Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomised, placebo controlled, crossover study
BMJ 2001; 322 doi: https://doi.org/10.1136/bmj.322.7277.19 (Published 06 January 2001) Cite this as: BMJ 2001;322:19All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
After reading the article written by H. Schrader et al. “Prophylactic
treatment of migraine with angiotensin converting enzyme inhibitor
(lisinopril):randomised, placebo controlled, crossover study” (5), some
considerations have arisen.
The use of ACE-inhibitors as prophylactics in headache treatment was
first proposed by F. Sicuteri in 1981 (6). The “rationale” for this was
the inhibition of dipeptidyl-carboxypeptidase, an enkephalin inactivating
enzyme. This hypothesis was supported in 1986 by Baldi et al. (1) who
found an increased plasma level of b-endorphynes in migraine sufferers
after assumption of a single oral dose of captopril.
In 1986 we wanted to try captopril in 42 migraine-hypertensive patients in
an open study (30 treated with captopril and 12 with other classic
antihypertensive drugs, excluding Ca2+ channel blockers, clonidine and â-
blockers). The result was a stable normalisation of arterial blood-
pressure but the symptom headache did not show any statistically
significant difference between the two groups .
Although more recent studies, Paterna et al -1992- (3), indicate the
clinical utility of captopril in preventing migraine, ACE-inhibitors are
still neither recommended nor used by headache-specialists.
We suggest that the efficacy of lisinopril as well as other ACE-inhibitors
should be proved by several investigations.
C.Canepari, M. Riva
Department of Neurological Sciences - Ospedale Niguarda,
p.zza Ospedale maggiore,3 -20162- Milano, Italy
e-mail : canepari@tiscalinet.it
REFERENCES
1.Baldi E, Conti P, Conti R, Fanciullacci M, Michelacci S, Salmon S,
Sicuteri F, Spillantini MG . Hypernociceptive syndromes and
pharmacological nhibition of endogenous opioid degradation. Int J Clin
Pharmacol Res 1986;6(3):193-7
2.Bender WI. ACE Inhibitors for Prophylaxis of Migraine Headaches.
Headache 1995;35: 470-1.
3.Paterna S, di Pasquale P, Martino S, Arrostuto A, Ingurgio NC,
Parrinello G, Gullotti D, Licata G. Captopril versus placebo nella
prevenzione dell’emicrania senza aura. Studio in doppio cieco
randomizzato. Clin. Ter. 1992 Dec.; 141(12): 475-81.
4.Riva M, Canepari C, Delzanno GB. Clinical experience with captopril in
migraine-hypertensive patients. Eur Rev Med & Pharmacol 1986; 8: 183-
8.
5.Schrader H, Stovner LJ, Helde G, Sand T, Bovin G. Prophylactic treatment
of migraine with angiotensin converting enzyme inhibitor (lisinopril):
randomised, placebo controlled, crossover study. BMJ 2001; 322:19.
6.Sicuteri F. Enkephalinase inhibition relieves pain syndromes of central
dysnociception (migraine and related headache). Cephalalgia 1981 Dec;
1(4):229-32.
Competing interests: No competing interests
Dear Sirs
We may inform you that comparable results in efficacy but without any
adverse reactions had been reached by a randomized double blind placebo-
controlled study (33 verum vs. 27 placebo patients) with an extract of
Petasites hybridus rhizoma (Butterbur root). The frequency of the migraine
-attacks per month was significantly reduced (50%) compared to placebo
(10%) after 12 weeks of therapy. The phytomedicament appeared to be even
more effective in the subgroup of patients with a frequency higher than 3
attacks per month. The Petasistes-capsules are available in Switzerland as
Petadolor and in Germany as Petadolex. Further details are presented in
the publication of M. Grossmann and H. Schmidramsl: An extract of
Petasites hybridus is effective in the prophylaxis of migraine. Internat.
J. Clin. Pharm. & Ther. 38: 430-435 (2000).
Competing interests: No competing interests
Response to the letter of Sally Kerry, 16 January 2001.
Dear Editor
The “50 % cut-off point” mentioned in Kerry’s response [1] to our
study on migraine-prophylaxis with lisinopril [2] refers to so-called
responders, who according to a standard definition are patients who during
active treatment have a reduction of 50 % or more in efficacy parameters.
Several previous studies on migraine prophylaxis refer to this definition.
We used, of course, this definition prior to the analysis of data and did
thus not choose some cut-off point after seeing our results. It seemed
necessary to us to report the results concerning number of “responders” in
order to enable comparisons to what other authors have found. We disagree
with Kerry and Peacock that one sentence in the abstract referring these
results justify the notion that this analysis is given too much
prominence.
Unfortunately, the editors made the mistake to repeat most of this
sentence in the abstract, an error which was not present in the editorial
typescript seen by us. Hopefully, this has not contributed to what this
criticism calls misleading impression.
We agree with Kerry and Peacock that the great natural variability in
attack frequency in some patients may lead to large differences in
efficacy parameters even in the absence of a treatment effect. However, in
the present study this variability seemed to be of minor importance since
a similar number of responders (n=17) was seen when comparing the active
drug treatment period with the run-in period. These 17 patients included
all 14 patients who had a 50 % or more reduction of migraine days when
comparing the active treatment period with the placebo period. Most
importantly, however, only one of the fully evaluable patients (n = 47)
and two of the patients who entered the intention to treat analysis (n =
55) had a 50% or more reduction of migraine days during the placebo
period as compared to the active treatment period.
Originally, we intended
to report the positive changes for placebo versus active treatment, but
omitted it because we already had reached the maximum length of our
article. In view of the relevant response by Kerry and Peacock we
recognize that we should have given these data in order to avoid any
misinterpretation as to the efficacy of the treatment.
Harald Schrader
Professor of Neurology
Lars Jacob Stovner
Professor of Neurology
Norwegian University of Science and Technology ,
Department of Neurology,
7006 Trondheim,
Norway
1. Kelly S. Percentage of patients who respond well is misleading.
BMJ, 16 January 2001.
2. Schrader H, Stovner LJ, Helde H, Sand T, Bovim G. Prophylactic
treatment of migraine by an angiotensin converting enzyme inhibitor
(lisinopril): randomised, placebo controlled crossover study. BMJ 2001;
322:19.
Competing interests: No competing interests
Dear Editor
We agree with the conclusion of Schrader et al1 that their study
shows that lisinopril has a prophylactic effect in migraine. However
comparing treatment period with placebo, the effect on days with migraine
and hours with headache is modest, about 20%. The authors then state that
'a reduction of at least 50% for days with migraine were seen in 30% of
patients during the lisinopril treatment compared with the placebo
period'. We believe that this statement gives a misleading impression of
the effectiveness of the treatment.
Firstly, it is not clear whether this was part of the initial
analysis plan - it was not stated as such. In particular was the 50% cut-
off point chosen prior to the analysis of the data or after? If the
latter, then the choice of cut-off is data-dependent and hence biased.
Secondly, in most trials some patients will appear to respond better
than others. This may be due to true variability in effectiveness or
random variability in the outcome variable. In a crossover trial with
considerable natural variability in outcome from one time period to
another, some patients may be observed to have large positive changes in
outcome between time periods even in the absence of a treatment effect. At
the same time, some patients may show large negative changes in outcome.
To simply report the positive changes for active versus placebo in a
crossover design is meaningless and gives the impression of greater
treatment effect than there really is.
In addition, we noted that in fact a very similar number of patients
failed to complete the study as were reported to respond well (13/60
dropped out or failed to comply, of the 47 remaining 14 were reported to
have responded well).
We suggest that in abstracts, the emphasis should be on the results
of primary analyses and that subgroup or post-hoc analyses are given less
prominence.
Sally Kerry
Lecturer in Medical Statistics
Department of General Practice and Primary Care
Janet Peacock
Senior Lecturer in Medical Statistics
Department of Public Health Sciences
St. George's Hospital Medical School,
Cranmer Terrace,
London SW17 0RE
1. Schrader H, Stovner, LJ, Helde G, Sand T, Bovim G.Prophylactic
treatment of migraine with angiotensin converting inhibitor (lisinopril):
randomised ,placebo controlled, crossover study. BMJ 2001;322:1-5
Competing interests: No competing interests
LISINOPRIL AND OTHER ACE-INIBITHORS IN MIGRAINE
LISINOPRIL AND OTHER ACE-INHIBITORS IN MIGRAINE
The paper of Shrader et al is very interesting, but certain things
must be recorded. In the 80’ Sicuteri proposed the use of captopril, based
in encephalin studies. Federico Sicuteri is one of the grater names of the
field of headache treatment.However,must of the drugs in use for
prophylactic treatment of migraine are poor understood in regard of they
mechanism of action.Sicuteri,Lance,Graham,Antonaci and other great names
of the initial neurotransmitter basis of pathophysiology of migraine think
most in a serotonin-basis model. Despite the Sicuteri results, other
authors could not reproduce the reports of the Florence researchers. When
we think in migraine as a receptor disease, and this is of particular
useful way to explain triptan effects, we are lost to explain ACE-
inhibitors drugs in treatment of migraine.Topiramate seems to work: but in
witch way ?And I don't say nothing about propranolol and other beta-
blockers...
Although the well designed study, an ancient point must to be
pointed: placebo works well than nothing, as all people in the field of
pain treatment know: perhaps liberation of endorphins could explain this
fact, but the migraine patient produces endorphins with more difficulty
than normal ones.
All of us, neurologists with special interest in headache and pain,
want new drugs to the prophylaxis of the migraine – lisinopril could be
one of these drugs, but the placebo effect could not be discharged, and
also the pharmaceutical industry interests.
We must pray to lisinopril or other drugs acting as ACE-inhibitors
could be a good option; in the meantime, propranolol, amytriptiline,
flunarizine and even topiramate are the chooses of the moment.
Study pain treatment is not easy, and subjective factors could also
play a role in these studies. Let us treat migraine patients in an
individual way, and wait for must studies.
Competing interests:
None declared
Competing interests: No competing interests