Neuropathic pain in multiple sclerosis

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This article will describe chronic neuropathic pain in multiple sclerosis (MS), focusing mainly on classification, providing elements on anatomo-functional correlates, but without going into treatment.

First, how do we define pain in general? The International Association for the Study of Pain (IASP) defines it as “an unpleasant sensory and emotional experience associated with, or similar to that associated with, actual or potential tissue damage” [1].

Pain can be classified on the basis of the interpretation of pathogenetic mechanisms by symptom/sign correlation. In other words, we can recognize different types of pain by the clinician’s integration of all available information: the symptom characteristics described by the sufferer, observation of the sufferer’s behavior, signs evident on objective examination (e.g., coexistence of a sensitivity disorder, pain on mobilization of a joint, triggering through a trigger, etc.), and the results of laboratory and instrumental investigations [2,3].

However, the classification of pain is complex history in nosography and objectively difficult in light of the basic criterion used, with complex implications within the medical-scientific construct of reference [4].

To overcome this complexity, to date, we can refer to the IASP guidance.

Neuropathic pain has been defined by IASP as pain that is related to a primary injury or dysfunction at any level of the nervous system [5]. In fact, the IASP itself, more recently [6], refers to a definition that sees neuropathic pain simply described as that caused by an injury or disease that affects the nervous system in its somatosensory component [7]. Undoubtedly, the demonstration of a lesion at the level of the nervous system, which is clinically compatible, especially because of the topographical distribution of the algias, strengthens the classification of pain as neuropathic [3].

The recent IASP classification of chronic pain for the International Classification of Diseases (ICD-11) plans to classify chronic neuropathic pain associated with MS into the forms of “chronic secondary pain,” where the quality of “chronic” is defined on the basis of persistence of the algic syndrome for more than 3 months [6].

Neuropathic pain can be spontaneous or provoked by sensory stimuli, acquiring the character of hyperalgesia and/or allodynia. Hyperalgesia is defined as an exaggerated painful perception to a nociceptive stimulus. Hyperalgesia may be associated with a reduction in tactile sensitivity: for example, pinprick may cause intense, disproportionate pain, and at the same time recognition of the characteristics of the “pinprick” may be altered in comparison with other unaffected skin areas. Distinguished by the term allodynia is that condition in which pain occurs in response to a stimulus that under normal conditions does not evoke pain.

Chronic neuropathic pain is felt in the territory that is somatotopically correlated with the injured nervous system structure; in the case of forms secondary to MS, of course, reference is made to the central nervous system (“chronic central neuropathic pain”).

On the other hand, a classification problem arises for SM-related impairment of areas of the nervous system on the borderline between the classic and conventional anatomical distinction between peripheral and central nervous systems. Example of this is trigeminal neuralgia secondary to MS. The latter, although due to a demyelinating lesion at the level of the ventrolateral region of the pons, is in fact currently classified under “chronic peripheral neuropathic pain” [6] because it is actually due to the impairment of the intrapontine segment of the trigeminal nerve, in an anatomical area located between the trigeminal root entry zone and the trigeminal sensory nuclei. In MS, as in classic idiopathic trigeminal neuralgia, the pain is characterized by sudden painful paroxysms (lasting a few seconds to a few minutes) that are piercing, “stab-like” or “electric-shock-like,” unilateral, recurring, and distributed at one or more branches of the trigeminal nerve. Such paroxysms are typically evoked by cutaneous or mucosal stimulation within the affected trigeminal territory (trigger zones), e.g., by touching, sometimes just brushing, the face or by actions such as talking, chewing, etc. [8].

The aforementioned IASP classification of chronic pain for the International Classification of Diseases (ICD-11) specifically provides for “chronic central neuropathic pain caused by MS” [6]. This is pain that is believed to be caused by a demyelinating lesion of a region of the central nervous system that presides over areas of somatosensory integration or that affects an afferent sensory pathway or connection between such areas. Pain may be spontaneous or evoked and may take on the above characteristics of hyperalgesia or allodynia. As mentioned above in general, a coexisting deficit of sensation (hypoesthesia) or dysesthesia (touch, temperature, etc. arouse perceptions of the stimulus other than normal) and/or paresthesia (onset of an elemental sensation such as tingling, tickling, etc., in the absence of specific stimulation) is a key element of clinical recognition; sensory symptoms that indicate impairment of an area of the central nervous system in the body region where pain is projected.

In MS that is accompanied by pyramidal motor involvement, pain that is associated with spasticity is very common. In fact, this type of pain is not classified as neuropathic but as musculoskeletal pain [6].

Of difficult inclusion in the taxonomy of pain that, for years now, the IASP has been proposing, the “Lhermitte phenomenon” described by Jean Jacques Lhermitte, a French neuropsychiatrist, in a case of MS in 1924 remains difficult to classify [9]. Lhermitte’s phenomenon is characterized by a paroxysmal electrical discharge-like sensation, actually not always reported as painful by the patient, caused by head flexion, which propagates from the base of the neck along the spine or to other parts of the body; it occurs for a certain period of time (days to months usually) and then resolves; it is related to a demyelinating plaque at the dorsal columns of the cervical spine that causes ectopic generation of a nociceptive impulse along the sensory afferent pathways [10]. In fact, it is not found mentioned within the aforementioned chapter of “chronic central neuropathic pain caused by MS” [6], presumably as a result of the paroxysmal features and the fact that it tends to resolve even before 3 months (however, this is also true for trigeminal neuralgia, which instead finds its place in the IASP classification).

According to the PaIMS Study Group [11], neuropathic pain is the prevalent pain syndrome in MS. In particular, the absolute most frequent algic syndrome is what the researchers classified as “dysesthetic pain,” detected in 18 percent of cases in the Italian population studied. “Dysesthetic pain” can be classified into “chronic neuropathic pain secondary to MS” in the now oft-cited IASP classification [6]. There is sufficient evidence that dysesthetic pain is directly related to the formation and evolution of plaques in the encephalon and spinal cord of people with MS [12,13].

In MS, impairment of the sensory pathways including the spinothalamic tract (whose lesion correlates with more acute, stabbing, piercing, etc. pain characteristics) and the spinoreticulo-thalamic system (dull, dulling, not well localized pain, etc.) is common. These ascending systems project to different and complex neuronal structures (the so-called “pain matrix”), first of all at the level of the thalamus and the secondary somatosensory cortex, but then also at the level of the anterior cingulate cortex, the insula and the periacqueductal gray matter, as demonstrated in healthy subjects with functional MRI techniques [14,15].

Disruption of this “pain matrix,” as a result of classic demyelination plaques and more widespread neuroinflammation of the so-called “apparently normal white matter” and “diffusely abnormal white matter” [16], results in a continuous abnormal response to transient nociceptive stimuli causing chronic pain.

Another classic pathophysiological mechanism of neuropathic pain is that associated with hyperexcitability of dorsal root ganglion nociceptive neurons. In this regard, some studies in animal models of MS have allowed us to hypothesize an impairment of peripheral sensory neurons of the dorsal root ganglia (and also of the trigeminal ganglia) in response to the presence of neuroinflammation at the level of the central nervous system [17]. Such hyperexcitability of dorsal root ganglion neurons results in nociceptive signals being transmitted centrally even in the absence of actual peripheral nociceptive stimuli, eventually promoting the phenomenon of so-called “central sensitization” [18], in which thalamic neurons and other structures of the “pain matrix” can become autonomously hyperactive, with neuronal activity being triggered independently of afferent activation from the periphery.

In addition, there is the role played at the level of the dorsal horns of the spinal cord, highlighted by the fundamental research of Melzack and Wall (1965), fathers of the “gate theory” (Gate Control Theory) that represents a milestone in the pathophysiology of pain [19].

Simply put, the complexity of MS-associated chronic neuropathic pain may recognize pathological anatomo-functional correlates at different levels: from altered nociceptive afferents, to altered “pain matrix,” and from malfunction of descending inhibitory pathways.

Finally, a minimal mention is due to the fact that the anatomo-functional correlations of pain pathophysiology are underlain by an even more complex interaction between neurotransmitter systems (GABAergic over all) and neuro-inflammation [20].

The pathophysiology of pain, all the more so in MS, is therefore complex, and often different types of pain coexist in the same patient, especially in those with high motor disability in progressive forms of MS [11]. Pain is correlated with disability [11,21].

In addition, we should not forget the role of the emotional-affective sphere, which has a complex pathophysiological link with pain. The emotional component of pain is equally important to the somatosensory component. Pain in MS is closely related to MS-related fatigue, depression, and disability; changes in one of these symptoms are associated with changes in the others [21]. On the possible explanations and common pathophysiological mechanisms, there is no space to dwell. It is only worth mentioning here that pain itself is not the only element of “suffering,” because it is associated with other components including, as mentioned, lowered mood, with feelings of insecurity and reduced self-esteem, loss of libido, loss of appetite, anxiety, feelings of severe disability, and sleep disturbances; patients with pain may engage in “sick role” behaviors, often suffering from the anticipation of pain (of “thinking about feeling pain”) and the limitations imposed in certain activities that the patient associates with the possibility of pain being triggered [22]. On the other hand, psychological factors modulate the perception of pain.

Pain, in general, is associated with cognitive impairment in MS, particularly recently an association between pain and impaired executive functions has been reported [23]. Therefore, the more impaired the executive functions, the more frequent is pain, which moreover precisely as a result of cognitive impairment may be more difficult for the patient to describe, putting him or her at risk of treatment failure.

It is important to remember that the burden of pain on activities of daily living and quality of life of the MS patient [24,25], which apparently should be obvious, has actually been given due consideration by physicians for a short time. This is evidenced by the fact that, in the aforementioned Italian PaIMS study [11], only 9.4 percent of participants were taking pain therapy and that a North American study, based on the North American Research Committee on MS (NARCOMS) Patient Registry (10,176 patients), reported the presence of low patient satisfaction with pain management [26].

Attention to a palliative approach to MS as disability progresses is therefore also essential to intercept pain treatment needs [27] and this is what we hope can increasingly be realized in Italian MS Centers.


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