A potential nitrergic mechanism of action for indomethacin, but not of other COX inhibitors: relevance to indomethacin-sensitive headaches

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) that act as cyclo-oxygenase (COX) inhibitors are commonly used in the treatment of a range of headache disorders, although their mechanism of action is unclear. Indomethacin is of particular interest given its very special effect in some primary headaches. Here the in vivo technique of intravital microscopy in rats has been utilised as a model of trigeminovascular nociception to study the potential mechanism of action of indomethacin. Dural vascular changes were produced using electrical (neurogenic) dural vasodilation (NDV), calcitonin gene-related peptide (CGRP) induced dural vasodilation and nitric oxide (NO) induced dural vasodilation using NO donors. In each of these settings the effect of intravenously administered indomethacin (5 mg kg−1), naproxen (30 mg kg−1) and ibuprofen (30 mg kg−1) was tested. All of the tested drugs significantly inhibited NDV (between 30 and 52%). Whilst none of them was able to inhibit CGRP-induced dural vasodilation, only indomethacin reduced NO induced dural vasodilation (35 ± 7%, 10 min post administration). We conclude NSAIDs inhibit release of CGRP after NDV without an effect on CGRP directly. Further we describe a differentiating effect of indomethacin inhibiting nitric oxide induced dural vasodilation that is potentially relevant to understanding its unique action in disorders such as paroxysmal hemicrania and hemicrania continua.

Effect of NSAIDs on Na+/H+ exchanger activity in rat colonic crypts

“…NSAIDs are widely used for the treatment and prevention of both acute and chronic conditions, such as headache, arthritis, and CVD (30,41,49,50). Yet evidence shows that drugs such as aspirin and indomethacin, even when encapsulated or given as suppositories, may lead to lower GI injury (9, 10, 18, 37, 44).…”

“…Taken in high dosage, aspirin is also effective in the prevention of diabetic retinopathy (24) and is known to reduce the risk of venous thromboembolism in susceptible (i.e., postoperative) patients (22,40). Indomethacin, a highly potent NSAID (55), is prescribed for conditions such as rheumatoid arthritis (50), ocular inflammation (21), and primary headache disorders (49). Indomethacin can also be administered as a suppository, which has several advantages over traditional oral therapy including avoidance of a first-pass effect and reduction in gastric irritation (54).…”

In vitro study of the cytotoxic and genotoxic effects of indomethacin-loaded Eudragit® L 100 nanocapsules

“…Indomethacin is principally known for its anti-inflammatory effects, being widely used in the treatment of fever and inflammation in patients with osteoarthritis, rheumatoid arthritis, osteitis deformans, bursitis, tendonitis, and headache (Baber et al, 1980;Summ et al, 2010). However, side effects resulting from the use of this type of medication are a concern.…”

Indomethacin-Responsive Headaches

“…Indomethacin also inhibits the production of nitric oxide (NO) [87]. To this end, indomethacin, but not naproxen or ibuprofen, has been shown to effect NO-induced vasodilation [88]. It is known that application of NO donors induces acute headache [89].…”