Centrally Mediated Pain Common in Parkinson's Disease

Daniel M. Keller, PhD

October 16, 2018

HONG KONG — From a large and detailed study of pain in Parkinson's disease (PD), researchers discovered that peripheral factors are not an important cause of the different subtypes of pain and that central factors are a more important cause of PD-related pain than had been previously considered.

"This is kind of the largest and most detailed study of pain in Parkinson's ever performed, and we think we've shown that peripheral factors such as mobility issues don't really appear to contribute to pain as much as you would think," Monty Silverdale, MD, PhD, of the University of Manchester, United Kingdom, told delegates during a poster tour here at the International Congress of Parkinson's Disease and Movement Disorders (MDS) 2018.

"We conclude, therefore, that central factors are much more important than people have previously considered, and we think that this should make quite a big difference in the way that we investigate and diagnose and manage this over time," Silverdale said.

Chronic pain, often disabling, affects 60% to 80% of people with PD. The most common subtypes are musculoskeletal, radicular, and dystonic pain. Some musculoskeletal and radicular pain may be related to mobility and joint problems or to poor posture. Off-period mobility limitations and dystonic contractions can lead to off-period pain.

However, Silverdale said it is increasingly recognized that many, if not most, cases of chronic pain in PD are the result altered nociceptive processing in the central nervous system and amplification of pain signals in the brain, that is, "central sensitization." Such a mechanism would explain why, for example, "one person with osteoarthritis has severe pain [but] another person with the same level of osteoarthritis in the bone has no pain at all," he said.

Therefore, he and colleageues designed a large clinical study to try to find the extent to which PD pain is caused by central vs peripheral factors. They recruited 1957 people with fairly early PD (mean duration, 3 ± 2.1 years) from about 60 centers in the United Kingdom who had undergone detailed assessments of pain and motor and nonmotor symptoms.

Pain severity assessments were based on the Short Form McGill Pain Questionnaire (SFMPQ); the Visual Analogue Scale (VAS), performed in the previous month; and the King's Parkinson's Disease Pain Scale.

Detailed analyses of motor and nonmotor symptoms were performed to see whether there were any relationships between them and the severity of different pain types. Similarly, assessments of anxiety, depression, motor impairment, motor fluctuations, autonomic function, cognition, and quality of life were carried out. The researchers documented the presence of centrally generated neuropathic pain using the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale.

They found that 85% of participants reported pain at the time of assessment and that 42% reported moderate to severe pain (VAS of 5 or greater), compared with 13% of a large population of persons who did not have PD.

Multiple regression analysis showed that predictors of pain severity were motor complications (P = .034), autonomic symptoms to a small degree (P < .001), younger age (P = .005), affective symptoms (P < .001), and female sex (P = .001).

"The severity of mobility problems does not at all predict the severity of pain," Silverdale said. "Actually, it's the severity of autonomic symptoms...which predicts pain slightly more than all these other factors."

Other findings included the following:

  • No correlation between musculoskeletal pain and motor symptoms

  • No correlation between radicular pain and motor symptoms

  • Negligible correlation between off-pain and off–motor symptoms

  • Very weak correlation between dyskinetic pain and motor fluctuations

  • Very weak correlation between lower abdominal pain and constipation scores

Thirty-three percent of those with pain showed evidence of altered sensory processing over the area of pain, that is, cutaneous allodynia, altered pinprick threshold, or both. Of participants with pain, 10% had a LANSS score of 12 or greater, indicating neuropathic pain.

Because of the large size and the detail of the study, the investigators could evaluate the severity of individual subtypes of pain and their relationship to other symptoms. One important finding was the lack of correlation between musculoskeletal pain and the severity of mobility problems.

"So this whole idea that the mobility problems are causing the musculoskeletal pain is just not borne out by these data, similar with radicular pain," Silverdale explained. Likewise, the severity of dystonic or generalized off-period pain did not correlate with the severity of off-period motor scores.

With these findings in hand, an observer on the poster tour asked, "So then how can you manage pain?"

Silverdale replied that he had no definite answers to that question. He said, "What I'd suggest is looking at drugs that target central pain, drugs such as pregabalin [Lyrica, PF Prism], gabapentin [multiple brands], duloxetine [Cymbalta, Lilly]." He also mentioned that deep brain stimulation targets central pain, although there is no relation between the degree to which it helps mobility and the degree to which it helps pain.

Poster tour moderator Stephen Reich, MD, of the University of Maryland in Baltimore, asked whether many study participants were taking drugs that targeted peripheral pain, such as nonsteroidal anti-inflammatories. "So in other words, maybe they're on the wrong medication," he suggested.

Silverdale confirmed that many were taking nonsteroidal anti-inflammatory drugs, paracetamol (acetaminophen), or co-codamol (paracetamol and codeine), "but very, very few people were on drugs like pregabalin and gabapentin. The problem is, these drugs aren't very used for most people, but I think there are a cohort out there that these drugs are going to help."

Reich commented to Medscape Medical News, "Even in someone who has a clear musculoskeletal cause of pain, there may be something about Parkinson's disease that makes them more susceptible to pain than a level of pain that you might normally predict, or it may be more recalcitrant to treatment with medication...because of a very different physiology."

Silverdale mentioned that pain in the healthy state that would normally be subthreshold may become amplified in someone with PD because of altered brain neurotransmitters.

Reich added that it is important to recognize that pain is very common in PD and is probably a very underestimated symptom, so it is important to ask patients about pain, "and when patients with Parkinson's have pain, you can't just assume that it's a musculoskeletal cause of pain," he said. "You have to investigate and take a thorough history, and you may have to use some novel treatment approaches...looking at agents that work on the central mechanism of pain."

There was no commercial funding for the study. Dr Silverdale has received grants from the Michael J. Fox Foundation, Parkinson's UK, the National Institue of Health Research, and the Dystonia Society. Dr Reich reports consulting for Enterin, acting as a peer reviewer for UpToDate, and receiving royalties from Informa for Movement Disorders: 100 Instructive Cases.

International Congress of Parkinson's Disease and Movement Disorders (MDS) 2018. Abstract 1591, presented October 8, 2018.

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