Pain In Parkinson’s Disease – Insights gained from thermal testing

Parkinson’s Disease and Pain

An estimated 6.1 million patients suffer from Parkinson’s Disease (PD) in the world today. A progressive neurogenerative disease, that is both chronic and complex, PD’s etiology is not completely understood. Aside from the classically defined motor symptoms, there is a wide range of accompanying non-motor symptoms including somatosensory impairments and chronic pain that affect the patients’ Quality of Life.

Chronic, persistent pain is a common accompanying non-motor symptom, and affects approximately 85% of all PD patients. Since the chronic pain of PD patients is often both unrecognized and under reported, 50% of these sufferers receive inadequate, or no pain-relief treatment. Clearly, the lack of adequate pain treatment is a significant additional burden to the pain itself, having further negative impact on their quality of life (Bannister, 2021). Furthermore, in ~ 20% of patients pain may appear before the motor symptoms of PD. (Barboza, 2023) Pain may be neuropathic in nature, nociceptive, for instance due to muscular rigidity, or nociplastic. Given the occurrence of pain in PD patients, the ability to measure/quantify this pain could be an important step to better understanding these patients and perhaps open a window to improving their quality of life.

Small-fiber sensory impairments in Parkinson’s Disease

Quantitative sensory testing (QST), a valuable psychophysical technique used in both in clinical research and in the clinic, can be useful for enhancing the understanding of the underlying processes contributing to chronic pain in PD patients.

In separate studies, Qiu et al. and Krämer et al. explore somatosensory impairments in PD patients using QST (Qiu, 2020) (Krämer, 2021).

For assessment of the somatosensory profiles of twenty early-to-intermediate PD patients compared to healthy controls, Krämer et. al. used the commonly accepted QST study protocol of the DFNS using a TSA-II by Medoc Ltd. with the standard 30*30 mm thermode with the Method of Limits.. Thermal QST in the DFNS protocol includes cold detection, warm detection thresholds, thermal sensory limen, cold pain threshold and heat pain threshold. Additionally, paradoxical heat sensations -reports of hot or burning sensations to innocuous cold stimuli were assessed in the thermal sensory limen (TSL) protocol. The TSL protocol consists of using alternating warm and cold stimuli repeatedly, they demonstrated sensory impairment in PD patients. Compared to healthy controls, PD patients showed significantly higher cold detection thresholds, while warm detection thresholds were higher but did not reach significance. The authors state this pattern of sensory abnormalities are an indication of small fiber dysfunction or degeneration. Moreover, these sensory abnormalities were detected by QST among PD patients who had not yet reported sensory symptoms or any clinical signs such as neuropathic pain due to small fiber neuropathies (Krämer, 2021).

Qiu et. al. performed the assessment of thermal sensation and pain (tolerance) thresholds among fifty PD patients at early stage of disease progression with mild to moderate symptoms and compared results to fifty age-matched healthy subjects. Sensation testing of the feet were performed using the TSA with a standard 30*30 mm thermode using the Method of Limits. In their results of warm sensation (WS) and cold sensation (CS) assessments, the PD group showed a significant lower ability to detect temperature changes, with CS thresholds of 21.3 for PD vs. 28.2°C in healthy and WS thresholds of 43.1 in PD vs. 40.2 °C in healthy. PD patients also demonstrated inaccurate response to temperature changes as they could not sense an increasing or a decreasing change in temperature (getting hotter/colder). Cold- and hot-induced pain was also assessed, where the patients pressed a stop button when the thermode reached a temperature that was too hot or too cold to tolerate. These assessments showed no differences between the two groups. In line with the findings by (Krämer, 2021), these PD patients demonstrated increased thermal thresholds (Qiu, 2020).

Psychophysical Assessment of Mechanistically Classified PD-related pain

Quantitative sensory testing and other psychophysical assessments, like temporal summation and conditioned pain modulation, are clinical research techniques demonstrated to enhance our comprehension of the mechanisms driving the onset of persistent pain.

“Personalized pain management" aims to understand the neuronal mechanisms which underlie persistent pain in individual PD patients and treat their pain based on these underlying mechanisms. Psychophysical assessment, as QST, can also be used in the identification of patient subgroups prone to developing persistent pain. This may be crucial in the effort to devise and monitor personalized pain management strategies prior to chronification.

Researchers Barbosa et al. theorized that a mechanistic classification of PD-related pain may be what is needed for the development of an individualized treatment of PD related pain, even though it is still unclear if the mechanistic classifications are related to ‘somatosensory or cortical excitability profiles.’ Furthermore, should these relationships reveal ‘potential psychosocial or neurophysiological markers for different PD related pain subtypes’, this could lead to a more precise manner of classifying patients’ pain. The revelation of these relationships could have a positive impact on prognosis, as well as therapeutic choices.

The researchers (Barboza, 2023) compared chronic pain subtypes among PD patients. Twenty patients suffering from nociceptive pain, the most common PD-related pain subtype, present in ~50% PD patients, were compared to fifteen patients suffering from non-nociceptive pain (neuropathic or nociplastic). For assessment of the somatosensory profiles, they measured thermal thresholds using a TSA device (Medoc). For the identification of the cold and warm detection thresholds they used the Levels method to avoid bias due to increased motor reaction time related to bradykinesia and rigidity. Heat and cold pain thresholds were assessed using the Method of Limits.

Although in comparison to age and sex matched healthy individuals, as whole PD patient had abnormal QST parameters of similar frequency, demonstrating lower thermal detection thresholds (i.e., hyperesthesia), as well as lower thermal pain thresholds (i.e., thermal allodynia). ). While comparisons between chronic pain subtypes within the PD patients showed nociceptive pain patients only differed in lower WS compared to patients with non-nociceptive pain. PD patients’ pain subtype was classified according to the Parkison’s Disease Pain Classification system, a relatively new questionnaire. Considering the findings of this study which show location-nonspecific hyperesthesia and allodynia in this patient group, it leaves to wonder whether there is an overlap between the nociceptive and nociplastic / neuropathic pain in the PD patients that participated in this study.

Does Spinal Cord Stimulation help in Parkinson’s Disease pain?

PD pain can be treated with pharmacotherapy or non-pharmacologic therapies such as deep brain stimulation (DBS) and spinal cord stimulation (SCS). The proposed primary mechanism of pain relief by SCS is segmental inhibition at the level of the stimulated spinal segments, though this was thus unclear. A study by Katsuhara et al. demonstrated the impact of pain relief by SCS in PD patients suffering from low back pain and lower extremity pain and how it involves modulation of the pain thresholds at the level of the stimulated spinal cord segments (Katsuhara, 2024). Pain thresholds to thermal nociceptive stimulation were measured in seven female PD patients with intractable PD pain in the lower extremities during SCS-off and SCS-on using the Pathway Thermal Sensory Analyzer by Medoc. They demonstrated that SCS increases the pain threshold for thermal nociceptive stimulation in PD patients. They found that cold pain threshold, but not heat pain threshold significantly differed on the hand between the ON-SCS and OFF-SCS state, while in the leg there was a significant difference, with higher thresholds for both heat and cold pain in the ON-SCS state. Interestingly, a significant difference was found between the most painful limb and the non-painful limb in the ON vs. the OFF state for cold pain threshold. The difference was clinically significant for the painful limb while non-significant for the non-painful limb. The most significant results for all sites were obtained with the cold pain threshold measure. According to the authors the effect witnessed in the upper extremity cannot be entirely accounted for by the SCS effect, but may be the cumulative effect of SCS-ON phase and Levodopa administration prior to commencing the Quantitative Sensory Testing. (Katsuhara, 2024)

According to Bannister, dopaminergic therapies, such as Levodopa, for motor symptoms also have the added effects on PD-related pain symptoms. (Bannister, 2021)

QST’s role in Parkinson’s Disease pain

There are different underlying causes for the different pain types and understanding the intricate mechanisms of the ‘pain circuitry’ of that individual is key to identifying the optimal treatment for their pain. That is to say, the identification of the distinctive pathophysiological characteristics specific to persistent pain and PD states, and finding adequate mechanism-based treatment, is of paramount importance.

Psychophysical testing, as QST, is a critical clinical technique that has the potential to enhance our insight of pain in PD and achieve personalized pain management objectives. (Bannister, 2021) Given the high percentage of PD patients who suffer from persistent pain, the importance of understanding its measure would seem to be an obvious step in the effort to improve their quality of life.