Introduction

The word "opioid" elicits many associations when mentioned: pain, relief and, more recently, epidemic, to name a few. Initially, there were just opiates, natural derivatives of opium, such as morphine and heroin. Opioids such as fentanyl and oxycodone were introduced in the 20th century as synthetically and semi-synthetically derived versions of natural opiates. The term opioid is currently used to refer to any natural or synthetic substance that binds to opioid receptors in the body. Regardless of their origin, opiates and opioids are agents commonly administered during anesthesia to dull the senses, relieve pain and induce sleep.1 However, there are significant adverse effects associated with intraoperative opioid use: nausea, vomiting, pruritus, impaired gastric motility, urinary retention, opioid-induced hyperalgesia and opioid-induced ventilatory impairment. Additionally, a recent study has reintroduced a hypothesis from the 1990s suggesting that intraoperative opioid administration is associated with prolonged postoperative use.2,3 This emerging research places intraoperative opioid use on the front line of the nation's battle to combat the current opioid epidemic.

In November 2018, the U.S. Health Resources and Services Administration reported that opioid-related overdoses claimed the lives of more than 130 people every day.4 The National Survey on Drug Use and Health estimated that in 2016, 11.5 million people in the United States misused prescription opioids.5 Based on the Council of Economic Advisers' 2015 cost analysis, this equated to an economic cost of $504 billion.6 In 2016 alone, the Centers for Disease Control and Prevention reported that 63,632 people died of a drug overdose in the United States, and 66.4% of those deaths involved opioid use.7 The opioid-related death rate reached such significance that in 2017, former Secretary of the U.S. Department of Health and Human Services, Dr. Thomas Price, declared a public health emergency and announced a 5-Point Strategy to Combat the Opioid Crisis.8 The five priorities are:

* Improving access to treatment and recovery services.

* Promoting the use of overdose-reversing drugs.

* Strengthening our understanding of the epidemic through better public health surveillance.

* Providing support for cutting-edge research on pain and addiction.

* Advancing better practices for pain management.

With an increased focus on overall opioid use and the adverse effects of opioids in the perioperative period, it is logical to review alternative pharmacological adjuncts that have a proven efficacy in treating perioperative pain. The most common adjuncts include acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), dexamethasone, esmolol, lidocaine, magnesium sulfate, ketamine, gabapentinoids (gabapentin or pregabalin), dexmedetomidine and caffeine. Acetaminophen produces an analgesic effect by inhibiting cyclooxygenase-3. In a systematic review and meta-analysis, Doleman et al. reported that perioperative acetaminophen reduced postoperative 24-hour opioid consumption by a standard mean difference of -0.52, which they considered to be a clinically significant effect.9 Another example is a non-steroidal anti-inflammatory agent such as ketorolac, a non-selective cyclooxygenase inhibitor. Inhibition of cyclooxygenase produces an analgesic effect by reducing the synthesis of prostaglandins and inflammatory mediators that cause pain sensitization.10 Zeng et al. determined in their meta-analysis that NSAIDs were efficacious in reducing opioid use by a mean of 12 morphine equivalents.11 In a meta-analysis using six high-quality randomized controlled trials, the perioperative administration of intravenous lidocaine resulted in a reduction in postoperative pain and opioid consumption at 12, 24 and 48 hours postoperatively.12 In another meta-analysis evaluating the use of intraoperative dexamethasone for pain control after total joint arthroplasty, data showed that dexamethasone significantly decreased pain scores and was also associated with reduced opioid consumption at 12, 24 and 48 hours postoperatively.13 To date, there are more than 80 systematic reviews or meta-analyses that support the efficacy and opioid-sparing effects of perioperatively administered acetaminophen, NSAIDs, lidocaine, dexamethasone, ketamine, magnesium sulfate, dexmedetomidine, esmolol, gabapentinoids and caffeine.14-17

The generalized absence of standardized perioperative non-opioid pain treatment strategies in the literature has illuminated the need for a large-scale evidence-based review to provide medical facilities worldwide with a pathway to multimodal opioid-sparing medications for use during the perioperative period. Anesthesia providers can most effectively impact the current opioid epidemic by implementing non-opioid-centric anesthetic medications.18 The results of the umbrella review will provide the essential, rapid and timely synopsis of the extensive available literature to create a foundation for an evidence-based multimodal opioid-sparing anesthetic pathway for acute surgical pain. Rather than performing additional systematic reviews or meta-analyses on the opioid-sparing effects of the 10 medications of interest, an umbrella review will compile the results of existing studies. To date, an umbrella review on this topic has not been previously published. Additionally, there is a degree of controversy within the literature that has not been investigated systematically. For example, while the intraoperative administration of intravenous lidocaine has been shown to decrease postoperative opioid consumption for intra-abdominal surgeries (colon resection and laparoscopic cholecystectomy), its use during hysterectomies has been shown to be ineffective when looking at the same outcomes.19 This umbrella review seeks to bring clarity, uniformity and evidenced-based decision making for the perioperative use of non-opioid pharmacological adjuncts.

Review question

What is the effectiveness of non-opioid pharmacological adjuncts in decreasing perioperative morphine equivalents and acute postoperative pain scores in the adult surgical patient?

We will also determine if there is sufficient evidence from the literature to initiate an opioid-sparing anesthetic pathway to give anesthesia providers an alternative to opioid-centric anesthesia.

Inclusion criteria

Participants

The review will consider systematic reviews and meta-analyses that include studies of male and female adults who are 19 years of age or older undergoing surgical procedures. This age corresponds with the age of adulthood set by the searched databases and is supported by ambulatory surgery data collected in the 2010 U.S. National Hospital Ambulatory Medical Care Survey, which concluded that adults make up most of the ambulatory surgical population.20 Additionally, the majority of research available is in the adult population.

Systematic reviews and meta-analyses that included patients who received regional or neuraxial techniques as a component of an opioid-sparing technique will be excluded. The administration of regional and neuraxial anesthesia requires a unique set of skills that must be developed over time. There are differences among providers regarding the quality and success rates of these techniques due to individual skill level. Regional anesthetics can also vary in pain relief and duration of effect depending on medications and additives administered. With an ineffective regional anesthetic, the amount of opioid prescribed as a rescue analgesic is provider dependent.

Patients who received a non-opioid medication given as a local infiltrate (intravenous medication injected directly on the surgical site or within the tissue surrounding the site) by the surgical team will also be excluded. The focus of this umbrella review will be limited to oral or intravenous perioperative medications administered by the anesthesia team.

Interventions/comparators

The umbrella review will consider systematic reviews and meta-analyses that include the administration of non-opioid medications used as analgesics during the perioperative time frame for acute surgical pain. Included studies will evaluate interventions given preoperatively and intraoperatively to reduce overall perioperative opioid administration. The non-opioid medications of interest will include acetaminophen, NSAIDs, dexamethasone, esmolol, lidocaine infusion, magnesium sulfate, ketamine, gabapentanoids, dexmedetomidine and caffeine. Furthermore, dosages and time of administration of each adjunct will be examined.

Outcomes

This review will consider studies that include the following outcomes: opioid-centric acute surgical pain management, non-opioid pharmacological adjuncts administered, dose range summary, pain scores and amount of opioid administered measured in morphine equivalents. The frequency of opioid-related adverse effects will also be of interest. These adverse effects include opioid-induced hyperalgesia, opioid-induced ventilatory impairment, nausea, vomiting, pruritus, impaired gastric motility, urinary retention and chronic postoperative use.

Types of studies

This umbrella review will consider any systematic reviews and meta-analyses of effectiveness data, including the quantitative component of comprehensive studies. Additionally it will include systematic reviews and meta-analyses embedded in evidence-based guidelines. Systematic reviews provide a detailed, orderly and transparent means of gathering, appraising and synthesizing evidence to answer a well-defined question. Meta-analyses encompass statistical procedures for combining numerical data from multiple individual studies in an effort to increase power, improve estimates of the size of effect or resolve uncertainty when reports disagree, producing a weighted average of the results.21 Included material will demonstrate a clearly articulated and comprehensive search strategy, and evidence of critical appraisal of the included studies using an accepted standardized appraisal tool from well-known library or research institute, such as Cochrane or Joanna Briggs Institute (JBI). To maximize the review of relevant available research on opioid-sparing pharmacological adjuncts in the perioperative period, the search will include only systematic reviews and meta-analyses published in English after 2007. The completion of this process, and ultimately the review, will create a compendium of high-tier evidence-based primary research on each of the opioid-sparing pharmacological adjuncts.

Methods

The proposed umbrella review will be conducted in accordance with the JBI methodology for umbrella reviews of systematic reviews and meta-analyses.22

Search strategy

The search strategy will aim to locate both published and unpublished systematic reviews and meta-analyses. An initial limited search of MEDLINE (PubMed), CINAHL, and JBI Database of Systematic Reviews and Implementation Reports was undertaken to identify articles or pre-existing umbrella reviews on this topic. The keywords contained in the titles and abstracts of relevant articles and the index terms used to describe the articles were used to develop a full search strategy for MEDLINE (PubMed). A comprehensive search strategy for MEDLINE (PubMed) is detailed in Appendix I. This search strategy, including all identified keywords and index terms, will be adapted for each included database or information source. The reference list of all systematic reviews and meta-analyses selected for critical appraisal will be screened for additional reviews.

Information sources

The databases to be searched will include MEDLINE (PubMed), CINAHL and Embase. The review registers to be searched will include JBI Database of Systematic Reviews and Implementation Reports and Cochrane Database of Systematic Reviews. The search for unpublished reviews will include ProQuest Dissertations and Theses Global and Turning Research Into Practice medical database.

Keywords to be used in the detailed search of the selected databases include the following: opioid sparing, opioid-sparing, pain, postoperative, perioperative, analges*, postoperative pain, anti-inflammatory agents, non-steroidal, NSAID, non-steroidal anti-inflammatory drug, celecoxib, ketorolac, Toradol, cox-1 inhibitor, cox-2 inhibitor, acetaminophen, paracetamol, Tylenol, dexamethasone, glucocorticoid, corticosteroid, esmolol, beta-blocker, beta-receptor antagonist, lidocaine, magnesium sulfate, magnesium, ketamine, NMDA-antagonist, gabapentin*, GABA analogue, dexmedetomidine, alpha-2 agonist, Precedex, caffeine, systematic review and meta-analysis.

Study selection

Following the search, all identified citations will be collected and uploaded into EndNote, version x8.2 (Clarivate Analytics, PA, USA) and duplicates removed. Two independent reviewers will then screen titles and abstracts for conformity to the inclusion criteria for the review. Potentially relevant papers will be retrieved in full and their citation details imported into the Joanna Briggs Institute System for the Unified Management, Assessment and Review of Information (JBI SUMARI; Joanna Briggs Institute, Adelaide, Australia).22 The full text of selected citations will be assessed for conformity to the inclusion criteria by two independent reviewers. Reasons for exclusion of full-text articles that do not meet the inclusion criteria will be reported in the umbrella review. Any disagreements that arise between the reviewers at each stage of the selection process will be resolved through discussion or with a third reviewer. In the event that a peer-viewed article appears in more than one of the included systematic reviews or meta-analyses, the following protocol will be implemented. If the results of two or more systematic reviews and/or meta-analyses with overlapping articles differ in regards to statistical or clinical significance, a comprehensive identification method will be used to calculate and assess the degree of overlap. Varying degrees of either statistical or clinical significance are acceptable. The amount of overlap will be presented in a table as the corrected coverage area (CCA) as described by Pieper et al.23 Pieper's classification matrix includes slight, moderate, high and very high CCA. The CCA will be addressed by providing evidence both for and against the competing conclusions. The results of the search will be presented in a Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow diagram.24

Assessment of methodological quality

Two independent reviewers will critically appraise selected systematic reviews and meta-analyses for methodological quality using the standardized critical appraisal checklist from JBI.22 Any disagreements between reviewers will be resolved through discussion or with a third reviewer. Following critical appraisal, reviews that do not meet a pre-defined quality threshold will be excluded. The minimum allowable score will be questions two through eight answered with "Yes" responses. Any literature that receives either a "No" response from appraisal questions two through eight or a score equal to or less than 6 out of 11 positive responses will not be considered. The critical appraisal checklist represents quality benchmarks based on the JBI systematic review methodology. Studies that fail to meet these benchmarks will be considered poorly conducted, lacking critical appraisal of included studies or literature reviews described as a systematic review but not including any features of an accepted systematic review methodology.

Data extraction

Data will be extracted from papers included in the review by two independent reviewers using the standardized data extraction tool available in JBI SUMARI.22 The data obtained will include specific details about the interventions, populations, review methods and outcomes of significance to the review question and specific objectives. Any disagreements that arise between the reviewers will be resolved through a third reviewer. Authors of papers will be contacted to request missing or additional data where required.

Data synthesis

Extracted findings will be presented in a tabular format for each pair of interventions and outcomes. The data summary for each article will be based on the strength of the evidence for the effectiveness of the intervention and depicted using the three colors of the traffic light: an effective intervention (green), no effect or difference compared to a control intervention (amber) and a detrimental intervention or one that is less effective than control (red).22

Assessing certainty in the findings

The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach for grading the certainty of evidence will be followed, and a Summary of Findings (SoF) will be created using GRADEpro (McMaster University, ON, Canada).25 The SoF will present the following information where appropriate: absolute risks for the treatment and control, estimates of relative risk and a ranking of the quality of the evidence based on the risk of bias, directness, heterogeneity, precision and risk of publication bias of the review results. The outcomes reported in the SoF will include the following: non-opioid pharmacological adjuncts administered, dose range summary, pain scores and amount of opioid administered measured in morphine equivalents.

Acknowledgments

This review will contribute towards the award of a Doctor of Nursing Practice degree (TJH and JAM).

Appendix I: Search strategy for MEDLINE (PubMed)

1. (opioid sparing) OR opioid-sparing

2. (((pain, postoperative) OR perioperative) OR analges*) OR postoperative pain

3. ((((((((anti-inflammatory agents, non-steroidal) OR NSAID) OR non-steroidal anti-inflammatory drug) OR celecoxib) OR ketorolac) OR Toradol) OR cox-1 inhibitor) OR cox-2 inhibitor) OR ibuprofen

4. ((acetaminophen) OR paracetamol) OR Tylenol

5. ((dexamethasone) OR glucocorticoid) OR corticosteroid

6. ((esmolol) OR beta-blocker) OR beta-receptor antagonist

7. lidocaine

8. (magnesium sulfate) OR magnesium

9. (ketamine) OR NMDA-antagonist

10. (gabapentin) OR GABA analogue

11. ((dexmedetomidine) OR (alpha-2 agonist) OR Precedex

12. caffeine

13. 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12

14. 1 AND 2 AND 13

15. 14 AND (English language)

16. Filters: systematic reviews, meta-analysis, full text, humans, adult: 19+ years and 10 years (after 2007)

References