Ibuprofen (IBU) is an over-the-counter (OTC) non-steroidal anti-inflammatory drug (NSAID) (Figure 1). It is sold as the racemic S enantiomer to produce the desired pharmacologic action. IBU has an elimination half-life of 2 hours [1][2]. IBU is used to treat fever, pain, and inflammation [3]-[5]. IBU may not be as effective an anti-inflammatory agent when compared to other NSAIDs [6]. Literature on the safety of IBU is plentiful [1]. NSAIDs, when combined with

Figure 1.Schematic of the chemical structure of ibuprofen.

acetaminophen, are highly effective for postoperative pain control [2]. Combining ibuprofen 200 mg with acetaminophen 500 mg has a significantly greater analgesic effect than an opioid medication such as oxycodone 15 mg with acetaminophen [2]. Thus, it may be appropriate to use opioids only for severe or refractory pain [2].

There may be a misconception that NSAIDs have an unacceptable risk of bleeding. Nonetheless, the bleeding risk profile of OTC IBU and the prescription strength (600 - 800 mg) is not well defined. That is, with the OTC use of IBU, there are few controlled studies regarding the anticoagulation effect of OTC use in the general population [1][2].

Gastrointestinal bleeding can occur with OTC IBU use. IBU inhibits COX-1 and induces a reduction of gastric prostaglandins, which in turn reduces gastric protective mucus production, thus directly exposing the underlying cells to low pH gastric acid and enzymes such as pepsin [1][2].

The GI-bleeding complication hospitalization rate for OTC-comparable doses of IBU is less than 0.2% [1]. With increasing age and concomitant medication use, the incidence of bleeding events does increase [1]. Nonetheless, there has been no consistent IBU dose-anticoagulation response relationship elucidated. This may mean that patients are poor historians when describing their side effects, or there are genetic metabolic differences that produce different outcomes, along with other potential reasons [7]. It is agreed that there appears to be a low incidence of bleeding events with OTC IBU.

OTC drugs for pain control are intended for short-term use and should not be taken for analgesia for more than 10 days. Longer use increases possible side effects. To avoid gastric side effects, IBU should be taken with food. Increased age, anemia, smoking, carcinoma, alcohol use, liver disease, frailty, anticoagulants, and selective serotonin reuptake inhibitors (SSRIs) are comorbidities that may increase the risk for gastric side effects [2][4][5][8]-[11].

A PubMed search was done using the terms ibuprofen, ibuprofen AND anticoagulant, ibuprofen AND drug interactions, and ibuprofen AND complications. No other search engine was used. Articles published between 1998 and 2024 were collected. Only articles addressing interactions with anticoagulants were considered; all others were excluded. The articles retrieved were assessed for relevance, and those deemed relevant are included herein. No human or animal subjects were used whatsoever in this work.

IBU inhibits the cyclooxygenase-1 and -2 (COX-1 and COX-2) enzymes. Inhibition of COX-1 affects the prostaglandin-induced protection of the gastrointestinal tract, and this action is well understood [10]. Nonetheless, various isoforms of IBU can cause varying degrees of gastric damage [12]. Selective COX-2 inhibitors are known to induce less gastric damage [12]. COX-2 leads to the production of prostaglandin E2 (PGE2), which produces redness, pain, and swelling; inhibition of COX-2 produces analgesia [5]. Prostaglandins are converted to thromboxane A₂ (TxA2) by COX-1 enzymes [5][13]. TxA2 stimulates platelet aggregation for blood clotting. Thus, COX enzymes are inhibited, and then ultimately TxA2 production is reduced, along with platelet aggregation and coagulation [12][14][15].

Blood coagulation or thrombosis is the biological action in which liquid blood is converted to a gel or a clot. Coagulation involves platelets and vascular protein factors [16] (Figure 2). When vascular subendothelial collagen is damaged and exposed to platelets, coagulation begins. Platelets bind directly to the subendothelial collagen to form a plug to occlude the injury. Platelets release stored granules of several clotting factors that then bind fibrinogen. The fibrinogen crosslinks to a glycoprotein and aggregates more platelets, completing initial hemostasis [17]. Factor VII then induces fibrin formation to strengthen the platelet plug.

Figure 2.Schematic of the coagulation cascade.

The second stage of coagulation has two pathways that are artificially named: 1) extrinsic or tissue factor and 2) intrinsic or contact activation pathways. Both pathways play a role in fibrin formation to seal off bleeding or leaking blood vessels.

The extrinsic or tissue factor pathway is the more important. This pathway is a cascade of enzymatic reactions involving coagulation factors. The main role of the extrinsic pathway is the rapid release of thrombin [18].

The intrinsic pathway is a cascade of reactions that aid clot formation, but its main role appears to be in inflammation and immunity [18][19]. A therapeutic blockage of the intrinsic pathway does not increase the risk of significant bleeding but can contribute to the prevention of thrombosis [19].

In the end, the extrinsic and intrinsic pathways both end in a final common interactive pathway of factor X, thrombin, and fibrin.

Coagulation is a complex physiological series of chemical and enzymatic reactions that are activated and inhibited by a wide variety of enzymes and chemicals. In the end, without interference, a thrombus forms and bleeding ceases [18]-[20].

IBU has the lowest risk for gastrointestinal bleeding and platelet inactivation of all NSAIDs [21]. A single preoperative dose of 400 mg of IBU does not have a significantly increased occurrence of intraoperative or postoperative bleeding [22]-[24].

To reduce the risk of GI bleeding, IBU should not be taken for more than 10 days [25]. The lowest dose that produces the appropriate clinical effect is the dose that should be taken [26][27].

Some studies report a low incidence of GI bleeding events with the use of 200-600 mg IBU for 10 days [1]. The gastrointestinal bleeding incidence among those using OTC-comparable doses ranged from 0 to 3.19 per 1000 patient years. The incidence of GI bleeding-related events increased with age and polypharmacy [1]. However, there was an inconsistent, statistically significant, ibuprofen dose-dependent anticoagulant response relationship. The relative risk of any GI bleeding-related events ranges from 1.1% to 2.4% for users of 200 - 600 mg IBU doses for 10 days when compared to non-users [1].

There are few published studies that have specifically investigated OTC IBU use [1]. Unfortunately, the large variety of methodologies, exposures, and outcomes precludes a direct comparison of many studies by means of a meta-analysis [1]. The various outcomes may imply that there are human differences in IBU metabolism [1]. Thus, patients with susceptible phenotypes that affect IBU metabolism may react with varying degrees of gastrointestinal bleeding severity [28].

Anticoagulants inhibit clot formation. There are many available with various mechanisms of action. Since IBU acts to inhibit platelet aggregation, there may be an increased clinical anticoagulation effect when co-administered with other anticoagulants, antithrombotic, or antiplatelet agents [28][29].

Current information shows that IBU affects coagulation by mildly inhibiting platelet aggregation when taken for less than 10 days. IBU 400 mg every 6 hours taken for less than 48 hours is unlikely to induce an adverse bleeding event in patients taking anticoagulants. However, after 10 days of daily dosing, there may be an increased risk for bleeding.

Most patients have poor compliance, and if IBU is to be administered, the clinician should be certain that the patient understands the implications of IBU dosing and potential drug interactions.

Investigations of these interactions are needed to provide the clinician with appropriate prescribing protocols.