1. Chronic Daily Headaches & Medication Overuse Headache Diagnosis and Management
4th Biennial Hull-BASH Headache Meeting
Jan 20th 2011
Dr Brendan Davies
North Midlands Regional Headache Clinic
University Hospital of North Staffordshire

2. Frequent Headaches (or Chronic Daily headache)
A headache syndrome (not a diagnosis) characterised by
Headache present on more than 15 days per month for at least 3 months duration
= >180 days per year,
~ 50% of the time!
4-5% of the general population
30-80% of clinic populations
Several possible causes
Chronic daily headache
A Headache syndrome characterised by
 Which occurs on at least 15 out of 30 days in any one month.
This equates to 180 days per year
 Which has occurred at that frequency for at least 6 months
 |Several possible causes (Not all tension type headache!!!)

3. Chronic daily headache prevalence
USA, Spain, Greece, Italy, China
Population studies - 4%-5%
Women > Men
(Adapted from Castillo et al., 1999 and Guitera et al., 1999)

4. Recognition of the Problem is the first step !!
Recognition of the problem is the first step towards successful management.
Recognition of the Problem is the first step !!

5. Chronic Daily headache - Subtypes
Primary Headache disorders
Secondary Headache disorders
Paroxysmal Headache
Attack Duration < 4 hours +/or
Discrete episodes
Long lasting Headache
Daily or near daily headache
Duration > 4 hours per day
With or without medication overuse
Chronic Migraine
Chronic Tension-type headache
Hemicrania Continua
New Daily Persistent headache
Adapted from Silberstein et al., Neurology (1996) 47: 871-

6. The FrHE Study Case control and cohort analyses identified
FrHE=Frequent Headache Epidemiology Study
Scher AI et al. Pain. 2003;106:81-89.
Case control and cohort analyses identified
Independent risk factors for CDH
Not readily modifiable Potentially modifiable
Migraine Attack frequency
Female Gender Obesity
Low education/socioeconomic status Medication overuse
Head injury Stressful life events
Snoring (sleep apnea, sleep disturbance)
Key Point: Some of the risk factors for CDH, such as attack frequency
and obesity, are modifiable.
The incidence of chronic daily headache is 3 per 100 person-years, meaning 3% of the general population will develop chronic daily headache over the next year
Case control and cohort analyses have identified risk factors for chronic daily headache. There are risk factors that are not readily modifiable and there are risk factors that are readily modifiable
Inherited genetic predisposition for migraine, or being female, or education or social economic status, or a history of head injury can not be modified
Attack frequency, obesity, and medication overuse may be modified through clinical interventions. Response to stressful life events may also be addressed by appropriate means
Physicians paying attention to these factors in patients with frequent headaches may help modify them to prevent development of chronic daily headache. They also may be risk factors that, if modified, may increase the remission rate of chronic daily headache, with the patients reverting to episodic headache
Scher AI, Stewart WF, Ricci JA, Lipton RB. Factors associated with the onset and remission of chronic
daily headache in a population-based study. Pain. 2003;106:81-89.

7. The Scope of the Problem Primary CDH Epidemiology Pascual, Colas and Castillo. Current Pain & Headache Reports 2001
USA & European studies
Prevalence Population HA Clinic
New Daily Persistent Headache 0.1% 20%
Chronic Migraine* 2% %
Chronic Tension Type headache 2-3% %
Hemicrania Continua ? ?
With associated Medication Overuse 0.5-1% 30 < 80%
* = previous term Transformed in some studies

8. Consultations for headache with emergency healthcare practitioners: chronic vs episodic migraine
Varon SF et al. Poster 14th International Headache Congress, 2009, USA.
Pooled
5.4
Episodic migraine
Chronic migraine
9.0 US
3.5
5.8
3.5
Canada
5.5
Germany
4.8
7.7 UK
3.4
14.0
France
2.3
1.8
Italy
7.0
5.5
Spain
14.7
23.2
Notes
Chronic migraine is characterised by high frequency of migraine days – as frequency increases, so does the cost of care.1
Patients are more likely to consult their primary care physician or neurologist due to the disabling nature of their disorder.1
People with chronic migraine are more likely than those with episodic migraine to visit the emergency department and be hospitalised.2
People with chronic migraine are also more likely to use additional healthcare resources compared with those with episodic migraine.1
References
Blumenfeld AM et al. Cephalalgia 2010 (published online 2 September 2010; doi: / )
Varon SF et al. Poster presented at the 14th International Headache Congress, September 10– , Philadelphia, PA, USA.
Austrialia
10.4
10.9
Taiwan
6.2
12.5 5%
10%
15%
20%
25%
Proportion of patients consulting an emergency healthcare professional in the last 3 months 8

9. How does Chronic Daily Headache start ?
De novo (Acute?) headache onset
NDPH
Headache Free before daily headache
Headache severity
Time
Evolving CDH
Time

10. New Daily Persistent Headache (NDPH) The IHS (2004) Definition
A daily headache with onset over < 3 days
Unremitting from onset & persistent > 3 months
No Secondary cause
2 of: Bilateral headache
Pressure/ tight (Non-pulsating)
Mild-moderate
Not worsened by physical activity
<1 of: Photophobia, phonophobia & mild nausea

11. New Daily Persistent Headache “De novo headache” or “CDH with acute onset”
A more useful concept ?
A “ a headache syndrome” needing investigation to exclude secondary causes that guide specific treatments
A new headache problem having previously been “Headache free” implies a potentially new pathophysiological process ?
Highlights the need to consider/exclude a possible
2° headache disorders (NDPH mimics) before diagnosis

12. A daily unremitting headache syndrome Initial onset over < 3 days
Persistent for > 3/12
* All may have abrupt onset

13. NDPH - Clinical Features
“Classically” - Patient remembers the day & date the headache started & the circumstances
Prompts investigation for secondary causes?
Not usually Unilateral – Think of alternatives
TACs & Hemicrania Continua if ANS symptoms
Temporal Arteritis, Intracranial lesions in elderly etc
Cervicogenic headache?
1○ NDPH
“Feature-Full” Migrainous or “FeatureLess” TTH
“Benign vs. Refractory forms”
Robbins et al Neurology April 74;
71 patients over 4 years: 45% NON-MIGRAINOUS – 55% MIGRAOINOUS SYMPTOMS
30% recalled the specific onset day; 80% the specific month or day
1/3 only recall a triggering event; 10% recall a viral flu like illness or URT infection
1 in 4 had Past History of primary headache
½ had family History of frequent headaches
Most common onset month March & Sept in this series
80% reported Bilateral headache
1/3 triptan responsive
Prognosis: 15% Remit months Median 21 months
¾ had persistent symptoms; >50% more than 2 years
Median duration if Migrainous = 31 months
Aetiology: Post-Infectious?
Acute onset Migraine 13

14. Diagnostic Studies in NDPH if Suspected Low CSF volume/pressure
Always ask about effect of posture & otological symptoms?
CT Brain Normal !! “Beware” Bilateral Subdurals?
CSF Pressure < 60mm H20 ? (but can be normal!)
Normal glucose but may -  WCC,  Protein,  RBC
Gd-DTPA is investigation
of choice
Diffuse linear Non-nodular
Pachymeningeal enhancement
Tonsillar descent & Brain sagging
Bilateral subdural

15. Recognition of Migraine The IHS criteria 2004 > 90% specificity
5 Headache attacks lasting 4 < 72 hours
with at least 2 of:
Unilateral
Pulsating
Moderate or severe
Worsened by +/or avoidance
of physical activity
and at least 1 of
Nausea +/or vomiting
 Light sensitivity
 Noise sensitivity
IHCD II Classification 2004 Cephalagia Vol 24; Suppl 1 15

16. Chronic migraine development
Infrequent episodic migraine “transforms” into frequent migraine
With or without medication overuse
Analgesics overused by 65%
Background daily headache
Time months/years
H/A intensity 10
Migraine attack
& migraine attack
Primary CDH
The majority of patients with headache that persists have a primary headache syndrome.
92% of chronic daily headache was previously episodic
The most common antecedent episodic headaches that transform into chronic daily headache are:
1. Migraine at 72%, followed by
2. Episodic tension type headache at20%, then
3. New daily persistent headache at 8%.
65% of patients with chronic daily headache overuse analgesics or ergots.
Clinical features of headache resemble those of initial episodic primary headache apart from frequency
This implies a common pathophysiological state.
Overusing painkillers?

17. Chronic Migraine The IHS 2006 Revised Classification
previously Triptan/Ergot responsive?
Headache on > 15 days month
with
features of Migraine type headache
On > 8 days / month*
for > 3 months
without other cause
of headache
*ICHD-2 = Previously >15
With or without Analgesic Medication Overuse Headache?

18. 1 year longitudinal follow-up study
450 headache sufferers (Migraine +/- Tension type)
14% developed CDH from an initial intermittent pattern (mean 7 days/month) baseline
1/3 were not overusing medication
Odds Ratio
Factors implicated: High initial headache frequency
Medication Overuse
Moderate initial HA frequency

19. Tips for recognising Chronic Migraine
History of episodic headache in earlier life?
Insidious onset of frequent or daily headache
“Background headache with worsening”
Worse Headache episodes
Migrainous
Often triggered by recognised by migraine triggers
May be triptan responsive
Family history of migraine?
& No “red flag” features

21. Chronic Migraine Comorbidities
Mental Health Disorders
Zwart et al., 2003; Buse et al., 2010
Depression
Generalised Anxiety Disorder
Bipolar disorder
Chronic Musculoskeletal pain
Hagen et al., 2002; Buse et al., 2010
Restless Legs Syndrome & Sleep Disoders
Rhode et al., 2007; Chen et al., 2010
Thanks to Dr David Kernick for graphic

22. Clinical trial data for preventive pharmacotherapy in “chronic migraine”
Evidence for use in chronic migraine
Anticonvulsants:
Valproate Topiramate Gabapentin
Small double-blind, placebo-controlled trials in CM1,2 Double-blind, placebo-controlled trials in CM3,4 One double-blind, placebo-controlled trial in CDH5
Botox
Double-blind, placebo-controlled trials in CM 10-12
Antidepressants:
Amitriptyline Fluoxetine
Small open-label trial in TM6 Small double-blind treatment, placebo-controlled trial in CDH7
Alpha-2-adrenergic agonist:
Tizandine
Small double-blind treatment, placebo-controlled trial in CDH8
Glutamate NMDA Antagonists:
Memantine
Small open-label trial9
Beta-blockers
No evidence that they are effective in CM
Serotonergic modulators
Calcium channel blockers
ACE inhibitors and ARBs
Potential problems with the evidence
Lack of controlled trials
Lack of placebo control
Difficult to extract relevant data
Failure to classify CDH subtype in trials
Failure to separate Medication overuse patients
Case reports
Open Label studies No. Pts
Gabapentin
Valproate
Amitryptiline
Tizanadine
Memantine
Randomized Controlled Trials
Topiramate
Botox. inj.– 2009
Occipital Nerve stimulation 2009
Notes
There is evidence for the use of many treatments as first line in episodic migraine,1,2 but few clinical trials have focused on chronic migraine specifically and there are no treatment guidelines available.
Randomised trials of the use of preventive medications in chronic migraine are scarce, and available studies are limited by small numbers of patients.3
Only a few pharmacological options have been tested in randomised, double-blind, placebo-controlled studies or active comparator-controlled trials and these include amitriptyline, topiramate, gabapentin, tizanidine, valproate, and fluoxetine.4
References
1. Silberstein SD. Neurology 2000;55:754–762.
2. Evers S et al. Eur J Neurol 2006;13:560–572.
3. Vargas BB, Dodick DW. Neurol Clin 2009;27:467–479.
4. Yurekli VA et al. J Headache Pain 2008;9:37–41.
1. Yurekli VA et al. J Headache Pain 2008;9:37–41.
2. Bartolini M et al. Clin Neuropharmacol 2005;28:277–279.
3. Diener HC et al. Cephalalgia 2007;27:814–823.
4. Silberstein SD et al. Headache 2007;47:170–180.
5. Spira PJ, Beran RG. Neurology 2003;61:1753–1759.
6. Krymchantowski AV et al. Headache 2002;45:510–514.
7. Saper JR et al. Headache 1994;34:497–502.
8. Saper JR et al. Headache 2002;42:470–482.
9. Bigal M et al., Headache 2008; 48;
10. Diener HC et al., Cephalalgia Jul;30(7):804-14
11. Aurora SK et al., Cephalalgia Jul;30(7):
12. Dodick DW et al., Headache Jun;50(6):921-36 22

23. Analgesic Medication Use
1-3 % of the population take analgesics on a regular basis
7% take analgesics at least 1x/wk
Medication overuse is defined as the use of an acute attack treatment on more than two days a week on a regular basis.
The dose taken usually escalates over time.
1-3% of the general population take analgesics on a daily basis.
7% take analgesics up to once a week.

24. Medication Overuse Headache IHS 2004 & revised 2005 Classification
Chronic daily headache >15 days/month for >3 months
Regular intake for > 3 months of
And return to Pre-overuse pattern with
cessation of Overuse
Triptan or ergot medication > 10 days / month
Opiate or Combination analgesics > 10 days / month
Simple Analgesics or combinations of above > 15 days month*
1-3 % of the population take analgesics on a regular basis
7% take them up to once per week
Commonest OTC medications
Syndol / Solpadeine / Ultramol / Anadin Xtra
Migraleve & caffeine & opiate preparations
* 15 = consensus figure rather than evidence based

25. Medication Overuse Headache Clinical Features
Katsarvara et al, Drug Safety, 2001; 24:
Characteristics may vary
Usually dull, generalised
Early morning worsening
May differ depending on the drug being overused
Triptans  Daily migrainous headache
Analgesics  Diffuse featureless headache
Ergots  Diffuse pulsating headache
There is a drug dependent rhythmicity of headaches.
Predictable early morning headaches are frequent which typically come on between the hours of 2 and 5 am.
Many patients take medication in anticipation of headache because of a fear of pain.
Patients will often have an underlying headache disorder for which they have received treatment and there is frequent use or overuse of these treatments.
Some symptoms are side effects of the overused drug, for example tachycardia, cold extremities and parasthesias with ergotamine derivatives.

26. Chronic Migraine and Medication Overuse headache (MOH)
45-70% sufferers of chronic primary headache experience
> 50% improvement in headache with analgesic withdrawal
Bigal et al., Cephalagia (2004) 24; 483-; Zeeberg et al, Neurology (2006) 66; 1894-
“In the absence of data it is generally accepted that patients are refractory to prophylactic medication while overusing analgesic medications and that they become responsive after analgesic medication withdrawal”

27. Does medication overuse matter? Topiramate in Chronic Migraine
Reduction in headache days
What does this trial tell us about therapy in Chronic Migraine +/- MOH
Treatment reduced migraine days
similarly in MOH & Non-MOH patients
Does MOH really limit efficacy in Chronic Migraine?
Effect size
i.e > 50% REDUCTION IN HEADACHE FREQUENCY
in MOH only 20% compared to 50% in pivotal trials? * **
(* P < 0.02; ** P < 0.03)

28. Does Medication Overuse always reduce efficacy ?
PREEMPT pooled efficacy of BOTOX® in medication overuse subgroup* at week 24
Change in frequency from baseline
Headache days/mth†
Moderate/severe headache days
Migraine days -1 -2 -3 -4
Improvement
Number of days -5 -6
-5.7
-6.2 -6
Notes
Patients with chronic migraine who were overusing acute headache pain medications during the 28-day baseline screening period of PREEMPT were designated as “medication overuse–yes” (MedO–yes) using the patient’s baseline diary.1
Patients in the MedO–yes subgroup had taken acute headache medications at least 2 times per week, with intake over at least 15 days for simple analgesics and/or intake over at least 10 days for other medications.1
Acute medications included simple analgesics, ergotamine/dihydroergotamine (DHE), triptans, opioids, combination analgesics or any combination of the above classes.1
BOTOX® significantly improved several headache symptoms within the MedO–yes subgroup over placebo, including the primary efficacy variable: reduction in frequency of headache days (p<0.001).1
Reference
1. Silberstein SD et al. Poster presented at: 14th International Headache Congress, September 10-13, 2009, Philadelphia, PA. -7 -8
BOTOX® (n=445)
Placebo (n=459)
-7.7‡
-8.2‡
-8.1‡ -9
-10
*Of the total pooled PREEMPT population, 64.8% and 66.1% of BOTOX® and placebo groups, respectively, overused acute headache pain medication (simple analgesics, ergotamine/DHE, triptans, opioids, combination of analgesics or any combination of the preceding classes).
†Headache days are reported as headache days per 28 days; change in frequency of headache days was the primary endpoint of the pooled analysis. ‡p<0.001.
Silberstein SD et al. IHC 2009.
Dodick DW et al., Headache Jun;50(6):921-36 28

29. Analgesic Overuse Cessation improves Headache frequency & Drug responsiveness
Tertiary referral centre study – n=175
Refractory CDH population with MOH
55% with migraine
Previously refractory to 1-5 migraine preventatives
% of individuals became responsive to Migraine preventatives post MOH treatment
(8 month mean follow-up)

30. What is the most effective strategy for initial MOH management?
Chronic Migraine & Medication Overuse Headache “Management controversies?”
What is the most effective strategy for initial MOH management?

31. MOH can be effectively managed initially as an OPD in most cases
Excluded Psychiatric comorbidity & Opiate or benzo overuse or serios systemic conditoon
OPD Advice & NSAIDs vs
OPD Advice & NSAIDs, Prednisalone & Preventative
Inpatient Advice & NSAIDs Prednisalone & Preventative & iv Fluids, iv Anti-emetics
85% responders/  2/3 reduction in headache frequency

32. Rebound Headache & “Pain killer rebound symptoms” (Katsarava et al, Neurology, 2002)
Headache intensity worsens at day 2-4 before improvement
Headache gets worse before better
in at least 70%
Withdrawal symptoms
Nausea, vomiting
Autonomic activation
Sleep disturbance & agitation
Mean Duration & severity determined by overused drug class
Triptans  4 days (85%)
Ergots  7 days (57%)
Analgesics  9-10 days + ( 23%)
Withdrawal of the offending medication is the appropriate management of medication overuse headache but this will result in a rebound worsening of headache in around 70% of patients. The headache usually worsens by day 2-4 of withdrawal before improvement is seen.
There may also be other symptoms in the withdrawal period such as nausea, vomiting, autonomic symptoms and sleep disturbances or agitation.
The duration and severity of withdrawal differs depending upon the class of drug being removed. Although the triptans can cause MOH more quickly and at lower doses than the other drugs, the withdrawal period is also shorter
The management of MOH may take place in either an in- or out-patient setting.
14 day outcome: 85% > 57% > 23% for Triptans vs Ergots vs Analgesics

33. Prednisolone for Medication Overuse withdrawal headache?
DB RCT n = 100 (65 with CM)
Prednisolone 60mg taper over 6 days in MOH
No effect on withdrawal headache in placebo vs. active treatment group
Pilot DB RC n = 18 only
Prednisolone 100mg 5 days in MOH
50%  in moderate-severe rebound headache in 1st 72 hrs compared with placebo
Dose response?
Sample size?
Triptan only MOH?

34. The “Stop - Start Strategy” in MOH
OPD Based MOH withdrawal
Abrupt GP supervised Analgesic withdrawal for 4 weeks when on established prophylaxis
Worse before better !!!
Written Support protocol & patient education
Prednisolone Rescue option ?
Early follow-up – better outcome ?
Start early new Migraine Drug Prophylaxis – When? What?
Failed OPD withdrawal or no change in Headache
Review comorbidities again & Consider Inpatient strategy

35. * Multiple observational studies
Prognosis of MOH treatment Headache free +/or > 50% reduction in headache frequency
Withdrawal rates at 2 weeks
85%
57%
23%
Short term
20-85% @ 2-4 wks
6 months
Medium to long term
1 yr
 50% @ 5 yrs
In the short-term 20-80% of patients can be expected to have improved within 2 -4 weeks.
In the longer term around 50% will have continued improvement at 5 years.
Relapse rates remain high which emphasises the need for continued review, support and education.
* Multiple observational studies

36. Medication Overuse Headache
If 6-8 weeks after
acute analgesic medication withdrawal there is no improvement
The initial diagnosis of
Medication Overuse Headache
is not tenable
Review the Initial Diagnosis !

37. 1st described 1984 –Sjaastad & Speirings
Rare !!
93+ cases in world literature to 2001…..
Female > males 2-3:1
Onset 4th & 5th decade
No obvious triggers
c.f. Migraine

38. Hemicrania Continua “Women with constant Hemicrania tearing & nasal congestion”
(Daily) mild-moderate Strictly side-locked unilateral pain
Mild-moderate background intensity with exacerbations
Exacerbations associated with
Ipsilateral autonomic symptoms in up to ¾ patients
Minimal or Absent autonomic symptoms in up to 1/3
Photophobia, phonophobia & nausea in ~1/2
Absolute headache response to Indometacin treatment
Mean oral dosage <150mg / day (ensure tried up to 225mg)
+/- “ blinded Indotest”
Rare cause but very treatable cause of CDH/NDPH
Consider Indometacin trial in all with
new onset side locked especially refractory hemicrania

39. A pragmatic approach to Long lasting Primary Chronic Daily headache diagnosis
Bigal ME, Lipton RB. J Headache Pain 2007;8:263–272.
Chronic Daily Headache
Lasting ≥4 hours per day
Continuous strictly unilateral pain with autonomic features
Hemicrania continua
YES NO
Clear onset as a daily syndrome
New Daily Persistent Headache
YES
Associated symptoms define the CDH syndrome NO
Notes
If the frequency of the headache is 15 days or more per month and the duration is 4 hours or more a day, then a diagnosis of chronic daily headache is likely. A differential diagnosis of chronic daily headache then encompasses chronic migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua.1
The exclusion of secondary headache disorder should be made first, after which the differential diagnosis may proceed based on type of pain or onset of pain.1
Reference
Bigal ME, Lipton RB. J Headache Pain 2007;8:263–272.
Migraine or specific acute medications ≥8 days/month
Chronic Migraine
YES NO
Featureless holocranial Headaches with minimal impairment
YES
Chronic Tension-Type Headache

40. Need to know more about best practice in Headache management
Join BASH !!
&
Go & buy this book !!!

41. Questions? Chronic Daily Headache is a symptom & not a diagnosis
Accurate diagnosis determines both treatment choice & prognosis
Medication Overuse is ubiquitous and must always be considered
And more importantly properly addressed !!
Questions?

42. Backup slides

43. Chronic Refractory Migraine What do I do?
& possible “Horizon” therapies?

44. Short term Chronic migraine prevention by greater occipital nerve blockade
Occipital nerve blockade (ONB)
2% Lidocaine (2 ml) +/- 80 mg depo-medrone
Response rate: 50% for up to 1 month
Afridi et al. Pain 2006
Ashkenazi et al. JNNP 2007
AEs
local discomfort
alopecia (1-2%)
Shields et al., Neurology 2004
Open label outcome data Tobin & Flitman Headache 2009
108 ONB patients
No benefit in 20%

45. In-Patient Management of Chronic Migraine +/- MOH
When?
Failure of outpatient approach & significant impairment
Medication type +/or comorbidities
How?
Inpatient Supportive care
Hydration/drugs to combat withdrawal symptoms
iv Dihydroergotamine, i.v lidocaine
Steroids, Neuroleptics, Anti-emetics & Anxiolytics?
Clonidine or lofexidine if opiates
Identify & Treat Comorbidity
In some cases, in-patient care will be required, for example if the patient has other medical conditions or if out-patient management has failed.
Whilst on the ward, the causative medication will be stopped and supportive treatment given for withdrawal symptoms.
Again education is important and clinical psychology may be helpful to help tackle illness behaviour and provide coping strategies.

46. In-Patient Management of Medication Overuse Headache
When?
Failure of outpatient approach
Medication type +/or comorbidities
How?
Supportive care
Hydration/drugs to combat withdrawal symptoms
Clonidine if opiates
Anti-emetics & Neuroleptics
Iv Anti-nocioceptive drugs
i.v. Aspirin & iv Dihydroergotamine
i.v. AEDs
In some cases, in-patient care will be required, for example if the patient has other medical conditions or if out-patient management has failed.
Whilst on the ward, the causative medication will be stopped and supportive treatment given for withdrawal symptoms.
Again education is important and clinical psychology may be helpful to help tackle illness behaviour and provide coping strategies.

47. Intravenous Inpatient Therapies for Chronic Migraine at UHNS
Data on iv DHE inpatients at UHNS
42 patients audited
Age yrs
5 day iv therapy course
Most had failed on >3 preventatives
iv Dihydroergotamine (DHE)
Central 5HT receptor agonist
5HT 1A, 1B, 1D & 5HT2A & 2C Receptors
CGRP & Sub-P release blocked
α-Adrenergic antagonist
D1 &D2 receptor agonism
USA since 1986
Indications:
Status Migrainosis
Chronic Migraine +/- MOH
Refractory Chronic Cluster Headache
USA -Open label data
11/34 less than 25% benefit
21/34 > 50% improvement
5/34 headache resolution for up to 3 months
63% HAD SIDE EFFECTS
Nausea, diarrhorea, Abdo cramps

48. Comparison of side effects at UHNS with USA

50. Evidence based treatment of Chronic migraine
USA – 46 sites
N=328
Headache on >15 days/month
ICHD-2 Migraine criteria for at least 8 of these days
Excluded patients with MOH
Europe – 3 sites
N=59
MO > 12 day/month
Investigator initiated
UK, Germany, Italy
Included patients with MOH 50

51. Migraine/Migrainous Days
Change From Baseline in Monthly (28-day) Rate of Migraine/Migrainous Days
Silberstein SD et al. Headache 2007;47:170–180.
Primary Outcome
Migraine/Migrainous Days
Mean Change
From Baseline
Mean baseline ± SD
-6.4 ± 5.8
-4.7 ± 6.1
P = 0.010
17.1 ± 5.4
Topiramate
17.0 ± 5.0
Placebo
Topiramate Placebo
n = n = 163
Intent to treat, n (%) 153 (93) (94)
Completers, n (%) 92 (56) 90 (55)
Females (%)
Age (years)
Age at migraine onset (years)
Duration of CDH (years)
Baseline monthly (28-day) rate of migraine/migrainous
headaches (± SD) ± ± 5.0
Baseline monthly (28-day) rate of total headache days ± ± 4.6
Population Therapeutic gain
= 1.7 days
N=153 for topiramate and placebo groups.
P-value based on ANCOVA model including treatment and center as main effect, and baseline monthly migraine/migrainous or migraine days as covariates. 51

52. Responder Rates Patients (%) ≥30% ≥40% ≥50% P = 0.012 P = 0.031
Silberstein SD et al. Headache 2007;47:170–180.
Patients
(%)
≥30%
≥40%
≥50%
P = 0.012
P = 0.031
P = 0.093
Percent Reduction in Mean Monthly Migraine/Migrainous Days
(NB. - No adjustment for multiplicity) 52

53. Botulinum Toxin A in Chronic Migraine PREEMPT Studies
2 Trials: PREEMPT1 and PREEMPT 2
Phase 3, parallel-group, placebo-controlled studies of Botulinum toxin A U in Chronic Migraine
1384 patients randomised (Botulinum toxin A 688, Placebo 696)
31 injections per treatment session
CSR p89 Figure 11-2
Diener HC et al., Cephalalgia Jul;30(7):804-14
Aurora SK et al., Cephalalgia Jul;30(7):
Dodick DW et al., Headache Jun;50(6):921-36 53

54. Botulinum Toxin A in Chronic Migraine PREEMPT 1 & 2 Studies pooled analysis Mean change from baseline in frequency of headache days
Double-blind phase:
BOTOX® vs. placebo
Open-label phase:
All patients on BOTOX®
Study week
At Week 24
BOTOX® treated patients
Mean 8.4 fewer headache days/month
vs. 6.6 with placebo (p<0.001)1,2 4 8 12 16 20 24 28 32 36 40 44 48 52 56
BOTOX® (n=688)
Placebo (n=696) -2 -4
Mean change in frequency of headache days from baseline (days/28-day period) -6
p<0.001 -8
p<0.001
Notes
In the double-blind phase of PREEMPT, both patient groups experienced large reductions in the frequencies of almost all the key variables evaluated, including the primary PREEMPT endpoint: reduction in frequency of headache days.1 Mean reductions from baseline in frequencies in the BOTOX® group were statistically significantly greater than those in the placebo group.
During the open-label phase, when all patients were treated with BOTOX®, the 95% confidence interval (CI) indicated that there were statistically significant within- group improvements from baseline at all time points for frequency of headache days
(Week 24 95% CIs: BOTOX®/BOTOX® –8.9, –7.92; placebo/BOTOX® –7.07, – 6.08.
Week 56 95% CIs: BOTOX®/BOTOX® –12.17, –11.20; placebo/BOTOX® –11.32, – 10.31).1
When patient groups were compared based on the double-blind phase treatment, for all variables at many of the open-label visits there were significant between-group differences that favoured the group who had received BOTOX® in the double-blind phase (BOTOX®/BOTOX® group) over those who only received BOTOX® in the open-label phase (placebo/BOTOX®).1
Clinical studies of the prophylactic treatment of episodic migraine have indicated a high variability in rates of placebo response in comparison to acute migraine treatment studies.2 This may reflect differences in primary trial endpoints as well as an inherent likelihood for discrepancies between responses measured over a period of months compared with those measured over only a period of hours.2 In migraine prophylaxis, placebo response rates have also been found to be higher in parallel group studies than in crossover trials.2
Clinical trials of parenteral pain treatments consistently report higher placebo rates than those seen in trials using oral medication. Heightened expectation for results from an injection may elevate the placebo response rates.2 The presence of the placebo response suggests that the blind was maintained.2
References
1. Aurora SK, Winner P, Freeman MC, et al. OnabotulinumtoxinA for Treatment of Chronic Migraine: Pooled Analyses of the PREEMPT Clinical Program, Including 32-Week, Open-Label Phase. Poster presented at: 14th International Headache Congress, September 10-13, 2009, Philadelphia, PA.
2. Dodick DW et al. Headache 2010;50:921–936.
p<0.001
p<0.001
p<0.001
p<0.001
-10
p<0.001
p=0.008
p=0.01
p=0.047
-12
p=0.007
p=0.019
p=0.011
p=0.019
-14
Mean ± standard error.
The double-blind phase included 688 subjects in the BOTOX® group and 696 in the placebo group.
Headache days at baseline: 19.9 BOTOX® group vs placebo group, p=0.498.
Dodick DW et al., Headache Jun;50(6):921-36 54

55. Why Chronic Migraine and not Chronic tension type headache?
Several cohort studies identified CDH with neurobiological features of Migraine – (not tension type !)
Messinger et al., (1991), Pfaffenrath et al., (1993), Sanin et al (1994), Sandrini et al.,(1993)
Silberstein & a new concepts in CDH classification
“Transformed Migraine” – evolving from an initial episodic pattern
Subjective classification ? Scientific basis ?
Natural history studies – supportive (Mathew et al., 1982, Sandrini et al, 1993)
“Positive “family history of Migraine in ¾ of patients
Response to Conventional anti-migraine preventatives (Lipton et al, 2000)
Biochemistry of Throbbing “Tension type” CDH & ↑CGRP (Ashina et al, 2000)