Pediatric Epilepsy Diagnosis and Therapy - part 6 ppt

437 31 • EVIDENCE-BASED MEDICINE ISSUES RELATED TO DRUG SELECTION TABLE 31-3 Relationship Between Clinical Trial Ratings, Level of Evidence and Conclusions for ILAE Guideline on Initial Monotherapy for Adults and Children with Epilepsy (1) RECOMMENDATION (BASED ON COMBINATION(S) OF CLINICAL LEVEL OF EFFICACY AND EFFECTIVENESS TRIAL RATINGS EVIDENCE CONCLUSIONS DATA ONLY) Ն1 Class I studies or meta-analysis meeting Class I criteria sources OR Ն 2 Class II studies 1 Class II study or meta-analysis meeting Class II criteria Ն2 Class III double-blind or open label studies 1 Class III double blind or open label study OR Ն1 Class IV clinical studies OR Data from expert committee reports, opinions from experienced clinicians Absence of directly applicable clinical evidence upon which to base a recommendation Positive evidence of lack of efficacy or effectiveness based on Class I to IV studies OR Significant risk of seizure aggravation based on Class I to IV studies A B C D E F AED established as efficacious or effective as initial monotherapy AED probably efficacious or effective as initial monotherapy AED possibly efficacious or effective as initial monotherapy AED potentially efficacious or effective as initial monotherapy No data available to assess if AED is effective as initial monotherapy AED established as ineffective or significant risk of seizure aggravation AED should be considered for initial monotherapy—First-line monotherapy candidate AED may be considered for initial monotherapy—Alternative first-line monotherapy candidates Weak efficacy or effectiveness data available to support the use of the AED for initial monotherapy Either no data or inadequate efficacy or effectiveness data available to decide whether AED could be considered for initial monotherapy AED should not be used for initial monotherapy FIGURE 31-3 Comparison of AAN/AES guideline (77) and ILAE guideline (1) for initial monotherapy in children and adults with new-onset epilepsy. 438 IV • GENERAL PRINCIPLES OF THERAPY guidelines, and practice parameters are critical tools for practicing evidence-based medicine. However, these “external” knowledge sources should not be used alone; they need to be integrated with a clinician’s experience and background, with both AED-specific factors (“internal” knowledge) and patient-specific variables (“interface” knowledge) to select the appropriate antiepileptic medication for a patient. Clinical decisions should not be driven by only one type of knowledge. For example, ignoring evidence-based guidelines and practice parameters can lead to practicing anecdotal medicine. In contrast, ignoring one’s own clinical TABLE 31-4 Comparison of Evidence Based and Consensus Guidelines Recommendations for the Treatment for different pediatric seizure types and epilepsy syndromes. (ref. 84) SEIZURE TYPE OR PEDIATRIC E PILEPSY EXPERT CONSENSUS FRENCH FDA S YNDROME SURVEY ILAE SIGN NICE STUDY APPROVED Partial-onset OXC, CBZ A: OXC; PHT, VPA, CBZ, VPA, OXC, CBZ, PB, PHT, B: none CBZ LTG LTG CBZ C: CBZ, LTG, TPM, OXC, OXC, TPM, (adult males) OXC, TPM PB, PHT VGB, CLB TPM, VPA BECT OXC, CBZ A, B: none not specifically CBZ, OXC, not surveyed none C: CBZ, mentioned LTG, VPA VPA Childhood absence ESM A, B: none VPA, ESM, VPA, ESM, VPA, LTG ESM, VPA epilepsy LTG LTG Juvenile myoclonic VPA, LTG A, B, C: VPA, LTG, VPA, LTG VPA, LTG TPM epilepsy none TPM Lennox-Gastaut VPA, TPM, not reviewed not specifically LTG, VPA, not surveyed FLB, TPM, syndrome LTG mentioned TPM LTG Infantile spasms VGB, ACTH not reviewed not specifically VGB, not surveyed none mentioned corticosteroids ACTH, adrenocorticotropin; CBZ, carbamazepine; CLB, clobazam; ESM, ethosuximide; FLB, felbamate; LTG, lamotrigine; OXC, oxcarbazepine; PB, phenobarbital; PHT, phenytoin; TPM, topiramate; VGB, vigabatrin; VPA, valproic acid. experience in favor of solely relying on guidelines and practice parameters can lead to a cookbook approach. The physician’s background, the patient’s characteristics, each AED’s characteristics, and evidence-based evaluations are all important components of making the best patient care decisions. Through better understanding of guidelines and practice parameter methodology, clinicians should feel more comfortable integrating these evidence-based assessments into their clinical decision-making process. Practicing evidence-based medicine should lead to better personalized and comprehensive care of our patients. References 1. Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2006; 47(7):1094–1120. 2. Mulrow CD, Cook DJ, Davidoff F. Systematic reviews: critical links in the great chain of evidence. Ann Intern Med 1997; 126(5):389–391. 3. Claridge JA, Fabian TC. History and development of evidence-based medicine. World J Surg 2005; 29(5):547–553. 4. Doherty S. History of evidence-based medicine. Oranges, chloride of lime and leeches: barriers to teaching old dogs new tricks. Emerg Med Australas 2005; 17(4): 314–321. 5. Cochrane A. Effectiveness and efficiency. Random reflections on health services. London: Nuffield Provincial Hospitals Trust, 1972. 6. Cochrane Collaboration. What is The Cochrane Collaboration? 2007. Available from: http://www.cochrane.org/docs/descrip.htm. 7. The Cochrane Collaboration. Glossary of terms. In: Higgins J, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions 425 (updated May 2005). In: The Cochrane Library, Issue 3. Chichester, UK: John Wiley & Sons, 2005. 8. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, et al. Evidence based medicine: what it is and what it isn’t. BMJ 1996; 312(7023):71–72. 9. Sackett DL, Straus SE. Finding and applying evidence during clinical rounds: the “evidence cart.” JAMA 1998; 280(15):1336–1338. 10. Sackett DL. Evidence-based medicine. Spine 1998; 23(10):1085–1086. 11. Sackett DL. Evidence-based medicine. Semin Perinatol 1997; 21(1):3–5. 12. Sackett DL. Evidence-based medicine and treatment choices. Lancet 1997; 349(9051): 572–573. 13. Sackett DL, Rosenberg WM. On the need for evidence-based medicine. Health Econ 1995; 4(4):249–254. 14. Sackett DL, Rosenberg WM. On the need for evidence-based medicine. J Public Health Med 1995; 17(3):330–334. 15. Sackett DL, Rosenberg WM. The need for evidence-based medicine. J R Soc Med 1995; 88(11):620–624. 16. Sackett D. Evidence-based medicine. Lancet 1995; 346(8983):1171. 17. Sackett DL, Straus S, Richardson S, Rosenberg W, et al. Evidence-based medicine: how to practice and teach EBM. 2nd ed. London: Churchill Livingstone, 2000. 439 31 • EVIDENCE-BASED MEDICINE ISSUES RELATED TO DRUG SELECTION 18. Sackett DL, Richardson SW, Rosenberg W, Haynes RB. Evidence-Based Medicine. London: Churchill Livingstone, 1996. 19. Cohen L. McMaster’s pioneer in evidence-based medicine now spreading his message in England. CMAJ 1996; 154(3):388–390. 20. Rosenberg J, Greenberg MK. Practice parameters: strategies for survival into the nineties. Neurology 1992; 42(5):1110–1115. 21. Web site offers database of national guidelines. Healthcare Benchmarks 1999; 6(3):30–31. 22. Evidence-based medicine. A new approach to teaching the practice of medicine. Evidence- Based Medicine Working Group. JAMA 1992; 268(17):2420–2425. 23. Tonelli MR. The limits of evidence-based medicine. Respir Care 2001; 46(12):1435–1440; discussion 1440–1441. 24. Institute of Medicine. Definition of key terms. In: Field MJ, Lohr KN, eds. Clinical Practice Guidelines: Directions for a New Program. Washington, DC: National Academy Press, 1990:33–51. 25. Cochrane Collaboration. Cochrane Review structure. 2007. Available from: http://www. cochrane.org/reviews/revstruc.htm. 26. Marson AG, Williamson PR, Clough H, Hutton JL, et al. Carbamazepine versus valproate monotherapy for epilepsy: a meta-analysis. Epilepsia 2002; 43(5):505–513. 27. Taylor S, Tudur Smith C, Williamson PR, Marson AG. Phenobarbitone versus phenytoin monotherapy for partial onset seizures and generalized onset tonic-clonic seizures. Cochrane Database Syst Rev 2001(4):CD002217. 28. Tudur Smith C, Marson AG, Williamson PR. Phenytoin versus valproate monotherapy for partial onset seizures and generalized onset tonic-clonic seizures. Cochrane Database Syst Rev 2001(4):CD001769. 29. Tudur Smith C, Marson AG, Clough HE, Williamson PR. Carbamazepine versus phenytoin monotherapy for epilepsy. Cochrane Database Syst Rev 2002(2): CD001911. 30. Tudur Smith C, Marson AG, Williamson PR. Carbamazepine versus phenobarbitone monotherapy for epilepsy. Cochrane Database Syst Rev 2003(1):CD001904. 31. Muller M, Marson AG, Williamson PR. Oxcarbazepine versus phenytoin monotherapy for epilepsy. Cochrane Database Syst Rev 2006(2):CD003615. 32. Gamble CL, Williamson PR, Marson AG. Lamotrigine versus carbamazepine monotherapy for epilepsy. Cochrane Database Syst Rev 2006(1):CD001031. 33. Jette NJ, Marson AG, Hutton JL. Topiramate add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2002(3):CD001417. 34. Chadwick DW, Marson AG. Zonisamide add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2005(4):CD001416. 35. Leach JP, Marson AG, Hutton JL. Remacemide for drug-resistant localization related epilepsy. Cochrane Database Syst Rev 2002(4):CD001900. 36. Pereira J, Marson AG, Hutton JL. Tiagabine add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2002(3):CD001908. 37. Chadwick DW, Marson AG. Zonisamide add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2002(2):CD001416. 38. Chaisewikul R, Baillie N, Marson AG. Calcium antagonists as an add-on therapy for drug-resistant epilepsy. Cochrane Database Syst Rev 2001(4):CD002750. 39. Ramaratnam S, Marson AG, Baker GA. Lamotrigine add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2001(3):CD001909. 40. Marson AG, Hutton JL, Leach JP, Castillo S, et al. Levetiracetam, oxcarbazepine, remacemide and zonisamide for drug resistant localization-related epilepsy: a systematic review. Epilepsy Res 2001; 46(3):259–270. 41. Chaisewikul R, Privitera MD, Hutton JL, Marson AG. Levetiracetam add-on for drug-resistant localization related (partial) epilepsy. Cochrane Database Syst Rev 2001(1):CD001901. 42. Castillo S, Schmidt DB, White S. Oxcarbazepine add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2000(3):CD002028. 43. Marson AG, Kadir ZA, Hutton JL, Chadwick DW. Gabapentin add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2000(3):CD001415. 44. Marson AG, Kadir ZA, Hutton JL, Chadwick DW. Gabapentin for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2000(2):CD001415. 45. Posner EB, Mohamed K, Marson AG. Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents. Cochrane Database Syst Rev 2003(3): CD003032. 46. Hancock E, Osborne J, Milner P. Treatment of infantile spasms. Cochrane Database Syst Rev 2003(3):CD001770. 47. Hancock E, Cross H. Treatment of Lennox-Gastaut syndrome. Cochrane Database Syst Rev 2003(3):CD003277. 48. Booth D, Evans DJ. Anticonvulsants for neonates with seizures. Cochrane Database Syst Rev 2004(4):CD004218. 49. Gayatri N, Ferrie C, Cross H. Corticosteroids including ACTH for childhood epilepsy other than epileptic spasms. Cochrane Database Syst Rev 2007(1):CD005222. 50. Prasad K, Al-Roomi K, Krishnan PR, Sequeira R. Anticonvulsant therapy for status epilepticus. Cochrane Database Syst Rev 2005(4):CD003723. 51. Appleton R, Martland T, Phillips B. Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children. Cochrane Database Syst Rev 2002(4): CD001905. 52. Cochrane HC, Marson AG, Baker GA, Chadwick DW. Neuropsychological outcomes in randomized controlled trials of antiepileptic drugs: a systematic review of methodology and reporting standards. Epilepsia 1998; 39(10):1088–1097. 53. Levy R, Cooper P. Ketogenic diet for epilepsy. Cochrane Database Syst Rev 2003(3): CD001903. 54. Ross S, Estok R, Chopra S, French J. Management of Newly Diagnosed Patients with Epilepsy: a Systematic Review of the Liter ature. Evidence Report/Technology Assessment No. 39 (Contract 290-97-0016 to MetaWorks, Inc.) AHRQ Publication No. 01-E038. Rockville, MD: Agency for Healthcare Research and Quality, 2001. 55. Consensus statements: medical management of epilepsy. Neurology 1998 Nov; 51 5 Suppl 4:S39–S43. 56. Southern Clinical Neurological Society. Management of newly diagnosed patients with epilepsy: a systematic review of the literature. Summary, Evidence Report/Technology Assessment: Number 39. AHRQ Publication Number 01-E037, February 2001. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/ wpcsums/epilepsum.htm(accessed 9/17/07). 57. Armijo JA, Sanchez B, Gonzalez AB. [Evidence based treatment of epilepsy]. Rev Neurol 2002; 35 Suppl 1:S59–S73. 58. Ramsay RE, DeToledo J. Tonic-clonic seizures: a systematic review of antiepilepsy drug efficacy and safety. Clin Ther 1997; 19(3):433–446; discussion 367–368. 59. Clinical guidelines for the management of epilepsy in adults with an intellectual disability. Seizure 2001; 10(6):401–409. 60. Camfield P, Camfield C. Childhood epilepsy: what is the evidence for what we think and what we do? J Child Neurol 2003; 18(4):272–287. 61. Gram L, Bentsen KD, Parnas J, Flachs H. Controlled trials in epilepsy: a review. Epilepsia 1982; 23(5):491–519. 62. Brunbech L, Sabers A. Effect of antiepileptic drugs on cognitive function in individuals with epilepsy: a comparative review of newer versus older agents. Drugs 2002; 62(4): 593–604. 63. Keene DL. A systematic review of the use of the ketogenic diet in childhood epilepsy. Pediatr Neurol 2006; 35(1):1–5. 64. Lefevre F, Aronson N. Ketogenic diet for the treatment of refractory epilepsy in children: a systematic review of efficacy. Pediatrics 2000; 105(4):E46. 65. Baker GA, Hesdon B, Marson AG. Quality-of-life and behavioral outcome measures in randomized controlled trials of antiepileptic drugs: a systematic review of methodology and reporting standards [in process citation]. Epilepsia 2000; 41(11):1357–1363. 66. Kotsopoulos IA, Evers SM, Ament AJ, de Krom MC. Estimating the costs of epilepsy: an international comparison of epilepsy cost studies. Epilepsia 2001; 42(5):634–640. 67. Levy P. Economic evaluation of antiepileptic drug therapy: a methodologic review. Epilepsia 2002; 43(5):550–558. 68. Woolf SH. Practice guidelines, a new reality in medicine. II. Methods of developing guidelines. Arch Intern Med 1992; 152(5):946–952. 69. Eddy DM. Practice policies: where do they come from? Jama 1990; 263(9):1265, 9, 72 passim. 70. Ferguson JH. The NIH Consensus Development Program. The evolution of guidelines. Int J Technol Assess Health Care 1996; 12(3):460–474. 71. Ferguson JH. The NIH Consensus Development Program. Jt Comm J Qual Improv 1995; 21(7):332–336. 72. Ferguson JH. NIH consensus conferences: dissemination and impact. Ann N Y Acad Sci 1993; 703:180–198; discussion 198–199. 73. Surgical treatment of epilepsy. Proceedings of a consensus conference. March 19–21, 1990. Epilepsy Res Suppl 1992; 5:1–250. 74. Febrile seizures—long-term management of children with fever-associated seizures. NIH Consensus Development Conference. Neuropediatrics 1980; 11(3):192–202. 75. Febrile seizures: long-term management of children with fever-associated seizures. Summary of an NIH Consensus Statement. Br Med J 1980; 281(6235):277–279. 76. Epilepsy Foundation of America’s Working Group on Status Epilepticus. Treatment of convulsive status epilepticus. JAMA 1993; 270(7):854–859. 77. French JA, Kanner AM, Bautista J, Abou-Khalil B, et al. Efficacy and tolerability of the new antiepileptic drugs, I: Treatment of new-onset epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 2004; 45(5):401–409. 78. French JA, Kanner AM, Bautista J, Abou-Khalil B, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technol- ogy Assessment Subcommittee and Quality Standards Subcommittee of the American Acad- emy of Neurology and the American Epilepsy Society. Neurology 2004; 62(8):1252–1260. 79. French JA, Kanner AM, Bautista J, Abou-Khalil B, et al. Efficacy and tolerability of the new antiepileptic drugs, II: Treatment of refractory epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 2004; 45(5):410–423. 80. French JA, Kanner AM, Bautista J, Abou-Khalil B, et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2004; 62(8):1261–1273. 81. French J, Smith M, Faught E, Brown L. Practice advisory: the use of felbamate in the treatment of patients with intractable epilepsy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 1999; 52(8):1540–1545. 82. Mackay MT, Weiss SK, Adams-Webber T, Ashwal S, et al. Practice parameter: medical treatment of infantile spasms: report of the American Academy of Neurology and the Child Neurology Society. Neurology 2004; 62(10):1668–1681. 83. Diagnosis and management of epilepsy in children and young people: A national clinical guidelines. Edinburgh: Scottish Intercollegiate Guidelines Network, March 2005. 84. Wheless JW, Clarke DF, Carpenter D. Treatment of pediatric epilepsy: expert opinion, 2005. J Child Neurol 2005; 20 Suppl 1:S1–S56; quiz S9–S60. 85. Semah F, Picot MC, Derambure P, Dupont S, et al. The choice of antiepileptic drugs in newly diagnosed epilepsy: a national French survey. Epileptic Disord 2004; 6(4): 255–265. 86. Maynard A. Evidence-based medicine: an incomplete method for informing treatment choices. Lancet 1997; 349(9045):126–128. 87. Maynard A. Evidence based medicine. Cost effectiveness and equity are ignored. BMJ 1996; 313(7050):170–171. 441 Combination Drug Therapy: Monotherapy Versus Polytherapy he trends of predominant combination therapy versus predominant monotherapy in the medical treatment of epilepsy can be histori- cally divided into three sequential currents. Following the introduction of phenytoin in 1938, several addi- tional antiepileptic drugs (AEDs) became available, and patients whose seizures were not controlled by one drug were commonly prescribed multiple drugs. It is likely that the rationale for this approach was mostly based on the assumption that AEDs interact synergistically and that multiple drugs can provide more seizure protection together than one drug alone. This reasoning does not take into account the undesirable other side of this equation—namely, that multiple drugs can provide more side effects together than one drug alone. Therefore, the concept of monotherapy and sequential monotherapy gained wide acceptance in the late 1970s and early 1980s, because the frequent negative impact of polytherapy on the number and intensity of side effects was increasingly recognized. Recommendations for monotherapy were based on repeated observations that the severity or number of side effects often dimin- ished following a reduction in the number of AEDs, in Blaise F. D. Bourgeois most cases without appreciable loss in seizure control (1–6), and that the beneficial effect of adding a second drug after the failure of a first drug was modest (7). Patients who had undergone a temporal lobe resection were randomized to ongoing polytherapy or to reduction to carbamazepine monotherapy (8). The seizure recurrence rate was the same in both groups, but drug- related side effects were less common in the monotherapy group (10%) than in the polytherapy group (30%). The concept of monotherapy was extended to the practice of “high-dose monotherapy” (9). However, two main factors prompted the transition to a third era: (1) the real- ization that about one-third of patients still remained refractory even to high-dose monotherapy, and (2) the release of several newer AEDs after 1993 with fewer or no pharmacokinetic interactions. In the 1990s, the concept of “rational polytherapy” was promoted, with intense discussion and speculation but few rigorous clinical studies. When single-drug therapy fails to ren- der patients seizure free, the temptation to combine AEDs will endure. Because of this, it will always remain important to evaluate and identify potentially beneficial specific drug combinations and to carefully assess the advantages and disadvantages of AED combinations. T 32 442 IV • GENERAL PRINCIPLES OF THERAPY DISADVANTAGES OF COMBINATION DRUG THERAPY Pharmacokinetic Interactions Adding or removing a drug from the treatment regimen may alter the established relationship between dose and blood level of drugs already in use, either AEDs or other drugs. In general, pharmacokinetic interactions make more frequent drug level determinations and dosage readjustments necessary, and they also increase the probability of the occurrence of a drug level that is either too low or too high. It is more likely that an interaction will be overlooked when a drug causing an interaction is removed than when it is added. It should also be noted that enzyme-inducing drugs cause interactions that reach their maximum only after days to weeks and are only slowly reversible, whereas enzyme inhibi- tors cause reactions that reach their full impacts within hours to a few days and are rapidly reversible. Most newer AEDs have a lower potential for interactions, in particular for enzyme induction, and some have prac- tically no interactions. Pharmacokinetic interactions are reviewed in detail in Chapter 39. Pharmacokinetic interactions are only rarely beneficial. For instance, the inhibitory effect of valproate on lamotrigine kinetics can have the theoretical advantages of reducing the fluctuations of the levels of lamotrigine by prolong- ing its elimination half-life and of reducing the dosage requirements of lamotrigine for a desired blood level. In most instances, however, pharmacokinetic interactions are at best harmless and only if they are anticipated or recognized early. Valproate levels are particularly sensitive to comedication with enzyme-inducing drugs, especially in children. Even at very high doses of more than 100 mg/kg/day, some children cannot achieve therapeutic levels of valproate when in combination therapy with enzyme-inducing drugs (10). The carbamazepine dose-to-level ratio can also be markedly affected by inducing drugs, and the increased dose requirement is associated with an increase in the concentration of the active metabolite carbamazepine-10,11-epoxide. The accelerated biotransformation of such drugs as valproate and carbamazepine usually shortens their half-life and lowers their concentration, causing larger fluctuations in blood levels between doses. Larger fluctuations may increase the risk of seizures just before the dose or increase the risk of toxic side effects at the time of the peak level. Inversely, the inhibition of lamotrigine elimination by valproate increases the level- to-dose ratio of lamotrigine and is likely to be responsible for the observed increase in the incidence of rashes associated with lamotrigine (11), an observation that led to a downward readjustment of the titration rate of lamotrigine dosage in these patients. Cumulative Toxicity Experimental data on the pharmacodynamic interactions of AEDs suggest that neurological toxicity is often additive, although it can be at times infra-additive or supra- additive (12) (Table 32-1). This finding implies that two drugs with a concentration in the recommended therapeutic range are more likely to cause side effects than each drug alone at the same concentration. Correspond- ingly, in several clinical studies in which polypharmacy was reduced, there was an associated decrease in side effects, especially a reduction in sedation (2, 3, 5, 6). This increased alertness was especially apparent after withdrawal of barbiturates or benzodiazepines (4). Con- trolled monotherapy trials with some of the newer AEDs have demonstrated a lower incidence of side effects than in the corresponding add-on trials with the same drug. The notion of cumulative toxicity becomes particularly important if one considers the fact that toxicity is often subtle and can be associated with chronic impairment of cognitive function (13). In addition to cumulative toxicity, when two or more drugs are prescribed together, there is a greater likelihood that one of the drug concentrations will even- tually be in the toxic range. In a longitudinal study of children with epilepsy, the number of children with one or more drug levels in the toxic range increased with the numbers of drugs prescribed (14). Toxic levels occurred in 14% of those taking one drug, 50% of those taking two drugs, and 100% of those taking three or more drugs. Therefore, polytherapy is likely to increase the frequency of dose-related side effects. It also increases the probability of idiosyncratic adverse effects and organ toxicity. Deckers and coworkers (15) reviewed the literature to reassess the relationship between AED polytherapy and adverse effects. They found some evidence suggest- ing that the toxicity of polytherapy may be related to total drug load (that is, total dose of all drugs) rather than to the number of drugs. In other words, one drug at a relatively high dose may cause more adverse effects than two drugs at low doses. Combination therapy may result not only in stronger side effects but also in more side effects of different types. For example, a given patient could have thrombocytopenia from valproate, nephrolithiasis from topiramate, and gingival hyperplasia from phenytoin. However, one could also observe cancellation of opposite side effects of different drugs, as for instance a normalization of excessive weight on valproate after the introduction of topiramate, the latter being known to potentially cause excessive weight loss. Differences in Therapeutic Range The therapeutic range is a statistical compromise based on studies of groups of patients. It provides loose guidelines 443 32 • COMBINATION DRUG THERAPY: MONOTHERAPY VERSUS POLYTHERAPY with regard to the minimal effective concentration and the concentration at which side effects become frequent. Based on the experimental evidence for additive interactions between AEDs, it is unlikely that the therapeutic range of a drug will be the same when it is taken alone as when it is taken in combination with other drugs. Polytherapy is more likely to be associated with toxicity when drug levels are within the therapeutic range. Clinical observations indeed suggest that toxic side effects from carbamazepine or phenytoin (9) and from valproate (16) appear at higher levels when these drugs are taken alone. Therefore, when side effects occur at a certain level of a drug during combination therapy, this finding does not necessarily imply that the side effects will recur at similar levels in monotherapy in the same patient. Interpretation of Drug Effect In patients on AED polytherapy, it may be difficult to determine which drug has caused a reduction in seizure frequency and which drug is responsible for side effects, unless the adverse reaction is unique to one of the drugs. Idiosyncratic toxic reactions, such as an allergic rash, do not necessarily appear promptly after the introduction of a new drug; therefore, they may not necessarily be caused by the last drug added to the regimen. This can TABLE 32-1 Pharmacodynamic Interactions Between Antiepileptic Drugs in Animal Models INTERACTION OLDER DRUGS ANTIEPILEPTIC NEUROTOXIC REFERENCE PHT ϩ PB Additive Infra-additive 23 PHT ϩ CBZ Additive Additive 24 CBZ ϩ PB Additive Additive 25 VPA ϩ PB Additive Additive 26 VPA ϩ ESM Additive Infra-additive 27 VPA ϩ CBZ Additive Infra-additive 26 VPA ϩ PHT Supra-additive Additive 28 VPA ϩ CZP Supra-additive Supra-additive 29 ESM ϩ CZP Supra-additive Supra-additive 29 CBZ ϩ CBZ-E Additive Additive 30 PRM ϩ PB Supra-additive Infra-additive 31 PB ϩ PEMA Supra-additive Supra-additive 31 I NTERACTION NEWER DRUGS ANTIEPILEPTIC NEUROTOXIC REFERENCE LTG ϩ TPM Supra-additive Infra-additive 32 LTG ϩ VPA Supra-additive Infra-additive 32 LTG ϩ CBZ Infra-additive Additive 32 LTG ϩ PB Supra-additive Supra-additive 32 LTG ϩ PHT Additive Additive 32 TGB ϩ GBP Supra-additive Additive 33 TPM ϩ FBM Supra-additive Infra-additive 34 TPM ϩ OXC Supra-additive Additive 34 OXC ϩ FBM Infra-additive Additive 34 OXC ϩ LTG Infra-additive Supra-additive 34 LTG ϩ FBM Additive Infra-additive 35 OXC ϩ GBP Supra-additive Additive 36 LEV ϩ TPM Supra-additive Infra-additive 37 LEV ϩ CBZ Supra-additive Infra-additive 37 LEV ϩ OXC supra-additive infra-additive 37 Reproduced, with permission from reference Levy and Bourgeois (12). CBZ, carbamazepine; CBZ-E, carbamazepine epoxide; CZP, clonazepam; ESM, ethosuximide; FBM, felbamate; GBP, gabapentin; LEV, levetiracetam; LTG, lamotrigine; OXC, oxcarbazepine; PB, phenobarbital; PEMA, phenyo-ethyl-malonamide (primidone metabolite); PHT, phenytoin; PRM, primidone; TGB, tiagabine; TPM, topiramate; VPA, valproate. 444 IV • GENERAL PRINCIPLES OF THERAPY create a dilemma, especially when two drugs known for their potential for allergic reactions have been introduced within a relatively short time interval. These problems are compounded by frequent dose changes and short periods of observation. A carry-over effect or delayed maximal efficacy of a drug contributes to confusion when several drugs are prescribed simultaneously. Idiosyncratic Toxic Reactions Idiosyncratic adverse side effects of drugs are not dose related. Certain idiosyncratic reactions are more likely to occur when two drugs are taken in combination. As mentioned earlier, valproate can increase the incidence of rashes associated with lamotrigine (11). Also, the combination of valproate with other AEDs, more often than valproate monotherapy, can result in a dramatic encepha- lopathic state that does not result from toxic drug levels or from a pharmacokinetic interaction (16, 17). This is characterized by alteration of consciousness, usually a stuporous state, and by sudden and pronounced slowing of the background activity in the electroencephalogram. It is important to recognize the cause of these stuporous episodes because they are rapidly reversible upon discontinuation of valproate or of the last introduced drug. The mechanism of this encephalopathy has not been elucidated, but it does not appear to be related to hyperammonemia. Finally, one of the disadvantages of taking two or more drugs is the higher cost. For patients who are prescribed multiple drugs for several years, this is a tangible factor and there must be some evidence that the higher cost is associated with an increased benefit. There can also be an exacerbation of the dose-related side effects of one AED by another. In two reports, an increase in the known tremor associated with valproate therapy was described following the addition of lamotrigine (18, 19). Also, an increase in side effects characteristic of carbamazepine, but not of levetiracetam, was noted in four patients after the addition of levetiracetam to carbamazepine (20), and after the addition of lamotrigine to carbamazepine (21). Finally, three patients experienced chorea while taking phenytoin and lamotrigine in combination only, with resolution when either one of the medications was withdrawn (22). POTENTIAL ADVANTAGES OF COMBINATION DRUG THERAPY Compared with single-drug therapy there are two potential advantages of combination drug therapy: better seizure control or a similar degree of seizure control with fewer dose-related side effects. For any combination of AEDs to meet either of these criteria, the particular combination must have either a wider antiepileptic spectrum or a better therapeutic index than either drug alone. For example, a patient with both primarily generalized tonic-clonic seizures and myoclonic seizures who failed to have both seizure types controlled by lamotrigine alone or by clonazepam alone might do well on both drugs. Although lamotrigine may not have controlled the myoclonic seizures and clonazepam may not have controlled the generalized tonic-clonic seizures, together they may complement each other and have a wider antiepileptic spectrum than either one alone. In another hypothetical case, consider a patient whose partial seizures were not controlled by the maximal tolerated doses of either levetiracetam alone or oxcarbazepine alone, leading to both drugs being prescribed together. If the seizures can be controlled by the combination of levetiracetam and oxcarbazepine at doses tolerated by the patient, a superior therapeutic index for the combination of levetiracetam and carbamazepine would have been demonstrated. Unfortunately, there are very few data in the clinical literature demonstrating for any combination of AEDs a better effectiveness than for either drug alone. Furthermore, although a great deal of information is available on the pharmacokinetic interactions between AEDs, less is known about pharmacodynamic interactions—interactions that occur in the central ner- vous system—because they are more difficult to quan- tify. However, increasing attention is being paid to the theoretical, experimental, and clinical background for the practice of combining AEDs. A supra-additive pharmacodynamic interaction (potentiation or synergism) between two drugs with regard to their protective effect against seizures has often been used as supportive evidence that these two drugs represent a superior combination. However, this antiepileptic interaction in itself has little meaning unless the neurotoxic effects are also evaluated. If toxicity is also supra-additive to a same or greater extent as the antiepileptic effect, the therapeutic index of the combination is equal to or inferior to the therapeutic index of each drug alone. In other words, at the same level of neurotoxicity, the drug combination does not provide more seizure protection than either of the two drugs alone. Clinically, it is very difficult to study the individual and combined therapeutic index of AEDs, because both seizure protection and neurotoxic side effects of single drugs and of combinations of drugs must be assessed quantitatively in a homogeneous population of patients with epilepsy. Therefore, most of the available information on the pharmacodynamic effect of combining AEDs has been obtained from animal experiments. Experimental Studies Table 32-1 summarizes the results of studies on antiepileptic and neurotoxic interactions between many of 445 32 • COMBINATION DRUG THERAPY: MONOTHERAPY VERSUS POLYTHERAPY the established and newer AEDs, including interactions between drugs and their active metabolites (12, 23–37). All results in these studies are based on the analysis of brain drug concentrations in mice. Seizure protection was assessed by standardized experimental seizure models. Neurotoxicity was assessed by various standardized models of motor incoordination in animals. Although this is a rough assessment of dose-related neurotoxicity, there is no reliable animal model that reflects the scope of dose- related neurotoxicity of AEDs in humans. The methods used for the quantitative assessment of the pharmacodynamic drug interactions were either the isobolographic analysis, the fractional effective concentration index, or both (23, 25, 27). The majority of the neurotoxic interactions are additive or infra-additive, less commonly supra-additive. Thus, in most instances, neurotoxicity of AEDs is not potentiated when they are combined. Inversely, antiepileptic interactions are mostly additive or supra- additive, less commonly infra-additive. Drug pairs with supra-additive antiepileptic interactions can be advantageous even when the neurotoxic interaction is additive. When the antiepileptic interaction is additive, only combinations with an infra-additive neurotoxic interaction can have a better protective index than the single drug. According to Table 32-1, several pairs of drugs appear to meet these criteria for an advantageous combination in this animal model. When carrying out such studies of pharmacodynamic interactions, drug concentrations and not doses must be used because of the effect of pos- sible pharmacokinetic interactions. For example, earlier studies of the antiepileptic interaction between phenytoin and phenobarbital, based on the analysis of doses admin- istered, suggested a supra-additive interaction. A purely additive interaction was found when brain levels were measured in two independent studies (23, 38). Indeed, an acute elevation of the phenytoin level-to-dose ratio in the presence of phenobarbital could be demonstrated (23). The combinations of clonazepam with valproate and clonazepam with ethosuximide were also tested in mice (29). Nonprotective and nontoxic doses of clonazepam increased the protective effect and the neurotoxicity of valproate and ethosuximide, indicating supra-additive effects. The two drug combinations had a better protective index than each drug alone despite supra-additive neurotoxicity. Using a similar model, Gordon and coworkers (39) studied pharmacodynamic interactions between felbamate and phenytoin, carbamazepine, valproate, and phenobarbital. They found that nonprotective doses of the latter four drugs decreased the median effective dose (ED 50 ) values of felbamate against maximal electroshock seizures. However, neurotoxicity was not potentiated, and the protective index of felbamate was more than doubled by the addition of any one of the four drugs. Although the analysis was based on doses, the authors did measure plasma drug levels and demonstrated the absence of pharmacokinetic interaction. Clinical Studies The results of the above studies in animals cannot be extrapolated to patients. There have been very few clinical studies of AED combinations based on systematic comparisons between the effect of two drugs adminis- tered both in monotherapy and their effect in combination. Comparing the effect of adding a second drug with the result of monotherapy with the first drug is not sufficient to demonstrate the superiority of the combination. Success with add-on therapy should be considered as success of alternative therapy until proven otherwise. In 30 adult patients who had failed to respond to the maximal tolerated dose of carbamazepine, phenytoin, phenobarbital, or primidone, a second drug (carbamazepine, phenytoin, phenobarbital, primidone, valproic acid, clonazepam, or clobazam) was added, if necessary up to the maximum tolerated dose (7). A reduction in seizure frequency by 75% or more was observed in 4 patients (13%). However, no patient became seizure free, and 3 patients (10%) experienced an increase in seizure frequency by more than 100%. In a study of 157 patients whose seizures were not controlled on a monotherapy, their treatment was randomized to alternative monotherapy or to adjunctive therapy (40). The outcome in the two groups in terms of seizure control and adverse effects did not differ. Schapel and coworkers (41) evaluated the combination of vigabatrin with lamotrigine in 42 patients with intractable epilepsy. On the combination, the median seizure frequency was reduced by 18% when vigabatrin was added to lamotrigine (n ϭ 27) and by 24% when lamotrigine was added to vigabatrin (n ϭ 15). However, this study does not document superiority of the combination. Because patients did not receive both drugs in monotherapy before the combination, the results may just reflect the effect of the second drug added, not of the combination. In a sequential study, some patients whose seizures were not controlled by valproate alone and by carbamazepine alone had a response to the combination of these two drugs (42). The combination of carbamazepine and phenytoin was assessed in a well-designed study, which was published only as an abstract (43). Initial treatment in 100 newly diagnosed patients was monotherapy with either carbamazepine or with phenytoin, in a randomized design. Fifty patients were not seizure free after 1 year and were switched to the other drug; 17 (34%) became seizure free. The remaining 33 patients received both medications, and only 5 (15%) were fully controlled. The potential benefit of the combination of carbamazepine with vigabatrin was assessed in newly diagnosed patients whose treatment was randomized to monotherapy with 446 IV • GENERAL PRINCIPLES OF THERAPY either one of these two drugs (44). Seizure control was not achieved in 25 patients, but 11 of them (44%) became seizure free when switched to the other drug. The remaining still refractory 14 patients were treated with the two drugs in combination, and 5 (36%) achieved full seizure control. At least two clinical studies provided evidence suggestive of a synergism between valproate and lamotrigine. Brodie and Yuen (45) found evidence suggestive of a synergism between lamotrigine and valproate in a lamotrigine substitution study. In 347 uncontrolled patients on monotherapy with valproate, carbamazepine, phenytoin, or phenobarbital, lamotrigine was added. An attempt was made to withdraw the first drug in patients with a 50% or greater seizure reduction. A synergism between lamotrigine and valproate was suggested on the basis of two observations: (1) a significantly better response after adding lamotrigine to valproate than to carbamazepine or phenytoin (P Ͻ 0.001), both for partial seizures (P Ͻ 0.02) and for generalized tonic-clonic seizures (not statistically significant), and (2) a poorer response after valproate was withdrawn. A smaller, but very systematic, study addressed the same combination (18). Valproate was added to a pre-existing drug regimen in 20 patients with refractory complex partial seizures. Only three experienced a Ͼ50% reduction in seizure frequency. Valproate was replaced by lamotrigine (added to the same pre-exisitng regimen) in the remaining 17 patients. A Ͼ50% seizure reduction was observed in 4 of the 17 patients. When valproate was reintroduced in addition to the lamotrigine in the remaining 13 patients, 8 of the patients had a favorable response, 4 had a Ͼ50% seizure reduction, and 4 became seizure free. Among the drugs used in the treatment of absence seizures, one clinical study suggests that the combination of valproate and ethosuximide is possibly beneficial. Five patients with absence seizures that had remained refractory to ethosuximide or to sodium valproate alone (or to both) became seizure free when the two drugs were combined (46). The experimental evidence discussed earlier also suggests that valproate with ethosuximide is one of the combinations with a favorable protective index. HOW SHOULD ANTIEPILEPTIC DRUG COMBINATIONS BE SELECTED? Considering the fact that there are no definitive clinical studies documenting the superiority of any specific drug combination, selecting a combination of two AEDs remains at the present time an educated guess at best. The choice may be based on several consid- erations that include the mechanisms of action, the clinical spectrum of activity, side effects, and pharmacokinetic interactions. The mechanism of action of AEDs has been suggested as a consideration for rational combinations (47, 48) based on the concept that drugs to be combined should have different mechanisms of action that could be complemen- tary. This is an elegant hypothesis, which has never been proved experimentally or clinically. For the time being, choosing a drug combination based on the mechanisms of action remains purely hypothetical, and no specific drug pair can be recommended. When a patient has two or more seizure types that cannot be controlled by one drug alone, two drugs can be selected according to their spectrum of efficacy. For each seizure type, the most effective and best tolerated drug should be selected. An example of epilepsy with multiple seizure types is Lennox-Gastaut syndrome. Valproate has long been a preferred drug in patients with Lennox- Gastaut syndrome, but three drugs have now been shown in double-blind studies to be effective: felbamate (49), lamotrigine (50), and topiramate (51). Combinations between these four drugs might be more effective in reducing drop attacks as well as atypical absences and tonic seizures than only one drug alone. On the other hand, phenytoin and carbamazepine usually are not effective and can even exacerbate certain seizures in these patients (52). The absence of pharmacokinetic interactions between two drugs certainly makes it easier to use them together. However, pharmacokinetic interactions are known and predictable, and it is the physician’s responsibility to make appropriate dosage adjustments, either as a corrective measure or preferably as a preventive measure. Therefore, pharmacokinetic interactions should not be a reason to avoid a drug combination that could be beneficial to the patient. Combinations to be avoided are those between drugs with similar side effects, such as barbiturates and benzodiazepines or barbiturates and topiramate (sedation, cognitive effects), topiramate with zonisamide or acetazolamide (nephrolithiasis, acidosis, weight loss), or carbamazepine with oxcarbazepine (hyponatremia), valproate and gabapentin (weight gain). As opposed to the classic concept of “high-dose monotherapy” (9), a concept of “low-dose polytherapy” could be advocated. The rationale would be that AEDs share their antiepileptic effect but do not always share their adverse effects. Therefore, if a patient has a good seizure response to two drugs in monotherapy, but with side effects, the two drugs might achieve the same seizure reduction together, at lower doses that could be below the clinical threshold for their side effects. An example would be a child with absence seizures who has thrombocytopenia or tremor at effective doses of valproate and persisting gastrointestinal side effects at effective doses of ethosuximide. The same seizure control without the side effects might be achieved with the two drugs at lower doses. Any two drugs with different side effects, but efficacy against the same seizure type, could be combined [...]... administration of valproic acid to patients receiving other antiepileptic drugs Epilepsia 1979; 20 :69 7–703 458 IV 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 • GENERAL PRINCIPLES OF THERAPY Triggs WJ, Bohan TP, Lin S-N, Willmore LJ Valproate induced coma with ketosis and carnitine insufficiency Arch Neurol 1990; 47:1131–1133 Millington DS, Bohan TP, Roe... Psychologic and behavioral effects of antiepileptic drugs in children, a double-blind comparison between phenobarbital and valproic acid Pediatrics 1987; 80: 165 –174 Reynolds EH, Chanarin I, Milner G, Matthews DM Anticonvulsant therapy, folic acid and vitamin B12 metabolism and mental symptoms Epilepsia 1 966 ; 7: 261 –270 Granick S Hepatic porphyria and drug-induced or chemical porphyria Ann NY Acad Sci 1 965 ;... conversion of acyl-carnitine to acyl-CoA, favoring omega oxidation with resultant dicarboxylic aciduria Coenzyme A deficiency also could impair cleavage of 3-ketoacyl-CoA by thiolase activity, 4 56 IV • GENERAL PRINCIPLES OF THERAPY causing accumulation of acetoacetyl-CoA, butyryl-CoA, and hexanoyl-CoA, producing ketosis with excretion of ethylmalonic and adipic acids Because butyryl-CoA and hexanoyl-CoA dehydrogenases... Schmidt D Reduction of two-drug therapy in intractable epilepsy Epilepsia 1983; 24: 368 –3 76 Schmidt D Two antiepileptic drugs for intractable epilepsy with complex-partial seizures J Neurol Psychiatry 1982; 45:1119–1124 Kuzniecky R, Rubin ZK, Faught E, Morawetz R Anti-epileptic drug treatment after temporal lobe epilepsy surgery: a randomized study comparing carbamazepine and polytherapy Epilepsia 1992;... al Dose-response trial of pregabalin adjunctive therapy in patients with partial seizures Neurology 2003; 60 : 163 1– 163 7 Beydoun A, Uthman BM, Kugler AR, Greiner MJ, et al, Pregabalin 100 8-0 09 Study Group Safety and efficacy of two pregabalin regimens for add-on treatment of partial epilepsy Neurology 2005; 64 :475–480 Marson AG, Hutton JL, Leach JP, et al Levetiracetam, oxcarbazepine, remacemide and zonisamide... carbamazepine monotherapy in newly diagnosed focal epilepsy: a randomized response conditional cross-over study Epilepsy Res 19 96; 25:257– 262 Brodie MJ, Yuen AW Lamotrigine substitution study: evidence for synergism with sodium valproate? 105 Study Group Epilepsy Res 1997; 26: 423–432 Rowan AJ, Meijer JW, de Beer-Pawlikowski N, van der Geest P, et al Valproate-ethosuximide combination therapy for refractory... lipase and amylase levels ( 56) Age-related changes in pharmacokinetics of VPA should be anticipated because of the high percentage of drug that is protein bound (57) Valproic acid is a branched-chain carboxylic acid that may be metabolized either through mitochondrial mechanisms or via cytoplasmic enzymes Dehydrogenation of VPA results in the accumulation of 2-en-, 3-en-, and 4-en-VPA compounds The 4-en... 34: 367 –371 Beghi E, Gatti G, Tonini C, Ben-Menachem E, et al, BASE Study Group Adjunctive therapy versus alternative monotherapy in patients with partial epilepsy failing on a single drug: a multicentre, randomized, pragmatic controlled trial Epilepsy Res 2003; 57:1–13 Schapel GJ, Black AB, Lam EL, Robinson M, et al Combination vigabatrin and lamotrigine therapy for intractable epilepsy Seizure 19 96; ... new antiepileptic drugs in children Epilepsia 19 96; 37 Suppl 1:S 66 S73 Binnie CD, Debets RM, Engelsman M, et al Double-blind crossover trial of lamotrigine (Lamictal) as add-on therapy in intractable epilepsy Epilepsy Res 1989; 4:222–229 Matsuo F, Bergen D, Faught E, et al Placebo-controlled study of the efficacy and safety of lamotrigine in patients with partial seizures Neurology 1993; 43:2284–2291... Anticonvulsants-induced chorea: a role for pharmacodynamic drug interaction? Seizure 2001; 10:5 96 599 Bourgeois BFD Antiepileptic drug combinations and experimental background: the case of phenobarbital and phenytoin Naunyn-Schmiedeberg’s Arch Pharmacol 19 86; 333:4 06 411 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 Morris JC, Dodson WE, Hatlelid JM, Ferrendelli JA Phenytoin and carbamazepine alone and . Additive 26 VPA ϩ ESM Additive Infra-additive 27 VPA ϩ CBZ Additive Infra-additive 26 VPA ϩ PHT Supra-additive Additive 28 VPA ϩ CZP Supra-additive Supra-additive 29 ESM ϩ CZP Supra-additive Supra-additive. (95, 96) . Levetiracetam Levetiracetam has an effect against partial onset seizures, primary generalized tonic-clonic seizures, juvenile myoclonic epilepsy, and photosensitivity-related epilepsy. for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2002(2):CD0014 16. 38. Chaisewikul R, Baillie N, Marson AG. Calcium antagonists as an add-on therapy for drug-resistant epilepsy.

Định dạng
Số trang	92
Dung lượng	709,6 KB