Long-term Efficacy and Safety with Continuous Dopaminergic Stimulation Pump Treatments in Parkinson’s Disease

Abstract

Continuous dopaminergic stimulation (CDS) is important for symptom control in advanced stages of Parkinson's disease (PD). The most efficacious approaches are pump treatments with dopaminergic drugs: subcutaneous infusion of the dopamine receptor agonist apomorphine and intestinal infusion of levodopa/carbidopa gel. Both methods decrease motor fluctuations in long-term follow-ups, including parkinsonian and dyskinetic states, when compared to conventional optimised oral therapy. Also non-motor symptoms may be improved. Adverse drug reactions are usually less pronounced although high levodopa doses, which are common with levodopa/carbidopa infusion, may cause hyperhomocysteinaemia and cobalamin deficiency. Technical complications are specific for each infusion strategy. Formation of subcutaneous nodules is the most common problem with apomorphine infusion. Dislocation of the intestinal tube is the most common problem with levodopa/carbidopa infusion. Both pump treatments may be used for 24-hour infusion in selected patients. The long-term experience is reviewed. To conclude, CDS pump treatments may be successfully used for several years in advanced PD. KeywordsApomorphine, continuous dopaminergic stimulation, infusion, levodopa/carbidopa, Parkinson's disease, pump The background is a combination of a number of findings, mainly that:• striatal dopaminergic stimulation is fairly constant in a healthy brain;• striatal dopaminergic stimulation in PD is pulsatile when oral levodopa is used; • pulsatile dopaminergic stimulation causes motor fluctuations and dyskinesias; and • continuous administration of dopaminergic agents may decrease motor fluctuations and reverse dyskinesias.PD is associated with a more widespread pathology than nigro-striatal degeneration and CDS is not the remedy for all problems. But there is firm evidence that continuous dopaminergic drug delivery, probably providing CDS, produces a significant benefit compared to conventional therapy in patients with advanced PD. The evidence mainly stems from studies of levodopa and apomorphine infusions.

Why do ‘OFF’ periods still occur during continuous drug delivery in Parkinson’s disease?

“…The persistence of ‘OFF’ periods despite the clear efficacy of CSAI in advanced PD, can be due, as with rotigotine, to the under-dosing, although ‘OFF’ periods are emergent even with high-dose infusion of apomorphine, either in monotherapy or as an add-on to oral levodopa, as in most of the studies which have evaluated apomorphine efficacy [ 64 ]. It is feasible that occasional technical issues related to the device, such as pump failure, line blockage or inaccurate needle insertion, can cause a reduction of CSAI efficacy [ 61 , 65 ]. The extent of apomorphine delivery from the subcutaneous site to the systemic circulation may be determined by the site of injection (the abdomen seems to be the best site), the state of the skin (warm skin increases the absorption compared to cold skin), and volume and depth of the injection (a greater volume is associated with a better absorption) [ 61 , 66 ].…”