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R State of the Art

Pathophysiology Diagnosis Evaluation Therapy

Cl au di o S o l aro M i che l e Me ssme r Ucce l l i

IN TR OD UCTION Multiple sclerosis (MS) is one of the most common neurological diseases and involves inflammatory demyelination of the central nervous system. MS typically manifests between 20 and 40 years of age, although diagnosis can, less frequently, occur in childhood and later in life. The hallmarks of MS are its unpredictability and variability, across affected subjects as well as within the same individual. Common symptoms, among others, include visual impairment, sensory alterations, limb weakness, urinary dysfunction, fatigue, spasticity, cognitive dysfunction and pain (Paty and Ebers, 1998). Pain may be the most commonly treated symptom in MS, estimated to comprise 30% of all symptomatic treatment (Brichetto et al., 2003). Pain sufferers experience disruption in daily life activities, work, mood, recreation and overall quality of life, and report low satisfaction with pain management (Hadjimichael et al., 2007). Literature on pain management is lacking, particularly reports of randomised, double-blind trials, and treatment decisions are often based on clinicians experience. C L ASSIF ICATION OF PAIN SYNDRO M E S Pain is defined as an unpleasant sensory experience associated with actual or potential tissue damage or described in terms of such damage (IASP). Treede et al. classify pain syndromes as nociceptive somatic/visceral and neuropathic pain (Treede et al., 2008). Nociceptive pain occurs as an appropriate encoding of noxious stimuli and represents a physiological response transmitted to a conscious level when nociceptors in bone, muscle or any body tissue are activated, warning the organism of tissue damage, in turn, eliciting coordinated reflexes and behavioural responses. Neuropathic pain is typically initiated by a primary lesion or dysfunction in the peripheral or central nervous system, with no biological advantage (such as warning), causing suffering

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and distress. Clinical hallmarks are burning, dysesthetic, piercing pain, painful responses to non-painful stimuli (allodynia) and/or increased pain sensation when noxious stimuli are applied (hyperalgesia) (Treede et al., 2008). A 2008 report classifies pain associated with MS in four categories: continuous central neuropathic pain; intermittent central neuropathic pain (i.e. trigeminal neuralgia, Lhermittes; glossopharyngeal neuralgia); musculoskeletal pain (i.e. painful tonic spasms, pain secondary to spasticity, pain related to being wheelchair bound) and mixed neuropathic and non-neuropathic pain (i.e. headache) (OConnor et al., 2008). PREVAL ENCE OF PAIN Early estimates of the occurrence of pain in patients with MS ranged from 29% to 86% (Kraft et al., 1986; Moulin et al., 1988; Ehde et al., 2003; Svendsen et al., 2003; Solaro et al., 2004; Hadjimichael et al., 2007) although these numbers have been reconsidered based on more recent studies with large numbers of subjects. One of the largest epidemiological studies performed included 1,672 subjects and reported that 43% of patients with MS experience at least one type of pain (Solaro et al., 2004). In this study the presence of pain correlated with disability, disease course, disease duration and age but not with gender. PAIN SC ALE S Unfortunately, for assessing pain in patients with MS currently only generic pain scales are utilized since no disease-specific scale exists. Studies of pain in MS utilize visual analogue scales and numerical rating scales. While these certainly have some use in assessing pain intensity and unpleasantness, they may lack sufficient depth required to accurately describe the significance of neuropathic pain. PAIN AN D H E ALTH -RE LATE D QUA LI T Y OF LI FE Pain is linked to quality of life (QoL) in MS (Ehde et al., 2003; Kalia and OConnor, 2005). The influence of pain on QoL may be independent of the effect of disease impact, suggesting an interdependent relationship between depression, fatigue and pain. This confirms the importance of addressing MS comprehensively rather than adhering to a singlesymptom approach, since the successful management of one or more symptoms can often impact the status of others. C ON TIN UOUS CENTRAL NE URO PAT H I C PA I N

While important advances have been made in peripheral nervous system injury-related changes, the pathophysiology of central neuropathic pain is poorly defined. MS pain is thought to be a type of central pain due to demyelinating lesions in areas involved in pain perception.

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Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS, inducible in various rodent strains by immunization with several myelin antigens, widely used in order to better understand the pathophysiology of the disease as well as the efficacy of medication. Although few reports in the literature have specifically studied pain in EAE, the availability of an animal model could represent an important step for understanding the mechanism underlying pain in MS and an opportunity to test pharmacological therapies. Aicher et al. (2004) used proteolipid protein (PLP) to induce active immunization (chronicrelapsing form) and PLP-splenocytes for passive induction in SJL mice. Nociceptive testing was done with withdrawal latencies to a radiant stimulus. In both models hypoalgesia peaked prior to the peak of motor deficits, while during the chronic phase of the disease the animals developed hyperalgesia. Thus, suggesting that EAE may be a useful model for pain. In a chronic-relapsing model of EAE, Olechowski et al. (2009) studied pain sensitivity and found a significant decrease in elicited pain behaviour. This behaviour was found to involve the glutamatergic system, suggesting a potential mechanism underlying neuropathic pain. Thibault et al. (2011) characterised sensory abnormalities including thermal and mechanical hyperalgesia and showed a partial effect of medications (gabapentin, duloxetine and tramadol) in two EAE models. Recently, it has been hypothesized that MS is an acquired channelopathy, sodium channel Nav1.8, of which expression is normally restricted to the peripheral nervous system, present in cerebellar Purkinje cells in a mouse model of MS. The ectopic expression of Nav 1.8 contributes to symptom development in the model. Dysregulated sodium channel expression on sensory fibers can lead to a functional change in axonal conduction contributing to neuropathic pain (Waxman, 2001). Although the theory is intriguing and several hypotheses can be made regarding the mechanisms of action of sodium channel blockers, such as antiepileptic drugs on pain in MS (i.e. carbamazepine), no data are available to draw definitive conclusions. Finally, while the field has gained insights into the pathophysiology of the mechanisms of neuropathic pain, particularly in animal models, their replication in human subjects is unknown.

Prevalence of central neuropathic pain

A number of studies have reported central neuropathic pain to be among the most common pain syndrome in MS with a prevalence of nearly 50% (Solaro et al., 2004). The classic signs of central pain such as hyperalgesia and allodynia have been reported in 38% of MS patients, although this frequency may seem lower in clinical practice perhaps in part due to patients difficulty in describing pain (Svendsen et al., 2003). Approximately 40% of patients describe a constant and burning sensation usually involving lower limbs, more frequently distally than proximally. Thirty percent describe this pain as a deep or muscular aching (Beiske et al., 2004). A recent study evaluated the location of lesions in MS patients with or without chronic pain using brain and spinal cord MRI. Thirteen MS patients with chronic pain and ten MS patients without pain were evaluated. There was no association between pain and site of demyelination (spinothalamic tract, dorsal column-medial lemniscus, dorsolateral funiculus, grey substance, thalamus or capsula interna) (Svendsen et al., 2011).

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Treatment of central neuropathic pain

The treatment includes tryciclic antidepressants, antiepileptic medications, intrathecal baclofen, opioid analgesics, anesthetic and antiarrhythmic agents, cannabinoids.

T r i c yc l i c a n t i d e p r e s s a n t s For addressing central neuropathic pain in MS amitriptyline, nortriptyline and clomipramine, all tricyclic antidepressants, are the drugs of choice. Drowsiness, constipation, urinary retention and hypotension are common adverse effects. There are no indications, based on randomised, clinical studies, as to overall efficacy or the most advantageous dosing schedules. A n t i e p i l e p t i c m e d i c at i o n s Antiepileptic medications are also used in treating central neuropathic pain associated with MS. Anecdotally, carbamazepine is commonly utilized, although often with inadequate results (Solaro et al., 2005). Adherence is problematic due to adverse effects, particularly when compared to other antiepileptic drugs, like gabapentin and lamotrigine. Discontinuation of carbamazepine occurs even at low doses. Only one randomized, double-blind, placebo-controlled, crossover study of lamotrigine has been reported, with only 12 subjects. At 400 mg/daily there was no difference between the treatment and placebo groups for change on mean pain intensity (Breuer et al., 2007). Levetiracetam has also been studied in a randomized, single-blind, placebo-controlled study, including 20 patients with MS with central pain. Levetiracetam significantly reduced pain at maximum dosage of 3,000 mg daily. Adverse events occurred in eight treated versus five placebo subjects, with one drop-out due to somnolence (Rossi et al., 2009). Gabapentin and pregabalin have not been assessed in randomized, placebo-controlled studies for the treatment of central neuropathic pain in MS. Reports of open-label studies including small numbers of subjects found these drugs to be moderately effective in relieving pain, although the occurrence of adverse events leading to discontinuation is common (Solaro et al., 2009; Houtchens et al., 1997). It is worth noting that in older patients a careful evaluation of the initiation dose and possible drug interactions should be undertaken since pregabalin can have a negative interaction with other drugs that act on the central nervous system, such as benzodiazepine, baclofen and tramadol (Solaro et al., 2009). The overall potential of antiepileptic drugs has not been substantiated in rigorous clinical trials. Unfortunately, many subjects never advance to the dose necessary for ameliorating pain due to intolerable adverse effects (Solaro et al., 2005). I n t r at h e c a l
bac lo f e n , o p i o i d a na lg e s i c s , a na e s t h e t i c

a n d a n t i a r r h y t h m i c ag e n t s

Intrathecal baclofen, opioid analgesics, anaesthetic and antiarrhythmic agents have been tested in patients with MS experiencing neuropathic pain, although with too few subjects and lacking sufficient scientific rigor. At this time, there is inadequate support for these drugs for the treatment of neuropathic pain in MS.

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Cannabinoids Cannabinoids (CB) have been rigorously assessed for the treatment of pain in MS. Four clinical trials have been reported in the literature. In one trial dronabinol, a synthetic CB, was successful in lowering pain intensity and improving pain relief at a daily dose of 10 mg, compared to a placebo group (Svendsen et al., 2004). Further, the treatment group reported improvement in bodily pain on the SF-36, a quality of life scale used in MS (Solari, 2005). A second, 5-week trial of an oromucosal spray form of a cannabis extract, D9-tetrahydrocannabinol (D9-THC), reported benefit in the treatment group on pain intensity, although treatment subjects experienced deficits in long-term memory storage. Sixty three of the original subjects continued in an open-label extension trial for up to two years in order to determine long-term tolerability and effectiveness (Rog et al., 2007). Improvement was reported on a VAS, although 51% of subjects experienced adverse events considered to be severe by investigators. A third, 15-week trial involved 630 subjects with a stable disease course experiencing spasticity (Zajicek et al., 2003). Pain was assessed as a secondary outcome, along with a number of other symptoms, using subjective scales. While most subjects in the treatment arm reported improvement in pain, 20% reported worsening while on treatment with CB. Finally, sublingual D9-THC, cannabidiol (CBD), D9-THC:CBD and placebo were compared in a consecutive series of double-blind, randomized, placebo-controlled, singlesubject, crossover trials. The design consisted of 2-week treatment phases and a subsequent double-blind phase of 8 weeks duration. Based on a VAS diary, active treatment significantly improved pain (Wade et al., 2004). In summary, while there does appear to be a positive effect, the efficacy of CB above conventional therapies has not been substantiated. Randomized trials comparing CB to traditional drugs for pain associated with MS is an important next step, in order to determine the most effective therapy, as well as to weigh the impact of adverse events. Studying different origins of pain syndromes associated with MS may also help explain individual response variability. Opioids Only one non-randomized, single-blind, placebo-controlled study of 14 subjects with MS-related central neuropathic pain used intravenous morphine at a median dose of 0.67 mg/kg body weight (Kalman et al., 2002). Four patients reported that pain was reduced by more than 50% after treatment. Clearly, insufficient evidence exists for the use of morphine for neuropathic pain in MS.

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Trigeminal neuralgia
The prevalence of trigeminal neuralgia (TN) in subjects with MS ranges from 1.9% to 6.3% (Putzki et al., 2009). Although comparatively uncommon, TN has been extensively studied in MS. TN is exemplified by typically unilateral, intense, lancinating, paroxysmal pain deriving from one or more branches of the trigeminal nerve, although it is unclear whether there is a relationship between trigeminal lesions and clinical symptoms, despite extensive involvement of the entire trigeminal complex in some cases (Mills et al., 2010). The classic description by patients suffering from TN as an electrical discharge, as well as non-altered sensation and clear trigger points, makes idiopathic TN indistinguishable from TN seen in patients with MS.

P at h o p h y s i o l o g y TN is likely due to an electric ectopic discharge caused by a plaque at the TN nerve entry zone in the pons. The presence of a plaque in the proximal part of the trigeminal root was reported in an MS patient who underwent a rhizotomy for TN (Lazar e Kirkpatrick, 1979). Mixed results have been reported using MRI studies demonstrating multiple causes. A study reported enhancement on T1-weighted images and hyperintense lesions on T2weighted images of the cisternal portion of the nerve or at the root entry zone in eight out of 275 scans, although TN was not present (Da Silva et al., 2005). In a study of 74 Japanese subjects studied retrospectively, five (6.8%) showed a T1-hypointense and T2hyperintense, non-enhanced, linear lesion in the pons, in the intramedullary portion of the nerve that was associated with different sensory symptoms. Only one subject had TN (Nakashima et al., 2001). A further study of six MS patients with TN demonstrated that all subjects had a plaque in the pons, while no vascular compression was observed (Gass et al., 1997). The role of neurovascular compromise in TN has also been proposed. Meaney et al. (1995) found a plaque in the pons on MRI in one patient out of seven, while vascular compression of the nerve by an artery at the root entry zone was demonstrated in five subjects. A further study reported nerve compression in 23 of 35 (60%) cases (Broggi et al., 2004), while T2-weighted imaging demonstrated a brainstem lesion in 26 of 35 (74%) subjects. Trigeminal evoked potentials, infrequently used for MS patiens with TN, can help to indicate the site of lesions, as demonstrated in two studies in which 5/5 and 11/13 cases showed abnormal findings (Cruccu et al., 1990; Bergamaschi et al., 1994). M e d i c a l t r e at m e n t TN is reportedly extremely painful and can significantly interfere with everyday life. Due to ethical considerations, placebo-controlled studies are not possible. Treatment of TN in MS is based on studies of idiopathic TN and primarily consists of antiepileptic medications. Carbamazepine (Ramsaransing et al., 2000), lamotrigine (Leandri et al., 2000), gabapentin (Solaro et al., 1998), topiramate (Solaro et al., 2001) and misoprostol (DMKG Study Group, 2003) have all been assessed in open label studies, with small numbers of subjects. Table 1.1 provides a summary. The evidence is inadequate in providing indications as to the effectiveness of these drugs. It should be noted that carbamazepine may result in adverse effects that mimic an MS exacerbation (Ramsaransing et al., 2000).

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TabLE 1.1

Studies of medications for trigeminal neuralgia in MS. Authors Medications Number Mean dose of subjects 7 6 6 2 18 7 5 5 18 5 6 Efficacy Number of subjects with ae Not specified 0 0 Not specified 4 0 1 Not specified 0 0 0

Khan (1998) Solaro et al. (1998) Zvartau-Hind et al. (2000) Solaro et al. (2001) DMKG (2003) Reder and Arnason (1995) Espir and Millac (1970) Lunardi et al. (1997) Leandri et al. (2000) Solaro et al. (2000)

GBP GBP TPM TPM Misoprostol Misoprostol* CBZ LMT LMT LMT + GBP CBZ + GBP

1,400 mg/daily 6/7 complete 1/7 partial 900 mg/daily 100 mg/bid 200 mg/daily 200 mcg/tid 570 mcg/daily 760 mg/daily 165 mg/daily 170 mg/daily 140 mg + 650 mg/daily 400 mg + 800 mg/daily 5/6 5/6 2/2 5/18 4/7 complete 2/7 partial 4/5 5/5 17/18 5/5 6/6

*previous therapy maintained; AE: adverse events; CBZ: carbamazepine; GBP: gabapentin; LMT: lamotrigine; TPM: topiramate.

S u rg i c a l i n t e rv e n t i o n s Glicerol injection (Berk et al., 2003), radiofrequency lesioning (Broggi and Franzini, 1982) and radiosurgery (Rogers et al., 2002) are procedures that ablate the retrogasserian ganglion in order to interrupt the trigeminal pathway. These procedures have been used in MS patients with TN who have not responded to pharmacological treatment. These procedures cause nerve damage that may lead to adverse effects including hypoesthesia/hyperesthesia, decreased corneal reflex, transitory masticatory weakness and hearing loss, although these effects are uncommon. Microvascular decompression of the trigeminal root may be effective in carefully selected subjects, although recurrence of pain is relevant suggesting that combined mechanisms other than nerve compression have a role in the generation of TN in MS (Broggi et al., 1999). A lack of long-term benefit and the occurrence of potentially serious adverse effects dictates that surgical interventions should be reserved for critical non-responders to medications.

Atypical facial pain

Atypical facial pain is reported in MS although it is distinct from TN in that it is a dull and nearly continuous pain, whose site of origin is imprecise, without trigger points. One

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study underlined the complexity of differentiating facial pain syndromes in MS, finding six subjects out of 83 with TN and MS and two subjects with both atypical facial pain and TN, in addition to MS. Tricyclic antidepressants are commonly used for the treatment of atypical facial pain, with a regimen consisting of a single dose at bedtime of up to 100 mg prolonged over time up to several months (Elrasheed et al., 2004).

Lhermittes sign
Lhermittes sign, experienced by 40% of MS patients, is described as a painful electrical sensation that runs down the back and into the limbs from involvement of the posterior columns. Pain is elicited by flexing or extending the neck. Lhermittes sign is a common feature of MS but is not exclusive to the disease. Patients rarely request treatment (Al-Araji and Oger, 2005).

Glossopharyngeal neuralgia
Glossopharyngeal neuralgia is rare in MS. Pain is intense and occurs in the posterior pharynx, tonsillar fossa and base of the tongue. One report on three individuals with MS found a daily mean dose of 633 mg of carbamazepine to be successful in reducing pain (Minagar and Sheremata, 2000). M USC ULO SK E LE TAL PAIN

Painful tonic spasms

Painful tonic spasms (PTS) are described as cramping, pulling pain, more commonly occurring in the lower extremities although upper limbs can be affected as well, triggered by movements or sensory stimuli, often occurring during the night. It is estimated that 11% of subjects with MS experience PTS (Solaro et al., 2004). In MS the origin of the pain in PTS is caused by noxious stimuli of the muscle although the lesion eliciting the painful spasm is in the central nervous system.

T r e at m e n t o f P T S Anecdotally, medications such as baclofen, benzodiazepines, gabapentin and carbamazepine are used for treating PTS. Reports in the literature are limited to open-label studies of small numbers of subjects and thus cannot provide sufficient evidence for treatment recommendations.

Pain related to being wheelchair bound

In MS, patients with a moderate to advanced level of disability may have abnormal gait and often require technical aids for mobility and, for those more disabled, many may spend the majority of time in a wheelchair. Compromised posture, incorrect use of technical aids and prolonged wheelchair use can be causes of nociceptive pain in these patients. Specific studies regarding treatment are not available. Anecdotally treatment consists of anti-inflammatory drugs or opioids.

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C ON C L USIONS Unfortunately the literature on the treatment of pain in MS is seriously lacking and therefore does not provide indications based on rigorous scientific methods. Clinicians facing patients with MS and pain base treatment decisions on experience and on reports involving too few subjects in studies with insufficient levels of evidence. Studies on CB have produced useful scientific evidence, based on careful study design and adequate numbers of subjects, compared to studies on other medications for pain associated with MS. CB does appear to be useful for pain treatment, although a complete profile of adverse effects is lacking, including long-term data. Randomized trials comparing CB to traditional drugs for pain associated with MS is an important next step in order to examine whether CB is superior to conventional therapies. Further, since pain in MS is quite heterogeneous, future studies of CB should differentiate the origins of pain syndromes in order to help identify CB responders. Unfortunately MS does not occur in isolation and patients often have co-morbidities, particularly in the aging segment of the MS population. Clinicians should be aware that pain may have various origins and can be unrelated to MS. Pain can significantly impact quality of life, influencing everyday activities, work, recreation, mood, as well as other aspects. Therefore its correct identification and effective management are crucial. In addition to the complex nature of pain in MS, there are other factors that influence the approach to treatment. Firstly, scales are only partially effective in evaluating pain since they are based on subjectivity that can be influenced by various external factors. A further important aspect for clinicians to consider is that MS patients have difficulty describing neuropathic pain and this of course has a bearing on the clinical evaluation and subsequent decision-making regarding treatment. Progress in the area of pain associated with MS will depend on the development of multiple-arm, randomized, clinical trials with adequate numbers of subjects with specific pain characteristics, in order to produce useful scientific evidence as to the optimal treatment strategies.

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