Killing two birds with one stone: successful opioid monotherapy in intractable migraine-triggered epilepsy,a case series

Introduction

The causal relationship between migraine and epilepsy is demonstrated by the curative effect of ketogenic diets in preventing the migraines as well as forestalling the ensuing epilepsy [Urbizu et al. 2010; Di Lorenzo et al. 2013, 2015]. Pharmacological elimination of headaches by lamotrigine has also been shown to have a similar effect [Pascual et al. 2004]. A similar phenomenon has been demonstrated by the salutary effects of sleep in forestalling migraine-triggered epilepsies [Marks and Ehrenberg, 1993; Velioğlu et al. 2005; Devinsky, 1999; Orr, 2015; Rodriguez-Sainz et al. 2013; Niedermeyer, 1993].

The present article reports the occurrence of the same phenomenon in five cases of intractable headaches associated with epilepsy. All patients had a combination of drug resistant epilepsy and migraine. In these cases, however, the primary role of migraines in triggering seizures was demonstrated by the total abolition of epilepsy once the migraines were fully controlled following a regimen of maintenance opioid reported earlier [Piekos and Spierings, 2009; Miller, 1968; Macpherson, 2009; Ziegler, 1997].

In the series described here seizures returned whenever the patient abandoned the maintenance opiate therapy, causing the return of the migraines forthwith. This sequence of events is against the recently expressed concept that the headaches observed in migralepsy are simply part of an ‘ictal epileptic headache’ [Verrotti et al. 2011, 2016]. Similarly, the fact that the continued occurrence of migraines is associated with presence of antiepileptic drug resistance points to an independent role of headaches in perpetuating the seizures, thus making the case for opioid monotherapy even stronger in those who suffer from migralepsy [Marks and Ehrenberg, 1993; Verrotti et al. 2016; Comi et al. 2003]. All patients in this series were seen as outpatients in my office practice. They were among many other similar cases suffering from migralepsy.

Case 1

Patient 1, a 50-year-old woman, was first seen in 2013. She complained of seizures since 2002. A total of four of the eight headaches she endured in the month of October 2013 ended with seizures, despite daily use of one or more of the following anticonvulsants: Devalproex sodium, Topiramate, and Gabapentin (taken in appropriate amounts). Neurological examination and the initial unenhanced computerized tomography (CT) of the brain were normal. She was titrated on daily scheduled opioid for the prevention of migraine, resulting in complete abatement of headaches and seizure once the dose of oxycodone reached 180 mg per day. She remained asymptomatic when last seen in January 2016.

Case 2

Patient 2, born in 1957, was first seen in the office in 2004. His main complaint was occurrences of debilitating headaches with features of migraine often associated with seizures. After initial evaluations (initial neurological examination and a CT of the brain which were both normal) he was put on different anticonvulsants for prevention of headaches and the attendant seizures with only partial effectiveness despite laboratory confirmed therapeutic levels of felbamate, zonisamide and lamotrigine in different occasions. Daily scheduled opioid therapy for prevention of migraine and seizures were then started, with hydrocodone 10/325 mg tablet, culminating in two tablets three times daily. This resulted in lessening of the number of headaches and seizures but did not completely suppress them, despite the continuation of anticonvulsants. Later he was switched to oxycodone 30 mg tablets which was titrated to two tablets three times daily as the anticonvulsants were slowly withdrawn. This resulted in complete suppression of seizures and headaches as long as he maintained the opiate. He was last seen in December 2015.

Case 3

Patient 3, a 24-year-old married man, was first seen in November 2014 for frequent occurrences of severe headaches, often associated with loss of consciousness and convulsions, witnessed by his wife. An abbreviated account of DHW has been accepted for publication elsewhere. His headaches began at age 9 while under the care of a pediatric neurologist in Charleston, West Virginia, USA. His condition worsened after a motor vehicle accident, particularly the headaches of which he had 3–4 bad ones per week. Gabapentin, 400 mg, two tablets three times per day and 400 mg of felbamate daily did not reduce the headaches in number or in severity nor did the seizures changed. After switching to daily scheduled opioid therapy, both the severity and the number of headaches and seizures diminished when the opiate was titrated to 30 mg of oxycodone, two tablets three times daily; a dose which suppressed both the migraines and seizures. After several months of the above-mentioned regimen, pharmacists refused to supply him with the prescriptions given and his symptoms returned in earnest; these symptoms did not respond to the resumption of previously prescribed anticonvulsants. He was last seen in January 016.

Case 4

Patient 4, a 35-year-old woman was first seen in 2008 for the chief complaints of migraine and severe backache radiating into her legs. The headaches had been present since her early childhood. Neurological examination was unremarkable. She was prescribed Levetiracetam, Imipramine PM and Eletriptan for symptom relief in addition to hydrocodone/acetaminophen (10/350 mg, 1–2 tablets twice daily) on as-needed basis. Although she improved somewhat in the ensuing months, she required trials of other medication in a quest for better relief. These included Topiramate, Zonisomide, Naratriptan and various sedatives. Because of continued occurrences of debilitating headaches on a biweekly basis, all prophylactic medication were stopped in August 2014 in favor of daily scheduled opioid treatment of migraine, using oxycodone 30 mg 2 tablets twice daily. Rare headaches followed, resulting in an increase of the oxycodone to 180 mg per day, following which the headaches stopped completely. Unfortunately, due her inability to obtain opioid medication in December 2015, the headaches resumed their appearance but this time were associated with generalized seizures requiring hospitalization (due to loss of consciousness, associated with incontinence). She was last seen in June 2016.

Case 5

Patient 5, a 42-year-old woman, was first seen in 2002. She complained of headaches all her life, becoming worse in severity in the years prior to her visit. Diabetes ran in her family but not headaches. Neurological findings in the examination were limited to carpal tunnel syndrome and peripheral neuropathy. Grand mal seizures were added to the picture soon thereafter and remained so until daily scheduled opioid therapy for chronic daily headache was started in 2005, having exhausted nonopioid analgesic options among several anticonvulsants. She remained symptom-free as long as she was able to continue with her regimen of oxycodone, 30 mg 2 tablets three times daily. She was last seen in January 2016.

Discussion

Although daily scheduled opioid therapy has been a recognized method for preventing headaches [Urbizu et al. 2010; Di Lorenzo et al. 2013, 2015] there have been no precedents for its use in preventing epilepsy, particularly those associated with migraine. In fact, in recent decades, opiates have been unjustifiably maligned for causing the so-called ‘medication overuse headache’ [Derakhshan, 2015; Robbins, 2014a; Westergaard et al. 2015]. However, in a series of recent articles involving analysis of data from thousands of patients with epilepsy, Wilner and colleagues found that a large majority of the population had suffered from an ensemble of headache, migraine and cervicalgia (i.e. a surrogate for migraine). This amounted to a fourfold discrepancy in the rate of developing migraine/headache between the populations with epilepsy compared with the matched nonepileptic [Wilner et al. 2014, 2016]. Clearly, despite Wilner and colleagues’ expressed puzzlement, what seems to have been driving the request for opioid pain medication by these epileptic patients was the fact that a vast majority of them had migraine-triggered epilepsy for the relief of which patients had found maintenance opioids an effective prophylactic agent (on an empirical basis).

As a clinical neurologist with an interest in headaches, I share the sentiment of those clinical neurologists for whom opioids are irreplaceable, well tolerated and effective medications for treating acute and chronic headaches [Levin, 2014a, 2014b; Robbins, 2014b; Miller, 1968; Macpherson, 2009; Ziegler, 1997]. However, the importance of the present case reports is in their striking similarity to the results seen in patients with migralepsy after following a ketogenic diet or with restoring the sleeping pattern, indicating a decrease of epileptogenicity within the brain once the migraines are fully controlled [Urbizu et al. 2010; Di Lorenzo et al. 2013, 2015; Pascual et al. 2004; Niedermeyer, 1993; Comi et al. 2003]. In summary, in managing migralepsy it is the migraine that must receive therapeutic priority despite the more impressive scene presented by epilepsy.

Conclusion

In migralepsy, there a tight physiological connectivity between headache and seizure. To prevent the seizure, preventing the headache takes priority as the migraine is the driving factor. Maintenance opioid treatment is the best-tolerated and most effective method for preventing migraines.