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I16 The effect of NSAIDS and glucocorticoids on postoperative pain
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Abstracts / Scandinavian Journal of Pain 1 (2009) S27 S36
Oxymorphone is formed after oxidative reaction mainly catalysed by CYP 2D1 in rats which resembles CYP 2D6 in humans [9]. Noroxymorphone is formed mainly from noroxycodone by CYP 2D6 [2]. Although the analgesic properties of oxycodone are mainly due to its own activity, CYP inhibitors and inductors may alter the oxycodone-induced analgesia as a result of higher and lower oxycodone concentration.
experimental pain and reflect the clinical situation to a higher degree than acute models.
Reference(s) [1] Lalovic B, Kharasch E, Hoffer C, Risler L, Liu-Chen L-Y, Shen DD. Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clin Pharmacol Ther 2006;79:461 479. [2] Lemberg K, Kontinen VK, Siiskonen A, Viljakka K, Yli-Kauhaluoma J, Korpi E, Kalso E. Antinociception by spinal and systemic oxycodone: why does the route make a difference? In vitro and in vivo studies in rats. Anesthesiology 2006;105:801 812. [3] Lemberg K, Kontinen VK, Viljakka K, Kylanlahti I, Yli-Kauhaluoma J, Kalso E. Morphine, oxycodone, methadone and its enantiomers in different models of nociception in the rat. Anesthesia and Analgesia 2006;102:1768 1774. [4] Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology 1998;50:1837 1841. [5] Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology 2003;60:927 934. [6] Yanagidate F, Dohi S. Epidural oxycodone or morphine following gynaecological surgery. Br J Anaesth 2004;93:362 367. [7] Backlund M, Lindgren L, Kajimoto Y, Rosenberg PH. Comparison of epidural morphine and oxycodone for pain after abdominal surgery. J Clin Anesth 1997;9:30 35. [8] Lalovic B, Phillips B, Risler LL, Howald W, Shen DD. Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes. Drug Metab Dispos 2004;32:447 454. [9] Cleary J, Mikus G, Somogyi A, Bochner F. The influence of pharmacogenetics on opioid analgesia: studies with codeine and oxycodone in the Sprague-Dawley/Dark Agouti rat model. J Pharmacol Exp Ther 1994;271:1528 1534.
A surgical trauma results in an inflammatory reaction with release of prostaglandins and inflammatory enzymes such as the inducible cyclooxygenase-2. Inflammatory mediators activate nociceptors, evoking pain. Prostaglandin E2 (PGE2 ) greatly potensiates the pain produced by the mediators. Inhibition of prostaglandin synthesis is central for the analgesic effect of all anti-inflammatory drugs. NSAIDs and COX-2 inhibitors block cyclooxygenase that convert arachidonic acid into inflammatory prostaglandins. Paracetamol inhibits weakly COX-1 and COX-2 in vitro, but reduces prostaglandin synthesis markedly in vivo. Glucocorticoids reduce the prostaglandin synthesis by inhibiting phospholipase A2 (PLA2 ), and by blocking the expression of COX-2 mRNA. There are potential analgesic mechanisms for the anti-inflammatory drugs other than COX inhibition. All groups affect endocannabinoid systems. Paracetamol is a serotonin receptor agonist. But compared with paracetamol and NSAIDs, the glucocorticoids have a wider spectre of effects both on inflammation and on nerve cells. It is now well established that glucocorticoids reduce acute postoperative pain. However, a recent study indicates an increased risk for late postoperative bleeding after adenotonsillectomy. The most potent NSAIDs are very effective in postoperative pain with a NNT <2. Most anaesthesiologists administer these drugs preincisionally to achieve a maximal antiinflammatory effect during surgery. A metaanalysis (Møiniche et al., Anesthesiology 2002) cannot document that this is advantageous compared with a postoperative administration, while a later meta analysis (Ong et al., Anesth & Analg 2005) indicated that this praxis may be better, although some of the positive studies reviewed may have been based on fabricated data. Since the NSAIDs and paracetamol work via partly different mechanisms, they may have additive effects on pain. Some studies have confirmed this, but others have not. Since the last systematic review on this were done in 2002 by Møiniche et al, the majority of the studies of good quality on this combination indicate at least an additive effect. Secondary hyperalgesia is revealed by a tender area around the wound where there are no signs of tissue injury, but where the skin has a lower pain threshold and enhanced pain response to mechanical stimuli. Secondary hyperalgesia outside the injury is due to neuroplastic changes in the dorsal horn. Hyperalgesia and allodynia is typical for chronic postoperative pain. Thus, drugs that can reduce secondary hyperalgesia have been proposed a role preventing chronic pain after surgery. It has been shown that a glucocorticoid (methylprednisolone), and a traditional NSAID (ketorolac) decrease secondary hyperalgesia, indicating central anti-hyperalgesic effects of these drugs (Stubhaug et al., Acta Anaesthesiol Scand 2007). In a study on the effect of peroperative methylprednisolon or parecoxib or placebo on chronic pain and sensory disturbances after cosmetic breast surgery methylprednisolon reduced hyperaesthesia, but not chronic pain. Parecoxib had no effect on chronic sensory disturbances or on chronic pain (Romundstad et al., PAIN 2006). In order to augment non-opioid analgesia for acute pain, it is appropriate to combine an NSAID with paracetamol. A single perioperative dose of a glucocorticoid seems to be a valuable adjunct analgesic that also has positive effects on other postoperative symptoms, most importantly fatigue, nausea and vomiting, and chronic hyperesthesia.
I15 Can we bridge experimental human volunteer pain studies to patients? A.E. Olesen. 1 Mech-Sense, Department of Gastroenterology, Aalborg Hospital, 2 Center for Sensory-Motor Interactions (SMI), Aalborg University, Denmark A broad range of species, from rodents to primates, is currently used in pain research. However, while providing an understanding of some of the common pain pathways and the role of neurotransmitters and membrane channels, animal models are insufficiently representative of the multidimensional aspects of human pain. In the clinical setting analgesic effects are also difficult to evaluate due to a number of confounding factors such as sedation, nausea, general malaise etc. This makes experimental pain models advantageous in evaluation of analgesics. In experimental pain models the pain stimulus and assessment can be controlled and quantified. However, traditional experimental pain models are short lasting and have many limitations compared to the complex clinical pain conditions. Experimental pain models including hyperalgesia have been developed and proved more consistent with pain mechanisms observed in patients. This was demonstrated in a recent human experimental pain study evoking widespread hyperalgesia in healthy volunteers. Here the differential effect of morphine and oxycodone was comparable to the differential effect demonstrated on experimental pain stimulation in patients with chronic visceral pain. Therefore, human experimental pain models of hyperalgesia may help to predict analgesic efficacy in a sensitized pain system. Models evoking controlled hyperalgesia have the advantages of
I16 The effect of NSAIDS and glucocorticoids on postoperative pain L. Romundstad. Department of Anaesthesiology, Rikshospitalet University Hospital, Oslo, Norway
Abstracts / Scandinavian Journal of Pain 1 (2009) S27 S36
Oxymorphone is formed after oxidative reaction mainly catalysed by CYP 2D1 in rats which resembles CYP 2D6 in humans [9]. Noroxymorphone is formed mainly from noroxycodone by CYP 2D6 [2]. Although the analgesic properties of oxycodone are mainly due to its own activity, CYP inhibitors and inductors may alter the oxycodone-induced analgesia as a result of higher and lower oxycodone concentration.
experimental pain and reflect the clinical situation to a higher degree than acute models.
Reference(s) [1] Lalovic B, Kharasch E, Hoffer C, Risler L, Liu-Chen L-Y, Shen DD. Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clin Pharmacol Ther 2006;79:461 479. [2] Lemberg K, Kontinen VK, Siiskonen A, Viljakka K, Yli-Kauhaluoma J, Korpi E, Kalso E. Antinociception by spinal and systemic oxycodone: why does the route make a difference? In vitro and in vivo studies in rats. Anesthesiology 2006;105:801 812. [3] Lemberg K, Kontinen VK, Viljakka K, Kylanlahti I, Yli-Kauhaluoma J, Kalso E. Morphine, oxycodone, methadone and its enantiomers in different models of nociception in the rat. Anesthesia and Analgesia 2006;102:1768 1774. [4] Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology 1998;50:1837 1841. [5] Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology 2003;60:927 934. [6] Yanagidate F, Dohi S. Epidural oxycodone or morphine following gynaecological surgery. Br J Anaesth 2004;93:362 367. [7] Backlund M, Lindgren L, Kajimoto Y, Rosenberg PH. Comparison of epidural morphine and oxycodone for pain after abdominal surgery. J Clin Anesth 1997;9:30 35. [8] Lalovic B, Phillips B, Risler LL, Howald W, Shen DD. Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes. Drug Metab Dispos 2004;32:447 454. [9] Cleary J, Mikus G, Somogyi A, Bochner F. The influence of pharmacogenetics on opioid analgesia: studies with codeine and oxycodone in the Sprague-Dawley/Dark Agouti rat model. J Pharmacol Exp Ther 1994;271:1528 1534.
A surgical trauma results in an inflammatory reaction with release of prostaglandins and inflammatory enzymes such as the inducible cyclooxygenase-2. Inflammatory mediators activate nociceptors, evoking pain. Prostaglandin E2 (PGE2 ) greatly potensiates the pain produced by the mediators. Inhibition of prostaglandin synthesis is central for the analgesic effect of all anti-inflammatory drugs. NSAIDs and COX-2 inhibitors block cyclooxygenase that convert arachidonic acid into inflammatory prostaglandins. Paracetamol inhibits weakly COX-1 and COX-2 in vitro, but reduces prostaglandin synthesis markedly in vivo. Glucocorticoids reduce the prostaglandin synthesis by inhibiting phospholipase A2 (PLA2 ), and by blocking the expression of COX-2 mRNA. There are potential analgesic mechanisms for the anti-inflammatory drugs other than COX inhibition. All groups affect endocannabinoid systems. Paracetamol is a serotonin receptor agonist. But compared with paracetamol and NSAIDs, the glucocorticoids have a wider spectre of effects both on inflammation and on nerve cells. It is now well established that glucocorticoids reduce acute postoperative pain. However, a recent study indicates an increased risk for late postoperative bleeding after adenotonsillectomy. The most potent NSAIDs are very effective in postoperative pain with a NNT <2. Most anaesthesiologists administer these drugs preincisionally to achieve a maximal antiinflammatory effect during surgery. A metaanalysis (Møiniche et al., Anesthesiology 2002) cannot document that this is advantageous compared with a postoperative administration, while a later meta analysis (Ong et al., Anesth & Analg 2005) indicated that this praxis may be better, although some of the positive studies reviewed may have been based on fabricated data. Since the NSAIDs and paracetamol work via partly different mechanisms, they may have additive effects on pain. Some studies have confirmed this, but others have not. Since the last systematic review on this were done in 2002 by Møiniche et al, the majority of the studies of good quality on this combination indicate at least an additive effect. Secondary hyperalgesia is revealed by a tender area around the wound where there are no signs of tissue injury, but where the skin has a lower pain threshold and enhanced pain response to mechanical stimuli. Secondary hyperalgesia outside the injury is due to neuroplastic changes in the dorsal horn. Hyperalgesia and allodynia is typical for chronic postoperative pain. Thus, drugs that can reduce secondary hyperalgesia have been proposed a role preventing chronic pain after surgery. It has been shown that a glucocorticoid (methylprednisolone), and a traditional NSAID (ketorolac) decrease secondary hyperalgesia, indicating central anti-hyperalgesic effects of these drugs (Stubhaug et al., Acta Anaesthesiol Scand 2007). In a study on the effect of peroperative methylprednisolon or parecoxib or placebo on chronic pain and sensory disturbances after cosmetic breast surgery methylprednisolon reduced hyperaesthesia, but not chronic pain. Parecoxib had no effect on chronic sensory disturbances or on chronic pain (Romundstad et al., PAIN 2006). In order to augment non-opioid analgesia for acute pain, it is appropriate to combine an NSAID with paracetamol. A single perioperative dose of a glucocorticoid seems to be a valuable adjunct analgesic that also has positive effects on other postoperative symptoms, most importantly fatigue, nausea and vomiting, and chronic hyperesthesia.
I15 Can we bridge experimental human volunteer pain studies to patients? A.E. Olesen. 1 Mech-Sense, Department of Gastroenterology, Aalborg Hospital, 2 Center for Sensory-Motor Interactions (SMI), Aalborg University, Denmark A broad range of species, from rodents to primates, is currently used in pain research. However, while providing an understanding of some of the common pain pathways and the role of neurotransmitters and membrane channels, animal models are insufficiently representative of the multidimensional aspects of human pain. In the clinical setting analgesic effects are also difficult to evaluate due to a number of confounding factors such as sedation, nausea, general malaise etc. This makes experimental pain models advantageous in evaluation of analgesics. In experimental pain models the pain stimulus and assessment can be controlled and quantified. However, traditional experimental pain models are short lasting and have many limitations compared to the complex clinical pain conditions. Experimental pain models including hyperalgesia have been developed and proved more consistent with pain mechanisms observed in patients. This was demonstrated in a recent human experimental pain study evoking widespread hyperalgesia in healthy volunteers. Here the differential effect of morphine and oxycodone was comparable to the differential effect demonstrated on experimental pain stimulation in patients with chronic visceral pain. Therefore, human experimental pain models of hyperalgesia may help to predict analgesic efficacy in a sensitized pain system. Models evoking controlled hyperalgesia have the advantages of
I16 The effect of NSAIDS and glucocorticoids on postoperative pain L. Romundstad. Department of Anaesthesiology, Rikshospitalet University Hospital, Oslo, Norway