The prevalence of pain in Parkinson’s disease (PD) can range from 34% [1] to 83% [2]; this early symptom can precede motor symptoms by years [3]. In individuals who have had the disease for less than six years, pain can be the most disturbing non-motor symptom. Although it is common in any stage of the disease [4], around 40.5% of patients may not report this complaint in routine visits to a physician [5].

Chronic pain is defined as pain that persists after the normal period of injury healing and continues for at least three months [6]. There is no consensus on assessment, classification, or duration of pain in PD patients. The first classification, published by Ford [7], is most commonly used and classifies PD-related pain into five groups (musculoskeletal, dystonic, neuropathic/radicular, central or primary, and akathisia), but this classification is not complete enough to characterize the various aspects of pain in PD. A new classification associated with a novel scale, the Parkinson’s Disease Pain Classification System (PD-PCS), was recently proposed, defining PD-associated pain as nociceptive, neuropathic, or neuroclastic and generating scores by multiplying intensity by the frequency and impact of pain on activities of daily living [8]. In nociceptive pain, nociceptors are activated by stimuli related to actual or potential lesion to nonneural tissues. It includes most of inflammatory conditions where tissue lesion or inflammation predominates. Neuropathic pain is associated to a lesion or disease of the peripheral or central somatosensory system, with specific characteristics (tingling, burning, or electric-shock-like sensations) and location (neurologically plausible). Nociplastic pain syndromes comprise instances where the nociceptive system is overactive without any evidence of somatosensory system lesion or peripheral activation of nociceptors due to actual or potential tissue damage [7-9].

PD pain may be related to low levels of dopamine and dysfunction in the nigral and extranigral pathways [2, 4]. Dopamine is secreted in several central nervous system structures involved in pain and analgesia such as periaqueductal gray matter, hypothalamic paraventricular nucleus, amygdala, and substantia gelatinosa in the spinal cord [10]. There is a state of hyperalgesia with a reduced pain threshold in PD patients that is reversed with dopaminergic medications [11]. Levodopa is still the most widely used and effective dopaminergic medication for treating motor signs of PD, but long-term management of chronic patients on levodopa is hampered by the occurrence of motor fluctuations and dyskinesias, which tend to become major causes of disability and reduced quality of life as the disease progresses [12]. Although non-motor fluctuations have only been recently recognized, they occur similarly [13]. Pain is frequently reported during the “off” phases when treatment loses effectiveness and motor fluctuations appear, and occurs in around 50% of patients [14, 15]. The clinical characteristics of pain during off phases are not well established [16, 17], and investigating pain in these phases can help improve the understanding of this symptom in PD patients and contribute to the study of chronic pain in individuals without this disease [9]. This study describes the characteristics of chronic pain in a group of PD patients, analyzing the difference between pain in the “on” and “off” phases of levodopa therapy.

The mean scores for the Hoehn and Yahr staging (2.35±1.19), MDS-UPDRS-III during the ON stage (17.95±10.03), and MDS-UPDRS-IV (6±3.17) indicate a group in the intermediate stage of the disease with treatment complications. Demographic and clinical data are summarized in Table 1.

The pain was not influenced by sex or age in our sample, although recent data from the literature indicate predominance in women [11]. An increase in the prevalence of pain should also be expected throughout the clinical and neurodegenerative progression of the disease, in line with the findings of Sung et al. [11], even though previous isolated studies indicated otherwise [2, 25].

The legs were the most frequent location for pain reported by our study participants. In the review by Rana et al. [26], the lumbar region and legs were most affected. The DoPaMiP study [27] found leg pain in 67% of patients with pain directly related to PD, while lumbar pain was most prevalent in the group with pain related to a cause other than PD and not aggravated by PD. Some cases of spontaneous leg pain with normal lumbosacral spine imaging and no association with motor fluctuations could be a variant of PD central pain [9, 28].

As in other studies, the most common type of pain in our sample was musculoskeletal [2, 25, 29, 30]. However, our study found neuropathic and central pain more prevalent than dystonic pain. We revisited our results to fit them into the new Parkinson's disease pain classification tool developed by Mylius et al. [8], the PD-PCS. We found a similar number of patients with neuropathic pain as described in the study by Mylius et al. [8] (19.1% vs. this group’s 16%), but we found more patients with nociceptive pain (71.4% vs. 55%) and fewer patients with neuroplastic pain (9.5% vs. 22%). Our scores for nociceptive pain (25.26±21.26 vs. 22.6±29.1) were similar to those found by Mylius et al. [8], and the lowest scores were also found in patients with nociplastic pain (13±7.07 vs. 6.0±16.4). However, the results for neuropathic pain (45.5±30.08 vs. 7.3±19.1) were quite different, which may be justified by the use of a specific tool to diagnose neuropathic pain (LANSS) [21]. Furthermore, the small sample size in our study was a limitation that may have distorted the results.

The higher MDS-UPDRS-IV score observed in the patients in our sample with chronic pain was related to a higher frequency of levodopa complications in this group and reinforces the association between pain and motor complications, as reported by other authors [29-31]. Most patients with wearing-off had associated motor and non-motor symptoms, and 90% of the patients presented pain during this phenomenon. Cheon et al. [14] described similar findings in this group’s assessment of symptoms during wearing-off, reporting that approximately 70% of patients with motor fluctuations exhibited associated non-motor symptoms, with diffuse pain the most common complaint in 51% of patients. Recent evidence supports an association between the off phase and the development of chronic pain; dopamine-depleted patients seem to have an increased sensitivity to pain [11].

Patients in the WOFFP group had more recent onset of pain, 12 months versus 36 months in the NWOP group. The DoPaMiP study [27] reported similar findings; the subgroup with pain directly related to PD reported a shorter time to pain onset than the groups with pain indirectly related to PD and pain not related to PD. The group with pain directly related to PD presented similar characteristics to the patients in this study in the WOFFP group: a higher prevalence of patients with motor complications and exacerbation of pain during the off phase, in addition to a good response to antiparkinsonian medication, regardless of the type of pain (nociceptive, nociplastic, or neuropathic). Storch et al. [16] observed that most episodes of pain were intensified or restricted to the off phase in patients with motor fluctuations. Martinez-Martin et al. [31] reported an interesting finding that nocturnal pain (when the off phase is commonly expected) is significantly more frequent in PD patients than controls.

A relevant finding of this study was the greater number of words chosen in the affective/motivational dimension of the MPQ pain evaluation by the individuals in the WOFFP group; this was also observed in the pain rating index for this dimension. In the DoPaMiP study, the group with PD-related pain scored higher in this dimension than the group with non-PD-related pain [27]. This finding may be related to the hypothesis of dopaminergic dysfunction in the mesocorticolimbic pathway, which is associated with the affective/motivational dimension of pain, the ascending reticular activator system, the central modulation of pain perception, and the reward system [9, 10]. A study utilizing positron emission tomography found increased activation in the insula, prefrontal cortex, and anterior cingulate cortex during the off phase [32]; these areas of the limbic system are associated with the affective/motivational dimension of pain. In other words, degeneration of dopaminergic neurons in the ventral tegmental area may reduce pain thresholds and simultaneously activate structures in the limbic system associated with the unpleasant perception of pain [9, 10].

Although our sample was small, we could corroborate a good response to levodopa in Parkinson's disease-related pain by using a new pain classification and scoring tool. These results are expected to stimulate further studies to clarify the role of dopaminergic and non-dopaminergic pathways in nociception, central modulation of pain, and the affective/motivational dimensions of pain perception.