Movement Disorders Moment: Pain & Palliative Care in Movement Disorders

Although there is no disease-modifying treatment approved for Parkinson disease (PD) yet, symptomatic treatment of motor symptoms has improved dramatically with advances in pharmacotherapy and neuromodulation. Compared with motor symptoms, however, nonmotor symptoms collectively have a larger effect on health-related quality of life (HRQoL) measures.¹ Pain is a frequently underrecognized nonmotor symptom, despite being quite common with reported prevalence of up to 85% in people with PD. As with other nonmotor symptoms, pain tends to worsen as motor symptoms do.^2-7 Clinicians can address the underdiagnosis and undertreatment of pain by screening for the 5 categories of PD-related pain (Table)⁸ Pain is also common in other neurodegenerative movement disorders.

In advanced PD, individuals may be more sensitive to medication side effects, particularly as polypharmacy becomes more common with different medication classes complexly layered to maximize motor on-time while attempting to reduce levodopa-induced dyskinesias. Special attention must be paid to cognition as well, because people with advanced PD are susceptible to delirium. Additionally, if significant hypophonia, dysarthria, or cognitive impairment are present, it may be difficult to understand the precise location, nature, or etiology of pain. This complexity may necessitate a broader diagnostic approach (eg, exam with gentle palpation, urinalysis, basic labs, or plain films) and sometimes empiric pain treatment with nonnarcotic analgesics. Exercise and therapy are a mainstay of PD care and continue to be important in advanced PD, even if only for maintaining flexibility and preventing painful contractures.⁹ The concept of neuropalliative care related to movement disorders and how neurologists can help optimize quality of life and alleviate suffering becomes ever more important as PD progresses.

Categories of Pain in Parkinson Disease

Musculoskeletal Pain

Pain in people with PD most commonly presents as musculoskeletal, frequently related to secondary spine or joint arthrosis and amplified by akinesia, rigidity, and dystonia. There is not always a correlation to motor symptom severity, however. Pain can manifest at any stage of PD, including premotor and early stages. For example, “shoulder-arm” syndrome can mimic rotator cuff injury masking early rigidity and bradykinesia.¹⁰

People with PD also have a higher rate of osteoporosis, increasing their risk of fractures, immobility, and pain.¹⁰ Osteoarthritic joint pain is also common in PD and tends to increase during “off” medication periods. Joint pain can also be exacerbated by comorbid dystonia. For example, camptocormia and Pisa syndrome are thought to be dystonic phenomena associated with musculoskeletal pathology.¹⁰ It is important to treat these concomitant factors to prevent these postures from becoming fixed.

Musculoskeletal pain in PD can masquerade as primary rheumatologic or orthopedic conditions. A striatal hand may present with features suggestive of rheumatoid arthritis (eg, ulnar deviation of the metacarpophalangeal [MCP] joints or Dupuytren contracture with flexion of MCP joints).^3,11 Careful examination revealing symptoms predominantly ipsilateral to PD should prompt the treatment of motor symptoms, before referral for rheumatologic workup or surgery.

Neuropathic Pain

Postural changes and skeletal deformities can exert pressure on neural foramina, which can lead to radiculopathy. Careful examination of muscle power, reflexes, and sensation may reveal a motor decline secondary to neuromuscular issues rather than motor symptom progression. In these situations, physical therapy rather than up-titration of dopaminergic medications may be most appropriate.

Peripheral neuropathy in PD can present as a small fiber neuropathy because of the accumulation of Lewy body pathology (LBP) in autonomic and nociceptive nerve fibers.¹² Additionally, people with PD have a higher prevalence of large fiber neuropathy, possibly from levodopa use. Levodopa catabolism can result in overproduction of homocysteine and methylmalonic acid, depleting the cofactor B₁₂ and causing neuropathy.¹³ Neuropathy is slowly progressive, usually, but can be subacute in those with PD being treated with levodopa-carbidopa intestinal gel. Prospective, randomized clinical trials are required to clarify the role of vitamin B group supplementation in PD-associated neuropathy.¹³

Dystonic Pain

Dystonic pain can be dopamine-dependent or -independent. Prior to PD diagnosis, dopamine-independent dystonia (eg, kinesiogenic foot dystonia) after exercise may be reported by individuals with early-onset PD, associated with parkin.^3,14 Dopamine-dependent dystonia is related to levodopa-dosing schedules and can be more difficult to manage in advanced PD with oral medications alone, because of worsening motor fluctuations and a narrowing therapeutic window. Toe curling and foot inversion occur in evenings or early mornings when the last dose of levodopa has fully worn off and may be described by patients as a “charley horse” or muscle spasm. Limb dystonia, blepharospasm, or cervical dystonia are also related to peak dose or diphasic motor fluctuations.¹⁴ Careful attention to the timing of dystonia in relation to a dose of levodopa is crucial to treat dopamine-dependent dystonia.

Akathitic pain

Akathisia is a sensation of restlessness or discontent that can occur anywhere in the body at any time of day and is related to levodopa fluctuations in about 50% of patients. Individuals may have an inability to sit still that is partially suppressible but can be distressing in social situations that require prolonged sitting.^8,15 Difficulty sitting still can be mistaken for anxiety or dyskinesia, resulting in unnecessary medication additions or reductions.

Akathisia should not be confused with restless legs syndrome (RLS), which is specifically an urge to move the legs that occurs most frequently at night. Although RLS is common in PD, it also occurs in people with neuropathy and iron-deficiency anemia, and a clear association with PD is unproven.^3,16

Central Pain

Central pain occurs during wearing-off and off periods and responds to dopaminergic medications, suggesting a relationship to dopamine deficiency.⁴ Examples include formication; oral, genital, and rectal paresthesias; abdominal pain largely caused by constipation; and coat-hanger pain, characterized by a posterior headache and neck pain in the setting of orthostatic hypotension.^2,4,6 Because it is a diagnosis of exclusion, screening for central pain should be done after evaluating for other causes of pain.

In this review, depression is included in this category, considering pathophysiologic similarity to the central pain syndromes with dopamine deficiency and altered serotonergic and noradrenergic transmission. Up to 40% of people with PD experience depression as an emotional form of pain that can lower the threshold for other causes of pain.⁸

Pain in Other Movement Disorders

Pain is also common in other neurodegenerative movement disorders. Corticobasal degeneration is an atypical parkinsonism and tauopathy in which limb dystonia is present in over 50% of cases, 42% of which include pain. The upper limb is most often affected, and patients frequently describe hand pain. Multiple system atrophy is an atypical parkinsonism and α-synucleinopathy that causes pain in at least 50% of cases, most commonly in the back, neck, and shoulders, representing the classically described coat-hanger pain in dysautonomia.¹⁷ In Huntington disease (HD), chorea can be painful, and there is consideration that striatal atrophy may contribute to a person’s interpretation of pain.^18,19 A recent systematic review found a mean pain prevalence of 41.3% with a range of 10% to 75%, although the same analysis found that pain might be less burdensome for those with HD compared with the general population. This finding could suggest that pain is eclipsed by the severity of other motor and nonmotor symptoms of HD.¹⁸

Pathophysiology of Pain

The pathophysiology of pain in PD is complex and not fully understood. For the purposes of this review, a few potential pathways are highlighted given their practical implications for the treatment of PD-related pain (Figure 1).

The anterolateral spinothalamic (ALS) tract relays signals from skin nociceptors to the primary somatosensory cortex to localize a painful stimulus. The ALS also projects widely to multiple cortical areas via intralaminar thalamic nuclei for higher order pain processing. Additionally, ALS descending collaterals suppress pain via serotoninergic and noradrenergic signaling.¹² In PD, the accumulation of Lewy body pathology in several of the aforementioned areas alters pain signaling. Additionally, the basal ganglia are not communicating normally with crucial pain-processing cortices including somatosensory, orbitofrontal, anterior cingulate, and the amygdala (Figure 1), altering pain perception.¹²

Pain Management

Despite the high prevalence of pain in PD, only about 50% of people with PD receive pain treatment. Among the commonly used medications, patients report benefit with nonsteroidal anti-inflammatory drugs (NSAIDs), safinamide, and catechol-O-methyltransferase (COMT) inhibitors.^2,20 See Figure 2 for treatment of pain by category. For musculoskeletal pain, first compare the Unified Parkinson’s Disease Rating Scale (UPDRS) score at the current visit with scores from prior visits, because motor symptoms can exacerbate musculoskeletal pain and radiculopathy. In such cases, uptitration of the PD regimen may provide relief. If the UPDRS in the affected limb is unchanged, consider NSAIDs for pain reduction to facilitate participation in physical therapy.² Medical marijuana for pain management in PD is a clinical question that comes up often. There is evidence to suggest it may be helpful with primary and secondary pain syndromes, but none of that evidence is specific to treatment of pain in people with PD.

Neuropathy can be treated symptomatically with gabapentin and antidepressants, although there are no pharmacotherapy guidelines for neuropathic pain in PD.² Screen for and treat any B₁₂ deficiency in people being treated with levodopa.¹³

For dopamine-dependent dystonia, first optimize the dopaminergic regimen to minimize motor fluctuations. The addition of amantadine or anticholinergics can be helpful. Botulinum toxin injections are an excellent option for focal dystonia³ and other aspects of movement disorders.²¹ There have been mixed results when studied in PD, although many movement disorder specialists target focal off dystonia such as painful toe curling with botulinum toxin injections.^21-24 Increased efficacy may occur with ultrasound guided injections.²³

In people with dystonia refractory to medication, modulation of dysfunctional striato-thalamo-cortical circuits with deep brain stimulation (DBS) is a well-established treatment for reducing painful off dystonia while also decreasing levodopa-induced dyskinesias.^3,4,12 DBS may also reduce pain in PD independent of its effects on motor symptoms, although pain is not a current indication for DBS in PD.^25,26 Recent investigation has shown that DBS can improve quality of life even in patients with early motor fluctuations, which is important to keep in mind because surgical risk increases with age.^26,27

Akathitic pain in PD may be related to the effects of nigrostriatal dopamine deficiency on mesolimbic dopamine transmission, resembling akathisia seen with dopamine antagonists. Thus, up-titration of dopaminergic medication may help akathitic pain.^10,15 RLS should be worked up and treated as it would in people without PD.¹⁶

Central pain treatment should start with optimizing dopaminergic medications. The addition of rotigotine or a serotonin-norepinephrine reuptake inhibitor (SNRI) can be effective.^2,28 For refractory central pain, DBS has shown benefit in some studies.^2,29

Palliative Care

People with neurodegenerative movement disorders face presently incurable disease with progressive symptoms that threaten to cause suffering and limit independence and quality of life. Even without curative or disease-modifying therapy, however, neurologists can meet patients’ care needs with symptomatic treatment, a focus on quality of life, and a goal of alleviating suffering. This is the basis of a neuropalliative approach.

In PD, nonmotor symptoms, mood, and gait problems are most associated with poor perceived quality of life. Pain and discomfort are the factors most related to impaired quality of life, even in those without advanced disease.³⁰ These symptoms, among others, offer an opportunity to introduce palliative care focused on improving quality of life by treating symptoms, alleviating suffering, and promoting advanced care planning. Although palliative care is often underutilized for neurologic diseases including PD,³¹ palliative care improves quality of life and reduces caregiver burden of PD, alongside providing improvement in motor symptoms.³²

Neurologists, patients and caregivers alike are often hesitant and misunderstand palliative care, leading to underutilization. Palliative care is: 1) not equivalent to hospice or end-of-life care; 2) not only for advanced disease; and 3) not a replacement for having a neurologist who provides longitudinal care. Specifically, palliative care in neurodegenerative disease may focus on: 1) coping with new diagnoses or an uncertain future; 2) addressing bothersome symptoms such as pain, anxiety, or depression; 3) discussing levels of support needed and place-of-care transitions; 4) advanced-care planning (eg, decisions about resuscitation, artificial nutrition, and intubation); 5) appointing decision makers and completing important legal documents; and 6) considering when, where, and how hospice care may be useful.^32,33

Palliative care has a role at every stage of disease and should not be avoided in early stages. Early involvement of palliative care ensures patients’ desires can be heard before they may be unable to express them.³³ Specific clinical triggers for considering palliative care referral include:

• recurrent falls, infections, or hospitalizations
• swallowing dysfunction or weight loss
• cognitive decline
• diagnosis of atypical parkinsonism (eg, multisystem atrophy [MSA], corticobasal degeneration [CBD], or progressive supranuclear palsy [PSP])

Listening closely to a patient’s concerns often reveals opportunities to openly discuss quality of life and suffering and more easily offer a referral to palliative care. In the past, palliative care often has been misunderstood as only helping patients die well. Rather, a more accurate understanding (and certainly more hopeful for patients and those who care for them) is that palliative care can help those with neurodegenerative movement disorders to live well.³⁴

Conclusion

Pain is common in people with PD and other movement disorders. Although the pathophysiology of pain in PD is complex and not fully understood, as with all pain, neurodegeneration at multiple points in pain-processing pathways (Figure 1) likely plays a role and can provide targets for intervention. Identifying categories of PD-related pain can guide management (Figure 2). Core aspects of treating pain in PD are the use of exercise and physical therapy, optimization of dopaminergic treatment, and the use of empiric pain treatments as needed. Palliative care at all stages of PD is beneficial for helping people live as well as they can with their disease, providing symptomatic improvement, improving quality of life, and alleviating suffering.