Literature Reviews

Procedure-specific systematic review summary


Radical Prostatectomy 2012

Huang et al 2001

Preoperative oral rofecoxib does not decrease postoperative pain or morphine consumption in patients after radical prostatectomy: a prospective, randomized, double-blinded, placebo-controlled trial

Huang JJ, Taguchi A, Hsu H, Andriole Jr GL, Kurz A.

Journal of Clinical Anesthesia 2001;13(2):94–97

Derry and Moore 2012

Single dose oral celecoxib for acute postoperative pain in adults.

Derry S, Moore RA.

Cochrane Database Syst Rev 2012;3:CD004233

Xu et al 2013

Effect of postoperative analgesia on energy metabolism and role of cyclooxygenase-2 inhibitors for postoperative pain management after abdominal surgery in adults

Xu Z, Li Y, Wang J, Li J.

Clin J Pain 2013 Jan 16. [Epub ahead of print]

White et al 2011

The effects of oral ibuprofen and celecoxib in preventing pain, improving recovery outcomes and patient satisfaction after ambulatory surgery.

White PF, Tang J, Wender RH, Zhao M, Time M, Zaentz A, Yumul R, Sloninsky A, Naruse R, Kariger R, Webb T, Fermelia DE, Tsushima GK.

Anesth Analg 2011;112(2):323–329

Rømsing et al 2004

A systematic review of COX-2 inhibitors compared with traditional NSAIDs, or different COX-2 inhibitors for post-operative pain.

Rømsing J, Moiniche S.

Acta Anaesthesiol Scand 2004;48(5):525–546.

BACKGROUND: We have reviewed the analgesic efficacy of cyclooxygenase-2 (COX-2) inhibitors compared with traditional non-steroidal anti-inflammatory drugs (NSAIDs), different COX-2 inhibitors, and placebo in post-operative pain. METHODS: Randomized controlled trials were evaluated. Outcome measures were pain scores and demand for supplementary analgesia 0-24 h after surgery. RESULTS: Thirty-three studies were included in which four COX-2 inhibitors, rofecoxib 50 mg, celecoxib 200 and 400 mg, parecoxib 20, 40 and 80 mg, and valdecoxib 10, 20, 40, 80 mg were evaluated. Ten of these studies included 18 comparisons of rofecoxib, celecoxib, or parecoxib with NSAIDs. Rofecoxib 50 mg and parecoxib 40 mg provided analgesic efficacy comparable to that of the NSAIDs in the comparisons, and with a longer duration of action after dental surgery but possibly not after major procedures. Celecoxib 200 mg and parecoxib 20 mg provided less effective pain relief. Four studies included five comparisons of rofecoxib 50 mg with celecoxib 200 and 400 mg. Rofecoxib 50 mg provided superior analgesic effect compared with celecoxib 200 mg. Data on celecoxib 400 mg were too sparse for firm conclusions. Thirty-three studies included 62 comparisons of the four COX-2 inhibitors with placebo and the COX-2 inhibitors significantly decreased post-operative pain. CONCLUSION: Rofecoxib 50 mg and parecoxib 40 mg have an equipotent analgesic efficacy relative to traditional NSAIDs in post-operative pain after minor and major surgical procedures, and after dental surgery these COX-2 inhibitors have a longer duration of action. Besides, rofecoxib 50 mg provides superior analgesic effect compared with celecoxib 200 mg.

Maund et al 2011

Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs for the reduction in morphine-related side-effects after major surgery: a systematic review.

Maund E, McDaid C, Rice S, Wright K, Jenkins B, Woolacott N.

Br J Anaesth 2011;106(3):292–297

Harris et al 2001

Upper gastrointestinal safety evaluation of parecoxib sodium, a new parenteral cyclooxygenase-2-specific inhibitor, compared with ketorolac, naproxen, and placebo.

Harris SI, Kuss M, Hubbard RC, Goldstein JL

Clin Ther 2001;23(9):1422–1428.

BACKGROUND: Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of ulcers and upper gastrointestinal (GI) ulcer complications, which has been attributed to the inhibition of cyclooxygenase-1. These risks are usually increased in elderly populations. Parecoxib sodium is an injectable prodrug of the cyclooxygenase-2-specific inhibitor valdecoxib that has exhibited analgesic activity in previous trials. OBJECTIVE: The purpose of this study was to compare the GI safety and tolerability profile of parecoxib sodium with that of ketorolac, naproxen, and placebo in a 7-day endoscopic trial in elderly subjects. METHODS: This was a randomized, double-blind, double-dummy, placebo-controlled, parallel-group study. After a normal baseline endoscopy, healthy elderly subjects aged 66 to 75 years were randomized to receive i.v. parecoxib sodium (10 mg BID), oral naproxen (500 mg BID), or placebo for 7 days, or placebo for 2 days followed by i.v. ketorolac (15 mg QID) for 5 days. Endoscopy was performed again after 7 days. RESULTS: Among the first 17 subjects enrolled, ulcers were observed in all treatment groups except the parecoxib sodium group (ketorolac, 4/4 subjects; naproxen, 2/4 subjects; and placebo, 2/5 subjects). Four subjects in the ketorolac group and 1 subject in the naproxen group had multiple gastric ulcers or combined gastric and duodenal ulcers. Because of the unexpectedly high incidence of gastroduodenal ulcers observed, the study was terminated early and the randomization blind broken. CONCLUSION: These findings suggest that elderly patients may be at risk for GI ulceration even after short-term use of the conventional NSAIDs ketorolac and naproxen.

Noveck et al 2001

Parecoxib sodium does not impair platelet function in healthy elderly and non-elderly individuals. Two randomised, controlled trials.

Noveck RJ, Laurent A, Kuss M, Talwalker S, Hubbard RC.

Clin Drug Invest 2001;21(7):465–476.

Objective: To compare the effects of parecoxib sodium, an injectable prodrug of a cyclo-oxygenase-2-specific inhibitor, and ketorolac on platelet function and bleeding time in elderly individuals and non-elderly adults. Design and Setting: Double-blind, randomised, active- and placebo-controlled, parallel-group studies. Patients and Participants: Healthy men and women, between the ages of 65 and 95 years (62 elderly individuals) or 18 and 55 years (48 non-elderly individuals). Methods: Participants received placebo or active medication: parecoxib sodium 40mg twice daily intravenously for 8 days (both studies), ketorolac 15mg four times daily intravenously for 5 days (elderly individuals) or 30mg four times daily intravenously for 5 days (non-elderly individuals). Ex vivo platelet aggregation responses to arachidonate, collagen and adenosine diphosphate (ADP), bleeding time and serum thromboxane B (TxB) levels were measured. Results: In both studies, parecoxib sodium had little or no effect on arachidonate-induced platelet aggregation, whereas ketorolac caused statistically significant and sustained decreases in platelet aggregation throughout the entire drug administration period. Parecoxib sodium also had little or no effect on collagen- or ADP-induced aggregation compared with ketorolac. Although there was a high degree of variability in bleeding times, significant prolongation of bleeding times was observed only in the ketorolac groups in both studies. Parecoxib sodium had no effect on serum TxB concentrations in non-elderly individuals. In elderly individuals, ketorolac significantly and profoundly reduced TxB levels at all assessments, whereas parecoxib sodium showed less of a reduction. Conclusion: Although a direct correlation has not been proven, patients with reduced platelet function do appear to be at a higher risk of experiencing increased bleeding during surgery. Thus, the absence of effect on platelet aggregation and bleeding time observed in these studies suggests that parecoxib sodium is less likely to be associated with excessive bleeding during surgery, and therefore is potentially safer than ketorolac for use in patients undergoing surgery, irrespective of age.

Hegi et al 2004

Effect of rofecoxib on platelet aggregation and blood loss in gynaecological and breast surgery compared with diclofenac.

Hegi TR, Bombeli T, Seifert B, Baumann PC, Haller U, Zalunardo MP, Pasch T, Spahn DR.

Br J Anaesth 2004;92(4):523–531.

BACKGROUND: Non-selective cyclooxygenase (COX) inhibitors or non-steroidal anti- inflammatory drugs (NSAIDs) are frequently omitted for perioperative pain relief because of potential side-effects. COX-2-selective inhibitors may have a more favourable side-effect profile. This study tested the hypothesis that the COX-2-selective inhibitor rofecoxib has less influence on platelet function than the NSAID diclofenac in gynaecological surgery. In addition, analgesic efficacy and side-effects of the two drugs were compared. METHODS: In this single-centre, prospective, double-blind, active controlled study, women undergoing vaginal hysterectomy (n = 25) or breast surgery (n = 25) under general anaesthesia received preoperatively 50 mg of rofecoxib p.o. followed 8 and 16 h later by two doses of placebo or three doses of diclofenac 50 mg p.o. at the same time points. We assessed arachidonic acid-stimulated platelet aggregation before and 4 h after the first dose of study medication, estimated intraoperative blood loss, and haemoglobin loss until the first morning after surgery. Analgesic efficacy, use of rescue analgesics, and side-effects were also recorded. RESULTS: In the rofecoxib group, stimulated platelet aggregation was disturbed less (p = 0.02), and estimated intraoperative blood loss (p = 0.01) and the decrease in haemoglobin were lower (p = 0.01). At similar pain ratings, the use of anti-emetic drugs was less in the rofecoxib group (p = 0.03). CONCLUSION: Besides having a smaller effect on platelet aggregation, one oral dose of rofecoxib 50 mg given before surgery provided postoperative analgesia similar to that given by three doses of diclofenac 50 mg and was associated with less use of anti-emetics and less surgical blood loss in gynaecological surgery compared with diclofenac.

Bavbek et al 2004

Safety of selective COX-2 inhibitors in aspirin/nonsteroidal anti-inflammatory drug-intolerant patients: comparison of nimesulide, meloxicam, and rofecoxib.

Bavbek S, Celik G, Ozer F, Mungan D, Misirligil Z.

J Asthma 2004;41(1):67–75.

BACKGROUND: Intolerance to acetylsalicylic acid (ASA) and other nonsteroidal anti-inflammatory drugs (NSAIDs) is a crucial problem in clinical practice. There is, therefore, a need for safer NSAIDs in patients with analgesic intolerance. OBJECTIVE: To assess the safety of nimesulide, meloxicam, and rofecoxib, selective COX-2 inhibitors, in a group of ASA/NSAIDs-intolerant patients. METHOD: Tolerances to nimesulide, meloxicam, and rofecoxib were assessed by single-blind placebo-controlled oral challenges. One hundred twenty-seven subjects with history of adverse reaction to ASA/NSAIDs received oral challenges with nimesulide, 61 subjects were challenged with meloxicam, 51 subjects were challenged with rofecoxib, and 37 subjects were challenged with all three drugs. Placebos were given to all patients on the first day of the study. On the second day, one-fourth and three-fourths of the therapeutic doses of the active drugs (nimesulide 100 mg, meloxicam 7.5 mg, or rofecoxib 25 mg) were given at 60-minute intervals. There was at least a 3-day interval between challenge tests. Erythema, pruritus accompanied by erythema, urticaria/angioedema, rhinorrhea, nasal obstruction, sneezing, dyspnea, or cough associated with a decrease of at least 20% in the forced expiratory volume (FEV1) and hypotension were considered as positive reactions. RESULTS: Positive reactions to the nimesulide, meloxicam, and rofecoxib challenges were observed in 18/127 (14.3%), 5/61 (8.1%), and 1/51 (2.0%) patients, respectively. In each group of nine patients, there were two patients with asthma and four who developed skin type reactions and asthmatic reactions, respectively, to the nimesulide challenge. Among five patients who reacted to the meloxicam challenge, asthmatic type reactions were detected in two asthmatics. Only one urticarial type reaction was observed with rofecoxib challenge in one patient who presented with anaphylaxis to ASA/NSAIDs. All patients with asthma tolerated rofecoxib without any adverse effects. None of the patients reacted to the placebo. Among 37 patients challenged with all three drugs, 11 reacted to nimesulide, and one patient reacted only to meloxicam. Three patients reacted to more than one of the drugs tested, and one of them reacted to all drugs. CONCLUSION: This is the first placebo-controlled report comparing these three drugs. The results indicate that among these alternative drugs for ASA/NSAIDs-intolerant patients, rofecoxib seems to have the most favorable tolerability.

Nussmeier et al 2006

Safety and efficacy of the cyclooxygenase-2 inhibitors parecoxib and valdecoxib after noncardiac surgery.

Nussmeier NA, Whelton AA, Brown MT, Joshi GP, Langford RM, Singla NK, Boye ME, Verburg KM.

Anesthesiology 2006;104(3):518–526.

Background: Valdecoxib and its intravenous prodrug parecoxib are reported to increase thromboembolic risk after coronary artery bypass grafting. The authors conducted a randomized trial to examine their safety and analgesic efficacy in patients recovering from major noncardiac surgical procedures. Methods: The trial was randomized and double-blind, with 10 days of treatment and 30 days of follow-up. Patients (n = 1,062) received either parenteral parecoxib for 3 days and oral valdecoxib for the rest of the treatment period or placebo medications throughout. The frequency of predefined adjudicated postrandomization adverse events, including cardiovascular thromboembolism, renal dysfunction, gastroduodenal ulceration, and wound-healing complications, was assessed in each group. Secondary efficacy endpoints included patients' pain ratings, opioid analgesic consumption (recorded as morphine equivalents), and reports of opioid-related adverse effects. Results: Predefined adjudicated adverse events had similar frequencies among patients who received parecoxib and valdecoxib (2.7%) and placebo patients (3.2%) (P = 0.58), including cardiovascular thromboembolic events (1.0% in each group; P = 1.0). Placebo patients consumed more morphine equivalents (66.2 +/- 92.4 mg) than did patients receiving parecoxib and valdecoxib (43.2 +/- 65.7 mg) (P < 0.001). Placebo patients had higher mean pain ratings on each of study days 2-10 (P < 0.01) and reported more opioid-related symptom distress on days 2-6 (P < 0.01). Conclusions: Parecoxib and valdecoxib are useful adjuncts to opioids for the treatment of postoperative pain in noncardiac surgical patients. Further study will be required to determine the safety profile of parecoxib and valdecoxib administered to patients with known atherosclerotic disease after noncardiac surgery.

Schug 2006

The role of COX-2 inhibitors in the treatment of postoperative pain.

Schug SA.

J Cardiovasc Pharmacol 2006;47 Suppl 1:S82-86.

Postoperative pain requires treatment not only to provide comfort to patients but also to improve postoperative outcome. Anti-inflammatory compounds are an important component of multimodal analgesia in the postoperative period. The newer cyclooxygenase (COX)-2 inhibitors are as effective as classical nonsteroidal anti-inflammatory drugs (NSAIDs) in this setting. However, COX-2 inhibitors offer a number of advantages over NSAIDs when used to treat postoperative pain. These include a reduced incidence of gastrointestinal ulceration and no inhibitory effect on platelet function and thereby a reduced risk of blood loss. Other benefits are less impairment of bone healing and no induction of bronchospasm in patients with aspirin-sensitive asthma. Increased cardiovascular thromboembolic events by COX-2 inhibitors have been reported after coronary artery bypass graft surgery only, but in general, surgery studies the incidence of such complications was comparable to placebo. Overall, COX-2 inhibitors offer a number of advantages over classical NSAIDs in the postoperative pain setting, but require the same caution with regard to renal effects.

Schug et al 2009

Cardiovascular safety of the cyclooxygenase-2 selective inhibitors parecoxib and valdecoxib in the postoperative setting: an analysis of integrated data.

Schug SA, Joshi GP, Camu F, Pan S, Cheung R.

Anesth Analg 2009;108(1):299-307.

BACKGROUND: Studies of parecoxib, the inactive prodrug of the cyclooxygenase-2 selective inhibitor valdecoxib, and valdecoxib for postoperative pain relief in patients undergoing coronary artery bypass graft surgery revealed an increased risk of cardiovascular (CV) adverse events compared with placebo. We conducted this study to address whether parecoxib and valdecoxib increased CV risk in noncardiac surgery patients. METHODS: A pooled post hoc analysis was conducted using 2 large datasets: 17 controlled trials of parecoxib for noncardiac studies and 32 studies, including the 17 noncardiac parecoxib studies plus 15 studies of valdecoxib. The 32-study dataset provided 95% power to detect a twofold increase in the incidence of CV adverse events assuming a placebo group incidence of 1% (estimated from previous study data), and 69% power to detect a twofold increase from a 0.5% incidence. RESULTS: The incidence of total CV events for the 17 parecoxib studies was 0.44% (13 of 2966) in patients who received parecoxib and 0.37% (7 of 1915) in those receiving placebo (P > 0.20). In the analysis of 32 studies, the incidence of total CV events was 0.40% (21 of 5285) in the parecoxib/valdecoxib group compared with 0.50% (16 of 3226) in the placebo group (P > 0.20). No significant differences in the incidence of total or any individual CV event category were observed between the parecoxib or parecoxib/valdecoxib and placebo groups in the two analyses. When patients were stratified by number of baseline CV risk factors, no significant difference in CV events was detected in parecoxib/valdecoxib patients compared with placebo. CONCLUSIONS: In the largest analysis of the CV risk of cyclooxygenase selective inhibitors or nonsteroidal antiinflammatory drugs for perioperative pain management, parecoxib and valdecoxib were not found to increase the risk of CV adverse events after noncardiac surgery.

Lafrance and Miller 2009

Selective and non-selective non-steroidal anti-inflammatory drugs and the risk of acute kidney injury

Lafrance JP, Miller DR

Pharmacoepidemiol Drug Saf 2009; 18:923-31

Møiniche et al 2002

A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief: the role of timing of analgesia.

Møiniche S, Kehlet H, Dahl JB.

Anesthesiology 2002;96(3):725–741.

Nussmeier et al 2005

Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery.

Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, Boyce SW, Verburg KM.

N Engl J Med 2005;352(11):1081–1091.

Background Valdecoxib and its intravenous prodrug parecoxib are used to treat postoperative pain but may involve risk after coronary-artery bypass grafting (CABG). We conducted a randomized trial to assess the safety of these drugs after CABG. Methods In this randomized, double-blind study involving 10 days of treatment and 30 days of follow-up, 1671 patients were randomly assigned to receive intravenous parecoxib for at least 3 days, followed by oral valdecoxib through day 10; intravenous placebo followed by oral valdecoxib; or placebo for 10 days. All patients had access to standard opioid medications. The primary end point was the frequency of predefined adverse events, including cardiovascular events, renal failure or dysfunction, gastroduodenal ulceration, and wound-healing complications. Results As compared with the group given placebo alone, both the group given parecoxib and valdecoxib and the group given placebo and valdecoxib had a higher proportion of patients with at least one confirmed adverse event (7.4% in each of these two groups vs. 4.0% in the placebo group; risk ratio for each comparison, 1.9; 95% confidence interval, 1.1 to 3.2; p = 0.02 for each comparison with the placebo group). In particular, cardiovascular events (including myocardial infarction, cardiac arrest, stroke, and pulmonary embolism) were more frequent among the patients given parecoxib and valdecoxib than among those given placebo (2.0% vs. 0.5%; risk ratio, 3.7; 95% confidence interval, 1.0 to 13.5; p = 0.03). Conclusions The use of parecoxib and valdecoxib after CABG was associated with an increased incidence of cardiovascular events, arousing serious concern about the use of these drugs in such circumstances.

EMEA 2004a

Committee for Medicinal Products for Human Use, European Public Assessment Report (EPAR): Bextra.


Available at

O'Connor et al 2003

Hepatocellular damage from non-steroidal anti-inflammatory drugs.

O'Connor N, Dargan PI, Jones AL.

QJM 2003;96(11):787–791.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the management of rheumatological disorders, and as analgesics and antipyretics. Hepatotoxicity is an uncommon, but potentially lethal complication, which usually occurs within 12 weeks of starting therapy. It can occur with all NSAIDs, but appears to be more common with diclofenac and particularly sulindac. Female patients aged >50 years, with autoimmune disease, and those on other potentially hepatotoxic drugs, appear to be particularly susceptible. Liver function test abnormalities generally settle within 4-6 weeks of stopping the causative drug. However, some patients may develop acute liver failure and successful orthotopic liver transplantation may be undertaken in such patients. Recent in vitro animal studies have shown that the mechanism of diclofenac toxicity relates both to impairment of ATP synthesis by mitochondria, and to production of active metabolites, particularly n,5-dihydroxydiclofenac, which causes direct cytotoxicity. Mitochondrial permeability transition (MPT) has also been shown to be important in diclofenac-induced liver injury, resulting in generation of reactive oxygen species, mitochondrial swelling and oxidation of NADP and protein thiols. Physicians and hepatologists must be vigilant to the hepatotoxic potential of any NSAID, as increased awareness, surveillance and reporting of these events will lead to a better understanding of the risk factors and the pathophysiology of NSAID-related hepatotoxicity.

Cheng et al 2004

Cyclooxygenases, the kidney, and hypertension.

Cheng HF, Harris RC.

Hypertension 2004;43(3):525–530.

Selective cyclooxygenase (COX)-2 inhibitors that are in widespread clinical use were developed to avoid side effects of conventional NSAIDs, including gastrointestinal and renal toxicity. However, COX-2 is constitutively expressed in the kidney and is highly regulated in response to alterations in intravascular volume. COX-2 metabolites have been implicated in maintenance of renal blood flow, mediation of renin release, and regulation of sodium excretion. COX-2 inhibition may transiently decrease urine sodium excretion in some subjects and induce mild to moderate elevation of blood pressure. Furthermore, in conditions of relative intravascular volume depletion and/or renal hypoperfusion, interference with COX-2 activity can have deleterious effects on maintenance of renal blood flow and glomerular filtration rate. In addition to physiological regulation of COX-2 expression in the kidney, increased renal cortical COX-2 expression is seen in experimental models associated with altered renal hemodynamics and progressive renal injury (decreased renal mass, poorly controlled diabetes), and long-term treatment with selective COX-2 inhibitors ameliorates functional and structural renal damage in these conditions.

Harris 2002

Cyclooxygenase-2 inhibition and renal physiology.

Harris RC, Jr.

Am J Cardiol 2002;89(6A):10D–17D.

In the adult mammalian kidney, high levels of cyclooxygenase (COX)-2 expression can be detected in the macula densa and associated cortical thick ascending limb cells and medullary interstitial cells. In the renal cortex, COX-2 expression increases in high renin states, and selective COX-2 inhibitors significantly decrease plasma renin levels. In the medullary region of the kidney, the expression of COX-2 increases in response to a high-salt diet and water deprivation. The most important prostanoids in the kidney are prostaglandin (PG)I(2), or prostacyclin, and PGE(2). PGE(2) diminishes sodium reabsorption; thereby, its inhibition results in sodium retention that can manifest clinically in a variety of ways, such as peripheral edema, increased blood pressure (mainly in treated hypertensive patients), weight gain, and occasionally deterioration of heart failure. PGI(2) increases potassium secretion. As such, its inhibition can result in hyperkalemia, particularly in patients with underlying renal insufficiency. PGI(2) is also a potent vasodilator and helps maintain renal perfusion in conditions of decreased actual or effective circulating volume; its inhibition in such patients can result in acute renal failure. A variety of studies has been conducted to examine the effects of celecoxib and rofecoxib on renal function. These incorporate various study designs directly, making it virtually impossible to compare data across studies. It is apparent from such studies, coupled with published case reports, that the impact of both celecoxib and rofecoxib on renal function (including development of edema and hypertension) is similar to that of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). Studies comparing the 2 COX-2 inhibitors conflict in their interpretation. Overall, the data suggest similar effects on renal function among all NSAIDs when used at comparable doses.

Blomme et al 2003

Selective cyclooxygenase-2 inhibition does not affect the healing of cutaneous full-thickness incisional wounds in SKH-1 mice.

Blomme EA, Chinn KS, Hardy MM, Casler JJ, Kim SH, Opsahl AC, Hall WA, Trajkovic D, Khan KN, Tripp CS

Br J Dermatol 2003;148(2):211–223.

BACKGROUND: The inducible cyclooxygenase-2 (COX-2) enzyme is upregulated in inflammatory diseases, as well as in epithelial cancers, and has an established role in angiogenesis and tissue repair. OBJECTIVE: Because of these physiological effects and the widespread use of the selective COX-2 inhibitor, celecoxib, we wanted to determine if inhibition of COX-2 would affect incisional skin wound healing. METHODS: Using a cutaneous full-thickness, sutured, incisional wound model in hairless SKH-1 mice, we evaluated the role of COX-2 in the wound healing process by comparing the effects of a nonselective COX inhibitor, diclofenac, with a selective COX-2 inhibitor, SC-791. Healing was monitored for up to 28 days postincision histologically and for recovery of wound strength. RESULTS: COX-2 expression was observed over the first week of healing, peaking at day 3 and was not affected by treatment with the selective COX-2 or nonselective COX inhibitors. Infiltrating macrophages, as well as keratinocytes and dermal fibroblasts at the wound site, expressed COX-2. Neither selective COX-2, nor nonselective COX inhibition had a significant effect on the macroscopic or microscopic morphology of the wounds, whereas dexamethasone treatment resulted in epidermal and granulation tissue atrophy. In addition, neither selective COX-2, nor nonselective COX inhibition altered keratinocyte proliferation and differentiation, dermal angiogenesis or the recovery of wound tensile strength, whereas dexamethasone reduced the tensile strength of the wounds by 30-38% throughout the healing period. CONCLUSIONS: These data indicate that selective COX-2 inhibition does not affect the healing of surgical skin wounds.

Waldron et al 2013

Impact of perioperative dexamethasone on postoperative analgesia and side-effects: systematic review and meta-analysis.

Waldron NH, Jones CA, Gan TJ, Allen TK, Habib AS.

Br J Anaesth 2013;110(2):191–200

Henzi et al 2000

Dexamethasone for the prevention of postoperative nausea and vomiting: a quantitative systematic review.

Henzi I, Walder B, Tramér MR.

Anesth Analg 2000;90:186–194.

The role of dexamethasone in the prevention of postoperative nausea and vomiting (PONV) is unclear. We reviewed efficacy and safety data of dexamethasone for prevention of PONV. A systematic search (MEDLINE, EMBASE, Cochrane Library, hand searching, bibliographies, all languages, up to April 1999) was done for full reports of randomized comparisons of dexamethasone with other antiemetics or placebo in surgical patients. Relevant end points were prevention of early PONV (0 to 6 h postoperatively), late PONV (0 to 24 h), and adverse effects. Data from 1,946 patients from 17 trials were analyzed: 598 received dexamethasone; 582 received ondansetron, granisetron, droperidol, metoclopramide, or perphenazine; 423 received a placebo; and 343 received a combination of dexamethasone with ondansetron or granisetron. With placebo, the incidence of early and late PONV was 35% and 50%, respectively. Sixteen different regimens of dexamethasone were tested, most frequently, 8 or 10 mg IV in adults, and 1 or 1.5 mg/kg IV in children. With these doses, the number needed to treat to prevent early and late vomiting compared with placebo in adults and children was 7.1 (95% CI 4.5 to 18), and 3.8 (2.9 to 5), respectively. In adults, the number needed to treat to prevent late nausea was 4.3 (2.3 to 26). The combination of dexamethasone with ondansetron or granisetron further decreased the risk of PONV; the number needed to treat to prevent late nausea and vomiting with the combined regimen compared with the 5-HT3 receptor antagonists alone was 7.7 (4.8 to 19) and 7.8 (4.1 to 66), respectively. There was a lack of data from comparisons with other antiemetics for sensible conclusions. There were no reports on dexamethasone-related adverse effects. IMPLICATIONS: When there is a high risk of postoperative nausea and vomiting, a single prophylactic dose of dexamethasone is antiemetic compared with placebo, without evidence of any clinically relevant toxicity in otherwise healthy patients. Late efficacy seems to be most pronounced. It is very likely that the best prophylaxis of postoperative nausea and vomiting currently available is achieved by combining dexamethasone with a 5-HT3 receptor antagonist. Optimal doses of this combination need to be identified.

Apfel et al 2004

A factorial trial of six interventions for the prevention of postoperative nausea and vomiting.

Apfel CC, Korttila K, Abdalla M, Kerger H, Turan A, Vedder I, Zernak C, Danner K, Jokela R, Pocock SJ, Trenkler S, Kredel M, Biedler A, Sessler DI, Roewer N.

N Engl J Med 2004;350(24):2441–2451.

BACKGROUND: Untreated, one third of patients who undergo surgery will have postoperative nausea and vomiting. Although many trials have been conducted, the relative benefits of prophylactic antiemetic interventions given alone or in combination remain unknown. METHODS: We enrolled 5199 patients at high risk for postoperative nausea and vomiting in a randomized, controlled trial of factorial design that was powered to evaluate interactions among as many as three antiemetic interventions. Of these patients, 4123 were randomly assigned to 1 of 64 possible combinations of six prophylactic interventions: 4 mg of ondansetron or no ondansetron; 4 mg of dexamethasone or no dexamethasone; 1.25 mg of droperidol or no droperidol; propofol or a volatile anesthetic; nitrogen or nitrous oxide; and remifentanil or fentanyl. The remaining patients were randomly assigned with respect to the first four interventions. The primary outcome was nausea and vomiting within 24 hours after surgery, which was evaluated blindly. RESULTS: Ondansetron, dexamethasone, and droperidol each reduced the risk of postoperative nausea and vomiting by about 26 percent. Propofol reduced the risk by 19 percent, and nitrogen by 12 percent; the risk reduction with both of these agents (i.e., total intravenous anesthesia) was thus similar to that observed with each of the antiemetics. All the interventions acted independently of one another and independently of the patients' baseline risk. Consequently, the relative risks associated with the combined interventions could be estimated by multiplying the relative risks associated with each intervention. Absolute risk reduction, though, was a critical function of patients' baseline risk. CONCLUSIONS: Because antiemetic interventions are similarly effective and act independently, the safest or least expensive should be used first. Prophylaxis is rarely warranted in low-risk patients, moderate-risk patients may benefit from a single intervention, and multiple interventions should be reserved for high-risk patients.

Ho et al 2006

Gabapentin and postoperative pain--a systematic review of randomized controlled trials

Ho KY, Gan TJ, Habib AS

Pain. 2006 Dec 15;126(1-3):91-101. Epub 2006 Jul 18

The objective of this systematic review was to evaluate the efficacy and tolerability of perioperative gabapentin administration for the control of acute postoperative pain. We searched Medline (1966-2006), the Cochrane Library (2006), Scopus, CINAHL and bibliographies from clinical trials and review articles. We included randomized controlled trials (RCTs) comparing gabapentin with inactive controls in surgical patients. Sixteen valid RCTs were included. Weighted mean difference (WMD) for postoperative pain intensity (0-100 mm visual analogue scale) was -16.55 mm at 6 h and -10.87 mm at 24 h for treatment with a single preoperative dose of gabapentin 1200 mg. Cumulative opioid consumption at 24 h was also significantly decreased with gabapentin (WMD, -27.90 mg). When gabapentin was administered at doses less than 1200 mg, pain intensity was also lower at 6 h (WMD, -22.43 mm) and 24 h (WMD, -13.18 mm). Cumulative 24 h opioid consumption was also lower (WMD, -7.25 mg). Gabapentin was associated with an increased risk of sedation (Peto OR 3.86; 95% CI 2.50-5.94) but less opioid-related side effects such as vomiting (Peto OR 0.58; 95% CI 0.39-0.86) and pruritus (Peto OR 0.27; 95% CI 0.10-0.74). In conclusion, gabapentin has an analgesic and opioid-sparing effect in acute postoperative pain management when used in conjunction with opioids.

Peng et al 2007

Use of gabapentin for perioperative pain control -- a meta-analysis

Peng PW, Wijeysundera DN, Li CC.

Pain Res Manag 2007; 12:85-92

Borazan et al 2010

Effects of preoperative oral melatonin medication on postoperative analgesia, sleep quality, and sedation in patients undergoing elective prostatectomy: A randomized clinical trial

H, Tuncer S, Yalcin N, Erol A, Otelcioglu S.

Journal of Anesthesia 2010;24(2):155–160

Snijdelaar et al 2004

Effects of perioperative oral amantadine on postoperative pain and morphine consumption in patients after radical prostatectomy: results of a preliminary study

Snijdelaar DG, Koren G, Katz J.

Anesthesiology 2004;100(1):134–141

Maysonet al 2000

Premedication with low dose oral clonidine does not enhance postoperative analgesia of intrathecal morphine

Mayson KV, Gofton EA, Chambers KG.

Can J Anaesth 2000;47(8):752–7

PURPOSE: A number of studies have demonstrated that perioperative intravenous, intrathecal, and epidural clonidine enhance postoperative analgesia. The results of previous studies on the usefulness of oral clonidine on enhancing postoperative analgesia have been mixed. The effect of a single preoperative dose of oral clonidine on postoperative analgesia was assessed in this study. METHODS: Forty-three male patients undergoing radical prostectomy were randomized to receive either 3 microg x kg(-1) clonidine or placebo po 90 min prior to surgery. All patients received isobaric 15 mg bupivacaine and intrathecal 5 microg x kg morphine, followed by a standardized general anesthetic, consisting of thiopental, sufentanil, rocuronium, isoflurane, oxygen and air. Postoperatively, PCA morphine use and visual analogue pain scores were recorded for the first 48 hr. The incidence and severity of side effects such as sedation, nausea, and pruritus were assessed, as well as patient satisfaction. Usage of PCA morphine was compared. RESULTS: There was no difference in total morphine requirements between the placebo and oral clonidine groups, nor in six hourly morphine usage (P = 0.96). Second, there was no difference in visual analogue pain scores, or the incidence of side effects. Patient satisfaction was high in both groups and again, no differences between groups was noted. CONCLUSIONS: Oral clonidine 3 microg x kg(-1) as a premedication does not prolong the effect of intrathecal morphine: there was no difference in PCA morphine requirements (P = 0.96). Clonidine did not effect the incidence or severity of nausea or pruritus.

Lukasewycz et al 2010

Does a perioperative belladonna and opium suppository improve postoperative pain following robotic assisted laparoscopic radical prostatectomy? Results of a single institution randomized study

Lukasewycz S, Holman M, Kozlowski P, Porter CR, Odom E, Bernards C, Neil N, Corman JM.

The Canadian Journal of Urology 2010;17(5):5377–5382

Guazzoni et al 2006

Intra- and peri-operative outcomes comparing radical retropubic and laparoscopic radical prostatectomy: results from a prospective, randomised, single-surgeon study

Guazzoni G, Cestari A, Naspro R, Riva M, Centemero A, Zanoni M, Rigatti L, Rigatti P.

European Urology 2006;50(1):98–104

Greenberg et al 2000

A new cyclooxygenase-2 inhibitor, rofecoxib (VIOXX), did not alter the antiplatelet effects of low-dose aspirin in healthy volunteers.

Greenberg HE, Gottesdiener K, Huntington M, Wong P, Larson P, Wildonger L, Gillen L, Dorval E, Waldm

J Clin Pharmacol 2000;40(12 Pt 2):1509–1515.

The present study examined whether rofecoxib (VIOXX), a new specific inhibitor of cyclooxygenase-2 (COX-2), would interfere with the desired antiplatelet effects of aspirin. Thus, the effects of rofecoxib on inhibition of ex vivo serum-generated thromboxane B2 (TXB2) and platelet aggregation by low doses (81 mg) of aspirin were examined in healthy volunteers. This was a double-blind, randomized, placebo-controlled, parallel study of two treatment groups (n=12 per group) in which subjects received 50 mg of rofecoxib or placebo for 10 days in a blinded fashion. Subjects also received 81 mg aspirin once on each of days 4 through 10 in an open-label fashion. Blood for measurement of serum TXB2 production and platelet aggregation studies was collected on day 1 (prior to rofecoxib/placebo), on day 4 (prior to aspirin), and on day 10 (before and 4 hours following the seventh dose of aspirin). Platelet-derived serum TXB2 (COX-1 assay) was measured in blood clotted for 1 hour at 37oC. Platelet aggregation was independently induced employing 1 mM arachidonic acid and 1 µg/ml collagen as agonists. Rofecoxib administered alone had no significant effect on serum TXB2 production or platelet aggregation (day 4). TXB2 production was inhibited 98.4% by aspirin coadministered with either rofecoxib or placebo (day 10). Similarly, platelet aggregation induced by arachidonic acid was inhibited 93.7% and 93.5% by aspirin coadministered with either rofecoxib or placebo, respectively (day 10). The comparable values for inhibition of collagen-induced platelet aggregation were 86.8% and 90.8%, respectively. No important clinical or laboratory adverse experiences were observed. In conclusion, rofecoxib alone (50 mg QD for 4 days) did not inhibit serum TXB2 production or platelet aggregation. In addition, rofecoxib (50 mg QD for 10 days) did not alter the antiplatelet effects of low-dose aspirin (inhibition of platelet aggregation and TXB2 production). Rofecoxib was generally well tolerated when administered alone or in combination with low-dose aspirin.

Schug et al 2009

Cardiovascular safety of the cyclooxygenase-2 selective inhibitors parecoxib and valdecoxib in the postoperative setting: an analysis of integrated data.

Schug SA, Joshi GP, Camu F, et al.

Anesth Analg 2009; 108:299-307

Mazaris et al 2008

Use of nonsteroidal anti-inflammatory drugs after radical retropubic prostatectomy: a prospective, randomized trial

Mazaris EM, Varkarakis I, Chrisofos M, Skolarikos A, Ioannidis K, Dellis A, Papatsoris A, Deliveliotis C.

Urology 2008;72(6):1293–1297

Ormiston et al 1981

The comparative effectiveness of tiaprofenic acid and aspirin in the treatment of post-prostatectomy pain

Ormiston MC, Vaughton KC, Thornton EJ

British Journal of Clinical Practice 1981;35(10):360–362

Barden et al 2004

Single dose oral diclofenac for postoperative pain.

Barden J, Edwards J, Moore RA, McQuay HJ.

Cochrane Database Syst Rev 2004(2):CD004768.

BACKGROUND: Diclofenac is a benzene-acetic acid derivative that acts, like other NSAIDs, by inhibiting cyclo-oxygenase isoforms that mediate the body's production of the prostaglandins implicated in pain and inflammation. Diclofenac is widely available as a sodium or potassium salt. Diclofenac potassium tablets are known as 'immediate-release' diclofenac as absorption takes place in the gastrointestinal tract whereas 'delayed-release' (enteric-coated) diclofenac tablets resist dissolution until reaching the duodenum. An existing review showed that diclofenac was an effective treatment for acute postoperative pain but did not address the distinction between potassium and sodium salts due to lack of data. The aim of this update is to gather and add appropriate information published subsequently and, data permitting, examine any potential differences between the two different diclofenac formulations. OBJECTIVES: To assess single dose oral diclofenac for the treatment of acute postoperative pain and determine whether there are differences between the different formulations. SEARCH STRATEGY: We searched the Cochrane Library (Issue 2, 2003), MEDLINE (1966 to May 1996), EMBASE (1980 to 1996), Biological Abstracts (1985 to 2003), the Oxford Pain Relief Database (1950 to 1994), PubMed (1996 to 2003) and reference lists of articles. SELECTION CRITERIA: Randomised, double-blind, placebo-controlled clinical trials of single dose, oral diclofenac sodium or diclofenac potassium for acute postoperative pain in adults. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trials for inclusion in the review, quality and extracted data. The area under the pain relief versus time curve was used to derive the proportion of patients prescribed diclofenac or placebo with at least 50% pain relief over four to six hours using validated equations. The number needed to treat (NNT) was calculated. Information on adverse effects was also collected. MAIN RESULTS: One additional trial was included and added to the six trials included in the original review. All seven trials provided data for quantitative analysis: 581 patients were treated with diclofenac and 364 were treated with placebo. The NNT for at least 50% relief over four to six hours with diclofenac 25 mg, 50 mg and 100 mg compared with placebo was 2.8 (95% CI 2.1 to 4.3), 2.3 (2.0 to 2.7) and 1.9 (1.6 to 2.2) respectively. Though higher doses produced lower (better) NNTs, statistical significance was not achieved. There was no significant difference between diclofenac 50 mg and placebo in the proportion of patients experiencing dizziness, headache, nausea or vomiting. The weighted median duration of analgesia was 2 hours for placebo, 6.7 hours for diclofenac 50 mg and 7.2 hours for diclofenac 100 mg. Sensitivity analyses for drug formulation, pain model, trial size and quality did not reveal any statistically significant differences. REVIEWERS' CONCLUSIONS: Oral diclofenac is an effective single-dose treatment for moderate to severe postoperative pain. There was no significant difference between diclofenac and placebo in the incidence of adverse effects, or between diclofenac sodium and potassium, different pain models, smaller and larger trials and trials of higher and lower quality.

Marret et al 2005

Effects of nonsteroidal antiinflammatory drugs on patient-controlled analgesia morphine side effects: meta-analysis of randomized controlled trials.

Marret E, Kurdi O, Zufferey P, Bonnet F.

Anesthesiology 2005;102(6):1249–1260.

Nonsteroidal antiinflammatory drugs (NSAIDs) are commonly combined with intravenous morphine patient-controlled analgesia to relieve postoperative pain. NSAIDs have a documented 30-50% sparing effect on morphine consumption. However, most of the studies have not demonstrated a decrease in morphine adverse effects. A meta-analysis of randomized controlled trials was performed to evaluate the risk of morphine adverse effects in patients treated with NSAIDs. Twenty-two prospective, randomized, double-blind studies including 2,307 patients were selected. NSAIDs decreased significantly postoperative nausea and vomiting by 30%, nausea alone by 12%, vomiting alone by 32% and sedation by 29%. A regression analysis yielded findings indicating that morphine consumption was positively correlated with the incidence of nausea and vomiting. Pruritus, urinary retention, and respiratory depression were not significantly decreased by NSAIDs.

Schlachta et al 2007

Optimizing recovery after laparoscopic colon surgery (ORAL-CS): effect of intravenous ketorolac on length of hospital stay.

Schlachta CM, Burpee SE, Fernandez C, Chan B, Mamazza J, Poulin EC.

Surg Endosc 2007;21(12):2212-2219.

BACKGROUND: The objective of this study was to determine if intravenous ketorolac can reduce ileus following laparoscopic colorectal surgery, thus shortening hospital stay. METHODS: This was a prospective, randomized, double-blind, placebo-controlled, clinical trial of patients undergoing laparoscopic colorectal resection and receiving morphine patient controlled analgesia (PCA) and either intravenous ketorolac (group A) or placebo (group B), for 48 h after surgery. Daily assessments were made by a blinded assistant for level of pain control. Diet advancement and discharge were decided according to strictly defined criteria. RESULTS: From October 2002 to March 2005, 190 patients underwent laparoscopic colorectal surgery. Of this total, 84 patients were eligible for this study and 70 consented. Another 26 patients were excluded, leaving 22 patients in each group. Two patients who suffered anastomotic leaks in the early postoperative period were excluded from further analysis. Median length of stay for the entire study was 4.0 days, with significant correlation between milligrams of morphine consumed and time to first flatus (r = 0.422, p = 0.005), full diet (r = 0.522, p < 0.001), and discharge (r = 0.437, p = 0.004). There we no differences between groups in age, body mass index, or operating time. Patients in group A consumed less morphine (33 +/- 31 mg versus 63 +/- 41 mg, p = 0.011), and had less time to first flatus (median 2.0 days versus 3.0 days, p < 0.001) and full diet (median 2.5 days versus 3.0 days, p = 0.033). The reduction in length of stay was not significant (mean 3.6 days versus 4.5 days, median 4.0 days versus 4.0 days, p = 0.142). Pain control was superior in group A. Three patients required readmission for treatment of five anastomotic leaks (4 in group A versus 1 in group B, p = 0.15). Two of them underwent reoperation. CONCLUSIONS: Intravenous ketorolac was efficacious in improving pain control and reducing postoperative ileus when anastomotic leaks were excluded. This simple intervention shows promise in reducing hospital stay, although the outcome was not statistically significant. The high number of leaks is inconsistent with this group's experience and is of concern.

Ng et al 2002a

Does the opioid-sparing effect of rectal diclofenac following total abdominal hysterectomy benefit the patient?

Ng A, Parker J, Toogood L, Cotton BR, Smith G.

Br J Anaesth 2002;88(5):714–716.

BACKGROUND: The aim of this prospective, double-blind, randomized, placebo-controlled clinical trial was to investigate the opioid-sparing effects of rectal diclofenac following total abdominal hysterectomy. METHODS: Forty ASA I-II patients, aged 20-60 yr, were randomized to receive identical-looking suppositories of either diclofenac 75 mg or placebo, twice daily. All patients were given a standardized anaesthetic, with intravenous morphine via a patient-controlled analgesia device and either diclofenac or placebo for postoperative analgesia. RESULTS: The median 24 h morphine consumption (interquartile range) was significantly higher (P=0.02) in the placebo group [59 (45-85) mg] than in the diclofenac group [31 (14-65) mg]. In comparison with the placebo group, there were significant reductions in total pain score in the diclofenac group at rest (P=0.04) and on movement (P<0.01). Total (SD) sedation score was significantly lower (P=0.04) in the diclofenac group [90 (73) mm] than in the placebo group [148 (89) mm]. Total (interquartile range) nausea score was significantly lower (P<0.01) in the diclofenac group [14 (0-53) mm] than in the placebo group [64 (30-109) mm]. There was no significant difference between the two groups of patients in episodes of vomiting or number of rescue antiemetics. CONCLUSIONS: Rectal diclofenac reduces morphine consumption, improves postoperative analgesia, and reduces the incidence of adverse effects such as sedation and nausea.

Bricker et al 1987

Peri-operative blood loss and non-steroidal anti-inflammatory drugs: an investigation using diclofenac in patients undergoing transurethral resection of the prostate

Bricker S, Savage M, Hanning C.

Eur J Anaesthesiol 1987;4(6):429–434.

Peri-operative blood loss was compared in a prospective, randomized double-blind study between two groups of patients undergoing transurethral prostatectomy (TURP) under spinal (subarachnoid) analgesia: the first received the non-steroidal anti-inflammatory drug diclofenac sodium, the second group received placebo. The total blood loss and the blood loss per gram of prostate resected did not differ significantly. Some 80% of patients were completely pain free at 8 and 24 h post-operation, and low pain scores recorded by the remaining 20% of patients supported the conclusion that TURP performed under spinal analgesia is not commonly associated with severe post-operative pain.

Blackburn et al 1995

Balanced analgesia with intravenous ketorolac and patient-controlled morphine following lower abdominal surgery.

Blackburn A, Stevens JD, Wheatley RG, Madej TH, Hunter D.

J Clin Anesth 1995;7(2):103.

STUDY OBJECTIVE: To investigate the efficacy, opioid-sparing effects and any reduction in adverse events of a continuous intravenous (i.v.) infusion of ketorolac following lower abdominal surgery. DESIGN: Randomized, double-blind, placebo-controlled, parallel-group study. SETTING: Inpatient elective gynecologic surgical patients. PATIENTS: 60 ASA physical status I or II patients aged 18 to 70 years scheduled for elective abdominal hysterectomy. INTERVENTIONS: Following standardized preparation and anesthesia, continuous i.v. infusions of either ketorolac or placebo were administered for 24 hours postoperatively with a patients' standardized postoperative protocol. Supplementary analgesia was administered by an i.v. patient-controlled analgesia (PCA) system. MEASUREMENTS AND MAIN RESULTS: A significantly lower proportion of the patients in the ketorolac group (6%) rated their pain at 24 hours as moderate or severe compared with patients in the placebo group (34%) (p = 0.04). Mean 24-hour morphine consumption was significantly lower in the ketorolac group (43 mg; SEM 5 mg) compared with the placebo group (55 mg SEM 5 mg) (p = 0.02). There was no significant difference in the incidence of postoperative hypoxemia between the groups with respect to mean times per hour spent with oxygen saturation (SPO2) less than 85%, more than 85% but less than 90%, or more than 90% but less than 94%, mean hourly SPO2, or the incidence and duration of severe hypoxemic episodes. Nausea and vomiting were the only significant adverse events, and they occurred in 30% of patients in both groups. CONCLUSION: Intravenous infusion of ketorolac combined with morphine delivered via a PCA device would appear to be a valuable method of providing balanced analgesia following lower abdominal surgery.

Greer et al 1999

Effect of ketorolac and low-molecular-weight heparin individually and in combination on haemostasis.

Greer I, Gibson J, Young A, Johnstone J, Walker I.

Blood Coagul Fibrinolysis 1999;10(6):367–373.

Low-molecular-weight heparins, when used in surgical patients for thromboprophylaxis, may be used concurrently with ketorolac, a non-steroidal anti-inflammatory drug that is used for analgesia. Because these two agents can influence the haemostatic system, it is important to identify any such effect. The haemostatic interaction between dalteparin and ketorolac was assessed in a double-blind, placebo-controlled, randomized, crossover study of healthy male volunteers each given all four combinations of ketorolac/placebo and dalteparin/placebo. The effect of ketorolac and dalteparin on haemostasis was assessed by measuring in-vitro platelet aggregation, anti-factor-Xa, activated partial thromboplastin times and skin bleeding time. The results were analysed for evidence of an interaction between ketorolac and dalteparin. Ketorolac inhibited platelet aggregation in whole blood and platelet-rich plasma. The administration of dalteparin led to a significant increase in levels of anti-factor-Xa and a significant prolongation in the activated partial thromboplastin time, although it remained within the range of the normal population. There was no evidence of any interaction between ketorolac and dalteparin with regard to platelet aggregation, anti-factor-Xa activity or activated partial thromboplastin time. The administration of ketorolac significantly prolonged the skin bleeding time. There was a significant interaction between ketorolac and dalteparin to prolong the bleeding time, although dalteparin alone had no effect on bleeding time. There was an interaction between ketorolac and dalteparin, which affected bleeding times. Such an interaction raises the possibility of haemorrhagic complications developing perioperatively when these agents are used concomitantly. Further studies are required to examine the clinical importance of this interaction.

Elia et al 2005

Ketamine and postoperative pain--a quantitative systematic review of randomised trials.

Elia N, Tramer MR.

Pain 2005;113(1-2):61–70.

Ketamine, an N-methyl-D-aspartate receptor antagonist, is known to be analgesic and to induce psychomimetic effects. Benefits and risks of ketamine for the control of postoperative pain are not well understood. We systematically searched for randomised comparisons of ketamine with inactive controls in surgical patients, reporting on pain outcomes, opioid sparing, and adverse effects. Data were combined using a fixed effect model. Fifty-three trials (2839 patients) from 25 countries reported on a large variety of different ketamine regimens and surgical settings. Sixteen studies tested prophylactic intravenous ketamine (median dose 0.4 mg/kg, range (0.1-1.6)) in 850 adults. Weighted mean difference (WMD) for postoperative pain intensity (0-10 cm visual analogue scale) was -0.89 cm at 6 h, -0.42 at 12 h, -0.35 at 24 h and -0.27 at 48 h. Cumulative morphine consumption at 24 h was significantly decreased with ketamine (WMD -15.7 mg). There was no difference in morphine-related adverse effects. The other 37 trials tested in adults or children, prophylactic or therapeutic ketamine orally, intramuscularly, subcutaneously, intra-articulary, caudally, epidurally, transdermally, peripherally or added to a PCA device; meta-analyses were deemed inappropriate. The highest risk of hallucinations was in awake or sedated patients receiving ketamine without benzodiazepine; compared with controls, the odds ratio (OR) was 2.32 (95%CI, 1.09-4.92), number-needed-to-harm (NNH) 21. In patients undergoing general anaesthesia, the incidence of hallucinations was low and independent of benzodiazepine premedication; OR 1.49 (95%CI 0.18-12.6), NNH 286. Despite many published randomised trials, the role of ketamine, as a component of perioperative analgesia, remains unclear.

Marret et al 2003

Effects of postoperative, nonsteroidal, antiinflammatory drugs on bleeding risk after tonsillectomy: meta-analysis of randomized, controlled trials.

Marret E, Flahault A, Samama CM, Bonnet F.

Anesthesiology 2003;98(6):1497–1502.

Niemi et al 1997

Comparison of the effect of intravenous ketoprofen, ketorolac and diclofenac on platelet function in volunteers.

Niemi T, Taxell C, Rosenberg P.

Acta Anaesthesiol Scand 1997;41(10):1353–1358.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis which may result in impaired platelet function. Because NSAIDs have different abilities to inhibit cyclo-oxygenases we compared the effect of intravenous ketoprofen, ketorolac and diclofenac on platelet function in volunteers. METHODS: Ten healthy male volunteers were given ketoprofen 1.4 mg/kg, ketorolac 0.4 mg/kg and diclofenac 1.1 mg/kg in saline i.v. on three different occasions, at more than one-week intervals, in a randomized double-blind crossover study. Platelet function was evaluated before (sample 0), 2 (sample 2) and 24 h (sample 3) after the beginning of the infusion. RESULTS: Two of the volunteers had no secondary platelet aggregation in their aggregation curves before the experiment (sample 0, studied three times) and their results were excluded from the final analysis. Diclofenac inhibited adrenaline (0.9 µg/ml) induced platelet aggregation less (median maximal aggregation 22.5%) than ketoprofen (18.3%) and ketorolac (15.7%) (p < 0.05) in sample 2. In the ketorolac group in sample 3 an impairment of adrenaline (0.9 µg/ml) induced platelet aggregation was still seen (26.7%) (p < 0.05) but not in the other groups. Diclofenac did not affect adenosine diphosphate (ADP) induced platelet aggregation. However, ketorolac caused an impairment in ADP (3 µM and 6 µM ) induced platelet aggregation and ketoprofen in ADP (6 µM ) induced platelet aggregation in sample 2. Bleeding time was prolonged (p < 0.05) after ketoprofen and ketorolac (sample 2) but not after diclofenac. Platelet retention on glass beads was unaffected by the tested drugs. CONCLUSION: Ketoprofen, ketorolac and diclofenac caused a reversible platelet dysfunction. Diclofenac had the mildest effect, while platelet dysfunction was still seen 24 h after the beginning of ketorolac.

Forrest et al 2002

Ketorolac, diclofenac, and ketoprofen are equally safe for pain relief after major surgery.

Forrest J, Camu F, Greer I, Kehlet H, Abdalla M, Bonnet F, Ebrahim S, Escolar G, Jage J, Pocock S, Velo G, Langman M, Bianchi P, Samama M, Heitlinger E.

Br J Anaesth 2002;88(2):227–233.

BACKGROUND: Ketorolac is approved for the relief of postoperative pain but concerns have been raised over a possible risk of serious adverse effects and death. Two regulatory reviews in Europe on the safety of ketorolac found the data were inconclusive and lacked comparison with other non-steroidal anti-inflammatory drugs. The aim of this study was to compare the risk of serious adverse effects with ketorolac vs diclofenac or ketoprofen in adult patients after elective major surgery. METHODS: This prospective, randomized multicentre trial evaluated the risks of death, increased surgical site bleeding, gastrointestinal bleeding, acute renal failure, and allergic reactions, with ketorolac vs diclofenac or ketoprofen administered according to their approved parenteral and oral dose and duration of treatment. Patients were followed for 30 days after surgery. RESULTS: A total of 11,245 patients completed the trial at 49 European hospitals. Of these, 5634 patients received ketorolac and 5611 patients received one of the comparators. 155 patients (1.38%) had a serious adverse outcome, with 19 deaths (0. 17%), 117 patients with surgical site bleeding (1.04%), 12 patients with allergic reactions (0.12%), 10 patients with acute renal failure (0.09%), and four patients with gastrointestinal bleeding (0.04%). There were no differences between ketorolac and ketoprofen or diclofenac. Postoperative anticoagulants increased the risk of surgical site bleeding equally with ketorolac (odds ratio=2.65, 95% CI=1.51-4.67) and the comparators (odds ratio=3.58, 95% CI=1.93-6.70). Other risk factors for serious adverse outcomes were age, ASA score, and some types of surgery (plastic/ear, nose and throat, gynaecology, and urology). CONCLUSION: We conclude that ketorolac is as safe as ketoprofen and diclofenac for the treatment of pain after major surgery.

Stevenson 2004

Aspirin and NSAID sensitivity.

Stevenson DD.

Immunol Allergy Clin North Am 2004;24(3):491–505, vii.

Aspirin and the older nonsteroidal anti-inflammatory drugs (NSAIDs) that block cyclo-oxygenase-1 (COX-1) induce asthma attacks in patients with aspirin-exacerbated respiratory disease and urticaria in patients with chronic idiopathic urticaria. Weak inhibitors of COX-1, such as acetaminophen and salsalate, crossreact also but only with high doses of the drugs. Partial inhibitors of both COX-1 and COX-2, such as nimesulide and meloxicam, also cross-react but only at high drug doses. COX-2 inhibitors do not cross-react; however, all NSAIDs, including the selective COX-2 inhibitors, can sensitize patients and induce urticaria or anaphylaxis on next exposure to the drug.

Snijdelaar et al 2004

A randomised, controlled study of peri-operative low dose s(+)-ketamine in combination with postoperative patient-controlled s(+)-ketamine and morphine after radical prostatectomy

Snijdelaar DG, Cornelisse HB, Schmid RL, Katz J.

Anaesthesia 2004;59(3):222–228

Katz et al 2004

Pre-emptive analgesia using intravenous fentanyl plus low-dose ketamine for radical prostatectomy under general anesthesia does not produce short-term or long-term reductions in pain or analgesic use

Katz J, Schmid R, Snijdelaar DG, Coderre TJ, McCartney CJL, Wowk A.

Pain 2004;110(3):707–718

Laskowski et al 2011

A systematic review of intravenous ketamine for postoperative analgesia

Laskowski K, Stirling A, McKay WP, Lim HJ.

Can J Anaesth 2011;58(10):911–923

Bell et al 2006

Perioperative ketamine for acute postoperative pain

Bell RF, Dahl JB, Moore RA, Kalso E.

Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004603

BACKGROUND: Postoperative pain management is often limited by adverse effects such as nausea and vomiting. Adjuvant treatment with an inexpensive opioid-sparing drug such as ketamine may be of value in giving better analgesia with fewer adverse effects. OBJECTIVES: To evaluate the effectiveness and tolerability of ketamine administered perioperatively in the treatment of acute postoperative pain in adults. SEARCH STRATEGY: Studies were identified from MEDLINE (1966-2004), EMBASE (1980-2004), the Cochrane Library (2004) and by handsearching reference lists from review articles and trials. The manufacturer of ketamine (Pfizer) provided search results from their in-house database, PARDLARS. SELECTION CRITERIA: Randomised controlled trials (RCTs) of adult patients undergoing surgery, being treated with perioperative ketamine or placebo. Studies where ketamine was administered in addition to a basic analgesic (such as morphine or NSAID) in one study group, and compared with a group receiving the same basic analgesic (but without ketamine) in another group, were also included. DATA COLLECTION AND ANALYSIS: Two independent reviewers identified fifty five RCTs for potential inclusion. Quality and validity assessment was performed by two independent reviewers. In the case of discrepancy, a third reviewer was consulted. Patient reported pain intensity and pain relief was assessed using visual analogue scales or verbal rating scales and adverse effects data were collated. MAIN RESULTS: Thirty-seven trials were included (2240 participants). Eighteen trials were excluded.Twenty-seven of the 37 trials found that perioperative subanaesthetic doses of ketamine reduced rescue analgesic requirements or pain intensity, or both. Quantitative analysis showed that treatment with ketamine reduced 24 hour PCA morphine consumption and postoperative nausea or vomiting (PONV). Adverse effects were mild or absent. AUTHORS' CONCLUSIONS: Ketamine in subanaesthetic dose (that is a dose which is below that required to produce anaesthesia) is effective in reducing morphine requirements in the first 24 hours after surgery. Ketamine also reduces postoperative nausea and vomiting. Adverse effects are mild or absent.

Habib et al 2009

Lidocaine patch for postoperative analgesia after radical retropubic prostatectomy

Habib AS, Polascik TJ, Weizer AZ, White WD, Moul JW, Elgasim MA, Gan TJ.

Anesthesia and Analgesia 2009;108(6):1950–1953

Groudine et al 1998

Intravenous lidocaine speeds the return of bowel function, decreases postoperative pain, and shortens hospital stay in patients undergoing radical retropubic prostatectomy

Groudine SB, Fisher HA, Kaufman RP, Jr., Patel MK, Wilkins LJ, Mehta SA, Lumb PD.

Anesth Analg 1998;86(2):235–239

Lauwick et al 2009

Functional walking capacity as an outcome measure of laparoscopic prostatectomy: the effect of lidocaine infusion

Lauwick S, Kim DJ, Mistraletti G, Carli F.

British Journal of Anaesthesia 2009;103(2):213–219

Marret et al 2008

Meta-analysis of intravenous lidocaine and postoperative recovery after abdominal surgery.

Marret E, Rolin M, Beaussier M, Bonnet F.

Br J Surg 2008;95(11):1331-1338.

BACKGROUND: Continuous intravenous administration of lidocaine may decrease the duration of ileus and pain after abdominal surgery. METHODS: Three databases (Medline, Embase and the Cochrane Controlled Trials Register) were searched to retrieve randomized controlled trials comparing continuous intravenous lidocaine infusion during and after abdominal surgery with placebo. Study design was scored using the Oxford Quality Score based on randomization, double-blinding and follow-up. Outcome measures were duration of ileus, length of hospital stay, postoperative pain, and incidence of nausea and vomiting. RESULTS: Eight trials were selected. A total of 161 patients received intravenous lidocaine, with 159 controls. Intravenous lidocaine administration decreased the duration of ileus (weighted mean difference (WMD) - 8.36 h; P < 0.001), length of hospital stay (WMD - 0.84 days; P = 0.002), postoperative pain intensity at 24 h after operation on a 0-100-mm visual analogue scale (WMD - 5.93 mm; P = 0.002), and the incidence of nausea and vomiting (odds ratio 0.39; P = 0.006). CONCLUSION: Continuous intravenous administration of lidocaine during and after abdominal surgery improves patient rehabilitation and shortens hospital stay.

Kaba et al 2007

Intravenous lidocaine infusion facilitates acute rehabilitation after laparoscopic colectomy.

Kaba A, Laurent SR, Detroz BJ, Sessler DI, Durieux ME, Lamy ML, Joris JL.

Anesthesiology 2007;106(1):11-18;discussion 15-16.

BACKGROUND: Intravenous infusion of lidocaine decreases postoperative pain and speeds the return of bowel function. The authors therefore tested the hypothesis that perioperative lidocaine infusion facilitates acute rehabilitation protocol in patients undergoing laparoscopic colectomy. METHODS: Forty patients scheduled to undergo laparoscopic colectomy were randomly allocated to receive intravenous lidocaine (bolus injection of 1.5 mg/kg lidocaine at induction of anesthesia, then a continuous infusion of 2 intraoperatively and 1.33 for 24 h postoperatively) or an equal volume of saline. All patients received similar intensive postoperative rehabilitation. Postoperative pain scores, opioid consumption, and fatigue scores were measured. Times to first flatus, defecation, and hospital discharge were recorded. Postoperative endocrine (cortisol and catecholamines) and metabolic (leukocytes, C-reactive protein, and glucose) responses were measured for 48 h. Data (presented as median [25-75% interquartile range], lidocaine vs. saline groups) were analyzed using Mann-Whitney tests. P<0.05 was considered statistically significant. RESULTS: Patient demographics were similar in the two groups. Times to first flatus (17 [11-24] vs. 28 [25-33] h; P<0.001), defecation (28 [24-37] vs. 51 [41-70] h; P=0.001), and hospital discharge (2 [2-3] vs. 3 [3-4] days; P=0.001) were significantly shorter in patients who received lidocaine. Lidocaine significantly reduced opioid consumption (8 [5-18] vs. 22 [14-36] mg; P=0.005) and postoperative pain and fatigue scores. In contrast, endocrine and metabolic responses were similar in the two groups. CONCLUSIONS: Intravenous lidocaine improves postoperative analgesia, fatigue, and bowel function after laparoscopic colectomy. These benefits are associated with a significant reduction in hospital stay.

Sun et al 2012

Perioperative systemic lidocaine for postoperative analgesia and recovery after abdominal surgery: a meta-analysis of randomized controlled trials.

Sun Y, Li T, Wang N, Yun Y, Gan TJ.

Dis Colon Rectum 2012;55(11):1183–1194.

Larijani et al 2004

Analgesic and hemodynamic effects of a single 7.5-mg intravenous dose of morphine in patients with moderate-to-severe postoperative pain

Larijani GE, Goldberg ME, Gratz I, Warshal DP.

Pharmacotherapy 2004;24(12):1675–80

STUDY OBJECTIVES: To evaluate the analgesic and hemodynamic effects of a single dose of intravenous morphine 7.5 mg in patients experiencing moderate-to-severe postoperative pain, and to determine any gender differences in analgesic response. DESIGN: Randomized, double-blind, parallel-group, multicenter study. SETTING: Postanesthesia care unit of a university teaching hospital. PATIENTS: Eighty-eight patients who underwent total abdominal hysterectomy or prostatectomy. INTERVENTION: Thirty-seven patients received a single dose of morphine sulfate 7.5 mg and 51 patients received placebo, both administered intravenously for 1 minute. MEASUREMENTS AND MAIN RESULTS: Overall, morphine had no significant effect on systolic or diastolic blood pressure, heart rate, oxygen saturation, or respiratory rate. Compared with baseline, morphine significantly reduced pain intensity at 2, 5, and 10 minutes after administration (p<0.05). The difference in pain intensity between patients who received morphine and those who received placebo, however, was significant only at the 5-minute time point (p<0.02). Patients receiving morphine also reported mild pain relief at 2 and 5 minutes after its administration. Peak analgesic effect was reported 2 minutes after its administration in three quarters of the patients. Significant gender differences also were observed in response to analgesic effect. In women, no significant differences in pain intensity were seen at any time between the morphine and placebo groups, whereas in men receiving morphine, pain intensity was significantly less at 2, 5, and 10 minutes compared with baseline and that seen in the placebo group. Women were generally more satisfied with their pain treatment than were men. CONCLUSION: A single 7.5-mg intravenous bolus dose of morphine did not appear to provide adequate reduction in perceived pain intensity in patients with moderate-to- severe postoperative pain. In addition, in contrast to the findings of other experimental pain studies, our data suggest that women are more tolerant of postoperative pain than are men

Gaitini et al 1996

Sublingual buprenorphine compared to morphine delivered by a patient-controlled analgesia system as postoperative analgesia after prostatectomy

Gaitini L, Moskovitz B, Katz E, Vaisberg A, Vaida S, Nativ O.

Urologia Internationalis 1996;57(4):227–229

Allaire et al 1992

A prospective randomized comparison of epidural infusion of fentanyl and intravenous administration of morphine by patient-controlled analgesia after radical retropubic prostatectomy.

Allaire PH, Messick JM, Oesterling JE, Byer DE, Myers RP, Lieber MM, Chantigian RC, Welna JO, Patterson DE, Blute ML.

Mayo Clin Proc 1992;67(11):1031–41

McQuay et al 1999

Injected morphine in postoperative pain: a quantitative systematic review.

McQuay HJ, Carroll D, Moore RA.

J Pain Symptom Manage 1999;17(3):164–174.

This systematic review of single-dose, placebo-controlled, randomized trials assessed pain relief from subcutaneous, intramuscular or intravenous morphine compared with placebo in postoperative pain. Pain relief or pain intensity difference over 4 to 6 hours was extracted and converted into the number of patients with at least 50% pain relief. This was used to calculate the relative benefit and the number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief. In 15 trials, comparing intramuscular morphine 10 mg (486 patients) with placebo (460 patients) morphine had an NNT of 2.9 (95% confidence interval 2.6-3.6). This meant that one of every three patients with moderate or severe postoperative pain treated with 10 mg intramuscular morphine had at least 50% pain relief, and would not have achieved this had they been given placebo. Minor adverse effects were more common with morphine (34%) than with placebo (23%) (relative risk 1.49 [1.09-2.04]), but drug related study withdrawal was rare (1.2% overall) and no different from placebo.

Walder et al 2001

Efficacy and safety of patient-controlled opioid analgesia for acute postoperative pain. A quantitative systematic review.

Walder B, Schafer M, Henzi I, Tramer MR.

Acta Anaesthesiol Scand 2001;45(7):795–804.

BACKGROUND: The usefulness of intravenous patient-controlled analgesia (PCA) with opioids for postoperative analgesia is not well defined. METHODS: We systematically searched (MEDLINE, EMBASE, Cochrane Library, bibliographies, any language, to January 2000) for randomised trials comparing opioid-based PCA with the same opioid given intramuscularly, intravenously, or subcutaneously. Weighted mean differences (WMD) for continuous data, relative risks (RR) and numbers-needed-to-treat (NNT) for dichotomous data were calculated with 95% confidence intervals (CI) using fixed and random effects models. RESULTS: Data from 32 trials were analysed: 22 (1139 patients) were with morphine, five (682) with pethidine, three (184) with piritramide, one (47) with nalbuphine and one (20) with tramadol. In three morphine and one pethidine trial (352 patients), more patients preferred PCA (89.7% vs. 65.8%, RR 1.41 (95%CI 1.11 to 1.80), NNT 4.2). Combined dichotomous data on pain intensity and relief, and the need for rescue analgesics from eight morphine, one pethidine, one piritramide, and one nalbuphine trial (691 patients), were in favour of PCA (RR 1.22 (1.00 to 1.50), NNT 8). In two morphine trials (152), pulmonary complications were more frequently prevented with PCA (100% vs. 93.3%, RR 1.07 (1.01 to 1.14), NNT 15). There was equivalence for cumulative opioid consumption, pain scores, duration of hospital stay, and opioid-related adverse effects. CONCLUSION: These trials provide some evidence that in the postoperative pain setting, PCA with opioids, compared with conventional opioid treatment, improve analgesia and decrease the risk of pulmonary complications, and that patients prefer them.

Wheeler M et all 2002

Adverse events associated with postoperative opioid analgesia: a systematic review.

Wheeler M, Oderda GM, Ashburn MA, Lipman AG

J Pain 2002;3(3):159-80.

No abstract available

Moore et al 1997

Single-patient data meta-analysis of 3453 postoperative patients: oral tramadol versus placebo, codeine and combination analgesics.

Moore RA, McQuay HJ.

Pain. 1997; 69: 287–94.

The analgesic effectiveness and safety of oral tramadol were compared with standard analgesics using a meta-analysis of individual patient data from randomised controlled trials in patients with moderate or severe pain after surgery or dental extraction. Calculation of %maxTOTPAR from individual patient data, and the use of > 50%maxTOTPAR defined clinically acceptable pain relief. Number-needed-to-treat (NNT) for one patient to have > 50%maxTOTPAR compared with placebo was used to examine the effectiveness of different single oral doses of tramadol and comparator drugs. Eighteen randomised, double-blind, parallel-group single-dose trials with 3453 patients using categorical pain relief scales allowed the calculation of %maxTOTPAR. The use of > 50%maxTOTPAR was a sensitive measure to discriminate between analgesics. Tramadol and comparator drugs gave significantly more analgesia than placebo. In postsurgical pain tramadol 50, 100 and 150 mg had NNTs for > 50%maxTOTPAR of 7.1 (95% confidence intervals 4.6-18), 4.8 (3.4-8.2) and 2.4 (2.0-3.1), comparable with aspirin 650 mg plus codeine 60 mg (NNT 3.6 (2.5-6.3)) and acetaminophen 650 mg plus propoxyphene 100 mg (NNT 4.0 (3.0-5.7)). With the same dose of drug postsurgical patients had more pain relief than those having dental surgery. Tramadol showed a dose-response for analgesia in both postsurgical and dental pain patients. With the same dose of drug postsurgical pain patients had fewer adverse events than those having dental surgery. Adverse events (headache, nausea, vomiting, dizziness, somnolence) with tramadol 50 mg and 100 mg had a similar incidence to comparator drugs. There was a dose response with tramadol, tending towards higher incidences at higher doses. Single-patient meta-analysis using more than half pain relief provides a sensitive description of the analgesic properties of a drug, and NNT calculations allow comparisons to be made with standard analgesics. Absolute ranking of analgesic performance should be done separately for postsurgical and dental pain.


McQuay H et al 2003

Meta-analysis of single dose oral tramadol plus acetaminophen in acute postoperative pain.

McQuay H, Edwards J.

Eur J Anaesthesiol 2003;20 Suppl 28:19–22.

BACKGROUND AND OBJECTIVE: Trials in acute postoperative pain are usually small. Pooling homogenous data from a number of trials in a meta-analysis enables a truer estimate of efficacy. The aims of the present meta-analysis were to assess the analgesic efficacy and adverse effects of single-dose oral tramadol plus acetaminophen (paracetamol) in acute postoperative pain, and to demonstrate the efficacy of the combination formulation compared with its components. METHODS: Individual data from > 1400 adult dental or gynaecologic/orthopaedic patients with moderate-to-severe pain were taken from seven randomised, double-blind, placebo controlled trials of tramadol (75 mg or 112.5 mg) plus acetaminophen (650 mg or 975 mg) with identical methods. The primary outcome measure was the number of patients needed to be treated (NNT) for one patient to obtain at least 50% pain relief. Information on adverse effects was also collected and the number needed to harm (NNH) was estimated. RESULTS: The tramadol/acetaminophen combination was more effective than either of its two components administered alone. For dental patients, who formed the bulk of the population, the combination formulation also had a significantly lower (better) NNT (approximately 3) than the components al one (approximately 8-12), comparable to ibuprofen 400 mg. The adverse effects associated with tramadol/acetaminophen were similar to those associated with the components alone. The commonest were dizziness, drowsiness, nausea, vomiting and headache. CONCLUSIONS: Meta-analysis confirmed the analgesic superiority of the combination treatment over its components, without additional toxicity. Combination analgesic formulations are an important and effective means of pain relief, and should prove useful in treating elderly and other groups of patients who often cannot tolerate non-steroidal anti-inflammatory drugs, including the newer COX-2 inhibitors.

Collins et al 2000

Single dose dextropropoxyphene, alone and with paracetamol (acetaminophen), for postoperative pain

Collins SL, Edwards JE, Moore RA, McQuay HJ

Cochrane Database Syst Rev 2000; CD001440(2)

BACKGROUND: Patient surveys have shown that postoperative pain is often not managed well, and there is a need to assess the efficacy and safety of commonly used analgesics as newer treatments become available. Dextropropoxyphene is one example of an opioid analgesic in current use, and is widely prescribed for pain relief in combination with paracetamol under names such as Co-proxamol and Distalgesic. OBJECTIVES: To determine the analgesic efficacy and adverse effects of single dose oral Dextropropoxyphene alone and in combination with paracetamol (acetaminophen) for moderate to severe postoperative pain. SEARCH STRATEGY: Published reports were identified from: Medline (1966 - November 1996), Biological Abstracts (1985 - 1996), Embase (1980 - 1996), the Cochrane Library (Issue 4 1996), and the Oxford Pain Relief Database (1954 - 1994). Additional studies were identified from the reference lists of retrieved reports. Date of the most recent searches: July 1998. SELECTION CRITERIA: The inclusion criteria used were: full journal publication, postoperative pain, postoperative oral administration, adult patients, baseline pain of moderate to severe intensity, double-blind design, and random allocation to treatment groups which included dextropropoxyphene and placebo or a combination of dextropropoxyphene plus paracetamol and placebo. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent reviewers, and trials were quality scored. Summed pain intensity and pain relief data were extracted and converted into dichotomous information to yield the number of patients with at least 50% pain relief. This was used to calculate the relative benefit and number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief. MAIN RESULTS: Six trials (440 patients) compared dextropropoxyphene with placebo and five (963 patients) compared dextropropoxyphene plus paracetamol 650 mg with placebo. For a single dose of dextropropoxyphene 65 mg in postoperative pain the NNT for at least 50% pain relief was 7.7 (95% confidence interval 4.6 to 22) when compared with placebo over 4-6 hours. For the equivalent dose of dextropropoxyphene combined with paracetamol 650 mg the NNT was 4.4 (3.5 to 5.6) when compared with placebo. These results were compared with those for other analgesics obtained from equivalent systematic reviews. Pooled data showed increased incidence of central nervous system adverse effects for dextropropoxyphene plus paracetamol compared with placebo. REVIEWER'S CONCLUSIONS: The combination of dextropropoxyphene 65 mg with paracetamol 650 mg shows similar efficacy to tramadol 100 mg for single dose studies in postoperative pain but with a lower incidence of adverse effects. The same dose of paracetamol combined with 60 mg codeine appears more effective but, with the slight overlap in the 95% confidence intervals, this conclusion is not robust. Adverse effects of both combinations were similar. Ibuprofen 400 mg has a lower (better) NNT than both dextropropoxyphene 65 mg plus paracetamol 650 mg and tramadol 100 mg.

Moore et al 2000

Single dose paracetamol (acetaminophen), with and without codeine, for postoperative pain.

Moore A, Collins S, Carroll D, McQuay H, Edwards J.

Cochrane Database Syst Rev. 2000;(2):CD001547

BACKGROUND: Patient surveys have shown that postoperative pain is often not managed well, and there is a need to assess the efficacy and safety of commonly used analgesics as newer treatments become available. Paracetamol (acetaminophen) is an important non-opiate analgesic, commonly prescribed, as well as being available for retail sale. This review seeks to examine the efficacy of paracetamol alone and in combination with codeine, and also considers adverse effects. OBJECTIVES: To assess the analgesic efficacy and adverse effects of a single dose of oral paracetamol (acetaminophen) alone and in combination with codeine for moderate to severe postoperative pain. SEARCH STRATEGY: Published trials were identified from: Medline (1966 to May 1996), Embase (1980 to 1996), Cochrane Library (Issue 2 1996) and the Oxford Pain Relief Database (1950 to 1994). Additional trials were identified from reference lists of retrieved studies. Date of most recent searches: July 1998. SELECTION CRITERIA: Inclusion criteria were: full journal publication, postoperative pain, postoperative oral administration, adult patients, baseline pain of moderate to severe intensity, double-blind design, and random allocation to treatment groups which compared paracetamol with placebo or a combination of paracetamol and codeine with either placebo or the same dose of paracetamol alone. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent reviewers, and trials were quality scored. Summed pain intensity and pain relief data were extracted and converted into dichotomous information to yield the number of patients with at least 50% pain relief. This was used to calculate the relative benefit and number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief over 4 to 6 hours compared with placebo. Adverse effects were used to calculate relative risk and number-needed-to-harm (NNH). MAIN RESULTS: We found 40 trials of paracetamol against placebo (4171 patients), 22 trials of paracetamol plus codeine against placebo (1407 patients) and 12 trials of paracetamol plus codeine against the same dose of paracetamol (794 patients). In postoperative pain paracetamol 1000 mg had an NNT of 4.6 (3.8-5.4) for at least 50% pain relief when compared with placebo, and paracetamol 600/650 mg had an NNT of 5.3 (4.1-7.2). Paracetamol 600/650 mg plus codeine 60 mg had an NNT of 3. 6 (2.9-4.5). Comparing paracetamol plus codeine 60 mg with the same dose of paracetamol alone gave an NNT of 7.7 (5.1-17) for at least 50% pain relief. Adverse effects: Relative risk estimates for paracetamol 600/650 mg plus codeine 60 mg versus placebo showed a significant difference for 'drowsiness'/somnolence (NNH 11 (7.5- 0)) and dizziness (NNH 27 (15-164)) but no significant difference for nausea/vomiting. REVIEWER'S CONCLUSIONS: Paracetamol is an effective analgesic with a low incidence of adverse effects. The addition of codeine 60 mg to paracetamol produces additional pain relief even in single oral doses, but may be accompanied by an increase in drowsiness and dizziness.

Rømsing et al 2002

Rectal and parenteral paracetamol, and paracetamol in combination with NSAIDs, for postoperative analgesia.

Rømsing J, Moiniche S, Dahl JB.

Br J Anaesth 2002;88(2):215–226.

BACKGROUND: We have reviewed the analgesic efficacies of rectal and parenteral paracetamol and tested the evidence for a possible additive analgesic effect of the combination of paracetamol with a non-steroidal anti-inflammatory drug (NSAID) in postoperative pain. METHODS: Randomized controlled trials were evaluated. Outcome measures were pain scores and demand for supplementary analgesia. RESULTS: Eight studies compared rectal paracetamol with placebo. One study of single-dose administration of rectal paracetamol 40–60 mg/kg and three studies of repeat dosing with 14–20 mg/kg showed significant analgesic efficacy, while studies of a single dose of 10–20 mg/kg were negative. Ten studies compared parenteral paracetamol with placebo and eight studies showed improved pain relief with paracetamol. Of the nine studies comparing paracetamol with a combination of paracetamol and an NSAID, six studies showed improved pain relief for the combination while only two of the six studies comparing an NSAID with a combination of an NSAID and paracetamol showed improved pain relief for the combination. CONCLUSIONS: Considering the few studies available, evidence was found of a clinically relevant analgesic effect of rectal and parenteral paracetamol. Concurrent use of paracetamol and an NSAID was superior to paracetamol alone but no evidence was found of superior analgesic effect of the combination compared with the NSAID alone.

Remy 2005

Effects of acetaminophen on morphine side-effects and consumption after major surgery: meta-analysis of randomized controlled trials.

Remy C, Marret E, Bonnet F.

Br J Anaesth 2005;94(4):505–13.

BACKGROUND: Acetaminophen is commonly used for the management of perioperative pain. However, there is a marked discrepancy between the extent to which acetaminophen is used and the available evidence for an analgesic effect after major surgery. The aim of this systematic review is to determine the morphine-sparing effect of acetaminophen combined with patient-controlled analgesia (PCA) with morphine and to evaluate its effects on opioid-related adverse effects. METHODS: MEDLINE and the Cochrane Library were searched to select randomized controlled trials which compared PCA morphine alone with PCA morphine plus acetaminophen administered orally or intravenously. Studies were evaluated for their quality based on the Oxford Quality Scale. Outcome measures were morphine consumption over the first 24 h after surgery, patient satisfaction and the incidence of morphine side-effects, including nausea and vomiting, sedation, urinary retention, pruritus and/or respiratory depression. RESULTS: Seven prospective randomized controlled trials, including 265 patients in the group with PCA morphine plus acetaminophen and 226 patients in the group with PCA morphine alone, were selected. Acetaminophen administration was not associated with a decrease in the incidence of morphine-related adverse effects or an increase in patient satisfaction. Adding acetaminophen to PCA was associated with a morphine-sparing effect of 20% (mean, -9 mg; CI -15 to -3 mg; P=0.003) over the first postoperative 24 h. CONCLUSION: Acetaminophen combined with PCA morphine induced a significant morphine-sparing effect but did not change the incidence of morphine-related adverse effects in the postoperative period.

Altman 2004

A rationale for combining acetaminophen and NSAIDs for mild-to-moderate pain.

Altman RD.

Clin Exp Rheumatol 2004;22(1):110–7.

Analgesic therapy that combines individual agents with different mechanisms of action has potential advantages for the management of mild-to-moderate pain in the outpatient setting. Theoretically, this approach can lead to greater efficacy and fewer adverse events. While the precise mechanism of action for the analgesic effect of acetaminophen remains uncertain, accumulating evidence suggests that its activity resides primarily in the central nervous system. In contrast, the site of action for the analgesic effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is predominantly peripheral, within injured or inflamed tissue. Several controlled clinical studies among patients with musculoskeletal conditions, dental pain, or postoperative pain have shown that combinations of acetaminophen and NSAIDs provide additive pain-relieving activity, thereby leading to dose-sparing effects and improved safety. Further studies are warranted to determine the clinical utility and safety of acetaminophen/NSAID combinations as analgesic therapy for common conditions associated with mild-to-moderate pain.

Tauzin-Fin et al 2007

Sublingual oxybutynin reduces postoperative pain related to indwelling bladder catheter after radical retropubic prostatectomy

Tauzin-Fin P, Sesay M, Svartz L, Krol-Houdek MC, Maurette P.

British Journal of Anaesthesia 2007;99(4):572–575

Chelly et al 2011

Multimodal analgesic approach incorporating paravertebral blocks for open radical retropubic prostatectomy: a randomized double-blind placebo-controlled study

Chelly JE, Ploskanych T, Dai F, Nelson JB.

Canadian Journal of Anesthesia 2011;58(4):371–378

Habib et al 2008

Transdermal Nicotine for Analgesia after Radical Retropubic Prostatectomy

Habib AS, White WD, El Gasim MA, Saleh G, Polascik TJ, Moul JW, Gan TJ.

Anesthesia and Analgesia 2008;107(3):999–1004

Tauzin-Fin et al 2006

Intravenous magnesium sulphate decreases postoperative tramadol requirement after radical prostatectomy

Tauzin-Fin P, Sesay M, Delort-Laval S, Krol-Houdek MC, Maurette P.

European Journal of Anaesthesiology 2006;23(12):1055–1059

Agarwal et al 2006

Comparison of efficacy of oxybutynin and tolterodine for prevention of catheter related bladder discomfort: a prospective, randomized, placebo-controlled, double-blind study

Agarwal A, Dhiraaj S, Singhal V, Kapoor R, Tandon M.

Br J Anaesth 2006;96(3):377–380

Agarwal et al 2005

The efficacy of tolterodine for prevention of catheter-related bladder discomfort: a prospective, randomized, placebo-controlled, double-blind study

Agarwal A, Raza M, Singhal V, Dhiraaj S, Kapoor R, Srivastava A, Gupta D, Singh PK, Pandey CK, Singh U.

Anesth Analg 2005;101(4):1065–1067

Norris et al 2008

A prospective, randomized, double-blinded placebo-controlled comparison of extended release oxybutynin versus phenazopyridine for the management of postoperative ureteral stent discomfort.

Norris RD, Sur RL, Springhart WP, Marguet CG, Mathias BJ, Pietrow PK, Albala DM, Preminger GM.

Urology 2008;71(5):792–795

Lysakowski 2007

Magnesium as an adjuvant to postoperative analgesia: a systematic review of randomized trials

Lysakowski C, Dumont L, Czarnetzki C, Tramèr MR.

Anesth Analg. 2007 Jun;104(6):1532-9.

BACKGROUND: Randomized trials have reached different conclusions as to whether magnesium is a useful adjuvant to postoperative analgesia. METHODS: We performed a comprehensive search (electronic databases, bibliographies, all languages, to 4.2006) for randomized comparisons of magnesium and placebo in the surgical setting. Information on postoperative pain intensity and analgesic requirements was extracted from the trials and compared qualitatively. Dichotomous data on adverse effects were combined using classic methods of meta-analysis. RESULTS: Fourteen randomized trials (778 patients, 404 received magnesium) tested magnesium laevulinate, gluconate or sulfate. With magnesium, postoperative pain intensity was significantly decreased in four (29%) trials, was no different from placebo in seven (50%), and was increased in one (7%); two trials (14%) did not report on pain intensity. With magnesium, postoperative analgesic requirements were significantly reduced in eight (57%) trials, were no different from placebo in five (36%), and were increased in one (7%). Magnesium-treated patients had less postoperative shivering (relative risk 0.38, 95% confidence interval 0.17-0.88, number-needed-to-treat 14). Seven trials reported on magnesium serum levels. In all, serum levels were increased in patients who received magnesium; in six, serum levels were decreased in those who received placebo. CONCLUSIONS: These trials do not provide convincing evidence that perioperative magnesium may have favorable effects on postoperative pain intensity and analgesic requirements. Perioperative magnesium supplementation prevents postoperative hypomagnesemia and decreases the incidence of postoperative shivering. It may be worthwhile to further study the role of magnesium as a supplement to postoperative analgesia, since this relatively harmless molecule is inexpensive, and the biological basis for its potential antinociceptive effect is promising.

Gupta et al 2006

Postoperative analgesia after radical retropubic prostatectomy: A double-blind comparison between low thoracic epidural and patient-controlled intravenous analgesia

Gupta A, Fant F, Axelsson K, Sandblom D, Rykowski J, Johansson JE, Andersson SO.

Anesthesiology 2006;105:784–793

Maestroni et al 2007

Postoperative analgesia by epidural infusion of ropivacaine and fentanyl versus intravenous administration of morphine in patients undergoing radical retropubic prostatectomy: results of a prospective

Maestroni U, Astesana L, Ferretti S, Ciuffreda M, Troglio R, Simonazzi M, Cortellini P.

Archivio Italiano di Urologia e Andrologia 2007;79(1):7–11

Hong et al 2009

Effects of thoracic epidural analgesia combined with general anesthesia on intraoperative ventilation/oxygenation and postoperative pulmonary complications in robot-assisted laparoscopic radical prost

Hong JY, Lee SJ, Rha KH, Roh GU, Kwon SY, Kil HK

Journal of Endourology(Endourological Society) 2009;23(11)1843–1849

Liu et al 1995

Intravenous versus epidural administration of hydromorphone: Effects on analgesia and recovery after radical retropubic prostatectomy

Liu S, Carpenter RL, Mulroy MF, Weissman RM, McGill TJ, Rupp SM, Allen HW

Anesthesiology 1995;82(3):682–688

Hohwu et al 2006

Oral oxycodone hydrochloride versus epidural anaesthesia for pain control after radical retropubic prostatectomy

Hohwu L, Akre O, Bergenwald L, Tornblom M, Gustafsson O.

Scandinavian Journal of Urology and Nephrology 2006;40(3):192–197

Shir et al 1994

The effect of epidural versus general anesthesia on postoperative pain and analgesic requirements in patients undergoing radical prostatectomy

Shir Y, Raja SN, Frank SM.

Anesthesiology 1994;80(1)49–56

Gottschalk et al 1998

Preemptive epidural analgesia and recovery from radical prostatectomy: a randomized controlled trial.

Gottschalk A, Smith DS, Jobes DR, Kennedy SK, Lally SE, Noble VE, Grugan KF, Seifert HA, Cheung A, Malkowicz SB, Gutsche BB, Wein AJ.

Journal of the American Medical Association 1998;279(14):1076–1082

Hong et al 2011

Epidural ropivacaine and sufentanil and the perioperative stress response after a radical retropubic prostatectomy

Hong JY, Yang SC, Yi J, Kil HK.

Acta Anaesthesiologica Scandinavica 2011;55(3):282–289

Fant et al 2011

Thoracic epidural analgesia or patient-controlled local analgesia for radical retropubic prostatectomy: a randomized, double-blind study.

F, Axelsson K, Sandblom D, Magnuson A, Andersson SO, Gupta A.

British Journal of Anaesthesia 2011;107(5):782–789

Aribogan et al 2003

Patient-controlled epidural analgesia after major urologic surgeries. A comparison of tramadol with or without bupivacaine

Aribogan A, Doruk N, Aridogan A, Akin S, Balcioglu O.

Urologia Internationalis 2003;71(2):168–175

Heid et al 2007

Epidural ropivacaine – where are the benefits? A prospective, randomized, double-blind trial in patients with retropubic prostatectomy

Heid F, Schmidt-Glintzer A, Piepho T, Jage J.

Acta Anaesthesiologica Scandinavica 2007;51(3):294–298

Hindsholm et al 1993

Continuous subcutaneous infusion of morphine – an alternative to extradural morphine for postoperative pain relief.

Hindsholm KB, Bredahl C, Jensen MK, Kidmose L, Herlevsen P, Nielsen FB, Olesen AS.

Br J Anaesth 1993;71(4):580–582.

In a randomized, double-blind study of 40 patients undergoing total abdominal hysterectomy, we have compared continuous subcutaneous infusion (CSCI) of morphine with discontinuous extradural injection of morphine for postoperative analgesia at rest and during cough. The CSCI group received a bolus of morphine 0.1 mg kg-1 i.v. at the end of the operation and continued with s.c. infusion of morphine 30 micrograms kg-1 h-1. The extradural group received morphine 4 mg extradurally at 0, 2, 10 and 18 h after operation. Pain and side effects were evaluated at 2, 4, 8, 12 and 24 h after operation. In the extradural group, significantly smaller pain-scores were observed both at rest and during cough compared with the CSCI group. No significant difference was observed between the groups regarding supplementary doses of morphine, peak expiratory flow values or side effects. We conclude that morphine by CSCI is not as effective as morphine injected extradurally. However, CSCI seems to provide simple and relatively effective analgesia with a low rate of side effects.

Eriksson-Mjoberg et al 1997b

Extradural morphine gives better pain relief than patient-controlled i.v. morphine after hysterectomy.

Eriksson-Mjoberg M, Svensson JO, Almkvist O, Olund A, Gustafsson LL.

Br J Anaesth 1997b;78(1):10–16.

We examined if patient-controlled analgesia (PCA) with i.v. morphine provided comparable postoperative analgesia after hysterectomy as extradural morphine, without increasing the incidence of side effects. The study (n = 40) was randomized and double-blind. An extradural catheter was inserted before surgery and anaesthesia was standardized. The extradural group received extradural morphine 0.06 mg kg-1 by the end of surgery and a second dose 6 h later. The i.v. group received an i.v. infusion of morphine 0.2 mg kg-1 after surgery. PCA with morphine 0.04 mg kg-1 i.v. was used in both groups. Pain relief (VAS), side effects and cognitive functions were evaluated for 18 h. Plasma samples were obtained for analysis of morphine concentrations. Mean consumption of PCA morphine was 2.4 mg h-1 for the i.v. group and 1 mg h-1 for the extradural group. Despite unlimited access to morphine, the i.v. group had higher VAS scores as the extradural group (P < 0.001). Plasma concentrations of morphine varied 8-10-fold in both groups. In the i.v. group itching, tiredness, blurred vision and vertigo correlated with cumulative consumption of i.v. morphine whereas in the extradural group this correlation existed only for tiredness. Both groups showed reduced ability to perform tests of cognitive function, indicating a central effect of both i.v. and extradural morphine, despite markedly lower plasma morphine concentrations in the extradural group.

Camu et al 1991

Alfentanil infusion for postoperative pain: a comparison of epidural and intravenous routes.

Camu F, Debucquoy F.

Anesthesiology 1991;75(2):171–178.

The efficacy of intravenous (iv) and epidural infusions of alfentanil for postoperative pain relief was investigated in 24 patients (ASA physical status 1-2) who were scheduled for abdominal hysterectomy. The patients were allocated randomly to receive either epidural or iv alfentanil. In both groups, a loading dose of 15 was administered, followed by a constant rate infusion of 18 alfentanil for 20 h. Both routes provided similar degrees of analgesia; however, analgesia occurred earlier in the intravenously treated group (P less than 0.03). Mean plasma alfentanil concentrations (Cps) varied between 42 and 82 in the iv group and 23 and 68 in the epidural group, with higher concentrations in the iv group for the first 60 min only (P less than 0.01). Cps increased with infusion time, suggesting accumulation of alfentanil. After infusion ended, pain recurred at the same time in both groups, whereas the alfentanil Cps still were greater than 45 ng/ml. Postoperative epinephrine concentrations decreased after 60 min of infusion (P less than 0.02), whereas, after 6 h, cortisol levels decreased to preoperative values. Norepinephrine concentrations decreased only slightly. The only clinically meaningful effect on vital signs that occurred was an abrupt reduction of respiratory rate after the iv loading dose. PaCO2 increased to the same extent in both groups during the first 15 min only. The incidence of opioid-related side effects was similar in both groups. These results suggest that the iv and epidural routes were equally effective for providing postoperative pain control and controlling the postoperative response to surgical stress.

Fujii et al 1998

Efficacy of thoracic epidural analgesia following laparoscopic cholecystectomy.

Fujii Y, Toyooka H, Tanaka H.

Eur J Anaesthiol 1998;15:342–344.

This study was undertaken to determine whether epidural analgesia has any benefit for post-operative pain relief in patients undergoing laparoscopic cholecystectomy. Patients were randomly assigned to receive post-operative epidural analgesia with a morphine-bupivacaine combination (Group A, n = 22) or placebo (saline) (Group B, n = 22). The same standard general anaesthetic technique, which consists of nitrous oxide and isoflurane in oxygen was used. Analgesia was assessed using visual analogue pain scores (0-10 cm). The evaluation was carried out 24 and 48 h post-operatively. At 24 h after anaesthesia, pain scores in Group A (2.3 +/- 1.2) were lower than those in Group B (4.4 +/- 1.5) (p < 0.05). However, at 48 h post-operatively, no difference in scores was observed between the two groups. In conclusion, epidural analgesia with a morphine-bupivacaine combination improves pain relief during the first 24 h following laparoscopic cholecystectomy.

Wu et al 2005

Efficacy of postoperative patient-controlled and continuous infusion epidural analgesia versus intravenous patient-controlled analgesia with opioids: a meta-analysis

Wu CL, Cohen SR, Richman JM, Rowlingson AJ, Courpas GE, Cheung K, Lin EE, Liu SS.

Anesthesiology 2005;103(5):1079–88

The authors performed a meta-analysis and found that epidural analgesia overall provided superior postoperative analgesia compared with intravenous patient-controlled analgesia. For all types of surgery and pain assessments, all forms of epidural analgesia (both continuous epidural infusion and patient-controlled epidural analgesia) provided significantly superior postoperative analgesia compared with intravenous patient-controlled analgesia, with the exception of hydrophilic opioid-only epidural regimens. Continuous epidural infusion provided statistically significantly superior analgesia versus patient-controlled epidural analgesia for overall pain, pain at rest, and pain with activity; however, patients receiving continuous epidural infusion had a significantly higher incidence of nausea-vomiting and motor block but lower incidence of pruritus. In summary, almost without exception, epidural analgesia, regardless of analgesic agent, epidural regimen, and type and time of pain assessment, provided superior postoperative analgesia compared to intravenous patient-controlled analgesia.

Jorgensen et al 2000b

Epidural local anaesthetics versus opioid-based analgesic regimens on postoperative gastrointestinal paralysis, PONV and pain after abdominal surgery.

Jorgensen H, Wetterslev J, Moiniche S, Dahl JB.

Cochrane Database Syst Rev 2000b;(4):CD001893.

BACKGROUND: Gastrointestinal paralysis, nausea and vomiting, and pain, are major clinical problems following abdominal surgery. Anaesthetic and analgesic techniques that reduce pain and postoperative nausea and vomiting (PONV), and prevent or reduce postoperative ileus, may reduce postoperative morbidity, duration of hospitalisation and hospital costs. OBJECTIVES: To compare effects of postoperative epidural local anaesthetic with regimens based on systemic or epidural opioids, on postoperative gastrointestinal function, postoperative pain, PONV and surgical/anaesthetic complications. SEARCH STRATEGY: Trials were identified by computerised searches of the Cochrane Controlled Trials Register, MEDLINE, EMBASE and by checking the reference lists of trials and review articles. SELECTION CRITERIA: Randomised controlled trials comparing the effects of postoperative epidural local anaesthetic with systemic or epidural opioids. DATA COLLECTION AND ANALYSIS: Collected data included treatment in active (local anaesthetic) and control (opioid based) groups, time to first postoperative stool, time to first postoperative flatus, gastric emptying measured by the paracetamol absorption test, duration of the passage of barium sulphate, pain assessments, use of supplementary analgesics, nausea, vomiting and surgical/anaesthetic complications. MAIN RESULTS: Most studies in this review involved a small number of patients. Furthermore half of the studies indicated a poor level of methodology in particular regarding blinding and report of withdrawals. Heterogeneity of included studies was substantial. Results consistently showed reduced time to return of gastrointestinal function in the epidural local anaesthetic group compared with groups receiving systemic or epidural opioid (37 hours and 24 hours, respectively). Postoperative pain was comparable. Two studies compared the effect of epidural local anaesthetic with a combination of epidural local anaesthetic and opioid on gastrointestinal function. One study favoured epidural local anaesthetic and one study was indifferent. A meta analysis of five of eight studies comparing the effect of epidural local anaesthetic with a combination of epidural local anaesthetic and opioid on postoperative pain, yielded a reduction in VAS pain scores (0-100 mm) on the first postoperative day of 15 mm, in favour of the combination. No significant differences in PONV were observed between epidural local anaesthetic and opioid based regimens. REVIEWER'S CONCLUSIONS: Administration of epidural local anaesthetics to patients undergoing laparotomy reduce gastrointestinal paralysis compared with systemic or epidural opioids, with comparable postoperative pain relief. Addition of opioid to epidural local anaesthetic may provide superior postoperative analgesia compared with epidural local anaesthetics alone. The effect of additional epidural opioid on gastrointestinal function is so far unsettled. Randomized, controlled trials comparing the effect of combinations of epidural local anaesthetic and opioid with epidural local anaesthetic alone on postoperative gastrointestinal function and pain are warranted.

Chaney 1995

Side effects of intrathecal and epidural opioids.

Chaney MA.

Can J Anaesth. 1995;42:891–903.

The purpose of this article is to review the literature on the side effects of intrathecal and epidural opioids. English-language articles were identified through a MEDLINE search and through review of the bibliographies of identified articles. With the increasing utilization of intrathecal and epidural opioids in humans during the 1980s, a wide variety of clinically relevant side effects have been reported. The four classic side effects are pruritus, nausea and vomiting, urinary retention, and respiratory depression. Numerous other side effects have also been described. Most side effects are dose-dependent and may be more common if the opioid is administered intrathecally. Side effects are less common in patients chronically exposed to either intrathecal, epidural, or systemic opioids. Some side effects are mediated via interaction with specific opioid receptors while others are not. It is concluded that the introduction of intrathecal and epidural opioids marks one of the most important breakthroughs in pain management in the last two decades. However, a wide variety of clinically relevant non-nociceptive side effects may occur. All physicians utilizing intrathecal and epidural opioids must be aware of these side effects, for while most are minor, others are potentially lethal.

Abdallah et al 2012

Transversus abdominis plane block: a systematic review.

Abdallah FW, Chan VW, Brull R.

Reg Anesth Pain Med 2012;37(2):193–209

Johns et al 2012

Clinical effectiveness of transversus abdominis plane (TAP) block in abdominal surgery: a systematic review and meta-analysis.

Johns N, O'Neill S, Ventham NT, Barron F, Brady RR, Daniel T.

Colorectal Dis 2012;14(10):e635–42

De Oliveira, Milad et al 2011

Transversus abdominis plane infiltration and quality of recovery after laparoscopic hysterectomy: a randomized controlled trial.

De Oliveira GS Jr, Milad MP, Fitzgerald P, Rahmani R, McCarthy RJ.

Obstet Gynecol 2011;118(6):1230–1237

Kane et al 2012

Randomized trial of transversus abdominis plane block at total laparoscopic hysterectomy: effect of regional analgesia on quality of recovery.

Kane SM, Garcia-Tomas V, Alejandro-Rodriguez M, Astley B, Pollard RR.

Am J Obstet Gynecol 2012;207(5):419.e1–5

Andrieu et al 2009

The efficacy of intrathecal morphine with or without clonidine for postoperative analgesia after radical prostatectomy

G, Roth B, Ousmane L, Castaner M, Petillot P, Vallet B, Villers A, Lebuffe G.

Anesthesia and Analgesia 2009;108(6):1954–1957

Salonia et al 2004

General versus spinal anesthesia in patients undergoing radical retropubic prostatectomy: results of a prospective, randomized study

Salonia A, Crescenti A, Suardi N, Memmo A, Naspro R, Bocciardi AM, Colombo R, Da Pozzo LF, Rigatti P, Montorsi F.

Urology 2004;64(1):95–100

Brown et al 2004

Intrathecal Anesthesia and Recovery from Radical Prostatectomy: A Prospective, Randomized, Controlled Trial

Brown DR, Hofer RE, Patterson DE, Fronapfel PJ, Maxson PM, Narr BJ, Eisenach JH, Blute ML, Schroeder DR, Warner DO.

Anesthesiology 2004;100(4):926–934

Meylan et al 2009

Benefit and risk of intrathecal morphine without local anaesthetic in patients undergoing major surgery: meta-analysis of randomized trials.

Meylan N, Elia N, Lysakowski C, Tramèr MR.

Br J Anaesth 2009;102(2):156–167

Bilgin et al 2011

Wound infiltration with bupivacaine and intramuscular diclofenac reduces postoperative tramadol consumption in patients undergoing radical retropubic prostatectomy: A prospective, double-blind, placeb

Bilgin TE, Bozlu M, Atici S, Cayan S, Tasdelen B.

Urology 2011;78:1281–1285

Lee et al 2011

The effects of magnesium sulfate infiltration on perioperative opioid consumption and opioid-induced hyperalgesia in patients undergoing robot-assisted laparoscopic prostatectomy with remifentanil-bas

Lee C, Song YK, Jeong HM, Park SN.

Korean Journal of Anesthesiology 2011;61(3):244–250

Wu et al 2005

Efficacy of continuous local anesthetic infusion for postoperative pain after radical retropubic prostatectomy

Wu CL, Partin AW, Rowlingson AJ, Kalish MA, Walsh PC, Fleisher LA.

Urology 2005;66(2):366–370

Tauzin-Fin et al 2009

Wound infiltration with magnesium sulphate and ropivacaine mixture reduces postoperative tramadol requirements after radical prostatectomy

Tauzin-Fin P, Sesay M, Svartz L, Krol-Houdek MC, Maurette P.

Acta Anaesthesiologica Scandinavica 2009;53(4):464–469

Bugedo et al 1990

Preoperative percutaneous ilioinguinal and iliohypogastric nerve block with 0.5% bupivacaine for post-herniorrhaphy pain management in adults.

Bugedo GJ, Carcamo CR, Mertens RA, Dagnino JA, Munoz HR.

Reg Anesth 1990;15(3):130–133.

The safety, effectiveness and duration of a percutaneous ilioinguinal-iliohypogastric nerve block with 10 ml 0.5% bupivacaine, as a method for postoperative analgesia, were studied prospectively in adult patients undergoing unilateral inguinal herniorrhaphy under spinal anesthesia. Group I (n = 20) blocked patients were compared with Group II (n = 25), non-blocked control patients. A blinded observer assessed pain scores and analgesic requirements after surgery. Group I patients had less pain at 3, 6, 24 and 48 hours after surgery and also required less analgesics during the first two postoperative days. This technique appears to be a simple and safe method for providing effective and long-lasting postoperative analgesia following inguinal hernia repair in adults.

Dierking et al 1994

The effects of wound infiltration with bupivacaine versus saline on postoperative pain and opioid requirements after herniorrhaphy.

Dierking GW, Ostergaard E, Ostergard HT, Dahl JB.

Acta Anaesthesiol Scand 1994;38(3):289–292.

In a prospective, double-blind, placebo-controlled study, twenty-eight healthy, male patients, aged 20-69 years, scheduled for unilateral elective inguinal herniorrhaphy ad modum Bassini were randomized to receive postoperative infiltration of the surgical wound with either bupivacaine 0.25%, or isotonic saline. General anaesthesia was induced with thiopentone 3-5 and alfentanyl 10, and maintained with alfentanyl 5 15 min and N2O/O2. After herniorrhaphy, the internal fascia was infiltrated with bupivacaine 0.25% or saline, 10 ml. After closure of the external fascia, the subcutaneous tissue was infiltrated with bupivacaine 0.25% or saline, 15 ml on both sides of the surgical wound. Pain at rest, during mobilisation and during cough was significantly decreased in patients receiving bupivacaine compared to placebo. Median time to first request for morphine was increased from 25 min to 135 min, and the consumption of supplementary morphine during the 24 h study period reduced from four to two doses of 0.1 iv or 0.125 im, in patients who received bupivacaine compared to placebo.

Dierking et al 1992

Effect of pre- vs postoperative inguinal field block on postoperative pain after herniorrhaphy. see comment.

Dierking GW, Dahl JB, Kanstrup J, Dahl A, Kehlet H.

Br J Anaesth 1992;68(4):344–348.

The analgesic effects of an identical inguinal field block, performed before or immediately after inguinal herniorrhaphy, were evaluated in 32 healthy patients in a double-blind, randomized study. During surgery, all patients received a light general anaesthesia with thiopentone, alfentanil and nitrous oxide in oxygen. After induction of general anaesthesia, patients were allocated randomly to receive an inguinal field block with lignocaine, either 15 min before operation or immediately after operation, after closure of the surgical wound, but before the patients were awake. Pain score on a visual analogue scale and on a verbal scale at rest, during mobilization from supine into sitting position and during cough was assessed 1, 2, 4, 6, 8 and 24 h, and 7 days after operation. No significant differences between the groups were observed in VAS scores or verbal pain scores during rest or ambulation at any time. There was no significant difference in time to first request for morphine or total morphine consumption. These results do not show pre-emptive analgesia with a conventional inguinal field block to be of clinical importance compared with a similar block administered after operation.

Gupta A.

Local anaesthesia for pain relief after laparoscopic cholecystectomy--a systematic review

Gupta A.

Best Pract Res Clin Anaesthesiol 2005;19(2):275-292

Cobby et al 1997

Wound infiltration with local anaesthetic after abdominal hysterectomy.

Cobby TF, Reid MF.

Br J Anaesth 1997;78(4):431–432.

The study was performed to investigate if wound infiltration with 20 ml of 0.5% bupivacaine after abdominal hysterectomy improved analgesia and reduced morphine requirements from a patient-controlled analgesia system during the first 6 h after operation. Forty patients undergoing abdominal hysterectomy were allocated randomly to one of two groups. The study was performed in a double-blind controlled manner. Morphine requirements in the first 6 h after operation were similar in both the control (30.3 mg) and bupivacaine (29.0 mg) groups. Cumulative hourly morphine requirements did not differ significantly between the two groups. Pain scores assessed by visual analogue were similar in both groups.

Møiniche et al 2000

Local anesthetic infiltration for postoperative pain relief after laparoscopy: A qualitative and quantitative systematic review of intraperitoneal, port-site infiltration and mesosalpinx block.

Møiniche S, Jorgensen H, Wetterslev J, Dahl JB

Anesth Analg 2000; 90: 899–912.

In a systematic review, we evaluated randomized controlled trials (RCTs) of peripheral local anesthetics (LA) compared with placebo or no treatment in the control of postoperative pain after laparoscopic surgery. A total of 41 trials with data from 2794 patients were considered appropriate for analysis. Of these 41 RCTs, 13 evaluated intraperitoneal LA after cholecystectomy, four RCTs assessed intraperitoneal LA after other procedures, eight RCTs evaluated port-site infiltration after various procedures, 12 RCTs evaluated mesosalpinx or fallopian tube block after sterilization, and four RCTs considered combined LA regimens. Outcome measures were pain scores, analgesic consumption, and time to first analgesic request. Efficacy was estimated by significant difference (P < 0.05), as reported in the original reports, and by calculation of the weighted mean difference of visual analog scale pain scores between treatment groups. Improved pain relief was observed in seven of the 13 RCTs of intraperitoneal LA after cholecystectomy and in four RCTs of other procedures. A statistically significant weighted mean difference of -13 mm visual analog scale (95% confidence intervals [CI]: -20 to -6) in favor of the treatment groups was observed after cholecystectomy. Three of eight trials of port-site infiltration showed significant differences but questionable clinical importance and validity in two; weighted mean difference was not statistically significant between treatment groups (95% CI -9 to 1). All RCTs of mesosalpinx or fallopian tube block after sterilization showed improved pain relief with a statistically significant weighted mean difference of -19 mm (95% CI -25 to -14) in favor of treatment groups. Data of combined regimens were positive, however, sparse. We conclude that there was evidence for a statistically significant but clinically questionable, important effect of intraperitoneal LA for postoperative pain control. There was evidence for a significant but short-lasting effect of mesosalpinx/fallopian tube block after sterilization, but there was a lack of evidence for any important effect of port-site infiltration. Data from combined regimens were too sparse for conclusions. IMPLICATIONS: A systematic review summarizes, through transparent methodology, available information from randomized, controlled trials to produce the best available evidence-based estimate of a "true" clinical effect of an intervention. This systematic review confirms intraperitoneal and mesosalpinx local anesthetic block, not port-site infiltration, to have some impact on postoperative pain after laparoscopy.