Pain in Multiple Sclerosis Pain in Multiple Sclerosis Dr:Moallemy

INTRODUCTION Multiple sclerosis is an autoimmune disease affecting the central nervous system that seems to occur in genetically susceptible persons. There are also geographic associations with this disease, which reaches its highest incidence in northern Europe, southern Australia, and North America. However, no clear genetic, environmental, or infectious causes have yet been identified also no clear understanding of the immunopathogenic processes that determine the sites of tissue damage in the central nervous system.

Pathologically, multiple sclerosis is characterized by diverse combinations of inflammation, demyelination, and axonal damage in the central nervous system. The loss of myelin covering the axons is followed by formation of demyelinative plaques. Peripheral nerves are not affected by multiple sclerosis. Clinical manifestations of multiple sclerosis reflect its multifocal involvement. The course may be subacute, with relapses followed by remissions, or the course may be chronic and progressive. Manifestations of multiple sclerosis reflect the sites of demyelination in the central nervous system and spinal cord. For example, inflammation of the optic nerves (optic neuritis) causes visual disturbances, involvement of the cerebellum leads to gait disturbances, and lesions of the spinal cord cause limb paresthesias and weakness as well as urinary incontinence and impotence

Typically, symptoms develop over the course of a few days, remain stable for a few weeks, and then improve. Because remyelination probably does not occur in the central nervous system, remission of symptoms most likely results from correction of transient chemical and physiologic disturbances that have interfered with nerve conduction in the areas of demyelination. Increases in body temperature can also cause exacerbation of symptoms due to further alterations in nerve conduction in regions of demyelination. The course of multiple sclerosis is characterized by exacerbations and remissions at unpredictable intervals over a period of several years.

Symptoms eventually persist during remissions, leading to severe disability from visual failure,ataxia, spastic skeletal muscle weakness, and urinary incontinence. However, in some patients the disease remains benign, with infrequent, mild episodes of demyelination, followed by prolonged remissions. The onset of multiple sclerosis after 35 years of age is typically associated with slow disease progression. The diagnosis of multiple sclerosis can be established with different degrees of confidence—that is, probable or definite— on the basis of clinical features alone or clinical features in combination with oligoclonal immunoglobulin abnormalities in the CSF, prolonged latency of evoked potentials reflecting slowing of nerve conduction resulting from demyelination, and signal changes in white matter seen on cranial MRI.

No treatment is curative for multiple sclerosis, so treatment is directed at symptom control and slowing of disease progression. Treatment with corticosteroids shortens the duration of a relapse and accelerates recovery, but whether the overall degree of recovery or progression of the disease is altered is not known. Interferon-β is the treatment of choice for patients with relapsing- remitting multiple sclerosis. Glatiramer acetate is an alternative to interferon-β and is most useful in patients who become resistant to interferon-β treatment caused by serum interferon-β–neutralizing activity. Azathioprine is a purine analogue that depresses both cell mediated and humoral immunity. Azathioprine is considered when patients show no response to therapy with interferon-β or glatiramer acetate.

Central pain in multiple sclerosis The demyelination seen in the central nervous system in MS is the likely cause of acute and chronic central pain conditions. Central pain conditions associated with MS disease include: trigeminal neuralgia (TN), L’Hermitte’s sign, painful tonic seizures paroxysmal extremity pain chronic ongoing central pain mostly located in the lower extremities In addition to central pain, nociceptive pain conditions (including spasm-related pain and low back pain) and pain associated with optic neuritis are frequently seen in this population of patients.

It may be difficult to differentiate between nociceptive pain conditions and central pain. Central pain is experienced by around 30–40% of the MS population. In a few patients CP may be the first symptom of the disease and may precede other symptoms for months or even years.

trigeminal neuralgia The prevalence of trigeminal neuralgia in MS patients is estimated at 2–5% and is thus much more common than in the background population. bilateral TN is more frequently seen in MS patients and TN associated with MS has a lower age of onset. The pain condition may be explained by focal demyelination of the sensory nerve fibers within the nerve root or the brainstem. Increased excitability in the trigeminal afferent neurones and altered threshold for repetitive firing may be the consequence of focal demyelination leading to spontaneous firing and pain paroxysms.

L’Hermitte’s sign L’Hermitte’s sign is described as an electric/tingling sensation radiating down the limbs and body that may be painful. It may be provoked by neck flexion. Around 5–10% of MS patients may experience painful L’Hermitte’s sign. Pathophysiologically, this pain syndrome may be explained by demyelinating lesions of sensory axons in the cervical posterior column

Painful tonic seizures PTS are described as paroxysms of uncontrollable uni- or bilaterally dystonic posturing, lasting minutes, preceded and accompanied by a cramp-like, radiating pain. Painful tonic seizures (PTS) are reported in 1–19% of the MS population. Movements or nonpainful tactile stimulation may provoke PTS. Electroencephalography shows no abnormalities and the patient is conscious during attacks. It may be argued that pain associated with dystonic posturing in PTS is rather classified as a nociceptive pain condition. However, pain precedes other symptoms in PTS and part of the pain reported by patients is probably of central origin.

Acute paroxysmal extremity pain Acute paroxysmal extremity pain not associated with PTS has been described as lasting seconds to minutes. often located to the extremities. It has been suggested that paroxysmal extremity pain in MS occurs on the basis of ectopic activity at sites of demyelination in CNS Paroxysmal limb pain occurs in about 1–4% of MS patients.

Chronic ongoing central pain Chronic ongoing central pain is seen in around 25% of MS patients As chronic CP in MS most often affects the lower extremities and often is bilateral, it may be speculated that medullar lesions (plaques) In particular may give rise to CP conditions The MS patients with pain (58% with central pain), however, more frequently reported cold allodynia (acetone), abnormal temporal summation, lower threshold for mechanical pressure and pinprick hyperalgesia This suggests that MS pain is associated with some degree of hyperexcitability in the CNS

Risk factors of CP in MS Longer disease duration, higher age, higher degree of disability (higher Expanded Disability Status Scale (EDSS) score) and a progressive disease course

TREATMENT The first-line treatment for both idiopathic and MS-related TN is carbamazepine which in RCT has been shown to reduce TN pain and paroxysms. Alternatively, oxcarbazepine may be used, though with a lower strength of evidence. The efficacy of antiepileptics in treating MS-related TN has not been documented so far. Painful tonic seizures in MS are normally treated with anticonvulsants including carbamazepine,phenytoin and gabapentin. Both IV lidocaine and mexiletine were found to be superior to placebo in treating PTS in a nonrandomized placebocontrolled study

In a recent randomized placebo-controlled study concerning the effect of cannabinoids on CP in MS,seven of the included patients had PTS and the authors stated that treatment response for this subgroup was as good as treatment response for patients with dysesthetic limb pain. The efficacy of cannabinoids in the treatment of central pain in MS has recently been evaluated in two RCT Three weeks’ treatment with orally administered synthetic δ-9- tetrahydrocannabinol(THC) (dronabinol) in a maximal dose of 10 mg reduced the intensity of ongoing and paroxysmal pain.

In a randomized placebo-controlled parallel trial by Rog et al. whole-plant cannabisbased oromucusal spray (CBM) was administered to MS patients with central pain. Intrathecally administered baclofen (50 μg) had a pain-relieving effect in a small randomized trial including four MS patients, Both dysesthetic and spasm-related pain were reduced. Chronic and recurrent central pain conditions including paroxysmal limb pain are often treated with antiepileptics or tricyclic antidepressants. In MS patients the efficacy of opioids in CP has not been documented