Part 3 · Treatment
Levodopa over time
Early on, levodopa seems to work all day. Over the years each dose wears off sooner, and the peaks can bring involuntary movements. Drag the years, play a day, then try the ways of smoothing the curve.
Schematic.
How often, and in whom
The model above is a sketch. These are the measured figures: how many people develop motor complications, by when, and who is most at risk.
Published figures only; no curve is fitted.
What smooths the curve: trial results
How much each approach changed daily off-time, or on-time without troublesome dyskinesia, against its own trial's comparator. The trials differ in people, length and comparison, so the bars are not a ranking.
Hours a day, treatment minus comparator.
The words used
Wearing-off
Symptoms return in a regular way towards the end of each dose. Predictable wearing-off is the most frequent type of fluctuation. 114
On-off ("yo-yoing")
Rapid, abrupt switching between on and off. Unpredictable "sudden offs" come regardless of dose timing, are commoner in advanced disease and can develop within a few seconds. On-off fluctuation is described as now rare, because doses are lower. 114
Delayed-on and partial on
A dose takes much longer than usual to work, or works only partly. Both are put down mainly to erratic absorption, 114 including slow stomach emptying. 164
No-on (dose failure)
A dose does not work at all. Like delayed-on, it is attributed mainly to erratic levodopa absorption. 114
Peak-dose dyskinesia
Involuntary movements at the time of peak levodopa action. Chorea is the most common form. 114
Diphasic dyskinesia
Movements as levels rise and again as they fall, at the start and end of a dose: the "dystonia-improvement-dystonia" pattern. It mainly affects the legs and occurs in about 15 to 20% of people. 114 Low levels can cause dyskinesia, as well as high ones. 65
Off-period dystonia
Dystonia during off periods or at the switch from on to off, often painful and especially in the legs. Some people also have worse symptoms at the start of a dose, or a rebound at the end that is worse than before treatment. 114
How on and off are counted
The Hauser home diary records each half-hour as asleep, off, on without dyskinesia, on with non-troublesome dyskinesia, or on with troublesome dyskinesia. Off-time and on-time with troublesome dyskinesia count as "bad time". Completion fell off after 3 days. 136
Infusions and devices
When tablets can no longer give a smooth day, the options deliver medicine continuously or change the circuit itself. NICE asks for best medical therapy first, which may include apomorphine, and DBS only when that does not control symptoms. 241 See Deep-brain stimulation.
Levodopa-carbidopa intestinal gel
Duopa: pumped into the jejunum through a PEG-J tube over 16 hours, up to 2000 mg of levodopa a day; US approval 9 January 2015. 87 Against oral levodopa: off-time −1.91 hours a day, good on-time +1.86. Adverse events were mostly tube-related. 254 The label lists bezoar, intussusception, obstruction, perforation, pancreatitis, peritonitis and sepsis, and polyneuropathy in 5% of trial patients. 87
Foslevodopa-foscarbidopa
Vyalev (Produodopa in the EU): a 24-hour infusion under the skin by a small pump; US approval 16 October 2024. 4,87 Against oral levodopa: good on-time +1.75 hours, off-time −1.79. Site redness 27%, pain 26%, cellulitis 19%; 22% stopped for adverse events against 1%. 340 NICE (TA934) reserves it for when apomorphine or DBS cannot be used or no longer work. 241
ND0612
Continuous subcutaneous levodopa-carbidopa. In BouNDless: +1.72 hours good on-time (95% CI 1.08 to 2.36) and 1.40 hours less off-time; site reactions in 83% during the open-label run-in. 94 Both arms started on ND0612, so the "gain" reflects losing benefit after switching to tablets. 94 The FDA issued complete response letters in June 2024 and on 23 October 2025. 87,286
Apomorphine infusion
A dopamine agonist given under the skin through the waking day. TOLEDO (107 people): off-time −2.47 versus −0.58 hours with placebo. 170 Onapgo, US approval 3 February 2025: off-time −2.55 versus −0.90 hours; common reactions included infusion-site nodules, nausea and sleepiness. 7,87
Levodopa-entacapone-carbidopa gel
Lecigon adds entacapone to the intestinal gel: in an 11-person crossover, a 20% lower levodopa dose gave the same exposure. 328 In the Swedish registry (150 people) complications were mainly tube-related (30%); 13.3% stopped. 260
Deep-brain stimulation
In the VA trial, bilateral STN or GPi stimulation gave 4.6 more hours a day of on-time without troubling dyskinesia, against 0 with best medical therapy. 369 The MDS review rates both targets clinically useful for fluctuations and dyskinesia. 111 See Deep-brain stimulation.
Reading the evidence
Does the window really narrow?
The picture of a window closing from above, with the dyskinesia threshold falling towards the on threshold, is widely taught. In 20 people followed from their first levodopa for 4 years, dyskinesia and benefit always began and ended together, which the authors judged not consistent with a falling threshold. 250 No source gives the window's width in numbers, so the model above is a drawing, not a measurement.
The buffer runs down
In 18 people tested over 4 years, the long-duration response decayed faster after 3 days off levodopa and the short-duration response grew, while its duration did not change. Dyskinesia became more severe. 249 How the body handles levodopa does not change; what changes is in the brain. 96
Dose and the young
In STRIDE-PD (745 analysed), dyskinesia and wearing-off became more likely as the levodopa dose rose (p<0.001 for both). Young onset was the strongest predictor of dyskinesia. 368 Starting with entacapone did not prevent dyskinesia: 42% versus 32% at week 134. 345
"Save levodopa for later"
The Parkinson's Foundation answers the belief that levodopa stops working after five years: it works for decades, and works best taken on time, just before the previous dose wears off. 285 LEAP found no harm from starting early. 361
On time, every time
NICE's standard is levodopa within 30 minutes of the person's own prescribed time in hospital or a care home. 242 Parkinson's UK says a delay of as little as 30 minutes can decide whether someone can move, walk, talk or swallow. 298 See Nursing care.