INTRODUCTION

Parkinson's disease (PD) is presented as a chronic, long-term, irreversible pathology with symptoms that worsen over time. PD is the second most frequent neurodegenerative disease after Alzheimer's disease. In countries such as the United States, a prevalence of 350 per 100,000 inhabitants is estimated; it is approximately twice more frequent in males than in females ^1,2.

The PD was first described in 1817 by the British neurologist James Parkinson, who initially called it "alteration of the motor system" ³. Currently, PD is defined as a progressive neurodegenerative condition that arises as a consequence of an alteration in the production of dopamine by the dopaminergic neurons of the substantia nigra (SN), which causes an imbalance in the extrapyramidal control of the motor system; it is included within the movement disorders ^4,5.

Symptoms usually appear after the age of 60 and it is very rare before the age of 30, although there is a minority of patients with early or juvenile onset ^6,7. The prevalence ranges from 1% in the population around 65 years of age, to 5% at 85 years of age ⁸. After 90 years old, the onset of the disease is uncommon ^2,9.

Despite the research efforts, the causes that trigger this disease are still unknown. In the pathogenesis of PD, several mechanisms are proposed as the cause of the lesion of the group of neurons present in the SN, without there being a directly related cause to date. Among these mechanisms, a combination of genetic predisposition with environmental factors is proposed ^4,5,9,10. The genetic factor, which initially was proposed as the only cause, is more associated with the atypical form of early onset of PD that represents a minority of cases ^1,6, which supports the theory stating that more than one factor (besides the genetic) can be the cause of this disease ^9,11. It has been demonstrated with the identification of at least nine loci and the cloning of genes involved in the familiar form ¹¹.

The oxidation triggered by the presence of free radicals (Table I), the action of exogenous toxins such as manganese and organophosphorus pesticides are among the proposed environmental factors; other still unknown environmental factors have been considered ^7,9; thus, acute exposure to 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine, a toxic analogue to meperidine that is commonly found as a contaminant in illicit psychostimulants, is a known cause of rapid development of the PD and it has been used to obtain experimental models for their study.

Table I. Findings indicative of oxidative stress in Parkinson's disease 

This neurodegenerative disease is characterized by the presence of tremor at rest, bradykinesia or hypokinesia, unstable gait and muscle rigidity, together with other manifestations such as the alteration of postural reflexes, flexion posture and the phenomenon of freezing. To diagnose the disease, a patient should present at least two of the symptoms above mentioned, being essential the presence of tremor or bradykinesia. Other frequent findings are unexplained pain, constipation, urinary retention, sexual dysfunction, dementia, depression, altered sleep patterns or weight loss ^9,12,13. They can be detected some years before the onset of any of the cardinal motor signs ¹⁴. A landmark study showed that virtually all PD patients report at least one nonmotor symptom when these manifestations are actively investigated using specific questionnaires, reaching an average of eight different symptoms per patient. In this study, the most frequent nonmotor symptoms were neuropsychiatric, gastrointestinal and pain-related symptoms ¹⁵. Others report that, in the early stages of the disease, the most common nonmotor symptoms are hyposmia, pain and sleep disorders ¹⁶.

Although pain has never been considered a primary symptom of PD, several researchers, including Charcot ¹⁷, had already referred to painful aspects of the disease: Sometimes Parkinson's is preceded by neuralgic or rheumatoid pains, which are occasionally of great intensity, being located in the extremity (...) that will soon be affected (...) by the convulsive agitation.

NEUROANATOMIC AND NEUROPHYSIOLOGICAL CONSIDERATIONS OF PARKINSON'S DISEASE. NEUROCHEMICAL SCHEME OF THE BASAL GANGLIA CIRCUIT

Normally there is a balance between the contractile activity caused by acetylcholine and the inhibitory activity mediated by dopamine, which allows adequate tone and muscle function. There are five types of dopamine receptors: D1, D2, D3, D4 and D5. The types D1 and D5 are excitatory, whereas the remaining receptors are inhibitory, which means that the net effect of dopamine is the inhibition of cell action. By binding to its receptor, dopamine activates the G protein coupled to it. This causes the alpha subunits to separate from the rest of the protein and activates the adenyl cyclase that manages to increase the levels of cyclic AMP. Finally, there is an inhibitory effect on the action of the cell which, in the case of the muscle cell, would inhibit the contraction. In PD, the production of dopamine is impaired, and prevails the contractile effect of acetylcholine, whose striatal concentration remains normal ¹⁸.

In a healthy individual, the generation of coordinated motor movements by the brain lies in a balance between the activation of voluntary movements or direct pathway and the action of the inhibitory pathway or indirect pathway. Neurotransmitter dopamine and its receptors are involved in both pathways. Thus, under normal conditions, dopamine type 1 receptors (D1) are involved, located in the internal globus pallidus (GPi) and in the reticular part of the SN, and dopaminergic neurons that project to the external globus pallidus (GPe), represented by D2 receptors, are also involved. In patients with PD, due to the presence of a dopaminergic degeneration, these pathways are affected, resulting in a hypoactivity in the direct pathway and a hyperactivation in the inhibitory pathway.

The dorsal striatum (caudate-putamen) receives excitatory stimuli, glutamatergic, from the cortical motor areas. The final feedback of the dorsal striatum to the cortex is conducted by the motor thalamus and it is directed directly toward the motor cortex, where the areas involved in the movement organization are located. More than 90% of striatal neurons are medium-sized GABAergic neurons projecting outside the striatum. A simplified model of the functioning of the basal ganglia comprises two circuits already mentioned: one Direct and one Indirect (Figure 1). The glutamatergic neurons of the motor cortex innervate two main types of striatal GABAergic neurons. One type of neurons co-expresses the neuropeptides dynorphin (dyn) and substance P (SP) and has D1 dopaminergic receptors. These neurons directly project the GPi and the SN (compacta and reticulata), with an inhibitory action on both (direct pathway). The other type of GABAergic neurons expresses enkephalin (enk) and D2 dopaminergic receptors. These neurons indirectly project the GPi and SN through the GPe and the subthalamic nucleus (STN). First, they send inhibitory stimuli to the GPe, which in turn exerts an inhibitory effect (GABA action) on the STN. The latter exerts glutamatergic excitatory effect on the GPe, GPi and SN (indirect pathway). The dopaminergic neurons of the SN pars compacta (SNc) modulate the striatal impulses. It seems that they exert an excitatory effect on striatal GABAergic neurons with D1 receptors and exert an inhibitory effect on GABAergic neurons with D2 receptors. The activity of these dopaminergic neurons is controlled by the GABAergic projections from the striatum and by the glutamatergic projections of the STN. The main exit route of the basal ganglia takes place from GABAergic neurons of GPi, which project to the motor thalamus. The mentioned model is simplified, and does not explain the role of a percentage (10%) of GABAergic neurons of the striatum that express both D1 and D2 receptors, as well as the role of the cholinergic interneurons of the striatum, which also express somatostatin ^19,20.

Fig. 1. Direct and indirect pathways in the basal ganglia circuit. 

PATHOPHYSIOLOGY OF PARKINSON'S DISEASE

PD is characterized by the progressive loss of dopaminergic neurons in certain regions of the central nervous system, such as in the SNc, the locus coeruleus and raphe nuclei and neurons of the olfactory bulb; cholinergic, catecholaminergic and serotonergic neurons are also affected.

All this leads to an inability to perform the coordinated movements. The loss of dopaminergic communication between the basal ganglia and the striatum will generate a series of events that cause the classic symptomatology in patients with Parkinson's disease.

The death of dopaminergic neurons in the SNc leads to the loss of dopamine in the caudate nucleus and putamen. The pathological manifestations include degenerative changes, such as neuronal death, depigmentation in the SN and the appearance of intracellular inclusions in dopaminergic neurons called Lewy bodies (see below). The functional effects of the loss of dopamine in patients with Parkinson's can be understood according to the commented mechanism of the basal ganglia circuit (Figure 1, Figure 2). Normally, dopamine exerts an inhibitory effect on GABAergic striatal neurons with D2 receptors (indirect pathway) and an excitatory effect on neurons with D1 receptors (direct pathway). By decreasing the inhibitory effect on neurons with D2 receptors, the GABAergic inhibitory action of the striatum on the GPe increases, slowing down the inhibitory action of GPe on the STN. This produces a release of the STN when this slowing down disappears, which increases the excitatory stimulus of the STN at all levels: SN, GPe and GPi. Furthermore, the decrease of the dopaminergic action on neurons with striatal D1 receptors leads to an attenuation of the GABAergic inhibitory action of the striatal neurons on the GPi. Therefore, as a final result, there is an increase in the GABAergic action of GPi in both direct and indirect pathways. This hyperactivity causes the inhibition of the motor thalamus that is responsible for the motor control of the cortical areas involved in the initiation of movements. The thalamus-cortex glutamatergic hypoactivity is related to symptoms such as rigidity, slowness of movement, akinesia, etc. The tremor is attributed to the "escape" of the motor thalamus from the powerful inhibition from the GPi, originating burst firing (every 125-250 ms) towards the cortex that are causing the muscular tremor (4-8 times per second) ^21).

Source: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J. Harrison. Principios de Medicina Interna. 18.ª edición.

Fig. 2. Model of motor circuit operation of the basal ganglia. A. Normal condition. B. Parkinson's disease. VL: ventral lateral nucleus of the thalamus. VA: ventral anterior nucleus of the thalamus. D1 and D2: dopaminergic receptors. GLU: glutamate (excitatory). DA: dopamine. STN: subthalamic nucleus. SNc: substantia nigra pars compacta. GPm: medial globus pallidus. GPi: internal globus pallidus. 

The appearance of parkinsonian symptoms does not occur until approximately 80% of the neurons in the SN have been lost (the cell count does not exceed 100 thousand) ²². The rest of the unaffected neurons present mechanisms of neuronal plasticity, producing an increase in the amount of dopamine and the development of hypersensitivity of dopaminergic receptors. Functional reserve through these adaptations explains the progression of PD, delaying the onset of the symptoms of the disease. Rapidly evolving lesions, such as those produced by neurotoxins, also produce parkinsonian symptoms. It has been postulated that some insult of toxic or viral type could accelerate the progressive neuronal degeneration. The anatomopathological studies of brains of post mortem patients who have suffered PD reveals the presence, already mentioned, of eosinophilic inclusions, called Lewy bodies, which contain proteins such as ubiquitin and alpha synuclein. The latter protein participates in the recycling of synaptic vesicles ^23,24. These proteins accumulate forming "aggresomes", which promote oxidative stress and apoptosis. These aggregates are not exclusive to PD and can be observed in patients with Alzheimer's disease, Hallervorden-Spatz syndrome, and even in subjects without neurological disease ¹⁰.

Histopathology reveals the presence of dystrophic neurites throughout the central nervous system, as well as a variable loss of neurons in subcortical nuclei, particularly the SNc, the locus coeruleus, and the basal nucleus of Meynert and the dorsal motor nucleous of the vagus. Additionally, there is an intense depletion of melanized neurons (45-66%), as well as immunoreactive dopaminergic neurons for tyrosine hydroxylase (60-88%) of the SNc, particularly in the ventrolateral third (91-97%), which is projected to the striatum, followed by the mid-ventral, dorsal and lateral areas ²⁵.

ENVIRONMENTAL FACTORS. ROLE OF OXIDATIVE STRESS

Although there is no direct evidence, different findings in humans and experimental animals support the hypothesis that oxidative stress is responsible for the death of dopaminergic cells in PD (Table I).

The dopaminergic neurons of the SN are more dependent on energy metabolism and mitochondrial oxidative phosphorylation than other brainstem populations (so they are more sensitive to oxidative stress); they also have low levels of calcium binding proteins, which implies a decrease in neuroprotective function.

As described, oxidative stress is the "driving force" of neurodegeneration and its cause is unknown ²⁶. The evidence suggests that, in situations where antioxidant cellular defense fails to compensate for the increase in reactive oxygen species (ROS), it would be the prelude to cell death.

One of the possible explanations is that an increase in the accumulation of iron (cation) has been found inside the mentioned neurons of PD patients. The concentrations of iron are increased by 129% ^27,28, whereas the concentrations of the antioxidant peptide glutathione are reduced by 40% ²⁹, which could facilitate the appearance of reactions with the formation of strongly oxidizing radicals, such as superoxide ion. The nitric oxide synthetase enzyme is also increased in the glia of the SN ³⁰, which leads to the formation of peroxynitrites and hydroxyl radicals, highly oxidizing. Excessive formation of reactive oxygen and nitrogen species leads to damage to proteins, lipids, DNA and RNA. The levels of protein carbonyls, protein oxidation markers, are twice elevated in the SN of patients with PD ³¹. The levels of lipid hydroperoxides, indicators of lipid oxidation, are tenfold increased ³². Finally, 8-hydroxyguanine, an indicator of oxidative damage in RNA and DNA, is also increased ³³. In addition to oxidative stress, there is a toxic neurodegenerative cycle characterized by mitochondrial dysfunction, glutamate-mediated excitotoxicity and inflammation in the SN. All this explains the rapid progression of PD once the symptomatology manifests.

Because dopamine participates as a neurotransmitter at the systemic level in other body functions, a decrease in the levels of dopamine can be associated with other clinical alterations affecting, for example, blood pressure and cardiac contraction or hormonal regulation of prolactin. Therefore, additional events may occur in patients with PD, such as central hypoventilation, marked orthostatic hypotension, myoclonus or urinary incontinence ²⁶.

PAIN IN THE PD. IMPORTANCE OF THE PROBLEM

The interest in the study of motor symptoms in PD (Table II) has historically been larger than that shown by the assessment of nonmotor symptoms (Table III). Patients with PD may present with severe or untreatable pain, which may be more intense than motor symptoms, but still remains an underestimated symptom despite the fact that the correlation between pain and PD was described by James Parkinson as " rheumatic pain that extends from the arms to the fingers "³⁴.

Table II. Parkinson's disease. More frequent motor symptoms 

Table III. Parkinson's disease. Nonmotor symptoms 

Although some studies place gradual importance to nonmotor symptoms, only a minority of studies have focused on the painful experience suffered by patients with PD.

Ability to diagnose and clinical experience to determine the cause of the pain are required. The most important diagnostic tool is the patient's medical record.

Perhaps the most important task for people with PD experiencing pain is to describe as accurately as they can if the drugs induce, exacerbate or alleviate their pain. More than half of people with PD declare that they have suffered painful symptoms, stiffness, numbness and tingling at some point in the course of their illness. Pain in PD is an early symptom and can precede motor symptoms by several years ^14,35,36.

The prevalence of pain in PD may vary from 34% ³⁷to 83% ³⁸, depending on methodological evaluations.

Pain occurs two or three times more frequently in patients with PD than in individuals of similar age without PD ^38,39,40.

Pain does not seem to be influenced by sex, age or geographic/cultural variables ⁴¹.

Pain usually occurs on the side where the motor symptoms appear or are more severe ⁴². However, this is not always the case, as some patients may have pain on the side not affected by the disease ⁴³.

In terms of pain localization, although it can be quite variable, the lower back and legs are the most affected regions ⁴¹. Pain in the shoulder, commonly reported by patients with PD ^15,43, may be the first symptom in 2-8% and may even precede the onset of motor symptoms ⁴⁴.

Pain is believed to come from two different mechanisms: one mechanism directly related to the neurological symptom (pseudorheumatic and dopamine-sensitive), and the other mechanism could be associated with degenerative lesions that may worsen with the progression of PD.

People with pain and PD have higher scores on depression assessment scales ⁴⁵. Therefore, it is important that in any assessment of the pain of an individual with PD, the possibility of the contribution of depression, which could require treatment, should be taken into account.

Another element to take into account are cognitive disorders, which can influence the perception of pain felt by the patient.

Systemic diseases, such as diabetes mellitus, osteoporosis and rheumatic diseases, are also associated with a higher prevalence of pain in PD ⁴⁶. Finally, there is also evidence of an association between genetic factors and musculoskeletal pain; for example, mutations in the SCN9A (sodium channel Nav1.7) and FAAH (fatty acid amide hydrolase, a cannabinoid metabolizing enzyme) genes have been associated with an increased susceptibility to this symptom in PD ⁴⁷.

ASSESSMENT AND DIAGNOSIS OF PAIN IN PATIENTS WITH PD

There is great variability in the characteristics of pain in PD, which can be mild to severe intensity, and of nociceptive and/or neuropathic components.

Lee et al. showed that 41.5% of patients in their series with pain and PD did not receive any analgesic treatment ^48,49,50.

Among the diagnostic tools for assessing pain in PD, the most commonly used are: Brief Pain Inventory ^{36,38,51,52,53,54,55,56}and the Short Form (SF) 36 ^49,57. The McGil pain questionnaire ^38,58,59,60is also very useful. More specifically, the pain of PD can be assessed through the DoPaMiP Study (Douleur et maladie de Parkinson in Midi-Pyrénées), which suggests that an initial distinction can be made between pain related to PD (PRPD) and pain not related to PD (PUPD) ³⁸.

"King's Parkinson's disease pain scale", which was proposed by a multicenter group at King's College Hospital in London, is officially defended by the "International Parkinson and Movement Disorder Society Non-Motor PD Study Group" to evaluate the pain in the PD. It is a questionnaire with fourteen questions covering seven domains: 1) musculoskeletal pain; 2) chronic pain; 3) pain related to fluctuation; 4) night pain; 5) orofacial pain; 6) discoloration and edema/swelling; and 7) radicular pain ⁶¹. This is a new approach to pain in PD, which will allow more in-depth testing in clinical trials for treatments of this aspect of PD.

As above mentioned, pain may be the first symptom of the disease or it may present in advanced stages ^62,63. The two keys that help to recognize that a pain is related to the PD itself are: its presentation or its maximum intensity on the side most affected by PD and that improves after the administration of dopaminergic medication. The characteristic is that the pain is present in "off" periods and pain improves during the "on" periods ⁶⁴. Of course, a thorough general and neurological examination should be performed to rule out other pathologies.

The need or not to request complementary tests to determine the origin of the pain must be personalized in relation to the data obtained in the case history and in the physical examination of the patients. If the pain is lumbar and radiates to the legs, alterations of the sensitivity, force or reflexes are observed in the exploration, it would be necessary to rule out the presence of herniated discs or stenosis of the lumbar canal, so frequent in this age group. Sometimes, the pain is localized in the joints, and if it does not respond to the dopaminergic medication it would be necessary to perform imaging tests of the joint.

In the case of neuralgic pain, or if it has characteristics of polyneuropathy, an EMG should be requested if the pain persists with dopaminergic medication. If the pain has characteristics of thalamic pain, a brain MRI would be indicated.

The request for complementary tests in patients with pain and PD should be occasional if the patient clearly improves with dopaminergic medication.

For a systematic approach to diagnosis, please, see Table IV.

Table IV. Diagnosis of pain in Parkinson's disease (PD) 

Source: Santos García D, Aneiros Días A, Macias Arribi M, Llaneza González MA, Abella-Corral J, Santos-Canelles H. Síntomas sensoriales en la enfermedad de Parkinson. Rev Neurol 2010;50(Supl 2): S65-S74. DOI: 10.33588/rn.50S02.2009742.

Quinn et al. ⁶⁴classified PA pain into four categories:

For other authors, painful and disturbing syndromes in PD usually arise from these five causes, following the classification proposed by Ford ^65,66, who was based on the studies of Goetz and Quinn ^(64.67)and that it implies the etiology of pain and its association with motor symptoms (Table II):

PAIN CONTROL

Bearing in mind that there is a biochemical imbalance in which acetylcholine predominates over dopamine, pharmacological therapy is based on the administration of anticholinergic agents, dopamine substitutes, dopamine agonists, dopamine degradation blockers and adjuvant therapy ^1,9,100.

The sensory phenomena occurring in states of dopaminergic hypofunction could be interpreted as a direct effect of the disinhibition of the sensory pathways from the ganglia of the base ^64,101. Fil et al. ¹⁰²establish the following factors that potentially affect pain in PD:

Pain in PD is usually the result of inadequate dopaminergic therapy ¹⁰³. People with PD who are in the "on" state, when the medication is at maximum efficacy, they report less pain than those in the "off" state (Table V). Pain due to dystonia or stiffness can be relieved with dopamine drugs, but on the other hand, it can lead to the development of dyskinesias. Therefore, effective management of levodopa medication for patients with PD can help to reduce pain.

When pain is very severe and we cannot suppress it during the off periods, we could try subcutaneous injections of apomorphine ^104,105. In case of fluctuations that are not controlled using the usual medical treatment, the placement of an apomorphine pump or a continuous infusion of levodopa could be considered.

Table V. Drugs used in parkinson's dise 

Source: Gómez Ayala A. Enfermedad de Parkinson abordaje terapéutico y farmacológico. Farmacoterapia 2007;26(5).

If the pain is associated with an "off" dystonia, it can be improved with local injections of botulinum toxin ¹⁰⁶, applied to the muscles affected by dystonia.

Techniques such as cognitive-behavioral therapy (which helps to control the psychological response to pain, the teaching of diaphragmatic breathing, visual image exercises, relaxation techniques, etc.) and biofeedback have also proven useful.

Within some of these pharmacological pathways we have ¹⁸:

COMT inhibitors

These drugs increase the brain values of levodopa by inhibiting its metabolism. Its use is, therefore, indicated in association with levodopa in patients with dopa therapy and motor fluctuations. In this sense, the "on" periods increase and the "off" periods decrease in patients with these fluctuations, in mild to moderate illness.

The fact that apparently COMT inhibitors also improves motor function in patients without fluctuations, makes some authors propose the use of COMT inhibitors associated with levodopa since the beginning of treatment, although this point is not yet clearly established. The use of COMT inhibitors, however, may increase the risk of dyskinesias.

Table VI. Treatment of pain in Parkinson's disease (PD) 

Source: Santos García D, Aneiros Días A, Macias Arribi M, Llaneza González MA, Abella-Corral J, Santos-Canelles H. Síntomas sensoriales en la enfermedad de Parkinson. Rev Neurol 2010;50(Supl 2): S65-S74. DOI: 10.33588/rn.50S02.2009742.

CONCLUSIONS

In recent years, nonmotor symptoms in PD have received increasing attention from physicians and researchers. Pain is present in the preclinical and initial stages of the disease and it is a cause of suffering and disability in patients with PD, causing a great impact on the quality of life and unfortunately, very often, pain goes unnoticed in clinical practice because usually the greatest attention is given to motor alterations. The prevalence of pain in patients with PD varies between 34% and 83%. It has been described that in the early stages of the disease, there is back and neck pain, which can result from stiffness in the shoulder girdle, and pain in the legs that can be a result of the syndrome of restless legs or dystonia. In advanced stages, pain can be caused by dyskinesia, akathisia, dystonia of the "off" period (40%) and nondystonic pain of skeletal muscle, articular or radicular type (20%), as described by James Parkinson in his original article on "paralysis agitans". In general, pain in PD is usually the result of inadequate dopaminergic therapy, improving if a more continuous stimulation of dopaminergic receptors with levodopa is achieved, adding COMT inhibitors or dopamine agonists. Although the pain in PD is generalized and incapacitating in some cases, its clinical and pathophysiological characteristics have not been fully defined. Further studies are needed to clarify these points and to elucidate the role of dopaminergic and nondopaminergic pathways in nociception, central modulation of pain and affective/motivational dimensions in the perception of pain.