Methylprednisolone intravenously 1 day after surgery has sustained analgesic and opioid-sparing effects

BACKGROUND: In previous studies on glucocorticoids for postoperative pain, the test drug has been given perioperatively, usually before measurement of baseline pain. In order to evaluate the time course and magnitude of the analgesic effect of a glucocorticoid in well-established postoperative pain, we compared methylprednisolone with ketorolac and placebo, after assessment of baseline pain on the first postoperative day. METHODS: This was a double-blind, single dose, randomized, parallel comparison of intravenous (i.v.) methylprednisolone 125 mg, ketorolac 30 mg as an active control, and placebo in 75 patients with moderate to severe pain 1 day after orthopaedic surgery. Outcome variables were pain intensity (0-100 VAS), pain relief (0-4 PAR) and rescue opioid consumption. RESULTS: Methylprednisolone was not significantly different from ketorolac and gave significantly lower pain intensity from 1 h (0-6 h, P < 0.02), and more pain relief 2-6 h after test drugs (P < 0.05) compared with placebo. After 24 h, pain intensity was lower in both active drug groups compared with placebo (methylprednisolone, P < 0.0001; ketorolac, P < 0.007). Number needed to treat (NNT) calculated from patients having more than at least 50% of maximum obtainable total pain relief during the first 6 h (>50%maxTOTPAR(6 h)) was 3.6 for methylprednisolone and 3.1 for ketorolac. Number needed to treat calculated from the percentage reporting at least 50% pain relief for at least 4 h (>50%PAR(4 h)) was 2.8 for both groups. Opioid consumption was significantly reduced for 72 h after methylprednisolone compared with ketorolac (P < 0.02) and placebo (P < 0.003). CONCLUSION: Methylprednisolone 125 mg i.v. 1 day after surgery gave similar early reduction of pain as i.v. ketorolac 30 mg. Less pain than placebo 24 h after methylprednisolone, and lower opioid consumption for 72 h compared with ketorolac and placebo indicate sustained analgesic effects of methylprednisolone.     

Parecoxib sodium administered over several days reduces pain after gynecologic surgery via laparotomy

STUDY OBJECTIVE: To assess the analgesic efficacy of a multidose, multiday regimen of intravenous (IV) parecoxib sodium (parecoxib). DESIGN: Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. SETTING: Postoperative recovery area and inpatient care facility. PATIENTS: 422 patients who had undergone gynecologic surgery via laparotomy participated (day 1), and 414 patients were randomized (day 2). INTERVENTIONS: After surgery on day 1, all patients received parecoxib 40 mg (IV), followed by 20 mg (IV) one to 12 hours later; patients were then randomized to receive parecoxib 20 mg (IV) twice daily (n = 211) or placebo (IV) twice daily (n = 203) on days 2 to 5. Patients were permitted rescue medication as needed. MEASUREMENTS: Primary efficacy measures were summed pain intensity through 24 hours (SPI-24) and Patient's Global Evaluation of Study Medication on days 2 and 3. MAIN RESULTS: In the parecoxib treatment group, 24-hour summed pain intensity scores were significantly lower than in the placebo treatment group (P < 0.001) on days 2 and 3. More patients in the parecoxib treatment group rated their treatment as "excellent" or "good" using the Patient's Global Evaluation of Study Medication (P < 0.001) on days 2 and 3. Patients treated with parecoxib had lower pain intensity and consumed less rescue medication compared with the placebo-treated patients. CONCLUSION: Multidose parecoxib was well tolerated over several days and provided improved pain control after gynecologic surgery.     

Parecoxib Sodium, a Parenteral Cyclooxygenase 2 Selective Inhibitor, Improves Morphine Analgesia and Is Opioid-sparing following Total Hip Arthroplasty

Background: This study examined the opioid-sparing effectiveness, analgesic efficacy, and tolerability of postoperative administration of the parenteral cyclooxygenase 2 selective inhibitor, parecoxib sodium, in total hip arthroplasty patients.

Methods: This was a multicenter, multiple-dose, randomized, double-blind, placebo-controlled study to compare the opioid-sparing effects, analgesic efficacy, and tolerability of postoperative 20 and 40 mg intravenous parecoxib sodium with placebo in hip arthroplasty patients. The first dose of study medication was administered after surgery with an intravenous bolus dose of 4 mg morphine when patients first requested pain medication; remedication with the study medication occurred at 12 and 24 h. Subsequent morphine doses (1-2 mg) were administered by patient-controlled analgesia. Efficacy was assessed by total morphine used, pain relief and pain intensity, time to last dose of morphine, and Global Evaluation rating of the study medication.

Results: Parecoxib sodium, 20 and 40 mg, reduced the total amount of morphine required over 36 h by 22.1% (56.5 mg morphine) and 40.5% (43.1 mg morphine), respectively, compared with placebo (72.5 mg morphine;P < 0.01). Patients receiving 20 and 40 mg parecoxib sodium experienced significantly greater maximum pain relief compared with those in the placebo group (P < 0.05). Patients who received 20 and 40 mg parecoxib sodium discontinued PCA morphine earlier than patients receiving placebo and had significantly higher Global Evaluation ratings. Parecoxib sodium, 40 mg, plus morphine demonstrated a significantly lower incidence of fever and vomiting compared with placebo plus morphine.     

Preoperative parenteral parecoxib and follow-up oral valdecoxib reduce length of stay and improve quality of patient recovery after laparoscopic cholecystectomy surgery

In this randomized, double-blinded, placebo-controlled study, we evaluated the effects of preoperative IV parecoxib sodium (parecoxib) followed by postoperative oral valdecoxib on length of stay, resource utilization, opioid-related side effects, and patient recovery after elective laparoscopic cholecystectomy. Patients were randomized to receive a single IV dose of parecoxib 40 mg (n = 134) or placebo (n = 129) 30-45 min before the induction of anesthesia. Six to 12 h after the IV dose, the parecoxib group received a single oral dose of valdecoxib 40 mg, followed by valdecoxib 40 mg once daily on postoperative Days 1-4 and then 40 mg once daily as needed on Days 5-7. Patients in the parecoxib/valdecoxib group had a shorter length of stay in the postanesthesia care unit (78 +/- 47 min) compared with those taking placebo (90 +/- 49 min; P < 0.05). Patients in the parecoxib/valdecoxib group also had reduced pain intensity and, after discharge, experienced a significant reduction in vomiting in the first 24 h, slept better, returned to normal activity earlier, and expressed greater satisfaction than placebo patients (P < 0.05). Preoperative parecoxib followed by postoperative valdecoxib is a valuable adjunct for treating pain and improving patient outcome after laparoscopic cholecystectomy. IMPLICATIONS: The administration of preoperative IV parecoxib followed by oral valdecoxib after surgery resulted in a shorter length of stay in the postoperative anesthesia care unit, a better quality of postoperative recovery, and a faster return to normal activity, with greater patient satisfaction, after laparoscopic cholecystectomy.     

Parecoxib sodium,a parenteral cyclooxygenase 2 selective inhibitor,improves morphine analgesia and is opioid-sparing following total hip arthroplasty

BACKGROUND: This study examined the opioid-sparing effectiveness, analgesic efficacy, and tolerability of postoperative administration of the parenteral cyclooxygenase 2 selective inhibitor, parecoxib sodium, in total hip arthroplasty patients. METHODS: This was a multicenter, multiple-dose, randomized, double-blind, placebo-controlled study to compare the opioid-sparing effects, analgesic efficacy, and tolerability of postoperative 20 and 40 mg intravenous parecoxib sodium with placebo in hip arthroplasty patients. The first dose of study medication was administered after surgery with an intravenous bolus dose of 4 mg morphine when patients first requested pain medication; remedication with the study medication occurred at 12 and 24 h. Subsequent morphine doses (1-2 mg) were administered by patient-controlled analgesia. Efficacy was assessed by total morphine used, pain relief and pain intensity, time to last dose of morphine, and Global Evaluation rating of the study medication. RESULTS: Parecoxib sodium, 20 and 40 mg, reduced the total amount of morphine required over 36 h by 22.1% (56.5 mg morphine) and 40.5% (43.1 mg morphine), respectively, compared with placebo (72.5 mg morphine; P < 0.01). Patients receiving 20 and 40 mg parecoxib sodium experienced significantly greater maximum pain relief compared with those in the placebo group (P < 0.05). Patients who received 20 and 40 mg parecoxib sodium discontinued PCA morphine earlier than patients receiving placebo and had significantly higher Global Evaluation ratings. Parecoxib sodium, 40 mg, plus morphine demonstrated a significantly lower incidence of fever and vomiting compared with placebo plus morphine. CONCLUSIONS: Administration of parecoxib sodium with PCA morphine resulted in significantly improved postoperative analgesic management as defined by reduction in opioid requirement, lower pain scores, reduced time on PCA morphine, and higher Global Evaluation ratings.     

Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery: a randomized, double-blind, placebo-controlled study

In this randomized, double-blind, placebo-controlled, multicenter study we assessed the analgesic effect of etoricoxib (a new cyclooxygenase-2 inhibitor) in patients having had knee or hip replacement surgery. A total of 228 patients with moderate or severe pain were randomly allocated within 72 h after surgery to receive etoricoxib 120 mg, controlled-release naproxen sodium 1100 mg, or placebo (1:1:1) on day 1 followed by etoricoxib and placebo (1:2) on days 2 to 7. Patients reported pain scores, rescue (opioid-combination) medication use, and the response to study drug. On day 1, etoricoxib provided an analgesic effect superior to placebo and similar to controlled-release naproxen sodium as demonstrated by the total pain relief score over 8 h, the primary end-point; least-squares mean scores were 11.0, 11.5, and 5.6, respectively (P < 0.001 versus placebo). Similarly, a larger percentage of patients receiving etoricoxib and naproxen sodium than those receiving placebo reported good to excellent responses to study drug: 53%, 60%, and 26% respectively. On days 2-7, etoricoxib demonstrated a significant reduction of rescue medication use, 35% (P < 0.001 versus placebo). The clinical relevance of the decrease was confirmed by Patient's Global Evaluation (P < 0.05 versus placebo). Patients receiving etoricoxib also experienced significantly less "worst" and "average" pain than did those on placebo. Etoricoxib was generally well tolerated in this study; the incidence of adverse experiences was infrequent and similar across treatment groups. In summary, etoricoxib provided analgesia that was similar to controlled-release naproxen sodium on day 1 and superior to placebo with reduced supplemental opioid use over 7 days. IMPLICATIONS: In a postsurgery setting (knee and hip replacements), etoricoxib 120 mg provided analgesia superior to placebo and similar to controlled-release naproxen sodium 1100 mg. Patients receiving etoricoxib suffered less pain and took less opioid rescue medication compared with patients on placebo.     

Propacetamol versus ketorolac for treatment of acute postoperative pain after total hip or knee replacement

We assessed the analgesic efficacy of IV propacetamol and ketorolac in a double-blinded, placebo-controlled study involving patients undergoing total hip or knee replacement procedures. On the first morning after major joint replacement surgery, 164 patients experiencing moderate-to-severe pain were randomly assigned to receive an IV infusion of propacetamol (2 g), ketorolac (15 or 30 mg), or placebo (saline). Patient-controlled analgesia with morphine was made available as a "rescue" analgesic on patient's request during the 6-h postdosing evaluation period. The median time to onset of analgesia with propacetamol (8 [95% confidence interval 6,10] min) was shorter than ketorolac 15 mg (14 [7,16] min), and placebo (16 [8; not estimable] min) although the differences did not reach statistical significance. However, compared with ketorolac 30 mg, propacetamol had a shorter duration of analgesia (3.5 [2;5.4] vs 6 [3.3; not estimable] h). Analysis of pain intensity and pain relief scores demonstrated that propacetamol produced a significantly greater improvement in pain relief than saline from 45 min until 5 h after the injection. Propacetamol was not significantly different from ketorolac 15 mg and 30 mg with respect to the main analgesic efficacy variables during the 6-h assessment period. The most frequently reported adverse event with propacetamol was injection site pain (28% vs 19% for ketorolac 15 mg, 29% for ketorolac 30 mg, and 10% for placebo, respectively). In conclusion, propacetamol (2 g IV) possesses a similar analgesic efficacy to ketorolac (15 or 30 mg IV) after total hip or knee replacement surgery.     

Presurgical intravenous parecoxib sodium and follow-up oral valdecoxib for pain management after laparoscopic cholecystectomy surgery reduces opioid requirements and opioid-related adverse effects

BACKGROUND: Opioids are associated with numerous adverse effects. It is unclear if reduced postoperative opioid consumption lowers the incidence and severity of opioid-related adverse effects. This analysis -- from a multicenter, randomized, double-blind trial -- tested if the reduction of opioid consumption among patients who received intravenous preoperative parecoxib 40 mg, followed by oral valdecoxib 40 mg qd postoperatively, in Days 1-4 after outpatient laparoscopic cholecystectomy surgery, reduced opioid-related symptoms. METHODS: Patients received intravenous fentanyl for pain before discharge, and oral acetaminophen 500 mg hydrocodone 5 mg q 4-6 h prn postdischarge for up to 7 days postsurgery. Patients also received intravenous parecoxib 40 mg administered 30-45 min preoperatively, and valdecoxib 40 mg qd up to Day 4 and prn Days 5-7 postsurgery, or placebo. Patients completed an opioid-related Symptoms Distress Scale (SDS) questionnaire every 24 h for 7 days. Opioid use was converted to morphine-equivalent doses (MEDs). Clinically meaningful events (CMEs) for 12 opioid-related symptoms were assessed by three ordinal measures: frequency, severity, and bothersomeness. Reduction of CMEs on Day 1 and number of patient-days with CMEs on Days 1-4 were examined. RESULTS: Cumulative MEDs on Day 0, Day 1, and Days 1-4 were significantly lower in the parecoxib/valdecoxib group compared with the placebo group (P < 0.001). At the end of Day 1, parecoxib/valdecoxib-treated patients had significantly lower SDS scores (P < 0.02), a significantly reduced incidence of CMEs (P < 0.05), and significantly fewer patient-days with CMEs in Days 1-4 than placebo patients (P < 0.05). Patients in the parecoxib/valdecoxib group were less likely to have CMEs for multiple symptoms than those in the placebo group (P < 0.001). CONCLUSIONS: Treatment with parecoxib and valdecoxib significantly reduced the cumulative MED requirements, the incidence of opioid-related adverse effects, and patient-days with CMEs.     

腹腔镜子宫切除术后地塞米松镇痛有效剂量的探讨

背景糖皮质激素不仅具有止吐作用，还具有镇痛的特性，但手术后地塞米松镇痛的适宜剂量尚未确定。在此项安慰剂对照及对有效剂量探讨的研究中，我们对腹腔镜子宫切除术后3个不同剂量组地塞米松的镇痛效果进行了评估。方法将129例择期行腹腔镜子宫切除术的女性患者随机分成4组，分别在麻醉诱导前静脉注射安慰剂和地塞米松5mg（D5）、10mg（D10）、15mg（D15）。按照统一的模式对患者进行丙泊酚和瑞芬太尼复合麻醉。手术结束至手术后第1天上午，使用静脉羟考酮患者自控镇痛（PCA）进行手术后镇痛。记录手术后3天内视觉模拟评分（VAS评分）、不良反应以及镇痛药的用量。结果手术后0—24小时D15组的羟考酮累积使用量为0．34（0．11—0．87）mg／kg，低于对照组0．55（0．19—1．13）mg／kg，P=0．003。手术后0—2小时D10组羟考酮的用量为0．17（0．03—0．36）mg／kg，D15组为0．17（0．03—0．35）mg／kg，均低于对照组0．26（0．10—0．48）mg／kg（D10组与对照组相比，P=0．001；D15与对照组相比，P〈0．001）。但在手术后2—24小时的这段时间内，对照组、D5、D10、D15羟考酮的使用量相近，分别为0．31（0．03～0．78）mg／kg、0．22（0．03—0．92）mg／kg、0．24（0．05—0．87）mg／kg和0．20（0—0．65）mg／kg。本实验中各组静息、运动和咳嗽时的VAS评分的差异无显著性。手术后首个24小时内D15组头晕的发生率低于对照组（P=0．001）、D5组（P=0．006）和D10组（P=0．030）。在后续的恢复过程中，4个组间头晕的发生率无明显差异。结论麻醉诱导前静脉注射地塞米松15mg，可以减少腹腔镜下子宫切除手术后24小时内羟考酮的累积使用量。与静脉注射地塞米松15mg相比，静脉注射地塞米松10mg同样能减少手术后2小时内羟考酮的累积使用量。     

Low dose intravenous dexamethasone (4 mg and 10 mg) significantly prolongs the analgesic duration of single-shot interscalene block after arthroscopic shoulder surgery: a prospective randomized placebo-controlled study

Background

Although intravenous dexamethasone prolongs the analgesic duration of interscalene brachial plexus block, it is uncertain whether this effect can be observed using lower doses of dexamethasone. This study evaluated the impact of intravenous dexamethasone (4 mg and 10 mg) on the analgesic duration of single-shot interscalene block after arthroscopic shoulder surgery. We hypothesized that both doses would prolong the analgesic duration compared with placebo.

Methods

This was a prospective double-blind randomized placebo-controlled study in patients undergoing elective arthroscopic shoulder surgery under regional anesthesia with a single-shot interscalene block (0.5% ropivacaine 20 mL). Patients received dexamethasone 4 mg (D4), dexamethasone 10 mg (D10), or a placebo (normal saline [NS]) intravenously at the time of block completion. The primary outcome was the duration of analgesia, defined as the time from the onset of sensory blockade to the first analgesic request. The primary outcome was first analyzed with a Kruskal-Wallis test and then with a Mann-Whitney test for pairwise between-group comparison.

Results

Sixty-nine patients completed the study. The median [interquartile range] duration of analgesia was significantly different between the three groups (D4, 19.7 [16.9-23.3] hr; D10, 19.1 [11.5-22.8] hr; and NS, 11.8 [9.3-14.0] hr; P = 0.001). This difference was statistically significant for D4 and D10 compared with placebo (median difference [MD], 7.8 hr; 95% confidence interval [CI], 4.6 to 11.1 hr; P < 0.001; and MD, 7.4 hr; 95% CI, 4.2 to 10.5 hr; P = 0.001, respectively) but not for D4 compared with D10 (MD, 0.5 hr; 95% CI, ?2.8 to 3.7 hr; P = 0.38).

Conclusions

Low doses of intravenous dexamethasone (4 mg and 10 mg) significantly prolong the analgesic duration of interscalene block. This trial was registered at ClinicalTrials.gov (NCT02412657).

     

Patients' global evaluation of analgesia and safety of injected parecoxib for postoperative pain: a quantitative systematic review

Parecoxib is the only parenterally administered cyclooxygenase-2-selective inhibitor available. We performed a systematic review, including full reports of randomized comparisons of parecoxib compared with any other analgesic intervention for prophylaxis or treatment of postoperative pain. Dichotomous data on patients' global evaluation of their analgesic regimen were extracted by means of the fraction of patients who rated their medication as "good" or "excellent." For safety analysis, data on any reported adverse effects were extracted. Relative risk (RR), number needed to treat (NNT), or number-needed-to-harm were calculated with 95% confidence intervals (CI). Data from 9 trials of 50 initially screened were finally analyzed. One thousand thirteen patients were randomized to receive parecoxib, 218 patients were allocated to an active control, and 507 patients received a placebo. With prophylactic administration, the pooled NNT to obtain the desired outcome ("good"/"excellent" rating) with parecoxib 20 and 40 mg compared with placebo was 4.5 (RR, 1.42; 95% CI, 0.91-2.24) and 4.0 (RR, 1.40; 95% CI, 1.10-1.79), respectively. In the treatment trials, the NNT to obtain the outcome of interest with parecoxib 20 mg was 2.1 (RR, 3.44; 95% CI, 1.49-7.96), 5.3 (RR, 1.43; 95% CI, 1.01-2.02), and -8.3 (RR, 0.85; 95% CI, 0.75-0.97) for the comparisons with placebo, morphine, and ketorolac, respectively. The corresponding NNT for treatment with parecoxib 40 mg was 1.7 (RR, 4.65; 95% CI, 2.04-10.61), 3.7 (RR, 1.62; 95% CI, 1.21-2.16), and 50 (RR, 1.03; 95% CI, 0.89-1.18) for the comparisons with placebo, morphine, and ketorolac, respectively. Overall adverse effects for parecoxib 20 and 40 mg were not different from those with placebo, morphine, or ketorolac. These results suggest a favorable profile for parecoxib compared with inactive or active controls. The optimal dose, timing, and frequency of administration need to be determined.     

Methylprednisolone and ketorolac rapidly reduce hyperalgesia around a skin burn injury and increase pressure pain thresholds

BACKGROUND: Glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs) decrease acute postoperative pain and hyperalgesia. The objectives of this study were to investigate the effects of methylprednisolone and ketorolac on hyperalgesia around a skin burn injury and on pressure pain thresholds. METHODS: In a double-blind, placebo-controlled, randomized trial with cross-over design, methylprednisolone 125 mg, ketorolac 60 mg or placebo was administered intravenously in 12 male volunteers on three separate days at least 4 days apart. Primary and secondary hyperalgesia were produced by a first-degree burn injury on abdominal skin 45 min before injection of the test medicines. The area of secondary mechanical hyperalgesia outside the site of injury was measured. Pressure pain stimuli were applied on the base of a fingernail, increasing until the pressure pain detection threshold (PPDT) and pressure pain tolerance threshold (PPTT) were reached. RESULTS: Compared with placebo, the active drugs reduced the area of secondary hyperalgesia (methylprednisolone, P < 0.001; ketorolac, P < 0.01). Ketorolac but not methylprednisolone increased PPDT compared with placebo (P < 0.05). Both active drugs increased PPTT compared with placebo (methylprednisolone, P < 0.01; ketorolac, P < 0.001). Ketorolac increased PPTT more than methylprednisolone (P < 0.05). CONCLUSIONS: Methylprednisolone and ketorolac increased PPTT attenuated secondary hyperalgesia around a skin burn injury. PPTT increased after both methylprednisolone and ketorolac. The present study demonstrates analgesic and anti-hyperalgesic properties of a glucocorticoid and a non-selective NSAID that have not been demonstrated previously in human subjects.     

The effect of intravenous ketoprofen on postoperative epidural sufentanil analgesia in children.

We compared the effect of IV ketoprofen and placebo as an adjuvant to epidural sufentanil analgesia after major surgery. We used a prospective, randomized, double-blinded, placebo-controlled, parallel-group study design in 54 children aged 1-15 yr who received a standardized anesthetic. Either IV ketoprofen or saline was administered in addition to an epidural sufentanil infusion, which was adjusted as required clinically. The study drug infusions were discontinued when pain scores were <3 on 0-10 scale for 6 h at a sufentanil infusion rate of 0.03 microg x kg(-1) x h(-1). Children in the ketoprofen group had a better analgesic effect, as shown by decreased need for sufentanil (mean [10th-90th percentiles] 8.3 [3.1-15.1] microg/kg vs 12.5 [6.2-18.9] microg/kg; P = 0.002) and earlier possibility to discontinuation of the epidural sufentanil (11 [46%] vs 3 [13%]; P = 0.014) before the end of the 72-h study period. In the ketoprofen group, median (range) pain scores were lower during activity at 24 h (2 [0-5] vs 5 [0-7]; P = 0.01) and at 72 h (0 [0-3] vs 2 [0-6]; P = 0.033), and fewer children had inadequate pain relief during activity at 24 h (0 vs 5; P = 0.037). Children who received ketoprofen required fewer infusion rate adjustments (12 [4-20] vs 17 [6-42]; P = 0.016). In the ketoprofen group, the incidence of desaturation (1 [4%] vs 6 [26%]; P = 0.035) and fever (3 [12%] vs 11 [48%]; P = 0.008) was less than that in the placebo group. We conclude that ketoprofen improved postoperative pain in children. IMPLICATIONS: We compared the effect of the IV nonsteroidal antiinflammatory drug ketoprofen versus placebo as adjuvants to epidural opioid analgesia with sufentanil. The continuous IV nonsteroidal antiinflammatory drug improved pain after major surgery in children receiving an epidural opioid. Although ketoprofen reduced epidural sufentanil requirements, the incidence of opioid-related adverse effects was not changed.     

The analgesic effects of gabapentin in monitored anesthesia care for ear-nose-throat surgery

We investigated the efficacy and safety of gabapentin in rhinoplasty or endoscopic sinus surgery patients. Patients received either oral placebo or gabapentin 1200 mg 1 h before surgery. After standard premedication, 25 patients in each group received propofol, fentanyl, and local anesthesia at the operative site. Sedation was maintained by a continuous infusion of propofol adjusted according to the Ramsay scale. Sedation and pain scores were obtained at 5, 15, 30, 45, and 60 min during surgery and 30 min and 2, 4, 6, 8, 12, 16, 20, and 24 h after the procedure. Diclofenac 75 mg IM was administered as a rescue analgesic. Postoperative pain scores and intraoperative pain scores at 45 and 60 min were significantly lower in the gabapentin group. Fentanyl (122 +/- 40 microg versus 148 +/- 42 microg; P < 0.05) and diclofenac (33 +/- 53 mg versus 111 +/- 92 mg; P < 0.001) consumption was smaller and the time to first analgesic request (18 +/- 9 h versus 9 +/- 7 h; P < 0.001) was longer in the gabapentin group. A more frequent incidence of dizziness was found in the gabapentin (versus placebo) group (24% versus 4%, respectively). We conclude that gabapentin provided a significant analgesic benefit for intraoperative and postoperative pain relief in patients undergoing ambulatory rhinoplasty or endoscopic sinus surgery; however, dizziness may be a handicap for ambulatory use.     

The use of intravenous atropine after a saline infusion in the prevention of spinal anesthesia-induced hypotension in elderly patients

We investigated the efficacy of IV atropine for preventing spinal anesthesia-induced hypotension in elderly patients. Seventy-five patients undergoing transurethral prostate or bladder surgery were randomized to receive either placebo (n = 25), atropine 5 microg/kg (small-dose atropine, n = 25) or atropine 10 microg/kg (large-dose atropine, n = 25) after the induction of spinal anesthesia. All the patients received an IV infusion of 10 mL/kg 0.9% normal saline over 10 min before the induction of anesthesia. The systolic blood pressure decreased in all three groups after spinal anesthesia. There was a significant increase in the mean heart rate in both atropine groups as compared to the placebo group (placebo group: 78 bpm, 95% confidence interval [CI]: 76.6-78.5; small-dose atropine group: 86 bpm, 95% CI 83.9-88.8; large-dose atropine group: 97 bpm, 95% CI 94.5-100.3; P: = 0.001). There was a significant decrease in the incidence of hypotension in patients who received atropine (placebo group: 76%, small-dose atropine group: 52%, large-dose atropine group: 40%, P: = 0.03). The mean dose of ephedrine required was significantly decreased in the atropine groups (placebo group: 12.2 mg [SD= 10.5], small-dose atropine group: 7.4 mg [SD= 10.0], large-dose atropine group: 5.4 mg [SD= 8.7 mg], P: = 0.048). The total amount of IV fluid and number of patients requiring metaraminol in addition to 30 mg of ephedrine were not significantly different among the three groups. Significant side effects, such as confusion, ST segment changes or angina were not detected in any of the patients. We conclude that IV atropine may be a useful supplement to the existing methods in preventing hypotension induced by spinal anesthesia. Implications: IV atropine increases heart rate in a dose-dependent manner in elderly patients undergoing spinal anesthesia. It reduces the incidence of hypotension and the dose of ephedrine required. Small-dose atropine may be a useful supplement in preventing spinal anesthesia-induced hypotension in elderly patients.     

Perspectives on transdermal scopolamine for the treatment of postoperative nausea and vomiting

Transdermal scopolamine, a patch system that delivers 1.5 mg of scopolamine gradually over 72 hours following an initial bolus, was approved in the United States in 2001 for the prevention of postoperative nausea and vomiting (PONV) in adults. Scopolamine (hyoscine) is a selective competitive anatagonist of muscarinic cholinergic receptors. Low serum concentrations of scopolamine produce an antiemetic effect. Transdermal scopolamine is effective in preventing PONV versus placebo [relative risk (RR)=0.77, 95% confidence interval (CI), 0.61-0.98, P = 0.03] and a significantly reduced risk for postoperative nausea (RR=0.59, 95% CI, 0.48-0.73, P < 0.001), postoperative vomiting (RR=0.68, 95% CI, 0.61-0.76, P < 0.001), and PONV (RR 0.73, 95% CI, 0.60-0.88, P = 001) in the first 24 hours after the start of anesthesia.     

Effective treatment of laparoscopic cholecystectomy pain with intravenous followed by oral COX-2 specific inhibitor

In this multicenter, double-blinded, randomized, placebo-controlled study we evaluated the analgesic and opioid-sparing efficacy of a preoperative dose of i.v. parecoxib followed by oral valdecoxib in treating pain associated with elective laparoscopic cholecystectomy. Patients were randomized to receive a single i.v. dose of parecoxib 40 mg (n = 134) or placebo (n = 129) 30-45 min before induction of anesthesia. Six to 12 h after the i.v. dose, the parecoxib group received a single oral dose of valdecoxib 40 mg, followed by valdecoxib 40 mg qd on postoperative days 1-4, then 40 mg qd prn days 5-7. The placebo i.v. group received oral placebo on an identical schedule. All patients were allowed supplemental i.v. fentanyl as needed during the first 4 h postoperatively (T0-240 min) followed by hydrocodone 5 mg/acetaminophen 500 mg (Vicodin(R); 1-2 tablets orally every 4-6 h as needed). Patients taking parecoxib used 21% less fentanyl than those receiving placebo (P = 0.011). The mean area under the curve of pain intensity (PI) scores over time from T0-240 min was 55.2 for parecoxib and 61.2 for placebo (P = 0.083). At T180 and T240 min, mean PI score was 7.0 and 7.6 points lower in the parecoxib group, respectively (P < 0.02). Fewer patients on valdecoxib required supplemental analgesics (P < 0.05) after discharge. At T240 min and at day 7, Patient's and Physician's/Nurse's Global Evaluations were significantly better in the parecoxib/valdecoxib group (P < 0.05). Incidences of adverse events, adverse events causing withdrawal, and serious adverse events were less for parecoxib/valdecoxib than for placebo. The authors conclude that preoperative parecoxib is a valuable opioid-sparing adjunct to the standard of care for treating pain after laparoscopic cholecystectomy, and subsequent treatment with oral valdecoxib extends this clinical benefit. IMPLICATIONS: Parecoxib 40 mg i.v., 30-45 min preoperatively followed by oral valdecoxib 40 mg qd reduced opioid requirements and provided superior pain relief as well as improved patient global evaluation after laparoscopic cholecystectomy.     

The injectable cyclooxygenase-2-specific inhibitor parecoxib sodium has analgesic efficacy when administered preoperatively

Preoperative administration of analgesics may prevent or reduce hyperalgesia and inhibit inflammation and pain by reducing the synthesis of prostaglandins in response to surgical injury. We evaluated in this placebo-controlled study the analgesic efficacy and safety of single doses of parecoxib sodium (20, 40, and 80 mg IV) when administered before oral surgery. Efficacy assessments were recorded during the 24-h period after completion of surgery. All doses of parecoxib sodium were consistently and significantly superior to placebo as measured by time to rescue medication, proportion of patients requiring rescue medication, patient's global assessment, and pain intensity. There were no significant differences between the Parecoxib Sodium 40- and 80-mg groups, suggesting that the analgesic effect of preoperatively administered parecoxib sodium reaches a plateau at 40 mg in this model. Forty-eight percent of the Parecoxib Sodium 40-mg group required rescue medication in the 24-h study period, compared with 93% of patients in the Placebo group. Overall, there were fewer adverse events in parecoxib sodium-treated patients compared with placebo. These findings suggest that preoperative administration of parecoxib sodium, the injectable prodrug of the cyclooxygenase-2 specific inhibitor valdecoxib, is effective, safe, and well tolerated for treating postoperative pain.     

Dextromethorphan-associated epidural patient-controlled analgesia provides better pain- and analgesics-sparing effects than dextromethorphan-associated intravenous patient-controlled analgesia after bone-malignancy resection: a randomized, placebo-controlled, double-blinded study

Pain after bone malignancy surgery is intense and requires large amounts of analgesics. The augmented antinociceptive effects of dextromethorphan (DM), a N-methyl-D-aspartate receptor antagonist, were demonstrated previously. We assessed the use of postoperative patient-controlled epidural analgesia (PCEA) or IV patient-controlled analgesia (PCA) in patients undergoing surgery for bone malignancy under standardized combined general and epidural anesthesia with or without DM. Patients (n = 120) were randomly allocated to receive PCEA (ropivacaine 3.2 mg plus fentanyl 8 microg/dose) or IV-PCA (morphine 2 mg/dose) postoperatively, starting at subjective visual analog scale pain intensity >or=4 of 10 for up to 96 h. Placebo or DM 90 mg orally (30 patients/group/set) was given in a double-blinded manner before surgery and for 2 days afterwards. Diclofenac 75 mg IM was available as a rescue drug. DM patients used PCA and rated their pain >50% less than their placebo counterparts in each set, especially during the first 2 postoperative days (P < 0.01). Hourly and overall maximal pain intensity among PCEA patients was approximately 50% less than in the IV-PCA set (P < 0.01). Diclofenac was used 42% less (P < 0.01) by the PCA-DM patients compared with their placebo counterparts. Seven PCEA-DM and 11 IV-PCA-DM individuals reported having side effects compared with 44 in the PCEA-placebo and the IV-PCA-placebo groups (P < 0.01). Time to first ambulation was similar with both analgesia techniques but shorter among the DM-treated patients compared with the placebo recipients (1.5 +/- 0.8 versus 2.1 +/- 1.1 days, P = 0.02). Thus, DM afforded better pain control and reduced the demand for analgesics, augmented the PCEA effect versus IV-PCA, and was associated with minimal untoward effects in each analgesia set. DM patients ambulated earlier than placebo recipients. IMPLICATIONS: Patients undergoing bone-malignancy surgery under combined general and epidural anesthesia received randomly patient-controlled epidural analgesia (PCEA) or IV patient-controlled analgesia (PCA) postoperatively and dextromethorphan (DM) 90 mg or placebo double-blindly for 3 days (n = 30/group/set). The DM effect was recorded with minimal untoward effects: it afforded better pain control and reduced the demand for analgesics compared with the placebo, especially when associated with PCEA. DM patients ambulated earlier than placebo recipients.     

Simultaneous Assessment of Drug Interactions with Low- and High-Extraction Opioids: Application to Parecoxib Effects on the Pharmacokinetics and Pharmacodynamics of Fentanyl and Alfentanil

Background: Parecoxib is a parenteral cyclooxygenase-2 (COX-2) inhibitor intended for perioperative analgesia. It is an inactive prodrug hydrolyzed in vivo to the active inhibitor valdecoxib, a substrate for hepatic cytochrome P450 3A4 (CYP3A4); hence, a potential exists for metabolic interactions with other CYP3A substrates. This study determined the effects of parecoxib on the pharmacokinetics and pharmacodynamics of the CYP3A substrates fentanyl and alfentanil compared with the CYP3A inhibitor troleandomycin. Alfentanil is a low-extraction drug with a clearance that is highly susceptible to drug interactions; fentanyl is a high-extraction drug and, thus, is theoretically less vulnerable. We therefore also tested the hypothesis that the extraction ratio influences the consequence of altered hepatic metabolism of these opioids.

Methods: After Institutional Review Board-approved, written, informed consent was obtained, 12 22- to 40-yr-old healthy volunteers were enrolled in the study. The protocol was a randomized, double-blinded, balanced, placebo-controlled, three-session (placebo, parecoxib, or troleandomycin pretreatment) crossover. Subjects received both alfentanil (15 [mu]g/kg) and fentanyl (5 [mu]g/kg; 15-min intravenous infusion) 1 h after placebo, parecoxib (40 mg intravenously every 12 h), or troleandomycin (every 6 h). Study sessions were separated by 7 or more days. Opioid concentrations in venous blood were determined by liquid chromatography-mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental analysis. Opioid effects were determined by pupillometry, respiratory rate, and Visual Analog Scale scores.

Results: There were no significant differences between the placebo and parecoxib treatments in alfentanil or fentanyl plasma concentration, maximum observed plasma concentration, area under the plasma time-concentration time curve, clearance, elimination half-life, or volume of distribution. However, disposition of alfentanil, and to a lesser extent fentanyl, was significantly altered by troleandomycin. Clearances were reduced to 12% (0.64 +/- 0.25 ml [middle dot] kg-1 [middle dot] min-1) and 61% (9.35 +/- 3.07) of control (5.53 +/- 2.16 and 15.3 +/- 5.0) for alfentanil and fentanyl (P < 0.001). Pupil diameter versus time curves were similar between placebo and parecoxib treatments but were significantly different after troleandomycin.