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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
profile and mechanism of action they are likely to have 1. Goldstein I, Lue TF, Padma Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment The risk of inducing migraine seems dose-related of erectile dysfunction. Sildenafil Study Group. N Engl just as the headache in healthy patients. Another group reported in an abstract, that sildenafil 20 mg induced 2. Keating GM, Scott LJ. Vardenafil: A review of its use a mild transient headache in all, but only migraine in in erectile dysfunction. Drugs. 2003;63:2673-2703.
1 out of 7 patients with migraine without aura, within 3. Curran M, Keating G. Tadalafil. Drugs. 2003;63:2203- In the study on migraine patents using sildenafil 4. Iversen HK, Thomsen LL. Nitroglycerin-Induced 100 mg, the headache was slowly progressing and me- dian time to peak headache score was 4.5 hours with Model. Philidelphia: Lippencott-Raven Publishers, 5 patients fulfilling the criteria for migraine within the first 3 hours. All patients except 1 reported good ef- 5. Kruuse C, Thomsen LL, Jacobsen TB, Olesen J. The fects of their usual triptans in treating the induced mi- phosphodiesterase 5 inhibitor sildenafil has no effecton cerebral blood flow or blood velocity, but never- graine attack. There are no reports on the effect of theless induces headache in healthy subjects. J Cereb ”pretreating” the attack with triptans, but, like in usual Blood Flow Metab. 2002;22:1124-1131.
attacks, an effect of pretreatment would not be ex- 6. Kruuse C, Thomsen LL, Birk S, Olesen J. Migraine pected. Theoretically, tadalafil, which has the longest can be induced by sildenafil without changes in middle half-life could induce longer lasting migraine or an in- cerebral artery diameter. Brain. 2003;126:241-247.
7. Fusco B, Colantoni O, Bianchi A, Geppetti P. Phar- So far, there are no reports of preventive medica- macological exploration of nitrogen pathways in mi- tion being effective in reducing sildenafil-induced mi- graine and cluster headache [abstract]. Cephalalgia.
graine. It must be taken into consideration, however,

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