Medicine & Research

When Medication Stops Working, or Causes Complications

By Maria Adelita Reyes-Velarde, MD, MPH

In general there are two basic reasons to consider switching MS treatments (or for that matter, any other medication): You cannot tolerate the side effects, or the medications aren’t working for you. Let’s start by talking about side effects. 

All medications have side effects (including those called naturals), but not all medications may give you side effects. The way we react to the medications is as unique as we are. Therefore, we need to know the possible side effects of the medications before we begin taking them so we can talk to our doctors as soon as we experience them.

Right now, the MS approved treatments are based on drugs that influence the immune system and are used to help prevent further attacks and progression of the disease. Six of these treatments are considered immunomodulatory drugs and one is a chemotherapeutic immunosupressant. Both of the new oral therapies that are close to coming out, Gilenia® (fingolimod) and cladribine, are immunosupressants.

Immunomodulatory Drug Side Effects

The interferon beta 1-a (Avonex®, Rebif®) and interferon beta 1-b (Betaseron®, Extavia®) drugs have flu-like symptoms following injection, which can be minimized by taking acetaminophen (Tylenol®), naproxen (Aleve®), or ibuprofen (Advil® or Motrin®). Their less common side effects include allergic reactions, depression, suicidal ideas, liver and thyroid functions affected (altered thyroid test and elevated liver enzymes), and low red or white blood cell counts.

Because they affect the liver, you may bruise more easily or your skin may change color (make sure you inform your doctor). Avonex® has been associated with heart problems, although it’s not clear that the drug was the culprit. Since they are all injected, you may have localized reaction in the injection site like redness in the skin, bumps, bruises, pain, and infections. Learning how to correctly inject yourself or using auto-injecting devices may help to minimize these effects.

Glatiramer acetate (Copaxone®) has a unique potential side effect that shows up right after the injection and lasts approximately 15 minutes. The person can have hot flashes and redness of the skin, chest pain, palpitations, anxiety, and difficulty breathing. It has also been reported that it can affect the results of a Pap test. Since glatiramer acetate is injectable, it can also have the injection site side effects described above.

Natalizumab (Tysabri®), administered by infusion, can cause headache, fatigue, urinary tract infections, depression, lower respiratory tract infections, joint pain, and chest discomfort. It is less common to have allergic or hypersensitivity reactions within two hours of infusion (dizziness, fever, rash, itching, nausea, flushing, low blood pressure, difficulty breathing, chest pain and liver function abnormalities). This is why you have to wait at the center one hour after the infusion before leaving. 

Tysabri has the risk of progressive multifocal leukoencephalopathy (PML), a serious and sometimes deadly viral infection of the brain. The risk of developing PML increases with the number of Tysabri infusions received, according to the U.S. Food and Drug Administration. In the U.S., the rate is approximately one case per 1,000 patients treated. PML symptoms may begin slowly, progress rapidly, and can include changes in thinking and memory, confusion, vision problems, difficulty walking, clumsiness, and occasional seizures.

Immunosuppressant Drug Side Effects

The side effects of immunosuppresant drugs may be more severe because they suppress the immune system, making you more vulnerable to infections and other complications.

Mitroxantrone (Novantrone®), given by infusion, can cause blue-green urine 24 hours after administration, bone marrow suppression (fatigue, bruising, low blood cell counts), nausea, hair loss, bladder infections, mouth sores, and serious liver and heart damage. People taking this drug, which is given every three months, require close monitoring by doing an echocardiogram (ultrasound of the heart) before each dose. Cardiac monitoring is recommended annually for life for those who have been given mitoxantrone. Mitoxatrone has also been associated with a type of leukemia.

If a person cannot deal with the side effects, or the side effects are so serious that the overall well-being of the person is adversely affected, then a switch of medications must be considered.

Evaluating Effectiveness of Your Drug Treatment

The second reason to change medications is when it is not working for you. But how do you and the doctor determine that the treatment is not working?

The goal of current treatments in MS is to prevent further disability; they do not cure or reverse existing deficits. To evaluate whether your medication is effective, the doctor will monitor your clinical relapses, changes in your MRI, and changes in disability levels. Most experts say that you need at least six months to decide if the treatment is not working – a couple of months for the medication to reach desirable levels, and a few more to see if it stops the attacks.

Monitoring your clinical relapses involves knowing how many relapses you have within one year; determining if the number decreases within six months of treatment; evaluating how severe they are and how much time it takes you to recover; and noting if they respond to steroid treatment.

When using MRI to monitor your MS, you should know that MRI can show the disease activity only when you can compare with previous MRIs. Experts say that two or more new T2 lesions on each repeated scan separated by at least quarterly intervals can be indicators of treatment failure.

It is also important to evaluate disability progression. The Expanded Disability Status Scale (EDSS) is the measure used to determine neurologic disability. An EDSS done after an attack only measures the severity of the attack and not the acquired disability. When you start with a score of 3.0 to 5.5, an annual increase of one point in the EDSS is considered worrisome. The same happens if you start with a score of 6.0 or greater and in the absence of an attack have a 0.5 increase. This may indicate that the previously relapsing-remitting patient has transitioned to secondary-progressive disease or that the person with secondary-progressive MS has only a partial response to therapy. 

Another way to know if the medication is not working is testing for neutralizing antibodies. As the name implies, these antibodies neutralize the medication, preventing it from working properly. Studies have demonstrated that up to 41 percent of patients develop persistent neutralizing antibodies on high dose interferon therapy within the first 12 to 24 months. Other studies have questioned how important these antibodies are, and there is no clear consensus on testing for them. 

If you have high levels of neutralizing antibodies and no major relapses or MRI activity, your doctor may recommend that you be retested in three to six months. If you have neutralizing antibodies to interferon and frequent relapses or excessive MRI activity, your doctor may recommend switching to another treatment not related to interferon.

When the therapy fails, you may be switched within interferon-beta formulas; for example, from Avonex® to Rebif® or Betaseron® (if you don’t have neutralizing antibodies). This is because sometimes you may benefit from a different concentration and formulation of the interferon. You may also change therapy from an interferon to glatiramer acetate or vice versa, or switch to natalizumab, mitroxantone, another chemotherapy, or possible combination of treatments. It really depends on which treatment you and your doctor decide is best for you. 

You may decide to stop using MS treatments altogether. Please take into account that the natural history data suggest that of the 85 percent of the persons with relapsing remitting MS, 50 percent develop secondary progressive MS within 10 years and 90 percent within 25. Delaying that progression until a better therapy option comes around may be the best option.

On the other hand, you may be in the 50 percent that doesn’t progress or in the smallest group that doesn’t have major problems. But there are no guarantees.  

Maria Adelita Reyes-Velarde, MD, MPH is the author of “Con los pies en la tierra, aprendiendo a vivir con la EM” 3rd edition, the only book written in Spanish for people living with MS. Her bilingual blog, Desde mi balcón, can be found at:

(Last reviewed 5/2010)