The management of central Parkinsonian pain (CP) is unsatisfactory, although it affects 10 to 28% of patients. Understanding the biological mechanisms involved allows us to suspect two molecular pathways within the basal ganglia: dopaminergic dysfunction, altering pain pathways and their modulation processes, and the involvement of opiate receptors. However, the benefit of levodopa and opiates on CP has never been explored. Therefore, this randomized study versus placebo is the first to evaluate the comparative effectiveness of targeting these two pathways.
Eight weeks of stable dose analgesia after gradual titration
OXYDOPA is a randomized, prospective, multicenter study that was conducted in France in 15 French expert centers for Parkinson’s disease (PD) belonging to the NS-Park/FCRIN network. This study included PD patients aged 45 to 75 years suffering from PCD for ⩾ 3 months with an intensity of ⩾ 30 mm on a visual analog scale (VAS) of pain during the last month.
To be included, they had to be on stable anti-Parkinsonian treatment, alone or in combination with stable level 1 analgesic treatment (nonsteroidal anti-inflammatory drugs, acetaminophen) or co-analgesic treatment (antidepressants, antiepileptics) for at least 4 weeks. They were randomized (1:1:1) between administration of oxycodone LP (extended release, 40 mg/day maximum), administration of levodopa/benserazide (200 mg maximum) and placebo. These treatments were administered for 8 weeks at a stable dose after a progressive titration phase of 2 weeks until the optimal dose. Then, an 8-day withdrawal phase was observed. The primary endpoint was the change in mean pain intensity between D0 and D71.
Effectiveness comparable to placebo
A total of 63 patients were included in the study (mean age 62 – 66 years, 39-55% men, mean VAS 51.7 to 60.2 mm). Over the 8 weeks, the average daily doses were 20.7 mg for oxycodone LP and 183.3 mg for levodopa/benserazide, respectively.
There was no significant difference between the three groups on the primary criterion: the reduction in pain at the end of the 8 weeks was respectively -17 mm for oxycodone LP, -8.3 mm for levodopa/benserazide and -14.3 mm for placebo. There was also no significant difference in the maximum intensity of pain felt during the last week. The percentage of responders (30% reduction in mean intensity) was however significantly higher in the oxycodone LP group compared with the levodopa/benserazide group (52.2% vs 15% respectively).
The incidence of adverse events was comparable in the three arms of the study (90%) and specific to the molecules used (mainly nausea, constipation, somnolence in the oxycodone group, pain and dyskinesia in the levodopa/benserazide group, pain and nausea in the placebo group).
The authors emphasize that the placebo response is particularly important, knowing that 40% and 15% respectively in this arm of the study reported an improvement of at least 30% or at least 50% in average pain. Furthermore, the average tolerated dose of oxycodone LP was lower than the 40 mg initially planned, ” which may have reduced the chances of detecting a more powerful analgesic effectt ».
Concerning the levodopa/benserazide arm, it is possible that the analgesic effect of the drug is already effective since the patients were already receiving it at the start of the trial. But a dosage increase beyond that implemented here is undoubtedly difficult to envisage given the risk of dyskinesia, which already concerned a portion of the patients allocated to this group. “ Other approaches merit evaluation, such as norepinephrine and serotonin reuptake inhibitors, gabapentin and pregabalin, as well as non-pharmacological interventions. »
