MAEDICA – a Journal of Clinical Medicine 2014; 9(4): 401-404
Mædica - a Journal of Clinical Medicine S TATE - OF - THE - ART
Chronic Migraine – New Treatment Options Adina ROCEANU; Florina ANTOCHI; Ovidiu BAJENARU Department of Neurology, Emergency University Hospital, Bucharest, Romania
ABSTRACT Chronic migraine (CM) is defined as headache occurring more than fifteen days/month for at least three consecutive months, with headache having the clinical features of migraine without aura for at least eight days per month. Recently, new treatment options became available in chronic migraine patients. Topiramate is effective in chronic migraine, in the presence or absence of medication overuse, and/or other migraine prophylaxis. Efficacy of onabotulinumtoxin A as a preventive treatment of chronic migraine has been shown in the PREEMPT studies. Occipital nerve stimulation (ONS) is an invasive treatment for refractory chronic headaches. ONS has encouraging results in refractory chronic migraine patients in commercially funded, multi-centre randomized trials Keywords: chronic migraine, topiramate, onabotulimumtoxin A, occipital nerve stimulation
C
hronic daily headache (CDH) is the term used for primary headaches occurring in more than fourteen days per month. CDH includes four types of headaches: chronic migraine (CM), chronic tension-type headache (CTTH), new daily persistent headache (NDPH) and hemicrania continua (HC). Frequently chronic daily headache is due to secondary headache disorders (medicationoveruse-headache – MOH). Chronic migraine is a complication of episodic migraine. The process of transformation of episodic into chronic daily headache is accompanied by increased use of analgesics and migraine drugs. CM is the most common form of seriously disabling headache and preventive treatment is essential to its management.
Chronic migraine (CM) is defined as headache occurring more than fifteen days/month for at least three consecutive months, with headache having the clinical features of migraine with or without aura for at least eight days per month (1). In order to fulfill the ICHD-3 beta criteria (1) headache must be present at least fifteen days per month, for at least three month. Frequently migraine is associated with tension-type headache. Clinical features could be of tension-type-like and/or migraine-like. The patient must be instructed to recognize the two types of headaches and to take triptans or ergot derivatives only for migraine headache. Patient must have migraine without aura or with aura for at least eight days/month, fulfilling criteria ICHD-3.
Address for correspondence: Adina Roceanu, Department of Neurology, Emergency University Hospital, 169 Splaiul Independentei, 5th District, Bucharest, Romania. E-mail: [email protected] Article received on the 3rd of September 2014. Article accepted on the 19th of November 2014.
Maedica
A Journal of Clinical Medicine, Volume 9 No.4 2014
401
CHRONIC MIGRAINE – NEW TREATMENT OPTIONS For migraine without aura patient must have at least five attacks of headache, lasting 4-72 hours (untreated or unsuccessfully treated); with unilateral location, pulsating quality, moderate to severe pain intensity, aggravated by routine physical activity – walking or climbing stairs – resulting in avoidance of this activity (at least two of four characteristic must be present); associated with nausea and/or vomiting, photo- and phonophobia (at least one of associated signs). Other diagnostics were ruled out according to ICHD-2. For migraine with aura patient must have at least two attacks of headache with one or more fully reversible aura symptoms (visual, sensory, speech ad/or language, motor, brainstem, retinal); with at least one aura symptom spreads gradually over five minutes, and/or two or more symptoms occur in succession, each individual aura symptom lasts 5-60 minutes, at least one aura symptom is unilateral, the aura is accompanied, or followed within 60 minutes, by headache (at least two of the four characteristics). Other diagnostics were ruled out according to ICHD-3. Also we can count the days believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative. In episodic migraine attacks current therapies are non-specific drugs (non-steroidal antiinflammatory drugs, aspirin, antiemetics) and specific antimigraine drugs (ergot alkaloids, serotonin 5-HT1B/1D receptor agonists – triptans). When there are very frequent, long attacks, unresponsive to acute drugs, that impair business duties prophylactic treatment is recommended in episodic migraine with beta-blockers (metoprolol, propranolol), calcium channel blockers (flunarizine), antiepileptic drugs (valproic acid, topiramate), antidepressants (amitriptilyne, fluoxetine). Chronic migraine is a complex, progressive headache disorder affecting approximately 1.3-2.4% of the general population (2-4). Chronic migraine is a prevalent, disabling and undertreated neurological disorder. Few preventive treatments have been investigated and none is specifically indicated for chronic migraine. Topiramate in chronic migraine Topiramate [2,3:4,5-Bis-O-(1-methylethyledene)--D-fructo-pyranose sulfamate] is a sul402
Maedica
A Journal of Clinical Medicine, Volume 9 No.4 2014
famate-substituted monosaccharide, derived from D-fructose. Topiramate has different mechanisms of action: • inhibitory effects on voltage-gated Na+ and Ca++ Channels • modulation of glutamate-mediated neurotransmission (reducing depolarization induced by AMPS and kainite mediated currents) • enhancement of some GABAA receptors • inhibition of carbonic anhydrase (5). The drug reduces excitatory neurotransmission and enhances inhibitory neurotransmission. Topiramate might act at different levels: inhibiting cortical spreading depression (6) and reducing nociceptive transmission through trigeminovascular modulation (7). Two multicenter, randomized, double-blind, placebo controlled trials, one performed in USA and another in Europe demonstrated that topiramate is effective in chronic migraine, in the presence or absence of medication overuse, and/or other migraine prophylaxis (8,9). Onabotulinumtoxin A Onabotulinumtoxin A blocks the release of neurotransmitters associated with genesis of pain from the peripheral termination of primary afferents. Such neurotransmiters are substance P, calcitonin gene-related peptide CGRP and glutamate (10-13). The 2 multicenter, pivotal studies PREEMPT (Phase 3 Research Evaluating Migraine Prophylaxis Therapy) 1384 adults were randomized to onabotulinumtoxin A (n=688) or placebo (n=696). Clinical program each included 24week randomized, double-blind phase followed by a 32-week open-label phase (ClinicalTrials.gov identifiers NCT00156910, NCT00168428) (14). Each study had a 28-day baseline screening phase and a 24-week, double-blind phase (DB) with two injection cycles, followed by a 32week, open-label phase (OL) with three injection cycles. Onabotulinumtoxin A 155 U or placebo was administered as 31 fixed-sites, fixed-dose injections across 7 specific head/neck muscle areas. At investigator’s discretion an additional 40 U could be administered using a “followthe-pain” strategy. The maximum dose was 195 U across 39 sites.
CHRONIC MIGRAINE – NEW TREATMENT OPTIONS The primary endpoint for pooled analysis was mean change from baseline in frequency of headache days at 24 weeks. The secondary endpoints were mean change from baseline to week 24 in: • frequency of migraine/probable migraine days • frequency of moderate/severe headache days • total cumulative hours of headache on headache days • frequency of headache episodes • frequency of migraine/probable migraine episodes • frequency of acute headache medication intakes. Pooled analyses demonstrated a large mean decrease from baseline in frequency of headache days, with statistically significant betweengroup differences favoring onabotulinumtoxin A over placebo at week 24 (-8.4 vs-6.6; p
Mædica - a Journal of Clinical Medicine S TATE - OF - THE - ART
Chronic Migraine – New Treatment Options Adina ROCEANU; Florina ANTOCHI; Ovidiu BAJENARU Department of Neurology, Emergency University Hospital, Bucharest, Romania
ABSTRACT Chronic migraine (CM) is defined as headache occurring more than fifteen days/month for at least three consecutive months, with headache having the clinical features of migraine without aura for at least eight days per month. Recently, new treatment options became available in chronic migraine patients. Topiramate is effective in chronic migraine, in the presence or absence of medication overuse, and/or other migraine prophylaxis. Efficacy of onabotulinumtoxin A as a preventive treatment of chronic migraine has been shown in the PREEMPT studies. Occipital nerve stimulation (ONS) is an invasive treatment for refractory chronic headaches. ONS has encouraging results in refractory chronic migraine patients in commercially funded, multi-centre randomized trials Keywords: chronic migraine, topiramate, onabotulimumtoxin A, occipital nerve stimulation
C
hronic daily headache (CDH) is the term used for primary headaches occurring in more than fourteen days per month. CDH includes four types of headaches: chronic migraine (CM), chronic tension-type headache (CTTH), new daily persistent headache (NDPH) and hemicrania continua (HC). Frequently chronic daily headache is due to secondary headache disorders (medicationoveruse-headache – MOH). Chronic migraine is a complication of episodic migraine. The process of transformation of episodic into chronic daily headache is accompanied by increased use of analgesics and migraine drugs. CM is the most common form of seriously disabling headache and preventive treatment is essential to its management.
Chronic migraine (CM) is defined as headache occurring more than fifteen days/month for at least three consecutive months, with headache having the clinical features of migraine with or without aura for at least eight days per month (1). In order to fulfill the ICHD-3 beta criteria (1) headache must be present at least fifteen days per month, for at least three month. Frequently migraine is associated with tension-type headache. Clinical features could be of tension-type-like and/or migraine-like. The patient must be instructed to recognize the two types of headaches and to take triptans or ergot derivatives only for migraine headache. Patient must have migraine without aura or with aura for at least eight days/month, fulfilling criteria ICHD-3.
Address for correspondence: Adina Roceanu, Department of Neurology, Emergency University Hospital, 169 Splaiul Independentei, 5th District, Bucharest, Romania. E-mail: [email protected] Article received on the 3rd of September 2014. Article accepted on the 19th of November 2014.
Maedica
A Journal of Clinical Medicine, Volume 9 No.4 2014
401
CHRONIC MIGRAINE – NEW TREATMENT OPTIONS For migraine without aura patient must have at least five attacks of headache, lasting 4-72 hours (untreated or unsuccessfully treated); with unilateral location, pulsating quality, moderate to severe pain intensity, aggravated by routine physical activity – walking or climbing stairs – resulting in avoidance of this activity (at least two of four characteristic must be present); associated with nausea and/or vomiting, photo- and phonophobia (at least one of associated signs). Other diagnostics were ruled out according to ICHD-2. For migraine with aura patient must have at least two attacks of headache with one or more fully reversible aura symptoms (visual, sensory, speech ad/or language, motor, brainstem, retinal); with at least one aura symptom spreads gradually over five minutes, and/or two or more symptoms occur in succession, each individual aura symptom lasts 5-60 minutes, at least one aura symptom is unilateral, the aura is accompanied, or followed within 60 minutes, by headache (at least two of the four characteristics). Other diagnostics were ruled out according to ICHD-3. Also we can count the days believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative. In episodic migraine attacks current therapies are non-specific drugs (non-steroidal antiinflammatory drugs, aspirin, antiemetics) and specific antimigraine drugs (ergot alkaloids, serotonin 5-HT1B/1D receptor agonists – triptans). When there are very frequent, long attacks, unresponsive to acute drugs, that impair business duties prophylactic treatment is recommended in episodic migraine with beta-blockers (metoprolol, propranolol), calcium channel blockers (flunarizine), antiepileptic drugs (valproic acid, topiramate), antidepressants (amitriptilyne, fluoxetine). Chronic migraine is a complex, progressive headache disorder affecting approximately 1.3-2.4% of the general population (2-4). Chronic migraine is a prevalent, disabling and undertreated neurological disorder. Few preventive treatments have been investigated and none is specifically indicated for chronic migraine. Topiramate in chronic migraine Topiramate [2,3:4,5-Bis-O-(1-methylethyledene)--D-fructo-pyranose sulfamate] is a sul402
Maedica
A Journal of Clinical Medicine, Volume 9 No.4 2014
famate-substituted monosaccharide, derived from D-fructose. Topiramate has different mechanisms of action: • inhibitory effects on voltage-gated Na+ and Ca++ Channels • modulation of glutamate-mediated neurotransmission (reducing depolarization induced by AMPS and kainite mediated currents) • enhancement of some GABAA receptors • inhibition of carbonic anhydrase (5). The drug reduces excitatory neurotransmission and enhances inhibitory neurotransmission. Topiramate might act at different levels: inhibiting cortical spreading depression (6) and reducing nociceptive transmission through trigeminovascular modulation (7). Two multicenter, randomized, double-blind, placebo controlled trials, one performed in USA and another in Europe demonstrated that topiramate is effective in chronic migraine, in the presence or absence of medication overuse, and/or other migraine prophylaxis (8,9). Onabotulinumtoxin A Onabotulinumtoxin A blocks the release of neurotransmitters associated with genesis of pain from the peripheral termination of primary afferents. Such neurotransmiters are substance P, calcitonin gene-related peptide CGRP and glutamate (10-13). The 2 multicenter, pivotal studies PREEMPT (Phase 3 Research Evaluating Migraine Prophylaxis Therapy) 1384 adults were randomized to onabotulinumtoxin A (n=688) or placebo (n=696). Clinical program each included 24week randomized, double-blind phase followed by a 32-week open-label phase (ClinicalTrials.gov identifiers NCT00156910, NCT00168428) (14). Each study had a 28-day baseline screening phase and a 24-week, double-blind phase (DB) with two injection cycles, followed by a 32week, open-label phase (OL) with three injection cycles. Onabotulinumtoxin A 155 U or placebo was administered as 31 fixed-sites, fixed-dose injections across 7 specific head/neck muscle areas. At investigator’s discretion an additional 40 U could be administered using a “followthe-pain” strategy. The maximum dose was 195 U across 39 sites.
CHRONIC MIGRAINE – NEW TREATMENT OPTIONS The primary endpoint for pooled analysis was mean change from baseline in frequency of headache days at 24 weeks. The secondary endpoints were mean change from baseline to week 24 in: • frequency of migraine/probable migraine days • frequency of moderate/severe headache days • total cumulative hours of headache on headache days • frequency of headache episodes • frequency of migraine/probable migraine episodes • frequency of acute headache medication intakes. Pooled analyses demonstrated a large mean decrease from baseline in frequency of headache days, with statistically significant betweengroup differences favoring onabotulinumtoxin A over placebo at week 24 (-8.4 vs-6.6; p
