Faught_edit_Cardiology_book_temp 25/09/2009 17:26 Page 61
Should Monotherapy for Epilepsy Be Reconsidered?
We still do not know for sure. A few older studies suggested that the option.
9
However, circumstances will often determine which is best.
combination of phenytoin and phenobarbital is more effective than Who should be considered for a total switch? If the first drug proves
the combination of phenytoin and carbamazepine.
10
There are worthless (no improvement in seizures) or is intolerable, the choice is
suggestive, but not definitive, data that the combination of valproate easy. It must be stopped and a second monotherapy started. Who
and lamotrigine is synergistic with regard to seizure control.
11
should be considered for an additive regimen? If the first drug is
Furthermore, that combination presents a difficult pharmacokinetic almost, but not quite, completely effective, it makes sense to retain
it and to gradually add a second drug to achieve the final summit
of seizure control.
In summary, using two drugs with different The more difficult scenario is when there is a modest effect of the first
major mechanisms of action makes some
drug. In that circumstance, a common past practice has been to try to
switch over completely to a second monotherapy. However, suppose
sense, but cannot be considered truly that the two drugs are synergistic? It is even theoretically possible for
scientifically rational until we know more.
a drug to be completely ineffective as monotherapy, but to contribute
to efficacy as a component of a combination. There is probably not
such a drug but, based on animal studies, there is good evidence that
many drug combinations are synergistic; that is, that lower doses of
challenge. To make matters worse, most of our drugs have multiple each drug in combination may work as well as full doses of either. If
mechanisms of action. Nevertheless, these sparse human data such a combination happens to be chosen in this scenario, it might be
provide hints that combinations of drugs with differing primary more effective to use lower doses of both drugs; switching
mechanisms of action are more likely to work.
5
This makes sense, but completely could be the wrong course of action.
is very difficult to prove in clinical trials.
Two things are clear: there is some risk of more seizures during a
Animal data are thus important because of the problems of titrating switch from one monotherapy to another, and it is a tricky process. It
two drugs to several proportions of an effective dose in an individual can be done safely, and has been done in several clinical trials,
15
but
patient and the low numbers of patients on any one combination in a care and vigilance on the part of the physician is necessary. Gradually
particular clinical trial. There are several published studies using the reducing the first drug while gradually increasing the second is
‘isobolographic’ method;
12
this involves determining the ED
50
(dose of complicated, and more seizures may occur because it is impossible to
drug that is effective in producing a given end-point in 50% of guess the equivalent proportions of each drug as the transition is
animals, such as abolition of hind limb extension in the mouse made. Holding the first drug at full dose while ramping up the second
maximal electroshock seizure model), then trying various drug to full dose is safer, but more likely to produce side effects.
percentages of the ED
50
of each drug in combination.
Nevertheless, if this process is chosen, the new drugs still make it
From these and other animal studies, there is some evidence that drugs easier because one must consider only the PD properties of the
with different mechanisms of action are synergistic with regard to drugs—relative efficacy and side effects—not usually the PK
potency. These include sodium channel blockers plus GABAergic agents, interactions. For example, in switching from monotherapy phenytoin
or α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)-type to monotherapy valproate, one must worry about how long the
glutamate receptor blockers with other agents.
12,13
However, using the phenytoin-caused induction of hepatic metabolism will last. For a
same methods, two GABAergic drugs used together were found to be time, which is hard to estimate, valproate will be metabolized fast,
synergistic in some experiments,
13
so the answers remain elusive. then, as the hepatic induction wanes, it will be metabolized more
In summary, using two drugs with different major mechanisms of
action makes some sense, but cannot be considered truly
If it is possible to combine two drugs at
scientifically rational until we know more. However, avoiding two
drugs with significant PK interactions or two drugs with similar PD
lower doses than the toxic dose of either
side effects is a good idea, other considerations being equal. To that
with better efficacy, the overall ‘drug load,’
extent, rational polytherapy exists. If it is possible to combine two
drugs at lower doses than the toxic dose of either with better efficacy,
and thus risk of toxicity, may actually be
the overall ‘drug load,’ and thus risk of toxicity, may actually be less
less than with a high level of a single drug.
than with a high level of a single drug.
14
When to Switch and When to Add slowly. Translating this into a titration schedule for a patient so that
Based on Efficacy therapeutic levels of some drug are always maintained is challenging
There are some good reasons to seriously consider ‘adding rather indeed. On the other hand, transitioning from lamotrigine to
than switching’—a course of action heretofore considered heretical. oxcarbazepine monotherapy requires only an estimation of what are
An earlier resort to polytherapy should be considered as a viable equivalent efficacy dosages of each medication. That is still not easy;
US NEUROLOGY 61
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84