Treatment of migraine by intravenous histamine

Treatment

of Migraine

by Intravenous

Histamine* THOMAS, M.D. and STUYVESANT BUTLER, M.D.

WILLIAM A.

Assistant Prqfessor (Rush), UniuersiQ of Illinois College of Medicine

Pmfesmr (Rush) of Medicine, liniuersity qf Illinois College of Medicine CHICAGO,

0

NE

of the current

the

cause

attacks

anaphylactic

tration

theories regarding

of migraine

result

ILLINOIS

from

reaction,

is that

the

an allergic

or

with release

characteristic

to this substance, regardless of introduction-intradermally, ously

or intravenously.

generally organs

believed

thus exQuantitative determination tremely difficult, and little data are at hand regarding the concentration necessary to produce reactions in sensitive and non-sensi-

of his-

or

great

tissues

vascularity,

The fallacy

are

characterized

stance.

it is

face,

certain by

While

constriction

splanchnic

in-

areas,

may be a lowering

tracts)

vation

may be designated

there

of the

is a corre-

in the hands, legs and

to the extent

cluding skin, liver, spleen and mucous memand gastrointestinal branes (respiratory which

histamine

it causes vasodilatation

neck and shoulders,

sponding

their

capillaries,

of the intradermal

test lies in the peculiar and poorly understood pharmacological action of that sub-

of its method subcutane-

there

especially

tive subjects.

of exposure

Furthermore

that

responses. is

tamine into the circulation, causing in those individuals whose tolerance to histamine is low, the reactions

it causes its characteristic

that

5”~. in the feet, with corresponding

as shock

of body

there

of skin temperature

heat

and

of

conser-

systemic

blood

organs, and even though remote from the source of histamine formation, may respond

pressure offsetting

the loss from the flushing

areas.

sensitive

in a characteristic

shoulder

to wrist, a slight alteration

location

of the

tities

manner

by vasodilatation,

nomena such as Endothelium and,

to minute with clinical

urticaria through

quanphe-

or asthma. the carotid

arteries,

the brain,

can be classified

organs,

and it is in this category

With

this

intradermal

result in definite Furthermore,

that mi-

on both

graine may be placed. These organ responses may be evoked by production and release

body

forearm,

of histamine from many causes-trauma, changes in temperature, chemicals or bacterial toxins, or by an allergic reaction otherwise not particularly noted. In the circulating blood, histamine remains but momentarily, being rapidly taken up by the cells, where in sufficient concen-

and external

a blanket

JOURNAL

OF

MEDICINE

over

factors,

brunettes,

one

such two

of the uninsulated

this reaction

all such

is minimal

in

great in blondes and maximal

in

red heads.

39

in each

to become

area on the other arm. Disregarding variable

* Fromthe Presbyterian Hospital,Chicago,Illinois. AMERICAN

placed

depends

temperatures,

injections

area will cause the reaction to five times the intensity

will

variations

of the reaction.

the degree of reaction

such that, with identical

from in the

injection

and significant

in the size and character

as shock

gradient

40

Thomas, Butler-Migraine It has been

cluding

the

the contention authors,

types of migraine, vasoconstricted. recognized tively

high

the cycle attack,

tartrate

two

and the

attacks.

and by

In a rela-

of cases parenteral

will ameliorate obtain of

this medication,

early

or terminate

there remain

aggravation

menstrual attack,

in the

a substantial

no relief

or ex-

their

symptoms

regardless

of having

cycle) will ameliorate

whereas

diminished

out by well

administered

who either

perience

is borne

in-

are

of both etiology

percentage

whereas

number from

This

of individual

ergotamine

there

the vasodilated

features

treatment

of many,

that

Wolff3

delay

in

or total loss of effect. has

demonstrated

period of pulsation, ternal

or defer an

in its use results

carotid

that

the branches

become

rigidly

after

a

of the ex-

dilated,

which

vasoconstrictors

value,

and that pain derives from sustained

contraction which

or no

of muscles of the scalp and neck,

contract

vascular

are of little

after

reflexly

from

the

pain

of

origin.

It seems fitting

to make

a few observa-

tions at this point before proceeding

to the

received it early or even on anticipating an attack. Obviously, the former are in a state

next phase of the study of migraine: (1) Histamine cephalgia, as described by Horton,

of vasodilatation

is due to dilatation

strictor.

and respond

Furthermore

unresponsive prompt

to

to a vasocon-

many of these patients, ergotamine,

and sometimes

lasting

of branches

of the inter-

experience

nal carotid artery, and the attacks may be relieved by spinal puncture and raising the

relief

intrathecal

from

pressure

to 700 mm.

of water.

vasodilators, particularly nitroglycerine, nitrites and nicotinic acid. Experience with

tomata,

alcohol indicates that many persons are certain to precipitate an attack of migraine

branches of the internal carotid, are cortical in origin and involve chiefly cranial, espe-

with as little as one cocktail (vasodilators), while others obtain definite relief from one

cially sensory nerves. (3) Migraine headache involves principally and eventually vasodi-

or two drinks. Atkinson,’ after testing

carotid

of migraine histamine ence no

by

the

hyper-reactors,

preted, vasodilators, exhibited a primary anism.

standard

He believes

cases

intradermal to his experi-

disease, that there were or as generally interand

Pre-headache,

latation twenty-one

test, found contrary

in M&n&e’s

(2)

that

every

vasoconstrictor that there

one

mech-

is a primary

constriction followed by vasodilatation causing the headache and advocates an early attack by nicotinic acid, rather than waiting for the secondary vasodilatation and then treating that phase with a potentially dangerous vasoconstrictor. This is at variance with the generally confirmed fact that use of ergotamine tartrate, a vasoconstrictor, very early (with the first intimation of aura, or in anticipation of attacks expected because of cycle, dissipation, indulgence in food known to be harmful, or impending

are

aura,

due

of the artery,

to

prodromes,

vasoconstriction

branches

of the

particularly

To

study

this aspect

external

the retinal

vessels

mid-

of the mechanism

we have instituted

any reflection

of

the superficial

temporal and occipital, less frequently dle meningeal and internal maxillary. further,

sco-

careful

in order

of the state

study of

to ascertain

if

of the cerebral

vessels (carotid and branches) mined. With the cooperation

can be deterof members

of the Department of Ophthalmology, we have studied eye grounds during intervals between the attacks, and when possible persuade patients to present themselves to us, in the hospital or offices, at the first premonition of an attack. Careful observations with accurate notes upon the state of retinal vessels are carried out at frequent intervals, in some instances without therapy, in others with our various therapeutic agents. Frequently with administration of intravenous AMERICANJOURNAL OF

MEDICINE

41

Thomas, Butler-Migraine histamine,

typical headache

will result, necessitating

of flow or its discontinuance, times frequent can

be carried

Results

stages,

of

at the

and when relieved

showed

was

the state

prodromal

otinic acid or ascorbic there

of eye grounds

out, observing

height of attack,

the rate

during which

examinations

the vessels during

While

of great severity

decreasing

by nic-

acid.

be protein sist

of

case in which of

the

retinal

allergists, that

above

Thus, with

albumin,

specificity,

globulin,

relatively

are antigenic

nological

con-

a somewhat

zone in the scale of pro-

tein degradation. albumoses

as do

must first,

and secondly,

aggregate

loosely demarcated and

we believe,

an antigen

in character,

an

molecules,

no single

vasodilatation

not

immunologists,

enormous

with great immu-

while

the low end of the scale,

ascending amino

acids and

vessels even when there was flushing of the

peptone

skin due to intravenous histamine injection. A large proportion of the cases showed no

They may be injected

observable

bodies and without resulting anaphylactic reactions. Somewhere in the polypeptid

change

in the diameter

of the vessels. However, very

definite,

and

vasoconstriction of the retina, intermittent areas

in some

cases,

marked

of the arteries and arterioles the vasoconstriction being

in character

of the

or state

a few cases showed

retina

and involving

visible

to us.

all

These

patients were not hypertensive’ and examinations between attacks of migraine without therapy showed normal with no such contractions. It

seems

tamine

that

the

contention

vasodilatation

branches

eye

involves

of the external

carotid

grounds that

his-

chiefly

the

artery

is

correct. However, vasoconstriction observed in these few cases did indicate that at times the widespread vasoconstriction in migraine may involve the

postulated ophthalmic

branch of the internal carotid. Much confusion of thought exists regarding the mechanism especially sitization,”

of histamine

with reference which

therapy,

to the term “desen-

in this context

is ambig-

are non-specific

from

various channels

range, this specific antigenic its debut,

and becomes

and specific

as each

boxylated

MEDICINE

increasingly

potent

molecule

as-

configuration.

histidine

(an amino

produce

a state of sensitization

nor that

its parenteral

desensitize word. Therefore,

are

and that successful production physiological tobacco,

the formation

the

and

exhibit

results from the tolerance, case

of

either alcohol,

drugs,

or

produc-

which does not prevent

and release and available

of histamine,

but

to neutralize

Keeping

further

with which histamine

the blood,

why its long continued venously,

but

these

to histamine,

numerous

that substance. from

of the

that

from the increased

tion of histaminase,

appears

therapy

as in

caffein

quite probably

destroy

tolerance

of an increased

can

meaning

not sensitized

of lowered

could

or allergy,

we must conclude

individuals degrees

acid)

administration

in the accepted

mind the rapidity

OF

of anti-

With these facts in mind, we can neither assume that histamine, which is decar-

sitization” should be restricted to conditions of true allergy, or the anaphylactic status, in which antibodies exist as the result of

JOURNAL

through

property makes

protein

sumes its characteristic

is mobilized

AMERICAN

or absorbed

without production

uous and leads to erroneous concepts. Consequently, we believe the term “desen-

previous exposure or reaction to an antigen by whatever route, with the response to subsequent exposures characteristic of the shock organ or organs involved (asthma, hay fever, urticaria, etc.).

and non-antigenic.

it becomes

administration

to the limit of the patient’s

or in dis-

clear intracapa-

city, often for a period of six to ten hours, will

be more

creased

effective

tolerance

than

in creating repeated

an in-

injections

Thomas, Butler-Migraine

42 which

result only in a very brief exposure

to its action.

to

great

severity.

cases have been rejected

Rainey’s*

report

of MCniere’s

of a number

disease

with subcutaneous

of cases

unsuccessfully injections

which were benefited

treated

of histamine,

by its prolonged

venous administration,

encouraged

point of view. Histamine

remains

intra-

us in our for only a

brief time in the blood, being rapidly

taken

up by the cells in which it is normally

found.

Hence,

moderate

it is to be presumed

that brief ex-

Migraine

headaches

usually

unilateral,

orbital.

Characteristic

freedom tacks.

from

appearing

are

any

are

a few minutes of the onset, involving ularly sensory cranial hearing

to histamine. Presuming

At times objective changes, of the skin or a distinctive

necessary

that this reaction

is is it

be specific to one

report

als lack the capacity to decompose some, many or ail proteins to the amino acid level,

than

or at least below

the antigenic

aggregate.

This point of view is reflected by the fairly general failure of skin tests for food allergies to solve the problem brilliant

of migraine.

tion diets, are well recognized, majority foods.

Occasional

results from such tests, or eliminaof cases Why

give

but the great

no clue

is it not probable

individuals

with

no

definite

such tests, have an inability break

down

protein

simple

components,

to specific that

these

results

from

completely

aggregates

to

and periodically

to their

build

up a state of anaphylaxis

which is released

by an attack

much as desensi-

tization

of migraine,

is accomplished? SELECTION

We

OF

CASES

have used no patients

who could conceivably

in this series

have headaches

from

any other cause, such as sinusitis,

neuralgia

of the face or scalp, hypertension,

infection,

skull injury, date

eye disease or brain tumor.

we have

headaches

of

accepted great

patients

severity

or

To

only with those

of

or equilibrium,

various

ceptible to others history is frequent,

or more definite proteins? Suppose that we say that it is not, and that certain individu-

the

that

the

to specific

urticaria

such as dryness body odor per-

of migraine

is usually

distaff

line.

more

from severe

Evidence

foods, notably

and of other allergic and

and

sensations.

may be noted. Familial and numerous observers

side

from

partic-

taste

cutaneous

inheritance

paternal

allergy

not

nerves, predominantly

with

reaction,

but

by aura or prodromes,

smell,

that the source of histamine

is at-

from six hours or more to within

vision,

or an anaphylactic

post-

between

usually,

posure, such as result from single injections, cannot effect any great increase in tolerance

an allergic

and

of the condition symptoms

preceded

doubtful

paroxysmal,

temporal

Headaches

invariably,

All

in this series.

of

chocolate,

states such as hay fever

is common.

Freedom

from

attacks in pregnancy after the first trimester is almost universal. Attacks usually involve nausea and vomiting or nausea alone. Migraine equivalents are frequently

en-

countered either as a complete change in pattern of the attack, or as totally unrelated to sick headaches. authors

(W. A. T.)

paroxysmal

Dr. Post, and one of the in 1924 indicated that

tachycardia

all cases a migraine

was in practically

equivalent,

or cardiac

migraine, and collected nearly fifty cases in which the tachycardia entirely replaced the typical headache, or for longer or shorter periods alternated with the headache. Vasovagal attacks (Gower’s “Borderland of Epilepsy”) are largely constituted of prodromes or aura which fail to materialize as a full blown attack. Determination of specific food allergies by elimination diets is made difficult by a refractory period. Patients, after partaking of food known definitely to produce an attack, may thereafter for a period of from AMERICAN

JOURNAL

OF

MEDICINE

Thomas, Butler-Migraine two to eight without

or ten

indulge

further

ill effect. All patients

Treatment.

by the

intravenous

histamine diluted

days

are now treated

injection

base as histamine

of 1 mg.

of

acid phosphate

in 500 cc. of physiological

salt solu-

gastric

acid

danger

of thrombosis

blood

pressure flow.

which

hypertension,

treatments

central

gradually

modified

on successive

to giving

days. Injections

six injections are given very

slowly, about five drops per minute, beginning

and the rate increased

fied according The

entire

to the individual

procedure

at the

or modiresponse.

takes from

three

to

of

and

No

impairment which

days has now been

secretion,

blood

tion. The initial method of giving three such on alternate

43

versally

or

system

to

was

larger

at a more

an indication

for reduction

or

in or

Evidence

almost

uni-

100 cc., usually because of severe headache, at the rate of five drops per minute at the

the entire

sidered

exist,

present in the rate of flow at which

minute,

will suffice. Blood pressure is taken every half hour, and any decided drop is con-

or renal

successive doses were tolerated. Many patients were unable to take more than 50 to

and tolerated

to four hours

in

disease.

tolerance

first treatment,

case three

of

treated

of mental

eight or more hours. When possible the rate is increased to thirty or even forty drops per in which

velocity

cardiac

evidence

the

of falling

were

found

was

nervous

increasing

decreased

patients

were

there

particularly in event

amounts

progressively

rapid

rate until

500 cc. was taken. Only then was

the course of treatment considered started and four or more additional doses given.

of the

rate or termination of that treatment, usually temporarily. Too rapid an injection

EVALUATION

Evaluation

OF

of results

RESULTS

has not

been

ar-

will result first in flushing of the face, later

rived at haphazardly,

the chest and shoulders, often tachycardia, and finally a typical headache, mild to

possibly

from analysis of objective

severe, which may be relieved by slowing the rate? or by injection directly into the

patients from a follow-up sent every three months.

tubing or otherwise of epinephrine or ascorbic acid (1,000 mg.). The onset of ur-

This questionnaire contains data as to dates of treatment, filled in by us with the

ticaria

or asthma is an indication

procedures. Gastric analysis,

for similar

amount

with each of us having

standards

name and hospital

done in most of the re-

of secretion,

with

as compared

My headaches

questionnaire

number.

They

Well--better-unchanged-worse-with other columns

for:

Frequency Severity

tions, the patients experience no distress, otherwise many complain of heartburn, which is relieved by alkaline powder, or

Duration Nausea and vomiting

prevented by routine frequent powder. Two hemorrhages

feedings and from unsus-

pected ulcers have constrained us to careful histories and adequate acid control. Precautions must necessarily be taken in the long continued use of a substance having such marked effects on circulation and JOURNAI.

but

by the

are:

with fasting or control aspirations. With half-hour aspirations or continuous aspira-

AMERICAN

or ideals,

statements

report:

cent cases, shows a very high acidity a large

patient’s

different

OF

MEDICINE

Prodromes Data as to relation of relief to treatment: Hospital treatment Later treatment Space below for expression of own opinion regarding success or failure of treatment-of actual attacks, modifications of attacks, aura, etc.

Thomas, Butler-Migraine Classification of Results. four

different

relief

types

is concerned:

(1) Those

was immediate-complete permanent (2)

those

but

subsequently peating

whose relief

was immediate

whose

headaches

or months,

and

improved

injections

who

did

after

the intravenous

not

or relieved

by sub-

immediate

complete

or

satisfac-

tory relief either spontaneously or by later subcutaneous injections of histamine; and (4) those who obtained

no relief.

TABLE I CRITERIA FOR SELECTION OF CASES OF MXCRAlNE They are: Paroxysmal Usually unilateral-post-orbital, supra-orbital or occasionally occipital The patient is: Free of symptoms between attacks Free of symptoms during second and third trimesters of pregnancy Frequently allergic The aura: May involve all sensory cranial nerves, especially II (scotomata, blindness, diplopia, hemianopsia) VIII (deafness, tinnitus, vertigo, equilibrium) I (smell) Cutaneous sensory, pruritis, subjective changes in temperature Equivalents: Paroxysmal tachycardia Vasovagal attacks

One

hundred

migraine

of

four

great

or

I

patients moderate

with

pure

severity

have been

treated. The definite values for are age, sex, age of onset and duration essentially similar to the statistics of seventyfive cases reported in the Bulletin of the New York Academy of Medicine, March, 1946. No patients have been treated whose attacks were not sufficiently severe to interfere with routine daily life, expectancy of meeting engagements or obligations.

104 :‘;; 87 36 years

. 19 years 20 years

. . 25 hours

I

/ Mod. Severe

Relief

relief

but who

II

TABLE III RELIEF OBTAINED

were

(3) those

treatments,

obtained

TABLE

of patients. . Sex-Male. Female. Average age. Average age at onset. Average duration of migraine. Average length of attacks. (excluding cases of migraine state) No.

or by re-

program;

experience

and

recurred

which

of histamine

the intravenous

gradually

as

(up to three years eight months) ;

weeks

cutaneous

found

as far

and apparently

whose relief

complete, after

have

We

of response.

Complete, permanent. Complete, temporary. Partial. . . None. .

. .. .

I Very Severe

I-I-I14

6 18 7 ______.-

Total.

45

Total

28 10 16 5

42 16 34 12

59

104

CONCLUSIONS

A method cephalgia applied severe results

found successful

and in M&S-e’s to

in histaminic

disease has been

approximately

100

cases

provement

may

tinued injection,

be found perhaps

in longer

twenty-four

conhours

at each treatment. In a process which is potentially gastric gerous, both from increased production creased choose

of

headache due to migraine. The have been satisfactory and an im-

and possible

blood

pressure,

for treatment

collapse

danacid

from de-

it is important

to

only those cases that

cannot be other than migraine moderate to great severity.

and are of

REFERENCES 1. ATKINSON, M. Migraine headache. Some clinical observations on the vascular mechanism and its control. Ann. Znt. Med., 21: 290, 1944. 2. RAINEY, J. J. Histamine in treatment of Meniere’s syndrome. 3. A. M. A., 122: 850, 1943. 3. WOLFF, H. G., CAHAN, A. M. and SCHUMACHER,G. D. Studies on migraine. The contrast of vascular mechanism in headache and pre-headache. Tr. Am. Neural. A., 66: 150, 1940.

AMERICAN

JOURNAL

OF

MEDICINE