Which are Better: Older or Newer Antiepileptic Medications?

Are the newer antiepileptic drugs different than the older ones?

We are fortunate in 2006 that physicians have a great deal more choice when deciding the best drug treatment options for their patients than they did even a short while ago. In the last 10 to 15 years, eight new antiepileptic drugs have been approved for use in people with epilepsy, with four approvals in the last five years alone. Yet, it is still equally as common for physicians to prescribe the older drugs, some of which have been around for decades. The average person is bombarded with pharmaceutical messages touting the benefits of new drugs versus old. Therefore, it is very reasonable to ask the question whether the new drugs offer a substantial benefit, and whether patients should be asking their physicians specifically for these drugs.

The answer to this question differs, depending on a number of variables. These include age, gender, type of epilepsy, other medications that a person might be taking, as well as the presence of other medical conditions unrelated to epilepsy. The answer will also clearly be different depending on whether a new drug is about to be started for initial treatment of epilepsy, or whether a person has already been established on effective therapy.

Decisions about selection of antiepileptic drugs are based on three major factors. Firstly, will the drug effectively treat seizures? Obviously, in many ways this is the most important issue. The ability of a medication to control seizures is called its efficacy.

The second factor is how well tolerated the treatment is, and how likely there are to be serious adverse consequences or health risks. And a third factor, which people might not think about as much, but turns out to be quite important, is how likely the medicine is to cause changes in how different substances are removed from the body, and also how the body handles and eliminates the medicine. This is called pharmacokinetics.

Which are the new and old drugs?

The most common older drugs are: valproic acid (Depakote, Depakene), phenytoin (Dilantin, Phenytek) carbamazepine (Tegretol, Tegretol XR, Carbatrol), mysoline (Primidone) and phenobarbital.

The newer drugs are: gabapentin (Neurontin), lamotrigine (Lamictal), topiramate (Topamax), tiagabine (Gabatril), levetiracetam (Keppra), zonisamide (Zonegran), oxcarbazepine (Trileptal) and pregabalin (Lyrica). A ninth drug, felbamate (Felbatol), is now rarely used because of potential for serious side effects.

Efficacy

Many studies have been done of how effective the new and old drugs are in treating seizures, and some studies have even been performed comparing the efficacy of the new drugs with the older drugs. All of the drugs have been proven to be effective in controlling seizures associated with partial epilepsy. But another type of epilepsy, called generalized epilepsy, has been less well studied. Most of the studies have been performed in patients who have not responded well to medicine and are continuing to have many seizures. In these studies, the new drug is usually compared to a sugar pill (placebo), rather than another medication. The fact that the newer drugs are able to reduce seizures in these patients is good news. However, it is difficult to tell from the studies whether one drug is more likely to control seizures than another.Which are the new and old drugs?

The most common older drugs are: valproic acid (Depakote, Depakene), phenytoin (Dilantin, Phenytek) carbamazepine (Tegretol, Tegretol XR, Carbatrol), mysoline (Primidone) and phenobarbital.

The newer drugs are: gabapentin (Neurontin), lamotrigine (Lamictal), topiramate (Topamax), tiagabine (Gabatril), levetiracetam (Keppra), zonisamide (Zonegran), oxcarbazepine (Trileptal) and pregabalin (Lyrica). A ninth drug, felbamate (Felbatol), is now rarely used because of potential for serious side effects.

Efficacy

Many studies have been done of how effective the new and old drugs are in treating seizures, and some studies have even been performed comparing the efficacy of the new drugs with the older drugs. All of the drugs have been proven to be effective in controlling seizures associated with partial epilepsy. But another type of epilepsy, called generalized epilepsy, has been less well studied. Most of the studies have been performed in patients who have not responded well to medicine and are continuing to have many seizures. In these studies, the new drug is usually compared to a sugar pill (placebo), rather than another medication. The fact that the newer drugs are able to reduce seizures in these patients is good news. However, it is difficult to tell from the studies whether one drug is more likely to control seizures than another.

The studies that compared old drugs to new drugs were performed in patients newly diagnosed with epilepsy. These patients usually respond quite well to medicine, and it appears from the studies that there are not significant differences in the likelihood that one drug, either old or new, is more likely to control seizures than another. Therefore, it is difficult to choose among the drugs based on their efficacy.

Tolerability

Every drug, either old or new, has been associated with the occurrence of unwanted effects, which are called side effects. Side effects are very individual. They usually occur in only a portion of patients who received a certain medication, and may be bothersome to one person, but not to another. A good example of this is the weight loss that is seen with several of the newer antiepileptic drugs. This might be considered a good thing by some people, but could potentially limit therapy in others.

The studies in newly diagnosed patients, which have compared new drugs to old drugs, have demonstrated that in many cases, the newer drugs were less likely to cause people to discontinue use than the older drugs. This was due to problematic side effects. This was the case for lamotrigine, gabapentin oxcarbazepine and topiramate. In addition, it is known that the older drugs are associated with the possibility of serious, even life-threatening health risks in a very small number of individuals, usually less than 1-in-50,000. So far, the newer drugs seem to be safer, and have the potential for either few or no life-threatening consequences.

However, it may take some time after a drug is approved before all of the health risks are fully understood. This is certainly true for drugs that have just been released to the marketplace. Also, since the serious side effects are so rare, even for the older drugs, they shouldn’t be of enormous concern, except under certain circumstances.

The older drugs, as a rule, tend to require more monitoring of liver functions, blood counts and other types of blood tests, which definitely puts the newer drugs at an advantage. Another issue with the older drugs is that they are all known to have the potential to cause birth defects. Unfortunately, we cannot be entirely sure whether the new drugs are better in this regard, although there is great promise. None of the new drugs have been clearly associated with birth defects, but there is not enough data to say that they are safe in pregnancy.

Pharmacokinetics

Four of the older drugs, namely carbamazepine, phenytoin, phenobarbital and mysoline, all have an effect on how the liver does its job. The liver is the site where many substances are cleared from the body. This includes hormones, such as estrogen and testosterone, vitamins, such as vitamins D and K, as well as medications that may be prescribed for other medical conditions. These older drugs increase the speed at which all these compounds are cleared from the body. This may have consequences, including alteration in sexual function and increased likelihood of thinning of the bones (osteoporosis).

Since some drugs are cleared faster, they may not work as well, particularly if the dose is not adjusted properly. For example, the oral contraceptive (birth-control) pill may not work as well, leading to unexpected pregnancy. Drugs given for high blood pressure, high cholesterol and depression may also be affected. The consequences of these changes are only currently being investigated, and it is not truly known how important this effect on the liver will be in an individual patient. The impact may be the highest in patients with many medical conditions who require other medications, the elderly and other special populations.

Cost

The new drugs are much more expensive than the older drugs. This will clearly be an issue for individuals who need to pay for their own medication. Research is currently underway, looking at the economic benefits of the newer drugs, including the fact that they are better tolerated, as well as the other issues described above.

Summary

There are reasons, mostly related to tolerability, safety and pharmacokinetics, to believe that the newer drugs may be advantageous for some individuals. However, this will not be true for everyone, or in all circumstances. If seizures are well controlled on an older drug, with minimal side effects, it is usually not necessary or desirable to switch in the absence of a specific reason. However, the goal of treatment should be no seizures, no side effects for those individuals who are still having seizures or having unacceptable side effects. Patients are encouraged not to settle with unsatisfactory outcomes and, instead, work with their doctor to find a suitable treatment. Individuals starting on medication for the first time should discuss the relative advantages and disadvantages of different drug choices with an informed physician.

Editor’s note: Jacqueline French, M.D., is professor of neurology at the University of Pennsylvania Medical Center and a member of the Epilepsy Foundation’s professional advisory board.

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