Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are some of the most common orthopaedic surgeries, which are expected to be increasing significantly in the future (Singh et al., 2019). Over 450 000 THAs and nearly 800 000 TKAs are performed annually in the United States (US) (Foran, 2020). Postoperative pain, a manifestation of inflammation owing to surgical injury of tissues and/or nerves (Derry et al., 2016), is inevitable. Patients undergoing THA or TKA often reported moderate to severe pain post operation (Petersen et al., 2015; Sayers et al., 2016). This can influence postoperative functional recovery and as a result, prolong hospitalization and increase healthcare costs (Derry et al., 2016; Gan et al., 2017). If not effectively managed, acute postoperative pain may result in a higher risk of chronic pain development and prolonged opioid use as well as opioid-related adverse events (Gan et al., 2017).
Opioids including tramadol, morphine sulfate, oxycodone and other formulas remain the mainstay therapeutic of postoperative pain management (Derry et al., 2016; Gan et al., 2017). Opioids produce analgesic effects by binding to opioid receptors, inhibiting the release of neurotransmitters in the central and peripheral nervous system (Pathan et al., 2012). On the other hand, opioids can induce adverse effects such as nausea, vomiting, dizziness, depression of temperature regulation, and if used in high dose or for longer duration, neuroendocrine dysfunction and dependence can occur (Derry et al., 2016; Pathan et al., 2012).
There has been a trend of opioid overprescribing after surgery (Wunsch et al., 2016; Goesling et al., 2016). A retrospective cohort study of over 236 000 patients after THA or TKA in the US showed that the proportion of patients receiving an opioid prescription within 60 days after surgery increased from 82% in 2014 to 90% in 2017, while the mean score of pain reduction during the same period of time (between post discharge and 60 days after discharge) remained similar across the years, which was always less than 0.5 on a 0-10 pain scale (Shah et al, 2020).
Using opioids for postoperative pain management takes into consideration an acceptable balance between efficacy in pain control and potential harm of adverse effects and dependency. In this OE Original, we conducted a systematic review and meta-analysis outlining the evidence from randomized controlled trials (RCTs) regarding the use of oral opioids among THA or TKA patients.
We searched for RCTs in which oral opioids were investigated as a treatment or prophylactic of postoperative pain in 3 databases for peer-reviewed studies (i.e., Ovid Medline, Embase, and PsychInfo). We assessed the risk of bias (RoB) and quality of evidence using the Cochrane RoB and the GRADE approach, respectively.
We identified 10 eligible RCTs, published between 1983 and 2016. The sample sizes ranged from 37 to 483 patients. Interventions included tramadol in 3 studies (McQuay et al., 2016; Stubhaug et al., 1995; Fu et al., 2010), morphine sulphate in 3 studies (Manoir et al., 2006; Musclow et al., 2012; Reiter et al., 2003), and oxycodone, tapentadol, oxymorphone, buprenorphine and sufentanil in 1 study (Hartrick et al., 2009; Gimbel et al., 2004; O'Sullivan et al., 1983; Jove et al., 2015), respectively. The comparator from all the included studies was placebo.
We present the characteristics of the included RCTs in Table 1 and a summary of their risk of bias in Figure 1.
Table 1. Characteristics of included RCTs (Comparator, placebo)
Number of patients
Fu et al., 2010
Tramadol 0.1 mg twice a day
Gimbel et al., 2004 *
Endo Pharmaceuticals Inc.
THR and TKR
Single dose of oxycodone IR 10 mg; Single dose of oxymorphone IR 30 mg, 20 mg or 10 mg
Hartrick et al., 2009 **
Johnson & Johnson Pharmaceutical, Grünenthal
THR and TKR
Single dose of oxycodone Hydrochloride IR; Single dose of tapentadol IR 50 mg
Jove et al., 2015 **
AcelRx Pharmaceuticals Inc.
THR and TKR
Sufentanil 15 µg via sublingual tablet system
Manoir et al., 2006
Morphine sulphate IR 20 mg every 4 h for 24 h
McQuay et al., 2016
Ten countries ***
Single dose of tramadol hydrochloride 100 mg
Musclow et al., 2012
THR and TKR
Morphine sulfate 30 mg twice daily for 3 days
O'Sullivan et al., 1983
Reckitt and Colman Pharmaceutical
Sublingual buprenorphine 0.4 mg
Reiter et al., 2003
Single dose of morphine sulfate 20 mg before the operation
Stubhaug et al., 1995
Single dose of tramadol 100 mg
Note: IR=immediate release; THA=total hip arthroplasty; TKA=total knee arthroplasty; THR=total hip replacement; TKR=total knee replacement.
* The pain outcome in this study was not able to be pooled in the meta-analysis because the dispersion of pain score was neither reported nor could be imputed from other studies using the same measure.
** Only two-day total pain relief (TOTPAR) was reported in this study. TOTPAR was calculated as the total score of pain relief (time elapsed since the previous observation), with the sum including all observations of pain relief collected from the observational period.
*** Thirty-seven study sites in 10 countries (Czech Republic, Germany, Hungary, Latvia, Lithuania, Poland, Serbia, Spain, Taiwan, and Ukraine).
We meta-analyzed outcomes of postoperative pain and treatment-related adverse events at the longest follow-up durations.
- Postoperative pain: oral opioids versus placebo
1.1 Pain on 0-100 visual analogue scale (VAS)
Of the 7 RCTs comprising 826 patients that reported pain on a 0 to 100 VAS (a higher score indicates worse pain), tramadol was used in 3 studies, morphine sulphate was used in 3 studies and buprenorphine was used in 1 study as the active intervention drug, to be compared with identical matching placebos. Oral opioids showed an overall efficacy of greater operative pain reduction compared to placebo with a weighted mean difference (MD) of 5.5 points less pain (95% CI, 2.16 points less to 8.84 points less pain, P=0.001, moderate quality of evidence) up to 3 days after THA or TKA (Figure 2). The MD did not reach the recommended minimally important difference (MID) of 10 mm on a 100 VAS when reporting treatment effects regarding pain (Busse et al., 2015).
If we look at the subgroup analysis by specific type of opioids, effects of pain reduction maintained for tramadol and buprenorphine while morphine did not show a significant effect (MD, 5.66 points less pain, 95% CI, 14.48 points less to 3.17 points more pain, P=0.21, low quality of evidence) compared to placebo (Figure 2).
1.2 Pain on total pain relief (TOTPAR) scale
We also meta-analyzed the pain outcome of the two-day total pain relief (TOTPAR, no range, a higher score indicates a better outcome) reported by two studies (Hatrick et al., 2009; Jove et al., 2015) that compared opioids to placebo. TOTPAR was calculated as the total score of pain relief measured at 15, 30, 45, and 60 minutes, and then every 1 hour until 12 hours, as well as every 2 hours until 48 hours after therapy. Opioids showed greater pain relief compared to placebo with a weighted MD of 33.15 points more pain relief (95% CI, 26.52 points more to 39.78 points more pain relief, P < 0.001, high quality of evidence) up to 2 days after THA or TKA (Figure 3).
1.3 Pain evaluated by the sum of pain intensity (SPID)
The pain outcome in one study (Gimbel et al., 2004) was not able to be pooled in the meta-analysis because the dispersion of pain score was neither reported nor could be imputed from other eligible studies using the same measure. This 5-arm study showed that among patients undergoing THA or TKA, a single dose of oxymorphone at 30 mg, 20 mg or 10 mg significantly reduced postoperative pain up to 8 hours compared to placebo (P < 0.05). Greater pain reduction was observed for a single dose of 10 mg oxycodone compared to placebo but the difference was not statistically significant. Risk of bias was low.
- Treatment-related adverse events (AEs): oral opioids versus placebo
2.1 Overall AEs
Patients who received opioids had a higher risk of experiencing AEs (427/908=47.0%) compared to those received placebo (116/537=21.6%) with a risk ratio (RR) of 1.64 (95% CI, 1.24 to 2.16, P < 0.001, moderate quality of evidence) (Figure 4).
In the result of subgroup analysis by type of opioids, tramadol did not show a statistically significant difference in AEs compared to placebo (RR 1.19; 95% CI, 0.76 to 1.87, P=0.45, moderate quality of evidence). Other types of opioids (oxycodone, tapentadol,buprenorphine and sufentanil) showed a higher risk of AEs compared to placebo. In one study, patients received a single dose of 20 mg morphine sulfate and were followed for 24 hours after the treatment, and reported no adverse events from either morphine or placebo groups (Figure 4).
3.2 Specific AEs
Data for 6 specific AEs were available for meta-analysis (Table 2). There was a higher risk of nausea, dizziness and pruritus with oral opioids over placebo up to 3 days’ follow-up. We did not find statistically significant differences between opioids and placebo with respect to the proportion of patients experiencing vomiting, headache and drowsiness.
Table 2. Specific adverse events reported by the included RCTs (opioids versus placebo)
Event rates with placebo
Risk difference with opioid
Note: RR=risk ratio; CI=confidence interval.
In our systematic review and meta-analysis, moderate to high quality of evidence showed the efficacy of oral opioids on postoperative pain management among patients after THA or TKA at short-term follow-up. The most investigated formulas were 100 mg of tramadol given either as a single dose or twice a day before discharge, and morphine sulfate 20 mg to 30 mg per dose for not more than 3 days. The effect size of any opioid did not surpass the recommended MID of 10 points on a 0 to 100 pain scale. A higher risk of nausea, dizziness and pruritus is associated with oral opioids compared to placebo.
It is crucial to treat acute postoperative pain, in order to reduce the risk of developing chronic pain, poorer function and recovery, and increased healthcare costs (Gan, 2017; Petersen et al., 2015). In many settings, conventional opioids are considered to be a standard treatment regimen for acute postoperative pain. Oral analgesics are easy to use. No serious AEs were reported with the short-term use of oral opioids in our included studies. Specifically, tramadol showed a statistically but not clinically significant effect on acute postoperative pain control and did not increase the risk of overall AEs.
The implications of opioid use for different durations is an area that remains largely unexplored. However, it is an area that does require further research as there is evidence indicating that opioids are commonly prescribed to patients after THA and TKA up to 2 months after discharge (Shah et al., 2020). When it comes to opioids following surgery, the most critical concern that surgeons are facing at the moment is opioid dependence. There is a lack of data from RCTs regarding dependency, but this has been examined in some non-randomized studies. One study reported that 41% of opioid-naive patients requested at least one refill of opioids after THA and TKA, and 12% of patients requested more than two refills (Dwyer et al., 2018). More research evaluating the impact of opioids on dependency following joint arthroplasty is critically needed, including studies examining how different prescription protocols may influence long-term opioid use.
We did not restrict our literature search for length of follow-up and the available studies only provide data that could be meta-analyzed for up to 3 days. The number of eligible studies was also small. Reasons for post charge prescription of opioids, as well as their effectiveness and harm from use are yet to be investigated. Large, well-conducted trials are needed to address these important questions.
Evidence from the observational study shows that opioids are commonly prescribed to patients after THA and TKA for postoperative pain management up to 2 months post charge (Shah et al., 2017). There is a lack of high-level evidence of efficacy and safety of oral opioids for longer than 3 days among this group of patients. More studies with longer follow-up are needed to provide evidence for the best selection of duration and dose of opioids with an optimal balance between pain management and tolerability, while also taking into account the potential for dependence.
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