Antinociception and the New COX Inhibitors: Research Approaches and Clinical Perspectives

Abstract

New generations of cyclooxygenase (COX) inhibitors are more potent and efficacious than their traditional parent compounds. They are also safer than the classic non-steroidal anti-inflammatory drugs (NSAIDs) and are starting to be used not only for low to moderate intensity pain, but also for high intensity pain. Three different strategies have been followed to improve the pharmacological profile of COX inhibitors:1. Development of COX-2 selective inhibitors. This is based on the initial hypothesis that considered COX-2 as the enzyme responsible for the generation of prostaglandins only in inflammation, and, therefore, uniquely responsible for inflammation, pain and fever. Initial expectations gave rise to controversial results, still under discussion. The second generation of these compounds is being developed and should contribute to clarifying both their efficacy and the specific functions of the COX enzymes.2. Modified non-selective COX inhibitors. Molecules like nitro-NSAIDs or tromethamine salt derivatives have been synthesized considering that both COX-1 and COX-2 are responsible for the synthesis of prostaglandins involved either in homeostatic functions or inflammation. Nitroaspirin, nitroparacetamol or dexketoprofen trometamol are some examples of molecules that are already showing an important clinical efficacy. The modifications performed in their structures seem to lower the unwanted side effects as well as to enhance their analgesic efficacy.3. Combined therapy of classic NSAIDs with other drugs. This strategy looks for improvements in the incidence of adverse effects or to take advantage of the synergistic enhancement of their therapeutic effects. Some of the molecules resulting from these strat-227 egies are very valuable as therapeutic agents and open a wide range of possibilities in the treatment of high intensity pain, including neuropathic pain, and opiate sparing therapy.

Hypothalamo-pituitary-adrenal axis dysfunction as a contributory factor to chronic pain and depression

“…In other respects, the current treatment of chronic pain reflects the etiology of the disease process itself in many ways. The treatment of inflammatory pain is largely based on the use of nonsteroidal anti-inflammatory drugs, including the recently developed selective cyclooxygenase inhibitors with a moderate amount of success [20]. The off-label use of anticonvulsants such as lamotrigine and gabapentin have shown reasonable efficacy in the treatment of neuropathic pain [21].…”

The Analgesic Effect of Dexketoprofen When Added to Lidocaine for Intravenous Regional Anaesthesia: A Prospective, Randomized, Placebo-Controlled Study

“…3,5,7 to be effective adjuncts for IVRA, reducing tourniquet pain and prolonging postoperative anaesthesia. 2 -7 The mechanism of action of NSAIDs is commonly believed to be via inhibition of the cyclo-oxygenase (COX)-2 enzyme and a subsequent decrease in prostaglandin levels 22 that are normally upregulated by surgical trauma. 2,22,23 An alternative mechanism is NSAID-mediated activation of the nitric oxide-cyclic guanosine monophosphate pathway, resulting in an antinociceptive effect.…”

“…2 -7 The mechanism of action of NSAIDs is commonly believed to be via inhibition of the cyclo-oxygenase (COX)-2 enzyme and a subsequent decrease in prostaglandin levels 22 that are normally upregulated by surgical trauma. 2,22,23 An alternative mechanism is NSAID-mediated activation of the nitric oxide-cyclic guanosine monophosphate pathway, resulting in an antinociceptive effect. 24 Dexketoprofen is a non-selective COX inhibitor, and a concentrated dose at the surgical site may provide fast and efficient inhibition of COX-2 leading to decreased levels of local prostaglandins.…”

Dor neuropática após trauma com agulha de peridural

“…Non-steroidal anti-inflammatories inhibit the activity of cyclooxygenase, reducing the synthesis and release of prostaglandins by the cells 24 . They can also show good results in the treatment of neuropathic pain 25 . Vitamins B1, B6, and B12 influence the process of neural regeneration in peripheral neuritis and neuralgias, and are also indicated in this situation 26 .…”

“…Os antiinflamatórios não-hormonais agem inibindo a atividade da ciclooxigenase, reduzindo a síntese e liberação de prostaglandinas das células 24 . Também podem apresentar bons resultados no tratamento da dor neuropática 25 . As vitaminas B1, B6 e B12 agem nos processos de regeneração neural das neurites periféricas e neuralgias, sendo indicadas, também, nessas situações 26 .…”