Headache Currents
HEADACHE CURRENTS
Antiepilepsy Drugs in Migraine Prevention: Editorial Stewart J. Tepper, MD Key words: migraine, prophylaxis, editorial
This issue of Headache Currents includes a review article by Drs. Bagnato and Good on the evidence for antiepilepsy drug (AED) use in migraine prevention.1 They take their cue from the 2012 American Headache Society migraine prevention guidelines.2 Therefore, the two Level A AEDs are divalproex and topiramate (TPM). The authors consider evidence, adverse events (AEs), potential mechanisms of action, and utility of these medications in the first part of this review. Then, they briefly and cogently explore the practicality of AED use in their own clinical practice. The combination of literature review and clinical application makes this monograph particularly helpful for the clinician. They also consider some of the frequently used AEDs with much less evidence or much more controversial evidence for effectiveness. These include zonisamide (ZON), lamotrigine (LTG), and gabapentin (GBP). ZON is often used clinically in patients who respond to TPM, but have significant AEs with TPM. Drs. Bagnato and Good wisely summarize only the randomized controlled trials (RCTs), which are contradictory. There are, in addition, a number of open label case series, which, in essence, say, “We had patients who could not tolerate TPM, we tried ZON on them, and in the majority of these patients, it worked and was better tolerated.”3,4 This can be the case clinically when TPM causes central nervous system (CNS), cognitive, or affective changes, but some of the AEs are the same for both of these carbonic anhydrase inhibitors, such as the risk of kidney stones and hyperchloremic acidosis, so a history of why a patient did not tolerate TPM is critical in deciding whether to make the switch. There is speculation that slower release forms of TPM (despite the 23 hour half life [t1/2)] of the generic forms) may be better tolerated. As the evidence for TPM in prevention of migraine is more extensive and more consistent than that for ZON, the clinical question then becomes whether we should be switching patients with generic TPM CNS AEs to nongeneric slow release TPM, with the knowledge of the stronger prevention evidence base, or to ZON, with less evidence and less cost. This is a significant and unanswered conundrum. As
the authors state in their conclusion, comparative effectiveness trials would be the way to clear this up, but the question is always, who will bear the cost of these studies? The Guidelines suggest LTG is ineffective in migraine prevention, and Drs. Bagnato and Good summarize the RCTs that led to this evidence-based statement. Again, open label studies may provide some interesting sidelights on this absolute position. There are many positive case reports on LTG for prevention of migraine specifically with aura, including increasing numbers of patients with each case series.5–8 These reports have spread to include more refractory, disabling, and complex auras such as basilar-type (now called brainstem aura), vertigo, and hemiplegic.9–12 The possibility that LTG may have a special role in the treatment of aura has led me to try it in patients with difficult to treat aura. This potential use for LTG needs to be explored with an RCT in these patients, but again, who pays? Finally, at the risk of stirring the hornets’ nest, a few words on GBP for migraine prevention. There is enough discrepancy between the full data set that was made available by Pfizer, who bought Warner Lambert, who did many of the original studies, that the Cochrane group re-ran and published their most recent analysis in 2013.13 Their conclusions were, “The pooled evidence derived from trials of GBP suggests that it is not efficacious for the prophylaxis of episodic migraine in adults. As AEs were common among the GBPtreated patients, it is advocated that gabapentin should not be used in routine clinical practice. Gabapentin enacarbil is not efficacious for the prophylaxis of episodic migraine in adults. There is no published evidence from controlled trials of pregabalin for the prophylaxis of episodic migraine in adults.” I agree with the authors that use of GBP in patients with concomitant neuropathic pain is sometimes helpful, but my use of GBP and pregabalin for migraine prevention plummeted after the Cochrane group made the complete data set available. References
From the Geisel School of Medicine at Dartmouth, Hanover, NH, USA. Address all correspondence to S.J. Tepper, Department of Neurology, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, USA. Accepted for publication February 1, 2016. ............. Headache C 2016 American Headache Society V
601
1. Bagnato F, Good J. The use of anti-epileptics in migraine prophylaxis. Headache. 2016;55:XXX. 2. Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C. Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults. Neurology. 2012;78:1337-1345. 3. Villani V, Ciuffoli A, Prosperini L, Sette G. Zonisamide for migraine prophylaxis in topiramate-intolerant patients: An observational study. Headache. 2011;51:287-291.
602 | Headache | March 2016
4. Bermejo PE, Dorado R. Zonisamide for migraine prophylaxis in patients refractory to topiramate. Clin Neuropharmacol. 2009;32: 103-106. 5. Pascual J, Caminero AB, Mateos V, et al. Preventing disturbing migraine aura with lamotrigine: An open study. Headache. 2004; 44:1024-1028. 6. D’Andrea G, Granella F, Cadaldini M, Manzoni GC. Effectiveness of lamotrigine in the prophylaxis of migraine with aura: An open pilot study. Cephalalgia. 1999;19:64-66. 7. Lampl C, Buzath A, Klinger D, Neumann K. Lamotrigine in the prophylactic treatment of migraine aura–a pilot study. Cephalalgia. 1999;19:58-63. 8. Lampl C, Katsarava Z, Diener HC, Limmroth V. Lamotrigine reduces migraine aura and migraine attacks in patients with migraine with aura. J Neurol Neurosurg Psychiatry. 2005;76: 1730-1732.
Headache Currents 9. Bisdorff AR. Treatment of migraine related vertigo with lamotrigine: An observational study. Bull Soc Sci Med Grand Duche Luxemb. 2004;2:103-108. 10. d’Onofrio F, Cologno D, Petretta V, Casucci G, Bussone G. Basilar-type migraine responsive to lamotrigine: Three case reports. Neurol Sci. 2007;28(Suppl. 2):S239-241. 11. Cologno D, d’Onofrio F, Castriota O, et al. Basilar-type migraine patients responsive to lamotrigine: A 5-year follow-up. Neurol Sci. 2013;34(Suppl. 1):S165-166. 12. Pelzer N, Stam AH, Carpay JA, et al. Familial hemiplegic migraine treated by sodium valproate and lamotrigine. Cephalalgia. 2014;34:708-711. 13. Linde M, Mulleners WM, Chronicle EP, McCrory DC. Gabapentin or pregabalin for preventing migraine attacks in adults. Cochrane Pain, Palliative and Supportive Care Group. 15 Jan 2013. DOI: 10.1002/14651858.CD010609
HEADACHE CURRENTS
Antiepilepsy Drugs in Migraine Prevention: Editorial Stewart J. Tepper, MD Key words: migraine, prophylaxis, editorial
This issue of Headache Currents includes a review article by Drs. Bagnato and Good on the evidence for antiepilepsy drug (AED) use in migraine prevention.1 They take their cue from the 2012 American Headache Society migraine prevention guidelines.2 Therefore, the two Level A AEDs are divalproex and topiramate (TPM). The authors consider evidence, adverse events (AEs), potential mechanisms of action, and utility of these medications in the first part of this review. Then, they briefly and cogently explore the practicality of AED use in their own clinical practice. The combination of literature review and clinical application makes this monograph particularly helpful for the clinician. They also consider some of the frequently used AEDs with much less evidence or much more controversial evidence for effectiveness. These include zonisamide (ZON), lamotrigine (LTG), and gabapentin (GBP). ZON is often used clinically in patients who respond to TPM, but have significant AEs with TPM. Drs. Bagnato and Good wisely summarize only the randomized controlled trials (RCTs), which are contradictory. There are, in addition, a number of open label case series, which, in essence, say, “We had patients who could not tolerate TPM, we tried ZON on them, and in the majority of these patients, it worked and was better tolerated.”3,4 This can be the case clinically when TPM causes central nervous system (CNS), cognitive, or affective changes, but some of the AEs are the same for both of these carbonic anhydrase inhibitors, such as the risk of kidney stones and hyperchloremic acidosis, so a history of why a patient did not tolerate TPM is critical in deciding whether to make the switch. There is speculation that slower release forms of TPM (despite the 23 hour half life [t1/2)] of the generic forms) may be better tolerated. As the evidence for TPM in prevention of migraine is more extensive and more consistent than that for ZON, the clinical question then becomes whether we should be switching patients with generic TPM CNS AEs to nongeneric slow release TPM, with the knowledge of the stronger prevention evidence base, or to ZON, with less evidence and less cost. This is a significant and unanswered conundrum. As
the authors state in their conclusion, comparative effectiveness trials would be the way to clear this up, but the question is always, who will bear the cost of these studies? The Guidelines suggest LTG is ineffective in migraine prevention, and Drs. Bagnato and Good summarize the RCTs that led to this evidence-based statement. Again, open label studies may provide some interesting sidelights on this absolute position. There are many positive case reports on LTG for prevention of migraine specifically with aura, including increasing numbers of patients with each case series.5–8 These reports have spread to include more refractory, disabling, and complex auras such as basilar-type (now called brainstem aura), vertigo, and hemiplegic.9–12 The possibility that LTG may have a special role in the treatment of aura has led me to try it in patients with difficult to treat aura. This potential use for LTG needs to be explored with an RCT in these patients, but again, who pays? Finally, at the risk of stirring the hornets’ nest, a few words on GBP for migraine prevention. There is enough discrepancy between the full data set that was made available by Pfizer, who bought Warner Lambert, who did many of the original studies, that the Cochrane group re-ran and published their most recent analysis in 2013.13 Their conclusions were, “The pooled evidence derived from trials of GBP suggests that it is not efficacious for the prophylaxis of episodic migraine in adults. As AEs were common among the GBPtreated patients, it is advocated that gabapentin should not be used in routine clinical practice. Gabapentin enacarbil is not efficacious for the prophylaxis of episodic migraine in adults. There is no published evidence from controlled trials of pregabalin for the prophylaxis of episodic migraine in adults.” I agree with the authors that use of GBP in patients with concomitant neuropathic pain is sometimes helpful, but my use of GBP and pregabalin for migraine prevention plummeted after the Cochrane group made the complete data set available. References
From the Geisel School of Medicine at Dartmouth, Hanover, NH, USA. Address all correspondence to S.J. Tepper, Department of Neurology, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, USA. Accepted for publication February 1, 2016. ............. Headache C 2016 American Headache Society V
601
1. Bagnato F, Good J. The use of anti-epileptics in migraine prophylaxis. Headache. 2016;55:XXX. 2. Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C. Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults. Neurology. 2012;78:1337-1345. 3. Villani V, Ciuffoli A, Prosperini L, Sette G. Zonisamide for migraine prophylaxis in topiramate-intolerant patients: An observational study. Headache. 2011;51:287-291.
602 | Headache | March 2016
4. Bermejo PE, Dorado R. Zonisamide for migraine prophylaxis in patients refractory to topiramate. Clin Neuropharmacol. 2009;32: 103-106. 5. Pascual J, Caminero AB, Mateos V, et al. Preventing disturbing migraine aura with lamotrigine: An open study. Headache. 2004; 44:1024-1028. 6. D’Andrea G, Granella F, Cadaldini M, Manzoni GC. Effectiveness of lamotrigine in the prophylaxis of migraine with aura: An open pilot study. Cephalalgia. 1999;19:64-66. 7. Lampl C, Buzath A, Klinger D, Neumann K. Lamotrigine in the prophylactic treatment of migraine aura–a pilot study. Cephalalgia. 1999;19:58-63. 8. Lampl C, Katsarava Z, Diener HC, Limmroth V. Lamotrigine reduces migraine aura and migraine attacks in patients with migraine with aura. J Neurol Neurosurg Psychiatry. 2005;76: 1730-1732.
Headache Currents 9. Bisdorff AR. Treatment of migraine related vertigo with lamotrigine: An observational study. Bull Soc Sci Med Grand Duche Luxemb. 2004;2:103-108. 10. d’Onofrio F, Cologno D, Petretta V, Casucci G, Bussone G. Basilar-type migraine responsive to lamotrigine: Three case reports. Neurol Sci. 2007;28(Suppl. 2):S239-241. 11. Cologno D, d’Onofrio F, Castriota O, et al. Basilar-type migraine patients responsive to lamotrigine: A 5-year follow-up. Neurol Sci. 2013;34(Suppl. 1):S165-166. 12. Pelzer N, Stam AH, Carpay JA, et al. Familial hemiplegic migraine treated by sodium valproate and lamotrigine. Cephalalgia. 2014;34:708-711. 13. Linde M, Mulleners WM, Chronicle EP, McCrory DC. Gabapentin or pregabalin for preventing migraine attacks in adults. Cochrane Pain, Palliative and Supportive Care Group. 15 Jan 2013. DOI: 10.1002/14651858.CD010609
