The Nuts and Bolts of a Successful Non-Narcotic Perioperative Enhanced Recovery After Surgery Protocol

Abstract

Background

Enhanced recovery after surgery (ERAS) protocols are widely utilized approaches to perioperative care that advocate preoperative counseling, multimodal perioperative medication management, and early postoperative mobilization to improve post-surgical patient outcomes and satisfaction.

Objectives

The authors aimed to elucidate the mechanism by which each medication utilized in the senior author’s ERAS protocol acts, determine the efficacy of this protocol in postoperative pain management, and reveal other factors that may play a role in patients’ degree of postoperative pain.

Methods

A literature review was performed on the medications utilized in the senior author’s ERAS protocol. Evidence from the author’s previous study on the efficacy of this regimen and anecdotal evidence regarding the psychological component of pain was also compiled.

Results

There is evidence that an ERAS protocol is as effective if not more effective than regimens involving opioid medications in management of postoperative pain. These medications act synergistically to block perception of pain by multiple pathways, while minimizing adverse effects that may be associated with high doses of a single medication and are affordable for both the patient and the surgeon.

Conclusions

ERAS protocols effectively manage postoperative pain while avoiding the adverse effects associated with opioid medications. Although an emphasis has often been placed on the medications involved in various protocols and avoidance of opioid medications, appropriate counseling on patients’ expectations concerning postoperative “pain” or discomfort and a systemic shift in the approach to perioperative pain are perhaps the most important components to holistic non-narcotic postoperative care.

Enhanced recovery after surgery (ERAS) protocols provide an evidence-based, holistic approach to post-surgical care in an effort to improve outcomes and patient satisfaction.¹ This is accomplished by reducing physiologic stress via optimization of nutrition, minimization of opioid medications, and early postoperative ambulation, facilitating prompt return to a patient’s preoperative functional state.

The concept of ERAS was first described in 1977 after being thoroughly studied in colorectal surgery literature.² In recent years, it has been applied to other surgical fields and, since first described in plastic surgery literature in 2014, has shown efficacy in postoperative care of patients undergoing abdominal wall reconstruction as well as implant-based and autologous breast reconstruction.^3-6 ERAS protocols are now routine postoperative protocols in many surgical specialties, including vascular, hepatobiliary, thoracic, urologic, and gynecologic surgery, and aim to minimize postoperative pain, nausea, fatigue, barriers to mobilization, and risk of narcotic dependence to increase patient satisfaction and well-being. Although a large emphasis is often placed on ERAS protocols’ pharmacologic regimens in light of the ongoing opioid epidemic, perioperative counseling, proper management of patient expectations, and a shift from focused assessment of “pain” are critical to effectively improve patient outcomes and safety. The authors detail the senior author’s ERAS protocol, offer an explanation as to how this pharmacologic regimen is able to achieve the desired effects, as previously described in his previous study, “Enhanced Recovery After Surgery: The Plastic Surgery Paradigm Shift,” ⁷ and describe systemic shifts in the approach to perioperative care that the authors believe may further improve patient outcomes.

THE DRIVING FORCE

Two major trends have forced a change in traditional approaches to the care of surgical patients. The first is the continuously increasing cost of healthcare at every level, which has forced an effort to reduce the duration of postoperative hospital stays. An effort to expedite patient recovery results in decreased hospital-acquired complications, reduced costs, and increased patient satisfaction.^7,8 Postoperative pain, if not adequately controlled, prolongs time to recovery milestones, such as mobilization or ambulation, and delays postoperative hospital discharge.⁹ Similarly, expedited recovery is essential for efficiency of the operation of ambulatory and office-based surgical facilities.

Secondly, the dramatically increased abuse of prescription opioid medications over the past 20 years has found healthcare providers, medical associations, and politicians advocating for minimal narcotic consumption or elimination of narcotic medications entirely.¹⁰ Additionally, opioid medications are also associated with many shorter-term adverse effects, including nausea, ileus, and respiratory depression, which may further delay mobilization and prolong hospital admission.¹ Although these drugs affect patients’ perception of somatic pain, they fail to address neuropathic or inflammatory causes of pain, effectively targeted by other well-studied medications utilized in ERAS protocols.¹¹

ERAS PROTOCOL AND PHARMACOLOGY

The ERAS protocol utilized by the senior author follows the general guidelines set forth by the ERAS Society, which include preoperative counseling; nutritional optimization; multimodal, non-narcotic analgesia; and early mobilization.¹ In a previous study, patients who underwent this ERAS protocol were found to have significantly decreased postoperative pain on postoperative days 0 through 3 (P < 0.01); decreased nausea, fatigue, and drowsiness on postoperative days 0 and 1 (P < 0.01); and increased ability to ambulate on postoperative days 0 and 2 (P < 0.05) compared with those who followed a traditional pain regimen, which included narcotic medications.⁷

The senior author’s current perioperative medication regimens and each medication’s mechanism of action are outlined in the following sections. Representative facility cost of medications used intraoperatively and retail pricing of medications prescribed for utilization preoperatively and postoperatively are shown in Table 1.

Perioperative Medication Regimen

The night before and morning of surgery, patients are instructed to take celecoxib, gabapentin, and ondansetron, because the utilization of preoperative celecoxib and gabapentin were previously shown to effectively reduce postoperative pain and opioid requirements in patients undergoing subpectoral breast augmentation.¹² These medications are titrated appropriately according to age and other patient factors. Intraoperatively, IV dexamethasone and promethazine are administered in an effort to reduce postoperative nausea and vomiting.⁷ Just prior to conclusion of the procedure, Exparel (Pacira BioSciences, Inc., Parsippany-Troy Hills, NJ) is injected below the rectus sheath in patients undergoing abdominoplasty or into the surgical pocket in patients undergoing breast augmentation or reconstruction; 0.25% Marcaine (Pfizer Inc., New York, NY) with epinephrine is injected into the surgical field in patients undergoing all other surgical procedures.

Prior to extubation, a single dose of IV Tylenol (McNeil Consumer Healthcare, Fort Washington, PA), or Ofirmev (Cadence Pharmaceuticals, San Diego, CA), is given. Finally, in the post-anesthetic care unit, an additional 600 mg of gabapentin is administered to augment the aforementioned analgesics once the patient is able to take oral fluids.

After discharge, each patient is instructed to take scheduled celecoxib or an alternative nonsteroidal anti-inflammatory drug (NSAID) twice daily, gabapentin 3 times daily, and/or oral acetaminophen for 3 to 5 days as well as a 5-day methylprednisolone dose pack.

Pharmacology

Celecoxib is a cyclooxygenase inhibitor that effectively suppresses the production of prostaglandins released in the inflammatory response to pain or tissue trauma. It selectively targets COX-2 isoenzymes, expressed specifically in highly inflamed tissue, and spares COX-1 isoenzymes, which are widely expressed and play a protective role in the gastrointestinal tract.^11,13 Celecoxib is commercially available in 100-mg and 200-mg standard release capsules, with standard dosing being 200 to 400 mg in healthy adult patients and reaching maximum plasma drug concentration 2 to 4 hours following consumption.¹³

Gabapentin is a first-line agent in treatment of neuropathic pain that suppresses neuronal hyperexcitability via the afferent nociceptive pain pathway.¹⁴ It selectively binds the α2δ-1 subunit of voltage gated calcium channels, which are upregulated after surgical trauma, inhibiting nerve injury–induced trafficking of neurotransmitters at the presynaptic terminals of dorsal root ganglion and dorsal horn neurons.^15,16 Perioperative utilization of gabapentin is off-label, but previous trials have demonstrated efficacy of dosages between 300 mg and 1200 mg in reduction of postoperative pain. Increased dosages are associated with drowsiness and peripheral edema.¹¹

Ondansetron or Zofran (GlaxoSmithKline plc., Brentford, UK) is an antiemetic that competitively inhibits binding of serotonin to 5HT3 receptors, effectively blocking the effects of serotonin in the chemoreceptor trigger zone and solitary tract nucleus in the brainstem as well as vagal afferent nerves in the gastrointestinal tract.¹⁷ It is one of the most efficacious, safe, and cost-effective medications for priority conditions according to the World Health Organization’s list of essential medications, but caution should be taken in patients with prolonged QT intervals and those at risk for serotonin syndrome.¹⁸

Dexamethasone, or Decadron (Merck & Co., Kenilworth, NJ), is a potent, long-acting glucocorticoid with strong anti-inflammatory and moderate anti-emetic properties. Analgesia is achieved by its anti-inflammatory effect, which occurs by binding of glucocorticoid receptors in the cytosol of cells, increased transcription of anti-inflammatory proteins (eg, annexin-1, a phospholipase A₂ inhibitor), decreased transcription of pro-inflammatory proteins (eg, cytokines), and downstream inhibition of COX-2.^19-21 Its anti-emetic mechanism is less well understood but is proposed to occur partially by activation of glucocorticoid receptors in the medulla at the solitary tract nucleus.²¹ Unfavorable side effects associated with long-term utilization include hyperglycemia (particularly in patients with diabetes mellitus), wound healing complications, and adrenal suppression via negative feedback on the hypothalamic-pituitary-adrenal axis, but these are likely insignificant with a single perioperative dose.¹⁹

Promethazine, or Phenergan (Baxter International Inc., Deerfield, IL), is a first-generation antihistamine that acts as a strong H1 receptor antagonist with moderate anticholinergic and weak dopaminergic properties.²² Its antiemetic properties occur primarily through antagonism of D2 dopamine receptors in the chemoreceptor trigger zone. Promethazine is safely administered in the operative setting as unwanted anticholinergic effects, such as confusion, dry mouth, constipation, and drowsiness are effectively masked by general anesthesia. In suppository formulation, the onset of action is 20 minutes and duration of action is 4 to 6 hours.²³

Bupivacaine is a local anesthetic that blocks propagation of neuronal action potentials by inhibition of voltage gated sodium channels. Exparel is a form of liposomal bupivacaine that allows a much longer duration of action than standard preparations (72-96 hours vs <10 hours) and is the only long-acting non-opioid medication FDA approved for reduction of postoperative pain.²⁴ Adverse effects are similar to those of other local anesthetics that often occur after inadvertent intra-arterial injection or at unsafe dosages.

Acetaminophen, or Tylenol, is a first-line, universally employed analgesic and antipyretic medication. It acts both centrally via direct inhibition of N-methyl-D-aspartate receptors and downstream synthesis of nitric oxide, a mediator of nociception, and peripherally via COX-2 inhibition but does not carry the renal and gastrointestinal adverse effects associated with NSAIDs.²⁵ Acetaminophen is hepatically metabolized and at toxic doses depletes hepatic glutathione, which can cause accumulation of a quinone intermediate that may result in hepatic necrosis. For this reason, the maximum recommended daily dose for an adult is 4 g, and it should be carefully dosed in patients with preexisting liver disease.²² Studies suggest that IV acetaminophen minimizes the first-pass hepatic effect of oral acetaminophen and reaches analgesic levels in a greater percentage of patients than the same oral dose preoperatively, reaching peak analgesic effects within an hour and acting for a duration of 4 to 6 hours.^16,25,26

Methylprednisolone is a glucocorticoid medication, similar to dexamethasone, that reduces postoperative inflammation by transcription modification of inflammatory metabolites. As previously discussed, steroid medications have been associated with many long-term side effects, such as hyperglycemia, immunosuppression, muscle wasting, fat redistribution, and adrenal suppression, but when taken orally over a limited 5-day period are relatively inconsequential.

Drug Synergy

Drugs routinely employed in postoperative pain regimens can be classified as agents that prevent central sensitization (eg, voltage gated calcium channel blockers such as gabapentin), agents that prevent peripheral sensitization (eg, NSAIDs, acetaminophen, and corticosteroids), membrane stabilizers (eg, voltage gated sodium channel blockers such as bupivacaine), and agents that act on descending modulation (eg, serotonin reuptake inhibitors).¹⁶ Administration of combinations of 2 or more drugs in different categories strategically blocks perception of pain at multiple locations in the peripheral and central nervous systems while minimizing adverse effects that may be associated with high doses of a single medication.²⁷ Of those utilized in the senior author’s previously discussed ERAS protocol, gabapentin acts by preventing central sensitization; celecoxib, acetaminophen, dexamethasone, and methylprednisolone prevent peripheral sensitization; and Exparel stabilizes the neuronal membrane.

Although it is difficult to systemically study the additive, sub-additive, or synergistic effects of all drugs in a given regimen, there is substantial evidence that synergistic relationships among these medications exist. In a review by Ong et al, the combination of acetaminophen and an NSAID provided superior analgesia by 64% to 85% more than that of either drug alone.²⁸ In addition, NSAIDs in combination with local anesthetics, such as bupivacaine, have been shown to synergistically decrease the inflammatory response to surgical trauma.¹⁶

Similarly, dexamethasone and 5HT₃ receptor antagonists, such as ondansetron, in combination have an additive or synergistic effect and are the most effective regimen in prevention of postoperative nausea and vomiting.²⁹ Although data do not show glucocorticoids to have a clinically significant effect on postoperative pain, the senior author believes they synergistically augment the effects of the other medications by reducing the overall state of inflammation as well as contributing to an overall state of well-being.²¹

A HOLISTIC APPROACH TO PERIOPERATIVE CARE

With thorough understanding of how these medications interact on a pharmacologic level, attention may then be turned to the psychological components of a patient’s perioperative care. An ERAS protocol is not simply an effort to decrease the utilization of narcotic medications in light of growing evidence on the harmful implications of opioids but rather a paradigm shift in the way surgeons counsel patients on their postoperative recovery and the approach to pain in the postoperative setting. Detailed counseling and early discussion with the patient regarding their procedure and postoperative pain expectations are critical components of any ERAS protocol that should not be overlooked. Patients who are overweight are more likely to experience complications after surgery, so nutritional optimization, conditioning, and exercise should be emphasized prior to any surgical intervention. In the plastic surgery literature, patients with a BMI of 30 or greater have been shown to have increased rates of both early (<30 days after surgery) and late (>30 days after surgery) complications, including infection, skin necrosis, fat necrosis, hematoma, seroma, wound breakdown, and need for additional surgery.³⁰ The senior author typically considers a BMI of 30 the cap for elective procedures.

The level of a patient’s postoperative “pain” has been shown to be directly correlated with the information provided to the patient about pain expectations as well as psychosocial factors such as previous pain experiences, anxiety, and pain catastrophizing, in which patients perseverate on or amplify the threat value of pain.³¹ With this in mind, preoperative counseling on each patient’s expected postoperative course, expected degree of discomfort, and pain regimen is a critical first step in management of postoperative pain and should be tailored to the individual patient’s psychosocial situation.³² Furthermore, the senior author emphasizes that the word “discomfort” rather than “pain” is employed because it carries a less negative connotation and is reasonable to expect postoperatively.

In the perioperative period, the senior author has suggested a shift from “What is your pain level” to the simple question “Are you comfortable?” while still employing the universally accepted Faces Pain Scale. Anecdotally, patients require less aggressive pain management with assessment in this framework; however, future studies with formal psychological assessments given to patients being asked to rate their pain vs comment on their level of comfort will be exceedingly useful in determining the efficacy of this model at the nursing level prior to widespread implementation and are in development.

One critique often cited by physicians reluctant to adopt such a protocol is the supposed financial burden. Exparel is the most expensive of the included medications. On average, it costs a private practice physician $350 per 20-mL vial, which is usually included in the patient’s surgical fee. Patients have a wide variety of insurance coverage plans making accurate analysis of out-of-pocket expenses challenging. After speaking with recent patients, the senior author quotes $15 to $40 as the average out-of-pocket cost to patients for all of their postoperative medications.

CONCLUSIONS

ERAS protocols are now widely utilized across surgical subspecialties and more frequently within plastic surgery. These protocols outline a comprehensive approach to preoperative counseling, perioperative medication administration, and postoperative management that aim to decrease postoperative recovery time, minimize utilization of opioid medications, and promote early mobilization in an effort to improve overall patient satisfaction and measurable outcomes. Multimodal pain regimens are now quite well understood and have shown quantifiable synergistic effects in postoperative pain management to the extent that the senior author does not prescribe narcotics with a favorable response from his patients; however, there remains significant value and room for further improvement in perioperative care with preoperative expectation management and a shift to assessment of comfort or discomfort rather than “pain” that remains to be studied.

Disclosures

The authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article.

Funding

The authors received no financial support for the research, authorship, and publication of this article.

REFERENCES