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11 Articles in Volume 21, Issue #1
Advanced Practice Matters with Theresa & Jeremy: Mentorship
Ask the PharmD: What is a true opioid allergy?
Behavioral Medicine: How Clinicians Can Reduce the Stigma Attached to Chronic Pain
Cardiovascular Disease and COVID-19 Infection: A Look at Long Haulers
Chronic Headache: How to Conduct a Virtual Neurological Examination
How COVID Has Changed Pain Practice and Policies
How to Conduct a Pain Evaluation Using Telemedicine
Inside the Potential of Biologics for the Treatment of Rheumatoid Arthritis
Managing Pain in Parkinson’s Disease
Spinal Cord Stimulation Shown to Improve Pain and Movement in Parkinson’s Disease
TeleRheumatology Before and During the COVID-19 Pandemic

Managing Pain in Parkinson’s Disease

Pain affects 40% to 85% of people with Parkinson’s disease – often presenting before motor symptoms. In this review, interventions and strategies for involving patients in their own care are presented as is evidence for current and evolving pharmacologic treatments.

Reviewed by Michael Gabay, PharmD, JD

Background

Parkinson’s disease (PD) is a progressive, neurodegenerative, movement disorder, involving degradation of the dopaminergic tract within the central nervous system (CNS).1,2 Symptoms are characterized by tremors and rigidity, worsening over time, as well as nonmotor symptoms. Currently, no interventions exist to prevent PD progression.3

The goal of therapy is to reduce movement dysfunction while managing cognitive changes.1,3 Episodes of poor movement, including worsening rigidity, tremors, and slowness, may be referred to as an “off” period. An “on” period, conversely, refers to functional movement, when medication controls motor symptoms. The most effective pharmacologic therapy for symptomatic treatment of severe disease and “off” periods includes dopaminergic agents, specifically, levodopa, a precursor to dopamine, given with carbidopa, which reduces peripheral conversion of levodopa to dopamine. Monoamine oxidase type B (MAO-B) inhibitors and non-ergot dopamine agonists are effective as monotherapy in mild to moderate symptomatic PD. Dopaminergic agents are to be used first-line in combatting motor and nonmotor symptoms.

Pain is one of the most common nonmotor symptoms among people diagnosed with Parkinson's disease, often presenting early before motor symptoms. (Image: iStock)

Pain is one of the most common nonmotor symptoms among people diagnosed with PD.3 Pain presents early and can even precede motor symptoms. The prevalence of pain is estimated to be between 40% and 85% in those with Parkinson’s, with reported variability likely due to differences in study design, pain assessment methods, or characterization of pain.4 Literature is lacking on pain predictors in patients with PD.5,6 Pain in PD is classified into one of five descriptors based on its etiology, as described by the widely accepted Ford criteria.7 Patients may experience multiple pain types at once, complicating assessment.8 Table I summarizes these classifications of pain.

Individuals with Parkinson’s may have increased pain sensitivity, which may be a result of a reduced nociception threshold that can occur regardless of the stage of progression of the disease.6,8 Lewy bodies, abnormal protein deposits seen in PD, can impact areas of the brain responsible for pain perception and emotional response to painful stimuli.5 Additionally, lower levels of dopamine may enhance the propagation of painful stimuli signals, causing hypersensitivity to pain in patients with PD compared to healthy controls.10,11

During “off” periods (described above), when dopaminergic agents are not optimized and motor symptoms are uncontrolled, patients report pain more frequently than when motor symptoms are controlled during “on” periods.12

Despite connections between dopamine and pain perception, there is not always an association between dopaminergic augmentation and sensory changes, suggesting that pain can manifest independently via non-dopaminergic mechanisms.8,13 Due to the complex mechanisms and pathophysiology of pain in patients with PD, clinicians should offer a multimodal, patient-centered approach to treatment.

Managing patient expectations is an important cornerstone of pain management in any patient population. The literature demonstrates that patient involvement in their own care can improve quality of life.14,15 A conversation about a patient’s goals in pain management may bridge the gap between patient and clinician expectations of success and help clinicians and patients address concerns and make better-informed decisions regarding pain management. Table II provides recommendations on how to involve patients with Parkinson's in their own pain management.

 

Approaches to Pain Assessment

When assessing pain in patients with PD, using a validated pain scale that targets symptoms specific to PD whenever possible will more accurately categorize pain type. The first pain tool designed specifically for patients with PD is the King’s PD Pain Scale (KPPS).4,12 This scale has 14 questions that measure severity and frequency of different types of pain specific to PD. A complementary patient screening tool, the King’s College PD Pain Questionnaire (KPPQ), is designed for assessing whether or not specific pain types are present. All questions on the KPPQ correspond with a specific question on the KPPS. Screening patients with the KPPQ can facilitate identifying pain types that correspond to the KPPS assessment tool.

If unable to assess pain with scales specific to PD, validated general pain scales, such as the Likert scale, can be utilized to determine quality and severity of any type of pain.18 Using PD-specific pain scales may better characterize a patient’s pain symptoms, however, which may lead to more targeted treatment options. 

Pain Management Principles in Parkinson's Disease

Non-pharmacologic methods with a multidisciplinary pain team should be utilized to provide optimal multimodal treatment in patients with PD.4 Muscle relaxation exercises and walking regularly can improve flexibility and dampen experiences of pain associated with motor symptoms.6 Rehabilitation with a physical therapist can improve gait and balance, targeting pain caused by motor symptoms. Surgical interventions, such as deep brain stimulation or an implanted spinal cord stimulator, may be appropriate for those patients experiencing pain with PD who do not respond to pharmacologic or rehabilitation interventions.1,6,9 (See new research on SCS for Parkinson's related pain and motor improvement.)

Optimization of treatment with levodopa and other antiparkinsonian medications should be the first pharmacological step in managing PD-related pain.6,8 Beyond this recommendation, no evidence encourages the use of specific analgesic agents in any stepwise order, making patient input and assessment of pain type critical to appropriate treatment.

Patients should be prescribed analgesics if optimization of dopaminergic agents is not effective on its own (more on this below).4

Optimization of Dopaminergic Agents

The goal of optimizing dopaminergic agents is to minimize “off” periods and decrease objective pain perception.1 Optimization may include dose titration toward a target dose, increasing dosing frequency, or adding an agent if already at maximum doses of current medications. Although they do not possess an FDA-approved indication for PD pain, three dopaminergic agents have shown additional pain modulation benefit beyond motor symptom control in clinical trials: levodopa, safinamide, and rotigotine.

Levodopa’s effect on pain sensation is uncertain, but is thought to increase the threshold for acute noxious pain signals through increased dopamine levels within pain processing regions, normalizing pain perceptions for patients with PD.6,8,12 As PD progresses and levodopa is used for a longer time, the duration of action of a single dose of carbidopa-levodopa progressively shortens, requiring more frequent dosing.

Safinamide is a selective, reversible MAO-B inhibitor that reduces degradation and reuptake of dopamine to increase levels in the striatum.19 Safinamide also has non-dopaminergic properties that modulate glutamate release via inhibition of voltage-gated sodium channels. This dual mechanism may mitigate pain, especially during “off” periods.

Rotigotine is a non-ergot dopamine agonist that stimulates dopamine receptors and has shown benefit in reducing “off” time with symptom fluctuations.1

Table III summarizes notable clinical evidence examining optimization of these agents in pain management.

Use of Analgesic Agents to Manage Parkinson's Related Pain

After dopaminergic therapy has been optimized in patients with PD-related pain, remaining pain symptoms should be assessed and treated.6,8 Analgesic agents should be considered if pain is not controlled with dopaminergic therapy optimization alone. Although no evidence-based stepwise approach exists for pain in PD, agents should be added based on the type of pain the patient is experiencing, additional comorbidities, and a risk-benefit analysis. In general, non-opioid analgesics should be utilized prior to initiating opioid therapy for chronic pain.

The effects of NSAIDs have not been studied in patients with PD and pain, yet there are no specific contraindications.4 This class of medications does not interfere with dopaminergic medications and is not associated with PD symptomatic worsening. The anti-inflammatory properties of NSAIDs may provide benefit specifically for the treatment of musculoskeletal pain.23 Patient benefit versus risk should be discussed before initiating long-term NSAID therapy. Chronic NSAID use is associated with increased risk of bleeding, especially in older patients, and consequently may be more appropriate as short-term treatment. Acetaminophen, while also associated with increased bleeding risk, is a relatively benign analgesic in patients with healthy hepatic function. This agent is recommended for patients with PD based on clinical experience in other neurological diseases for central pain.6

The CDC guidelines for the treatment of general chronic pain recommend serotonin-norepinephrine reuptake inhibitors (SNRIs), GABA analogs, or tricyclic antidepressants as first-line therapy for neuropathic pain, regardless of the cause; however, no clinical trials exist addressing the use of these medication classes in patients with PD.24,25 GABA analogs such as pregabalin or gabapentin may be used for widespread neuropathic pain to avoid opioids.4 Antidepressant agents, such as duloxetine or amitriptyline, might be considered in patients with neuropathic or central pain regardless of concomitant depression since doses that target pain are less than those that target depressive symptoms (more on dementia and psychosis in patients with Parkinson's on our sister site).12,26 Topical agents, such as capsaicin and lidocaine, may be appropriate for patients with localized neuropathic pain to limit systemic medication exposure.

Caution should be taken with prescribing opioids or opioid-like agents in general due to psychotropic effects and the potential influence over other nonmotor PD symptoms, such as worsening constipation, somnolence, or cognition.12

The combination of oxycodone with naloxone (OXN) was studied against placebo in the PANDA trial to test the tolerability and efficacy in pain reduction in patients with PD.27 The addition of naloxone to the oxycodone formulation was hypothesized to minimize the risk of constipation compared to other opioid agents. Patients with PD and severe pain (defined as mean 24-hour pain score > 6 on a 0- to 10- point rating scale, n=202) were randomized to receive OXN twice daily at a starting dose of 5 mg/2.5 mg (could be titrated to 20 mg/10 mg twice daily) or placebo twice daily for 16 weeks. After 16 weeks, 48% of the patients taking OXN experienced > 30% reduction from baseline in mean 24-hour pain score versus 34% of patients taking placebo (P=0.021, the number needed to treat = 8). At the end of the trial, the primary endpoint mean 24-hour pain score was 5 in the OXN group versus 5.6 in the placebo group (P=0.058), which was not statistically significant.

Augmentation with levodopa-benserazide 100 mg/25 mg up to 3 times daily was permitted for breakthrough pain but use did not differ between groups (OXN, 0.3 tablets/day vs placebo, 0.4 tablets/day). Levodopa-benserazide is not available in the United States but has a similar mechanism to levodopa-carbidopa.26 Subgroup analyses demonstrated that the additional benefit of OXN may be seen in patients experiencing musculoskeletal pain.27 At baseline, 67 patients in the OXN group and 77 patients in the placebo group had musculoskeletal pain, compared to 44 and 54 patients, respectively, at 16 weeks (least-squares mean difference, -0.9; 95% confidence interval [CI], -1.7 to -0.1; P=0.023). The patients taking OXN experienced increased treatment-related nausea and constipation (20% and 17%, respectively) compared to the placebo group (12% and 6%, respectively); however, the authors did not consider this to be clinically relevant. The drop-out rate was high, which may have been due to adverse events (placebo, 10/109 patients [9%] vs treatment group, 17/93 patients [18%]). Based on these results, the International Parkinson and Movement Disorder Society Evidence-Based Medicine Committee offered that OXN could possibly be useful for chronic pain relief.28

Innovative Treatment Modalities for Managing Pain in Parkinson's

Botulinum toxin

Non-dopaminergic pharmacotherapy may benefit patients with PD-related pain. Botulinum toxin (BTX), both A and B derivatives, should be considered in patients who do not respond to dopaminergic treatment optimization.1,8 Botulinum toxin injection provides localized treatment by blocking the release of acetylcholine at the neuromuscular junction.4 Local injections of BTX type A or B can be effective for persistent dystonia-related pain and central pain, based on its neuromuscular action in movement disorders plus analgesic mechanism.

A randomized, double-blind, crossover, placebo-controlled trial concluded that BTX-A in patients with PD is safe and potentially useful in treating limb pain.29 The study was conducted in patients with PD over the age of 30 years with painful limbs not responding to the optimization of anti-Parkinsonian medications. Patients (n=12) were randomized to receive BTX-A injection or placebo, followed by the other treatment per the crossover design. Depending on the location of pain, patients received up to 200 units in upper limbs or up to 300 units in lower limbs. Patients experienced a significant reduction in their self-reported numerical pain score 4 weeks after the BTX-A injection (average dose 241.66 units; mean change, -1.75 points; range, -3 to 7; P=0.033), but not with placebo (mean change, 1.17; range, -4 to 5; P=0.17). There was no difference between the change with BTX-A compared to placebo (P=0.70). This study demonstrated that targeted BTX-A injections are safe in patients with PD.

Positive, decreased responses to pain have been seen with BTX used to treat abnormal postures, such as Pisa syndrome.6 This research may provide the basis for future studies into pain caused by abnormal PD-related postures. Currently, at least one clinical trial is planned to examine the effects of BTX-A on dystonia-associated foot pain in patients with PD.30 While literature is scarce in this patient population, BTX-A and -B injections show promise as an emerging therapy for pain in patients with PD.

Cannabinoids

Cannabinoids act via cannabinoid receptor agonism, affecting nociceptive thresholds.21,31 Anecdotally, cannabis has been reported to act as an analgesic.32 Cannabis contains substances known as cannabinoids, the main cannabinoids being tetrahydrocannabinol (THC) and cannabidiol (CBD). The euphoric effects of cannabis are mediated by THC, which potentially increases the risk of PD-symptom exacerbation. However, CBD targets cannabinoid receptors to decrease pain without psychoactive properties. Clinical data on cannabinoid use in pain mediation are lacking. Federally, cannabis is a schedule-I controlled substance, meaning there is no accepted medical use in the United States, along with a high potential for abuse, limiting research potential.33

High-quality evidence is limited to the use of cannabis in PD for pain. An early, double-blind, crossover-controlled study of cannabis oil in patients with PD (n=17) demonstrated that cannabis was well tolerated and had no pro- or antiparkinsonian action.34 However, cannabis use resulted in no objective or subjective improvement in dyskinesia-pain compared to placebo over an 8-week trial period. An open-label study (n=22) assessing motor function in patients with PD 30 minutes post-smoking cannabis reported mild improvements in rigidity and pain.31,35

There is currently an ongoing clinical trial studying the effects of cannabis oil on pain response in patients with PD.36 While there is limited evidence to elucidate the impact of cannabinoids on pain in this population, it may be an option for patients who have not responded to traditional therapies. 

 

Conclusion

Pain is a common non-motor symptom in those with Parkinson’s disease that can negatively impact quality of life.9,12 PD-related pain can be caused by motor symptoms or separate mechanisms involving neurotransmission and pain perception.6,8,13 Assessment and management of pain in patients with PD should always involve patient input in goal setting. Optimization of treatment with antiparkinsonian medications should be the first pharmacological step in managing PD-related pain. Beyond this, no evidence encourages the use of specific analgesic agents in any stepwise order. Innovative treatment options are being studied to treat pain in this patient population.

Last updated on: January 22, 2021
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