TBD Meeting (5128)

LONDON – A simple, straightforward protocol for management of medication-overuse headache has established its clinical utility in the large joint European/Latin American COMOESTAS study.

"These findings confirm the efficacy, the usability worldwide, and the low economic cost of detoxifying patients with medication-overuse headache," Dr. Cristina Tassorelli said in presenting the COMOESTAS data at the European Headache and Migraine Trust International Congress.

The protocol utilized in COMOESTAS (continuous monitoring of medication-overuse headache in Europe and Latin America: development and standardization of an alert and decision support system) consists of abrupt detoxification, patient education, early initiation of individualized prophylactic therapy, and regular scheduled follow-up by one dedicated physician guided by electronic support. Patients maintain an electronic medical diary which automatically signals their physician if they begin to slide down the slope toward relapse, explained Dr. Tassorelli, a neurologist at the University of Pavia (Italy).

Medication-overuse headache (MOH) is a common and disabling condition. It affects 1%-3% of the general population and 20%-60% of patients in specialized headache clinics. It occurs when patients with chronic headache, most often migraine without aura, experience a worsening of their headaches and respond by using more and more acute medication – triptans and/or NSAIDs – which in turn paradoxically exacerbates their headache pattern. MOH is defined by the occurrence of headache on at least 15 days/month coupled with use of triptans on 10 or more days/month or NSAIDs on at least 15 days/month.

MOH is treatable via detoxification but typically has a relapse rate of 30%-40% within the following 6 months. The COMOESTAS protocol, in contrast, had a 6-month relapse rate of 10%.

The COMOESTAS protocol for MOH was devised by expert consensus. It is designed as a first-line intervention for MOH patients who are detoxification-naive.

"Three-quarters of first timers will do well with this approach. It’s a good tool for stratifying patients: If they relapse, then they need a more intensive multidisciplinary approach," Dr. Tassorelli explained.

In a separate presentation, COMOESTAS coinvestigator Dr. Lars Bendsten reported that the management protocol proved successful not only in terms of the primary outcome measures of reduced headache frequency and fewer days per month of acute medication use but also from the standpoint of reduced depression, anxiety, and disability along with improved quality of life.

Among 519 COMOESTAS participants who completed 6 months of follow-up at centers in Spain, Italy, Denmark, Germany, Argentina, and Chile, the mean number of headache days per month fell from 23.6 at baseline to 9.8. Days of acute drug therapy dropped in sync.

Moreover, quality of life as assessed using the MIDAS (Migraine Disability Assessment Score) scale improved from 59.8 to 25.5. The mean HADS (Hospital Anxiety and Depression Scale) depression score fell from 6.6 at baseline to 4.1, while the HADS anxiety score dropped from 9.3 to 7.1. All of these differences were statistically significant and clinically meaningful, commented Dr. Bendsten of the University of Copenhagen.

Dr. Tassorelli noted that detoxification in the COMOESTAS study could be carried out on either an inpatient or outpatient basis, depending upon local practice. The 6-month results were closely similar regardless of the detoxification setting, meaning that outpatient detoxification, which is vastly less expensive, is clearly the winning strategy.

The COMOESTAS protocol began with a day 1 detailed explanation of the vicious cycle of MOH and advice to the patient to abruptly stop the overused medication. Rescue medication could be employed on days 1-7 to combat withdrawal headaches, with the drug, dose, and route of administration to be chosen from a menu based upon the patient’s medical history and headache characteristics. Options included a variety of antiemetics, acetaminophen, and naproxen.

Preventive therapy was started within the first 7 days. The options were propranolol, atenolol, metoprolol, valproic acid, topiramate, candesartan, flunarizine, or amitriptyline. The selection was based upon comorbid conditions, patient preference, and side effect profiles.

Acute headache medication was permitted beginning on day 8 for a maximum of 2 days per week. The inviolable rule was that patients could not use the same drug that was previously overused.

Elsewhere at the conference, European Headache Federation president and COMOESTAS coinvestigator Dr. Rigmor Højland Jensen diverged from providing an update on the therapeutic pipeline for migraine to draw special attention to the importance of detoxifying patients with MOH.

"This is something we can do starting Monday morning. We don’t have to have a bag full of new drugs. We can do a lot for these patients now," said Dr. Jensen, professor of neurology at the University of Copenhagen.

The COMOESTAS project is funded by the European Commission. The investigators reported having no financial conflicts.

b.jancin@elsevier.com

LONDON – A simple, straightforward protocol for management of medication-overuse headache has established its clinical utility in the large joint European/Latin American COMOESTAS study.

"These findings confirm the efficacy, the usability worldwide, and the low economic cost of detoxifying patients with medication-overuse headache," Dr. Cristina Tassorelli said in presenting the COMOESTAS data at the European Headache and Migraine Trust International Congress.

The protocol utilized in COMOESTAS (continuous monitoring of medication-overuse headache in Europe and Latin America: development and standardization of an alert and decision support system) consists of abrupt detoxification, patient education, early initiation of individualized prophylactic therapy, and regular scheduled follow-up by one dedicated physician guided by electronic support. Patients maintain an electronic medical diary which automatically signals their physician if they begin to slide down the slope toward relapse, explained Dr. Tassorelli, a neurologist at the University of Pavia (Italy).

Medication-overuse headache (MOH) is a common and disabling condition. It affects 1%-3% of the general population and 20%-60% of patients in specialized headache clinics. It occurs when patients with chronic headache, most often migraine without aura, experience a worsening of their headaches and respond by using more and more acute medication – triptans and/or NSAIDs – which in turn paradoxically exacerbates their headache pattern. MOH is defined by the occurrence of headache on at least 15 days/month coupled with use of triptans on 10 or more days/month or NSAIDs on at least 15 days/month.

MOH is treatable via detoxification but typically has a relapse rate of 30%-40% within the following 6 months. The COMOESTAS protocol, in contrast, had a 6-month relapse rate of 10%.

The COMOESTAS protocol for MOH was devised by expert consensus. It is designed as a first-line intervention for MOH patients who are detoxification-naive.

"Three-quarters of first timers will do well with this approach. It’s a good tool for stratifying patients: If they relapse, then they need a more intensive multidisciplinary approach," Dr. Tassorelli explained.

In a separate presentation, COMOESTAS coinvestigator Dr. Lars Bendsten reported that the management protocol proved successful not only in terms of the primary outcome measures of reduced headache frequency and fewer days per month of acute medication use but also from the standpoint of reduced depression, anxiety, and disability along with improved quality of life.

Among 519 COMOESTAS participants who completed 6 months of follow-up at centers in Spain, Italy, Denmark, Germany, Argentina, and Chile, the mean number of headache days per month fell from 23.6 at baseline to 9.8. Days of acute drug therapy dropped in sync.

Moreover, quality of life as assessed using the MIDAS (Migraine Disability Assessment Score) scale improved from 59.8 to 25.5. The mean HADS (Hospital Anxiety and Depression Scale) depression score fell from 6.6 at baseline to 4.1, while the HADS anxiety score dropped from 9.3 to 7.1. All of these differences were statistically significant and clinically meaningful, commented Dr. Bendsten of the University of Copenhagen.

Dr. Tassorelli noted that detoxification in the COMOESTAS study could be carried out on either an inpatient or outpatient basis, depending upon local practice. The 6-month results were closely similar regardless of the detoxification setting, meaning that outpatient detoxification, which is vastly less expensive, is clearly the winning strategy.

The COMOESTAS protocol began with a day 1 detailed explanation of the vicious cycle of MOH and advice to the patient to abruptly stop the overused medication. Rescue medication could be employed on days 1-7 to combat withdrawal headaches, with the drug, dose, and route of administration to be chosen from a menu based upon the patient’s medical history and headache characteristics. Options included a variety of antiemetics, acetaminophen, and naproxen.

Preventive therapy was started within the first 7 days. The options were propranolol, atenolol, metoprolol, valproic acid, topiramate, candesartan, flunarizine, or amitriptyline. The selection was based upon comorbid conditions, patient preference, and side effect profiles.

Acute headache medication was permitted beginning on day 8 for a maximum of 2 days per week. The inviolable rule was that patients could not use the same drug that was previously overused.

Elsewhere at the conference, European Headache Federation president and COMOESTAS coinvestigator Dr. Rigmor Højland Jensen diverged from providing an update on the therapeutic pipeline for migraine to draw special attention to the importance of detoxifying patients with MOH.

"This is something we can do starting Monday morning. We don’t have to have a bag full of new drugs. We can do a lot for these patients now," said Dr. Jensen, professor of neurology at the University of Copenhagen.

The COMOESTAS project is funded by the European Commission. The investigators reported having no financial conflicts.

b.jancin@elsevier.com

LONDON – A simple, straightforward protocol for management of medication-overuse headache has established its clinical utility in the large joint European/Latin American COMOESTAS study.

"These findings confirm the efficacy, the usability worldwide, and the low economic cost of detoxifying patients with medication-overuse headache," Dr. Cristina Tassorelli said in presenting the COMOESTAS data at the European Headache and Migraine Trust International Congress.

The protocol utilized in COMOESTAS (continuous monitoring of medication-overuse headache in Europe and Latin America: development and standardization of an alert and decision support system) consists of abrupt detoxification, patient education, early initiation of individualized prophylactic therapy, and regular scheduled follow-up by one dedicated physician guided by electronic support. Patients maintain an electronic medical diary which automatically signals their physician if they begin to slide down the slope toward relapse, explained Dr. Tassorelli, a neurologist at the University of Pavia (Italy).

Medication-overuse headache (MOH) is a common and disabling condition. It affects 1%-3% of the general population and 20%-60% of patients in specialized headache clinics. It occurs when patients with chronic headache, most often migraine without aura, experience a worsening of their headaches and respond by using more and more acute medication – triptans and/or NSAIDs – which in turn paradoxically exacerbates their headache pattern. MOH is defined by the occurrence of headache on at least 15 days/month coupled with use of triptans on 10 or more days/month or NSAIDs on at least 15 days/month.

MOH is treatable via detoxification but typically has a relapse rate of 30%-40% within the following 6 months. The COMOESTAS protocol, in contrast, had a 6-month relapse rate of 10%.

The COMOESTAS protocol for MOH was devised by expert consensus. It is designed as a first-line intervention for MOH patients who are detoxification-naive.

"Three-quarters of first timers will do well with this approach. It’s a good tool for stratifying patients: If they relapse, then they need a more intensive multidisciplinary approach," Dr. Tassorelli explained.

In a separate presentation, COMOESTAS coinvestigator Dr. Lars Bendsten reported that the management protocol proved successful not only in terms of the primary outcome measures of reduced headache frequency and fewer days per month of acute medication use but also from the standpoint of reduced depression, anxiety, and disability along with improved quality of life.

Among 519 COMOESTAS participants who completed 6 months of follow-up at centers in Spain, Italy, Denmark, Germany, Argentina, and Chile, the mean number of headache days per month fell from 23.6 at baseline to 9.8. Days of acute drug therapy dropped in sync.

Moreover, quality of life as assessed using the MIDAS (Migraine Disability Assessment Score) scale improved from 59.8 to 25.5. The mean HADS (Hospital Anxiety and Depression Scale) depression score fell from 6.6 at baseline to 4.1, while the HADS anxiety score dropped from 9.3 to 7.1. All of these differences were statistically significant and clinically meaningful, commented Dr. Bendsten of the University of Copenhagen.

Dr. Tassorelli noted that detoxification in the COMOESTAS study could be carried out on either an inpatient or outpatient basis, depending upon local practice. The 6-month results were closely similar regardless of the detoxification setting, meaning that outpatient detoxification, which is vastly less expensive, is clearly the winning strategy.

The COMOESTAS protocol began with a day 1 detailed explanation of the vicious cycle of MOH and advice to the patient to abruptly stop the overused medication. Rescue medication could be employed on days 1-7 to combat withdrawal headaches, with the drug, dose, and route of administration to be chosen from a menu based upon the patient’s medical history and headache characteristics. Options included a variety of antiemetics, acetaminophen, and naproxen.

Preventive therapy was started within the first 7 days. The options were propranolol, atenolol, metoprolol, valproic acid, topiramate, candesartan, flunarizine, or amitriptyline. The selection was based upon comorbid conditions, patient preference, and side effect profiles.

Acute headache medication was permitted beginning on day 8 for a maximum of 2 days per week. The inviolable rule was that patients could not use the same drug that was previously overused.

Elsewhere at the conference, European Headache Federation president and COMOESTAS coinvestigator Dr. Rigmor Højland Jensen diverged from providing an update on the therapeutic pipeline for migraine to draw special attention to the importance of detoxifying patients with MOH.

"This is something we can do starting Monday morning. We don’t have to have a bag full of new drugs. We can do a lot for these patients now," said Dr. Jensen, professor of neurology at the University of Copenhagen.

The COMOESTAS project is funded by the European Commission. The investigators reported having no financial conflicts.

b.jancin@elsevier.com

LONDON – The drug development pipeline for migraine holds numerous promising new classes of medications addressing novel therapeutic targets – and that’s welcome news because recent surveys indicate a substantial proportion of migraineurs aren’t satisfied with their current options for acute treatment and prophylaxis.

However, most of the novel agents are in only phase II studies. And snares abound on the path ahead to the marketplace, as recent history demonstrates.

The pharmaceutical industry seems less enthusiastic overall about developing new drugs for headache now than it was 15 years ago. It’s a shame because an enormous underserved market exists for new agents that can offer the triad of efficacy, convenience, and tolerability, Dr. Rigmor Højland Jensen said at the European Headache and Migraine Trust International Congress.

A chill was cast over the field of headache treatment development last year when Merck abruptly announced a halt to further development of telcagepant, a previously highly promising, first-in-class calcitonin gene-related peptide (CGRP) antagonist, after elevated liver enzymes emerged as a concern in analysis of a completed phase III randomized clinical trial, she said.

CGRP plays a key role in neurovasoconstriction. The promise of the CGRP antagonists for short-term treatment of migraine is that they will provide the cerebral vasodilatory efficacy of the triptans without the cardiovascular side effects. However, the future post-telcagepant remains uncertain for other agents in this class, including Boehringer Ingelheim’s olcegepant as well as other CGRP antagonists in phase II studies being developed by Bristol-Myers Squibb, Eli Lilly, and Merck, noted Dr. Jensen, president of the European Headache Federation and professor of neurology at the University of Copenhagen.

Meanwhile, the development of highly selective antibodies to CGRP looks very promising, although these agents are still in the preclinical stage.

Dr. Jensen said surveys indicate roughly 40% of patients with migraine are unhappy with the triptans and simple analgesics used as first-line short-term therapy, either because of lack of efficacy or side effects. Moreover, the current options for migraine prophylaxis leave much to be desired.

"We don’t know how prophylaxis works. It’s nonspecific, often ineffective, and has side effects. We really need good prophylactics without side effects," Dr. Jensen said.

The drug furthest along in development for acute migraine is oral lasmiditan, a selective serotonin 5-hydroxytryptamine 1F receptor antagonist with no vascular effects. Lasmiditan, being developed by CoLucid Pharmaceuticals, is currently in phase III trials.

"This one is just around the corner," according to the neurologist.

In a recent phase II study, lasmiditan showed an excellent response rate 2 hours after administration, with no vasoconstriction (Lancet Neurol. 2012;11:405-13).

Nitric oxide synthase (NOS) has emerged as a promising new nonvascular target for acute migraine therapy. NeurAxon, a Canadian company, has developed a first-in-class selective inhibitor of the neuronal form of NOS, which modulates the central and peripheral response to pain and neuronal sensitization.

In a recent randomized, placebo-controlled phase II study of 179 patients with migraine without aura, this agent, known for now as NXN-188, produced prolonged pain relief that became significant beginning 3 hours after administration and remained so for 24 hours even though rescue medication wasn’t permitted. The side effect profile was reassuringly benign.

Other companies have developed selective inhibitors of the inducible form of NOS, which is released by macrophages. Inducible NOS participates in the immune response to stress and inflammation, making it another attractive target for acute migraine therapy, Dr. Jensen continued.

Turning to emerging agents for migraine prophylaxis, she highlighted several novel drugs now in phase II studies: DP-VPA, a valproic acid prodrug being developed by the Israeli company D-Pharm; a botanically sourced compound, MGX-008, that comes from the bark of the Monterey pine and is under development by Migco; an oral leukotriene D₄ receptor antagonist backed by Lilly; and lacosamide, also known as BGG492, an AMPA/kainate glutamate receptor antagonist under development by Novartis.

In addition, a couple of very familiar drugs – the angiotensin receptor blocker candesartan and the muscle relaxant cyclobenzaprine – are now in phase III trials for migraine prevention.

Dr. Jensen reported serving on the advisory boards for ATI, Medotech, Neurocore, and Linde Gas and on the speakers bureaus for Pfizer, Merck, and NorPharma.

LONDON – The drug development pipeline for migraine holds numerous promising new classes of medications addressing novel therapeutic targets – and that’s welcome news because recent surveys indicate a substantial proportion of migraineurs aren’t satisfied with their current options for acute treatment and prophylaxis.

However, most of the novel agents are in only phase II studies. And snares abound on the path ahead to the marketplace, as recent history demonstrates.

The pharmaceutical industry seems less enthusiastic overall about developing new drugs for headache now than it was 15 years ago. It’s a shame because an enormous underserved market exists for new agents that can offer the triad of efficacy, convenience, and tolerability, Dr. Rigmor Højland Jensen said at the European Headache and Migraine Trust International Congress.

A chill was cast over the field of headache treatment development last year when Merck abruptly announced a halt to further development of telcagepant, a previously highly promising, first-in-class calcitonin gene-related peptide (CGRP) antagonist, after elevated liver enzymes emerged as a concern in analysis of a completed phase III randomized clinical trial, she said.

CGRP plays a key role in neurovasoconstriction. The promise of the CGRP antagonists for short-term treatment of migraine is that they will provide the cerebral vasodilatory efficacy of the triptans without the cardiovascular side effects. However, the future post-telcagepant remains uncertain for other agents in this class, including Boehringer Ingelheim’s olcegepant as well as other CGRP antagonists in phase II studies being developed by Bristol-Myers Squibb, Eli Lilly, and Merck, noted Dr. Jensen, president of the European Headache Federation and professor of neurology at the University of Copenhagen.

Meanwhile, the development of highly selective antibodies to CGRP looks very promising, although these agents are still in the preclinical stage.

Dr. Jensen said surveys indicate roughly 40% of patients with migraine are unhappy with the triptans and simple analgesics used as first-line short-term therapy, either because of lack of efficacy or side effects. Moreover, the current options for migraine prophylaxis leave much to be desired.

"We don’t know how prophylaxis works. It’s nonspecific, often ineffective, and has side effects. We really need good prophylactics without side effects," Dr. Jensen said.

The drug furthest along in development for acute migraine is oral lasmiditan, a selective serotonin 5-hydroxytryptamine 1F receptor antagonist with no vascular effects. Lasmiditan, being developed by CoLucid Pharmaceuticals, is currently in phase III trials.

"This one is just around the corner," according to the neurologist.

In a recent phase II study, lasmiditan showed an excellent response rate 2 hours after administration, with no vasoconstriction (Lancet Neurol. 2012;11:405-13).

Nitric oxide synthase (NOS) has emerged as a promising new nonvascular target for acute migraine therapy. NeurAxon, a Canadian company, has developed a first-in-class selective inhibitor of the neuronal form of NOS, which modulates the central and peripheral response to pain and neuronal sensitization.

In a recent randomized, placebo-controlled phase II study of 179 patients with migraine without aura, this agent, known for now as NXN-188, produced prolonged pain relief that became significant beginning 3 hours after administration and remained so for 24 hours even though rescue medication wasn’t permitted. The side effect profile was reassuringly benign.

Other companies have developed selective inhibitors of the inducible form of NOS, which is released by macrophages. Inducible NOS participates in the immune response to stress and inflammation, making it another attractive target for acute migraine therapy, Dr. Jensen continued.

Turning to emerging agents for migraine prophylaxis, she highlighted several novel drugs now in phase II studies: DP-VPA, a valproic acid prodrug being developed by the Israeli company D-Pharm; a botanically sourced compound, MGX-008, that comes from the bark of the Monterey pine and is under development by Migco; an oral leukotriene D₄ receptor antagonist backed by Lilly; and lacosamide, also known as BGG492, an AMPA/kainate glutamate receptor antagonist under development by Novartis.

In addition, a couple of very familiar drugs – the angiotensin receptor blocker candesartan and the muscle relaxant cyclobenzaprine – are now in phase III trials for migraine prevention.

Dr. Jensen reported serving on the advisory boards for ATI, Medotech, Neurocore, and Linde Gas and on the speakers bureaus for Pfizer, Merck, and NorPharma.

LONDON – The drug development pipeline for migraine holds numerous promising new classes of medications addressing novel therapeutic targets – and that’s welcome news because recent surveys indicate a substantial proportion of migraineurs aren’t satisfied with their current options for acute treatment and prophylaxis.

However, most of the novel agents are in only phase II studies. And snares abound on the path ahead to the marketplace, as recent history demonstrates.

The pharmaceutical industry seems less enthusiastic overall about developing new drugs for headache now than it was 15 years ago. It’s a shame because an enormous underserved market exists for new agents that can offer the triad of efficacy, convenience, and tolerability, Dr. Rigmor Højland Jensen said at the European Headache and Migraine Trust International Congress.

A chill was cast over the field of headache treatment development last year when Merck abruptly announced a halt to further development of telcagepant, a previously highly promising, first-in-class calcitonin gene-related peptide (CGRP) antagonist, after elevated liver enzymes emerged as a concern in analysis of a completed phase III randomized clinical trial, she said.

CGRP plays a key role in neurovasoconstriction. The promise of the CGRP antagonists for short-term treatment of migraine is that they will provide the cerebral vasodilatory efficacy of the triptans without the cardiovascular side effects. However, the future post-telcagepant remains uncertain for other agents in this class, including Boehringer Ingelheim’s olcegepant as well as other CGRP antagonists in phase II studies being developed by Bristol-Myers Squibb, Eli Lilly, and Merck, noted Dr. Jensen, president of the European Headache Federation and professor of neurology at the University of Copenhagen.

Meanwhile, the development of highly selective antibodies to CGRP looks very promising, although these agents are still in the preclinical stage.

Dr. Jensen said surveys indicate roughly 40% of patients with migraine are unhappy with the triptans and simple analgesics used as first-line short-term therapy, either because of lack of efficacy or side effects. Moreover, the current options for migraine prophylaxis leave much to be desired.

"We don’t know how prophylaxis works. It’s nonspecific, often ineffective, and has side effects. We really need good prophylactics without side effects," Dr. Jensen said.

The drug furthest along in development for acute migraine is oral lasmiditan, a selective serotonin 5-hydroxytryptamine 1F receptor antagonist with no vascular effects. Lasmiditan, being developed by CoLucid Pharmaceuticals, is currently in phase III trials.

"This one is just around the corner," according to the neurologist.

In a recent phase II study, lasmiditan showed an excellent response rate 2 hours after administration, with no vasoconstriction (Lancet Neurol. 2012;11:405-13).

Nitric oxide synthase (NOS) has emerged as a promising new nonvascular target for acute migraine therapy. NeurAxon, a Canadian company, has developed a first-in-class selective inhibitor of the neuronal form of NOS, which modulates the central and peripheral response to pain and neuronal sensitization.

In a recent randomized, placebo-controlled phase II study of 179 patients with migraine without aura, this agent, known for now as NXN-188, produced prolonged pain relief that became significant beginning 3 hours after administration and remained so for 24 hours even though rescue medication wasn’t permitted. The side effect profile was reassuringly benign.

Other companies have developed selective inhibitors of the inducible form of NOS, which is released by macrophages. Inducible NOS participates in the immune response to stress and inflammation, making it another attractive target for acute migraine therapy, Dr. Jensen continued.

Turning to emerging agents for migraine prophylaxis, she highlighted several novel drugs now in phase II studies: DP-VPA, a valproic acid prodrug being developed by the Israeli company D-Pharm; a botanically sourced compound, MGX-008, that comes from the bark of the Monterey pine and is under development by Migco; an oral leukotriene D₄ receptor antagonist backed by Lilly; and lacosamide, also known as BGG492, an AMPA/kainate glutamate receptor antagonist under development by Novartis.

In addition, a couple of very familiar drugs – the angiotensin receptor blocker candesartan and the muscle relaxant cyclobenzaprine – are now in phase III trials for migraine prevention.

Dr. Jensen reported serving on the advisory boards for ATI, Medotech, Neurocore, and Linde Gas and on the speakers bureaus for Pfizer, Merck, and NorPharma.