Duodopa pump treatment in patients with advanced Parkinson‘s disease

Currently, we have in our department evaluated 25 patients for Duodopa therapy. The treatment is costly and resource-consuming. Furthermore, it is a specialist task and multidisciplinary team cooperation is needed to ensure optimal patient care. The positive treatment effects include less fluctuations and side effects and therefore improved quality of life for patients, a reduction of the burden of care for families and home care services, and a decrease in the number of undesirable, acute hospital admissions.

Treatment of patients with advanced Parkinson’s disease (PD) is a medical challenge. Despite optimal oral medication, patients usually develop motor complications in the form of fluctuations – so called "on-off" phenomena – and involuntary movements (dyskinesias) [1, 2]. The cause of this is longstanding unphysiological, pulsatile stimulation of postsynaptic dopamine receptors in the striatum as a result of the short half-life of levodopa, loss of dopaminergic cells and slower gastric emptying due to disease progression.

In Denmark, advanced treatment for PD patients with unsatisfactory effect of oral treatment has comprised Deep Brain Stimulation (DBS) since the late 1990s [3]. There may, however, be contraindications to surgery, e.g. advanced age, dementia or significant psychiatric illness/symptoms. Furthermore, some patients do not want to undergo surgery, and DBS also carries a risk of neuropsychiatric side effects [4].

Since 2002, a limited number of neurological departments in Denmark have also been treating advanced PD patients with continuous apomorphine using a pump for subcutaneous injection into the abdomen [5]. Apomorphine is a liquid dopamine agonist (DA). However, patients with significant psychiatric illness/symptoms usually do not tolerate apomorphine. Furthermore, psychiatrically healthy patients may develop psychiatric side effects (hallucinations or impulse control disorders). Disabling sedation and formation of subcutaneous nodules at the injection sites are not uncommon. Finally, treatment with apomorphine pump has only limited effect on dyskinesias [6].

Continuous intestinal levodopa infusion to the duodenum would theoretically reduce motor complications owing to a smoother intestinal drug uptake. This would produce more stable plasma concentrations [7] and a more sustained stimulation of the dopamine receptors.

As from September 2004, treatment with liquid sinemet (Duodopa) administered via a tube into the duodenum (Figure 1. and Figure 2. ) has been possible in Denmark, using a method developed in Uppsala, Sweden, in the 1990s [8].

The treatment was initially introduced at Bispebjerg Hospital, but has now also been implemented at Glostrup Hospital, Roskilde Hospital, Aalborg University Hospital and Aarhus University Hospital. In all, approximately 75 patients have received this kind of treatment in Denmark. Throughout Europe, in excess of 1,500 patients have presently received Duodopa treatment.

An advantage of Duodopa is that it is usually administered as monotherapy during the patient’s waking hours and accompanied by a night-time levodopa slow-release formulation. Treatment for any non-dopaminergic symptoms continues as scheduled. Some patients require 24-hour Duodopa pump treatment (the night-time dose constitutes approx. two thirds of the dose administered during the day).

To our knowledge, comparative studies on the efficacy of the three therapies have not yet been published, but a multicenter study to such effect is under preparation. The effect of the three modalities is probably comparable.

The aim of the present paper is to report the effect of Duodopa treatment on 14 PD patients’ "on" state as measured by the Unified Parkinson Disease Rating Scale (UPDRS) III and their motor fluctuations and dyskinesias.

MATERIAL AND METHODS

Fourteen patients with advanced idiopathic PD (four men and ten women, mean age 64.9 ± 13.5 (mean ± standard deviation (SD)) years, Hoehn and Yahr Stage: 3.3 ± 0.7, disease duration: 16.2 ± 7.4 years) (Table 1.) with unsatisfactory effect of oral medication were assessed for Duodopa treatment at the Neurological Department of Bispebjerg Hospital in the period 2004-2008. The patients were either followed at our Outpatient Clinic or Parkinson Day Hospital, or they were newly referred for evaluation at our Department.

All patients required advanced treatment, and neither DBS nor apomorphine pump treatment was possible: Four patients had insufficient effect of oral DA, four could no longer be adequately treated with apomorphine pump, four suffered side effects to DA and one young patient (no. 1 in Table 1) opposed to DBS. Furthermore, one patient (no. 3 in Table 1) initially received apomorphine pump treatment during admission, but developed visual hallucinations after a few days. The patient had dementia (Mini-Mental State Examination < 24). Only one of the other patients (no. 7 in Table 1) had clinical dementia.

Twelve of the 14 patients are still being treated with the pump and have been followed for 2-43 months (mean 16.3 ± 15.7 months) after treatment initiation.

Patients were switched directly from their previous treatment to Duodopa, but high-dose DA patients tapered out DA treatment before admission. On the first day of admission, patients were scored using the UPDRS III and recorded on video in the "on" and "off" state. Furthermore, patients or staff started to write Parkinson’s diaries covering the whole day to document motor complications. Before discharge and after one month of treatment, the above measures were repeated. The best objective motor scores (UPDRS III) were compared before and after Duodopa initiation. The last three patients also completed a validated Quality of Life scale (SF36).

Duodopa (Solvay Pharmaceuticals GmbH, Hannover, Germany) is liquid Sinemet: a solution of levodopa in carboxymethyl cellulose 20 mg/ml and carbidopa 5 mg/ml. The medication comes in pre-mixed cassettes of 100 ml for approximately one day’s consumption. The pump used is a portable CADD pump (Smiths Medical, Minneapolis, MN, USA) (size 9 × 19 cm, weight 500 g).

Before initiating treatment, the expected consumption of Duodopa was calculated on the basis of the patient’s current total consumption of medication (l-dopa equivalent):

– As morning dose: 80% of oral l-dopa equivalent morning dose.

– As continuous dose: 90% of the remaining days l-dopa equivalent dose spread over 16 hours.

– As extra dose: Start with 1 ml (20 mg l-dopa).

All patients participated in a 4-7-day test period in which Duodopa was administered through a nasoduodenal test tube and adjusted as needed. Upon observation of a satisfactory effect during the test period, experienced surgeons at our Endoscopic Department inserted a percutaneous endoscopic gastrostomy (PEG) tube containing a jejunal inner extension, the point of which was placed at the ligament of Treitz. The location of the point of the inner tube in the duodenum was confirmed radiographically before the patient left the Endoscopic Department. The vast majority of patients were discharged one week after insertion of the permanent tube. Prior to discharge, the patient along with his or her relatives and home care nurses were trained in the handling of the the pump by staff at the Department and a nurse from Solvay.

After discharge, patients were followed at our Parkinson Day Hospital by a specialised Parkinson nurse and/or physician at 1-2 month intervals as needed.

RESULTS

Two patients discontinued Duodopa treatment after the test period at their own request. Three patients received Duodopa as 24-hour treatment with good effect on severe nocturnal dystonic pain. None of these patients experienced the decrease in effect which might have been expected due to continuous treatment (tolerance). No patients developed hallucinations. There was good agreement between subjective and objective assessments as well as video recordings.

For nine patients the total consumption of levodopa was significantly higher after changing to Duodopa; The mean increase constituted 199% (range: 6-477%). Three patients experienced a reduction in levodopa consumption: 33% (range: 18-53%). Motor condition was stabilised within the first month.

The mean reduction in the UPDRS III was 34% (from 85% improvement to 50% deterioration) (Table 1). Quality of life assessment using the SF-36 demonstrated a reduction in the score of one patient from 118 to 74 after one month and to 45 after two months (62% reduction). The maximum score (worst possible condition) is 149. Another patient had scores of 81, 89 and 91, respectively, representing a score increase; but during the test period, the patient was psychosocially burdened by issues other than his PD.

Complications: One patient suffered from continued hyperkinesias causing secretion of large quantities of gastric juice, which irritated the skin around the tube insertion site and resulted in several tube shifts.

In two patients, the inner tube slipped out. One patient underwent surgery for acute peritonitis one week after PEG because the tube had perforated the stomach. The tube was not replaced, as the patient died some months after surgery. The cause death was unrelated to the surgery. In three patients, the tube slid into the stomach, leading to reduced and more varying medication effects. The tube was returned to its correct position at our Endoscopic Department under X-ray guidance.

DISCUSSION

All twelve patients experienced significant improve-ment after switching to Duodopa treatment. Most patients described a decrease in motor fluctuations (six patients) and dyskinesias (five patients) and im-proved gait function (five patients) (Table 1). These findings are in accordance with the results achieved by other groups [9-11]. A total of four patients reported reduced dystonic pain. This symptom is not scored in the UPDRS III.

The total consumption of levodopa per day in-creased significantly in most patients, while their hyperkinesias simultaneously decreased. This phenomenon indicates that it is the pulsatile stimulation of dopamine receptors by oral medication that causes motor complications rather than the total quantity of medication per day. Pulsatile stimulation up-regulates the glutamate receptors in the postsynaptic GABAergic neurons in the striatum, which overstimulates the neurons leading to dysfunction and dyskinesia [12-14].

The efficacy of Duodopa was unchanged in the follow-up period. Several patients’ doses were reduced by approximately 5% at follow-up, as also described in other studies [15].

We have currently evaluated 25 patients for Duodopa. Treatment is costly and a specialist task. It should therefore only be offered at main centers for Parkinson’s patients in Denmark. It is important that the treatment team comprises neurologists, gastroenterologists, nurses as well as an outbound contact to cooperate in the care of the patient. Thorough training of the patient and any relatives and caregivers is important to ensure that everyone feels capable of handling the pump after discharge.

The average daily treatment cost (DDD) for Duodopa is 339 DKK (a Euro is approximately equivalent to 7.5 DKK) including the pump. Apomorphine treatment costs are 102 DKK per day plus an additional pump cost of 12,850 DKK, and the cost of tubing, needles, etc. is 2,000 DKK. DBS is associated with one-off costs in the order of 250,000 DKK, to which should be added the cost of battery change every 4-5 years (80,000 DKK). Under the assumption of a long life expectancy, DBS is the most inexpensive of the three treatment options currently available.

Conversely, Duodopa treatment is associated with substantial savings owing to fewer hospital admissions, a reduced need for home care and personal assistance services as well as residential care facilities and finally less strain on the spouse and other family members. It is well-documented [16] that motor complications such as nocturnal akinesia and dyskinesias affect quality of life substantially.

CONCLUSIONS

Duodopa pump treatment is an expedient offer for selected patients with advanced PD who have experienced unsatisfactory effect of oral treatment, and for whom the DBS and apomorphine pump treatment are not possible. The disadvantages of being "tied" to a rather bulky pump, and any stomach tube discomfort experienced were clearly outweighed by Duodopa’s symptom-relieving and stabilising effect with few side effects, but the risk of surgical complications, especially in the form of peritonitis, should be taken into consideration. Duodopa pump treatment is difficult to implement successfully without the assistance of a care system based on home care or relatives. Further tech-nical development leading to a smaller pump and an optimized PEG-tube system is desirable.

In the light of the positive results, it would be expedient to offer Duodopa pump treatment to fluctuating PD patients earlier in the disease course.

Correspondence: Merete Karlsborg, , Neurologisk Afdeling, Bispebjerg Hospital, 2400 København NV, Denmark. E-mail: merete.karlsborg@dadlnet.dk

Accepted: 4 March 2010

Conflicts of interest: None