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Trends Pharmacol Sci. 2006 Jul;27(7):348-54. Antidepressants and pain. Micó JA, Ardid D, Berrocoso E, Eschalier A. Pharmacology and Neuroscience Research Group, Department of Neuroscience (Pharmacology and Psychiatry), School of Medicine, University of Cádiz, Plaza Fragela 9, 11003 Cádiz, Spain. [email protected] Abstract Tricyclic antidepressants, together with anticonvulsants, are considered to be first-line drugs for the treatment of neuropathic pain. Antidepressants are analgesic in patients with chronic pain and no concomitant depression, indicating that the analgesic and antidepressant effects occur independently. The analgesia induced by these drugs seems to be centrally mediated but consistent evidence also indicates a peripheral site of action. Several pharmacological mechanisms account for their antinociceptive effect but the inhibition of monoamine transporters (and, consequently, the facilitation of descending inhibition pain systems) is implicated on the basis of mechanistic and knockout-mouse studies. However, pain is a common symptom of depression, and depression is frequent in chronic pain patients, supporting the hypothesis that pain and depression share some common biochemical mechanisms. We suggest that antidepressants have a genuine analgesic effect and that research into their mechanisms of action will help to facilitate the development of new drugs. Basic Clin Pharmacol Toxicol. 2005 Jun;96(6):399-409. Antidepressants in the treatment of neuropathic pain. Sindrup SH, Otto M, Finnerup NB, Jensen TS. Department of Neurology, Odense University Hospital, DK-5000 Odense, Denmark. [email protected] Abstract Neuropathic pain is due to lesion or dysfunction of the peripheral or central nervous system. Tricyclic antidepressants and anticonvulsants have long been the mainstay of treatment of this type of pain. Tricyclic antidepressants may relieve neuropathic pain by their unique ability to inhibit presynaptic reuptake of the biogenic amines serotonin and noradrenaline, but other mechanisms such as N-methyl-D-aspartate receptor and ion channel blockade probably also play a role in their pain-relieving effect. The effect of tricyclic antidepressants in neuropathic pain in man has been demonstrated in numerous randomised, controlled trials, and a few trials have shown that serotonin noradrenaline and selective serotonin reuptake inhibitor antidepressants also relieve neuropathic pain although with lower efficacy. Tricyclic antidepressants will relieve one in every 2-3 patients with peripheral neuropathic pain, serotonin noradrenaline reuptake inhibitors one in every 4-5 and selective serotonin reuptake inhibitors one in every 7 patients. Thus, based on efficacy measures such as numbers needed to treat, tricyclic antidepressants tend to work better than the anticonvulsant gabapentin and treatment options such as tramadol and oxycodone, whereas the serotonin noradrenaline reuptake inhibitor venlafaxine appears to be equally effective with these drugs and selective serotonin reuptake inhibitors apparently have lower efficacy. Head-to-head comparisons between antidepressants and the other analgesics are lacking. Contraindications towards the use of tricyclic antidepressants and low tolerability in general of this drug class--may among the antidepressants--favour the use of the serotonin noradrenaline reuptake inhibitors. A recent study on bupropion, which is a noradrenaline and dopamine uptake inhibitor, indicated a surprisingly high efficacy of this drug in peripheral neuropathic pain. In conclusion, antidepressants represent useful tools in neuropathic pain treatment and must still be considered as first line treatments of neuropathic pain. However, without head-to-head comparisons between antidepressants and other analgesics, it is not possible to provide real evidence-based treatment algorithms for neuropathic pain. Adv Psychosom Med. 2011;30:125-38. Epub 2011 Apr 19. Cannabinoids for pain management. Thaler A, Gupta A, Cohen SP. Pain Management Division, Department of Anesthesiology, University of Pennsylvania School of Medicine, Philadelphia, PA 21029, USA. Abstract Cannabinoids have been used for thousands of years to provide relief from suffering, but only recently have they been critically evaluated in clinical trials. This review provides an in-depth examination of the evidence supporting cannabinoids in various pain states, along with an overview of potential adverse effects. In summary, there is strong evidence for a moderate analgesic effect in peripheral neuropathic and central pain conditions, and conflicting evidence for their use in nociceptive pain. For spasticity, most controlled studies demonstrate significant improvement. Adverse effects are not uncommon with cannabinoids, though most are not serious and self-limiting. In view of the limited effect size and low but not inconsequential risk of serious adverse events, cannabinoids should be employed as analgesics only when safer and more effective medication trials have failed, or as part of a multimodal treatment regimen. Top Curr Chem. 2011;299:29-62. Opioids in preclinical and clinical trials. Nagase H, Fujii H. School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, Japan. [email protected] Abstract Since 1952, when Gates determined the stereo structure of morphine, numerous groups have focused on discovering a nonnarcotic opioid drug. Although several natural, semisynthetic, and synthetic opioid ligands (alkaloids and peptides) have been developed in clinical studies, very few were nonnarcotic opioid drugs. One of the most important studies in the opioid field appeared in 1976, when Martin and colleagues established types of opioid receptors (these are now classified into mu, delta, and kappa types). Later, Portoghese discovered a highly selective mu type opioid receptor antagonist, beta-funaltrexamine. This led to the finding that the mu type opioid receptor was correlated to drug dependence. Consequently, delta, and particularly kappa, opioid agonists were expected to lead to ideal opioid drugs. Moreover, opioid antagonists were evaluated for the treatment of symptoms related to undesirable opioid system activation. In this chapter, we pro J Fam Pract. 2011 May;60(5):288-9. Clinical inquiries. What are the adverse effects of prolonged opioid use in patients with chronic pain? Edgerton L, Loven B. New Hanover Regional, Medical Center Residency in Family Medicine, Wilmington, NC, USA. Adv Psychosom Med. 2011;30:139-61. Ketamine in pain management. Cohen SP, Liao W, Gupta A, Plunkett A. Pain Management Division, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21029, USA. [email protected] Abstract Ketamine is an N-methyl-D-aspartate receptor antagonist that has been in clinical use in the USA for over 30 years. Its ability to provide profound analgesia and amnesia while maintaining spontaneous respiration makes it an ideal medication for procedure-related pain and trauma. In the chronic pain arena, its use continues to evolve. There is strong evidence to support its short- term use for neuropathic and nociceptive pain, and conflicting evidence for preemptive analgesia. Its potential ability to prevent 'windup' and, possibly, 'reboot' aberrant neurologic pathways in neuropathic and central pain states has generated intense interest. However, the long-term use of ketamine for chronic neuropathic pain is limited by its side effect profile, and is largely anecdotal. More research is needed to better ascertain its long-term efficacy and side effects, to determine the ideal candidates for sustained treatment and to develop means of exploiting the antinociceptive properties of ketamine while minimizing the adverse effects. Adv Psychosom Med. 2011;30:61-91. Opioid therapy in patients with chronic noncancer pain: diagnostic and clinical challenges. Cheatle MD, O'Brien CP. Center for Studies of Addiction, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA. [email protected] Abstract Chronic opioid therapy for patients with chronic noncancer pain has become controversial, given the rising prevalence of opioid abuse. The prevailing literature suggests that the rate of addiction in chronic noncancer pain patients exposed to opioid therapy is relatively low, especially in those patients without significant concomitant psychiatric disorders and personal and family history of addiction. However, the escalating rate of misuse of prescription opioids has resulted in many clinicians caring for these patients to be more judicious in prescribing opioids. Accurately diagnos ing addiction in chronic pain patients receiving opioids is complex. Managing the patient with pain and co-occurring opioid abuse is equally challenging. Diagnostic issues, current guidelines for the appropriate use of opioids in the chronic pain population and risk stratification models are examined. Pharmacologic and nonpharmacologic treatment strategies for the patient with pain and opioid addiction are reviewed. Adv Psychosom Med. 2011;30:22-60. Epub 2011 Apr 19. Addiction and brain reward and antireward pathways. Gardner EL. Neuropsychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA. [email protected] Abstract Addictive drugs have in common that they are voluntarily self-administered by laboratory animals (usually avidly), and that they enhance the functioning of the reward circuitry of the brain (producing the 'high' that the drug user seeks). The core reward circuitry consists of an 'in-series' circuit linking the ventral tegmental area, nucleus accumbens and ventral pallidum via the medial forebrain bundle. Although originally believed to simply encode the set point of hedonic tone, these circuits are now believed to be functionally far more complex, also encoding attention, expectancy of reward, disconfirmation of reward expectancy, and incentive motivation. 'Hedonic dysregulation' within these circuits may lead to addiction. The 'second-stage' dopaminergic component in this reward circuitry is the crucial addictive-drug-sensitive component. All addictive drugs have in common that they enhance (directly or indirectly or even transsynaptically) dop-aminergic reward synaptic function in the nucleus accumbens. Drug self-administration is regulated by nucleus accumbens dopamine levels, and is done to keep nucleus accumbens dopamine within a specific elevated range (to maintain a desired hedonic level). For some classes of addictive drugs (e.g. opiates), tolerance to the euphoric effects develops with chronic use. Postuse dysphoria then comes to dominate reward circuit hedonic tone, and addicts no longer use drugs to get high, but simply to get back to normal ('get straight'). The brain circuits mediating the pleasurable effects of addictive drugs are anatomically, neurophysiologically and neurochemically different from those mediating physical dependence, and from those mediating craving and relapse. There are important genetic variations in vulnerability to drug addiction, yet environmental factors such as stress and social defeat also alter brain-reward mechanisms in such a manner as to impart vulnerability to addiction. In short, the 'bio-psycho-social' model of etiology holds very well for addiction. Addiction appears to correlate with a hypodopaminergic dysfunctional state within the reward circuitry of the brain. Neuroimaging studies in humans add credence to this hypothesis. Credible evidence also implicates serotonergic, opioid, endocannabinoid, GABAergic and glutamatergic mechanisms in addiction. Critically, drug addiction progresses from occasional recreational use to impulsive use to habitual compulsive use. This correlates with a progression from reward-driven to habitdriven drug-seeking behavior. This behavioral progression correlates with a neuroanatomical progression from ventral striatal (nucleus accumbens) to dorsal striatal control over drug-seeking behavior. The three classical sets of craving and relapse triggers are (a) reexposure to addictive drugs, (b) stress, and (c) reexposure to environmental cues (people, places, things) previously associated with drug-taking behavior. Drug-triggered relapse involves the nucleus accumbens and the neurotransmitter dopamine. Stress-triggered relapse involves (a) the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and the neurotransmitter corticotrophin-releasing factor, and (b) the lateral tegmental noradrenergic nuclei of the brain stem and the neurotransmitter norepinephrine. Cue-triggered relapse involves the basolateral nucleus of the amygdala, the hippocampus and the neurotransmitter glutamate. Knowledge of the neuroanatomy, neurophysiology, neurochemistry and neuropharmacology of addictive drug action in the brain is currently producing a variety of strategies for pharmacotherapeutic treatment of drug addiction, some of which appear promising. Postgrad Med. 2011 Mar;123(2):119-30. Pain management in primary care: strategies to mitigate opioid misuse, abuse, and diversion. McCarberg BH. Chronic Pain Management Program, Kaiser Permanente, San Diego, CA, USA. [email protected] Abstract Pain is among the most common reasons patients seek medical attention, and the care of patients with pain is a significant problem in the United States. Acute pain (mild-to-moderate intensity) represents one of the most frequent complaints encountered by primary care physicians (PCPs) and accounts for nearly half of patient visits. However, the overall quality of pain management remains unacceptable for millions of US patients with acute or chronic pain, and underrecognition and undertreatment of pain are of particular concern in primary care. Primary care physicians face dual challenges from the emerging epidemics of undertreated pain and prescription opioid abuse. Negative impacts of untreated pain on patient activities of daily living and public health expenditures, combined with the success of opioid analgesics in treating pain provide a strong rationale for PCPs to learn best practices for pain management. These clinicians must address the challenge of maintaining therapeutic access for patients with a legitimate medical need for opioids, while simultaneously minimizing the risk of abuse and addiction. Safe and effective pain management requires clinical skill and knowledge of the principles of opioid treatment as well as the effective assessment of risks associated with opioid abuse, addiction, and diversion. Easily implementable patient selection and screening, with selective use of safeguards, can mitigate potential risks of opioids in the busy primary practice setting. Primary care physicians can become advocates for proper pain management and ensure that all patients with pain are treated appropriately. J Fam Pract. 2011 Apr;60(4):206-12. Opioids for osteoarthritis? Weighing benefits and risks: a Cochrane Musculoskeletal Group review. Howes F, Buchbinder R, Winzenberg TB. Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia. [email protected] Abstract Untreated pain is a major public health problem, but concerns about opioid misuse remain. This evidence-based look at when--or whether--opioids are indicated for OA patients will help you achieve the right balance. J Pediatr Hematol Oncol. 2011 Apr;33 Suppl 1:S6-S11. Choice of opioids and the WHO Ladder. Glare P. Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. [email protected] Abstract Physicians in developing countries who start to develop new, palliative care services face real barriers because of opiophobia in their countries. These physicians need to convince their colleagues in their own institutions about the need to adopt clear policies concerning pain management and palliative care in general. Moreover, these physicians need to explain the importance of such new services to their administrators and often legislators at the national level. People in the Middle East are facing cultural, traditional, and religious obstacles with regard to the introduction of opioids into regular use both in hospitals and in the community. In many countries, these drugs are believed to be drugs of addiction and in some cases, even dangerous drugs. Our goal is to enhance the establishment of pain units, being it within the framework of the Oncology Center, Palliative Care Services, or as stand-alone units. J Opioid Manag. 2011 Jan-Feb;7(1):69-79. Opioid delivery in the treatment of cancer breakthrough pain: a review of routes of administration. Nicholson B, Agarwala SS. Division of Pain Medicine, Pain Specialists of Greater Lehigh Valley, Pennsylvania, USA. Abstract Analgesics delivered via the oral route of administration (capsules, tablets, or solutions) are most commonly used to treat cancer breakthrough pain (BTP); however, the effectiveness of oral opioids may be limited by slow gastrointestinal absorption and first-pass metabolic effects. Although the limitations presented by oral opioid delivery are acknowledged and formulations and delivery systems that mirror the temporal characteristics of the majority of cancer BTP episodes are available, short-acting oral opioids are the accepted standard of care. The purpose of this review is to provide an overview of the different routes of opioid administration used in the treatment of cancer BTP and briefly discuss the characteristics of different delivery systems. J Opioid Manag. 2011 Jan-Feb;7(1):35-45. A systematic problems. compilation of reports published on opioid-related Butts M, Jatoi A. Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA. Abstract OBJECTIVES: This study examined the published literature on case reports of opioid-related problems to create a compendium that might lead to greater awareness and fewer such events. METHODS: PubMed, Ovid, and the Cumulative Index to Nursing and Allied Health Literature were searched for case reports. A problem was defined as a healthcare provider's or patient's administration of an opioid in an unintended manner resulting in harm. RESULTS: From more than 2200+ unique articles, 104 met the inclusion criteria. Fentanyl was most implicated. Problems included pump programming errors, patients' chewing transdermal patches, and pediatric overdosing with an oral droplet dispenser. Of 105 articles, 19 focused on patients with cancer and 86 on patients without cancer. CONCLUSIONS: This compendium of opioid-related problems might generate further discussion about how best to reduce their number and morbidity. Drug Ther Bull. 2011 Feb;49(2):18-21; quiz i-ii. Reducing NSAID-induced gastrointestinal complications. Abstract Around 17 million items for non-steroidal anti-inflammatory drugs (NSAIDs) are prescribed annually in England alone.1 These drugs are associated with upper gastrointestinal complications.2 For example, each year, NSAIDs cause about 3,500 hospitalisations for, and 400 deaths from, ulcer bleeding in people aged 60 years or above.3 Aspirin, even in low doses, is also associated with gastrointestinal complications.4 5 Here we assess strategies for reducing gastrointestinal complications induced by NSAIDs, including aspirin and selective inhibitors of cyclo-oxygenase-2 (coxibs). Br J Anaesth. 2011 Mar;106(3):292-7. Paracetamol and selective and non-selective non-steroidal antiinflammatory drugs for the reduction in morphine-related side-effects after major surgery: a systematic review. Maund E, McDaid C, Rice S, Wright K, Jenkins B, Woolacott N. Centre for Reviews and Dissemination, University of York, York YO10 5DD, UK. [email protected] Abstract Non-opioid analgesics, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), or cyclo-oxygenase 2 (COX-2) inhibitors are often given along with morphine as part of multimodal analgesia after major surgery. We have undertaken a systematic review and a mixed treatment comparison (MTC) analysis in order to determine explicitly which class of non-opioid analgesic, paracetamol, NSAIDs, or COX-2 inhibitors is the most effective in reducing morphine consumption and morphine-related adverse effects. Sixty relevant studies were identified. The MTC found that when paracetamol, NSAIDs, or COX-2 inhibitors were added to patient-controlled analgesia (PCA) morphine, there was a statistically significant reduction in morphine consumption: paracetamol [mean difference (MD) -6.34 mg; 95% credibility interval (CrI) 9.02, -3.65], NSAIDs (MD -10.18; 95% CrI -11.65, -8.72), and COX-2 inhibitors (MD -10.92; 95% CrI -12.77, -9.08). There was a significant reduction in nausea and postoperative nausea and vomiting with NSAIDs compared with placebo (odds ratio 0.70; 95% CrI 0.53, 0.88) but not for paracetamol or COX-2 inhibitors, nor for NSAIDs compared with paracetamol or COX-2 inhibitors. There was no statistically significant difference in sedation between any intervention and comparator. On the basis of six trials (n=695), 2.4% of participants receiving an NSAID experienced surgical-related bleeding compared with 0.4% with placebo. The MTC found that there is a decrease in 24 h morphine consumption when paracetamol, NSAID, or COX-2 inhibitors are given in addition to PCA morphine after surgery, with no clear difference between them. Similarly, the benefits in terms of reduction in morphine-related adverse effects do not strongly favour one of the three non-opioid analgesics. J Fam Pract. 2010 Nov;59(11):E1-6. Which NSAID for your patient with osteoarthritis? Scheiman JM, Sidote D. University of Michigan Medical School, Ann Arbor, USA. [email protected] Curr Med Res Opin. 2010 Dec;26(12):2871-6. Epub 2010 Nov 11. New guidelines for topical NSAIDs in the osteoarthritis treatment paradigm. Altman RD. David Geffen School of Medicine, University of California, Los Angeles, CA, USA. [email protected] Abstract BACKGROUND: Osteoarthritis (OA), the most common form of arthritis, often affects hands, hips, and knees and involves an estimated 26.9 million US adults. Women have a higher prevalence of OA, and the risk of developing OA increases with age, obesity, and joint malalignment. OA typically presents with pain and reduced function. Therapeutic programs are often multimodal and must take into account pharmaceutical toxicities and patient comorbidities. For example, nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with cardiovascular, gastrointestinal, and renal adverse events. Topical NSAIDs offer efficacy with reduced systemic drug exposure. RESEARCH DESIGN AND METHODS: This is a review of current guideline recommendations regarding the use of topical NSAIDs in OA of the hand and knee. Articles were identified by PubMed search (January 1, 2000 to May 21, 2010). RESULTS: Several current guidelines for management of OA recommend topical NSAIDs, indicating them as a safe and effective treatment. One guideline recommends that topical NSAIDs be considered as first-line pharmacologic therapy. A US guideline for knee OA recommends topical NSAIDs in older patients and in patients with increased gastrointestinal risk. CONCLUSIONS: The consensus across US and European OA guidelines is that topical NSAIDs are a safe and effective treatment for OA. Because the research base on topical NSAIDs for OA is small, guidelines will continue to evolve. Reumatismo. 2010 Jul-Sep;62(3):172-88. Pain and ketoprofen: what is its role in clinical practice? Sarzi-Puttini P, Atzeni F, Lanata L, Bagnasco M, Colombo M, Fischer F, D'Imporzano M. Source Rheumatology Unit, L. Sacco University Hospital, Milan, Italy. [email protected] Abstract Ketoprofen is a drug belonging to the family of non-steroidal anti-inflammatory drugs (NSAIDs). The present review examines the main available clinical evidence of ketoprofen in the treatment of acute and chronic pain, of both rheumatic and traumatic origin, as well as postoperative pain. Ketoprofen has shown to be an excellent choice of drug for the treatment of chronic pain in patients with osteoarthritis, rheumatoid arthritis or gout, demonstrating a high level of efficacy with good tolerability also in elderly patients. Even in the treatment of acute forms of pain such as bursitis, tendinitis and back pain, ketoprofen compares favourably to other NSAIDs (e.g., ibuprofen and diclofenac) in terms of efficacy. Ketoprofen has been shown to be effective also for the treatment of post-operative pain, particularly in the orthopaedic field, with an efficacy similar to opioids in some studies. In this setting, some evidence indicates that ketoprofen exhibits additional important benefits, showing to be effective in the prophylaxis of heterotopic calcification following hip or pelvic major intervention, without affecting the bone healing process. Moreover, the use of ketoprofen in elastomeric pump in combination with opioids or other NSAIDs has proven to be effective and safe. In conclusion, available data confirm that ketoprofen is effective and well tolerated, through different administration Intern Emerg Med. 2010 Oct;5 Suppl 1:S31-5. Management of cancer pain. Mercadante S. Anesthesia and Intensive Care Unit, Pain Relief and Palliative Care Unit, La Maddalena Cancer Center, Via San Lorenzo 312, 90146, Palermo, Italy. [email protected] Abstract In the last decades, studies validating the WHO analgesic ladder have been shown to have methodological limitations and different problems are unresolved due to a lack of controlled studies on this subject. These problems include a better definition of the role of NSAIDs, the prolonged use of NSAIDs in cancer pain, and the utility of step 2. Moreover, the indications for using different strong opioids and alternate routes of administration to improve pain relief in difficult pain situations are not well established. The proportion of patients who do not benefit from these treatments remain unclear, and how the opioid response may be improved with the use of adjuvants is also uncertain. This review will offer an update on these problems and the existing therapeutic opportunities. Curr Med Chem. 2010;17(32):3769-805. Selective COX-1 inhibition: A therapeutic target to be reconsidered. Perrone MG, Scilimati A, Simone L, Vitale P. Department of Medicinal Chemistry, University of Bari A. Moro, Via Orabona 4, 70125 (Bari), Italy. Abstract Since cyclooxygenase (COX) isozymes discovery, many papers and reviews have been published to describe the structural bases of COX inhibition, and to debate on the therapeutic and adverse effects of worldwide clinically used nonsteroidal anti-inflammatory drugs (NSAIDs), included COX-2 selective inhibitors (well known as Coxibs). COX-2 inhibition has been widely investigated, whereas the role of COX-1 in human pathophysiology is mostly not yet well ascertained. As time goes on, the cliché that the constitutively expressed isoform COX-1 is only involved in normal physiological functions, such as platelet aggregation, gastric mucosa protection and renal electrolyte homeostasis is going to be shattered. Low-dose aspirin, behaving as a preferential inhibitor of platelet COX-1, allowed to enlighten the role exerted by this isoenzyme in many mammalian cell types. This review would elucidate the most recent findings on selective COX-1 inhibition and their relevance to human pathology such as cancer, neuro-inflammation, cardioprotection, fever and pain. It would also focus on the design and development of new highly selective COX-1 inhibitors, useful tools in pharmacological studies aimed at gaining a deeper insight of the role of COX-1 in human health and disease. Among the traditional NSAIDs, other then aspirin and indomethacin, only few examples of selective COX-1 inhibitors (SC-560, FR122047, mofezolac, P6 and TFAP) have been so far identified. This review has also the scope to stimulate the development of novel drugs, which activity is COX-1 mediated. Subcell Biochem. 2007;42:3-27. Anti-inflammatory drugs in the 21st century. Rainsford KD. Biomedical Research Centre, Faculty of Health & Wellbeing, Sheffield Hallam University, Howard Street, Sheffield, SI 1WB, UK. [email protected] Abstract Historically, anti-inflammatory drugs had their origins in the serendipitous discovery of certain plants and their extracts being applied for the relief of pain, fever and inflammation. When salicylates were discovered in the mid-19th century to be the active components of Willow Spp., this enabled these compounds to be synthesized and from this, acetyl-salicylic acid or Aspirin was developed. Likewise, the chemical advances of the 19th-20th centuries lead to development of the non-steroidal anti-inflammatory drugs (NSAIDs), most of which were initially organic acids, but later non-acidic compounds were discovered. There were two periods of NSAID drug discovery post-World War 2, the period up to the 1970's which was the pre-prostaglandin period and thereafter up to the latter part of the last century in which their effects on prostaglandin production formed part of the screening in the drug-discovery process. Those drugs developed up to the 1980-late 90's were largely discovered empirically following screening for anti-inflammatory, analgesic and antipyretic activities in laboratory animal models. Some were successfully developed that showed low incidence of gastro-intestinal (GI) side effects (the principal adverse reaction seen with NSAIDs) than seen with their predecessors (e.g. aspirin, indomethacin, phenylbutazone); the GI reactions being detected and screened out in animal assays. In the 1990's an important discovery was made from elegant molecular and cellular biological studies that there are two cyclo-oxygenase (COX) enzyme systems controlling the production of prostanoids [prostaglandins (PGs) and thromboxane (TxA2)]; COX-1 that produces PGs and TxA2 that regulate gastrointestinal, renal, vascular and other physiological functions, and COX-2 that regulates production of PGs involved in inflammation, pain and fever. The stage was set in the 1990's for the discovery and development of drugs to selectively control COX-2 and spare the COX-1 that is central to physiological processes whose inhibition was considered a major factor in development of adverse reactions, including those in the GI tract. At the turn of this century, there was enormous commercial development following the introduction of two new highly selective COX-2 inhibitors, known as coxibs (celecoxib and rofecoxib) which were claimed to have low GI side effects. While found to have fulfilled these aims in part, an alarming turn of events took place in the late 2004 period when rofecoxib was withdrawn worldwide because of serious cardiovascular events and other coxibs were subsequently suspected to have this adverse reaction, although to a varying degree. Major efforts are currently underway to discover why cardiovascular reactions took place with coxibs, identify safer coxibs, as well as elucidate the roles of COX-2 and COX-1 in cardiovascular diseases and stroke in the hope that there may be some basis for developing newer agents (e.g. nitric oxidedonating NSAIDs) to control these conditions. The discovery of the COX isoforms led to establishing their importance in many non-arthritic or non-pain states where there is an inflammatory component to pathogenesis, including cancer, Alzheimer's and other neurodegenerative diseases. The applications of NSAIDs and the coxibs in the prevention and treatment of these conditions as well as aspirin and other analogues in the prevention of thrombo-embolic diseases now constitute one of the major therapeutic developments of the this century. Moreover, new anti-inflammatory drugs are being discovered and developed based on their effects on signal transduction and as anti-cytokine agents and these drugs are now being heralded as the new therapies to control those diseases where cytokines and other nonprostaglandin components of chronic inflammatory and neurodegenerative diseases are manifest. To a lesser extent safer application of corticosteroids and the applications of novel drug delivery systems for use with these drugs as well as with NSAIDs also represent newer technological developments of the 21st century. What started out as drugs to control inflammation, pain and fever in the last two centuries now has exploded to reveal an enormous range and type of anti-inflammatory agents and discovery of new therapeutic targets to treat a whole range of conditions that were never hitherto envisaged. World J Gastroenterol. 2010 Dec 7;16(45):5651-61. Non-steroidal anti-inflammatory drugs: What is the actual risk of liver damage? Bessone F. Abstract Non-steroidal anti-inflammatory drugs (NSAIDs) constitute a family of drugs, which taken as a group, represents one of the most frequently prescribed around the world. Thus, not surprisingly NSAIDs, along with anti-infectious agents, list on the top for causes of Drug-Induced Liver Injury (DILI). The incidence of liver disease induced by NSAIDs reported in clinical studies is fairly uniform ranging from 0.29/100 000 [95% confidence interval (CI): 0.17-051] to 9/100 000 (95% CI: 6-15). However, compared with these results, a higher risk of liver-related hospitalizations was reported (3-23 per 100 000 patients). NSAIDs exhibit a broad spectrum of liver damage ranging from asymptomatic, transient, hyper-transaminasemia to fulminant hepatic failure. However, underreporting of asymptomatic, mild cases, as well as of those with transient livertests alteration, in conjunction with reports non-compliant with pharmacovigilance criteria to ascertain DILI and flawed epidemiological studies, jeopardize the chance to ascertain the actual risk of NSAIDs hepatotoxicity. Several NSAIDs, namely bromfenac, ibufenac and benoxaprofen, have been withdrawn from the market due to hepatotoxicity; others like nimesulide were never marketed in some countries and withdrawn in others. Indeed, the controversy concerning the actual risk of severe liver disease persists within NSAIDs research. The present work intends (1) to provide a critical analysis of the dissimilar results currently available in the literature concerning the epidemiology of NSAIDS hepatotoxicity; and (2) to review the risk of hepatotoxicity for each one of the most commonly employed compounds of the NSAIDs family, based on past and recently published data. Rev Med Interne. 2000 Nov;21(11):978-88. [Non-steroidal anti-inflammatory agents with selective inhibitory activity on cyclooxygenase-2. Interest and future prospects]. Blain H, Jouzeau JY, Netter P, Jeandel C. Service de médecine interne C et gérontologie clinique, centre Antonin-Balmes, CHU, Montpellier, France. Abstract INTRODUCTION: Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the production of primary prostanoids by blocking the access of arachidonic acid to the active site of the cyclooxygenases (COXs). Because the prostanoids produced by COX-1 appear to play a physiological role (protection of the gastric mucosa, platelet aggregation, vascular homeostasis, maintenance of renal sodium-water balance) while those produced by COX-2 seem mainly to intervene in the inflammatory response and in certain processes associated with cell proliferation, the hypothesis has been put forward that the NSAIDs that are selective COX-2 inhibitors should theoretically be capable of maintaining NSAID therapeutic properties but also have fewer adverse side effects due to the maintenance of prostaglandin production at normal physiological levels. CURRENT KNOWLEDGE AND KEY POINTS: The hypothesis of COX isoenzyme selectivity has led to a proposed classification for COX inhibitors: 1) COX-1 selective inhibitors (low-dosage aspirin); 2) COX non-selective inhibitors (the majority of classified NSAIDs, which when administered over the long term, e.g., in cases of rheumatoid arthritis, cause duodenal ulcers in 20% of cases and gastric hemorrhage in 1-4% of cases/year); 3) COX-2 preferential inhibitors (meloxicam and nimesulide, which have fewer gastric side effects than standard NSAIDs, but which are not risk-free at high doses); 4) COX-2 selective inhibitors (celecoxib and rofecoxib). Preliminary clinical studies have shown that COX-2 selective inhibitors are as efficient as standard NSAIDs and have fewer adverse digestive side effects, thereby confirming the interest of this proposed classification. In the UK, the aforementioned studies have led to the commercialization of rofecoxib for the treatment of pain and osteoarthritis, while celecoxib has been introduced in medical practice in the USA and other countries for the treatment of rheumatoid arthritis and osteoarthritis. FUTURE PROSPECTS AND PROJECTS: Various epidemiological and laboratory studies have indicated that NSAIDs may be able to reduce the risk of cancer (colorectal cancer in particular) and Alzheimer's disease due to their inhibitory activity on COXs, especially COX-2. The therapeutic contribution of COX-2 specific inhibitors has to be more fully evaluated, particularly as these agents could delay the healing of duodenal ulcers and interfere with several COX-2-induced physiological functions. It is therefore suggested that until further information becomes available, this new class of NSAIDs should be used with caution in certain patient populations. Gut. 2010 Dec;59(12):1670-9. Effect of aspirin and NSAIDs on risk and survival from colorectal cancer. Din FV, Theodoratou E, Farrington SM, Tenesa A, Barnetson RA, Cetnarskyj R, Stark L, Porteous ME, Campbell H, Dunlop MG. Colon Cancer Genetics Group and Academic Coloproctology, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK. Abstract BACKGROUND: Previous studies have shown that aspirin and other non-steroidal antiinflammatory drugs (NSAIDs) lower colorectal cancer (CRC) risk. However, the lowest effective NSAID dose, treatment duration, and effects on survival are not defined. In a large population-based case-control study, we have explored the relationship between NSAID dose and duration, CRC risk and overall CRCspecific survival. METHODS: The relationship between NSAID use and CRC risk was examined in 2279 cases and 2907 controls. Subjects completed food-frequency and lifestyle questionnaires. NSAID categories were low-dose aspirin (75 mg), non-aspirin NSAIDs (NA-NSAIDs) and any NSAID. Users were defined as taking >4 tablets/week for >1 month. ORs were calculated by logistic regression models and adjusted for potential confounding factors. Effect of NSAID use on all-cause and CRC-specific mortality was estimated using Logrank tests and Cox's hazard models. RESULTS: In all, 354 cases (15.5%) were taking low-dose aspirin compared to 526 controls (18.1%). Low-dose aspirin use was associated with decreased CRC risk (OR 0.78 95% CI 0.65 to 0.92, p=0.004), evident after 1 year and increasing with duration of use (p(trend)=0.004). NA-NSAID and any NSAID use were also inversely associated with CRC. There was no demonstrable effect of NSAIDS on all-cause (HR 1.11, p=0.22, 0.94-1.33) or CRC-specific survival (HR 1.01, p=0.93, 0.83-1.23). CONCLUSION: This is the first study to demonstrate a protective effect against CRC associated with the lowest dose of aspirin (75 mg per day) after only 5 years use in the general population. NSAID use prior to CRC diagnosis does not influence survival from the disease. Ann Rheum Dis. 2011 May;70(5):818-22. Epub 2010 Sep 10. The appropriate use of non-steroidal anti-inflammatory drugs in rheumatic disease: opinions of a multidisciplinary European expert panel. Burmester G, Lanas A, Biasucci L, Hermann M, Lohmander S, Olivieri I, Scarpignato C, Smolen J, Hawkey C, Bajkowski A, Berenbaum F, Breedveld F, Dieleman P, Dougados M, MacDonald T, Mola EM, Mets T, Van den Noortgate N, Stoevelaar H. Department of Rheumatology and Clinical Immunology, Charité - University Medicine, Free University and Humboldt University Berlin, Charitéplatz 1 10117, Berlin, Germany. [email protected] Abstract INTRODUCTION: Given the safety issues of non-steroidal anti-inflammatory drugs (NSAID) and the robustness of guidelines, making treatment choices in daily clinical practice is increasingly difficult. This study aimed systematically to analyse the opinions of a multidisciplinary European expert panel on the appropriateness of different NSAID, with or without the use of a proton pump inhibitor (PPI), in individual patients with chronic rheumatic disease. METHODS: /Using the Research and Development/University of California at Los Angeles appropriateness method, the appropriateness of five (non-)selective NSAID with or without a PPI was assessed for 144 hypothetical patient profiles, ie, unique combinations of cardiovascular and gastrointestinal risk factors. Appropriateness statements were calculated for all indications. RESULTS: All options without PPI were considered appropriate in patients with no gastrointestinal/cardiovascular risk factors. Cyclooxygenase-2 selective inhibitors (C2SI) alone and non-selective NSAID plus PPI were preferred for patients with elevated gastrointestinal risk and low cardiovascular risk. Naproxen plus PPI was favoured in patients with high cardiovascular risk. For the combination of high gastrointestinal/high cardiovascular risk the use of any NSAID was discouraged; if needed, naproxen plus PPI or a C2SI plus PPI could be considered. DISCUSSION: The panel results may support treatment considerations at the level of individual patients, according to their gastrointestinal/cardiovascular risk profile. Cochrane Database Syst Rev. 2011 Jan 19;(1):CD007854. Acupuncture for primary dysmenorrhoea. Smith CA, Zhu X, He L, Song J. Centre for Complementary Medicine Research, The University of Western Sydney, Locked Bag 1797, Penrith South DC, New South Wales, Australia, 2751. Abstract BACKGROUND: This review examined the currently available evidence supporting the use of acupuncture to treat primary dysmenorrhoea. OBJECTIVES: To determine the efficacy and safety of acupuncture in the treatment of primary dysmenorrhoea when compared with a placebo, no treatment, or conventional medical treatment (for example oral contraceptives and non-steroidal antiinflammatory medication (NSAIDs)). SEARCH STRATEGY: The following databases were searched (from inception until March 2010): the Cochrane Menstrual Disorders and Subfertillity Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), PubMed, CINAHL, PsycINFO, Chinese Biomedical Literature Database (CBM), Chinese Medical Current Content (CMCC), China National Knowledge Infrastructure (CNKI), VIP database, Dissertation Abstracts International, BIOSIS, AMED (The Allied and Complementary Medicine Database), Acubriefs, and Acubase. SELECTION CRITERIA: Inclusion criteria included all published and unpublished randomised controlled trials comparing acupuncture with placebo control, usual care, and pharmacological treatment. The following modes of treatment were included: acupuncture, electro-acupuncture, and acupressure. Participants were women of reproductive age with primary dysmenorrhoea during the majority of the menstrual cycles or for three consecutive menstrual cycles, and moderate to severe symptoms. DATA COLLECTION AND ANALYSIS: Meta-analyses were performed using odds ratios (OR) for dichotomous outcomes and mean differences or standard mean differences (SMD) for continuous outcomes, with 95% confidence intervals (CI). Primary outcomes were pain relief and improved menstrual symptoms, measured by self-rating scales. Other outcomes included use of analgesics, quality of life, and absence from school or work. MAIN RESULTS: Ten trials were included in the review with data reporting on 944 participants. Six trials reported on acupuncture (n = 673) and four trials (n = 271) reported on acupressure. There was an improvement in pain relief from acupuncture compared with a placebo control (OR 9.5, 95% CI 21.17 to 51.8), NSAIDs (SMD -0.70, 95% CI -1.08 to -0.32) and Chinese herbs (SMD -1.34, 95% CI -1.74 to 0.95). In two trials acupuncture reduced menstrual symptoms (for example nausea, back pain) compared with medication (OR 3.25, 95% CI 1.53 to 6.86); in one trial acupuncture reduced menstrual symptoms compared with Chinese herbs (OR 7.0, 95% CI 2.22, 22.06); and in one trial acupuncture improved quality of life compared with usual care.There was an improvement in pain relief from acupressure compared with a placebo control (SMD -0.99, 95% CI -1.48 to -0.49), and in one trial acupressure reduced menstrual symptoms compared with a placebo control (SMD -0.58, 95% CI -1.06 to -0.10). The risk of bias was low in 50% of trials. AUTHORS' CONCLUSIONS: Acupuncture may reduce period pain, however there is a need for further welldesigned randomised controlled trials.