Prophylactic Activity of Increasing Doses of
Intravenous Histamine in Refractory Migraine:
Retrospective Observations of a Series of Patients
With Migraine Without Aura
U m b e r t o Pietrini, M D , 1'2 Massimo De Luca, M D , 1'2 Enrico Del Bene, M D , 1'2 Francesco De Cesaris, M D , 1'2 Luca Bertinotti, M D , 2 Nicola Colangelo, M D , 2 and Alberto M o g g i Pignone, M D 2
1Headache Center, Department of Intemal Medicine, University of Florence, Villa Monna Tessa, Italy, and 2Department of Internal Medicine, Clinica Medica IV, Villa Monna Tessa, Italy
ABSTRACT
Background:
Histamine is thought to play a pivotal role in the modulation of peripheral and central pain. The administration of increasing doses of hista- mine may lead to desensitization of receptors of histamine types 1 and 2, causing meningeal vasodilation, and to depletion of neuropeptides in the tri- geminal ganglion, thus inhibiting the initiation of migraine.Objective:
In this study, the efficacy and tolerability of increasing doses of IV histamine in migraine prophylaxis were investigated.Methods:
This single-center, open-label, retrospective, controlled study was conducted at the Headache Center (Department of Internal Medicine, Univer- sity of Florence, Villa Monna Tessa, Italy). Patients included in the study had 3 to 6 migraines without aura per month that were refractory to common symptomatic and prophylactic agents in the 6 months preceding the study. Patients were treated with IV histamine hydrochloride for 21 days starting with a dosage of 0.5 mg/d and increasing to 4.0 mg/d. To assess the efficacy of the treatment, these patients were matched for age; sex; and frequency, duration, and severity of attacks with untreated migraineurs. Clinical benefit was defined as -< 1 migraine of mild intensity per month. Tolerability was assessed during the hospitalization period, and patients were instructed to contact the Head- ache Center to report any adverse effects after hospital discharge.Results:
The histamine group comprised 47 patients (40 women, 7 men; mean [SD] age, 42.0 [8.6] years) and the control group comprised 23 patients (20 women, 3 men; mean [SD] age, 38.8 [8.4] years). The histamine-treated patients showed a clinical benefit lasting for a mean of 10.4 (4.2) months, while the patients in the control group showed a clinical benefit of 3.8 (1.9) months. Accepted for publication December 3, 2003.U. Pietrini et aL
The difference in the duration of the clinical benefit between the 2 groups was 6.6 months (95% CI, 5.15-7.99). Adverse effects consisted of flushing, heat sen- sation during infusion, headache, and palpitations.
Conclusions: In this study, histamine showed lasting prophylactic efficacy in migraineurs. If further research confirms this preliminary finding, histamine could be c o n s i d e r e d when established prophylactic drugs, such as beta- blockers, calcium antagonists, antidepressants, and antiepileptics, have not been effective. (Curr Ther Res Clin Exp. 2004;65:70-78) Copyright © 2004 Excerpta Medica, Inc.
Key words:
histamine, migraine, prophylaxis.INTRODUCTION
Histamine is thought to play a pivotal role in the modulation of pain. Histamine is involved peripherally in the stimulation of nociceptive fibers, while it seems to have a centrally important role in antinociception. 1 Histamine seems to be involved in the pathophysiology of pain in migraine through different mecha- nisms. In migraine patients, the administration of histamine or the nitric oxide (NO) donor glyceryl trinitrate induces headache during infusion, followed by a typical migraine. 2'3 Histamine probably induces migraine by activating NO syn- thase, thereby promoting endogenous NO production. 4'5 NO causes immediate dilation of meningeal blood vessels, which provokes headache; this dilation is partially blocked by sumatriptan succinate and indomethacin. 6 Migraineurs experience a stronger headache than nonmigraineurs, possibly because of hy- persensitivity in the NO-cyclic guanosine m o n o p h o s p h a t e pathway. 3 Also, some evidence shows that neurogenic inflammatory processes of the meninges cause the severe pain in migraine and cluster headaches. 7'8 Substance P (SP) and neurokinin A (NKA) are responsible for plasma extravasation in the dura mater, and calcitonin gene-related peptide (CGRP) seems to mediate the in- crease in meningeal blood flow. During migraine, an increase in CGRP levels has been described in venous flow from the head. 9 The release of neuropeptides lead- ing to neurogenic inflammation in the vessels of the dura mater may be secondary to algesiogenic mediators (bradykinin, histamine, serotonin), which primarily ac- tivate the trigeminal nociceptive afferent nerves. These inflammatory mediators cause a massive release of CGRP and prostaglandin E 2 from the dura mater. The same effect can be obtained by electrical stimulation of the trigeminal ganglion. 1° We hypothesized that administration of increasing doses of histamine would lead to desensitization of histamine types 1 and 2 (H~ and H 2, respectively) receptors, causing meningeal vasodilation, and to depletion of neuropeptides in the trigeminal ganglion, thus inhibiting the initiation of migraine. Several classes of drugs (eg, beta-blockers, calcium antagonists, antidepressants, and antiepileptics) have shown prophylactic activity in migraine. H-22 However, in our experience, these drugs are not always effective. At the Headache Center (Department of Internal Medicine, University of Florence, Villa Monna Tessa,
Italy) in the past, many patients with disabling migraines that were unrespon- sive or poorly responsive to the usual symptomatic treatments (nonsteroidal anti-inflammatory drugs [NSAIDs], dihydroergotamine mesylate) and prophylac- tic treatment with beta-blockers, calcium antagonists, and antidepressants (pro- pranolol hydrochloride, flunarizine hydrochloride, and amitriptyline hydrochlo- ride, respectively) who were given prophylactic treatment with increasing doses of IV histamine showed dramatic, long-lasting improvement in their symptoms. Various doses of histamine and durations of treatment have been used.
In this study, we compared the results obtained with the most frequently used dosing regimen in our clinic with those in untreated patients matched for age; sex; and frequency, duration, and severity of migraines. The clinical benefit of histamine prophylaxis was defined to endure as long as -< 1 mild attack per month was reported. Tolerability of the treatment was assessed during and after hospitalization.
PATIENTS A N D M E T H O D S
This open-label, retrospective, controlled study was conducted at the Head- ache Center (Department of Internal Medicine, University of Florence, Villa Monna Tessa, Italy) according to the principles of the Declaration of Helsinki. We retrieved data from our files for all patients treated with the most fre- quently used dosing regimen of histamine from 1990 to 1995 who were followed up for -<2 years. Patients were eligible for the study if they had had 3 to 6 migraines without aura per month in the 6 months preceding the study. Exclusion criteria were age <18 or >65 years, peptic ulcer, asthma, chronic obstructive pulmonary disease, or any other disorder requiring medical treat- ment. Pregnant, possibly pregnant, or breastfeeding women were excluded from the study. Treatment with oral contraceptives, if used, was continued during hospitalization. All patients provided verbal informed consent to hista- mine treatment and pharmacologic testing. Any prophylactic treatment for mi- graine was suspended in the 3 weeks preceding hospitalization, which lasted 23 to 30 days for both the histamine and control groups. The study was un- blinded, as both physicians and patients were aware of treatments. Data ex- traction and matching with untreated patients were performed during 2003.
The treatment group (histamine group) comprised patients with migraine without aura diagnosed according to the International Headache Society crite- ria 23 totally or partially unresponsive to symptomatic (NSAIDs, dihydroergota- mine) and prophylactic treatments (propranolol, flunarizine, amitriptyline). They were treated with a 21-day regimen of IV histamine hydrochloride (in 250 mg of saline 0.9%) in increasing doses, starting with 0.5 mg/d for 2 days, and increasing by 0.5 mg every 2 days until a 4.0-mg dose was reached; that dose was maintained for 1 week, and then was interrupted. The rate of infusion was self-controlled by the patients, who were instructed to reduce the rate of infu- sion at the onset of headache, palpitations, or flushing.
U. Pietrini et aL
The control group c o m p r i s e d patients who were also poorly r e s p o n s i v e to the usual s y m p t o m a t i c and pharmacologic t r e a t m e n t s and who were m a t c h e d to the histamine group by age; sex; and frequency, duration, and severity of migraines. Furthermore, patients included in the control group had been hos- pitalized during the same period but did not tolerate histamine infusion (these patients received only the first 0.5-mg dose) and u n d e r w e n t only diagnostic examinations. T h e s e e x a m i n a t i o n s included p h a r m a c o l o g i c t e s t s (pupillo- metric tests with tyramine 2% e y e d r o p s and p h e n y l e p h r i n e h y d r o c h l o r i d e 1% e y e d r o p s ) to assess pupillary adrenergic activity and v e n o c o n s t r i c t i o n tests to serotonin, dopamine, and n o r e p i n e p h r i n e administered in the dorsal vein of the hand at doses that elicited only local effects to assess reactivity to serotonin and monoamines. T h e s e tests were r e p e a t e d every 2 or 3 days during days 0 to 21 for consistency. The pharmacologic tests were c o n d u c t e d to s t u d y a pos- sible adrenergic peripheral impairment in migraine patients and are described elsewhere. 24-26 After the first dose, patients in the control group received only saline infusions for the t r e a t m e n t of migraine symptoms.
In b o t h groups, clinical and l a b o r a t o r y examinations were p e r f o r m e d every 2 or 3 days. The use of drugs for the relief of migraine s y m p t o m s was allowed in b o t h groups except during histamine infusion in the t r e a t m e n t group, which usually lasted 30 minutes to 2 hours. At hospital discharge, patients were given s y m p t o m a t i c t r e a t m e n t and were instructed to maintain a daily r e c o r d of their migraines, specifying the intensity (on a 4-point rating scale: 0 = none, 1 = mild, 2 = moderate, and 3 = severe) and duration of migraine (in hours). Control visits were scheduled at 6-month intervals for -<2 years after t r e a t m e n t for each patient, and patients were instructed to c o n t a c t the clinic if they had >3 mi- graines in a month. Clinical benefit was defined to last as long as -< 1 attack of mild intensity per m o n t h was r e p o r t e d .
Statistical Analysis
To assess the efficacy of the prophylactic treatment, the duration of clinical benefit in the 2 groups was c o m p a r e d using the Student t test. The 95% CI was calculated for the difference in the duration of clinical benefit b e t w e e n the 2 groups. Statistical analysis was p e r f o r m e d using the Statistical Package for Social Sciences version 10.0 (SPSS Inc., Chicago, Illinois). Statistical significance was set at P -< 0.05.
RESULTS
The histamine group c o m p r i s e d 47 patients (40 women, 7 men; mean [SD] age, 42.0 [8.6] years) and the control group c o m p r i s e d 23 patients (20 women, 3 men; mean [SD] age, 38.8 [8.4] years) (Table I). The mean (SD) history of migraine also was similar in the histamine and control groups (22.0 [8.5] years and 21.5 [13.8] years, respectively). The mean (SD) f r e q u e n c y of migraines per m o n t h was similar in the 2 groups (5.1 [1.2] and 5.0 [0.9], respectively), as was
Table I. Demographic and clinical characteristics of study patients (N = 70).*
Histamine Group Control Group
Characteristic (n = 47) (n = 23) Age, y Mean (SD) 42.0 (8.6) 38.8 (8.4) Range 26-58 26-56 Sex, no. (%) Women 40 (85.1) 20 (87.0) Men 7 (14.9) 3 (1 3.0) Migraine characteristics History, mean (SD), y 22.0 (8.5) 21.5 (13.8) No./mo, mean (SD) 5.1 (1.2) 5.0 (0.9) Duration, mean (SD), h 43.9 (15.5) 46.4 (15.1) Prophylaxis, no. (%)t Propranolol 40 (85.1) 18 (78.3) Flunarizine 22 (46.8) 10 (43.5) Amitriptyline 9 (19.1) 3 (13.0)
*No significant between-group differences were found.
tSome patients received >1 prophylactic drug, either in association or in sequence; that is, prophylaxis with propranolol was usually established at first, and then, in case of no clinical benefit within 2 months, propranolol was substituted with amitriptyline or flunarizine, or amitriptyline was added to the propranolol regimen.
the choice of prophylaxis, with most patients (85.1% and 90.0% of patients, respectively) having received propranolol. Some patients had been treated with >1 prophylactic agent, in association or in sequence; that is, prophylaxis with propranolol was usually established at first, and then, in case of no clinical benefit within 2 months, propranolol was substituted with amitriptyline or flunarizine, or amitriptyline was added to the propranolol regimen.
Analysis of the results showed a significant difference in the duration of clinical benefit in the 2 groups, with patients in the histamine group demon- strating a clinical benefit of 3 to 19 months (mean [SD], 10.4 [4.2] months [range, 3-19 months]) and patients in the control group demonstrating a clini- cal benefit of 1 to 7 months (mean [SD], 3.8 [1.9] months [range, 1-7 months]) (P < 0.001) (Figure). The difference between groups was large, with the mean duration being 6.6 months longer in the histamine group (95% CI, 5.15-7.99).
Histamine administration was fairly well tolerated. In the 47 patients receiv- ing the full course, adverse effects (AEs) consisted of flushing (30 patients [63.8%]), heat sensation during infusion (27 patients [57.4%]), h e a d a c h e (pul- sating and bilateral) (20 patients [42.6%]), and palpitations (15 patients [31.9%]) (Table If). None of the AEs were considered serious, and patients could limit them by controlling the rate of infusion. AEs resolved in 15 to 30 minutes after reducing the rate of infusion. No clinically significant alter- ations in laboratory findings were noted.
U. Pietrini et aL 12 10 8 r~e- 6 .o 4 T Histamine Control Group Group (n -- 47) (n -- 23)
Figure. Duration of clinical benefit (defined as -~1 migraine of mild intensity per month). *P < 0.001 versus the control group.
D I S C O S S I O N
Histamine showed lasting clinical benefit (mean, 10.4 m o n t h s ) c o m p a r e d with 3.8 m o n t h s in control patients. Control patients also showed clinical benefit, although this could have been due to prolonged hospitalization, with the likely reduction in stressful factors, which are certainly important in precipitating migraines. The clinical benefit shown by histamine in our trial was similar to t h a t o b s e r v e d in t h e only 2 trials 27'28 of t h e efficacy of h i s t a m i n e and N-methylhistamine in migraine prophylaxis according to a MEDLINE s e a r c h (key terms:
migraine, prophylaxis,
andhistamine;
years: 1970-2003). In t h o s e 2 studies, much lower doses were used (histamine 0.1-1.0 ng subcutaneously and N-methylhistamine 1-10 ng subcutaneously). Although the mechanism of action of histamine as a p r o p h y l a c t i c agent in migraine remains to be elucidated, administering histamine in increasing doses might desensitize H 1 and H 2 recep-Table II. No. (%) of patients experiencing ---1 adverse effect (AE) with histamine adminis- tration in those receiving the full course of histamine therapy (N = 47).
AE No. (%) of Patients
Flushing 30 (63.8)
Heat sensation during infusion 27 (57.4)
Headache (pulsating and bilateral) 20 (42.6)
tors, p r e v e n t i n g t h e initiation of a migraine. Also, histamine, in t h e large d o s e s u s e d in o u r study, m a y h a v e d e p l e t e d SP, NKA, and CGRP in t h e trigeminal ganglion, t h e r e b y r e d u c i n g t h e r e s p o n s e to p r e c i p i t a t i n g factors. A n o t h e r pos- sibility is t h a t h i s t a m i n e d i r e c t l y e v o k e d a n t i n o c i c e p t i v e action29; it h a s b e e n s h o w n t h a t injection of h i s t a m i n e into t h e p e r i a q u e d u c t a l gray has an antino- c i c e p t i v e effect in rats and t h a t t r e a t m e n t s t h a t i n c r e a s e t h e levels of endog- e n o u s h i s t a m i n e in t h e b r a i n relieve pain. 3°'31 In fact, blocking t h e n e g a t i v e f e e d b a c k m e d i a t e d b y h i s t a m i n e t y p e 3 (H3) a u t o r e c e p t o r s and inhibiting h i s t a m i n e - N - m e t h y l t r a n s f e r a s e ( t h e p r i m a r y h i s t a m i n e - d e g r a d i n g e n z y m e ) b o t h r e s u l t in a n t i n o c i c e p t i o n . 32'33 F u r t h e r m o r e , H3-receptor agonists are c u r r e n t l y being p r o p o s e d for a v a r i e t y of i n f l a m m a t o r y d i s e a s e s and pain d i s o r d e r s , including migraine. 34'35 Finally, t h e a d m i n i s t r a t i o n of h i s t a m i n e might n o r m a l i z e s e r u m b e t a - e n d o r p h i n c o n c e n t r a t i o n s . 36
Our s t u d y s u g g e s t s lasting efficacy of h i s t a m i n e a d m i n i s t e r e d i n t r a v e n o u s l y in i n c r e a s i n g d o s e s f r o m 0.5 to 4.0 mg for 21 d a y s in migraine p r o p h y l a x i s . Our s t u d y h a d s o m e limitations in t h a t it was n o t a p r o s p e c t i v e , r a n d o m i z e d , double-blind trial; i n v e s t i g a t o r s s e l e c t e d t h e p a t i e n t s w h o w e r e i n c l u d e d in t h e h i s t a m i n e t r e a t m e n t group, and b o t h i n v e s t i g a t o r s and p a t i e n t s w e r e a w a r e of t h e a s s i g n e d t r e a t m e n t . Our p r e l i m i n a r y findings d e s e r v e f u r t h e r investigation in p r o s p e c t i v e double-blind trials. H o w e v e r , t h e 2 t r e a t m e n t g r o u p s w e r e ho- m o g e n e o u s and w e r e h o s p i t a l i z e d in t h e s a m e institution for t h e s a m e time p e r i o d u n d e r similar c o n d i t i o n s , m e a n i n g t h a t t h e 2 g r o u p s w e r e c o m p a r a b l e .
CONCLUSIONS
In this s t u d y , h i s t a m i n e s h o w e d lasting p r o p h y l a c t i c efficacy in migraineurs. If f u r t h e r r e s e a r c h c o n f i r m s this p r e l i m i n a r y finding, h i s t a m i n e c o u l d b e consid- e r e d w h e n e s t a b l i s h e d p r o p h y l a c t i c drugs, s u c h as b e t a - b l o c k e r s , c a l c i u m an- tagonists, a n t i d e p r e s s a n t s , and antiepileptics, h a v e n o t b e e n effective.
ACKNOWLEDGMENTS
This study was sponsored by Merck, Sharp, & Dohme (Italy) S.p.A. (Rome,
Italy).
T h e a u t h o r s t h a n k Prof. Marcello Fanciullacci for his v a l u a b l e c o m m e n t s .
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Address correspondence to: U m b e r t o P i e t r i n i , MD, H e a d a c h e C e n t e r , D e p a r t - m e n t of I n t e r n a l M e d i c i n e , U n i v e r s i t y of F l o r e n c e , Villa M o n n a T e s s a , V.le P i e r - a c c i n i 18, 50139 F i r e n z e , I t a l y . E-mail: u . p i e t r i n i @ l i b e r o . i t
