switching to another DR agonist.
④Add a COMT inhibitor that produces sustained DAergic stimulation of the striatum, with entocapone as Class A evidence and tolcapone as Class B evidence.
(v) Addition of an MAO-B inhibitor, of which resagiline is level A evidence and sellegran is level C evidence.
(vi) Avoid the effect of diet (containing protein) on levodopa absorption and passage through the blood-brain barrier; it is advisable to take the drug 1 h before or 1.5 h after meals; adjustment of the protein diet may be effective.
(vii) 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, and oral DR agonists can be used, or continuous infusion of levodopa methyl or ethyl ester or DR agonists (such as ergocalciferol, etc.) can be used by micropump.
b, treatment of isokinetic disorders: isokinetic disorders (AIMs), also known as movement disorders, including agent-peak isokinetic disorder, biphasic isokinetic disorder and dystonia.
The treatment of agent-peak isokinetic disorder is as follows: (1) reduce the dose of compound levodopa each time; (2) if the patient is using compound levodopa alone, reduce the dose appropriately and add DR agonist, or add COMT inhibitor; (3) add amantadine (level C evidence); (4) add atypical antipsychotics such as clozapine; (5) if using compound levodopa controlled-release, switch to normal-release to avoid the cumulative effects of controlled-release agents.
The management of biphasic dyskinesia (including initial and end-dose dyskinesia) is as follows: (1) if a compounded levodopa controlled-release agent is used, it should be switched to a regular-release agent, preferably with a water-based solvent, which can effectively alleviate initial dyskinesia; (2) the addition of a DR agonist with a long half-life or a COMT inhibitor with an extended levodopa plasma clearance half-life can alleviate end-dose dyskinesia and may also help improve initial dyskinesia. Continuous infusion of a DR agonist or levodopa methyl or ethyl ester by micropump can improve both ochronosis 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 dystonia such as adenosine A2A receptor antagonists that act 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 anisocoria. Surgical treatment is mainly DBS, which can be beneficial.
(3) 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.
3.Summary
There is no absolute fixed pattern of treatment for Parkinson’s disease, as symptoms may differ between patients and sensitivity to treatment may vary 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 be applicable to general rules, 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), and the presence of side effects. When applying the drug in clinical practice, you 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” periods, and whether there are side effects or complications), and combine your own treatment experience to follow the guidelines and reflect the principle of individualization in order to achieve more ideal treatment results.