Pain perception in Parkinson’s disease: A systematic review and meta-analysis of experimental studies
Introduction
Chronic pain is a common non-motor symptom of Parkinson’s disease (PD). A recent systematic review indicated a mean pain prevalence of 68% in PD patients (Broen et al., 2012), with another study finding that chronic pain complaints, especially musculoskeletal pain, were twice as likely and reported as twice as intense in PD patients compared to age-matched controls with other chronic disorders (Nègre-Pagès et al., 2008). Pain often appears early in the development of PD and may be present years before clinical diagnosis (Schrag et al., 2015). Pain has been rated as the most burdensome non-motor symptom (Chaudhuri and Odin, 2010), and contributes to PD-related disability, sleep disturbance, and impaired quality of life (Chaudhuri and Schapira, 2009, Fil et al., 2013, Quittenbaum and Grahn, 2004). Non-motor symptoms including pain are also a frequent cause of hospitalisation and institutionalisation of PD patients and can increase healthcare costs by up to four times (Chaudhuri and Schapira, 2009). Nevertheless, pain is a frequently overlooked symptom of PD, often unreported by patients unaware that painful symptoms are linked to the disease (Mitra et al., 2008), and consequently under-treated (Broen et al., 2012) which can increase the overall burden of PD. This is especially unfortunate given that pain represents a non-motor symptom that is eminently treatable (Chaudhuri et al., 2010).
While pain in PD is often precipitated by muscular rigidity and/or postural abnormalities (Ford, 2010), neurodegenerative processes could potentially affect not only motor function, but also peripheral (Nolano et al., 2008) and brain (Fil et al., 2013) pathways involved in pain processing. For example, degradation of dopamine-producing cells in the substantia nigra may impair natural analgesia by disrupting the dopamine-mediated descending pathways that block transmission of ascending nociceptive signals from the spinal cord (Fil et al., 2013). A role of dopamine in pain is consistent with reduced pain sensitivity seen in schizophrenia (Stubbs et al., 2015), a disorder linked to dopamine dysregulation, and the possible partial restoration of normal pain thresholds in PD during functional ON states following treatment with dopaminergic agents (Cury et al., 2016).
If pain processing is affected centrally in PD, as hypothesised, this could result in a generalised hypersensitivity to noxious sensations (Cury et al., 2016), which may influence the onset of and/or exacerbate painful symptoms in PD (Broen et al., 2012). Evidence for this hypersensitivity is, however, inconsistent. While several studies have found increased pain sensitivity in PD patients compared to healthy controls (HCs) in response to noxious experimental stimulation (Chen et al., 2015, Lim et al., 2008, Mylius et al., 2009), others have failed to find such an effect (Granovsky et al., 2013, Massetani et al., 1989, Vela et al., 2007). This inconsistency may be influenced by methodological differences across studies, including variation in sample size, dopaminergic and analgesic medications, disease duration and symptom severity (Fil et al., 2013, Priebe et al., 2016). Nevertheless, to our knowledge, there has been no systematic effort to synthesize available evidence from experimental studies and to explore potential sources of study heterogeneity using meta-analytic techniques. Examining the influence of dopamine medication may be especially revealing, both to provide evidence for possible mechanisms of action and for informing potential analgesic treatment.
We therefore conducted a systematic review and meta-analysis of studies comparing PD patients and HCs in their response to noxious experimental stimuli to: (1) examine whether PD patients and HCs differ in their response to experimentally-induced pain; (2) quantify the magnitude of this difference; and (3) explore potential moderators of this association including dopaminergic agents, disease duration, and symptom severity.
Section snippets
Method
This systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (Moher et al., 2009) and the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines (Stroup et al., 2000) for observational studies. An a priori established but unpublished protocol was followed.
Study selection
3047 unique hits were identified through database searches, with 6 additional records identified through manual searching of reference lists. Following the initial screening of abstracts, 47 articles were retained for full text review of which 21 were excluded, resulting in a total of 26 studies retained for analysis (Fig. 1).
Participant characteristics
The 26 retained studies provided aggregated data for N = 1292 participants, consisting of 739 patients and 553 HCs. The mean study age (k = 26 studies) was 63.8 years (SD = 3.0,
Discussion
The current meta-analysis is the first to examine whether patients with PD exhibit increased pain sensitivity compared to HCs and to investigate potential moderators. Our comprehensive analysis of 26 studies, primarily assessing pain threshold, with a combined total of 739 PD patients and 553 controls yielded several key findings: (1) Overall pain threshold was lower in PD patients (indicating greater pain sensitivity) compared to HCs; (2) Suprathreshold pain was lower in PD patients, although
Disclosures
TT, KG, NV, EW and BS have no conflicts of interest. AFC is supported by a research fellowship award from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; Brazil). CUC has been a consultant and/or advisor to or has received honoraria from: Alkermes, Allergan, Bristol-Myers Squibb, Forum, Gerson Lehrman Group, IntraCellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, Medavante, Medscape, Neurocrine, Otsuka, Pfizer, ProPhase, Sunovion, Supernus, Takeda, and Teva. He has
Acknowledgements
We are especially grateful to Drs Gergely Orsi, Yelena Granovsky, Jon Stoessl, Maria Nolano, Tomohiko Nakamura, Masanaka Takeda, Janosch Priebe for their rapid and exceptionally helpful responses to requests for additional study data. We are also extremely grateful to Professor John Lees and Dr Alastair Noyce of University College London for their invaluable advice and extremely helpful commentary on the manuscript.
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