1. Introduction

The continually industrializing world has introduced major medical advancements that have significantly improved the quality of health care we now possess. As a result, there are more people alive today and living longer than ever before. However, such progress does not develop without further challenge, as we now see neurological disorders becoming the primary cause of disability, of which Parkinson’s disease (PD) is the fastest growing with a doubling in cases between 1995 and 2015 (to 6 million) and another doubling projected by 2040 [1]. As age-related illnesses such as PD increase in prevalence, it should be of primary concern to a new generation of health care providers to equip themselves with the necessary knowledge and tools to diagnose and treat them.

Parkinson’s disease is a widely described, physically and mentally disabling neurodegenerative disorder that is most often recognizable in patients by the presence of three cardinal motor signs: resting tremor, bradykinesia, and muscular rigidity. Any one of these symptoms are present in 70–90% of Parkinson’s patients and allow for a good diagnostic potential [2]. Accompanying the motor symptoms are the non-motor presentations of PD, such as depression, insomnia, and cognitive decline, all of which are well-known to negatively affect the quality of life in the Parkinson’s patient [3,4]. One symptom often poorly recognized and under-treated by health care providers despite being reported as the most common non-motor symptom is the finding of chronic pain [5–8]. Chronic pain was noted in PD since its original description in 1817 by James Parkinson in such ways as, “[…] great pain in both arms, extending from the shoulder to the finger ends. […] leaving both the arms and hands in a very weakened and trembling state.” Further, it continues to be a lesser-known characteristic of the disease in the greater number of Parkinson’s patients seen today [7,9]. While it is understood that some level of pain is caused and/or made worse by PD, the presentation of pain in patients is greatly varied in type and severity, with some patients reporting no pain and others experiencing several modalities of pain ranging from minor to moderate and severe [6,10]. If the health care provider is made better aware of the presentations of chronic pain in PD, then a diagnosis and effective treatment plan is more likely.

2. Chronic Pain in Parkinson’s Disease

Resting tremor, stiffness, loss of balance, trouble speaking, and eventually, neurocognitive decline are the symptoms commonly associated with Parkinson’s disease. Lesser known, but severely contributing to the degrading quality of life in Parkinson’s, are the various manifestations of chronic pain that can present [6,10,39]. Compared to the general population of similar age, Parkinson’s patients have been confirmed to suffer from a significantly higher level and prevalence of pain [5,6]. It is important to categorize and describe this pain in Parkinson’s, as it often persists unrecognized in patients suffering from the disease who otherwise could benefit from tailored treatment [5,6]. The types of chronic pain understood to be resulting from or exacerbated in the Parkinson’s patient are musculoskeletal pain, dystonic pain, nerve pain, primary pain, akathitic pain, and gastrointestinal [39–41]. An overview of the types of pain and their treatments can be found summarized in table 1.

Table 1. Treatment and Pain Type.

2.1. Musculoskeletal Pain

The most common form of pain reported by Parkinson’s patients is of musculoskeletal origin, in 45–90% of patients [5,10,39,42]. This type of pain arises as a result of the postural changes and muscular rigidity that is seen in Parkinson’s and includes conditions such as frozen shoulder, low back pain (LBP), arthritis, and osteoporosis. Frozen shoulder can be described as a “premotor” symptom for PD, occasionally presenting in an individual within 1 or 2 years before disease onset [43]. It is a gradual decrease in range of motion accompanied with pain, insomnia, and possible atrophy of the infraspinatus [44]. Of all musculoskeletal pain seen in PD patients, back pain makes up the majority [6]. One 2018 study investigated PD patients with LBP and found lumbar arthrosis in 79.6%, scoliosis in 38.8%, and spondylolisthesis in 24.1% [45]. When scoliosis was present, it was strongly correlated with progression of PD [45]. The study noted that only a small portion of these PD patients were receiving orthopedic care respective of their condition. Secondary to back pain (71.4%) in PD is joint pain in ~52% of patients with pain, which is thought to be associated with skeletal deformation and muscle wasting [6]. Because this type of pain is common in the general population, it is difficult to say whether PD causes it, or only accentuates a preexisting condition. Loss of bone density is another characteristic of PD, possibly attributable to immobility, decreased strength and weight, or levodopa use, that poses an additional risk for fracture-related pain in a fall-risk patient [46,47]. Understanding how PD affects the musculoskeletal system is paramount in improving the quality of life for the Parkinson’s patient [6,42].

2.2. Dystonic Pain

Dystonia is an uncontrolled muscle contraction accompanied by a deformed posture, usually in the hands and feet of a Parkinson’s patient [48]. It causes pain and inconvenience when there is prolonged muscle contraction recurring, such as plantar flexion of the toe, which impairs simple tasks like walking or wearing shoes [49]. Studies show that 15–40% of Parkinson’s patients with pain report dystonic character [5,10]. Unlike musculoskeletal symptoms mentioned above, dystonia is rarely reported in the untreated Parkinson’s patient. Current belief is that chronic treatment with levodopa dysregulates striatal cholinergic signaling and synaptic plasticity, possibly due to epigenetic alterations taking place over time [48,50–53].

2.3. Peripheral and Central Neuropathic Pain

Nerve pain in PD can be subdivided into two separate etiologies. The first is radicular origin, and is presumably caused or exacerbated by the postural changes and bone deformities seen in PD [39,45]. The second can be referred to as peripheral neuropathic, and includes symptoms such as tingling, numbness, and general pain. Pathology behind the occurrence of this pain in PD is not confirmed, but it is suggested to be associated with decreased levels of vitamin B12, methylmalonic acid, and/or homocysteine due to levodopa-induced malabsorption [54,55]. Another hypothesis points toward PD as being the cause itself, with phosphorylated α-synuclein depositing in nerve fibers to produce symptoms [56]. Regardless of cause, about a quarter of Parkinson’s patients with pain report nerve pain as discussed here (20% and 31.5%), presenting an additional challenge in improving quality of life [5,10,57].

Primary, or central pain, is thought to be driven directly by PD pathology and is described to be unexplainable stabbing, burning, or scalding sensations in 4–10% of patients with pain [5,10,39,58,59]. It is known to be very painful, poorly understood, and difficult to treat [60,61]. The leading hypotheses as to the cause is some dysfunction in the pain pathways or processing of pain inputs within the central nervous system [62,63]. Concerning general chronic pain, some studies suggest that it is not the sensory perception that is modulated in PD, but the motivation to endure or avoid it that is altered [64]. This concept stems from studies that have shown dopamine, which is the neurotransmitter at loss in PD, to be involved in the emotional-motivation aspect of pain rather than the sensory-discriminative [65,66]. Additionally, it is observed that accumulation of Lewy bodies, an abnormal protein aggregate indicative of PD, occurs in the area of the brain associated with the emotional-motivational aspect of pain [67–69]. If this is indeed the case, then it could explain why chronic pain, especially in PD, is difficult to treat using the conventional approach to sensory-discriminative pain processing [64]. Perhaps the answer to chronic pain in PD lies in investigating the emotional-motivational aspect of pain perception [70,71].

2.4. Other Pain Conditions Associated with Parkinson’s Disease

Akathisia refers to an unpleasant agitating sensation that is reported in about 20% of Parkinson’s patients usually in the form of “restless legs syndrome” [72–74]. Although not all patients report akathisia as being a strictly painful sensation, it is known to cause insomnia and discomfort that can be treated if the health provider is able to recognize it [5]. In addition, a potential source for chronic pain are the various gastrointestinal abnormalities seen in PD. These include dysphagia, constipation, impaired gastric emptying, and problematic absorption, which could lessen the effects of oral antiparkinsonian treatments and diminishes quality of life in about half of patients with PD [75–77]. Pathology behind enteric symptoms appears to correlate with α-synuclein deposition and subsequent degradation of gastric innervation [78–80]. In the long term, this has been noted to increase susceptibility to potentially painful infections [81,82].

3. Treatment of Chronic Pain in Parkinson’s Disease

Effective management of chronic pain conditions is a difficult task, with up to two thirds of patients reporting dissatisfaction with their treatment results [36]. Unfortunately, PD is not exempt from this reality and achieving satisfactory outcomes when managing chronic pain in PD patients is exceptionally challenging. The extensive heterogeneity of pain that is experienced in PD patients presents obstacles in identifying targets for treatment. Furthermore, a lack of controlled studies has left a dearth of evidenced based treatment recommendations, and current regimens are largely based on case reports and empirical evidence [83–85]. Nevertheless, an array of pharmacological and nonpharmacological treatment options is available to attempt to relieve the chronic pain symptoms of PD patients. The treatment options are summarized in table 2.

Table 2. Treatment Options.

3.1. Dopaminergic Agents

Many of the clinical manifestations of PD are the result of neurodegeneration involving dopaminergic pathways in the CNS. As such, dopaminergic agents have long been a mainstay of PD treatment. The influence of dopamine specifically in PD related pain is less defined however, and thus, the role of dopamine agonism in the treatment of these symptoms is unclear [63,85,86]. There is some evidence that the basal ganglia and dopaminergic activity are related to the occurrence and perception of pain. Research in anaesthetized monkeys demonstrated that painful stimuli evokes depression in the activity of dopaminergic nigrostriatal neurons. Similarly, in rats, dopamine has been shown to exert an inhibitory effect on neuronal responses of the substantia nigra to noxious stimuli [87,88]. It would follow then that the disruption of dopamine pathways in PD may contribute to pain in the disease.

One of the most common used drugs in PD is Carbidopa-Levodopa, a combination medication that includes a dopamine precursor that is converted to dopamine in the central nervous system by the enzyme aromatic l-amino acid decarboxylase, also known as DOPA decarboxylase. Carbidopa is in a class of medications described as decarboxylase inhibitors. It works by preventing levodopa from break down before it reaches the brain, allowing for a lower dose of levodopa and causing less nausea and vomiting. Case reports have pointed to potential analgesic effects of this drug as it has been shown to lessen herpetic neuropathic pain, bone pain from breast cancer and diabetic polyneuropathy [87]. In a study conducted by Honig et al., administration of jejunal levodopa was found to significantly improve the “miscellaneous” sub score of the Nonmotor Symptoms Scale in PD patients. Pain is a component of this subscore in the Nonmotor Symptoms Scale [89]. Other dopaminergic agents have also shown potential in treatment of pain syndromes. Pramipexole, a D2 dopamine agonist, was used to effectively treat a woman with burning mouth syndrome [90]. Likewise, it decreased visual analog scale (VAS) scores in patients with fibromyalgia. This change was not significant, however, pain was a secondary outcome in this trial and therefore patients were not selected for inclusion based on their degree of pain [91]. Apomorphine, a dopamine agonist, showed efficacy in a case series in which three patients reported relief of pelvic pain and two reported relief of painful dystonic symptoms with use of the drug [92]. The drug’s analgesic properties were demonstrated again when it was found to be the only effective treatment for intractable pain in a 68 year old PD patient who had failed management with various other interventions including nerve blocks, regular analgesics, and other antiparkinsonian drugs [93]. Rascol et al. conducted a double-blind placebo-controlled study to investigate the effect of rotigotine, a dopamine receptor agonist, on PD-associated pain. Patients were treated either with a transdermal rotigotine patch or a placebo patch. At the end of 12 weeks, the study demonstrated an improvement in average pain severity over the preceding seven days in those patches receiving rotigotine, however these results did not reach significance. Significant improvements were observed in secondary outcomes such as responses to the Parkinson’s Disease Questionnaire (PDQ-8) [83]. Monoamine oxidase inhibitors (MAOI-B), such as selegiline, may also be beneficial in treating PD related pain. A post-hoc analysis revealed that safinamide reduced the number of concomitant pain treatments that PD patients relied on, and also the scores of the “bodily discomfort” domain of the Parkinson’s Disease Questionnaire-39 [84,94,95].

Perhaps the most convincing evidence for dopaminergic therapy in the treatment of chronic pain in PD is the observation that many patients report experiencing more pain during their “off states,” or times when their medication is not working optimally to control other PD related symptoms, than they do in their “on states” [63,84–86]. While further research is needed to help to refine the use of dopaminergic agents to treat PD related pain, this suggests that optimizing dopaminergic therapy is a valuable step.

3.2. Other Pharmacologic Agents

As with the dopaminergic agents, there is a paucity of literature examining other pharmacologic agents in the treatment of chronic pain in PD. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and diclofenac were reported by PD patients to be the medication most frequently used to treat their pain [94]. The use of these drugs has not been linked to constipation. Opioids and opioid-like medications such as oxycodone, morphine, tramadol, and codeine are also commonly employed in treatment of chronic pain in PD. These medications must be used with caution related to the risk of unpleasant neuropsychiatric and GI side effects [84,86]. A multicenter, double-blind, randomized, placebo-controlled trial showed that Targinact, a combination of the opioid agonist oxycodone and the opioid antagonist naloxone, was significantly better than placebo in delivering pain relief. The opioid antagonist in this formulation helps to minimize the unwanted adverse effects of the opioid medication [96]. Tapentadol, a central-acting oral analgesic with combined opioid and noradrenergic properties demonstrated potential as a treatment in a retrospective study of 21 PD patients. After six months of treatment, patient’s reported lower severity of pain and improved anxiety, depression, and quality of life [97]. Other drugs such as cyclooxygenase-2 (COX-2) inhibitors are also widely used [94].

Care must be taken as to not induce anticholinergic side effects when using medications including the TCAs due to additive constipation complications. [85,86]. The selective serotonin and noradrenaline reuptake inhibitors (SNRIs) also possess pain relieving and antidepressant properties, but carry less risk of anticholinergic side effects. One of these medications, duloxetine, was studied in a six-week open-label trial. A total 65% of patients reported relief with use of the medication [98]. Patients and physicians must be vigilant as there is a risk for precipitating serotonin symptom if used in combination with other treatments such as monoamine oxidase type B (MAO-B).

Localized treatments may be a useful adjunct or alternative to the aforementioned systemic treatments. Botulinum toxin (BTX) injections have been shown to be safe and effective in the treatment of various PD associated symptoms including dystonic posturing, Pisa syndrome and chronic pain [99–102]. In addition to BTX’s effect on reducing neuromuscular hyperactivity, some findings suggest that it may exert direct analgesic effects [103]. A double-blind placebo-controlled crossover study to evaluate the efficacy of BTX type A for treating pain in advanced PD began in 2014. The status of this trial is currently unclear [104].

3.3. Non-Pharmacologic Therapies

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown in multiple studies to be effective against various types of PD associated pain symptoms. Kim et al. followed a group of PD patients scheduled for DBS. Out of 23 patients who reported pain preoperatively, they observed that DBS improved dystonic pain in 100% of patients, central pain in 92%, radicular pain in 63% and musculoskeletal pain in 61% [105]. DBS of the STN has also been demonstrated to increase pain thresholds and pain tolerance, and reduce pain-induced cerebral activity in the somatosensory cortex [106,107]. These benefits are long-lasting as pain improvement was found to endure for up to eight years [108–111]. Pain relief from DBS is likely the result of a combination of mechanisms including decreasing pathologically increased muscle tone, altering pain threshold and tolerance, and improving motor function [86]. Surgical ablation of the globus pallidus, or pallidotomy, is an alternative to DBS for PD related pain. While the literature demonstrating the efficacy of pallidotomy is not as robust as that supporting DBS, a fair amount of studies have detailed its successful use in PD related pain [87,112–114]. Other therapies such as repetitive transcranial magnetic stimulation (rTMS), cranial electrotherapy stimulation, and spinal cord stimulation (SCS) are being evaluated for their utility in treating PD pain symptoms [86,87]. rTMS involves repeated magnetic pulses to a brain area within a short amount of time through a stimulation coil that is placed over the scalp. Cranial electrotherapy stimulation involves giving a small amount of electric current through the head via an ear-clip electrode. Both rTMS and cranial electrotherapy stimulation are noninvasive which could make them attractive alternatives to other treatments. SCS involves the placement of percutaneous electrodes to be placed at the level of the thoracic or cervical spine which involves giving electromagnetic stimulation to the dorsal columns. More research is needed before these treatments to become common place.

3.4. Complementary and Alternative Medicine

In addition to pharmacologic and interventional treatments, several complementary and alternative therapies have also been investigated for alleviating PD pain. The designation of ‘alternative’ medicine is a bit of a misnomer as these treatments are typically used alongside traditional pharmacologic and surgical interventions. A number of studies have examined the benefits of complementary therapies, but there is a lack of large-scale, high-level research and results are mixed regarding their effectiveness. Fortunately, most complementary therapies are safe and well-tolerated, and current literature, though limited, does suggest a role for including these therapies as a component of a multimodal approach to pain treatment.

Massage therapy (MT) is one of the most common forms of complementary and alternative medicine [115]. Studies have shown that pressure applied during MT may stimulate vagal activity, promoting reduced anxiety and pain, as well as increasing levels of serotonin [7]. In a systematic review of 12 studies on MT for PD, Angelopoulou et al. found that MT can lessen pain, induce relaxation, and improve overall quality of life in PD patients. Specific techniques that have proven effective are classical deep therapeutic massage, traditional Japanese massage, and Thai massage [115]. Acupuncture is another technique that has been studied extensively for the treatment of pain conditions. Studies in PD patients have found that patients who received acupuncture had significant improvement in pain scores compared to controls [116].

Exercise and physical therapy, though often employed for improvement of motor symptoms in PD patients, have also been evaluated for positive effects on pain. These techniques have shown some benefits especially in improving musculoskeletal pain. In a survey study of PD patients, rehabilitative therapy and physical therapy were rated as the most effective for pain reduction, though with only temporary relief [6]. An uncontrolled study of 20 PD patients, found that a 12-week exercise program resulted in a slight, though nonsignificant improvement of pain symptoms [117]. Reuter et al. conducted a randomized controlled trial of 90 PD patients, comparing walking, Nordic walking, and flexibility and relaxation programs. The walking groups had further reduction of pain intensity as compared to a flexibility and relaxation regimen, and also had decreased numbers of patients with neck, hip and sacroiliac joint pain [118]. Yoga has been studied for patients with a wide array of neurological disorders. A recent systematic review of 94 studies concluded that yoga can be an effective adjunct to medical treatment [119]. In a study of PD patients, Myers et al. found that yoga reduced the incidence of low back pain and improved balance [120].

Finally, there has been some research into the use of cannabis for pain treatment in the setting of PD. In two small, open-label, observational trials in PD patients, cannabis was found to improve pain scores as well as significantly decrease heat and cold pain tolerance [121,122]. The authors postulated that cannabis acts on PD pain via modulation of the peripheral and central pathways [122]. While no adverse effects were found in these trials, unlike with other complimentary therapies, cannabis use carries the risk of unpleasant side effects. Patients must be aware of the potential for paranoia, delusions, breathing problems, increased heart rate, and nausea. These side effects are typically dose related with incidence increasing with higher doses.

This entry is adapted from the peer-reviewed paper 10.3390/neurolint12030014