Expert Opinion Phosphodiesterase-5 Inhibitors and Migraine Case History Submitted by Randolph W. Evans, MD
Expert Opinion by C. Kruuse, MD, PhD
Key words: migraine, phosphodiesterase-5 inhibitors, sildenafil
The age of Viagra has been a boon for many, but
messengers cAMP and cGMP. So far 11 different types
a new source of drug-induced migraine for others.
of PDEs have been characterized with different speci-ficity, mode of regulation, and tissue distribution and
there are several isoforms and splice variants of each
A 45-year-old man has a 10-year history of mi-
PDE. Because of the specific role and distribution of
graine without aura occurring about once a week re-
each PDE type, specific inhibitors for various diseases
lieved by an oral triptan. When he sought treatment
have been designed. The most widely known are prob-
for erectile dysfunction from a urologist, the side ef-
ably the PDE-5 inhibitors for male impotence, where
fect of triggering migraine was brought up. Now the pa-
sildenafil was the first on the marked list and recently
tient and the urologist want my opinion about whether
vardenafil and tadalafil have followed. They all inhibit
the patient should try an oral phosphodiesterase-5 in-
the cGMP-degrading PDE-5 and work by increasing
hibitor (PDE-5) and, if so, do I have a preference?
the intracellular level of cGMP, thus causing smooth
Questions.—What is the risk of PDE-5 triggering
muscle cell relaxation or neuronal stimulation. Silde-
migraines? Does the risk vary among the three medi-
nafil, however, also affects PDE-6 causing a minor de-
cations, sildenafil (Viagra), vardenafil (Levitra), and
gree of visual side effects and tadalafil inhibits PDE-
tadalafil (Cialis)? Is the risk dose-related? What is
11, the significance of which is still unknown. Varde-
the latency from taking the PDE-5 medication un-
nafil is more selective than both tadalafil and sildenafil
til onset of the headache? Would taking a migraine
with IC50 of 0.1-0.8, 1-7, and 1-9 nM, respectively. The
symptomatic medication along with the PDE-5 in-
tmax is almost identical for vardenafil and sildenafil,
hibitor prevent the migraine from occurring? Does
∼0.8 hours, just as the T1/2 is approximately 4 hours,
the long-duration agent, tadalafil, cause long-duration
whereas for tadalafil tmax is ∼2 hours and T1/2 is 17.5
migraines? Do PDE-5-triggered migraines respond to
hours. The side effect profiles for all of the PDE-5 in-
the patient’s usual acute migraine medications? Are
hibitors are almost identical, headache being the most
preventative medications useful in reducing the risk
common, dose-dependent side effect. Headache is re-
of PDE-5-triggered migraines? How might PDE-5 in-
ported in up to 30% of patients after sildenafil,1 21%
of patients after vardenafil,2 and 16% of patients after
EXPERT COMMENTARY
tadalafil.3 The most frequent reason for discontinu-
Phosphodiesterases (PDEs) are intracellular en-
ation of the PDE-5 inhibitors is headache causing a
zymes responsible for the degradation of the second
discontinuation rate of 1.2% after sildenafil 100 mg.
Recently two studies were performed investigat-
Address all correspondence to Dr. Randolph W. Evans, Suite
ing the effects of sildenafil on headache, cerebral blood
1370, 1200 Binz, Houston, TX 77004 or Dr. Kruuse, Department
flow, and artery dilation since sildenafil is an obvi-
of Neurology, Glostrup Hospital, DK-2600 Glostrup.
ous tool to investigate the role of endogenously pro-
Accepted for publication June 15, 2004.
duced cGMP as part of the nitric oxide-cGMP cascade
in headache induction. One study was performed in
that some preventive medication may itself induce im-
healthy subjects5 and the other in patients with mi-
potence, and thus these compounds should be avoided
graine without aura.6 Out of 10 healthy subjects (6
in the case of already established impotence.
men/4 women), 10 reported headaches and 3 of these
Considering the lifetime prevalence of migraine
fulfilled the criteria for one attack of migraine with-
in the general population of 16%, and given the
out aura despite no previous history of migraine and
migraine-inducing effects of sildenafil and possibly
no first degree relatives with migraine. Out of 12 mi-
also of the other PDE-5 inhibitors, it must be rec-
graine patients (12 women), 10 reported induction of
ommended that the labeling of these drugs include
a migraine attack similar to their usual migraine at-
a warning to migraine patients, unless the drug com-
tack after ingestion of sildenafil. To our surprise no
panies provide data proving otherwise. Also, in light
dilation of the large intracranial or extracranial arter-
of the proposed new indications for the use of silde-
ies was found, indicating that the previously reported
nafil in other patient groups including women, the
large artery dilation of the nitric oxide donors may be
migraine potential of the PDE-5 inhibitors should be
an epiphenomenon in migraine induction rather than
the actual course of migraine. Thus, sildenafil seems to
In conclusion, migraine patients should be made
work through other mechanisms than artery dilation
aware of the risk of inducing a migraine attack be-
in the migraine induction, most likely the perivascular
fore initiation of treatment with PDE-5 inhibitors.
pain-sensitive nerve-fibers or more centrally located
The most short lasting PDE-5 inhibitors, vardenafil or
sildenafil, in the lowest doses should be used first.
No similar studies have been performed using var-
denafil or tadalafil, however given a similar side effect
REFERENCES
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Application and experience of CAN as a low cost OBDH bus system MAPLD 2004, Washington D.C. USA, 8th – 10th September, 2004 Surrey Satel ite Technology Ltd, University of Surrey, Guildford, GU2 7XH, UK. Abstract This paper gives an overview of Surrey Satel ite Technology Ltd. (SSTL) use of CAN bus on its recent missions. It gives a description of the SSTL CAN topology and goes i