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.