What are the side effects of levodopa/carbidopa (L-dopa) in Parkinson's disease treatment?

From the Guidelines

Levodopa/carbidopa therapy for Parkinson's disease is associated with several side effects, including nausea, vomiting, abdominal pain, dyspepsia, constipation, weight decrease, dry mouth, diarrhea, anorexia, and GI disorders, as well as metabolic effects such as hyperhomocysteinemia and changes in lipid and carbohydrate metabolism 1. The most frequent immediate side effects of levodopa/carbidopa include:

• Nausea and vomiting
• Abdominal pain and dyspepsia
• Constipation and diarrhea
• Weight decrease and anorexia
• Dry mouth and GI disorders These side effects can be managed by taking the medication with food, although this may slightly reduce absorption. With long-term use, more concerning side effects often develop, including:
• Motor fluctuations, such as "wearing-off" of medication effectiveness
• Dyskinesias, or involuntary movements, that typically occur when levodopa levels peak
• Non-motor side effects, such as vivid dreams, hallucinations, confusion, and impulse control disorders like gambling or hypersexuality These psychiatric effects result from dopamine's influence on brain regions beyond those controlling movement. Additionally, levodopa/carbidopa has been found to induce metabolic effects, including:
• Hyperhomocysteinemia, which may be associated with cardiovascular diseases, dementia, and depression
• Changes in lipid and carbohydrate metabolism, including reduction in muscle glucose uptake and increase in plasma free fatty acids, glucose, growth hormone, and cortisol
• Weight loss, particularly in women, and reduction in body fat mass It is essential for patients to report any concerning side effects to their healthcare provider, as dosage adjustments or additional medications may help manage these complications while maintaining effective symptom control 1.

From the FDA Drug Label

ADVERSE REACTIONS The most common adverse reactions reported with carbidopa and levodopa therapy have included dyskinesias, such as choreiform, dystonic, and other involuntary movements and nausea. The following other adverse reactions have been reported with carbidopa and levodopa: Body as a Whole: chest pain, asthenia Cardiovascular: cardiac irregularities, hypotension, orthostatic effects including orthostatic hypotension, hypertension, syncope, phlebitis, palpitation. Gastrointestinal: dark saliva, gastrointestinal bleeding, development of duodenal ulcer, anorexia, vomiting, diarrhea, constipation, dyspepsia, dry mouth, taste alterations Hematologic: agranulocytosis, hemolytic and nonhemolytic anemia, thrombocytopenia, leukopenia. Hypersensitivity: angioedema, urticaria, pruritus, Henoch-Schönlein purpura, bullous lesions (including pemphigus-like reactions). Musculoskeletal: back pain, shoulder pain, muscle cramps Nervous System/Psychiatric: psychotic episodes including delusions, hallucinations, and paranoid ideation, bradykinetic episodes (“on-off" phenomenon), confusion, agitation, dizziness, somnolence, dream abnormalities including nightmares, insomnia, paresthesia, headache, depression with or without development of suicidal tendencies, dementia, pathological gambling, increased libido including hypersexuality, impulse control symptoms. Convulsions also have occurred; however, a causal relationship with carbidopa and levodopa has not been established. Respiratory: dyspnea, upper respiratory infection. Skin: rash, increased sweating, alopecia, dark sweat. Urogenital: urinary tract infection, urinary frequency, dark urine Laboratory Tests: decreased hemoglobin and hematocrit; abnormalities in alkaline phosphatase, SGOT (AST), SGPT (ALT), LDH, bilirubin, BUN, Coombs test; elevated serum glucose; white blood cells, bacteria, and blood in the urine Other adverse reactions that have been reported with levodopa alone and with various carbidopa and levodopa formulations, and may occur with carbidopa and levodopa orally disintegrating tablets are: Body as a Whole: abdominal pain and distress, fatigue. Cardiovascular: myocardial infarction Gastrointestinal: gastrointestinal pain, dysphagia, sialorrhea, flatulence, bruxism, burning sensation of the tongue, heartburn, hiccups. Metabolic: edema, weight gain, weight loss. Musculoskeletal: leg pain Nervous System/Psychiatric: ataxia, extrapyramidal disorder, falling, anxiety, gait abnormalities, nervousness, decreased mental acuity, memory impairment, disorientation, euphoria, blepharospasm (which may be taken as an early sign of excess dosage; consideration of dosage reduction may be made at this time), trismus, increased tremor, numbness, muscle twitching, activation of latent Horner’s syndrome, peripheral neuropathy. Respiratory: pharyngeal pain, cough. Skin: malignant melanoma, flushing. Special Senses: oculogyric crises, diplopia, blurred vision, dilated pupils. Urogenital: urinary retention, urinary incontinence, priapism. Miscellaneous: bizarre breathing patterns, faintness, hoarseness, malaise, hot flashes, sense of stimulation Laboratory Tests: decreased white blood cell count and serum potassium; increased serum creatinine and uric acid; protein and glucose in urine.

The side effects of levodopa/carbidopa in Parkinson's disease treatment include:

• Common adverse reactions: dyskinesias and nausea
• Body as a Whole: chest pain, asthenia, abdominal pain and distress, fatigue
• Cardiovascular: cardiac irregularities, hypotension, orthostatic effects, hypertension, syncope, phlebitis, palpitation, myocardial infarction
• Gastrointestinal: dark saliva, gastrointestinal bleeding, development of duodenal ulcer, anorexia, vomiting, diarrhea, constipation, dyspepsia, dry mouth, taste alterations, gastrointestinal pain, dysphagia, sialorrhea, flatulence, bruxism, burning sensation of the tongue, heartburn, hiccups
• Hematologic: agranulocytosis, hemolytic and nonhemolytic anemia, thrombocytopenia, leukopenia
• Hypersensitivity: angioedema, urticaria, pruritus, Henoch-Schönlein purpura, bullous lesions
• Musculoskeletal: back pain, shoulder pain, muscle cramps, leg pain
• Nervous System/Psychiatric: psychotic episodes, bradykinetic episodes, confusion, agitation, dizziness, somnolence, dream abnormalities, insomnia, paresthesia, headache, depression, dementia, pathological gambling, increased libido, impulse control symptoms, ataxia, extrapyramidal disorder, falling, anxiety, gait abnormalities, nervousness, decreased mental acuity, memory impairment, disorientation, euphoria, blepharospasm, trismus, increased tremor, numbness, muscle twitching, activation of latent Horner’s syndrome, peripheral neuropathy
• Respiratory: dyspnea, upper respiratory infection, pharyngeal pain, cough
• Skin: rash, increased sweating, alopecia, dark sweat, malignant melanoma, flushing
• Urogenital: urinary tract infection, urinary frequency, dark urine, urinary retention, urinary incontinence, priapism
• Laboratory Tests: decreased hemoglobin and hematocrit, abnormalities in alkaline phosphatase, SGOT, SGPT, LDH, bilirubin, BUN, Coombs test, elevated serum glucose, decreased white blood cell count and serum potassium, increased serum creatinine and uric acid, protein and glucose in urine 2

From the Research

Side Effects of Levodopa/Carbidopa

The combination of levodopa and carbidopa is a common treatment for Parkinson's disease. However, it can cause several side effects, including:

• Dyskinesia: abnormal involuntary movements 3, 4, 5, 6, 7
• Motor fluctuations: fluctuations in motor symptoms, such as "wearing off" or "on-off" effects 3, 4, 5, 6, 7
• Psychiatric problems: hallucinations, delusions, and other psychiatric symptoms 3, 4, 5
• Nausea and vomiting: due to the peripheral conversion of levodopa to dopamine 6
• Toxicity: increased doses of levodopa can lead to toxicity 5
• Loss of efficacy: levodopa may become less effective over time 5
• Frozen gait: a gait disturbance characterized by a inability to initiate or maintain walking 7

Management of Side Effects

Several strategies can be used to manage the side effects of levodopa/carbidopa, including:

• Adjusting the dose or frequency of levodopa/carbidopa 3, 4, 5
• Adding other medications, such as dopamine agonists or COMT inhibitors 3, 4, 6
• Using a combination of levodopa/carbidopa and entacapone, a COMT inhibitor 6
• Considering surgical options, such as pallidotomy or deep brain stimulation, for patients with severe motor fluctuations or dyskinesia 4