1.

INTRODUCTION
In the Stone Age. headaches were sometimes treated in South America by
trephining holes in patients skulls with flints to let the demons out.
Survivors with recurrent headaches underwent (even survived) repeat
trephining, a practice that continued until the Middle Ages. In the ninth
century British isles. medicines against headache consisted of potions of
juicfe of elderseed. cows brain. and goats dung dissolved in vinegar.
Understandably, severe headache sufferers will do almost anything to
relieve their terrible pain. Today more palatable and effective
pharmaceutical treatments have been developed. although effectiveness
may remain suboptimal for many, prompting investigations into other
treatment modalities.

2. VASCULAR HEADACHES
Vascular headaches include migraine headaches with and without aura as
well as cluster headaches. Migraine encompasses a group of severe,
recurring headaches usually affecting one side of the head, accompanied
by nausea, photophobia, sonophobia, and vomiting. In about 30-40% of
migraineurs. there is an aura with transient neurological symptoms which
precedes the attacks and last about twenty minutes. The aura of migraine
is associated with focal reduction of cerebral blood flow which seem to be
secondary to arteriolar vasoconstriction (Friberg et al 1994 ). The aura
may include flashing or zigzag lights, lines, or dots, dimmed vision, tingling
in the face or hands, weakness of an arm or leg, speech difficulties, and
confusion. Migraine wrth aura used to be called classic migraine".
Migraine without aura used to be called common migraine", as it is more
common than migraine with aura. The name migraine" derives from the
Greek hemikranion, (contacted through usage to mikrania or megrem or
migraine) meaning half the head." Pain can be so severe that even the
word meaning depression or unhappiness (megrems) comes from the
Middle English variant of migraine".
Cluster headaches occur mostly in men. presenting as a severely painful,
unilateral and retroorbital characteristic pattern of pain, with lacrimation of
one eye, lid drooping, papillary change and nasal stuffiness. Sufferers
experience extreme bouts of pain on one side of the head for about an
hour, one to three times per day. Often, the headaches occur at the same
time each day. clustered", hence the name, into periods of weeks or
months, but may disappear for months to years, then recur. Sufferers may
become irritable, pace, rock, and bang their heads against the wall during
an attack. The pain can be so intense, that it has been called suicide
headache. Some cases become chronic and occur daily.

1
3. EPIDEMIOLOGY OF VASCULAR HEADACHE
Cluster headaches are rare, affecting less then 0.1 % of the population
and more frequently in men. By comparison, about 10-20% of Americans
experience migraine headaches mostly in women With the young suffering
more headaches than the elderly (Kaminski and Ruff 1991). Incidence of
diagnosis of migraine has increased by nearly 60% in the last decade
probably due to improved education about this disease. Headaches are
painful and costly. Productivity lost through absenteeism and working at
reduced levels of effectiveness ranges from an estimated $6.5 billion to
$17.2 billion each year (Siegelman 1992).

4. MECHANISMS OF VASCULAR HEADACHE

Ten to Fifteen years ago. the prevailing theory was that migraine began
with spasm of brain blood vessels. Today there is some evidence that
migraine sufferers may have a lowered threshold to a migraine generator"
within the brain (Young 1997). One theory is that this generator is in the
brainstem. involving serotonergic system of nerve cells. Another theory is
that the aura. and aura-like phenomenon. begin in the cortex of the brain
and start a cascade of events culminating in migraine pain. including
inflammatory response ofblood vessels surrounding the brain. The
trigemino-vascular theory includes all these concepts (Moskowitz 1984),
Migraine pain was previously thought to result simply from vasodilatton
and pulsation of cerebral vessels. Ergotamine drugs and their derivatives.
which Were then the gold standard of migraine pharmacologic agents.
were thought to ease pain through vasoconstrictive properties. Current
thinking is that migraine may involve, at least in part, an inherited
abnormality of serotonin metabolism. Serotonin levels drop during a
migraine attack. Anthony el al (1967) induced migraine using serotonin
depleting drugs, and relieved the resulting migraine headache with
intravenous serotonin. The migraine drug sumatriptan is now known to act.
not only as a vasoconstrictive agent. but to stimulate subtypes of serotonin
receptors responsible for controlling serotonin levels in the central
synapses and vascular innervation. The drug DHE-45 (dihydroergotamine
mesylate). another direct serotonin receptor agonist. also appears to act
on a subtype of receptors that controls serotonin levels. DHE directly
stimulates these serotonin receptors and turns the pain off (Starr 1992).
Other theories of etiology of classic migraine (migraine with aura) include
the tn'gemino-vascular theory (Moskowitz 1984), spreading conical
depression hypothesis (Ferrari et al 1990), spreading depression as a
characteristic of both classic and common migraine (Dalessio 1985). the

2
combination of both spreading conical depression and potassium-induced
vasoconstriction producing localized ischemia (Young and Van Vliet l992),
previous trauma (Borzyskowski 1989), and reduced ability to deaminate
monoamines, particularly phenylethylamine. in susceptible individuals
(McCulloch and Harper 1977). Olesen (1986) ruled out disturbances of
adrenergic substances in blood as cause of migraine by intracarotid
infusion of noradrenaline, adrenaline, and isoprenalinc, with no headache-
related effect. In contrast to this, Chang and Detar (1980) demonstrated
enhanced vasoconstrictive response to catecholaminergic drugs. The
increased sympathetic activity inherent in migraine with and without aura.
affects the cerebral vasculature, neurons, and metabolism, increasing
oxygen demand, which further worsens local hypoxia (Amery 1982).

5. COMMONLY USED ANTI-MIGRAINE DRUGS

Abortive medications for migraine are shown in Table 21.1. These include
sumatriptan (Imitrex). the newer synthesized triptans. indomethacin,
Cafergot, and corticosteroids. In cluster headache, subcutaneous
sumatriptan is usually effective and well tolerated. Prophylactically.
calcium channel blockers are effective. lntranasal capsaicin and leuprolide
(a synthetic slow-release gonadotrophin-releasing hormone) may be
useful. in chronic paroxysmal hemicrania. which clinically resembles
cluster headache, indomethachin is effective for many (Stovner and
Sjaastad 1995). Individual patients may respond to salrcylates, naproxin,
or prednisone (Brandt et al 1991).

6. NON-PHARMACOLOGIC APPROACHES
Pharmacologic agents combating migraine and cluster headaches are
generally effective with relatively few side effects, and are now usually
self-administered. therefore. the need for treatment alternatives is
relatively low. However, several factors illustrate the need for investigation
and availability of other modalities. Potential candidates for treatment with
hyperbaric oxygen (HBO); therapy are those whose vascular headaches
are unresponsive to oral or injected medications or accepted nutritional
management involving avoidance of trigger foods. HBO can be considered
for patients in whom have common pharmacologic agents are
contraindicated. such as those with peripheral vascqu disease, coronary
artery disease or pregnancy. Patients with substantial side effects to
standard pharmacologic agents and in those with hypertension can also
be considered. Overuse of abortive agents, such as ergotamine, can lead
to rebound effects, prompting the sufferer to take more medication,
creating a vicious cycle of headaches and rebound headache that may

3
continue for days or weeks or become chronic daily headaches. HBO
might be useful for breaking such a cycle.

7. RATIONALE FOR USE OF HYPERBARIC OXYGEN IN MIGRAINE

The rationale for the use of HBO in migraine is based on two mechanisms
of its action on the blood vessels: vasoconstriction and influence on other
headache pathways.
Vasoconstriction
Exposure to HBO has been shown effective for both cluster and migraine
headaches. One of the contributing mechanisms is assumed to be
cerebral vasoconstriction in response to high oxygen tensions. invoked as
a protective response against the effects of both hyperoxia and
corresponding decreases in end-tidal carbon dioxide.
Hyperbaric oxygen provides much higher levels of blood oxygenation than
normobaric oxygen, and presumably greater ability to constrict painfully
dilated cerebral arteries. HBO has been used to combat cerebral edema.
its effects decrease cerebral blood flow and increase cerebral oxygenation
(Sukoff and Ragatz 1982).
Transcranial Doppler (TCD) is used in migraine research to determine
blood flow velocity changes in cerebral arteries. Changes in vessel diamet
r are Inferred from changes in velocity measurements. Using transcranial
Doppler. Thomsen et al (I995) found decreased mean blood flow velocity.
indicating an increase in middle cerebral artery cross-sectional area on the
affected side during migraine without aura Demarin et al (I994) found
cerebral vasoreactivity to be Within normal ranges in the majority of
migraine patients. and that subjects experiencing migraine with aura were
found to have a lower blood flow velocity (indicating vasodilation)
compared to subject without aura.
For evaluation of the effect of HBO. some modification of TCD technique
was needed. Fife et al (1994. I995) passed a Doppler probe through the
HBO Chambers steel vessel hull via a custom fitted port. The Doppler
image was projected into the chamber Via a closed circuit camera and
single lens projection television. Two examiners. one control ling the
instrument panel outside the chamber and the other positioning the
Doppler probe within the chamber, performed the study.
In studies sponsored by the National Headache Foundation. TCD
examinations were carried out during hyperbaric exposures on 27
volunteers. Middle cerebral artery (MCA) signals were monitored in a
series of separate exposures while subjects respired oxygen at sea level
(1 ATA), 2 ATA and 3 ATA. after breathing the appropnate control gas (air.

4
10% oxygen/nitrogen, and 7% oxygen/nitrogen. respectively) via face
mask. Mean flow velocity (MFV), pulsatility index (PI), blood pressure and
pulse were recorded at 10 min intervals. As expected, there was no
change in MCA MFV and P1 between baseline (room air), 10% Oxygen at
2ATA, or 7% oxygen at 3 ATA. This is consistent with the assumption that
altering ambient pressure alone, without changing the inspired partial
pressure of oxygen. has no measurable vascular etfects. However. upon
HBO exposure. all subjects demonstrated a statistically significant
decrease in MCA MFV (p =< 0.001), and a significant increase in
pulsatility. MCA MFV returned to baseline values almost immediately upon
surfacing.
These findings are consistent with an increase in distal vascular tone
caused by hyperoxic vasoconstriction This decrease appeared greater at 3
ATA p02 than 2 ATA pO2 suggesting that this vasoconstrictive effect may
increase as p02 rises from 2 ATA to 3 ATA. However, a corresponding
decrease in end-tidal CO2 was noted during HBO exposure, a well
described etfect of oxygen breathing. A decrease in CO 2 is an even more
potent vasoconstiction than an increase in p0 2. When calculations were
checked for this effect. nearly all of the changes in MCA velocity could
have been accounted for on the basis of a decrease in CO 2. Thus, the
mechanism of blood flow changes during HBO exposure may be related
as much to carbon dioxide as to oxygen.
Effects of HBO on Other Headache Pathways
The effect of HBO is not limited to vasomotor change. Serotonergic
pathways seem to be involved but the mechanisms has not been
elucidated as yet.
Di Sabato et al (1997) assessed the therapeutic efficacy of HBO on
serotonergic pathways in cluster headache patients. They studied
serotonin binding to mononuclear cells before and after the treatment in
study and control subgroups. Appearance of plateau in the binding curves
in the HBO subgroup indicated that HBO could act as a serotonergic
agonist.
Di Sabato et al (1997) assesed the effect of HBO exposure on substance
P in the nasal mucosa of cluster headache patients. Substance P (for
pain) is a shortchain neuropeptide present in primary nociceptive
neurons and serves to transmit pain impulses from peripheral nociceptive
neurons to the central nervous system. Nasal mucosa samples were
analyzed using blinded immunocytochemical methods Compared to the
placebo control group. the HBO group showed a significantly decreased
immunoreactivity for substance P. indicating that an influence on the
content of peripheral neuropeptides could be involved in the mechanism of
action of the beneficial effect of HBO on cluster headache."

5
8. USE OF OXYGEN IN MIGRAINE TREATMENT
The effect of inhalation of l00% normobaric oxygen on migraine is
immediate and can be evaluated like that of any other headache
medication (Jain 1989). The varied nature and course of headache pain,
the difficulty inherent in quantifying headache pain and outcomes. and the
significant placebo effect in unblinded studies are some of the obstacles to
performrng well-designed, randomized, clinical trials, and interpreting
headache treatment results.
Robbins (1996) reported oxygen inhalation to be useful in two of ten
patients with menstrual migraine with features of cluster headache,
although Evers and Husstedt (1996) found no significant influence of
oxygen inhalation on chronic paroxysmal hemicrania. Shalkevich er al
(1981) found hyperbaric oxygen relieved headache pain in patients with
vertebral basilar headache. Isakov and Romansenko (1985) reported that
HBO treatment relieved headaches in post-operative neurosurgical
patients.
Myers and Myers (1995) compared efficacy of HBO to normobaric oxygen
on global headache severity before and after exposure to oxygen
treatment for a typical" migraine attack. Twenty migraineurs were divided
into a normobaric treatment subgroup of ten patients receiving 100%
oxygen at 1 atmosphere of pressure while the hyperbaric treatment
subgroup of ten patients received l00% oxygen at 2 ATA. In the
normobaric treatment subgroup. one of the 10 patients reported significant
relief, while in the hyperbaric treatment subgroup, 9 of 10 found relief, a
significant difference between groups. Normobaric subgroup patients who
did not experience significant relief were administered HBO, with all nine
experiencing significant relief.
in an unblinded study by Fife and Fife (1989), resolution of acute migraine
pain was observed in 92% of patients treated with hyperbaric oxygen. A
subsequent double-blinded randomized trial was sponsored by the
National Headache Foundation and camed out at the University of Texas,
Houston. Volunteers with a history of migraine, documented by
neurological evaluation and in most cases xenon cerebral blood flow
Studies. were enrolled and oriented to the hyperbaric chamber prior to
headache onset. Fourteen subjects. 6 males and 9 females, age 23 to 67
years. received either 100% oxygen at 2 ATA. or normoxic controlled gas,
l0% oxygen/90% nitrogen (nitrox) at 2 ATA via a tight fitting, demand type
face mask in a multi-place chamber. The subjects, the attendant and the
physician were blinded as to the nature of the treatment gas. Subjects
graded headache pain from 05 on a modified Blanchard pain inventory
before and after a 45 minute HBOT treatment. Treatment was initiated only

6
for scores of 3 or more and in the absence of recent narcotic or other
medication ingestion. Response was defined as a decrease of 2 or more
grades. Of the 10 patients who received HBO initially, 7 (70%) obtained
headache pain relief: 4 (29%) had no relief. None of 3 HBO failures
responded to nitrox. Of the 4 receiving nitrox initially, 2 indicated that their
headache had improved. One of 2 nitrox failures responded to HBO. The
overall response to HBOT was 72%. and the overall response to nitrox
was 29%. This study underscores the importance of controlled trials in
headache research. where significant placebo effects can be observed. In
a blinded man by Fife et al (1992), fourteen subjects with migraine
documented by neurological evaluations and, in most cases by xenon
cerebral blood fiow studies as well, received either l00% oxygen at 2 ATA.
or a normoxic controlled gas l0% oxygen/90% nitrogen (nitrox) at 2
ATA. Subjects graded headache pain from 05 on a modified Blanchard
pain inventory before and after a 45 minute treatment. Treatment was
initiated only for scores of 3 or more and in the absence of recent narcotic
or other medication ingestion. Response was defined as a decrease of 2
or more grades. Ten patients received HBO initially. of which 7 (70%)
obtained headache pain relief; 4 (29%) had no relief. Statistically
significant results were not attained due to small sample size.
In one unreported case study by C. Fife, a migraneur with ptosis was able
to open his eye after HBO treatment (Figure 21.1). The patient was a 52-
year old white male with a history of basilar artery migraine attacks.
thalamic infarctions and 3rd nerve palsy (Bickerstaff Syndrome).
lnfarctions were confirmed by MRI and the patient had complained of
headaches intermittently for five days. He awoke pain free but with a
partial third nerve palsy manifested as ptosis of the right eye. right medial
recurs paresis. an ataxic gait and past pointing on finger-to-nose testing.
Approximately 12 hours after the onset of neurologic deficit, he underwent
a HBO treatment at a pressure of 2ATA for 2 hours. He was noted to have
significant improvement but his ptosis did not resolve immediately
following the treatment. He underwent two further treatments over a two
day period, but noted no further improvement on subsequent exposures.
HBO therapy was, therefore, discontinued. This case raises the question
whether HBO may be useful for differentiation of transient ischemic attacks
associated with migraine from fixed neurological deficits due to stroke.
Use of HBO in stroke is the subject of considerable discussion currently
and is dealt with in Chapter 17.
There are several unpublished anecdotal reports of decrease in frequency
of migraine after undergoing HBO treatments but it would be difficult to
demonstrate it conclusrvely in a condition as unpredictable in onset as
migraine.

7
9. USE OF HBO FOR TREATMENT OF CLUSTER HEADACHE
Di Sabato et al (1993) compared HBO to placebo for the treatment of
episodic cluster headaches. Six of seven patrents in the HBO treatment
Subgroup expenenccd an improvement compared to none in the placebo
treatment subgroup. Three of the six patients remained free from pain
attacks for up to six days. The authors stated that their results indicate that
HBO is effective in the case of a srngle attack of cluster headache, and
might also be useful to prevent subsequent attacks However,
interpretation of the result of continued protection against repeat attacks
must be weighed carefully, as a refractory period follows attacks, where
further attacks cannot be induced (Krabbe 1986)
Pascual et al (1995) treated four cluster headache patients with no clear
response to pharmacological treatments using a 2-week HBO course."
Two patients had reduced duration and frequency of cluster headache with
benefits remaining for 2 and 31 days post treatment. Patient three had a
reduced frequency of attacks only while patient four experienced no
change.
Di Sabato et al (1997) compared the effect ofHBO (n of 10) to that With
environmental air (placebo control) treatments (n of 4) on patients with
chronic cluster headache. The placebo control group experienced no
change in number of attacks or analgesic consumption. The HBO group
reported relief of symptoms.
Weiss et al (1989) reported a single case of a Cluster headache treated
With HBO in a patient with symptoms refractory to other treatments
including normobaric oxygen inhalation. In both of two treatments pain
was relieved at two atmospheres breathing 100% oxygen.

10. SUMMARY
Hyperbaric oxygen (HBO). for the treatment of vascular headaches, due to
serotonergic or neurogenic mechanisms. seems to be effective and safe.
and potentially detrimental effects of oxygen that might develop at a
particular p02. Treatment pressures which have been successful in
unblinded trials of migraine headache have ranged from 1.6 to a maximum
of 2.5 ATA. There is data to suggest that presswes greater than 1.5 ATA
may increase cerebral lactate levels in the injured brain (Holbach et al
1977). However, there is no cerebral injury in migraine unless the
complication of cerebrovascular ischemia occurs and pressures higher
than 1.5 ATA may be well tolerated.
Many of the new migraine medications have 70% or better efficacy.
Exceptions may lie in complicated migraine with neurologic deficits, and in

8
those migraineurs refractive to established pharmacologic and nutritional
interventions. The future for HBO may lie in treating migraine headaches
that run for days with severe debility, for treating chronic daily headaches
with migraine components, and for treatment and prevention of cluster
headaches. which often take days or weeks to resolve, are extremely
painful, and are less responsive to currently available medications.
Patients with chronic recurring vascular headache attacks benefit best
from a continuous preventative treatment plans including medication; diet,
exercise, and lifestyle changes, with exercise plus stress reduction
techniques. This approach is better than relying on use of HBO (or other
abortive interventions) treatment programs.

Editorial Comments
The authors have presented a straightforward review of their experience
and review of the current literature indicting the usefulness of HBO in the
management of migraine and cluster headaches. For clinical studies. the
evaluation of relief of pain remains somewhat of a problem. This is the
same situation as for the evaluation of various pharmaceuticals for
migraine.
Wilson et al (1998) have used a visual analog pain scale, algometry, and
manual palpation over tender areas to document relief of pain with HBO
treatments. Resolution of tenderness and edema following both treatments
was observable by manual palpation while algometry showed no
differences between the two. Subjective pain was significantly decreased
following HBO treatments but not following the control treatment (100%
oxygen. no pressure). Results suggest that HBO treatment reduces
migraine headache pain and that the patients subjective assessment is
the best indicator of relief.
Economic aspects of treatment of migraine with HBO need to be
investigated. Reduction of medication use and their adverse effects would
reduce the costs. Decreased frequency of attacks with less work missed
would Increase producttvrty. Finally, HBO may improve the quality of life of
migraine sufferers.

9
10