Is nitric oxide (NO) a suitable treatment for a patient with erectile dysfunction (ED)?

Nitric Oxide for Erectile Dysfunction

Nitric oxide (NO) donors are not recommended as first-line treatment for erectile dysfunction—instead, use oral PDE5 inhibitors (sildenafil, tadalafil, vardenafil, avanafil) which work by enhancing the NO-cGMP pathway and have proven efficacy, safety, and FDA approval. 1, 2

Why PDE5 Inhibitors Are Preferred Over Direct NO Donors

PDE5 inhibitors are the established first-line pharmacologic therapy for ED because they enhance the body's natural NO-mediated erectile mechanism rather than bypassing it. 1, 2

The Nitric Oxide Pathway in Erections

• NO is the primary neurotransmitter mediating penile erection, released by nerve and endothelial cells in the corpora cavernosa. 3
• NO activates soluble guanylyl cyclase, increasing cGMP levels, which relaxes corpus cavernosum smooth muscle and allows blood flow for erection. 3, 4
• Both neuronal NOS (nNOS) and endothelial NOS (eNOS) contribute to erectile function—nNOS initiates relaxation while blood-flow-activated eNOS maintains full erection. 4

Why PDE5 Inhibitors Work Better Than Direct NO Donors

PDE5 inhibitors prevent the breakdown of NO-generated cGMP, amplifying the natural erectile response, which explains their superior clinical success compared to experimental NO donors. 3

• Sildenafil and tadalafil achieve approximately 69% successful intercourse attempts versus 33% with placebo. 2
• These medications require sexual stimulation to work, meaning they enhance rather than replace physiologic mechanisms. 2
• Avanafil demonstrates 64-71% successful intercourse attempts within 15 minutes versus 27% with placebo. 5

Evidence on Direct NO Donors (Why They're Not Used Clinically)

While research has explored NO donors, they remain experimental and are not part of standard clinical practice:

Intracavernous NO Donors (Not Oral Therapy)

• Linsidomine chlorhydrate (SIN-1) showed 69% response rates when injected intracavernously, but this is an invasive route requiring injection directly into the penis. 6, 7
• S-nitroso-glutathione (GSNO) and NCX 911 (sildenafil nitrate) showed promise in isolated tissue studies but lack clinical trial data in humans. 8
• These compounds were investigated in the 1990s-early 2000s but never advanced to FDA approval or clinical use. 6, 8, 7

Critical Limitations of NO Donors

Direct NO donors bypass the requirement for sexual stimulation, which is both a theoretical disadvantage (non-physiologic) and a practical concern (potential for unwanted erections). 3

• Intracavernous injection is invasive, requires patient training, and carries risks of penile fibrosis and priapism with other agents. 1
• No oral NO donor formulations have been developed or approved for ED treatment. 3, 8

Recommended Treatment Algorithm

First-Line: Oral PDE5 Inhibitors

Start with a PDE5 inhibitor as first-line therapy unless contraindicated (absolute contraindication: concurrent nitrate use). 1, 2

Choice of agent:

• Tadalafil 10-20 mg as-needed or 2.5-5 mg daily if patient values spontaneity (effective up to 36 hours; can treat concurrent BPH with 5 mg daily dose). 2
• Sildenafil 50-100 mg as-needed if patient prefers scheduled activity with predictable window or if concern about emergency nitrate need (shorter half-life). 2
• Avanafil 50-200 mg offers rapid onset (15 minutes) with lowest dyspepsia rates among PDE5 inhibitors. 5

Critical Pre-Treatment Safety Steps

Before prescribing any PDE5 inhibitor:

• Verify no nitrate use in any form (oral, sublingual, transdermal, recreational)—combination causes potentially fatal hypotension. 2
• Assess cardiovascular fitness: Can patient walk 1 mile in 20 minutes or climb 2 flights of stairs without symptoms? If no, refer to cardiology first. 1, 2
• High-risk patients (unstable angina, uncontrolled hypertension, recent MI/stroke, NYHA Class II-IV heart failure) should defer ED treatment until cardiac condition stabilized. 1

Defining Treatment Success vs. Failure

An adequate trial requires at least 5 separate attempts at maximum tolerated dose before declaring treatment failure. 2

Before escalating dose or switching agents, verify:

• Adequate sexual stimulation is occurring (PDE5 inhibitors require arousal to work). 2
• Proper timing (sildenafil/vardenafil: 30-60 minutes before; tadalafil: anytime within 36 hours). 2
• Not taking with large/fatty meals (reduces absorption). 2
• Avoiding heavy alcohol use (impairs erectile function independently). 2
• No unaddressed hormonal abnormalities (check testosterone if not done). 1, 2

Special Populations

Patients with diabetes or post-prostatectomy have more severe baseline ED and respond less robustly to all PDE5 inhibitors—may require maximum doses or combination therapy. 2, 5

Patients with testosterone deficiency and ED: Combining PDE5 inhibitor with testosterone therapy is more effective than PDE5 inhibitor alone. 2

Second-Line Options (After PDE5 Inhibitor Failure)

Only proceed to second-line therapies after failure of at least two different PDE5 inhibitors at maximum dose with proper technique. 2

Second-line options include:

• Vacuum erection devices
• Intraurethral alprostadil suppositories
• Intracavernosal injection therapy (alprostadil, not NO donors)
• Penile prosthesis implantation

1, 2

Why NO Donors Are Not Clinically Recommended

The success of PDE5 inhibitors has made experimental NO donor research largely obsolete—they offer superior efficacy, oral administration, physiologic mechanism, and extensive safety data. 3

• NO donors investigated in the 1990s-2000s required intracavernous injection, limiting practical use. 6, 7
• Oral NO donor formulations remain investigational with no FDA-approved products available. 3, 8
• PDE5 inhibitors work by enhancing the NO-cGMP pathway, making direct NO donation unnecessary in most patients. 3

Common Pitfalls to Avoid

• Do not declare PDE5 inhibitor failure without completing adequate trial (5 attempts at maximum dose with proper technique)—up to 30% of apparent non-responders become responders with optimization. 2
• Do not prescribe PDE5 inhibitors without explicitly asking about all forms of nitrate use including recreational ("poppers"). 2
• Do not assume higher PDE5 inhibitor doses are always more effective—tadalafil shows no dose-dependent improvement between 5-20 mg, so choose based on tolerability. 2
• Do not overlook testosterone deficiency—men with low testosterone respond less robustly to PDE5 inhibitors alone and may benefit from combination therapy. 2