Pre-operative

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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