A NEW TREATMENT FOR HEADACHE: PATHOPHYSIOLOGIC

CONSIDERATIONS

Fuad Lechin, M.D.

Bertha van der Dijs, M.D.

Departmento de Patologia General y Fisiopatolgia, Escuela de Medicina and Departamento de

Bioquimica, Escuela de Bioanalisis, Facultad de Medicina, Universidad Central de Venezuela,
Caracas, Venezuela

Accepted for publication: 9/10/76

SYNOPSIS

The oral administration of d-amphetamine with propranolol led to an immediate improvement of

161 out of 163 treated headache patients. Total disappearance of headache and other associated
symptoms occurred after a few days. No relapses were observed while on this therapy. This
therapeutic trial lasted 16 months and indicated the safety of the treatment. The addition of the
beta-blocker propranolol appears necessary to counteract undesirable side effects of amphetamines.
Low doses of d-amphetamine are necessary for therapeutic success. We suggest that headache and
depression are due to a predominance of the serotonergic over the noradrenergic system. Activation
of the serotonergic system could be triggered by beta-adrenergic effects of the noradrenergic
system. We postulate also that serotonin acts like a weak alpha-adrenergic agonist and competes
with nor-epinephrine for alpha-receptors on cell membranes. Low doses of d-amphetamine, by
stimulating the noradrenergic system only, and propranolol by interfering with serotonin synthesis in
neurons, reestablish normal physiologic conditions.

(Headache 16:318-321, 1977)

VASCULAR HEADACHE of the migrainous type and muscle contraction headache are common
complaints. Intracranial arterial vasoconstriction followed by extracranial arterial vasodilatation, and sustained
contraction of the scalp and neck muscles, nausea, vomiting, hyperacidity, abdominal distention, cold hands
and feet, chills, dizziness, abdominal and thoracic pains, tachycardia and psychic disturbances may
accompany or substitute headache. Repression of anger, hostile impulses and other emotions trigger
headache attacks in susceptible patients, who are often depressed.

Serotonin, histamine, catecholamines, bradykinin, and other humoral substances have been implicated in
the genesis of these symptoms.1 Therefore, serotonin and histamine antagonists, amphetamine,
alpha-adrenoceptor blockers, beta-adrenoceptor blockers, beta-adrenoceptor stimulants, amine-precursors,
and MAO-inhibitor drugs have been used in the treatment of headache and depression.2,3,4,5,6 We reported
the disappearance of headache in 93.2% of 165 "spastic colon" patients treated with low doses of
d-amphetamine and propranolol.7 Because of this success, we instituted a trial of this therapy in headache
patients.

PATIENTS AND METHODS

We have treated 163 headache patients; 91 females, and 72 males. Ages ranged from 12 to 75 years,
(mean 35.2 years). All were thoroughly studied and no organic disease triggering headaches was found.
Headache frequency was from daily to 3 times monthly. Duration of attacks ranged from a few hours to many
days. All patients had prior treatment with more than 3 different drugs. Each patient was treated orally with
d-amphetamine (2.5 mg) and propranolol (10-20 mg) simultaneously, one to three daily for 3 to 16 months
(mean 7 months). Thirty two patients were chosen for a double blind study; 18 females and 14 males (age
range 23-56 years, mean 37.5 years). These patients were selected because they had the best relief (40 to
50%) with other treatments.

Patients kept a record of the frequency, intensity, and duration of their symptoms. Records over the last 3
months of treatment with other drugs were compared with the records during the first 3 months of
treatment with d-amphetamine and propranolol. Neither patients nor doctors knew the medications given
because they were administered in identical dark capsules.

RESULTS

All but two patients improved immediately after the first 24-48 hours of treatment. Total disappearance of
headache and associated symptoms occurred after a few days. No relapses were observed while on the
drugs. The double blind study showed relief by previous treatments 45.6% ± 4.2 (mean ± S.E.); relief by
d-amphetamine and propranolol 94.3 % ±3.8 (p<0.001).

Complications during treatment were: 42 patients with moderate insomnia, 23 anorexia, 27 hemorrhoidal
bleeding, 11 intestinal colic, 15 dizziness or "light" headedness. Lowering the dosage of the test drugs or
symptomatic treatment controlled complications. Frequently, one daily dose of d-amphetamine and
propranolol was enough to eliminate headache. The patients learned to adjust their dose according to need,
interrupting treatment during "good" days. After 4-5 weeks of treatment, reduced doses were controlling
symptoms. No withdrawal symptoms occurred after cessation of therapy. When treatment was restarted, it
was equally successful as the initial treatment. Seven hypertensive, 9 diabetic, 5 asthmatic and 2 coronary
patients were treated without complications. The two patients not improved by d-amphetamine and
propranolol were a mother and daughter; both were helped by antihistaminic drugs.

DISCUSSION

In spite of failure of d-amphetamine as an antidepressant,8 this drug given together with propranolol
eliminated headache and other depressive manifestations in our patients. The low doses used and blockade
of beta-adrenoceptors with propranolol could account for the success of therapy. The use of propranolol
could explain the lack of psychomotor hyperexcitability usually observed when amphetamine is given. Our
patients felt reassured, fearless, mentally lucid, and in good condition for sexual activity. Premature
ejaculation, when present, was often improved. Spontaneous aggressiveness was not observed, and
improved self-defense capability was noted.

High epinephrine to norepinephrine ratios were found in adrenal glands of nonagressive species, "hunted"
animals; and low epinephrine/norepinephrine ratios in aggressive, "hunting" animals. The greater
beta-adrenergic effects of epinephrine could be associated with these behavioural differences. This could
account, also for the finding that epinephrine excretion in urine is linked with passive, anxious emotions;
whereas norepinephrine excretion is associated with active and outward physically expressed emotions.9 In
support of these relationships, Shintomi10 found 2 types of behaviour in amphetamine treated rats: a) fighting,
and b) locomotor hyperactivity (running and jumping). Haloperidol which antagonizes clonidine, a central
alpha-adrenergic agonist, suppressed selectively fighting behaviour only.

In our experience, the administration of d-amphetamine alone to headache patients induced therapeutic
effects which decreased after a few days. This resistance was temporarily surmounted by increasing the
doses, but thereafter, depressive symptoms increased. On the contrary, when propranolol was administered
along with d-amphetamine, the therapeutic benefits persisted, even after decreasing the doses of the drugs.
We think that both low doses of d-amphetamine and beta-blockade are the keys to the therapeutic success
of d-amphetamine. Low doses would stimulate the noradrenergic system selectively,11 and hence,
alpha-adrenergic effects would predominate. On the other hand, large doses of d-amphetamine increase
whole brain levels of serotonin.12 Furthermore, we have reason to think that beta-adrenergic actions include
stimulation of the serotonergic system. Thus cAMP intracellular levels are increased by beta-adrenergic
stimulation, and this nucleotide in cultured pineal gland enhanced the synthesis of 5-HT.13 Furthermore,
injection of dibutyril
cAMP into the lateral ventricles of the rat increased 5-HT turnover in the brain.14 Other experimental evidence
suggests that serotonin synthesis depends partly on adrenergic influences.15,16 Moreover, it has been suggested
that serotonergic-cell bodies innervated by sympathetic nerves could be regulated through beta-adrenoceptors.
Because of this, it is note-worthy that in the intestine, post-ganglionic adrenergic fibers end at the mucosal layer,
where the enterochromaffin cells are located. 17
An antagonism between serotonergic and catecholaminergic systems has been postulated.18 In spite of
paradoxical reports, new evidence 19,20 suggests that aggressiveness may be correlated with the NE system, and
that the 5-HT system antagonizes this. The dopaminergic (DA) system can also be correlated with aggressiveness,
when it is the only activated catecholaminergic system. However, when this is accompanied by NE system activity,
elevated brain DA levels can act by decreasing the effects of norepinephrine. D-amphetamine stimulates the
catecholaminergic system. Given in low doses, the drug activates NE neurons, whereas large doses of the drug,
activate DA and 5-HT neurons, preferentially. The serotonergic enhancement induced by large doses of
d-amphetamine, could be due to the action of catecholamines released by the drug, although a direct effect of
amphetamine on 5-HT neurons can not be excluded.

The results of experimental investigations and our own findings suggest that headache and other depressive
manifestations could be due to an initial adrenergic state with a secondary serotonergic state triggered by the
former. The link between both is provided through catecholamines acting on beta-adrenoceptors of 5-HT neurons.
This hypothesis fits the two steps of classic migraine, an initial intracranial vasoconstriction, followed by extracranial
vaso-dilatation. If headache and other depressive manifestations relate to the predominance of 5-HT system over
NE system, one could revert this situation by inducing an alpha-adrenergic state through the administration of
d-amphetamine with propranolol. This could induce a specific antagonism between serotonergic and
alpha-adrenergic states.

We infer that serotonin could act sometimes as an alpha-adrenergic agonist, and at other times as an
antagonist. By accepting serotonin as a weak alpha-adrenergic agonist which competes with NE for
alpha-receptors on membranes, we could reconcile a number of contradictory findings. Alpha-adrenergic effects
would occur when serotonin alone is present, whereas, competitive inhibition results when both serotonin and NE
are present. We speculate that serotonin has a modulating influence on alpha-adrenoceptors.

Dr. Albert Fanchamps read and revised the manuscript.

REFERENCES

1. Sicuteri, F.: Vasoneuroactive substances and their implication in vascular pain. In Friedman AP (Editor):
Research and clinical studies in headache: An internal review. Basel, S. Karger, 1967, vol. 1, pp 6-45.

2. Friedman, A. P.: Headache. Post-graduate Med. 53:172-178, 1973.

3. Wheatley, D.: An adrenergic drug in depression. Arch Gen Psychiatry 32:653-655, 1975.

4. Wideroe, T. E., Vigander, T,: Propranolol in the treatment of migraine. Brit Med J 2:699-701, 1974.

5. Liston, E. H., Levine, M.D., Philippart, M.: Psychosis in fabry disease and treatment with phenoxybenzamine,
Arch Gen Psychiatry 29:402-403, 1973.

6. Mendels, J., Stinett, J. L., Burns, D., Frazer, A.: Amine precursors and depression. Arch Gen Psychiatry
32:22-30, 1975.

7. Lechin, F., van der Dijs, B., Bentolila, A., Pena, F.: The "spastic colon" syndrome: therapeutic and
pathophysiological considerations. (Submitted for publication).

8. WheatIey, D.: Amphetamines in general practice: Their use in depression and anxiety. Sem Psychiatry
1:163-173, 1969.

9. Fuller, R. W.: Control of epinephrine synthesis and secretion. Fed Proc 32:1772-1781, 1973.

10.. Shintomi, K.: Effects of psychotropic drugs on metaamphetamine-induced behavioural excitation in grouped
mice. European J Pharmacol 31:195-206, 1975.

11. Snyder, S. H., Taylor, K. M., Horn, A. S., Coyle, J. T.: Psychoactive drugs and neuro-transmitters:
differentiating dopamine and norepinephrine neuronal functions with drugs. Res Pub Assoc Nerv Ment Dis
50:359, 1972.
12. Welch, B. L., Welch, A. S.: Control of brain catecholamines and serotonin during acute stress and
after d-amphetamine by natural inhibition of monoamine oxidase: a hypothesis, in: International
Symposium on Amphetamines and Related Compounds, eds. E. Costa and S. Garattini (Raven Press,
New York) p. 415, 1970.

13. Shein, H. M., Wurtman, R. J.: Cyclic adenosine monophosphate stimulation of melatonin and
serotonin synthesis in cultured rat pineals. Science (Washington) 166: 519- 520, 1969.

14. Tagliamonte, A., Tagliamonte, P., Forn, J., Perez-cruet, J., Krishna, G., Gessa, G. L.: Stimulation of
brain serotonin synthesis by dibutyril cyclic AMP in rats. J Neurochem 18:1191-1196, 1971.

15. Modigh, K.: Functional aspects of 5-hydroxy-tryptamine turnover in the central nervous system. Acta
physiol scand Suppl 403:27-35, 1974.

16. Brownstein, M., Holz, R., Axelrod, J.: The regulation of pineal serotonin by a beta adrenergic receptor.
J Pharmacol exp Ther 186: 109-113, 1973.

17. Christensen, J.: The adrenergic nerves and gastrointestinal smooth muscle function. Gastroenterology
55:135-138, 1968.

18. Brodie, B. B., Shore, P. A.: A concept for the role of serotonin and norepinephrine as chemical
mediators in brain. Ann NY Acad Sci 66:631-642, 1957.

19. Breese, G. R., Cooper, B. R., Mueller, R. A.: Evidence for involvement of 5-HT in the actions of
amphetamine. Br J Pharmac 52:307-314, 1974.

20. Hodge, G. K., Butcher, L.: Catecholamines correlates of isolation-induced aggression in mice.
European J Pharmacol 31:81-93, 1975.

Reprint requests to:

Fuad Lechin, M.D.
Titular Professor
Universidad Central de Venezuela
Apartado de Correos 50587 - Sabana Grande
Caracas, Venezuela