Introduction

Post-operative pain management is a critical component of surgical recovery, influencing patient comfort, functional rehabilitation, and overall outcomes.1 Effective pain control enhances patient satisfaction and mitigates complications such as delayed mobilization, chronic pain, and prolonged hospital stays.2 Traditionally, opioids have been the cornerstone of post-operative pain management due to their potent analgesic effects.3 However, the opioid crisis has highlighted the significant risks associated with opioid use, including dependence, respiratory depression, nausea, and constipation. These concerns have led to a growing emphasis on opioid-sparing strategies, with multimodal analgesia (MMA) gaining prominence as a preferred approach.4,5

Need for MMA

MMA involves multiple pharmacologic agents targeting different pain pathways, creating a synergistic effect that enhances pain relief while reducing side effects.6 By integrating multiple classes of analgesics, MMA aims to reduce reliance on opioids, improve patient outcomes, and decrease opioid-related adverse effects.7 The use of oral multi-modal agents is particularly advantageous due to their ease of administration, cost-effectiveness, and potential for outpatient pain management.

Advantages of Oral Multi-Modal Pain Management

The use of oral formulations for MMA provides several benefits. Oral medications are generally more convenient and well-tolerated than intravenous options, making them the preferred choice for many patients. This is especially beneficial in outpatient settings, where ease of administration and adherence are crucial to treatment success.8,9 Utilizing a multimodal approach by combining different analgesic agents helps reduce the necessary opioid dose, thereby minimizing opioid-related side effects, dependency risks, and overall opioid exposure.10 Combining different agents reduces the required opioid dose, mitigating opioid-related side effects and risks. Different pharmacologic mechanisms (e.g., anti-inflammatory, central sensitization, and peripheral pain modulation) improve analgesia. Oral multimodal regimens help lower healthcare expenses by reducing the need for intravenous administration, decreasing hospital stays, and minimizing resource utilization, ultimately contributing to more cost-effective patient care.

Purpose of the Review

This review examines the role of oral multimodal agents in postoperative pain management, emphasizing their mechanisms of action, clinical effectiveness, safety profiles, and patient-centered benefits. By analyzing current evidence, it aims to identify best practices for integrating oral MMA into surgical recovery protocols, enhancing pain control while minimizing opioid reliance.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

NSAIDs are a cornerstone of MMA due to their anti-inflammatory, analgesic, and antipyretic properties. When used as part of an oral MMA regimen, NSAIDs effectively reduce post-operative pain, minimize opioid consumption, and improve functional recovery.5,11 NSAIDs exert their effects by inhibiting cyclooxygenase (COX) enzymes, which are critical in synthesizing prostaglandins—lipid compounds involved in pain, inflammation, and fever. COX-1 inhibition affects prostaglandins that regulate gastric mucosal protection, renal function, and platelet aggregation, which can lead to gastrointestinal and renal side effects. COX-2 inhibition targets prostaglandins primarily involved in inflammation and pain, making selective COX-2 inhibitors potentially safer for prolonged use.12,13

Numerous studies have demonstrated that NSAIDs significantly reduce post-operative pain and opioid consumption in orthopedic patients.14,15 Their use is associated with improved pain scores compared to both placebo and opioid monotherapy. Additionally, they contribute to faster mobilization and earlier hospital discharge. Furthermore, they help reduce opioid-related side effects, including nausea, constipation, and sedation. NSAIDs should be administered at the lowest effective dose for the shortest duration required to minimize risks. In high-risk patients, gastroprotective agents, such as proton pump inhibitors, should be considered to safeguard against potential gastrointestinal complications (Table 1).16

Table 1.Common Non-Steroidal Anti-Inflammatory Drugs
Drug Dosage Side Effects Considerations
Ibuprofen (Advil, Motrin) 400–800 mg every 6–8 hours (max 3,200 mg/day) Gastrointestinal irritation, nausea, dizziness, kidney issues Short half-life; may cause GI irritation; take with food
Naproxen (Aleve, Naprosyn) 250–500 mg every 8–12 hours (max 1,500 mg/day) GI bleeding, renal impairment, hypertension Increased cardiovascular risk with long-term use
Celecoxib (Celebrex) (COX-2 inhibitor) 200 mg every 12 hours (max 400 mg/day) Cardiovascular risk, headache, GI upset Lower GI side effects; prefer in patients at risk for GI bleeding
Meloxicam (Mobic) 7.5–15 mg once daily GI upset, renal issues, headache, dizziness Long-acting, once-daily dosing; monitor renal function

Acetaminophen

Acetaminophen (also known as paracetamol) is an essential analgesic and antipyretic commonly used in post-operative pain management.17 It is a first-line agent for mild to moderate pain. It is frequently incorporated into MMA regimens due to its efficacy and minimal side effect profile compared to opioids and NSAIDs. Acetaminophen works through central mechanisms and is often combined with NSAIDs or opioids to enhance pain relief while minimizing opioid consumption and reducing the risk of opioid-related side effects.18

Acetaminophen works primarily within the central nervous system which is believed to inhibit COX-2 enzymes in the brain and spinal cord.19,20 Unlike NSAIDs, it has minimal peripheral action and lacks significant anti-inflammatory effects. Its analgesic properties are enhanced through modulation of serotonin pathways and potential interaction with cannabinoid receptors.19,20

For post-operative pain, acetaminophen is available in both regular-release (325–650 mg every 4–6 hours, max 3,000–4,000 mg/day) and extended-release (1,000 mg every 8 hours, max 4,000 mg/day) formulations. Regular-release acetaminophen is effective for mild to moderate pain and is often combined with other analgesics to reduce opioid use. Extended-release formulations provide longer-lasting relief for continuous pain management, reducing the need for frequent dosing.

Acetaminophen’s primary safety concern is the risk of liver toxicity, particularly with doses exceeding 4,000 mg per day, which can lead to acute liver failure. Regular alcohol consumption increases the risk of liver damage, so patients who drink alcohol should avoid high doses. While renal damage is less common, it can occur with excessive use, especially in patients with existing kidney conditions. Unlike NSAIDs, acetaminophen does not irritate the gastrointestinal tract, making it a safer option for patients with a history of ulcers or gastrointestinal bleeding.21

Gabapentinoids

Gabapentinoids, including gabapentin and pregabalin, are integral to MMA for managing post-operative pain. Initially developed as anticonvulsants, they exhibit significant analgesic properties, particularly in neuropathic and postoperative pain, and their inclusion in MMA regimens has been shown to reduce opioid consumption while enhancing pain control.22 Their mechanism of action involves binding to the α2δ subunit of voltage-gated calcium channels in the central nervous system, leading to decreased excitatory neurotransmitter release (e.g., glutamate, substance P), reduced neuronal excitability in pain pathways and modulation of central sensitization, thereby preventing the amplification of post-operative pain.23 By diminishing central sensitization, gabapentinoids help prevent hyperalgesia (exaggerated pain response) and allodynia (pain from non-painful stimuli), which are common post-surgical pain phenomena.24

Gabapentinoids play a crucial role in post-operative pain management by reducing opioid consumption by 30–50% within the first 24–48 hours.24 Their ability to prevent central sensitization helps mitigate the transition from acute to chronic pain, lowering the risk of chronic post-surgical pain. Additionally, by reducing opioid reliance, gabapentinoids contribute to fewer opioid-related side effects such as nausea, vomiting, and respiratory depression, ultimately enhancing early mobilization and improving discharge rates (Table 2).25

Table 2.Gabapentinoids
Drug (Brand Name) Dosage Side Effects Considerations
Gabapentin (Neurontin) 300–600 mg every 8 hours (max 3,600 mg/day) Sedation, dizziness, ataxia, peripheral edema Requires dose adjustment in renal impairment; titration needed to reduce side effects
Pregabalin (Lyrica) 75–150 mg every 12 hours (max 600 mg/day) Drowsiness, weight gain, blurred vision, dizziness More potent than gabapentin with faster onset; better bioavailability

Corticosteroids

Corticosteroids are powerful anti-inflammatory agents increasingly utilized in post-operative pain management as part of the MMA regimen. By reducing inflammation, suppressing immune responses, and mitigating postoperative nausea and vomiting (PONV), they serve as an effective adjunct to pain control strategies.26 Their effects help reduce post-operative pain, swelling, and stiffness, particularly in procedures involving extensive tissue manipulation, such as total joint arthroplasty, spine surgery, and rotator cuff repair. Mechanism of action involves inhibiting phospholipase A2 to decrease prostaglandin and leukotriene production, suppressing pro-inflammatory cytokine release (e.g., TNF-α, IL-6) to reduce swelling and tissue damage, stabilizing cell membranes to prevent neutrophil migration and capillary permeability, and potentially modulating nociceptive pathways through central and peripheral mechanisms. When administered orally, corticosteroids effectively reduce pain and opioid consumption, enhancing post-operative recovery.27

Table 3.Corticosteroids
Drug (Brand Name) Dosage Side Effects Considerations
Dexamethasone (Decadron) 4–8 mg once daily for 3–5 days Hyperglycemia, delayed wound healing, immunosuppression Often used as a single perioperative dose to minimize adverse effects
Prednisone (Deltasone) 10–20 mg daily for 3–5 days Gastric irritation, fluid retention, adrenal suppression Short-term use is preferred to limit systemic effects
Methylprednisolone (Medrol) 4–16 mg daily (dose tapering over a few days) Increased infection risk, hyperglycemia It may be used in a dose-pack for gradual tapering

Opioids

Opioids have traditionally been a mainstay in post-operative pain management in orthopedic surgery due to their potent analgesic effects. While MMA strategies have reduced their use, opioids remain essential for managing moderate to severe pain.28–30 Modern pain management aims to minimize opioid use while still ensuring adequate pain relief to reduce the risks of dependence, respiratory depression, and other complications. Opioids achieve their analgesic effects by binding to mu-opioid receptors (MORs) in the central nervous system, inhibiting pain signal transmission at the spinal cord, activating descending pain modulation pathways to reduce pain perception, and altering emotional responses to pain through their effects on the limbic system.31–33

Table 4.Corticosteroids
Drug (Brand Name) Dosage Side Effects Considerations
Oxycodone (OxyContin, Roxicodone) 5–10 mg every 4–6 hours as needed Respiratory depression, nausea, constipation, drowsiness, addiction potential It can be combined with acetaminophen for enhanced efficacy
Hydrocodone (Vicodin, Norco, Lortab) 5–10 mg every 4–6 hours as needed Dizziness, sedation, GI distress, risk of dependence Usually combined with acetaminophen. Consider liver toxicity risk
Tramadol (Ultram) 50–100 mg every 4–6 hours (max 400 mg/day) Seizure risk, serotonin syndrome, nausea, dizziness Weak opioid. It also acts on serotonin and norepinephrine pathways

Conclusion

Oral multi-modal analgesia holds significant promise in improving post-operative pain management, particularly in orthopedic surgery, by combining non-opioid agents like NSAIDs, corticosteroids, and acetaminophen with opioids to provide adequate pain relief while minimizing opioid use and its associated risks. Future research should focus on optimizing MMA regimens through personalized approaches, developing improved delivery systems, and exploring the long-term effects of these strategies, particularly concerning opioid dependence and chronic pain. Standardizing MMA protocols and evaluating their implementation in diverse orthopedic procedures will be crucial in advancing post-operative pain management and reducing reliance on opioids.

Declaration of conflict of interest

The author does NOT have any potential conflicts of interest for this manuscript.

Declaration of funding

The author received NO financial support for the preparation, research, authorship, and publication of this manuscript.

Declaration of ethical approval for study

The institution does not require ethical approval for review articles.

There is no identifiable patient information, and the information provided is essential for scientific reasons.