Multiple Sclerosis Medication
- Author: Christopher Luzzio, MD; Chief Editor: Jasvinder Chawla, MD, MBA more...
Treatment and management of multiple sclerosis should be targeted toward relieving symptoms of the disease, treating acute exacerbations, shortening the duration of an acute relapse, reducing frequency of relapses, and preventing disease progression.
Drugs approved for use in MS that reduce the frequency of exacerbations or slow disability progression are referred to as disease-modifying drugs (DMDs). These DMDs can be further classified as immunomodulating (or receptor modulating) or immunosuppressives. Some immunosuppressants are also FDA-approved as antineoplastic agents.
Drugs that treat MS-related symptoms (eg, acute exacerbations, cognitive dysfunction, fatigue, spasticity, bowel and bladder problems, and pain) but do not modify the course of the disease are referred to as symptom-management medications.
Immunomodulators or receptor modulators are indicated for the treatment of patients with relapsing forms of MS. They help to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations.
Interferon beta-1b was the first medication approved by the FDA for MS. It is approved for the treatment of relapsing forms of MS to reduce the frequency of clinical exacerbations. It has shown efficacy in patients who have experienced a first clinical episode and have MRI features consistent with MS.
The exact mechanism by which interferon beta-1b exerts its effects is unknown. Interferon beta inhibits the expression of pro-inflammatory cytokines, including interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha and TNF-beta, interferon gamma (IFN-γ), and IL-6. IFN-γ is believed to be a major factor responsible for triggering the autoimmune reaction leading to MS.
Dalfampridine, a broad-spectrum potassium blocker is approved as a treatment to improve walking in patients with MS. The improvement in walking was demonstrated by an increase in walking speed.
Interferon beta-1a is approved for the treatment of patients with relapsing forms of MS. It helps to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations.
The exact mechanism by which interferon beta-1a exerts its effects is not fully defined. Interferon beta inhibits the expression of proinflammatory cytokines, including interferon gamma (IFN-γ), which is believed to be a major factor responsible for triggering the autoimmune reaction leading to MS.
Alemtuzumab is a recombinant monoclonal antibody against CD52 (lymphocyte antigen). This action promotes antibody-dependent cell lysis. It is indicated for relapsing forms of multiple sclerosis. Because of the risk for severe and lasting autoimmune adverse effects, use is reserved for patients who have an inadequate response to 2 or more other drugs for MS.
Precise mechanism by which peginterferon beta-1a exerts its effects in patients with multiple sclerosis is unknown. Interferons are thought to alter response to surface antigen and may enhance immune cell activities. It is indicated for treatment of relapsing forms of multiple sclerosis.
Natalizumab is indicated as monotherapy for MS to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. Natalizumab is a recombinant humanized monoclonal antibody that binds with alpha-4 integrins and inhibits their adherence to their counterreceptors. The specific mechanism by which natalizumab exerts its effects in MS has not been defined.
Natalizumab has a black-box warning for progressive multifocal leukoencephalopathy (PML). Because of the risk of PML, natalizumab is available only through a special restricted distribution prescribing program called the Tysabri Outreach Unified Commitment to Health (TOUCH).
Glatiramer acetate is approved for the reduction of the frequency of relapses in patients with relapsing-remitting MS, including patients who have experienced a first clinical episode and have MRI features consistent with MS. Glatiramer acetate's mechanism of action is unknown, but this agent is thought to modify immune processes believed to be responsible for the pathogenesis of MS. The recommended dosage is 20 mg/day administered subcutaneously. The sites for injection include the arms, abdomen, hips, and thighs.
Fingolimod is the first oral therapy for relapsing forms of MS approved by the FDA. Like other disease-modifying drugs (DMDs) for MS, fingolimod can reduce the frequency of clinical exacerbations and delay the accumulation of physical disability. The recommended dosage for fingolimod is 0.5 mg once a day.
The mechanism by which fingolimod exerts therapeutic effects in MS is unknown, but it appears to be fundamentally different from that of other MS medications. Its activity may involve a reduction of lymphocyte migration into the central nervous system.
Teriflunomide is an oral immunomodulatory agent that elicits anti-inflammatory effects by inhibiting dihydroorotate dehydrogenase, a mitochondrial enzyme involved in pyrimidine synthesis. It is indicated for relapsing forms of MS.
Dimethyl fumarate (DMF) is an oral Nrf2 pathway activator indicated for relapsing forms of multiple sclerosis. DMF is metabolized rapidly by presystemic hydrolysis by esterases in the GI tract, blood, and tissues (before it reaches systemic circulation) and is converted to its active metabolite, monomethyl fumarate (MMF). MMF activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, a transcription factor encoded by the NFE2L2 gene. The Nrf2 antioxidant response pathway is a cellular defense against oxidative stress. MMF has been identified as a nicotinic acid receptor agonist in vitro.
Humanized monoclonal antibody that binds to the high-affinity interleukin-2 (IL-2) receptor subunit (CD25). It is indicated for relapsing forms of MS.
Corticosteroids are used to reduce inflammation and expedite recovery from acute relapses. The most commonly used corticosteroids in MS include methylprednisolone, dexamethasone and prednisone. Short courses of intravenous methylprednisolone with or without a short prednisone taper have been used.
Methylprednisolone is given for acute exacerbations of MS. By reversing increased capillary permeability and suppressing polymorphonuclear neutrophil (PMN) activity, methylprednisolone may decrease inflammation. In addition, it may alter the expression of some proinflammatory cytokines.
Dexamethasone can be given for acute exacerbations of MS. It stabilizes cell and lysosomal membranes, increases surfactant synthesis, increases serum vitamin A concentration, and inhibits prostaglandin and proinflammatory cytokines. Dexamethasone is available as an injection that can be administered intravenously or intramuscularly and in various oral formulations (tablets, elixir, and solution).
Prednisone prevents or suppresses inflammation and immune responses when administered at pharmacological doses. Prednisone's actions include inhibition of leukocyte infiltration at the site of inflammation, interference in the function of mediators of inflammatory response, and suppression of humoral immune responses. Oral prednisone tapers are commonly administered with or without methylprednisolone.
Immunosuppressants are used for their ability to suppress immune reactions. Agents such as methotrexate have shown some effectiveness in delaying progression of impairment of the upper extremities in patients with secondary progressive MS. Azathioprine has been studied in clinical trials and has shown modest effects on relapses and progression of disease. Methotrexate and azathioprine have not been approved by the US Food and Drug Administration for use in MS.
This immunosuppressive antimetabolite drug is an imidazolyl derivative of 6-mercaptopurine. It is cleaved in vivo to mercaptopurine and converted to 6-thiouric acid by xanthine oxidase. Azathioprine is generally used in the treatment of transplant rejection or severe, active, erosive rheumatoid arthritis, but it has been used off-label for MS.
Methotrexate interferes with DNA synthesis, repair, and cellular replication. It inhibits dihydrofolic acid reductase, which participates in the synthesis of thymidylate and purine nucleotides. Methotrexate has been used off-label for MS.
Antineoplastic agents such as cyclophosphamide and mitoxantrone have been used in MS patients.
Mitoxantrone is an immunosuppressive agent approved for the treatment of secondary progressive or aggressive relapsing-remitting MS. It is used for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (long-term) progressive, progressive relapsing, or worsening relapsing-remitting MS (ie, patients whose neurologic status is significantly abnormal between relapses). Mitoxantrone is not indicated in the treatment of patients with primary progressive MS.
Mitoxantrone therapy can increase the risk of developing secondary acute myeloid leukemia (AML) in MS patients and in patients with cancer.
Cyclophosphamide has been used for the treatment of progressive MS. Evidence of benefit is mixed. This agent has not been approved for MS but has been used off-label in MS patients. Cyclophosphamide is associated with leukemia, lymphoma, infection, and hemorrhagic cystitis.
Amantadine is approved for the prophylaxis and treatment of influenza A and Parkinson disease and has been used off-label to relieve fatigue in patients with MS. It has relatively few side effects and is well tolerated .
Amantadine is not FDA approved for use in MS, but dosages of 100 mg given orally twice a day have commonly been used for fatigue. The mechanism by which amantadine counteracts fatigue in MS patients is unclear.
Skeletal Muscle Relaxant
Pharmacologic treatment of spasticity includes baclofen (Lioresal, Gablofen) as a first-line agent. Baclofen can be titrated easily in divided doses. Patients using this medication may report fatigue or weakness as an adverse effect. Dantrolene (Dantrium) acts within muscles on excitation-contraction coupling; however, it is rarely used because it can cause liver damage.
Baclofen is a skeletal muscle relaxant used as a first-line treatment for spasticity in patients with MS. It can effectively relieve spasms and has modest effects in improving performance. Intrathecal baclofen via an implanted pump can be effective against spasticity in suitable patients. The pump can be electronically regulated to deliver small amounts of baclofen at a constant or variable dose over a 24-hour period to increase efficacy and decrease side effects.
Dantrolene is a skeletal muscle relaxant that acts directly on skeletal muscle to decrease spasticity. Dantrolene is believed to decrease muscle contraction by directly interfering with calcium ion release from the sarcoplasmic reticulum within skeletal muscle cells. It affects all muscles of the body and is used less frequently than baclofen because of hepatotoxicity at higher doses and numerous drug interactions.
Neuromuscular Blockers, Botulinum Toxins
The FDA has approved the use of botulinum toxin (Botox) for the treatment of upper limb spasticity in MS. The FDA has also approved this agent for the treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition (eg, MS) in adults who have an inadequate response to, or are intolerant of, an anticholinergic medication.
OnabotulinumtoxinA toxin is an injectable neurotoxin that temporarily blocks connections between the nerves and the muscles, leading to short-term relaxation of the targeted muscle. The drug can be injected again when the muscle-relaxing effects have worn off, but not more frequently than every 3 months.
It is approved for the treatment of upper limb spasticity in adults to decrease the severity of increased muscle tone in elbow flexors (biceps), wrist flexors (flexor carpi radialis and flexor carpi ulnaris), and finger flexors (flexor digitorum profundus and flexor digitorum sublimis).
Tizanidine (Zanaflex) is a centrally active alpha2 -adrenergic agonist that is also used to treat spasticity in patients with MS. It can be used alone or in combination with baclofen.
This centrally acting alpha-adrenergic agonist is presumed to decrease spasticity by increasing presynaptic inhibition of motor neurons. Tizanidine has effects similar to those of baclofen, but it produces less weakness and more sedation. This drug can be titrated starting with 2 mg, with maximum doses of 36 mg/day.
Benzodiazepines are used as second-line agents for the treatment of spasticity in patients with MS. Agents in the benzodiazepine class that are commonly used include diazepam and clonazepam. While these compounds can be useful adjunct medications, they can be sedating and habit-forming and are not FDA approved for use in MS.
For patients who also experience sleep disorders, the provider may take advantage of the sedating 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.
Clonazepam is a long-acting benzodiazepine that increases presynaptic gamma-aminobutyric acid (GABA) inhibition and reduces monosynaptic and polysynaptic reflexes. It suppresses muscle contractions by facilitating inhibitory GABA neurotransmission and other inhibitory transmitters.
Diazepam modulates the postsynaptic effects of GABA-A transmission, resulting in an increase in presynaptic inhibition. It appears to act on part of the limbic system, the thalamus, and the hypothalamus to induce a calming effect. Diazepam also has been found to be an effective adjunct for the relief of skeletal muscle spasms caused by upper motor neuron disorders.
Modafinil (Provigil), armodafinil (Nuvigil), dextroamphetamine (Dexedrine), and methylphenidate (Concerta, Metadate CD, Metadate ER, Ritalin, Ritalin SR) are wakefulness-promoting agents approved for the treatment of narcolepsy. These agents are also used for the treatment of fatigue without interfering with normal sleep architecture in patients with MS. Modafinil and methylphenidate have also been used as cognitive-enhancing drugs to treat cognitive dysfunction in MS.
Modafinil is listed in Schedule IV of the Controlled Substances Act. It promotes wakefulness, and is used for treatment of fatigue without interfering with normal sleep architecture. Patients should be observed for signs of use or abuse, as the drug has psychoactive and euphoric effects similar to those seen with other scheduled CNS stimulants (eg, methylphenidate). The mechanism of action of modafinil is unknown.
Armodafinil elicits wakefulness-promoting actions similar to those of sympathomimetic agents, although its pharmacologic profile is not identical to sympathomimetic amines. It is indicated to improve wakefulness in individuals with excessive sleepiness associated with narcolepsy, obstructive sleep apnea–hypopnea syndrome (OSAHS), or shift-work sleep disorder. It is also used for treatment of fatigue without interfering with normal sleep architecture. It may also be used as a cognitive-enhancing drug to treat cognitive dysfunction in MS.
Methylphenidate (Concerta, Daytrana, Metadate CD, Metadate ER, Methylin, Methylin ER, Ritalin, Ritalin LA, Ritalin SR)
Methylphenidate is a piperidine derivative. It stimulates the cerebral cortex and subcortical structures.
This agent increases the amount of circulating dopamine and norepinephrine in the cerebral cortex by blocking the reuptake of norepinephrine or dopamine from synapses.
Gabapentin is an anticonvulsant drug that is particularly useful in patients who experience spasticity and neuropathic pain. Anticonvulsants (eg, carbamazepine, phenytoin) can also be used for the treatment of secondary pain in MS. Topiramate (Topamax) is an anticonvulsant that can be used for MS patients with tremor or spasms and has also been used for paroxysmal symptoms.
Gabapentin is a membrane stabilizer, a structural analogue of the inhibitory neurotransmitter GABA. Paradoxically, gabapentin is thought not to exert an effect on GABA receptors. It is used to manage pain and provide sedation in patients with neuropathic pain.
Carbamazepine is a sodium channel blocker that typically provides substantial or complete relief of pain in 80% of individuals with MS within 24-48 hours. It reduces sustained high-frequency repetitive neural firing and is a potent enzyme inducer that can induce its own metabolism.
Pregabalin is a structural derivative of GABA with an unknown mechanism of action. It is used to relieve neuropathic pain.
The exact mechanism of topiramate's anticonvulsant effects is unknown. Topiramate's actions involve several mechanisms, including reduction of the duration of abnormal discharges and the number of action potentials within each discharge. This is probably secondary to its ability to block voltage-sensitive sodium channels. Topiramate also increases the frequency at which GABA activates GABA-A receptors. Finally, it inhibits excitatory transmission by antagonizing some types of glutamate receptors.
Anticonvulsants, such as phenytoin, can also be used for the treatment of secondary pain in MS.
Phenytoin blocks sodium channels nonspecifically and therefore reduces neuronal excitability in sensitized C-nociceptors. It is effective in neuropathic pain, but it suppresses insulin secretion and may precipitate hyperosmolar coma in patients with diabetes.
Selective Serotonin/Norepinephrine Reuptake Inhibitors
Selective serotonin/norepinephrine reuptake inhibitors (SNRIs) are principally used as antidepressants; however, duloxetine is also indicated for relief of several types of pain.
A potent inhibitor of neuronal serotonin and norepinephrine uptake, duloxetine is used as an antidepressant and for relief of neuropathic pain.
Nonsteroidal Anti-Inflammatory Drugs
Pharmacologic agents used for the treatment of secondary pain in MS are nonsteroidal anti-inflammatory drugs (NSAIDs) or other analgesics. Ibuprofen has also been cited as potentially having beneficial effects with paroxysmal symptoms. The use of narcotics seldom is indicated. Commonly used NSAIDs include ibuprofen (Motrin, Advil) and naproxen (Naprosyn, Aleve, Anaprox, Anaprox DS, Naprelan).
Ibuprofen is the drug of choice for patients with mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.
Naproxen is used for relief of mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis.
Antispasmodic Agents, Urinary
Treatment of bladder dysfunction in MS patients includes suppressing urgency and ensuring effective urinary drainage. Antispasmodic agents that help decrease muscle spasms of the bladder and the frequent urge to urinate caused by spasms include oxybutynin (Ditropan, Ditropan XL) or tolterodine (Detrol, Detrol LA).
Tolterodine is a competitive muscarinic receptor antagonist. Both urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors.
Oxybutynin is an antispasmodic that exerts a direct effect on smooth muscle and inhibits the muscarinic effects of acetylcholine on smooth muscle. This results in relaxation of bladder smooth muscle. It is indicated for the relief of urinary symptoms in patients with uninhibited and reflex neurogenic bladder. It is metabolized by the liver and excreted renally.
Acetylcholinesterase Inhibitors, Central
Multiple sclerosis may affect cognition, and cognition-enhancing drugs have been met with some success in MS patients. Treatments used in Alzheimer disease, such as donepezil (Aricept), may have some potential beneficial effects; however, it has not been proven in clinical trials. Donepezil is not FDA-approved for use in MS. Depression may also contribute to cognitive dysfunction and should be treated if it is diagnosed.
Donepezil selectively inhibits acetylcholinesterase, the enzyme responsible for the destruction of acetylcholine, and improves the availability of acetylcholine.
Pharmacologic management of constipation in patients with MS includes the use of stool softeners. Stool softeners, such as docusate sodium (Colace), work by decreasing surface tension, allowing water to enter the stool.
Docusate sodium allows the incorporation of water and fat into stools, causing stools to soften. By its surface active properties, docusate sodium keeps stools soft for easy, natural passage. Docusate sodium is not a laxative and, thus, is not habit-forming. Tachyphylaxis may occur with long-term use. This agent is effective acutely and does not induce defecation.
Psyllium is administered orally and absorbs liquid in the GI tract, thereby altering intestinal fluid and electrolyte transport. Absorption of liquid also causes expansion of the stool, and the resultant bulk facilitates peristalsis and bowel motility.
Methylcellulose increases the bulk of the stool and thereby stimulates peristalsis, which increases bowel motility and decreases GI transit time. These actions of methylcellulose result in easy passage of stool in patients with chronic constipation.
Diarrhea, if it occurs, typically is not related to MS per se; it is more likely due to fecal impaction, diet, irritation of the bowel, or overuse of laxatives or stool softeners, or it is an adverse effect of medications. Diphenoxylate and atropine (Lomotil) is an antidiarrheal that helps slow the muscles of the bowel.
Diphenoxylate appears to exert its effect locally and centrally on the smooth muscle cells of the GI tract to inhibit GI motility and slow excess GI propulsion. A subtherapeutic dose of anticholinergic atropine sulfate is added to discourage overdosage, in which case diphenoxylate may clinically mimic the effects of codeine.
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|Clinical Presentation||Additional Data Needed for MS Diagnosis|
||None; clinical evidence will suffice. Additional evidence (eg, brain MRI) desirable,
but must be consistent with MS
||Dissemination in space demonstrated by MRI or
Await further clinical attack implicating a different site
||Dissemination in time demonstrated by
MRI or second clinical attack
||Dissemination in space demonstrated by
MRI or await a second clinical attack implicating a different CNS site
Dissemination in time, demonstrated by MRI or second clinical attack
|· Insidious neurologic progression suggestive of MS||One year of disease progression and dissemination in space, demonstrated by 2 of the following:
|Notes: An attack is defined as a neurologic disturbance of the kind seen in MS. It can be documented by subjective report or by objective observation, but it must last for at least 24 hours. Pseudoattacks and single paroxysmal episodes must be excluded. To be considered separate attacks, at least 30 days must elapse between onset of one event and onset of another event.|