A fixed dose combination of ibuprofen and famotidine

The NSAID class of medications is frequently used for mild to moderate pain. While overall safe, NSAIDs have several important adverse effects including esophageal, gastric and duodenal ulceration which limit their use. This has led to the development of NSAIDs with either less gastrointestinal side effects or concurrent use of medications to prevent NSAID gastrointestinal side effects. While several classes of medications exist for the prevention of gastrointestinal side effects, few combination treatments are available in a single pill. Towards this end, a combination pill of ibuprofen and famotidine (HZT-501, Horizon Therapeutics, Skokie, IL. USA) has been developed.     

Therapeutic potential of neuronal nicotinic acetylcholine receptor agonists as novel analgesics.

Pharmacological treatments for pain have come largely from two classes of compounds--the opioids and the nonsteroidal anti-inflammatory drugs (NSAIDs). Because of deficiencies associated with these two classes of compounds, exploration of novel approaches to pain relief has intensified of late. Nicotine, a neuronal nicotinic acetylcholine receptor (nAChR) agonist, has long been known to have antinociceptive effects in both experimental animals and humans. The relatively modest antinociceptive effects and the toxicities associated with nicotine preclude its development as an analgesic agent. However, recent discoveries in the nAChR field have stimulated interest in nAChR-targeted compounds as potential analgesic agents. Epibatidine, a potent nAChR agonist, was found to have full efficacy relative to opioids in preclinical pain models. Although epibatidine is toxic, these observations demonstrated that modest efficacy is not a general limitation of nAChR agonists. Moreover, exploration of the molecular biology of nAChRs revealed evidence of receptor diversity, suggesting that nAChR subtype-selective agents less toxic than nicotine might be discovered; and early medicinal chemistry efforts already have resulted in compounds with improved safety profiles. For example, ABT-594 is a nAChR agonist with the antinociceptive efficacy of epibatidine, but with an improved safety profile. This commentary reviews recent findings with nAChR-targeted compounds, explores potential mechanisms responsible for nAChR-mediated antinociception, and raises issues that must be addressed in developing compounds of this class as analgesics.     

Strategy for development of NSAIDs with lower risk for side effects

Nonsteroidal antiinflammatory drugs (NSAIDs) are one of the most frequently used classes of medicines worldwide. The major clinical problem encountered with the use of NSAIDs is gastrointestinal complications. In the USA, about 16,500 people per year die as a result of NSAID-associated gastrointestinal complications. COX-2-specific NSAIDs have been developed as safer for the gastrointestinal tract, although the risk of cardiovascular thrombotic disease has recently been noted with the use of COX-2-specific NSAIDs. To find the strategy for the development of gastrointestinally safe NSAIDs other than COX-2-specific NSAIDs, we examined the molecular mechanism for NSAID-induced gastric ulcer formation. We found that NSAIDs induce gastric mucosal cell death in a manner independent of COX inhibition and that this cytotoxic effect is due to their membrane permeabilization activity, which is not required for the antiinflammatory activity of NSAIDs. Furthermore, we showed that in addition to COX inhibition by NSAIDs, direct cytotoxicity of NSAIDs is required for NSAID-induced gastric ulcer formation. These results suggest that NSAIDs that have neither membrane permeabilization activity nor COX-2 specificity would be safe for both the gastrointestinal tract and cardiovascular system and we are now chemically synthesizing such NSAIDs.     

Nefopam analgesia and its role in multimodal analgesia: A review of preclinical and clinical studies

Nefopam is a non‐opioid, non‐steroidal, centrally acting analgesic drug used to prevent postoperative pain, primarily in the context of multimodal analgesia. This paper reviews preclinical and clinical studies in which nefopam has been combined with opioids, non‐steroidal anti‐inflammatory compounds, and paracetamol. This report focuses on the literature during the last decade and discusses the translational efforts between animal and clinical studies in the context of multimodal or balanced analgesia. In preclinical rodent models of acute and inflammatory pain, nefopam combinations including opioids revealed a synergistic interaction or enhanced morphine analgesia in six out of seven studies. Nefopam combinations including non‐steroidal anti‐inflammatory drugs (NSAIDs) (aspirin, ketoprofen or nimesulide) or paracetamol likewise showed enhanced analgesic effects for the associated compound in all instances. Clinical studies have been performed in various types of surgeries involving different pain intensities. Nefopam combinations including opioids resulted in a reduction in morphine consumption in 8 out of 10 studies of severe or moderate pain. Nefopam combinations including NSAIDs (ketoprofen or tenoxicam) or paracetamol also demonstrated a synergic interaction or an enhancement of the analgesic effect of the associated compound. In conclusion, this review of nefopam combinations including various analgesic drugs (opioids, NSAIDs and paracetamol) reveals that enhanced analgesia was demonstrated in most preclinical and clinical studies, suggesting a role for nefopam in multimodal analgesia based on its distinct characteristics as an analgesic. Further clinical studies are needed to evaluate the analgesic effects of nefopam combinations including NSAIDs or paracetamol.     

Pharmacological management of renal colic in the older patient

Renal colic affects up to 12% of the population. Initial management of most patients is expectant. Acute symptom management of renal colic is best accomplished with a combination of parenteral opioids and NSAIDs. The elderly patient with a kidney stone should be screened for contraindications to NSAID therapy, such as renal failure or previous peptic ulcer disease. Use of parenteral opioids is often necessary during the acute setting, and downward-adjusted doses and monitoring are necessary to prevent associated confusion and respiratory depression. Novel therapy with desmopressin may also be effective for symptom control at the initial presentation, without the adverse effects of opioids or NSAIDs. However, use of desmopressin in the elderly must be undertaken cautiously, given the potential adverse effects of this agent. Many small, distal ureteral stones are treated initially with watchful waiting for the first 2-4 weeks after presentation. The patient should have effective, non-parenteral analgesics for use at home. Included in these agents are oral or suppository NSAIDs and oral opioids. Medical expulsion therapy with alpha-adrenoceptor antagonists or calcium channel antagonists is efficacious. alpha-Adrenoceptor antagonists such as the alpha(1A/)(1)(D)-selective tamsulosin are well tolerated in the elderly and increase the rate of spontaneous stone passage by approximately 50% for small distal stones. These agents also appear to decrease the severity of renal colic. Corticosteroids and calcium channel antagonists are also effective but their use in the elderly is not recommended as first-line therapy.     

非甾体类抗炎镇痛药在围术期的应用

非甾体类抗炎药(Non-steroid anti-inflammatory drugs,NSAIDs)作为多模式镇痛的重要成分,主要用于围术期超前镇痛,加强阿片类药物的镇痛效果和减少阿片类药物的用量和不良反应。NSAIDs主要通过抑制环氧化酶、减少前列腺素等炎症介质的产生,起镇痛作用。本文对此进行综述。     

Pharmacology of drugs used to treat osteoarthritis in veterinary practice

As in humans, pain in animals may be associated with a wide range of conditions and circumstances, ranging from acute trauma to joint diseases. Joint diseases are common in companion animal medicine (horse, dog, cat) and at least 80% of cases are classified as osteoarthritis (OA). Several drug classes are available for OA therapy, including corticosteroids, non-steroidal antiinflammatory drugs (NSAIDs), agents with potential disease modifying properties and nutraceuticals. For long-term maintenance OA treatment, particularly in the horse and dog, NSAIDs are routinely and extensively used. This review outlines the pharmacokinetics (PK) and pharmacodynamics (PD) of NSAIDs in companion and farm animal species. NSAID PK and PD have been studied in models of acute inflammation, which enable use of PK-PD modeling to facilitate (a) studies of mechanism of action at the molecular level and (b) prediction of dosages for clinical use. The PK-PD approach is a powerful but underutilized tool which also facilitates inter-species comparisons.     

Pharmacology of drugs used to treat osteoarthritis in veterinary practice

As in humans, pain in animals may be associated with a wide range of conditions and circumstances, ranging from acute trauma to joint diseases. Joint diseases are common in companion animal medicine (horse, dog, cat) and at least 80% of cases are classified as osteoarthritis (OA). Several drug classes are available for OA therapy, including corticosteroids, non-steroidal antiinflammatory drugs (NSAIDs), agents with potential disease modifying properties and nutraceuticals. For long-term maintenance OA treatment, particularly in the horse and dog, NSAIDs are routinely and extensively used. This review outlines the pharmacokinetics (PK) and pharmacodynamics (PD) of NSAIDs in companion and farm animal species. NSAID PK and PD have been studied in models of acute inflammation, which enable use of PK-PD modeling to facilitate (a) studies of mechanism of action at the molecular level and (b) prediction of dosages for clinical use. The PK-PD approach is a powerful but underutilized tool which also facilitates inter-species comparisons.     

Postoperative pain control in children: a guide to drug choice

Postoperative pain in children can usually be well controlled with a combination of analgesics, including acetaminophen (paracetamol), NSAIDs, opioids, and local/regional anesthesia. Recent research has shown that the dosage of acetaminophen required to provide analgesia is higher than the traditional dosages used for the regulation of elevated body temperature. Rectal administration of acetaminophen gives a lower and more variable bioavailability compared with oral administration. There is growing experience with the use of NSAIDs in children and several studies have demonstrated the relatively strong analgesic potential of these drugs. Titration of opioids to analgesic effect, and the use of nurse- and patient-controlled continuous opioid infusions in children have gained widespread use and, with proper education and supervision, are considered excellent methods of pain control. Local peripheral and central blocks decrease the need for anesthetics during surgery and provide effective postoperative pain relief.     

The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings

Paracetamol is used worldwide for its analgesic and antipyretic actions. It has a spectrum of action similar to that of NSAIDs and resembles particularly the COX-2 selective inhibitors. Paracetamol is, on average, a weaker analgesic than NSAIDs or COX-2 selective inhibitors but is often preferred because of its better tolerance. Despite the similarities to NSAIDs, the mode of action of paracetamol has been uncertain, but it is now generally accepted that it inhibits COX-1 and COX-2 through metabolism by the peroxidase function of these isoenzymes. This results in inhibition of phenoxyl radical formation from a critical tyrosine residue essential for the cyclooxygenase activity of COX-1 and COX-2 and prostaglandin (PG) synthesis. Paracetamol shows selectivity for inhibition of the synthesis of PGs and related factors when low levels of arachidonic acid and peroxides are available but conversely, it has little activity at substantial levels of arachidonic acid and peroxides. The result is that paracetamol does not suppress the severe inflammation of rheumatoid arthritis and acute gout but does inhibit the lesser inflammation resulting from extraction of teeth and is also active in a variety of inflammatory tests in experimental animals. Paracetamol often appears to have COX-2 selectivity. The apparent COX-2 selectivity of action of paracetamol is shown by its poor anti-platelet activity and good gastrointestinal tolerance. Unlike both non-selective NSAIDs and selective COX-2 inhibitors, paracetamol inhibits other peroxidase enzymes including myeloperoxidase. Inhibition of myeloperoxidase involves paracetamol oxidation and concomitant decreased formation of halogenating oxidants (e.g. hypochlorous acid, hypobromous acid) that may be associated with multiple inflammatory pathologies including atherosclerosis and rheumatic diseases. Paracetamol may, therefore, slow the development of these diseases. Paracetamol, NSAIDs and selective COX-2 inhibitors all have central and peripheral effects. As is the case with the NSAIDs, including the selective COX-2 inhibitors, the analgesic effects of paracetamol are reduced by inhibitors of many endogenous neurotransmitter systems including serotonergic, opioid and cannabinoid systems. There is considerable debate about the hepatotoxicity of therapeutic doses of paracetamol. Much of the toxicity may result from overuse of combinations of paracetamol with opioids which are widely used, particularly in USA.     

The management of fibromyalgia

Fibromyalgia is one of a number of overlapping "functional somatic syndromes", including irritable bowel syndrome, tension headache, chronic idiopathic lower back pain, chronic fatigue syndrome and others. These conditions affect females more frequently than males and probably share common underlying neurobiological mechanisms, as well as frequent psychological, cognitive and behavioral comorbidities. Since the pain in these conditions is most likely "central" in origin, classes of drugs such as nonsteroidal antiinflammatory drugs (NSAIDs) and opioids, which are quite effective for "peripheral" pain, are relatively ineffective for the pain seen in these syndromes. Instead, tricyclic and other classes of antidepressants, antiseizure drugs and a number of other neuroactive compounds seem to be more effective. In addition, nonpharmacological therapies such as aerobic exercise and cognitive behavioral therapy are quite effective and frequently underutilized in clinical practice.     

Section Review: Pulmonary-Allergy,Dermatological, Gastrointestinal & Arthritis: Development of NSAIDs with reduced gastrointestinal and renal toxicity

While nonsteroidal anti-inflammatory drugs remain among the most widely used medications, their use continues to be associated with significant toxicity, particularly in the gastrointestinal tract and kidney. As more is learned about the pathogenesis of these adverse effects, several strategies have been taken to develop NSAIDs that are less toxic. Many such strategies have failed to have significant impact on the frequency and/or severity of NSAID-related adverse effects. However, recently, two new approaches have been taken which show great promise. Selective inhibitors of the inducible isoform of prostaglandin synthase are reported to spare the gastrointestinal tract. As we know little about the possible physiological role of this isoform of prostaglandin synthase, there are some concerns about the true potential for these compounds. A second approach is the linking of standard NSAIDs to a nitric oxide-releasing moiety. Studies in experimental models are extremely encouraging, demonstrating that these compounds retain the desired effects of the NSAID, but do not produce injury in the gastrointestinal tract or kidney.     

Lack of effect of naltrexone on the spinal synergism between morphine and non steroidal anti-inflammatory drugs

To enhance analgesia, the combinatorial use of analgesic drugs with proven efficacies is a widely-used strategy to reduce adverse side effects. The present study charcaterizes the antinociceptive interaction of intrathecal morphine co-administered with different NSAIDs using isobolographic analysis.Antinoceptive activity was evaluated using a model for acute visceral pain, the writhing test of mice. The possible involvement of opioid receptors in the mechanism of action of the intrathecal co-administration of morphine and NSAIDs was investigated using the non-selective receptor antagonist naltrexone. The study demonstrated a synergistic antinociception of intrathecal administered combinations of morphine with the following NSAIDs: diclofenac, ketoprofen, meloxicam, metamizol, naproxen, nimesulide, parecoxib and piroxicam. The supra additive effect was obtained with very low doses of each drug and it appeared to be independent of the COX-1 or COX-2 inhibition selectivity of each NSAID and was not significantly modified by intrathecal naltrexone. The findings of the present work suggest that the combination of opioids and NSAIDs has a direct action on spinal nociceptive processing, which may be achieved via mechanisms that are independent of the activation of opioid receptors. The ineffectiveness of naltrexone to reverse the analgesic activity of opioids + NSAIDs combinations indicates that other complex pain regulatory systems are involved in this effect.     

Exploring the role of COX-2 in Alzheimer's disease: Potential therapeutic implications of COX-2 inhibitors

This review highlights the potential role of cyclooxygenase-2 enzyme (COX-2) in the pathogenesis of Alzheimer's disease (AD) and the potential therapeutic use of non-steroidal anti-inflammatory drugs (NSAIDs) in the management of AD. In addition to COX-2 enzymes role in inflammation, the formation of amyloid plaques and neurofibrillary tangles in the brain, the review emphasizes that COXs-2 have a crucial role in normal synaptic activity and plasticity, and have a relationship with acetylcholine, tau protein, and beta-amyloid (Aβ) which are the main causes of Alzheimer's disease. Furthermore, the review points out that COX-2 enzymes have a relationship with kinase enzymes, including Cyclin Dependent Kinase 5 (CDK5) and Glycogen Synthase Kinase 3β (GSK3β), which are known to play a role in tau phosphorylation and are strongly associated with Alzheimer's disease. Therefore, the use of drugs like NSAIDs may be a hopeful approach for managing AD.However, results from studies examining the effectiveness of NSAIDs in treating AD have been mixed and further research is needed to fully understand the mechanisms by which COX-2 and NSAIDs may be involved in the development and progression of AD and to identify new therapeutic strategies.     

Back to the future: postoperative pain management beyond COX-2 inhibitors

In the aftermath of the heated dispute on COX-2 selective nonsteroidal anti-inflammatory drugs (NSAID) that led to the national and international withdrawal of several of the recently introduced coxibs, a balanced discussion of pros and cons for their short term use is warranted. Further debate and research has highlighted risks with both classical NSAIDs and coxibs when administered to patients with cardiovascular disease. For several decades discussion about indications, risks and contraindications for the perioperative use of classical NSAIDs has been ongoing. The COX debate has further added some uncertainty amongst practitioners. With a vast amount of research available on this topic, it should however be feasible to reach some consensus for the perioperative use of NSAIDs as well as for coxibs. This would ensure that the right patients take advantage of our present knowledge of NSAIDs as part of a multimodal and balanced perioperative analgesic regimen and at the same time that the patients at risk are not prescribed such drugs. Rational use of NSAIDs in the perioperative period would benefit a major group of patients who at present are deprived of such therapy due to unfounded fears of side effects and lack of knowledge among prescribers. This review highlights some of the aspects of short term (i.e. less than 5 days) perioperative use of NSAIDs.     

Age-related differences in sensitivity to the antinociceptive effects of kappa opioids in adult male rats

RATIONALE: Significant differences in the potency and effectiveness of opioid analgesics have been reported in subject populations differing in age. Although the relationship between aging and sensitivity to the antinociceptive effects of mu opioids has been examined extensively, relatively few studies have examined this relationship in kappa opioids. OBJECTIVES: The purpose of the present investigation was to examine the antinociceptive effects of selected kappa and mixed-action opioids in young (3 months) and aged (21 months) male rats. METHODS: In a warm-water, tail-withdrawal procedure, rats were restrained and the latencies to remove their tails from 50 degrees C (low temperature) and 55 degrees C (high temperature) water were measured. Selected kappa (U69,593, U50,488) and mixed-action (butorphanol, nalbuphine) opioids were tested alone, and in combination with the high-efficacy, kappa-opioid spiradoline. RESULTS: All test drugs were more effective (i.e., produced a greater maximal effect) in aged rats than in young rats at both water temperatures. In drug combination tests, U69,593 and U50,488 enhanced the effects of spiradoline under conditions in which they failed to produce high levels of antinociception when administered alone. In contrast, butorphanol and nalbuphine antagonized the effects of spiradoline under conditions in which they failed to produce high levels of antinociception when administered alone. CONCLUSIONS: These data may be taken as evidence that: (1) aged male rats are more sensitive than young male rats to the antinociceptive effects of kappa opioids, (2) U69,593 and U50,488 display agonist activity in the warm-water, tail-withdrawal procedure under some conditions in which they fail to produce antinociceptive effects, and (3) butorphanol and nalbuphine possess only limited agonist activity at the kappa receptor.     

Carbonic anhydrase inhibition: insight into non-COX-2 pharmacological effect of some coxibs

Nonsteroidal anti-inflammatory drugs (NSAIDs) represent the most commonly used medications for the treatment of pain and inflammation, but numerous well-described adverse drug reactions (ADRs) limit their use. These drugs act via the inhibition of cyclooxygenase (COX) enzyme of which at least two isoforms were described: COX-1 which plays important roles in homeostatic processes such as thrombogenesis and homeostasis of the gastrointestinal tract and kidneys and COX-2 expressed in pathological conditions such as inflammation or cancer proliferation. Selective COX-2 inhibitors or "coxibs" were initially developed as a therapeutic strategy to avoid not only the gastrointestinal but also the renal and cardiovascular side effects of non specific NSAIDs. However, this class of drug did not fulfill all their promises. Indeed, numerous unexpected side effects have limited their use and some of them have been withdrawn or suspended from the market for different safety reasons including cardiovascular, hepatic and skin adverse reactions. For instance, cardiovascular warnings have been applied to the whole class of coxibs and more recently for all classical NSAIDs as well. However, differences in the chemical structures should be taken into consideration in order to discriminate between coxibs and the development of some ADRs of which renal events and hypertension. The aim of this paper is to focus on the differences in chemical structures of all marketed COX-2 inhibitors and their unexpected effects on carbonic anhydrase in order to provide non-COX-2 mechanistic insights into some of the differences observed between coxibs.     

Nonsteroidal anti-inflammatory drugs for postoperative pain: a focus on children

Pain is a common symptom after surgery in children, and the need for effective pain management is obvious. For example, after myringotomy, despite the brief nature of the procedure, at least one-half of children have significant pain. After more extended surgery, such as tonsillectomy, almost all children have considerable pain longer than 7 days. Nonsteroidal anti-inflammatory drugs (NSAIDs) are useful for postoperative pain management because surgery causes both pain and inflammation. Several pediatric studies indicate NSAIDs are effective analgesics in the management of mild and moderate pain. In the treatment of severe pain, NSAIDs should be given with acetaminophen (paracetamol) or opioids, and the use of an appropriate regional analgesic technique should be considered. NSAIDs are more effective in preventing pain than in the relief of established pain. Pain following surgery is best managed by providing medication on a regular basis, preventing the pain from recurring. This proactive approach should be implemented for any procedure where postoperative pain is the likely outcome. In children, the choice of formulation can be more important than the choice of drug. Intravenous administration is preferred for children with an intravenous line in place; thereafter mixtures and small tablets are feasible options. Children dislike suppositories, and intramuscular administration should not be used in nonsedated children. Ibuprofen, diclofenac, ketoprofen and ketorolac are the most extensively evaluated NSAIDs in children. Only a few trials have compared different NSAIDs, but no major differences in the analgesic action are expected when appropriate doses of each drug are used. Whether NSAIDs differ in the incidence and severity of adverse effects is open to discussion. Because NSAIDs prevent platelet aggregation they may increase bleeding. A few studies indicate that ketorolac may increase bleeding more so than other NSAIDs, but the evidence is conflicting. Severe adverse effects of NSAIDs in children are very rare, but it is important to know about adverse effects in order to recognize and treat them when they do occur. NSAIDs are contraindicated in patients in whom sensitivity reactions are precipitated by aspirin (acetylsalicylic acid) or other NSAIDs. They should be used with caution in children with liver dysfunction, impaired renal function, hypovolemia or hypotension, coagulation disorders, thrombocytopenia, or active bleeding from any cause. In contrast, it seems that most children with mild asthma may use NSAIDs.