Pain in Parkinson's Disease: A Research Vista for Innovative Treatments

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Parkinson's patients receiving electro-acupuncture treatment had improved balance.
Parkinson's patients receiving electro-acupuncture treatment had improved balance.

Parkinson's disease is a movement disorder commonly associated with hallmark symptoms such as resting tremor, bradykinesia, and rigidity. The foregoing motor symptoms are attributed to insufficient dopamine production and activity with the progressive neurodegeneration of dopamine-producing cells and neurons of the substantia nigra.1 In the general population, the incidence of Parkinson's disease is estimated to be 0.15%, increasing ten-fold to 1.5% among individuals over the age of 70.1 The latter statistic is of particular concern in an aging population, with the number of adults age 65 and over projected to double by the year 2050.2

Notwithstanding the prominence of motor features in Parkinson's disease, non-motor symptoms – such as pain – are increasingly being recognized as a central feature of Parkinson's disease with a significant impact on quality of life outcomes.3, 4 Two common types of pain described in Parkinson's disease are nociceptive pain and neuropathic pain. Nociceptive pain is often described in association with prolonged physical activity, frequently manifesting as muscle stiffness/cramps, dystonia, and/or akathisia, whereas neuropathic pain is a complex and chronic pain state that affects neurosensory systems and central pain center signaling.3 

The prevalence of pain in this clinical population has been estimated to range from 60% to 83%, exceeding estimates in age- and sex-matched healthy controls; moreover, it has been documented that approximately 25% to 65% of patients experience pain independent of motor disturbances, suggesting that motor and non-motor symptoms in Parkinson's disease do not necessarily share the same mechanistic pathways. However, few studies have specifically sought to examine pain treatment and management in Parkinson's disease.3, 4 Taken together, the impact of pain on patients' quality of life has generated interest in the repurposing/discovery of novel treatments and/or therapeutic strategies targeting this highly prevalent non-motor symptom among patients with Parkinson's disease.5

In the absence of specific pathoetiologic knowledge of Parkinson's disease and the mechanisms subserving its natural progression, the treatment and therapeutic strategies for managing pain in this clinical population is often predicated on the underlying assumption that pain is a sequela of chronic motor symptoms. However, recent technological advances demonstrate promise in generating a novel non-invasive treatment for Parkinson's disease, essential tremor and neuropathic pain.1 Preliminary evidence suggests that magnetic resonance-guided focused ultrasound is an effective and precise method of performing thermal ablations targeting tremor-dominant brain regions such as the thalamus, subthalamus, and globus pallidus.

Notably, Dobrakowski et al. (2014) described the prospect of using a combination of high intensity frequency ultrasound and magnetic resonance imaging for visualizing target anatomical structures, referred to as magnetic resonance-guided focused ultrasound – a non-invasive procedure to destroy target tissue via thermal ablation – in disorders including, but not limited to, Parkinson's disease.1 For example, in a recent clinical study evaluating the utility of sonication in Parkinson's disease, thermal ablations were performed on the fibres connecting the thalamus and globus pallidus. 

Subjects were treated with either one impulse or five-to-six impulses during the procedure. Three months post-administration, subjects who were treated with one impulse improved by approximately 8% on the Unified Parkinson's Disease Rating Scale as assessed by independent neurologists, whereas subjects treated with repeated impulses improved by approximately 57% with no undesirable side effects reported by either group.1, 6 Similarly, a clinical study evaluating the effect of magnetic resonance-guided focused ultrasound on the central lateral thalamic nucleus in a small group of subjects (n=11) experiencing chronic treatment-resistant neuropathic pain, reported a mean improvement of 42% and 41% at 3 and 12 month follow-up, respectively – as assessed by the visual analogue scale.1, 7

The main advantage to magnetic resonance-guided focused ultrasound is its non-invasive application using a head piece to prevent heating of the skull bones with a special phased array system that operates at frequencies of 0.5 – 1.5 MHz. The foregoing apparatus and procedures eliminate the need for anesthesia, incision, and post-operative analgesics, while maintaining high precision via intraoperative magnetic resonance guidance and minimal risk of iatrogenic complications (e.g., allergic reaction, shift of brain structures, infection).

In addition to advancing technological treatments, accumulating data investigating the utility of complementary and alternative therapies for Parkinson's disease as part of an integrative strategy are emerging. For example, Toosizadeh et al. (2015) conducted a randomized, controlled, proof-of-concept trial evaluating the benefit of electro-acupuncture therapy in fifteen adults with idiopathic Parkinson's disease (mean age 70.2 ± 7.3 years) and 44 healthy age-matched controls. 

Subjects with Parkinson's disease were randomized into two groups with a ratio of 2:1:1) 30-minute electro-acupuncture treatment (n=10) and 2) 30-minute sham treatment (n=5).2 The primary outcome measure was balance performance, as assessed by the ratio of medial-lateral center of gravity sway to anterior posterior sway and ankle-to-hip sway during eyes-open, eyes-closed, and eyes-open dual-tasks trials; subjective evaluations of pain were assessed using the visual analog scale and explored in secondary analyses.

Subjects in the electro-acupuncture group demonstrated improvement in balance performance with reductions in medial-lateral center of gravity sway to anterior posterior sway by 31% and significant reduction in rigidity by 48%; however, although visual analog scale scores decreased following treatment in the intervention group this change was not significant.2

Abnormalities in pain processing in Parkinson's patients may result from decreased basal ganglia dopamine production and neurotransmission. Evidence suggests that alternate pain mechanisms, independent of dopaminergic pathways may contribute to the experience of nociceptive and neuropathic pain, providing an avenue for novel treatment options and/or therapeutic strategies targeting this highly prevalent non-motor symptom among patients with Parkinson's disease.

References

            1. Dobrakowski PP, Machowska-Majchrzak AK, Labuz-Roszak B, Majchrzak KG, Kluczewska E, Pierzchala KB. MR-guided focused ultrasound: a new generation treatment of Parkinson's disease, essential tremor and neuropathic pain. Interv Neuroradiol 2014;20(3):275-282.

            2. Toosizadeh N, Lei H, Schwenk M et al. Does integrative medicine enhance balance in aging adults? Proof of concept for the benefit of electroacupuncture therapy in Parkinson's disease. Gerontology 2015;61(1):3-14.

            3. Zhu M, Li M, Ye D, Jiang W, Lei T, Shu K. Sensory symptoms in Parkinson's disease: Clinical features, pathophysiology, and treatment. J Neurosci Res 2016;94(8):685-692.

            4. Oazturk EA, Gundogdu I, Kocer B, Comoglu S, Cakci A. Chronic pain in Parkinson's disease: Frequency, characteristics, independent factors, and relationship with health-related quality of life. J Back Musculoskelet Rehabil 2016.

            5. Defazio G, Tinazzi M, Berardelli A. How pain arises in Parkinson's disease? Eur J Neurol 2013;20(12):1517-1523.

            6. Jeanmonod D MDMDeal. Study on incisionless transcranial MR-guided focused ultrasound treatment of Parkinson's disease: safety accuracy and initial clinical outcomes. Washington: 2012.

            7. Jeanmonod D MMMAeal. Surgical control of the human thalamocortical dysrhythmia: I. Central lateral thalamotomy in neurogenic pain.  Thalamus & Related Systems 2001;(1):245-254.

 

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