Aspirin is the mainstay in prophylaxis of cardiovascular diseases. Impaired aspirin antiplatelet effects are associated with enhanced incidence of cardiovascular events. Comedication with non-opioid analgesic drugs has been described to interfere with aspirin, resulting in impaired aspirin antiplatelet effects. Additionally, non-opioid analgesic medication has been shown to enhance the risk of cardiovascular events and death. Pain is very frequent and many patients rely on analgesic drugs to control pain. Therefore effective analgesic options without increased risk of cardiovascular events are desirable. This review focuses on commonly used non-opioid analgesics, interactions with aspirin medication and impact on cardiovascular risk.

Approximately 20% of European adults suffer of acute or chronic pain and rely on analgesic drugs[1,2]. The incidence of pain and usage of non-opioid analgesics is even higher in patients with cardiovascular diseases. Forty percent of patients with coronary artery disease reported intake of non-opioid analgesic drugs[3]. This is not surprising, as the incidence of pain correlates with increasing age[4] and cardiovascular diseases are morbidities of middle to older age patients[5].

Aspirin (acetylsalicylic acid; ASA) is essential secondary prevention of cardio-and cerebrovascular events[6]. It inhibits cyclooxygenase (COX)-1 by irreversible acetylating serine 530 near the active site. This hampers conversion of arachidonic acid to thromboxane (TX) A2 for the life span of the affected platelet[7]. Aspirin has been shown to reduce the incidence of death, myocardial infarction and stroke[8-10]. However, during the last decade substantial inter-individual variation in pharmacodynamic response to aspirin has been described. This is called high on-treatment platelet reactivity (HTPR) (formerly known as “aspirin resistance”). Patients with HTPR have an increased incidence of death, myocardial infarction and stroke[11]. Many potential mechanisms including non-compliance[12,13], impaired absorption[14], genetic polymorphisms[15] increased turnover rate, enteric coating of aspirin[16,17] and COX-1 independent pathways may cause this HTPR[18]. Besides that, non-opioid analgesic medication may impair aspirin antiplatelet effects. In contrast to above mentioned internal factors, this drug-drug interaction is avoidable. Therefore special attention should be paid to this interaction leading to impaired aspirin antiplatelet effects. This review focuses on (1) mechanisms-; (2) laboratory-; and (3) clinical evidence of the aspirin drug-drug interaction with commonly used non-opioid analgesics.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used drugs in the world[19]. They are available on prescription as well as over the counter. In the United States, 70 million NSAID prescriptions- and 30 billion over the counter sales per year were registered[20]. Approximately 83% of United States - American adults use NSAID to relief pain at least once a year, 29% once a week and 15% daily[21]. In Australia, 55% of people consume NSAIDs at least once per month[22].

The term “NSAID” subsumes a variety of drugs with different chemical structures, pharmacokinetics, pharmacodynamics and mechanism of action but similar effects[23]. The main common feature is prevention of prostaglandin formation by inhibition of COX isoforms. This results in desirable anti-inflammatory and analgesic effects due to COX-2 inhibition in inflamed tissues[24]. On the other hand, inhibition of COX-1 in the gastric mucosa impairs maintenance of the mucosal barrier. This results in an increased risk of gastrointestinal events[25]. Additionally NSAIDs may worsen renal function[26] and affect platelets[27]. Based on the above mentioned differences in pharmacokinetics and pharmacodynamics between different NSAIDs, a considerable variability in analgesic as well as anti-inflammatory and antiplatelet effects is not surprising[23,27]. NSAIDs may also impair cardiovascular prognosis[28,29], possibly by inhibition of prostaglandin synthesis in the vasculature resulting in an increase in blood pressure and disturbed endothelial control of thrombogenesis. This aspect must not be confounded with the pharmacodynamic interaction of non-opioid analgesics with aspirin, which is discussed here. However, it is possible that this interaction contributes to the overall cardiovascular risk of NSAIDs. In the following, we will discuss the most commonly used NSAIDs with respect to their potential to interfere with platelet inhibition by low dose aspirin.

Anti-inflammatory and analgesic effects of COX- inhibitors are largely mediated by prevention of COX-2 induced prostaglandin formation in inflamed tissues[24]. Impairment of the gastric mucosal barrier resulting in increased incidence of gastrointestinal events, and affection of platelets are mostly caused by COX-1 inhibition[25,27]. Therefore, during the 90’s NSAIDs with COX-2 selectivity were developed[55].

Conflicting data has been reported regarding impairment of aspirin antiplatelet effects by COX-2 inhibitors. Despite COX-2 selectivity, celecoxib was shown to form a hydrogen bond in the hydrophobic channel of COX-1 with tyrosine 355[27]. This goes in line with in-vitro experiments, demonstrating inhibition of thromboxane formation and platelet aggregation by celecoxib incubation. In ASA and celecoxib co-incubated platelets, ASA antiplatelet effects were inhibited[27]. Celecoxib administration in dogs interfered with the ability of aspirin to inhibit platelet aggregation[56]. In contrast, no impact on platelet function was observed in healthy individuals on celecoxib treatment[35]. Additionally, different groups reported that COX-2 inhibiting co-treatment in aspirin treated healthy individuals did not impair the pharmacodynamic response to aspirin[33,35,37,57]. Regardless, multiple studies reported increased risk of cardiovascular events and death in patients receiving COX-2 inhibitors independently of concomitant aspirin intake[28,58-60].

Paracetamol is an aniline derivative. It is one of the most widely used antipyretic and analgesic drugs worldwide, especially as the risk of gastrointestinal bleeding events are lower in comparison to NSAIDs[61]. It is available over the counter in many countries[62]. However, in supra-therapeutic doses depletion of endogenous glutathione occurs, resulting in paracetamol metabolism shunting to toxic pathways causing severe, even fatal, hepatotoxicity[63,64]. To date, the mechanisms of analgesia by paracetamol remain unclear despite of extensive investigations[65]. A plethora of mechanisms have been postulated including activation of the endocannabinoid pathway[66,67], inhibition of the nitric oxide synthase[68,69], and indirect activation of descending serotonergic pathways[70-72]. Additionally, inhibition of cyclooxygenases in a direct-[73-75], or indirect (by converting to their oxidized, inactive form[76]) way has been described. Current opinion suggests that paracetamol performs its analgesic actions by multiple mechanisms predominantly in the central nervous system[65].

In-vitro addition of paracetamol to human platelets was reported to inhibit collagen, epinephrine and arachidonic acid induced platelet aggregation and TX formation[77]. Accordingly, in healthy individuals a reduced arachidonic acid-induced TX formation one hour after single dose of paracetamol was shown. However an effect on platelet aggregation was observed in only one of five investigated individuals[77]. Munsterhjelm et al[78] detected an inhibition of platelet aggregation in healthy individuals 10 min after ingestion of paracetamol. Already 90 min after intake of paracetamol, platelet aggregation was restored. Additionally, a combination of paracetamol and diclofenac exhibits an additive effect on platelet inhibition. In comparison to diclofenac treatment in healthy individuals alone, addition of paracetamol preserves inhibition of platelet aggregation and TX formation 90 min after intake. Nevertheless, platelet function normalized after 24 h[52]. In patients, a single dose of paracetamol reduced arachidonic acid induced TX formation, but did not inhibit platelet aggregation in patients[54]. Molecular modelling and docking analyses revealed that paracetamol forms only one single hydrogen-bond to arginine 120 in the hydrophobic channel of COX-1[27]. No aspirin interaction resulting in inhibition of aspirin antiplatelet effects was seen, suggesting that one hydrogen-bond might not be sufficient to induce impairment of aspirin antiplatelet effects[27]. These findings were supported by the results of Catella-Lawson et al[33] and Rao et al[79], both did not observe altered aspirin antiplatelet effects in presence of paracetamol, either. However an increased incidence of first cardiovascular event in patients with frequent use of paracetamol was observed[80]. Potential reasons for this observation may be a dose dependent risk of renal insufficiency of paracetamol[81] which is a predictor of cardiovascular events[82]. Secondly, an increased blood pressure in patients with paracetamol usage has been described[83-86]. Also, an impairment of endothelial function by depletion of glutathione is thinkable to induce this enhanced risk of cardiovascular events[87].

Dipyrone is a pyrazolinone analgesic with favorable analgesic, spasmolytic and antipyretic effects. Gastrointestinal complications are rare in comparison to NSAIDs like ibuprofen or diclofenac[88]. Due to the risk of agranulocytosis, it has been withdrawn in many countries including the United States. Nevertheless, it is extensively used in Central- and South America and freely available over the counter in Mexico. Therefore despite of the withdrawal by the Food and Drug Administration, there is a wide spread use in the United States as well[89]. Moreover, it is freely available and the most used analgesic in Eastern European countries like Bulgaria[90]. Guidelines of the European Society of Cardiology do not recommend the use of NSAIDs in patients with cardiovascular diseases[91,92]. This may be one of the reasons why dipyrone daily doses tripled during the last decade in European countries like Germany[93]. The exact mechanism of its analgesic effects is complex and not completely understood, yet. Besides COX inhibition, an activation of opioidergic- and cannabinoid system in combination with inhibition of central COX-3 appears to contribute to its analgesic effects. Comedication with opioids causes superadditive analgesic effects. It inhibits both prostaglandin dependent and - independent pathways of fever and exhibits its spasmolytic effects by inhibition of intracellular calcium release[94]. Dipyrone inhibits all COX isoforms. It reversibly binds near the active site of COX, forming hydrogen bonds to tyrosin 385 and serine 530[27]. Dipyrone sterically hinders aspirin access to the active site and serine 530 of COX-1. Plasma half-life of dipyrone is about 2.5 h. Therefore it is 7.5 fold longer available than aspirin with a plasma half-life of only 20 min[95]. In-vitro experiments revealed that dipyrone active metabolite impairs ASA induced inhibition of microsomal platelet COX. The active metabolite of dipyrone in therapeutically relevant (low micromolar) concentrations showed little inhibition of platelet aggregation and TX formation. However, it prevented ASA dependent inhibition of platelet aggregation and thromboxane formation caused by arachidonic acid as well as collagen. The effect was reproducible in terms of microsomal platelet COX activity and p-selectin expression as well[96]. Increasing ASA concentrations in-vitro overcame this effect[97]. Additionally, previous incubation with ASA before addition of dipyrone preserves ASA antiplatelet effects[98].

In healthy individuals, aspirin intake sufficiently inhibits platelet aggregation, seven days of additional dipyrone intake completely blunts aspirin antiplatelet effects. This effect was reversible within three days of continued aspirin administration after termination of dipyrone intake. However, multiple daily doses of dipyrone were not tested[97]. Interestingly, Börgermann et al[99] reported that there was no impaired pharmacodynamic response to aspirin in dipyrone treated healthy individuals. However the duration of aspirin and dipyrone co-treatment was only two days. As aspirin antiplatelet effects are irreversible and persist for the remainder of the affected platelets life-span, it is not surprising, that no relevant differences were observed after two days of additional dipyrone treatment. A partial inhibition of aspirin antiplatelet effects has been described after four days of concomitant intake and complete inhibition after seven days[100]. Furthermore, it has been shown that aspirin intake prior to dipyrone preserves aspirin antiplatelet effects, whereas dipyrone intake prior to aspirin completely blunts aspirin antiplatelet effects measured by platelet aggregation in healthy individuals[97].

In patients with coronary artery disease, residual platelet reactivity despite of aspirin was detected in 50% of dipyrone comedicated patients[101]. Residual platelet TX formation in patients with coronary artery disease correlated with the concentration of dipyrone metabolites. Additionally, in dipyrone treated patients after cardiac surgery, the incidence of HTPR to aspirin nearly tripled postoperatively[99]. The impact of this in-vitro and ex-vivo effects on clinical outcome has not been investigated yet.

The optimal analgesic regimen in patients with pain is challenging. Considering laboratory and clinical data, naproxen and paracetamol seem to display the most favourable benefit/risk ratio. However, increased incidence of adverse events has been described with these analgesics as well. Alternatively, aspirin would be a possible alternative to relieve pain and inhibit platelet function. Yet it is well known, that analgesic doses of aspirin increase the risk of gastrointestinal complications (Figure 1 and Table 1). If medication with non-opioid analgesics is considered indispensable, a strict order of intake, with aspirin medication at least two hours prior to analgesic medication is advisable. However, the optimal analgesic and antiplatelet regimen in patients with increased risk of cardiovascular disease is still unknown and requires further investigation.

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Figure 1 Graphical abstract. Non-opioid analgesics form reversible hydrogen bonds near the active centrum of cyclooxygenase (COX)-1. This prevents (1) aspirin entrance to the hydrophobic channel; (2) irreversible acetylation of Ser530; and (3) platelet inhibition for the remainder of the platelets life-span.