Pain around surgery is a big challenge affecting millions each year. Poorly managed pain can slow recovery, lengthen hospital stays, increase complications, and raise the chance of long-lasting pain after surgery. Opioids have been widely used because they are strong at blocking acute pain signals. But concerns about their side effects and the opioid crisis have led to look for ways to reduce or avoid opioids during surgery (opioid-sparing or opioid-free anesthesia). Using opioids during surgery can cause problems depending on the dose-such as breathing difficulties, nausea and vomiting after surgery (PONV), constipation (ileus), urinary retention and increased sensitivity to pain (hyperalgesia), weakened immune response, and risk of addiction. In addition, exposure to opioids around surgery has been linked to up to 6% of patients who had never used opioids before becoming long-term users after major operations¹.Non-opioid pain relief methods have become good alternatives that control pain well while reducing these risks. These include drugs like acetaminophen, NSAIDs, dexmedetomidine, ketamine, IV lidocaine, gabapentinoids combined with regional anesthesia techniques and other non-drug therapies. When used as part of enhanced recovery after surgery (ERAS) programs, these approaches lead to better results with shorter hospital stays and higher patient satisfaction². This review summarizes current knowledge about non-opioid drug treatments and regional anesthesia for surgical pain control and looks forward to future possibilities for fully opioid-free anesthesia. Pathophysiology of Perioperative Pain: Pain after surgery is complex and comes from several sources, including nerve damage, inflammation, and nerve-related issues. Surgery causes injury that activates pain sensors in the body, releasing chemicals like prostaglandins, bradykinin, and cytokines, which make pain signals stronger.3 The spinal cord also becomes more sensitive, making pain feel worse than the original injury. If these pain signals keep going, they can cause long-term changes that lead to chronic pain after surgery.4 Opioids mainly work by targeting µ-opioid receptors to reduce pain signals. Non-opioid drugs work on different parts of the nervous system, such as NMDA receptors, α2-adrenergic receptors, calcium channels, enzymes involved in inflammation, and sodium channels. Using multiple types of non-opioid drugs together can provide better pain relief with fewer side effects.5

This narrative review was conducted to summarize current knowledge and clinical evidence regarding non-opioid methods for perioperative pain management and the concept of opioid-free anesthesia.A comprehensive search of PubMed, Scopus, Google Scholar, and Cochrane Library databases was performed for articles published between 2010 and 2024 using the keywords: opioid-free anesthesia, non-opioid analgesia, perioperative pain management, multimodal analgesia, and surgical pain relief. The data were synthesized qualitatively to highlight pharmacologic, regional, and non-pharmacologic non-opioid modalities and their role in opioid-free anesthesia. Inclusion Criteria: • Randomized controlled trials, meta-analysis, systematic reviews, and high-quality narrative reviews • Studies evaluating pharmacologic, regional, or non-pharmacologic non-opioid analgesic modalities in surgical settings Exclusion Criteria: • Case reports, non-surgical pain studies and studies with inadequate methodology. Data Extraction: A total of 120 articles were screened, and 40 met the inclusion criteria and finally 25 studies were included in the review and cited in the reference list. Findings were synthesized qualitatively under categories: pharmacologic, regional, and supportive modalities.

Non-Opioid Drug Options 1 Acetaminophen Acetaminophen (paracetamol) is a common non-opioid pain reliever that works in the brain by blocking certain enzymes and affecting serotonin pathways. IV acetaminophen works quickly and is helpful for patients who can’t take pills. Studies show it reduces the need for opioids, especially when used with NSAIDs.6 2 NSAIDs and COX-2 Inhibitors NSAIDs reduce inflammation, fever, and pain by blocking prostaglandin production. Common ones given around surgery include ibuprofen, ketorolac, diclofenac, and celecoxib (a COX-2 selective drug). They lower opioid needs but can cause stomach bleeding, kidney problems, or affect blood clotting.7 3 NMDA Antagonists: Ketamine and S-ketamine Low doses of ketamine block NMDA receptors to reduce pain and prevent increased sensitivity caused by opioids. It helps lower opioid use during major surgeries like abdominal or orthopedic operations. S-ketamine is a safer and stronger form with growing support for use during surgery.8,9 4 α2-Adrenergic Agonists: Dexmedetomidine and clonidine, dexmedetomidine calms patients while providing pain relief by stimulating α2-adrenergic receptors. It reduces opioid needs during surgery and helps with recovery by lowering stress responses. Clonidine works similarly but may cause more effects on blood pressure and heart rate.10 5 Intravenous Lidocaine Infusion: Lidocaine reduces pain, inflammation, and nerve sensitivity when given continuously during surgery. It helps patients recover bowel function faster after abdominal operations and lowers opioid use and hospital stay length.11 6 Gabapentinoids Gabapentin and pregabalin work on calcium channels to calm nerve activity involved in pain sensitivity. They slightly reduce opioid needs but can cause side effects like drowsiness or dizziness, especially when combined with opioids.12 7 Magnesium Sulfate Magnesium blocks NMDA receptors and calcium channels naturally in the body. Giving magnesium during surgery lowers opioid use and improves pain control in many types of surgeries.13 8 Cannabinoids Drugs acting on cannabinoid receptors (CB1 and CB2) are being studied as extra options for managing surgical pain. Early research suggests they may reduce opioid use and nausea but more evidence is needed.14 Regional and Local Anesthesia Methods Regional anesthesia helps control pain by blocking nerves near the surgery site without using opioids. 1 Neuraxial Techniques Spinal and epidural anesthesia provide strong pain relief for surgeries on the abdomen, chest, or legs. Epidurals with local anesthetics (sometimes with added drugs) greatly reduce the need for opioids during recovery.15 2 Peripheral Nerve Blocks Using ultrasound guided block has improved nerve blocks to target specific areas like the abdomen or chest wall (e.g., TAP block, erector spinae plane block). These provide good pain relief with few side effects.16 3 Continuous Catheter Techniques Perineural catheter placement allows delivery of local anesthetics continuously for longer-lasting opioid-free pain control after major orthopedic or throcic surgeries.17 4 ERAS Protocols: Including regional anesthesia in Enhanced Recovery after Surgery (ERAS) plans leads to better recovery outcomes, less opioid use and shorter hospital stays across many types of surgery.18 Non-Drug and Supportive Strategies: Additional therapies can improve pain control without adding more medications. • Acupuncture and TENS (electrical stimulation) have been shown to lower pain medicine needs in some surgeries.19 • Cognitive-behavioral therapy (CBT) helps patients with high anxiety or chronic pain manage their surgical experience better.20 • Music therapy and virtual reality reduce anxiety and how much pain patients feel.21 • Mindfulness exercises and relaxation techniques help decrease stress around surgery time and improve patient satisfaction.22 Clinical Evidence and Outcomes: Many studies show that using non-opioid pain relief methods helps reduce opioid use, improves patient satisfaction and lowers opioid-related side effects. • Beloeil et al. (2021) found that opioid-free anesthesia using dexmedetomidine and ketamine controlled pain as well as remifentanil-based anesthesia but with fewer side effects.23 • Weibel et al. (2018) confirmed that IV lidocaine is helpful in abdominal surgery.11,24 • Recent ERAS protocols using multiple non-opioid methods have led to faster recovery and less nausea and vomiting after surgery. Some challenges include differences in treatment plans, varied patient groups, and concerns about side effects from some non-opioid drugs. Still, the evidence supports including these methods in surgical care.

Future Directions: The future of pain control around surgery focuses on personalized and new approaches: • Artificial intelligence may help predict pain relief needs and side effects in real time.24 • Genetic testing could help choose the best drugs for each person.25 • New drugs targeting nerves outside the brain are being studied to reduce side effects.25 • Expanding these practices worldwide, especially in low-income countries, is both a challenge and an opportunity for safer, opioid-reducing care.25

The global opioid crisis and increasing awareness of opioid-related adverse effects have shifted perioperative pain management toward safer, evidence-based, non-opioid and multimodal strategies. Current literature strongly supports the use of multimodal analgesia incorporating non-opioid pharmacologic agents—such as acetaminophen, NSAIDs, ketamine, dexmedetomidine, intravenous lidocaine, magnesium, and gabapentinoids—along with regional anesthesia techniques (neuraxial blocks, peripheral nerve blocks, and continuous catheter infusions). These modalities, when integrated into Enhanced Recovery After Surgery protocols, significantly reduce perioperative opioid consumption, opioid-related side effects (PONV, ileus, respiratory depression), and hospital stay, while improving patient satisfaction and functional recovery. Emerging technologies like artificial intelligence, pharmacogenomics and personalized medicine hold promise for tailoring analgesic plans to individual patient profiles, optimizing safety and efficacy. Despite encouraging evidence, universal adoption of opioid-free anesthesia (OFA) is still evolving and must be tailored to patient characteristics, surgical complexity and institutional protocols.

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