Elliot V. Hersh

Over-the-counter analgesics and antipyretics : A critical assessment

BACKGROUND It is just 100 years since the introduction of aspirin to medicine. Since then, aspirin and its derivatives have been joined by acetaminophen, and the nonsteroidal anti-inflammatory drugs--ibuprofen, naproxen sodium, and ketoprofen--as the only over-the-counter (OTC) agents approved by the US Food and Drug Administration for the short-term treatment of pain, headache, dysmenorrhea, and fever. Recently the prescription use of aspirin has expanded to include a number of antiplatelet indications. OBJECTIVE The purpose of this paper is to review critically the history, mechanisms of action, efficacy, and tolerability of OTC analgesic and antipyretic products. Relatively new and potential future indications for these drugs are also discussed. CONCLUSION Although all of the OTC analgesic/antipyretic agents seem to share a common mechanism of prostaglandin inhibition, there are important differences in their pharmacology, efficacy, and side-effect profiles. Considering their often-unsupervised use, the risk-benefit ratio of this class of drugs has been extremely favorable. However, when used inappropriately, even these drugs pose significant risks to certain patient populations.

Adverse Drug Interactions Involving Common Prescription and Over-the-Counter Analgesic Agents

BACKGROUND Eight analgesic preparations with approved indications for acute pain were among the top 200 drugs prescribed in the United States in 2006. In addition, an estimated 36 million Americans use over-the-counter (OTC) analgesics daily. Given this volume of use, it is not surprising that a number of drug interactions involving analgesic drugs have been reported. OBJECTIVES This article examines the pharmacologic factors that enhance the clinical relevance of potential drug interactions and reviews the literature on drug interactions involving the most commonly used analgesic preparations in the United States. METHODS A PubMed search was conducted for English-language articles published between January 1967 and July 2007. Among the search terms were drug interactions, acetaminophen, aspirin, ibuprofen, naproxen, celecoxib, NSAIDs, hydrocodone, oxycodone, codeine, tramadol, OTC analgesics, alcohol, ethanol, antihypertensive drugs, methotrexate, warfarin, SSRIs, paroxetine, fluoxetine, sertraline, citalopram, serotonin syndrome, MAOIs, and overdose. Controlled clinical trials, case-control studies, and case reports were included in the review. RESULTS A number of case reports and well-controlled clinical trials were identified that provided evidence of the relatively well known drug-drug interactions between prescription/OTC NSAIDs and alcohol, antihypertensive drugs, high-dose methotrexate, and lithium, as well as between frequently prescribed narcotics and other central nervous system depressants. In contrast, the ability of recent alcohol ingestion to exacerbate the hepatotoxic potential of therapeutic doses of acetaminophen is not supported by either case reports or clinical research. Use of ibuprofen according to OTC guidelines in patients taking cardioprotective doses of aspirin does not appear to interfere with aspirins antiplatelet activity, whereas chronic prescription use of ibuprofen and other NSAIDs may interfere. Low-dose aspirin intake appears to abolish the gastroprotective effects of cyclooxygenase-2-selective inhibitors, including celecoxib. There is evidence of other less well known and potentially clinically significant drug-drug interactions, including the ability of selective serotonin reuptake inhibitors to inhibit the analgesic activity of tramadol and codeine through inhibition of their metabolic activation, to induce serotonin syndrome when used chronically in the presence of high doses of tramadol through synergistic serotonergic action, and to increase the potential for gastrointestinal bleeding associated with NSAID therapy through additive or supra-additive antiplatelet activity. CONCLUSIONS Considering the widespread use of analgesic agents, the overall incidence of serious drug-drug interactions involving these agents has been relatively low. The most serious interactions usually involved other interacting drugs with low therapeutic indices or chronic and/or high-dose use of an analgesic and the interacting drug.

Update on cyclooxygenase inhibitors: has a third COX isoform entered the fray?

ABSTRACT It has been more than 30 years since Sir John Vane first reported that the pharmacological actions of aspirin-like drugs could be explained by their ability to inhibit cyclooxygenase (COX). Since then, a second isoform of COX, named COX‐2, has been discovered and highly selective inhibitors of this isoform have been marketed. Most recently, a splice variant of COX‐1 mRNA, retaining intron 1, and given the names COX‐3, COX‐1b or COX‐1v, has been described. Non‐selective NSAIDs such as ibuprofen and naproxen, which inhibit both COX‐1 and COX‐2, have proven highly effective and safe in the short-term management of acute pain. Highly selective COX‐2 inhibitors including celecoxib, rofecoxib, valdecoxib, lumiracoxib, and etoricoxib were developed with the hope of significantly reducing the serious gastrointestinal toxicities associated with chronic high‐dose NSAID use. While long-term studies demonstrated that rofecoxib and lumiracoxib reduced the incidence of GI perforations, ulcerations and bleeds by approximately 60% compared to non-selective NSAIDs, recent reports also demonstrated that the chronic use of rofecoxib and celecoxib in arthritis and colorectal polyp patients, and the short-term use of parecoxib and valdecoxib in patients who had undergone coronary artery bypass surgery, resulted in a significant increase in serious cardiovascular events, including myocardial infarction and stroke compared to naproxen or placebo. COX‐3 mRNA has been isolated in many tissues including canine and human cerebral cortex, human aorta, and rodent cerebral endothelium, heart, kidney and neuronal tissues. In transfected insect cells, canine COX‐3 protein is expressed and was selectively inhibited by acetaminophen. However, in humans and rodents an acetaminophen sensitive COX‐3 protein is not expressed because the retention of intron‐1 adds 94 and 98 nucleotides to the COX‐3 mRNA structure respectively. Since the genetic code is a triplicate code (3 nucleotides to form one amino acid), the retention of the intron in both species results in a frame shift in the RNA message and the production of a truncated protein with a completely different amino acid sequence than COX‐1 or COX‐2 lacking acetaminophen sensitivity. Advances made through a combination of basic molecular biological and pharmacological techniques, and well designed randomized controlled clinical trials have demonstrated that the apparent gastrointestinal advantage of selective COX‐2 inhibitors appears to be outweighed by their potential for cardiovascular toxicity and that acetaminophens analgesic and antipyretic effects do not involve the inhibition of the COX-1 splice variant protein, putative COX‐3.

Local Anesthetics: Pharmacology and Toxicity

The development of safe and effective local anesthetic agents has possibly been the most important advancement in dental science to occur in the last century. The agents currently available in dentistry are extremely safe and fulfill most of the characteristics of an ideal local anesthetic. These local anesthetic agents can be administered with minimal tissue irritation and with little likelihood of inducing allergic reactions. A variety of agents are available that provide rapid onset and adequate duration of surgical anesthesia. This introductory article provides a brief update of the clinical pharmacology of local anesthetic agents and formulations used in dentistry at present.

Ibuprofen Liquigel for Oral Surgery Pain

BACKGROUND Ibuprofen liquigel is a solubilized potassium ibuprofen 200-mg gelatin capsule formulation that was approved for over-the-counter use in 1995. OBJECTIVE This study compared the analgesic efficacy and tolerability of ibuprofen liquigel 200 mg, ibuprofen liquigel 400 mg, acetaminophen caplets 1000 mg, and placebo in patients experiencing moderate or severe pain after surgical removal of impacted third molars. METHODS This randomized, double-blind, parallel-group, 6-hour study was conducted in 210 patients experiencing moderate or severe postoperative pain. Ratings of pain intensity and pain relief were recorded every 15 minutes for the first hour, at 90 and 120 minutes, and then hourly through hour 6. The onsets of first perceptible relief and meaningful relief were recorded using 2 stopwatches. An analysis of variance model was employed to test for significant differences (P < or = 0.05) between treatment groups with respect to pain relief, pain intensity difference, total pain relief (TOTPAR), and summed pain intensity difference (SPID). Stopwatch measures were analyzed using the Cox proportional hazards model. Drug tolerability was assessed by monitoring the occurrence of adverse events. RESULTS During the first 2 hours of the study (TOTPAR 2 and SPID 2), all active treatments were significantly more efficacious than placebo (P < 0.001), with ibuprofen liquigel 200 and 400 mg significantly more efficacious than acetaminophen 1000 mg (P < 0.05 and P < 0.01, respectively). For the entire duration of the study (TOTPAR 6 and SPID 6), only the 2 doses of ibuprofen liquigel were significantly more efficacious than placebo (P < 0.001). Ibuprofen liquigel 200 and 400 mg were also significantly more efficacious than acetaminophen 1000 mg on the summary measures TOTPAR 6 and SPID 6 (P < 0.01 and P < 0.001, respectively). Analysis of the stopwatch data revealed that all active treatments displayed significantly more rapid onsets to confirmed first perceptible relief (P < 0.001 to < 0.05) and meaningful relief (P < 0.001 to < 0.01) than did placebo, with ibuprofen liquigel 400 mg displaying a significantly more rapid onset to meaningful relief than acetaminophen 1000 mg (P < 0.05) and a significantly more rapid onset to confirmed first perceptible relief than acetaminophen 1000 mg (P < 0.001) and ibuprofen liquigel 200 mg (P < 0.01). All adverse events were considered mild or moderate, with an overall incidence of 11.5% in the ibuprofen liquigel 200-mg group, 6.8% in the ibuprofen liquigel 400-mg group, 19.0% in the acetaminophen 1000-mg group, and 25.9% in the placebo group. CONCLUSIONS Ibuprofen liquigel provided greater peak and overall analgesic effects and a more rapid onset to analgesia than did acetaminophen 1000 mg.

Actinobacillus actinomycetemcomitans leukotoxin requires lipid microdomains for target cell cytotoxicity

Actinobacillus actinomycetemcomitans produces a leukotoxin (Ltx) that kills leukocyte function‐associated antigen‐1 (LFA‐1)‐bearing cells from man, the Great Apes and Old World monkeys. The unique specificity of Ltx for the β2 integrin, LFA‐1, suggests it is capable of providing insight into the pathogenic mechanisms of Ltx and other RTX toxins. Using the Jurkat T cell line and an LFA‐1‐deficient Jurkat mutant (Jβ2.7) as models, we found the initial effect of Ltx is to elevate cytosolic Ca2+[Ca2+]c, an event that is independent of the Ltx/LFA‐1 interaction. [Ca2+]c increases initiate a series of events that involve the activation of calpain, talin cleavage, mobilization to, and subsequent clustering of, LFA‐1 in cholesterol and sphingolipid‐rich regions of the plasma membrane known as lipid rafts. The association of Ltx and LFA‐1 within lipid rafts is essential for cell lysis. Jβ2.7 cells fail to accumulate Ltx in their raft fractions and are not killed, while cholesterol depletion experiments demonstrate the necessity of raft integrity for Ltx function. We propose that toxin‐induced Ca2+ fluxes mobilize LFA‐1 to lipid rafts where it associates with Ltx. These findings suggest that Ltx utilizes the raft to stimulate an integrin signalling pathway that leads to apoptosis of target cells.

Pharmacologic Management of Temporomandibular Disorders

Although there are theoretically numerous pharmacologic targets for relieving temporomandibular disorder (TMD)-associated pains, evidence-based literature clearly establishing the efficacy and safety of drugs in the TMD population is limited at best. This article reviews the pharmacology, toxicology, and research supporting the use of a host of pharmacologic agents that have been used in patients who have TMD, including nonsteroidal anti-inflammatory drugs, corticosteroids, benzodiazepines, nonbenzodiazepine sedative hypnotics, opioids, skeletal muscle relaxants, capsaicin, transdermal lidocaine, antidepressants, and anticonvulsants. Recommendations regarding the proper use of each drug class are also made.

Dose-ranging analgesic study of Prosorb diclofenac potassium in postsurgical dental pain.

BACKGROUND ProSorb diclofenac potassium (K) is a novel, liquid-filled rapid-dispersion formulation of the nonsteroidal anti-inflammatory drug diclofenac, placed into soft gelatin capsules. Its time to maximal plasma drug concentration has been shown to be approximately half, and its maximal plasma drug concentration nearly twice, that of immediate-release diclofenac K tablets. OBJECTIVE This study compared the analgesic dose-response relationship and tolerability of 3 doses of ProSorb diclofenac K and placebo in the treatment of pain after dental impaction surgery. METHODS This randomized, double-blind, double-dummy, placebo-controlled parallel-group study was conducted at 6 centers across the United States. Patients aged 18 to 65 years with moderate or severe pain after the removal of > or =1 impacted mandibular third molar were randomly assigned to receive a single dose of ProSorb diclofenac K 25, 50, or 100 mg or placebo. Pain intensity and relief were assessed up to 6 hours after dosing. Rescue treatment was allowed after 1 hour. Efficacy end points included the summed pain intensity difference over 3 and 6 hours (SPID3 and 6); total pain relief at 3 and 6 hours (TOTPAR3 and 6); median times to onset of perceptible and meaningful relief (analgesic onset) and rescue medication use (analgesic duration); and cumulative percentage of patients using rescue medication. Tolerability was assessed using vital sign measurements and spontaneous reporting of adverse events. RESULTS A total of 265 patients (154 women, 111 men; mean age, 23.3 years) were enrolled. All 3 ProSorb diclofenac K groups showed higher SPID6 and TOTPAR6 scores and longer median times to rescue medication use than the placebo group (all, P < 0.001). For these end points, a dose-response relationship was evident between the 100-mg dose and the 25- and 50-mg doses (P < or = 0.05); the 25- and 50-mg doses were similar. In the diclofenac groups, median onset times for first perceptible (< or =22.5 min) and meaningful (< or =53.0 min) relief were significantly more rapid than placebo (P < or = 0.01). Proportions of patients requiring rescue analgesic were < or =50.8% with diclofenac compared with 79.4% with placebo. Proportions of patients assigning a global evaluation of good or better was > or =68% with diclofenac compared with 21% for placebo. Tolerability was similar across all treatment groups. CONCLUSION In this study of patients treated for pain following dental impaction surgery, single doses of ProSorb diclofenac K 25, 50, and 100 mg were more efficacious than placebo with respect to reduction of pain. All 3 doses provided a rapid analgesic onset and were well tolerated.

Single dose and multidose analgesic study of ibuprofen and meclofenamate sodium after third molar surgery

The purpose of this study was to compare the analgesic efficacy and safety of meclofenamate sodium with ibuprofen after dental impaction surgery. This study was double-blind and used a unique methodology. Patients (N = 254) were first randomized into the single dose phase of the study that included placebo, meclofenamate 50 mg, meclofenamate 100 mg, ibuprofen 200 mg, and ibuprofen 400 mg, followed by a 7-day multidose phase in which patients in the placebo group were rerandomized into one of the active treatment cells. In the single dose phase, all active treatments were significantly more efficacious than placebo for every summary analgesic measure. A positive dose-response was seen for both active drugs with meclofenamate 100 mg and ibuprofen 400 mg exhibiting the greatest efficacy for pain relief, pain reduction, time to remedication, and overall evaluation. Side effects were reported by 26 patients. They were evenly distributed among treatment groups with headache and drowsiness being the most common. During the multidose phase, there were only small differences in efficacy measures among active treatment groups. However, meclofenamate produced a higher incidence of stomach cramps and diarrhea than did ibuprofen (8.8% and 7.2% versus 0.8% and 0.8%). This study indicates that higher doses of nonsteroidal anti-inflammatory drugs are most effective immediately after surgery and that lower doses of these drugs can be used after the first postoperative day. The side effect profile of nonsteroidal anti-inflammatory analgesics is best observed with the use of a multidose study design.

Adverse drug interactions in dentistry

According to the United States Food and Drug Administration web site, there are more than 15,000 currently approved prescription and over-the-counter drugs, diagnostics and intravenous supplementation products in the United States (78). Couple these with the hundreds of herbal and dietary supplements that undergo little if any scrutiny by the Food and Drug Administration (48), and it is no wonder that the potential for adverse drug interactions is a growing concern for all fields of patient care including dental medicine. To further complicate matters, common food products, such as grapefruit juice, that are consumed by many patients because of their reported cardiovascular and cancer-preventing benefits, have been involved in some of the most serious adverse drug interactions reported to date (19, 74, 158). There is no doubt that our patient population is consuming more and more drugs and herbal products. The geriatric dental population is increasing (75) and because of the presence of multiple disease states such as hypertension, congestive heart failure, diabetes, arthritis, and osteoporosis in these individuals, polypharmacy in this population is the norm (99, 182). In addition, decreases in cardiac output resulting in less blood flow and less drug being presented to the liver and kidney, decreases in hepatic and pre-hepatic drug metabolizing efficiency, decreases in renal excretory ability and increased receptor sensitivity to a variety of the central nervous system-acting drugs such as antidepressants, narcotics, and benzodiazepines, and a progressive decline in counter-regulatory (homeostatic) mechanisms make this population especially vulnerable to the adverse effects of drugs (232). Unlike 30 years ago, when many of these patients were coming to dental practices completely or partially edentulous, these patients are now maintaining their teeth longer and even when there is risk of tooth loss or there are edentulous spaces, many of these patients are opting for complex periodontal, implant, and restorative procedures over full or partial dentures (60). As a consequence, these patients need local anesthesia ⁄ vasoconstrictors, analgesics, anxiolytics, and antibiotics, which on occasion could adversely interact with a variety of the medications they are on. Even among young to middle-aged adults, the intake of certain prescription medications, especially those within the cardiovascular classes of drugs, is on the rise. With the new guidelines from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, patients with what was previously considered normal or borderline blood pressure are now being placed on a variety of antihypertensive agents (45). Patients with concomitant cardiovascular risk factors such as diabetes are being more aggressively treated, with multi-drug regimens often being recommended at the initiation of antihypertensive therapy. Classes of drugs that did not exist 20 years ago are being widely administered to young and old alike. On December 29, 1987, fluoxetine (Prozac ) became the first selective serotonin reuptake inhibitor approved by the Food and Drug Administration for the treatment of adult depression (233). Today there are five selective serotonin reuptake inhibitors in the top 100 prescribed drugs in the United States (229). In addition to adult depression, they are being prescribed for a variety of psychiatric conditions including childhood depression, social anxiety disorder, general anxiety disorder, panic attacks, and obsessive–compulsive disorder. Because of their more recent arrival on the market compared to other drug classes, our knowledge of potential adverse drug interactions with these agents is still evolving. Like the geriatric patient population, the pediatric dental patients have their own unique physiology and anatomy compared to young adult patients that