Transcript Botulinum Toxin in the Treatment of Chronic Pain and Headaches

New York Headache Center
Magnesium and other non-pharmacological
treatments for headaches
Alexander Mauskop, MD
Disclosure
Speaker for: Allergan, Zogenix
Clinical trials: ElectroCore, Allergan
Owner: Migralex, Inc
Lecture outline

Cognitive approaches

Physical methods

Magnesium

Vitamins and herbs

Botulinum toxin

Nerve blocks & trigger point injections
Lecture outline, cont’d

Peripheral nerve stimulation

Sphenopalatine ganglion stimulation

Vagus nerve stimulation

Transcranial magnetic stimulation

Deep brain stimulation
[email protected]
www.NYHeadache.com
Mind-body therapy

Progressive relaxation

Imagery & visualization

Cognitive - behavioral therapy

Hypnotherapy

Meditation

Biofeedback / neurofeedback
Exercise and headaches
Physical activity and headache: results from the NordTrøndelag Health Study (HUNT). Varkey E, Hagen K,
Zwart J-A, Linde M. Cephalalgia 2008;28:1292–1297.
A study of 46,648 subjects
“Low physical activity was associated with higher
prevalence of migraine and non-migraine headache. In
both headache groups, there was a strong linear trend
(P< 0.001) of higher prevalence of ‘low physical activity’
with increasing headache frequency”
Exercise and headaches
Exercise as migraine prophylaxis: A randomized study
using relaxation and topiramate as controls. Varkey E,
Cider Å, J. Carlsson J, Linde M. Cephalalgia 2011;31:1428-1438.
91 patients divided into 3 groups:
 aerobic exercise (40 minutes three times a week)
 topiramate
 relaxation training
All three treatments equally effective. Only topiramate
caused side effects, which occurred in 33% of patients
Magnesium and migraine
Low brain magnesium in migraine
N.M. Ramadan, H. Halvorson, A. Vande-Linde et al.
Headache 1989;29:590-593.
Phosphorus magnetic resonance spectroscopy
Magnesium and headache
Deficient energy metabolism is associated
with low free magnesium in the brains of
patients with migraine and cluster headache
R. Lodi, S. Iotti, P. Cortelli et al. Brain Research Bulletin,
Vol. 54, No. 4, pp. 437–441, 2001
Phosphorus magnetic resonance spectroscopy in 78 patients:
7 – migraine stroke, 13 – migraine with prolonged aura, 37 –
migraine with typical aura or basilar migraine, 21 – migraine without
aura, 13 – cluster headache
In the occipital lobes of all migraine and all cluster headache
patients cytosolic free Mg2+ as well as the free energy released by
the reaction of ATP hydrolysis were significantly reduced.
Magnesium and migraine
Oral magnesium load test in
patients with migraine
Trauninger et al. Headache 42:114-119;2002
Conclusions:
Magnesium retention occurs in patients with migraine
after oral loading, suggesting a systemic magnesium
deficiency
Magnesium and migraine
Potential causes of
magnesium deficiency

Stress

Genetics

Low dietary intake

Caffeine, alcohol, calcium
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Gastro-intestinal disorders

Chronic illness
Practical considerations
Clinical symptoms of hypomagnesemia

Headaches

Leg muscle cramps

Coldness of extremities or body

PMS

Mental fog

Irritability, depression
Magnesium and migraine
Known effects of IMg2+

glutamate

acetylcholine

angiotensin II

nitric oxide

potassium

norepinephrine

serotonin

calcium

G proteins

enzyme complexes (325)
NMDA receptor
IV MgSO4 for acute migraine
0.58
0.56
0.54
xxx
x
xx
x
xx
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0.52
IMg2+
mmol/L
0.50
0.48
x
xx
o
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oo
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x = non-responders
o = responders
oo
o
0.46
0.44
0.42
o
Mauskop et al, Clin
Science 1995;89:633-6
IV MgSO4 for acute migraine
Efficacy of intravenous magnesium sulfate
in the treatment of acute migraine attacks.
Demirkaya S, Vural O, Dora B, et al.
Headache 2001;41:171-177.
1 gram of magnesium sulfate intravenously or placebo
 13 of 15 patients (87%) receiving magnesium obtained
 complete pain relief
 none of the 15 patients in the placebo group
Magnesium and migraine
Intravenous magnesium sulphate in the acute
treatment of migraine without aura and
migraine with aura. A randomized, doubleblind, placebo-controlled study.
Bigal ME, Bordini CA, Tepper SJ, et al.
Cephalalgia 2002 Jun;22(5):345-53.
60 patients; 1 gram of MgSo4 – IV push
Relief of all symptoms in MA, relief of photo, phonophobia in
MWA; all trends in favor of magnesium
IV MgSO4 for
cluster headaches
0.76
x
x
o
0.60
0.58
x
x
0.56
0.54
IMg2+
mmol/L
xxx
xxx
xxx
0.52
0.50
0.48
0.46
0.44
x
x
o
o
o
ooo
oooo
o
o
ooo
o
o
oo
o
o
x = non-responders
o = responders
Mauskop et al, Headache
1995;35:597-600.
Magnesium and migraine
Prophylaxis of migraine with oral magnesium: results from
a prospective, multicenter, placebo-controlled and doubleblind randomized study.
A. Peikert, C. Wilimzig, R. Kohne-Volland, Cephalagia
1996; 16:257-263.
Trimagnesium dicitrate – 600 mg, 81 patients
 Attack frequency reduced 41.6% vs 15.8% (p<0.05)
 Days with migraine reduced 52.3% vs 19.5% (p<0.05)
Magnesium and migraine
Magnesium prophylaxis of menstrual migraine:
Effects on intracellular magnesium.
F. Facchinetti, G. Sances, A.R. Genazzani, G. Nappi.
Headache; 1991;31:298-310.
Magnesium pyrrolidone carboxylic acid – 360 mg
 Days with migraine reduced 4.7 to 2.4 (p<0.01)
 Significant reduction in MDQ scores (p<0.05)
Magnesium and migraine
Oral magnesium oxide prophylaxis of frequent
migrainous headache in children: A randomized,
double-blind, placebo-controlled trial.
Wang F, Van Den Eeden S, Ackerson L, et al.
Headache 2003;43:601-610.
Magnesium oxide 9 mg/kg
86 of 118 completed;
“statistically significant downward trend in HA
frequency over time in MgO but not placebo group”
Magnesium and migraine
Magnesium in the prophylaxis of migraine:
A double-blind, placebo-controlled study.
Pfaffenrath V, Wessely P, Meyer C, et al.
Cephalagia 1996; 16:436-440.
Magnesium-u-aspartate-hydrochloride-trihydrate – 20 mmol
No relief of headaches – interim analysis of 69 patients.
Diarrhea: 45.7% on magnesium, 23.5 on placebo
Magnesium and migraine
Oral magnesium absorption issues
Schuette SA et al. Bioavailability of magnesium diglycinate vs
magnesium oxide in patients with ileal resection.
J Parenter Enter Nutr 1994;18:430-435.
Equal absorption, diglycinate better tolerated (fewer stools).
White et al. Blood and urinary magnesium kinetics after oral
magnesium supplements. Clin Ther 1992:14(5)678-687.
No difference in total serum Mg AUC:
chloride solution, slow release chloride tabs, gluconate tabs
Practical considerations
Oral supplementation

Start with 400 mg of magnesium oxide or

chelated magnesium (aspartate, diglycinate, etc.)

If not tolerated, try magnesium citrate, Slow-Mag

If tolerated but ineffective, consider increasing
the dose to 400 mg BID – TID; always with food
Migralex
A rapidly dissolving combination of:
 Aspirin – 500 mg
 Magnesium oxide – 75 mg
Migralex
Usual dose is two tablets
(Aspirin – 1,000 mg and magnesium oxide – 150 mg)
 Both magnesium and aspirin relieve headaches
 Magnesium reduces GI side effects of aspirin
 Rapidly dissolving formulation
 Works for migraine, tension, sinus, hangover headaches
Riboflavin
Effectiveness of High-dose Riboflavin in
Migraine Prophylaxis
4
No. of
Attacks
per
Month
3
Placebo
Riboflavin
2
*
*
1
1
2
3
4
Month
J. Shoenen, J. Jacquy, M. Lenaerts. Neurology 1998; 50:466-440.
P=0.001
Headache genetics
MTHFR gene variant C677T has been implicated as a
genetic risk factor in susceptibility to migraine with aura.
C677T polymorphism reduces enzymatic capability and
causes elevated homocysteine levels.
Disruption of neurovascular endothelium by elevated
homocysteine levels is a possible trigger for migraine with
aura. It is also a possible cause of white matter lesions
and strokes seen in patients with migraine with aura.
Headache genetics
Lea R, Colson N, Quinlan S, et al. The effects of vitamin
supplementation and MTHFR (C677T) genotype on
homocysteine-lowering and migraine disability.
Pharmacogenet Genomics. 2009 Jun;19(6):422-8.
Daily supplementation for 6 months with 2 mg of folic acid,
25 mg vitamin B6, and 400 mcg of vitamin B12 vs placebo.
1. Homocysteine – ↓ by 39%, p=0.001
2. Prevalence of disability – ↓ from 60% to 30%, p=0.01
3. Headache frequency and pain severity ↓, p<0.05
1 and 2 were associated with MTHFRC677T genotype
Coenzyme Q10
Efficacy of coenzyme Q10 in migraine
prophylaxis: A randomized controlled trial
P. S. Sándor, L. Di Clemente, G. Coppola
Neurology 2005;64:713-715
Double-blind, randomized, placebo-controlled trial
42 patients; CoQ10 100 mg TID vs placebo
50% responder rate for attack frequency
14.4% for placebo and 47.6% for CoQ10
Coenzyme Q10
Coenzyme Q10 deficiency and response to
supplementation in pediatric and adolescent
migraine
Hershey AD, et al. Headache 2007;47:73-80





1550 patients – 32.9% deficient
Supplementation with 1-3 mg/kg/day
CoQ10 levels improved, p<.0001
HA frequency improved from 19.2 to 12.5, p<.001
HA disability improved from 47.4 to 22.8, p<.001
Botanical Remedies
Feverfew
Efficacy and safety of 6.25 mg t.i.d. feverfew CO2-extract (MIG-99) in migraine prevention – a
randomized, double-blind, multicenter, placebocontrolled study.
Diener HC, Pfaffenrath V, Schnitker et al.
Cephalalgia 2005;25:1031-1041
N=170, 89 - feverfew, 81 - placebo, 4 - 6 attacks/month
No prophylactic drugs
Feverfew (Diener)
Results

Reduction in number of attacks in 28 days–
1.9 vs 1.3 (p<0.0456)

Global assessment of efficacy – statistically
significant difference

No difference in averse events (25.2% active,
26.6% – placebo)

No effect on duration of attacks
Petasites hybridusbutterbur (Petadolex®)
Petasites hybridus root (butterbur) is an
effective preventive treatment for migraine.
Lipton RB, Gobel H, Einhaupl KM, Wilks, K and
Mauskop A. Neurology 2004;63:2240-2244

245 patients

Three groups: placebo, 100 mg and 150
mg

Main outcome measure: attack
frequency
Petasites hybridusbutterbur (Petadolex®)
Petasites hybridus root (butterbur) is an
effective preventive treatment for migraine.
Lipton RB, Gobel H, Einhaupl KM, Wilks, K and
Mauskop A. Neurology 2004;63:2240-2244
Attack frequency reduced by:

48% in 150 mg group (p=0.0012)

36% in 100 mg group (p=0.127)

26% in placebo
Petasites hybridusbutterbur (Petadolex®)
We no longer recommend butterbur (Petadolex)
Raw butterbur contains chemicals that can cause
liver damage and are dangerous to the fetus.
Petadolex was a brand proven safe and approved for
sale in Germany, but recently it was taken off the
market because the manufacturer changed the
extraction method and did not repeat the safety
studies. Other brands of butterbur sold in the US are
probably even less safe. All forms of butterbur are
banned in the UK.
Acupuncture
Acupuncture for recurrent headaches: a systematic
review of randomized controlled trials. Melchart D,
Linde K, Fischer P, et al. Cephalalgia 1999;19:779786.
Majority of 14 trials comparing true and sham
acupuncture showed at least a trend in favor of true
acupuncture
Acupuncture
Acupuncture in patients with headache
Jena S, et al. Cephalalgia 2008;28(9):969-979
15,056 patients with migraine and tension-type
headaches randomized to receive over 3 months:

conventional treatment (1,569) or

conventional treatment plus up to 15 acupuncture
treatments (1,613)

11,874 refused to be randomized, received
acupuncture and were placed into a third group
Acupuncture
Acupuncture in patients with headache
Jena S, et al. Cephalalgia 2008;28(9):969-979
Significant difference in QOL and in headache days
per month:
two acupuncture groups – drop from 8.4 to 4.7 days
control group – 8.1 to 7.5 days
Improvement persisted for subsequent 3 months
Acupuncture
Acupuncture for the treatment of headaches:
more than sticking needles into humans?
H-C Diener Cephalalgia 2008;28:911-913
…acupuncture is as effective as drug therapy, but
…sham acupuncture is as effective as 'real' acupuncture.
…acupuncture should be offered to patients who do not
respond to prophylactic treatment with drugs, terminate
drug treatment because of AEs or have contraindications
to drug treatment.
CAM for headaches
What to recommend?

aerobic exercise, neck exercise

biofeedback / meditation / yoga / music

magnesium

CoQ10, butterbur, riboflavin, feverfew

folic acid, pyridoxine, vit. B12 (if homocysteine is
high)

acupuncture

massage, reflexology, aromatherapy
Botulinum Toxin Type A
Mechanism of Action
CGRP and
Botulinum Toxin
Synaptobrevin I mediates exocytosis of CGRP from
sensory neurons and inhibition by botulinum toxins
reflects their anti-nociceptive potential.
Meng J, Wang J, Lawrence G, Dolly JO. J Cell Sci.
2007;120(16):2864-74
Botox for chronic migraine:
Phase III trials
 Aurora SK, Schim JD, Cutrer FM, et al. Botulinum
neurotoxin type A for treatment of chronic migraine:
PREEMPT 1 trial double-blind phase. Cephalalgia
2009;29 (suppl 1):29.
 Dodick DW, Smith TR, Becker WJ, et al. Botulinum
neurotoxin type A for treatment of chronic migraine:
PREEMPT 2 trial double-blind phase. Cephalalgia
2009;29 (suppl 1):29.
FDA: Approved for the prophylaxis of headaches in adult
patients with chronic migraine (≥15 days/month with
headache lasting 4 hours a day or longer)
Botox for migraines

The only FDA-approved treatment for chronic
migraine

Efficacy – 70%

Safer than any systemic drug

Covered by most insurers if three prophylactic
drugs fail

Easy to learn and to perform
Occipital Neuralgia
Pain within the distribution of the greater
and/or lesser occipital nerves
Neuralgic variant
Sharp, shooting, electric-like pain
Almost always unilateral
Bursts of pain lasting for seconds to few minutes
Non-neuralgic variant
Dull, aching, throbbing, pounding pain
More constant, often bilateral
Sensory dysfunction in C2 nerve territory
Responds to local blockade of occipital nerve
Greater occipital nerve block
in migraine

GON block in 19 patients with acute migraine and
allodynia, headache was relieved in 17, and allodynia
decreased in all patients (Ashkenazi and Young, 2005).

Another study of 25 migraine patients found that 60% of
subjects had significant improvement of migraine pain
within 5 minutes of injection (Cook et al., 2006).

Long-lasting relief was seen in 26 of 54 migraine
patients who received a unilateral GON block with
lidocaine and methylprednisolone (Afridi et al., 2006).

A recent comparative controlled study of the benefits of
GON block in chronic daily headache (CDH) was
positive (Ashkenazi et al., 2006).
Greater occipital nerve block
in cluster headache
Shown to be effective in the acute, and
perhaps preventive, treatment of cluster headache

In a study of 14 CH patients treated with GON block, 4
had a good response and 5 had a moderate response
(Peres et al., 2002).

DBPC of GON block ipsilateral to the pain side in CH
patients: 85% of the treated group responded (10/13)
and none in the placebo group (0/10) improved. Effect
persisted for at least 4 weeks. (Ambrosini, 2005)

12 of 22 CH patients responded to GON block and the
response lasted for weeks. Tenderness around the
GON predictive of response to GON block in migraine
and CH patients, although the degree of anesthesia
was not. (Afridi, 2006)
Sphenopalatine ganglion
block
The procedure is done with the patient supine, with the
tip of the nose pointed at the ceiling and the head turned
slightly to the side of the block. A long, cotton-tipped
applicator is saturated with 4% lidocaine and applied to
the lateral posterior wall of the nasal cavity.
An alternate method involves instilling drops of 4%
Lidocaine.
Sphenopalatine ganglion
blocks for cluster headaches

Because cocaine applied to the sphenopalatine
ganglion region is known to abort a CH attack, local
anesthetics have been proposed as a less addictive
alternative.

Results - positive (Costa et al., 2000; Hardebo and
Elner, 1987; Kittrelle et al., 1985), although in one
study of 30 male patients with CH, results were mostly
negative (Robbins, 1995).

A reasonable alternative for CH patients, who can
learn to do this technique themselves, particularly if
they are relatively resistant to other prophylactic and
abortive therapies.
Peripheral nerve stimulation
Cefaly - TENS
Occipital nerve stimulation

Implantable cylindrical or paddle electrodes in the
region of the occipital nerve unilaterally or bilaterally

Continuous or prn, various frequencies, pulse duration
and voltage

Implantable pulse generator – subclavic., abd., axilla

Patient selection based on intractability of HA, no
MOH, response to GON block, sometimes initial
response to stim with external generator

However, benefit may occur after several weeks
GON stimulation in
chronic migraine
Occipital nerve stimulation for the treatment of intractable
chronic migraine headache: ONSTIM feasibility study.
Saper et al. Cephalalgia 2011;31(3):271-85.

Multicenter, randomized, blinded, controlled study

110 patients: Adjustable stim, Preset stim or Medical Rx

Responder - at least 50% reduction in number of
headache days per month or at least a three-point
reduction in average overall pain intensity compared
with baseline.

Responder rates: 39% for AS, 6% for PS and 0% for MM
GON stimulation in
cluster headaches

Burns et al. (Lancet, 2007) reported on 8 pts – 6/8 had
meaningful improvement

Magis and colleagues (Lancet Neurology,2007) also 8
patients, 7/8 with meaningful improvement – 2 pain
free
Uncontrolled
Vagus nerve stimulation
Vagus Nerve Stimulation Relieves Chronic Refractory
Migraine and Cluster Headaches.
Mauskop A. Cephalalgia 2005;25:82-86.

Highly refractory and disabled 4 chronic migraine and
2 chronic cluster patients

2 out of 4 migraine and both cluster patients
responded
Vagus nerve stimulation
Gammacore
 Acute treatment of up to 4 migraine
attacks
 Treatment consisted of two, 90second doses, at 15-minute intervals.
 Of 30 enrolled, 26 treated 79
migraines headaches.
 At 2 hours, 46 of 79 headaches (58%)
responded, and in 22 out of 79 (28%)
pain was completely gone.
 Of 26 patients 20 (77%) reported mild
or nor pain at 2 hours, for at least one
treated headache
TMS for migraine
Single-pulse transcranial magnetic stimulation for acute
treatment of migraine with aura: a randomised, doubleblind, parallel-group, sham-controlled trial
Lipton RB et al, The Lancet Neurology, 2010;9:373-380
164 patients
Pain free at 2 hours: 39% vs 22%
Limitations: bulky device, only for migraines with aura
TMS for migraine
Cerena TMS by eNeura Therapeutics
Sphenopalatine ganglion
stimulation
ATI™ Neurostimulation System
Sphenopalatine ganglion
stimulation
DBS: Current indications
Movement
Disorders
 Parkinson’s Disease
 Tremor Syndromes
 Dystonia
Pain
Syndromes:
 Central pain syndromes: Post CVA, Cluster headaches
 Nociceptive pain: Failed back syndrome, Cancer pain
 Neuropathic pain: Denervation syndromes, Trigeminal
neuropathy
DBS for cluster headaches
Study
No. of implanted Mean follow
patients
up (years)
No. of patients
improved^
Percentage
improved
Leone et al. (2006b)
16
4
10
62
Fontaine et al. (2010)
11
>1
6
55
Starr et al. (2007), Sillay et al.
(2009)
8
1
5
62
Bartsch et al. (2008)
6
1.4
3
50
Schoenen et al. (2005)
4
4
2
50
Owen et al. (2007) and Brittain et 3
al.(2009)
1
3
100
D’Andrea et al. (2006) (abstr)
3
2.5
2
66
Black et al. (2007) (abstr)
2
2.6
2
100
Mateos et al. (2007) (abstr)
2
1
2
100
Benabid et al. (2006) (abstr)
1
1
1
100
Nikka et al. (2006)ast;
2
2
0
0
Totals
58
36
62
DBS Complications
Neurologic
 Intracranial hemorrhage
 Infection
 Seizures
Device-related
1 - 5%
3 -14%
3 - 4%
2 - 26%
 Lead fracture
 Lead migration
Stimulation-related
 Usually transient, resolve with adjustments to stimulation:
 Headache, nausea, diplopia, vertica gaze palsy,
nystagmus, uncomfortable paresthesias, unpleasant
stimulation side effects
DBS: Side effects
Compulsive thalamic self-stimulation: A case with
metabolic, electrophysiologic and behavioral
correlates.
RK Portenoy et al., Pain 1986, 27(3); 277–290