2Update on the role of non-opioids for postoperative pain treatment
Introduction
Non-opioid analgesics are the group of medications most commonly used worldwide, usually for the treatment of acute and chronic pain states. Over the last 20 years, they have gained increasing usage for the treatment of postoperative pain; for pain of mild or moderate intensity used on their own, but even more importantly as components of multimodal analgesia.1 Therefore, a thorough understanding of their pharmacology, their efficacy and their adverse effects is essential for the successful use of this important group of medications in the treatment of postoperative pain.
In principle, non-opioid analgesics can be classified as acid and non-acid antipyretic drugs.2 This classification is based on the pKa value, i.e. the pH at which 50% of the compound is dissociated and 50% is undissociated. Compounds with a pKa value less than 5 are regarded as acid antipyretic analgesics. These physicochemical properties influence the pharmacodynamics of antipyretic analgesics in so far as acidic antipyretic analgesia distributes preferentially to organs with a lower pH such as the kidneys, stomach and inflamed tissues, while non-acidic analgesics are found ubiquitously in the body.2
The group of non-acidic antipyretic drugs contains the aniline derivatives with its only representative paracetamol, and the phenazone derivatives with its major representative dipyrone. These compounds are analgesic and antipyretic, but devoid of anti-inflammatory effects.
Acidic antipyretic drugs are represented by acetylic salicylic acid (ASA) and the non-steroidal anti-inflammatory drugs (NSAIDs). The term NSAIDs has historical origins, when an attempt was made to distinguish NSAIDs from steroids, which also show anti-inflammatory effects. The mechanism of action of these compounds is interference with the formation of prostanoids, primarily by inhibition of the enzyme cyclo-oxygenase.3 All NSAIDs discovered until recently were non-selective for the isoenzymes of cyclo-oxygenase (COX); however, selective inhibitors of the isoenzyme COX-2 have now become available in the form of the coxibs. New research on the role of prostaglandins in peripheral and central sensitization processes occurring after injury seems to open new opportunities for the use of nonopioid analgesics with an anti-inflammatory effect in the postoperative period. The results of these processes are the symptoms of hyperalgesia and allodynia, i.e. increased sensitivity to suprathreshold and subthreshold stimulation.4 Understanding these mechanisms makes it obvious, that although opioids will be able to provide significant relief of postoperative pain and will remain the gold standard of severe pain treatment, compounds such as the non-selective NSAIDs and the selective coxibs, can provide analgesia by a more causal approach.5
Section snippets
Paracetamol (Acetaminophen)
Discovered in the late 19th century, paracetamol is a non-acidic antipyretic analgesic.6 It is the active metabolite of two other aniline derivatives which were used as antipyretic and analgesic medications in the past, acetanilide and phenacetin, but devoid of their toxic effects. Today, paracetamol is not only the most popular and most widely used antipyretic and analgesic compound worldwide, but also ranks usually number one or two of all drugs worldwide by turnover (http://www.imshealth.com
Dipyrone (Metamizol)
Dipyrone is, like paracetamol, a non-acidic anti-pyretic analgesic, but belongs to the chemical group of phenazones (phenylpyrazolones). While other phenazones have been used widely in the past, metamizol, first synthesized in 1920, is now the main representative of this group still in clinical usage.6 This usage differs between regions; while it is popular in parts of Europe, the Middle East, Asia, South Africa and Latin America, it is not registered, or is even banned, in some other countries
Cyclo-oxygenase inhibitors
Perioperative use of cyclo-oxygenase inhibitors has gained increasing interest due to the fact that the pathophysiology of nociceptive pain after surgery and other trauma has been better understood recently. While it is obvious that the acute tissue injury by a surgeon causes discharge of nociceptors, subsequently an ‘inflammatory soup’ of mediators is released at the site of the injury.70 This soup consists, among others, of prostaglandins, bradykinin, serotonin, histamine, ATP and protons. In
Mechanism of action
As described above, NSAIDs inhibit the enzyme cyclo-oxygenase which converts arachidonic acid to prostanoids, precursors of prostaglandins.3 Prostaglandins play a key role in the inflammatory pathway, but are also relevant in maintaining physiological function of the gastro-intestinal tract, the renal system, platelets and the cardiovascular system. The non-selective blockade of the two isoenzymes, cyclooxygenase-1 and cyclooxygenase-2, by traditional NSAIDs including aspirin, explains not only
Coxibs
The introduction of selective coxib has resulted in further increased interest in the peri-operative use of anti-inflammatory substances. Only recently, their beneficial effect on central prostaglandin formation after injury could be confirmed in humans.86
Summary
Non-opioid analgesics play an important role in the treatment of postoperative pain; in mild and moderate pain they can be the only analgesic utilised and thereby provide the chance to avoid adverse effects of opioids completely. More importantly, in severe pain, they are a relevant component of multi-modal analgesia. In such a setting they are not only opioid-sparing, but can also improve analgesia and carry the potential to reduce adverse effects of opioids. Among these non-opioids,
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