Part 3 · Treatment
Levodopa and carbidopa
Levodopa gives more improvement in movement symptoms than the other first-choice medicine classes. 241 Follow one dose from the tablet to the striatum, where dopamine is missing. Then change the conditions and play it again.
Schematic, not to scale.
Does levodopa harm the brain?
An old worry was that levodopa might be toxic to the remaining dopamine cells, so that starting it early would speed the disease. Two randomised trials tested this. Then the label figures behind carbidopa's dose.
Published figures. Bars start at zero.
Formulations
The same molecule comes in forms that release it differently. The shape of the blood level after each dose matters more as the years pass; see Levodopa over time.
| Form | How it releases (label figures) | Trial or label notes |
|---|---|---|
| Immediate-release carbidopa-levodopa Sinemet; Dhivy scored tablets | Taken fasting, the levodopa peak comes at about 1 hour. A high-fat, high-calorie meal cut the peak by about 25% (total exposure unchanged) and delayed it by about 30 minutes. Half-life about 1.5 hours with carbidopa. 189 | Usually takes at least 20 to 30 minutes to work. 114 US first approvals: levodopa alone (Larodopa) 4 June 1970, Sinemet 2 May 1975, Dhivy 12 November 2021. 86 |
| Controlled-release tablets Sinemet CR and generics | A modified-release tablet. Its label says they should not be chewed or crushed. 102 | Sinemet CR was approved on 30 May 1991. 86 Parkinson's UK advises never crushing or splitting modified-release products. 300 |
| Rytary (IPX066) extended-release capsules | Bioavailability about 70% and peak about 30% of immediate-release. The level peaks at about 1 hour and holds for about 4 to 5 hours. Fluctuation index about 1.5 versus 3.2. 189 | ADVANCE-PD (393 randomised): off-time 23.82% versus 29.79% of waking hours, 1.17 hours a day less, with 3.6 versus 5.0 doses a day. 137 Approved 7 January 2015. 86 |
| Crexont (IPX203) extended-release capsules | Peak 38% of immediate-release. After a first peak at about 1 hour the level holds for about 6 to 7 hours. Fluctuation index about 1.7 versus 2.7. 189 | Pivotal trial (506 randomised), week 20: off-time 4.18 versus 4.75 hours, good on-time 11.35 versus 10.77 hours; mean dose 1487 mg a day. 189 Approved 7 August 2024. 86 |
| Inbrija inhaled levodopa | Median time to peak about 0.5 hours. Bioavailability about 70% of oral. 84 mg as needed for off symptoms, up to 5 times a day (420 mg a day at most), only alongside oral carbidopa-levodopa. 189 | SPAN-PD (351 people): 30 minutes after a dose, UPDRS III improved 9.83 points versus 5.91 on placebo. 191 58% versus 36% returned to on and stayed on through 60 minutes. 189 Approved 21 December 2018. 86 |
| Dispersible levodopa for example dispersible co-beneldopa (levodopa with benserazide) | Used when tablets cannot be swallowed: in thickened fluids, or down a nasogastric tube, because levodopa is absorbed mainly in the jejunum. 12,300 | Controlled-release doses are converted to a dispersible equivalent because of their lower bioavailability. 300 Benserazide has no US application. 86 |
| Infusions | Into the jejunum (intestinal gel) or under the skin (foslevodopa). They bypass the stomach. | See Levodopa over time. |
Published label information
What the Sinemet prescribing information says about starting and raising the dose. It is reported here as published, for study. It is not dosing advice for any person: doses are set with a prescriber, nothing should be changed without one, and Parkinson's medicines must never be stopped suddenly.
| Situation | Label wording (as published) |
|---|---|
| Starting | One 25/100 tablet three times a day, which gives 75 mg of carbidopa a day. 189 |
| Raising | By one tablet every day or every other day, up to eight 25/100 tablets a day. With the 25/250 strength, the maximum is eight tablets a day (by arithmetic, 200 mg carbidopa and 2000 mg levodopa). Experience above 200 mg of carbidopa a day is limited. 189 |
| Maintenance | Should provide at least 70 to 100 mg of carbidopa a day. 189 |
| Switching from levodopa alone | Levodopa is stopped at least 12 hours before; Sinemet is dosed at about 25% of the previous levodopa dose. 189 |
| A sign of excess | Blepharospasm (forced eyelid closure) "may be a useful early sign of excess dosage". 189 |
| Contraindications | Non-selective MAO inhibitors (stopped at least two weeks before) and narrow-angle glaucoma. Selegiline with carbidopa-levodopa may cause severe orthostatic hypotension. 189 |
| Stopping | Cases resembling neuroleptic malignant syndrome have followed dose reduction or withdrawal: high temperature, rigidity, altered consciousness and unstable blood pressure and pulse. The Dhivy label says to avoid sudden discontinuation and to taper. 189 |
| Age | In people with Parkinson's aged 65 or over, levodopa exposure (AUC) was 28% higher and the peak 24% higher than under 65. 189 |
Reading the evidence
Not toxic to the course
In ELLDOPA, people who had taken levodopa were still better than placebo after a 2-week washout. In LEAP, starting 40 weeks earlier made no difference at week 80 (UPDRS difference 1.0; 95% CI −1.5 to 3.5). Neither trial found that levodopa speeds the disease, and LEAP found it does not slow it either. 97,361
The imaging puzzle
ELLDOPA's dopamine-transporter scans fell more on levodopa (−6%, −4%, −7.2%) than on placebo (−1.4%; p=0.036), the opposite of the clinical scores. LEAP, 15 years later, again found no harm on clinical scores. 97,361
Vitamin B6
Pyridoxine (vitamin B6) at 10 to 25 mg can reverse levodopa given alone by speeding its breakdown outside the brain; carbidopa blocks this. The current labels also warn of vitamin B6 deficiency and seizures: postmarketing seizures resisted anti-seizure drugs and stopped only with B6. The labels say B6 should be checked before starting and from time to time. 189
Food, iron and other drugs
A high-protein diet may delay and reduce absorption, and iron salts, including those in multivitamins, bind levodopa. Metoclopramide speeds stomach emptying but blocks dopamine receptors. Phenothiazines, butyrophenones, risperidone and isoniazid may reduce the effect. 102,189
Never stopped suddenly
NICE says Parkinson's medicines should not be withdrawn abruptly or allowed to fail through poor absorption, advises against "drug holidays" because of the risk of neuroleptic malignant syndrome, and asks hospitals and care homes to give them at the right times. 241 NICE's quality standard is within 30 minutes of the prescribed time. 242 See Nursing care.
Sudden sleep
Falling asleep without warning, including while driving, has been reported on carbidopa-levodopa, as late as one year after starting. 189
"It stops working after five years"
The Parkinson's Foundation calls this perhaps the most pervasive myth about Parkinson's treatment and answers that levodopa works for decades. What changes is how smoothly each dose works. 285 See Levodopa over time.