Oxycodone versus other opioids analgesia after laparoscopic surgery: a meta-analysis

Background: Intravenous opioids are administered for management of visceral pain after laparoscopic surgery. Whether oxycodone has an advantage over other opioids in the treatment of visceral pain is not yet clear. Methods: This article evaluates the analgesic e�ciency and adverse events of oxycodone and other opioids including alfentany, sufentanyl, fentanyl and morphine for the treatment of post laparoscopic surgery visceral pain. This review was conducted according to the methodological standards described in the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. The PubMed, Embase and Cochrane libraries were searched in December 2018. Results: Ten studies were included in this review. The sample size was 815 participants. The results showed that compared with morphine and fentanyl, oxycodone had a more potent analgesic e�cacy at the �rst day after laparoscopic surgery, especially during the �rst 0.5h. There was no signi�cant difference in sedation between the two groups. Compared to morphine and fentanyl, oxycodone was more likely to increase the risk of dizziness and drowsiness. The overall patients satisfaction had no signi�cant difference between oxycodone versus other opioids. Conclusions: Oxycodone is a superior analgesic within 24h after laparoscopic surgery with careful regards to its adverse effects. Abstract Background: Intravenous opioids are administered for management of visceral pain after laparoscopic surgery. Whether oxycodone has an advantage over other opioids in the treatment of visceral pain is not yet clear. Methods: This article evaluates the analgesic e�ciency and adverse events of oxycodone and other opioids including alfentany, sufentanyl, fentanyl and morphine for the treatment of post laparoscopic surgery visceral pain. This review was conducted according to the methodological standards described in the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. The PubMed, Embase and Cochrane libraries were searched in December 2018. Results: Ten studies were included in this review. The sample size was 815 participants. The results showed that compared with morphine and fentanyl, oxycodone had a more potent analgesic e�cacy at the �rst day after laparoscopic surgery, especially during the �rst 0.5h. There was no signi�cant difference in sedation between the two groups. Compared to morphine and fentanyl, oxycodone was more likely to increase the risk of dizziness and drowsiness. The overall patients satisfaction had no signi�cant difference between oxycodone versus other opioids. Conclusions: Oxycodone is a superior analgesic within 24h after laparoscopic surgery with careful regards to its adverse effects.


Background
Visceral pain is one of the most frequent reasons for patients to seek medical attention after laparoscopic surgery [1].Opioids are the most common means for the treatment of postoperative visceral pain, whether they can be used prior to the completion of the operation or in the patient controlled analgesia (PCA) pump after surgery [2].However, it is still controversial that which kind of opioids is most appropriate.
Oxycodone is a semisynthetic drug that is derived from thebaine, an opium alkaloid, which acts as a μopioid receptor agonist exerting its effects in the central nervous system.Experiments in rodents suggest that oxycodone also has an effect at the κ-opioid receptor, which in visceral nervous system was believed to inhibit visceral pain [3].In animal experiments and clinical observations have shown that oxycodone may occasionally be superior to, e.g., morphine and fentanyl in the treatment of visceral pain [4].However, by utilizing a meta-analysis, one can detect treatment effects with greater power and estimate these effects with greater precision [5].To allow an indirect comparison with existing evidence on the e cacy of oxycodone and other opioids options used in postoperative pain management after laparoscopic surgery a meta-analysis was performed.

Design
Meta-analysis was performed in this study.

Information source
The PubMed, Excerpta Medica (EMBASE), Cocharane Library databases were searched for trials published from inception to December, 2018, with no language restrictions.Hand searches of the reference lists of the included studies or relevant reviews were also employed.The search method included relevant text and medical subject headings related to oxycodone, laparoscopic surgery and randomized controlled trails (RCTs).
The search strategy for each database were presented in Appendix 1.

Inclusion criteria
Type of study: RCTs Participants: The participants must be patients with clinical diagnosis of visceral pain after laparoscopic surgery.
Type of interventions: oxycodone versus other opioids including alfentany, sufentanyl, fentanyl and morphine.
Outcomes: Pain intensity measured by Visual Analogue Scale (VAS) or Numeric Rating Scale (NRS), Sedation status, adverse event and patient satisfaction that measured by validated scales.

Study records
All retrieved studies were imported into Endnote X7.To ensure a high level of con dence between researchers, we conducted a pilot-test on literature screening.Two researchers independently reviewed the titles and abstracts of the literatures and selected studies that met the eligibility criteria.Then, the full text of all the literatures that meet the requirements were obtained.

Data items
Using a standardized data sheet in Microsoft Excel 2013 (Microsoft Corp, Redmond, WA, www.microsoft.com),two investigators independently extracted data for study characteristics (eg, rst author's name, publication year, region where the study was conducted), characteristics of study subjects (eg, number of participants, gender distribution), interventions details (eg, treatment and comparision), outcome variables (eg, adverse event).Any discrepancies observed between the data extracted by the two extractors were resolved by consensus.

Risk of bias individual studies
The risk of bias of included RCTs was assessed according to the Cochrane Handbook version 5.1.0[6] including method of random sequence generation (selection bias), allocation concealment (selection bias), blinding (performance bias and detection bias), incomplete outcome data (detection bias), selective reporting (detection bias), and other bias.We evaluated risk of bias as low, high, or unclear.The risk of bias assessment was completed by two independent reviewers, and con icts were resolved by a third reviewer.

Meta-analysis
Meta-analysis was conducted by using Revman 5.3 software.Calculate the combined risk ratio (RR) for the 95% con dence interval (CI) for the dichotomous results.The heterogeneity of the therapeutic effects in the trials was assessed by χ2 and I2.If there was no statistical heterogeneity (the p value was ≥ 0.1 and I 2 ≤ 50%), the Mantel-Haenszel xed effect model was used for meta-analysis [6].Otherwise, we explored the potential causes of heterogeneity through subgroup analysis and meta-regression.If no clinical heterogeneity is determined, a meta-analysis was performed using the Mantel-Haenszel random effects model.

Literature selection
The derivation of the databases and published articles was described in Figure 1.There were 145 studies by searching database.Of them, 121 articles were excluded by screening the title and abstract.The remaining 24 studies concerning the oxycodone for visceral pain after laparoscopic surgery were identi ed.Among them, 14 studies were excluded due to non-randomized controlled trials (n=1), ineligible patients (n=2), ineligible comparator (n=9), and absent of eligible outcome reporting (n=2).Therefore, 10 studies [7-16] met our inclusion criteria.

Characteristics of included studies
A total of 815 participants (including 410 oxycodone subjects and 405 controls) matched the inclusion criteria and were selected for the data analysis; study design and location, characteristics of patients (diagnose, duration of surgery, duration of anesthesia, ASA (American Society of Anesthesiologists) physical status I/II), details about interventions and measured outcomes were presented in Table 1.

Results of risk of bias individual studies
Risk of bias of included studies according to the Cochrane Risk of Bias tool was provided in Figure 2. Of the included 10 studies, seven studies were rated as low risk of bias on randomization, as they used computer-generated random number sequence.Three studies [8,9,14] did not describe the method of randomization.Most studies stated that the allocation concealment was conducted, however four studies [8,9,12,14] did not report the information.Only half of the included studies stated that the participants and personnel were blinded.The other ve studies [8,9,[12][13][14] did not report the information.For blinding of outcome assessor, one study [11] stated that partial of the outcome assessor knew the group assignment during treatment, so it was rated as high risk of bias on this domain.One study [13] did not report data for some measured outcomes including nausea, vomiting, or itching, therefore was rated as high risk of selective reporting.

Pain intensity
Nine studies[7-15] measured pain intensity by VAS or NRS scale.However, only four of them [8,10,12,13] contributed data for meta-analysis.Result showed that oxycodone can signi cantly reduce the pain intensity than other opioids (fentanyl, alfentanil or morphine) in 30 minutes (2 RCTs, N = 218, MD -11.9, 95% CI -16.16 to -7.63), 4 hours (3 RCTs, N = 290, MD -4.73, 95% CI -8.9 to -0.57), and 24 hours post operation (2 RCTs, N = 208, MD -3.00, 95% CI -4.02 to -1.98), but not for 48 hours post operation (2 RCTs, N = 208, MD -0.62, 95% CI -3.00 to 1.76) (Figure 3).The data of the other ve studies are not available to do meta-analysis as their data were skewed.Kim 2015[9] also found a similar results as above.Choi 2018 [15] and Park 2015[14] concluded that oxycodone and fentanyl have equal effectiveness in relieving postoperative pain.Choi 2015[7] found that the pain intensity in oxycodone is signi cantly lower than fentanyl group in half hours post operation, but this effect did not last longer than 0.5 hours.Koch 2008 [11] stated that the intensity of deep abdominal pain was signi cantly lower in the oxycodone group at arrival, after 30, 60 and 90 min and at discharge from the PACU.

Patient satisfaction
Patient satisfaction was classi ed into four levels: very satis ed, satis ed, neutral, dissatis ed.Metaanalysis was performed to assess the number of patients with satisfaction or very satisfaction in both groups.Result from four studies [8][9][10]12] showed that there are no signi cant difference between oxycodone versus other opioids for this outcome (4 RCTs, N = 350, RR 0.88, 95% CI 0.66 to 1.17, Figure 6).

Summary of ndings
This meta-analysis identi ed 10 studies, including 815 patients, to compare the analgesic effect of oxycodone and other opioids including fentanyl, morphine, sulfentanil and alfentanil.Most of the included studies indicate the e cacy of oxycodone and support it as an superior analgesia to treat visceral pain within 24 hours after laparoscopic surgery [8-10, 12, 13].However, there was no signi cant difference in pain scores between either of the oxycodone group and other opioid groups at 48 hours after surgery.There appears to be no uniformity in the ndings of sedation level adverse events and patient's satisfaction.However, it suggests that oxycodone may induce higher risk of dizziness and drowsiness than other opioids.We also found no signi cant difference in patient satisfaction among those other opioids versus oxycodone.

Quality of the evidence
The quality of the evidence was fair.As most studies were rated as low risk of bias in randomization, allocation concealment, blinding, attrition rates and selective reporting.Only two studies (Koch, Lenz) were rated as poor quality, owing to issues of imprecision (small sample size and a sparse number of events observed) and risk of bias (unclear reporting of allocation concealment and blinding).

Analgesic e cacy
Postoperative pain after laparoscopic surgery consists of three components: incisional pain (somatic), deep abdominal pain (visceral) and in ammatory pain after carbon dioxide was absorbed by the peritoneum (can also be referred as visceral pain) [11].This is an ideal clinical model to test the effectiveness of visceral pain treatment, where the somatic pain component is minimized.
Four of the included studies found that oxycodone is more potent in the treatment of visceral pain than morphine or fentanyl during the rst 0.5h after surgery.In these studies, the intensity of analgesic drugs has peaked at this time point.Fentanyl has a rapid onset of action (5-7 min), which is much faster than oxycodone (10-15min) [17].Although morphine is considered to be a slower-acting drug, it was given to patients 10-15min before the end of surgery in Lens's study [13].Therefore, the onset time cannot be used to explain the difference in their initial pain relief.
It may have an analgesic mechanism explanation.Several recent studies have suggested that oxycodone attenuates visceral pain better than other opioids [4,18,19].Oxycodone has a proposed effect at the κopioid receptor, that is a different pharmacological pro le from other opioids.κ-opioid receptors on peripheral nerves in the gut have been suggested as an important feature for antinociception in the visceral pain system [20].The analgesic effect of oxycodone correlated to plasma concentrations indicating an effect in the periphery perhaps mediated via κ-receptors[21].This meta-analysis was also found that at 4 hours and 24 hours, the analgesic effect of oxycodone was also superior to other opioids, regardless of whether the administration method was a single dose at the end of the surgery or using a PCA pump.These contents indicated that oxycodone was more potent than other opioids in the treatment of postoperative visceral pain at the equivalent dose.However, the antalgic advantage of oxycodone did not last up to 48 hours after surgery, whether it was a single dose [8] or PCA [10].A possible explanation is that the pain intensity 48h after such minimal surgery may be too low to yield a signi cant difference in pain scores [22].

Safety evaluation
Sedation is an important indicator for evaluating the safety of a drug for postoperative analgesia [23].
Although Lenz et al found that sedation level was signi cantly less in oxycodone group compared with Morphine group [13].The meta-analysis found that the oxycodone groups had similar sedation levels compared with morphine and fentanyl and there was no incidence of excessive sedation or respiratory depression in either group.
According to previous studies, adverse effects associated with opioid use include constipation, nausea, vomiting, drowsiness, dizziness, and pruritus [24,25].The speci c incidence varies greatly depending on the dosage.A higher incidence of dizziness was reported with oxycodone compared to fentanyl and morphine in our study.The precise mechanism of opioid-induced dizziness is unknown.Vestibular sensitivity caused by opioids activating on the μ receptors in the vestibular epithelium may be involved in [17].Nevertheless, the potential causes of the different incidence in dizziness till need to be further explored.As with previous studies, the reported incidences of side effects differ widely, probably because most researches were powered to investigate analgesic e cacy and not differences in side effects.

Strength and limitations
There are several strengths of this meta-analysis, rst of all, our search strategy was developed by information specialist to avoid missing of any relevant trial.Secondly, two reviewers screened and extracted the data to reduce system error in the fabrication process.Like other studies, our meta-analysis also have some limitations: there were only a small number of clinical trials available, and that contributed a relatively small sample size for meta-analysis.Second, age may also alter the opioid pharmacokinetics and in uence the pain, and the mean age was relatively high in the present patient population (40-69).Third, publication bias may have resulted in over-estimation of some outcomes, as positive results are more likely to be published than negative ones [26].

Conclusion
Choosing the best opioid for postoperative visceral pain treatment is complicated with no recommended ''gold standard'' choice globally.The results of this meta-analysis suggest that oxycodone is a superior analgesic within 24h after laparoscopic surgery.However, in some cases, even if it is effective, its incidence of adverse reactions is higher, especially dizziness.Clinicians must choose appropriate opioids