Opioid-free anesthesia and opioid-based anesthesia in oral and maxillofacial surgery: a systematic review and meta-analysis of randomized controlled trials

Introduction

Background

Oral and maxillofacial surgery (OMS) spans a wide scope of surgical treatments for the mouth, face, head, and neck region. The extensive scope of procedures in turn necessitates diverse and nuanced anesthesia approaches.

A multitude of anesthetic options, including benzodiazepines, propofol, ketamine, dexmedetomidine, and opioids agonists, enable OMS to conducted in an office-based environment (1). Commonly used opioid anesthetic options include morphine, hydromorphone, and fentanyl (2). Opioids are often used in combination with other hypnotic or sedative agents to achieve a balanced anesthetic strategy. These strategies are named opioid-based anesthesia (OBA).

Rationale and knowledge gap

Due to increasing awareness regarding the risks of using opioids, such as the development of hyperalgesia, as well as addiction and misuse, discussion regarding opioid-free anesthesia (OFA) strategies have increased in recent years (3-5). However, it remains unclear whether OFA can serve as a safe and effective anesthetic option to replace OBA (2,3,6).

Objective

In this study, we aimed to compare the safety and efficacy of OFA versus OBA for oral and maxillofacial surgical procedures, with specific outcomes including postoperative pain, duration of anesthesia, and incidence of pos-operative nausea. We present this article in accordance with the PRISMA reporting checklist (available at https://joma.amegroups.org/article/view/10.21037/joma-22-20/rc).

Methods

Literature searches

Bibliographic databases including PubMed, Embase, Cochrane Library, and Web of Science were searched comprehensively from the inception of each database to January 25, 2022 to identify all relevant articles. Moreover, abstracts and presentations of all major conference proceedings were also reviewed. The results were combined using the Boolean operator “OR” with the search terms with Mesh and text words including Tramadol, Tapentadol, Sufentanil, Remifentanil, Promedol, Pirinitramide, Phenoperidine, Phenazocine, Pentazocine, Oxymorphone, Oxycodone, Opium, Opiate Alkaloids, Nalbuphine, Morphine, Methadyl Acetate, Methadone, Meptazinol, Meperidine, Levorphanol, Hydromorphone, Hydrocodone, Heroin, Fentanyl, Etorphine, Ethylmorphine, Ethylketocyclazocine, Enkephalin, Enkephalin, Diphenoxylate, Dihydromorphine, Dextropropoxyphene, Dextromoramide, Codeine, Butorphanol, Buprenorphine, Alphaprodine, Alfentanil, Anesthesia, AND Oral Surgery, Maxillofacial Surgery, Exodontics. All words available for Medical Subject Headings (MeSH) were searched by MeSH. Reference lists were also reviewed in a snowball sampling technique to identify additional studies. Two investigators (Y Qi and H Dong) independently screened the titles and abstracts of identified articles. Major conflicts were resolved by another researcher (X Kong). The full texts of identified studies were further reviewed by two independent reviewers (Jingping Wang and Jing Wang). The search was again extended by review of references of articles included in the final selection. Additionally, this review prepared no protocol and it was not registered.

Selection criteria and data extraction

Eligibility criteria were as follows: (I) studies reporting data regarding efficacy and safety between OBA and OFA applied among patients undergoing OMS; (II) randomized controlled trials (RCTs); (III) the intervention under study was OBA procedure compared with OFA procedure; (IV) studies limited to humans; (V) reports available in English. Exclusion criteria were as follows: (I) non-RCTs studies, letters, reviews, guidelines, conference proceedings, commentaries and publications in which the relevant data could not be ascertained; (II) studies done in other than the OMS; (III) study designed lack of OFA or OBA group; (IV) opioid agents applied post-operations; (V) studies with no efficacy or safety information; (VI) duplicate studies from the same population or database. Two investigators (Y Qi and H Dong) independently reviewed the list of retrieved articles to choose potentially relevant articles; disagreements were discussed and resolved by consensus with another investigator (X Kong). Both reviewers also independently extracted data from all studies; discrepancies were resolved by consensus with another investigator (X Kong). The following information was extracted from each publication: country, study design, data type, surgery type, participants randomly allocated, follow-up time, participants followed up (%), intervention design, comparator design, mean age (range) (years), female (%), duration of operation (min), pain measurement at 1 h post-operation, duration of anesthesia (min), area under the curve of pain assessment, nausea event.

Data synthesis and analysis

Y Qi and H Dong independently viewed titles, abstracts and full texts according to the selection criteria, and then extracted relevant data (as listed above) using a standardized data sheet. Statistical heterogeneity among studies was evaluated using Cochran’s Q test and the I² statistic; I² (% residual variation due to heterogeneity) values of 25%, 50%, and 75% were considered to represent low, moderate, and high heterogeneity, respectively (7). Forest plots were created to illustrate heterogeneity for outcomes of safety and efficacy. Incidence and relative risk (RR) were calculated. Heterogeneity between studies was assessed by Q test and I² statistics. If the I² value was less than 50%, the meta-analysis was performed using the fixed effects model. Otherwise, the random-effects model was selected. An alpha of P<0.05 was considered statistically significant. Analyses were performed using R software version 4.1.2.

Qualitative assessment and risk of publication bias assessment

The risk of bias for the studies included was also assessed by two independent investigators according to the Cochrane Risk of Bias Tool version 2.0 (https://training.cochrane.org/handbook/current/chapter-08#section-8-2). This tool measured the key aspects of the methodology in selected studies with regard to design quality and risk of bias estimates based on three design criteria: (A) bias arising from the randomization process; (B) bias due to deviations from intended interventions; (C) bias due to missing outcome data; (D) bias in measurement of the outcome; (E) bias in selection of the reported results; (F) overall bias. Issues with “L” valuation represented low risk of bias; with “S” valuation represented some concerns; with “S” valuation represented high risk of bias. Any scoring differences were resolved by group discussion. Egger’s test and Begg’s funnel plots to examine publication bias were unable to be performed because only four studies were included in the analyses (8).

Results

Literature search

Figure 1 shows the study selection flowchart. After screening and eligibility assessment, we included a total of four studies which reported the data regarding efficacy and safety between OBA and OFA applied among patients undergoing OMS (9-12). Near-misses studies were excluded because these randomized studies were designed differently from included studies (13-17). The PICOS were: population: patients who required anesthesia for OMS; intervention: OBA; comparison: OFA; outcome: duration of anesthesia, duration of operation time, AUC of pain assessment, postoperative pain assessment at the first 1 and 2 h; study design: RCTs. The included studies totally contained information regarding 161 patients. Summary of basic characteristics and information of included studies were shown in Table 1.

Figure 1 Study eligibility flowchart.

Efficacy analysis

There was no statistically difference of duration of operation time between OBA group and OFA group [standard mean difference (SMD) −0.21, 95% CI: −0.54 to 0.12, P=0.73, I²=0%]. The duration of anesthesia time of OBA group was statistically shorter than OFA group (SMD 0.73, 95% CI: 0.29–1.16, P<0.01) (Figure 2). There was no statistically difference of AUC of postoperative pain assessment between OBA group and OFA group (SMD −1.00, 95% CI: −1.52 to −0.49, P=0.81). Patients in OBA group had slighter postoperative pain at both 1 and 2 h than OFA group (1 h: SMD −1.13, 95% CI: −1.71 to −0.55, P<0.01; 2 h: SMD −1.17, 95% CI: −1.73 to −0.61, P<0.01) (Figure 3).

Figure 2 Duration of operation and anesthesia time between OBA and OFA groups. (A) Duration of operation time: there was no statistically difference of duration of operation time between OBA group and OFA group (SMD −0.21, 95% CI: −0.54 to 0.12, P=0.73). (B) Duration of anesthesia time: the duration of anesthesia time of OBA group was statistically shorter than OFA group (SMD 0.73, 95% CI: 0.29–1.16, P<0.01). SD, standard deviation; SMD, standard mean difference; CI, confidence interval; OBA, opioid-based anesthesia; OFA, opioid-free anesthesia.

Figure 3 Anesthesia efficacy between OBA group and OFA group. (A) Area under the curve of postoperative pain assessment. There was no statistically difference between OBA group and OFA group (SMD −1.00, 95% CI: −1.52 to −0.49, P=0.81). (B) Postoperative pain assessment at 1 h. OBA group had slighter postoperative pain at 1 h than OFA group (SMD −1.13, 95% CI: −1.71 to −0.55, P<0.01). (C) Postoperative pain assessment at 2 h. OBA group had slighter postoperative pain at 2 h than OFA group (SMD −1.17, 95% CI: −1.73 to −0.61, P<0.01). SD, standard deviation; SMD, standard mean difference; CI, confidence interval; OBA, opioid-based anesthesia; OFA, opioid-free anesthesia.

Safety analysis

There totally 161 patients from four studies enrolled in safety analysis: 81 patients from intervention group and 80 patients from comparator group, respectively. There was no statistically difference between OBA and OFA group concerning about nausea event incidence (RR 0.36, 95% CI: 0.11–1.17, P=0.64) (Figure 4).

Figure 4 Nausea event incidence between OBA and OFA group. There was no statistically difference between OBA and OFA group concerning about nausea event incidence (RR 0.36, 95% CI: 0.11–1.17, P=0.64). RR, relative risk; CI, confidence interval; OBA, opioid-based anesthesia; OFA, opioid-free anesthesia.

Heterogeneity, meta-regression, and qualitative assessment

Forest plots of safety analysis showed low heterogeneity, while efficacy analysis forest plots revealed high heterogeneity. However, since only four studies were included in some analysis, the meta-regressions of those analysis were difficult to perform. The risk of bias tool was used to conduct a qualitative assessment of the selected studies to review their quality and detect possible bias. As shown in Table S1, all of the four RCTs studies exhibited a low risk of bias.

Discussion

Key findings and explanation

We conducted this meta-analysis to evaluate the efficacy and safety of OBA versus OFA strategies during OMS procedures. Four studies with 161 subjects were included, and the overall risk of bias valuation was low. Subjects were randomized into two groups: one with OFA strategies such as lidocaine, mepivacaine, articaine and propofol, and the other group with OBA strategies such as the addition of tramadol or morphine. Our analysis demonstrated that the duration of anesthesia time of the OBA group was statistically shorter than OFA group, while the duration of operation showed no statistical difference.

While OBA had superior pain control 1 and 2 h post-operatively, there was no difference in total pain assessment between OBA and OFA. The difference in short-term pain control may be due to the fact that some opioids used may have rapid onset to peak effects within minutes. Nevertheless, these results suggest that OFA strategy is a promising analgesic alternative to OBA.

Strengths and limitations

This meta-analysis has several limitations. Firstly, there were only four RCT studies included in this meta-analysis with only 161 patients, in which there were discrepancies in population age, operation types, anesthesia agents, follow-up time, assessment tools and valuation items, further leading to substantial variation in several of the outcomes. Secondly, the evaluation of the data and sample was considered to be too small for statistical and/or visual examination of publication bias, subsequently the probable existence of such bias could not be well-determined. Therefore, the results were generalizable only to population eligible for included clinical trials.

Comparison with similar research

Perioperative high-dose use of opioids may cause continuously postoperative use and increase the risk of dependence, addiction and overdose. With these concerns increasing, OFA was introduced by some clinicians to avoid hyperalgesia and tolerance (3-5). In 2019, a systematic review conducted by Frauenknecht et al. investigated 1,304 patients from 23 randomized trials, which demonstrated that pain scores were not statistically different between OFA and OBA groups, but the OFA group had lower incidence of vomiting and nausea (RR 0.78, 95% CI: 0.61–0.97) (18). In 2020, King et al. studied 48 women receiving mastectomy, and reported that the pain scores were not significantly different between OFA and OBA groups, while OFA had decreased rate of postoperative nausea and vomiting events (P=0.02), which was consistent to previous studies (19).

However, scholars such as Lirk et al. (6) held the view that it might be too early to adopt OFA today. Concerns about tolerance and hyperalgesia are the leading cause of the acknowledged fact that opioids serve as sub-optimal analgesics, and the management of opioids is becoming time-dependently difficult. Poor-controlled pain, high-doses and long-periods postoperative use were reported as associated factors of persistent opioid use (20). Therefore, multimodal management that under the premise of adequate pain control, opioids administration with minimum doses for a short term is feasible and effective to help minify long-term opioid use, which subsequently improve the tolerance (21-24). The opioid-related hyperalgesia is most induced by remifentanil, which is dose-dependent and especially appears in procedures with strong pain or long period (25). This can be attenuated by low-dose ketamine, especially in acute post-operation occasion (26). Additionally, Chia et al. proposed the limitations and challenges of OFA (5). The challenge lies in the efficacy of pain control, the unexpected adverse events or drugs interactions arising from multimodal analgesics and insufficient management of cancer pain (27-29), and further persuasive studies should be conducted to discovery and ascertain the long-term negative effects resulted from intraoperative opioids (2).

Implications and actions needed

While the results of this study are promising for the safety and efficacy of OFA, there is a current dearth of evidence comparing OBA and OFA. These results are in concordant with the current expert consensus that additional data are needed to formulate recommendations regarding whether OFA can be a suitable alternative for OBA (3,21,30,31). In the meantime, it remains critical that providers using opioid-based strategies remain vigilant and only use the minimal required dosage and duration.

Conclusions

While there are relatively few studies comparing the use of OBA and OFA in OMS, the data suggest that OFA and OBA may have similar outcomes in terms of safety and efficacy. Nevertheless, OBA has superior early-stage pain control and no increase in nausea. Further studies are needed to evaluate the potential of using OFA for OMS procedures.

Acknowledgments

We would like to thank our colleagues at Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA, and the Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical and Peking Union Medical College.

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Oral and Maxillofacial Anesthesia, for the series “Opioid-Free Anesthesia and Opioid-Sparing Anesthesia in OMF Surgery”. The article has undergone external peer review.

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://joma.amegroups.org/article/view/10.21037/joma-22-20/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://joma.amegroups.org/article/view/10.21037/joma-22-20/coif). The series “Opioid-Free Anesthesia and Opioid-Sparing Anesthesia in OMF Surgery” was commissioned by the editorial office without any funding or sponsorship. Jingping W serves as the unpaid editorial board member of Journal of Oral and Maxillofacial Anesthesia from August 2021 to July 2023 and served as unpaid Guest Editor of the series. All authors declare the support by the Natural Science Foundation of China (Nos. 81872160, 82072940, 82103047, and 82102887). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Kramer KJ, Brady JW. Anesthetic Agents Commonly Used by Oral and Maxillofacial Surgeons. Oral Maxillofac Surg Clin North Am 2018;30:155-64. [Crossref] [PubMed]
2. Shanthanna H, Ladha KS, Kehlet H, et al. Perioperative Opioid Administration. Anesthesiology 2021;134:645-59. [Crossref] [PubMed]
3. Wu CL, King AB, Geiger TM, et al. American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on Perioperative Opioid Minimization in Opioid-Naïve Patients. Anesth Analg 2019;129:567-77. [Crossref] [PubMed]
4. Mulier JP. Is opioid-free general anesthesia for breast and gynecological surgery a viable option? Curr Opin Anaesthesiol 2019;32:257-62. [Crossref] [PubMed]
5. Chia PA, Cannesson M, Bui CCM. Opioid free anesthesia: feasible? Curr Opin Anaesthesiol 2020;33:512-7. [Crossref] [PubMed]
6. Lirk P, Rathmell JP. Opioid-free anaesthesia: Con: it is too early to adopt opioid-free anaesthesia today. Eur J Anaesthesiol 2019;36:250-4. [Crossref] [PubMed]
7. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539-58. [Crossref] [PubMed]
8. Lin L, Chu H. Quantifying publication bias in meta-analysis. Biometrics 2018;74:785-94. [Crossref] [PubMed]
9. Kolacz M, Karlinski M, Walerzak K, et al. Preoperative Local Administration of Morphine as an Add-on Therapy in Patients Undergoing Surgical Removal of an Odontogenic Maxillary Cyst. A Randomized, Double-Blind Pilot Study. J Oral Facial Pain Headache 2015;29:378-83. [Crossref] [PubMed]
10. Isiordia-Espinoza MA, Orozco-Solis M, Tobías-Azúa FJ, et al. Submucous tramadol increases the anesthetic efficacy of mepivacaine with epinephrine in inferior alveolar nerve block. Br J Oral Maxillofac Surg 2012;50:157-60. [Crossref] [PubMed]
11. Pozos AJ, Martinez R, Aguirre P, et al. The effects of tramadol added to articaine on anesthesia duration. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;102:614-7. [Crossref] [PubMed]
12. Shipton EA, Roelofse JA, Blignaut RJ. An evaluation of analgesic efficacy and clinical acceptability of intravenous tramadol as an adjunct to propofol sedation for third molar surgery. Anesth Prog 2003;50:121-8.
13. Ege B, Ege M, Koparal M, et al. Comparison of the Anesthetic Efficiency of Lidocaine and Tramadol Hydrochloride in Orthodontic Extractions: A Split-Mouth, Prospective, Randomized, Double-Blind Study. J Oral Maxillofac Surg 2020;78:52-62. [Crossref] [PubMed]
14. Eshghpour M, Samieirad S, Attar AS, et al. Propofol Versus Remifentanil: Which One Is More Effective in Reducing Blood Loss During Orthognathic Surgery? A Randomized Clinical Trial. J Oral Maxillofac Surg 2018;76:1882.e1-7. [Crossref] [PubMed]
15. Ege B, Calisir M, Al-Haideri Y, et al. Comparison of Local Anesthetic Efficiency of Tramadol Hydrochloride and Lidocaine Hydrochloride. J Oral Maxillofac Surg 2018;76:744-51. [Crossref] [PubMed]
16. Wakasugi Y, Matsuura N, Ichinohe T. Intraoperative Blood Loss During Orthognathic Surgery: A Comparison of Remifentanil-Based Anesthesia With Sevoflurane or Isoflurane. J Oral Maxillofac Surg 2015;73:2294-9. [Crossref] [PubMed]
17. Ceccheti MM, Negrato GV, Peres MP, et al. Analgesic and adjuvant anesthetic effect of submucosal tramadol after mandibular third molar surgery. Oral Surg Oral Med Oral Pathol Oral Radiol 2014;117:e249-54. [Crossref] [PubMed]
18. Frauenknecht J, Kirkham KR, Jacot-Guillarmod A, et al. Analgesic impact of intra-operative opioids vs. opioid-free anaesthesia: a systematic review and meta-analysis. Anaesthesia 2019;74:651-62. [Crossref] [PubMed]
19. King CA, Perez-Alvarez IM, Bartholomew AJ, et al. Opioid-free anesthesia for patients undergoing mastectomy: A matched comparison. Breast J 2020;26:1742-7. [Crossref] [PubMed]
20. Sun EC, Darnall BD, Baker LC, et al. Incidence of and Risk Factors for Chronic Opioid Use Among Opioid-Naive Patients in the Postoperative Period. JAMA Intern Med 2016;176:1286-93. [Crossref] [PubMed]
21. Egan TD. Are opioids indispensable for general anaesthesia? Br J Anaesth 2019;122:e127-35. [Crossref] [PubMed]
22. Mauermann E, Ruppen W, Bandschapp O. Different protocols used today to achieve total opioid-free general anesthesia without locoregional blocks. Best Pract Res Clin Anaesthesiol 2017;31:533-45. [Crossref] [PubMed]
23. Soffin EM, Lee BH, Kumar KK, et al. The prescription opioid crisis: role of the anaesthesiologist in reducing opioid use and misuse. Br J Anaesth 2019;122:e198-208. [Crossref] [PubMed]
24. Veyckemans F. Opioid-free anaesthesia: Still a debate? Eur J Anaesthesiol 2019;36:245-6. [Crossref] [PubMed]
25. Angst MS. Intraoperative Use of Remifentanil for TIVA: Postoperative Pain, Acute Tolerance, and Opioid-Induced Hyperalgesia. J Cardiothorac Vasc Anesth 2015;29:S16-22. [Crossref] [PubMed]
26. Joly V, Richebe P, Guignard B, et al. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology 2005;103:147-55. [Crossref] [PubMed]
27. Cata JP, Corrales G, Speer B, et al. Postoperative acute pain challenges in patients with cancer. Best Pract Res Clin Anaesthesiol 2019;33:361-71. [Crossref] [PubMed]
28. Nassif GJ, Miller TE. Evolving the management of acute perioperative pain towards opioid free protocols: a narrative review. Curr Med Res Opin 2019;35:2129-36. [Crossref] [PubMed]
29. Wigmore T, Farquhar-Smith P. Opioids and cancer: friend or foe? Curr Opin Support Palliat Care 2016;10:109-18. [Crossref] [PubMed]
30. Kent ML, Hurley RW, Oderda GM, et al. American Society for Enhanced Recovery and Perioperative Quality Initiative-4 Joint Consensus Statement on Persistent Postoperative Opioid Use: Definition, Incidence, Risk Factors, and Health Care System Initiatives. Anesth Analg 2019;129:543-52. [Crossref] [PubMed]
31. Elkassabany NM, Mariano ER. Opioid-free anaesthesia - what would Inigo Montoya say? Anaesthesia 2019;74:560-3. [Crossref] [PubMed]