Since its introduction in the 1960s, levodopa is considered to be the first drug to be highly effective in improving the clinical symptoms of Parkinson’s disease, with rapid onset of action and rapid improvement of the main motor symptoms: tremor, hyperkinesia, and tonicity. After more than 30 years of clinical use, levodopa therapy remains the “gold standard” of Parkinson’s disease treatment. However, after decades of use, it has become clear that long-term levodopa therapy is associated with many problems. Although levodopa therapy may improve clinical symptoms, the disease continues to progress, and the long-term complications of long-term levodopa therapy can increase the degree of disability in patients. How to prevent and delay the occurrence of long-term complications is a current clinical problem that needs to be addressed. (i) Long-term motor complications of levodopa therapy: Most patients with Parkinson’s disease who take levodopa for a long period of time (two compound preparations are available in China: Medopa, i.e., dobutamine, and Xanax, i.e., carzodopa controlled-release tablets) develop motor complications as well as psychiatric disorders, and these problems affect the greater efficacy of patients from levodopa therapy. Dyskinesia: This refers to involuntary movements associated with levodopa treatment. These include dose crestal dyskinesia, biphasic dyskinesia, off-phase dystonia, and myoclonus. Among them, dose peak heterokinesia is the most common, manifesting as choreiform movements, similar to tardive dyskinesia or dystonia, and mostly occurs when the drug plasma concentration is the highest and the clinical effect is the best. Biphasic isokinetic disorder is most often seen in patients with mid- to late-stage Parkinson’s disease. This movement disorder often occurs when levodopa plasma concentrations begin to rise as well as when they begin to fall. It does not usually occur at peak plasma concentrations. The dyskinesia is mostly seen in the lower extremities and is asymmetric. The incidence of dyskinesia increases with increasing duration of levodopa treatment. The exact incidence has been reported differently. In general, about 30-50% of patients treated with levodopa for more than 5 years will develop dyskinesia, and patients with early-onset Parkinson’s disease are more likely to develop it, and it is more severe. Patients generally cannot detect their dyskinesia and dystonia abnormalities, and only a minority of patients complain of dystonia. Symptom fluctuation: After 2 to 5 years of levodopa treatment, approximately 50% of patients begin to experience end-of-dose phenomenon: a shortening of the duration of the effect of a single dose of levodopa and an exacerbation of symptoms before the next dose of levodopa; the “switch” phenomenon: unpredictable improvement (on) and exacerbation (off) of symptoms. The “on” phase is characterized by a good response to the drug and may be accompanied by dystonia. The severity of symptoms during the “off” phase correlates with the severity of the disease itself. The incidence of symptom fluctuations has been reported to vary from family to family. However, as the disease progresses and the duration of treatment increases, the onset of drug action is progressively slower (kick-in phenomenon). The pathophysiological mechanisms of dyskinesia are not known. It was once thought to be related to the neurotoxicity of levodopa. However, to date there is no direct evidence of a toxic effect of levodopa in humans or animal models of Parkinson’s disease. It is now believed that two main factors are associated with motor complications: 1) progression of Parkinson’s disease. As more dopamine neurons are reduced, there are fewer dopaminergic nerve terminals in the striatum, allowing for further reduction in dopamine storage and regulation; and (ii) pulse-like dopamine stimulation. Under normal conditions the dopaminergic system stimulates striatal dopamine less frequently, with high-frequency stimulation occurring during planned exercise. Intersynaptic dopamine is modulated by the dopaminergic system. In the case of Parkinson’s disease, exogenous levodopa is stored by the uptake of residual nerve endings. As the disease progresses, dopamine receptors are directly stimulated with dopamine and the intensity of stimulation is directly related to plasma levodopa concentration. Motor complications arise due to prolonged exogenous supplementation with short plasma half-life drugs such as levodopa that produce pulse-like dopaminergic stimulation. Some evidence suggests that pulse-like dopaminergic stimulation leading to secondary genetic alterations and altered projection patterns of nerve fibers play an important role in the development of movement disorders. Because the latter can be intervened by the choice of drug type as well as the method of administration, pulse-like stimulation of dopamine receptors has become a focus of research for many scholars… (ii) Continuous dopaminergic stimulation As mentioned above, the distant motor complications of levodopa are associated with further reduction of dopamine neurons and pulse-like stimulation of striatal dopamine receptors. It is then essential to adopt continuous dopaminergic stimulation as much as possible to reduce pulse-like stimulation and reduce the chance of motor complications in future treatment. Studies have found that continuous intravenous infusion or continuous enteral infusion of levodopa improves motor fluctuations, increases “on” time, and reduces allodynia. Continuous intravenous or subcutaneous infusion of apomorphine also reduces motor complications, which supports the theory of the importance of continuous dopaminergic stimulation in a murine model of PD made with 6-OHDA, which found that long-term administration of levodopa resulted in end-of-dose like manifestations and motor deficits in a murine model of PD. Because of the large difference between rodents and humans and the relatively large amount of levodopa kept in the PD mouse model, some scholars have studied the MPTP-manufactured PD monkey model. Although the pathological changes were limited to the site of destruction, the PD monkey model responded to drug treatment similarly to PD patients, so it is often used to evaluate the effect of drugs. the PD monkey model showed choreiform movements and dystonia rapidly after levodopa administration, similar to the dyskinesia in PD patients, but appeared earlier than in PD patients. This suggests that continuous dopaminergic stimulation is important to avoid dystonia. Unlike levodopa, the incidence of dystonia was significantly reduced with long-term use of long half-life dopamine agonists such as bromocriptine, lopinilol, and cartegolide. Whereas repeated subcutaneous infusions of D1 and D2 receptor agonists with short half-lives resulted in a monkey model of PD that was more prone to dystonia, sustained subcutaneous infusions of dopamine receptor agonists with short half-lives resulted in a lesser degree of drug-induced involuntary movements. All of the above studies support the importance of continuous dopaminergic stimulation. (iii) Management of motor complications But to date, levodopa remains the most effective drug for the treatment of Parkinson’s disease, despite the limitations of distant complications. How to take levodopa, obtain relatively continuous dopaminergic stimulation, and reduce the incidence of drug-induced dyskinesia are current issues that need to be addressed. The following measures can be taken for those who experience motor fluctuations or dyskinesia: (1) find the crossover point: to achieve better efficacy without causing dyskinesia; (2) increase the number of doses, reduce each dose, and keep the daily dose unchanged; the drawback of this method is poor compliance; (3) switch to controlled-release dosage forms; our previous studies have shown that switching to restorative controlled-release tablets has improved motor fluctuations and increased the “on period” time. However, the disadvantage is that to achieve the same efficacy, the dose needs to be increased by about 26%, which increases the patient’s burden; ④Adding other drugs with relatively long half-lives, such as dopamine agonists, to provide relatively continuous dopaminergic stimulation, while levodopa dosage can be reduced; ⑤Adding catechol-oxy-methyltransferase inhibitor (COMT-I) to increase the bioavailability of levodopa, which has a The half-life of levodopa is 1~1.5 hours, and only about 1% of levodopa can enter the brain after a single dose. After adding peripheral decarboxylase inhibitor, the amount of levodopa entering the brain rises to 5~10%, in which case COMT becomes the main peripheral metabolic pathway of levodopa. Studies have found that taking levodopa in combination with a COMT inhibitor provides smooth plasma levodopa levels and reduces the risk of exercise complications. Surgical treatments such as pallidum destruction, pallidum bulb, and deep hypothalamic electrical stimulation therapy can alleviate movement disorders. Although effective in relieving symptoms, none of these methods can obtain more effective symptom improvement than levodopa, and they are expensive and involve the risk of surgery. Therefore, early measures to prevent the onset of movement disorders are essential. Several investigators have explored the use of long-acting levodopa preparations, including Xanax controlled-release tablets and Medopar extended-release tablets (Madopar HBS), in patients with new-onset Parkinson’s disease, but the results all showed no difference in the incidence and timing of motor complications between the groups taking levodopa regular tablets and the long-acting preparations. Plasma drug concentration studies showed that the pharmacokinetics of the regular and extended-release formulations were similar, except that the peak concentrations were slightly lower for the extended-release tablets. In contrast, the addition of entocapone resulted in a lower dosage of levodopa, while pharmacokinetic studies showed to provide more stable levodopa plasma concentrations, presumably possibly preventing the development of long-term motor complications, but clinical evidence is lacking. Dopamine agonists are a class of drugs that directly stimulate dopamine receptors and whose molecular structure may be partially similar to that of dopamine. The advantages are: (i) direct action on the receptor; (ii) no competitive absorption of circulating plasma amino acids with the agonist, and transport to the brain; (iii) long half-life of the listed agonist, providing continuous stimulation; and (iv) no oxidative metabolism and no production of free radicals. Several studies suggest that the use of dopamine receptor agonists at the outset may reduce the incidence of exercise complications. One study showed that the incidence of motor fluctuations was 6.1% after one year of treatment and 16.3% after 3 years in the pergolide group, compared with 18.5% after one year of treatment and 32.9% after 3 years in the levodopa group. The incidence of isokinetic disorder was significantly lower in those who started treatment with Ropinirole, another non-ergot agonist, regardless of whether levodopa was added (20%) than in those who started treatment with levodopa (45%). Pramipexole is another non-ergot D2 and D3 agonist. A comparative study (2-year, double-blind randomized) showed that the incidence of motor fluctuations at trial endpoint was 28% in the Pramipexole group and 51% in the levodopa group; the incidence of isokinetic disorder was 10% in the Pramipexole group and 31% in the levodopa group. The mechanism for the reduction of complications with dopamine agonists may be that the long-acting agonists provide sustained dopaminergic stimulation. As mentioned above, motor complications in patients with Parkinson’s disease are due to two factors: progression of the disease and the limited availability of levodopa therapy. In addition, motor complications are more likely to occur at a younger age of onset than at a higher age of onset. There are several strategies that can be used clinically to stop and delay the onset of motor complications, improve the quality of life of patients, and reduce the degree of disability. The main strategies include: slowing the process of dopaminergic apoptosis, i.e., neuroprotective therapy; delaying the initiation of levodopa in patients under 65 to 70 years of age; using relatively low doses of levodopa; and using longer-acting drugs to produce sustained dopaminergic stimulation. The use of a dopamine agonist or compounded levodopa (medroxyprogesterone or xylazine) plus cortane first may play a more important role in these strategies.