Clinical Issue: Opioid-Free Anesthesia

Ning Luo, BSN, RN, DNAP Candidate

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The conviction of Purdue Pharma for instigating the opioid epidemic in the United States (U.S.) symbolized a righteous public win against the avaricious big pharma and a major leap toward opioid stewardship. The pharmacodynamic contributor to opioid dependence is thought to be opioid-induced hyperalgesia (OIH). According to Guichard et al. (2021) and Beauchamp et al. (2020), OIH, clinically demonstrated as suboptimal pain control out of proportion with clinical conditions and pharmacological regimens, is usually associated with chronic opioid use. However, OIH is also significantly associated with the intraoperative use of remifentanil, especially at higher doses. Currently, the impact of intraoperative opioids on long-term opioid dependence and use disorder is not definitive and cannot be omitted, despite the duration of the exposure. Moreover, opioids also frequently elicit many complications, such as oversedation, respiratory depression, ileus, urinary retention, nausea, and vomiting, all of which may consequently prolong the length of hospital stay via delayed recovery, reduce patient satisfaction, and aggravate the already rampant healthcare costs (Lavand’homme, 2019; Frauenknecht et al., 2019).

The extensive adaptation of multimodal pain regimens substantiates the attainable potential of performing anesthesia without opioids, or opioid-free anesthesia (OFA), eradicating undesirable opioid-related clinical outcomes. As the latest research publications with more substantial evidence emerge, we will continue to comprehend and evaluate the ramifications of the traditional practice while embracing the OFA’s rising popularity and superior outcomes in anesthesia and pain control. Even though OFA is still a relatively nascent clinical area, the research literature has already sprouted fruitful results, urging anesthesia providers to implement OFA in an evidence-based manner while being cognizant of the U.S. social implications and opioid stewardship.

Clinical Outcomes of Opioid-Free Anesthesia

Opioid-free anesthesia utilizes opioid substitutes, such as dexmedetomidine, ketamine, magnesium sulfate, and esmolol, to achieve the desirable while eradicating the undesirable effects of opioid anesthetics. This quality improvement (QI) aims to explore the clinical outcomes pertinent to OFA-associated analgesic properties, opioid-sparing effects, and clinical safety. Multiple systemic reviews and meta-analyses will be discussed. These research findings related to OFA may help improve the quality of care, promote satisfactory postoperative experience, shorten hospital stays, and even alleviate the ongoing opioid crisis, all of which will optimize the hospital’s operation and economize healthcare spending.

Literature Overview

This article constitutes six pieces of systemic reviews and meta-analyses that compared the clinical outcomes of various OFA agents with OBA agents or placebo controls. The articles by Olausson et al. (2021), Salomé et al. (2021), and Frauenknecht et al. (2019) investigated a range of OFA agents as a whole, such as dexmedetomidine, lidocaine, ketamine, magnesium sulfate, and esmolol. The article by Grape et al. (2019), Gelineau et al. (2018), and Brinck et al. (2018) examined a singular OFA agent like dexmedetomidine, esmolol, and ketamine, respectively. The OBA agents scrutinized, ranked by their prevalence in all six systemic reviews and meta-analyses, were remifentanil, fentanyl, alfentanil, and sufentanil. Each of the six publications contains 21–130 randomized controlled trials (RCT) from 1991–2021 with 1304–8341 adult participants, most of whom underwent general anesthesia for gynecological, obstetric, gastrointestinal, neurological, orthopedic, thoracic, and otorhinolaryngological operations.

Results

Pain Control

All articles analyzed the objective of pain control using pain scales, but pain ratings were measured at various postoperative intervals. Acute pain scores were tracked up to 48 hours post-operation, and chronic pain was monitored for at least three months post-operation. Frauenknecht et al. (2019) and Salomé et al. (2021) concluded no statistically significant acute pain difference, while Olausson et al. (2021) only found a mean difference (MD) in pain reduction of 0.7 on a scale of 10 at 2-hour post-operation but no overall difference, either. In the single-agent systemic reviews by Grape et al. (2019), Gelineau et al. (2018), and Brinck et al. (2018), patients in the dexmedetomidine groups steadily rated less acute pain for 24 hours post-operation with a significant reduction in MD of approximately one on a scale of 10 and participants who received ketamine scored 5 to 6 points less (MD) out of 100 up to the 48th postoperative hour, contrasting the pain rating similarities in the esmolol groups comparing with the control groups. Only Salomé et al. (2021) reviewed chronic pain and detected no significant difference. Additionally, the time to the first postoperative opioid request is included in two systemic reviews. Grape et al. (2019) summarized a significantly longer but unspecified time in dexmedetomidine groups, while Brinck et al. (2018) presented a 54 minutes (MD) postponement in the first opioid request in the ketamine groups, indicating endured analgesic effects.

Postoperative Opioid Consumption

Postoperative opioid consumption is measured by converting the dosage of other opioids into the intravenous (IV) morphine equivalence in milligrams (mg) in different time intervals up to 48 hours post-operation. Except for Frauenknecht et al. (2019) found no significant opioid-curtailing effect, all other analyses reveal a decline in opioid use in varying dosages. Brinck et al. (2018) discovered ketamine with the most remarkable result­–MD of -7.6 mg and -12.6 mg at the 24th- and 48th-hour marks, respectively, followed by -7.54 mg (MD) at the 48th hour by Salomé et al. (2021) and -6 mg (MD) by Olausson et al. (2021). Others saw significant but less than 5 mg (MD) of abatements (Grape et al., 2019; Gelineau et al., 2018).

Adverse Events

All studies inspected perioperative adverse events, such as postoperative nausea and vomiting (PONV), central nervous system (CNS) events, hemodynamic instability, and shivering. For PONV, only Gelineau et al. (2018) found an equivocal result related to esmolol, in which the culprit may be the presence of opioids in all esmolol and control groups. The remaining reviews show a significant PONV mitigation among OFA groups (14–50% reduction rate), with two articles also reporting the lack of PONV alleviation when opioids were introduced during induction, potentially explaining the review limitation leading to the result deviation with esmolol (Olausson et al., 2021; Salomé et al., 2021; Frauenknecht et al., 2019; Grape et al., 2019; Brinck et al., 2018). Only two articles analyzed CNS events, Salomé et al. (2021) observed less oversedation in OFA groups and no significant difference in respiratory depression. Brinck et al. (2018) established no significant difference between patients administered ketamine and placebo. Three reviews investigated hemodynamic tolerance, such as clinically significant hypertension, hypotension, tachycardia, and bradycardia. Salomé et al. (2021) described similar hemodynamic tolerance for OFA agents. In contrast, Grape et al. (2019) recorded comparable incidences of bradycardia in the dexmedetomidine group. Still, twice less frequent hypotensive episodes were observed. For esmolol, Gelineau et al. (2018) arrived with mixed results of bradycardia and hypotension. However, no incidents guaranteed clinical interventions. For the occurrence of shivering, only two reviews contain this objective and document at least a 50% decrease (Salomé et al., 2021; Grape et al., 2019).

Discussion

This section will illustrate the quality, subjectivity, and clinical applicability of the research results. All six systemic reviews and meta-analyses incorporated the Cochrane risk-of-bias tool for randomized trials (RoB) for judging the impartiality of research results. The majority of the RTCs included in the six systemic reviews and meta-analyses have a low risk of bias, attesting to the clinical findings’ objectivity and validity.

All authors but Gelineau et al. (2018), who conducted the systemic review and meta-analysis of esmolol, assessed the merits of clinical recommendations using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) instrument. Inevitably, some limitations exist, such as result inconsistency, inadequate sample size, insufficient trial quantity, and inferior data quality, that resulted in the relegation of GRADE level in many clinical results. Moderate to high GRADE is assigned to the mixed-OFA systemic reviews and meta-analyses by Frauenknecht et al. (2019), Salomé et al. (2021), and Olausson et al. (2021) that found no significant overall acute pain difference, indicating the commensurate analgesic effect of OFA, potentially advocating for their role as opioid surrogates. The acute pain-mitigating effect of ketamine and dexmedetomidine has a high and moderate GRADE, respectively. The lengthened request time of the first pain medication for dexmedetomidine and ketamine are both rated moderate GRADE, further bolstering its use to replace opioids for pain control. The findings related to pain are statistically significant, but some may not be clinically noteworthy due to the smaller percentage reduced in average pain scores. Hence, a multimodal approach may synergically augment the analgesic action.

For postoperative opioid consumption, the GRADE is averaged at moderate to high. All authors but Frauenknecht et al. (2019) observed the opioid dosage-diminishing effect of OFA agents. The dosage spared varied among OFA agents, but a positive association with postoperative hours in the acute phase appears plausible. Furthermore, all six systemic reviews and meta-analyses neglected other contributors to opioid consumption, such as healthcare providers’ opioid prescribing practices in the postoperative period. Salomé et al. (2021) also noted the failure to account for individual patient characteristics, such as prior opioid use, preexisting chronic pain, psychological factors, and genetic predisposition. Although the clinical interpretations and significance are debatable, the total opioid-sparing effect of OFA can be maximized by combining multiple agents.

For perioperative adverse events, OFA curbed PONV by up to 50% with a high GRADE and deterred postoperative shivering by at least 50% with a moderate to high GRADE. Considering the most common incident of surgeries, PONV is concerned as one of the most unfavorable adverse events from the patient’s perspective and is associated with an extended length of hospital stay, clinical complications, and readmissions, all of which are financially pressing for the healthcare budget (Gress et al., 2020). This confers the extra benefits of espousing OFA, which may improve patient experience and satisfaction, decrease the length of hospital stay, and increase healthcare cost-efficiency. The claim that OFA induced fewer CNS incidences is supported by low-GRADE evidence, whereas high-GRADE evidence endorses ketamine’s safety in CNS events. Moreover, OFA incurred a proportional hemodynamic instability backed by evidence with only low to moderate GRADE, whereas high-GRADE evidence buttresses dexmedetomidine’s safety concerning bradycardia and hypotension. The pattern of clinical GRADE exhibit higher ranks in single-agent reviews and lower ratings in mixed-OFA reviews, suggesting clinical safety considerations when administering multimodal OFA agents and prompting further research on larger-sized and better-designed RTCs on multimodal OFA agents to improve safety GRADE.

Clinical Recommendations

Following the discussion of the literature findings, clinical recommendations can be deduced and formulated. The reliability of OFA’s clinical outcomes on pain and postoperative opioid consumption affirms anesthesia professionals to espouse OFA, especially when caring for patients who are at high risk of experiencing opioid adverse events, such as patients with obesity, obstructive sleep apnea (OSA), chronic opioid use and dependence, and women (Lavand’homme, 2019; Olausson et al., 2021). Whenever risks and benefits are balanced, multimodal OFA should be deployed to amplify the analgesic, opioid-sparing, and PONV-deterring properties of OFA while progressively eliminating the exposure of OBA. As healthcare leaders, anesthesia providers should collaborate with acute care, primary care, pain specialists, nurses, and pharmacists to maximize the benefits of multimodal opioid-free pain regimens while minimizing opioid prescription and consumption in inpatient and outpatient settings. As clinical educators, anesthetists must keep abreast of the latest evidence-based practice (EBP), disseminate findings to other healthcare professionals, and educate patients about the benefits of multimodal analgesics and the risks of chronic opioid therapy. In addition, the widespread adaptation of OFA in the future must rely on the safety of OFA agents, primarily when used in combinations. As future research aims to bridge this gap with more robust evidence, anesthesia professionals must be proficient in the pharmacology of OFA medications and be cognizant and vigilant of their interactions. Finally, anesthesia providers as advocates for change must help steer organizational practice, protocol, and policy development to facilitate the actualization of OFA research findings into EBP in clinical settings so more patients can benefit and the opioid crisis can be attenuated.

Conclusions

The traditional OBA practice corresponds to suboptimal outcomes, such as unmerited PONV, excessive opioid use, and unwarranted complications, which are avertible and should be addressed in a preventative approach. OFA renders an invaluable opportunity to ameliorate these opioid-induced consequences, as it may improve clinical outcomes and patient satisfaction, achieve greater population health, and mediate healthcare cost-efficiency. As the profession that performs the most anesthesia cases in the U.S. each year, nurse anesthetists must fulfill the responsibility of public guardianship by enacting QI of OBA and OFA with the most relevant research literature to help enhance clinical outcomes and mitigate the opioid crisis. Patient-provider, multidisciplinary, inter-organizational, and systematic collaborations serve a pivotal role in realizing the full potential of OFA, which may help engender the next critical transformation of anesthesia and the healthcare system.

References

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