Anesthesia and Analgesia in Total Joint Arthroplasty
Developed by: American Association of Hip and Knee Surgeons, American Society of Regional Anesthesia and Pain Medicine, American Academy of Orthopaedic Surgeons, The Hip Society, and The Knee Society
Acetaminophen and Postoperative Pain and/or Opiod Use
Administration of IV or oral acetaminophen reduces pain and opioid consumption during the perioperative period of a primary TJA
Moderate Evidence Moderate Evidence

We reviewed seventeen randomized clinical trials that represented the best available evidence including fifteen high quality and two moderate quality studies to assess the ability of IV or oral acetaminophen to reduce pain and/or opioid consumption during the perioperative period following TJA. ADDIN EN.CITE.DATA [2-18] Among the included studies, eleven studies investigated IV acetaminophen compared to placebo, five studies investigated IV acetaminophen compared to oral acetaminophen, and three studies compared oral acetaminophen to placebo. ADDIN EN.CITE.DATA [2-18] Despite the numerous high and moderate quality randomized clinical trials, only a limited amount of meta-analyses were able to be performed due to inconsistency in the reporting of outcomes and timepoints for reporting the outcomes.

            Intravenous acetaminophen has been shown with limited heterogeneity in direct meta-analyses to demonstrate favorable reductions in postoperative pain and opioid consumption compared to placebo. Among the studies reporting on postoperative pain, direct meta-analysis of IV acetaminophen demonstrated lower 6-hour sum of pain intensity differences (outcome is a four-point scale that summarizes the treatment benefit over a specific time period) and postoperative pain scores (i.e. visual analogue scale and numeric pain rating scale) between 24- and 48-hours compared to placebo following surgery. Additionally, direct meta-analysis of opioid consumption measured 24-hours following TJA had improved outcomes for IV acetaminophen compared to placebo.

            Due to the lack of consistent outcomes, no meta-analysis could be performed comparing IV and oral acetaminophen. However, among the five high quality randomized clinical trials investigating the comparison of IV and oral acetaminophen, no difference was observed between the routes of administration to reduce postoperative pain and/or opioid consumption.[4, 9, 10, 14, 17] Similarly, no meta-analysis could be performed comparing oral acetaminophen and placebo. Only three high quality randomized studies were available to assess the ability of oral acetaminophen to reduce postoperative pain and/or opioid consumption compared to placebo.[6, 9, 16] Qualitative review of the available literature would suggest oral acetaminophen reduces postoperative pain and opioid consumption, but the results do not consistently favor oral acetaminophen over placebo at statistically significant levels.

            Although IV acetaminophen has been shown to be superior to placebo and equivalent to oral acetaminophen with regards to reduction in postoperative pain and/or opioid consumption, the lack of overwhelming evidence supporting the superiority of oral acetaminophen compared to placebo has resulted in a downgrade of the recommendation from strong to moderate for oral acetaminophen. Furthermore, the strength of the recommendation for IV acetaminophen was downgraded from strong to moderate due to concerns regarding the significantly higher cost of IV acetaminophen compared to oral acetaminophen. However, the US Food and Drug Administration has granted approval for marketing of a generic IV acetaminophen starting in December 2020, which is has the potential to dramatically reduce the cost and change the downgrade of the recommendation of IV acetaminophen.

Acetaminophen Use After Discharge
In the absence of reliable evidence, it is the opinion of the workgroup that oral acetaminophen may be used after discharge as part of a multimodal pain regimen, as it is a low-cost and low-risk treatment for pain after discharge from a primary TJA.
Consensus Consensus

Oral acetaminophen has widely been accepted as a safe, effective, and low-cost analgesic medication. Despite the numerous high and moderate quality randomized clinical trials investigating perioperative acetaminophen in the setting of a primary TJA, we lack specific evidence to guide a recommendation on the use of oral acetaminophen after discharge. As a result, we must rely on the available evidence regarding acetaminophen in the nonsurgical treatment of osteoarthritis and its use during the perioperative period of primary TJA to guide our recommendation. In the setting of nonsurgical treatment of osteoarthritis of the knee, direct meta-analysis of oral acetaminophen showed a significant improvement in pain and function compared to an oral placebo.[19] Lastly, the results from the current clinical practice guidelines has shown the effectiveness of oral acetaminophen to reduce postoperative pain and opioid consumption during the inpatient period following primary TJA.

Although acetaminophen has not been proven to be effective in isolation for postoperative pain management following primary TJA, it has been demonstrated as an effective adjunct as part of a multimodal pain management protocol.[20] When used in conjunction with other non-opioid analgesic medications, patients experienced a decreased risk of medical complications.[20] Therefore, we can support the use of oral acetaminophen after discharge as part of a multimodal pain regimen.

Acetaminophen and Postoperative Complications
Administration of IV or oral acetaminophen does not increase the risk of complications following primary TJA
Strong Evidence Strong Evidence

Among the reviewed high and moderate quality randomized clinical trials, eleven studies reported on complications related to the administration of acetaminophen.[2-6, 12, 13, 15-18] Qualitative examination demonstrated no consistent difference between IV acetaminophen, oral acetaminophen, and placebo. Direct meta-analysis was only capable of being performed for IV acetaminophen, which showed no significant difference with regards to any complication (0.98 relative risk; 95% confidence interval of 0.83 to 1.16) or vomiting (1.16 relative risk; 95% confidence interval of 0.30 to 4.45). Therefore, IV and oral acetaminophen are considered to be safe analgesic medications to administer during the perioperative episode of a primary TJA.

 

Gabapentinoids and Postoperative Pain and/or Opioid Use
In the perioperative period after primary TJA, gabapentinoids do not reduce postoperative pain, but pregabalin reduces opioid consumption.
Strong Evidence Strong Evidence

We reviewed thirteen high quality prospective randomized controlled trials that represented the best available evidence to assess the efficacy of gabapentinoids in reducing postoperative pain and opioid consumption after TJA.[2–14] Among the included studies, seven studies investigated gabapentin compared to placebo and six studies investigated pregabalin compared to placebo.[2–14] Despite these high quality studies, only a limited amount of meta-analyses were performed due to inconsistency in outcomes reported and the timepoints at which these outcomes were reported.  

            Gabapentin did not have any impact on postoperative pain in the perioperative period at all time points after TJA compared to placebo in the seven high quality studies included. Five studies specifically evaluated pain scores within 3 days postoperatively and found there was no difference in pain scores between patients treated with gabapentin and patients treated with placebo.[4–6,9,12] Of the five studies reporting opioid consumption, one study reported gabapentin reduced opioid consumption compared to placebo, while the other 4 studies found no difference.[4,5,9,11,12] Two of these studies were able to be included in a direct meta-analysis with limited heterogeneity, which determined gabapentin had no impact on morphine consumption measured at 72 hours postoperatively compared to placebo.[11,12] Direct meta-analyses evaluating complications associated with gabapentin compared to placebo found there was no difference in rates of nausea, vomiting, pruritus, dizziness, and sedation. 

            Pregabalin reduced opioid consumption, but did not show a consistently significant impact on postoperative pain compared to placebo in the perioperative period after primary TJA. Of the six studies included, five studies evaluated pain scores within 3 days postoperatively. Three of these studies found no difference in pain scores between placebo and pregabalin, while two studies found pregabalin reduced pain compared to placebo.[3,8,10,13,14] One study that demonstrated a favorable reduction in pain scores evaluated pregabalin for treatment of pain after total hip arthroplasty (THA) while the other study evaluated total knee arthroplasty (TKA) patients.  Due to heterogeneity of the pain scores reported and the timepoints at which the pain scores were reported a direct meta-analysis was not able to be completed. However, a direct meta-analysis of four studies evaluating the efficacy of pregabalin on opioid consumption found that pregabalin moderately reduces opioid consumption compared to placebo after TJA.[3,8,10,13] Direct meta-analyses were performed to evaluate complications associated with pregabalin compared to placebo. There were no differences between pregabalin and placebo in rates of vomiting, pruritus, and dizziness. However, a direct meta-analysis of three studies evaluating sedation found that pregabalin moderately increases the risk of sedation compared to placebo after TJA. A direct meta-analysis of four studies evaluating nausea after TJA found pregabalin reduces the incidence of nausea compared to placebo. 

Gabapentinoid Use Following Discharge
Pregabalin after discharge reduces postoperative pain, neuropathic pain, and opioid consumption after primary TJA, but gabapentin does not reduce pain or opioid consumption.
Strong Evidence Strong Evidence

Six high quality studies evaluated the efficacy of post-discharge gabapentinoids on pain and opioid consumption after TJA.[2–4,7,9,13] Three of these studies evaluated gabapentin prescribed for 4 - 7 days after TKA. One study evaluated two weeks of pregabalin after TKA, one study evaluated 6 weeks of pregabalin after TKA, and one study evaluated one week of pregabalin after THA. Due to heterogeneity of outcomes reported, no meta-analyses were completed.

Qualitative review of the three studies that evaluated treatment with gabapentin for less than 7 days after TKA found that it had no impact on postoperative pain in all three studies.[4,7,9] One of these studies evaluated chronic and neuropathic pain at 3 – 4 years postoperatively and found no effect of gabapentin compared to placebo.[7] Only one study evaluated opioid consumption after discharge and found there was no difference in opioid consumption at 6 days postoperatively between gabapentin and placebo.[9]

              There were two pregabalin studies that evaluated pain scores between 3 days and 1 week postoperatively and one that evaluated pain scores at 3 months and 6 months postoperatively. All three of these studies found favorable reductions in pain scores with pregabalin compared to placebo.[2,3,14] Two of these studies evaluated opioid consumption after discharge.[2,3] Buvanendran et al. found no difference in opioid use at 6 months postoperatively between patients who received pregabalin and placebo. However, they did find that rates of neuropathic pain were lower in patients who received pregabalin compared to placebo. [2] Clarke et al. found at 1 week postoperatively patients who received pregabalin consumed fewer opioids than patients who received placebo.[3]

Efficacy Between Low- and High-Dose Gabapentinoids
There is no difference in postoperative pain, opioid consumption, or complications between low-dose and high-dose gabapentinoids. However, the use of gabapentinoids may lead to increased risk of confusion among elderly patients and respiratory depression with concurrent use of opioids.
Moderate Evidence Moderate Evidence

Three high quality studies evaluated the difference in dosing of gabapentinoids and their effects on postoperative pain, opioid consumption, and complications after primary TJA.[7,9,13] Two studies evaluated high- and low-doses of gabapentin while one study evaluated high- and low-doses of pregabalin. Both studies that evaluated gabapentin found that there was no difference in pain scores between high- and low-dose gabapentin.[7,9] One of these studies also evaluated opioid consumption and found there was no difference in opioid consumption between high- and low-dose gabapentin groups.[9]

One study directly compared 75 mg of pregabalin twice a day for 6 weeks compared to 150 mg of pregabalin twice a day for 6 weeks postoperatively.[13] The study found no difference in opioid consumption or complications between the two doses except for constipation which was more frequent in the low-dose group.

The strength of recommendation is moderate given there is only one high quality study comparing high- and low-dose pregabalin, and studies comparing gabapentin to placebo found no difference in postoperative pain and opioid consumption with a lack of consistency in measures/scales for these high priority outcomes. It is the opinion of the workgroup that gabapentinoids be used cautiously especially when given concurrently with opioids or used in the elderly given pregabalin is associated with increased risk of postoperative sedation. Recent publications by the Food and Drug Administration (FDA) and other surgical subspecialties have highlighted these concerns regarding respiratory depression with concurrent use of opioids and gabapentinoids.[15–18] A recent database study by Ohnuma et al. also found a dose-dependent association with gabapentinoids and postoperative pulmonary complications after total hip and knee arthroplasty.[19] It is the opinion of the workgroup that pregabalin may cause increased sedative effects in the elderly and should be used with caution in this population. Given the limited high quality evidence evaluating safety and dosage, it is the consensus of this group that when gabapentinoids are utilized after primary TJA, the lowest clinically efficacious dose should be used to minimize the risk of complications.

Oral NSAIDs and Postoperatiave Pain and/or Opioid Use
An oral NSAID administered either preoperatively and/or in the early postoperative period reduces pain and opioid consumption following primary TJA.
Strong Evidence Strong Evidence

We reviewed seventeen randomized clinical trials that represented the best available evidence including nine high quality and eight moderate quality studies to assess the effectiveness of selective COX-2 (includes selective [i.e. Celecoxib] and preferential [i.e. Meloxicam] COX-2 inhibitory agents) and non-selective (COX-1 and -2 inhibitory agents) oral NSAIDs to reduce pain and/or opioid consumption postoperatively following TJA. ADDIN EN.CITE.DATA [2-18] Among the included studies comparing either a selective and/or non-selective NSAID to placebo, ten studies investigated a selective NSAID and five studies investigated a non-selective NSAID.[2-5, 7-15, 17] Similar to other topics within the clinical practice guidelines, only a limited amount of meta-analyses was able to be performed due to inconsistency in the reporting of outcomes and timepoints for reporting the outcomes.

            Oral NSAIDs demonstrated with limited heterogeneity in direct meta-analysis to reduce opioid consumption and sum of pain intensity differences (outcome is a four-point scale that summarizes the treatment benefit over a specific time period) compared to placebo. When direct meta-analysis was performed individually for primary total hip and knee arthroplasty, opioid consumption was lower when patients were administered preoperative and/or postoperative oral NSAIDs. Combined analysis of primary hip and knee arthroplasties demonstrated similar results favoring reduced opioid consumption and improved sum of pain intensity differences for oral NSAIDs compared to placebo.

            Due to a lack of consistent outcomes, no direct or network meta-analysis could be performed comparing selective or non-selective NSAIDs. However, qualitative analysis of selective and non-selective oral NSAIDs consistently demonstrate an overwhelmingly significant response of a reduction in postoperative pain and opioid consumption for both types of NSAIDs. Three studies have directly compared selective and non-selective oral NSAIDs, which showed no significant difference in the outcomes of postoperative opioid consumption or pain scale.[13, 18] Similarly, no direct or network meta-analysis could be performed to investigate preoperative verses postoperative dosing of oral NSAIDs. Among the studies comparing a selective NSAID to placebo, three studies included preoperative dosing, four studies included postoperative dosing, and four studies included both preoperative and postoperative doses.[2, 3, 5, 7-9, 11-14] The studies comparing a non-selective NSAID to placebo included four studies utilizing postoperative dosing and one study utilizing both preoperative and postoperative doses.[4, 10, 13, 15, 17] However, one high quality study comparing preoperative and postoperative administration of a single dose of a selective NSAID showed a reduction in opioid consumption with the preoperative administration of the oral selective NSAID.[12]

Oral COX-2 NSAID and Postoperative Pain and/or Opioid Use
Administration of an oral selective clyclooxygenase-2 (COX-2) NSAID immediately preoperatively, compared to early postoperative administration, provides improved postoperative pain control and reduced opioid consumption following primary TJA.
Moderate Evidence Moderate Evidence

We reviewed seventeen randomized clinical trials that represented the best available evidence including nine high quality and eight moderate quality studies to assess the effectiveness of selective COX-2 (includes selective [i.e. Celecoxib] and preferential [i.e. Meloxicam] COX-2 inhibitory agents) and non-selective (COX-1 and -2 inhibitory agents) oral NSAIDs to reduce pain and/or opioid consumption postoperatively following TJA. ADDIN EN.CITE.DATA [2-18] Among the included studies comparing either a selective and/or non-selective NSAID to placebo, ten studies investigated a selective NSAID and five studies investigated a non-selective NSAID.[2-5, 7-15, 17] Similar to other topics within the clinical practice guidelines, only a limited amount of meta-analyses was able to be performed due to inconsistency in the reporting of outcomes and timepoints for reporting the outcomes.

            Oral NSAIDs demonstrated with limited heterogeneity in direct meta-analysis to reduce opioid consumption and sum of pain intensity differences (outcome is a four-point scale that summarizes the treatment benefit over a specific time period) compared to placebo. When direct meta-analysis was performed individually for primary total hip and knee arthroplasty, opioid consumption was lower when patients were administered preoperative and/or postoperative oral NSAIDs. Combined analysis of primary hip and knee arthroplasties demonstrated similar results favoring reduced opioid consumption and improved sum of pain intensity differences for oral NSAIDs compared to placebo.

            Due to a lack of consistent outcomes, no direct or network meta-analysis could be performed comparing selective or non-selective NSAIDs. However, qualitative analysis of selective and non-selective oral NSAIDs consistently demonstrate an overwhelmingly significant response of a reduction in postoperative pain and opioid consumption for both types of NSAIDs. Three studies have directly compared selective and non-selective oral NSAIDs, which showed no significant difference in the outcomes of postoperative opioid consumption or pain scale.[13, 18] Similarly, no direct or network meta-analysis could be performed to investigate preoperative verses postoperative dosing of oral NSAIDs. Among the studies comparing a selective NSAID to placebo, three studies included preoperative dosing, four studies included postoperative dosing, and four studies included both preoperative and postoperative doses.[2, 3, 5, 7-9, 11-14] The studies comparing a non-selective NSAID to placebo included four studies utilizing postoperative dosing and one study utilizing both preoperative and postoperative doses.[4, 10, 13, 15, 17] However, one high quality study comparing preoperative and postoperative administration of a single dose of a selective NSAID showed a reduction in opioid consumption with the preoperative administration of the oral selective NSAID.[12]

Oral NSAID Use After Discharge Following TKA
Administration of an oral selective COX-2 NSAID after discharge reduces pain and opioid consumption during the six-week period following a primary total knee arthroplasty (TKA).
Moderate Evidence Moderate Evidence

Despite the numerous high and moderate quality randomized clinical trials investigating administration of oral NSAIDs during the perioperative period, such as preoperatively or during the postoperative admission, we lack the same level of evidence to evaluate the use of oral NSAIDs after discharge. Because of concerns regarding the safety of non-selective oral NSAID administration for an extended duration and lack of specific evidence for non-selective oral NSAIDs after discharge, the workgroup has elected to only make a recommendation regarding the use of selective oral NSAIDs after discharge from a primary TJA.

            Similar to the administration of oral selective COX-2 (includes selective [i.e. Celecoxib] and preferential [i.e. Meloxicam] COX-2 inhibitory agents) NSAIDs during the perioperative period, such as preoperatively or during the postoperative admission, utilization of an extended duration of oral selective COX-2 NSAIDs reduces the postoperative pain and opioid consumption. A single high quality study investigating the administration of an oral selective COX-2 NSAID compared to placebo for six-weeks provides overwhelming evidence favoring oral selective COX-2 NSAID use following a primary TKA.[19] Because we lack similar evidence after a primary THA, the workgroup provides a consensus recommendation favoring the administration of an oral selective COX-2 NSAID after discharge from primary THA. Furthermore, the inclusion of an oral NSAID as a component of a postoperative multimodal pain management protocol following primary TJA has demonstrated a reduction in pain, opioid consumption, and the risk of opioid-related adverse effects, such as respiratory depression, nausea/vomiting, sedation, or urinary retention.[20] Therefore, we can support the use of oral selective COX-2 NSAIDs after discharge from a primary TJA as part of a multimodal pain regimen.

Oral NSAID Use After Discharge Following THA
In the absence of reliable evidence, it is the opinion of the workgroup that oral selective COX-2 NSAIDs may be used after discharge as part of a multimodal pain regimen to reduce postoperative pain and opioid consumption in patients undergoing primary total hip arthroplasty (THA).
Consensus Consensus

Despite the numerous high and moderate quality randomized clinical trials investigating administration of oral NSAIDs during the perioperative period, such as preoperatively or during the postoperative admission, we lack the same level of evidence to evaluate the use of oral NSAIDs after discharge. Because of concerns regarding the safety of non-selective oral NSAID administration for an extended duration and lack of specific evidence for non-selective oral NSAIDs after discharge, the workgroup has elected to only make a recommendation regarding the use of selective oral NSAIDs after discharge from a primary TJA.

            Similar to the administration of oral selective COX-2 (includes selective [i.e. Celecoxib] and preferential [i.e. Meloxicam] COX-2 inhibitory agents) NSAIDs during the perioperative period, such as preoperatively or during the postoperative admission, utilization of an extended duration of oral selective COX-2 NSAIDs reduces the postoperative pain and opioid consumption. A single high quality study investigating the administration of an oral selective COX-2 NSAID compared to placebo for six-weeks provides overwhelming evidence favoring oral selective COX-2 NSAID use following a primary TKA.[19] Because we lack similar evidence after a primary THA, the workgroup provides a consensus recommendation favoring the administration of an oral selective COX-2 NSAID after discharge from primary THA. Furthermore, the inclusion of an oral NSAID as a component of a postoperative multimodal pain management protocol following primary TJA has demonstrated a reduction in pain, opioid consumption, and the risk of opioid-related adverse effects, such as respiratory depression, nausea/vomiting, sedation, or urinary retention.[20] Therefore, we can support the use of oral selective COX-2 NSAIDs after discharge from a primary TJA as part of a multimodal pain regimen.

Intravenous Ketorolac and Postoperative Pain and/or Opioid Consumption
Administration of IV ketorolac preoperatively, intraoperatively, or within 24 hours postoperatively reduces pain and opioid consumption postoperatively (within the first 48 hours) following primary TJA.
Strong Evidence Strong Evidence

We reviewed seven randomized clinical trials that represented the best available evidence including four high quality and three moderate quality studies to assess the ability of IV ketorolac to reduce postoperative pain and/or opioid consumption following TJA.[21-27] Qualitative analysis consistently demonstrated statistically favorable outcomes for IV ketorolac compared to placebo regarding the reduction in postoperative pain and opioid consumption with no significant increase of medical complications such as adverse events, nausea/vomiting, blood loss, pruritus, urinary retention, or respiratory depression. Despite the high and moderate quality randomized clinical trials, only direct meta-analysis of opioid consumption could be performed due to inconsistency in the reporting of pain outcomes and timepoints for reporting the outcomes. The direct meta-analysis of opioid consumption significantly favored IV ketorolac compared to placebo with limited heterogeneity.

             Among the included studies, the total dosage of IV ketorolac administered to patients ranged between 15 mg and 150 mg given within the first 24 hours after surgery.[21-27] However, only one high quality study compared low- and high-doses of IV ketorolac, which demonstrated no difference between a single postoperative dose of 15 mg or 30 mg of IV ketorolac.[27] Although no difference was observed between the low- and high-dose treatments, 15 mg and 30 mg IV ketorolac doses are still considered relatively low-doses compared to the other published doses of IV ketorolac. Therefore, the lack of an observed difference could simply be the result of not having a large enough difference between the dose amounts to observe a dose response. Despite the potential for reduced postoperative pain and opioid consumption with higher IV ketorolac doses, the workgroup suggests the use of minimally effective doses to diminish the risk of medical complications such as acute kidney failure.

Postoperative IV Ketorolac
Low-dose (15 mg) and high-dose (30 mg) administration of IV ketorolac immediately postoperatively are equivalent at reducing pain and opioid consumption postoperatively (within the first six hours) following primary TJA.
Moderate Evidence Moderate Evidence

We reviewed seven randomized clinical trials that represented the best available evidence including four high quality and three moderate quality studies to assess the ability of IV ketorolac to reduce postoperative pain and/or opioid consumption following TJA.[21-27] Qualitative analysis consistently demonstrated statistically favorable outcomes for IV ketorolac compared to placebo regarding the reduction in postoperative pain and opioid consumption with no significant increase of medical complications such as adverse events, nausea/vomiting, blood loss, pruritus, urinary retention, or respiratory depression. Despite the high and moderate quality randomized clinical trials, only direct meta-analysis of opioid consumption could be performed due to inconsistency in the reporting of pain outcomes and timepoints for reporting the outcomes. The direct meta-analysis of opioid consumption significantly favored IV ketorolac compared to placebo with limited heterogeneity.

           Among the included studies, the total dosage of IV ketorolac administered to patients ranged between 15 mg and 150 mg given within the first 24 hours after surgery.[21-27] However, only one high quality study compared low- and high-doses of IV ketorolac, which demonstrated no difference between a single postoperative dose of 15 mg or 30 mg of IV ketorolac.[27] Although no difference was observed between the low- and high-dose treatments, 15 mg and 30 mg IV ketorolac doses are still considered relatively low-doses compared to the other published doses of IV ketorolac. Therefore, the lack of an observed difference could simply be the result of not having a large enough difference between the dose amounts to observe a dose response. Despite the potential for reduced postoperative pain and opioid consumption with higher IV ketorolac doses, the workgroup suggests the use of minimally effective doses to diminish the risk of medical complications such as acute kidney failure.

NSAIDs Use and Postoperative Medical Complications
Oral or IV NSAIDs administered preoperatively, intraoperatively, or postoperatively do not appear to increase the risk of medical complications following primary TJA; however, providers should consider patient comorbidities, the type of NSAID administered, dose, and duration of administration.
Limited Evidence Limited Evidence

Among the reviewed high and moderate quality randomized clinical trials comparing perioperative oral NSAIDs and placebo, twelve studies reported on medical complications related to the administration of NSAIDs.[2-5, 7-9, 11-15] Qualitative examination demonstrated no consistent difference between oral selective COX-2 (includes selective [i.e. Celecoxib] and preferential [i.e. Meloxicam] COX-2 inhibitory agents) NSAIDs, oral non-selective (COX-1 and -2 inhibitory agents) NSAIDs, and placebo with the exception of a lower incidence of postoperative fever with patients receiving an oral NSAID. Direct meta-analysis was capable of being performed comparing various complications between perioperative NSAIDs and placebo, which showed no significant difference with regards to any adverse event (0.93 relative risk; 95% confidence interval of 0.85 to 1.02), vomiting (0.82 relative risk; 95% confidence interval of 0.52 to 1.31), nausea (0.84 relative risk; 95% confidence interval of 0.68 to 1.04), blood loss (-0.23 standard mean difference; 95% confidence interval of -0.54 to 0.08), pruritus (1.73 relative risk; 95% confidence interval of 0.96 to 3.13), urinary retention (1.24 relative risk; 95% confidence interval of 0.34 to 4.59), and sedation (0.46 relative risk; 95% confidence interval of 0.16 to 1.26). Similar to oral NSAIDs, direct meta-analysis of medical complications between IV ketorolac and placebo were not significant with regards to any adverse events (0.94 relative risk; 95% confidence interval of 0.59 to 1.50), nausea (0.89 relative risk; 95% confidence interval of 0.70 to 1.12), vomiting (0.73 relative risk; 95% confidence interval of 0.47 to 1.14), blood loss (-0.14 standard mean difference; 95% confidence interval of -0.46 to 0.17), pruritus (0.50 relative risk; 95% confidence interval of 0.22 to 1.12), urinary retention (0.75 relative risk; 95% confidence interval of 0.43 to 1.32), or respiratory depression (-0.05 standard mean difference; 95% confidence interval of -0.28 to 0.18).

           Despite the evidence favoring oral and IV NSAIDs in the qualitative and quantitative analysis of numerous high and moderate quality studies to reduce postoperative pain and opioid consumption, the gastrointestinal and renal safety profile of oral and IV NSAIDs have not been thoroughly studied in patients following primary TJA. Although nausea and vomiting were frequently reported among the studies, more severe complications including upper gastrointestinal bleeding and acute renal failure were not reported. It is possible the lack of reporting an upper gastrointestinal bleed is due to the rarity of the complication. As a result, clinicians should consider the safety of perioperative NSAIDs as it relates to severe gastrointestinal and renal failure complications. Therefore, the work group downgraded the recommendation strength by only assigning a limited strength to the recommendation.

TJA and Preoperative Opioid Use
Preoperative opioid use is associated with inferior patient reported outcomes, increased opioid consumption after surgery, an increased risk for chronic opioid use, and an increased risk of complications after TJA.
Moderate Evidence Moderate Evidence

We reviewed fourteen studies that evaluated the influence of preoperative opioid use on outcomes after TJA.[2–15] All studies were assessed as low quality and thus a limited amount of meta-analyses were performed due to inconsistency in outcomes reported and the timepoints at which these outcomes were reported. 

Nine studies evaluated the effects of preoperative opioid use on patient reported outcomes.[2,5–11,15] Seven studies found that when compared to opioid naïve patients, patients taking preoperative opioids had inferior patient reported outcome scores in all outcomes measured.[2,5–8,11,15] Three of these studies were included in a direct meta-analysis with limited heterogeneity, which found that preoperative opioid use is associated with inferior pain scores postoperatively compared to opioid naïve patients (0.52 standard mean difference; 95% confidence interval 0.28 to 0.76).[5,9,15] Two studies found mixed effects of preoperative opioid use on patient reported outcome scores. Hansen et al. found that preoperative opioid users had no difference in patient reported outcome scores, but had significantly decreased range of motion following total knee arthroplasty (TKA) compared to opioid naïve patients.[9] Manalo et al. found no difference in range of motion after TKA or the University of California Los Angeles (UCLA) activity scores, but inferior visual analogue scores (VAS) among patients taking preoperative opioids compared to opioid naïve patients.[10]

            Opioid consumption after TJA among patients taking opioids preoperatively was evaluated by seven studies.[2,4–7,9,14] All seven studies found that patients taking opioids preoperatively consume significantly more opioids after TJA compared to opioid naïve patients. Seven studies evaluated chronic opioid use and found that preoperative opioid use is a major risk factor for chronic opioid use after TJA.[4,6–8,12–14] Due to heterogeneity of the timepoints at which opioid consumption were reported, a direct meta-analysis was not able to be completed.     

Five studies compared complication rates after TJA between patients taking opioids preoperatively and opioid naïve patients.[5–9] Three studies found that complications were more frequent among patients who took opioids preoperatively, while two studies found no difference between opioid naïve patients and patients that took opioids preoperatively. Three studies found no difference in reoperation rates while one study found increased reoperation rates among patients taking opioids preoperatively.[5–8] It is the opinion of the workgroup that it is likely these studies were underpowered to detect differences in reoperation and revision rates between the two groups. The current literature suggests that complications are more common among patients taking opioids preoperatively, but is inconclusive regarding reoperation and revision rates.

Reduction of Opioid Use Prior to TJA
Reduction of opioid use prior to TJA may lead to improved patient reported outcomes after TJA compared to patients who do not reduce opioid consumption prior to surgery.
Limited Evidence Limited Evidence

           One low quality study evaluated the influence of reducing preoperative opioid use on patient reported outcome scores and opioid consumption after TJA.10 In their retrospective case control study, Nguyen et al. found that patients on chronic opioids prior to TJA who reduced their opioid consumption by more than 50% prior to surgery had significantly better patient reported outcome scores after TJA compared to patients who did not reduce their opioid intake prior to surgery. The percent change of improvement in patient reported outcome scores was similar to a control group of opioid naïve patients. Based on this low-quality evidence and the evidence presented above that demonstrates that patients on preoperative opioids have inferior outcomes compared to opioid naïve patients, it is the opinion of the workgroup that reduction of preoperative opioid use may lead to improved patient reported outcomes after TJA. This recommendation was upgraded from consensus to recommendation given the importance of reducing opioid use in light of the current epidemic.

Opioids Administered Immediately Prior to TJA Surgery
An opioid administered immediately prior to surgery reduces postoperative pain and opioid consumption within the first 72 hours after TJA, but may increase the risk of complications, such as respiratory depression or sedation, especially if combined with other opioids administered intraoperatively or postoperatively.
Strong Evidence Strong Evidence

We reviewed six studies that compared the influence of an opioid administered pre-emptively immediately prior to TJA to placebo on postoperative outcomes after TJA.[16–21] Five studies are high quality and one is moderate quality. Three studies evaluated transdermal fentanyl patches placed 10 – 12 hours prior to surgery, one study evaluated intramuscular morphine, one study evaluated oral morphine, and one study evaluated intravenous morphine. A very limited amount of meta-analyses was performed due to inconsistency in outcomes reported and the timepoints at which these outcomes were reported. 

            All six studies reported visual analogue pain scores (VAS) within 72 hours after TJA after administration of an opioid pre-emptively prior to TJA. Four of the high quality studies found that an opioid administered pre-emptively prior to surgery resulted in lower VAS scores within 72 hours after TJA compared to placebo.[16–19] Three of these studies evaluated transdermal fentanyl and the fourth study evaluated intramuscular morphine. The two remaining studies, which evaluated intravenous morphine and oral morphine, found no difference in VAS scores compared to placebo.[20,21]

All six studies evaluated opioid consumption within 72 hours after TJA. Five of the six studies found that administration of an opioid pre-emptively prior to TJA resulted in lower morphine consumption after TJA compared to placebo.[16,18–21] The other study found no difference in opioid consumption after TJA when comparing pre-emptive opioid administration to placebo.[17] Only one study evaluated range of motion after TJA and found no difference amongst patients who received a pre-emptive opioid prior to TJA compared to placebo.[16] Three studies included a direct meta-analysis with moderate heterogeneity found that patients who received an opioid preemptively prior to surgery had decreased opioid consumption compared to placebo (-1.51 standard mean difference; 95% confidence interval -2.37 to -0.64).

             Direct meta-analyses were performed to compare rates of nausea, vomiting, and urinary retention. The direct meta-analyses found no difference between patients who received a pre-emptive opioid prior to TJA and placebo in rates of nausea (0.88 relative risk; 95% confidence interval 0.62 to 1.25), vomiting (0.60 relative risk; 95% confidence interval 0.33 to 1.10), and urinary retention (1.08 relative risk; 95% confidence interval 0.34 to 3.40). Four studies evaluated sedation and respiratory depression and found no difference between pre-emptive opioids and placebo. [16,17,19,21]

             However, it is the opinion of the workgroup that when combined with other opioids administered during the perioperative period, such as intraoperatively or postoperatively, opioids administered prior to surgery may increase the risk of complications including respiratory depression and sedation.

Opioids Administered Intraoperatively
An opioid administered intraoperatively reduces opioid consumption, but does not affect postoperative pain within 72 hours after surgery. An opioid administered intraoperatively may increase the risk of complications, such as respiratory depression or sedation, especially if combined with other opioids administered preoperatively or postoperatively.
Moderate Evidence Moderate Evidence

We reviewed two high quality studies that evaluated the influence of an opioid administered intraoperatively during primary TJA on postoperative pain, opioid consumption, and complications.[22,23] Given the differences in outcome measures utilized and the timepoints at which were measured at no meta-analyses could be performed.

Both studies evaluated postoperative opioid consumption after administering an intraoperative opioid during primary TJA. They both found that administering an intraoperative opioid reduced postoperative opioid consumption compared to placebo within the first 72 hours after surgery.[22,23]  These two studies also evaluated VAS pain scores and found no difference between patients who received an intraoperative opioid and placebo within the first 72 hours postoperatively. Similarly, there was no difference in the rates of nausea or vomiting between patients who received intraoperative opioids and those who received placebo. However, it is the opinion of the workgroup that when combined with other opioids administered preoperatively or postoperatively, opioids administered during surgery may increase the risk of complications including respiratory depression and sedation. Given there is not significant evidence on the risk of complications associated with intraoperative opioid use we downgraded this recommendation from a strong recommendation to a moderate recommendation. 

Opioid Use Following TJA Surgery
Scheduled opioid administration without multimodal analgesia within 72 hours after primary TJA reduces the need for additional opioid pain medications for breakthrough pain and may reduce postoperative pain within 72 hours after surgery, but providing scheduled opioids is discouraged. Scheduled opioid administration postoperatively may increase the risk of complications, such as respiratory depression and sedation, especially if combined with other opioids administered during the perioperative period.
Moderate Evidence Moderate Evidence

          Nine studies including six high quality studies and three moderate quality studies evaluated the influence of postoperative opioids on outcomes after primary TJA. A limited number of direct meta-analyses were performed due to inconsistency in outcomes reported and the timepoints at which these outcomes were reported. 

            Eight studies evaluated the postoperative consumption of opioids for breakthrough pain either delivered orally or with patient controlled analgesia between patients who received scheduled opioids postoperatively and patients who received placebo. All eight studies found that the administration of scheduled opioids postoperatively reduced the consumption of opioids for breakthrough pain.[24–31] Two studies were included in a direct meta-analysis with moderate heterogeneity and found that patients who were administered scheduled opioids postoperatively routinely required less opioids for breakthrough pain compared to placebo (-0.54 standard mean difference; 95% confidence interval of -0.92 to -0.15).

All nine studies evaluated postoperative pain and reported mixed results.[24–32]  Three studies reported no difference in pain control between patients who received scheduled opioids postoperatively and placebo.[25,26,31] Three studies reported mixed results where some pain measures were improved among patients who received opioids scheduled postoperatively while others pain parameters were no different between these patients and placebo.[28,29,32] The final three studies found that opioids administered after primary TJA reduce postoperative pain compared to placebo.[24,27,30] 

Direct meta-analyses evaluating complications associated with postoperative opioid use compared to placebo found no differences between the two groups in rates of respiratory depression (-0.17 standard mean difference; 95% confidence interval of -0.45 to 0.10), pruritus (1.01 relative risk; 95% confidence interval of 0.70 to 1.47), nausea (1.30 relative risk, 95% confidence interval of 1.03 to 1.65), vomiting (1.10 relative risk; 95% confidence interval of 0.69 to 1.74), confusion (1.82 relative risk; 95% confidence interval 0.35 to 9.49), dizziness (1.50 relative risk; 95% confidence interval 0.60 to 3.71), headache (0.69 relative risk; 95% confidence interval 0.30 to 1.59), and constipation (1.71 relative risk; 95% confidence interval 0.82 to 3.59). While the current literature does not demonstrate significant differences in rates of adverse events, it is the opinion of the workgroup that opioids pose significant risks to patients when not safely administered. The cumulative dose of opioids administered as well as the timing between opioid doses must be carefully monitored in TJA patients. Patients who receive excess opioid pain medication are at significant risk for adverse events such as sedation and respiratory depression. It is the recommendation of the workgroup that extended release opioids should be avoided to help mitigate this risk. In addition, it is the opinion of the workgroup that the lowest clinically effective dose of opioids be prescribed and administered to patients to help curb these adverse events in addition to the risk for chronic opioid dependence. Given the inconsistency in results with regards to postoperative pain as well as complications associated with postoperative opioid use this recommendation was downgraded from strong to moderate.

Opioid Use Following TJA Surgery
Prescribing lower quantities of opioid pills at discharge may lead to equivalent patient reported outcomes, pain relief, reduced opioid consumption, and fewer unused opioid pills after TJA.
Moderate Evidence Moderate Evidence

           One high quality study evaluated the influence of the number of opioid pills prescribed at discharge after TJA on patient reported outcome scores, pain control, and opioid consumption after TJA.[33] In their prospective blinded randomized controlled trial, Hannon et al. found that patients who received 30 oxycodone immediate release pills (OxyIR) as opposed to 90 pills had equivalent patient reported outcome scores and significantly fewer unused pills at 6 weeks postoperatively. Patients who received 90 OxyIR pills had on median 73 unused pills while patients who received 30 OxyIR pills had on median 15 unused pills. Opioid consumption within 6 weeks after surgery was equivalent between the two groups, however regression analysis determined that being prescribed 90 OxyIR pills was independently associated with taking more oxycodone pills. Given the risks associated with diversion of unused opioid pills, it is the opinion of the workgroup that patients be prescribed the fewest number of opioid pills possible without jeopardizing pain control and clinical outcomes after TJA. 

Tramadol Use Following TJA Surgery
Tramadol administered within 24 hours after surgery may reduce postoperative pain and opioid consumption after TJA within 72 hours after surgery, but may be associated with adverse events such as dizziness and dry mouth.
Moderate Evidence Moderate Evidence

Three studies evaluated the effects of tramadol on postoperative pain, opioid consumption, and complications after primary TJA. One high quality study compared the use of tramadol versus a placebo for treatment of pain after TJA.[34] Another high quality study compared tramadol to placebo and to paracetamol with codeine.[35] One additional high quality study compared tramadol to other opioid medications for treatment of pain after TJA. There were mixed results among all studies on the effects of tramadol on pain, patient-reported outcome scores, opioid consumption and adverse events after TJA.

            Both studies that compared tramadol to a non-opioid control found that there was no difference in pain relief between the control and tramadol.[34,35] However, each study found different results with regards to opioid consumption. Stiller et al. found that intravenous tramadol 100 mg/mL administered every 6 hours for 24 hours after surgery led to 31% lower morphine consumption in TKA patients measured via a morphine patient controlled analgesia (PCA) device.[34] Stubhaug et al. found that after THA the addition of either 50 mg or 100 mg oral tramadol did not result in any change in opioid consumption when compared to placebo.[35] When compared to paracetamol with codeine, both 50 mg and 100 mg oral tramadol resulted in less efficacious pain relief and opioid consumption. Pang et al. found that tramadol reduced opioids administered via a patient controlled analgesic device compared to placebo.[36]

            Adverse events including dizziness, dry mouth, and nausea were more common among patients who received tramadol compared to placebo.  A direct meta-analysis of two studies found that rates of dry mouth (1.97 relative risk; 95% confidence interval 1.04 to 3.75) and dizziness (1.50 relative risk; 95% confidence interval 1.12 to 2.00) were more common among patients who took tramadol compared to placebo.[35,36]

            Given the conflicting evidence with regards to opioid consumption, the fact that two studies evaluated intravenous tramadol which is not approved by the Food and Drug Administration in the United States, and that there was inconclusive evidence comparing the efficacy of tramadol to other opioids the strength of the recommendation was downgraded to moderate.


Acknowledgements:

Guideline Work Group:

  • Yale A. Fillingham, MD
  • Charles P. Hannon, MD, MBA
  • Greg A. Erens, MD
  • Asokumar Buvanendran, MD
  • William G. Hamilton, MD
  • Craig J. Della Valle, MD
  • Justin T. Deen, MD
  • Greg A. Erens, MD
  • Jess H. Lonner, MD
  • Aidin E. Pour, MD
  • Robert S. Sterling, MD
  • James A. Browne, MD
  • Emil H. Schemitsch, MD, FRCS(C)
  • Karl C. Roberts, MD, FAAOS
  • Dennis Nam, MD
  • Brian M. Curtain, MD
  • Jonathan M. Vigdorchik, MD

 

AAOS Staff:

  • Jayson Murray, MA, Director, Department of Clinical Quality and Value
  • Kyle Mullen, MPH, Manager, Department of Clinical Quality and Value
  • Frank Casambre, MPH, Research Analyst, Department of Clinical Quality and Value
  • Vidya Visvabharathy, Research Analyst, Department of Clinical Quality and Value
  • Connor Riley, MPH, Research Analyst, Department of Clinical Quality and Value

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