How long does it take for a patient to see the benefits in symptoms from starting carbidopa/levodopa?

Comment by InpharmD Researcher

Carbidopa/levodopa is available in multiple dosage forms: immediate-release tablets, orally disintegrating tablets, oral suspension, extended-release tablets, and extended-release capsules. Immediate-release formulations generally exhibit an onset of action within approximately 20 to 50 minutes, whereas extended-release formulations have a typical onset around 50 minutes. Absorption and onset of activity may be delayed by certain factors, including gastric acidity and the consumption of high-protein foods near the time of dosing. Therefore, administration is generally recommended 1 to 2 hours prior to meals. When administered via enteral feeding tubes (e.g., gastrostomy tubes), carbidopa/levodopa is often delivered as an initial dose over 10 to 30 minutes followed by continuous infusion over a 16-hour period. Maximal clinical effect is usually observed 2 to 3 hours into the infusion. While some patients may exhibit a relatively rapid response to treatment, it may take a few weeks before full benefits are observed. Many patients develop reduced responsiveness over time and require dose escalation titrated to clinical response.

carbidopa/levodopa + onset

Background

A 2021 systematic review evaluates the durability of benefit over time with levodopa/carbidopa intestinal gel (LCIG) in advanced Parkinson’s disease, focusing specifically on how long reductions in daily “off”-time are sustained. Across 27 included studies with follow-up durations ranging from 12 to 120 months, LCIG demonstrated a rapid onset of benefit, with meaningful reductions in “off”-time evident within 3 months of initiation and consistently maintained thereafter. Short- to intermediate-term follow-up (3–6 months) showed mean relative reductions in “off”-time of approximately 47–82%, indicating early and robust efficacy. Importantly, this effect was durable over the long term: among studies with follow-up of ≥24 months, all reported statistically significant reductions in “off”-time at study end, with reductions generally ranging from 38–83% from baseline. In the longest observational horizons, extending to 3–5 years, available data continued to show substantial and sustained benefit, with “off”-time reductions of up to 83%, without evidence of systematic waning of effect. Overall, the review concludes that LCIG provides a long-lasting therapeutic effect, maintaining clinically meaningful reductions in “off”-time for multiple years following initiation, rather than representing a transient improvement. [1]

References: [1] Antonini A, Odin P, Pahwa R, et al. The Long-Term Impact of Levodopa/Carbidopa Intestinal Gel on 'Off'-time in Patients with Advanced Parkinson's Disease: A Systematic Review. Adv Ther. 2021;38(6):2854-2890. doi:10.1007/s12325-021-01747-1
Relevant Prescribing Information

DOSAGE AND ADMINISTRATION [2]
The optimum daily dosage of carbidopa and levodopa tablets must be determined by careful titration in each patient. Carbidopa and levodopa tablets are available in a 1:4 ratio of carbidopa to levodopa (25 mg/100 mg) as well as 1:10 ratio (25 mg/250 mg and 10 mg/100 mg). Tablets of the two ratios may be given separately or combined as needed to provide the optimum dosage. [2]
Dosage is best initiated with one tablet of carbidopa and levodopa tablets 25 mg/100 mg three times a day. This dosage schedule provides 75 mg of carbidopa per day. Dosage may be increased by one tablet every day or every other day, as necessary, until a dosage of eight tablets of carbidopa and levodopa tablets 25 mg/100 mg a day is reached. [2]

DOSAGE AND ADMINISTRATION [3]
DUOPA is administered over a 16-hour infusion period. The daily dose is determined by
individualized patient titration and composed of: A Morning Dose A Continuous Dose Extra Doses
The maximum recommended daily dose of DUOPA is 2000 mg of the levodopa
component (i.e., one cassette per day) administered over 16 hours. At the end of the
daily 16-hour infusion, patients will disconnect the pump from the PEG-J and take their
night-time dose of oral immediate-release carbidopa-levodopa tablets.
Treatment with DUOPA is initiated in 3 steps:
1. Conversion of patients to oral immediate-release carbidopa-levodopa tablets in
preparation for DUOPA treatment.
2. Calculation and administration of the DUOPA starting dose (Morning Dose and
Continuous Dose) for Day 1.
3. Titration of the dose as needed based on individual clinical response and tolerability.

References: [2] Carbidopa and Levodopa tablet. Prescribing information. Dr. Reddy's Laboratories Inc. 2025
[3] Carbidopa/Levodopa Suspension (DUOPA). Prescribing information. AbbVie Inc. 2025
Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

How long does it take for a patient to see the benefits in symptoms from starting carbidopa/levodopa?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-4 for your response.

Population Pharmacodynamics of IPX066: An Oral Extended‐Release Capsule Formulation of Carbidopa–Levodopa, and Immediate‐Release Carbidopa–Levodopa in Patients With Advanced Parkinson’s Disease
Design

Open-label, randomized, single- and multiple-dose, crossover study

N= 27
Objective To describe the motor effects of levodopa in patients with advanced idiopathic Parkinson’s disease treated with immediate-release carbidopa–levodopa or an extended-release formulation of carbidopa–levodopa (IPX066)
Study Groups IPX066 followed by IR CD–LD IR CD–LD followed by IPX066
Inclusion Criteria Patients with idiopathic Parkinson’s disease with motor fluctuations
Exclusion Criteria Not specified
Methods Open-label, multicenter, randomized, two-period, two-treatment, single- and multiple-dose, crossover study comparing IPX066 and IR CD–LD. Subjects received 8 days of medication per treatment period. Tapping speed and UPDRS Part III were assessed, and investigator staff evaluated motor effects and dyskinesia every 30 minutes on Day 1 and every hour on Day 8
Duration 8 days per treatment period
Outcome Measures Primary: Tapping rate, UPDRS Part III, investigator-rating of ON/OFF, including dyskinesia
Baseline Characteristics   All patients (n= 27)
Male 78%
White 89%
Hoehn and Yahr Stage 2 or 3 85%
Results   IPX066 IR CD–LD
Duration of effect (hours) on Day 1 - Tapping 7.6 5.6
Duration of effect (hours) on Day 1 - UPDRS Part III 7.4 4.5
Time to onset of effect (hours) on Day 1 - Tapping 0.39 0.36
Time to onset of effect (hours) on Day 1 - UPDRS Part III 0.61 0.46
Adverse Events The incidence of patients reporting troublesome dyskinesia was relatively low. The probability of being "ON" was higher with IPX066 than with IR CD–LD.
Study Author Conclusions IPX066 had a rapid onset and longer duration of effect compared to IR CD–LD, with a similar concentration–effect relationship. The favorable pharmacodynamic effects noted with IPX066 in this short-term study in advanced PD patients merit further examination in longer-term studies.
Critique The study was limited by its small sample size and short duration. The open-label design may introduce bias. The lack of a placebo group limits the ability to assess the placebo effect. The study did not account for potential diurnal variations in response.
References:
[1] Mao Z, Hsu A, Gupta S, Modi NB. Population pharmacodynamics of IPX066: an oral extended-release capsule formulation of carbidopa-levodopa, and immediate-release carbidopa-levodopa in patients with advanced Parkinson's disease. J Clin Pharmacol. 2013;53(5):523-531. doi:10.1002/jcph.63p-

 

Onset and duration of effect of extended-release carbidopa-levodopa in advanced Parkinson’s disease
Design

Phase II crossover study

N= 27
Objective To compare the onset and duration of ER CD-LD benefit with those of immediate-release carbidopa-levodopa (IR CD-LD) in PD patients with motor fluctuations, using crossover data, and to evaluate which threshold values of improvement in finger-tapping and Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores yield results most similar to those for trained raters’ “on”/“off” assessments
Study Groups

ER CD-LD (n= 27)

IR CD-LD (n= 27)
Inclusion Criteria Patients with advanced PD taking IR CD-LD at least four times/day with a stable regimen for at least 1 month, experiencing at least 3 hours/day of “off” time, and showing a 10% increase in finger-tapping rate in the “on” state compared to the “off” state
Exclusion Criteria Not specified
Methods Patients underwent serial “on”/“off” rating and provided serial finger-tapping and UPDRS motor scores after receiving, in an “off” state, their usual morning IR dose or an ER dose designed to produce a similar levodopa peak concentration. Predefined improvement thresholds for analysis were 10%, 15%, and 20% increases in finger-tapping score and 2.5, 5, 7, and 11-point decreases in UPDRS motor score. Serial plasma samples were assayed for levodopa.
Duration 8 hours post-dose assessment period
Outcome Measures

Primary: Time to onset and duration of “on” state

Secondary: Improvement in finger-tapping score, improvement in UPDRS Part III score, levodopa plasma concentration
Baseline Characteristics   All patients (n= 27)
Age, years (mean ± SD) 62.7 ± 8.6
Male, n (%) 21 (78%)
Caucasian, n (%) 24 (89%)
Weight, kg (mean ± SD) 84.5 ± 14.8
Age at PD onset, years (mean ± SD) 52.3 ± 8.7
Off time, h/day (mean ± SD) 5.9 ± 2.2
Levodopa IR dosage, mg/day (mean ± SD) 815.7 ± 249.7
Finger-tapping score, on state (mean ± SD) 170.4 ± 64.6
Finger-tapping score, off state (mean ± SD) 117.9 ± 44.1
UPDRS Part III score, on state (mean ± SD) 17.6 ± 8.5
UPDRS Part III score, off state (mean ± SD) 35.9 ± 9.4
Results   ER CD-LD IR CD-LD p-value
Time to onset of 'on' state, hours (mean ± SD) 0.83 ± 0.52 0.81 ± 0.45 0.89
Duration of 'on' state, hours (mean ± SD) 5.56 ± 1.78 2.69 ± 0.92 <0.0001
Improvement in finger-tapping score, % 20% - -
Improvement in UPDRS Part III score, points 11 - -
Adverse Events Not specified
Study Author Conclusions For ER CD-LD, observer assessments of “on” state were corroborated by sustained treatment effects. Correlations among “on”-state duration, finger-tapping score, and UPDRS motor score may suggest clinically relevant thresholds for acute assessment of treatment benefit.
Critique The study was limited by its open-label design and relatively small sample size. Although doses were designed to achieve similar Cmax, the ER CD-LD group had a higher Cmax than the IR CD-LD group, which may affect the duration of benefit. The identified thresholds for benefit are most applicable to patients with similar motor fluctuations as those in the study.
References:
[1] Hauser RA, Ellenbogen A, Khanna S, Gupta S, Modi NB. Onset and duration of effect of extended-release carbidopa-levodopa in advanced Parkinson's disease. Neuropsychiatr Dis Treat. 2018;14:839-845. Published 2018 Mar 22. doi:10.2147/NDT.S153321

Duration of “Good On” time per dose: Immediate-release carbidopa-levodopa vs. extended-release carbidopa-levodopa (IPX203, CREXONT®)
Design

Randomized, double-blind, double-dummy, active-controlled, parallel-group, multicenter, phase 3 trial

N= 506
Objective To determine the difference in mean durations of “Good On” time per dose of subjects randomized to extended-release carbidopa-levodopa (ER CD-LD; IPX203; CREXONT®) vs. immediate-release (IR) CD-LD in the RISE-PD trial
Study Groups

IPX203 (n= 256)

IR CD-LD (n= 250)
Inclusion Criteria Diagnosed with PD according to United Kingdom Parkinson’s Disease Brain Bank criteria, ≥40 years old at time of diagnosis, Hoehn and Yahr stage I-IV in the “On” state, treated with a stable regimen of IR CD-LD for at least 4 weeks prior to screening, receiving LD 4 to 9 times per day with a total daily LD dose of 400–2400 mg, and had ≥2.5 h “Off” time per day on 3-day home PD diaries
Exclusion Criteria Controlled-release CD-LD apart from a single daily bedtime dose, Rytary®, and additional CD or COMT inhibitors were not permitted
Methods Patients were randomized to 13 weeks of double-blind treatment with either IR CD-LD or IPX203 at their optimized dosing regimen using a double-dummy design. “Good On” time per dose was assessed at the end of the IR CD-LD dose adjustment phase and compared to End of Study between IPX203 and IR CD-LD groups. Changes in “Good On” time per dose were compared for each quartile from Visit 2 to EOS.
Duration 13 weeks
Outcome Measures

Primary: Mean duration of “Good On” time per dose

Secondary: Changes in “Good On” time per dose between IPX203 and IR CD-LD groups for each quartile
Baseline Characteristics   IPX203 (n= 256) IR CD-LD (n= 250)
Mean age, years (SD) 66.3 (8.94) 66.5 (8.95)
Mean age of PD onset, years (SD) 58 (9.37) 58 (9.42)
Men, % 65.9% 62.9%
Mean daily 'Off' time, hours (SD) 3.95 (2.52) 4.02 (2.47)
Results   IR CD-LD IPX203 p-value
Mean change in 'Good On' time per dose (hours) 0.11 1.69 <0.0001
Percent change in 'Good On' time per dose 5.12% 78.97% <0.0001
Adverse Events Not specifically detailed in the provided text
Study Author Conclusions IPX203 significantly increased “Good On” time per dose regardless of the duration of “Good On” time per dose observed with IR CD-LD. These findings may help clinicians plan conversion regimens and anticipate clinical responses.
Critique The study provides robust evidence of the efficacy of IPX203 in increasing 'Good On' time per dose compared to IR CD-LD. However, the study may underestimate the actual durations of 'Good On' time per dose due to potential biases such as late evening dosing not captured in patient diaries and overlapping benefits of doses. Additionally, the study's design limits the frequency of IPX203 dosing, which may have impacted the observed outcomes.
References:
[1] Hauser RA, Fernandez HH, Jimenez-Shahed J, et al. Duration of "Good On" time per dose: Immediate-release carbidopa-levodopa vs. extended-release carbidopa-levodopa (IPX203, CREXONT®). Parkinsonism Relat Disord. 2025;131:107239. doi:10.1016/j.parkreldis.2024.107239

Restless legs syndrome (RLS) augmentation associated with dopamine agonist and levodopa usage in a community sample
Design

Observational, cross-sectional study

N= 266
Objective To assess the rate of augmentation during standard long-term dopaminergic treatment of RLS, identify potential risk factors or predictors of augmentation, examine the relationship between treatment duration and augmentation, and evaluate the clinical impact of augmentation on health outcomes
Study Groups All patients (n= 266)
Inclusion Criteria US residency; minimum age of 18; RLS diagnosis for at least 1 year; current primary RLS treated with levodopa or a dopamine agonist for at least 6 months; symptom frequency of at least 2–3 days per week before treatment
Exclusion Criteria Diagnosis of peripheral neuropathy, kidney failure, or pregnancy
Methods A one-time, 20-minute online survey was administered to 266 subjects identified by their doctor as being treated with dopaminergic agents for RLS. The survey assessed RLS treatment characteristics, treatment satisfaction and adherence, comorbid conditions, disease severity and impact, quality of life, and occurrence of clinical factors related to augmentation and early morning rebound (EMR). Validated scales used included the International RLS Rating Scale (IRLS), Johns Hopkins RLS Quality of Life Questionnaire (RLS-QOL), and Medical Outcomes Study Sleep Scale (MOS Sleep Scale).
Duration Not specified
Outcome Measures

Primary: Rate of augmentation, potential risk factors, relationship between treatment duration and augmentation

Secondary: Clinical impact of augmentation on health outcomes
Baseline Characteristics   All patients (n= 266)
Gender (% female) 66%
Age in years - mean (SD) 57.6 (13.1)
Race - Caucasian 85%
Years since RLS symptom onset - mean (SD) 9.6 (12.0)
Years since RLS diagnosis - mean (SD) 4.3 (5.1)
Current primary RLS treatment - Ropinirole 57%
Current primary RLS treatment - Pramipexole 34%
Current primary RLS treatment - Levodopa 8%
Results   All patients (n= 266)
Definitive Clinical Indications 4%
Highly Suggestive Clinical Indications 16%
Possible Clinical Indications 56%
No Clinical Indications 24%
Adverse Events Not specified
Study Author Conclusions Long-term dopaminergic treatment for RLS produced significant augmentation problems in at least 20% of patients, with only 25% free of this issue. Physicians should screen for changes in RLS symptoms, especially in patients with severe symptoms prior to treatment. Early detection and intervention are crucial for effective management.
Critique The study provides valuable insights into augmentation in RLS treatment, but its retrospective, self-reported nature may introduce bias. The lack of direct clinical assessments and potential selection bias due to the recruitment process may limit the generalizability of the findings. Additionally, the study did not account for changes in medication timing, which could affect augmentation detection.
References:
[1] Allen RP, Ondo WG, Ball E, et al. Restless legs syndrome (RLS) augmentation associated with dopamine agonist and levodopa usage in a community sample. Sleep Med. 2011;12(5):431-439. doi:10.1016/j.sleep.2011.03.003