Nitric Oxide in Peripheral Arterial Insufficiency - NO-PAIN


The goal of the trial was to evaluate the effect of long-term therapy with oral L-arginine on vascular reactivity and functional capacity in patients with intermittent claudication due to peripheral arterial disease (PAD).

Study Design

Study Design:

Patients Screened: 2,365
Patients Enrolled: 133
Mean Follow Up: 6 months
Mean Patient Age: Mean age, 73 years
Female: 24

Patient Populations:

Age ≥45 years, unilateral or bilateral PAD confirmed by a resting ABI <0.9, stable intermittent claudication for the previous 3 months, and the ability to walk 1-12 minutes on a treadmill


Ischemic rest pain; ulceration or gangrene; history in the previous 3 months of acute coronary syndrome or revascularization involving the peripheral or coronary arteries; major amputation; malignancy within the previous 5 years (except for treated nonmelanoma skin cancer); proliferative retinopathy; uncontrolled hypertension; or active inflammatory, infectious, or autoimmune diseases

Primary Endpoints:

Change at 6 months in the absolute claudication distance, as assessed by the Skinner-Gardner treadmill protocol

Secondary Endpoints:

Change at 6 months in implanted cardioverter defibrillator, Short Form-36, and Walking Impairment Questionnaire measures, ABI, flow-mediated vasodilation, vascular compliance, urinary and plasma nitrogen oxides, and plasma amino acid levels

Drug/Procedures Used:

Patients at a single center were randomized in a double-blind manner to either oral L-arginine (3 g per day; n = 66) or placebo (n = 67) for 6 months. Vascular and functional capacity evaluation was performed at baseline and at 3 and 6 months.

Principal Findings:

At study entry, 20% of patients had diabetes and 65% were on statin therapy. Mean index leg ankle-brachial index (ABI) was 0.58. Median absolute claudication distance was 258 in the L-arginine group and 292 in the placebo group.

Urinary nitrogen oxides rose from baseline in the placebo group (396.7 to 472.6, p = 0.04), but not in the L-arginine group (384.5 to 376.5, p = 0.71). There was no difference in change in ABI between groups at 6 months (0.11 with L-arginine vs. 0.12 with placebo, p = 0.67).

The primary endpoint of absolute claudication distance improved from baseline in both the L-arginine and placebo groups (increased by 36 m in the L-arginine group and 78 m in the placebo group), but there was no difference in the absolute change between groups (p = 0.09) and significantly less improvement with L-arginine when comparing the relative change between groups (mean improvement 11.5% in the L-arginine group vs. 28.3% in the placebo group, p = 0.024).

Likewise, change in initial claudication distance trended to be less in the L-arginine group versus placebo (39.6% vs. 47.1%; p = 0.06). There were also no differences in quality-of-life measures. Adverse events did not differ between groups.


Among patients with intermittent claudication due to PAD, treatment with L-arginine was unexpectedly associated with a worsening of relative change in claudication distance from baseline to 6 months compared with placebo.

The study was designed to test the hypothesis that L-arginine would improve functional capacity due to its influence on vascular reactivity; these findings were not observed. Absolute claudication distance was actually worsened in the L-arginine group compared to placebo.

The authors speculated that the long-term administration of the drug may partially explain these negative findings, given that benefit was observed with L-arginine when administed for a short time period in other trials.


Wilson AM, Harada R, Nair N, Balasubramanian N, Cooke JP. L-arginine supplementation in peripheral arterial disease: no benefit and possible harm. Circulation 2007;116:188-95.

Clinical Topics: Diabetes and Cardiometabolic Disease, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Exercise

Keywords: Intermittent Claudication, Nitrogen Oxides, Walking, Ankle Brachial Index, Peripheral Arterial Disease, Lower Extremity, Diabetes Mellitus, Exercise Test

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