Elsevier

The Lancet Neurology

Volume 9, Issue 12, December 2010, Pages 1182-1199
The Lancet Neurology

Review
Pharmacological management of symptoms in multiple sclerosis: current approaches and future directions

https://doi.org/10.1016/S1474-4422(10)70249-0Get rights and content

Summary

Management of symptoms in multiple sclerosis (MS) has received little attention compared with disease-modifying treatments. However, the effect of these symptoms on quality of life can be profound. Clinical trials of pharmacological drugs to treat symptoms of MS have often been underpowered and have used inappropriate measures of outcome. Many currently used symptomatic drugs were introduced decades ago, when study quality was considerably below current standards. Therefore, the evidence base on which to make clinical decisions is less than adequate. Interest in pharmacological treatment of symptoms in MS has increased in recent years, and several large randomised controlled trials have been reported. Pharmacological strategies are a core component of the treatment of these symptoms, but it is imperative to remember that a multidisciplinary rehabilitation approach is needed for effective management.

Introduction

Multiple sclerosis (MS) has a substantial economic and social burden. The total financial cost per patient per year has been estimated at about US$48 000 in the UK in 2007, with a lifetime cost of $1·2 million.1 People with this disorder can have many disabling symptoms that result in high emotional, psychological, and physical burden for the patients and carers. Therefore, the effective management of symptoms of MS is crucial, since it can improve quality of life, reduce the effect of disability on daily activities, and help patients to continue employment or education.

Pharmacological treatment is an essential component in the management of symptoms of MS and a patient-centred approach is central to its success. Physicians need to educate patients appropriately, discuss their priorities and expectations, and help them to select the right treatment to optimise compliance, especially with invasive interventions. Symptoms can change during the course of the disease; hence serial monitoring helps to optimise interventions. With oral drugs, the initial dose should be low and increased slowly according to response and tolerability. If one drug is insufficient because it is partially effective or has intolerable side-effects, then a combination of drugs, perhaps at lower doses, is advisable.

In this Review, we will describe pharmacological treatments for these symptoms, which represent an important component of a multidisciplinary approach to improve quality of life, ease care, and ensure independence. Surgical interventions will also be covered where relevant, but rehabilitation approaches such as physiotherapy are beyond the scope of this Review and are mentioned only briefly. Some recent large and well conducted trials that have assessed the efficacy of symptomatic medications such as fampridine2 and cannabinoids3 represent a clear improvement in the quality of trial design. Future trials of good quality should provide a strong evidence base for identification of optimum treatments. In the meantime, in this Review, we provide an update on the available evidence for optimum treatment of symptoms in MS, discuss the issues that need to be addressed before starting treatment, and provide recommendations for the most appropriate drug treatments.

For the management of individual symptoms, we group the wide range of symptoms of MS, beginning with mobility-related symptoms, such as spasticity, ataxia, and impaired ambulation. We then discuss bladder, bowel, and sexual dysfunction. The next group, which is often overlooked despite being very disabling for patients, consists of fatigue, cognitive dysfunction, and mood disturbance. These symptoms can interact, as can their treatments. This is also true for pain, another overlooked symptom discussed here. Finally, we will briefly discuss symptoms resulting from visual and brainstem involvement.

Section snippets

Spasticity

Spasticity is seen in more than 60% of patients with MS. This increased muscle tone (or hypertonia) results from injury to the corticospinal system and unmodulated activity of local spinal neurons and sensory afferent pathways. If not well managed, it can lead to pain, spasms, reduced mobility, limited range of movement, and contractures.

Bladder dysfunction

About three-quarters of patients with MS have bladder symptoms.53 The key CNS regions involved in the regulation of micturition include the periaqueductal grey matter, pontine micturition centre, medial frontal cortex, hypothalamus, and sacral micturition centre.54 In MS, bladder symptoms arise mainly from interruption of connections between the pontine and sacral micturition centres caused by spinal cord pathology.

Fatigue

Fatigue is a complex symptom that defies definition and measurement. Patients complain of different types of fatigue, such as relapse-related fatigue, excessive tiredness after exercise, and excessive daytime sleepiness. It is present in up to 74% of patients with MS97 and is often described as their most disabling symptom.

Pain

Pain occurs frequently in patients with MS, even in the early stages,142 and is often severe. Many studies have examined the epidemiology of pain in this disorder and have reported a prevalence ranging from 30%143 to 90%.144 Pain in these patients can have either neurogenic or non-neurogenic causes, or a combination of both. Neurogenic pain includes paroxysmal pain (trigeminal neuralgia, painful tonic spasms, and Lhermitte's phenomenon), persistent pain (burning dysaesthesia of the limbs and

Visual dysfunction

Nystagmus results from the disruption of mechanisms that control foveation. Management of nystagmus in MS is challenging with a poor rate of treatment response.174 A few trials with small numbers of patients with MS have been done. These trials focused on acquired pendular nystagmus, which includes quasi-sinusoidal oscillations thought to result from deficiencies in feedback circuits between the brainstem and cerebellum.175 Memantine (mainly an NMDA glutamate antagonist) and gabapentin have

Conclusions

A diverse and wide range of symptoms can occur in MS. Optimum management requires a multidisciplinary approach, and is focused on the needs of the patients and their priorities. For most treatments, however, the supporting evidence for their use in MS is weak and often relies on evidence provided by other disciplines (eg, general psychiatry, and urology). This restricted evidence base is attributable not only to the paucity of trials done so far and their methodological limitations, but also to

Search strategy and selection criteria

We searched PubMed for articles published from 1970 to September, 2010, with the search term “multiple sclerosis” combined with specific search terms that constituted the subheadings (eg, “spasticity”, “ataxia”, “bladder dysfunction”, “fatigue”). References from identified studies were also checked and included if felt appropriate. Articles published in English were considered. References from our own files were also searched. More recent publications (within the past 10 years) were

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