Neuropharmacology & Neurotherapeutics
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May. 19, 2023
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Since its introduction into clinical use for Parkinson disease more than half a century ago, levodopa, a precursor of dopamine, remains the gold standard. It is used in combination with carbidopa, and various preparations are being developed to enhance its bioavailability as well as improve its delivery for reducing complications due to plasma level fluctuations. This article reviews the pharmacology, clinical trials, and adverse effects of levodopa. Several movement disorders can occur as adverse effects of levodopa therapy, eg, choreoathetosis, dystonia, akathisia, myoclonus, tremor, and dyskinesias.
• Levodopa is a precursor for dopamine, and its anti–Parkinson disease effects are mediated by the synthesis of dopamine, which subsequently interacts with dopamine receptors.
• More than half a century after its introduction into clinical use, levodopa remains the gold standard for the treatment of Parkinson disease.
• To overcome the short half-life of levodopa, it is usually combined with the decarboxylase inhibitor, carbidopa, and various preparations are being developed to enhance its bioavailability as well as improve its delivery for reducing complications due to plasma level fluctuations.
• Several movement disorders can occur as adverse effects of levodopa therapy, eg, choreoathetosis, dystonia, akathisia, myoclonus, tremor, and dyskinesias.
• Levodopa-induced dyskinesias are problematic, and to prevent peak dose dyskinesias, levodopa concentrations should be steadily maintained in the therapeutic range.
Levodopa was demonstrated in nature, and a simplified manufacturing process was described in 1913 (16). Experimental studies in the 1950s showed that levodopa could reverse reserpine-induced akinesia in rabbits, but the biochemical basis of this action was not clear until Carlsson demonstrated that dopamine in the brain was depleted with reserpine and could be restored with levodopa (07). In 1961 Birkmayer and Hornykiewicz showed that intravenous dopa briefly improved symptoms in patients with Parkinson disease (03). Seven years later, Cotzias showed the effectiveness of levodopa for Parkinson disease by clinical trial (10). Since its introduction into the clinical use in the early 1970s, levodopa remains the single most effective treatment for Parkinson disease. Stable and controlled formulations that ensure clinical response need to be developed to reduce the undesirable effects that restrict its efficacy (40). More than half a century after its introduction into clinical practice, levodopa remains the gold standard for treatment of Parkinson disease.
Pharmacokinetics. Levodopa is a precursor for dopamine and is actively transported across the intestinal wall and the blood-brain barrier by a branched chain amino acid carrier. This is important because dopamine itself cannot cross the blood-brain barrier. It is taken up by the dopaminergic neurons and decarboxylated in the presynaptic terminal to form dopamine; this then replaces the dopamine lost in the degeneration of substantia nigra pars compacta. The major urinary metabolite of levodopa in humans appears to be dopamine and homovanillic acid. In a 24-hour urine specimen, homovanillic acid accounts for 13% to 42% of the ingested dose of levodopa. Because of the short plasma half-life of levodopa, there are marked fluctuations in plasma drug concentration, which may lead to fluctuations in the therapeutic response. Strategies to optimize levodopa pharmacokinetics include liquid preparations, controlled release formulations, and the use of inhibitors of levodopa metabolism (09). However, these efforts have been only partly successful so far.
Pharmacodynamics. It is generally recognized that the antiparkinsonian effects of levodopa are mediated by the synthesis of dopamine and its subsequent interaction with dopamine receptors. This concept is supported by clinical and experimental observations that dopamine receptor antagonist drugs block the antiparkinsonian effect of levodopa.
Pharmacokinetics of levodopa explains some of the problems that arise during chronic therapy, which may be due to irregular uptake variations in plasma concentrations, and new approaches to delivery and uptake of levodopa are likely to improve its anti-parkinsonian effect (23). Pharmacokinetic-pharmacodynamic modeling has been used to study the concentration effect relationship of levodopa in patients with Parkinson disease. The findings support the concept that reduced dopamine storage in the striatum is responsible for the occurrence of response fluctuations. There is some evidence that the reduced efficacy of the controlled release preparations, (formerly considered to be due lower bioavailability alone) also has a pharmacodynamic basis. A pharmacokinetic-pharmacodynamic model for duodenal levodopa infusion has shown that in an unmedicated subject, it takes approximately 51.4 minutes until the peak levodopa effect is reached after a bolus dose (54).
Preparations of levodopa. Levodopa is available as immediate-release tablets, disintegrating tablets, controlled-release tablets, and extended-release capsules. Levodopa is so extensively metabolized in the periphery that only 1% of the ingested drug reaches the central nervous system. To overcome this, levodopa is often combined with a decarboxylase inhibitor. The most used of these decarboxylase inhibitors is carbidopa combined with levodopa. In most countries outside the United States, levodopa is sold in combination with a peripheral decarboxylase inhibitor benserazide. A controlled release version of this is also available.
Efficacy of levodopa is significantly reduced due to metabolism, subsequent low bioavailability, and irregular fluctuations in its plasma levels. Considerable progress has been made to improve the delivery of levodopa to enhance its bioavailability and reduce plasma fluctuations as well as motor complications experienced by patients that can result from pulsatile stimulation of the striatal dopamine receptors (33). Products under development or recently released include intestinal infusion, sustained-release microtablets, gastric-retentive formulations, and methods for delivery of the drug by inhalation or subcutaneous infusion (24). Transdermal levodopa micropumps are also being investigated for efficacy (41).
Sustained/extended release preparations. Controlled studies have shown that immediate release and sustained release levodopa and carbidopa both maintain a similar level of control in Parkinson disease after 5 years, as compared with baseline.
IPX066 (levodopa and carbidopa), an extended-release carbidopa-levodopa formulation, is rapidly absorbed with onset of benefit like the immediate-release preparation, but it provides more sustained therapeutic levodopa levels and longer duration of clinical benefit. In various studies, levodopa and carbidopa improved symptoms in patients with both early and advanced Parkinson disease and led to significantly improved Unified Parkinson Disease Rating Scale scores and ON times, without troublesome dyskinesias as compared to other levodopa formulations (11). Phase 3 studies of IPX066 in patients with Parkinson disease have shown a significant reduction in OFF time compared with immediate-release carbidopa-levodopa and carbidopa-levodopa-entacapone; it is approved in the United States as Rytary and in the European Union as Numient (30).
Gel formulations for gastrointestinal administration. Intrajejunal infusion of a gel formulation of L-dopa/carbidopa is in clinical use in Europe, and its efficacy in controlling motor fluctuations has been shown in a randomized, controlled trial.
A systematic review of the various studies has shown that levodopa-carbidopa intestinal gel reduces OFF time, increases ON time without increasing troublesome dyskinesias, and improves quality of life in patients with Parkinson disease, but data evaluating long-term efficacy as well as safety are still limited (55). It is a useful treatment option in patients with severe motor fluctuations.
Preparations for pulmonary delivery. A levodopa-containing powder formulation for pulmonary delivery of levodopa has been developed through a process of micronization, along with a high-dose dry powder inhaler (Cyclops), for fast action and improving bioavailability in OFF periods of Parkinson disease (27). A randomized, double-blind, placebo-controlled, phase 3 trial showed that CVT-301 (Inbrija), a powder formation of levodopa for inhalation, can improve Unified Parkinson Disease Rating Scale motor scores of patients with Parkinson disease during OFF periods, with few severe or serious adverse events, but the long-term safety and efficacy need to be investigated in future studies (25). In December 2018, the U.S. Food and Drug Administration approved Inbrija for the intermittent treatment of OFF episodes in patients with Parkinson disease treated with carbidopa-levodopa. Although some pulmonary adverse events have been reported following inhalation of levodopa, these are mostly mild, and inhaled levodopa remains a useful rescue treatment of OFF episodes in Parkinson disease patients (46).
Pharmacogenetics. Response of motor symptoms of Parkinson disease is variable in individual patients, and different doses are required for control. Parkinson disease patients were genotyping for SV2C and SLC6A3 polymorphisms along with comedication, and demographic data for dosage prediction explain 23% of dose variation but needs to be validated by further studies (01).
Levodopa was introduced in practice before clinical trials were required for drug approval. Several clinical trials have been conducted, and some of these are for new formulations of levodopa to improve delivery or for disorders other than Parkinson disease.
Interim results of a phase I study of levodopa-carbidopa intestinal gel delivered continuously via percutaneous endoscopic gastrojejunostomy tube showed that it was generally well tolerated and produced meaningful clinical improvements (14). A 12-week, randomized, controlled, double-blind clinical trial has tested continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson disease (36). Results showed that this method of delivery of levodopa is a promising option for control of advanced disease with motor complications, and benefits were of a greater magnitude than those obtained with other medical therapies thus far. A prospective, observational study included patients with advanced, levodopa-responsive Parkinson disease with either 2 to 4 hours of “off” time or 2 hours of dyskinesia daily showed significant and clinically relevant improvements in measures of activities of daily living, quality of life, and a specific subset of nonmotor symptoms such as sleep/fatigue after treatment with levodopa-carbidopa intestinal gel (22).
In a randomized, delayed-start, double-blind, placebo-controlled, multicenter trial of levodopa in patients with early-stage Parkinson disease (LEAP) who did not yet require medication were randomized to either 40 weeks of treatment with levodopa/carbidopa 100/25 mg TID, including 2 weeks of dose escalation, or to 40 weeks of placebo to determine possible disease-modifying effects of early levodopa therapy. Among patients with early Parkinson disease who were evaluated over the course of 80 weeks, treatment with levodopa-carbidopa 100/25 mg 3 times a day had no disease-modifying effect (52). The LEAP trial failed to confirm the hypothesis of levodopa as a potential disease-modifying intervention. Because of the heterogeneity of Parkinson disease, differences in underlying disease mechanisms, genotype, and other factors such as brain imaging and inflammatory biomarkers should be considered in future trials (05).
A phase 4 randomized trial was ongoing as of March 2019 to assess whether long-acting levodopa taken at bedtime improves obstructive sleep apnea in patients with Parkinson disease as compared with placebo (NCT03111485). The primary outcome will be the apnea-hypopnea index change from baseline to on-medication, comparing active medication to placebo. Other outcomes will include various polysomnographic parameters.
A 12-month, phase 3 safety and efficacy study of Inbrija (CVT-301), a levodopa inhalation powder, in Parkinson disease patients with OFF episodes met its primary endpoint, with patients showing a statistically significant improvement in motor function as measured by a reduction in Unified Parkinson Disease Rating Scale scores (NCT02242487).
Levodopa is indicated in the treatment of idiopathic Parkinson disease, postencephalitic parkinsonism, and parkinsonism that may follow injury to the nervous system by carbon monoxide intoxication. It is indicated in those elderly patients believed to have developed parkinsonism in association with cerebral arteriosclerosis.
(1) Dopa-responsive dystonia.
(2) Rapid eye movement sleep behavior disorder preceding Parkinson disease.
(3) According to a systematic review of controlled clinical trials, levodopa is effective for the short-term treatment of restless legs syndrome (45).
(5) As an adjunct therapy for the treatment of spastic quadriplegic cerebral palsy.
(6) Levodopa, in combination with physiotherapy, has been used to enhance motor recovery in patients with chronic stroke.
(7) Levodopa combined with behavioral contingency management is effective for treatment of cocaine dependence disorder (44).
(8) Available evidence supports the traditional view that dysphagia of Parkinson disease is responsive to levodopa (50).
(9) Parkinsonism developing after radiation and chemotherapy following surgery of malignant brain tumors in children is resistant to levodopa (29).
(10) Results of a retrospective study show that levodopa improves central visual acuity in non-arteritic anterior ischemic optic neuropathy and may promote neuroprotection of the maculopapular retinal ganglion cell fibers (28).
(11) A retrospective study has shown that age-related macular degeneration occurs significantly later in life in patients with a levodopa prescription as compared to those without a levodopa prescription (06). The protective effect of levodopa is plausible because GPR143, a G protein-coupled receptor that is exclusively expressed by melanocytes and retinal pigment epithelium, is the only known receptor for levodopa and is a promising target to combat age-related macular degeneration. A phase 2 clinical trial will assess the safety and tolerability of carbidopa-levodopa in patients with neovascular age-related macular degeneration who are already on treatment with anti-VEGF intraocular injections (NCT03023059).
Levodopa is contraindicated in patients with a known hypersensitivity to the drug and in those with narrow angle glaucoma. It should not be used in patients with skin lesions suspected to be melanoma, as it may activate a malignant melanoma. Monoamine oxidase inhibitors and levodopa should not be used concomitantly. Warnings and precautions are as listed in the Physicians’ Desk Reference.
The levodopa challenge test (LCT) is a reliable assessment for diagnosis of de novo Parkinson disease and determining response to levodopa therapy. The patient receives a 250 mg dose of levodopa. Motor assessments at baseline using the motor portion (part III) of the Unified Parkinson Disease Rating Scale is done before and 1 hour after drug administration. The levodopa challenge test is an easy and generally safe procedure. The results of the test have significant implications in the management of patients, from preoperative evaluation for deep brain stimulation to providing guidance for medication adjustments for motor or nonmotor fluctuations and dyskinesias (42).
The goal of treatment is the control of parkinsonian symptoms, and treatment is continued on a long-term basis. Initially, levodopa is taken 3 or 4 times a day, and it reduces the signs and symptoms of the disease and may return the patient to full function. With continued treatment, fluctuations in motor response may appear, and the patient may notice a "wearing off" effect at the end of each dose cycle. Later, the response may become less predictable in relation to the dose, and dyskinesias may appear. The patient may go into an OFF-ON state, fluctuating between full functional recovery and complete disability. Negative response to levodopa and levodopa-induced dyskinesias accentuate fluctuations. Besides well-known motor and nonmotor symptoms of Parkinson disease, other manifestations can respond to levodopa therapy. One example is stridor due to bilateral vocal cord muscle dysfunction that may be related to nigrostriatal dopaminergic dysfunction in patients with Parkinson disease, and levodopa uptitration may be beneficial in relieving stridor and prevention of respiratory failure (51).
The issue of long-term effects of levodopa therapy, beneficial versus adverse, and the mechanism of these is not yet settled. No disease-modifying effect of levodopa has been demonstrated in the long-term follow-up of patients with Parkinson disease, although some studies have shown slowing of the disease progression.
Long-term levodopa/dopa decarboxylase inhibitor application with concomitant inhibition of both catechol-O-methyltransferase and monoamine oxidase-B supports a more continuous dopamine substitution, which ameliorates fluctuations of motor behavior (31).
The dose of levodopa should be tailored to the needs of an individual patient. Reduction of drug dose or drug discontinuation should be carried out if there are adverse effects of the drug.
The initial dose is 0.5 mg to 1 g daily divided into 2 or more doses. It is given with meals. The dose should be titrated according to clinical response and tolerability of an individual patient but should not exceed 8 g per day.
Pediatrics. Safety and efficacy in pediatric patients have not been established.
Pregnancy. The safety of levodopa in women who are or may become pregnant has not been established. Levodopa crosses the placenta and can be metabolized by the fetus. Doses of greater than 200 mg/kg per day have an adverse effect on the postnatal growth of the offspring.
Levodopa can decrease serum prolactin during lactation but does not affect the ability of a mother to breastfeed with established lactation. The effect of long-term use of levodopa on breastfeeding has not been adequately studied, although some mothers on low doses of levodopa and carbidopa are able to successfully breastfeed their infants without apparent harm.
Levodopa interacts negatively with nonselective monoamine oxidase (MAO) inhibitors, which should be discontinued before starting levodopa therapy. However, levodopa is compatible with selective MAO-B inhibitors. Long-term treatment with levodopa affects the interaction among vitamin B12, folate, and homocysteine leading to an increase in homocysteine levels and deficiencies of vitamin B12 and folate.
Levodopa infusion may improve some aspects of motor performance while worsening others. Different components of the motor cortico-striato-pallido-thalamo-cortical loop and related pathways may underlie motor improvement and adverse motor effects of levodopa therapy for Parkinson disease. Clinically, levodopa improves the symptoms of the disease and delays its progression. Although levodopa therapy may induce a decline in imaging measures of dopaminergic function as compared to placebo or dopamine agonists, indicating neurotoxic effects, a study of nigral neuronal count and Lewy body density in Parkinson disease showed that use of levodopa during lifetime does not enhance progression of Parkinson disease pathology (39). Neurologic complications are considered to be due to the nonphysiological replacement of dopamine. Various complications of levodopa therapy are discussed in the following paragraphs.
Movement disorders. The following types of movement disorders have been reported (18):
• Choreoathetosis. This is the most common.
Continuous levodopa infusion with steady plasma levels of the drug is associated with reduced motor complications compared with the standard oral formulation of the drug that is associated with fluctuation of plasma levels, particularly low levels, in patients with advanced Parkinson disease. Continuous intraduodenal infusion of the levodopa/carbidopa enteral gel as monotherapy is safe and clinically superior to several individually optimized combinations of conventional oral and subcutaneous medications in patients with motor fluctuations. A retrospective, long-term follow-up analysis of the clinical experience with application of levodopa/carbidopa-gel suspension directly in the duodenum showed that a continuous delivery by a portable pump resulted in smoother plasma concentrations of levodopa, whereas the daily dose of levodopa decreased by 5% (34). Continuous jejunal levodopa infusion is an effective and feasible alternative treatment option for patients with advanced Parkinson disease, although there may be technical problems with the device (12).
Findings of PET studies suggest that dissociation between cerebral blood flow and cerebral metabolism is a distinctive feature of levodopa treatment and may be especially pronounced in patients with levodopa-induced dyskinesia (17).Chronic levodopa treatment leads to the development of microvascular changes such as angiogenesis, which can increase cerebral blood flow as well as enhance transport of the drug across the blood-brain barrier, but more research is needed to determine whether the degree of flow-metabolism dissociation seen in Parkinson disease patients is predictive of the subsequent development of levodopa-induced dyskinesias (20).
Peripheral side effects. These include nausea, vomiting, and postural hypotension.
Central side effects. These include visual hallucinations, psychoses, and disturbed sleep with vivid dreams. The rare complication of disordered respiration is described as a levodopa-induced dyskinesia, but irregular breathing patterns may be due to the effect of levodopa on the central control of respiration.
Levodopa withdrawal. A neuroleptic malignant-like syndrome (fever, akinetic crisis, rigidity, autonomic disturbances) has been reported following withdrawal of levodopa. This condition has been termed the parkinsonism hyperpyrexia syndrome. Withdrawal is more likely to precipitate a neuroleptic malignant-like syndrome when the patient is receiving concomitant neuroleptic therapy for psychiatric problems. Management includes replacing levodopa at the prior doses and aggressive supportive care in an intensive care unit.
Wearing-off. This is a complication of long-term levodopa therapy and is defined as re-emergence of symptoms of Parkinson disease before the next scheduled levodopa dose. It may require modification of the levodopa dose, switching to another levodopa formulation, and adjunct therapies, such as catechol-O-methyltransferase inhibitors and monoamine oxidase-B inhibitors (37).
Dopaminergic dysregulation syndrome. This syndrome can occur in patients with Parkinson disease due to long-term exposure to dopamine replacement therapy and is characterized by self-control problems such as addiction to medication, gambling, or sexual behavior. An experimental study in rats has shown that levodopa treatment restores the decreased spine density in spiny neurons in nucleus accumbens, which is caused by dopamine denervation, but can lead to the development of dyskinesia, and enlargement of the spine may be involved in dopaminergic dysregulation syndrome (15). A systematic review of literature revealed 98 cases of dopamine dysregulation syndrome that met substance use disorder criteria of DSM-5 (53). Past history showed substance disorder in 15.3% and psychiatric disorder in 10.2% of cases. Common comorbid conditions included impulse control disorders in 61%, psychosis in 32%, and panic attacks in 14%. Despite various management strategies, only 56% of cases were resolved. The authors of the study emphasized the importance of early detection of dopaminergic dysregulation disorder.
Progression of neurodegeneration in Parkinson disease. There is a suspicion that long-term use of levodopa may accelerate neurodegeneration in Parkinson disease. Levodopa can induce degeneration of dopaminergic neurons in cultures, but there is no conclusive evidence for neurotoxicity of levodopa in vivo. Deterioration in Parkinson disease patients may be due to natural progression of the disease and not due to levodopa. In the absence of prospective and properly controlled studies with unbiased counting, the issue of the neurotoxicity of levodopa has not been fully resolved and it is recommended that levodopa use should continue, but the lowest dose that provides clinical control of symptoms should be employed (35).
See also the Physicians’ Desk Reference.
Management of adverse effects. Levodopa-induced dyskinesias are problematic.
Levodopa-induced dyskinesias. To prevent peak dose dyskinesias, levodopa concentrations should be maintained in the therapeutic range, but below the dyskinesia threshold. According to the finding of an exploratory trial, levodopa in doses slowly titrated to 1000 mg/day could be useful in improving levodopa-induced dyskinesias (48). A metaanalysis of various studies has shown that adjuvant therapy such as dopamine agonists reduces off-time and levodopa dose and improves United Parkinson Disease Rating Scale scores in patients who develop motor complications on levodopa therapy, but this may be at the expense of increased dyskinesia and numerous other side effects (49). Safinamide, a monoamine oxidase-B inhibitor, blocks the enzyme that breaks down dopamine, thereby helping to restore dopamine levels in the brain and improving the patient's symptoms. In a double-blind, placebo-controlled study of Parkinson disease patients with motor fluctuations, safinamide increased ON time without increasing dyskinesia (04). It is approved in Europe as add-on therapy to a stable dose of levodopa alone or in combination with other therapies for mid-to late-stage Parkinson disease with fluctuations. Bilateral subthalamic nucleus deep brain stimulation attenuates levodopa-induced dyskinesia in patients with Parkinson disease without having to reduce the drug dosage (19).
Modified preparations of levodopa such as controlled release preparations and liquid levodopa, catecholamine-O-methyltransferase inhibitors, and dopamine agonists have been used in the prevention and treatment of motor complications.
A randomized, double-blind, placebo-controlled clinical trial has shown that extended release amantadine (ADS-5102), 274 mg at bedtime, may be an effective treatment for levodopa-induced dyskinesia (38). The FDA has approved an extended-release amantadine formulation that improved dyskinesia and OFF states in a once-daily evening dose in clinical trials, which provides higher as well as more continuous amantadine plasma bioavailability than conventional immediate-release formulations requiring 3 daily doses (32).
Serotonergic system and mGluR5 glutamate receptors are involved in complex molecular mechanisms that sustain levodopa-induced dyskinesias. Partial 5-HT1A/5-HT1B receptor agonist eltoprazine and mGluR5 negative allosteric modulator dipraglurant have shown encouraging results in phase 2 trials but large phase 3 trials are needed to confirm these results (08).
Deep brain stimulation of the subthalamic nucleus is effective in treating levodopa-induced dyskinesias (56). Repetitive transcranial magnetic stimulation over the cerebellum as continuous theta burst stimulation has an antidyskinetic effect in Parkinson disease patients with levodopa-induced dyskinesia (21). Strategies of continuous dopaminergic stimulation appear to be promising for preventing or ameliorating levodopa-induced dyskinesias (43).
Levodopa-induced psychoses. These may be treated with clozapine. If reduction of levodopa dose or alternative mode of delivery does not resolve neuropsychiatric symptoms, use of nondopaminergic agents and deep brain stimulation may enable control of symptoms of Parkinson disease with less risk of behavioral disorders (02).
Dopaminergic dysregulation syndrome. The first step in the management of dopaminergic dysregulation syndrome is levodopa dosage reduction, and symptoms may resolve. Some behavioral problems may respond to psychotherapy and social support. Antipsychotic drugs may be required in some cases with psychosis, aggression, compulsive gambling, or hypersexuality. Dopaminergic dysregulation syndrome has been treated successfully with valproic acid (13). Deep brain stimulation of the subthalamic region has been used for the treatment of dopaminergic treatment abuse in Parkinson disease (26).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
K K Jain MD†
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.See Profile
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