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
ReviewPharmacological management of symptoms in multiple sclerosis: current approaches and future directions
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
References (184)
- et al.
Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial
Lancet
(2009) - et al.
Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial
Lancet
(2003) - et al.
Gabapentin for relief of upper motor neuron symptoms in multiple sclerosis
Arch Phys Med Rehabil
(1997) - et al.
Gabapentin effect on spasticity in multiple sclerosis: a placebo-controlled, randomized trial
Arch Phys Med Rehabil
(2000) - et al.
Rating scales as outcome measures for clinical trials in neurology: problems, solutions, and recommendations
Lancet Neurol
(2007) - et al.
Functional outcome of intrathecal baclofen administration for severe spasticity
Clin Neurol Neurosurg
(2005) - et al.
Thalamotomy versus thalamic stimulation for multiple sclerosis tremor
J Clin Neurosci
(2005) - et al.
Gamma knife thalamotomy for multiple sclerosis tremor
Surg Neurol
(2007) - et al.
Improving function: a new treatment era for multiple sclerosis?
Lancet
(2009) - et al.
Do alpha-blockers have a role in lower urinary tract dysfunction in multiple sclerosis?
J Urol
(1995)
Oxybutynin versus propantheline in patients with multiple sclerosis and detrusor hyperreflexia
J Urol
Intravesical atropine compared to oral oxybutynin for neurogenic detrusor overactivity: a double-blind, randomized crossover trial
J Urol
Effective treatment of neurogenic detrusor dysfunction by combined high-dosed antimuscarinics without increased side-effects
Eur Urol
Evaluation of the safety and efficacy of sildenafil citrate for erectile dysfunction in men with multiple sclerosis: a double-blind, placebo controlled, randomized study
J Urol
Efficacy of sildenafil in the treatment of female sexual dysfunction due to multiple sclerosis
J Urol
Efficacy and safety of tadalafil for erectile dysfunction in patients with multiple sclerosis
J Sex Med
Global economic impact of multiple sclerosis. Multiple Sclerosis International Federation 2010
Anti-spasticity agents for multiple sclerosis
Cochrane Database Syst Rev
A double-blind, placebo-controlled trial of tizanidine in the treatment of spasticity caused by multiple sclerosis
Neurology
Relationship of the antispasticity effect of tizanidine to plasma concentration in patients with multiple sclerosis
Arch Neurol
Tizanidine treatment of spasticity caused by multiple sclerosis: results of a double-blind, placebo-controlled trial
Neurology
Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up
J Neurol Neurosurg Psychiatry
Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients
Mult Scler
Multi-centre, double-blind trial of a novel antispastic agent, tizanidine, in spasticity associated with multiple sclerosis
Curr Med Res Opin
Tizanidine treatment of spasticity: a meta-analysis of controlled, double-blind, comparative studies with baclofen and diazepam
Adv Ther
Treatments for spasticity and pain in multiple sclerosis: a systematic review
Health Technol Assess
High-dose oral baclofen: experience in patients with multiple sclerosis
Neurology
A randomized, double-blind, placebo-controlled study of the efficacy and safety of tolperisone in spasticity following cerebral stroke
Eur J Neurol
Cannabinoids control spasticity and tremor in a multiple sclerosis model
Nature
Getting the measure of spasticity in multiple sclerosis: the Multiple Sclerosis Spasticity Scale (MSSS-88)
Brain
Meta-analysis of the efficacy and safety of Sativex (nabiximols), on spasticity in people with multiple sclerosis
Mult Scler
Long term effect (more than five years) of intrathecal baclofen on impairment, disability, and quality of life in patients with severe spasticity of spinal origin
J Neurol Neurosurg Psychiatry
Effect of intrathecal baclofen on sleep and respiratory function in patients with spasticity
Neurology
Response of intrathecal baclofen resistance to dose reduction
Neurology
Incidence of seizures in patients with multiple sclerosis treated with intrathecal baclofen
Neurology
The safety of baclofen in pregnancy: intrathecal therapy in multiple sclerosis
Mult Scler
Intrathecal baclofen and morphine in multiple sclerosis patients with severe pain and spasticity
J Neurol
Managing severe lower limb spasticity in multiple sclerosis: does intrathecal phenol have a role?
J Neurol Neurosurg Psychiatry
Botulinum toxin (Dysport) treatment of hip adductor spasticity in multiple sclerosis: a prospective, randomised, double blind, placebo controlled, dose ranging study
J Neurol Neurosurg Psychiatry
The structure and mode of action of different botulinum toxins
Eur J Neurol
Early physiotherapy after injection of botulinum toxin increases the beneficial effects on spasticity in patients with multiple sclerosis
Clin Rehabil
Treatment for ataxia in multiple sclerosis
Cochrane Database Syst Rev
Controlled trial of isoniazid therapy for severe postural cerebellar tremor in multiple sclerosis
Neurology
Isoniazid for tremor in multiple sclerosis: a controlled trial
Neurology
Pharmacologic trials in the treatment of cerebellar tremor
Arch Neurol
Ondansetron, a 5-HT3 antagonist, improves cerebellar tremor
J Neurol Neurosurg Psychiatry
Failure of ondansetron in treating cerebellar tremor in MS patients—an open-label pilot study
Acta Neurol Scand
Double-blind crossover study with dolasetron mesilate, a 5-HT3 receptor antagonist in cerebellar syndrome secondary to multiple sclerosis
J Neurol
The effect of cannabis on tremor in patients with multiple sclerosis
Neurology
The effect of levetiracetam on tremor severity and functionality in patients with multiple sclerosis
Mult Scler
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