eMedicine Specialties > Physical Medicine and Rehabilitation > Medical Diseases

Multiple Sclerosis: Treatment & Medication

Author: Denise I Campagnolo, MD, MS, Director of Multiple Sclerosis Clinical Research and Staff Physiatrist, Barrow Neurology Clinics, St Joseph's Hospital and Medical Center; Investigator for Barrow Neurology Clinics; Director, NARCOMS Project for Consortium of MS Centers
Coauthor(s): Timothy Lee Vollmer, MD, Van Denburgh Chair, Barrow Neurological Institute, Division of Neurology, Director of Neuroimmunology Program, St Joseph's Hospital and Medical Center; Fu-Dong Shi, MD, PhD, Director of Neuroimmunology Laboratory, Barrow Neurological Institute, St Joseph's Hospital and Medical Center; Daniel D Scott, MD, MA, BS, Associate Professor, Department of Physical Medicine and Rehabilitation, University of Colorado at Denver and Health Sciences Center; Sandra F Williamson, MS, ANP-C, CRRN, Clinic Coordinator, Department of Rehabilitation Medicine, Denver Veterans Affairs Medical Center
Contributor Information and Disclosures

Updated: Jul 17, 2009

Treatment

Rehabilitation Program

Physical Therapy

Physical therapists provide assessment of gross motor skills (eg, ambulation) and assessment and training in appropriate assistive devices to improve mobility in patients with multiple sclerosis. They evaluate and train the patient in appropriate exercise programs to decrease spasticity, maintain range of motion, strengthen muscles, and improve coordination. They also provide invaluable input into the prescription of appropriate seating systems for the nonambulatory patient.

Occupational Therapy

Occupational therapists are skilled in assessing the patient's functional abilities in completing ADL, assessing fine motor skills, and evaluating for adaptive equipment and assistive technology needs.

Speech Therapy

Speech therapists assess the patient's speech, language, and swallowing and may work with the patient on compensatory techniques to manage cognitive problems.

Medical Issues/Complications

• Fatigue
  • Fatigue is one of the most commonly reported symptoms, experienced in up to 90% of patients with MS. Fatigue is described as an overwhelming feeling of lassitude or lack of physical or mental energy that interferes with activities. An estimated 50-60% of persons with MS describe it as one of their most bothersome symptoms, and it is a major reason for unemployment among MS patients. Rule out comorbid medical conditions, such as infections, anemia, or thyroid disease, before attributing fatigue to MS. Medications used in MS management often can contribute to fatigue. These drugs include analgesics, anticonvulsants, antidepressants, muscle relaxants, sedatives, and immune-modulating medications.
  • Amantadine is perhaps the first-line drug used to treat fatigue. Approximately 40% of people experience some relief of fatigue. The starting dose is 100 mg qd. If no response is noted, increase to 100 mg bid with the last dose taken at noon to decrease potential for insomnia. Pemoline has been effective in some people, but the manufacturer has issued warnings advising of the need for frequent monitoring of liver function due to the potential for hepatotoxicity. In May 2005, Abbott chose to stop sales and marketing of their brand of pemoline (Cylert) in the United States. In October 2005, all manufacturers of the generic drug also agreed to stop sales and marketing of pemoline after the US Food and Drug Administration (FDA) concluded that the overall risk of liver toxicity from pemoline outweighs the benefits.
  • Other drugs that have been tried in fatigue management include methylphenidate and fluoxetine. A disadvantage of methylphenidate use is that it is a controlled substance. For those with concurrent depression, fluoxetine may be tried to manage both problems. Provigil, a drug approved for treatment of narcolepsy, has demonstrated some success in MS patients.
  • Nonpharmacologic treatment of fatigue involves energy conservation, work simplification, scheduled rest periods, and the use of cooling garments (eg, vest, hat, collar).
• Spasticity
  • Spasticity in MS is characterized by increased muscle tone and resistance to movement, which occurs most frequently in muscles that function to maintain upright posture. As a result of increased stiffness, much more energy is expended to perform ADL, which, in turn, contributes to fatigue. With decrease in spasticity, the patient experiences more freedom of movement with less energy expenditure. Treat spasticity when it interferes with function, mobility, positioning, hygiene, or activities of daily living. Spasticity can be managed through nonpharmacologic and pharmacologic means. Complications of inadequately controlled spasticity include pain, contractures, and decubitus.
  • The first step in spasticity management is establishing a stretching program in which each joint is moved slowly to a position where the spastic muscles are stretched. Each position is held for at least a minute to allow the muscle to relax slowly. Stretching exercises may be performed in a cool (85°F) pool with the benefit of the water providing buoyancy and serving to cool the body. Mechanical aids, such as ankle-foot orthoses, also can be useful in spasticity management.
  • Pharmacologic treatment of spasticity includes baclofen (Lioresal) as a first-line drug. Baclofen is effective in most people, is inexpensive, and is titrated easily from 10-140 mg/d in divided doses. Patients may report fatigue or weakness as an adverse effect. Second-line agents include benzodiazepines, such as diazepam and clonazepam. While these compounds can be useful adjunct medications, they can be sedating and habit-forming. For patients who also experience sleep disorders, the provider may take advantage of the sedating adverse effects of the benzodiazepines to manage the spasticity and sleep problem with a single medication. For patients with cognitive impairment, benzodiazepines may be contraindicated due to their adverse CNS effects. Dantrolene sodium (Dantrium) acts directly on skeletal muscle to decrease spasticity. It affects all muscles of the body and is used less frequently than baclofen, due to hepatotoxicity at higher doses and numerous drug interactions.
  • Newer medications to manage spasticity include gabapentin (Neurontin) and tizanidine (Zanaflex). Gabapentin is an anticonvulsant drug, which is particularly useful in patients who experience both spasticity and neuropathic pain. This drug is titrated easily from 300-3600 mg/d in divided doses. Besides being relatively expensive, it may have limited usefulness as patients often experience significant sedation, which is effectively dose limiting.
  • Tizanidine has effects similar to baclofen, producing less weakness but more sedation. This drug is titrated from 2-32 mg/d in divided doses.
  • Additional treatments for severe spasticity management include intramuscular botulinum toxin, phenol nerve blocks, and intrathecal baclofen pump placement. These treatments are more invasive and usually are required in the most difficult cases.
• Bladder problems
  • Urinary symptoms are common in MS, with most patients experiencing problems at some point in their disease. Bladder problems are a source of significant morbidity, affecting the person's family, social, and work responsibilities. Bladder dysfunction can be classified as failure to store, failure to empty, or combined dysfunction.
  • Patients with failure to store difficulties have a small spastic bladder with hypercontractility of the detrusor muscle. Symptoms experienced may include urgency, frequency, incontinence, and nocturia. Interventions include scheduled voiding, limiting fluid intake in the evening, using anticholinergic medications (eg, oxybutynin), and eliminating diuretics (eg, caffeine).⁶ Failure to empty is characterized by a large flaccid bladder and an inability of the urinary sphincter to relax. Symptoms include urgency, frequency, hesitancy, nocturia, incontinence, incomplete emptying, and frequent urinary tract infections. Interventions include intermittent catheterization or use of alpha-blockers (eg, prazosin).
  • Combined dysfunction is due to incoordination of the detrusor and sphincter (dyssynergia). Symptoms in combined dysfunction are similar to those of failure to empty. Interventions may include anticholinergic medications or intermittent catheterization.
  • Bladder problems usually can be managed appropriately after a careful history, physical examination, and urinalysis. If initial attempts at symptom management are not effective, more studies, such as renal ultrasound, voiding cystourethrogram, renal scan, or urodynamic studies, may be indicated.
• Bowel problems
  • Constipation is the most frequent complaint concerning the bowels in patients with MS and is characterized as the infrequent or difficult passage of stools. Constipation may be the result of a neurogenic bowel or of immobility, which leads to slowed bowel activity. Finally, patients who have limited their fluid intake in an attempt to manage bladder symptoms or those with limited access to fluids due to immobility tend to have dry hard stools.
  • The first step in management of constipation is to increase fluid intake to 8-10 cups/d and increase dietary fiber to 15 g. Next, it is essential to establish a consistent bowel program time. A bowel program is most effective if done at least every other day and preferably after a meal, which takes advantage of the body's gastrocolic reflex. Sitting in an upright position, rather than lying in bed, permits gravity to assist in evacuation. The patient should be involved in an exercise program, consisting of walking or simply performing chair exercises.
  • Diarrhea, if it occurs, typically is not related to MS per se, but it is more likely due to fecal impaction, diet, irritation of the bowel, overuse of laxatives or stool softeners, or as an adverse effect of medications. Diarrhea is treated first by eliminating the cause, then, possibly, by use of bulk formers (eg, psyllium). Drugs that slow the muscles of the bowel, such as Lomotil, rarely are indicated. Nonpharmacologic techniques of bowel management include proper positioning, abdominal massage, and digital stimulation. Abdominal massage performed in the direction of bowel peristalsis, from ascending toward the descending colon, can be useful. Finally, digital stimulation, in which a lubricated finger is inserted gently into the rectum and moved side to side along the wall of the rectum, can stimulate a bowel movement.
  • Pharmacologic management of constipation includes stool softeners, bulk formers, or laxatives. Stool softeners, such as docusate sodium, work by decreasing surface tension, allowing water to enter the stool. Bulk formers (eg, Metamucil, Per Diem, Citrucel, FiberCon) work by increasing the bulk and weight of the stool. Laxatives act as an irritant to the bowel, increasing peristalsis; they generally work within 8-12 hours. Examples include milk of magnesia and Peri-Colace. For patients with a neurogenic bowel or with poor abdominal muscle tone, rectal suppositories may be part of an effective bowel program that can help prevent incontinent episodes. Suppositories provide rectal stimulation and lubricate the stool. Typically, they act within 30 minutes to 1 hour. Examples include bisacodyl or glycerin.
• Cognitive dysfunction
  • Estimates of prevalence of cognitive dysfunction in MS range from 40-70%. No correlation exists with the degree of physical disability, and cognitive dysfunction may occur early in the course of disease. This complication of MS can be a significant problem affecting family and social relationships, as well as employment. Areas of cognition affected include comprehension and use of speech, attention, memory, visual perception, planning, problem solving, and abstract reasoning.
  • Treatment approaches for cognitive dysfunction include cognitive retraining and use of compensatory strategies. Cognitive retraining involves use of repetitive drills and mentally stimulating exercises designed to strengthen those areas of cognition that are weak. Compensatory strategies emphasize coping methods or organizational skills to help the individual use his strengths to compensate for areas of relative weakness, including such strategies as maintaining a consistent routine, making lists, keeping a daily planner, and organizing the home or work environment.
  • In providing education on MS management to patients with cognitive impairment, it is important to involve family or caregivers in training, provide step-by-step instructions, and present information in a visual and verbal format. New topics should be presented at times when fatigue is less likely to be an issue.
  • Cognition-enhancing drugs have met with some success in MS patients.
• Pain
  • Pain is a common occurrence in MS, with 30-50% of patients experiencing pain at some time in the course of their illness. Pain typically is not associated with a less favorable prognosis, nor does it necessarily impair function; however, since it can have significant impact on quality of life, it needs to be treated appropriately. Pain in MS can be classified as primary or secondary.
  • Primary pain is related to the demyelinating process itself. This neuropathic pain is characterized often as having a burning, gnawing, or shooting quality. Nonpharmacologic techniques, such as use of imagery or distraction, can be helpful. Transcutaneous electrical nerve stimulation is useful in some patients. Pharmacologic approaches include prescription of tricyclic antidepressants as first-line drugs. Anticonvulsants, such as carbamazepine, phenytoin, or gabapentin, can be added as second-line agents.
  • Secondary pain in MS is primarily musculoskeletal in nature, possibly due to poor posture, poor balance, or abnormal use of muscles or joints as a result of spasticity. Nonpharmacologic treatment for secondary pain includes moist moderate heat, massage, physical therapy, and exercise (eg, stretching). Pharmacologic agents include nonsteroidal anti-inflammatory drugs or other analgesics. Use of narcotics seldom is indicated.
• Heat intolerance
  • Persons with MS often experience an increase in symptoms of fatigue or weakness when exposed to high temperatures, due to weather, exercise, or fever. To manage heat intolerance, outside activities should be timed for early morning or evening hours to avoid the heat of the day.
  • Activities should be spread throughout the course of the day to avoid overheating.
  • Air conditioning in homes and cars, cooling garments, light colored clothes, and wide-brimmed hats can be used to manage heat intolerance.
  • Exposure to saunas, hot tubs, or even hot showers or baths should be avoided.

Consultations

The care provider may wish to consult various specialists, depending on the members present on the multidisciplinary team. Include consultations with specialists in urology, ophthalmology, neuropsychology, and social work, as indicated.

Other Treatment

Botulinum toxin injections may be useful for spasticity that is difficult to manage and refractory to medications.

Medication

Medications used to treat multiple sclerosis (MS) can be classified as immunomodulating or symptom management medications. For acute exacerbations, methylprednisolone (Solu-Medrol) is given at 500-1000 mg IV for 3-7 days. This has been shown to hasten recovery from the given attack, but it has uncertain long-term effects. Also, plasma exchange can be used short term for severe attacks for patients in whom steroids are contraindicated or not effective.

The disease-modifying agents for MS (DMAMS) currently approved for use in relapsing forms of MS in the United States include interferon beta (Avonex, Betaseron, and Rebif), glatiramer acetate (Copaxone), and mitoxantrone (Novantrone). The drugs all are available in injectable form and are currently FDA approved only for relapsing-remitting MS. In a European study on secondary progressive MS, patients in the interferon beta-1b group showed a highly significant delay in time to disease progression; however, FDA approval has not been granted yet for this indication.

A literature review by Rojas et al indicated that interferon beta could not be linked to reduced disability progression in patients with primary progressive MS.⁷ The authors also stated, however, that the studies reviewed employed too few patients to permit a definitive conclusion to be drawn.

To a certain extent, health care provider preference and experience with the medications, as well as the patient's preference, play a role in determining which drug is appropriate in a particular situation. Head-to-head comparison studies with the different interferon preparations suggest higher-dose interferon is more effective in preventing relapses than lower-dose formulations. In persons with a history of depression, interferons should be used with caution; thus, glatiramer acetate may be an appropriate choice in such cases.

Patient lifestyle and tolerance of injections should be considered in the choice of DMAMS. Adverse effect profiles also must be considered. If the adverse profile of one agent is intolerable in a patient, then a different class of agent may be recommended.

Treatment of progressive disease is more controversial. Mitoxantrone (Novantrone) is an immunosuppressive agent approved for the treatment of secondary progressive or aggressive relapsing remitting MS. This agent has been shown, however, to have idiosyncratic cardiac toxicities. Cyclophosphamide (Cytoxan) has also been used in MS patients. Cyclophosphamide is associated with risks for leukemia, lymphoma, infection, and hemorrhagic cystitis. Cyclophosphamide has been used at 1000 mg/m² IV, given 2 months in a row, again 3 months from the second dose, and then every 3 months after that for 24 months.

Currently, no approved treatments are available for primary progressive MS. Patients with secondary progressive disease who experience relapses are sometimes started on the currently approved DMAMS. Methotrexate has shown some effectiveness in delaying progression of impairment of the upper extremities in patients with secondary progressive MS.

Oral, sustained-release fampridine (4-aminopyridine), which is being investigated as a means of improving motor function in people with MS, was employed in a phase III trial on approximately 300 patients.⁸ In the randomized, multicenter, double-blind study, which was not limited to any specific form of MS, fampridine was administered to patients for 14 weeks and was found to improve walking ability in a significant percentage of patients.

Immunomodulating agents

These drugs currently are approved by the FDA only for relapsing-remitting MS, except for mitoxantrone and interferon beta-1b, which are indicated for secondary progressive MS.⁹ The beta-interferons are biochemically produced immunosuppressive cytokines that have been shown to reduce the number of relapses and decrease the severity of the relapses. Glatiramer acetate seems to work by inducing a regulatory immune mechanism that inhibits the immune attack on the CNS. This drug has also been effective in decreasing relapse rates and the severity of relapses. The beta-interferons have flulike adverse effects, and the interferons and glatiramer acetate may cause local injection site reactions.

Interferon beta-1a (Avonex, Rebif)

Biological response modulator used to decrease frequency of exacerbations and slow accumulation of physical disability. The most common adverse effects are flulike symptoms (eg, myalgia, malaise, fever, headache, chills), which usually can be managed by administering the drug at bedtime, as well as by using ibuprofen or acetaminophen prior to the injection and for 24 h postinjection.

Interferon beta-1b (Betaseron)

Biological response modulator that reduces frequency of exacerbations in relapsing-remitting MS; mechanism of action in MS is unknown.
Interferons are thought to alter expression and response to cell surface antigens and enhance immune cell activities. Adverse effects include flulike symptoms similar to Avonex.
Betaseron showed favorable results in a European study of secondary progressive MS and is pending FDA approval for this new indication.

Glatiramer acetate (Copaxone)

Synthetic polypeptide of 4 naturally occurring amino acids; indicated for reducing frequency of relapses in relapsing-remitting MS; adverse effects include injection site reactions (eg, erythema, pruritus) and, rarely, systemic reactions consisting of chest tightness and shortness of breath.

Natalizumab (Tysabri)

Recombinant humanized IgG4-_1C monoclonal antibody produced in murine myeloma cells. Binds to alpha-4 subunits of alpha-4-beta-1 and alpha-4-beta-7 integrins expressed on leukocyte surface, which inhibits alpha-4-mediated leukocyte adhesion to their receptors. Clinical effect in MS may be secondary to blocking alpha-4-beta-1 expressed by inflammatory cells with VCAM-1 on vascular endothelial cells and with CS-1 and/or osteopontin expressed by parenchymal brain cells. Indicated for relapsing MS and to reduce symptom exacerbation frequency.

Antispasticity agents

This category of medications is used to control increased tone. The medications vary from skeletal muscle relaxants to anticonvulsants and alpha-adrenergic agonists. The mechanisms of actions for spasticity relief are unknown for the benzodiazepines and gabapentin. Tizanidine is presumed to decrease spasticity by increasing presynaptic inhibition of motor neurons.

Baclofen (Lioresal)

First-line drug in spasticity management; skeletal muscle relaxant whose precise mechanism of action is unknown. Believed to inhibit transmission of reflexes at the spinal cord level. Approximately 15% metabolized by the liver; remainder excreted primarily unchanged in the urine.

Clonazepam (Klonopin)

Indicated for use in absence and atypical absence seizures, akinetic and myoclonic seizures, and nocturnal myoclonus; off-label use for spasticity management; mechanism of action unknown; metabolized by liver and excreted in urine; elderly may require reduced dose due to diminished renal function; long-term safety in children not established.

Tizanidine (Zanaflex)

Centrally acting alpha-adrenergic agonist presumed to decrease spasticity by increasing presynaptic inhibition of motor neurons. Short-acting drug for management of spasticity. Extensive hepatic first-pass metabolism; excreted in urine and feces.

Gabapentin (Neurontin)

Adjunct treatment of partial and generalized seizures. Off-label use for spasticity and neuropathic pain. Mechanism of action is unknown. Eliminated in urine unchanged. If discontinuing medication, taper off gradually to decrease risk of seizures.

Bladder antispasmodics

These medications are useful to decrease bladder spasms, which present as urinary urgency and frequency. They exert their effects on smooth muscle and are antimuscarinic in effect.

Tolterodine tartrate (Detrol)

A selective muscarinic receptor antagonist used for treatment of patients with overactive bladder with symptoms of urinary frequency, urgency, or urge incontinence. Extensively metabolized by the liver and excreted primarily in urine, but also in feces.

Oxybutynin (Ditropan)

Antispasmodic that exerts a direct effect on smooth muscle and inhibits the muscarinic effects of acetylcholine on smooth muscle. Results in relaxation of bladder smooth muscle. Indicated for relief of urinary symptoms in patients with uninhibited and reflex neurogenic bladder. Metabolized by liver and excreted renally.

Antiparkinson agents

Useful to decrease fatigue in approximately 40% of patients; mechanism of action unknown.

Amantadine (Symmetrel)

As an antiviral, it may act by blocking the uncoating of influenza A virus that prevents penetration of virus into the host. Anti-Parkinson action may be due to blocking reuptake of dopamine into presynaptic neurons. Used for fatigue management in patients with MS. About 10% is metabolized, with remainder excreted unchanged in urine.

Selective serotonin reuptake inhibitors

These medications are used for management of depression. They decrease reuptake of serotonin and are useful for fatigue management.

Sertraline (Zoloft)

Presumed to act by blocking the reuptake of serotonin into presynaptic neurons in the CNS, thereby prolonging the action of serotonin. Metabolized by the liver with significant first-pass effect; metabolites excreted in urine and feces.

Fluoxetine (Prozac)

Selectively inhibits presynaptic serotonin reuptake with minimal or no effect in the reuptake of norepinephrine or dopamine.

Tricyclic antidepressants

Used for management of depression; thought to increase synaptic concentration of serotonin and/or norepinephrine in the CNS by inhibition of their uptake by the presynaptic neuronal membrane; useful in the management of neuropathic pain.

Nortriptyline (Pamelor)

Used for relief of depression. Mechanism of action unknown. Thought to increase synaptic concentration of serotonin and/or norepinephrine in the CNS by inhibition of uptake by the presynaptic neuronal membrane. Metabolized by the liver; excreted in urine and bile.

Antineoplastic agents

Inhibit cell growth and proliferation.

Mitoxantrone (Novantrone)

Inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II. Reduces neurologic disability and/or frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (such as patients whose neurologic status is significantly abnormal between relapses). Not indicated in the treatment of patients with primary progressive multiple sclerosis.

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