Transdermal fentanyl patch provides better pain relief and faster functional recovery after total knee arthroplasty:a meta-analysis

Background : Pain after total knee arthroplasty (TKA) was severe and should be effectively managed. This meta-analysis aimed to compare transdermal fentanyl patch (TFP) versus placebo for pain control after TKA. Methods : PubMed, Embase, Cochrane library and Chinese National Knowledge Infrastructure (CNKI) were electronically searched. Potential clinical studies that investigated the effect and safety of TFP versus control in TKA patients were searched. The primary outcomes were total morphine consumption. Stata 12.0 was used for meta-analysis. Results : Four randomized controlled trials (RCTs) involving 110 TKA patients were included in this meta-analysis. Compared with control group, TFP was associated with a reduction of total morphine consumption (WMD: -16.14; 95% CI: -25.82 to -6.46; P=0.001). Moreover, TFP could significantly reduce VAS at 2 h, 4 h, 6 h, 12 h, 24 h, 48 h and 72 h (P<0.05). There was no statistically significance between the nausea, vomiting, hypertension, sweating, respiratory depression, pruritus and urine retention (P>0.05). Conclusion : The present meta-analysis showed that use of TFP for the management of moderate or severe TKA postoperative pain had more advantages compared to placebo. Further large-scale, prospective RCTs are required to verify the effect of TFP and optimal dose of TFP in TKA patients.


Introduction
Total knee arthroplasty (TKA) was applied for treatment end-staged osteoarthritis (OA) to restoring knee function, and improving life quality (1). However, approximately 30%-50% TKA patients suffered from moderate to severe postoperative pain (2). Severe postoperative pain could affect the patients' satisfaction and rehabilitation (3). 3 Pain management has become an important factor for evaluating the quality of life and the clinical approach. Due to the emphasis on postoperative pain management in joint replacement surgery, many studies have been conducted in the past decade, which improved postoperative pain control, including patient-controlled analgesia (PCA), patientcontrolled epidural analgesia, spinal morphine, peripheral nerve block, and local intraarticular or peri-articular analgesic injection. However, there was no literature providing clear answers which method was the best, and most patients still suffer from acute or subacute pain after TKA.
Fentanyl, a low molecular weight synthetic opioid, has high potency analgesic effect which is 50 to 100 times than that of morphine (4). Due to its small molecule structure and high lipid solubility, it could be a good choice for transdermal use (5). The transdermal fentanyl patch (TFP) is a skin patch opioid that could constantly release fentanyl into the bloodstream according to the dosage used (6). Although these patches release the drug via the skin at a steady rate, the subsequent plasma level and clearance resemble the intravenous fentanyl (7). The blood concentration of fentanyl through transdermal method was equal to that of intravenous method after 8-12 h, and at least remained steady over 72 h till the patch was worn (8). If TFP was applied 12-14 h before surgery, it would powerfully and durably relieve postoperative acute and subacute pain after TKA (9).
Several randomized controlled trials (RCTs) have been performed recently to compare TFPs and other analgesic strategies in TKA. Thus, a meta-analysis and systematic review was conducted to investigate whether the TFPs provides better pain relief, faster functional recovery and better clinical outcomes.

Materials And Methods
This systematic review and meta-analysis was conducted according to the guidelines outlined in Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) 4 statement.

Literature search
A systematic retrieving of literature was performed through platforms of PubMed, Embase, Cochrane library and Chinese National Knowledge Infrastructure (CNKI) from the inception dates to January 2020, using key words including: "total knee arthroplasty", "total knee replacement", "transdermal fentanyl patch", "TFP", etc. The study searches were conducted by two independent researchers. In addition, the reference lists from identified articles were screened to detect other potential eligible studies.

Eligibility criteria
Studies were selected based on the following inclusion criteria for eligibility:

Quality assessment
We assessed the study quality of each included trial according to the Cochrane risk of bias tool for RCTs. We assessed the following items: the generation for random sequence, concealment for allocation sequence, blinding of participants, incomplete outcome data, selective outcome reporting, and other sources of bias. For each included study, each type of bias was rated as high, low, or unclear and entered into the risk of bias table. The risk of bias was examined by two reviewers concurrently, and discrepancies were resolved by consensus.

Data extraction
Two investigators independently extract form data from included RCTs, which mainly including general characteristic (author, published year, country, anesthesia, number, age and BMI of the patients), intervention, control, study and follow-up. Moreover, outcomes were also extracted. The data were checked by a third reviewer, and any disagreements were resolved through discussion. When relevant data had not been reported, we contacted the authors by email or in other ways to attempt to obtain the missing information(10).

Statistical analysis
The statistical analysis was performed by Stata 12.0 (Stata Corp., College Station, TX) and a P-value of < 0.05 was considered statistically significant. We used weighted mean difference (WMD) and the risk ratio (RR) variables with 95% confidence intervals (CIs) to assess continuous and dichotomous variables respectively. We used the value of P and I 2 to assess the statistical heterogeneity among included studies. When I 2 < 50% and P > 0.05 we applied a fixed-effect model, otherwise a random-effect model was applied.

General characteristic of the included studies
A total of 335 studies were identified from the electronic search, the manual search of the reference lists of relevant reviews did not yield new eligible studies. Of which 7 studies were excluded due to duplication. The full text was retrieved for the remaining 328 studies, 324 studies were excluded and 4 studies (5,(11)(12)(13) were selected for the final analysis after detailed evaluations. The results of the study selection process are shown in Figure 1, and the general characteristics of the included studies are presented in Table 1.

Total morphine consumption
A total of two studies compared the effect of TFP and control on total morphine consumption postoperatively. Compared with control group, administration with TFP was associated with a reduction of the total morphine consumption (WMD: -16.14; 95% CI: -25.82 to -6.46; P=0.001; Figure. Table 2.

Adverse effects
The summary results on occurrence of nausea, vomiting, hypertension, sweating, respiratory depression, pruritus and urine retention were shown in Table 2

Discussion
The most significant finding of this present study was that TFP provided an alternative to the other analgesic strategies with significantly better pain relief, morphine-sparing effects, faster functional recovery, without increasing complications after TKA. This is the first meta-analysis that assess TFP for pain control after TKA. We Some authors argued that TFP could prevent acute opioid tolerance and hyperalgesia in 8 the early postoperative period (14). Many studies have identified that TFP has a positive role in reducing pain intensity in patients undergoing abdominal hysterectomy (15), abdominal surgery (16) and osteoarthritis patients (17).
However, other scholar argued that there was no statistically significant difference in postoperative VAS pain scores between the TFP group and the control group (18). The reason may be that they administrated with TFP just within two hours before surgery, and thus the plasma concentration of TFP could not reach for effective dose. We identified total morphine consumption as the primary outcome. Compared with control group, administration TFP was associated with a reduction of morphine about 16.14 mg.
Minivlle et al (19) found that TFP application decreases pain scores and morphine consumption in the first 48 postoperative hours. Thus, TFP may be an alternative for patients-controlled analgesia. Moreover, we found that TFP has a beneficial role in reducing pain intensity until 72 h. This pain-relieving effect was enough to control pain after TKA. TKA causes severe postoperative pain during the first 24-72 h (20). This metaanalysis revealed that TFP was associated with reduced pain scores at 48 and 72 hours, this corresponded to a reduction of 17.08 and 11.62 point on an 110-point numeric rating scale.
Moreover, we compared the complications between TFP and control groups. Results found that there was no significant difference between the occurrence of nausea and vomiting.
This can be explained as the TFP could significantly decreased the morphine consumption, and thus the morphine-related complications (nausea and vomiting) were decreased. This meta-analysis had several limitations. The number of participants in most of the included studies was small, and need for more studies to further identify the pooled results. Further, many included trials also had methodological deficits, such as the description of the randomization process and/or the explanation of withdrawal and 9 dropouts. The outcomes of several studies were criticized for their inaccuracy. Further, dose and frequency of TFP administration was different, further studies should be performed to identify the optimal dose of TFP for TKA. Finally, high heterogeneity was observed in places, limiting the ability to make strong inferences.

Conclusion
The present meta-analysis showed that TFP had favorable efficacy for pain control and

Ethics approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
Not applicable.

Authors' contributions
JQW, YML, and LFL conceived and designed the study. JW and LBM participated in the acquisition of data. JQW, YML, and LFL analyzed and interpreted the data. JW and LBM drafted the article. JW and LBM critically revised the article. JW and LBM contributed to important intellectual content. All authors gave final approval of the version to be submitted.   Table 2 Results summary for the clinical outcomes and adverse effects.

Figures
14 Figure 1 Study flow diagram for inclusion. RCTs, randomized clinical trials.
15 Figure 2 Risk of bias summary of the included RCTs 16 Figure 3 Risk of bias graph of the included RCTs. Forest plot that comparing total morphine consumption between TFP and control groups.