Recent advances in postoperative pain therapy

Abstract

Despite many advances in the provision of pain services, acute pain after surgery remains a serious cause of severe suffering that is often undermanaged despite our best efforts.6Apfelbaum JL Chen C Mehta SS Gan TJ Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged.Anesth Analg. 2003; 97: 534-540Crossref PubMed Scopus (1470) Google Scholar34Dahl JL Gordon D Ward S Skemp M Wochos S Schurr M Institutionalizing pain management: The post-operative pain management quality improvement project.J Pain. 2003; 4: 361-371Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar37Dolin SJ Cashman JN Bland JM Effectiveness of acute postoperative pain management: I. Evidence from published data.Br J Anaesth. 2002; 89: 409-423Crossref PubMed Scopus (530) Google Scholar Acute pain teams have been introduced in many hospitals, but recent evidence from a UK national postal questionnaire suggests that they are struggling with the problem of alleviating acute pain successfully.90Powell AE Davies HTO Bannister J Macrae WA Rhetoric and reality on acute pain services in the UK: a national postal questionnaire survey.Br J Anaesth. 2004; 92: 689-693Crossref PubMed Scopus (70) Google Scholar In a review of published data of pooled pain scores from nearly 20 000 surgical patients having intramuscular, patient controlled analgesia (PCA) or extradural analgesia, the overall mean (95% confidence interval) incidence of moderate to severe and severe pain was 29.7 (26.4–33.0)% and 10.9 (8.4–13.4)%, respectively.37Dolin SJ Cashman JN Bland JM Effectiveness of acute postoperative pain management: I. Evidence from published data.Br J Anaesth. 2002; 89: 409-423Crossref PubMed Scopus (530) Google Scholar Often the provision of effective postoperative analgesia is limited by side-effects, and these have been quantified in contemporary anaesthetic practice by Cashman and Dolin with special attention to respiratory depression and hypotension after intramuscular, PCA and extradural analgesia,28Cashman JN Dolin SJ Respiratory and haemodynamic effects of acute postoperative pain management: evidence from published data.Br J Anaesth. 2004; 93: 212-223Crossref PubMed Scopus (251) Google Scholar in a companion paper to their study of analgesic efficacy.37Dolin SJ Cashman JN Bland JM Effectiveness of acute postoperative pain management: I. Evidence from published data.Br J Anaesth. 2002; 89: 409-423Crossref PubMed Scopus (530) Google Scholar Cashman and Dolin concluded that assuming an acute pain service uses a mixture of the three analgesic techniques studied (intramuscular, PCA, and extradural analgesia), then the expected incidence of respiratory depression (defined by a low ventilatory frequency) should be less than 1%, and the expected incidence of hypotension related to analgesic technique should be less than 5%. Interestingly, while the incidence of respiratory depression decreased over the period 1980–99, the incidence of hypotension did not.28Cashman JN Dolin SJ Respiratory and haemodynamic effects of acute postoperative pain management: evidence from published data.Br J Anaesth. 2004; 93: 212-223Crossref PubMed Scopus (251) Google Scholar The risk of side-effects from other analgesics in use for acute postoperative pain therapy is well defined. NSAIDs, for example, are effective analgesics, but have potential adverse effects that may render them contraindicated in many patients having surgery.47Gillis JC Brogden RN Ketorolac. A reappraisal of its pharmacodynamic and pharmacokinetic properties and therapeutic use in pain management.Drugs. 1997; 53: 139-188Crossref PubMed Scopus (290) Google Scholar76Merry A Power I Perioperative NSAIDs: towards greater safety.Pain Rev. 1995; 2: 268-291Google Scholar Acute pain can be persistent, the tissue damage of surgery setting up pathophysiological processes in the peripheral and central nervous systems that may produce chronicity.32Cousins MJ Power I Smith G Pain—a persistent problem.Reg Analg Pain Med. 2000; 25: 6-21PubMed Google Scholar The association between surgery, acute postoperative pain and ongoing severe chronic pain is well defined,72Macrae WA Chronic pain after surgery.Br J Anaesth. 2001; 87: 88-98Crossref PubMed Scopus (530) Google Scholar85Perkins FM Kehlet H Chronic pain as an outcome of surgery—a review of predictive factors.Anesthesiology. 2000; 93: 1123-1133Crossref PubMed Scopus (1083) Google Scholar one paper noting that the severity of acute pain was a predictive factor for chronic ongoing pain.85Perkins FM Kehlet H Chronic pain as an outcome of surgery—a review of predictive factors.Anesthesiology. 2000; 93: 1123-1133Crossref PubMed Scopus (1083) Google Scholar The significance of this association has been reinforced by recent studies demonstrating that it is a problem even in previously healthy young women having Caesarian section,82Nikolajsen L Sorensen HC Jensen TS Kehlet H Chronic pain following Caesarean section.Acta Anaesthesiol Scand. 2004; 48: 111-116Crossref PubMed Scopus (306) Google Scholar and is a source of long-term pain and disability after the relatively minor procedure of inguinal hernia repair.14Bay-Nielsen M Perkins FM Kehlet H Pain and functional impairment 1 year after inguinal herniorrhaphy: A nationwide questionnaire study.Ann Surg. 2001; 233: 1-7Crossref PubMed Scopus (482) Google Scholar There is therefore a pressing need for advances in the agents and techniques we can use to improve analgesia efficacy, and perhaps reduce the incidence of chronic suffering after surgery. The methods that have been at our disposal for some years for acute pain relief have been assessed critically81NHMRC Acute pain management: scientific evidence. National Health and Medical Research Council, Canberra1999Google Scholar and are summarized in Table 1.Table 1Methods of acute pain relief assessed for by the NHMRC and ANZCA Acute Pain Management: Scientific Evidence working party81NHMRC Acute pain management: scientific evidence. National Health and Medical Research Council, Canberra1999Google ScholarNon-pharmacological Cognitive-behavioural approaches Physical therapyPharmacological Opioids NSAIDs Local anaesthetics Paracetamol Ketamine Adjuvants Open table in a new tab In this review of postoperative pain relief, consideration will be given to advances in our understanding of the role of non-pharmacological techniques, peripheral opioid analgesia, selective cyclooxygenase 2 inhibitors, i.v. paracetamol and nitroxyparacetamol, and the diagnosis and management of acute postsurgical neuropathic pain. Although the accepted definition of pain emphasizes the cognitive, emotional response to tissue damage, the role of psychological techniques in the relief of acute pain has been minimized. An example of the importance of this is that such factors affect recovery after acute sports injury. After anterior cruciate ligament repair, ‘catastrophizing’ is displayed and is associated with higher pain scores.106Tripp DA Stanish WD Reardon G Coady C Sullivan MJL Comparing postoperative pain experiences of the adolescent and adult athlete after anterior cruciate ligament surgery.J Athl Train. 2003; 38: 154-157PubMed Google Scholar Perhaps surprisingly, catastrophizing was a particularly strong factor in postoperative pain differences between adolescents and adults, being more pronounced in the younger patients.106Tripp DA Stanish WD Reardon G Coady C Sullivan MJL Comparing postoperative pain experiences of the adolescent and adult athlete after anterior cruciate ligament surgery.J Athl Train. 2003; 38: 154-157PubMed Google Scholar Over 10 yr ago a meta-analysis of 191 studies of surgical patients demonstrated that ‘psychoeducational care’ has beneficial effects on recovery, postoperative pain and psychological distress after surgery.36Devine EC Effects of psychoeducational care for adult surgical patients—a metaanalysis of 191 studies.Patient Educ Couns. 1992; 19: 129-142Abstract Full Text PDF PubMed Scopus (261) Google Scholar Psychoeducational care was classed as health-care information (information in preparation for surgery, timing of procedures, functions and roles of health-care providers, self-care actions, and pain and discomfort information); skills teaching (coughing, breathing and bed exercises, relaxation, hypnosis, cognitive reappraisal); and psychosocial support (identifying and alleviating concerns, reassurance, problem-solving, encouraging questions, and increasing the frequency of support). Unfortunately, such non-pharmacological therapy is seldom used for acute postoperative pain relief, although it is beneficial and devoid of any significant adverse effects. Well-designed clinical studies are required to investigate the role of non-pharmacological techniques in relieving postsurgical pain. An example of this is acupuncture, which has been examined recently after shoulder surgery in a randomized study and found to reduce pain, improve movement and increase patient satisfaction.46Gilbertson B Wenner K Russell LC Acupuncture and arthroscopic acromioplasty.J Orthop Res. 2003; 21: 752-758Crossref PubMed Scopus (17) Google Scholar Moreover, in another well-designed study acupuncture has been shown to reduce somatosensory evoked potentials to noxious stimuli in anaesthetized volunteers.75Meissner W Weiss T Trippe RH Hecht H Krapp C Miltner WH Acupuncture decreases somatosensory evoked potential amplitudes to noxious stimuli in anesthetized volunteers.Anesth Analg. 2004; 98: 141-147Crossref PubMed Scopus (37) Google Scholar Traditionally, opioids are viewed as basic components of postoperative analgesia given into the systemic circulation by injection, but even their use is changing considerably. The use of oral opioid immediate- and sustained-release opioid preparations provides quick and effective analgesia and can be used to bridge the analgesic gap that is often apparent after patient-controlled or extradural analgesia has been stopped and when the patient eventually attains comfort on simple analgesics.99Smith G Power I Audit and bridging the ‘analgesic gap’.Anaesthesia. 1998; 53: 521-522Crossref PubMed Scopus (15) Google Scholar Indeed, prescriber confidence in using effective doses of oral opioids may allow the delivery of good analgesia without recourse to parental injections or invasive procedures. In a similar manner, the development of opioid nasal sprays may facilitate the delivery of effective analgesia.60Kendall JM Latter VS Intranasal diamorphine as an alternative to intramuscular morphine—pharmacokinetic and pharmacodynamic aspects.Clin Pharmacokinet. 2003; 42: 501-513Crossref PubMed Scopus (28) Google Scholar84Paech MJ Lim CB Banks SL Rucklidge MWM Doherty DA A new formulation of nasal fentanyl spray for postoperative analgesia: a pilot study.Anaesthesia. 2003; 58: 740-744Crossref PubMed Scopus (48) Google Scholar Whilst opioids are the mainstay for relief of severe pain, they are far from perfect analgesics as they have many significant adverse effects.104Stein C Schafer M Machelska H Why is morphine not the ultimate analgesic and what can be done to improve it?.J Pain. 2000; 1: 51-56Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar The common opioid side-effects of respiratory depression, sedation, depression of gastrointestinal motility, nausea and vomiting, and the potential risk of abuse reflect the striking and generalized role endogenous opioids play in general human physiology.19Bodnar RJ Hadjimarkou MM Endogenous opiates and behavior: 2002.Peptides. 2003; 24: 1241-1302Crossref PubMed Scopus (41) Google Scholar The majority of opioid-related side-effects are associated with their central nervous system actions, so much recent work has concentrated instead upon the presence and function of opioid receptors on peripheral sensory nerves,101Stein C Opioid receptors on peripheral sensory neurons.Adv Exp Med Biol. 2003; 521: 69-76PubMed Google Scholar112Zhou L Zhang Q Stein C Schafer M Contribution of opioid receptors on primary afferent versus sympathetic neurons to peripheral opioid analgesia.J Pharmacol Exp Ther. 1998; 286: 1000-1006PubMed Google Scholar endogenous opioid agonist production by inflammatory leucocytes,24Brack A Rittner HL Machelska H et al.Mobilization of opioid-containing polymorphonuclear cells by hematopoietic growth factors and influence on inflammatory pain.Anesthesiology. 2004; 100: 149-157Crossref PubMed Scopus (52) Google Scholar27Cabot PJ Carter L Schafer M Stein C Methionine-enkephalin-and dynorphin A-release from immune cells and control of inflammatory pain.Pain. 2001; 93: 207-212Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar79Mousa SA Bopaiah CP Stein C Schafer M Involvement of corticotropin-releasing hormone receptor subtypes 1 and 2 in peripheral opioid-mediated inhibition of inflammatory pain.Pain. 2003; 106: 297-307Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar reports of effective peripheral opioid analgesia,56Kalso E Smith L McQuay HJ Moore RA No pain, no gain: clinical excellence and scientific rigour—lessons learned from IA morphine.Pain. 2002; 98: 269-275Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar66Likar R Koppert W Blatnig H et al.Efficacy of peripheral morphine analgesia in inflamed, non-inflamed and perineural tissue of dental surgery patients.J Pain Symptom Manage. 2001; 21: 330-337Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar87Peyman GA Rahimy MH Fernandes ML Effects of morphine on corneal sensitivity and epithelial wound-healing—implications for topical ophthalmic analgesia.Br J Ophthalmol. 1994; 78: 138-141Crossref PubMed Scopus (88) Google Scholar92Reuben SS Vieira P Faruqi S Verghis A Kilaru PA Maciolek H Local administration of morphine for analgesia after iliac bone graft harvest.Anesthesiology. 2001; 95: 390-394Crossref PubMed Scopus (71) Google Scholar100Stein A Yassouridis A Szopko C Helmke K Stein C Intraarticular morphine versus dexamethasone in chronic arthritis.Pain. 1999; 83: 525-532Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar and work on the development of novel selectively peripherally acting opioid agonists with more favourable safety and efficacy profiles.40Eisenach JC Carpenter R Curry R Analgesia from a peripherally active kappa-opioid receptor agonist in patients with chronic pancreatitis.Pain. 2003; 101: 89-95Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar70Machelska H Pfluger M Weber W et al.Peripheral effects of the kappa-opioid agonist EMD 61753 on pain and inflammation in rats and humans.J Pharmacol Exp Ther. 1999; 290: 354-361PubMed Google Scholar103Stein C Schafer M Machelska H Attacking pain at its source: new perspectives on opioids.Nat Med. 2003; 9: 1003-1008Crossref PubMed Scopus (482) Google Scholar One group has paraphrased this new and exciting focus on the peripheral effects of opioids at the site of tissue damage as ‘attacking pain at its source’.103Stein C Schafer M Machelska H Attacking pain at its source: new perspectives on opioids.Nat Med. 2003; 9: 1003-1008Crossref PubMed Scopus (482) Google Scholar The hope is that drugs can be developed that activate peripheral opioids only, thus avoiding centrally mediated actions and many adverse effects. The μ, δ and κ opioid receptors (MOR, DOR, and KOR) are found throughout the nervous system and produce analgesia (KOR may have anti-analgesic effects in some circumstances). The cell bodies of sensory nerves in the dorsal root ganglion produce MOR, DOR and KOR,102Stein C Machelska H Schafer M Peripheral analgesic and antiinflammatory effects of opioids.Z Rheumatol. 2001; 60: 416-424Crossref PubMed Scopus (96) Google Scholar and the receptors are then transported peripherally in the nerve axons.101Stein C Opioid receptors on peripheral sensory neurons.Adv Exp Med Biol. 2003; 521: 69-76PubMed Google Scholar103Stein C Schafer M Machelska H Attacking pain at its source: new perspectives on opioids.Nat Med. 2003; 9: 1003-1008Crossref PubMed Scopus (482) Google Scholar When activated, opioid receptors in peripheral nerves modulate nerve activity by inhibition of high-voltage calcium channels102Stein C Machelska H Schafer M Peripheral analgesic and antiinflammatory effects of opioids.Z Rheumatol. 2001; 60: 416-424Crossref PubMed Scopus (96) Google Scholar and suppression of tetrodotoxin-resistant selective sodium channels and non-selective cation currents stimulated by inflammatory PGE2.103Stein C Schafer M Machelska H Attacking pain at its source: new perspectives on opioids.Nat Med. 2003; 9: 1003-1008Crossref PubMed Scopus (482) Google Scholar In summary, when activated, opioid receptors reduce the excitability of nociceptors, afferent action potential propagation and inflammatory peptide release from sensory nerve endings. Inflammatory cells play a central role in peripheral opioid analgesia by migrating to and delivering opioid peptides to the receptors expressed by the sensory nerve terminals at the very site of tissue damage. In injured tissue endorphin, enkephalin and dynorphin production is increased in lymphocytes, monocytes, macrophages and granulocytes, and these peptides bind to all three opioid receptors. Various stimuli, including cytokines, endotoxins, corticotropin releasing hormone (CRH) and catecholamines, increase the expression of opioids by inflammatory cells.17Binder W Mousa SA Sitte N Kaiser M Stein C Schafer M Sympathetic activation triggers endogenous opioid release and analgesia within peripheral inflamed tissue.Eur J Neurosci. 2004; 20: 92-100Crossref PubMed Scopus (112) Google Scholar71Machelska H Schopohl JK Mousa SA Labuz D Schafer M Stein C Different mechanisms of intrinsic pain inhibition in early and late inflammation.J Neuroimmunol. 2003; 141: 30-39Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar79Mousa SA Bopaiah CP Stein C Schafer M Involvement of corticotropin-releasing hormone receptor subtypes 1 and 2 in peripheral opioid-mediated inhibition of inflammatory pain.Pain. 2003; 106: 297-307Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar White cells are attracted to injured tissue by selectins (L selectin on leucocytes, and P and E selectin on endothelial cells), adhere to endothelia via the action of intracellular adhesion molecules, and migrate through the vessel wall under the direction of platelet–endothelial cell adhesion molecules.68Machelska H Cabot PJ Mousa SA Zhang Q Stein C Pain control in inflammation governed by selectins.Nat Med. 1998; 4: 1425-1428Crossref PubMed Scopus (154) Google Scholar69Machelska H Mousa SA Brack A et al.Opioid control of inflammatory pain regulated by intercellular adhesion molecule-1.J Neurosci. 2002; 22: 5588-5596Crossref PubMed Google Scholar80Mousa SA Machelska H Schafer M Stein C Co-expression of beta-endorphin with adhesion molecules in a model of inflammatory pain.J Neuroimmunol. 2000; 108: 160-170Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar103Stein C Schafer M Machelska H Attacking pain at its source: new perspectives on opioids.Nat Med. 2003; 9: 1003-1008Crossref PubMed Scopus (482) Google Scholar Having been attracted to injured, inflamed tissue, the extravasated inflammatory cells' production of opioids is governed by CRH, interleukin-1β and catecholamines.17Binder W Mousa SA Sitte N Kaiser M Stein C Schafer M Sympathetic activation triggers endogenous opioid release and analgesia within peripheral inflamed tissue.Eur J Neurosci. 2004; 20: 92-100Crossref PubMed Scopus (112) Google Scholar79Mousa SA Bopaiah CP Stein C Schafer M Involvement of corticotropin-releasing hormone receptor subtypes 1 and 2 in peripheral opioid-mediated inhibition of inflammatory pain.Pain. 2003; 106: 297-307Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar Interestingly, effective central afferent nerve blockade modulates the recruitment of opioid-producing inflammatory cells to damaged tissue.97Schmitt TK Mousa SA Brack A et al.Modulation of peripheral endogenous opioid analgesia by central afferent blockade.Anesthesiology. 2003; 98: 195-202Crossref PubMed Scopus (41) Google Scholar In conjunction with such advances in the understanding of endogenous peripheral opioid analgesia, the development of clinically useful peripherally acting opioid drugs has been stimulated. The aim is to produce substances that activate peripheral opioid receptors, but which do not cross the blood–brain barrier,9Barber A Bartoszyk GD Greiner HE et al.Central and peripheral actions of the novel kappa-opioid receptor agonist, Emd-60400.Br J Pharmacol. 1994; 111: 843-851Crossref PubMed Scopus (18) Google Scholar55Jonker JW Wagenaar E van Deemter L et al.Role of blood–brain barrier P-glycoprotein in limiting brain accumulation and sedative side-effects of asimadoline, a peripherally acting analgaesic drug.Br J Pharmacol. 1999; 127: 43-50Crossref PubMed Scopus (94) Google Scholar thus producing analgesia with less central adverse effects.25Brower V New paths to pain relief.Nat Biotechnol. 2000; 18: 387-391Crossref PubMed Scopus (40) Google Scholar Asimadoline is a peripherally active κ opioid agonist that initially produces analgesia then, unfortunately, delayed proinflammatory effects in animal models of chronic inflammation.8Barber A Bartoszyk GD Bender HM et al.A pharmacological profile of the novel, peripherally-selective kappa-opioid receptor agonist, Emd-61753.Br J Pharmacol. 1994; 113: 1317-1327Crossref PubMed Scopus (118) Google Scholar70Machelska H Pfluger M Weber W et al.Peripheral effects of the kappa-opioid agonist EMD 61753 on pain and inflammation in rats and humans.J Pharmacol Exp Ther. 1999; 290: 354-361PubMed Google Scholar Encouragingly, new tetrapeptide κ agonists with high peripheral selectivity due to their poor central nervous system penetration have been found to have potent analgesic and anti-inflammatory actions.16Binder W Machelska H Mousa S et al.Analgesic and antiinflammatory effects of two novel kappa-opioid peptides.Anesthesiology. 2001; 94: 1034-1044Crossref PubMed Scopus (95) Google Scholar From preclinical studies it appears that peripheral opioids are effective in various animal models of inflammatory, visceral, bone and neuropathic pain.103Stein C Schafer M Machelska H Attacking pain at its source: new perspectives on opioids.Nat Med. 2003; 9: 1003-1008Crossref PubMed Scopus (482) Google Scholar Clinical studies have demonstrated that small doses of morphine applied peripherally to the site of tissue damage can produce significant analgesia with minimal side-effects. Intra-articular morphine gives analgesia after knee surgery in a dose-dependent fashion,65Likar R Kapral S Steinkellner H Stein C Schafer M Dose-dependency of intra-articular morphine analgesia.Br J Anaesth. 1999; 83: 241-244Crossref PubMed Scopus (57) Google Scholar and 5 mg is effective for up to 24 h.56Kalso E Smith L McQuay HJ Moore RA No pain, no gain: clinical excellence and scientific rigour—lessons learned from IA morphine.Pain. 2002; 98: 269-275Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar Morphine injected at the site of iliac bone harvesting for spinal grafting produced intense prolonged analgesia and a reduction in persisting pain.92Reuben SS Vieira P Faruqi S Verghis A Kilaru PA Maciolek H Local administration of morphine for analgesia after iliac bone graft harvest.Anesthesiology. 2001; 95: 390-394Crossref PubMed Scopus (71) Google Scholar Importantly, a number of clinical studies have demonstrated that the analgesic effect of peripheral morphine is only apparent in the presence of inflammation. For example, in patients with a unilateral corneal abrasion, topically applied morphine produces effective analgesia in the injured eye only,87Peyman GA Rahimy MH Fernandes ML Effects of morphine on corneal sensitivity and epithelial wound-healing—implications for topical ophthalmic analgesia.Br J Ophthalmol. 1994; 78: 138-141Crossref PubMed Scopus (88) Google Scholar and after dental surgery 1 mg morphine injected locally into the submucosa is an effective analgesic67Likar R Sittl R Gragger K et al.Peripheral morphine analgesia in dental surgery.Pain. 1998; 76: 145-150Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar only when inflammation is present around the tooth.66Likar R Koppert W Blatnig H et al.Efficacy of peripheral morphine analgesia in inflamed, non-inflamed and perineural tissue of dental surgery patients.J Pain Symptom Manage. 2001; 21: 330-337Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar The negative results found in some studies of peripheral opioids88Picard PR Tramer MR McQuay HJ Moore RA Analgesic efficacy of peripheral opioids (all except intra-articular): a qualitative systematic review of randomised controlled trials.Pain. 1997; 72: 309-318Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar may in part be due to the opioid application to normal peripheral nerves in the absence of any inflammation, when the opioid may not have access to intraneuronal opioid receptors in transit to the periphery. Early clinical trials with peripherally acting κ opioid receptor agonists gave disappointing results.15Bickel A Dorfs S Schmelz M Forster C Uhl W Handwerker HO Effects of antihyperalgesic drugs on experimentally induced hyperalgesia in man.Pain. 1998; 76: 317-325Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar Indeed, systemic administration of asimadoline to patients after knee surgery had a hyperalgesic effect, possibly because the drug has a κ agonist antinociceptive effect followed by a non-opioid hyperalgesic and proinflammatory effect in experimental animals.70Machelska H Pfluger M Weber W et al.Peripheral effects of the kappa-opioid agonist EMD 61753 on pain and inflammation in rats and humans.J Pharmacol Exp Ther. 1999; 290: 354-361PubMed Google Scholar However, a recent clinical study using a peripherally selective κ opioid agonist given to patients with chronic pancreatitis and pain demonstrated a significant analgesic effect, supporting the hypothesis that human visceral afferents express KOR, and that peripherally restricted KOR agonists produce analgesia in patients with chronic visceral pain.40Eisenach JC Carpenter R Curry R Analgesia from a peripherally active kappa-opioid receptor agonist in patients with chronic pancreatitis.Pain. 2003; 101: 89-95Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar New drugs have been developed that selectively inhibit the inducible cyclooxygenase enzyme COX-2 and spare constitutive COX-1. The COX-2 inhibitors available at present include meloxicam, nimesulide, celecoxib, etoricoxib, lumaricoxib, valdecoxib and parecoxib, the injectable precursor of valdecoxib (rofecoxib having been withdrawn recently).5Anon Vioxx: an unequal partnership between safety and efficacy.Lancet. 2004; 364: 1287-1288Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar By sparing physiological tissue prostaglandin production whilst inhibiting inflammatory prostaglandin release, COX-2 inhibitors offered the potential of effective analgesia with fewer side effects than the NSAID, but this desired outcome has been achieved only partially. The COX enzyme was first isolated in 1976, but more recently isoenzymes have been isolated. The two isolated COX isoenzymes have 75% amino acid homology with complete preservation of the catalytic sites for cyclooxygenase and peroxidase activity, with almost identical enzyme kinetics. COX-1 is a membrane-bound haemoglycoprotein with a molecular weight of 71 kDa, found in the endoplasmic reticulum of prostaglandin (PG)-producing cells. The enzyme cyclizes arachidonic acid and then adds a 15-hydroperoxy group to form the endoperoxide PGG2, which is then reduced to the hydroxy form of PGH2 by a peroxidase in the same COX enzyme protein. The COX-1 isoenzyme integrates into only a single leaflet of the lipid bilayer, and this is described as a ‘monotopic’ arrangement. The enzyme has three independent folding units: an epidermal growth factor-like domain, a membrane-binding domain and an enzymatic domain. The α-helices of the membrane-binding domains form a channel entrance to the active site, are inserted into the membrane, and thereby allow arachidonic acid to gain access into the interior of the lipid bilayer. The sites for COX and peroxidase activity are spatially distinct but are adjacent to each other. The COX active site is a long hydrophobic channel with tyrosine 385 and serine 530 at the apex. NSAIDs block COX-1 halfway down the channel by hydrogen bonding to the polar arginine at position 120 (reversible). Aspirin acetylates serine 530, irreversibly preventing access for arachidonic acid. COX-2 has a molecular weight of 70 kDa, with similar sites to COX-1 for the attachment of arachidonic acid and a similar three-dimensional structure to COX-1. However, its active site has a greater volume, because it has a larger central channel with a wider entrance and a secondary internal pocket. Therefore, COX-2 can accommodate larger drugs than COX-1. A single amino acid difference at position 523 is critical for the COX-1 and COX-2 selectivity of the NSAID. In COX-2 a valine molecule replaces the isoleucine molecule present at position 523 in COX-1. This valine molecule in COX-2 is smaller (by one methyl group) and produces a gap in the wall of the channel, giving access to a side pocket, which is the binding site of the COX-2-selective inhibitors. The larger isoleucine at position 523 in COX-1 blocks access of drug molecules to the side pocket. The genes for the two isoenzymes are found on different chromosomes: chromosome 9 for COX-1 and chromosome 1 for CO