The effect of food on bromfenac, naproxen sodium, and acetaminophen in postoperative pain after orthopedic surgery

STUDY OBJECTIVES: To evaluate the effect of a standard meal on bioavailability of bromfenac, and on the relative analgesic efficacy and adverse effect liability of bromfenac 25 mg, naproxen sodium 550 mg, and acetaminophen 325 mg in the treatment of pain after orthopedic surgery. DESIGN: Randomized, double-blind, single-dose, parallel-group. SETTING: Two wards of the orthopedic surgery department at the Central Hospital, Karlstad, Sweden. PATIENTS: Three hundred ten patients with steady, moderate, or severe pain within 72 hours after orthopedic surgery. INTERVENTIONS: Patients were randomly assigned both to receive a standard meal or remain in a fasted state, and to treatment with a single oral dose of bromfenac 25 mg, naproxen sodium 550 mg, or acetaminophen 325 mg, when they experienced steady, moderate, or severe pain that required an analgesic. Using a self-rating record, subjects rated their pain and its relief for up to 8 hours after medicating. Blood samples were obtained from all patients using one of two schedules. MEASUREMENTS AND MAIN RESULTS: The peak plasma bromfenac concentration for fed patients was only 28% of that of fasted patients. Disregarding food intake, bromfenac 25 mg and naproxen sodium 550 mg were significantly superior to acetaminophen 325 mg for all summary measures of analgesia. Bromfenac and naproxen were superior to acetaminophen by hour 1 and this difference persisted for 8 hours. Food reduced bromfenac's analgesic effect, but not that of naproxen or acetaminophen; treatment by meal interaction was significant for five measures of efficacy. Analgesic response for fed bromfenac recipients, compared with those who were fasted, ranged from 37-71%. The percentage of patients reporting an adverse effect was significantly higher for bromfenac (25%) and naproxen (24%) than for acetaminophen (12%). CONCLUSIONS: Results of analgesic studies not taking patients' food status into consideration might be misleading. Although bromfenac 25 mg and naproxen sodium 550 mg produced significant analgesia compared with acetaminophen 325 mg, bromfenac's efficacy was significantly reduced when patients ate a standard meal. Adverse effects were transient and consistent with the pharmacologic profiles of the drugs.     

Sleep-promoting effects of melatonin: at what dose, in whom, under what conditions, and by what mechanisms?

Hydrocodone is a semisynthetic opioid with analgesic and antitussive properties qualitatively similar to other opioid agonists. Ibuprofen is a nonsteroidal antiinflammatory agent with analgesic and antipyretic activity and is an effective, primarily peripheral-acting antiinflammatory analgesic. The objective of this clinical trial was to determine the additive analgesic effect of the combination of 15 mg hydrocodone bitartrate with 400 mg ibuprofen, relative to 400 mg ibuprofen alone and placebo, in the treatment of postoperative pain. The single-dose analgesic efficacy of the combination of hydrocodone bitartrate with ibuprofen was compared with ibuprofen alone and placebo in 120 patients with moderate or severe postoperative pain after abdominal surgery. Analgesia was measured during the 6-hour period after dosing based on onset of relief, hourly and summary variables, and duration of effect. A significantly greater proportion of patients treated with the hydrocodone/ibuprofen combination reported onset of relief compared with ibuprofen or placebo; however, the distribution functions for time to onset of relief did not differ among treatments. Hydrocodone with ibuprofen and ibuprofen alone were significantly more effective than placebo for all measures of analgesia. The combination of hydrocodone with ibuprofen was significantly superior to ibuprofen for all hourly analgesic evaluations, weighted sum of pain intensity differences (SPID), total pain relief (TOTPAR), and global rating of study medication. No patients in the hydrocodone with ibuprofen group required analgesic remedication during the 6-hour study period, compared with 25% and 82% in the ibuprofen and placebo groups, respectively. The analgesic superiority of 15 mg hydrocodone bitartrate combined with 400 mg ibuprofen compared with 400 mg ibuprofen alone was demonstrated across many efficacy variables.     

Heme oxygenase and carbon monoxide: regulatory roles in islet hormone release: a biochemical, immunohistochemical, and confocal microscopic study

Two randomized, double-blind, parallel-group single-dose 2 x 2 factorial analgesic studies compared a single-dose or a 2-tablet dose of a combination of 7.5 mg hydrocodone bitartrate with 200 mg ibuprofen with each constituent alone and with a placebo in women with moderate or severe postoperative pain from abdominal or gynecologic surgery. A nurse-observer recorded patient reports of pain intensity and pain relief periodically for 8 hours. In both studies, the combination was significantly superior to placebo for sum of the pain intensity differences (SPID), total pain relief (TOTPAR), peak pain intensity difference (PID) and pain relief, global evaluation, and time to remedication. The combination was likewise significantly superior to both hydrocodone and ibuprofen for most of these summary measures of analgesia. In a factorial analysis, both the hydrocodone and ibuprofen effects were significant for most summary measures of analgesia, whereas results of the interaction contrast were consistent with the concept that the analgesic effect of the combination represents the additive analgesia of its 2 constituents.     

Possible pathophysiologic, diagnostic and therapeutic implications of new findings on leptin secretion within the scope of anorexia nervosa

Rational drug treatment of chronic musculoskeletal pain remains a challenge. Although commonly prescribed, the true efficacy of opioid analgesics or of nonsteroidal antiinflammatory drugs remains to be established. Using an N-of 1 design, eight patients with regional cervicobrachial pain received ibuprofen 800 mg/day, codeine 120 mg/day, or placebo during six 2 week periods. Clinical outcomes were assessed by pain diary, VAS of pain and change in pain, and uptime/downtime estimates. In none of the five subjects who completed the 12-week trial was analgesic efficacy of either drug shown. Major psychosocial and other medical influences on the subjects' status were encountered. The N-of 1 methodology is appropriated for evaluating true efficacy of pharmacotherapy in patients with regional musculoskeletal pain.     

Naratriptan is effective and well tolerated in the acute treatment of migraine. Results of a double-blind, placebo-controlled, crossover study. The Naratriptan S2WA3003 Study Group

The efficacy and tolerability of naratriptan tablets (2.5 mg, 1 mg, and 0.25 mg) compared with placebo in the acute treatment of migraine were evaluated in a randomized, double-blind, four-period crossover study. Five hundred eighty-six assessable patients received naratriptan 2.5 mg, 595 received 1 mg, 591 received 0.25 mg, 602 received placebo. Headache relief (moderate or severe pain reduced to mild or none) 4 hours postdose was reported in 68% of patients after treatment with naratriptan 2.5 mg compared with 57% after 1 mg, 39% after 0.25 mg, and 33% after placebo (p < 0.001 naratriptan 2.5 mg and 1 mg versus placebo and 1 mg and 2.5 mg versus 0.25 mg). Headache relief was maintained 8, 12, and 24 hours postdose with no use of rescue medication or a second dose of study medication by significantly (p < 0.001) greater percentages of patients after treatment with naratriptan 2.5 mg or 1 mg compared with naratriptan 0.25 mg or placebo. Naratriptan was also more effective than placebo in reducing clinical disability and the incidences of nausea, photophobia, and phonophobia. The overall incidence of adverse events and the incidences of specific adverse events did not differ in the naratriptan groups compared with placebo. No clinically relevant changes in ECG, blood pressure, or laboratory findings were reported. These data demonstrate that naratriptan is effective and well tolerated for the acute treatment of migraine. The 2.5-mg dose was associated with superior efficacy, whereas its adverse event profile was similar to that of placebo.     

The use of ketamine or etomidate to supplement sufentanil/N2O anesthesia does not disrupt monitoring of myogenic transcranial motor evoked responses

BACKGROUND: To compare the efficacy and tolerability of single doses of diclofenac dispersible and naproxen granular in patients with acute, painful, minor sports injuries. METHODS: Forty-eight adult outpatients with moderate-to-severe pain on movement, following a traumatic event < or = 36 hours previously, participated in this double-blind, between-patient comparative study. Patients were randomised in equal comparative study. Patients were randomised in equal number to receive diclofenac dispersible 50 mg or naproxen granular 500 mg. Pain on movement, pain on pressure, spontaneous pain and pain relief were assessed at 15, 30, 45, 60 minutes and 4 hours after dosing. RESULTS: Both treatments were effective at reducing pain from the 15 minute time point. At 15 minutes there was no significant difference between the treatments for pain on movement (p = 0.4) but diclofenac was significantly superior to naproxen with respect to pain on pressure (p = 0.004), spontaneous pain (p = 0.0022) and pain relief (p = 0.034). In addition, diclofenac was significantly superior to naproxen with respect to AUC0-4 hours for percentage reduction in intensity of pain on movement (p = 0.04) and spontaneous pain (p = 0.0047), and for pain relief scores (p = 0.015). Both treatments were well tolerated. CONCLUSIONS: The study results suggest that diclofenac dispersible 50 mg provides faster and overall better analgesia compared to naproxen granular 500 mg in the acute relief of pain following minor sports injuries.     

Analgesic efficacy of ibuprofen alone and in combination with codeine or caffeine in post-surgical pain: a meta-analysis

OBJECTIVE: To estimate the analgesic effect of ibuprofen and to test whether codeine and caffeine enhance its effect on post-surgical pain. METHOD: Systematic overview of the literature and meta-analysis of published randomised, controlled trials. RESULTS: Ibuprofen is effective in dental pain, episiotomy pain and other post-operative pain. There is a dose response relationship over the range 50-400 mg. The difference in total pain-relief score relative to placebo was 19-31%. On average, patients were over three times more likely to obtain moderate to excellent pain relief with ibuprofen than with placebo (response-rate ratio = 3.45) and the number needed to treat was 2.44. Codeine 60 mg enhanced the analgesic effect of ibuprofen 400 mg by about 8% in the total pain-relief scale, but it also increased its adverse effects. The additive effect of caffeine was inconsistent. CONCLUSION: Ibuprofen is an effective analgesic in post-operative pain. Codeine 60 mg adds to the analgesic effect of ibuprofen 400 mg. Any additive caffeine effect requires validation.     

Altered expression of membrane inhibitors of complement in human gastric epithelium during Helicobacter-associated gastritis

Tramadol hydrochloride is a novel, centrally acting analgesic with two complementary mechanisms of action: opioid and aminergic. Relative to codeine, tramadol has similar analgesic properties but may have fewer constipating, euphoric, and respiratory depressant effects. A two-center randomized double-blind controlled clinical trial was performed to assess the analgesic efficacy and reported side effects of tramadol 100 mg, tramadol 50 mg, codeine 60 mg, aspirin (ASA) 650 mg with codeine 60 mg, and placebo. Using a third molar extraction pain model, 200 healthy subjects were enrolled in a 6-hour evaluation after a single dose of drug. Of the 200 patients enrolled, seven provided incomplete efficacy data or discontinued prematurely and one was lost to follow-up. Using standard measures of analgesia, including total pain relief score (TOTPAR), maximum pain relief score (MaxPAR), sum of pain intensity difference scores (SPID), peak pain intensity difference (Peak PID), remedication, and global evaluations, all active treatments were found to be numerically superior to placebo. ASA/codeine was found to be statistically superior to placebo for all measures of efficacy. Tramadol 100 mg was statistically superior to placebo for TOTPAR, SPID, and time of remedication, whereas tramadol 50 mg was statistically superior to placebo onlyfor remedication time. Codeine was not found to be statistically superior to placebo for any efficacy measure. A greater TOTPAR response compared with all other active measures was seen for ASA/codeine during the first 3 hours of study. The 6-hour TOTPAR scores for the tramadol groups and ASA/ codeine group were not significantly different. Gastrointestinal side effects (nausea, dysphagia, vomiting) were reported more frequently with tramadol 100 mg, ASA/ codeine, and codeine 60 mg than with placebo.     

Building sound and regular teeth. The National Institute of Dental Research celebrates its golden anniversary

BACKGROUND: Peripheral nociceptive barrage after tissue injury results in acute pain and a variety of physiologic responses, including pituitary secretion of beta-endorphin. This study evaluated whether administration of the pharmacologically active S(+)-isomer of ibuprofen suppresses acute pain and plasma beta-endorphin levels in the oral surgery model of acute pain. METHODS: Subjects in a single-dose, double-blind, parallel-group study received either 200 mg S(+)-ibuprofen, 400 mg S(+)-ibuprofen, 400 mg racemic ibuprofen, or placebo. Both doses of S(+)-ibuprofen resulted in significantly greater analgesia over the first 60 minutes in comparison to racemic ibuprofen and placebo; the 400 mg dose of S(+)-ibuprofen also produced greater analgesia at 2 and 3 hours. Plasma levels of immunoreactive beta-endorphin decreased over time coincident with the onset of analgesia in all groups but were significantly less than placebo after both doses of S(+)-ibuprofen from 30 to 120 minutes. CONCLUSIONS: These findings show that, compared with racemic ibuprofen, administration of the S(+)-isomer of ibuprofen results in faster analgesic onset, greater peak analgesia, similar duration of action, and a low incidence of adverse effects, while suppressing nociceptive activation of the pituitary-adrenal axis.     

Pain control after dental surgery: a double-blind, randomised trial of lornoxicam versus morphine

Lornoxicam is a new non-steroidal anti-inflammatory drug of the oxicam class. This randomised, double-blind, placebo controlled trial compared the analgesic efficacy and tolerability of intramuscular (IM) injections of lornoxicam (4, 8, 16 and 20 mg) with morphine (10 and 20 mg) and placebo in 252 patients with mainly moderate to severe pain following surgical removal of an impacted mandibular third molar. Patients treated with lornoxicam or morphine experienced a significantly greater cumulative pain relief over the 4-h post-injection period (TOTPAR0-4) than placebo recipients. This effect appeared to be dose-dependent, with patients in the lornoxicam 4 mg or morphine 10 mg groups recording significantly lower TOTPAR0-4 scores than patients in the higher dosage groups of these drugs. No significant difference was detected between the morphine 20 mg group and the lornoxicam 8, 16 and 20 mg groups. Lornoxicam was well tolerated at all doses and was associated with a significantly lower incidence of adverse events than morphine 10 or 20 mg. Thus, the analgesic efficacy of IM lornoxicam at doses > or = 4 mg is superior to placebo, and doses > or = 8 mg are at least as effective as IM morphine 20 mg. Furthermore, lornoxicam possesses a more favourable tolerability profile than morphine and thus represents an attractive alternative for the treatment of moderate to severe acute pain.     

The clinical characteristics of intraoral herpes simplex virus infection in 52 immunocompetent patients

OBJECTIVES: To determine if nonsteroidal anti-inflammatory drugs provide adequate pain control for patients having laparoscopic hernia repair and to compare the effectiveness of ketorolac tromethamine with ibuprofen in reducing postoperative laparoscopic hernia pain. DESIGN AND SETTING: Prospective double-blind randomized study at a 100-bed community hospital. PATIENTS: Seventy patients ranging in age from 16 to 83 years scheduled for elective laparoscopic inguinal hernia repair. INTERVENTIONS: Patients undergoing laparoscopic hernia repair were enrolled in a double-blind randomized study to compare the 2 treatments. Group 1 received a placebo capsule 1 hour before surgery and ketorolac tromethamine, 60 mg intravenously, at the time of trocar insertion. Group 2 received ibuprofen, 800 mg an hour before surgery, and isotonic sodium chloride solution, 2 mL intravenously, at the time of trocar insertion. In addition, all patients received local infiltration of 30 mL of bupivacaine hydrochloride into their trocar sites. All patients were discharged within 5 hours of the operation and were instructed to take 400 mg of ibuprofen orally every 4 hours for 24 hours whether or not they were experiencing pain. A 24-hour supply of ibuprofen was provided to all study patients. Pain was assessed using the Visual Analog Pain Scale with a maximum pain rating of 100. Assessments were done at the time of and 18 hours after discharge. MAIN OUTCOME MEASURE: Postoperative pain 18 and 24 hours after discharge was assessed using a standardized questionnaire in a telephone interview by a registered nurse from the Outpatient Surgical Unit. RESULTS: There was no significant difference in the level of pain experienced by 35 patients who received ketorolac intravenously and 35 who received ibuprofen orally. There was no significant difference between the 2 treatment groups in the amount of pain experienced at discharge and 18 hours after discharge. CONCLUSIONS: Pain relief from ibuprofen, 800 mg, administered orally an hour before laparoscopic hernia repair was not statistically different from that obtained with intravenous ketorolac, 60 mg, administered intraoperatively when comparing the hospital discharge pain score and the mean and highest pain scores 18 hours after discharge. Ibuprofen offers equivalent pain control at a lower cost and reduced potential for adverse drug events compared with intravenous ketorolac in patients having laparoscopic hernia repair. No patient required narcotic supplementation, and pain control was judged satisfactory by all the patients.     

A systematic review of randomized controlled trials of pharmacological therapy in osteoarthritis of the knee, with an emphasis on trial methodology

We systematically reviewed randomized controlled trials (RCTs) of pharmacological therapy in knee osteoarthritis (OA), published between 1966 and August 1994. RCTs were identified by MEDLINE, supplemented by a manual search of reference lists. Qualitative assessment of RCTs was performed using Gotzsche's method; design and analysis features were rated on a scale of 0 (worst) to 8 (best). Heller et al's method was used to compare efficacy of nonsteroidal antiinflammatory drugs (NSAIDs) in comparative trials. A total of 80 RCTs were analyzed (45 involved NSAIDs, 3 analgesics, 5 intraarticular [IA] steroids, 9 biological agents, including IA hyaluronic acid, and 18 mixed modalities, including topical capsaicin). The median design and analysis scores for all 80 RCTs were 2 and 5, respectively. NSAIDs were superior to placebo in all short-term trials, but in the 32 comparative NSAID trials, only five (16%) found significant differences in efficacy. Heller et al's method identified differences in 14 NSAID comparisons; etodolac (600 mg/day) was superior in five of its nine comparisons. Indomethacin and aspirin were the most toxic NSAIDs. IA steroids were superior to placebo in short-term efficacy (< 1 month). Biological agents were superior to placebo and generally well tolerated over a mean follow-up of 48 weeks. Acetaminophen was superior to placebo and was comparably efficacious to low-dose naproxen and ibuprofen (< 2,400 mg/day). The data support the use of acetaminophen, topical capsaicin, IA steroids, IA hyaluronic acid, and NSAIDs in the treatment of patients with knee OA.     

A double-masked comparison of Naprelan and nabumetone in osteoarthritis of the knee. Naprelan Study Group

The efficacy and safety of Naprelan (naproxen sodium) 1000 mg once daily (QD) and nabumetone 1500 mg QD were compared in a multicenter, randomized, parallel-group, placebo-controlled, double-masked, 4-week study of adult outpatients with active osteoarthritis (OA) of the knee. Nabumetone 1500 mg was chosen for comparison because it is commonly prescribed in a QD dosing regimen for OA. After a washout period free of nonsteroidal anti-inflammatory drugs, 279 patients were enrolled and assigned randomly to treatment with either Naprelan 1000 mg QD (n = 92), nabumetone 1500 mg QD (n = 93), or placebo (n = 94). All treatments were evaluated for efficacy and safety at baseline and at weeks 2 and 4 of the treatment period or at discontinuation. Demographic characteristics were comparable among all treatment groups. As might be expected in a study of OA of the knee, a majority of patients enrolled were women (68.8%), and many were obese (mean weight, 195.6 lb; mean height, 66 in). Significantly fewer patients (13) treated with Naprelan prematurely discontinued the study than did patients treated with placebo (27); there was a lower rate of discontinuation for insufficient therapeutic effect in the Naprelan group compared with the nabumetone and placebo groups. Using an intent-to-treat model, the overall distribution of scores in all three primary efficacy assessments (investigator's global assessment of OA, patient's global assessment of OA, and walking pain) at week 2 and at the last visit was significantly better for the Naprelan group compared with both the nabumetone and placebo groups. The mean improvement from baseline was also significant for Naprelan compared with the nabumetone and placebo groups for all three assessments at week 2 and for investigator's global assessment of OA and walking pain at the last visit. The nabumetone-treated group showed significant improvement over the placebo-treated group in only one primary assessment: mean change from baseline in patient's global assessment of OA at week 2. At week 2, significant differences favoring Naprelan versus nabumetone and placebo were measured in overall distribution of scores for joint tenderness and nighttime pain. Distribution of quality of sleep and inactivity stiffness scores also improved relative to placebo at week 2. At the last visit, nighttime pain scores were still significantly better for patients receiving Naprelan versus nabumetone and placebo. Patients receiving nabumetone had statistically significant improvement from baseline in inactivity stiffness compared with placebo at week 2. There were no clinically important differences among treatment groups in the occurrence of adverse events or laboratory abnormalities. The results of this 4-week study of Naprelan 1000 mg QD compared with nabumetone 1500 mg QD demonstrate at least equal efficacy (superior efficacy was demonstrated for several parameters) and equal safety in adult outpatients with active OA of the knee.     

Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia

OBJECTIVE: Although opioid analgesics are used in the management of neuropathic pain syndromes, evidence of their efficacy remains to be established. We evaluated the clinical efficacy and safety of oxycodone in neuropathic pain using postherpetic neuralgia as a model. METHODS: Patients with postherpetic neuralgia of at least moderate intensity were randomized to controlled-release oxycodone 10 mg or placebo every 12 hours, each for 4 weeks, using a double-blind, crossover design. The dose was increased weekly up to a possible maximum of 30 mg every 12 hours. Pain intensity and pain relief were assessed daily, and steady (ongoing) pain, brief (paroxysmal) pain, skin pain (allodynia), and pain relief were recorded at weekly visits. Clinical effectiveness, disability, and treatment preference were also assessed. RESULTS: Fifty patients were enrolled and 38 completed the study (16 men, 22 women, age 70+/-11 years, onset of postherpetic neuralgia 31+/-29 months, duration of pain 18+/-5 hours per day). The oxycodone dose during the final week was 45+/-17 mg per day. Compared with placebo, oxycodone resulted in pain relief (2.9+/-1.2 versus 1.8+/-1.1, p=0.0001) and reductions in steady pain (34+/-26 versus 55+/-27 mm, p=0.0001), allodynia (32+/-26 versus 50+/-30 mm, p=0.0004), and paroxysmal spontaneous pain (22+/-24 versus 42+/-32 mm, p=0.0001). Global effectiveness, disability, and masked patient preference all showed superior scores with oxycodone relative to placebo (1.8+/-1.1 versus 0.7+/-1.0, p=0.0001; 0.3+/-0.8 versus 0.7+/-1.0, p=0.041; 67% versus 11%, p=0.001, respectively). CONCLUSIONS: Controlled-release oxycodone is an effective analgesic for the management of steady pain, paroxysmal spontaneous pain, and allodynia, which frequently characterize postherpetic neuralgia.     

Evaluation of the effectiveness of NSAIDs in the prevention of postoperative pain. Comparison between pre- and postoperative administration of sodium naproxen in orthopedic surgery

The aim of the study was to assess the efficacy of the preoperative sodium Naproxen administration to reduce analgesic requirements in the postoperative period. 75 patients (ASA I-II), 50 male and 25 female, aged between 25 and 70 years and weighed between 50 and 90 kg, undergoing lumbar laminectomy were subjected to the same anesthetic technique. Patients were allocated randomly to one of three groups. Group I received intravenous sodium naproxen (550 mg) immediately after induction of anesthesia. Group II received intravenous sodium Naproxen (550 mg) at the end of surgery. Group III received intravenous normal saline immediately after induction of anesthesia. Postoperative every patient was given by request intramuscular Buprenorphine (0.3 mg) for pain relief (at 6 h intervals). Buprenorphine requirements in the group I were significantly lower than in either of the other groups (p < 0.01 and p < 0.0001 respectively), while significant differences were not observed between group II and III. Moreover the 54% of patients in the group I did not require analgesic drugs in the postoperative period in opposition to the 20% of pts. in the group II and the 12% of pts. in the group III (p < 0.05 and p < 0.01 respectively). We conclude that NSAIDs when given before tissue damage may prevent nociceptor sensitisation and probably reduce hyperexcitability of the spinal cord. Preoperative administration of NSAIDs provides better protection against peripheral nerve sensitisation than postoperative administration.     

Effect of a non-steroidal anti-inflammatory drug on tissue levels of immunoreactive prostaglandin E2, immunoreactive leukotriene, and pain after periodontal surgery

The aim of this study was to measure tissue levels of immunoreactive prostaglandin E2 (iPGE2), immunoreactive leukotriene B4 (iLTB4), and pain after periodontal surgery and to evaluate the effect of the non-steroidal anti-inflammatory drug (NSAID), ibuprofen, on these levels. Two contralateral quadrants in each of nine patients were selected to undergo separate surgical procedures, one with ibuprofen (800 mg 1 hour presurgery and 400 mg postsurgery) and one with a placebo. Intra-operatively, a custom-made microdialysis probe, with a 3,000 dalton molecular weight cut-off, was inserted beneath the soft tissue flap and a dialysate collected every 20 minutes for 4 hours after surgery. Pain perception was measured at the same time intervals using two pain scales. Dialysate samples were assayed using two enzyme immunoassays. Mean tissue levels of iPGE2 in the placebo group increased from 74 nM at 40 minutes to a peak of 261 nM at 200 minutes. Mean tissue levels of iLTB4 in the placebo group fluctuated between 0.2 and 0.6 nM. Pain levels in this group increased continuously with time, peaking at 4 hours. Mean tissue levels of iPGE2 in the ibuprofen group were significantly suppressed, exhibiting more than a 95% reduction. This was accompanied by a significant reduction in pain. Ibuprofen had no detectable effect on tissue levels of iLTB4. These data indicate that iPGE2 and iLTB4 are present at relatively high concentrations in the periodontal tissues after surgery. Since these concentrations exceed the Kd values for binding to their respective receptors, PGE2 and LTB4 may be associated with the development of postsurgical pain and inflammation. These data also indicate that ibuprofen can successfully inhibit iPGE2 production in the periodontal tissues and in this way may help reduce postoperative pain and inflammation.     

Interposed bone grafts to accommodate endosteal implants for retaining mandibular overdentures. A 1-7 year follow-up study

STUDY OBJECTIVES: To examine the effect of timing of an intravenous (i.v.) dose (intraoperative vs. postoperative) of ketorolac tromethamine on pain scores and overall outcome after total abdominal hysterectomy (TAH) and myomectomy. DESIGN: Prospective, randomized, placebo-controlled study. PATIENTS: 248 ASA physical status I and II adult female patients scheduled for elective hysterectomy or myomectomy. INTERVENTIONS: General anesthesia was administered that consisted of thiopental sodium for induction, enflurane or isoflurane in nitrous oxide-oxygen for maintenance, and small doses of fentanyl and midazolam. Patients were randomized into three groups to receive toradol/placebo on a dosing schedule of dose 1 given one-half hour prior to expected end of surgery, dose 2 given on awakening in the postanesthesia care unit, and doses 3, 4, and 5 given at 6, 12, and 18 hours, respectively, after dose 2; Group 1 patients received placebo (saline) for dose 1, ketorolac 60 mg i.v. for dose 2, and ketorolac 30 mg i.v. for doses 3, 4, and 5. Group 2 patients received ketorolac 60 mg i.v. for dose 1, placebo for dose 2, and ketorolac 30 mg i.v. for doses 3, 4, and 5. Group 3 patients received placebo for all doses. All patients were given i.v. morphine PCA postoperatively, and morphine usages, visual analog pain intensity (VAS) scores, as well as adverse events and median times to recovery milestones were recorded. MEASUREMENTS AND MAIN RESULTS: VAS scores (mean) before dose 2 were significantly lower in Group 2 than Group 1, as were at-rest evaluations at 15 minutes and one hour. Group 2 patients also had decreased morphine requirements as compared to placebo. Both ketorolac groups (Groups 1 and 2) had significantly higher values for patient and observer overall ratings, case of nursing care, and tolerability as compared to placebo (Group 3). There were no significant differences among groups in adverse events or median times to recovery milestones. CONCLUSIONS: Although it is possible to demonstrate an improvement in early postoperative pain scores with intraoperative ketorolac and better overall ratings of ketorolac both intraoperatively and postoperatively as compared with placebo, the lack of clinically significant differences in analgesic efficacy in the two active study groups indicates the need for a careful consideration by the clinician of the risks versus benefits involved in the administration of antiplatelet medication in the perioperative period.     

Analgesic efficacy of paracetamol and its combination with codeine and caffeine in surgical pain--a meta-analysis

The objective of this study was to quantify the analgesic efficacy of paracetamol and its combination with codeine or caffeine through a systematic overview and meta-analysis of relevant randomized controlled trials (RCTs). Systematic retrieval of relevant clinical trials was carried out using computerized searches, historical searches and communication with manufacturers. The results of RCTs were pooled to estimate (i) the difference in percentage improvement of total pain relief (TOTPAR%) and the sum of pain intensity difference (SPID%); (ii) the proportions of patients obtaining moderate to excellent pain relief relative to placebo (ResRR) and (iii) the ratio of patients requiring analgesic re-medication (RemRR). Head-to-head comparisons were also undertaken for paracetamol versus its combination with codeine or caffeine. A total of 80 RCT reports describing 103 placebo comparisons and 26 head-to-head comparisons were identified. The total pain relief score in the single dose studies increased by 38 percentage points for paracetamol and by 24 points for placebo. The difference (d) in TOTPAR% between the two was highly significant (d = 14, 95% CI: 12, 16). For the difference in SPID%, d = 12, 95% CI: 11, 13. Patients were more than twice as likely to obtain moderate to excellent pain relief on paracetamol than on placebo (ResRR = 2.39, 95% CI: 1.89, 3.02), and less likely to require re-medication (RemRR = 0.78, 95% CI: 0.69, 0.88). There was no significant (P > 0.05) dose-response relationship. The analgesic efficacy of paracetamol 600 mg was enhanced with the addition of codeine 60 mg (using TOTPAR% as outcome) in both indirect and head-to-head comparisons. SPID%, but not ResRR and RemRR, data supported this conclusion. Much weaker effects were observed with the caffeine combination. Adverse effects were mild. Surprisingly, drowsiness was seen more often with paracetamol and paracetamol-codeine combinations than with placebo. The relative risks (95% CI) were 1.83 (1.29, 2.59) and 2.39 (1.58, 3.57), respectively. In conclusion paracetamol is an effective analgesic for post-surgical pain. Caffeine adds little to the analgesic effect of paracetamol. However, there is some evidence that codeine 60 mg adds to the analgesic effects of paracetamol 600 mg, using pain relief or pain intensity scores as outcomes, but this is not necessarily translated into an increase in number of patients who obtain moderate to excellent pain relief.