Continuing Medical Education

Failure of PDE5 Inhibitor Use: A Case of Nonresponder?jsm_1772 1321..1323

Eric Chung, MBBS

Department of Urology, St Joseph Health Care Hospital, London, ON, Canada

Case Study

A 55-year-old married man presented to ourservice with a 3-year history of erectile dysfunction(ED). Prior to seeing us, he had obtained a pre-scription from his local general practitioner forfour sildenafil (Viagra®) tablets (50 mg) and hadfound them to be ineffective. Subsequently, he alsotried two tadalafil (Cialis®) tablets (20 mg) andvardenafil (Levitra ® [20 mg]) with no improve-ment in his erection function.

His past medical history includes obesity (BMI32), hypertension (on atenolol), active smoker (20cigarettes per day) with a 40-pack year history anddiabetes (diet-controlled).

He reported that he is unable to achieve andmaintain his erection in nearly all circumstanceson all occasions with his wife, whom he describesas supportive. He denied previous penile trauma orany deformity, and believes that his erections havebecome progressively less rigid over the past 3years. He denied any sensory changes on the shaftor glans. His sexual interest remains strong buteven with self-stimulation he is unable to gainadequate rigidity, but reported that his ejaculationand orgasm remain intact.

On examination, he is obese, weighing 215pounds standing 5′6″ tall. There was no evidenceof induration along the penile shaft and both testeswere of normal size.

His family physician had highlighted to thepatient that ED is a marker of vascular disease ingeneral. He tried to lead a healthier lifestyle withregular exercise, cut down on cigarette smokingand lose excess weight, all without significantbenefit to his sexual functioning. His antihyper-tensive medication was changed in consultationwith his general practitioner to an angiotensionconverting enzyme inhibitor over concern thatbeta blockers have been associated with anincreased risk of de novo ED. His primary carephysician had ordered fasting lipids, glucose, and

triglycerides as well as serum testosterone, creati-nine, and electrolytes levels. There was no evi-dence of hypodonadism, but his sugars wereelevated as expected.

He was referred to our care, after failedattempts at lifestyle modification and with all 3phosphodiesterase type 5 inhibitor (PDE5i),requesting we perform a duplex scan to evaluatehis cavernous arterial flow and consider placementof a penile implant.

Commentary

While this is a very common reason for referral totertiary care sexual medicine specialists, with abouta third of men trying PDE5i reporting inadequateoutcomes, PDE5i salvage remains a viable thera-peutic approach. There exist a large number oftreatment algorithms providing a step-wiseapproach toward the management of ED that canbe clinically useful [1]. In our experience, whileintraurethral and intracavernous vasoactivetherapy remain highly effective alternatives to oraltherapy, the vast majority of men and partnersprefer noninvasive oral treatments. Salvage strate-gies, while well published, remain poorly utilizedin some centers and particularly among primarycare physicians.

In contrast to most clinical concerns faced byprimary care physicians, no diagnosis is generallynecessary among patients presenting with ED.The patient provides that information to the cli-nician. The utility of uncovering the underlyingetiology remains controversial. It almost always isvascular (atherosclerosis) and/or neural (auto-nomic neuropathy) in origin, with little possibil-ity of reversal, where defining the relativepathologic contributions of each will rarely alterchoice of treatment. The role of investigationsinto ED and the most appropriate progressionthrough treatment alternatives remain poorlydescribed.

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Continuing Medical Education

It has been more than a decade since sildenafilwas first introduced for the treatment of male ED[2]. PDE5i preferentially inhibit the breakdown ofcyclic guanosine monophosphate in penile tissues,thereby prolonging vascular smooth muscle relax-ation and facilitating erection. The published lit-erature has shown excellent results of PDE5i inpromoting erectile responses across the wide spec-trum of severity and causes of ED [3–5]. It is gen-erally agreed that PDE5i are the first line for thetreatment of ED because of the ease of adminis-tration, efficacy, and tolerable side effects.

ED can be defined as persistent or repeatedinability to attain and/or maintain an erection suf-ficient for satisfactory sexual performance [5]. Thecauses of ED can be divided into organic or psy-chogenic (non-organic); a significant proportionof men have coexisting factors that affect theirsexual performance. Therefore, the ideal evalua-tion for these men with ED should involve biop-sychosocial review of male sexual function.Medical co-morbidities such as cardiovascular,endocrine, and neurologic conditions; localurinary tract diseases; drugs and alcohol problems;psychosocial issues and social stressors; as well aspotential partner issues should be evaluated [3–5].

Prior to commencing PDE5i for the treatmentof ED, possible causative factors should beaddressed. Simple conservative measures such aschanges to lifestyle to address the metabolic syn-drome [4] (obesity, hyperlipidemia, hypertension,and diabetes), alteration in medications, and avoid-ance of psychosexual stressors, should be per-formed. It is important to note whether this ED isan acute or chronic failure of sexual function; thelatter associated with failure of other organssystems [5].

As with any medication, PDE5i pharmacokinet-ics and dynamics determine its efficacy. One of themost common reasons for being a “nonresponder” to PDE5i is the failure of the patient toadhere to drug use instructions with respect totiming in relation to food intake, the use of con-comitant medications, and adequacy of sexualstimulation/arousal [4]. Critical aspects in themanagement of ED patients following commence-ment of PDE5i should include counseling thatsexual stimulation is mandatory, appropriatetiming of administration in relation to food intakewith the short acting PDE5i, as well as optimiza-tion of PDE5i dosage. Published literature hasshown the need for multiple doses and titration to

the maximum tolerated dose of PDE5i to increasethe cumulative probability of successful inter-course [6,7]. One study has reported greater effi-cacy of one class of PDE5i over another [8].Recently, the use of daily dosing of tadalafil mayoffer improved efficacy as well as greater flexibilityand spontaneity in sexual involvement [9]. Com-bination strategies such as the adjunctive testoster-one therapy in men with low testosterone level[10] and concomitant use of vacuum erectiondevice with PDE5i as salvage therapy in the non-responder have been reported [11].

Despite strict adherence to all the necessarysteps to maximize PDE5i efficacy, lack of successbecause of end-organ failure and progression ofunderlying disease are possible [4]. Among thetrue nonresponders, vacuum device, intraurethraland intracavernous vasoactive agents remain viablealternative treatment strategies for these patients.Particularly among men with severe vascularinsufficiency or alternatively when cavernousnerve injury (post-radical prostatectomy) limitsthe ability of PDE5i to enhance vascular flow,direct vasoactive therapy remains a useful choice.In our practice, the low cost of intracavernousinjection therapy, the rapid onset of action, and thenerve independent nature of its action make it avaluable treatment alternative to oral therapy.Additionally, advances in penile prosthetics con-tinue to evolve and now represent a highly reliableand physiologic option for many men and theirpartners.

In summary, our approach to the PDE5i non-responder is:

1. Identify any reversible causes of ED (smoking,alcohol or substance abuse, hormonal defi-ciency state, or situational cause).

2. Engage the partner when possible and reviewthe manner in which the pill is used (take atleast 60 minutes prior to adequate sexual activ-ity, take the pill when sex will be possible in aconducive environment with a supportive andwilling partner).

3. Understand that several attempts may beneeded, particularly until a successful encoun-ter is experienced in couples who have not beensexual for a period of time.

4. Food can interfere with the efficacy of theshort-acting PDE5i.

5. Side effects like facial flushing or mild headacheare simply indicators of when the agent is

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Continuing Medical Education

maximally effective and should not be inter-preted as reasons to stop.

6. Use of a PDE5i on successive days may salvagethe nonresponder.

7. Consider intra-urethral or intracavernousagents if PDE5i fails.

8. Vacuum constriction devices or their constric-tive rings may be a reasonable adjunctive aid incases where veno-occlusion is inadequate andmay salvage a PDE5i nonresponder

9. Surgical options remain important in 2010.

References

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2 Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, SteersWD, Wicker PA. Oral sildenafil in the treatment of erectiledysfunction. Sildenafil Study Group. N Engl J Med 1998;338:1397–404.

3 Lue TF. Erectile dysfunction. N Engl J Med 2000;342:1802–13.

4 Carson CC, Lue TF. Phosphodiesterase type 5 inhibitors forerectile dysfunction. BJU Int 2005;96:256–80.

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7 Gruenwald I, Shenfeld O, Chen J, Raviv G, Richter S, CohenA, Vardi Y. Positive effect of counselling and dose adjustmentin patients with erectile dysfunction who failed treatment withsildenafil. Eur Urol 2006;50:134–40.

8 Berner MM, Kriston L, Harms A. Efficacy of PDE-5-inbitorsfor erectile dysfunction. A comparative meta-analysis of fixed-dose regimen randomized controlled trials administering theInternational Index of Erectile Function in broad-spectrumpopulations. Int J Impot Res 2006;18:229–35.

9 McMahon C. Efficacy and safety of daily tadalafil in men witherectile dysfunction previously unresponsive to on-demandtadalafil. J Sex Med 2004;1:292–300.

10 Shabsigh R, Kaufman JM, Steidle C, Padma-Nathan H. Ran-domized study of testosterone gel as adjunctive therapy tosildenafil in hypogonadal men with erectile dysfunction whodo not respond to sildenafil alone. J Urol 2008;179(5 Suppl):S97–102.

11 Canguven O, Bailen J, Fredriksson W, Bock D, BurnettAL. Combination of vacuum erection device and PDE5inhibitors as salavage therapy in PDE5 inhibitor nonre-sponders with erectile dysfunction. J Sex Med 2009;6:2561–7.

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