Total Knee Arthroplasty

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PROSPECT Total Knee Arthroplasty Subgroup For each review, a Subgroup of the prospect Working Group performs an initial evaluation of the evidence and also drafts clinical practice statements and recommendations, which are then discussed by the whole Working Group before a final consensus is reached. The Subgroup may sometimes include a non-Working Group member, to provide additional expertise in the procedure being reviewed. For the total knee arthroplasty review, the Subgroup members were: Dr Christian Simanski Dr Barrie Fischer Grades of Recommendation Recommendations are graded according to the overall level of evidence (LoE) on which the recommendations are based, which is determined by the quality and source of evidence: (Levels of evidence and grades of recommendation in PROSPECT reviews (from 2006)) PROSPECT provides clinicians with supporting arguments for and against the use of various interventions in postoperative pain based on published evidence and expert opinion. Clinicians must make judgements based upon the clinical circumstances and local regulations. At all times, local prescribing information for the drugs referred to must be consulted. Summary Recommendations Pre-, intra- and postoperative interventions have been evaluated for the management of postoperative pain following total knee arthroplasty. Unless otherwise stated, ‘pre-operative’ refers to interventions applied before surgical incision, ‘intra-operative’ refers to interventions applied after incision and before wound closure, ‘postoperative’ refers to interventions applied at or after wound closure. The following peri-operative interventions for total knee arthroplasty have been reviewed: Pre-operative Recommendations for total knee arthroplasty Intra-operative Recommendations for total knee arthroplasty Postoperative Recommendations for total knee arthroplasty Not recommended for total knee arthroplasty for postoperative analgesia See Overall Recommendations for the overall strategy for managing pain after total knee arthroplasty.

PROSPECT overall recommendations for postoperative pain management following total knee arthroplasty:

Description of studies

Literature search

Study quality assessments, levels of evidence and grades of recommendation Recommendations are graded according to the overall level of evidence (LoE) on which the recommendations are based, which is determined by the quality and source of evidence: (Levels of evidence and grades of recommendation in PROSPECT reviews (from 2006)

Quantitative analyses

Overall, few meta-analyses could be performed that used data from more than two studies. This is because there are a limited number of studies of homogeneous design that report similar outcome measures. Therefore, the majority of the procedure-specific evidence was assessed only qualitatively.

Transferable evidence

Transferable evidence of analgesic efficacy from comparable procedures or evidence of other outcomes, such as adverse effects, has been included to support the procedure-specific evidence where this is insufficient to formulate the recommendations.

Many studies that were identified in the literature search included patients undergoing total knee or hip replacement and reported data pooled from all these patients. Such studies are excluded from the procedure-specific systematic review but have been used as additional transferable evidence where required. Data from other types of orthopaedic surgery (e.g. ACL reconstruction, spinal surgery, hip surgery) were not used for transferable evidence of analgesic efficacy in most instances because it was considered that the pain profile of these procedures was too different from that of TKA. However, data from studies in a variety of procedures have been used for evidence of adverse-effects, which can occur regardless of the procedure.

Topics for future research:

  • Pre-operative corticosteroids
  • Alpha-2-delta subunit ligands (gabapentinoids)
  • Peri-operative ketamine
  • Single injection versus continuous infusion peripheral nerve block
  • Combination femoral and sciatic/obturator nerve block
  • Intra-articular/incisional techniques
  • Pre- versus post-incisional administration of various agents
  • Dose- and duration-dependent effects of conventional NSAIDs and COX-2-selective inhibitors on bone healing
  • Combination of conventional NSAIDs with regional analgesic techniques
  • Combination of COX-2-selective inhibitors with regional analgesic techniques

 

Abbreviations

bd

twice per day

GA

general anaesthetic

IM

intramuscular

Intra-op

intra-operatively

IV

intravenous

LA

local anaesthetic

NRS

numerical rating scale

PACU

post-anaesthesia care unit

PCA

patient-controlled analgesia

PCEA

patient-controlled epidural analgesia

POD

postoperative day

PONV

postoperative nausea and vomiting

Pre-op

pre-operatively

Postop

postoperatively

RCT

randomised controlled trial

ROM

range of motion

SpO2

median oxygen saturation

TKA

total knee arthroplasty

VAS

visual analogue scale

VRS

verbal rating scale

PROSPECT Recommendations

  • Peripheral nerve blocks are not recommended to be performed intra-operatively (Grade D, LoE 4). PROSPECT definition of pre-operative, intra-operative and postoperative administration Click here for more information

Clinical practice

  • None cited

Transferable evidence

  • None cited

Total knee arthroplasty-specific evidence

  • Evidence suggests that the time of administration of femoral nerve blocks has no effect on postoperative pain outcomes after TKA. Therefore, included studies of such techniques have been pooled for analysis irrespective of the timing of administration. All of the procedure-specific evidence is presented in the Postoperative section

PROSPECT Recommendations

  • GA + femoral nerve block, or spinal anaesthesia (with LA) + femoral nerve block are recommended as first choices for anaesthesia/analgesia (Grade D, LoE 4) (see also Pre-operative Peripheral nerve block techniques for evidence and recommendations about femoral nerve block)
  • Spinal LA + morphine is recommended but not as the first choice of anaesthetic/analgesic technique (Grade D, LoE 4), because of a greater potential for adverse events compared with femoral nerve block (transferable evidence, LoE 3) (see also Pre-operative Spinal techniques)
  • GA or spinal anaesthesia without any local or regional analgesic technique is not recommended (Grade D, LoE 4)
  • Epidural anaesthesia is not recommended (Grade D, LoE 4) because postoperative epidural analgesia is not recommended

Clinical practice

  • It is considered that analgesic drugs should be administered in time to secure sufficient pain relief when the patient wakes
  • Spinal anaesthesia provides a more complete surgical block than epidural anaesthesia
  • Epidural analgesia is associated with a relatively high degree of patient monitoring and serious (although rare) major complications
  • Epidural analgesia is a relatively complicated and invasive technique compared with peripheral nerve blocks

Transferable evidence

  • Epidural analgesia was superior to systemic analgesia for postoperative pain outcomes following hip or knee replacement Choi et al 2003 Click here for more information
  • A combination of epidural local anaesthetic plus opioid produced superior analgesic benefits compared with either drug administered alone in three studies of hip or knee surgery Lorenzini et al 2002 Click here for more information
  • Epidural analgesia was associated with a lower incidence of sedation compared with systemic analgesia Choi et al 2003 Click here for more information
  • Epidural anaesthesia reduces the frequency of deep vein thrombosis and pulmonary embolism, and reduces intra-operative and postoperative blood loss, compared with general anaesthesia, particularly in total hip arthroplasty patients, as shown in a review
  • Two studies showed superior analgesic effects of spinal LA plus opioid compared with LA alone, following total hip or knee arthroplasty Drakeford et al 1991 Click here for more information
  • Bupivacaine administered via spinal infusion (0.5% at 0.4 ml/h or 0.2 ml/h) resulted in an increase in the incidence of sensory and motor block compared with saline infusion
  • Diamorphine administered spinally in combination with bupivacaine showed a significantly higher incidence of nausea and vomiting compared with the bupivacaine alone group (p<0.05) following knee or hip replacement surgery
  • Epidural infusion of ropivacaine (2 mg/ml) plus sufentanil (1 µg/ml) produced a significantly higher incidence of adverse events (pruritus, nausea and vomiting) than ropivacaine alone following major knee surgery (p<0.01; n=115)
  • Epidural administration of strong opioids is associated with side-effects including pruritus, PONV, urinary retention, and respiratory depression
  • Epidural analgesia was associated with more frequent urinary retention, pruritus and low blood pressure compared with systemic analgesia in hip or knee replacement Choi et al 2003 Click here for more information
  • Neuraxial opioids are associated with a greater risk of side-effects compared with continuous plexus and peripheral neural blockades after major orthopaedic surgery

Total knee arthroplasty-specific evidence

  • Pain scores during ROM were significantly lower in the epidural group compared with the spinal anaesthesia + IV PCA morphine group on postoperative days 1–10 (p<0.001, in all cases)
  • Pain scores at rest were significantly lower in the epidural group compared with the spinal anaesthesia + IV PCA morphine group on postoperative day 1 (p<0.001), but not on days 2–10
  • There was significantly less sedation in the epidural group compared with the spinal anaesthesia + IV PCA morphine group on postoperative day 1 (p=0.04), but not on day 2
  • VAS pain scores were significantly lower in the IV propofol + spinal anaesthesia group compared with the IV propofol + fentanyl group at 3–4 days postoperatively (p<0.05), but not at 8 h or 1–2 days following surgery (
  • IV propofol + spinal anaesthesia was associated with significantly reduced time to extubation, emergence, response to command, and orientation (p<0.001, in all cases) compared with IV propofol + fentanyl anaesthesia (
  • IV propofol + spinal anaesthesia was associated with significantly reduced requirement for antihypertensive therapy compared with IV propofol + fentanyl anaesthesia (p<0.01) (
  • The incidence of sore throat (p=0.002), hoarseness (p=0.009), and nausea (p=0.049) was significantly lower in the IV propofol + spinal anaesthesia group compared with the IV propofol + fentanyl group; the incidence of vomiting, dizziness and back pain was similar in both groups (
  • Significantly more patients reported feeling comfortable (p=0.01) and having good dreams (p<0.0001) in the IV propofol + spinal anaesthesia group than in the IV propofol + fentanyl group (
  • Postoperative pentazocine consumption was significantly higher in the IV propofol + spinal anaesthesia group compared with the IV propofol + fentanyl group in the first 8 h postoperatively (p<0.05); there were no significant differences between the two groups in the consumption of diclofenac sodium at 8 h postoperatively (postoperative analgesia was diclofenac sodium [50 mg] administered rectally every 6 h, and pentazocine, as required) (
  • Study Details Farag et al 2005 Click here for more information
  • Study Details Kudoh et al 2004 Click here for more information
  • Lumbar epidural versus spinal anaesthesia
  • Spinal versus IV anaesthesia

PROSPECT Recommendations

  • Intra-articular LA and/or morphine is not recommended at this time (Grade D, LoE 4) because of inconsistent analgesic efficacy in procedure-specific and transferable evidence (see Postoperative Intra-articular Analgesia)
  • Intra-articular NSAIDs, neostigmine, or clonidine are not recommended (Grade D, LoE 4) because there is no procedure-specific and inconsistent transferable evidence
  • Intra-articular corticosteroid is not recommended at this time (Grade D, LoE 4) because there is no procedure-specific evidence, despite positive transferable evidence from minor orthopaedic procedures (LoE 1)
  • After the cut-off date of the systematic literature search, additional studies of combined intra-articular and incisional LA have shown an analgesic benefit (procedure-specific evidence, LoE 1) (see Postoperative Intra-articular Analgesia)

Clinical practice

  • Doses of IA morphine in some studies (5–10 mg) represent systemic, not IA doses

Transferable evidence

  • A systematic review of knee joint surgery RCTs looked at the effects of IA morphine, compared with saline Kalso E et al 2002 Click here for more information
  • Several randomised studies in arthroscopic knee or ankle surgery have shown that intra-articular corticosteroid reduced pain after surgery
  • A second systematic review of RCTs examining the effects of IA morphine following knee joint surgery suggested that there were no significant analgesic effects of morphine compared with saline Rosseland LA 2005 Click here for more information

Total knee arthroplasty-specific evidence

  • There is no evidence that the timing of administration of intra-articular analgesia has a significant effect on postoperative pain outcomes. All studies of intra-articular analgesia are presented in the Postoperative Intra-articular section, except for studies comparing different times of administration.

PROSPECT Recommendations

  • After the cut-off date of the systematic literature search, additional studies of combined intra-articular and incisional LA have shown an analgesic benefit (procedure-specific evidence, LoE 1)

Clinical practice

  • None cited

Transferable evidence

  • None cited

Total knee arthroplasty-specific evidence

PROSPECT Recommendations

  • Drains are not recommended (Grade A), as they do not provide analgesic or other recovery benefits (procedure-specific evidence, LoE 1) and are associated with pain on removal (LoE 4)

Clinical practice

  • Drains are associated with pain on removal

Transferable evidence

  • Wound drains without suction produced less postoperative pain intensity on removal compared with drains with suction in intra-articular procedures (n=126; p<0.05)
  • Several studies showed no significant benefit of drained compared with un-drained wounds for a range of postoperative pain outcomes, including postoperative pain scores, in orthopaedic surgery Parker et al 2003 Click here for more information
  • Wound drains were associated with higher pain scores than no drains (no statistical analysis) in one study of patients undergoing total hip arthroplasty (n=23)
  • A meta-analysis evaluating the effectiveness of closed suction drainage systems during orthopaedic surgery found no difference in the incidence of wound infection, haematoma or dehiscence between patients with drains and those with un-drained wounds, and concluded that the evidence was insufficient to support or refute the use of drains

Total knee arthroplasty-specific evidence

  • Three studies out of three showed that drainage was not associated with any significant difference compared with no drainage for VAS pain scores, see Table 5 for details ( Click here for more information
  • Only one study out of three reported analgesic use following the use of drainage or no drainage and showed no significant difference for the number of requests for analgesia (
  • Three studies out of three showed no significant difference between drainage and no drainage for knee flexion; see Table 5 for details Click here for more information
  • One of three studies showed that drainage significantly increased the circumference of the knee on day 3 (p<0.0096) compared with no drainage, but there was no significant difference at 1 week, 1 month or 4 months postoperatively, or for the circumference of the thigh or the calf ( Click here for more information
  • One out of one study showed that drainage significantly increased the time to regain active straight-leg raising (p=0.02) compared with no drainage (
  • Two studies comparing drainage with no drainage reported hospital stay and showed no significant difference between groups (
  • Two studies comparing drainage with no drainage reported blood loss and transfusion requirements, with mixed results: one study reported no significant difference for blood loss or incidence of blood transfusion, but drainage was associated with a significant increase in units of transfused blood (p=0.03) (
  • One study reported no significant difference between drainage and no drainage for postoperative complications ( Click here for more information
  • Study details and Table 5 Click here for more information

PROSPECT Recommendations

  • No recommendation can be made for tourniquet use, as this depends on surgical/anatomical requirements, rather than pain

Clinical practice

  • Tourniquet use provides a better intra-operative surgical overview of the anatomy and avoids nerve damage (med vastus approach). Decision to use rests with the surgeon, depending on the individual patient’s anatomy and the surgeon’s experience
  • Results are difficult to interpret, due to insufficient description of anaesthetic techniques

Transferable evidence

  • None cited

Total knee arthroplasty-specific evidence

  • Release of a pneumatic tourniquet around the thigh before suturing and bandaging was significantly superior to release after suturing and bandaging for reducing VAS pain scores at 4 h postoperatively (p<0.001) (
  • Use of tourniquet was not found to be associated with any significant effect on postoperative complications, except for a significant reduction in overall blood loss in one of the two studies ( Click here for more information
  • Release of a pneumatic tourniquet around the thigh before suturing and bandaging was significantly superior to release after suturing and bandaging for the time to achieve a straight leg (p<0.00001) (
  • Release of a pneumatic tourniquet around the thigh before suturing and bandaging was significantly superior to release after suturing and bandaging for reducing the incidence of minor wound complications (p=0.04) and excessive swelling (p=0.02) (
  • Two out of three studies found that surgery with tourniquet was associated with increased pain scores compared with no tourniquet; see Table 6 for details ( Click here for more information
  • Two out of three studies reported no differences between treatment groups in terms of supplemental analgesic use; see Table 6 for details ( Click here for more information
  • Three out of three studies reported that short-term functional outcomes were superior among patients who had not had a tourniquet (see Table 6 for details), although longer-term (>3 months) joint flexibility was not found to differ significantly according to tourniquet use ( Click here for more information
  • Release of a pneumatic tourniquet around the thigh after suturing and bandaging was not significantly different from release before suturing and bandaging for the mean range of flexion at 5 or 10 days or 6 weeks (
  • Two out of two studies reported no significant difference between use of tourniquet and no tourniquet for length of hospital stay (
  • Release of a pneumatic tourniquet around the thigh after suturing and bandaging was similar to release before suturing and bandaging for hospital stay (
  • Study details and Table 6 Barwell et al 1997 Click here for more information

PROSPECT Recommendations

  • No recommendation can be made for one type of approach over another, as use depends on individual patient factors and surgical requirements, rather than pain

Clinical practice

  • Type of approach depends on individual patient factors and surgical requirements, rather than pain

Transferable evidence

  • None cited

Total knee arthroplasty-specific evidence

  • The medial trivector approach and the parapatellar approach were associated with similar Knee Society pain scores at 6 weeks and 6 months postoperatively (
  • The subvastus and medial parapatellar approaches were not significantly different for postoperative VAS pain scores (
  • Patients in the posterior cruciate ligament (PCL) excised, PCL retained, posterior stabilised and valgus groups had significantly better Knee Society mean pain scores than those in the PCL released group (p=0.03); no significant differences were observed between the PCL excised, PCL retained and posterior stabilised groups (
  • The medial trivector approach was associated with a significant decrease in the number of days to achieve straight leg raising (p<0.05) compared with the parapatellar approach (
  • The subvastus approach was significantly superior to the medial parapatellar approach for the time to attainment of 90-degree flexion (p<0.01), but there was no significant difference for the time to attainment of full extension or active straight leg raising (
  • Patients in the PCL excised, PCL retained, posterior stabilised and valgus groups had significantly better knee scores than those in the PCL released group (p=0.002) (
  • No significant differences were observed between the PCL excised, PCL retained and posterior stabilised groups with regards to ROM, knee scores or function scores (
  • The medial trivector approach and the parapatellar approach were associated with similar quadriceps strength at 6 months, Knee Society function scores at 6 weeks and 6 months, and ROM at discharge, 6 weeks and 6 months (
  • The subvastus and medial parapatellar approaches were not significantly different for walking ability with full weight-bearing (
  • A meta-analysis evaluating the effects of retention and sacrifice of the posterior cruciate ligament (PCL) in total knee arthroplasty concluded that there was no basis for a decision regarding the benefits of either retaining or sacrificing the PCL, with or without posterior stabilisation, due to heterogeneity in study quality
  • Study details Fisher et al 1998 Click here for more information

PROSPECT Recommendations

  • No recommendation can be made for choice of prosthesis, as this depends on individual patient factors and surgical requirements, rather than pain

Clinical practice

  • The choice of prosthesis depends on factors such as patient’s age, activity level, bone quality and osteoporosis (leg position/axis, ligamentous knee stability), rather than pain

Transferable evidence

Total knee arthroplasty-specific evidence

  • A mobile-bearing knee replacement was significantly superior to a fixed-bearing prosthesis for reducing Oxford knee pain scores at 1 year postoperatively (p=0.009), and also American Knee Society pain score (p=0.015) (
  • Different designs of prosthesis (Tricon-M, Tricon stem, and PCA resurfacing) were similar for pain at rest or "first-step pain" at 6 months, and 1, 2 and 4 years; the Tricon stem design was significantly superior to the other designs for pain during activity at 4 years (p=0.04) (
  • Resurfacing of the patella was associated with superior pain control, for measures of pain other than Knee Society Pain Scores, and especially for anterior knee pain, compared with non-resurfacing ( Click here for more information
  • A meta-analysis of patellar resurfacing during total knee arthroplasty demonstrated that the incidence of anterior knee pain was significantly less in knees with resurfaced patellas compared with non-resurfaced patellas (p=0.00001), although functional outcomes improved regardless of whether or not the patella was resurfaced. Patients in the resurfaced patella group reported better satisfaction (p=0.00001) and a reduced risk of reoperation compared with those in the non-resurfaced patella group
  • A meta-analysis evaluating patellar resurfacing in total knee arthroplasty showed a reduced risk of anterior knee pain and reoperation with patellar resurfacing compared with knees without patellar resurfacing
  • A mobile-bearing knee replacement was similar to a fixed-bearing prosthesis for range of flexion postoperatively (
  • A meta-analysis of two studies evaluating mobile bearing versus fixed bearing prostheses for total knee arthroplasty found that ROM and functional performance were similar with both types of prosthesis
  • Different designs of prosthesis (Tricon-M, Tricon stem, and PCA resurfacing) were similar for Nottingham Health Profile scores e.g. sleep, pain, mobility, house work, hobbies (
  • A meta-analysis of patellar replacement during total knee replacement showed that the resurfaced patella performed better than the non-resurfaced patella (which had a higher risk for re-operation, significant anterior knee pain, and pain during stair climbing), although there were no differences observed between groups for knee scores or patient satisfaction, and the authors concluded that many confounding factors could influence the outcome (
  • Different designs of prosthesis (Tricon-M, Tricon stem, and PCA resurfacing) were similar for activity at 2 and 4 years postoperatively (
  • Patient preference was not significantly different between a mobile-bearing knee replacement and a fixed-bearing prosthesis (
  • Six out of six studies that used the Knee Society Pain Score to evaluate pain at follow-up after knee surgery (months to years) reported no significant difference in pain between patients with resurfaced patella versus retained patella Barrack et al 2001 Click here for more information
  • Different designs of prosthesis (Tricon-M, Tricon stem, and PCA resurfacing) were similar for Hospital for Special Surgery (HSS) clinical scores, except at 4 years postoperatively when HSS scores had deteriorated significantly with the Tricon stem compared with the other two designs (p=0.02) (
  • Pain scores (frequency, severity and pain at night, measured using the Nottingham scale) were not significantly different in the cemented and cementless groups at 5 years postoperatively (
  • Six studies out of six Click here for more information
  • Six studies out of six ( Click here for more information
  • One study out of one reported a significantly better Knee Society Clinical Rating Score 2 years postoperatively with the non-resurfaced patella group compared with the resurfaced group; however, the scores were not significantly different between groups at 1, 4, 6, 8 or 9 years postoperatively (
  • The degrees of flexion contracture and the total range of movement at 5 years after surgery were not significantly different beween the cemented and cementless groups (
  • Study details and Table 7 Barrack et al 2001 Click here for more information

Data are available from studies that assessed intra-operative analgesia versus intra-operative placebo, as well as those that assessed intra-operative analgesia versus the same analgesia given pre- or postoperatively. It is considered that analgesic medication needs to be initiated in time to ensure an adequate analgesic effect in the immediate postoperative period. This may necessitate administration prior to the postoperative period.

Where there is evidence that the time of administration of analgesics has no significant effect on postoperative pain outcomes, studies are presented in the Postoperative section only, except for those studies specifically comparing different times of administration.

Studies of analgesics that are given peri-operatively (pre-/intra- and postoperatively) are also presented in the Postoperative section only.

PROSPECT Recommendations

  • Intra-operative dextromethorphan is not recommended (Grade D, LoE 4) because of inconsistent analgesic effects in procedure-specific and transferable evidence
  • Intra-operative ketamine cannot be recommended at this time (Grade D, LoE 4) because there is limited procedure-specific evidence (LoE 1; see Postoperative NMDA receptor antagonists), despite analgesic efficacy in other procedures (transferable evidence, LoE 1)

Clinical practice

  • None cited

Transferable evidence

  • Studies of intravenous or neuraxial ketamine in a variety of surgeries, including abdominal, gynaecological, orthopaedic, gastric, hepatic, and genitourinary surgery, showed a reduction in postoperative pain and opioid use when used as an adjunct to morphine
  • A quantitative systematic review found that dextromethorphan does not reduce postoperative pain scores with a clinically significant magnitude, and although significant decreases in supplemental opioid consumption were observed, these were of questionable clinical importance in most cases

Total knee arthroplasty-specific evidence

  • VAS scores at rest were significantly lower in the dextromethorphan + chlorpheniramine maleate (CPM) after skin incision group compared with the CPM alone before skin incision group at 8 (p<0.05) and 24 h (p<0.001) postoperatively only; there was no effect at 1, 2, 4, 48 and 72 h (
  • The time to first postoperative PCA analgesia was significantly increased in the dextromethorphan + CPM after skin incision group compared with the CPM alone before skin incision group (p<0.05) (
  • Total morphine consumption over days 1–3 and mean morphine consumption on each day was reduced in the dextromethorphan + CPM after skin incision group compared with the CPM alone before skin incision group (p<0.05) (
  • There were no significant differences in morphine-related side-effects between the dextromethorphan + CPM after skin incision and CPM alone before skin incision groups (
  • Study details Yeh et al 2000 Click here for more information

PROSPECT Recommendations

  • Intra-operative weak opioids are not recommended (Grade D, LoE 4) because there is no evidence that intra-operative administration is of greater analgesic benefit than postoperative administration

Clinical practice

  • It is considered that weak opioids are ineffective as a single therapy for postoperative pain following total knee arthroplasty, and are ineffective for treatment of high-intensity pain (VAS >/=50 mm)

Transferable evidence

  • Tramadol was more effective than placebo for pain relief in a meta-analysis of post-surgical patients
  • The combination of tramadol and paracetamol enhances analgesic efficacy compared with either agent alone (
  • Tramadol (50 or 100 mg orally) provided no benefit over placebo for postoperative pain scores up to 5 h after total hip arthroplasty (n=137)
  • Codeine (60 mg orally) provided no benefit over placebo for postoperative pain scores up to 6 h after total hip arthroplasty (n=121)
  • Tramadol (100 mg bolus IV) provided no benefit over placebo for postoperative pain scores after total hip or knee arthroplasty (n=48)
  • Two studies found that codeine 30 mg + paracetamol 300 mg was associated with a higher incidence of constipation and vomiting than tramadol 37.5 mg + paracetamol 325 mg following arthroscopy

Total knee arthroplasty-specific evidence

  • The VAS pain scores of the lowest dose tramadol group (1.25 mg/kg) were significantly higher than those of all the other groups (2.5 mg/kg, 3.75 mg/kg and 5 mg/kg) at 0 and 10 min (p<0.05, in both cases) after arrival in PACU, but there were no significant differences between groups at later time points (recorded every 10 min until 60 min post-PACU) (
  • The total number of patients requiring supplemental analgesic in PACU to achieve a VAS pain score </=3 was significantly higher in the low dose tramadol group compared with all the other groups (2.5 mg/kg, 3.75 mg/kg and 5 mg/kg) (p<0.05, in all cases) (
  • The frequency of PCA use was significantly higher in the low dose tramadol group compared with all other groups (2.5 mg/kg, 3.75 mg/kg and 5 mg/kg) (p<0.05, in all cases) (postoperative analgesia was tramadol 20 mg/ml PCA bolus doses, 5-min lockout) (
  • Study details Pang et al 2003 Click here for more information

PROSPECT Recommendations

  • Femoral nerve block is recommended (Grade A) based on evidence for a reduction in pain scores and supplemental analgesia (procedure-specific evidence, LoE 1)
  • No recommendation can be made concerning continuous femoral infusion techniques versus a single bolus because of heterogeneity in study design and inconsistency of procedure-specific data (LoE 4). Only one study, published after the cut-off date for the literature search, directly compared continuous and single bolus techniques. This study shows a benefit of continuous femoral nerve block for reducing pain scores and analgesic use compared with single injection femoral nerve block, although no d
  • A combination of femoral and sciatic nerve blocks cannot be recommended (Grade D, LoE 4) at this time because of limited and inconsistent procedure-specific evidence
  • A combination of femoral and obturator nerve blocks cannot be recommended (Grade D, LoE 4) because of limited procedure-specific evidence (LoE 1) (see Postoperative Peripheral Nerve Blocks)
  • Pre-operative lumbar plexus block (posterior approach) is not recommended (Grade C, LoE 3) because femoral nerve block is equally effective (transferable evidence, LoE 1) and is associated with fewer complications (transferable evidence, LoE 3)
  • Alpha-2-adrenoceptor agonists (clonidine, epinephrine) are not recommended as part of the LA solution in peripheral nerve blocks (Grade A) because of lack of efficacy in procedure-specific studies (LoE 1; see Postoperative Peripheral Nerve Blocks)

Clinical practice

  • The evidence shows important effects of peripheral nerve blocks on reducing pain scores and improving functional recovery after TKA
  • Peripheral nerve blocks require appropriate training
  • Performance of continuous infusion peripheral nerve blocks is associated with greater technical difficulty, and may be associated with a higher failure rate, than performance of single injection peripheral nerve blocks
  • Continuous infusion peripheral nerve blocks require a greater intensity of nursing care than single injection peripheral nerve blocks
  • Continuous infusion peripheral nerve blocks may delay early mobilisation
  • Although the combination of femoral and sciatic nerve blocks may provide more effective analgesia than femoral nerve block alone, the combination may increase the density and duration of motor blockade, delay mobilisation and increase the risk of nerve damage

Transferable evidence

  • Continuous plexus and peripheral neural blocks are associated with a reduced risk of side-effects compared with neuraxial opioids, in pain management after major orthopaedic surgery
  • The posterior approach to the lumbar plexus (psoas sheath block) produces more reliable analgesia to the hip joint than the distal approach (femoral nerve or 3-in-1 blocks), whereas both techniques produced equivalent analgesia distally
  • Femoral nerve block is associated with a lower risk of serious complications than spinal anaesthesia (using bupivacaine or lidocaine)
  • Posterior lumbar plexus block provided no significant benefit over femoral nerve block or control (no nerve block) for postoperative pain scores on movement, PONV or articular mobility during rehabilitation in total hip arthroplasty (n=45)
  • As with all regional anaesthetic techniques, peripheral neural blockade has a failure rate and can cause neural injury and local anaesthetic toxicity

Total knee arthroplasty-specific evidence

  • Evidence suggests that the time of administration of femoral nerve blocks has no effect on postoperative pain outcomes after TKA. Therefore, included studies of such techniques have been pooled for analysis irrespective of the time of administration. All of the procedure-specific evidence is presented in the Postoperative section

PROSPECT Recommendations

  • Pre-operative epidural analgesia (LA and/or opioid) is not recommended (Grade B); see Intra-operative Anaesthetic techniques and Postoperative Epidural sections
  • Epidural ketamine is not recommended (Grade B) because of sedative side-effects and inconclusive analgesic effects (procedure-specific evidence, LoE 1; see Postoperative Epidural section)
  • Epidural tramadol is not recommended (Grade B) because it does not provide sufficient analgesia (procedure-specific evidence, LoE 1; see Postoperative Epidural section)

Clinical practice

  • It is considered that analgesic drugs should be administered in time to secure sufficient pain relief when the patient wakes
  • Epidural analgesia is associated with a relatively high degree of patient monitoring and serious (although rare) major complications
  • Epidural analgesia is a relatively complicated and invasive technique compared with peripheral nerve blocks

Transferable evidence

  • Epidural analgesia was superior to systemic analgesia for postoperative pain outcomes following hip or knee replacement Choi et al 2003 Click here for more information
  • A combination of epidural local anaesthetic plus opioid produced superior analgesic benefits compared with either drug administered alone in three studies of hip or knee surgery Lorenzini et al 2002 Click here for more information
  • Epidural analgesia was associated with a lower incidence of sedation compared with systemic analgesia Choi et al 2003 Click here for more information
  • Epidural anaesthesia reduces the frequency of deep vein thrombosis and pulmonary embolism, and reduces intra-operative and postoperative blood loss, compared with general anaesthesia, particularly in total hip arthroplasty patients, as shown in a review
  • Epidural infusion of ropivacaine (2 mg/ml) plus sufentanil (1 µg/ml) produced a significantly higher incidence of adverse events (pruritus, nausea and vomiting) than ropivacaine alone following major knee surgery (p<0.01; n=115)
  • Epidural administration of strong opioids is associated with side-effects including pruritus, PONV, urinary retention, and respiratory depression
  • Epidural analgesia was associated with more frequent urinary retention, pruritus and low blood pressure compared with systemic analgesia in hip or knee replacement Choi et al 2003 Click here for more information
  • Neuraxial opioids are associated with a greater risk of side-effects compared with continuous plexus and peripheral neural blockades after major orthopaedic surgery

Total knee arthroplasty-specific evidence

  • VAS pain scores were significantly lower in the pre-operative epidural combination (lidocaine + morphine + ketamine) group compared with the intra-operative epidural combination group at 6, 12 and 72 h postoperatively (p<0.05, in all cases), but not at 24 or 48 h (
  • IV PCA-morphine consumption was significantly lower in the pre-operative epidural combination (lidocaine + morphine + ketamine) group compared with the intra-operative epidural combination group on postoperative day 1 (p<0.05), but not on days 2 or 3 (
  • Time to first PCA use was longer in the pre-operative epidural combination (lidocaine + morphine + ketamine) group compared with the intra-operative epidural combination group (p<0.05) (
  • VAS pain scores at rest or on movement were not significantly different between pre- + postoperative and the postoperative lumbar epidural bupivacaine plus morphine groups at postoperative days 0.3–7 and 1–7, respectively ( Dahl et al 1994 Click here for more information
  • Consumption of IM and IV morphine during the first 24 h postoperatively was not significantly different between the pre- + postoperative and the postoperative lumbar epidural bupivacaine plus morphine groups; no significant differences were observed in the requirement for morphine/ketobemidone, orally or rectally, between the two groups after 2–7 days postoperatively ( Click here for more information
  • The incidence of nausea, vomiting, drowsiness and pruritus one day after surgery was similar in the pre-operative epidural combination (lidocaine + morphine + ketamine) group compared with the intra-operative epidural combination group (
  • Study details Dahl et al 1994 Click here for more information

PROSPECT Recommendations

  • Spinal LA + opioid is recommended (Grade A, LoE 1), but not as the first choice of analgesic technique because of a greater potential for adverse events compared with femoral nerve block (transferable evidence, LoE 3)
  • Morphine is recommended as the opioid in the spinal LA + opioid combination (Grade A) based on evidence for a longer duration of analgesic effect than other opioids (procedure-specific evidence, LoE 1)
  • Spinal clonidine is not recommended (Grade D, LoE 4) because there is limited and inconsistent procedure-specific evidence
  • Spinal neostigmine is not recommended (Grade D, LoE 4) because procedure-specific evidence of analgesic efficacy (LoE 1) is limited, and because of side-effects (transferable evidence, LoE 1)

Clinical practice

  • None cited

Transferable evidence

  • Two studies showed superior analgesic effects of spinal LA plus opioid compared with LA alone, following total hip or knee arthroplasty Drakeford et al Click here for more information
  • Bupivacaine plus fentanyl plus clonidine showed superior analgesic efficacy compared with bupivacaine plus fentanyl following hip or knee replacement Fernandez-Galinski D et al 2005 Click here for more information
  • Patients receiving bupivacaine (0.5%) via spinal infusion at a rate of 0.4 ml/h for 24 h following knee or hip replacement required significantly less post-operative oxycodone than those receiving spinal bupivacaine at 0.2 ml/h or saline infusion (p<0.05) (n=35 patients;
  • Bupivacaine administered via spinal infusion (0.5% at 0.4 ml/h or 0.2 ml/h) resulted in an increase in the incidence of sensory and motor block compared with saline infusion
  • Diamorphine administered spinally in combination with bupivacaine showed a significantly higher incidence of nausea and vomiting compared with the bupivacaine alone group (p<0.05) following knee or hip replacement surgery
  • Neostigmine added to spinal anaesthesia in a randomised, double-blinded study in healthy volunteers produced a dose-dependent increase in nausea and vomiting
  • Two studies out of two showed that spinal neostigmine increased the incidence of nausea and vomiting following knee or below-the-knee surgery Lauretti GR et al 1997 Click here for more information

Total knee arthroplasty-specific evidence

  • Four out of five studies Cole et al 2000 Click here for more information
  • VAS pain scores were significantly lower in the spinal morphine (250 µg) + clonidine (75 µg) group compared with the saline group at 1 h (p<0.01) and 2, 4 and 6 h (p<0.0001, in all cases) postoperatively, but not at 12 or 24 h (all patients received spinal LA anaesthesia) (
  • VAS pain scores were significantly lower in the spinal morphine (250 µg) + clonidine (25 µg) group compared with the saline group at 1 h (p<0.01), and 2, 4, 6 h (p<0.0001, in all cases), and 12 h (p<0.05) postoperatively, but not at 24 h (all patients received spinal LA anaesthesia) (
  • VAS pain scores were significantly lower in the spinal neostigmine group compared with the saline group over the first 24 h postoperatively (p<0.05) (all patients received spinal LA anaesthesia) (
  • Two studies Click here for more information
  • Postoperative IV morphine consumption was significantly lower in both low-dose (25 µg) and high-dose (75 µg) spinal clonidine groups compared with the saline group (all patients received spinal LA anaesthesia) ( Sites et al 2003 Click here for more information
  • Two ( Click here for more information
  • The time to first diclofenac request was significantly longer in the spinal neostigmine group compared with the saline group (p<0.05) (
  • The incidence of patients having >/=1 episodes of moderate-to-severe vomiting and incidence of patients requiring >/= 1 dose anti-emetics was not significantly different between the morphine (250 µg) + low-dose (25 µg) and high-dose (75 µg) spinal clonidine groups and the saline group (all patients received spinal LA anaesthesia) (
  • The incidence of patients having >/=1 hypotensive or desaturation events was not significantly different between the morphine (250 µg) + low-dose (25 µg) and high-dose (75 µg) spinal clonidine groups and the saline group (all patients received spinal LA anaesthesia) (
  • Sedation scores were similar in the morphine (250 µg) + low-dose (25 µg) and high-dose (75 µg) spinal clonidine groups compared with the saline group (
  • VAS scores at rest or on movement were not significantly different between the pre-operative spinal morphine + bupivacaine group and the single injection femoral nerve block + spinal anaesthesia group at 1, 2, 4, 6, 12 or 24 h postoperatively
  • The cumulative morphine dose was not significantly different between the pre-operative spinal morphine + bupivacaine group and single injection femoral nerve block + spinal anaesthesia group at 1, 2, 4, 6, 12 or 24 h postoperatively (while in PACU patients received postoperative IV PCA-morphine [1 mg, 6-min lockout], if needed) (
  • VAS pain scores were significantly lower in the spinal morphine group compared with the spinal neostigmine group at 8 h postoperatively (p<0.05), but not at 4, 12, 16, 20 or 24 h (
  • NRS pain scores (scale 0–10) on movement were significantly lower in the spinal morphine group compared with the spinal diamorphine group at 4 (p=0.0046) and 8 h (p=0.0083) postoperatively, but not at 12, 16 or 24 h (
  • Spinal morphine and diamorphine were similar for the proportion of patients rating pain relief as good or excellent (
  • Postoperative morphine consumption was significantly lower in the spinal morphine group compared with the spinal diamorphine group at 4 (p=0.001), 8 (p<0.007) and 12 h postoperatively (p<0.043), but not at 16 or 24 h (IV PCA-morphine (1 mg, 5-min lockout) (
  • Time to first diclofenac request was significantly longer in the spinal morphine group compared with the spinal neostigmine group (p<0.05) (
  • The time to first request for supplemental analgesic (tramadol) was significantly longer in the high-dose (0.5 mg) spinal morphine group compared with the low-dose (0.2 mg) group (p=0.003) (
  • Supplemental analgesic requirements were reduced in the high-dose (0.5 mg) spinal morphine group compared with the low-dose (0.2 mg) spinal morphine group Bowrey et al 2005 Click here for more information
  • The time to first PCA demand was not significantly different between the spinal morphine and spinal diamorphine groups (
  • Requirement for IM diclofenac was not significantly different between the spinal neostigmine and saline groups at 24 h postoperatively (postoperative analgesia was IM diclofenac [75 mg] if VAS >4 and every 12 h, as required) (all patients received spinal LA anaesthesia) (
  • Four studies that reported the incidence of PONV, found no significant differences between spinal opioids and control, but quantitative analysis of the pooled data show an increased incidence with spinal opioids; see Table 4 for details Click here for more information
  • Two studies ( Click here for more information
  • The incidence of nausea/vomiting was significantly higher in the spinal neostigmine group compared with the saline group (p<0.05), but there was no significant difference between groups for the incidence of pruritus, dizziness, or anxiety and no respiratory depression was recorded (
  • One study (
  • The incidence of patients having >/=1 episodes of moderate-to-severe itching was significantly higher in the morphine (250 µg) + clonidine (75 µg) group compared with the saline group (p<0.05) (
  • VAS pain scores were significantly higher in the spinal block group compared with the combined sciatic-femoral block group at 0–12 (p<0.05) and 0–24 h postoperatively (p<0.01), but not at 24–36 or 36–48 h (scores were taken every 4 h for 48 h and averaged to give one pain score for each 12 h) (
  • Postoperative morphine consumption was significantly higher in the spinal block group compared with the combined sciatic-femoral block group at 0–12 (p<0.01) and 0–24 h postoperatively (p<0.05), but cumulative morphine consumption over 0–36 and 0–48 h postoperatively was not significantly different between the two groups (PCA-morphine [1 mg, 3-min lockout]) (
  • The incidence of nausea, vomiting and pruritus was significantly higher in the spinal morphine group compared with the femoral block group (p<0.05, in all cases), as was the proportion of patients requiring anti-emetic or anti-pruritus medication (p<0.05, in both cases) (
  • Spinal morphine and femoral block were associated with a similar incidence of hypotension and desaturation events, and sedation scores (
  • A significantly greater proportion of patients were unsatisfied with their anaesthetic experience in the spinal morphine group compared with the femoral block group (p=0.035) (
  • VAS pain scores were not significantly different between the high (0.5 mg) and low-dose (0.2 mg) morphine groups at 2 h intervals for the first 24 h postoperatively (
  • VAS pain scores, as assessed by an investigator, were not significantly different between the diamorphine dose groups (0.25 mg, 0.75mg, 1.5 mg and 2.5 mg) every hour in the first 2–8 h, and every 2 h from 10–22 h postoperatively (
  • Requirement for IM diclofenac was not significantly different between the spinal morphine and spinal neostigmine groups at 24 h postoperatively (postoperative analgesia was IM diclofenac [75 mg] if VAS >4 and every 12 h as required) (
  • Supplemental postoperative morphine consumption was not significantly different between the diamorphine groups (0.25 mg, 0.75mg, 1.5 mg and 2.5 mg) at 24 h postoperatively (postoperative analgesia was IV morphine until adequate analgesia was achieved, followed by IM morphine as required)
  • The incidence of nausea/vomiting, dizziness and anxiety was not significantly different between the spinal morphine and spinal neostigmine groups; the incidence of pruritus was significantly lower in the neostigmine group compared with the morphine group (p<0.05); no respiratory depression was recorded (
  • There were no significant differences between the spinal morphine and diamorphine groups in the incidence of nausea and/or vomiting, itching, urinary retention or catheterisation, or in the NRS for itching and vomiting; there was no incidence of respiratory depression (
  • There were no significant differences between the low-dose (0.2 mg) spinal morphine group and the high-dose (0.5 mg) spinal morphine group for the incidence of nausea, vomiting, urinary retention, sedation, respiratory depression or pruritus (
  • The incidence of nausea/vomiting, pruritus and urinary retention was similar in all diamorphine dose (0.25 mg, 0.75mg, 1.5 mg and 2.5 mg) groups (
  • The ability to straight-leg-raise was not significantly different between spinal morphine and diamorphine groups at 24 or 48 h postoperatively (
  • Study details and Table 4 Cole et al 2000 Click here for more information
  • Study details Sites et al 2004 Click here for more information
  • Study details Tan et al 2001 Click here for more information
  • Spinal analgesia versus control
  • Spinal anaesthesia/analgesia versus peripheral nerve block
  • Spinal anaesthesia/analgesia miscellaneous

PROSPECT Recommendations

  • Pre-operative intra-articular techniques are not recommended at this time (Grade D, LoE 4) because of inconsistent analgesic efficacy in procedure-specific and transferable evidence (see Postoperative intra-articular section)

Clinical practice

  • Doses of IA morphine in some studies (5–10 mg) represent systemic, not IA doses

Transferable evidence

  • A systematic review of knee joint surgery RCTs looked at the effects of IA morphine, compared with saline Kalso E et al 2002 Click here for more information
  • Several randomised studies in arthroscopic knee or ankle surgery have shown that intra-articular corticosteroid reduced pain after surgery
  • A second systematic review of RCTs examining the effects of IA morphine following knee joint surgery suggested that there were no significant analgesic effects of morphine compared with saline Rosseland LA 2005 Click here for more information

Total knee arthroplasty-specific evidence

  • There were no significant differences in VAS pain scores between the pre-operative and postoperative intra-articular bupivacaine groups at 1, 2, 4 or 24 h after arrival in PACU; there were also no significant differences in VRS pain scores (scale 0–4) between the two treatment groups (
  • ROM at discharge was significantly greater in the postoperative intra-articular bupivacaine group compared with the pre-operative intra-articular bupivacaine group (p=0.02) (
  • The incidence of nausea and vomiting, urinary retention and pruritus was similar in both pre-operative and postoperative intra-articular bupivacaine groups (
  • Study details Badner et al 1996 Click here for more information

PROSPECT Recommendations

  • Pre-operative physical therapy cannot be recommended (Grade D, LoE 4) based on postoperative analgesic effects alone (procedure-specific evidence, LoE 1)

Clinical practice

  • None cited

Transferable evidence

  • None cited

Total knee arthroplasty-specific evidence

  • Two out of two studies showed that pre-operative physical therapies were not associated with any significant reduction in pain scores compared with standard treatment ( D'Lima et al 1996 Click here for more information
  • Two out of two studies showed pre-operative physical therapies were not associated with any significant improvement in postoperative function compared with standard treatment ( D'Lima et al 1996 Click here for more information
  • Pre-operative physical therapies were not associated with any significant reduction in length of hospital stay or rate of complications compared with standard treatments (
  • There were no significant differences between home visit and outpatient physiotherapy treatment for WOMAC dimension scores for pain or SF-36 dimension scores for bodily pain (
  • There were no significant differences between home visit and outpatient physiotherapy treatment for WOMAC dimension scores for physical function or SF-36 dimension scores for physical function (
  • There was no significant difference between home visit and outpatient physiotherapy treatment for mean total costs, but home visit physiotherapy costs were significantly higher than outpatient physiotherapy costs (p=0.001) (
  • Study details Beaupre et al 2004 Click here for more information

Pre-operative analgesia

Data are available from studies that assessed pre-operative analgesia versus pre-operative placebo, as well as those that, to examine the concept of pre-emptive — or preventive — analgesia, assessed pre-operative analgesia versus the same analgesia given postoperatively.

A meta-analysis of studies comparing pre-operative interventions with similar postoperative interventions in various procedures found that pre-operative epidural analgesia resulted in improvements in pain scores, analgesic consumption and time to first rescue analgesic request, whereas pre-operative NSAIDs and local anaesthetic wound infiltration improved analgesic consumption and time to first rescue analgesic request, but not pain scores. Evidence did not support an improvement in postoperative analgesia following administration of pre-operative NMDA antagonists and opioids (Ong 2005).

A previous systematic review of pre-emptive analgesia for acute or chronic postoperative pain relief in a variety of surgical procedures — such as orthopaedic, dental, gynaecological and abdominal — has concluded that there is no benefit of pre-emptive over postoperative administration (Møiniche 2002; LoE 1). 

It is considered that analgesic medication needs to be initiated in time to ensure an adequate analgesic effect in the immediate postoperative period. This may necessitate administration prior to the postoperative period.

Where there is evidence that the time of administration of analgesics has no significant effect on postoperative pain outcomes, studies are presented in the Postoperative section only, except for those studies specifically comparing different times of administration. This is to simplify interpretation of the overall evidence for efficacy of each analgesic agent or intervention.

Studies of analgesics that are given peri-operatively (administration pre-/intra- and postoperatively) are also presented in the Postoperative section only.

PROSPECT Recommendations

  • Pre-operative conventional NSAIDs are not recommended (Grade B) because there is limited evidence (procedure-specific, LoE 1), and because they are associated with an increased risk of intra- and postoperative bleeding (transferable evidence, LoE 1)
  • There is no evidence that pre-operative administration of conventional NSAIDs is more effective than postoperative administration for reducing pain scores

Clinical practice

  • Conventional NSAIDs should not be given pre- or intra-operatively in TKA due to potential for bleeding complications.

Transferable evidence

  • Conventional NSAIDs have proven analgesic efficacy in a variety of surgical procedures
  • A meta-analysis of randomised controlled trials that was performed to evaluate the risk of morphine-related adverse effects in patients treated with NSAIDs demonstrated that NSAIDs decreased the incidence of nausea, vomiting and sedation, but not pruritus, urinary retention or respiratory depression
  • Two meta-analyses comparing pre-incisional and post-incisional NSAIDs/COX-2-selective inhibitors have found no significant benefit of pre-incisional administration for reducing pain scores
  • Randomised endoscopic trials in healthy elderly volunteers have shown that COX-2-selective inhibitors are associated with a lower incidence of upper gastrointestinal ulceration compared with conventional NSAIDs for short-term use
  • Randomised trials in healthy volunteers showed that conventional NSAIDs (ketorolac, naproxen or diclofenac) reduced the platelet aggregation response compared with placebo; ketorolac and naproxen also prolonged bleeding time compared with placebo (
  • Meta-analyses of randomised controlled trials showed that peri-operative conventional NSAIDs increased the risk of postoperative bleeding requiring treatment and/or the risk of re-operation for haemostasis after tonsillectomy compared with controls (
  • A randomised trial in healthy volunteers showed that three conventional NSAIDs (diclofenac, ketorolac and ketoprofen) caused a reversible platelet dysfunction
  • A randomised controlled trial showed that three conventional NSAIDs (diclofenac, ketorolac and ketoprofen) were associated with a similar incidence of surgical site bleeding after elective surgery
  • A randomised clinical trial showed that the conventional NSAID diclofenac was associated with significantly greater intra-operative blood loss than the COX-2-selective inhibitor rofecoxib in patients undergoing abdominal or vaginal hysterectomy or breast surgery
  • Pre-operative ibuprofen, 600 mg orally three times per day two weeks before total hip arthroplasty, significantly increased the median total peri-operative blood loss compared with placebo (1161 ml versus 796 ml; p<0.01; n=50)
  • Pre-operative conventional NSAIDs significantly increased peri-operative blood loss in patients undergoing total hip arthroplasty compared with other analgesic agents in four out of five studies An et al 1991 Click here for more information
  • Aspirin and conventional NSAIDs can induce asthma attacks in patients with aspirin-exacerbated respiratory disease
  • Conventional NSAIDs and COX-2-selective inhibitors have been associated with an increased risk of transient hepatotoxicity. Cases of acute hepatic failure have also been reported. Elderly females, with autoimmune disease, and taking other potentially hepatotoxic drugs, may be most susceptible (
  • Short-term use of conventional NSAIDs or COX-2-selective inhibitors can increase the risk of transient renal impairment, especially in patients with existing renal dysfunction, and both types of agent have been associated with cases of acute renal failure in high-risk patients (
  • Chronic administration of conventional NSAIDs and COX-2-selective inhibitors may elevate blood pressure, particularly in hypertensive patients receiving antihypertensive medication (
  • Conventional NSAIDs and COX-2-selective inhibitors have been associated with impaired bone healing in various animal models and in vitro studies (

Total knee arthroplasty-specific evidence

  • There was no significant difference between the pre-operative oral + postoperative IV/oral tenoxicam group and the postoperative IV/oral tenoxicam group for reducing VAS pain scores at rest at any time point (i.e. 0–48 h following surgery or days 3–9); and for reducing VAS pain scores on movement on days 3–9
  • Total morphine use over the initial 24-h period was similar in both the pre-operative oral + postoperative IV/oral tenoxicam group and the postoperative IV/oral tenoxicam group (1 mg IV PCA bolus doses, 5-min lockout, were given up to 48 h postoperatively; further IV boluses were given if rescue analgesia was required)
  • There was no significant difference in total co-dydramol use between the pre-operative oral + postoperative IV/oral tenoxicam group and the postoperative IV/oral tenoxicam group over 3–9 days postoperatively (dihydrocodeine tartrate 10 mg/paracetamol 500 mg was taken as required from the 48-h postoperatively to day 9)
  • There was no significant difference in the incidence of postoperative nausea or vomiting between pre-operative oral + postoperative oral/IV tenoxicam group and the postoperative IV/oral tenoxicam group
  • Study Details Eggers et al 1999 Click here for more information

PROSPECT Recommendations

  • Pre-operative corticosteroids are not recommended (Grade D, LoE 4) for analgesia, as there is no procedure-specific evidence, despite positive transferable evidence in minor orthopaedic procedures (LoE 1). However pre-operative corticosteroids may be used for reasons other than analgesia

Clinical practice

  • None cited

Transferable evidence

  • Intravenous methylprednisolone (125 mg) given one day after orthopaedic surgery reduced pain and opioid consumption compared with placebo (n=50)
  • A single prophylactic dose of corticosteroid is effective for preventing PONV in surgery associated with high emetic effects
  • A meta-analysis evaluated the effects of a single prophylactic dose of corticosteroid, and reported results from two orthopaedic surgery trials where both pulmonary and cardiac function were increased

Total knee arthroplasty-specific evidence

  • None cited

PROSPECT Recommendation

  • There is no procedure-specific evidence that pre-operative administration of COX-2-selective inhibitors is more effective than postoperative administration. As with all analgesics, it is recommended that COX-2-selective inhibitors should be administered at the appropriate time to provide sufficient analgesia in the early recovery period (Grade D, LoE 4)
  • No recommendations can be made at this time about combining pre-operative COX-2-selective inhibitors with regional analgesic techniques because of lack of data
  • It is recommended that the use of COX-2-selective inhibitors should depend upon assessment of individual patient risks (Grade B) (cardiovascular morbidity (transferable evidence, LoE 1), renal function and hepatic function (transferable evidence, LoE 3) or actual or recent gastroduodenal ulcer history (LoE 4))
  • Although there is concern about impairment of bone-healing with COX-2-selective inhibitors, there are no clinical studies on which to base a recommendation regarding whether or not these agents influence bone-healing

Clinical practice

  • COX-2-selective inhibitors should be administered at the appropriate time to provide sufficient analgesia when the patient wakes
  • Rofecoxib has been withdrawn from the market, and marketing of valdecoxib has been suspended in most countries
  • No recommendations can be made at this time about combining postoperative COX-2-selective inhibitors with regional analgesic techniques because of lack of data

Transferable evidence

  • Rofecoxib 50 mg and parecoxib 40 mg have an equipotent analgesic efficacy relative to traditional NSAIDs in postoperative pain after minor and major surgical procedures
  • Randomised endoscopic trials in healthy elderly volunteers have shown that COX-2-selective inhibitors are associated with a lower incidence of upper gastrointestinal ulceration compared with conventional NSAIDs for short-term use (
  • Studies in healthy volunteers demonstrated that COX-2-selective inhibitors had no effect on platelet aggregation or bleeding time compared with placebo Greenberg et al 2000 Click here for more information
  • A randomised clinical trial showed that the COX-2-selective inhibitor rofecoxib was associated with significantly less intra-operative blood loss than the conventional NSAID diclofenac in patients undergoing abdominal or vaginal hysterectomy or breast surgery
  • Clinical studies investigating the response to oral challenge with COX-2-selective inhibitors in patients with aspirin-induced asthma have demonstrated that COX-2-selective inhibitors do not have an effect on respiratory function (
  • A study to assess the safety of the COX-2-selective inhibitors parecoxib and valdecoxib following non-cardiac general surgery (including gastrointestinal, orthopaedic, gynaecological, urological, and thoracic surgeries) showed no difference in the incidence of cardiovascular thromboembolic events, renal dysfunction/failure, gastrointestinal ulcer complications, and surgical wound-healing complications, compared with placebo (n=1062)
  • Two meta-analyses comparing pre-incisional and post-incisional NSAIDs/COX-2-selective inhibitors have found no significant benefit of pre-incisional administration for reducing pain scores
  • Two clinical trials showed that in patients who had undergone CABG surgery, COX-2-selective inhibitors (valdecoxib and parecoxib) were associated with a higher rate of serious cardiovascular thromboembolic events (including myocardial infarction) compared with placebo (
  • Hypersensitivity reactions and serious skin reactions (e.g. toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme) can occur with all COX-2-selective inhibitors. Serious skin reactions have been reported in association with valdecoxib at a higher rate than with other COX-2-selective agents (
  • Conventional NSAIDs and COX-2-selective inhibitors have been associated with an increased risk of transient hepatotoxicity. Cases of acute hepatic failure have also been reported. Elderly females, with autoimmune disease, and taking other potentially hepatotoxic drugs, may be most susceptible (
  • Short-term use of COX-2-selective inhibitors or conventional NSAIDs can increase the risk of transient renal impairment, especially in patients with existing renal dysfunction, and both types of agent have been associated with cases of acute renal failure in high-risk patients (
  • Chronic administration of COX-2-selective inhibitors and conventional NSAIDs may elevate blood pressure, particularly in hypertensive patients receiving antihypertensive medication (
  • Although there is some concern that COX-2-selective inhibitors may impair wound healing, evidence from animal and clinical studies is conflicting (
  • Conventional NSAIDs and COX-2-selective inhibitors have been associated with impaired bone healing in various animal models and in vitro studies (

Total knee arthroplasty-specific evidence

  • None cited

PROSPECT Recommendations

  • Pre-operative dextromethorphan is not recommended (Grade D, LoE 4) because of inconsistent analgesic effects in procedure-specific and transferable evidence
  • Pre-operative ketamine cannot be recommended at this time (Grade D, LoE 4) because there is limited procedure-specific evidence (LoE 1; see Postoperative NMDA receptor antagonists), despite analgesic efficacy in other procedures (transferable evidence, LoE 1)

Clinical practice

  • None cited

Transferable evidence

  • Studies of intravenous or neuraxial ketamine in a variety of surgeries, including abdominal, gynaecological, orthopaedic, gastric, hepatic, and genitourinary surgery, showed a reduction in postoperative pain and opioid use when used as an adjunct to morphine
  • A quantitative systematic review found that dextromethorphan does not reduce postoperative pain scores with a clinically significant magnitude, and although significant decreases in supplemental opioid consumption were observed, these were of questionable clinical importance in most cases
  • Two meta-analyses comparing pre-incisional and postincisional treatments found no significant analgesic benefit of pre-incisional administration of NMDA receptor antagonists

Total knee arthroplasty-specific evidence

  • VAS scores at rest were significantly lower in the dextromethorphan + chlorpheniramine maleate (CPM) before skin incision group compared with the CPM alone before skin incision group at 8 (p<0.05) and 24 h (p<0.001) only; there was no effect at 1, 2, 4, 48 and 72 h (
  • VAS scores at rest were significantly lower in the dextromethorphan + CPM after skin incision group compared with the CPM alone before skin incision group at 8 (p<0.05) and 24 h (p<0.001) postoperatively only; there was no effect at 1, 2, 4, 48 and 72 h (
  • The time to first postoperative PCA analgesia was significantly increased in the dextromethorphan + CPM before skin incision group compared with the CPM alone before skin incision group (p<0.05) (
  • The time to first postoperative PCA analgesia was significantly increased in the dextromethorphan + CPM after skin incision group compared with the CPM alone before skin incision group (p<0.05) (
  • Total morphine consumption over days 1–3 was significantly reduced in the dextromethorphan + CPM before skin incision group compared with the CPM alone before skin incision group (p<0.05). Mean morphine consumption was significantly reduced in the dextromethorphan + CPM before skin incision group compared with the CPM alone before skin incision group on day 1 (p<0.05), but not on days 2 or 3 (
  • Total morphine consumption over days 1–3 and mean morphine consumption on each day was reduced in the dextromethorphan + CPM after skin incision group compared with the CPM alone before skin incision group (p<0.05) (
  • There were no significant differences in morphine-related side-effects between the dextromethorphan + CPM before skin incision and CPM alone before skin incision groups (
  • There were no significant differences in morphine-related side-effects between the dextromethorphan + CPM after skin incision and CPM alone before skin incision groups (
  • Study Details Yeh et al 2000 Click here for more information
  • Dextromethorphan

PROSPECT Recommendations

  • Pre-operative strong opioids are not recommended (Grade D, LoE 4) because there is no evidence that pre-operative administration is of any greater analgesic benefit than postoperative administration
  • As with all analgesia, strong opioids should be administered at the appropriate time to provide sufficient analgesia in the early postoperative recovery period (Grade D, LoE 4)

Clinical practice

  • As with all types of analgesia for postoperative pain, strong opioids should be administered at the appropriate time to secure sufficient analgesia when the patient wakes

Transferable evidence

  • Two studies showed that pre-operative administration of morphine reduced supplemental analgesia requirements compared with placebo in patients undergoing total hip or knee arthroplasty Reiter et al 2003 Click here for more information
  • Pre-operative oral administration of morphine sulphate 20 mg did not reduce postoperative pain scores compared with pre-operative placebo, in a group of patients undergoing total hip or knee arthroplasty (n=98)

Total knee arthroplasty-specific evidence

  • VAS pain scores were significantly reduced in the morphine group compared with the placebo group at 1–6 h (p<0.001), but not at 7–20 h; at 16 h the VAS scores of the morphine group were significantly higher than those of the placebo group (p<0.05) (
  • There were no significant differences in VAS pain scores between IV morphine in the exsanguinated operative leg + IM saline in the opposite leg versus IV saline in the exsanguinated operative leg + IM morphine in the opposite leg at the two time points assessed (i.e. at 6 and 24 h postoperatively) (
  • There was no significant difference between IV morphine in the exsanguinated operative leg + IM saline in the opposite leg versus IV saline in the exsanguinated operative leg + IM morphine in the opposite leg for supplemental analgesic requirement (postoperative analgesia was 1 mg PCA morphine, 5-min lockout) (
  • There were no significant differences between pre-operative morphine and placebo groups for the mean supplemental analgesic required (postoperative analgesia was PCA IV fentanyl 50 µg, 5-min lockout) (
  • There were no significant differences for the incidence of nausea, vomiting, pruritus, urinary retention or respiratory depression between the pre-operative morphine and placebo groups (
  • Study details Hendolin et al 1996 Click here for more information

PROSPECT Recommendations

  • Pre-operative alpha-2-delta agonists (gabapentin/pregabalin) cannot be recommended at this time (Grade D, LoE 4) because there is no procedure-specific evidence, despite analgesic efficacy in other procedures (transferable evidence, LoE 1)

Clinical practice

  • None cited

Transferable evidence

  • Two systematic reviews and a meta-analysis evaluated the use of gabapentin for postoperative analgesia and demonstrated significant reductions in postoperative pain and supplementary analgesic requirements compared with inactive controls
  • One systematic review
  • One systematic review

Total knee arthroplasty-specific evidence

  • None cited

PROSPECT Recommendations

  • Peri-operative clonidine is not recommended (Grade D, LoE 4), because of limited procedure-specific evidence (LoE 1)

Clinical practice

  • Clonidine has not been used extensively as an analgesic agent by itself.

Transferable Evidence

  • None cited

Total knee arthroplasty-specific evidence

  • Peri-operative clonidine was associated with a significantly reduced cumulative morphine dose at 36 h postoperatively (p=0.031) compared with placebo ( Park et al 1996 Click here for more information
  • Peri-operative clonidine significantly reduced the incidence of postoperative nausea and vomiting (p<0.01, in both cases) compared with placebo; antiemetics consumption was not significantly different between the two groups (
  • Peri-operative clonidine did not reduce VAS pain scores compared with placebo at any time point (i.e. 0–36 h after surgery) (
  • Study details Park et al 1996 Click here for more information

PROSPECT Recommendations

  • Postoperative alpha-2-delta agonists (gabapentin/pregabalin) cannot be recommended at this time (Grade D, LoE 4) because there is no procedure-specific evidence, despite analgesic efficacy in other procedures (transferable evidence, LoE 1)

Clinical practice

  • None cited

Transferable evidence

  • Two systematic reviews and a meta-analysis evaluated the use of gabapentin for postoperative analgesia and demonstrated significant reductions in postoperative pain and supplementary analgesic requirements compared with inactive controls (
  • One systematic review
  • One systematic review (

Total knee arthroplasty-specific evidence

  • None cited

PROSPECT Recommendations

  • Postoperative conventional NSAIDs are recommended (Grade A) for their analgesic and opioid-sparing effect (procedure-specific, LoE 1, and transferable evidence, LoE 1)
  • Postoperative conventional NSAIDs are recommended in combination with strong opioids for high-intensity pain (Grade D, LoE 4), or with weak opioids for moderate- or low-intensity pain (Grade D, LoE 4), or with paracetamol (Grade D, LoE 4)
  • No recommendations can be made at this time about combining postoperative conventional NSAIDs with regional analgesic techniques because of lack of data
  • The use of conventional NSAIDs should depend upon assessment of individual patient risks (Grade B), including bleeding complications, actual or recent gastroduodenal ulcer history (transferable evidence, LoE 1), cardiovascular morbidity (LoE 4), aspirin-sensitive asthma, renal function and hepatic function (transferable evidence, LoE 3)
  • Although there is concern about impairment of bone-healing with conventional NSAIDs and COX-2-selective inhibitors, there are no clinical studies on which to base a recommendation regarding whether or not these agents influence bone-healing

Clinical practice

  • No recommendations can be made at this time about combining postoperative conventional NSAIDs with regional analgesic techniques because of lack of data

Transferable evidence

  • Conventional NSAIDs have proven analgesic efficacy in a variety of surgical procedures
  • Conventional NSAIDs reduced pain and analgesic use following total hip and knee replacement in five studies Anderson SK et al 1991 Click here for more information
  • Ketorolac (30 mg bolus, then 5 mg/h infusion for 24 h) reduced the duration of myocardial ischaemic episodes — compared with placebo — for 24 h following the operation in patients undergoing total hip or knee arthroplasty
  • A meta-analysis of randomised controlled trials that was performed to evaluate the risk of morphine-related adverse effects in patients treated with NSAIDs demonstrated that NSAIDs decreased the incidence of nausea, vomiting and sedation, but not pruritus, urinary retention or respiratory depression
  • Patients receiving IV ketorolac experienced significantly less sedation at 6 and 24 h (p=0.007 and 0.034, respectively) following total hip or knee arthroplasty compared with those receiving placebo
  • Patients receiving IV ketorolac received anti-emetic therapy less frequently compared with those receiving placebo (p=0.03)
  • Randomised endoscopic trials in healthy volunteers have shown that conventional NSAIDs are associated with a higher incidence of upper gastrointestinal ulceration compared with COX-2-selective inhibitors for short-term use (
  • Randomised trials in healthy volunteers showed that conventional NSAIDs (ketorolac, naproxen or diclofenac) reduced the platelet aggregation response compared with placebo; ketorolac and naproxen also prolonged bleeding time compared with placebo (
  • Meta-analyses of randomised controlled trials showed that peri-operative conventional NSAIDs increased the risk of postoperative bleeding requiring treatment and/or the risk of re-operation for haemostasis after tonsillectomy compared with controls (
  • A randomised trial in healthy volunteers showed that three conventional NSAIDs (diclofenac, ketorolac and ketoprofen) caused a reversible platelet dysfunction
  • A randomised controlled trial showed that three conventional NSAIDs (diclofenac, ketorolac and ketoprofen) were associated with a similar incidence of surgical site bleeding after elective surgery
  • Aspirin and conventional NSAIDs can induce asthma attacks in patients with aspirin-exacerbated respiratory disease (
  • Conventional NSAIDs and COX-2-selective inhibitors have been associated with an increased risk of transient hepatotoxicity. Cases of acute hepatic failure have also been reported. Elderly females, with autoimmune disease, and taking other potentially hepatotoxic drugs, may be most susceptible (
  • Short-term use of conventional NSAIDs or COX-2-selective inhibitors can increase the risk of transient renal impairment, especially in patients with existing renal dysfunction, and both types of agent have been associated with cases of acute renal failure in high-risk patients (
  • Conventional NSAIDs and COX-2-selective inhibitors may elevate blood pressure, particularly in hypertensive patients receiving antihypertensive medication (
  • Conventional NSAIDs and COX-2-selective inhibitors have been associated with impaired bone healing in various animal models and in vitro studies (

Total knee arthroplasty-specific evidence

  • Three studies out of three showed a benefit of postoperative conventional NSAIDs compared with placebo for reducing supplemental analgesic use; see Table 8 for details Click here for more information
  • Total co-dydramol requirement, but not total morphine consumption, was significantly lower with peri-operative tenoxicam compared with placebo ( Eggers et al 1999 Click here for more information
  • Postoperative IV ketorolac showed similar analgesic efficacy to postoperative IV parecoxib ( Rasmussen et al 2002 Click here for more information
  • Time to first analgesic request was similar following postoperative IV ketorolac (single injection, 30 mg) and parecoxib (40 mg) (
  • Diclofenac significantly decreased the mean number of boluses of oxycodone at 49–60 h compared with ketoprofen (p<0.05), but not at any other study period (i.e. 0–12, 13–24, 25–36, 37–48 and 61–72 h) (postoperative analgesia was PCA IV 30 µg/kg oxycodone, 12-min lockout; if this was insufficient for pain relief, an extra dose of 30 µg/kg was given IV) (
  • One study (
  • Diclofenac significantly reduced the incidence of postoperative nausea and/or vomiting on day 3 (p<0.01) compared with ketoprofen, but not on days 0 or 1; on day 2, the incidence was identical between groups (
  • Irritation at the infusion site in the recovery room at 4 h after spinal anaesthesia was significantly reduced in the diclofenac group compared with the ketoprofen group (p<0.01) (
  • Only one study out of three showed a significant benefit of postoperative conventional NSAIDs over placebo for reducing VAS pain scores, see Table 8 for details ( Click here for more information
  • There was no significant difference between the peri-operative tenoxicam and placebo groups for reducing VAS pain scores at rest at any time point (i.e. 0–48 h following surgery or between days 3–9) and for reducing VAS pain scores on movement on days 3–9 (
  • There was no significant difference between the pre-operative oral tenoxicam group and the postoperative IV tenoxicam group for reducing VAS pain scores at rest at any time point (i.e. 0–48 h following surgery or between days 3–9); similarly, there was no significant difference between the two groups for reducing VAS pain scores on movement on days 3–9 (
  • There were no significant differences in mean VAS pain scores between the postoperative diclofenac and ketoprofen groups at any time point (i.e. between days 1–3) (
  • Total morphine use over the initial 24 h period was similar in both pre-operative oral tenoxicam group and the postoperative IV tenoxicam group; similarly, there was no significant difference in total co-dydramol use between the two groups over 3–9 days postoperatively Eggers et al 1999 Click here for more information
  • One study out of one ( Click here for more information
  • One study out of one found that placebo was significantly superior to conventional NSAIDs for the incidence of irritation at infusion site on day 0 (p<0.01, in both cases); there were no significant differences between conventional NSAIDs and placebo groups for the incidence of dizziness or drowsiness (
  • There was no significant difference in the incidence of postoperative nausea or vomiting between the pre-operative oral tenoxicam group and the postoperative IV tenoxicam groups (
  • Study details and Table 8 Boeckstyns et al 1992 Click here for more information

PROSPECT Recommendations

  • Postoperative COX-2 selective inhibitors are recommended (Grade A) based on evidence for a reduction in pain scores and supplemental analgesic requirements (procedure-specific evidence, LoE 1)
  • Postoperative COX-2 selective inhibitors are recommended in combination with strong opioids for high-intensity pain (Grade D, LoE 4), or with weak opioids for moderate- or low-intensity pain (Grade D, LoE 4), or with paracetamol (Grade D, LoE 4)
  • No recommendations can be made at this time about combining postoperative COX-2-selective inhibitors with regional analgesic techniques because of lack of data
  • It is recommended that the use of COX-2-selective inhibitors should depend upon assessment of individual patient risks (Grade B) (cardiovascular morbidity (transferable evidence, LoE 1), renal function and hepatic function (transferable evidence, LoE 3) or actual or recent gastroduodenal ulcer history (LoE 4)
  • Although there is concern about impairment of bone-healing with conventional NSAIDs and COX-2-selective inhibitors, there are no clinical studies on which to base a recommendation regarding whether or not these agents influence bone-healing

Clinical practice

  • Rofecoxib has been withdrawn from the market, and marketing of valdecoxib has been suspended in most countries
  • No recommendations can be made at this time about combining postoperative COX-2-selective inhibitors with regional analgesic techniques because of lack of data

Transferable evidence

  • Etoricoxib provided superior analgesic efficacy compared with placebo, and similar analgesic efficacy to naproxen, when administered orally following knee or hip replacement (n=186 patients; Rasmussen et al 2002 Click here for more information
  • 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
  • Randomised endoscopic trials in healthy elderly volunteers have shown that COX-2-selective inhibitors are associated with a lower incidence of upper gastrointestinal ulceration compared with conventional NSAIDs for short-term use (
  • Studies in healthy volunteers demonstrated that COX-2-selective inhibitors had no effect on platelet aggregation or bleeding time compared with placebo Greenberg et al 2000 Click here for more information
  • Clinical studies investigating the response to oral challenge with COX-2-selective inhibitors in patients with aspirin-induced asthma have demonstrated that COX-2-selective inhibitors do not have an effect on respiratory function (
  • A study to assess the safety of the COX-2-selective inhibitors parecoxib and valdecoxib following non-cardiac general surgery (including gastrointestinal, orthopaedic, gynaecological, urological, and thoracic surgeries) showed no difference in the incidence of cardiovascular thromboembolic events, renal dysfunction/failure, gastrointestinal ulcer complications, and surgical wound-healing complications, compared with placebo (n=1062)
  • IV paracetamol (1000 mg), IV parecoxib (40 mg) and placebo (saline IV) were similar for reducing NRS pain scores following orthopaedic surgery (2, 4 and 6 h after surgery, and on postoperative days 1–3). Rescue analgesia consumption (IV tramadol or piritramide) was significantly lower in the paracetamol compared with placebo groups on POD1 (p<0.05), but there were no other significant differences observed between the paracetamol, parecoxib and placebo groups at any other time point (on the da
  • Two clinical trials showed that in patients who had undergone CABG surgery, COX-2-selective inhibitors (valdecoxib and parecoxib) were associated with a higher rate of serious cardiovascular thromboembolic events (including myocardial infarction) compared with placebo (
  • Hypersensitivity reactions and serious skin reactions (e.g. toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme) can occur with all COX-2-selective inhibitors. Serious skin reactions have been reported in association with valdecoxib at a higher rate than with other COX-2-selective agents (
  • Conventional NSAIDs and COX-2-selective inhibitors have been associated with an increased risk of transient hepatotoxicity. Cases of acute hepatic failure have also been reported. Elderly females, with autoimmune disease, and taking other potentially hepatotoxic drugs, may be most susceptible (
  • Short-term use of COX-2-selective inhibitors or conventional NSAIDs can increase the risk of transient renal impairment, especially in patients with existing renal dysfunction, and both types of agent have been associated with cases of acute renal failure in high-risk patients (
  • Chronic administration of COX-2-selective inhibitors and conventional NSAIDs may elevate blood pressure, particularly in hypertensive patients receiving antihypertensive medication (
  • Although there is some concern that COX-2-selective inhibitors may impair wound healing, evidence from animal and clinical studies is conflicting (
  • Conventional NSAIDs and COX-2-selective inhibitors have been associated with impaired bone healing in various animal models and in vitro studies (

Total knee arthroplasty-specific evidence

  • Four studies out of four showed that COX-2-selective inhibitors were associated with reduced pain compared with placebo ( Buvanendran et al 2003 Click here for more information
  • Postoperative IV parecoxib showed similar analgesic efficacy to postoperative IV ketorolac ( Rasmussen et al 2002 Click here for more information
  • Postoperative IV parecoxib showed superior analgesic efficacy to postoperative IV morphine ( Rasmussen et al 2002 Click here for more information
  • Postoperative IV parecoxib at 40 mg showed superior analgesic efficacy to postoperative IV parecoxib at 20 mg ( Rasmussen et al 2002 Click here for more information
  • Three studies out of three showed that COX-2-selective inhibitors reduced supplemental analgesic requirements compared with placebo ( Buvanendran et al 2003 Click here for more information
  • A significantly higher number of patients rated their analgesic treatment as good or excellent following postoperative IV parecoxib (single injection, 40 mg) compared with placebo (no p values given) (
  • Time to first analgesic request was significantly longer following postoperative IV parecoxib (single injection, 20 and 40 mg) administration compared with placebo (no p value given) (
  • There was significantly improved ROM with rofecoxib compared with placebo at hospital discharge for both active (p=0.03) and passive flexion (p=0.05) and also at one month postoperatively for active flexion (p=0.01) (
  • Peri-operative rofecoxib significantly reduced the incidence of postoperative vomiting, but not nausea, compared with placebo (p=0.047) (
  • Incidence of fever was significantly lower in the low-dose and high-dose valdecoxib groups compared with the placebo group (p<0.001) (
  • Patient's global evaluation of study medication was significantly higher in the high-dose valdecoxib group compared with the placebo group (p<0.01)
  • Time to onset of analgesia was similar following postoperative IV parecoxib (single injection, 20 mg) and placebo (
  • There was no significant difference in the incidence of nausea and vomiting between the low-dose and high-dose valdecoxib groups and the placebo group (
  • Study details Buvanendran et al 2003 Click here for more information

PROSPECT Recommendations

  • Postoperative ketamine infusion cannot be recommended at this time (Grade D, LoE 4), because there is limited procedure-specific evidence (LoE 1), despite analgesic efficacy in other procedures (transferable evidence, LoE 1)

Clinical practice

  • None cited

Transferable evidence

  • Studies of intravenous or neuraxial ketamine in a variety of surgeries, including abdominal, gynaecological, orthopaedic, gastric, hepatic, renal and genitourinary surgery, showed a reduction in postoperative pain and opioid use when used as an adjunct to morphine (

Total knee arthroplasty-specific evidence

  • Morphine use was significantly reduced in the ketamine group compared with the placebo group ( Adam et al 2005 Click here for more information
  • Maximal knee flexion was greater in the ketamine group compared with the placebo group on days 6 and 7 (p<0.02, in both cases) postoperatively, but not on days 1–5 (
  • The time to reach active knee flexion was significantly shorter in the ketamine infusion group than in the placebo group (p<0.03) (
  • There were no significant differences between the ketamine infusion and placebo groups in VAS pain scores at rest or on mobilisation at any time point during the first 48 h or at any time thereafter until discharge (
  • There was no significant difference between the ketamine infusion and placebo groups in the delay before the first request for analgesics while in PACU (
  • There were no significant differences in active knee flexion after 6 weeks nor after 3 months between the ketamine infusion and placebo groups (
  • There were no significant differences in the incidence of nausea and/or vomiting between the ketamine infusion and placebo groups (
  • Study details Adam et al 2005 Click here for more information
  • Ketamine

PROSPECT Recommendations

  • Postoperative strong opioids are recommended (Grade A), in combination with non-opioid analgesia (Grade D, LoE 4) for managing high-intensity pain (procedure-specific evidence, LoE 1)
  • IV PCA is recommended in preference to other analgesic administration regimens (Grade B) because of improved pain control and higher patient satisfaction (transferable evidence, LoE 1)
  • IM administration is not recommended (Grade B) because of unfavourable pharmacokinetics, injection-associated pain (LoE 4) and patient dissatisfaction (transferable evidence, LoE 1)

Clinical practice

  • Regular administration, titrated for pain intensity, is generally accepted as an effective method of administering strong opioids
  • Strong opioids can provide similar levels of analgesia when equipotent doses are used
  • Most clinical trials showing benefits of intramuscular strong opioids use nurse-administered regimens. In regular clinical practice, full adherence to nurse-administered regimens is not usually achievable, and the full analgesic benefits of intramuscular strong opioids are also not achieved
  • Intramuscular administration of strong opioids is considered to be more painful than intravenous administration. However, the size and speed of intravenous dose should be assessed to minimise the risk of respiratory depression

Transferable evidence

  • Pethidine significantly reduced postoperative pain scores compared with placebo following hip or knee arthroplasty Tarradell et al 1996 Click here for more information
  • A quantitative systematic review showed that opioid by PCA provided better pain control and greater patient satisfaction than conventional opioid parenteral analgesia in a variety of surgical procedures (37/56 trials used IM analgesia in the control group) 
  • Oral flupirtine maleate 100–200 mg and pentazocine 50–100 mg had similar effects on pain scores and on the requirement for supplemental analgesia after total hip or knee arthroplasty (n=66)
  • Morphine administered by PCA device had a similar effect to continuous infusion on postoperative pain scores following total hip or knee arthroplasty (n=32)
  • Strong opioids are effective for reducing high- and moderate-intensity postoperative pain
  • Opioids administered by PCA improved analgesia and decreased the risk of pulmonary complications, and patients preferred them compared with conventional intramuscular, intravenous or subcutaneous opioid treatment, as determined in a quantitative systematic review of randomised trials of postoperative pain management following various surgical procedures
  • A systematic review comparing intravenous PCA opioids with intravenous, intramuscular or subcutaneous opioids by injection showed that PCA opioids were associated with greater pain relief, reduced supplemental analgesic requirements (analysis of eleven studies, total n=691), and more patients preferred PCA opioids (analysis of four trials, total n=352) compared with traditional opioid analgesia
  • Patients using PCA consumed a greater quantity of opioids than those treated using conventional opioid parenteral analgesia, and had a higher incidence of pruritus, but a similar incidence of other side-effects, in a variety of surgical procedures. There was no difference between groups in the length of hospital stay
  • Pethidine induced significantly higher sedation and respiratory depression compared with tramadol (both 100 mg intravenously) (n=48)
  • Strong opioids are associated with adverse effects, including nausea, vomiting, sedation, confusion, paralytic ileus and urinary retention
  • One study found no significant differences in PCA usage or adverse side-effects between the variable dose PCA and the fixed dose PCA groups following knee or hip replacement (n=32 patients; Love DR et al 1996 Click here for more information
  • One study comparing PCA with conventional pain therapy (CPT; IV piritramide or oral/IM tramadol) demonstrated an increased consumption of postoperative analgesic in the PCA group compared with the CPT group (p<0.01), although the PCA group reported a significantly greater satisfaction with pain therapy compared with the CPT group (p<0.01) (n=42 patients;

Total knee arthroplasty-specific evidence

  • Two out of two studies showed that extended-release opioid resulted in significantly lower VAS pain scores compared with placebo at all recorded time points (i.e. at 2 and 12 h postoperatively, p=0.0058; p=0.0324, respectively (
  • VRS pain scores, measured hourly for 40 h postoperatively, indicated that the frequency of moderate pain was significantly reduced in the IM morphine group compared with the IV morphine PCA group (p<0.05); however, there was no significant difference in the frequency of mild pain nor the frequency of severe pain between groups (
  • Two out of two studies showed a significant reduction in supplemental analgesic use in the extended-release opioid group compared with the placebo group Ahdieh et al 2004 Click here for more information
  • Time to onset of analgesia was similar following postoperative IV morphine (single injection, 4 mg) and parecoxib (40 mg) (
  • One study showed that the extended-release opioid group had significant improvements in functional outcomes parameters compared with the placebo group Cheville et al 2001 Click here for more information
  • Total pain relief (computed from pain relief scores with time-weighted methods) was significantly greater in the extended-release opioid group compared with the placebo group over 0 to 12 h (p=0.0056) (
  • The incidence of actual sleep over 40 h postoperatively was significantly higher in the IM group compared with the IV morphine PCA group (p<0.01) (
  • Hospital discharge occurred significantly earlier in the extended-release opioid group than in the placebo group (p=0.013) (
  • Following postoperative IV morphine (single injection, 4 mg), pain intensity reduction (relative to baseline) was significantly smaller at 1–24 h, and pain relief scores were significantly lower at 1.5–24 h, compared with postoperative IV parecoxib (single injection, 40 mg) (no p value given) (
  • The summed pain intensity difference (relative to baseline) was significantly lower in the postoperative IV morphine (single injection, 4 mg) group compared with the postoperative IV parecoxib (single injection, 40 mg) groups at 8–24 h after drug administration (p<0.001), and similar in the morphine group compared with the IV parecoxib 20 mg group (
  • Significantly fewer patients rated their analgesic treatment as good or excellent following postoperative IV morphine (single injection, 4 mg) administration compared with postoperative IV parecoxib (single injection, 40 mg) (no p value given) (
  • Time to first analgesic request was significantly shorter following postoperative IV morphine (single injection, 4 mg) administration compared with postoperative IV parecoxib (single injection, 20 or 40 mg) (no p value given) (
  • There was no significant difference between the incidence of nausea and/or vomiting in the extended-release opioid and placebo groups (
  • There was no significant difference between IM morphine group and IV morphine PCA group in opioid use in the recovery room (
  • Study details Cheville et al 2001 Click here for more information

PROSPECT Recommendations

  • Weak opioids are not recommended for controlling high-intensity pain (Grade D, LoE 4)
  • Weak opioids are recommended to be used (Grade B) for moderate- or low-intensity pain if non-opioid analgesia is insufficient or is contraindicated (transferable evidence, LoE 1)
  • Weak opioids are recommended (Grade B) to be used in combination with non-opioid analgesics (transferable evidence, LoE 1)

Clinical practice

  • It is considered that weak opioids are ineffective as a single therapy for postoperative pain following total knee arthroplasty, and are ineffective for treatment of high-intensity pain (VAS >/=50 mm)

Transferable evidence

  • Tramadol was more effective than placebo for pain relief in a meta-analysis of post-surgical patients
  • The combination of tramadol and paracetamol enhances analgesic efficacy compared with either agent alone (
  • Tramadol delivered via PCA was not significantly different from PCA morphine for VAS pain scores, although the mean frequency of PCA delivery was significantly less in the tramadol group at 24 and 48 h (both p<0.05) following knee or hip arthroplasty (n=80)
  • A systematic review found that the combination of dextropropoxyphene 65 mg with paracetamol 650 mg showed similar efficacy to tramadol 100 mg but with a lower incidence of adverse effects
  • A systematic review found that the combination of codeine with paracetamol provided additional pain relief compared with paracetamol alone
  • Tramadol (100 mg bolus intravenously) provided no benefit over placebo for postoperative pain scores after total hip or knee arthroplasty (n=48)
  • Tramadol (50 or 100 mg orally) provided no benefit over placebo for postoperative pain scores up to 5 h after total hip arthroplasty (n=137)
  • Codeine (60 mg orally) provided no benefit over placebo for postoperative pain scores up to 6 h after total hip arthroplasty (n=121)
  • Tramadol delivered via PCA showed a significant increase in the incidence of nausea and vomiting (p<0.05) compared with PCA morphine, although sleepiness occurred more often in the PCA morphine group (p<0.05) following knee or hip arthroplasty
  • Two studies found that codeine 30mg + paracetamol 300 mg was associated with a higher incidence of constipation and vomiting than tramadol 37.5 mg + paracetamol 325 mg following arthroscopy
  • Adverse effects associated with tramadol include headache, nausea, vomiting, dizziness, somnolence. A meta-analysis of individual patient data from randomised controlled trials found a dose-response of adverse effects with tramadol; postsurgical patients had fewer side-effects than dental patients
  • A systematic review found that the combination of codeine with paracetamol was associated with an increase in drowsiness and dizziness compared with paracetamol alone
  • A systematic review found an increased incidence of central nervous system adverse effects with paracetamol plus dextropropoxyphene compared with placebo

Total knee arthroplasty-specific evidence

  • None cited

PROSPECT Recommendations

  • Paracetamol alone is not recommended for high-intensity pain (Grade D, LoE 4)
  • Paracetamol is recommended to be used in combination with other analgesics (Grade B), based on evidence that it reduces supplemental analgesic use in orthopaedic surgeries (transferable evidence, LoE 1)

Clinical practice

  • It is considered that paracetamol is ineffective as a single therapy for treatment of high-intensity postoperative pain (VAS >/=50 mm) following total knee arthroplasty

Transferable evidence

  • Paracetamol is an effective analgesic for the treatment of postoperative pain of moderate intensity
  • In a qualitative review of 28 paracetamol studies, five out of seven studies of orthopaedic procedures reported a significant reduction in analgesic consumption with paracetamol compared with placebo
  • Propacetamol (an injectable prodrug of paracetamol) showed equivalent analgesic efficacy to ketorolac when given IV following knee or hip replacement (n=164 patients; Zhou TJ et al 2001 Click here for more information
  • Analgesic efficacy of paracetamol combined with weak opioids (codeine, tramadol) was superior to weak opioids alone in a review of dental, gynaecological and orthopaedic surgery (
  • In a randomised study, patients undergoing orthopaedic surgery had transiently impaired kidney function, but there were no significant differences between patients receiving IV paracetamol (1000 mg), IV parecoxib (40 mg) and placebo (saline IV) (
  • IV paracetamol (1000 mg), IV parecoxib (40 mg) and placebo (saline IV) were similar for reducing NRS pain scores following orthopaedic surgery (2, 4 and 6 h after surgery, and on postoperative days 1–3). Rescue analgesia consumption (IV tramadol or piritramide) was significantly lower in the paracetamol group compared with the placebo group on POD1 (p<0.05), but there were no other significant differences observed between the paracetamol, parecoxib and placebo groups at any other time point (
  • Although there is evidence that concurrent use of paracetamol and conventional NSAIDs improves pain relief compared with paracetamol alone, there is no evidence for a superior analgesic effect of the combination compared with conventional NSAIDs alone (

Total knee arthroplasty-specific evidence

  • None cited

PROSPECT Recommendations

  • Femoral nerve block is recommended (Grade A) based on evidence for a reduction in pain scores and supplemental analgesia (procedure-specific evidence, LoE 1)
  • No recommendation can be made concerning continuous femoral infusion techniques versus a single bolus because of heterogeneity in study design and inconsistency of procedure-specific data (LoE 4). Only one study, published after the cut-off date for the literature search, directly compared continuous and single bolus techniques. This study shows a benefit of continuous femoral nerve block for reducing pain scores and analgesic use compared with single injection femoral nerve block, although no d
  • A combination of femoral and sciatic nerve blocks cannot be recommended (Grade D, LoE 4) at this time because of limited and inconsistent procedure-specific evidence
  • A combination of femoral and obturator nerve blocks cannot be recommended (Grade D, LoE 4), because of limited procedure-specific evidence (LoE 1)
  • Postoperative lumbar plexus block (posterior approach) is not recommended (Grade C, LoE 3), because femoral nerve block is equally effective (transferable evidence, LoE 1) and is associated with fewer complications (transferable evidence, LoE 3)
  • Alpha-2-adrenoceptor agonists (clonidine, epinephrine) are not recommended as part of the LA solution in peripheral nerve block (Grade A) because of lack of efficacy in procedure-specific studies (LoE 1)

Clinical practice

  • The evidence shows important effects of peripheral nerve blocks on reducing pain scores and improving functional recovery after TKA
  • Peripheral nerve block may be administered by means of a patient-controlled infusion pump
  • Peripheral nerve blocks require appropriate training
  • Performance of continuous infusion peripheral nerve blocks is associated with greater technical difficulty, and may be associated with a higher failure rate, than performance of single injection peripheral nerve blocks
  • Continuous infusion peripheral nerve blocks require a greater intensity of nursing care than single injection peripheral nerve blocks
  • Although the combination of femoral and sciatic nerve blocks may provide more effective analgesia than femoral nerve block alone, the combination may increase the density and duration of motor blockade, delay mobilisation and increase the risk of nerve damage

Transferable evidence

  • A randomised trial in patients undergoing TKA or arthrolysis found that continuous epidural infusion and continuous femoral block (both with 1% lidocaine, 0.03 mg/ml morphine and 2 µg/ml clonidine at 0.1 ml/kg/h) groups had reduced pain scores at rest and on continuous passive motion compared with a PCA morphine group (p<0.01)
  • A randomised trial in patients undergoing TKA or arthrolysis found that pain scores during continuous passive motion, and supplemental morphine consumption, were similar in the continuous femoral block and continuous epidural infusion groups
  • A randomised trial in patients undergoing TKA or arthrolysis found that continuous epidural infusion and continuous femoral block groups had improved early postoperative knee mobilisation compared with the PCA morphine group (p<0.05), although no significant differences were observed between the epidural and femoral block groups
  • A randomised trial in patients undergoing TKA or arthrolysis found that continuous femoral block was associated with reduced frequency of urinary retention and dysesthesia compared with continuous epidural analgesia, and reduced frequency of urinary retention and nausea compared with PCA morphine (in each case, p<0.05)
  • Continuous plexus and peripheral neural blocks are associated with a reduced risk of side-effects compared with neuraxial opioids, in pain management after major orthopaedic surgery
  • The posterior approach to the lumbar plexus (psoas sheath block) produces more reliable analgesia to the hip joint than the distal approach (femoral nerve or 3-in-1 blocks), whereas both techniques produced equivalent analgesia distally
  • Femoral nerve block is associated with a lower risk of serious complications than spinal anaesthesia (using bupivacaine or lidocaine)
  • Posterior lumbar plexus block provided no significant benefit over femoral nerve block or control (no nerve block) for postoperative pain scores on movement, PONV or articular mobility during rehabilitation in total hip arthroplasty (n=45)
  • A randomised trial in patients undergoing TKA or arthrolysis found that continuous femoral block was associated with higher pain scores at rest compared with continuous epidural infusion (no p value given)
  • As with all regional anaesthetic techniques, peripheral neural blockade has a failure rate and can cause neural injury and local anaesthetic toxicity

Total knee arthroplasty-specific evidence

  • Six out of eight studies showed that single injection femoral nerve block was associated with significantly lower postoperative pain scores compared with placebo, no treatment or systemic analgesia ( Hirst et al 1996 Click here for more information
  • Five studies out of six reported significantly reduced postoperative VAS pain scores with continuous infusion femoral or lumbar plexus nerve block compared with placebo/no treatment ( Serpell et al 1991 Click here for more information
  • A femoral nerve block performed on the first postoperative day was associated with significantly reduced VAS pain scores compared with no such treatment at 1 and 3 h post-block (p=0.045; p=0.035, respectively), but not at 5, 7, 9 or 11 h post-block, or on the 2nd or 5th postoperative day (
  • Four out of seven studies showed that single injection femoral nerve block was associated with significantly lower supplemental analgesic use compared with placebo, no treatment or systemic analgesia Szczukowski et al 2004 Click here for more information
  • Four out of six studies showed that the use of supplemental analgesia was significantly reduced in the continuous infusion femoral or lumbar plexus nerve block group compared with the placebo/no treatment group Hirst et al 1996 Click here for more information
  • A femoral nerve block performed on the first postoperative day was associated with significantly reduced supplemental analgesia requirements compared with no such treatment both for number of IM oxycodone injections and total oxycodone dose (p=0.017; p=0.021, respectively) (
  • In two out of three studies, single injection femoral nerve block was associated with significant improvements in some functional outcomes parameters compared with placebo or no treatment ( Click here for more information
  • Two studies out of two reported significant improvements in some functional outcomes parameters in the continuous infusion femoral nerve block group compared with the placebo/no treatment group ( Click here for more information
  • One study out of one found that the length of hospital stay was significantly shorter in the continuous infusion femoral nerve block group compared with the no treatment group (p<0.001) (
  • VAS pain scores at rest were significantly lower in the pre-operative combined obturator and femoral block group compared with the sham femoral block group at 0, 0.5, 1 and 2 h (p<0.01, in all cases) and at 4 and 6 h postoperatively (p<0.03, in both cases), but not at 3 or 5 h (
  • VAS pain scores at rest were significantly lower in the pre-operative combined femoral and sciatic nerve block groups compared with the no block groups (at 8 h for bupivacaine and at 4 h for ropivacaine [p<0.05 in both cases], but not at 12, 16, 20, 24, 28, 32, 36, 40, 44 or 48 h) (all patients received spinal anaesthesia) (
  • VAS pain scores at rest were significantly lower in the postoperative combined femoral and sciatic block injection group compared with the combined sham block group for the first 8 h postoperatively (p<0.05), but there were no significant differences on postoperative days 1 or 2 ( Allen et al 1998 Click here for more information
  • VAS pain scores at rest were significantly lower in the pre-operative combined obturator and femoral block group compared with the femoral nerve block group at 0, 0.5, 1 and 2 h (p<0.01, in all cases) and at 4 and 6 h postoperatively (p<0.03, in both cases), but not at 3 or 5 h (
  • VAS pain scores at rest were significantly lower in the continuous combined femoral and sciatic block group compared with the femoral block group up to 36 h postoperatively (p<0.0001), but not at 42, 48 or 54 h; VAS pain scores on ambulation were not significantly different between the two groups (
  • Total morphine consumption in the first 6 h postoperatively was significantly lower in the pre-operative combined obturator and femoral block group compared with the sham femoral block group (p<0.001), as were the number of morphine boluses received via PCA (p<0.0001) and the number of requests for morphine via PCA (p=0.0058) ( Macalou et al 2004 Click here for more information
  • Morphine consumption was significantly lower in the pre-operative combined femoral and sciatic block groups compared with the no block groups (from 8–48 h in the bupivacaine group, p<0.05; 4–24 h in the ropivacaine group, p<0.05) (all patients received spinal anaesthesia) (
  • Morphine consumption was significantly lower in the postoperative combined femoral and sciatic block injection group compared with the combined sham block group on the day of surgery and on postoperative day 1 (p<0.02, in both cases), but not on postoperative days 2 or 3 (while in PACU patients received IV PCA-morphine [1 mg bolus, 10-min lockout]) (
  • Total morphine consumption in the first 6 h postoperatively was significantly lower in the pre-operative combined obturator and femoral block group compared with the femoral block group (p<0.001), as was the number of morphine boluses received via PCA (p<0.0001); the number of requests for morphine via PCA was similar between groups (
  • Total morphine consumption was significantly lower in the pre-operative femoral-sciatic and obturator block group compared with the femoral-sciatic block group at 20–48 h (p<0.05), but not in the early postoperative period (i.e. at 0–16 h) (postoperative analgesia comprised IV PCA-morphine [1 mg, 5-min lockout]) (
  • The time to first request for morphine was significantly longer in the pre-operative femoral-sciatic and obturator block group compared with the femoral-sciatic block group (p<0.05) (
  • The time to first request for morphine was significantly prolonged following pre-operative combined femoral and sciatic nerve block with bupivacaine or ropivacaine compared with no block (p<0.001) (all patients received spinal anaesthesia) (
  • Total morphine consumption in the continuous combined femoral and sciatic block group was significantly lower compared with the femoral block group (p<0.003) ( Dang et al 2005 Click here for more information
  • The incidence of nausea, but not vomiting, was significantly lower in the pre-operative combined obturator and femoral block group compared with the sham femoral block group (p=0.0117) (
  • Emesis scores were significantly lower in the pre-operative combined femoral and sciatic block with bupivacaine group compared with the no block group at 8 h (p<0.05), but there was no significant difference between the pre-operative femoral-sciatic block with ropivacaine and no block groups (all patients received spinal anaesthesia) (
  • The incidence of nausea, but not vomiting, was significantly lower in the pre-operative combined obturator and femoral block group compared with the femoral block group (p=0.0117) (
  • The incidence of nausea and vomiting was significantly lower in the continuous combined femoral and sciatic block group compared with the femoral block group (p=0.014; p=0.042, respectively) (
  • The continuous infusion femoral nerve block group had significantly lower VAS pain scores and consumed significantly less rescue analgesia compared with the single injection group Salinas et al 2006 Click here for more information
  • VAS pain scores on movement were significantly lower in the pre-operative combined femoral and sciatic block group compared with the epidural group at 24 h postoperatively (p=0.004), but not at discharge from the recovery room or at 6 or 48 h (
  • VAS pain scores were not significantly different between the postoperative single injection femoral nerve block and the epidural group at any time point assessed (i.e. at 15, 30, 60, 120 and 180 min after start of postoperative pain management) (
  • VAS pain scores at rest and on movement were not significantly different between the pre-operative femoral nerve block and the spinal morphine groups at 1, 2, 4, 6, 12 or 24 h postoperatively (
  • Morphine consumption was significantly lower in the pre-operative combined femoral and sciatic block group compared with the epidural group at discharge from the recovery room (p=0.02), but not at any other time point assessed (6, 24 or 48 h) (1 mg PCA-parenteral morphine sulphate, 5-min lockout) (
  • Supplemental analgesic use was similar in the continuous infusion femoral nerve block group and epidural analgesia group (LA + opioid + clonidine in both groups) over 48 h postoperatively ( Singelyn et al 1998 Click here for more information
  • The cumulative morphine dose was not significantly different between pre-operative femoral nerve block and the spinal morphine groups at 1, 2, 4, 6, 12 or 24 h postoperatively (while in PACU, patients received postoperative IV PCA-morphine [1 mg, 6-min lockout]) (
  • The frequency of urinary retention (p=0.05) and catheter-related problems (p<0.001) was reduced in the continuous infusion femoral nerve block group compared with the epidural analgesia group (
  • The incidence of nausea, vomiting and pruritus was significantly lower in the pre-operative femoral nerve block group compared with the spinal morphine group (p<0.05, in all cases) (
  • Time to straighten the knee and time to discharge, as well as 85-degree active knee flexion, were not significantly different between the pre-operative combined femoral and sciatic block group and the epidural group (
  • There were no significant differences in the degree of knee flexion or the time to achieve 90-degree flexion and the duration of hospital stay between the femoral nerve block and epidural analgesia groups (LA + opioid + clonidine in both groups) (
  • Pre-operative combined femoral and sciatic block with bupivacaine was associated with significantly lower VAS pain scores than the same block with ropivacaine at 24 and 28 h (p<0.05), but not at 4, 8, 12, 16, 20, 32, 36, 40, 44 and 48 h (all patients received spinal anaesthesia) (
  • Verbal pain scores (at rest and during movement) were not significantly different between the ropivacaine (low and high dose) and bupivacaine groups at 1, 4, 8, 24 or 48 h postoperatively (
  • 24-h consumption of ropivacaine was significantly lower in the 20 ml group compared with the 15 (p=0.009) and 25 ml (p=0.027) groups, but not the 30 ml group; the number of patients receiving rescue morphine, paracetamol and/or ibuprofen was not significantly different between the groups (
  • Cumulative morphine consumption was not significantly different between the ropivacaine (low and high dose) and bupivacaine groups at 1, 4, 8, 24 or 48 h postoperatively Click here for more information
  • Length of hospital stay was similar in the ropivacaine (low and high dose) and bupivacaine group (
  • Seven out of eight studies found that the incidence of PONV was not significantly different in the single injection femoral nerve block and placebo, no treatment or systemic analgesia groups, see Table 9 for details Hirst et al 1996 Click here for more information
  • Postoperative VAS nausea scores were similar in the femoral nerve block performed on the first postoperative day and no treatment groups at all time points (i.e. at 9, 10, 12, 14, 16, 18 and 20 h and on the 2nd and 5th postoperative days)
  • Three studies out of four found that continuous infusion femoral nerve block had no significant effect on the incidence of postoperative nausea and/or vomiting compared with placebo/no treatment ( Click here for more information
  • The incidence of complications, such as respiratory depression, pruritus, dizziness and urinary retention, was found to be similar in the single injection femoral nerve block and control groups in four studies out of four, see Table 9 for details Szczukowski et al 2004 Click here for more information
  • Three out of four studies found that there was no significant difference between the single injection femoral nerve block and placebo/no treatment groups for the length of hospital stay ( Click here for more information
  • VAS pain scores were not significantly different between the pre-operative femoral-sciatic and obturator block group compared with the femoral-sciatic block group (p<0.05) during 0–48 h (
  • VAS pain scores at rest and on physical therapy were not significantly different between the postoperative combined femoral and sciatic nerve block injection group and the femoral nerve block alone group on postoperative days 1 or 2 (
  • There were no significant differences between the continuous lumbar plexus block group and the continuous femoral nerve block group for reducing VAS pain scores at rest at 6, 24 or 48 h; also there were no significant differences between the two treatment groups for reducing VAS pain scores during physiotherapy (
  • VAS pain scores at rest and on movement were not significantly different between the continuous infusion femoral nerve block group, continuous infusion femoral nerve block plus PCA boluses group and the PCA boluses alone group at 4, 24 or 48 h postoperatively (
  • Morphine consumption was not significantly different between the postoperative combined femoral and sciatic nerve block injection group and the femoral nerve block alone group on the day of surgery or on postoperative days 1, 2 or 3 (while in PACU patients received IV PCA-morphine [1 mg bolus, 10-min lockout]) (
  • Supplemental morphine consumption (IV PCA-morphine [1 mg, 5-min lockout]) during 48 h postoperatively was similar in the lumbar plexus block and the femoral nerve block groups (
  • Requirements for supplemental analgesic were not significantly different between the continuous infusion femoral nerve block group, continuous infusion femoral nerve block plus PCA boluses group and the PCA boluses alone group over 48 h postoperatively ( Singelyn and Gouverneur 2000 Click here for more information
  • Knee flexion was not significantly different between the continuous combined femoral and sciatic block group and the femoral block group, on postoperative day 2 or after 1 month following hospital discharge (
  • There were no significant differences in the incidence of nausea or pruritus between the postoperative combined femoral and sciatic block injection group and combined sham block group (
  • The incidence of postoperative complications (sedation, hypotension, respiratory depression, and bradycardia) was similar in both the pre-operative combined obturator and femoral block group and the sham femoral block group (
  • The incidence of other postoperative complications (sedation, hypotension, respiratory depression and bradycardia) was similar in both the pre-operative combined obturator and femoral block group and the femoral block group (
  • Sedation scores were not significantly different between the pre-operative combined femoral and sciatic block (with bupivacaine or ropivacaine) and the no block groups (all patients received spinal anaesthesia) (
  • The incidence of nausea and pruritus was similar in postoperative combined femoral and sciatic nerve block injection group and the femoral nerve block alone group (
  • The incidence of nausea and/or vomiting was not significantly different between the continuous infusion femoral nerve block group, continuous infusion femoral nerve block plus PCA boluses group and the PCA boluses alone group (
  • Motor blockade was greater in the pre-operative combined femoral and sciatic block with ropivacaine group (but not the bupivacaine group) compared with the no block group at 12, 16 and 20 h (p<0.05), but this did not prevent mobilisation of any patient on the day following surgery (all patients received spinal anaesthesia) (
  • VAS pain scores at rest and on movement were significantly higher in the continuous infusion femoral nerve block group compared with the epidural analgesia group at 4 h postoperatively (p<0.001, in both cases), but not at 24 or 48 h (LA + opioid + clonidine in both groups) ( Singelyn et al 1998 Click here for more information
  • The incidence of postoperative complications (nausea, vomiting, confusion, hypotension, pruritus) was similar in the pre-operative combined femoral and sciatic block group and the epidural group (
  • The incidence of nausea and/or vomiting was not significantly different between the postoperative single injection femoral nerve block and the epidural group (
  • There were no significant differences in the incidence of nausea and/or vomiting between the femoral nerve block and epidural analgesia groups (LA + opioid + clonidine in both groups) (
  • Intra-operative and postoperative blood loss was not significantly different between the pre-operative combined femoral and sciatic block group and the epidural group (
  • VAS pain scores were significantly higher in the 15 ml ropivacaine group compared with the 20 (p=0.02), 25 (p=0.031) and 30 ml (p=0.013) groups at 4 h after the initial injection, but not at 8, 12, 16, 20 or 24 h; there were no other significant differences in pain scores between groups (
  • VAS pain scores during activity were similar following femoral nerve block in both low-dose and high-dose bupivacaine groups (0.1% and 0.2% bupivacaine at 10 ml/hr) at all time points assessed (i.e. on the day of surgery, on postoperative days 1 and 2 and on the day of discharge) (
  • The incidence of inadequate analgesia (VAS >30 mm) was not significantly different between ropivacaine and bupivacaine in a pre-operative femoral and sciatic block (all patients received spinal anaesthesia) (
  • Adding alpha-2-adrenoceptor agonist to continuous infusion femoral nerve block was not associated with significantly different VAS pain scores compared with continuous infusion femoral nerve block without alpha-2-adrenoceptor agonist Casati et al 2005 Click here for more information
  • Morphine consumption was not significantly different between the low- and high-dose bupivacaine femoral nerve block groups (PCA-morphine [1.5 mg, 6-min lockout] increased to 2 mg if VAS >50 mm) (
  • Morphine consumption and the time to first request for morphine were not significantly different between ropivacaine and bupivacaine groups for pre-operative combined femoral and sciatic block (all patients received spinal anaesthesia) (
  • Adding alpha-2-adrenoceptor agonist to continuous infusion femoral nerve block did not significantly alter supplemental analgesia use compared with continuous infusion femoral nerve block without alpha-2-adrenoceptor agonist Weber et al 2001 Click here for more information
  • ROM was similar in the low and high- dose bupivacaine femoral nerve block groups (
  • A larger proportion of patients receiving clonidine infusion showed motor function impairment (i.e. the persistence of motor block) from 16–48 h of infusion, compared with the clonidine bolus and control groups (p<0.05, in both cases) (
  • Emesis and sedation scores were similar between bupivacaine and ropivacaine groups for pre-operative combined femoral and sciatic block (all patients received spinal anaesthesia) (
  • The incidence of nausea, vomiting, pruritus and sedation was not significantly different between the ropivacaine (low and high dose) and bupivacaine groups (
  • The incidence of nausea and vomiting was similar in the low and high- dose bupivacaine femoral nerve block groups (
  • The incidence of nausea and vomiting was not significantly different between the clonidine bolus, clonidine infusion and control groups (
  • Motor blockade was significantly greater following pre-operative femoral and sciatic nerve block with ropivacaine compared with bupivacaine at 12 h (p<0.05), but this did not prevent mobilisation of any patient on the day following surgery (all patients received spinal anaesthesia) (
  • Study details and Tables 9 & 10 Niskanen and Strandberg 2005 Click here for more information
  • Study details Macalou et al 2004 Click here for more information
  • Study details Sites et al 2004 Click here for more information
  • Study details Weber et al 2005 Click here for more information
  • Femoral nerve block versus placebo/no treatment/systemic analgesia
  • Alternative nerve block techniques
  • Peripheral nerve block versus other analgesic techniques
  • Peripheral nerve block, miscellaneous

PROSPECT Recommendations

  • Epidural analgesia (LA and/or opioid) is not recommended (Grade B) because of an increased risk of adverse events (procedure-specific evidence and transferable evidence, LoE 1) and no improvement in analgesia (procedure-specific evidence, LoE 1) compared with femoral nerve block
  • Epidural ketamine is not recommended (Grade B) because of sedative side-effects and inconclusive analgesic effects (procedure-specific evidence, LoE 1)
  • Epidural tramadol is not recommended (Grade B) because it does not provide sufficient analgesia (procedure-specific evidence, LoE 1)

Clinical practice

  • Epidural analgesia is associated with a relatively high degree of patient monitoring and serious (although rare) major complications
  • Epidural analgesia is a relatively complicated and invasive technique compared with peripheral nerve blocks

Transferable evidence

  • VAS pain scores at rest and during movement were significantly decreased at all time points (3, 6, 12, 24 and 48 h) following knee or hip replacement in the pre-operative epidural morphine group compared with the pre-operative IV morphine and IV saline groups (p<0.001) (n=60 patients)
  • Epidural analgesia was superior to systemic analgesia for postoperative pain outcomes following hip or knee replacement Choi et al 2003 Click here for more information
  • Epidural morphine (bolus 4 mg, infusion 12.5 mg/h over 13 h) was similar to epidural ketoprofen (200 mg over 30 min, 12.5 mg/h over 13 h) for postoperative pain scores following total hip or knee arthroplasty
  • Ropivacaine epidural infusion was superior to no epidural infusion for reducing postoperative pain scores in a group of patients undergoing total hip or knee arthroplasty (all groups received rescue IV morphine) Turner et al 1996 Click here for more information
  • A randomised trial in patients undergoing TKA or arthrolysis found that continuous epidural infusion and continuous femoral block (both with 1% lidocaine, 0.03 mg/ml morphine and 2 µg/ml clonidine at 0.1 ml/kg/h) groups had reduced pain scores at rest and on continuous passive motion compared with the PCA morphine group (p<0.01). Continuous epidural infusion was associated with lower pain scores at rest compared with continuous femoral block (no p value given)
  • A randomised trial in patients undergoing TKA or arthrolysis found that pain scores during continuous passive motion, and supplemental morphine consumption, were similar in the continuous epidural infusion and continuous femoral block groups
  • A randomised trial in patients undergoing TKA or arthrolysis found that continuous epidural infusion and continuous femoral block groups had improved early postoperative knee mobilisation compared with the PCA morphine group (p<0.05), although no significant differences were observed between the epidural and femoral block groups
  • A meta-analysis of randomised controlled trials found that both continuous epidural infusion and PCEA analgesia provided superior postoperative analgesia compared with intravenous PCA analgesia
  • A combination of epidural local anaesthetic plus opioid produced superior analgesic benefits compared with either drug administered alone in three studies of hip or knee surgery Lorenzini et al 2002 Click here for more information
  • A meta-analysis found that continuous epidural infusion provided superior analgesia and reduced the incidence of pruritus compared with PCEA analgesia, but was associated with a higher incidence of PONV and motor block
  • Epidural analgesia was associated with a lower incidence of sedation compared with systemic analgesia Choi et al 2003 Click here for more information
  • Epidural anaesthesia reduces the frequency of deep vein thrombosis and pulmonary embolism, and reduces intra-operative and postoperative blood loss, compared with general anaesthesia, particularly in total hip arthroplasty patients, as shown in a review
  • Postoperative morphine consumption was significantly increased in the pre-operative epidural morphine group (75 µg/kg) compared with the pre-operative IV morphine group (0.15 mg/kg), following knee or hip replacement (p<0.0003)
  • A randomised trial in patients undergoing TKA or arthrolysis found that continuous epidural analgesia was associated with increased frequency of urinary retention and dysesthesia compared with continuous femoral block (in each case, p<0.05)
  • Epidural infusion of ropivacaine (2 mg/ml) plus sufentanil (1 µg/ml) produced a significantly higher incidence of adverse events (pruritus, nausea and vomiting) than ropivacaine alone following major knee surgery (p<0.01; n=115)
  • Epidural administration of strong opioids is associated with side-effects including pruritus, PONV, urinary retention, and respiratory depression
  • Epidural analgesia was associated with more frequent urinary retention, pruritus and low blood pressure compared with systemic analgesia in hip or knee replacement Choi et al 2003 Click here for more information
  • Neuraxial and parenteral opioids are associated with a greater risk of side-effects compared with continuous plexus and peripheral neural blockades after major orthopaedic surgery

Total knee arthroplasty-specific evidence

  • One of two studies showed that VAS pain scores at rest and on movement were significantly lower in the pre-operative lumbar epidural LA plus ketamine group compared with placebo at 24 and 48 h postoperatively (p<0.05, in all cases), but not at 2, 4, 6 or 8 h ( Weir and Fee 1998 Click here for more information
  • VAS pain scores at rest and during movement were significantly lower in the clonidine group compared with the no clonidine group at 24:00 on the day of surgery (both p<0.025), although there were no significant differences between groups at 18:00 on the day of surgery or at 06:00 or 12:00 on postoperative day 1 (
  • Pain scores during ROM were significantly lower in the epidural group compared with the spinal anaesthesia + IV opioid PCA group on postoperative days 1–10 (p<0.001, in all cases) (
  • Pain scores at rest were significantly lower in the epidural group compared with the spinal anaesthesia + IV opioid PCA group on postoperative day 1 (p<0.001), but not days 2–10 (
  • PCEA-ropivacaine consumption was significantly lower in the pre-operative lumbar epidural LA plus ketamine group compared with the placebo group (p<0.01) ( Himmelseher et al 2001 Click here for more information
  • VAS pain scores were significantly lower in the pre-/intra-operative epidural LA groups compared with saline control (epidural morphine + ketamine in all groups) Wong et al 1997 Click here for more information
  • In three out of four studies, epidural LA plus opioid was associated with reduced postoperative VAS pain scores compared with systemic opioid, at different time points ( Møiniche et al 1994 Click here for more information
  • Consumption of IM oxycodone was significantly lower in the clonidine group compared with the group receiving no clonidine (p=0.027) (
  • Total morphine consumption in the pre-operative epidural combination group (lidocaine + morphine + ketamine) was significantly lower compared with epidural saline + morphine + ketamine on postoperative day 1 (p<0.001), but not on days 2 or 3 ( Wong et al 1997 Click here for more information
  • Total postoperative morphine use was significantly lower in the intra-operative combination (lidocaine + morphine + ketamine) group compared with epidural saline + morphine + ketamine on postoperative days 1 and 2 (p<0.001) and 3 (p<0.05) (
  • Two studies ( Nielsen et al 1989 Click here for more information
  • In three out of four studies epidural LA plus opioid significantly reduced supplemental analgesic use (including opioid use) ( Møiniche et al 1994 Click here for more information
  • Two studies ( Klasen et al 1999 Click here for more information
  • In two studies out of two ( Click here for more information
  • Supplemental analgesic requirement was reduced in the systemic morphine pre-medication plus epidural morphine group compared with the systemic morphine pre-medication group at 1–7 h and at 14, 16 and 20 h after surgery (p<0.01, in all cases) (postoperative analgesia was PCA IV fentanyl 50 µg, 5 min lockout) (
  • Total cumulative fentanyl consumption over 20 h was reduced in the systemic morphine pre-medication plus epidural morphine group compared with the systemic morphine pre-medication group (p<0.01) (
  • Time to first request for PCA-morphine was significantly longer in the pre-operative epidural combination (lidocaine + morphine + ketamine) group compared with the epidural saline + morphine + ketamine group (p<0.05), but there was no significant difference between the intra-operative epidural combination group and the epidural saline + morphine + ketamine group (
  • The incidence of hypotension was similar in both lumbar epidural LA plus ketamine and placebo/no treatment groups (
  • The incidence of pruritus was significantly reduced in the clonidine group at 24:00 on the day of surgery compared with the group receiving no clonidine (p<0.04), although this difference was not significant between groups at 18:00 on the day of surgery or at 06:00 or 12:00 on postoperative day 1 (
  • The incidence of postoperative side-effects (nausea, vomiting, drowsiness and pruritus) was reduced in the pre-operative epidural combination (lidocaine + morphine + ketamine) group and the intra-operative epidural combination group compared with the epidural saline + morphine + ketamine group (no p values given) (
  • There was significantly less sedation in the epidural group compared with the spinal anaesthesia + IV opioid PCA group on postoperative day 1 (p=0.04), but not on day 2 (
  • The time for cephalad level of pinprick anaesthesia to regress five dermatomal segments or for the verbal pain score (reported by patient, scale 1–10) to reach 5 (moderate) was significantly longer in the bupivacaine + pethidine group compared with the epidural bupivacaine alone group (p<0.05) (
  • VAS pain scores at rest and on movement were significantly lower in the epidural group compared with the femoral blockade group at 4 h postoperatively (p<0.05), but not at 24 or 48 h ( Singelyn et al 1998 Click here for more information
  • Pain scores during ROM were significantly lower in the epidural group compared with the spinal anaesthesia + IV opioid PCA group on postoperative days 1–10 (p<0.001, in all cases); pain scores at rest were significantly lower in the epidural group compared with the spinal anaesthesia group on postoperative day 1 (p<0.001), but not days 2–10 (
  • VAS pain scores were not significantly different between the epidural analgesia group and single injection femoral block group at any time point assessed (i.e. at 15, 30, 60, 120 and 180 min after application of LA or analgesics) (
  • Mean levels of supplemental analgesic were not significantly different between the epidural and continuous infusion femoral blockade groups over 48 h postoperatively ( Singelyn et al 1998 Click here for more information
  • There was significantly less sedation in the epidural group compared with the spinal anaesthesia plus IV opioid PCA group on postoperative day 1 (p=0.04), but not on day 2 (
  • Time to straighten the knee, intra-operative and postoperative blood loss, and time to discharge were not significantly different between the single injection femoral and sciatic block group and the epidural group (
  • There were no significant differences in the degree of knee flexion or the time taken to achieve 90-degree flexion between the epidural and continuous infusion femoral blockade groups (
  • There were no significant differences in the incidence of nausea or vomiting between the epidural and continuous infusion femoral blockade groups (
  • The incidence of postoperative complications (nausea, vomiting, confusion, hypotension, pruritus) was similar in the single injection femoral and sciatic block group and the epidural group (
  • The incidence of nausea and/or vomiting was not significantly different between the epidural analgesia group and single injection femoral block group (
  • There was no significant difference in the duration of hospital stay between the epidural and continuous infusion femoral blockade groups (
  • VAS pain scores at rest were significantly lower in the morphine group compared with both low-dose and high-dose tramadol groups at 0.5 and 2 h postoperatively (p<0.05, in all cases) but the trial was stopped due to inadequate analgesia ( Grace et al 1995 Click here for more information
  • VAS pain scores on movement were significantly lower in the morphine group compared with both tramadol groups at all times recorded (i.e. at 0.5, 2, 10 and 12 h postoperatively) (p<0.05, in all cases) but the trial was stopped due to inadequate analgesia
  • VAS pain scores at rest were significantly lower in the high-dose ropivacaine plus morphine group compared with the low-dose ropivacaine plus morphine group at 4–6 h postoperatively (p<0.05), but not at 0–3 or 9–48 h (
  • VAS pain scores on movement were significantly lower in the high-dose ropivacaine plus morphine group compared with the low-dose ropivacaine plus morphine group at 4–9 h postoperatively (p<0.05), but not at 0–3 or 12–48 h; there were no significant differences between the two groups in pain while sitting or walking (
  • The time taken for the verbal pain score (reported by patient, scale 1–10) to reach 5 (moderate) or the cephalad level of pinprick anaesthesia to regress five dermatomal segments was significantly longer in the epidural LA + pethidine group compared with the epidural LA + fentanyl group (p<0.05) (
  • The number of patients requiring morphine in the first 48 h postoperatively was significantly lower in the high-dose ropivacaine plus morphine group compared with the low-dose ropivacaine plus morphine group (p=0.01) ( Axelsson et al 2005 Click here for more information
  • Postoperative 20 h consumption of bupivacaine (1.1 mg/ml) and fentanyl (5 µg/ml) solution was significantly lower in the PCEA group compared with the epidural group (p<0.001); there were no significant differences between the two groups in the consumption of oxycodone (IM oxycodone [0.15 mg/kg] was available as rescue medication) (
  • Area under the curve measures of motor block were significantly lower for the epidural ropivacaine infusion group compared with the epidural bupivacaine infusion group at 0–4 (p=0.041), 4–8 (p=0.032) and 8–24 h postoperatively (p=0.012) (
  • VAS pain scores were significantly higher in the systemic morphine pre-medication plus epidural morphine group compared with the systemic morphine pre-medication group at 5 h postoperatively (p<0.05), but at 16 h, the opposite was evident (p<0.05)
  • Two studies out of three found no significant differences in postoperative VAS pain scores between epidural bupivacaine and PCA IV analgesia ( Click here for more information
  • There was no significant difference between the pre-operative lumbar epidural ketamine and placebo groups in the time to first analgesic request (
  • The number of separate painful episodes at rest (categorised as VAS 4–6 and VAS 7–10) was not significantly different in the clonidine and no clonidine groups (
  • There was no significant difference in the overall patient satisfaction with the pain management regimen between the clonidine and no clonidine groups (
  • Two of three studies showed no improvement in functional outcomes in the lumbar epidural LA plus opioid group compared with the systemic opioid group ( Møiniche et al 1994 Click here for more information
  • The incidence of postoperative side-effects (nausea, vomiting, and sedation) was similar in the clonidine and no clonidine groups (
  • The incidence of nausea and/or vomiting was not significantly different between the epidural LA + opioid and systemic opioid groups in any of the four studies (
  • There were no significant differences between patients receiving postoperative epidural bupivacaine versus IV PCA analgesia for the incidence of PONV in one study out of one (
  • In four out of four studies, the incidence of PONV was similar in both lumbar epidural morphine group and the placebo or systemic analgesia group ( Click here for more information
  • The incidences of nausea, vomiting, pruritus, urinary retention and respiratory depression were similar in the IM morphine pre-medication + epidural morphine group compared with the IM morphine pre-medication + epidural saline group (
  • More patients in the pre-operative lumbar epidural ketamine groups compared with the no treatment group exhibited sedation (p<0.0001, in all cases)
  • VAS fatigue scores were not significantly different between the epidural LA plus opioid and the GA plus systemic opioid groups (
  • Three of four studies (
  • The incidence of urinary retention was higher in the epidural LA plus opioid group versus the systemic opioid group (p=0.05) (
  • Catheter-related problems were significantly more common in the epidural LA plus opioid group versus the systemic opioid group (p<0.001) (
  • One study (
  • In two out of two studies ( Click here for more information
  • In one out of one study, there was no significant difference in ROM between the lumbar epidural morphine and IM ketobemidone groups (
  • The incidence of pruritus was significantly higher in patients receiving epidural LA plus opioid (high- and low-dose) compared with patients receiving saline control (p<0.05) (
  • Blood loss in the recovery room was similar in the clonidine and no clonidine groups (
  • Two of two studies showed that the length of hospital stay was not significantly different between the epidural LA plus opioid and systemic opioid groups (
  • VAS pain scores were not significantly different between the epidural LA plus opioid compared with lumbar epidural infusion with opioid alone at any time point recorded (i.e. at discharge from the recovery room and postoperative days 0 [pm], 1 [am and pm] and 2 [am]) (
  • There was no significant difference between epidural bupivacaine plus fentanyl (3 µg/ml) and bupivacaine alone in the rate of regression of sensory anaesthesia or the development of postoperative pain (n=48) (
  • Epidural infusion rates were not significantly different between lumbar epidural infusion with LA plus opioid compared with lumbar epidural infusion with opioid alone (postoperative analgesia comprised an additional epidural bolus of 3 ml and an increase in the infusion rate of 2 ml/h if VAS pain scores >33) (
  • The incidence of nausea, vomiting and pruritus was not significantly different between lumbar epidural infusion with LA plus opioid compared with lumbar epidural infusion with opioid alone (
  • VAS pain scores on movement were significantly lower in the single injection femoral and sciatic block group compared with the epidural group at 24 h postoperatively (p=0.004), but not at discharge from the recovery room or at 6 or 48 h (
  • Postoperative PCA morphine consumption was significantly higher in the epidural group compared with the single injection femoral and sciatic block group at 24 h postoperatively (p=0.004), but not at 6 or 48 h (
  • The frequency of urinary retention (p=0.05) and catheter-related problems (p<0.001) was increased in the continuous epidural analgesia group compared with the continuous infusion femoral nerve block group (
  • There were no significant differences between the PCEA-LA group and the continuous epidural infusion group in VAS or VRS pain scores at rest or on movement at any time point recorded (i.e. 3, 9 and 20 h after the start of treatment) (
  • Comparison of ropivacaine and bupivacaine for epidural infusion showed that ropivacaine was associated with higher pain scores, but only at certain time points ( Muldoon et al 1998 Click here for more information
  • VAS pain scores at rest or on movement were not significantly different between the low-dose and high-dose epidural ropivacaine plus sufentanil groups at any time point recorded (4, 8, 20, 32 and 44 h after start of infusion) (
  • VAS pain scores were not significantly different between three epidural ketamine dose groups (0.3 mg/kg, 0.5 mg/kg and 0.67 mg/kg) (
  • There were no significant differences between ketamine dose groups (0.3 mg/kg, 0.5 mg/kg and 0.67 mg/kg) in the time taken from epidural injection to threshold (VAS >30 mm) at which supplemental analgesia was administered (
  • Pethidine consumption was significantly greater in both low-dose and high-dose tramadol groups compared with the morphine group ( Grace et al 1995 Click here for more information
  • Morphine consumption was not significantly different between the epidural ropivacaine and bupivacaine infusion groups (postoperative analgesia was ropivacaine or bupivacaine (0.2%) at 8 ml/h postoperatively for 24 h; PCA-morphine [1 mg, 5-min lockout]) (
  • Postoperative piritramide consumption (postoperative analgesia was IV PCA-piritramide) was similar in low-dose and high-dose epidural ropivacaine plus sufentanil groups (
  • Time to first PCA pethidine demand was not significantly different between the two epidural tramadol groups and the morphine group (
  • The incidence of PONV and urinary retention was not significantly different between the PCEA-LA group and the continuous epidural infusion group (
  • There was no significant difference in the incidence of PONV and pruritus between the two tramadol groups and the morphine group; respiratory depression was absent in all three groups (
  • The incidence of nausea, vomiting and pruritus was not significantly different between the low-dose and high-dose epidural ropivacaine plus morphine groups (
  • The incidence of nausea was significantly higher in the high-dose epidural ropivacaine plus sufentanil group compared with the low-dose ropivacaine plus sufentanil group (p=0.042); there was no significant difference between the two dose groups for the incidence of vomiting, pruritus, sedation or hypotension (
  • There were no significant differences between the 0.3 mg/kg, 0.5 mg/kg and 0.67 mg/kg epidural ketamine groups in the number of patients who developed hypotension within 20 min of epidural injection (
  • Study details and Tables 11 & 12 Weir and Fee 1998 Click here for more information
  • Study details Badner et al 1991 Click here for more information
  • Study details Singelyn et al 1998 Click here for more information
  • Study details Silvasti and Pitkanen 2001 Click here for more information
  • Lumbar epidural analgesia versus placebo or systemic analgesia
  • Lumbar epidural LA plus opioid versus epidural LA/opioid alone
  • Lumbar epidural versus other regional techniques
  • Lumbar epidural, miscellaneous studies

PROSPECT Recommendations

  • Intra-articular LA and/or morphine is not recommended at this time (Grade D, LoE 4) because of inconsistent analgesic efficacy in procedure-specific and transferable evidence
  • Intra-articular NSAIDs, neostigmine, or clonidine are not recommended (Grade D, LoE 4) because there is no procedure-specific and inconsistent transferable evidence
  • Intra-articular corticosteroid is not recommended at this time (Grade D, LoE 4), because there is no procedure-specific evidence, despite positive transferable evidence from minor orthopaedic procedures (LoE 1)
  • After the cut-off date of the systematic literature search, additional studies of combined intra-articular and incisional LA have shown an analgesic benefit (procedure-specific evidence, LoE 1)

Clinical practice

  • Doses of IA morphine in some studies (5–10 mg) represent systemic, not IA doses

Transferable evidence

  • A systematic review of knee joint surgery RCTs looked at the effects of IA morphine, compared with saline Kalso E et al 2002 Click here for more information
  • Several randomised studies in arthroscopic knee or ankle surgery have shown that intra-articular corticosteroid reduced pain after surgery
  • A second systematic review of RCTs examining the effects of IA morphine following knee joint surgery suggested that there were no significant analgesic effects of morphine compared with saline Rosseland LA 2005 Click here for more information

Total knee arthroplasty-specific evidence

  • Two out of three studies ( Mauerhan et al 1997 Click here for more information
  • After the cut-off date of the systematic literature search, additional randomised studies of combined intra-articular and incisional LA versus placebo have shown a reduction in pain scores and analgesic use in the LA group
  • In one study out of one, the time to first analgesic use was significantly lengthened by postoperative intra-articular LA plus morphine compared with placebo (p<0.01) (
  • The length of time in PACU was significantly lower in the intra-operative intra-articular bupivacaine group compared with the placebo group (p=0.02) (
  • One study out of one (
  • There were no significant differences in VAS pain scores between the pre-operative intra-articular bupivacaine and placebo treatment groups at 1, 2, 4 or 24 h after arrival in PACU; there were also no significant differences in VRS pain scores (scale 0–4) between the two treatment groups (
  • VAS pain relief scores (scale 0–10) were significantly lower in the intra-operative intra-articular bupivacaine group compared with the placebo group in post-PACU (p=0.05), but not in PACU or at 24 h postoperatively (
  • VAS pain scores in PACU, post-PACU and for the first 24 h postoperatively were not significantly different between the intra-operative intra-articular bupivacaine group and the placebo group (
  • Two studies out of three reported no significant difference in VAS pain scores for intra-/postoperative intra-articular morphine compared with placebo, see Table 13b for details Click here for more information
  • Two out of three studies reported no significant effect of postoperative intra-articular LA bolus compared with placebo on postoperative VAS or McGill-Melzack pain scores ( Click here for more information
  • VAS pain scores were not significantly different between the continuous intra-articular bupivacaine versus placebo groups on the day of surgery or on postoperative days 1 or 2 (
  • Postoperative morphine consumption was not significantly different between the pre-operative intra-articular bupivacaine and placebo groups (postoperative analgesia was IV morphine [0.02 mg/kg at 5-min intervals] until comfortable, then PCA-morphine [0.02 mg/kg, 8-min lockout]) (
  • Narcotic dose equivalents consumption was not significantly different between the intra-operative intra-articular bupivacaine group and the placebo group in PACU, post-PACU or at 24 h postoperatively (postoperative analgesia was PCA-morphine or IM narcotics, supplemented by oral narcotics as needed) (
  • There were no consistent findings between studies comparing postoperative intra-articular LA plus morphine versus placebo for supplemental analgesic use ( Mauerhan et al 1997 Click here for more information
  • Two studies out of three reported no significant differences between intra-/postoperative intra-articular morphine group and control group for supplemental morphine use ( Klasen et al 1999 Click here for more information
  • Two out of three studies ( Click here for more information
  • The number of requests for narcotics (postoperative analgesia was PCA-morphine or hydromorphone) and the mean dose of narcotic were not significantly different between the continuous intra-articular bupivacaine and placebo groups; cumulative use of NSAIDs and oxycodone-based analgesia was also similar in both groups (
  • The incidence of nausea and vomiting, urinary retention and pruritus was similar in pre-operative intra-articular bupivacaine and placebo groups (
  • The incidence of nausea was similar in intra-operative intra-articular bupivacaine group compared with the placebo group
  • One study out of one reported that there were no significant differences between postoperative intra-articular LA plus morphine and placebo for the incidence of complications such as pruritus, respiratory depression, rash or urinary retention (
  • One study out of one reported no significant differences between postoperative intra-articular bolus bupivacaine and placebo in terms of nausea and vomiting, urinary retention and pruritus (
  • One study out of one ( Click here for more information
  • Requirement for anti-emetics was not significantly different between the continuous intra-articular bupivacaine and placebo groups (
  • ROM at discharge was similar in the pre-operative intra-articular bupivacaine and placebo groups (
  • There were no significant differences between the intra-operative intra-articular bupivacaine group and the placebo group in ROM or in distance ambulated on postoperative day 1 or at discharge
  • There were no significant differences between the continuous intra-articular bupivacaine and placebo groups for passive ROM or ambulation distance (
  • In one study out of one, the length of hospital stay was similar in both postoperative intra-articular LA plus morphine and placebo groups (
  • In one study out of one, the length of hospital stay was similar in both postoperative intra-articular bolus LA group and placebo group (
  • The length of hospital stay was similar in the continuous intra-articular bupivacaine group and the placebo group (
  • Three of three studies reported no significant differences between intra-articular LA + morphine compared with intra-articular LA alone for reducing postoperative VAS or McGill-Melzack pain scores at any time point during 0–48 h after surgery, ( Click here for more information
  • Three of three studies reported no significant difference between intra-articular injection of morphine versus LA in terms of postoperative VAS or McGill-Melzack pain scores at any time point during 0–48 h after surgery; ( Click here for more information
  • Three of three studies found no significant difference in VAS or McGill-Melzack pain scores between intra-articular LA plus morphine group and intra-articular morphine alone group ( Click here for more information
  • Two of three studies ( Click here for more information
  • Two of three studies ( Click here for more information
  • Three out of three studies found that intra-articular LA plus morphine and intra-articular morphine alone did not differ significantly in terms of their effect on supplemental analgesic requirements in the first 24 h after surgery, ( Click here for more information
  • In one study out of one, there were no significant differences between intra-articular LA plus morphine and intra-articular LA alone for the incidence of PONV or postoperative complications ( Click here for more information
  • In one study out of one, there were no significant differences between intra-articular morphine and intra-articular LA for the incidence of PONV or postoperative complications ( Click here for more information
  • One study out of one ( Click here for more information
  • In one study out of one, the length of hospital stay was similar in both intra-articular LA plus morphine group and intra-articular LA alone group (
  • In one study out of one, the length of hospital stay was similar in intra-articular morphine group and intra-articular LA group (
  • In one study out of one, there were no significant differences between the intra-articular LA plus morphine group and intra-articular morphine alone group for length of hospital stay (
  • In one study out of one, ROM was similar in both intra-articular LA plus morphine group and intra-articular LA alone group ( Click here for more information
  • In one study out of one, ROM was similar in both intra-articular morphine group and intra-articular LA group ( Click here for more information
  • In one study out of one, there were no significant differences between intra-articular LA plus morphine group and intra-articular morphine alone group for ROM (
  • There were no significant differences in VAS pain scores between the pre-operative versus postoperative intra-articular bupivacaine groups at 1, 2, 4 or 24 h after arrival in PACU; there were also no significant differences in VRS pain scores (scale 0–4) between the two treatment groups (
  • One study noted that patients receiving intra-articular bupivacaine pre-incision had significantly superior ROM at discharge compared with the postoperative intra-articular bupivacaine group (p=0.02) and placebo (p=0.009) (
  • The incidence of nausea and vomiting, urinary retention and pruritus was similar in pre-operative intra-articular bupivacaine versus postoperative intra-articular bupivacaine groups (
  • Study details and Tables 13a, 13b & 13c Badner et al 1996 Click here for more information
  • Study details and Tables 14a, 14b & 14c Click here for more information
  • Study details Badner et al 1996 Click here for more information
  • Intra-articular LA and/or morphine versus control
  • Intra-articular LA and/or morphine versus intra-articular LA/morphine alone
  • Intra-articular, miscellaneous

PROSPECT Recommendations

  • After the cut-off date of the systematic literature search, additional studies of combined intra-articular and incisional LA have shown an analgesic benefit (procedure-specific evidence, LoE 1)

Clinical practice

  • None cited

Transferable evidence

  • None cited

Total knee arthroplasty-specific evidence

  • After the cut-off date of the systematic literature search, additional randomised studies of combined intra-articular and incisional LA versus placebo have shown a reduction in pain scores and analgesic use in the LA group

PROSPECT Recommendations

  • Cooling and compression techniques are recommended (Grade B) for postoperative analgesia, based on limited procedure-specific evidence for a reduction in pain scores (LoE 2) and analgesic use (LoE 1)

Clinical practice

  • None cited

Transferable evidence

  • None cited

Total knee arthroplasty-specific evidence

  • A cold compressive dressing was significantly superior to a standard compressive dressing for reducing postoperative VAS pain scores on day 2 (p<0.01) and 3 (p<0.05), but there was no significant difference on day 1 (
  • Cryo/Cuff ® use and epidural bupivacaine use were not significantly different for reducing postoperative VAS pain scores at rest or on motion during the first 7 days postoperatively or at 6 weeks (
  • One of two studies found that pain scores (assessed using the visual analogue method of Huskisson) were significantly lower in the Cryo/Cuff ® group compared with the control group, in patients undergoing both unilateral (p<0.05) and bilateral (p<0.02) total knee replacement ( Holmstrom and Hardin 2005 Click here for more information
  • Two out of two studies showed a reduction in supplemental analgesia consumption with Cryo/Cuff ® compared with control Holmstrom and Hardin 2005 Click here for more information
  • A cold compressive dressing was significantly superior to a standard compressive dressing for reducing total use of injectable morphine in mg/kg/48 h (p<0.05) (
  • Cryo/Cuff ® and epidural bupivacaine groups were not significantly different for morphine consumption during days 1–7 postoperatively (
  • A cold compressive dressing was significantly superior to a standard compressive dressing for increasing the total arc ROM on day 7 (p<0.05) and 14 (p<0.01) (
  • Cryo/Cuff ® and epidural bupivacaine groups were not significantly different for passive or active ROM (
  • A cold compressive dressing was significantly superior to a standard compressive dressing for reducing blood loss (into the drain and into soft tissue, and total body blood loss) (p<0.001) (
  • Cryotherapy was significantly superior to a modified Robert Jones bandage for reducing blood loss (p<0.05), but there was no significant difference for transfusion requirements (
  • Cryo/Cuff ® and epidural bupivacaine groups were not significantly different for blood loss or swelling (
  • Cryo/Cuff ® was significantly superior to control for reducing the mean volume of suction drainage (p<0.05) (
  • A compression bandage and cold therapy were similar for postoperative VAS pain scores on days 1–3 and opiate use in 48 h (
  • Cryotherapy and a modified Robert Jones bandage were similar for postoperative VAS pain scores (
  • Cryotherapy and a modified Robert Jones bandage were similar for morphine consumption (standardised to patient's weight) and co-dydramol doses
  • Two out of two studies showed no differences in ROM between the Cryo/Cuff ® and control groups Holmstrom and Hardin 2005 Click here for more information
  • A compression bandage and cold therapy were similar for flexion at 24 and 48 h postoperatively (
  • Cryotherapy and a modified Robert Jones bandage were similar for ROM (
  • Two out of two studies demonstrated no difference in knee swelling with Cryo/Cuff ® compared with control (
  • Cryo/Cuff ® use was of no significant benefit for reducing blood loss compared with control (
  • A compression bandage and cold therapy were similar for knee swelling, wound drainage, transfusions, and haemoglobin, but cold therapy was associated with significantly higher INR (international normalised ratio for prothrombin time) compared with compression bandaging (p=0.03) (
  • A compression bandage and cold therapy were similar for total length of hospital stay (
  • Cryotherapy was associated with increased length of hospital stay (13 days) compared with a modified Robert Jones bandage (11 days) (no p value given) (
  • Study details Holmstrom and Hardin 2005 Click here for more information

PROSPECT Recommendations

  • TENS is not recommended (Grade B) because limited procedure-specific evidence suggests a lack of benefit (LoE 1)

Clinical practice

  • TENS may be used as a co-analgesic without detriment. Effect may depend on intensity and many studies may not use adequate intensity

Transferable evidence

  • A meta-analysis of randomised, placebo-controlled trials, found that TENS, when administered with a strong, subnoxious intensity at an adequate frequency in the wound area, significantly reduced analgesic use after various types of surgery (including abdominal, gynaecological, and thoracic procedures)
  • TENS reduced pain scores after minor rib fracture on days 1 and 3 (p<0.05), but not day 0, compared with NSAID, or NSAID plus inactive TENS, or control (placebo tablet, no TENS) (n=100)
  • TENS reduced pain scores during activity (p<0.05), but not at rest, compared with placebo TENS or no TENS, after abdominal surgery (n=30)

Total knee arthroplasty-specific evidence

  • Different levels of TENS (40 mA and 14 mA) were associated with similar decreases in postoperative VAS pain scores during days 1–3 (
  • Different levels of TENS (40 mA and 14 mA) were associated with similar doses of postoperative narcotics during days 1–3 (
  • Different levels of TENS (40 mA and 14 mA) were associated with similar knee flexion arc on postoperative day 3 or day of discharge (
  • Different levels of TENS (40 mA and 14 mA) were associated with similar lengths of hospital stay (
  • Study Details Angulo and Colwell 1990 Click here for more information

PROSPECT Recommendations

  • Continuous passive motion (Grade A) and intensive rehabilitation (Grade D) are recommended for reasons other than analgesia (procedure-specific evidence, LoE 1 and 2 respectively)

Clinical practice

  • None cited

Transferable evidence

  • None cited

Total knee arthroplasty-specific evidence

  • Two out of two studies of intensive rehabilitation protocols used measurements other than VAS pain score for knee pain, and one of the two showed that supervised intensive rehabilitation of 2–4 months duration was superior to standard care for reducing WOMAC pain scoring ( Click here for more information
  • One study comparing continuous passive motion (CPM) treatment with control found CPM was associated with increased ROM, and the CPM group found it easier to regain movement postoperatively compared with control ( Harms and Engstrom 1991 Click here for more information
  • One study out of two describing inter-group differences in functional outcome, showed that patients given intensive/accelerated rehabilitation had significantly better walking abilities postoperatively compared with control ( Click here for more information
  • One study out of one demonstrated superior active flexion in the continuous passive motion group compared with the control group (p=0.004), although there were no significant differences in postoperative active extension or passive extension between groups (
  • One study out of one showed that the number of days taken to achieve 70º ROM was significantly fewer with continuous passive motion compared with control, although knee flexion at discharge was not significantly different between the two groups
  • Two studies out of two reported a significant reduction in knee swelling with continuous passive motion compared with control (
  • A meta-analysis evaluating the effectiveness of continuous passive motion following total knee arthroplasty showed that continuous passive motion with physical therapy was more effective than physical therapy alone for significantly increasing active knee flexion, decreasing the length of hospital stay, and decreasing the need for post-operative manipulation. Continuous passive motion did not significantly improve passive knee flexion and passive or active knee extension
  • Three studies out of four showed no significant difference between continuous passive motion treatment and control for pain scores Can and Alpaslan 2003 Click here for more information
  • There were no significant differences in VAS pain scores at discharge between groups in a study comparing continuous passive motion with the use of a lower limb mobility board (
  • There were no significant differences between home visit and outpatient physiotherapy treatment for WOMAC dimension scores for pain or SF-36 dimension scores for bodily pain (
  • Two out of two studies showed no significant difference between continuous passive motion treatment group versus control group for postoperative rescue analgesic requirements Harms and Engstrom 1991 Click here for more information
  • There were no significant differences between home visit and outpatient physiotherapy treatment for WOMAC dimension scores for physical function or SF-36 dimension scores for physical function (
  • One study out of one reported no significant differences in 6 week ROM or function assessed by HAQ (Health Assessment Questionnaire) between the continuous passive motion and control groups (
  • Knee function was not significantly different between the continuous passive motion and lower limb mobility board groups May 1999 Click here for more information
  • Three out of three studies comparing continuous passive motion treatment with control reported no significant difference between groups for length of hospital stay (
  • Duration of hospital stay was not significantly different between the continuous passive motion and lower limb mobility board groups (
  • One study comparing continuous passive motion treatment with control reported no significant difference between groups for wound drainage (
  • There was no significant difference between home visit and outpatient physiotherapy treatment for mean total costs, but home visit physiotherapy costs were significantly higher than outpatient physiotherapy costs (p=0.001) (
  • Study details and Table 15 Can and Alpaslan 2003 Click here for more information
Testing the   Paragraphs
Testing the Paragraphs