Tolerance and the Honeymoon Effect

Some people with epilepsy find that over time they have to take larger and larger doses of their seizure medicine to achieve the same result. This effect is known as tolerance. Studies in both humans and animals have shown that tolerance is not much of a problem for most of the standard antiepileptic drugs. That is, most patients continue to enjoy good seizure control while taking the same dose and maintaining the same blood levels of medication.

There are two circumstances in which tolerance can be an important issue in the care of people with epilepsy, however. The first is when patients take certain antiepileptic drugs that commonly have high degrees of tolerance. The most commonly used medications of this kind are benzodiazepines: clobazam (Frisium, not sold in the U.S.), clonazepam (Klonopin), diazepam (Valium), and lorazepam (Ativan). These are very effective in stopping seizures in the emergency setting, especially when they are given intravenously, rectally, or under the tongue so that they are rapidly absorbed into the blood. But usually they are not used for the long-term treatment of epilepsy because of tolerance. Although they work extremely well for brief periods, their effectiveness diminishes over weeks, months, or years while their side effects continue. In many cases the side effects increase, since the dosage must be increased to maintain the same degree of seizure control.

Patients who rely on benzodiazepines often get caught in a vicious cycle. The medication is introduced at a very low dose, seizures are greatly reduced or completely controlled, and both the patient and doctor are extremely happy. But after a week or a month passes, the seizures slowly start to re-emerge. The dose is increased and again seizure control is achieved. This cycle repeats itself and side effects gradually become more prominent. These often include tiredness, irritability, decreased attention, decreased short-term memory, changes in mood, or changes in sleep pattern. At last the problem of the cycle is recognized, either by the patient or a physician. Then the challenge begins—lowering the dose. The only way to avoid a major increase in seizure frequency or severity is to reduce the benzodiazepine dosage very slowly, but some increase in seizure activity may occur even with gradual reductions. Ultimately, once things have stabilized, most patients enjoy a similar degree of seizure control off of the benzodiazepine, with a marked reduction in side effects. Avoiding the cycle is the best medicine.

The other circumstance in which tolerance can be important in the care of patients with epilepsy is what many refer to as the "honeymoon effect." For some individuals, the effectiveness of medication tends to wear off over time much more than for most other people, either because of the particular way in which their bodies function or because of the nature of their epilepsy and its underlying causes. These individuals often do very well with a new medication for some weeks or, more often, some months. Then the effectiveness of the medication begins to decrease and seizure control gradually may be lost. Many patients who are said to have "medically refractory epilepsy" are those for whom the honeymoon effect is most prominent. These patients often do well at first with a new medication, an increased dose, a change or adjustment in the distribution and timing of medicines during the day, or a new combination of antiepileptic drugs. But after a relatively brief period-as little as a few weeks or occasionally as long as 6 months or a year-their excellent seizure control has deserted them.

Besides tolerance, the honeymoon effect probably also involves some adaptation by the epilepsy process itself. How this process works is still speculation. One theory involves the way abnormal brain activity spreads. Seizure activity originates in a core area of abnormal brain tissue, called the seizure focus. Sometimes the abnormality is structural, as in the case of a scar from a head injury, an area of prior surgery, or an abnormal cell pattern that developed before birth. Even a seizure focus without an apparent structural difference will be marked by some disorder of chemical and electrical function. The abnormal electrical activity that the seizure focus generates needs to be dispersed or spread. In an ideal world, antiepileptic drugs would restore the normal balance and quiet the seizure focus so that no abnormal electrical activity is produced. In reality, however, it is likely that in many cases antiepileptic drugs are simply keeping the abnormal electrical activity from spreading out of the seizure focus, so that other areas of the brain are not affected. In some of these cases, the abnormal activity never disappears but instead is always there, trying to find a way out. One theory about the honeymoon effect is that if the abnormal seizure waves keep pushing over and over against the walls of resistance raised by natural brain processes and the beneficial effects of antiepileptic drugs, eventually they may find a way (or create one) through which they can spread beyond the seizure focus. Thus after some time, the seizures return —the honeymoon effect.

What can be done to prevent tolerance or the honeymoon effect? Unfortunately, our answers are limited. One important strategy is to avoid the long-term use of medications that have high rates of tolerance, such as the benzodiazepines. Those patients who gradually develop tolerance to the more standard antiepileptic drugs present a more difficult problem. One proposed strategy is for them to change antiepileptic drugs on a regular basis to prevent long-term tolerance from building up. Usually this idea does not work very well. For one thing, with each change in medication, the patient may need to adjust to new short-term side effects. Also, because many seizure medicines work in similar ways, tolerance to one may be followed by tolerance to another. Few studies have been done in this area and we need more information and answers.

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