Journal of Neuro-Ophthalmology:
Erectile Dysfunction Drugs and Non-Arteritic Anterior Ischemic Optic Neuropathy: Is There a Cause and Effect Relationship?
Hayreh, Sohan Singh MD, PhD, DSc, FRCS, FRCOphth
Department of Ophthalmology and Visual Sciences (SSH), College of Medicine, University of Iowa, Iowa City, Iowa.
Address correspondence to Sohan Singh Hayreh, MD, PhD, DSc, FRCS, FRCOphth, Department of Ophthalmology and Visual Sciences, College of Medicine, University of Iowa, Iowa City, IA 52242; E-mail: firstname.lastname@example.org
Abstract: The recent reports of non-arteritic anterior ischemic optic neuropathy (NAION) occurring shortly after ingestion of erectile dysfunction agents have raised the question of whether these agents have a cause-and-effect relationship to NAION. The nature of optic nerve head blood flow and the various factors that influence it, the systemic vascular effects of these agents, and the clinical features of NAION lead me to believe that these agents are contributory factors. Patients with the appropriate risk factors should, therefore, be warned of this possibility and advised to refrain from using these agents.
Since the U.S. Food and Drug Administration (FDA) approved sildenafil citrate (Viagra) on March 27, 1998 to treat male erectile dysfunction, it has become one of the most popular drugs worldwide. More recently, tadalafil (Cialis) and vardenafil hydrochloride (Levitra) have been introduced for the same purpose.
The FDA recently reported visual loss in 38 patients after use of sildenafil and in one patient after use of vardenafil. A Medline search revealed published reports of 15 patients who have developed non-arteritic anterior ischemic optic neuropathy (NAION) soon after the ingestion of sildenafil (1-7), and three patients who developed it after use of tadalafil (8-10). Varied opinions on the cause-and-effect relationship between these drugs and the development of NAION have been expressed by the FDA, the pharmaceutical industry, ophthalmologists, urologists, and other physicians, resulting in considerable confusion in the public mind. For example, in the New York Times, May 29, 2005, Suzanne Trevino, a spokesperson for the FDA, said “We're not able to specifically say that these 38 cases are a result of the patients taking Viagra.” The same newspaper article quoted Michael Berelowitz, MD, Pfizer's vice president, as saying, “We've studied all our databases right now, and we see no signal of causation with Viagra.” David Moskowitz, an analyst at Friedman, Billings, and Ramsey, is quoted as saying that “It may not be the drug at all; it may be just the patient population that's experiencing this blindness…We think this was an overreaction.” In the Archives of Ophthalmology, Egan and Fraunfelder (11) have stated that the connection between sildenafil use and the development of NAION does not meet World Health Organization criteria for a cause-and-effect relationship (12) but go on to state that “Despite a lack of mechanism of action, the strong re-challenge data (9) suggest the drug effect may be significant.”
To understand whether there is a cause-and-effect relationship between erectile dysfunction drugs and NAION, one must consider basic scientific facts related to NAION as well as to the drugs.
BLOOD SUPPLY OF THE OPTIC NERVE HEAD
Studies on the blood supply of the optic nerve head (ONH) (13,14), as well as experimental (15), pathologic, and clinical findings, have all shown that NAION is caused by ischemia of the ONH (16). Therefore, the most important considerations in understanding the development of NAION are the factors that influence blood flow in the ONH. Evidence shows that blood flow is influenced by many factors, including systemic arterial blood pressure, endothelial-derived vasoactive agents, and autoregulation of blood flow in the ONH (17). Autoregulation is deranged by many systemic and local causes, including the aging process, arterial hypertension, diabetes mellitus, marked arterial hypotension from any cause, arteriosclerosis, atherosclerosis, hypercholesterolemia, vasospasm, and probably regional vascular endothelial disorders (17-20).
RISK FACTORS FOR NAION
My studies have shown that NAION is a multifactorial disease, with many risk factors playing a role in its development (21,22). They can be divided into predisposing and precipitating risk factors.
Predisposing Risk Factors
Predisposing risk factors are those that make a person susceptible to develop NAION but do not necessarily produce it. They may be systemic or local in the ONH. Systemic risk factors include arterial hypertension, arterial hypotension (particularly nocturnal), diabetes mellitus, hyperlipidemia, atherosclerosis, arteriosclerosis, migraine and other vasospastic disorders, defective cardiovascular autoregulation, sleep apnea, hematologic disorders, and others (22). Local risk factors include increased intraocular pressure, marked optic disc edema from any cause, location of the watershed zone of the posterior ciliary arteries in relation to the optic disc, and vascular disorders in the nutrient vessels of the ONH (22). Pomeranz et al (5) concluded that “A small cup-to-disc ratio may be a risk factor for development of NAION in association with the use of sildenafil.” Our studies have shown that an absent or small cup is simply a secondary contributing factor, once the process of NAION has started, and not a primary factor (23).
Precipitating Risk Factors
In the presence of predisposing risk factors, precipitating risk factors act as the “last straw.” In a study of 925 episodes (involving 871 eyes) of NAION (24), 73.3% had a definite history of discovering the visual loss first upon awakening or at first opportunity to use vision critically after sleeping; in the remaining episodes, time of onset was generally uncertain. This shows that nocturnal arterial hypotension acted as the precipitating factor in the vast majority. Also, 24-hour ambulatory blood pressure monitoring studies (25,26) have shown a significant correlation between progressive visual loss in NAION and nocturnal arterial hypotension. Therefore, contrary to the prevalent misconception, NAION is largely a hypotensive disorder, not an embolic or thrombotic disorder. This is in sharp contrast to other strokes, which are primarily embolic or thrombotic phenomena.
Our 24-hour ambulatory blood pressure monitoring studies in over 700 patients so far have shown the following:
1. Taking blood pressure-lowering medication in the evening or at bedtime aggravates the physiological decrease of blood pressure during sleep, resulting in nocturnal arterial hypotension (26,27)
2. Daytime blood pressure often is no guide to the nighttime blood pressure or to the extent of decrease in blood pressure during sleep. We have not infrequently seen patients with ideal daytime blood pressure who developed a marked decrease during sleep without being on any treatment (22,26)
3. Patients with “white-coat hypertension” are often treated aggressively, resulting in marked nocturnal arterial hypotension, putting them at risk for developing NAION (25)
4. There is a significant correlation between progressive visual loss in NAION and nocturnal arterial hypotension (25,26)
ERECTILE DYSFUNCTION DRUGS AND NAION
In the light of this basic scientific information on NAION, let us evaluate the role of erectile dysfunction drugs in the development of NAION.
Cardiovascular Risk Factors Are Common in These Patients
Most reported cases are from middle-aged and elderly men. Arterial hypertension, diabetes mellitus, hyperlipidemia, and other systemic cardiovascular risk factors are common in this group. As discussed above, those factors predispose them to develop NAION.
NAION Has Occurred Shortly After Drug Use
In most of the reported cases of NAION after ingestion of sildenafil, the patient has detected visual loss upon awakening in the morning, as have most NAION patients (24).
Other Contributory Drugs Are Often Used
Patients with arterial hypertension and other cardiovascular disorders invariably take beta-blockers, angiotensin-converting enzyme-inhibitors, calcium channel blockers, or other drugs with arterial hypotensive effect. In their study on the combination of antihypertensive therapy with sildenafil or placebo, Mahmud et al (28) stated that “The extent of individual maximum reductions (in mm Hg) from baseline in systolic (24 ± 10 versus 6 ± 8; P < 0.05) and diastolic blood pressure (8 ± 5 versus 3 ± 2; P < 0.05) occurred on the sildenafil study day.” Patients with benign prostatic hypertrophy are often advised to take alpha adrenoreceptor blocking agents at bedtime which can produce nocturnal arterial hypotension (26,27). Erectile dysfunction is one side effect of these and many other arterial hypotensive drugs.
Erectile Dysfunction Drugs Cause Systemic Hypotension
It is well established that sildenafil use is associated with a decrease in blood pressure (28-30). Our 24-hour ambulatory blood pressure monitoring studies (26,27,31) have shown that arterial hypotensive medication taken in the evening or bedtime aggravates the normal physiological decrease of blood pressure during sleep, resulting in marked nocturnal arterial hypotension. Erectile dysfunction drugs are taken most often in the evening or before going to bed so that their arterial hypotensive effect is likely to aggravate physiologic nocturnal hypotension, especially if the patient takes other drugs with hypotensive effects.
Erectile Dysfunction Drugs Stimulate Release of Vasoconstrictors
Phillips et al (32) showed that sildenafil causes an increase in plasma norepinephrine levels by 31% ± 5% (P = 0.004) and concluded that sympathetic activation may have implications for understanding cardiovascular events associated with sildenafil use. It is well known that norepinephrine is a potent vasoconstrictor. In malignant arterial hypertension, ONH ischemia and NAION may be the result of diffusion of vasoconstrictor agents from the peripapillary choroid into the ONH (18). This phenomenon may be yet another contributory factor in development of NAION after sildenafil use.
Stroke and NAION May Follow Rechallenge with Erectile Dysfunction Drugs
Morgan et al (33) describe a patient who suffered a transient ischemic attack followed by a stroke in the same distribution six days later, with each event being associated with sildenafil use. In another study (34), Humphrey perimetry performed after ingestion of 200 mg sildenafil in a healthy young woman showed bilateral superior and inferonasal visual field depression. A critical review of all the reported cases shows a close temporal relationship between the ingestion of these drugs and the onset of NAION.
This evidence indicates that a cause-and-effect relationship between the drugs and development of NAION is likely. Skeptics may use the arguments that follow to dispute this point.
NAION Seems to Occur in Patients Using Erectile Dysfunction Drugs Who Have No Evident Systemic or Vascular Predisposing Risk Factors
Having studied more than a thousand patients with spontaneously-occurring NAION, I can confirm that many patients seem perfectly healthy by the usual standards. But there are serious limitations in our ability to detect NAION risk factors. For example, a patient may be having marked nocturnal arterial hypotension when the daytime blood pressure is absolutely ideal. Whereas it is always assumed that atherosclerosis is a disease of the elderly, atherosclerotic plaques in the coronary arteries have been seen among young (average age, 22 years), healthy American soldiers killed in the Korean War (35). Also, in humans, we have no means to determine the local risk factors in the ONH mentioned above (17,36).
Erectile Dysfunction Drugs Have Been Used for a Long Time before NAION Develops
Whereas it is true that many cases of NAION have occurred in patients who have been using erectile dysfunction drugs for a long time, it may be that a critical decrease in blood pressure is required to produce the degree of hypoperfusion of the ONH to cause NAION in susceptible persons. The requisite combination of factors to cause threshold perfusion failure in the ONH may not be present after every use of erectile dysfunction drugs. This is well illustrated by the fact that patients suffer successive attacks of NAION in the same eye (37) or the other eye (38) days, months, or even years apart.
Erectile Dysfunction Drugs Do Not Lower Perfusion of the Optic Nerve Head
Pomeranz and Bhavsar (7) have stated that Grunwald et al (39) found no significant change in the ONH blood flow with sildenafil as compared with placebo use. However, Grunwald et al (39) measured ONH blood flow with the laser Doppler flowmeter, a device that does not measure ONH blood flow reliably (40). Results based on this method may not be valid (41).
Despite these points, I believe that there is sufficient evidence to support a cause-and-effect relationship between the ingestion of erectile dysfunction drugs and the development of NAION. Most probably, the incidence of NAION after use of these drugs is much higher than is apparent from the reports because patients are not always forthcoming to physicians about their use of these drugs, owing to embarrassment or their belief that this is not relevant information. Given the information I have presented, patients with cardiovascular risk factors, diabetes mellitus, those who take arterial hypotensive drugs, and those who have a history of previous NAION should be advised against the use of erectile dysfunction drugs.
1. Egan R, Pomeranz H. Sildenafil (Viagra) associated anterior ischemic optic neuropathy. Arch Ophthalmol
2. Cunningham AV, Smith KH. Anterior ischemic optic neuropathy associated with Viagra. J Neuroophthalmol
3. Boshier A, Pambakian N, Shakir SA. A case of nonarteritic ischemic optic neuropathy (NAION) in a male patient taking sildenafil. Int J Clin Pharmacol Ther
4. Dheer S, Rekhi GS, Merlyn S. Sildenafil associated anterior ischaemic optic neuropathy. J Assoc Physicians India
5. Pomeranz HD, Smith KH, Hart WM Jr, et al. Sildenafil-associated nonarteritic anterior ischemic optic neuropathy. Ophthalmology
6. Gruhn N, Fledelius HC. Unilateral optic neuropathy associated with sildenafil intake. Acta Ophthalmol Scand
7. Pomeranz HD, Bhavsar AR. Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (Viagra): a report of seven new cases. J Neuroophthalmol
8. Escaravage GK Jr, Wright JD Jr, Givre SJ. Tadalafil associated with anterior ischemic optic neuropathy. Arch Ophthalmol
9. Bollinger K, Lee MS. Recurrent visual field defect and ischemic optic neuropathy associated with tadalafil rechallenge. Arch Ophthalmol
10. Peter NM, Singh MV, Fox PD. Tadalafil-associated anterior ischaemic optic neuropathy. Eye
11. Egan RA, Fraunfelder FW. Viagra and anterior ischemic optic neuropathy. Arch Ophthalmol
12. Edwards IR, Biriell C. Harmonisation in pharmacovigilance. Drug Saf
13. Hayreh SS. Blood supply of the optic nerve head and its role in optic atrophy, glaucoma and oedema of the optic disc. Br J Ophthalmol
14. Hayreh SS. The blood supply of the optic nerve head and the evaluation of it: myth and reality. Prog Retin Eye Res
15. Hayreh SS, Baines JAB. Occlusion of the posterior ciliary artery. III. Effects on the optic nerve head. Br J Ophthalmol
16. Hayreh SS. Anterior ischaemic optic neuropathy. I. Terminology and pathogenesis. Br J Ophthalmol
17. Hayreh SS. Blood flow in the optic nerve head and factors that may influence it. Prog Retin Eye Res
18. Hayreh SS, Servais GE, Virdi PS. Fundus lesions in malignant hypertension. V. Hypertensive optic neuropathy. Ophthalmology
19. Hayreh SS, Bill A, Sperber GO. Effects of high intraocular pressure on the glucose metabolism in the retina and optic nerve in old atherosclerotic monkeys. Graefes Arch Clin Exp Ophthalmol
20. Haefliger IO, Meyer P, Flammer J, et al. The vascular endothelium as a regulator of the ocular circulation: a new concept in ophthalmology? Surv Ophthalmol
21. Hayreh SS, Joos KM, Podhajsky PA, et al. Systemic diseases associated with non-arteritic anterior ischemic optic neuropathy. Am J Ophthalmol
22. Hayreh SS. Acute ischemic disorders of the optic nerve: pathogenesis, clinical manifestations and management. Ophthalmol Clin North Am
23. Beck RW, Servais GE, Hayreh SS. Anterior ischemic optic neuropathy. IX. Cup-to-disc ratio and its role in pathogenesis. Ophthalmology
24. Hayreh SS, Podhajsky PA, Zimmerman B. Non-arteritic anterior ischemic optic neuropathy: time of onset of visual loss. Am J Ophthalmol
25. Hayreh SS, Zimmerman MB, Podhajsky P, et al. Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol
26. Hayreh SS, Podhajsky PA, Zimmerman MB. Role of nocturnal arterial hypotension in optic nerve head ischemic disorders. Ophthalmologica
27. Hayreh SS. Role of nocturnal arterial hypotension in the development of ocular manifestations of systemic arterial hypertension. Curr Opin Ophthalmol
28. Mahmud A, Hennessy M, Feely J. Effect of sildenafil on blood pressure and arterial wave reflection in treated hypertensive men. J Hum Hypertens
29. Zusman RM, Morales A, Glasser DB, et al. Overall cardiovascular profile of sildenafil citrate. Am J Cardiol
31. Hayreh SS. Duke-Elder lecture: systemic arterial blood pressure and the eye. Eye
32. Phillips BG, Kato M, Pesek CA, et al. Sympathetic activation by sildenafil. Circulation
33. Morgan JC, Alhatou M, Oberlies J, et al. Transient ischemic attack and stroke associated with sildenafil (Viagra) use. Neurology
34. McCulley TJ, Lam BL, Marmor MF, et al. Acute effects of sildenafil (Viagra) on blue-on-yellow and white-on-white Humphrey perimetry. J Neuroophthalmol
35. Enos WF, Holmes RH, Beyer J. Coronary disease among United States soldiers killed in action in Korea: preliminary report. JAMA
36. Hayreh SS. Evaluation of optic nerve head circulation: review of the methods used. J Glaucoma
37. Hayreh SS, Podhajsky PA, Zimmerman B. Ipsilateral recurrence of nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol
38. Beri M, Klugman MR, Kohler JA, et al. Anterior ischemic optic neuropathy. VII. Incidence of bilaterality and various influencing factors. Ophthalmology
39. Grunwald JE, Siu KK, Jacob SS, et al. Effect of sildenafil citrate (Viagra) on the ocular circulation. Am J Ophthalmol
40. Petrig BL, Riva CE, Hayreh SS. Laser Doppler flowmetry and optic nerve head blood flow. Am J Ophthalmol
41. Hayreh SS. Effect of sildenafil citrate (Viagra) on the ocular circulation. Am J Ophthalmol
This article has been cited 26 time(s).
Medical HypothesesViagra, surgery and anesthesia: A dangerous cocktail with a risk of blindnessMedical Hypotheses
Drugs of TodayDrug-induced optic neuropathiesDrugs of Today
Nonarteritic ischaemic optic neuropathy (NAION) after 36 h of intake of sildenafil citrate: first Egyptian case
Graefes Archive for Clinical and Experimental OphthalmologyNon-arteritic anterior ischemic optic neuropathy and thrombophiliaGraefes Archive for Clinical and Experimental Ophthalmology
Canadian Journal of Ophthalmology-Journal Canadien D OphtalmologieVisual loss associated with erectile dysfunction drugsCanadian Journal of Ophthalmology-Journal Canadien D Ophtalmologie
Nature Reviews NeurologyThe optic nerve head in acquired optic neuropathiesNature Reviews Neurology
Progres En Urologie
Treatment of erectile dysfunction by phosphodiesterase-5 inhibitors and nonarteritic anterior ischemic optic neuropathy (NOIAN)
Progres En Urologie, 17(5):
Graefes Archive for Clinical and Experimental OphthalmologyFamilial non-arteritic anterior ischemic optic neuropathyGraefes Archive for Clinical and Experimental Ophthalmology
American Journal of OphthalmologyScientific challenges in postmarketing surveillance of ocular adverse drug reactionsAmerican Journal of Ophthalmology
Journal of the Neurological SciencesAnterior ischemic optic neuropathy and stroke with use of PDE-5 inhibitors for erectile dysfunction: Cause or coincidence?Journal of the Neurological Sciences
Expert Opinion on Drug Metabolism & ToxicologyTadalafil for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasiaExpert Opinion on Drug Metabolism & Toxicology
Versatile effects of sildenafil: recent pharmacological applications
Pharmacological Reports, 59(2):
International Journal of Impotence ResearchNonarteritic anterior ischemic optic neuropathy with PDE-5 inhibitors for erectile dysfunctionInternational Journal of Impotence Research
Vision Disorders and Phosphodiesterase Type 5 Inhibitors A Review of the Evidence to Date
Drug Safety, 32(1):
Bju InternationalThe safety profile of tadalafil as prescribed in general practice in England: results from a prescription-event monitoring study involving 16 129 patientsBju International
Expert Opinion on Drug Metabolism & ToxicologyVardenafil: efficacy, tolerability and future directionsExpert Opinion on Drug Metabolism & Toxicology
British Journal of OphthalmologyNon-arteritic anterior ischaemic optic neuropathy and phosphodiesterase-5 inhibitorsBritish Journal of Ophthalmology
Progress in Retinal and Eye ResearchIschemic optic neuropathyProgress in Retinal and Eye Research
Seminars in NeurologyIschemic optic neuropathySeminars in Neurology
OphthalmologyIncipient nonarteritic anterior ischemic optic neuroplathyOphthalmology
Investigative Ophthalmology & Visual ScienceSildenafil (viagra) evokes retinal arteriolar dilation: Dual pathways via NOS activation and phosphodiesterase inhibitionInvestigative Ophthalmology & Visual Science
Neuro-OphthalmologyErythropoietin in Recurrent Anterior Ischaemic Optic NeuropathyNeuro-Ophthalmology
Current Opinion in OphthalmologyNonarteritic anterior ischaemic optic neuropathyCurrent Opinion in Ophthalmology
Journal of Neuro-OphthalmologyAmiodarone, Erectile Dysfunction Drugs, and Non-Arteritic Ischemic Optic NeuropathyJournal of Neuro-Ophthalmology
Journal of Neuro-OphthalmologyBilateral Posterior Ischemic Optic Neuropathy Associated With Use of SildenafilJournal of Neuro-Ophthalmology
© 2005 Lippincott Williams & Wilkins, Inc.
- Articles in PubMed by Sohan Singh Hayreh, MD, PhD, DSc, FRCS, FRCOphth
- Articles in Google Scholar by Sohan Singh Hayreh, MD, PhD, DSc, FRCS, FRCOphth
- Other articles in this journal by Sohan Singh Hayreh, MD, PhD, DSc, FRCS, FRCOphth