Patients with refractory seizures have, by defini-tion, tried at least two appropriate AEDs and their
seizures have failed to be adequately controlled.
At this point the physician faces the decision to either
add a further AED to the current treatment or to pur-sue sequential monotherapy. If sequential monother-apy is chosen, the drugs that are failing to control
seizures are slowly tapered off and replaced with dif-ferent AEDs which can potentially improve seizure
control. Sequential monotherapy was the main treat-ment paradigm from the 1970s through to the 1990s,
when sodium channel blocking AEDs were the only
treatment option. Combining drugs with the same
mechanism of action lead to a slightly better seizure
control, but at the expense of a marked increase in
adverse drug interactions and pharmacodynamic
amplification of side effects.
22
This practice changed
in the 1990s, when new AEDs were introduced with
novel mechanisms of action. These drugs exhibited
fewer pharmacokinetic interactions, exhibited fewer
side effects when combined and raised the possibil-ity of synergistic drug combinations. Clinical prac-tice over the past 20 years has been characterized by
“rational polytherapy”: numerous drug combinations
combinations are most effective and where drug inter-actions are most likely to occur has accumulated.
23
When contemplating polypharmacy for a patient
with epilepsy, it is important to consider the concept
of “total drug load” in addition to the number of drugs
being prescribed. Although general agreement on the
definition has not been reached, drug load is usually
defined as the total amount of drug exposure for a
treatment regimen, and has been quantified as the pre-scribed daily dose of AED(s) divided by the defined
daily dose for the AED(s) as outlined by the World
correlate with the number of adverse events better
than the number of AEDs being prescribed.
24
It has been argued that for the use of multiple AEDs
to be rational, the combination of two drugs must
provide supra-additive therapeutic efficacy, whereby
the combined efficacy of the two drugs is greater
than when the drugs are given alone. Alternatively,
combining AEDs may be more advantageous than
prescribing monotherapy at standard doses if they
demonstrate simple additive efficacy but less than
additive side effects. However, pharmacokinetic
drug interactions often contraindicate specific drug
combinations.