Short-term cost and health consequences of duodenal levodopa infusion in advanced Parkinson's disease in Sweden: an exploratory study.

Background Parkinson's disease (PD) is a chronic neurological disease with disabling motor symptoms such as tremor, rigidity, bradykinesia and postural instability. PD patients also report considerable non-motor symptoms such as fatigue, pain and speech problems that, in combination with the motor symptoms, tend to make the patients isolated and depressed.[1] For decades, levodopa has been the cornerstone in the treatment of PD, but the short half-life of this agent causes adverse effects (peak-dose dyskinesia, nausea and postural hypotension). The consequent fluctuation in alleviation of motor symptoms has limited its usefulness, particularly in the advanced stages of PD.[2] Most patients with PD develop fluctuations in motor performance, i.e. motor fluctuations (wearing-off, start hesitation, unpredictable off, on-off) and dyskinesias (hyperkinesia and dystonia), when treated orally with levodopa.[3] Particularly disabling is the so-called 'on-off-phenomena'.[4] When the patient is 'on', the levodopa therapy is working relatively well, and the patient can move around. Unpredictably, and up to several times per day, the patient becomes 'off', in which case the levodopa effect is missing, the muscles become stiff and the patient is hardly able to move around. After 3-5 years of treatment, one-third of patients experience these problems; this increases to about half of all patients after 5-7 years and to nearly all patients after 10-12 years.[5,6] In addition, studies assessing slow-release formulations of levodopa have shown a high prevalence of motor fluctuations after 5 years of therapy.[7,8] It has been demonstrated that motor fluctuations and dyskinesias in advanced PD are at least partially related to variations in blood levodopa concentrations and that such fluctuations can be markedly reduced by keeping levodopa plasma concentrations constant.[9,10] Levodopa is absorbed by active transport mechanisms in the proximal small intestine, but due to erratic gastric emptying and the dose interval, orally administered levodopa tablets or capsules create variable plasma concentrations.[11] The declining effectiveness of oral levodopa has led to the development of other medications that enhance the levodopa effect or have other basic mechanisms of action. Polypharmacy is therefore typical for advanced-stage patients who are receiving conventional oral therapy. An alternative therapeutic principle is the use of administration types that ensure more stable levodopa plasma concentrations. Indeed, continuous intravenous or intraduodenal infusion of levodopa has been shown to improve motor function,[12-16] but the limited solubility of levodopa in water means that patients need to carry many litres of infusate for 1-day's use. To overcome this problem, a water-based suspension of levodopa (20 mg/mL) and the decarboxylase inhibitor carbidopa (5 mg/mL), Duodopa® (Solvay Pharmaceuticals, GmbH, Hannover, Germany), has been introduced. With a percutaneous gastroduodenal tube and a portable pump for continuous infusion, this formulation has proven effective in reducing motor symptoms in short-term studies in patients with advanced PD.[17,18] Furthermore, long-term duodenal levodopa infusion (DLI) with Duodopa® has been shown to provide reduced motor function variability for up to 10 years without waning effectiveness.[19-21] Duodopa® has received orphan drug status in the EU (2001) and the US (2000) because it is intended only for the sub-population of PD patients with severe motor fluctuations. DIREQT (Duodopa® Infusion - Randomised Efficacy and Quality of life Trial) was an open, randomized, controlled, crossover study over 3 + 3 weeks conducted to confirm the results of previous studies and clinical experience.[22] DLI with Duodopa® was used as monotherapy and was compared with individual combinations of conventional drugs. DLI significantly increased patients' 'functional on-time' and the median Unified Parkinson's Disease Rating Scale (UPDRS) score decreased from 53 to 35 in favour of DLI (p