Inadequate management of acute postoperative pain is associated with a longer hospital stay and increased health care costs.1 Despite the increasing use of minimally invasive surgery and advances in pain therapy, postoperative pain management often is challenging.1 Any approach that reduces opioid requirements and also produces earlier ambulation could be of benefit to patients and society.
In some studies, propofol-based anesthesia has been shown to be associated with reduced postoperative pain compared with that associated with volatile agent–based anesthesia,2–4 whereas other studies found no evidence of the superiority of propofol.5,6 Most previous studies were not designed to detect differences in postoperative opioid consumption or did not include pain intensity as a primary outcome.
To date, no quantitative literature analysis has been published focusing on their postoperative analgesic effects. In this systematic review, we compared postoperative pain outcomes associated with the use of propofol-based and volatile agent–based anesthesia.
This systematic review adheres with the current recommendations of the Cochrane Collaboration and is reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.7
Systematic Literature Search
Three authors (K.P., H.-Y.L., and S.-R.W.) independently searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases using the following search terms: (1) (balanced OR volatile OR inhalation* OR halothane OR desflurane OR isoflurane OR sevoflurane) AND propofol AND (analgesi* OR opioid OR pain) AND postoperative for the MEDLINE and Cochrane Central Register of Controlled Trials searches; and (2) (balanced OR volatile OR inhalation* OR “halothane”/exp OR halothane OR “desflurane”/exp OR desflurane OR “isoflurane”/exp OR isoflurane OR “sevoflurane”/exp OR sevoflurane) AND (“propofol”/exp OR propofol) AND (analgesi* OR opioid OR “pain”/exp OR pain) AND postoperative AND [humans]/lim for the EMBASE search.
The last search was performed in March 2015. No language or publication date restriction was used. Additional studies were retrieved by review of the reference lists from relevant articles. The search results were collated and deduplicated in Endnote X7 (Thomson Reuters, NY).
Selection of Included Studies
Three authors (K.P., H.-Y.L., and S.-R.W.) independently screened the abstracts of articles shortlisted by the initial search. The same authors reviewed the full texts to identify studies that met the inclusion criteria. Any disagreement over study selection was resolved with a consensus with the other authors (H.L., Z.-C.Z., and F.-H.J).
The inclusion and exclusion criteria were determined before the systematic search. Inclusion criteria were (1) design: randomized controlled trials (RCTs); (2) population: adult patients undergoing surgery under general anesthesia; (3) intervention: comparison of propofol-based intravenous anesthesia with inhalational anesthesia; and (4) outcomes: postoperative pain intensity, opioid consumption, need for rescue analgesics, and time to first analgesia. Exclusion criteria were (1) procedures performed under sedation only; (2) use of different analgesic regimens (ie, remifentanil in one group and fentanyl in the other, or nitrous oxide in one group but not in the other group); (3) the use of neuraxial or nerve block; (4) pediatric patients; (5) trials that did not report on specific outcomes; and (6) lack of access to full text.
Three authors (K.P., H.-Y.L., and S.-R.W.) independently extracted the following data from eligible studies: author details, publication year, number of patients, surgical procedure, premedication, anesthesia induction and maintenance, and intraoperative and postoperative analgesic regimens. Corresponding authors were contacted for missing data when necessary. Any disagreement over data extraction was resolved by discussion and consensus with the other authors (H.L., Z.-C.Z., and F.-H.J.).
Primary and Secondary Outcome Parameters
We designated postoperative pain score as the primary outcome, because it is the most direct data point representing pain intensity. Other data points representing supporting evidence associated with pain were designated as secondary outcomes.
The primary outcome was postoperative pain intensity rated on a numeric rating scale (0–10) at rest; and on movement at 8 time points (postoperative 30 minutes, 1, 2, 4, 6, 8, 12, and 24 hours). Pain intensity scores reported on a visual analog scale (0–10) or numerical analog scale (0–10) were rated as equivalent to a 0 to 10 numeric rating scale.
Secondary outcomes were (1) morphine-equivalent consumption during 0 to 2 hours (or in the postanesthesia care unit [PACU]), 0 to 4 hours, and 0 to 24 hours after surgery; (2) number of patients requiring analgesics during 0 to 2 hours (or in the PACU), 0 to 8 hours, and 0 to 24 hours after surgery; and (3) time to first postoperative analgesic administration.
Postoperative opioid consumption was transformed to morphine-equivalent consumption with the use of previously published equianalgesic conversion factors (morphine 10 mg = piritramide 10 mg = tramadol 100 mg = meperidine 100 mg = fentanyl 0.1 mg, intravenously).8–10
Risk of Bias Assessment
Three authors (K.P., H.-Y.L., and S.-R.W.) independently assessed the risk of bias in each identified study using the Cochrane Collaboration’s tool.11 This tool considered 6 different domains: (1) random sequence generation (selection bias); (2) allocation concealment (selection bias); (3) blinding of participants and personnel (performance bias); (4) blinding of outcome assessment (detection bias); (5) incomplete data on outcomes (attrition bias); and (6) selective reporting (reporting bias). The estimated overall risk of bias for each trial was categorized as “low,” “unclear,” or “high.” Any disagreement over assessment of bias was resolved by discussion and consensus with the other authors (H.L., Z.-C.Z., and F.-H.J.).
Statistical analyses were performed with Review Manager 5.3 (The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark). Standard deviation not stated or graphically represented was estimated as range/4 or interquartile range/1.35 (range = maximum value − minimum value and interquartile range = Q3 − Q1, with Q1 and Q3 representing the first and third quartiles, respectively).12 When standard error or confidence interval (CI) was reported, standard deviation was calculated with the calculator tool in the Review Manager. To increase the robustness of results, data were pooled only if at least 3 trials were included for an outcome.
Considering that the Z statistic in RevMan 5.3 does not perform optimally in highly heterogeneous samples among groups and procedures, or many combinations of groups and procedures with small sample sizes,13 we set the threshold for statistical significance at a conservative level of P value <.01. Continuous outcomes were reported as weighted mean differences (MDs) and 99% CI, whereas categorical outcomes were reported as risk ratios with 99% CI. To assess whether the studies in this meta-analysis were affected by publication bias, a funnel plot using one of the main outcomes as an end point, was constructed.
Heterogeneity was assessed with the I2 test. For outcome data with low heterogeneity (I2 ≤ 30%), a fixed-effect model was used; for outcome data with evidence of significant heterogeneity (I2 > 30%), a random-effects model was selected.11,14 Subgroup analyses were performed according to the use of remifentanil for intraoperative analgesia, and the use of patient-controlled analgesia (PCA) or opioids combined with nonsteroidal anti-inflammatory drugs (NSAIDs) for postoperative analgesia, when there were >8 trials included for an outcome.
As mentioned previously, 3 authors (K.P., H.-Y.L., and S.-R.W.) independently screened the abstracts, reviewed the full texts, and extracted the relevant data. As a result, they reached agreement for all the steps, without the need for additional discussion with the other authors (H.L., Z.-C.Z., and F.-H.J).
Characteristics of Included Trials
A total of 4375 potentially eligible publications were retrieved on online literature search, of which 322 studies were screened out after review of abstracts. Of these, only 39 articles, with a combined subject population of 4520 adult patients undergoing both minor and major surgery in different specialties (gynecology, ear-nose-throat surgery, urology, orthopedics, neurosurgery, and gastrointestinal surgery),2–6,15–48 were included eventually in this meta-analysis (Figure 1). The characteristics of the included studies are shown in Table 1. All studies were RCTs that compared propofol with inhalational anesthesia for at least one of the pain outcomes mentioned in the inclusion criteria. In 19 RCTs, remifentanil was used as intraoperative analgesic,3,6,17,18,21–24,29,30,32,34,37,41,43,44,46–48 whereas fentanyl, alfentanil, or morphine was used in 20 RCTs.2,4,5,15,16,19,20,25–28,31,33,35,36,38–40,42,45 Isoflurane was used in 11 trials,2,16,20,26,28,30,35,36,39,40,45 sevoflurane in 21 trials,3–6,18,19,24,25,27,29,31,32,34,37,38,40–44,46 and desflurane in 12 trials.5,15,17,20–23,33,36,40,47,48 PCA with opioids for postoperative analgesia was used in 7 trials2,5,6,23,43,46,47 and opioids combined with NSAIDs for postoperative analgesia in 19 trials.3–6,15,16,18,25,26,29,32,34,36–41,48
Postoperative Pain Intensity
Twenty-five trials investigated postoperative pain scores (N = 2609).2–6,15,16,20,21,23–25,29,31,34–38,40–43,46,47 The main outcomes of pain intensity at rest at the 8 time points and on movement at 3 time points after surgery are shown in Table 2. Lower pain scores at rest were reported by patients anesthetized with propofol, compared with those receiving volatile agents, at postoperative 30 minutes (Figure 2), 1 hour (Figure 3), and 12 hours (Figure 4). The MD in pain scores decreased from −0.48 (99% CI, −1.07 to 0.12; P = 0.04, I2 = 89%) at postoperative 30 minutes to −0.08 (99% CI, −0.30 to 0.14; P = 0.33, I2 = 43%) at postoperative 24 hours. Most of the pooled analyses, however, were affected by heterogeneity, and all the differences failed to show statistical significance given the P value cutoff <0.01.
In Figure 2, subgroup analysis was performed. Intraoperative administration of remifentanil was associated with a greater MD in pain scores and significantly reduced postoperative pain intensity at rest at 30 minutes (MD = −0.89; 99% CI, −1.63 to −0.16; P = 0.002), compared with fentanyl- or alfentanil-based intraoperative analgesia (MD, −0.17; 99% CI, −1.00 to 0.66; P = 0.60). Postoperative pain intensity was lower when PCA with opioids was used for postoperative analgesia (MD in pain scores, −0.72; 99% CI, −1.52 to 0.07; P = 0.02) than that achieved with opioids on demand. Compared with postoperative analgesia regimen of opioids only, opioids combined with NSAIDs resulted in a reduced postoperative pain intensity (MD in pain scores, −0.59; 99% CI, −1.34 to 0.15; P = 0.04). Subgroup analysis was also performed (Figure 3). To summarize in brief, all the subgroups reached the same point as those shown in Figure 2, except for opioids alone versus opioids combined with NSAIDs for postoperative analgesia.
Fourteen trials reported on postoperative opioid consumption (N = 1174; Table 3).2,4–6,22–24,28,33,35,40,43,44,48 Compared with patients anesthetized with volatile agents, morphine-equivalent consumption during 0 to 24 hours after surgery was lower in patients receiving propofol (MD in morphine-equivalent consumption, −2.68 mg; 99% CI, −6.17 to 0.82; P = 0.05, I2 = 62%; Figure 5). Morphine-equivalent consumption during 0 to 2 hours (or in PACU) and 0 to 4 hours after surgery was lower in patients treated with propofol, but the difference was also not statistically significant.
Twenty-six trials reported on the number of patients requiring rescue analgesics after surgery (N = 3236).3,4,15–21,23,25–30,32,34,36,37,39,41,42,44,45,47 Fewer patients required rescue analgesics during 0 to 24 hours postoperatively when receiving propofol (risk ratio = 0.87; 99% CI, 0.74 to 1.03; P = 0.04, I2 = 0%; Figure 6).
Three studies reported on the time to first analgesic administration postoperatively (N = 787).23,27,30 Patients anesthetized with propofol required postoperative analgesia later than those who were anesthetized with volatile agents (MD in time to first analgesic administration, 6.12 minutes; 99% CI, 0.02 to 12.21; P = 0.01; Figure 7).
Risk of Bias in Included Studies
Risk assessment is summarized in Table 4. All included trials were randomized; 30 trials clearly documented the randomization method, and 35 detailed the methods of blinding. A funnel plot showed a fairly symmetrical shape when pain intensity at rest and at 30 minutes as an end point were used, indicating that there was no substantial publication bias (Figure 8).
This meta-analysis included 39 RCTs that compared postoperative pain outcomes after propofol-based anesthesia with that after inhalational anesthesia. Use of propofol was associated with lower postoperative pain scores at rest and opioid consumption. In addition, fewer patients required rescue analgesics in the propofol group, as evidenced by the longer time to first analgesic administration. None of the differences remain significant, however, when a conservative P value of <.01 was applied.
Effects of Propofol or Volatile Agents on Acute Postoperative Pain
In this meta-analysis, we found lower pain scores and reduced pain intensity at rest (from 0.48 U at 30 minutes to 0.08 U at 24 hours postoperatively) associated with propofol anesthesia compared with inhalational anesthesia. Further, the use of propofol was associated with a lower morphine-equivalent consumption in the first 24 hours after surgery (MD, 2.68 mg), which indicates an opioid-sparing effect. Slightly superior postoperative pain relief with propofol anesthesia is indicated by reduced pain intensity and opioid consumption, a reduction in the use of rescue analgesia, and a longer time to first analgesia after surgery. This meta-analysis demonstrates for the first time the possible superiority of propofol anesthesia over inhalational anesthesia with respect to the analgesic effect, particularly in the early postoperative period. Although most of our results do indicate a benefit of propofol in this regard, it is noteworthy that all the differences are small and statistically nonsignificant if a P value cutoff of <.01 is used. Therefore, these differences may arguably not be clinically significant either.
Several possible mechanisms may help explain the effects of propofol and volatile agents on acute postoperative pain. Volatile agents are known to suppress the propagation of sensory afferent stimuli to the nervous system at anesthetic concentrations.49,50 It is worth noting that inhaled anesthetics tend to cause hyperalgesia at 0.1 minimum alveolar concentrations, which may be responsible for increased pain perception during recovery from anesthesia.51 The increased sensitivity to pain is mediated by modulation of central adrenergic and cholinergic transmission, as well as by 5-HT3 receptor–mediated currents.52,53 In contrast, propofol exhibits short-lasting analgesic properties with a trend toward reduced hyperalgesia and allodynia in healthy volunteers.54 In animal models, propofol suppresses nociception induced by spinal sensitization and decreases the lumbar dorsal horn neuronal responses to noxious stimuli.55,56 In addition, antioxidant and neuroprotective effects of propofol also have been documented.57,58
Use of opioids is the cornerstone of analgesic therapy for moderate-to-severe pain. Acute and chronic exposure to opioids, however, is associated with the development of hyperalgesia because of involvement of N-methyl-d-aspartate (NMDA) receptor in pain facilitating systems.59 Remifentanil, an ultra short–acting opioid, causes opioid-induced hyperalgesia through a cellular mechanism that involves rapid and prolonged up-regulation of NMDA receptor function.60,61 Moreover, propofol directly activates γ-aminobutyric acid type A receptors, inhibits NMDA receptors, and modulates calcium influx through the slow calcium–ion channels.62 Finally, maintenance of general anesthesia with propofol has been shown to prevent remifentanil-induced hyperalgesia.43,63
The subgroup analyses revealed better postoperative analgesia with propofol in patients who received concomitant intraoperative remifentanil. These findings suggest a synergistic effect between propofol and remifentanil leading to a more potent NMDA antagonistic effect on opioid-associated hyperalgesia than that observed with volatile agents.
There are several limitations of our study. First, when applying a conservative P value of <.01, the main differences between propofol and inhalational anesthesia are small and not statistically significant. The clinical relevance of these results needs to be further investigated. Second, there is difficulty in attributing the analgesic properties of propofol or hyperalgesic effects of sevoflurane, although there is evidence to support both. Complex interaction exists between general anesthetics and opioids in the pain facilitating systems. Third, the opioids used for postoperative pain relief varied between the studies, and the calculation of morphine-equivalents may have introduced a bias. Fourth, a multimodal analgesic approach with local anesthetics, NSAIDS, and opioids could mask any marginal difference that might exist between propofol and volatile agents. Fifth, despite subgroup analyses according to different techniques or analgesia regimens, this meta-analysis was affected by heterogeneity because of varied surgical procedures, different volatile anesthetics studied, various perioperative analgesic regimens used, and different indices used for titration of anesthesia depth; therefore, the results should be interpreted with caution. Finally, our study did not evaluate the effects of propofol or volatile agents on the long-term outcomes such as chronic pain. Further studies with adequate power to investigate long-term and short-term pain outcomes after propofol or inhalational anesthesia are required.
This meta-analysis did not demonstrate significant differences in postoperative pain control between propofol anesthesia and inhalational anesthesia because of substantial heterogeneity among studies. Large RCTs may be needed to verify whether the choice of anesthetics may contribute to a multimodal pain management and improved patient outcomes.
Name: Ke Peng, MS.
Contribution: This author helped conduct the study, analyze the data, and write the manuscript.
Name: Hua-Yue Liu, MS.
Contribution: This author helped conduct the study and analyze the data.
Name: Shao-Ru Wu, MS.
Contribution: This author helped conduct the study and analyze the data.
Name: Hong Liu, MD.
Contribution: This author helped conduct the study and write the manuscript.
Name: Zhao-Cai Zhang, MD.
Contribution: This author helped conduct the study and write the manuscript.
Name: Fu-Hai Ji, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
This manuscript was handled by: Ken B. Johnson, MD.
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