Nitroglycerin

What it is

Nitroglycerin is an organic nitrate, chemically 1,2,3-propanetriol trinitrate, the same molecule used as an explosive but formulated in milligram doses. For medical use it comes as sublingual tablets of 0.3, 0.4 or 0.6 mg, a sublingual spray, an ointment, a skin patch, slow-release capsules, and an intravenous solution. Taken under the tongue about 40 percent of the dose reaches the bloodstream, and the vasodilator effect starts approximately 1 to 3 minutes after the tablet is placed, peaks by 5 minutes and persists for at least 25 minutes.

What the research says

The honest summary is that nitroglycerin is a reliable symptom reliever and a poor outcome drug. Under the tongue it opens up veins, reduces the volume of blood returning to the heart and so reduces the heart's work, which relieves an angina attack within minutes; that use is well established. Where it has been tested against hard outcomes it has repeatedly failed: in ISIS-4, oral nitrate in 58,050 people with suspected heart attack gave 7.34 percent versus 7.54 percent five-week mortality, no significant difference; in RIGHT-2, a nitroglycerin patch given by paramedics in acute stroke did not improve function at 90 days; and in a 2023 trial for menopausal hot flushes it did nothing at 12 weeks while causing headache in 67 percent of users in the first week. As an ointment for chronic anal fissure it beats placebo, but marginally: 48.9 percent versus 35.5 percent healing in Cochrane, and 7.0 mm of pain difference on a 100 mm scale in the registration trial. Its two defining practical problems are tolerance with regular use and a dangerous interaction with erectile-dysfunction drugs.

Evidence grade: Well established.

How it works

Drug class: Organic nitrate vasodilator (nitric oxide donor)

Nitroglycerin releases nitric oxide, the same signalling molecule blood vessels make themselves. Nitric oxide switches on an enzyme called guanylate cyclase, which raises cyclic GMP inside smooth muscle cells, and that relaxes them. The veins relax most, so blood pools in the periphery and less returns to the heart; the pressure the heart has to fill against drops. Arteries relax too, lowering the pressure the heart pumps against, and the large coronary arteries widen. The net result is that the heart needs less oxygen, which is why chest pain from a narrowed coronary artery eases. (Source 1)

What it is used for

• This is the use nitroglycerin was approved for and the one the pharmacology supports best: the vasodilator effect starts within 1 to 3 minutes, peaks by 5 minutes, and persists at least 25 minutes. The label allows up to three tablets in 15 minutes, after which persisting pain means seeking urgent care. Evidence: established. (Source 2)
• Approved for pain, not for healing. The registration trial found a pain difference of only 7.0 mm on a 100 mm scale (95% CI -13.6 to -0.4), and 64 percent of users got headache versus 41 percent on placebo. Evidence: limited. (Source 3)
• Off-label in the US because the ointment is licensed for pain rather than healing. Cochrane pooled 75 randomised trials of medical therapies and found glyceryl trinitrate healed 48.9 percent versus 35.5 percent on placebo, with recurrence in about half of those initially cured and all medical therapies far less effective than surgery. Evidence: limited. (Source 4)
• Tested in 58,050 patients in ISIS-4 and found no significant reduction in five-week mortality (7.34% versus 7.54%), with no later survival advantage and an excess of hypotension of 15 per 1000. Evidence: not-supported. (Source 5)
• RIGHT-2 randomised 1,149 patients to a 5 mg transdermal patch or sham. Blood pressure fell by 5.8 mmHg systolic but functional outcome at 90 days did not improve, and there were numerically more treatment-related deaths (36 versus 23). Evidence: not-supported. (Source 6)
• A 141-woman randomised placebo-controlled trial of continuous transdermal nitroglycerin found no significant reduction in hot flash frequency at 12 weeks and a large early excess of headache (67.1% versus 5.6% at one week). Evidence: not-supported. (Source 7)

Interactions

• Sildenafil, tadalafil, vardenafil, avanafil (erectile dysfunction and pulmonary hypertension drugs) (pharmacokinetic study): These block the enzyme that breaks down cyclic GMP, the exact signal nitroglycerin generates, so the blood-pressure fall is multiplied. In a randomised crossover study the fall in systolic pressure after a sublingual tablet was four times greater on sildenafil. The combination is an absolute contraindication and the label says not to use them within a few days of each other. (Source 8)
• Riociguat and other soluble guanylate cyclase stimulators (label): These act on the same enzyme nitric oxide activates, so combining them with nitroglycerin can cause hypotension. The label contraindicates the combination. (Source 9)
• Alcohol (label): Alcohol is itself a vasodilator and its effect adds to nitroglycerin's, so dizziness, flushing and fainting become more likely. The nitroglycerin ointment label states the effects are additive. (Source 10)
• Aspirin at 500-1000 mg (pharmacokinetic study): High-dose aspirin raises nitroglycerin's peak concentration by as much as 67 percent and its total exposure by 73 percent after a single dose, so the vasodilator and blood-pressure effects may be stronger. Low-dose cardiac aspirin was not studied. (Source 11)
• Blood pressure medicines, beta-blockers and other nitrates (label): Additive blood-pressure lowering. Marked orthostatic hypotension has been reported with calcium channel blockers and organic nitrates together, and beta-blockers remove the reflex increase in heart rate that would otherwise compensate. (Source 11)
• Ergotamine and dihydroergotamine (migraine drugs) (label): Nitroglycerin reduces the first-pass breakdown of dihydroergotamine and so raises its blood level. Since ergotamine can itself trigger angina, the label says to avoid it or watch for symptoms of ergotism. (Source 12)
• Intravenous heparin (case reports): An interaction reducing heparin's anticoagulant effect has been reported but the data are not consistent; the label says to check anticoagulation status if both are given. (Source 11)
• Alteplase and other tissue plasminogen activators (label): Intravenous nitroglycerin lowers plasma t-PA levels and reduces its clot-dissolving effect, which matters during thrombolysis. (Source 13)
• Food and sublingual absorption (label): No food interaction is documented, but the label notes that absorption from a sublingual tablet depends on how moist the mouth is; for people with a dry mouth it suggests a small sip of water before placing the tablet. Absolute bioavailability is about 40 percent and variable. (Source 14)

Stopping it

• Nitroglycerin is not addictive, but regular use creates physiological tolerance, and that is what makes stopping and restarting matter. The label's own statement is that excessive use may lead to tolerance and that only the smallest dose needed for relief should be used; regular long-acting nitrates also blunt the response to a rescue sublingual tablet. (Source 15)
• For long-acting formulations, a nitrate-free interval each day is the standard way to limit tolerance, but the review of this literature is explicit that it reduces tolerance at the cost of leaving part of the day unprotected. (Source 16)
• The gap left by a nitrate-free interval is not harmless. Patients may be vulnerable to rebound angina and myocardial ischaemia overnight and in the early morning, and to worsening exercise capacity before the morning dose; this has been a concern with nitroglycerin patches but not with oral isosorbide-5-mononitrate, and has not been adequately studied for isosorbide dinitrate. (Source 16)
• For the topical ointment there is a built-in stopping point: treatment is limited to up to three weeks. (Source 17)

What goes wrong

In that same trial nearly two thirds of patients on nitroglycerin ointment got headache, against four in ten on placebo. (Source 18)

• Randomized trial, Moderate certainty.
• Size: 247 patients (123 RECTIV, 124 placebo)
• Who: Patients with painful chronic anal fissure.
• How long: 3 weeks.
• Result: Headache in 79 of 123 patients (64%) on nitroglycerin ointment with 938 events, versus 51 of 124 (41%) on placebo with 225 events; dizziness in 6 (5%) with 26 events versus 0 and 0 on placebo.
• Funding: industry-funded (sponsor's registration trial reported in the FDA label)

In Study REC-C-001, a double-blind, placebo-controlled trial in patients with a painful chronic anal fissure, the most frequent (≥ 2%) adverse reactions reported were as follows (Table 1): Table 1: Incidence of Adverse Reactions (≥ 2%) in Study REC-C-001 RECTIV N = 123 Placebo N = 124 System Organ Class Preferred term Patients n (%) Events n Patients n (%) Events n Nervous system disorders Headache 79 (64) 938 51 (41) 225 Dizziness 6 (5) 26 0 0

The same label records hypotension, including orthostatic hypotension, and rare methaemoglobinaemia with nitroglycerin ointment. (Source 18)

• Official position, Certainty not rated.
• Size: Not quantified in this section.
• Who: Patients with painful chronic anal fissure.
• How long: Ongoing treatment.
• Result: No rates given for these; the label calls hypotension infrequent but says it may be severe enough in some patients to warrant stopping treatment, and calls methaemoglobinaemia rare at therapeutic doses of organic nitrates.
• Funding: industry-funded (sponsor's registration trial reported in the FDA label)

Transient episodes of light-headedness, occasionally related to blood pressure changes, also may occur. Hypotension (including orthostatic hypotension) occurs infrequently, but in some patients may be severe enough to warrant discontinuation of therapy.

The only clear harm of the nitrate regimen in that trial was hypotension, in about 15 extra patients per 1000. (Source 5)

• Randomized trial, High certainty.
• Size: 58,050 patients.
• Who: Adults with suspected acute myocardial infarction.
• How long: 1 month.
• Result: An increase of 15 (SD 2) per 1000 in hypotension; the trialists noted fewer deaths on days 0-1 in the nitrate group, which they read as reassuring about early safety.
• Funding: not stated in the record fetched.

The only significant side-effect of the mononitrate regimen studied was an increase of 15 (SD 2) per 1000 in hypotension.

In that stroke trial there were numerically more treatment-related deaths in the nitroglycerin group, though the difference was not statistically significant. (Source 6)

• Randomized trial, Moderate certainty.
• Size: 1,149 participants.
• Who: Adults with presumed ultra-acute stroke.
• How long: 4 days of treatment, 90-day outcome.
• Result: Treatment-related deaths 36 with GTN versus 23 with sham (p=0.091); serious adverse events 188 versus 170 (p=0.16)
• Funding: British Heart Foundation (stated in the FUNDING section of the record fetched)

We found no difference in secondary outcomes, death (treatment-related deaths: 36 in the GTN group vs 23 in the sham group [p=0·091]), or serious adverse events (188 in the GTN group vs 170 in the sham group [p=0·16]) between treatment groups.

In that trial two thirds of women on nitroglycerin had headache in the first week, but it had almost completely settled by 12 weeks. (Source 7)

• Randomized trial, High certainty.
• Size: 141 participants.
• Who: Perimenopausal or postmenopausal women with frequent hot flashes.
• How long: 12 weeks.
• Result: Headache at 1 week in 47/70 (67.1%) on nitroglycerin versus 4/71 (5.6%) on placebo, P < .001; at 12 weeks only 1 participant in each group.
• Funding: not stated in the record fetched; PubMed indexes it as Research Support, N.I.H., Extramural.

At 1 week, 47 NTG (67.1%) and 4 placebo participants (5.6%) reported headache (P < .001), but only 1 participant in each group reported headache at 12 weeks.

Sildenafil multiplied nitroglycerin's blood-pressure-lowering effect several-fold in a randomised crossover study, which is why the combination is contraindicated. (Source 8)

• Randomized trial, High certainty.
• Size: Healthy male subjects (number not stated in the record fetched) in a double-blind placebo-controlled crossover study.
• Who: Healthy men given sildenafil 25 mg three times daily for 4 days, then challenged with intravenous and sublingual glyceryl trinitrate.
• How long: 4 days of sildenafil, with nitrate challenges on days 4 and 5.
• Result: Subjects were significantly less tolerant of intravenous glyceryl trinitrate on sildenafil, judged by a fall in blood pressure of more than 25 mmHg or symptomatic hypotension (p <0.01); after a 500 microgram sublingual tablet the fall in systolic blood pressure was 4-fold greater on sildenafil than on placebo.
• Funding: not stated in the record fetched.

Limit of this finding: These were healthy male volunteers given sildenafil 25 mg three times a day for four days and then challenged with glyceryl trinitrate, not patients taking nitrates for angina at ordinary doses. The abstract gives the four-fold figure with no confidence interval and no p value, and does not state how many men took part. It shows the direction and seriousness of the interaction, not its size in patients.

When a sublingual glyceryl trinitrate tablet was administered on day 5, a 4-fold greater decrease in systolic blood pressure was observed for the subjects during the sildenafil treatment period than during the placebo treatment period.

Regular use of long-acting nitrates produces tolerance, and the nitrate-free intervals used to prevent it can leave people exposed to rebound angina. (Source 16)

• Expert review, not systematic, Low certainty.
• Size: Not applicable; expert review with no stated systematic method.
• Who: Patients with ischaemic heart disease on long-acting nitrate formulations.
• How long: Not applicable.
• Result: No pooled figures; the review states tolerance develops with continued or frequent daily use, that a nitrate-free interval reduces but cannot abolish it, and that rebound angina and worsening exercise capacity before the morning dose have been a concern with nitroglycerin patches but not with oral isosorbide-5-mononitrate.
• Funding: not stated in the record fetched; PubMed indexes it as Research Support, Non-U.S. Gov't.

however, following their continued or frequent daily use, patients soon develop tolerance to these long-acting nitrate preparations. Once tolerance develops, patients begin losing the protective effects of the long-acting nitrate therapy.

The sublingual label itself warns that excessive use causes tolerance and that long-acting nitrates blunt the response to a rescue tablet. (Source 15)

• Official position, Certainty not rated.
• Size: Not quantified.
• Who: People using sublingual nitroglycerin.
• How long: Ongoing use.
• Result: No rates given; the label directs using only the smallest dose needed for relief.
• Funding: US regulatory document.

Excessive use may lead to the development of tolerance. Only the smallest dose required for effective relief of the acute angina attack should be used. A decrease in therapeutic effect of sublingual nitroglycerin may result from use of long-acting nitrates.

Severe low blood pressure can occur at ordinary nitroglycerin doses, sometimes with paradoxical slowing of the heart and more angina. (Source 15)

• Official position, Certainty not rated.
• Size: Not quantified.
• Who: People using nitroglycerin, especially with constrictive pericarditis, aortic or mitral stenosis, volume depletion or existing low blood pressure.
• How long: Any dose.
• Result: No rates given; the label lists nausea, vomiting, weakness, pallor, sweating and collapse or fainting as occurring even at therapeutic doses.
• Funding: US regulatory document.

Severe hypotension, particularly with upright posture, may occur with small doses of nitroglycerin particularly in patients with constrictive pericarditis, aortic or mitral stenosis, patients who may be volume-depleted, or are already hypotensive.

Nitroglycerin overdose can cause methemoglobinemia, and this is dose-related rather than idiosyncratic. (Source 19)

• Official position, Certainty not rated.
• Size: Case reports; described as rare at conventional doses.
• Who: People taking organic nitrates, including those with inherited haemoglobin abnormalities.
• How long: Overdose or high cumulative dose.
• Result: No rates given; the label notes that in people with genetic haemoglobin abnormalities favouring methemoglobin formation even conventional doses could produce harmful concentrations, and that treatment is methylene blue 1-2 mg/kg intravenously unless the patient has G-6-PD deficiency.
• Funding: US regulatory document.

Case reports of clinically significant methemoglobinemia are rare at conventional doses of organic nitrates. The formation of methemoglobin is dose-related and in the case of genetic abnormalities of hemoglobin that favor methemoglobin formation, even conventional doses of organic nitrates could produce harmful concentrations of methemoglobin.

The label records that no carcinogenicity study of sublingual nitroglycerin has been done; in rats fed nitroglycerin in the diet at up to 434 mg/kg/day for two years, liver and testicular tumours developed, while mice fed up to 1,058 mg/kg/day developed none. (Source 20)

• Animal study, Certainty not rated.
• Size: Rats given up to 434 mg/kg/day for 2 years; mice up to 1,058 mg/kg/day.
• Who: Rats and mice; these are animal data and the label states that animal carcinogenesis studies with sublingually administered nitroglycerin have not been performed.
• How long: 2 years in rats, lifetime in mice.
• Result: Dietary dosing, not sublingual: at the high dose of 434 mg/kg/day, hepatocellular carcinoma in 48% of male and 33% of female rats versus 0% in untreated controls, and testicular tumours in 52% versus 8%. Lifetime dietary nitroglycerin up to 1,058 mg/kg/day was not tumorigenic in mice. Nitroglycerin was mutagenic in Ames tests in 2 different laboratories, with no evidence of mutagenicity in an in vivo dominant lethal assay at up to about 363 mg/kg/day by mouth or in ex vivo cytogenetic tests in rat and dog cells.
• Funding: US regulatory document.

Animal carcinogenesis studies with sublingually administered nitroglycerin have not been performed. Carcinogenicity potential of nitroglycerin was evaluated in rats receiving up to 434 mg/kg/day of dietary nitroglycerin for 2 years. Rats developed dose-related fibrotic and neoplastic changes in liver, including carcinomas, and interstitial cell tumors in testes. At high dose, the incidences of hepatocellular carcinomas in males was 48% and in females was 33%, compared to 0% in untreated controls. Incidences of testicular tumors were 52% vs. 8% in controls.

Aspirin at 500-1000 mg raises nitroglycerin blood levels substantially, which may amplify its effects. (Source 11)

• Blood level study, Low certainty.
• Size: Not stated in the label section fetched.
• Who: People taking nitroglycerin with high-dose aspirin.
• How long: Single dose.
• Result: Nitroglycerin maximum concentration increased by as much as 67% and AUC by 73% after a single high aspirin dose.
• Funding: US regulatory document.

Coadministration of aspirin (at doses between 500 mg and 1000 mg) and nitroglycerin has been reported to result in increased nitroglycerin maximum concentrations by as much as 67% and AUC by 73% when administered as a single dose.

What the evidence supports

Topical glyceryl trinitrate ointment heals anal fissure slightly more often than placebo, but recurrence is common. (Source 4)

• Systematic review, Moderate certainty.
• Size: 5,031 participants across 75 randomised controlled trials, 49 different comparisons.
• Who: Adults and children with acute or chronic anal fissure.
• How long: Varied by trial; the review notes late recurrence.
• Result: Healing 48.9% with GTN versus 35.5% with placebo, p < 0.0009; late recurrence in the range of 50% of those initially cured. The review publishes no absolute risk difference and no number needed to treat for this comparison.
• Funding: not stated in the record fetched.

In this update 23 studies including 1236 participants is added to the 54 studies and 3904 participants in the 2008 publication, however 2 studies were from the last version reclassified as un included, so the final number of participants is 5031.49 different comparisons of the ability of medical therapies to heal anal fissure have been reported in 75 RCTs. Seventeen agents were used (nitroglycerin ointment (GTN), isosorbide mono & dinitrate, Botulinum toxin (Botox), diltiazem, nifedipine (Calcium channel blockers or CCBs), hydrocortisone, lignocaine, bran, minoxidil, indoramin, clove oil, L-arginine, sitz baths, sildenafil, "healer cream" and placebo) as well as Sitz baths, anal dilators and surgical sphincterotomy. GTN was found to be marginally but significantly better than placebo in healing anal fissure (48.9% vs. 35.5%, p < 0.0009), but late recurrence of fissure was common, in the range of 50% of those initially cured.

The registration trial for nitroglycerin ointment in chronic anal fissure found a small pain benefit whose confidence interval nearly touched zero. (Source 21)

• Randomized trial, Moderate certainty.
• Size: 247 patients (123 RECTIV, 124 placebo)
• Who: Patients with a painful chronic anal fissure for at least 6 weeks and pain of at least 50 mm on a 100 mm visual analogue scale.
• How long: 3 weeks, with pain assessed from baseline to days 14-18.
• Result: Mean change from baseline 44 mm with nitroglycerin ointment versus 37 mm with placebo; difference -7.0 mm (95% Confidence Interval: -13.6 to -0.4 mm)
• Funding: industry-funded (sponsor's registration trial reported in the FDA label)

The mean change from baseline was 44mm for RECTIV and 37mm for placebo. The difference in the mean change in pain between RECTIV and placebo was -7.0mm (95% Confidence Interval: -13.6 to -0.4mm).

What the evidence does not support

Oral nitrate given routinely after a suspected heart attack did not reduce death in the largest trial ever run on the question. (Source 5)

• Randomized trial, High certainty.
• Size: 58,050 patients in 1,086 hospitals; about 29,000 allocated active versus 29,000 control for each comparison.
• Who: Adults within 24 hours (median 8 hours) of suspected acute myocardial infarction, without cardiogenic shock or persistent severe hypotension.
• How long: 1 month of treatment, mortality assessed at 5 weeks with longer follow-up.
• Result: 5-week mortality 2,129 (7.34%) with controlled-release mononitrate versus 2,190 (7.54%) with placebo; no significant reduction overall or in any subgroup examined, and no later survival advantage.
• Funding: not stated in the record fetched.

There was no significant reduction in 5-week mortality, either overall (2129 [7.34%] mononitrate-allocated deaths vs 2190 [7.54%] placebo) or in any subgroup examined (including those receiving short-term non-study intravenous or oral nitrates at entry). Further follow-up did not indicate any later survival advantage.

A nitroglycerin patch given by paramedics in suspected acute stroke lowered blood pressure but did not improve disability. (Source 6)

• Randomized trial, High certainty.
• Size: 1,149 participants (568 GTN, 581 sham) recruited by 516 paramedics in 8 UK ambulance services.
• Who: Adults with presumed stroke within 4 hours of onset, FAST score 2 or 3, systolic blood pressure 120 mmHg or higher; median time to randomisation 71 minutes.
• How long: 5 mg patch once daily for 4 days; primary outcome at 90 days.
• Result: Modified Rankin Scale 3 (IQR 2-5) in both groups; adjusted common odds ratio for poor outcome 1.25 (95% CI 0.97-1.60; p=0.083) in cohort 1 and 1.04 (0.84-1.29; p=0.69) in all randomised patients.
• Funding: British Heart Foundation (stated in the FUNDING section of the record fetched)

We found no difference in mRS between the groups in participants with a final diagnosis of stroke or transient ischaemic stroke (cohort 1): 3 (IQR 2-5; n=420) in the GTN group versus 3 (2-5; n=408) in the sham group, adjusted common odds ratio for poor outcome 1·25 (95% CI 0·97-1·60; p=0·083); we also found no difference in mRS between all patients (cohort 2: 3 [2-5]; n=544, in the GTN group vs 3 [2-5]; n=558, in the sham group; 1·04 [0·84-1·29]; p=0·69).

Continuous transdermal nitroglycerin for menopausal hot flushes was no better than placebo at 12 weeks. (Source 7)

• Randomized trial, High certainty.
• Size: 141 participants randomised (70 nitroglycerin, 71 placebo); 134 completed 12 weeks.
• Who: Perimenopausal or postmenopausal women reporting 7 or more hot flashes a day, recruited at one academic centre in northern California; mean 10.8 hot flashes daily at baseline.
• How long: 12 weeks, with assessments at 5 and 12 weeks.
• Result: Change in any hot flash frequency at 12 weeks -0.1 episodes per day (95% CI -1.2 to 0.4) and moderate-to-severe -0.5 (95% CI -1.6 to 0.7) versus placebo; combined 5- and 12-week analysis -0.5 (95% CI -1.6 to 0.6; P = .25)
• Funding: not stated in the record fetched; PubMed indexes it as Research Support, N.I.H., Extramural.

At 12 weeks, treatment with NTG did not significantly decrease the frequency of any hot flashes (-0.1 episodes per day; 95% CI, -1.2 to 0.4) or moderate-to-severe hot flashes (-0.5 episodes per day; 95% CI, -1.6 to 0.7) relative to placebo.

Where the evidence is mixed

For anal fissure, botulinum toxin and calcium channel blockers matched topical glyceryl trinitrate on healing with fewer side effects, and no medical therapy approached surgery. (Source 4)

• Systematic review, Moderate certainty.
• Size: 5,031 participants across 75 randomised controlled trials.
• Who: Adults and children with anal fissure.
• How long: Varied by trial.
• Result: No pooled numbers given for the equivalence; the review states none of the medical therapies carried the incontinence risk of surgery.
• Funding: not stated in the record fetched.

Botox and CCBs were equivalent to GTN in efficacy with fewer adverse events.

Cochrane's overall verdict is that medical therapy for anal fissure as a class, glyceryl trinitrate among it, offers a chance of cure only marginally better than placebo, and that for chronic fissure in adults every medical therapy is far less effective than surgery. (Source 22)

• Systematic review, Moderate certainty.
• Size: 5,031 participants across 75 randomised controlled trials.
• Who: Adults and children with anal fissure.
• How long: Varied by trial.
• Result: No new figures in the conclusion; it restates the marginal advantage over placebo for the class of medical treatments rather than for glyceryl trinitrate alone.
• Funding: not stated in the record fetched.

Limit of this finding: The review's conclusion sentence contradicts itself about who it is talking about: it opens with medical therapy "for chronic anal fissure" and then, in the same sentence, describes those same treatments as used "in acute and chronic fissure and fissure in children". Read it as the authors' verdict on the whole class of medical treatments across all three of the groups the review pooled, not as a statement about chronic fissure on its own and not as a statement about glyceryl trinitrate on its own.

Medical therapy for chronic anal fissure, currently consisting of topical glyceryl trinitrate, botulinum toxin injection or the topical calcium channel blockers nifedipine or diltiazem in acute and chronic fissure and fissure in children may be applied with a chance of cure that is marginally better than placebo. For chronic fissure in adults all medical therapies are far less effective than surgery.

Where the research disagrees

Whether topical nitroglycerin is worth using for chronic anal fissure

• Nelson and colleagues, Cochrane 2012, Meta-analysis of 75 randomised trials, 5,031 participants: Medical therapy for chronic anal fissure, currently consisting of topical glyceryl trinitrate, botulinum toxin injection or the topical calcium channel blockers nifedipine or diltiazem in acute and chronic fissure and fissure in children may be applied with a chance of cure that is marginally better than placebo. For chronic fissure in adults all medical therapies are far less effective than surgery. (Source 22)
• The FDA-approved RECTIV label (SPL effective 8 September 2026), reporting the sponsor's registration trial, Single 3-week double-blind placebo-controlled trial in 247 patients, with pain rather than healing as the endpoint: The mean change from baseline was 44mm for RECTIV and 37mm for placebo. (Source 21)
• Nelson and colleagues, on the alternatives, Meta-analysis of 75 randomised trials: Botox and CCBs were equivalent to GTN in efficacy with fewer adverse events. (Source 4)

Whether nitrates help after a heart attack

• The ISIS-4 Collaborative Group (1995), Randomised factorial trial in 58,050 patients: There was no significant reduction in 5-week mortality, either overall (2129 [7.34%] mononitrate-allocated deaths vs 2190 [7.54%] placebo) or in any subgroup examined (Source 5)
• The sublingual nitroglycerin label (SPL effective 6 November 2025), Regulatory position; the approved claim is symptom relief, not survival: NITROSTAT is indicated for the acute relief of an attack or acute prophylaxis of angina pectoris due to coronary artery disease. (Source 2)

How much

• Reference intake: Dosing is set by the prescriber and by the formulation, not by a reference intake. The sublingual label (Nitrostat, SPL effective 6 November 2025) directs one tablet under the tongue at the first sign of an attack, which may be repeated every 5 minutes, and allows prophylactic use 5 to 10 minutes before exertion. Tablets are 0.3, 0.4 and 0.6 mg. (Source 23)
• Upper limit: The sublingual label's ceiling is no more than three tablets within a 15-minute period, after which persisting or atypical pain means seeking prompt medical attention. The ointment label caps treatment at 1 inch (1.5 mg of nitroglycerin) every 12 hours for up to 3 weeks. (Source 23)
• Studied: The anal fissure registration trial applied 0.4% ointment delivering 1.5 mg of nitroglycerin to the anal canal every 12 hours for 3 weeks. (Source 17)
• Studied: The sildenafil interaction study used a 500 microgram sublingual glyceryl trinitrate tablet one hour after sildenafil 25 mg. (Source 8)
• Studied: The RIGHT-2 stroke trial used a transdermal patch delivering 5 mg once daily for 4 days. (Source 24)
• Studied: The doses across these trials span three orders of magnitude depending on the formulation: 500 micrograms sublingually in the sildenafil interaction study, 1.5 mg topically every 12 hours for anal fissure, and 5 mg per day by patch in the stroke trial. Reading micrograms as milligrams here would be a thousandfold error. (Source 8)

A common belief, and what the research shows

The belief: Nitroglycerin is a heart-protecting drug, so taking it regularly, or taking it after a heart attack, reduces your risk of dying.

What the research shows: It relieves the symptom, not the disease. The approved claim is narrow: 'NITROSTAT is indicated for the acute relief of an attack or acute prophylaxis of angina pectoris due to coronary artery disease.' When a nitrate was tested for survival in 58,050 people with suspected heart attack, the result was flat: 'There was no significant reduction in 5-week mortality, either overall (2129 [7.34%] mononitrate-allocated deaths vs 2190 [7.54%] placebo) or in any subgroup examined'. Regular use also works against itself: 'Excessive use may lead to the development of tolerance.' And the most dangerous misconception is a separate one, that an erectile dysfunction tablet is fine alongside it. In a randomised crossover study, 'a 4-fold greater decrease in systolic blood pressure was observed for the subjects during the sildenafil treatment period'.

Questions and answers

What is it?

Nitroglycerin, also called glyceryl trinitrate or GTN, is an organic nitrate and a vasodilating agent. Its chemical name is 1,2,3 propanetriol trinitrate, the same compound used as an explosive, but the medical doses are fractions of a milligram. Sublingual tablets are stabilised compressed tablets containing 0.3 mg, 0.4 mg or 0.6 mg; it also comes as a spray, an ointment, a skin patch, slow-release capsules and an intravenous infusion. (Source 25)

What does it do in the body?

It releases nitric oxide, which switches on guanylate cyclase and raises cyclic GMP inside the smooth muscle of blood vessels, relaxing them. Veins relax most, so blood pools in the periphery, less returns to the heart and the pressure the heart fills against falls. Arteries relax too, lowering the resistance the heart pumps against, and the large coronary arteries widen. The heart therefore needs less oxygen, which relieves angina. Digital plethysmography puts the onset at approximately 1 to 3 minutes after a sublingual dose, with a maximum by 5 minutes and effects persisting at least 25 minutes. (Source 26)

Is it good or bad for you?

Good for the specific job of stopping an angina attack, and that benefit is immediate and well established. Bad in three ways. It does not change outcomes: a nitrate in 58,050 heart-attack patients produced no mortality reduction, and in acute stroke a patch did not improve disability. It causes predictable harms: dose-related headache (64 percent versus 41 percent on placebo with the ointment, 67 percent versus 6 percent in the first week with a patch), dizziness, fainting and sometimes severe hypotension at ordinary doses. And it becomes less effective with regular use. (Source 15)

How do you get more of it?

Only by prescription and by formulation choice; there is no dietary route to nitroglycerin. The sublingual label allows one tablet repeated every 5 minutes up to three tablets in 15 minutes, and prophylactic use 5 to 10 minutes before exertion. Absorption is incomplete and variable, about 40 percent, and depends on how moist the mouth is, which is why the label suggests a small sip of water first for people with a dry mouth. Long-acting patches, ointments and capsules give continuous exposure, which is what produces tolerance. (Source 14)

If it is harmful, what reduces it?

There is no antidote. For hypotension from overdose the label's approach is supportive: keep the person lying down and warm, move the limbs passively to help venous return, and give intravenous saline to expand circulating volume, since there is no specific antagonist to nitroglycerin's vasodilator effect. Adrenaline is explicitly not recommended because it does not reverse the hypotension. If methaemoglobinaemia has developed, methylene blue 1 to 2 mg per kilogram intravenously may be required, unless the person is known to have G-6-PD deficiency. A transdermal patch can simply be removed. (Source 27)

Why might someone be low in it or missing it?

For a drug the useful question is why it stops working, and nitroglycerin has a specific answer: tolerance. The label states that excessive use may lead to tolerance and that a decrease in the effect of a sublingual tablet may result from using long-acting nitrates. The review of this literature describes patients losing the protective effect of long-acting nitrates with continued or frequent daily use, which is why daily nitrate-free intervals are built into long-acting regimens. (Source 15)

Which whole foods contain it or feed it?

No whole food contains nitroglycerin. It is a synthetic nitrate ester manufactured as a stabilised sublingual tablet alongside lactose monohydrate, glyceryl monostearate, pregelatinized starch, calcium stearate and colloidal silicon dioxide. Dietary nitrate from vegetables such as beetroot is a chemically different thing handled by a different pathway, and none of the sources we read treat it as a substitute for or an interaction with nitroglycerin. The food-related point the label does make is about alcohol: its vasodilating effect adds to nitroglycerin's. (Source 25)

What happens if you do not have it?

Without it, an angina attack is not interrupted, and the attack is what the drug is for. In the anal fissure trials the placebo arms still improved, which shows how much of the benefit is not drug-specific: 35.5 percent of fissures healed on placebo versus 48.9 percent on glyceryl trinitrate, and pain fell by 37 mm on placebo versus 44 mm on the ointment. For survival, going without a nitrate after a heart attack made no measurable difference in a 58,050-patient trial. (Source 4)

How can you test for it?

There is no blood test for nitroglycerin in clinical use, and none would help, since it is cleared in minutes. What can be tested is a consequence of overdose: methaemoglobin can be measured, and the label notes that clinically significant methaemoglobinaemia is rare at conventional doses but dose-related, and more likely in people with inherited haemoglobin abnormalities. The practical monitoring is blood pressure and whether the drug still relieves pain, since loss of effect is the signal of tolerance. (Source 19)

References

1. DailyMed, U.S. National Library of Medicine. NITROSTAT (nitroglycerin) sublingual tablets - FDA prescribing information, Sections 12.1-12.2 Mechanism of Action and Pharmacodynamics (SPL effective 2025-11-06). 2025. Read the source
2. DailyMed, U.S. National Library of Medicine. NITROSTAT (nitroglycerin) sublingual tablets - FDA prescribing information, Section 1 INDICATIONS AND USAGE (SPL effective 2025-11-06). 2025. Read the source
3. DailyMed, U.S. National Library of Medicine. RECTIV (nitroglycerin) Ointment 0.4% - FDA prescribing information, Section 1 INDICATIONS AND USAGE (SPL effective 2026-09-08). 2026. Read the source
4. The Cochrane database of systematic reviews. Non surgical therapy for anal fissure.. 2012. PMID 22336789, DOI 10.1002/14651858.CD003431.pub3. Read the source
5. Lancet (London, England). ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group.. 1995. PMID 7661937. Read the source
6. Lancet (London, England). Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial.. 2019. PMID 30738649, DOI 10.1016/S0140-6736(19)30194-1. Read the source
7. JAMA internal medicine. Efficacy of Continuous Transdermal Nitroglycerin for Treating Hot Flashes by Inducing Nitrate Cross-tolerance in Perimenopausal and Postmenopausal Women: A Randomized Clinical Trial.. 2023. PMID 37273224, DOI 10.1001/jamainternmed.2023.1977. Read the source
8. The American journal of cardiology. Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist.. 1999. PMID 10078539, DOI 10.1016/s0002-9149(99)00044-2. Read the source
9. DailyMed, U.S. National Library of Medicine. NITROSTAT (nitroglycerin) sublingual tablets - FDA prescribing information, Section 4 CONTRAINDICATIONS (SPL effective 2025-11-06). 2025. Read the source
10. DailyMed, U.S. National Library of Medicine. RECTIV (nitroglycerin) Ointment 0.4% - FDA prescribing information, Sections 7.6-7.7 Drug Interactions (Ergotamine; Alcohol) (SPL effective 2026-09-08). 2026. Read the source
11. DailyMed, U.S. National Library of Medicine. RECTIV (nitroglycerin) Ointment 0.4% - FDA prescribing information, Sections 7.2-7.5 Drug Interactions (SPL effective 2026-09-08). 2026. Read the source
12. DailyMed, U.S. National Library of Medicine. NITROSTAT (nitroglycerin) sublingual tablets - FDA prescribing information, Section 7 DRUG INTERACTIONS (SPL effective 2025-11-06). 2025. Read the source
13. DailyMed, U.S. National Library of Medicine. NITROSTAT (nitroglycerin) sublingual tablets - FDA prescribing information, Section 12.3 Pharmacokinetics, Drug interactions (SPL effective 2025-11-06). 2025. Read the source
14. DailyMed, U.S. National Library of Medicine. NITROSTAT (nitroglycerin) sublingual tablets - FDA prescribing information, Section 12.3 Pharmacokinetics, Absorption (SPL effective 2025-11-06). 2025. Read the source
15. DailyMed, U.S. National Library of Medicine. NITROSTAT (nitroglycerin) sublingual tablets - FDA prescribing information, Section 5 WARNINGS AND PRECAUTIONS (SPL effective 2025-11-06). 2025. Read the source
16. American journal of cardiovascular drugs : drugs, devices, and other interventions. Challenges with nitrate therapy and nitrate tolerance: prevalence, prevention, and clinical relevance.. 2014. PMID 24664980, DOI 10.1007/s40256-014-0072-5. Read the source
17. DailyMed, U.S. National Library of Medicine. RECTIV (nitroglycerin) Ointment 0.4% - FDA prescribing information, Section 2 DOSAGE AND ADMINISTRATION (SPL effective 2026-09-08). 2026. Read the source
18. DailyMed, U.S. National Library of Medicine. RECTIV (nitroglycerin) Ointment 0.4% - FDA prescribing information, Section 6 ADVERSE REACTIONS (including Table 1) (SPL effective 2026-09-08). 2026. Read the source
19. DailyMed, U.S. National Library of Medicine. NITROSTAT (nitroglycerin) sublingual tablets - FDA prescribing information, Section 10.1 Signs and Symptoms, Methemoglobinemia (SPL effective 2025-11-06). 2025. Read the source
20. DailyMed, U.S. National Library of Medicine. NITROSTAT (nitroglycerin) sublingual tablets - FDA prescribing information, Section 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility (SPL effective 2025-11-06). 2025. Read the source
21. DailyMed, U.S. National Library of Medicine. RECTIV (nitroglycerin) Ointment 0.4% - FDA prescribing information, Section 14 CLINICAL STUDIES (SPL effective 2026-09-08). 2026. Read the source
22. The Cochrane database of systematic reviews. Non surgical therapy for anal fissure. (Authors' conclusions). 2012. PMID 22336789, DOI 10.1002/14651858.CD003431.pub3. Read the source
23. DailyMed, U.S. National Library of Medicine. NITROSTAT (nitroglycerin) sublingual tablets - FDA prescribing information, Section 2 DOSAGE AND ADMINISTRATION (SPL effective 2025-11-06). 2025. Read the source
24. Lancet (London, England). Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial. (Methods). 2019. PMID 30738649, DOI 10.1016/S0140-6736(19)30194-1. Read the source
25. DailyMed, U.S. National Library of Medicine. NITROSTAT (nitroglycerin) sublingual tablets - FDA prescribing information, Section 11 DESCRIPTION (SPL effective 2025-11-06). 2025. Read the source
26. DailyMed, U.S. National Library of Medicine. NITROSTAT (nitroglycerin) sublingual tablets - FDA prescribing information, Section 12.2 Pharmacodynamics (haemodynamic effects, onset and duration) (SPL effective 2025-11-06). 2025. Read the source
27. DailyMed, U.S. National Library of Medicine. NITROSTAT (nitroglycerin) sublingual tablets - FDA prescribing information, Section 10.2 Treatment of Overdosage (SPL effective 2025-11-06). 2025. Read the source