Parkinson's Disease: Pain Management, Challenges and Solutionsby Prof. Gianliuca Egidi, Pescara 🇮🇹

Parkinson's Disease: Pain Management, Challenges and Solutions - by Prof. Gianliuca Egidi, Pescara 🇮🇹


Parkinson's Disease: Pain Management, Challenges and Solutions

Pain Treatment in Parkinson's Disease Patients: Challenges and Solutions.

This article focuses on the diagnosis and management of Parkinson's-related pain which is one of the most frequent non-motor symptoms in Parkinson's disease, which is the second most common neurodegenerative disease after Alzheimer's disease. Pain is classified by patients as an annoying symptom at all stages of the disease. In the early stage of Parkinson's disease, pain is judged to be the most annoying symptom. Knowledge of the correct diagnosis of the origin of pain and the possible treatment methods for pain relief is of great importance. Symptoms have a major negative impact on health-related quality of life.

Distinguishing PD-related pain from pain of other origins is a major challenge and could be characterized by 'some symptoms under the same umbrella'. Among the different forms of pain related to Parkinson's disease, musculoskeletal pain is the most common form, accounting for 40-90% of the pain reported in patients with Parkinson's disease. An increase due to pathophysiological pathways other than those secondary to stiffness, tremor or any other motor manifestation of the disease seems more likely.

In Parkinson's disease, the basal ganglia manage somatosensory information differently and in patients with Parkinson's disease an increased sensitivity to subjective pain with a lower electrical and thermal pain threshold is reported. The mechanism is assumed to be a decrease in activity of the descending inhibitory control system of the basal ganglia. The pain of Parkinson's disease, like some non-motor symptoms, remains underdiagnosed and, therefore, poorly managed. A systematic collection of patient descriptions regarding the type, quality and duration of pain is therefore of utmost importance.


Recent studies have validated new and more specific dedicated pain scales for symptoms related to Parkinson's disease. Symptomatic treatments based on the clinical classification of pain include pharmacological and non-pharmacological methods, and in part, invasive approaches. In the clinic, pharmacological and interventions may not be effective at various levels - in single or combination therapy - and should be employed, as therapeutic strategies to manage the pain of Parkinson's disease have not been validated to date.

Multimodal approaches should always be taken into consideration, dopaminergic therapies should be modified, analgesics and antidepressants should be considered, including the use of different forms of complementary therapies.

Background

James Parkinson described the phenomenon of pain in Parkinson's Disease in 1817 in his original work "An Essay on Shaking Paralysis":

[...] the writer was called by a woman of about 40, for a great pain in both arms, which extended from the shoulders to the fingertips. She stated, that […] she had not found any benefit from any medicine used […] which left both arms and hands in a very weak and shaking state.

Now, nearly 200 years later, the stressful and frequent chronic pain related to Parkinson's disease remains an underestimated and underdiagnosed symptom in Parkinson's disease.

Parkinson's disease incidence and prevalence, general and Parkinson's disease-related pain

Estimates of the incidence and prevalence of Parkinson's disease have provided conflicting data. In Europe, the annual incidence is estimated between 5/100000 and 346/100000. Approximately 60,000 Americans are diagnosed with Parkinson's disease each year. The challenges involved in differential diagnosis and other forms of Parkinsonism, as well as the long time elapsed between the onset of symptoms similar to Parkinson's disease and the correct diagnosis, are often responsible for the discrepancy in the numbers.

The reported prevalence of Parkinson's disease pain and Parkinson's disease-related pain varies across studies. In 2008, Negre-Pages et al estimated a prevalence of chronic pain in Parkinson's disease to be over 60%.

Parkinson's disease pain is often reported as heterogeneous in its clinical presentations, with a disabling effect on quality of life assessment. In 1998, the Swedish Parkinson Association reported a survey of non-motor symptoms that included nearly 1,000 people with Parkinson's disease, revealing that pain was more common in females than males (54% and 45% respectively). However, general pain is also common in the population, around 18-19% in the general adult population according to prevalence data.

In the early stages of Parkinson's disease, pain is considered to be one of the most annoying non-motor symptoms, and appears to affect the side of the body initially affected by the motor symptoms of the disease. (Table 1)

DEGREE SYMPTOM / CONDITION FIRST CHOICE (%) SECOND CHOICE (%) THIRD CHOICE (%)

1 SLOWNESS 33 5 13

2 TREMOR 30 9 4

3 RIGIDITY 6 26 11

4 PAIN 10 10 5

5 LOSS OF SMELL / TASTE 3 10 3

6 MOOD 4 6 4

7 GRAPH 2 3 6

8 INTESTINAL SYMPTOMS 2 3 5

9 SLEEP 2 4 1

10 WEIGHT / APPETITE 0 3 8

Tab. 1: Ranking of the ten most troublesome symptoms related to PD in 92 patients with early onset disease lasting over 6 years (data obtained by Politis et al.)

Pathophysiological pathways of pain in Parkinson's disease


The origin of pain in Parkinson's disease remains poorly understood. Sometimes, it appears as dystonia when the dopaminergic effects wear off. The pathophysiological mechanism most likely behind this phenomenon is the interaction of dopamine in the system of other monoamines such as norepinephrine and serotonin, through both the inhibitory and excitatory pathways. Abnormalities in the descending pathway affect the processing of central pain. Furthermore, patients with Parkinson's disease describe clinically recognized neuropathic pain and other sensations of muscle pain. This led to the exploration of pathways other than those secondary to rigidity, tremor or any other motor manifestation of the disease, such as an abnormal processing of nociception in patients with Parkinson's disease suffering from pain as the most likely suspect. The basal ganglia process somatosensory information in different ways, and an increased sensitivity to subjective pain with lower electrical and thermal thresholds has been reported in patients with Parkinson's disease. This anomalous processing also includes disorders related to Parkinson's disease such as multiple systemic atrophy, which shows almost the same prevalence of pain in Parkinson's disease.

The anatomical-functional arrangement of the basal ganglia is characterized by multiple interconnected structures and systems. The basal ganglia act as an integration point for afferent fibers in the organization of behavioral responses to stimuli. The influence coming from the cortical and subcortical regions contributes to the system between the thalamus, cortex and basal ganglia. The cortical areas involved play an important role in the processing and modulation of pain. These territories include the frontal and parietal lobes, the insula and the hippocampus. Electrical stimulation of the substantia nigra, one of the basal ganglia nuclei, modulates pain from the dorsal horns of the spinal cord, which is likely mediated by a descending dopaminergic inhibitory pathway originating from the midbrain.

The two main dopaminergic pathways are well known. The nigrostriatal dopaminergic pathway projects from the substantia nigra to the striatal dorsal structures of the corpus striatum. This path has an established function in sensory-motor integration and control. The structures, such as the amygdala, the thalamus and the nucleus accumbens, are reached by neurons originating in the ventral tegmental area. Different projections from the ventral tegmental area also innervate specific cortical regions, such as the motor cortex and the prefrontal cortex. Consequently, there is a significant overlap between the dopaminergic system and the aforementioned brain regions involved in pain processing, and interference in dopaminergic concentrations in these areas could lead to motor and sensory disturbances.

Much evidence suggests that other areas such as brainstem nuclei and diencephalic structures are affected, as do extrabrain structures, spinal cord, and autonomic enteric plexus. Furthermore, as dopaminergic drugs may be effective for various non-motor symptoms, including pain in Parkinson's disease, evidence suggests that these symptoms are associated with dopaminergic denervation in brain areas not primarily related to motor symptoms.

Physiological ways of pain relief

In the early 1960s, the theories initially developed by Melzack and Wall were introduced. These proposed three aspects of afferent input approved for pain: the continuous activity that precedes the stimulus, the activity of the evolving stimulus, the relative balance of activity in the large versus small fibers. The concept of the "Gate Control Theory" was introduced. Painful messages encounter "nerve gates" in the spinal cord that open and close depending on a number of factors (possibly including instructions from the brain). When the gates are open, the painful message "passes" more easily and the pain can be intense. When the gates are closed, the painful message is not conveyed to the brain and may not be proven. Although the details of this process remain poorly understood, it can help explain why various treatments are effective.

The existence of low-threshold mechanoceptive C tactile afferents was initially described by Vallbo et al. These afferents comprise a second anatomically and functionally distinct system that signals touch in humans. The activation of these fibers is more closely related to limbic functions rather than cognitive and motor functions. Although a quick, accurate and information-rich A beta touch intensely reflects the outside world through skin events in an exteroceptive manner, the activation of tactile C fibers shares more characteristics with the intraceptive modalities. This slow, affective nature seems involved in maintaining physical well-being.

PAIN MEASUREMENTS

Pain, stress and stress biomarkers

Stress and pain are often closely linked. One affects the other, creating a vicious circle that lays the foundation for chronic pain and chronic stress. Therefore, stress management should be a component of pain therapy.

The Merriam-Webster Encyclopedia defines the term stress as a "physical, chemical, or emotional factor that causes physical or mental tension and may be a causative factor of illness." The effect of stress can be explained as a physical or mental tension due to factors that tend to alter an existing balance.

In humans, stress is often a reaction to difficulty and possibly dangerous situations. The search for humoral substrates that reflect physical experiences of stress is an area of ​​attractive scientific curiosity. The "fight or flight" response occurs when a person anticipates a threat and the body uses energy to fight or flee far "to live another day". This response is characterized by the release of epinephrine from the adrenal glands, which causes vasoconstriction and increased heart rate.

Measurements of cortisol concentration in saliva have been shown to be a simple and useful indirect biomarker of stress. From the study of the function of the hypothalamus-pituitary-adrenal axis and of cortisol secretion in patients with Parkinson's disease as a surrogate marker of stress and indirect pain, it is possible to study and objectify the effects of the intervention with the aim of providing relief. to stress / pain. Other biomarkers are the concentrations of epinephrine, norepinephrine and oxytocin. Blood pressure and heart and respiratory rates are examples of other markers for assessing stress reduction.

Examples of pain scales

Visual analog scale

The visual analog scale measures a continuum of chosen characteristics present. For example, the pain perceived by the patient extends over a continuum from painlessness to extreme pain intensity. This range of perceived pain appears continuous to the patient. Pain is not reported on an ordinary scale with jumps between values ​​such as fair, moderate and severe. Descriptive words are shown only on both terminus, usually on a line 100 mm long. This assessment is very subjective and best used on single individuals rather than on groups of individuals simultaneously. Many experts claim that VAS can produce serial data at best. This is important to consider in the statistical analysis of VAS data. A ranking in order of score rather than exact values ​​may be the best way to manage patient records on the 100 mm line.

Brief Pain Inventory

The Brief Pain Inventory was initially created with the aim of measuring pain in cancer patients. It measures pain relief, pain quality and understanding of the cause of pain in terms of pain intensity (sensory dimension) and pain interference (reactive dimension).

Examples of pain scales in Parkinson's disease

Pain-O-Meter

This is a pain self-assessment tool developed with the aim of improving pain assessment and management of patients with acute and chronic pain, not exclusively for Parkinson's disease pain. It is a rigid, white, plastic tool. Two methods of pain assessment are located on the Pain-O-Meter (POM). The first is a 10 cm VAS scale with a movable marker that patients use to assess their pain. The second is a list of 15 sensory and 11 affective descriptive words. Each descriptive word is assigned to an intensity value that can range from low (1) to high (5).

King's PD Pain Scale

To date, there is no specific validated scale that is widely used in the area of ​​pain related to Parkinson's disease (Parkinson's disease pain). Therefore, it is important to describe the context of the study in this field. The King's PD Pain Scale was unveiled very recently. The scale is simple to administer, requiring the examiner to ask the patient 14 questions and calculate the severity and frequency of pain in Parkinson's disease. The time required for the caregiver and the patient is estimated to be around 10-15 minutes. Data from seven domains provide information on the different types of pain in Parkinson's disease, broadly classified as a nociceptive and neuropathic pattern. Precisely, the scale captures pain from that connected to time linked to the disappearance of the effects of antiparkinsonian drugs, that is, to pain connected to the end of pharmacological effects, to central, orofacial and radicular pain.

Clinical diagnosis of pain related to Parkinson's disease

Classifications

Traditionally, pain in Parkinson's disease is classified into 5 domains: musculoskeletal, radicular / neuropathic, related to dystonia, akathisia and central. The most common pain syndromes are musculoskeletal and dystonic ones. The central pain of Parkinson's disease is the least common, but important to recognize; it can be intermittent or persistent on its own and is often described by patients as widespread pain, burning or cramping. There need not be any lesions in the peripheral nervous system. Different parts of the body can be affected and autonomic symptoms are often combined. There are no unusual descriptions of pain from facial, abdominal or genital locations.

However, the definition of central pain is not specific and the term is often confused with central neuropathic pain which has another definition. The central mechanisms are almost always involved in the pain syndromes of Parkinson's disease, but this is not the same as meeting the criteria for central neuropathic pain. (Figure 1)

Figure 1: Simplified diagram of pain assessment and its origin in PD

Clinical decisions

When patients with Parkinson's disease express painful symptoms, doctors should first determine if the pain is related to Parkinson's disease. The associations between painful sensations and on / off symptoms are crucial for determining the origin of pain and can support the use of dopamine substitutes to achieve pain relief. How the patient is evaluated is also crucial, since depression and anxiety require specific treatment options. However, the relationship between depression, chronic pain and Parkinson's disease remains unclear.

La depressione potrebbe essere secondaria al dolore della Malattia di Parkinson o viceversa, oppure le due condizioni potrebbero semplicemente coesistere. La ricerca dei neurotrasmettitori suggerisce che i sintomi di malattia, dolore e depressione potrebbe avere substrati fisiologici simili nei pazienti con Malattia di Parkinson.

Localizzazione specifica del dolore nella Malattia di Parkinson

Dolore addominale

Il dolore addominale ed altri tipi di malessere gastrointestinale, come la disfagia, sono comuni nella Malattia di Parkinson. Pertanto, è fondamentale distinguere il malessere addominale legato alle fluttuazioni del carico dopaminergico da altre forme di dolore addominale, come gastrite e reflusso gastroesofageo. Le correlazioni temporali con l’intake dopaminergico ed i sintomi on-off potrebbero fornire una guida.

Dolore dorsale

E’ stato riportato uno studio sulla prevalenza del dolore dorsale nei pazienti con Malattia di Parkinson, > 74%, che è significativamente più alta rispetto alla popolazione generale.

Dolore alle spalle

Il dolore alle spalle è stato osservato nell’11%, 43% o 80% dei pazienti con Malattia di Parkinson nei diversi studi ed è facilmente confuso con una condizione ortopedica. Pertanto, il medico dovrebbe essere consapevole che ciò può essere un sintomo precoce di dolore correlato con la Malattia di Parkinson.

Fluttuazioni delle esperienze dolorose nella Malattia di Parkinson

I pattern delle fluttuazioni dei sintomi non motori sono eterogenei e complessi. I sintomi non motori psichici sembrano fluttuare più frequentemente e severamente rispetto ai sintomi non psichici. Uno studio recente di dieci frequenti sintomi non motori nella Malattia di Parkinson avanzata (100 partecipanti), valutati utilizzando scale VAS come scala di classificazione per la definizione motoria degli stati on-off ed altrettanto bene autovalutazioni a casa, ha confermato i precedenti sospetti: il dolore è aumentato negli stati off e le fluttuazioni del dolore correlano con bassa qualità di vita salute correlata. Il dolore come sintomi non motori era più frequente nello stato off; più precisamente, era tre-quattro volte più comune durante lo stato off rispetto a quello on.

Stato mentale e rete sociale

Come precedentemente menzionato, depressione e dolore sono problemi clinici significativi che sono coesistenti con la Malattia di Parkinson. Lo stato civile, così come altre reti sociali, interferisce con queste condizioni. Il matrimonio/convivenza, che determina un supporto fisico ed emotivo, potrebbe avere un effetto attenuante sugli outcome del paziente in termini di prevalenza della depressione ed interferenza del dolore. I pazienti con Malattia di Parkinson single sembrano avere punteggi di interferenza del dolore maggiori rispetto a pazienti con Malattia di Parkinson che convivono.



TRATEGIE TERAPEUTICHE

Terapie farmacologiche

Farmaci dopaminergici

I pazienti con Malattia di Parkinson hanno uno scarso tono dopaminergico che richiede trattamento farmacologico dopaminergico, quali levodopa e dopamino-agonisti. L’efficacia dei farmaci dopaminergici è stata determinata in altri disordini dei sintomi non motori, come i disordini del sonno e dell’umore; i farmaci dopaminergici hanno il potenziale di ridurre il dolore concomitante così come i sintomi antidistonici diretti dovuti al deficit di dopamina esistente. Il dolore muscoloscheletrico correlato alla distonia spesso risponde bene ai farmaci anti-parkinsoniani.

Paracetamolo, farmaci anti-infiammatori non steroidei, ansiolitici e antidepressivi

La terapia polifarmacologica è comune nel dolore dei pazienti con Malattia di Parkinson. In uno studio precedente, ad un quarto dei partecipanti sono stati prescritti analgesici, principalmente paracetamolo. Comunque, solo un terzo riferiva sollievo dal dolore con gli analgesici. Quasi tutti (9 su 10) usava farmaci per insonnia/ansia e 1 su 5 usava antidepressivi.

Antagonisti dei recettori degli oppioidi

Pain is often a therapeutic target but is rarely managed appropriately. The effects of oxycodone, a semi-synthetic opioid receptor antagonist, were studied in 210 patients with various stages of Parkinson's disease. Participants included in the study reported subjectively experienced severe pain and were followed up for 16 weeks. Participants were randomly assigned (1: 1) to the extended-release oxycodone and naloxone group (5 mg and 2.5 mg, respectively) or to the placebo group. Curiously, the main end point of the mean pain score over 24 hours at 16 weeks was not significantly different in the two groups, reinforcing theories of unique characteristics of pain in Parkinson's disease.

Significant improvements in painful experience with the regimen with opioid receptor antagonists were identified only in the subgroup with severe musculoskeletal pain and in the pain types of severe nocturnal Parkinson's disease. They translated the results for patients with PD pain into daily treatment, clinical improvements could only be achieved if the type of pain is adequately identified, characterized and followed up over time.

Botulinum toxin and other pharmacological therapies with spasmolytic properties

A study was conducted using botulinum toxin for the treatment of dystonia. Of the 30 patients treated for lower limb dystonia, pain was reported to have disappeared for 4 months in about 2/3 of the patients. The injection sites were in many lower limb muscles with a mean total dose of 70 IU of botulinum toxin for each patient. No published controlled studies appear to have been conducted with baclofen or other spasmolytics.

Invasive therapies

Treatment of PD pain resistant to therapy with invasive therapies is rare, but the knowledge of the effects on pain modulation reveals the complexity of the origin of PD pain.

Deep Brain Stimulation of subthalamic nuclei and effects on pain

Deep Brain Stimulation of subthalamic nuclei is commonly used to treat the advanced stages of Parkinson's disease. However, pain modulation closely correlates with the inhibition of the pain experience. In an 8-year follow-up study on the effects of pain reduction in patients with Parkinson's disease treated with STN, the results were stable for several years; 20 out of 24 patients with preoperative chronic pain reported pain only in the off phases. More than 80% of patients still felt pain in the off phases 8 years after surgery, although the intensity and spread of pain recorded at baseline showed improvements. The number of body districts in which patients reported pain was reduced by 40%, and the mean and median pain scores improved.

Better results were also seen in a subgroup of 12 patients with fluctuations in pain equal to fluctuations in motor symptoms. Some of these patients reported continued complete pain relief in the 8-year period after surgery. However, the experience of complex pain and other / new forms of pain evolved in most of these patients over the years studied, which should be considered.

Spinal cord stimulation

The implantation of electrodes near the spinal cord has been described in a few cases (three) of patients with Parkinson's disease with intractable pain. Since the pain in these patients was of non-Parkinsonian origin, it is doubtful whether these findings will contribute to the proposals for invasive treatments in PD-related pain.

Complementary therapies

Complementary medicine (CAM) should not be confused with alternative medicine, in which traditionally accepted treatments are replaced by a wide range of health care practices, products and therapies, ranging from biologically plausible, but not well-tested, a directly contradicted by evidence and science or harmful or toxic. CAM is widely used; in Anglo-Saxon countries, 4 out of 10 adults have used some type of CAM. In a 2000 telephone interview with complete responses from 1000 participants in Stockholm County, 57% had used massage therapy (MT). Adult women with a high level of education are more represented in this consumption pattern.

Massage therapy

Effects of massage therapy on endogenous cortisol concentrations

One of the first attempts to comprehensively examine the effects of massage therapy in human beneficiaries of all ages was published by Field in 1998, and various theories have been hypothesized to explain its effects. The study also included the potential effects of massage therapy in facilitating the growth of infants, reducing pain, increasing attention, reducing depression, and increasing immune function. The decreasing effects of massage therapy on human adrenocorticotropic hormone and cortisol concentrations are consistent with the range of studies examined and have strongly established themselves as a precursor of the beneficial effects of massage therapy.

Although the acute effects of massage therapy on cortisol concentration are notable, they are not maintained in long-term follow-up studies. These findings suggest that cortisol is not a direct mediator of the established and beneficial effects of massage therapy on anxiety, depression and pain, but rather a surrogate marker for stress reduction.

Clinical benefits of massage therapy

Among the most obvious benefits of massage therapy in the treatment of pain is the lack of risk or harm to the patient. Side effects are rare but occasionally include fatigue, hypotension, and dizziness after sessions. Alone or in association with music therapy, massage therapy has been shown to have positive effects on the strength of the painful experience.

Conclusions

Parkinson's disease pain management strategies require a deep understanding of the mechanisms responsible for painful experiences in individual patients. Changes in the central pathways involved in sensory processing reduce the pain threshold in Parkinson's disease. Some studies have confirmed the existence of pathways other than those secondary to rigidity, tremor and other motor manifestations of the disease.

It has been shown that the basal ganglia process somatosensory information through different methods, and recent pain inhibition studies have shown the presence of CT fibers with projections to the insular cortex. The activation of these fibers plays a role in the inhibition of pain and correlates with the effects observed in different forms of massage therapy. Chronic pain related to Parkinson's disease is closely associated with stress, as well as with other forms of chronic and / or acute pain. A reduced concentration of cortisol in saliva or plasma is an example of a biomarker for stress reduction.

The first action that the doctor should take is to rule out other possible sources of pain besides Parkinson's disease. The dynamics over time and the correlation with on / off symptoms and therapy with levodopa / dopaminergic agonists should be evaluated, followed by the creation of a follow-up program of the painful experience. These should be measured in terms of strength, as well as some forms of VAS and in terms of verbal description, which can be done with POM. CAMs are often used in this population, albeit in addition to usual medical care and although they are expensive.

Patient-reported changes regarding painful experiences should be considered when making future treatment strategy choices. The effects of analgesics and NSAIDs on pain relief in Parkinson's disease are not absent, but the limited effects must be considered to understand the partially different pain mechanisms due to neurodegenerative disorders.

There are many indications that physical therapy may be effective in Parkinson's disease when broad outcome criteria are investigated beyond the treatment of pain. Regarding the relief of chronic pain related to Parkinson's disease, there is a need for further controlled studies. The subgroup of patients with Parkinson's disease needs to be defined more meticulously. Who benefits most from tactile touch or massage therapy, which standardized methods are best, the relevant and optimal doses, the duration and intervals of the sessions must all be properly evaluated.




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