More than 80% of surgical patients experience acute postoperative pain, and many report pain that is moderate, severe or extreme [1]. Poorly controlled pain can delay mobility, impair sleep, increase complications, and reduce quality of recovery. For decades, opioids have been central to postoperative analgesia because they are potent and fast acting. Yet their adverse effects, including nausea, vomiting, constipation, sedation, respiratory depression, tolerance, dependence, and potential misuse, have driven growing interest in non-opioid and opioid-sparing strategies for postoperative analgesia [1,2].
The modern approach to pain management is multimodal analgesia: the planned use of medications and techniques that act through different biological pathways. Clinical guidelines recommend multimodal analgesia for adults and children after surgery, emphasizing that the plan should be individualized according to the procedure, the patient’s medical history, prior pain experience, comorbidities, and treatment goals [1]. In practice, non-opioid medication may be used alone for selected mild-to-moderate pain states, or combined with opioids, regional anesthesia, local anesthetic infiltration, and/or nonpharmacologic strategies when pain is expected to be more intense.
Common non-opioid options include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), gabapentinoids, ketamine or esketamine, alpha-2 agonists such as dexmedetomidine and clonidine, intravenous lidocaine, magnesium, and corticosteroids [2,3]. These drugs work differently. Acetaminophen and NSAIDs reduce inflammatory pain pathways, with NSAIDs also lowering prostaglandin-mediated inflammation. Ketamine targets N-methyl-D-aspartate receptors involved in central sensitization and hyperalgesia. Gabapentin and pregabalin modulate calcium channels and may reduce neuropathic components of postoperative pain. Dexmedetomidine can provide analgesic and sedative effects without the same degree of respiratory depression associated with opioids. Lidocaine, when used intravenously in selected settings, may reduce nociceptive signaling and improve recovery after some procedures [1–3].
Multimodal approaches for postoperative analgesia are effective and safe in many patient populations. A 2024 network meta-analysis in adults with obesity found that NSAIDs, acetaminophen, lidocaine, alpha-2 agonists, ketamine, and oral gabapentinoids reduced early postoperative pain, and NSAIDs, acetaminophen, ketamine, and lidocaine showed benefits later in recovery [3]. Some non-opioid strategies also reduced postoperative nausea and vomiting and the need for rescue analgesia [3]. These findings are especially relevant for patients with obesity, who may have higher vulnerability to opioid-related airway and pulmonary complications.
Opioid-free patient-controlled analgesia is an emerging strategy, particularly for procedures associated with mild or moderate pain. Patient-controlled analgesia allows patients greater agency but adds additional requirements for safeguards to avoid overdosing. Recent reviews suggest that combinations such as NSAIDs with dexmedetomidine, gabapentin, or ketamine can provide useful analgesia and reduce opioid exposure in selected patients [2]. However, opioid-free regimens are not universally adequate. Severe postoperative pain after thoracotomy, laparotomy, major vascular surgery, or major joint replacement may still require opioids, epidural analgesia, continuous nerve blocks, or other potent techniques [2]. In such cases, the goal is opioid minimization rather than absolute opioid avoidance.
Non-opioid medications also have their own risks. NSAIDs can increase gastrointestinal bleeding, renal injury, and cardiovascular risk, and may be inappropriate after some operations. Acetaminophen can cause liver toxicity at excessive doses. Gabapentinoids can cause dizziness and sedation and require caution in renal impairment. Ketamine may cause hallucinations or dissociative symptoms, while dexmedetomidine can cause bradycardia and hypotension [1,2]. Evidence that perioperative drugs prevent chronic postsurgical pain remains uncertain; a 2021 systematic review found some statistically significant signals for pregabalin, intravenous lidocaine, and NSAIDs, but overall effects were small and of unclear clinical relevance [4].
Non-opioid postoperative analgesia is therefore best understood as a careful, evidence-based strategy rather than a universal substitute for opioids. When tailored to the patient and surgery, it can improve pain control, reduce opioid exposure, and support recovery. Its success depends on appropriate drug selection, dosing, monitoring, and honest recognition that some patients will still need opioids as one component of a broader pain plan.
References
- Chou, R. et al. Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J. Pain 17, 131–157 (2016). https://doi.org/10.1016/j.jpain.2015.12.008
- Luo, X., Rao, P.-G., Lei, X.-H., Yang, W.-W., Liao, B.-Z. & Guo, R. Opioid-free strategies for patient-controlled intravenous postoperative analgesia: a review of recent studies. Front. Pharmacol. 15, 1454112 (2024). https://doi.org/10.3389/fphar.2024.1454112
- Carron, M., Tamburini, E., Linassi, F., Pettenuzzo, T., Boscolo, A. & Navalesi, P. Non-opioid analgesics and adjuvants after surgery in adults with obesity: systematic review with network meta-analysis of randomized controlled trials. J. Clin. Med. 13, 2100 (2024). https://doi.org/10.3390/jcm13072100
- Carley, M. E. et al. Pharmacotherapy for the prevention of chronic pain after surgery in adults: an updated systematic review and meta-analysis. Anesthesiology 135, 304–325 (2021). https://doi.org/10.1097/ALN.0000000000003837