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Epilepsy
it requires assumptions about the relative potency of each drug combination? It is then not unreasonable then to accept this
milligram for milligram, and as discussed above this is not clear even regimen and to make no further changes. Go with it for a while to see
from animal studies. if this happy state of affairs persists. Of course, this is not always the
only reasonable course; the same categories of patients for whom a
simultaneous switch may be appropriate are those for whom a later
The answer to the question posed in the
discontinuation of the second drug may be the right plan. Patient
preferences, as well as the clinical situations, must be considered.
16
title is ‘yes’… However, this must be a
qualified ‘yes,’ because there are
Conclusions
The answer to the question posed in the title is ‘yes’: we should
categories of patients for whom serial reconsider the practice of second or third monotherapy treatment
monotherapy remains a better strategy.
sequences for epilepsy because early polytherapy is often effective
and well-tolerated with the new generation of drugs. However, this
must be a qualified ‘yes,’ because there are categories of patients for
whom serial monotherapy remains a better strategy. We certainly
When to Switch and When to Add— need more research on this issue.
17
Patient-related Considerations
Our primary job is to prevent seizures. If a so-called ‘breakthrough’ In our actual practice at our epilepsy center, 66% of patients are
seizure is more likely with a simultaneous switch of drugs, rather than taking two or more antiepileptic drugs. However, this is a refractory
with addition of a new drug to a full dose of the old one, which is patient population and it must be emphasized that most patients in
almost certainly true, why would we ever do this? community neurology practice can and should be treated with
monotherapy.
2
For most of these, though, this monotherapy will be
There are some patients for whom it is appropriate: those who are the very first drug tried, or at least the very first drug tolerated. Not
having significant side effects from the first drug; those with new- many will be on a monotherapy agent after failure of two or more
onset or very infrequent seizures, for whom the likelihood of a drugs because of lack of efficacy.
3,18
These patients tend to be
breakthrough seizure is low and for whom it is important to avoid side refractory, and most will end up on combination therapy. This is not
effects; and those with ‘mild’ seizures—such as simple partial such a bad thing, and does not signify physician failure. The new
events—for whom a breakthrough seizure would not be disastrous. drugs combine more easily for several reasons, so ‘polypharmacy’
should not be such a pejorative term. More often heard today is the
Other than these patients, then, it is a better strategy to hold the first term ‘polytherapy,’ and rightly so. n
drug at a therapeutic dose, or at least at the patient’s currently
tolerated dose, and to add the second drug gradually to a ‘full target
dose.’ The full target dose may or may not be the dose recommended
Edward Faught, MD, is a Professor and Vice Chairman of the Department of Neurology
and Director of the Epilepsy Center at the University of Alabama at Birmingham, and a
by the manufacturer for adjunctive therapy; it is often less because
staff physician at the Birmingham VA Medical Center. He is also a Colonel in the US
with experience physicians often find that lower doses are effective
Army Reserve (retired). His major research interest is antiepileptic drug development.
and better tolerated.
Professor Faught is a member of the American Epilepsy Society (AES) and the
American Neurological Association (ANA)and a Fellow of the American Academy of
Neurology (AAN). He is a graduate of Harvard College and Vanderbilt University School
Once the second drug reaches the target dose, the next question
of Medicine, and was Chief Resident in Neurology and a Fellow in Epilepsy and EEG at
arises: should the first drug be tapered off and stopped? What if
the University of Virginia.
the patient is doing fine, with no seizures and no side effects on the
1. Shorvon SD, Reynolds EH, Reduction in polypharmacy for 8. French JA, Kramer AM, Bautista J, Efficacy and tolerabilitye 2004;45(8):895–907.
epilepsy, Br Med J, 1979;2:1023–5. of the new antiepileptic drugs. I. Treatment of new-onset 13. Jonker D, Voskuyl RA, Danhof M, Synergistic combinations
2. Faught E, Monotherapy in adults and elderly persons, epilepsy: report of the TTA and QSS subcommittees of the of anticonvulsant agents: what is the evidence from animal
Neurology, 2007;69(Suppl. 3):S3–S9. American Academy of Neurology and the American experiments?, Epilepsia, 2007;48(3):412–34.
3. Kwan P, Brodie MJ, Early identification of refractory Epilepsy Society, Neurology, 2000;62(8):1252–60, and II. 14. Deckers CL, Hekster YA, Keyser A, et al., Reappraisal of
epilepsy, N Engl J Med, 2000;342(5):314–19. Treatment of refractory epilepsy (same committees), polytherapy in epilepsy: a critical review of drug load and
4. The renaissance of rational polytherapy: the new Neurology, 2000;62(8):1261–3. adverse effects, Epilepsia, 1997;38:570–75.
generation of antiepileptic medications, Neurology, 9. Deckers CLP, Place of polytherapy in the early treatment of 15. Beydoun A, Kutluay E, Conversion to monotherapy: clinical
1995;45:S35–8. epilepsy, CNS Drugs, 2002;16(3):155–63. trials in patients with refractory partial seizures, Neurology,
5. Faught E, Pharmacokinetic considerations in prescribing 10. Cereghino JJ, Brock JT, Van Meter JC, et al., The efficacy of 2003;60:S13–25.
antiepileptic drugs, Epilepsia, 2001;42(Suppl. 14):19–23. carbamazepine combinations in epilepsy, Clin Pharmacol 16. Scheiderman JH, Monotherapy versus polytherapy in
6. Sato S, White BG, Penry JK, et al., Valproic acid versus Therap, 1975;18(6):733–41. epilepsy: a framework for patient management, Can J Neurol
ethosuximide in the treatment of absence seizures, 11. Brodie MJ, Yuen AWC, 105 Study Group, Lamotrigine Sci, 1998;25:S9–S13.
Neurology, 1982;32(2):157–63. substitution study: evidence for synergism with sodium 17. French J, Groneth G, Lost in a jungle of evidence: we need
7. Beghi E, Gatti G, Tonini C, et al., Adjunctive therapy versus valproate?, Epilepsy Research, 1997;26:423–32. a compass, Neurology, 2008;72(20):1634–8.
alternative monotherapy in patients with partial epilepsy 12. Lusczczki JJ, Czuczwar SJ, Preclinical profile of 18. Kwan P, Brodie MJ, Combination therapy in epilepsy. When
failing on a single drug: a multicentre, randomised, combinations of some second-generation antiepileptic and What to Use, Drugs, 2006;66(14):1817–29.
pragmatic controlled trial, Epilepsy Research, 2003;57:1–13. drugs: an isobolographic analysis, Epilepsia,
62 US NEUROLOGY
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