Parkinson’s disease (PD) affects approximately 7 million people in the world  , estimated to affect 1.6% of patients aged 65 and above in some countries  . The disease costs up to 23 billion annually in the United States  . PD is widely recognized by its motor characteristics, however there are well-described non-motor manifestations such as dementia, major depression, sleep disorder, autonomic dysfunction, and pain. The estimated prevalence of pain in PD varies widely and can be up to 85% of patients  . This may largely reflect musculoskeletal     and arthralgias secondary to dystonia     . However, it is observed that pain persists in regions unaffected by dystonia   , which may involve a commonly overlooked and poorly understood etiology of central pain.
Early clinical descriptions of the disease by James Parkinson describe pain and involuntary movement suspected to be beyond that of a peripheral nervous system origin, unrelieved by remedies for inflammatory musculoskeletal disease  . Descriptions of pain include lancinating, aching, dull, or burning, and at times, poorly localized. These symptoms are thought to be from direct changes to the central nervous system from the disease itself   . The neurophysiological perception of central pain in PD remains poorly understood  , with an incidence of 1%  to 4.5%  in those with the disease. We present a case in which a PD patient was treated with a dopaminergic agonist, with drastic improvement of pain symptoms.
2. Case Report
A 67-year-old male, former transit operator, presented to our clinic with gradual onset of right upper and lower extremity pain and weakness for 6 months. The pain was characterized by “burning and aching”, and associated with subjective right upper extremity weakness. His pain was increased with emotional stress and was progressively exacerbated as he developed a tremor, rigidity, and bradykinesia within his right hemi body.
Oral analgesics at presentation included acetaminophen-oxycodone and NSAIDs. His physical examination revealed a resting tremor and hyperreflexia of the right upper and lower extremities. Imaging studies included a brain MRI without contrast which was unremarkable for an infarct, but of limited diagnostic value due to motion artifact. A cervical spine MRI revealed minimal degenerative changes involving C3-4, C5-6, and C6-7, and foraminal stenosis of C5-6 with no cord signal abnormalities. Shortly after his consultation, he underwent an evaluation for Parkinson’s disease with a neurologist. An EEG revealed frontotemporal slowing, most notable on the left, without epileptiform activity.
Trials of multiple analgesics, including short acting opioids and acetaminophen were not successful. His pain only mildly responded to NSAID therapy. The patient did not respond well to strong mu-opioid agonistic medications. His consulting neurologist initiated levodopa-carbidopa at 25/100mg every 3 hours for several months. The intensity of the burning pain in his right upper and lower extremity was decreased by the next clinic visit, and he was maintained on the same dosing schedule for one year. He was later trialed on scheduled pregabalin and tramadol with favorable results. He was thus encouraged to continue his medications, and during a subsequent visit, his pain had significantly resolved. Additionally, his rigidity improved, and he no longer had evidence of a tremor during his following clinic visits.
The exact factors which lead to a central pain syndrome in PD are complex and remain poorly understood. The cortical-basal ganglia-thalamic circuit appears to be seen as the integration site for sensory processes including pain, and changes in signaling have effects on functional, behavioral, and adaptive strategies important in central pain. It is known that electrophysiological conduction is normal in peripheral and central pain pathways in patients with the disease  . This may suggest that processes involved are related to neurochemical alterations including feedback and feed-forward loops that require further study.
Central pain was originally described in 1906 as primarily involving the thalamus, thus developing the name thalamic pain syndrome  . Regions of the thalamus typically implicated are the ventral posterolateral and ventral posteromedial regions, however it has been shown that central pain after stroke also known as central post-stroke pain [CPSP] may occur after any lesion throughout a tract  . The spinothalamic tract, along with the trigeminothalamic and lemniscal pathways composes the major pathway involved in the central processing of pain  . The accepted theory which explains pain after a cerebral lesion was first described in 1911, and was thought to be due to thalamic over activation triggered after an insult to a major sensory pathway involved in pain processing  .
In PD, the pathophysiology exists in the basal ganglia and its pathways involve adjacent structures including the thalamus and cerebral cortex, along with the complex regulation of dopaminergic activity  . This is known as the cortico-basal ganglia-thalamic pathway. The basal ganglia receive information from cortex as well as subcortical structures involved in the processing of pain.
Animal models have shown that dopamine depletion leads to increased responses to nociception and somatosensory input, including MPTP  and intrastriatal 6-OHDA models   . Electrolytic lesions of the substantia nigra have been observed to reduce analgesic effects of morphine  . Previous studies in cats  and rodents   have shown that the basal ganglia are important in the integration of motor and sensory input, which may play a role in coordination.
Further animal studies suggest dopaminergic activity plays a fundamental role in pain signaling in the cortico-basal ganglia-thalamic pathway. Aversive stimuli in rats were associated with increased dopaminergic activity in the substantia nigra when observed in vivo  . Activation of the D1 and D2 receptors in the nigrostriatal pathway and has been correlated with pain suppression in rodents    . However D2 antagonism has also been observed to have anti-nociception properties   , and this has been thought to be via an opioid related mechanism  . Burkey et al.  described a descending inhibitory mechanism of pain prevalent within a communicating pathway between the insular cortex and the basal ganglia. He later confirmed dose dependent anti-nociceptive activity through electrophysiological recording after introducing a dopamine reuptake inhibitor to the insular cortex  .
In humans, multiple clinical studies further elucidate the factors contributory to central pain after a lesion in the cortico-basal ganglia-thalamic pathway. Degeneration of the dopaminergic neurons in the nigrostriatal pathway plays a role in somatosensory function, including changes in pain signaling and processing. Observations from functional MRI studies suggest there is basal ganglia involvement in the report of acute and chronic pain  . Although the exact mechanism poorly understood, damage to the nigrostrial pathway may lead to alterations in pain perception responsive to dopamine therapy    . Alterations in dopaminergic autonomic centers, which are important in the inhibition of pain, lead to differences in pain threshold  and habituation  . This may manifest clinically as allodynia  or hyperalgesia  , which responds favorably to dopaminergic therapy when compared to controls     . This has also been clinically observed in other disorders consisting of neuropathic pain such as painful diabetic neuropathy  and herpes zoster  . However, not all studies involving the administration of dopaminergic activity has been correlated with decreased pain  .
Dopamine imbalance also has emotional consequences that may have a large impact on the response to certain stimuli. In healthy human volunteers, the variability of emotional  and cognitive  responses to pain such as negative affect and fear may be related to dopaminergic activity in the mesolimbic system. It was also suggested that dopamine activity within the nigrostriatal pathway was correlated with variations of sensory and affective interpretations of pain  . Martikainen  demonstrated that D2 and D3 receptors in the striatum modulate pain and not tactile sensation in healthy patients. This finding was supported by observing dopamine receptor activity  and cerebral blood flow  using positron emission tomography during transmission of pain.
In our patient, there was a clear description of musculoskeletal symptoms including dystonia and tremor, which worsened his pre-existing right hemibody pain and weakness. This was seen as “atypical Parkinsonism” as his motor and sensory complaints appeared to affect only one side of his body. Nonetheless, this suggests a complex, multifactorial origin of his pain and the need for direct treatment of the underlying disease as the first step in management. Steps following the initiation of anti-parkinsonism medications included acute rehabilitation, cognitive behavioral therapy, and the maintenance of neuropathic pain medications such as pregabalin and tramadol. The patient continues to undergo long-term multidisciplinary management.
Diagnosis and treatment of central pain remains challenging due to other overlapping pain etiologies more commonly seen in PD. Several groups        have classified pain in PD into different categories or stages for evaluation and treatment purposes. In the majority of cases, the etiology of pain in PD is multifactorial, involving both peripheral and central processes  contributed by motor and non-motor symptoms  . We present this case report to illustrate a clinical presentation of central pain in PD and to describe other contributors of pain in PD, which warrant equivocal consideration.
Further study is required to understand the dopaminergic pathophysiology in central pain to improve care for patients with PD. Non-motor symptoms including other types of pain may be exacerbated with dopamine therapy   , which suggest opportunities for targeted drug therapy, but studies are limited. Although a pharmacological approach to treatment was discussed above, a multidisciplinary strategy is crucial in managing central pain in PD. Other approaches, including transcutaneous nerve stimulation, acupuncture, massage therapy, and biofeedback have been used for pain related to a wide variety of neurological conditions. As providers, we must also address the rehabilitative, complementary, and psychological requirements, which are significant to the quality of life of all patients with PD  -  . This serves to minimize treatment delay and to address any unnecessary side effects, leading to optimal care.
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