Pharmacists can play a major role in the diagnosis and treatment of patients with this debilitating disease.




Pharmacists can play a major role in the diagnosis and treatment of patients with this debilitating disease

You have multiple sclerosis." These words can transform a vision of the future from bright to bleak. To the victims, mostly young women in their 20s and 30s, the diagnosis of MS conjures up a life of increasing disability, as an autoimmune process gradually destroys the myelin sheath in the white matter of their central nervous system (CNS).

As the disease progresses, patients can expect debilitating symptoms such as sensory disturbances in the limbs, loss of muscle coordination, problems with balance, visual disturbances, loss of bladder and bowel control, and sexual dysfunction. Studies have found that 30 years after diagnosis, 80% of MS patients require assistance with ambulation.

Nevertheless, for the 300,000 Americans with MS, the future today looks brighter than it ever has. While in the past, treatments could address only MS symptoms as they arose, new therapies have proven to decrease the frequency of exacerbations and possibly slow the progression of the disease, allowing patients to fulfill their dreams as much as possible.

Disease-modifying therapy

The most common form of MS at onset is relapsing-remitting MS (RRMS), and most immunomodulator therapy is aimed at this diagnosis. The first disease-modifying therapy, interferon beta (IFNß) has immunomodulatory and antiviral activities; it is known to interact with specific receptors on the surface of human cells. Betaseron (IFNß1b, Berlex), a nonglycosylated form of recombinant IFNß produced in modified E. coli cells, was approved in 1993.

IFNß1b was followed three years later by Avonex (IFNß1a, Biogen), a recombinant product with an amino acid sequence identical to that of natural human IFNß. While IFNß1b is injected subcutaneously every other day, IFNß-1a requires only once-weekly intramuscular administration.

Also approved in 1996 was Copaxone (glatiramer acetate, TEVA), a protein product unrelated to the interferons. Glatiramer appears to work by modifying immune processes believed to be responsible for the pathogenesis of MS.

The latest addition to the arsenal, Rebif (IFNß-1a, Serono), is chemically identical to Avonex but is administered SC three times a week. In March, Rebif overturned Avonex's orphan drug status with EVIDENCE, a 48-week study that proved it is superior to Avonex in relapse reduction.

The battle of the beta interferons

The EVIDENCE trial compared Rebif 44 mcg SC t.i.w. to Avonex 30 mcg IM once weekly in more than 600 patients. Over the initial 24 weeks of the study, 75% of Rebif patients did not have a relapse, as compared with 63% of patients who received Avonex. In the 48-week extension data, 62% of Rebif-treated patients remained relapse-free, as compared with 52% of Avonex-treated patients.

These results corroborate the opinion of many experts that higher and more frequent doses boost interferon efficacy. However, said Cary Pfeffer, M.D., v.p. of medical affairs at Biogen, Rebif's greatest benefit was shown in the first 24 weeks, which, "in a long-term chronic disease, is a very short amount of time." Biogen is launching an international study to compare the safety, tolerability, and efficacy of the two products over up to five years.

To support his belief that higher doses of IFNß are not necessarily better, Rob Perez, v.p. of the CNS business unit at Biogen, cited the firm's double-blinded European Dose- Comparison Study, which compared the efficacy of 30- and 60-mcg once-weekly IM doses of Avonex. In a four-year extension analysis of close to 500 patients, efficacy, as assessed by multiple disability progression and MRI outcomes, was nearly identical between the two groups.

Still, many experts believe dosing frequency plays an important role in IFNß efficacy. "There's not much doubt these interferons must be given more often than once a week" to have maximal benefit, said Kenneth P. Johnson, M.D., professor of neurology, director of the Maryland Center for MS at the University of Maryland. Another study he believes provides strong support for this concept was recently published in Lancet. The independent INCOMIN trial compared IFNß-1a and IFNß-1b in nearly 200 patients with RRMS. Over two years, 51% of IFNß-1ß-treated patients remained relapse-free, as compared with 36% of patients taking IFNß-1a.

Ayad Abdulahad, M.D., Ph.D., head of clinical development for CNS at Berlex, said IFNß-1b's higher dose and more frequent dosing gave it the upper hand. To investigate whether the drug may provide even more benefit at a higher dose, he said Berlex is launching a study of IFNß-1b 500 mcg every other day, double the currently approved dose.

Lasting effects

Long-term immunomodulator data have begun to demonstrate that therapy may actually result in an improvement in patient status, said Michael Silberman, R.Ph., health science adviser for Procter & Gamble and member of the advisory committee for South Florida chapter of the National MS Society. Disability progression is assessed using the Kurtzke Expanded Disability Status Scale (EDSS), a measure that takes into account various types of functioning.

The most compelling available data, according to Johnson, are on glatiramer, which, after eight years of therapy, maintained or improved EDSS scores in 65% of 140 patients. A 12-year follow-up of 31 patients from one center who participated in the first clinical trial of IFNß-1b showed these patients had a decrease in disease burden, as measured by MRI. Berlex is now extending the study to include all 372 patients who were in the original trial, Abdulahad reported.

The drug of choice and patient choice

For maximum benefit, immunomodulator therapy should begin as soon as RRMS is diagnosed. Although some prescribers prefer one drug to the others based on research findings, much of drug choice in early MS is based on patient factors (see Table 1).


Table 1
Comparison of immunomodulator products

Betaseron (IFNß-1b, Berlex)
Avonex (IFNß-1a, Biogen)
Rebif (IFNß-1a, Serono)
Copaxone (glatiramer acetate, TEVA)
Route of administration
Maintenance dose
0.25 mg
30 mcg
44 mcg
20 mg
Specific interferon activity
32 million IU/mg
200 million IU/mg
270 million IU/mg
Every other day
Once a week
Three times weekly
Once daily
Room temperature
How supplied
Vials for reconstitution
Vials for reconstitution
Prefilled syringes 22 mcg (starter pack) 44 mcg
Vials for reconstitution

Source: Compiled from drugs’ package inserts


Patients' aversion to needles is "one of the biggest barriers to implementing and continuing therapy," said Silberman, who counseled MS patients as a pharmacy service specialist for Athena Rx Home Pharmacy's Partnership for Care program, a 42-month project that ended last year. Although Avonex has the convenience of once-weekly dosing, some patients are so frightened of the size of the IM needle that they prefer more frequent SC injections, he said.

On the other hand, said Jill C. Chappell, Pharm.D., a former pharmacy resident in neurology at Mount Sinai Hospital in New York, some patients may have a nurse come to administer Avonex, while they would have to learn to inject the more frequent SC products themselves.

Side effects are another consideration. All interferons are associated with a flu-like reaction. Pretreatment with acetaminophen can attenuate these symptoms, and these effects usually subside after the first six months of therapy. The SC interferons—but not Avonex—are also associated with injection-site reactions.

Some patients prefer to restrict the flu-like symptoms to one day a week by taking Avonex, Silberman said. Glatiramer avoids the flu-like symptoms entirely but requires daily injections. Individuals who travel often have concerns related to storing their medication, Chappell said. For these patients, IFNß-1b, with new formulation designed for storage at room temperature, may be the best choice.

Third-party coverage may present barriers in drug selection. Some health maintenance organizations refuse to cover injectable drugs, Silberman said, while others limit choice to one or two of the immunomodulators. As of Aug. 1, Medicare will cover Avonex when administered by a physician but not for the SC immunomodulators, which are usually self-administered.

Addressing acute attacks

During flare-ups of MS, which can manifest neurologically in several ways, patients are hospitalized and placed on courses of steroid therapy. Corticosteroids such as Depo-Medrol (methylprednisolone injection, Pharmacia) have been shown to speed up functional recovery. Patients typically are discharged in three to seven days, often with step-down oral steroid therapy such as a Medrol DosePak (methylprednisolone, Pharmacia).

One of the highly neglected areas of MS management is an understanding of the long-term effects of high-dose steroids, Silberman said. "Steroid-induced osteoporosis is an effect due to cumulative dose, not due to time of exposure," he said. Osteoporosis and MS can be a dangerous combination, because balance and gait problems predispose MS patients to fall. He recommends bone density scans every few years, especially in patients with a history of steroid use. Patients should be advised to take calcium and vitamin D supplements in separate doses and to make sure to get some sun every day to activate the vitamin D, he said. And individuals with confirmed osteoporosis can be treated with the standard bone-resorbing therapies.

Slowing the decline in SPMS

For patients with RRMS who appear to be failing interferon therapy, based on clinical MRI findings—patients who are "transitioning into more progressive forms of MS," in Johnson's words—the treatment options include switching to glatiramer and adding an immunosuppressant, such as Novantrone (mitoxantrone, Immunex), cyclophosphamide, methotrexate, or azathioprine, to IFNß therapy.

Secondary progressive multiple sclerosis (SPMS) sufferers have a much narrower spectrum of therapeutic options than RRMS patients. The only FDA-approved therapy for them is the antineoplastic mitoxantrone, an immunosuppressant approved for SPMS, progressive relapsing multiple sclerosis (PRMS), and worsening RRMS in October 2000.

In a randomized, controlled clinical study in which patients received IV injections of mitoxantrone every three months for two years, 12 mg/m2 mitoxantrone was shown to be significantly better than placebo on several endpoints. In another study, mitoxantrone plus methylprednisolone were significantly more efficacious than mitoxantrone alone at reducing lesions on MRI at six months. But because mitoxantrone carries a warning of myocardial toxicity, its use is limited by a maximum lifetime cumulative dose of 140 mg/m2.

Several trials have examined the use of IFNß in SPMS, with mixed results. The SPECTRIMS trial found that Rebif had a significant effect on MRI measures and exacerbation-related outcomes but did not significantly affect disability progression. These findings were similar to those of a North American study of IFNß-1b in SPMS. However, in a European SPMS study, IFNß-1b demonstrated a significant effect on development of disability as well as the other outcome measures. Some experts attribute the conflicting findings to the difference in the patient populations recruited.

A study of Avonex in SPMS called IMPACT found a benefit on disability progression, relapses, quality of life, and MRI outcomes. But instead of using EDSS as a measure of disability progression, IMPACT used a new measure called the MS Functional Composite (MSFC). Most of Avonex's effect was apparent in quantitative tests of arm function and cognition; there was no benefit on the EDSS and the ambulation portion of the MSFC. While the researchers believe these results confirm the advantages of the MSFC, other experts find the IMPACT results difficult to evaluate because the MSFC is relatively untested.

Despite the equivocal research findings, both Biogen and Berlex have applied to the FDA for the addition of the SPMS indication.

Johnson believes the differences in interferons' effects in relapsing and progressing disease are due to differences in pathophysiology. "The interferons are primary anti-inflammatory drugs," he explained, and have a significant effect on MRI findings in RRMS. "Yet," he continued, "they seem to have little effect on the later stages of disease, which are becoming thought of as a degenerative, rather than an inflammatory, process." In general, he said, patients who still have "a fair number of inflammatory lesion on their MRI" may be candidates for IFNß even in more advanced stages of disease.

The jury is still out on whether glatiramer is beneficial in progressive disease. "Some data on Copaxone suggest it is more neuroprotective or it reduces the chance of the kind of MRI changes that we associate with increasing disability," Johnson said. He awaits the results of the PROMISE trial, which is studying glatiramer for primary progressive disease.

Struggling with symptoms

MS symptoms vary, partially depending on the location of the plaques in the CNS. Drug therapy is used to manage some of these symptoms. Fatigue, the most common symptom, and narcolepsy, which occurs in a subgroup of patients, are often dealt with by lifestyle management, Silberman said. For patients who require treatment, pemoline and amantadine have proven useful, and the antinarcolepsy drug Provigil (modafinil, Cephalon) has shown some promise.

Depression in MS is two-pronged, with both psychological and chemical origins, Silberman noted. On the one hand, patients become depressed by their deteriorating condition and loss of independence; on the other, the interferons have been shown to cause depression chemically. Fortunately, this depression usually responds well to therapy with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, or atypical agents.

Standard therapies for bladder incontinence include anticholinergics such as oxybutynin and Detrol (tolterodine, Pharmacia). Patients should be cautioned not to reduce their fluid intake overall, Silberman said, because MS patients have a limited ability to handle heat.

Spasticity is often treated with muscle relaxants such as Zanaflex (tizanidine, Elan Corp.), baclofen, and diazepam. Tizanidine is advantageous, Silberman noted, in that it "does not compromise muscle tone, so it allows patients to reach a degree of muscle relaxation without severely compromising posture and balance and gait." And clinicians should not neglect the simple solutions, he said, such as quinine for leg cramps.

Most pain associated with MS is neuropathic in nature, Silberman said, so standard painkillers, such as narcotics, are not usually effective. Clinicians must be very creative in treating neuropathies, he said, using drugs such as Elavil (amitriptyline, AstraZeneca), Neurontin (gabapentin, Pfizer), and other anticonvulsants.

To minimize the number of drugs patients must take, Chappell said, drugs can be used for overlapping indications. For example, she said, the anticholinergic side effects of tricyclic antidepressants can be used to treat urinary incontinence. Similarly, amitriptyline might be used to treat depression as well as neuropathic pain. Sometimes patients have tremors or seizures, she said, and an anticonvulsant will help their depression as well.

While many alternative therapies are touted for MS, none have been proven efficacious, and some may be harmful. Prokarin (formerly Procarin) is a proprietary formula developed by a nurse with MS. The fact that it must be compounded by R.Ph.s for transdermal application and, thus, does not require FDA approval, evokes concerns about the lack of standardization in compounding methods, Chappell said. In a recent clinical trial in 29 patients with RRMS or progressive MS, Prokarin demonstrated an improvement in fatigue, but experts said issues with the design of the study make it difficult to interpret.

Silberman said echinacea, used to minimize cold and flu symptoms, should be contraindicated in MS patients, because the herb is known to stimulate immune function and, thus, may trigger a relapse.

Future directions

Of the drugs in development, the furthest along is monoclonal antibody Antegren (natalizumab, Biogen and Elan Corp.), which is given by monthly intravenous infusions. Natalizumab blocks the adhesion of immune cells to blood vessel and can inhibit movement of immune cells from the blood into the brain.

In a six-month study in 213 patients with RRMS or SPMS, natalizumab caused a reduction in accumulations of new lesions detected by MRI and a reduction in relapses. No benefit on progression of disability was detected. Other trials will examine the use of natalizumab in combination with Avonex.

The pharmacist's role

There are various avenues by which pharmacists can get involved in helping MS patients. First, community R.Ph.s may have a hand in identifying patients with undiagnosed MS, Silberman said. If, for example, an R.Ph. notices a patient taking drugs for both neurogenic bladder and peripheral neuropathy, each prescribed by a different physician, that should trigger an alarm. Each prescriber may have evaluated a symptom that, by itself, has little significance, he said. "But put them together and they may lead to something beyond what's at the surface."

Pharmacists must stress to patients that immunomodulators are not a cure and must be taken consistently. Because in RRMS, patients may go a year or two years without suffering a relapse, Silberman explained, "it's very hard for them to materially see the benefit in injecting medication on a regular basis."

Pharmacists can get involved in teaching patients proper injection techniques, and they can also make patients aware of assistance and advocacy programs, Chappell said. Patients taking IFNß-1a should be reminded that they need periodic liver function tests.

Pharmacists can also help improve symptomatic therapy by recommending one drug for multiple indications, Chappell said. And for patients who are suffering side effects, Silberman said, the R.Ph. can help identify which drug is causing the effect and recommend strategies for minimizing problems.

Silberman urges hospital pharmacists to become involved in discharge planning for MS patients after hospitalization for relapses. Pharmacists should "counsel these patients on the dangers of chronic steroid use" and provide them with information on osteoporosis monitoring. Ideally, he'd like to see pharmacists "reach out more to the community, participate more in patient education, go and talk to support groups, because it really is sorely needed."

Tzipora R. Lieder, R.Ph.

The author is a clinical writer in Baltimore.

Clinical courses of multiple sclerosis

• Relapsing-remitting multiple sclerosis (RRMS) is characterized by self-limited demyelinating attacks, accompanied by neurological dysfunction. RRMS accounts for approximately 85%-90% of MS cases at onset.

• Secondary progressive multiple sclerosis (SPMS) develops in patients who initially have RRMS, but whose disease course changes and becomes characterized by a steady deterioration in function unrelated to acute attacks. SPMS, which eventually develops in about 80% of RRMS patients, ultimately results in significant disability.

• In primary progressive multiple sclerosis (PPMS), patients experience a steady decline in function from the onset of disease. PPMS represents only about 10% of MS cases.

• Progressive relapsing multiple sclerosis (PRMS) patients experience occasional attacks superimposed on their steadily progressive disease course. This form is rare.


Tzipora Lieder. LIVING WITH MULTIPLE SCLEROSIS. Drug Topics 2002;14:25.

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