Literature Reviews

Procedure-specific systematic review summary

Bibliography

Non-cosmetic Breast Surgery

Ong et al 2005

The efficacy of preemptive analgesia for acute postoperative pain management: a meta-analysis.

Ong CK, Lirk P, Seymour RA, Jenkins BJ.

Anesth Analg 2005;100(3):757–73


Dirks ET AL 2002

A randomized study of the effects of single-dose gabapentin versus placebo on postoperative pain and morphine consumption after mastectomy.

Dirks J, Fredensborg BB, Christensen D, Fomsgaard JS, Flyger H, Dahl JB

Anesthesiology 2002;97(3):560-4

BACKGROUND: The anticonvulsant gabapentin has proven effective for neuropathic pain in three large placebo-controlled clinical trials. Experimental and clinical studies have demonstrated antihyperalgesic effects in models involving central neuronal sensitization. It has been suggested that central neuronal sensitization may play an important role in postoperative pain. The aim of the study was to investigate the effect of gabapentin on morphine consumption and postoperative pain in patients undergoing radical mastectomy. METHODS: In a randomized, double-blind, placebo-controlled study, 70 patients received a single dose of oral gabapentin (1,200 mg) or placebo 1 h before surgery. Patients received patient-controlled analgesia with morphine at doses of 2.5 mg with a lock-out time of 10 min for 4 h postoperatively. Pain was assessed on a visual analog scale at rest and during movement, and side effects were assessed on a four-point verbal scale 2 and 4 h postoperatively. RESULTS: Thirty-one patients in the gabapentin group and 34 patients in the placebo group completed the study. Gabapentin reduced total morphine consumption from a median of 29 (interquartile range, 21-33) to 15 (10-19) mg (P< 0.0001). Pain during movement was reduced from 41 (31-59) to 22 (10-38) mm at 2 h postoperatively (P < 0.0001) and from 31 (12-40) to 9 (3-34) mm at 4 h postoperatively (P = 0.018). No significant differences between groups were observed with regard to pain at rest or side effects. CONCLUSION: A single dose of 1,200 mg oral gabapentin resulted in a substantial reduction in postoperative morphine consumption and movement-related pain after radical mastectomy, without significant side effects. These promising results should be validated in other acute pain models involving central neuronal sensitization.


Fassoulaki 2002

The analgesic effect of gabapentin and mexiletine after breast surgery for cancer.

Fassoulaki A, Patris K, Sarantopoulos C, Hogan Q

Anesthesia and analgesia 2002;95(4):985-91.

We evaluated the effect of multimodal analgesia on acute and chronic pain after breast surgery for cancer. Fifty patients scheduled for breast cancer surgery were blindly randomized to receive gabapentin, eutectic mixture of local anesthetics cream, and ropivacaine in the wound or three placebos. Pain (visual analog scale) and analgesics were recorded in the postanesthesia care unit (PACU) 3, 6, and 9 h and 8 days after surgery. Three and 6 mo later, patients were assessed for chronic pain. The treatment group consumed less paracetamol in the PACU (469 versus 991 mg; P < 0.002) and less Lonalgal (1.0 versus 4.4 tablets; P = 0.003) than the controls, exhibited lower visual analog scale scores at rest in the PACU (P = 0.001) and on postoperative Days 1, 3, and 5 (P = 0.040, P = 0.015, and P = 0.045, respectively), and after movement in the PACU (P = 0.001) and on postoperative Days 2, 4, and 8 (P = 0.028, P = 0.007, and P = 0.032, respectively). Three and 6 mo after surgery, 18 of 22 (82%) and 12 of 21 (57%) of the controls reported chronic pain versus 10 of 22 (45%) and 6 of 20 (30%) in the treatment group (P = 0.028 and P = 0.424, respectively); 5 of 22 and 4 of 21 of the controls required analgesics versus 0 of 22 and 0 of 20 of those treated (P = 0.048 and P = 0.107, respectively). Multimodal analgesia reduced acute and chronic pain after breast surgery for cancer.


Fassoulaki et al 2005

Multimodal analgesia with gabapentin and local anesthetics prevents acute and chronic pain after breast surgery for cancer.

Fassoulaki A, Triga A, Melemeni A, Sarantopoulos C.

Anesthesia and analgesia 2005;101(5):1427-32.

We evaluated the effect of multimodal analgesia on acute and chronic pain after breast surgery for cancer. Fifty patients scheduled for breast cancer surgery were blindly randomized to receive gabapentin, eutectic mixture of local anesthetics cream, and ropivacaine in the wound or three placebos. Pain (visual analog scale) and analgesics were recorded in the postanesthesia care unit (PACU) 3, 6, and 9 h and 8 days after surgery. Three and 6 mo later, patients were assessed for chronic pain. The treatment group consumed less paracetamol in the PACU (469 versus 991 mg; P < 0.002) and less Lonalgal (1.0 versus 4.4 tablets; P = 0.003) than the controls, exhibited lower visual analog scale scores at rest in the PACU (P = 0.001) and on postoperative Days 1, 3, and 5 (P = 0.040, P = 0.015, and P = 0.045, respectively), and after movement in the PACU (P = 0.001) and on postoperative Days 2, 4, and 8 (P = 0.028, P = 0.007, and P = 0.032, respectively). Three and 6 mo after surgery, 18 of 22 (82%) and 12 of 21 (57%) of the controls reported chronic pain versus 10 of 22 (45%) and 6 of 20 (30%) in the treatment group (P = 0.028 and P = 0.424, respectively); 5 of 22 and 4 of 21 of the controls required analgesics versus 0 of 22 and 0 of 20 of those treated (P = 0.048 and P = 0.107, respectively). Multimodal analgesia reduced acute and chronic pain after breast surgery for cancer.


Fassoulaki et al 2005

Multimodal analgesia with gabapentin and local anesthetics prevents acute and chronic pain after breast surgery for cancer.

Fassoulaki A, Triga A, Melemeni A, Sarantopoulos C

Anesthesia and analgesia 2005;101(5):1427-32.

No abstract available


Dahl et al 2004

'Protective premedication': an option with gabapentin and related drugs? A review of gabapentin and pregabalin in the treatment of post-operative pain.

Dahl JB, Mathiesen O, Moiniche S.

Acta Anaesthesiol Scand 2004;48:1130–1136.

Substantial progress has been made during the last decades in our understanding of acute pain mechanisms, and this knowledge has encouraged the search for novel treatments. Of particular interest has been the observation that tissue injury initiates a number of modulations of both the peripheral and the central pain pathways, which convert the system from a 'physiological' to a 'pathological' mode of processing afferent information. Gabapentin, which binds to the alpha(2)delta subunit of the voltage-dependent calcium channel, is active in animal models of 'pathological' but not in models of 'physiological' pain. Consequently, attention has so far been focused on neuropathic pain as a target for the clinical use of gabapentin and analogues. Recently, several reports have indicated that gabapentin may have a place in the treatment of post-operative pain. This article presents a brief summary of the potential mechanisms of post-operative pain, and a systematic review of the available data of gabapentin and pregabalin for post-operative analgesia. It is concluded that the results with gabapentin and pregabalin in post-operative pain treatment published so far are promising. It is suggested that future studies should explore the effects of 'protective premedication' with combinations of various antihyperanalgesic and analgesic drugs for post-operative analgesia.


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.


Nikolajsen 2006

A randomized study of the effects of gabapentin on postamputation pain.

Nikolajsen L, Finnerup NB, Kramp S, Vimtrup AS, Keller J, Jensen TS.

Anesthesiology. 2006 Nov;105(5):1008-15.

BACKGROUND: Pain after amputation is common but difficult to treat. Therefore, the authors examined whether postoperative treatment with gabapentin could reduce postamputation stump and phantom pain. METHODS: Forty-six patients scheduled to undergo lower limb amputation were randomly assigned to receive oral gabapentin or placebo. Treatment was started on the first postoperative day and continued for 30 days. The daily dose of gabapentin or placebo was gradually increased to 2,400 mg/day. The intensity of stump and phantom pain was recorded every day on a numeric rating scale (0-10) during the 30-day treatment period. Five interviews were performed after 7, 14, and 30 days and after 3 and 6 months. RESULTS: Results from 41 patients were included in the data analysis. The risk of phantom pain (gabapentin vs. placebo) was 55.0% versus 52.6% (risk difference, 2.4%; 95% confidence interval, -28.9 to 33.7%; P = 0.88; 30 days) and 58.8% versus 50.0% (risk difference, 8.8%; 95% confidence interval, -23.3 to 40.9%; P = 0.59; 6 months). The median intensity of phantom pain (gabapentin vs. placebo) was 1.5 (range, 0-9.0) versus 1.2 (range, 0-6.6) (P = 0.60; 30 days) and 1.0 (range, 0-6.0) versus 0.5 (range, 0-5.0) (P = 0.77; 6 months). The median intensity of stump pain was 0.85 (range, 0-8.2) versus 1.0 (range, 0-5.4) (P = 0.68; 30 days) and 0 (range, 0-8.0) versus 0 (range, 0-5.0) (P = 0.58; 6 months). CONCLUSION: Gabapentin administered in the first 30 postoperative days after amputation does not reduce the incidence or intensity of postamputation pain.


Chan et al 1996

Evaluation of the effect of diclofenac given before or after surgery with or without bupivacaine infiltration.

Chan A, Dore CJ, Ramachandra V

Anaesthesia 1996;51(6):592-595.

One hundred patients undergoing breast lump excision using a standard anaesthetic technique in the Day Care Unit were randomly divided into five groups. Groups A and B received either saline or diclofenac in a double-blinded fashion before and at the end of the procedure, with both groups receiving 10 ml of 0.5% bupivacaine infiltration at the end. Groups C and D also received saline or diclofenac before and after surgery but had no bupivacaine infiltration at the end. Group E did not receive any injections but had bupivacaine infiltration at the end of surgery. In the postoperative period, pain was assessed by a visual analogue scale at 30 min intervals until discharge. All patients were requested to complete a pain relief questionaire over the 48 h following surgery. There were highly significant differences between those who received bupivacaine and those who did not in the visual analogue scale scores at 30 min (p= 0.001),60 min (p < 0.001), 120 min postoperatively (p = 0.02) and at discharge (p = 0.03). Pain scores were lower in those who received bupivacaine and they were less likely to request rescue medication, although this did not reach significance (p = 0.07). There were significant differences between the groups who received bupivacaine and diclofenac injection and those who received bupivacaine alone for visual analogue scale scores at 60 min following surgery (p =0.05) and at 48 h (p = 0.002). Pain relief was better in those patients who received both bupivacaine and diclofenac injection. Although not significant (p =0.22), fewer patients required rescue medication when diclofenac was given before surgery (10%) rather than after surgery (22.5%). Fewer patients had a fair amount or a great deal of pain in the 48 h following surgery when diclofenac was injected before (7.5%) rather than after surgery (12.5%). The mean number of oral analgesics taken in the 48 h after surgery was also lower in those patients who had the diclofenac before the surgery rather than after.


Priya et al 2002

Efficacy of intravenous ketoprofen for pre-emptive analgesia.

Priya V, Divatia JV, Sareen R, Upadhye S.

Journal of postgraduate medicine 2002;48(2):109-12.

AIM: To determine whether intravenous ketoprofen is effective as pre- emptive analgesia for breast surgery. DESIGN: Randomised, controlled, double blind study. PATIENTS AND METHODS: 50 patients undergoing breast surgery under general anaesthesia randomised to receive either 100 mg intravenous ketoprofen 30 minutes before (Group I), or immediately after surgical incision (Group II). Postoperatively, pain scores (Visual Analogue Scale, VAS) and time to rescue analgesic were recorded by an independent, blinded observer. The study was terminated when rescue analgesic was required (VAS > or =4 or demand for analgesic). STATISTICAL ANALYSIS: Continuous variables were analysed by the unpaired 't' test, discrete variables with the chi square test, and survival curves by the log-rank test. RESULTS: Pain scores were significantly lower in Group I till 10 hours after surgery. The number of patients requiring analgesia at 4, 6, 8 and 10 hours was significantly lower in group I (0% vs. 47% (P <0.0001), 0% vs. 44% (P <0.003), 0% vs. 80% (P <0.0001), 0% vs. 100% (P <0.0001) respectively) . The mean time for rescue analgesic was 15.47 -/+ 2.87 hours in group I versus 4.22 -/+ 2.55 hours in group II (P <0.0001). CONCLUSION: Pre- emptive analgesia with Intravenous ketoprofen (100mg) produces better postoperative pain-relief in patients undergoing breast surgery.


Priya et al 2002

Efficacy of intravenous ketoprofen for pre-emptive analgesia.

Priya V, Divatia JV, Sareen R, Upadhye S

Journal of postgraduate medicine 2002;48(2):109-12.

AIM: To determine whether intravenous ketoprofen is effective as pre- emptive analgesia for breast surgery. DESIGN: Randomised, controlled, double blind study. PATIENTS AND METHODS: 50 patients undergoing breast surgery under general anaesthesia randomised to receive either 100 mg intravenous ketoprofen 30 minutes before (Group I), or immediately after surgical incision (Group II). Postoperatively, pain scores (Visual Analogue Scale, VAS) and time to rescue analgesic were recorded by an independent, blinded observer. The study was terminated when rescue analgesic was required (VAS > or =4 or demand for analgesic). STATISTICAL ANALYSIS: Continuous variables were analysed by the unpaired 't' test, discrete variables with the chi square test, and survival curves by the log-rank test. RESULTS: Pain scores were significantly lower in Group I till 10 hours after surgery. The number of patients requiring analgesia at 4, 6, 8 and 10 hours was significantly lower in group I (0% vs. 47% (P <0.0001), 0% vs. 44% (P <0.003), 0% vs. 80% (P <0.0001), 0% vs. 100% (P <0.0001) respectively) . The mean time for rescue analgesic was 15.47 -/+ 2.87 hours in group I versus 4.22 -/+ 2.55 hours in group II (P <0.0001). CONCLUSION: Pre- emptive analgesia with Intravenous ketoprofen (100mg) produces better postoperative pain-relief in patients undergoing breast surgery.


Chan et al 1996

Evaluation of the effect of diclofenac given before or after surgery with or without bupivacaine infiltration.

Chan A, Dore CJ, Ramachandra V.

Anaesthesia 1996;51(6):592-595

One hundred patients undergoing breast lump excision using a standard anaesthetic technique in the Day Care Unit were randomly divided into five groups. Groups A and B received either saline or diclofenac in a double-blinded fashion before and at the end of the procedure, with both groups receiving 10 ml of 0.5% bupivacaine infiltration at the end. Groups C and D also received saline or diclofenac before and after surgery but had no bupivacaine infiltration at the end. Group E did not receive any injections but had bupivacaine infiltration at the end of surgery. In the postoperative period, pain was assessed by a visual analogue scale at 30 min intervals until discharge. All patients were requested to complete a pain relief questionaire over the 48 h following surgery. There were highly significant differences between those who received bupivacaine and those who did not in the visual analogue scale scores at 30 min (p= 0.001),60 min (p < 0.001), 120 min postoperatively (p = 0.02) and at discharge (p = 0.03). Pain scores were lower in those who received bupivacaine and they were less likely to request rescue medication, although this did not reach significance (p = 0.07). There were significant differences between the groups who received bupivacaine and diclofenac injection and those who received bupivacaine alone for visual analogue scale scores at 60 min following surgery (p =0.05) and at 48 h (p = 0.002). Pain relief was better in those patients who received both bupivacaine and diclofenac injection. Although not significant (p =0.22), fewer patients required rescue medication when diclofenac was given before surgery (10%) rather than after surgery (22.5%). Fewer patients had a fair amount or a great deal of pain in the 48 h following surgery when diclofenac was injected before (7.5%) rather than after surgery (12.5%). The mean number of oral analgesics taken in the 48 h after surgery was also lower in those patients who had the diclofenac before the surgery rather than after.


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.


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.


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.


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.


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.


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.


Shi 2008

Clinical use and pharmacological properties of selective COX-2 inhibitors.

Shi S, Klotz U.

Eur J Clin Pharmacol. 2008 Mar;64(3):233-252.

Selective COX-2 inhibitors (coxibs) are approved for the relief of acute pain and symptoms of chronic inflammatory conditions such as osteoarthritis (OA) and rheumatoid arthritis (RA). They have similar pharmacological properties but a slightly improved gastrointestinal (GI) safety profile if compared to traditional nonsteroidal anti-inflammatory drugs (tNSAIDs). However, long-term use of coxibs can be associated with an increased risk for cardiovascular (CV) adverse events (AEs). For this reason, two coxibs were withdrawn from the market. Currently celecoxib, etoricoxib, and lumiracoxib are used. These three coxibs differ in their chemical structure and selectivity for COX-2, which might explain some of their pharmacological features. Following oral administration, the less lipophilic celecoxib has a lower bioavailability (20-40%) than the other two coxibs (74-100%). All are eliminated by hepatic metabolism involving mainly CYP2C9 (celecoxib, lumiracoxib) and CYP3A4 (etoricoxib). Elimination half-life varies from 5 to 8 h (lumiracoxib), 11 to 16 h (celecoxib) and 19 to 32 h (etoricoxib). In patients with liver disease, plasma levels of celecoxib and etoricoxib are increased about two-fold. Clinical efficacies of the coxibs are comparable to tNSAIDs. There is an ongoing discussion about whether the slightly better GI tolerability (which is lost if acetylsalicylic acid is coadministered) of the coxibs is offset by their elevated risks for CV AEs (also seen with tNSAIDs other than naproxen), which apparently increase with dose and duration of exposure. In addition, the higher costs for coxibs (if compared to tNSAIDs, even when a "gastroprotective" proton pump inhibitor is coadministered) should be taken into consideration, if a coxib will be selected for certain patients with a high risk for GI complications. For such treatment, the lowest effective dose should be used for a limited time. Monitoring of kidney function and blood pressure appears advisable. It is hoped that further controlled studies can better define the therapeutic place of the coxibs.


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.


Rawal 2006

Pain relief following breast augmentation surgery: a comparison between incisional patient-controlled regional analgesia and traditional oral analgesia.

Rawal N, Gupta A, Helsing M, Grell K, Allvin R.

Eur J Anaesthesiol. 2006 Dec;23(12):1010-7.

BACKGROUND AND OBJECTIVES: Postoperative pain is a common problem following ambulatory breast augmentation surgery. This study was performed to compare standard of care (oral analgesics) with patient-controlled incisional regional analgesia (PCRA) for postoperative pain management at home for 48 h. A second aim was to compare the analgesic efficacy of ropivacaine 0.25% vs. 0.5%. METHODS: Surgery was performed under local anaesthesia and monitored anesthesia care. Sixty adults (ASA 1-2) were randomized to one of two groups. Patients in Group PCRA could self-administer ropivacaine 0.25% 10 mL in the left breast and ropivacaine 0.5% in the right breast. Patients in Group T (tablets) received our standard of care treatment, i.e. oral paracetamol 1 g four times a day and oral ibuprofen 500 mg three times a day. Parameters measured included: analgesic requirements (in post-anesthesia care unit, PACU and post-discharge), pain intensity (visual analogue scale), patient satisfaction, global analgesia, side-effects, and quality of recovery. RESULTS: Pain scores were significantly lower in Group PCRA compared to Group T at all time periods (P < 0.05). No differences were found in pain scores between the right and left breasts. Significantly more patients in Group T requested analgesics in the recovery unit (27 vs. 7; P = 0.001) and also at home (20 vs. 11; P < 0.02). More patients in the tablet group had nausea and vomiting (10 vs. 3; P < 0.05). Global analgesia on day 2 was significantly better in PCRA group; however, patient satisfaction was similar in both groups. More patients in the tablet group had sleep disturbance and woke up at night due to pain. CONCLUSIONS: Pain relief after ambulatory breast augmentation is superior with incisional PCRA when compared to oral analgesic combination of paracetamol and ibuprofen. Incisional PCRA was associated with minimal side-effects and less sleep disturbance. There was no difference in the analgesic efficacy between ropivacaine 0.25% and 0.5%.


Abou Zeid 2002

Dolasetron decreases postoperative nausea and vomiting after breast surgery.

Abou Zeid H, Al-Gahamdi A, Abdul-Hadi M.

Breast J. 2002 Jul-Aug;8(4):216-21.

In a randomized, placebo-controlled, double-blind trial, we compared the efficacy of dolasetron, dexamethasone, and metoclopramide in a preventing postoperative nausea and vomiting in women undergoing breast surgery. Patients were allocated randomly to one of four groups (20 patients each): group A received 12.5 mg dolasetron, group B received 8 mg dexamethasone, group C received 20 mg metoclopramide, and group D received placebo intravenously. If patients complained of retching or vomiting or if patients demanded an antiemetic, 1.25 mg droperidol was administered intravenously. To quantify postoperative nausea and vomiting, the following score was used: 0 = no nausea, 1 = nausea, 2 = retching, 3 = single vomiting, 4 = multiple vomiting. Dolasetron and dexamethasone reduced the postoperative nausea and vomiting score significantly (p < 0.02 versus metoclopramide; p < 0.0001 versus placebo). Metoclopramide also reduced the postoperative nausea and vomiting score (p < 0.02 versus placebo). Fisher's exact test showed a significant reduction of vomiting in the dolasetron and dexamethasone groups compared with metoclopramide-treated patients (p < 0.007) and placebo-treated patients (p < 0.000006) and a significantly lower rate of nausea in comparison to the placebo group (p < 0.009). There were no significant differences between the metoclopramide and the placebo groups (using Fisher's exact test). The use of postoperative droperidol was significantly lower in both the dolasetron group (p < 0.04 versus metoclopramide; p < 0.0001 versus placebo) and dexamethasone group (p < 0.04 versus metoclopramide; p < 0.0001 versus placebo), as well as in the metoclopramide group (p < 0.02 versus placebo). Intravenous dolasetron and dexamethasone were equally effective and both are more effective than metoclopramide for preventing vomiting after breast surgery. Also both were significantly superior to either metoclopramide or placebo for postoperative nausea and vomiting and the need for droperidol rescue.


Bisgaard 2003

Bisgaard T, Klarskov B, Kehlet H, Rosenberg J. Preoperative dexamethasone improves surgical outcome after laparoscopic cholecystectomy: a randomized double-blind placebo-controlled trial.

Bisgaard T, Klarskov B, Kehlet H, Rosenberg J.

Ann Surg 2003;238(5):651-60.

OBJECTIVE: To determine the effects of preoperative dexamethasone on surgical outcome after laparoscopic cholecystectomy (LC). SUMMARY BACKGROUND DATA: Pain and fatigue are dominating symptoms after LC and may prolong convalescence. METHODS: In a double-blind, placebo-controlled study, 88 patients were randomized to intravenous dexamethasone (8 mg) or placebo 90 minutes before LC. Patients received a similar standardized anesthetic, surgical, and multimodal analgesic treatment. All patients were recommended 2 days postoperative duration of convalescence. The primary endpoints were fatigue and pain. Preoperatively and at several times during the first 24 postoperative hours, we measured C-reactive protein (CRP) and pulmonary function, pain scores, nausea, and number of vomiting episodes were registered. Analgesic and antiemetic requirements were recorded. Also, on a daily basis, patients reported scores of fatigue and pain before and during the first postoperative week and the dates for resumption of work and recreational activities. RESULTS: Eight patients were excluded from the study, leaving 40 patients in each study group for analysis. There were no apparent side effects of the study drug. Dexamethasone significantly reduced postoperative levels of CRP (P = 0.01), fatigue (P = 0.01), overall pain, and incisional pain during the first 24 postoperative hours (P < 0.05) and total requirements of opioids (P < 0.05). In addition, cumulated overall and visceral pain scores during the first postoperative week were significantly reduced (P < 0.05). Dexamethasone also reduced nausea and vomiting on the day of operation (P < 0.05). Resumption of recreational activities was significantly faster in the dexamethasone group versus placebo group (median 1 day versus 2 days) (P < 0.05). CONCLUSION: Preoperative dexamethasone (8 mg) reduced pain, fatigue, nausea and vomiting, and duration of convalescence in patients undergoing noncomplicated LC, when compared with placebo, and is recommended for routine use.


Carlisle 2006b

Drugs for preventing postoperative nausea and vomiting.

Carlisle JB, Stevenson CA.

Cochrane Database Syst Rev. 2006 Jul 19;3:CD004125

BACKGROUND: Drugs can prevent postoperative nausea and vomiting, but their relative efficacies and side effects have not been compared within one systematic review. OBJECTIVES: The objective of this review was to assess the prevention of postoperative nausea and vomiting by drugs and the development of any side effects. SEARCH STRATEGY: We searched The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 2, 2004), MEDLINE (January 1966 to May 2004), EMBASE (January 1985 to May 2004), CINAHL (1982 to May 2004), AMED (1985 to May 2004), SIGLE (to May 2004), ISI WOS (to May 2004), LILAC (to May 2004) and INGENTA bibliographies. SELECTION CRITERIA: We included randomized controlled trials that compared a drug with placebo or another drug, or compared doses or timing of administration, that reported postoperative nausea or vomiting as an outcome. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted outcome data. MAIN RESULTS: We included 737 studies involving 103,237 people. Compared to placebo, eight drugs prevented postoperative nausea and vomiting: droperidol, metoclopramide, ondansetron, tropisetron, dolasetron, dexamethasone, cyclizine and granisetron. Publication bias makes evidence for differences among these drugs unreliable. The relative risks (RR) versus placebo varied between 0.60 and 0.80, depending upon the drug and outcome. Evidence for side effects was sparse: droperidol was sedative (RR 1.32) and headache was more common after ondansetron (RR 1.16). AUTHORS' CONCLUSIONS: Either nausea or vomiting is reported to affect, at most, 80 out of 100 people after surgery. If all 100 of these people are given one of the listed drugs, about 28 would benefit and 72 would not. Nausea and vomiting are usually less common and, therefore, drugs are less useful. For 100 people, of whom 30 would vomit or feel sick after surgery if given placebo, 10 people would benefit from a drug and 90 would not. Between one to five patients out of every 100 people may experience a mild side effect, such as sedation or headache, when given an antiemetic drug. Collaborative research should focus on determining whether antiemetic drugs cause more severe, probably rare, side effects. Further comparison of the antiemetic effect of one drug versus another is not a research priority.


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.


Romundstad 2006

Methylprednisolone reduces pain, emesis, and fatigue after breast augmentation surgery: a single-dose, randomized, parallel-group study with methylprednisolone 125 mg, parecoxib 40 mg, and placebo.

Romundstad L, Breivik H, Roald H, Skolleborg K, Haugen T, Narum J, Stubhaug A.

Anesth Analg. 2006 Feb;102(2):418-25.

We compared methylprednisolone 125 mg IV (n = 68) and parecoxib 40 mg IV (n = 68) with placebo (n = 68) given before breast augmentation surgery in a randomized, double-blind parallel group study. Surgery was performed under local anesthesia combined with propofol/fentanyl sedation. Methylprednisolone and parecoxib decreased pain at rest and dynamic pain intensity from 1 to 6 h after surgery compared with placebo (mean summed pain intensity(1-6 h): methylprednisolone [17.25; 95% confidence interval [CI], 14.85-19.65] versus placebo [21.7; 95% CI, 19.3-24.1]; P < 0.03; parecoxib [15.25; 95% CI, 13.25-17.25] versus placebo; P < 0.001; mean summed dynamic pain intensity(1-6 h): methylprednisolone [22.7; 95% CI, 20.1-23.3] versus placebo [28.4; 95% CI, 26.0-30.8]; P < 0.01; parecoxib [20.9; 95% CI, 18.6-23.2] versus placebo; P < 0.001). Both rescue drug consumption and actual pain (all observations before and after rescue) during the first 6 h were similar in the two active drug groups and significantly reduced compared with placebo. Using a composite score of actual pain intensity and rescue analgesic use, the active drugs were significantly superior to placebo (P < 0.001 for both active drugs). Postoperative nausea and vomiting was reduced after methylprednisolone administration (incidence, 30%), but not after parecoxib (incidence, 37%), during the first 24 h compared with placebo (incidence, 60%; P < 0.001). Fatigue was reduced by methylprednisolone (incidence, 44%), but not by parecoxib (incidence, 59%), compared with placebo (incidence, 66%; P < 0.05). In conclusion, methylprednisolone 125 mg IV given before breast augmentation surgery had analgesic and rescue analgesic-sparing effects comparable with those of parecoxib 40 mg IV. Methylprednisolone, but not parecoxib, reduced nausea, vomiting, and fatigue.


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.


Barden 2003

Oral valdecoxib and injected parecoxib for acute postoperative pain: a quantitative systematic review.

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

BMC Anesthesiol. 2003 Jul 10;3(1):1.

BACKGROUND: Clinical trials suggest that cyclo-oxygenase-2 specific inhibitors (coxibs) are an effective treatment for acute postoperative pain. The aims of this systematic review were to examine the evidence for oral valdecoxib and injected parecoxib, and quantify efficacy and adverse effects. METHODS: Information from randomized, double-blind studies in acute postoperative pain was sought. The area under the pain relief versus time curve over four to six hours was dichotomized using validated equations to derive the proportion of patients with treatment and placebo with at least 50% pain relief over four to six hours and calculate the number-needed-to-treat (NNT). Information on duration of analgesia and adverse events was also collected. RESULTS: The NNT for one patient to experience at least 50% relief over six hours following a single oral dose of valdecoxib 20 mg and 40 mg was 1.7 (1.4 to 2.0) and 1.6 (1.4 to 1.8) respectively. The NNT for one patient to have at least 50% relief over four to six hours with parecoxib 20 mg IV and 40 mg IV was 3.0 (2.3 to 4.1) and 2.3 (2.0 to 2.6) respectively. Mean time to remedication (weighted by trial size) was >24 hours with valdecoxib 40 mg, 8.7 hours with parecoxib 40 mg IV and 1.7 to 1.8 hours with placebo. There were no statistical differences between treatment and placebo for any adverse effect. CONCLUSION: Both oral valdecoxib and injected parecoxib are effective treatments for acute postoperative pain.


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.


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.


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.

EMEA.

Available at http://www.emea.eu.int/humandocs/Humans/EPAR/bextra/bextra.htm


Wong et al 1999

Preincisional dextromethorphan decreases postoperative pain and opioid requirement after modified radical mastectomy

Wong CS, Wu CT, Yu JC, Yeh CC, Lee MM, Tao PL

Can J Anaesth 1999;46(12):1122–6

PURPOSE: To examine whether preincisional dextromethorphan (DM) improved analgesia after modified radical mastectomy (MRM). METHODS: Sixty patients (ASA I-II) scheduled for MRM were included and randomly allocated into two groups. Patients in the treatment group (DM) received 40 mg DM and 20 mg chlorpheniramine maleate (CPM) i.m., and those in the control group received 20 mg CPM i.m. alone 30 min before skin incision. Meperidine, 1 mg x kg(-1) i.m., was given for postoperative pain relief as required. The time to first meperidine injection, total meperidine consumption, worst pain score, bed-rest time, and side effects were recorded every 24 hr for 48 hr after surgery by a resident anesthesiologist on a double-blind basis. RESULTS: A longer time to first meperidine injection (19.2 +/- 1.6 vs 1.5 +/- 0.23 hr, P < 0.001) and lower meperidine consumption (0[10] vs 75[50] mg, median [interquartile range], P < 0.001) were observed in the DM group than in the control group. The bed-rest time was shorter in the DM than in the control group (18.0[4] vs 23.0[19] hr, P < 0.001). No difference was noted in worst VAS pain score. Meperidine-related side effects (nausea, vomiting, pruritus, dizziness, headache) were more frequent in the control (10/30) than in the DM group (3/30, P < 0.05). The number of patients who required meperidine injection for pain relief was lower in the DM (7/30) than in the control group (25/30, P < 0.005). No DM- or CPM-associated side effects were observed. CONCLUSION: Preincisional IM. DM treatment decreased postoperative pain and opioid requirement after MRM surgery.


Adam et al 1999

Preoperative small-dose ketamine has no preemptive analgesic effect in patients undergoing total mastectomy.

Adam F, Libier M, Oszustowicz T, Lefebvre D, Beal J, Meynadier J.

Anesthesia and analgesia 1999;89(2):444-7.

We evaluated the preemptive analgesic effect of a small dose of ketamine given before or immediately after surgery in a randomized, double-blinded study performed in 128 women undergoing total mastectomy. Group 1 patients received ketamine 0.15 mg/kg as a 5-mL i.v. injection 5 min before surgery and isotonic saline 5 mL i.v. at the time of skin closure. Group 2 received 5 mL i.v. of isotonic saline, then 0.15 mg/kg i.v. ketamine. A standard general anesthesia procedure including sufentanil was used. In the recovery room, patient-controlled analgesia i.v. morphine was used for postoperative analgesia. Postoperative pain was assessed by measuring morphine consumption and visual analog scale pain scores. No significant intergroup differences were seen in the pain scores. Patient- controlled analgesia morphine consumption was lower during the first 2 h after surgery in patients given ketamine at the time of skin closure. No patient complained of hallucinations or nightmares. The incidence of adverse effects was not different between the two groups. In conclusion, administering ketamine at the end of surgery is more effective in reducing morphine consumption than it is when given before surgery. Implications: We administered the same small dose of ketamine before or after surgery. The preoperative administration of 0.15 mg/kg ketamine in patients undergoing total mastectomy did not elicit a preemptive analgesic effect. Ketamine given at closure reduced the patient-controlled analgesia morphine requirement in the first 2 h after surgery.


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.


Duedahl et al 2006

A qualitative systematic review of peri-operative dextromethorphan in post-operative pain

Duedahl TH, Romsing J, Moiniche S, Dahl JB

Acta Anaesthesiol Scand 2006;50(1):1–13

BACKGROUND: The N-methyl-D-aspartate (NMDA) receptor antagonist, dextromethorphan (DM), has received interest as an adjunctive agent in post-operative pain management. Clinical trials have been contradictory. This systematic review aims to evaluate the available literature examining the analgesic efficacy of DM in post-operative patients. METHODS: Twenty-eight randomized, double-blind, clinical studies, with 40 comparisons, including a variety of dosing regimens comparing DM treatment with placebo, were included. Meta-analysis was intended but deemed to be inappropriate because of the substantial difference in methodology and reporting between trials. The outcome measures (pain scores at rest, time to first analgesic request and supplemental analgesic consumption) were evaluated qualitatively by significant difference (P<0.05) as reported in the original investigations. RESULTS: DM did not reduce the post-operative pain score with a clinically significant magnitude. The time to first analgesic request was significantly prolonged in most comparisons with DM. Significant decreases in supplemental opioid consumption were observed in the majority of parenteral DM studies and in about one-half of the oral studies. The decreases were of questionable clinical importance in most comparisons, although a relationship between a decrease in opioid consumption and opioid-related side-effects was established in some studies. CONCLUSION: Based on the studies available, DM has the potential to be a safe adjunctive agent to opioid analgesia in post-operative pain management, but the consistency of the potential opioid-sparing and pain-reducing effect must be questioned. Consequently, it is not possible to recommend dose regimens or routine clinical use of DM in post-operative pain. The route of administration may be important for the beneficial effect.


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.


Kampe et al 2004

Clinical efficacy of controlled-release oxycodone 20 mg administered on a 12-h dosing schedule on the management of postoperative pain after breast surgery for cancer.

Kampe S, Warm M, Kaufmann J, Hundegger S, Mellinghoff H, Kiencke P

Current medical research and opinion 2004;20(2):199-202.

OBJECTIVE: To assess clinical efficacy of controlled-release oxycodone (CRO) 20 mg on a 12-h dosing schedule in this prospective, randomised, placebo-controlled, double-blinded study of 40 ASA physical status I- III women undergoing breast surgery for cancer. RESEARCH DESIGN AND METHODS: General anaesthesia using remifentanil and propofol was performed for surgery. Both groups received premedication with oral midazolam 7.5 mg 1 h before surgery. In the controlled-release oxycodone group, one tablet of 20 mg CRO was administered with the premedication, and 12 h after the premedication another 20 mg CRO. In the placebo (PL) group, a placebo tablet was administered with the premedication, and 12 h later another placebo tablet. All patients had access to opioid rescue medication via an IV patient-controlled analgesia (PCA) device. MAIN OUTCOME MEASURES: Area under the curve (AUC), based on IV opioid rescue consumption over 24 h postoperatively. RESULTS: The AUC for IV PCA opioid consumption was significantly lower in the CRO group than in the PL group (p = 0.01). The CRO group required less IV opioid loading dose (p < 0.001), and consumed less opioid rescue medication 4 h (p = 0.036), 16 h (p = 0.01), and 24 h (p = 0.005) postoperatively. AUC for VAS scores at rest was significantly lower in the CRO group than in the PL group (p = 0.05). VAS scores at rest were lower in the CRO group 16 h (p = 0.04) and 24 h (p = 0.03) postoperatively. There was no difference in AUC for pain scores on movement (p = 0.103) and for quality of analgesia (p = 0.139). There was no difference in nausea between groups (p = 0.34). Pruritus, arterial hypotension or hypertension, bradycardia, and tachycardia were not observed in either treatment group. None of the patients showed signs of confusion, agitation, or respiratory depression. CONCLUSIONS: The administration of CRO 20 mg on a 12-h dosing schedule halves postoperative IV PCA opioid consumption. CRO 20mg is effective in preventing pain after breast surgery for cancer with only mild side-effects.


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.


Tarradell et al 1996

Respiratory and analgesic effects of meperidine and tramadol in patients undergoing orthopedic surgery.

Tarradell R, Pol O, Farre M, Barrera E, Puig MM.

Methods Find Exp Clin Pharmacol 1996;18(3):211–218.

The respiratory and analgesic effects of i.v. meperidine, tramadol and their correlation with plasma concentrations of meperidine, tramadol and O-demethyltramadol were determined. Forty-eight patients after total hip or knee replacement were randomly distributed into 3 groups (n = 16 each). At the time of analgesia request, they received in a double-blind manner, i.v. single doses of 100 mg meperidine, 100 mg tramadol, or saline. Thirty minutes after treatment, patients who requested additional analgesia were rescued with 75 mg diclofenac and morphine as required. Patients were evaluated at the time of analgesia request and at set intervals during 4 h. Meperidine induced sedation (p<0.05), respiratory depression (tidal volume, p<0.047; respiratory rate, p < 0.004; % O2 Sat, p<0.036), and hypercapnia (PaCO2, p<0.002). Incidence of nausea and vomiting was higher with tramadol (p<0.02). For the first 30 min, meperidine produced lower pain intensity scores than tramadol or saline (p<0.05). At this time, 14/16 patients on saline, 8/16 on meperidine and 11/16 on tramadol were rescued. Onset for meperidine analgesia was 10 min and > 30 min for tramadol. Both opioids produced similar degree of analgesia in patients who were not rescued. A negative correlation (r= -0.99) between analgesia and tramadol concentrations and a poor positive correlation (r= +0.54) with O-demethyltramadol (a metabolite of tramadol) was observed. Pain intensity differences correlated negatively with meperidine plasma concentrations during the first 30 min (r= -0.97) and positively thereafter (r= +0.92). In the present study, meperidine and tramadol produced comparable analgesia, with a different time course profile, but meperidine induced sedation and respiratory depression while tramadol did not.


Wheeler et al 2002

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

Wheeler M, Oderda GM, Ashburn MA, Lipman AG.

J Pain 2002;3(3):159–180.


Forst J et al 1999

Pain therapy following joint replacement. A randomized study of patient-controlled analgesia versus conventional pain therapy.

Forst J, Wolff S, Thamm P, Forst R

Archives of Orthopaedic & Trauma Surgery 1999;119(5-6):267-270

No abstract available


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.


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.


Farhat 1995

Efficacy of propacetamol in postoperative pain based on two modes of intravenous administration [Article in French]

Farhat F, Savoyen MC, Jayr C.

Cah Anesthesiol. 1995;43(4):351-6.

The analgesic and antipyretic efficacy of propacetamol is identical to paracetamol. Because the propacetamol is injectable and its side effects are uncommon and mild, it is the drug commonly used in France for postoperative pain relief. The aim of this prospective study was to compare the analgesic efficacy of propacetamol after breast surgery or thyroidectomy when it was administered either systematically or on the patients demand. After informed consent, 119 patients having undergone breast surgery or thyroidectomy, having received the same general anaesthesia and scheduled for receiving propacetamol postoperatively, were included in the study. Two groups of patients were compared, those who received propacetamol on demand (D Group) and those who received propacetamol systematically (S Group). During the first 24 hours, analgesia was evaluated on a visual analogical scale graded from 0 to 100 mm, at rest and during mobilization; the efficacy was also evaluated by the amount of additional analgesic drug injected. Side effects were also compared between the 2 treatment groups. In the 2 groups, demographic data, type of anaesthesia and type of surgery were identical. Postoperative pain relief and supplemental injection of morphine were not statistically different between the 2 groups. Propacetamol doses were statistically higher in the S group than in the D group (7.8 +/- 0.7 g and 3.9 +/- 2.3 g respectively, p < 0.05). Pain during propacetamol infusion was more frequent in the D group than in the S group (30% and 13% respectively, p < 0.05). No other adverse effects were observed during the study. Propacetamol alone is sufficient for pain relief after peripheral surgery; more than 90% of patients need no supplemental analgesic, and adverse effects are rare.


Kairaluoma 2004

Single-injection paravertebral block before general anesthesia enhances analgesia after breast cancer surgery with and without associated lymph node biopsy.

Kairaluoma PM, Bachmann MS, Korpinen AK, Rosenberg PH, Pere PJ

Anesthesia and analgesia 2004;99(6):1837-43

Paravertebral block (PVB) seems to decrease postoperative pain and postoperative nausea and vomiting (PONV) after breast surgery, but the studies have not been placebo controlled. We studied 60 patients scheduled for breast cancer surgery randomly given single-injection PVB at T3 with bupivacaine 5 mg/mL (1.5 mg/kg) or saline before general anesthesia. The patient and attending investigators were blinded; the PVB or the sham block was performed behind a curtain by an anesthesiologist not involved in the study. The patients given PVB with bupivacaine needed 40% less IV opioid medication (primary outcome variable) in the postanesthesia care unit, had a longer latency to the first opioid dose, and had less pain at rest after 24 h than the control patients (P < 0.01). They also had less PONV in the postanesthesia care unit (P < 0.05), were less sedated until 90 min (P < 0.05), and performed better in the digit symbol substitution test at 90 min and the ocular coordination test 60-120 min after surgery (P < 0.05). The average peak bupivacaine plasma concentration was 750 ng/m L. One patient had bilateral convulsions immediately after bupivacaine injection. We conclude that PVB before general anesthesia for breast cancer surgery reduced postoperative pain, opioid consumption, and occurrence of PONV and improved recovery from anesthesia.


Kairaluoma et al 2004

Single-injection paravertebral block before general anesthesia enhances analgesia after breast cancer surgery with and without associated lymph node biopsy.

Kairaluoma PM, Bachmann MS, Korpinen AK, Rosenberg PH, Pere PJ.

Anesth Analg 2004;99(6):1837–43.

Paravertebral block (PVB) seems to decrease postoperative pain and postoperative nausea and vomiting (PONV) after breast surgery, but the studies have not been placebo controlled. We studied 60 patients scheduled for breast cancer surgery randomly given single-injection PVB at T3 with bupivacaine 5 mg/mL (1.5 mg/kg) or saline before general anesthesia. The patient and attending investigators were blinded; the PVB or the sham block was performed behind a curtain by an anesthesiologist not involved in the study. The patients given PVB with bupivacaine needed 40% less IV opioid medication (primary outcome variable) in the postanesthesia care unit, had a longer latency to the first opioid dose, and had less pain at rest after 24 h than the control patients (P < 0.01). They also had less PONV in the postanesthesia care unit (P < 0.05), were less sedated until 90 min (P < 0.05), and performed better in the digit symbol substitution test at 90 min and the ocular coordination test 60-120 min after surgery (P < 0.05). The average peak bupivacaine plasma concentration was 750 ng/mL. One patient had bilateral convulsions immediately after bupivacaine injection. We conclude that PVB before general anesthesia for breast cancer surgery reduced postoperative pain, opioid consumption, and occurrence of PONV and improved recovery from anesthesia.


Terheggen et al 2002

Paravertebral blockade for minor breast surgery.

Terheggen MA, Wille F, Borel Rinkes IH, Ionescu TI, Knape JT.

Anesth Analg 2002;94(2):355–9.

Paravertebral blockade (PVB) has been advocated as a useful technique for breast surgery. We prospectively compared the efficacy of PVB via a catheter technique with the efficacy of general anesthesia (GA) for minor breast surgery. Thirty patients were randomized into two groups to receive either PVB or GA. Variables of efficacy were postoperative pain measured on a visual analog scale, postoperative nausea and vomiting (PONV), recovery time, and patient satisfaction. Postoperative visual analog scale scores in the PVB group were significantly lower in the early postoperative period (maximum, 12 vs 45 mm; P < 0.01). In both groups, PONV was nearly absent. There was no difference in recovery time. Patient satisfaction was better in the PVB group (2.8 vs 2.3; scale, 0-3; P < 0.01). There was one inadvertent epidural block and one inadvertent pleural puncture in the PVB group. Although PVB resulted in better postoperative pain relief, the advantages over GA were marginal in this patient group because postoperative pain was relatively mild and the incidence of PONV was small. Considering that the technique has a certain complication rate, we conclude that at present the risk/benefit ratio of PVB does not favor routine use for minor breast surgery. IMPLICATIONS: This study confirms the previously reported superior pain relief after paravertebral blockade (PVB) for breast surgery. However, considering the relatively mild postoperative pain and therefore the limited advantage of PVB for these patients, the risk/benefit ratio does not favor the routine use of PVB for minor breast surgery.


Buggy et al 2004

Paravertebral analgesia with levobupivacaine increases postoperative flap tissue oxygen tension after immediate latissimus dorsi breast reconstruction compared with intravenous opioid analgesia.

Buggy DJ, Kerin MJ

Anesthesiology 2004;100(2):375-80.

BACKGROUND: Directly measured tissue oxygen tension (Pto2) reflects the adequacy of local tissue oxygenation and influences surgical wound healing. Epidural analgesia increases Pto2 compared with intravenous morphine analgesia after abdominal surgery. The authors tested the hypothesis that paravertebral regional anesthesia and analgesia would increase Pto2 compared with intravenous opioid-based anesthesia and analgesia. METHODS: Twenty patients scheduled to undergo mastectomy with immediate latissimus dorsi breast reconstruction were randomized to receive either general anesthesia with postoperative intravenous morphine analgesia or combined general-paravertebral anesthesia with continuous paravertebral postoperative analgesia using levobupivacaine in this prospective, cohort study. All patients had a local tissue oxygen sensor implanted in the flap muscle. Data were downloaded continuously for 20 h postoperatively. RESULTS: The mean Pto2 over the 20-h period was significantly higher in patients receiving paravertebral anesthesia (75 +/- 38 vs. 44 +/- 23 mmHg (mean +/- SD); P = 0.03). Intraoperative blood loss was less in paravertebral patients (1.2 +/- 0.4 vs. 1.7 +/- 0.5 l; P = 0.04). Dynamic visual analog scale pain scores were significantly lower in paravertebral patients. Intraoperative and postoperative fluids administered, hemoglobin, core temperature, intraoperative end-tidal carbon dioxide, and mean arterial pressure were similar in both groups. CONCLUSION: The postoperative latissimus dorsi flap Pto2 was higher for 20 h after breast reconstruction with paravertebral analgesia compared with intravenous morphine analgesia.


Pusch et al 1999

Single-injection paravertebral block compared to general anaesthesia in breast surgery.

Pusch F, Freitag H, Weinstabl C, Obwegeser R, Huber E, Wildling E.

Acta Anaesthesiol Scand 1999;43(7):770–4.

BACKGROUND: Breast surgery is frequently associated with post-operative nausea, vomiting, pain and painful restricted movement. Paravertebral block may be an alternative to general anaesthesia for this type of surgery. We studied the single-injection paravertebral block at the level of T4 and report a comparison of single-injection paravertebral block to general anaesthesia for breast surgery. METHODS: After written informed consent was obtained, 86 patients were enrolled in this prospective study. Forty-four women were randomly allocated to receive a single-injection paravertebral block at the level of T4, while 42 women received general anaesthesia. The surgical procedures varied from lumpectomy (wide local excision of a tumour) to modified radical mastectomy with axillary dissection. The block was performed according to the guidelines described by Eason and Wyatt using 0.3 ml x kg(-1) (maximum dose 150 mg) of bupivacaine 0.5%. The skin and the underlying tissues were infiltrated with local anaesthetic solution two fingers (about 3 cm) from the anatomical midline and level with the cephalad end of the vertebral spine. RESULTS: Time for performance of blocks lasted from 4 to 9 min. Recovery from anaesthesia or sedation was shortened, while postoperative pain scores (VAS), the incidence of vomiting and the requirement for analgesics were lower in the paravertebral group. Less painful restricted movement was observed in the paravertebral block group. Paravertebral block was inadequate in 6.8% of patients. Epidural spread with paraparaesis and Horner triad was assumed in one patient. CONCLUSION: Single-injection paravertebral block at the level of T4 represents a suitable alternative to general anaesthesia in women undergoing breast surgery.


Naja et al 2003

Nerve-stimulator guided paravertebral blockade vs. general anaesthesia for breast surgery: a prospective randomized trial.

Naja MZ, Ziade MF, Lonnqvist PA.

Eur J Anaesthesiol 2003;20(11):897–903.

BACKGROUND AND OBJECTIVE: Different anaesthetic techniques are used during breast surgery but are frequently associated with unsatisfactory postoperative analgesia. Paravertebral nerve blockade has recently been proposed as a favourable alternative for this type of surgical procedure, providing excellent pain relief and a reduced incidence of postoperative nausea and vomiting. The aim of the present study was to compare the use of a nerve-stimulator guided paravertebral nerve blockade technique to regular general anaesthesia for breast surgery. METHODS: Sixty patients were prospectively randomized to receive either paravertebral nerve blockade or general anaesthesia for breast surgery. The primary end-point of the study was to assess postoperative analgesia (visual analogue scale and supplemental opioid requirements); the incidence of postoperative nausea and vomiting and length of hospital stay were considered as secondary outcome measures. RESULTS: Visual analogue scores both at rest and at movement, as well as the need for supplemental opioid administration during the first 3 days postoperatively, were significantly lower in patients handled with para-vertebral nerve blockade compared to patients receiving general anaesthesia (P < 0.05). The number of patients free from nausea and vomiting after operation was significantly higher in the paravertebral nerve blockade group (93%) compared to the general anaesthesia group (67%) (P < 0.05). The use of paravertebral nerve blockade was also associated with a significantly shorter hospital stay (median 1 day) compared to general anaesthesia (2 days) (P < 0.01). Both the performance of the block and the intraoperative conditions was well accepted by the vast majority of patients treated by paravertebral nerve blockade (97%). CONCLUSION: The use of paravertebral nerve blockade was associated with improved postoperative pain relief, a reduced incidence of nausea and vomiting after operation and a shorter duration of hospital stay compared to general anaesthesia in patients undergoing breast surgery.


Hura et al 2006

Sensory blockade after thoracic paravertebral injection of ropivacaine or bupivacaine.

Hura G, Knapik P, Misiolek H, Krakus A, Karpe J.

European journal of anaesthesiology 2006;23(8):658-64

Summary, Background and Objective: No clinical trials comparing the characteristics of sensory blockade caused by various local anaesthetics in thoracic paravertebral blockade have been published. The aim of this prospective study was a clinical assessment of sensory blockade after paravertebral injection of ropivacaine or bupivacaine in patients undergoing modified radical mastectomy. Methods: Seventy ASA I-II patients were randomized to receive a single injection of ropivacaine 0.5% (n = 35) or bupivacaine 0.5% (n = 35) at the T4 level. General anaesthesia with propofol and fentanyl was provided during the procedure and patients were not intubated. The following parameters were analysed: duration and dynamics of the sensory blockade and the patient's and surgeon's assessment. Results: Both ropivacaine and bupivacaine provided a similar level of analgesia. Ropivacaine was characterized by more rapid onset - after only 5 min 53% of patients in this group had the extent of sensory blockade wide enough to perform modified radical mastectomy in comparison to only 20% after bupivacaine (P 9 segments blocked) was noted more often in the ropivacaine group (88% vs. 65%, P < 0.05), lasted longer and appeared to be wider than sensory blockade produced by bupivacaine. Regression of sensory blockade was initially similar, but after 24 h sensory blockade in the ropivacaine group still had a potential to provide analgesia for modified radical mastectomy in 81% of patients in comparison to only 50% of such patients in the bupivacaine group (P < 0.05). Degree of postoperative pain, performance of the cardiovascular system, consumption of medications and complications were all similar between the study groups. Conclusions: Both agents provide satisfactory conditions for mastectomy, but ropivacaine seems to be superior to bupivacaine for thoracic paravertebral blockade during breast cancer surgery.


Klein et al 2002b

Thoracic paravertebral block for breast surgery.

Klein SM, Bergh A, Steele SM, Georgiade GS, Greengrass RA.

Anesth Analg 2000;90(6):1402–5.

Cosmetic and reconstructive breast augmentation is a frequently performed surgical procedure. Despite advances in medical treatment, surgical intervention is often associated with postoperative pain, nausea, and vomiting. Paravertebral nerve block (PVB) has the potential to offer long-lasting pain relief and fewer postoperative side effects when used for breast surgery. We compared thoracic PVB with general anesthesia for cosmetic breast surgery in a single-blinded, prospective, randomized study of 60 women scheduled for unilateral or bilateral breast augmentation or reconstruction. Patients were assigned (n = 30 per group) to receive a standardized general anesthetic (GA) or thoracic PVB (levels T1-7). Procedural data were collected, as well as verbal and visual analog pain and nausea scores. Verbal postoperative pain scores were significantly lower in the PVB group at 30 min (P = 0.0005), 1 h (P = 0.0001), and 24 h (P = 0.04) when compared with GA. Nausea was less severe in the PVB group at 24 h (P = 0.04), but not at 30 min or 1 h. We conclude that PVB is an alternative technique for cosmetic breast surgery that may offer superior pain relief and decreased nausea to GA alone. Implications: Paravertebral nerve block has the potential to offer long-lasting pain relief and few postoperative side effects when used for breast surgery. We demonstrated that paravertebral nerve block, when compared with general anesthesia, is an alternative technique for breast surgery that may offer pain relief superior to general anesthesia alone.


Marret 2006

[Effectiveness of analgesic techniques after breast surgery: a meta-analysis][Article in French]

Marret E, Vigneau A, Salengro A, Noirot A, Bonnet F.

Ann Fr Anesth Reanim. 2006 Sep;25(9):947-54.

OBJECTIVE: To evaluate the effectiveness of locoregional analgesic techniques (thoracic paravertebral block (TPVB), wound infiltration (WI)) after breast surgery. STUDY DESIGN: Meta-analysis. METHODS: Searches of Medline and Cochrane were performed using the search terms "breast surgery" and "local anaesthetics" and "infiltration" or "paravertebral block". Manual searches were also performed. Two independent investigators assessed the publications and extracted the data. Inclusion criteria were randomised controlled trials that evaluated effectiveness of single-injection TPVB or WI with local anaesthetics after breast surgery. Postoperative pain scores evaluated by visual analogic scale (VAS) during the first six hours (H6), at twelve hours (H12) and incidence of postoperative nausea and vomiting (PONV) were collected. RESULTS: Nine studies met inclusion criteria with five trials that evaluated paravertebral block (N=253) and 4 studies that evaluated wound infiltration (N=174). TPVB decreased significantly VAS at H6 (Weighted mean difference (WMD)=-18 [-5;-32] ; P=0.007) and at H12 (WMD=-12[-20;-4] ; P=0.001) and the risk of PONV (relative risk=0.39 [0.26; 0.57] ; P<0.00001). WI did not decrease significantly VAS for postoperative pain and PONV. CONCLUSION: Single injection TPVB in contrast to WI is effective for analgesia after breast surgery and decreases PONV.


Coveney 1998

Use of paravertebral block anesthesia in the surgical management of breast cancer: experience in 156 cases.

Coveney E, Weltz CR, Greengrass R, Iglehart JD, Leight GS, Steele SM, Lyerly HK.

Ann Surg. 1998 Apr;227(4):496-501.

OBJECTIVE: To assess safety and efficacy of the regional anesthetic technique paravertebral block for operative treatment of breast cancer, and to compare postoperative pain, nausea, vomiting, and length of hospital stay in patients undergoing breast surgery using paravertebral block and general anesthesia. BACKGROUND: General anesthesia is currently the standard technique used for surgical treatment of breast cancer. Increasing hospital costs have focused attention on reducing the length of hospital stay for these patients. However, the side effects and complications of general anesthesia preclude ambulatory surgery for most patients undergoing breast surgery. In April 1994, the authors initiated the use of paravertebral block anesthesia for patients undergoing primary breast cancer surgery. A review of our early experience revealed that this regional anesthetic technique enables effective anesthesia for operative procedures of the breast and axilla, reduces postoperative nausea and vomiting, and provides prolonged postoperative sensory block that minimizes narcotic requirements. METHODS: A retrospective analysis of 145 consecutive patients undergoing 156 breast cancer operations using paravertebral block and 100 patients undergoing general anesthesia during a 2-year period was performed. Anesthetic effectiveness and complications, inpatient experience with postoperative pain, nausea, vomiting, and length of stay were measured. RESULTS: Surgery was successfully completed in 85% of the cases attempted by using paravertebral block alone, and in 91% of the cases, surgery was completed by using paravertebral block supplemented with local anesthetic. There was a 2.6% incidence of complications associated with block placement. Twenty percent of patients in the paravertebral group required medication for nausea and vomiting during their hospital stay compared with 39% in the general anesthesia group. Narcotic analgesia was required in 98% of general anesthesia patients, as opposed to 25% of patients undergoing paravertebral block. Ninety-six percent of patients having paravertebral block anesthesia were discharged within the day of surgery, compared with 76% of patients who had a general anesthetic. CONCLUSIONS: Paravertebral block can be used to perform major operations for breast cancer with minimal complications and a low rate of conversion to general anesthesia. Paravertebral block markedly improves the quality of recovery after breast cancer surgery and provides the patient with the option of ambulatory discharge.


Weltz 1995

Ambulatory surgical management of breast carcinoma using paravertebral block.

Weltz CR, Greengrass RA, Lyerly HK.

Ann Surg. 1995 Jul;222(1):19-26.

OBJECTIVE: The authors describe an initial experience using paravertebral block for ambulatory or short-stay operations for breast cancer. BACKGROUND: Rising hospital costs have focused attention on limiting the length of stay for patients undergoing surgical treatment of breast cancer. Thus far, ambulatory surgery has been limited by side effects and complications of general anesthesia. Paravertebral block offers the potential benefit of effective analgesia, with limited postoperative nausea and vomiting. METHODS: The medical records of the first 15 patients with breast cancer who underwent 16 major operations for the treatment of breast cancer using paravertebral block were reviewed. Patients were either discharged directly from the recovery room or after overnight hospital admission. The effectiveness of anesthesia, surgical outcome, patient satisfaction, and hospital costs are reviewed. RESULTS: Paravertebral block achieved effective anesthesia for cancer operations of the breast and axilla; conversion to general anesthesia or supplementation with local anesthesia was not required. There was one postoperative hemorrhage, there were two seromas, and there was one superficial wound infection. Sensory block persisted for an average of 23 hours. Postoperative pain was effectively controlled, in fact, nine patients required no postoperative narcotic for pain control. Nausea and vomiting transiently afflicted three patients and prompted overnight observation in one patient originally scheduled for immediate discharge. Fourteen patients (93%) rated their experience as "very satisfactory." CONCLUSION: Breast operations for the surgical management of breast cancer using paravertebral block can be performed safely, with great patient satisfaction, and with potential for significant cost savings.


Lönnqvist 1995

Paravertebral blockade. Failure rate and complications.

Lönnqvist PA, MacKenzie J, Soni AK, Conacher ID.

Anaesthesia. 1995 Sep;50(9):813-5.

The failure rate and complications were studied prospectively in 367 paediatric and adult patients who had received a thoracic or lumbar paravertebral block. The overall failure rate was 10.1%; adults 10.7%; children 6.2%. The frequency of complications were: hypotension: 4.6%; vascular puncture: 3.8%; pleural puncture: 1.1%; pneumothorax: 0.5%. Since these results are similar to those found with alternative methods, e.g. epidural, intrapleural and intercostal blocks, paravertebral block can be recommended as an effective, safe technique for unilateral analgesia in both adults and children.


Ganapathy 2005

Outcomes after paravertebral blocks.

Ganapathy S, Nielsen KC, Steele SM.

Int Anesthesiol Clin. 2005;43(3):185-93.

Abstract not available


Yeh et al 1999

Thoracic epidural anesthesia for pain relief and postoperation recovery with modified radical mastectomy.

Yeh CC, Yu JC, Wu CT, Ho ST, Chang TM, Wong CS.

World journal of surgery 1999;23(3):256-60.

The purpose of this study was to investigate whether thoracic epidural anesthesia (TEA) provides better postoperative pain relief and recovery than general anesthesia (GA) for modified radical mastectomy (MRM) surgery. Sixty-four patients rated as American Society of Anesthesiologists (ASA) 1 to 3 who underwent MRM surgery were included in the study. In TEA group patients, 2% lidocaine (15-20 ml) was administered via the epidural route as primary anesthesia, in conjunction with midazolam (5-10 mg) and fentanyl (<250 microg) for amnesia. The GA patients were maintained with isoflurane and 50% nitrous oxide in oxygen. After operation the patients were given pethidine (1 mg/kg IM) as required for pain relief. The time to first pethidine requirement, total pethidine consumption, worst pain score, bed rest time, satisfaction score, and anesthesia-related side effects were recorded for 2 days after surgery. The results show that TEA provided a more prolonged analgesic effect than GA after operation. A longer time to first pethidine requirement (19.2 +/- 1.5 vs. 7.6 +/- 2.5 hours) (p < 0. 001) and decreased pethidine consumption (17.2 +/- 7.0 vs. 76.3 +/- 17.4 mg) (p < 0.001) were observed in the TEA group than in the GA group, respectively. A worse visual analog scale (VAS) pain score was observed in the GA group (5.7 +/- 0.6) than in TEA patients (4.3 +/- 0.4) (p < 0.01). The average bed rest time was significantly shorter in the TEA group (16.9 +/- 0.9 hours) (p < 0.01) than in the GA group (27.1 +/- 4.1 hours). Overall satisfaction scores were significantly higher in the TEA group (4.4 +/- 0.1) (p < 0.01) than in the GA group (3.5 +/- 0.2). Side effects were observed at a higher frequency in the GA group (16/32) (p < 0.0001) than in the TEA group (3/32). The frequency of pethidine injection for pain relief was significantly lower in the TEA group (8/32) (p < 0.0001) than in the GA group (24/32). The total hospital cost (NT 64,392 +/- 3,523 vs. NT 53,806 +/- 2,817) (p = 0.0342) and anesthesia cost (NT 7,968 +/- 246 vs. NT 5,268 +/- 262) (p < 0.0001) are also significantly lower in the TEA group than the GA group. In conclusion, TEA provided better postoperative pain relief and recovery and lower cost than GA for MRM surgery.


Sundarathiti et al 2005

Thoracic epidural anesthesia TEA with 02% ropivacaine in combination with ipsilateral brachial plexus block BPB for modified radical mastectomy MRM.

Sundarathiti P, Pasutharnchat K, Kongdan Y, Suranutkarin P.

Journal of the Medical Association of Thailand, 2005;88(4):513-20.

BACKGROUND: Breast cancer is the 2nd most common tumors in Thai women. Until now, oncologic breast surgeries are typically performed by general anesthesia (GA). However, GA cannot provide adequate postoperative pain control and routine use of parenteral opioids aggravate postoperative sedation, nausea, emesis, impaired oxygenation and depressed ventilation. Thoracic epidural anesthesia (TEA) is one of the regional anesthetic techniques that can be done by using a low dose of local anesthetic in combination with ipsilateral brachial plexus block (BPB) for axillary node dissection. TEA can provide a better pain relief without potential paralysis of respiratory muscle and sedation. MATERIAL AND METHOD: Fifty ASA PS I-III patients undergoing MRM were randomly assigned to two study groups of 25 patients each. In the TEA group, an epidural catheter was inserted at T4 to T5, and 10-15 ml of 0.2% ropivacaine was injected, then interscalene BPB was done with 8 ml of 0.2% ropivacaine. Anesthesia was maintained with 5-10 ml of 0.2% ropivacaine per hour. GA was induced with 1 microg/kg of fentanyl followed by 1.5-2 mg/kg of propofol and was maintained with sevoflurane and 70% N2O in oxygen. The authors evaluated the adequacy of anesthesia, surgical condition, postanesthetic recovery, postanesthetic analgesia and patients' satisfaction. RESULTS: The demographic data was similar in both groups. The number of patients immediately arrived at PACU with a sedation score of 1 was significantly greater in TEA group (p = 0.003) while the number of patients with an Aldrete score of 10 was greater but not statistically significant (p = 0.25). The verbal rating scale and analgesic requirement were significantly lower in the TEA group (p < 0.001 and p = 0.002 respectively). Patients' satisfaction was greater with TEA than with GA (p = 0.014). Surgical condition was similar in both groups. CONCLUSION: The present study shows that TEA combined with BPB by using a low dose of 0.2% ropivacaine is a safe and reliable alternative technique for MRM. It can provide not only effective anesthesia but also better postoperative pain relief faster anesthetic recovery and greater patient satisfaction than those of the GA technique.


Wulf 1996

Epidural anaesthesia and spinal haematoma.

Wulf H.

Can J Anaesth. 1996 Dec;43(12):1260-71.

PURPOSE: Haematoma formation in the spinal canal due to epidural anaesthesia is a very rare but serious complication. This paper presents a comprehensive review of case reports. SOURCE: Sampling of case reports over a 10 yr period, medline-research (1966-1995) and cross-check with former reviews. FINDINGS: Fifty-one confirmed spinal haematomas associated with epidural anaesthesia were found. Most were related to the insertion of a catheter, a procedure that was graded as difficult or traumatic in 21 patients. Other risk factors were: fibrinolytic therapy (n = 2), previously unknown spinal pathology (n = 2), low molecular weight heparin (n = 2), aspirin or other NSAID (n = 3), epidural catheter inserted during general anaesthesia (n = 3), thrombocytopenia (n = 5), ankylosing spondylitis (n = 5), preexisting coagulopathy (n = 14), and intravenous heparin therapy (n = 18). CONCLUSION: Coagulopathies or anticoagulant therapy (e.g., full heparinization) were the predominant risk factors, where-as low-dose heparin thromboprophylaxis or NSAID treatment was rarely associated with spinal bleeding complications. Ankylosing spondylitis was identified as a new, previously unreported risk factor. Analysis of reported clinical practice suggests an incidence of haematoma of 1:190,000 epidurals.


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.


Gan 2004

A randomized controlled comparison of electro-acupoint stimulation or ondansetron versus placebo for the prevention of postoperative nausea and vomiting.

Gan TJ, Jiao KR, Zenn M, Georgiade G.

Anesthesia and Analgesia 2004;99(4):1070-5.

In this study we evaluated the efficacy of electro-acupoint stimulation, ondansetron versus placebo for the prevention of postoperative nausea and vomiting (PONV). Patients undergoing major breast surgery under general anesthesia were randomized into active electro-acupoint stimulation (A), ondansetron 4 mg IV (O), or sham control (placement of electrodes without electro-acupoint stimulation; placebo [P]). The anesthetic regimen was standardized. The incidence of nausea, vomiting, rescue antiemetic use, pain, and patient satisfaction with management of PONV were assessed at 0, 30, 60, 90, 120 min, and at 24 h. The complete response (no nausea, vomiting, or use of rescue antiemetic) was significantly more frequent in the active treatment groups compared with placebo both at 2 h (A/O/P = 77%/64%/42%, respectively; P = 0.01) and 24 h postoperatively (A/O/P = 73%/52%/38%, respectively; P = 0.006). The need for rescue antiemetic was less in the treatment groups (A/O/P = 19%/28%/54%; P = 0.04). Specifically, the incidence and severity of nausea were significantly less in the A group compared with the other groups, and in the O group compared with the P group (A/O/P = 19%/40%/79%, respectively). The A group experienced less pain in the postanesthesia care unit, compared with the O and P groups. Patients in the treatment groups were more satisfied with their management of PONV compared with placebo. When used for the prevention of PONV, electro-acupoint stimulation or ondansetron was more effective than placebo with greater degree of patient satisfaction, but electro-acupoint stimulation seems to be more effective in controlling nausea, compared with ondansetron. Stimulation at P6 also has analgesic effects.


Sim 2002

Effects of electroacupuncture on intraoperative and postoperative analgesic requirement.

Sim CK, Xu PC, Pua HL, Zhang G, Lee TL.

Acupunct Med. 2002 Aug;20(2-3):56-65.

Acupuncture has been shown to be effective in experimental and clinical acute pain settings. This study aims to evaluate the effect of preoperative electroacupuncture (EA) on intraoperative and postoperative analgesic (alfentanil and morphine) requirement in patients scheduled for gynaecologic lower abdominal surgery. Ninety patients were randomly assigned to one of three groups: Group I (control group)--received placebo EA for 45 minutes before induction of general anaesthesia (GA); Group II--preoperative EA instituted 45 minutes before induction of GA; Group III--45 minutes of postoperative EA. The Bispectral Index monitor was used intraoperatively to monitor the hypnotic effect of anaesthetic drugs, and alfentanil was titrated to maintain the blood pressure and pulse rate within +/- 15% of basal values. Postoperative pain was managed by intravenous morphine via a patient-controlled analgesia (PCA) device. Patients in Group II (0.44 +/- .15microg/kg/min) received less alfentanil than those in Group III (0.58 +/- .22 microg/kg/min) (p = p.024), but not significantly less than those in Group I 10.51 +/- 0.21 microg/kg/min) (p = 0.472). Postoperative morphine consumption was numerically lower in Group II compared with the other groups; however, the difference was statistically significant only during the period of 6-12 hours between Group II [0.03 (0.05) mg/kg] and Group I [0.10 (0.11) mg/kg] (p = 0.015), and Group II and Group III [0.08 (0.10) mg/kg] (p = 0.010). The 24-hour cumulative morphine consumption for Group II (0.52 +/- .19mg/kg) was less than that for either Group I I0.68 +/- 38mg/kg) or Group III (0.58 +/- .27mg/kg), but the difference did not reach significance. In conclusion, preoperative EA leads to a reduced intraoperative alfentanil consumption, though this effect may not be specific, and has a morphine sparing effect during the early postoperative period.


Segerdahl et al 1995

Peroperative adenosine infusion reduces the requirements for isoflurane and postoperative analgesics.

Segerdahl M, Ekblom A, Sandelin K, Wickman M, Sollevi A

Anesthesia and Analgesia 1995;80(6):1145-9.

The aims of this study were to investigate the influence of adenosine infusion, firstly, on postoperative analgesic requirements, and secondly, on peroperative isoflurane requirements. Seventy-five women, aged 18-70 yrs, ASA grades I and II, scheduled for breast surgery, were randomly assigned to peroperatively receive a double-blind intravenous infusion of either adenosine, 80 micrograms.kg-1.min-1, or placebo, during surgery under isoflurane/N2O/O2 anesthesia. The peroperative isoflurane requirements were significantly reduced at 30 and 90 min of surgery during adenosine treatment. The number of patients reporting pain when regaining consciousness after surgery was reduced by 57% in the adenosine group, 8/31 vs 19/32 (P < 0.02). Further, the postoperative 24-h opioid requirements were reduced by 27% in the adenosine group (P < 0.03). In conclusion, we found that a peroperative infusion of a small dose of adenosine during breast surgery, reduces the peroperative anesthetic requirements, and the demand for post-operative analgesics.


Fassoulaki et al 2001

Regional block and mexiletine: the effect on pain after cancer breast surgery.

Fassoulaki A, Sarantopoulos C, Melemeni A, Hogan Q

Regional anesthesia and pain medicine 2001;26(3):223-8.

BACKGROUND AND OBJECTIVES: Breast surgery for cancer is associated with chronic pain and sensory abnormalities. The present study investigates the effect of regional block, oral mexiletine, and the combination of both, on acute and chronic pain associated with cancer breast surgery. METHODS: One hundred patients scheduled for cancer breast surgery received either regional block with 18 mL of 1% ropivacaine intraoperatively and oral mexiletine for the first 6 postoperative days (R + M group), or regional block and placebo (R + PL), or normal saline instead of ropivacaine and mexiletine (PL + M), or normal saline and placebo (PL + PL). Postoperative analgesic requirements were recorded daily. Pain was assessed 0, 3, 6, 9, and 24 hours in the postanesthesia care unit (PACU) and on the second to sixth day postoperatively, at rest, and after movement using the visual analog scale (VAS). Three months after surgery, patients were interviewed for the presence and intensity of pain, abnormal sensations, and analgesic requirements. RESULTS: Regional block reduced the number of intramuscular (IM) injections required the first 24 hours (P =.05), the R + PL group requiring less injections versus the PL + M group (P =.037). Lonarid tablet (paracetamol and codeine) consumption from the second to the fifth postoperative day differed among the 4 groups (P =.0304), the R + M group requiring fewer tablets than the PL + PL group (P =.009). Three hours postoperatively, the R +


Pakhira et al 2004

Regional block for postoperative analgesia following breast surgery: Comparison between bupivacaine and ropivacaine.

Pakhira A, Ray M, Sanyal S

Journal of Anaesthesiology Clinical Pharmacology 2004;20(4):393-396.

Efficacy of intercostal nerve block (T4-T8) along with subcutaneous infiltration at upper and medial border of breast with 0.25% bupivacaine and 0.25% ropivacaine was compared for controlling postoperative pain. Forty five adult female patient were randomly allocated in three groups to receive normal saline (group A), 0.25% bupivacaine (group B) or 0.25% ropivacaine (group C) for such block following breast surgery. Intensity of pain was significantly less during first six hour in bupivacaine group and ropivacaine group and duration of analgesia was 378±24.8 mins and 372±46.47 mins respectively. Requirement of tramadol hydrochloride was also significantly less (63.33±22.8 and 66.6±24.3 mg) in these patients as compared to control group (120±25.35mg). There was no difference between bupivacaine and ropivacaine group in terms of intensity of pain, duration of analgesia and incidence of complications. Patients remained haemodynamically stable. The only postoperative complication observed in this series was nausea, vomiting, which occurred in 20% patients of group A, 13.3% patient of group B and none in group C.


Atanassoff et al 1994

Intercostal nerve block for lumpectomy: superior postoperative pain relief with bupivacaine.

Atanassoff PG, Alon E, Weiss BM

Journal of Clinical Anesthesia 1994;6(1):47-51.

To investigate whether equipotent doses of lidocaine and bupivacaine were equally effective for intercoastal nerve blockade (ICNB) and whether a lower amount of lidocaine would be comparably effective. To see whether plasma levels of lidocaine with and without epinephrine and of plain bupivacaine would reach toxic ranges. Finally, to evaluate the duration of postoperative analgesia following general anesthesia and regional anesthesia with two different local anesthetics. DESIGN: Randomized, double-blind study, with control group administered general anesthesia. SETTING: Gynecologic operating room of a university hospital. PATIENTS: 48 adult ASA physical status I and II otherwise healthy patients undergoing lumpectomy. INTERVENTIONS: 36 patients received ICNB of T3-T6 unilaterally using either 4 ml/segment of 1.5% lidocaine with epinephrine 3.75 micrograms /ml (n = 10, Group A), 4 ml/segment of 2% lidocaine with epinephrine 5 micrograms/ml (n = 13, Group B), or 4 ml/segment of plain 0.5% bupivacaine (n = 13, Group C). The control group consisted of 12 patients (Group D) who received a general anesthetic using propofol, alfentanil, and nitrous oxide in oxygen for induction and maintenance of anesthesia. MEASUREMENTS AND MAIN RESULTS: In all three ICNB groups, the highest plasma concentrations were reached after 5 to 10 minutes following ICNB--i.e., a lidocaine plasma level of 2.77 +/- 0.5 micrograms/ml (mean +/- SEM) in Group A, a lidocaine plasma level of 2.78 +/- 0.2 micrograms/ml in Group B, and a bupivacaine plasma level of 1.44 +/- 0.2 micrograms/ml in Group C. There were no significant differences in plasma levels between 1.5% lidocaine and 2% lidocaine. For the first 90 minutes after surgery, higher postoperative pain scores were found in the control group than in the ICNB groups. Notably longer-lasting postoperative pain relief was achieved with plain bupivacaine. The number of women requiring postoperative analgesic medication, the time of first request, and the total amount of analgesic drugs administered during the 24 hours postoperatively were significantly lower in the regional anesthesia groups than in the general anesthesia group (p < 0.05). CONCLUSIONS: ICNB is an alternative to general anesthesia for female breast surgery. Both lidocaine with epinephrine and plain bupivacaine in the doses used did not raise venous plasma concentrations to levels considered potentially toxic. With respect to duration of postoperative pain relief and analgesic drug request, the local anesthetics (in particular, bupivacaine) were found to be superior to general anesthesia.


Shanti et al 2001

Incidence of pneumothorax from intercostal nerve block for analgesia in rib fractures.

Shanti CM, Carlin AM, Tyburski JG.

J Trauma 2001;51(3):536–9.

BACKGROUND: The incidence of pneumothorax (PTX) after individual intercostal nerve block (INB) for postoperative pain reportedly varies from 0.073% to 19%.1-3 This study investigated the incidence of PTX after INB for rib fractures. METHODS: We conducted a retrospective chart review of patients admitted between January 1996 and December 1999 with rib fractures who received INB. RESULTS: One hundred sixty-one patients received 249 intercostal nerve block procedures (INBPs). An INBP is one session where a set of intercostal nerves are blocked. A total of 1,020 individual intercostal nerves were blocked. There were 14 pneumothoraces. The overall incidence of PTX per patient was 8.7%, with an incidence of PTX per INBP of 5.6%. The incidence of PTX was 1.4% for each individual intercostal nerve blocked. CONCLUSION: The incidence of PTX per individual intercostal nerve blocked is low. INB is an effective form of analgesia, and for most patients with rib fractures one INBP is sufficient to allow adequate respiratory exercises and discharge from the hospital.


Purhonen et al 2006

Supplemental 80% oxygen does not attenuate post-operative nausea and vomiting after breast surgery.

Purhonen S, Niskanen M, Wüstefeld M, Hirvonen E, Hynynen M.

Acta anaesthesiologica Scandinavica 2006;50(1):26-31.

BACKGROUND: Although supplemental oxygen has been shown to be as effective as ondansetron in the prevention of post-operative nausea and vomiting (PONV) in one study in abdominal surgery patients, the antiemetic efficacy of supplemental oxygen is controversial on the basis of studies with other patients. We compared the efficacy of 80% and 30% oxygen in decreasing PONV in breast surgery. Ondansetron was used as an active control. METHODS: Ninety patients were given a standardized sevoflurane anesthetic. They were randomly assigned to three groups: 30% oxygen in nitrogen and saline 2 ml intravenously (i.v.) at the end of surgery (group 30); 80% oxygen in nitrogen and saline 2 ml (group 80); and 30% oxygen in nitrogen and ondansetron 4 mg (group O). Oxygen was administered during surgery and up to 2 h after surgery. RESULTS: The incidence of total response (no retching or vomiting, no nausea) during the first 24 post-operative hours was not different between group 80 (17%) and group 30 (11%) but was higher in group O (43%) than in group 30 (P<0.05). Compared with group O, patients in group 80 experienced more vomiting during the study period 0-24 h (66% vs. 32%; P<0.05) and more nausea during the period 6-24 h (72% vs. 39%; P<0.05). There was no difference between the groups in their risk for PONV, pain scores, opioid consumption, or patient satisfaction. CONCLUSIONS: In this study, supplemental 80% oxygen administration failed to decrease PONV in breast surgery.


Purhonen et al 2006

Supplemental 80% oxygen does not attenuate post-operative nausea and vomiting after breast surgery.

Purhonen S, Niskanen M, Wüstefeld M, Hirvonen E, Hynynen M

Acta anaesthesiologica Scandinavica 2006;50(1):26-31.

BACKGROUND: Although supplemental oxygen has been shown to be as effective as ondansetron in the prevention of post-operative nausea and vomiting (PONV) in one study in abdominal surgery patients, the antiemetic efficacy of supplemental oxygen is controversial on the basis of studies with other patients. We compared the efficacy of 80% and 30% oxygen in decreasing PONV in breast surgery. Ondansetron was used as an active control. METHODS: Ninety patients were given a standardized sevoflurane anesthetic. They were randomly assigned to three groups: 30% oxygen in nitrogen and saline 2 ml intravenously (i.v.) at the end of surgery (group 30); 80% oxygen in nitrogen and saline 2 ml (group 80); and 30% oxygen in nitrogen and ondansetron 4 mg (group O). Oxygen was administered during surgery and up to 2 h after surgery. RESULTS: The incidence of total response (no retching or vomiting, no nausea) during the first 24 post-operative hours was not different between group 80 (17%) and group 30 (11%) but was higher in group O (43%) than in group 30 (P<0.05). Compared with group O, patients in group 80 experienced more vomiting during the study period 0-24 h (66% vs. 32%; P<0.05) and more nausea during the period 6-24 h (72% vs. 39%; P<0.05). There was no difference between the groups in their risk for PONV, pain scores, opioid consumption, or patient satisfaction. CONCLUSIONS: In this study, supplemental 80% oxygen administration failed to decrease PONV in breast surgery.


Zavotsky 1998

Evaluation of axillary lymphadenectomy without axillary drainage for patients undergoing breast-conserving therapy.

Zavotsky J, Jones RC, Brennan MB, Giuliano AE.

Ann Surg Oncol. 1998 Apr-May;5(3):227-31.

BACKGROUND: The routine use of drainage after axillary node dissection in patients undergoing breast-conserving therapy (BCT) is being questioned. To determine the value of routine drainage, we evaluated the postoperative course of patients with primary breast carcinoma who underwent axillary dissection with or without axillary drainage. METHODS: A retrospective review of 69 patients prompted a prospective randomized trial of 46 patients undergoing BCT at our tertiary cancer center. Variables studied were age, treatment (drain or no drain), number and tumor status of excised lymph nodes, size of primary tumor, duration of drainage or aspiration, number and volume of aspirations, number of office visits, incidence of complications and degree of pain, change in arm or forearm circumference, and body mass index (BMI). Data from prospective and retrospective studies were pooled for analysis. RESULTS: Of 115 patients, 72 were treated with a drain (Drain group) and 43 were not (No-drain group). Overall there was no difference in the number or tumor status of excised nodes, the size of the primary tumor, or the incidence of complications between the two groups. Aspiration was required in 50% of the No-drain patients and 8.3% of the Drain patients. The incidence of drain placement or replacement postoperatively was 9.3% for the No-drain patients and 4.2% for the Drain patients. The No-drain patients had more office visits (5.1 +/- 0.4 vs. 3.6 +/- 0.1; P = .0002) and a longer interval between operation and last aspiration or drain removal (16.2 +/- 1.4 days vs. 11.3 +/- 0.6 days; P = .0040). Findings were similar in the subgroup of 46 prospectively studied patients, who included 24 Drain patients and 22 No-drain patients. In this group, pain evaluation using a scale of 0 to 10 showed a mean rating of 4.2 +/- 2.6 in Drain patients and 2.7 +/- 0.4 in No-drain patients (P = .0062). CONCLUSIONS: Axillary node dissection can be managed with or without a drain. More office visits but less pain can be expected if a drain is not used.


Randomized clinical trial investigating the use of drains and fibrin sealant following surgery for breast cancer.

Jain PK, Sowdi R, Anderson ADG, MacFie J.

The British Journal of Surgery 2004;91(1):54-60.

BACKGROUND: Despite limited evidence, closed suction drainage is often used to reduce the risk of seroma formation after breast cancer surgery. The aim of this study was to evaluate the effect of drains and fibrin sealant on the incidence of seroma formation. METHODS: A total of 116 patients undergoing surgery for breast cancer were randomized to receive suction drainage (group 1; n = 58), or to receive no drain (n = 58). Patients allocated to receive no drain were further randomized to have fibrin sealant applied to the dissected area (group 2; n = 29), or to no intervention (group 3; n = 29). Outcome measures were incidence and volume of postoperative seroma, length of hospital stay and postoperative pain scores. RESULTS: There was no significant difference in the incidence of seroma between group 1 (15 of 58) and either group with no drains (ten of 29 in group 2; 12 of 29 in group 3). There was a significant reduction in hospital stay and postoperative pain scores in patients who did not have a drain. Following mastectomy without a drain, the use of fibrin sealant was associated with a significant reduction in the incidence and total volume of seroma (190 versus 395 ml; P = 0.012). CONCLUSION: Drains did not prevent seroma formation, and were associated with a longer postoperative stay and higher pain scores after surgery for breast cancer. In patients who had mastectomy the use of fibrin sealant reduced the rate of seroma formation. Copyright 2004 British Journal of Surgery Society Ltd.


Jain et al 2004

Randomized clinical trial investigating the use of drains and fibrin sealant following surgery for breast cancer

Jain PK, Sowdi R, Anderson ADG, MacFie J

The British Journal of Surgery 2004;91(1):54-60.

Despite limited evidence, closed suction drainage is often used to reduce the risk of seroma formation after breast cancer surgery. The aim of this study was to evaluate the effect of drains and fibrin sealant on the incidence of seroma formation. METHODS: A total of 116 patients undergoing surgery for breast cancer were randomized to receive suction drainage (group 1; n = 58), or to receive no drain (n = 58). Patients allocated to receive no drain were further randomized to have fibrin sealant applied to the dissected area (group 2; n = 29), or to no intervention (group 3; n = 29). Outcome measures were incidence and volume of postoperative seroma, length of hospital stay and postoperative pain scores. RESULTS: There was no significant difference in the incidence of seroma between group 1 (15 of 58) and either group with no drains (ten of 29 in group 2; 12 of 29 in group 3). There was a significant reduction in hospital stay and postoperative pain scores in patients who did not have a drain. Following mastectomy without a drain, the use of fibrin sealant was associated with a significant reduction in the incidence and total volume of seroma (190 versus 395 ml; P = 0.012). CONCLUSION: Drains did not prevent seroma formation, and were associated with a longer postoperative stay and higher pain scores after surgery for breast cancer. In patients who had mastectomy the use of fibrin sealant reduced the rate of seroma formation. Copyright 2004 British Journal of Surgery Society Ltd.


Ansanelli etal 1996

A prospective, randomized trial of the use of CO2 laser vs. scalpel in breast cancer surgery

Ansanelli VW, Lesser ML

Breast Disease 1996;9(3):125-130.

Little information is available in the literature regarding the use of lasers in breast cancer surgery. The purpose of this clinical trial was to determine, in the short term, whether perioperative and postoperative parameters associated with breast cancer surgery differed according to whether the surgery was performed by scalpel or by laser. The study was designed as a prospective, clinical trial with 33 eligible women with clinical stage I and II breast cancer being randomized by computer. The patients were blinded as to treatment until time of discharge. This study revealed that the use of the CO2 laser in breast cancer surgery significantly reduces drainage, hospital stay, blood loss, and self-reported pain levels.


Wyman et al 1993

Randomized trial of laser scalpel for modified radical mastectomy.

Wyman A, Rogers K.

The British journal of surgery 1993;80(7):871-3.

The efficacy of a contact neodymium yttrium-aluminium-garnet laser scalpel was assessed during breast surgery. Forty consecutive women undergoing modified radical mastectomy were randomized to operation performed with a conventional or laser scalpel. The laser scalpel was associated with a significant reduction in mean operative blood loss (149 versus 421 ml; 95 per cent confidence interval of difference 176-368 ml, P < 0.001), but the mean operating time was longer (105 versus 80 min; 95 per cent confidence interval of difference 16-34 min, P < 0.001). No significant differences were found in the volume of postoperative wound drainage, incidence of axillary seroma, postoperative pain score or time to return of shoulder mobility. Use of a laser scalpel in breast surgery cannot be recommended.


Chan et al 1997

Chan KC, Watson D, Lennard TWJ. Outcome of a prospective randomized controlled study comparing perioperative blood loss and postoperative pain in total mastectomies performed by scalpel and electrocau

Chan KC, Watson D, Lennard TWJ

Breast 1997;6(6):379-380.

Outcome of a prospective randomized controlled study comparing perioperative blood loss and postoperative pain in total mastectomies performed by scalpel and electrocautery. Breast 1997;6(6):379-380.A comparison of blood loss and pain was undertaken in a prospective randomized controlled study. Twenty-eight patients were entered into the study, 14 in the scalpel group and 14 in the electrocautery group. A level II axillary clearance was performed by scissors dissection in each case. Using the Mann-Whitney U test, there were no significant differences in the two groups with respect to median perioperative blood loss and postoperative pain as measured by a 100 point visual analogue scale, a 5 point verbal rating scale and the patient controlled analgesia monitor. It is concluded that there is no difference in perioperative blood loss or postoperative pain between the two methods used, and either is acceptable as a technique of raising mastectomy flaps.


Gan et al 2004

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

Gan TJ, Joshi GP, Viscusi E, Cheung RY, Dodge W, Fort JG, Chen C

Anesthesia & Analgesia 2004;98(6):1665–1673

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


Bosek et al 1996

Comparison of analgesic effect of locally and systemically administered ketorolac in mastectomy patients.

Bosek V, Cox CE

Annals of surgical oncology : the official journal of the Society ofSurgical Oncology 1996;3(1):62-6

BACKGROUND: Ketorolac is a parenteral nonsteroidal antiinflammatory drug (NSAID). Two features have limited its clinical utility: tendency to elicit kidney failure and inability to produce complete analgesia. Because most NSAIDs are weak acids (pKa 3-5) and become concentrated in acidic tissues, such as injured and inflamed tissues, we hypothesized that local administration may enhance its analgesic efficacy while lowering the potential for systemic complications. METHODS: We conducted a randomized, placebo-controlled study of 60 group I-II (American Society of Anesthesiology criteria) mastectomy patients, 20 in each group. Near the end of surgery and every 6 h postoperatively, 20 ml of the study solution containing normal saline with or without 30 mg of ketorolac were administered simultaneously either via a Jackson-Pratt drain or intravenously in a double-blind fashion. The quality of pain control, the amount and character of the drain fluid, incidence of nausea and vomiting, length of stay in the postoperative care unit, and amount of morphine used for treatment of break-through pain were recorded. RESULTS: Intraoperative administration of ketorolac resulted in better quality of pain control in the immediate postoperative period regardless of route of administration. The incidence of nausea was significantly higher in the placebo group, and drain output in the ketorolac groups did not exceed the output in the placebo group. CONCLUSION: Analgesic of the locally administered ketorolac is equally effective to the efficacy of ketorolac administered intravenously.


Legeby et al 2005

Analgesic efficacy of diclofenac in combination with morphine and paracetamol after mastectomy and immediate breast reconstruction.

Legeby M, Sandelin K, Wickman M, Olofsson C

Acta anaesthesiologica Scandinavica 2005;49(9):1360-6.

BACKGROUND: Breast cancer treatment with mastectomy and immediate breast reconstruction (IBR) is associated with intense pain in the primary post-operative period. The present prospective, placebo- controlled and double-blind study aimed to evaluate the analgesic efficacy of diclofenac, a non-steroid anti-inflammatory drug (NSAID), in combination with paracetamol and opioids. This was done by 64-h assessment of post-operative pain intensity, opioid consumption, blood loss, nausea and tiredness. METHODS: Fifty women selected for mastectomy and IBR with submuscular implants with or without axillary lymph node dissection (ALND) were randomized to receive diclofenac 50 mg x 3 or placebo rectally in addition to oral paracetamol and intravenous opioids delivered using a patient-controlled analgesia (PCA) technique. RESULTS: During the first 20 h post-surgery, patients who received diclofenac experienced significantly less pain when resting than those who received placebo. When moving, a non- significant estimated difference in pain in favour of diclofenac was also noted. Opioid consumption during the first 6 h post-operatively was 34% less with diclofenac than with placebo. Means (SD) were 16.9 (10.3) mg and 25.6 (10.2) mg, respectively (P = 0.007). After 64 h, the difference was no longer statistically significant. Post-operative bleeding was significantly higher with diclofenac than with placebo (P < 0.01). Nausea and tiredness did not differ between the groups. CONCLUSIONS: The addition of NSAID to paracetamol and opioid-PCA reduced opioid consumption and improved pain relief during the first 20 h at rest but was not convincingly effective during mobilization. Post-operative blood loss was higher with diclofenac.


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.


Hudcova et al 2005

Patient controlled opioid analgesia versus conventional opioid analgesia for postoperative pain: A quantitative systematic review

Hudcova J, McNicol E, Quah C, Lau J, Carr DB

Cochrane Database Syst Rev 2005(4):CD003348

BACKGROUND: Patients may control postoperative pain by self-administration of intravenous opioids using devices designed for this purpose (patient controlled analgesia or PCA). A 1992 meta-analysis by Ballantyne found a strong patient preference for PCA over conventional analgesia but disclosed no differences in analgesic consumption or length of postoperative hospital stay. Although Ballantyne's meta-analysis found that PCA did have a small but statistically significant benefit upon pain intensity, Walder's review in 2001 did not find a significant differences in pain intensity and pain relief between PCA and conventionally treated groups. OBJECTIVES: To evaluate the efficacy of PCA versus conventional analgesia (such as a nurse administering an analgesic upon a patient's request) for postoperative pain control. SEARCH STRATEGY: Randomized controlled trials (RCTs) were identified from the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2004, Issue 3), MEDLINE (1966 to 2004), and EMBASE (1994 to 2004). Additional reports were identified from the reference lists of retrieved papers. SELECTION CRITERIA: RCTs of PCA versus conventional analgesia that employed pain intensity as a primary or secondary outcome were selected. These trials included RCTs that compared PCA without a continuous background infusion versus conventional parenteral analgesic regimens. Studies that explicitly stated they involved patients with chronic pain were excluded. DATA COLLECTION AND ANALYSIS: Trials were scored using the Oxford Quality Scale. Meta-analyses were performed of outcomes that included analgesic efficacy assessed by a Visual Analog Scale (VAS), analgesic consumption, patient satisfaction, length of stay and adverse effects. A sufficient number of the retrieved trials reported these parameters to permit meta-analyses. MAIN RESULTS: Fifty-five studies with 2023 patients receiving PCA and 1838 patients assigned to a control group met inclusion criteria. PCA provided better pain control and greater patient satisfaction than conventional parenteral 'as-needed' analgesia. Patients using PCA consumed higher amounts of opioids than the controls and had a higher incidence of pruritus (itching) but had a similar incidence of other adverse effects. There was no difference in the length of hospital stay. AUTHORS' CONCLUSIONS: This review provides evidence that PCA is an efficacious alternative to conventional systemic analgesia for postoperative pain control


Thienthong et al 2004

Two doses of oral sustained-release tramadol do not reduce pain or morphine consumption after modified radical mastectomy: a randomized, double blind, placebo-controlled trial.

Thienthong S, Krisanaprakornkit W, Taesiri W, Thaninsurat N, Utsahapanich S, Klaichanad C.

Journal of the Medical Association of Thailand 2004;87(1):24-32.

BACKGROUND: Tramadol is a weak opioid agonist with antinociceptive effects through its action on the mu-receptor and by inhibiting the neuronal re-uptake of both noradrenaline and serotonin. Tramadol is commonly used for treatment of mild to moderate post-operative pain. An oral form of sustained-release tramadol (SR) was recently formulated for reducing the administration frequency from qid to bid. OBJECTIVE: To evaluate the analgesic efficacy and safety of two doses of oral tramadol SR for the treatment of pain after modified radical mastectomy. STUDY DESIGN: Randomized, double blind, placebo-controlled trial. METHOD: Fifty women were randomly allocated to receive either tramadol SR 100 mg (group T), or placebo tablet (group P) orally approximately 1 hour before surgery with a repeat dose administered 12 hours later by nurses not apprised of the patient groupings. All patients received the standard general anesthesia. Post-operatively, nurses in the research team assessed pain using a visual analog scale 0-100 mm at rest (rVAS) and during arm movements (mVAS) at admission to postanesthesia care unit (PACU) (T0) and 2 (T2), 6 (T6), 12 (T12) and 24 (T24) hours after surgery. Rescue analgesia was provided for 24 hours via a morphine-loaded patient-controlled analgesia (PCA) device at 1 mg bolus with a 5-minute lockout interval. Cumulative morphine consumption and adverse events were recorded. RESULTS: Twenty-five patients with comparable baseline characteristics from each group were studied. The proportions of patients with VAS > 30 (both rVAS and m VAS) at each measurement period were not significantly different between the groups except for the mVAS at T24, where the proportion in group T was higher than group P (48% vs 20%, 95% CI of difference: -53%, -3%, p = 0.04). The median morphine consumption in both groups at T2, T6, T12 and T24 were comparable. No serious adverse effects were observed; however, patients in group T reported nausea and vomiting more than group P (56% vs 24%, p = 0.02). CONCLUSION: Two doses of oral tramadol SR 100 mg had no effect on post-operative pain scores and morphine consumption in patients who underwent modified radical mastectomy. In fact, more patients in the tramadol group reported nausea and vomiting than the placebo group.


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.


Bourne et al 2005

Tramadol/acetaminophen tablets in the treatment of postsurgical orthopedic pain

Tramadol/acetaminophen tablets in the treatment of postsurgical orthopedic pain

Am J Orthop 2005;34(12):592-7

No abstract available


Chow et al 2000

Clarithromycin attenuates mastectomy-induced acute inflammatory response.

Chow LW, Yuen KY, Woo PC, Wei WI.

Clinical and diagnostic laboratory immunology 2000;7(6):925-31.

Clarithromycin attenuates mastectomy-induced acute inflammatory response. Clinical and diagnostic laboratory immunology 2000;7(6):925-31.Based on the observation that administration of clarithromycin led to an attenuation of the inflammatory response induced by surgical trauma in a guinea pig model, we investigated the potential beneficial effects of clarithromycin on the local and systemic inflammatory response in patients undergoing mastectomy in an open-label prospective study. During a 16-month period, 54 patients who underwent mastectomy were randomly divided into two groups. In one group, the patients received oral clarithromycin at a dose of 500 mg twice a day, from the day before to 3 days after mastectomy. There was no significant difference in the incidence of antibiotic prophylaxis- related toxicities or postoperative infections between the patients who received clarithromycin and those who did not. Clarithromycin treatment was significantly associated with an attenuation of febrile response, tachycardia, tachypnea, and an increase in monocyte counts (P, <0.0001, <0.01, <0.05, and <0.01, respectively). Clarithromycin also reduced the intensity and duration of postoperative pain (P, <0.05 and <0.005, respectively) and increased the range of motion of the involved shoulder (P < 0.05 for abduction and flexion). We conclude that clarithromycin effectively modulates the acute inflammatory response associated with mastectomy and produces a better clinical outcome.


Rice et al 2000

Intraoperative topical tetracycline sclerotherapy following mastectomy: a prospective, randomized trial.

Rice DC, Morris SM, Sarr MG, Farnell MB, van HJA, Grant CS, Rowland CM, Ilstrup DM, Donohue JH

Journal of Surgical Oncology 2000;73(4):224-7.

BACKGROUND AND OBJECTIVES: Postoperative wound seromas are a frequent and troublesome occurrence after mastectomy. Recent reports have suggested the efficacy of topical sclerosants at reducing their formation. METHODS: A prospective, randomized, double-blinded trial was performed to examine the effect of intraoperatively administered topical tetracycline on the occurrence of postoperative mastectomy seromas. Thirty-two women were randomized to the control arm (normal saline) and 30 women to the tetracycline arm. In the treatment group, 100 ml (2 g) of tetracycline solution was administered topically to the chest wall and skin flaps prior to skin closure. The control group received an equal volume of normal saline. Patients were monitored for the development of postoperative wound seroma. RESULTS: There were no significant differences between groups regarding total volume of closed suction drainage, numbers of patients leaving hospital with drains in place, or duration of catheter drainage. Seroma formation 2 weeks postoperatively was greater in the tetracycline group than the control group (53% vs. 22%, P = 0.01). There were no differences between groups regarding the degree of postoperative pain, wound infection, or seroma formation 1 month postoperatively. CONCLUSIONS: Topical tetracycline is not effective at preventing post-mastectomy wound seromas.


Klein et al 2000

Infiltration of the abdominal wall with local anaesthetic after total abdominal hysterectomy has no opioid-sparing effect.

Klein JR, Heaton JP, Thompson JP, Cotton BR, Davidson AC, Smith G.

Br J Anaesth 2000;84(2):248–249.

We have measured the effect of infiltration of the deep and superficial layers of the abdominal wound on morphine consumption and pain for 48 h after operation, in 40 patients undergoing total abdominal hysterectomy, in a double-blind randomized study. Patients received wound infiltration with 0.9% normal saline 40 ml or 40 ml of 0.25% bupivacaine with epinephrine 1:200,000. There were no significant differences between groups in morphine consumption, linear analogue scores for pain at rest or on movement, nausea or sedation during the first 48 h after operation. We conclude that infiltration of the deep and superficial layers of the wound of a Pfannenstiel incision with local anaesthetic solution did not confer additional analgesia in patients undergoing major gynaecological surgery.


Davies et al 2006

A comparison of the analgesic efficacy and side-effects of paravertebral vs epidural blockade for thoracotomy--a systematic review and meta-analysis of randomized trials.

Davies RG, Myles PS, Graham JM.

Br J Anaesth 2006; 96(4):418–26.

Epidural analgesia is considered by many to be the best method of pain relief after major surgery. It is used routinely in many thoracic surgery centres. Although effective, side-effects include hypotension, urinary retention, incomplete (or failed) block, and, in rare cases, paraplegia. Paravertebral block (PVB) is an alternative technique that may offer comparable analgesic effectiveness and a better side-effect profile. We undertook a systematic review and meta-analysis of all relevant randomized trials comparing PVB with epidural analgesia in thoracic surgery. Data were abstracted and verified by both authors. Studies were tested for heterogeneity, and meta-analyses were done with random effects or fixed effects models. Weighted mean difference (WMD) was used for numerical outcomes and odds ratio (OR) for dichotomous outcomes, both with 95% CI. We identified 10 trials that had enrolled 520 thoracic surgery patients. All of the trials were small (n<130) and none were blinded. There was no significant difference between PVB and epidural groups for pain scores at 4-8, 24 or 48 h, WMD 0.37 (95% CI: -0.5, 121), 0.05 (-0.6, 0.7), -0.04 (-0.4, 0.3), respectively. Pulmonary complications occurred less often with PVB, OR 0.36 (0.14, 0.92). Urinary retention, OR 0.23 (0.10, 0.51), nausea and vomiting, OR 0.47 (0.24, 0.53), and hypotension, OR 0.23 (0.11, 0.48), were less common with PVB. Rates of failed block were lower in the PVB group, OR 0.28 (0.2, 0.6). PVB and epidural analgesia provide comparable pain relief after thoracic surgery, but PVB has a better side-effect profile and is associated with a reduction in pulmonary complications. PVB can be recommended for major thoracic surgery.


Aida et al 1999

The effectiveness of preemptive analgesia varies according to the type of surgery: a randomized, double-blind study.

Aida S, Baba H, Yamakura T, Taga K, Fukuda S, Shimoji K

Anesthesia and analgesia 1999;89(3):711-6.

The reliability of preemptive analgesia is controversial. Its effectiveness may vary among anatomical areas or surgical types. We evaluated preemptive analgesia by epidural morphine in six surgery types in a randomized, double-blind manner. Pain intensity was rated using a visual analog scale, a verbal report, and a measurement of postsurgical morphine consumption. Preemptive analgesia was effective in limb surgery and mastectomy, but ineffective for gastrectomy, hysterectomy, herniorrhaphy, and appendectomy. Relief of postsurgical pain in hemiorrhaphy was more rapid than that in the other surgery types. Preemptive analgesia was effective in limb surgery and mastectomy, but not in surgeries involving laparotomy, regardless of whether the surgery was major (gastrectomy and hysterectomy) or minor (herniorrhaphy and appendectomy). These results suggest that viscero- peritoneal nociception is involved in postsurgical pain. The abdominal viscera and peritoneum are innervated both heterosegmentally (in duplicate or triplicate by the vagus and/or phrenic nerves) and segmentally (by the spinal nerves). Therefore, supraspinal and/or cervical spinal neurons might be sensitized, despite the blockade of the segmental nerves with epidural morphine. The rapid retreat of the pain after hemiorrhaphy suggests that central sensitization remits soon after minor surgery, but that in appendicitis, it may be protracted by additional noxious stimuli, such as infection. IMPLICATIONS: Epidural preemptive analgesia was reliably effective in limb and breast surgeries but ineffective in abdominal surgery, suggesting involvement of the brainstem and cervical spinal cord via the vagus and phlenic nerves.


Correll ET AL 2001

Epidural analgesia compared with intravenous morphine patient- controlled analgesia: postoperative outcome measures after mastectomy with immediate TRAM flap breast reconstruction.

Correll DJ, Viscusi ER, Grunwald Z, Moore JH, Jr

Regional anesthesia and pain medicine 2001;26(5):444-9.

BACKGROUND AND OBJECTIVES: Epidural analgesia has been shown to provide superior pain control compared with intravenous (IV) opioids after major surgical procedures. In this study, we compared the effect of epidural analgesia and IV morphine patient-controlled analgesia (PCA) on pain relief, duration of hospitalization, oral nutrition, ambulation, and side effects in patients undergoing a major surgical procedure (i.e., unilateral mastectomy with immediate transverse rectus abdominis musculocutaneous flap reconstruction). METHODS: Eighteen patients were prospectively randomized to receive either epidural analgesia or PCA during the postoperative period. The intensity of pain was assessed daily by a 100-mm visual analog scale. The total length of hospital stay, time to ambulation, and time to oral nutrition were recorded. RESULTS: The epidural group had significantly lower pain scores at 3 evaluation times through postoperative day number 4 (P < .05). The total length of hospitalization for the epidural group (median, 101 hours) was significantly less than the PCA group (median, 126 hours; P = .0498). The time to first ambulation, time to first bowel sounds, time to tolerating oral nutrition, incidence of nausea/vomiting or pruritus, and time to first flatus were not statistically different between the groups. CONCLUSIONS: These results show that epidural analgesia compared with PCA offered improved pain control after breast reconstruction with immediate transverse rectus abdominis musculocutaneous flap reconstruction. It also resulted in a 25-hour reduction in time of hospitalization.


Sundarathiti et al 2005

Sundarathiti P, Pasutharnchat K, Kongdan Y, Suranutkarin Pe. Thoracic epidural anesthesia TEA with 02% ropivacaine in combination with ipsilateral brachial plexus block BPB for modified radical mastec

Sundarathiti P, Pasutharnchat K, Kongdan Y, Suranutkarin Pe

Journal of the Medical Association of Thailand = Chotmaihetthangphaet 2005;88(4):513-20.

BACKGROUND: Breast cancer is the 2nd most common tumors in Thai women. Until now, oncologic breast surgeries are typically performed by general anesthesia (GA). However, GA cannot provide adequate postoperative pain control and routine use of parenteral opioids aggravate postoperative sedation, nausea, emesis, impaired oxygenation and depressed ventilation. Thoracic epidural anesthesia (TEA) is one of the regional anesthetic techniques that can be done by using a low dose of local anesthetic in combination with ipsilateral brachial plexus block (BPB) for axillary node dissection. TEA can provide a better pain relief without potential paralysis of respiratory muscle and sedation. MATERIAL AND METHOD: Fifty ASA PS I-III patients undergoing MRM were randomly assigned to two study groups of 25 patients each. In the TEA group, an epidural catheter was inserted at T4 to T5, and 10-15 ml of 0.2% ropivacaine was injected, then interscalene BPB was done with 8 ml of 0.2% ropivacaine. Anesthesia was maintained with 5-10 ml of 0.2% ropivacaine per hour. GA was induced with 1 microg/kg of fentanyl followed by 1.5-2 mg/kg of propofol and was maintained with sevoflurane and 70% N2O in oxygen. The authors evaluated the adequacy of anesthesia, surgical condition, postanesthetic recovery, postanesthetic analgesia and patients' satisfaction. RESULTS: The demographic data was similar in both groups. The number of patients immediately arrived at PACU with a sedation score of 1 was significantly greater in TEA group (p = 0.003) while the number of patients with an Aldrete score of 10 was greater but not statistically significant (p = 0.25). The verbal rating scale and analgesic requirement were significantly lower in the TEA group (p < 0.001 and p = 0.002 respectively). Patients' satisfaction was greater with TEA than with GA (p = 0.014). Surgical condition was similar in both groups. CONCLUSION: The present study shows that TEA combined with BPB by using a low dose of 0.2% ropivacaine is a safe and reliable alternative technique for MRM. It can provide not only effective anesthesia but also better postoperative pain relief faster anesthetic recovery and greater patient satisfaction than those of the


Johansson et al 2000

Preoperative ropivacaine infiltration in breast surgery.

Johansson A, Axelson J, Ingvar C, Luttropp HH, Lundberg J

Acta anaesthesiologica Scandinavica 2000;44(9):1093-8.

The aim of the study was to investigate whether preoperative infiltration with ropivacaine in conjunction with breast surgery improves postoperative pain management and attenuates postoperative nausea and vomiting. METHOD: Prospective, randomised, double-blind study, including 60 healthy women (ASA 1-2) allocated to one of two groups. Thirty patients were given 0.3 ml/kg saline in the operating field before surgery. Another 30 patients received a similar volume of ropivacaine 3.75 mg/ml. A visual analogue scale (0-100 mm) was used for evaluation of postoperative pain, nausea and vomiting. If the score was more than 30 mm at rest, the patients were given ketobemidone i.v. as treatment for postoperative pain, and dixyrazine i.v. against nausea and vomiting. The intra-and postoperative analgesic requirements and postoperative nausea and vomiting were registered. RESULTS: The intraoperative fentanyl consumption was similar in the saline group 81 +/- 22 microg vs 76 +/- 28 microg; (ns) in the ropivacaine group. The postoperative 24-h ketobemidone consumption was also similar to those treated with ropivacaine (4.2 + /- 2.6 mg vs 4.2 +/- 4.3 mg; ns). Postoperative nausea and vomiting (PONV) occurred with similar frequencies in both groups. The 24-h dixyrazine consumption was the same in the two groups (2.1 +/- 2.7 mg in the saline group compared to 2.4 +/- 2.8 mg in the ropivacaine group; ns). After 6 h recovery, 41% of all patients had experienced nausea and 20% vomiting. CONCLUSION: We found no differences in postoperative pain management between 3.75 mg/ml ropivacaine and saline wound infiltration before breast surgery. The data show similar postoperative needs of analgesics and antiemetics with a similar frequency of PONV.


Vallejo et al 2006

Preemptive analgesia with bupivacaine for segmental mastectomy.

Vallejo MC, Phelps AL, Sah N, Romeo RC, Falk JS, Johnson RR, Keenan DM, Bonaventura MA, Edington HD

Regional anesthesia and pain medicine 2006;31(3):227-32.

BACKGROUND AND OBJECTIVES: Preemptive analgesia is the concept of providing analgesia before surgical incision, resulting in less postoperative pain. The purpose of this study is to determine if preemptive and/or postoperative local anesthetic infiltration of bupivacaine in patients undergoing segmental mastectomy results in less postoperative pain compared with patients receiving placebo. METHODS: In this prospective, double-blinded study, 120 patients were randomized into 4 groups: group 1, preincisional (10 mL) and postoperative (10 mL) wound infiltration of 0.5% bupivicaine, (+Pre +Post); group 2, preincisional bupivacaine (10 mL) and postoperative infiltration (10 mL) of placebo (normal saline solution), (+Pre-Post); group 3, preincisional placebo (10 mL) and postoperative bupivacaine (10 mL), (-Pre+Post); or group 4, preincisional (10 mL) and postoperative infiltration of placebo (10 mL), (-Pre-Post). All patients received a standardized laryngeal mask general anesthetic. Data were recorded at the following time intervals: preoperative admission, postanesthesia care unit (PACU) admission, PACU stay, stepdown-unit admission, stepdown-unit stay, hospital discharge, and 24 hours post operation. RESULTS: No difference was noted with respect to preoperative pain visual analog scale (VAS, 0-100 mm), surgical duration, PACU stay time, stepdown-unit stay time, incidence of postoperative nausea, or treatment for nausea in all measured time periods. The placebo group (group 4) had significantly higher mean pain VAS scores during the early postoperative period (PACU admission and PACU stay) compared to the other groups (PACU admission: group 1 = 2 +/- 8, group 2 = 4 +/- 11, group 3 = 3 +/- 15, group 4 = 17 +/- 21, P < .01; PACU stay: group 1 = 6 +/- 13, group 2 = 6 +/- 10, group 3 = 10 +/- 21, group 4 = 20 +/- 18, P < .01). Likewise, the number of patients who reported pain (pain frequency) was significantly higher in group 4 (placebo) compared with all other groups at PACU admission, PACU stay, stepdown-unit admission, and stepdown-unit stay (P < or = .01). CONCLUSION: Preincisional and/or postoperative wound bupivacaine infiltration lacks preemptive analgesic effects for segmental mastectomy.


Pettersson et al 2001

Efficacy of subcutaneous and topical local anaesthesia for pain relief after resection of malignant breast tumours.

Pettersson N, Perbeck L, Hahn RG

The European Journal of Aurgery = Acta Chirurgica 2001;167(11):825-30.

OBJECTIVE: Infiltration and topical application of local anaesthetics close to the surgical wound may be used to prevent postoperative pain. We evaluated the efficacy of these treatments after breast surgery for cancer. DESIGN: Double-blind randomised trial with two treatment groups and one control group. SETTING: University hospital, Sweden. INTERVENTIONS: Patients were allocated to treatment with bupivacaine infiltration (n = 29), topical application of lignocaine/prilocaine (n = 31), or no local treatment (n = 30). MAIN OUTCOME MEASURES: Difference and time related patterns in pain scores measured on a visual analogue scale (VAS), and morphine consumption. RESULTS. None of the local anaesthetics significantly reduced the VAS score or morphine consumption. However, fewer patients in the anaesthetic groups had high VAS scores than controls, the 75 centile for the mean score after operation being 2.7, 2.0 and 2.1 for the controls, infiltration, and topical anaesthetic groups, respectively. The controls had higher scores from 6 hours postoperatively onwards. The corresponding median morphine consumption was 24.5, 18.5, and 16.2 mg. CONCLUSIONS. Local anaesthesia slightly reduced the overall pain scores and the morphine consumption, but was of potential clinical value only in the patients who had the highest pain scores.


Johansson et al 2003

Wound infiltration with ropivacaine and fentanyl: effects on postoperative pain and PONV after breast surgery.

Johansson A, Kornfält J, Nordin L, Svensson L, Ingvar C, Lundberg J.

Journal of clinical anesthesia 2003;15(2):113-8.

No abstract available


Yarussi et al 1999

Evaluation of peripheral morphine analgesia for lumpectomy and axillary node dissection: a randomized, double-blind, placebo- controlled study.

Yarussi A, Sands R, Edge S, Lema MJ, de LCOA

Regional anesthesia and pain medicine 1999;24(2):142-5.

BACKGROUND AND OBJECTIVES: Morphine may elicit potent antinociceptive effects by binding and activating peripheral opioid receptors. However, the results in clinical studies have varied. We examined the postoperative analgesic effects of incisional morphine in patients undergoing lumpectomies and axillary node dissections for breast cancer. For this purpose, a concentration of morphine within the range (0.25-0.6%) of those utilized in previous studies for postarthroscopy analgesia was chosen (0.6%). METHODS: Forty-five patients scheduled to undergo a lumpectomy and axillary node dissections for breast cancer were enrolled in this study after receiving Ethics Committee approval and patient consent. Patients were randomized to undergo irrigation of the surgical sites for 5 minutes prior to skin closure with 6 mg morphine diluted in 100 mL 0.9% normal saline (NS) and placebo intramuscular (i.m.) (peripheral MS group), 100 mL of 0.9% NS alone and placebo i.m. (placebo group), or 100 mL of 0.9% NS and 6 mg morphine i.m. in the deltoid muscle (i.m. MS group) in a double-blind fashion. In the postanesthesia care unit, patients received fentanyl via a patient-controlled analgesia (PCA) device programmed to deliver 25 microg every 10 minutes to a maximum dose of 150 microg/h. Patients were evaluated for pain using a visual analog scale card from 0-10, opioid consumption, and incidences of side effects at 2, 6, 12, 18, and 24 hours after surgery. RESULTS: All patients had adequate analgesia at rest and during arm movement with visual analog pain scores (VAPS) <3/10 throughout the study period. There were no significant differences in demographics, total fentanyl consumption (500 vs. 475 vs 933 microg, respectively; P = .2), VAPS at rest and during arm movement as well as fentanyl consumption at the different evaluation points among the three groups. CONCLUSIONS: These results suggest that under the conditions of the study protocol, there is no value in utilizing morphine in solution at the surgical site for postoperative lumpectomy and axillary node dissection analgesia.


Talbot 2004

Evaluation of a local anaesthesia regimen following mastectomy

Talbot H, Hutchinson SP, Edbrooke DL, Wrench I, Kohlhardt SR

Anaesthesia 2004;59(7):664-7.

Breast surgery can be emotionally distressing and physically painful. Acute pain following surgery is often related mainly to the axillary surgery and is aggravated by arm and shoulder movement. We conducted a prospective double-blind, randomised, placebo-controlled trial to determine the influence of local anaesthetic irrigation of axillary wound drains on postoperative pain during the first 24 h following a modified Patey mastectomy (mastectomy with complete axillary node clearance). The treatment group received bupivacaine irrigation through the axillary wound drain 4-hourly for 24 h postoperatively. Controls received irrigation with normal saline. Morphine via a patient controlled analgesia pump was used for postoperative analgesia. Morphine consumption, visual analogue and verbal rating pain scores were recorded. There were no statistical differences in morphine requirements or pain scores between the two groups, nor were there differences in anti-emetic or supplemental analgesic consumption. Bupivacaine irrigation used in this manner does not appear to offer an effective contribution to postoperative analgesia.


Fassoulaki et al 2000

EMLA reduces acute and chronic pain after breast surgery for cancer.

Fassoulaki A, Sarantopoulos C, Melemeni A, Hogan Q

Regional anesthesia and pain medicine 2000;25(4):350-5.

We investigated the analgesic efficacy of mexiletine and gabapentin on acute and chronic pain associated with cancer breast surgery in 75 patients. They were randomized to receive, in a double-blinded manner, mexiletine 600 mg/d, gabapentin 1200 mg/d, or placebo for 10 days. Anesthesia was standardized, and all patients had access to routine postoperative analgesics on demand. The visual analog scale score assessed pain at rest and after movement. Three months later, all patients were interviewed to identify intensity of chronic pain and analgesic requirements. Mexiletine and gabapentin reduced codeine consumed from the second to tenth day by 50% (P = 0.029; P = 0.018 and P = 0.035 for mexiletine versus control and gabapentin versus control comparisons, respectively). Total paracetamol consumption was also reduced during the same time (P = 0.0085; P = 0.007 and P = 0.011 for the mexiletine and gabapentin groups when compared with the control, respectively). Pain at rest and after movement was reduced by both drugs on the third postoperative day. Pain after movement also was reduced by gabapentin between the second and fifth postoperative day. Three months later, the incidence of chronic pain, its intensity, and need for analgesics were not affected by either treatment. However, burning pain was more frequent in the control group (P = 0.033). IMPLICATIONS: Patients undergoing breast surgery for cancer may develop chronic pain. We evaluated the effect of mexiletine and gabapentin on the acute and chronic pain after breast surgery for cancer. Both drugs reduced the postoperative analgesic requirements, and particularly, gabapentin reduced pain after movement. The overall incidence of chronic pain was unaffected except for burning pain.