Elsevier

The Lancet Neurology

Volume 14, Issue 12, December 2015, Pages 1161-1170
The Lancet Neurology

Articles
Prolonged-release oxycodone–naloxone for treatment of severe pain in patients with Parkinson's disease (PANDA): a double-blind, randomised, placebo-controlled trial

https://doi.org/10.1016/S1474-4422(15)00243-4Get rights and content

Summary

Background

Pain is a common non-motor symptom of Parkinson's disease. We investigated the analgesic efficacy of prolonged-release oxycodone–naloxone (OXN PR) in patients with Parkinson's disease and chronic, severe pain.

Methods

We did this phase 2 study in 47 secondary care centres in the Czech Republic, Germany, Hungary, Poland, Romania, Spain, and the UK. We enrolled patients with Hoehn and Yahr Stage II–IV Parkinson's disease, at least one type of severe pain, and an average 24-h pain score of at least 6 (assessed on an 11-point rating scale from 0=no pain to 10=pain as bad as you can imagine). Participants were randomly assigned (1:1) with a validated automated system (block size four) to either oral OXN PR or placebo for 16 weeks (starting dose oxycodone 5 mg, naloxone 2·5 mg, twice daily). Patients and investigators were masked to treatment assignment. The primary endpoint was average 24-h pain score at 16 weeks in the full analysis population. This study is registered with EudraCT (2011-002901-31) and ClinicalTrials.gov (NCT01439100).

Findings

We enrolled 202 patients; 93 were assigned to OXN PR and 109 to placebo; the full analysis population consisted of 88 patients versus 106 patients. Least squares mean average 24-h pain score at 16 weeks in the full analysis population was 5·0 (95% CI 4·5 to 5·5) in the OXN PR group versus 5·6 (5·1 to 6·0) in the placebo group (difference −0·6, 95% CI −1·3 to 0·0; p=0·058). Similar proportions of patients in each group had adverse events (60/92 [65%] vs 76/109 [70%]), treatment-related adverse events (52/92 [57%] vs 62/109 [57%]), and serious adverse events (5/92 [5%] vs 7/109 [6%]). Treatment-related nausea was more common in the OXN PR group than in the placebo group (16/92 [17%] vs 10/109 [9%]), as was treatment-related constipation (16/92 [17%] vs 6/109 [6%]).

Interpretation

The primary endpoint, based on the full analysis population at week 16, was not significant. Nonetheless, the results of this study highlight the potential efficacy of OXN PR for patients with Parkinson's disease-related pain and might warrant further research on OXN PR in this setting.

Funding

Mundipharma Research.

Introduction

In addition to the cardinal motor symptoms of Parkinson's disease, non-motor symptoms are highly prevalent yet often under-reported.1 Non-motor symptoms, which include gastrointestinal symptoms, neuropsychiatric symptoms, sleep disorders, visual dysfunction, hyposmia, and pain, can have a substantial effect on patients' quality of life.1, 2, 3, 4 As with motor symptoms, some non-motor symptoms often worsen when the effects of dopaminergic treatment wear off.1, 4

Parkinson's disease-related pain affects approximately 60% of patients with Parkinson's disease, and multiple pain types are common,5, 6, 7 including musculoskeletal, central or visceral, nocturnal, orofacial, limb, and abdominal pain.1 Parkinson's disease-related pain is attributed to peripheral pain mechanisms, including motor symptoms causing or amplifying pain, and Parkinson's disease pathophysiology in pain processing.8 Pain in Parkinson's disease is a complex disorder and there is little awareness of the different types of Parkinson's disease-related pain among clinicians. Parkinson's disease-related pain is often treated by simply increasing doses of dopaminergic treatment.

Although Parkinson's disease-related pain can be more frequent and more intense than other types of pain in the general population, it is largely undertreated.6, 9 Patients with Parkinson's disease-related pain are less likely to be prescribed analgesic treatment than are patients with chronic pain-related diseases such as osteoarthritis.6, 7, 10 The reasons for this discrepancy are largely unknown, and, to our knowledge, treatment guidelines for Parkinson's disease-related pain do not exist because of an absence of randomised, controlled trials specifically investigating analgesia in this setting.8, 11, 12 Given the complexity of pain in Parkinson's disease and the various other non-motor symptoms that these patients often experience, studies are needed to ascertain the efficacy and tolerability of different analgesic drugs across the range of pain types in Parkinson's disease.

WHO step 3 (strong-acting) opioid analgesics are widely used to treat various moderate-to-severe pain conditions.13 The pain pathways mediated by dopaminergic and opioidergic neurons lie close to the spinal cord pain transmission pathways, which could explain the potential role of opiates in alleviating Parkinson's disease-related pain. Some side-effects of opioids overlap with Parkinson's disease symptoms (eg, constipation).14, 15 Opioid-induced constipation arises from the interaction of exogenous opioids with enteric μ-opioid receptors throughout the gastrointestinal tract.16 To address gastrointestinal opioid class effects, oxycodone was combined with naloxone, an opioid-receptor antagonist, in a prolonged-release formulation (OXN PR). Oral naloxone has negligible systemic availability as a result of extensive first-pass hepatic metabolism, and can normalise delayed gastrointestinal transit that occurs with oxycodone alone.17, 18 OXN PR is marketed worldwide and its safety and efficacy have been shown for several types of non-malignant and cancer-related pain.19, 20, 21, 22, 23, 24, 25, 26 Furthermore, at low doses (oxycodone 5·0 mg, naloxone 2·5 mg), it can provide symptomatic relief of severe restless legs syndrome and, at doses of oxycodone 10·0 mg, naloxone 5·0 mg, it has shown efficacy for chronic pain in a small prospective study of patients with Parkinson's disease.27, 28

Research in context

Evidence before this study

We searched PubMed and the Cochrane Database up to July 1, 2011, using the words “pain”, “Parkinson”, and “randomised controlled trial”. We did not find any placebo-controlled randomised trials specifically designed to investigate the analgesic efficacy of opioids in patients with Parkinson's disease-related pain or trials that used assessment of pain as the primary endpoint for efficacy. These findings are in agreement with a systematic review of treatments for the non-motor symptoms of Parkinson's disease published in 2011. A search of PubMed on May 1, 2015, using the terms “pain”, “Parkinson's” and “randomi*” in titles and abstracts revealed one randomised, controlled trial with pain as a post-hoc endpoint, but we did not find any trials with pain as a primary endpoint. Since submission of this paper, a study was published that suggests a positive effect of prolonged-release oxycodone–naloxone on Parkinson's disease-related pain, although it had an open-label design and small (n=16) number of patients.

Added value of this study

To our knowledge, this phase 2 study is the first randomised controlled trial specifically designed to investigate drug treatment of Parkinson's disease-related pain. Although we did not detect any significant difference for the primary endpoint of average 24-h pain scores at week 16, exploratory analyses of secondary endpoint data suggest a potential use of prolonged-release oxycodone–naloxone in this setting. Assessment of pain types in this study was based on the first validated scale for Parkinson's disease-related pain, and provides insight into the heterogeneity of Parkinson's disease pain as well as the types of Parkinson's disease-related pain for which prolonged-release oxycodone–naloxone might have positive effects. This study adds to the limited evidence of the safety and efficacy of opioid-based treatment of patients with complex Parkinson's disease-related pain.

Implications of all available evidence

Effective diagnosis and management of Parkinson's disease-related pain is essential to lessen the burden of this disease. The results of this study increase the evidence for the management of Parkinson's disease-related pain and will help the design of future trials in this setting, which should ultimately lead to improved management of Parkinson's disease-related pain.

We investigated the analgesic efficacy of OXN PR compared with placebo in patients with chronic, severe Parkinson's disease-related pain, and assessed its tolerability and effect on motor symptoms, non-motor symptoms, quality of life, and intake of rescue drugs.

Section snippets

Study design and participants

This phase 2 study consisted of 16 weeks of randomly assigned, double-blind treatment with OXN PR or placebo, followed by a 4-week extension phase of open-label OXN PR treatment to transition patients to subsequent pain treatment at the end of the study (figure 1). We did the study at 47 secondary care centres in the Czech Republic, Germany, Hungary, Poland, Romania, Spain, and the UK.

We included patients aged 25 years or older, who had Hoehn and Yahr Stage II–IV Parkinson's disease, an average

Results

We enrolled 202 patients between Feb 10, 2012, and Nov 5, 2013: 93 were assigned to OXN PR and 109 were assigned to placebo. 62 (67%) of 93 patients in the OXN PR group and 77 (71%) of 109 patients in the placebo group completed 16 weeks of double-blind treatment.

Discontinuations because of lack of efficacy were more common with placebo (14 of 109 patients; 13%) versus OXN PR (three of 93 patients; 3%), whereas discontinuations because of adverse events were less common with placebo (ten of 109

Discussion

OXN PR did not have a significant effect on the primary endpoint of improved average 24-h pain score at 16 weeks. However, the per-protocol analysis showed that appropriate adherence resulted in significantly improved average 24-h pain scores at 16 weeks of treatment with OXN PR compared with placebo. Assessments of 24-h pain at other points during the study also suggested that OXN PR had a positive effect on Parkinson's disease-related severe pain, although confirmatory statistical

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