Indomethacin: Uses, Clinical Significance, Combination With Copper, Treatments and Effects

It is commonly used in premature babies to treat hemodynamically significant ductus arteriosus (DAP).

Indomethacin blocks prostaglandin synthetase, causing vasoconstriction.

Spontaneous gastrointestinal perforation has been observed in low birth weight infants treated with high doses of Indomethacin.

It has been postulated that Indomethacin increases mesenteric vascular resistance and reduces mesenteric blood flow by 16% to 20%.

Norton showed that using Indomethacin as a tocolytic agent was associated with a higher incidence in babies born before 30 weeks of gestation (mean age at delivery, 27.6 weeks). However, Indomethacin did not increase the incidence in Babies born after 32 weeks of gestation.

Two randomized controlled trials that included more than 500 preterm infants who received early low dose indomethacin versus placebo for closure showed no difference in post-medication incidence.

Interestingly, although continuous indomethacin infusion leads to fewer alterations in cerebral, renal, and mesenteric blood flow compared to bolus infusion, to date, there is insufficient evidence to show that this results in reduced risk.


Clinical significance

Indomethacin has been used for more than four decades with few ocular side effects unless the drug is used for long periods at high doses. Its most serious side effect is retinal pigment retinopathy, with macular atrophy and a waxy disc (Burns 1968, Henkes et al. 1972).

Although blurred vision may appear after initiating this agent, it is rarely clinically significant. The medication is probably secreted in tears, causing deposits on the cornea, irritation, and occasionally keratitis. Intracranial hypertension and optic neuritis have been reported with the use of Indomethacin.

Keratorefractive surgery has brought topical ocular Indometacin back to clinical use mainly because it has fewer side effects than steroids. Its primary use is as a local anesthetic, which shows minor damage to the corneal epithelium (Badalá et al., 2004) in the immediate postoperative period.

Sheehan and Kutzner (1989) reported a case of possible acute asthma due to topical ocular Indometacin.

Indomethacin and copper

Indomethacin is commonly used in humans. It is a derivative of acetic acid and a member of the indoline class. Despite its short half-life in dogs (0.3 h), Indometacin is highly ulcerogenic at 1 mg/kg, 5% of the toxic dose in humans.

Indomethacin is marketed in Australia in combination with copper for use in dogs and horses. It is reported that copper has anti-inflammatory and antioxidant effects.

To date, controlled clinical trials have not been conducted to demonstrate or disprove the compound’s efficacy in treating inflammatory disorders in dogs and horses.

However, uncontrolled clinical trials support the relative lack of gastrointestinal toxicity when the drug is used in dogs compared to Indomethacin alone.


Indomethacin and lithium carbonate are the treatments of choice for hypnotic headaches, with Indomethacin being a little more effective for the unilateral form of the syndrome.

Indomethacin at an initial dose of 25 mg daily for two days and titration at 25 mg three times daily is a reasonable treatment approach.

This dose can be carefully increased up to 150 mg per day. Indomethacin should be used with caution, if at all, in patients with peptic ulcer disease or impaired renal function.

Headache specialists have noted anecdotal reports of a positive response to cyclooxygenase-2 (COX-2) inhibitors in treating benign hypnotic headaches.

Lithium carbonate is used in the same way as in treating cluster headaches. It is based on its proven efficacy in treating other diseases that are believed to have a chronobiological basis, such as cluster headache and bipolar disorders.

However, the therapeutic window of lithium carbonate is small, and this medication should be used with caution. An initial dose of 300 mg at bedtime may increase after 48 hours to 300 mg twice daily.

If side effects are not observed after 48 hours, the dose can be increased again to 300 mg daily.

There are anecdotal reports that gabapentin and pregabalin may also help decrease the frequency and intensity of hypnotic headache attacks.

Unlike cluster headache, oxygen inhalation has been ineffective in aborting hypnotic headache attacks once the patient has been awakened by pain.

Effects of Medication on Brain Blood Flow

Aleteoterazin reduces FSC in experimental animals, adults, and preterm infants.76 As mentioned above, a loss of typical CBF-CO2 reactivity in preterm infants has also been demonstrated.

The crucial question about the use of Indomethacin in preterm infants and its effect on FSC is whether Indomethacin reduces FSC to ischemic levels that result in brain injury.

Interestingly, although Indomethacin decreases the incidence of severe peri-intraventricular hemorrhage, this early effect does not translate into better long-term neurodevelopmental outcomes.

This increases the possibility that the overall decrease induced by Indometacin in FSC may represent a double-edged sword.

Unlike Indomethacin, ibuprofen has no significant cerebrovascular effects. However, it is not known whether using ibuprofen instead of Indomethacin for treating patent ductus arteriosus results in a better long-term neurodevelopmental outcome.

Among methylxanthines, aminophylline reduces FSC and Paco2 in experimental animals, adults and premature infants, but caffeine has a more negligible effect on the medication.

Methylxanthines are potent antagonists of the adenosine receptor. However, whether the reduction of FSC is the direct effect of methylxanthines, a result of the decrease in Paco2, or a combination of these two actions is not entirely clear. Dopamine increases blood pressure.

However, it does not seem to have a selective (dilatory) effect on cerebral vessels. In babies with blood pressure greater than 30 mm Hg, infusion of dopamine at 0.3 mg/kg / h was effective in increasing blood pressure and output of the left ventricle and did not increase FSC.

However, in babies with hypotension, a positive pressure-flow ratio of 1.9% per mm Hg (95% confidence interval [CI], 0.8 to 3.0) and 6% per mm Hg was found.

It is unclear whether the discrepancy between the findings of these two studies and those cited above can be explained by the presence or absence of hypotension, by the statistical uncertainty of the small studies, or by differences in the methodology and clinical status of the patients.