Inflammation Pain and Fever

Inflammation as a response to injury is an expression of the effective activation of cellular and humoral defense mechanisms. The local inflammatory syndrome is characterized by its five classical features: heat (calor), redness (rubor), pain (dolor), swelling (tumor), and tissue injury (functio laesa). These multiple symptoms of acute inflammation are caused by a complex interaction between inflammatory white cells, cell- and tissue-derived mediators, and the vessel wall endothelium [328]. Leukocyte-derived cytokines additionally cause an increase in core temperature (fever) that accelerates all of the numerous biochemical reactions designed to speed up the acute inflammatory response whereas (inflammatory) pain will act as an overall alarming signal, indicating tissue injury and its location. In pharmacological terms, this means that any effective anti-inflammatory treatment in turn will also inhibit the accompanying events fever and pain. Nevertheless, targeted removal of one of the mediator systems involved will never stop the whole process but rather ameliorate it. The inflammatory reaction as a whole is an essential life-preserving process, and in this aspect similar to the maintenance of hemostasis, which enables the organism to resist and to survive the exposure against a variety of noxious external stimuli [328].

The discovery by Sir John Vane that aspirin inhibits prostaglandin biosynthesis provided for the first time a unifying and simple explanation for the well-known anti-inflammatory, analgesic, and antipyretic actions ofsalicylates. This discovery was followed by the development of dozens of NSAIDs. These compounds were designed to reduce local prostaglandin levels via inhibition of injury-induced biosynthesis with prospective use as anti-inflammatory analgesics (Section 2.2.1). Second generation NSAIDs, the selective inhibitors of COX-2-derived prostanoids (coxibs), were even more specifically targeted to injury-induced upregulation of prostaglandin biosynthesis. Al though the future of coxibs is still uncertain, not because of lack of potency but because of unwanted adverse effects (see below), traditional NSAIDs have meanwhile largely displaced aspirin from its use in long-term treatment of inflammatory diseases (Section 4.2.2). However, with increasing knowledge about the complexity of the inflammatory response, specifically the key role of cytokines, the elucidation of major immune regulatory mechanisms, and the identification of a plethora of chemicals that mediate these multiple responses and in addition interact with each other in a very complex manner, it became also clear that prosta-glandins are neither the only nor the most important biomolecules that control the inflammatory process and its accompanying phenomen-pain and fever.

Inhibition of prostaglandin formation in an area of tissue injury is still the most widely accepted explanation for the analgesic/anti-inflammatory action of aspirin. However, the efficacy of aspirin as an anti-inflammatory analgesic can probably not solely be explained by inhibition of prostaglandin biosynthesis. For example, anti-inflammatory actions of aspirin are stronger at doses higher than those that cause maximum inhibition of prostaglandin formation. There are also no clear correlations between inhibition of prostaglandin biosynthesis and the analgesic efficacy of aspirin. Stimulation of the lipoxin pathway via 15-lipoxygenase of neutrophils might be one explanation, especially in inflammatory pain [329]. There might be a relation to the (endo) cannabinoid system [330] but clearly an interaction with pain transmission within the spinal cord and other parts of the central nervous system (Figure 2.31). Nevertheless, it is obvious that pain can result from many more reasons than just inflammation and the same is true for fever, for example, as a consequence of viral infections. This also means that the mode of action of aspirin to modify these processes might not be the same. Thus, the effects ofaspirin on inflammation, fever, and pain, and the possible mode of action will be discussed separately.

Figure2.31 Release of mediators ofinflammation and pain in acute tissue injury. Local tissue injury (inflammation, ischemia) is associated with generation and release of inflammatory mediators from local storage sites and invading white cells. This includes substance P (SP), bradykinin (BK), serotonin (5-HT), protons (acidic pH) and cytokines among others. Destruction of cell membranes results in release of arachidonic acid (AA), and generation of prostaglandins (PGs) and other eicosanoids. These eicosanoids amplify the local inflammatory reaction, including vessel dilatation, increase in vascular permeability, and sensitization of pain receptors.

Figure2.31 Release of mediators ofinflammation and pain in acute tissue injury. Local tissue injury (inflammation, ischemia) is associated with generation and release of inflammatory mediators from local storage sites and invading white cells. This includes substance P (SP), bradykinin (BK), serotonin (5-HT), protons (acidic pH) and cytokines among others. Destruction of cell membranes results in release of arachidonic acid (AA), and generation of prostaglandins (PGs) and other eicosanoids. These eicosanoids amplify the local inflammatory reaction, including vessel dilatation, increase in vascular permeability, and sensitization of pain receptors.

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