Natural Antiinflammatory Agents for Pain Relief in Athletes

Joseph C. Maroon, M.D.; Jeffrey W. Bost, P.A.-C.; Meghan K. Borden; Keith M. Lorenz; Nathan A. Ross


Neurosurg Focus. 2006;21(4) 

In This Article

Inflammatory Pathways

In 1971, Professor John Vane from Cornell University was awarded the Nobel Prize for his work in elucidating the mechanism of action of aspirin on prostaglandins.[108] Prostaglandins are short-lived localized hormones that can be released by any cell of the body during tissue, chemical, or traumatic injury, and can induce fever, inflammation, and pain once they are present in the intercellular space.[63,161] Thromboxanes, which are also hormone activators, regulate blood vessel tone, platelet aggregation, and clot formation; are manufactured in every cell of the body; and can be released in response to injury.[85,135,162] There is a complex biochemical pathway which, once stimulated by injury, will lead to the production of these and other inflammatory mediators whose initial effect is pain and tissue destruction, followed by healing and recovery.[52,77] This is called the arachidonic acid pathway, because arachidonic acid is released in the early stages from traumatized cellular membranes. This substance is transformed into prostaglandins and thromboxanes through the action of COX.[52,77,86] Vane[164,165] discovered that aspirin works by irreversibly disabling the COX enzymes so that they no longer produce the inflammatory prostaglandins and thromboxanes (Fig. 1). Aspirin therefore reduces inflammation, pain, fever, and blood clotting by decreasing prostaglandin and thromboxane production.[166]

Schematic showing that when a cell membrane is injured the arachidonic acid pathway is activated to initiate the local inflammatory response through the production of prostaglandins, thromboxanes, and leukotrienes. Their activation, however, requires the enzymes COX and LOX. The NSAIDs can block COX action and thereby prevent the formation of the COX-derived inflammatory mediators. 5-HPETE = 5-hydroperoxyeicosatetraenoic acid; LTC4 = leukotriene C4; PGE2 = prostaglandin E2; PGF2 = prostaglandin F2; PGI2 = prostacyclin; TXA2 = thromboxane.

Nonselective COX Inhibitors. The COX enzyme is found in two forms in the human body: COX-1, a constitutive enzyme that normally protects the gastrointestinal mucosa; and COX-2, which is activated by tissue damage and is considered to be an inducible enzyme because it exists during injury only (Fig. 2).[52,77,113,133,135,148,165] Gastrointestinal side effects associated with COX inhibitors, such as aspirin and the nonselective NSAIDs, which block both COX-1 and COX-2, have pushed researchers to find a way to block COX-2 selectively and thereby limit the complications of gastritis and ulcers that are common with long-term use.[49,75,86,135,154,172]

Schematic showing that the COX enzyme can exist in two forms: COX-1, constitutional or existing in small amounts at all times; or COX-2, inducible or only present during the inflammatory response. By selectively blocking only the COX-2–produced inflammatory prostaglandins, COX-2–inhibiting medications were believed to be superior to nonselective COX-1 and -2 inhibitors, and they were thought to have fewer gastric side effects.

Selective COX Inhibitors. In December 1998, celecoxib (Celebrex)[25] was approved by the FDA as the first selective COX-2 inhibitor for treatment of arthritis pain.[36,77,135] Rofecoxib (Vioxx) was approved several months later, followed by valdecoxib (Bextra).[41,45,105,114,135] These NSAIDs were designed to allow continued production of the gastrointestinally protective prostaglandins produced through the COX-1 enzyme system while blocking the COX-2 enzyme that produces the inflammatory prostaglandins.[52,77,114,129] The number of prescriptions for nonselective (COX-1 and -2) inhibitors such as ibuprofen (Motrin) quickly dropped as the new selective COX-2–inhibiting NSAIDs began to grow in popularity.[66] By its 7th week on the market, Celebrex had surpassed Viagra in generating record numbers of daily prescriptions early in its marketing.[66,80] The Big 3 (Celebrex, Vioxx, and Bextra) quickly became the mainstay for the treatment of chronic pain conditions related to inflammation.[108] Within a few years, an estimated 15 to 20 million people were using selective COX-2–inhibiting NSAIDs on a long-term basis in the US. These drugs became the most commonly used pharmaceutical agent, with more than 70 million NSAID prescriptions written each year and 30 billion over-the-counter NSAID tablets sold annually. It was estimated that 5 to 10% of the adult population used NSAIDs, and among the elderly (a group at higher risk of NSAID-induced gastrointestinal complications), use of these drugs was as high as 15%. In 2003, the sales of these three drugs surpassed $9 billion in the US alone. The general acceptance of these drugs was due to the perceived lack of serious gastrointestinal side effects that had been associated with the nonselective class of NSAIDs.[173]

Side Effects of COX-2 Inhibitors. On September 30, 2004, Merck Research Laboratories announced the global withdrawal of rofecoxib (Vioxx), its primary selective COX- 2–inhibiting NSAID.[23,80,179] Analysis of the results of the Adenomatous Polyps Prevention on Vioxx study (known as the APPROVe study) showed that there was double the risk of serious thromboembolic events, including myocardial infarction, which became apparent after 18 months of treatment[7,77,127] This mechanism of action is based on selectively allowing COX-1 to continue to produce platelet synthesis of thromboxane, a thrombogenic and atherogenic eicosanoid, and at the same time selectively inhibiting COX-2 production of endothelial cell synthesis of prostacyclin, which opposes the effects of thromboxane.[54] Thus, these drugs that were intended to reduce the levels of inflammatory prostaglandins were now also inhibiting prostacyclin, which led to the development of thrombotic cardiovascular and cerebrovascular events.[55,66,148] These complications were especially common in patients who were at high risk, such as those who had suffered a previous myocardial infarction or a recent bypass graft or vascular stent placement.[47,48,55,127] Furthermore, it was shown that not only were the COX-2 inhibitors associated with an increased incidence of myocardial infarction and stroke, but also that there was little improvement in the prevention of gastric ulcers.[52,77,87,127]

Since the discovery of COX in the 1970s, a number of additional pathways have been discovered that are more complex and are associated with persistent or chronic inflammation. The discovery of NF-κB and how it activates cytokines is critical to our new understanding of the inflammatory process. The NF-κB molecule is a protein that acts as a switch to turn inflammation on and off in the body. Some researchers refer to the NF-κB protein as acting like a smoke sensor in cells because it is able to detect noxious stimuli, such as infectious agents, free radicals, and other cellular injuries.[170] In response, it can literally turn on the particular genes that lead to the production of inflammatory cytokines.[64] The NF-κB proteins are localized in the cytoplasm of the cell and are associated with a family of inhibitory proteins known as IkB.[12,62,175] The IkB proteins are normally bound to NF-κB and block their nuclear localization signal. A variety of cytokine stimuli can degrade the IkB and result in the nuclear translocation of NF-κB. These stimuli can include trauma, viral infections, ultraviolet radiation, free radicals, and also the cytokines TNFα and IL-1β.[120,175] The TNFα and especially IL-1β can also directly stimulate enzymes known as matrix metalloproteinases, which break down extracellular collagen matrix, a hallmark of inflammatory joint disease.[50,111,112,156] The phosphorylation of the IkB proteins and unbinding of the NF-κB is the key step involved in the activation of NF-κB, and this is mediated by IkB kinases.[175,177] Once freed of the IkB subunit, the NF-κB proteins translocate to the nucleus, where they bind to target genes to activate gene expression[175] (Fig. 3).

Schematic showing another inflammatory pathway that is activated by tissue injury. This is the NF-κB activation, in which, once the protein is free as a result of tissue injury, it can enter the cell nucleus and activate the DNA to enhance the inflammatory response further by the production of additional cytokines, chemokines, and adhesion molecules. IKKB = IkB kinase.

The NF-κB Inflammatory Mechanism. The aforementioned genes then code for a host of inflammatory molecules that include the following. 1) Proinflammatory cytokines (for example, IL-1β, TNFα, IL-6, and IL-18), which are involved in the initiation and amplification of the inflammatory process.[27,43,119] 2) Protein kinases (mitogenactivated protein kinase and protein kinase C) that regulate the expression of other target genes necessary for maintaining the inflammatory state.[27,72,97] 3) Various adhesion molecules, E-selectin, integrins, intracellular adhesion molecule– 1, and vascular adhesion molecule–1.[16,27,44,72] 4) Chemokines, a group of cytokines that chemically attract and activate leukocytes at the site of inflammation.[27,104,174] In addition, activation of NF-κB can enhance cell proliferation and cell growth, which can lead to neoplasia.[15,27]

The described pathway is believed to be just one of many diverse routes that are involved in activating the NF-κB pathway. Research into potential inhibitors that can prevent NF-κB activation, and hence reduce the inflammatory process, will be the focus in elucidating the probable mechanism involved and developing the next blockbuster antiinflammatory medication. The identification of NF-κB as a critical switch that turns on inflammation has profound implications for therapeutic manipulation of regulatory circuits controlling the inflammatory process, regardless of its causes.[121]

Inhibition of COX and NF-κB Activity. As stated earlier, the most commonly accepted mechanism to account for the inhibitory effects of most NSAIDs is that they inhibit COX activity to prevent prostaglandin synthesis.[63,161] In recent reports, however, it has been suggested that additional mechanisms involving the NF-κB system are at work. Aspirin and sodium salicylate are now believed to target NF-κB as well as the COX system. These agents inhibit the NF-κB pathway in endothelial cells and block NF-κB activation to inhibit leukocyte recruitment.[164–166] Other nonsteroidal agents have also been found to inhibit both the COX system and the NF-κB pathway. Immunosuppressant drugs also reduce nuclear expression of NF-κB.[58,107,110,168,175]


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