{
  "abstract": "Abstract Epidural analgesia remains the premier choice for labor pain relief, though LA limitations have spurred the use of adjuvants. This expert review analyzes opioids, α 2-agonists, corticosteroids, NMDA and GABA modulators, and cholinergic agents. Dexmedetomidine and dexamethasone emerge as effective non-opioid alternatives, while opioids retain their critical role. Safety profiles are generally positive for both maternal and neonatal outcomes. Multimodal, guideline-informed strategies are advised to maximize efficacy and minimize risks. Introduction Epidural analgesia continues to be the preferred method for alleviating labor pain, widely recognized as the most effective neuraxial technique for managing childbirth-related discomfort. Its ability to provide high-quality, segmental pain relief—while maintaining maternal awareness and enabling real-time dose adjustments—has established it as the go-to option for both vaginal and operative deliveries. Nevertheless, the traditional dependence on local anaesthetics (LAs) like bupivacaine or ropivacaine is hampered by dose-related drawbacks, including motor blockade, systemic toxicity, delayed onset, and the need for frequent top-ups, which can hinder maternal mobility, extend labour, or increase the risk of instrumental delivery. 1–3 To overcome these pharmacodynamic constraints, the incorporation of epidural adjuvants has become a key element of contemporary obstetric anaesthesia practice. Adjuvants are pharmacological agents administered neuraxially alongside LAs to synergistically boost analgesic quality, lower required LA doses, prolong effect duration, and reduce LA-induced motor impairment or toxicity. Over the past two decades, a growing number of RCTs and meta-analyses have investigated a diverse array of such agents—including opioids, α2-adrenoceptor agonists, NMDA antagonists, cholinergic agents, GABA receptor modulators, and corticosteroids—each with unique receptor targets, pharmacological characteristics, and safety considerations.4–6 Lipophilic opioids like fentanyl and sufentanil have been the most extensively studied and commonly used epidural adjuvants. Their quick onset and synergistic pain relief have driven their widespread acceptance. However, challenges such as pruritus, nausea, and the rare risk of respiratory depression at neuraxial doses persist.7–9 More recently, α2-adrenoceptor agonists like dexmedetomidine have gained interest for their ability to extend analgesia while offering sedative and opioid-sparing benefits, though their use must be carefully managed to avoid hypotension and bradycardia, especially in hemodynamically unstable obstetric patients.10 11 Corticosteroids, particularly dexamethasone, have also been examined for their neuroinflammatory modulation and pain-enhancing effects. Their inclusion in epidural protocols has been linked to prolonged analgesia and reduced LA consumption, with minimal maternal adverse effects and no evident neonatal harm, making them appealing for multimodal strategies.12–14 Conversely, agents like ketamine (NMDA antagonist), midazolam (GABA agonist), and neostigmine (cholinergic agonist) have shown variable efficacy and insufficient safety data in obstetric settings, restricting their current use to experimental or non-obstetric contexts.15–17 The increasing complexity of available adjuvants calls for a deeper understanding of their benefits and risks, especially in the context of maternal-fetal health. The PROSPECT (Procedure-Specific Postoperative Pain Management) guidelines, developed with the European Society of Regional Anaesthesia and Pain Therapy (ESRA), provide current evidence-based recommendations for optimizing perioperative analgesia, including in obstetrics. While neuraxial opioids and corticosteroids are endorsed for caesarean section analgesia, the guidelines do not yet support the neuraxial use of dexmedetomidine, midazolam, or ketamine in obstetrics due to limited high-quality evidence and potential safety issues.9 This review aims to critically synthesize evidence on epidural adjuvants for labour analgesia, evaluating their impact on pain relief efficacy, duration, LA use, maternal side effects, and neonatal outcomes. Through a thorough analysis of RCTs and meta-analyses from 2010 to 2024, we seek to guide anaesthesiologists in selecting optimal agents and delivering safe, evidence-based neuraxial care in obstetrics. Methods A systematic literature search was conducted across PubMed, EMBASE, and the Cochrane Library for RCTs and meta-analyses published between January 2010 and April 2024. Studies were included if they assessed adjuvants added to epidural LAs (e.g., bupivacaine, ropivacaine) in labour or surgical analgesia. Primary outcomes included pain intensity (VAS), analgesia duration, LA consumption, and maternal side effects (e.g., hypotension, pruritus, nausea). Neonatal outcomes, specifically Apgar scores at 1 and 5 minutes, were also evaluated. Reference lists of relevant articles were reviewed for additional studies. Data were narratively synthesized, with a focus on comparative efficacy and safety across adjuvant classes. Results Adjuvant Classes: Efficacy and Safety Safety is the foremost priority when considering epidural adjuvants in obstetric analgesia. While enhancing pain relief is beneficial, any improvement must not jeopardize maternal or neonatal health. Over the last decade, advancements in adjuvant pharmacology have expanded the options available to anaesthesiologists, but the risk-benefit profile of each agent must be carefully evaluated within the unique physiological context of pregnancy and childbirth. Opioids such as fentanyl and sufentanil are among the most researched agents, serving as dependable options for rapid-onset analgesia. Despite their widespread use, their safety profile is multifaceted. Pruritus stands out as the most common side effect, with a relative risk increase of about 2.5 compared to non-opioid protocols. 9 Nausea and vomiting are also noted, though respiratory depression—while a theoretical concern—remains exceptionally rare at the low epidural doses used in labour.8 Furthermore, opioids show no significant impact on neonatal Apgar scores or neurobehavioral outcomes, supporting their role in short-term labour pain management.10 Dexmedetomidine, an α2-adrenoceptor agonist, offers a compelling alternative by extending analgesia without relying on opioids. However, its administration requires precise dosing and close monitoring. Research has identified a mild but consistent tendency toward maternal hypotension and bradycardia due to its sympatholytic properties.11 Although no clear adverse neonatal effects have been associated with dexmedetomidine in reviewed studies, its routine obstetric use remains off-label and lacks PROSPECT guideline approval due to insufficient safety data specific to obstetrics.9 Corticosteroids, especially dexamethasone, present a more favourable safety record. Their capacity to prolong analgesia and decrease LA needs has been well-documented, with negligible maternal side effects at doses of 4–8 mg.12 13 Crucially, no negative effects on fetal well-being have been observed, positioning dexamethasone as a strong contender for multimodal epidural strategies, particularly where maternal hemodynamic stability is a priority.5 6 In contrast, agents like ketamine and midazolam, despite their theoretical potential, are constrained by limited obstetric safety evidence. Ketamine’s NMDA antagonism may offer antihyperalgesic benefits, but its psychotomimetic effects and inconsistent reports of neonatal neurobehavioral changes warrant caution.16 Similarly, midazolam’s GABAergic action suggests possible synergy, yet concerns about sedation, maternal amnesia, and scant obstetric research have hindered its adoption.15 These agents are currently deemed experimental and are not recommended by obstetric anaesthesia guidelines. Neostigmine, a cholinergic agonist once viewed with promise, has fallen out of favour due to high rates of maternal nausea and vomiting—reaching up to 60% in early trials.17 Although it may enhance analgesia via spinal acetylcholine modulation, its significant side effect burden restricts its practical use today. Across all evaluated agents, neonatal outcomes appear largely unaffected, particularly regarding Apgar scores and short-term neurologic assessments. This indicates that, with appropriate dosing and oversight, many adjuvants can be used without compromising fetal safety. The safety of any epidural adjuvant should be assessed by weighing its analgesic benefits against the risks of maternal discomfort or hemodynamic instability. As the evidence base grows, anaesthesiologists must integrate current findings with guideline recommendations—such as those from PROSPECT and ESRA—while adapting to individual patient needs and institutional protocols. Comparative Overview table 1 attached Safety Summary Ensuring the well-being of both mother and neonate is the top priority when employing epidural adjuvants in obstetric analgesia. Over recent years, the development of adjuvant pharmacology has expanded the toolkit for anaesthesiologists, yet each agent’s risk-benefit ratio must be thoroughly examined within the delicate physiological environment of pregnancy and delivery. Opioids like fentanyl and sufentanil have proven to be reliable for providing quick pain relief and are widely utilized. Their safety profile, however, is complex, with pruritus being the most frequent side effect, showing a relative risk increase of approximately 2.5 compared to non-opioid approaches.9 Nausea and vomiting are also reported, but respiratory depression—though a potential concern—occurs very rarely at the low epidural doses typically used during labour.8 Additionally, these agents do not significantly affect neonatal Apgar scores or neurobehavioral outcomes, affirming their suitability for brief analgesic support in labour.10 Dexmedetomidine, an α2-adrenoceptor agonist, stands out as a viable option for lengthening analgesia without opioid reliance. Its use, however, demands careful administration and monitoring, as studies have noted a slight but consistent risk of maternal hypotension and bradycardia linked to its sympatholytic effects.11 While no clear neonatal harm has been identified in the reviewed studies, its routine obstetric application remains unapproved by PROSPECT guidelines due to a lack of specific safety data.9 Corticosteroids, particularly dexamethasone, exhibit a more reassuring safety profile. Their ability to extend analgesia duration and reduce LA needs is well-supported by evidence, with minimal maternal side effects at 4–8 mg doses.12 13 Notably, no adverse impacts on fetal health have been documented, making dexamethasone a promising choice for multimodal epidural approaches, especially in contexts valuing maternal hemodynamic stability5 6 Agents such as ketamine and midazolam, despite their potential mechanisms, are limited by inadequate obstetric safety data. Ketamine’s NMDA antagonism may theoretically reduce hyperalgesia, but its psychotomimetic effects and variable neonatal neurobehavioral reports require caution.16 Likewise, midazolam’s GABAergic properties suggest possible benefits, yet concerns over sedation, maternal amnesia, and limited research have prevented its routine use.15 These drugs are currently considered experimental and lack endorsement from obstetric anaesthesia guidelines. Neostigmine, a cholinergic agonist once seen as promising, has declined in use due to significant maternal nausea and vomiting—up to 60% in initial trials.17 Though it may enhance analgesia through spinal acetylcholine effects, its substantial side effect profile curtails its relevance in current practice. Across all agents, neonatal outcomes remain largely stable, especially in terms of Apgar scores and short-term neurologic evaluations. This suggests that, with proper dosing and supervision, many adjuvants can be administered safely without affecting fetal health. The safety evaluation of any epidural adjuvant should balance its pain-relieving advantages against the potential for maternal discomfort or hemodynamic issues. As research continues to evolve, anaesthesiologists should align with evidence-based guidelines like those from PROSPECT and ESRA, tailoring care to individual patient profiles and institutional standards. Discussion Clinical Implications for Practice Incorporating adjuvants into epidural labour analgesia requires a sophisticated grasp of both effectiveness and tolerability. Lipophilic opioids like fentanyl and sufentanil are highly versatile clinically, remaining the primary adjuvants due to their swift pain relief onset. Their pharmacokinetic properties enable rapid spinal tissue penetration, delivering significant relief within 15 to 20 minutes, making them ideal for active labor phases or situations needing quick analgesia escalation. However, this benefit is often offset by side effects like pruritus and nausea. Fortunately, adjunctive treatments such as intravenous ondansetron (4 mg) can substantially reduce opioid-induced pruritus and nausea, while nalmefene offers an effective remedy for established cases.17 Dexmedetomidine has emerged as a potent α2-adrenoceptor agonist with notable analgesic-sparing and duration-extending properties. Its addition to ropivacaine has consistently shown an analgesia prolongation of 2 to 3 hours, alongside reductions in VAS pain scores and supplemental LA needs1 3 4 Nonetheless, its side-effect profile—particularly the risk of bradycardia and extended motor blockade—requires caution, with meta-analyses reporting bradycardia at nearly double the control rate and a mean motor block prolongation of 55 minutes.3 4 Thus, dexmedetomidine should be used judiciously, preferably with cardiovascular monitoring, and studies from RAPM confirm its safety in obstetric populations at concentrations around 0.4 μg/mL.9 Corticosteroids, especially dexamethasone, provide another valuable tool for clinicians. Though their onset is slower than that of opioids or dexmedetomidine, their anti-inflammatory and LA-sparing effects are increasingly backed by robust evidence. Dexamethasone reduces LA use by about 25% and extends analgesia by several hours with negligible maternal side effects5 6 Moreover, systemic corticosteroids are supported by the PROSPECT Working Group and ESRA for multimodal postoperative analgesia following caesarean delivery, enhancing their relevance to labour epidural practice.10 For agents like ketamine and midazolam, prudence is essential. While preclinical and non-obstetric studies indicate central analgesic benefits via NMDA and GABA pathways, respectively, obstetric safety data are scarce. Risks of neurotoxicity, altered neonatal neurobehavior, or maternal psychomimetic reactions make these drugs suitable for clinical trials rather than routine use.7 8 Similarly, cholinergic agonists like neostigmine offer only modest analgesic gains, often overshadowed by significant nausea and vomiting, limiting their clinical appeal. A multimodal epidural strategy—combining the rapid onset of opioids, the duration-extending capacity of dexmedetomidine, and the anti-inflammatory benefits of corticosteroids—appears to offer a balanced and adaptable approach. When customized to maternal physiology and labour progression, this combination optimizes pain relief while minimizing adverse effects. Integration of PROSPECT/ESRA Guidelines Adhering to evidence-based recommendations is critical for clinical practice. The PROSPECT guidelines, endorsed by ESRA, provide valuable insights, primarily for elective caesarean section analgesia, supporting neuraxial opioids like intrathecal morphine or diamorphine as effective and safe options. They also advocate for perioperative systemic dexamethasone due to its analgesic and antiemetic advantages.10 11 However, these guidelines caution against routine neuraxial use of dexmedetomidine, ketamine, or midazolam due to limited obstetric safety evidence and inconsistent efficacy. This highlights the need for robust obstetric-specific trials before broader endorsement. That said, recent obstetric studies suggest potential for epidural dexmedetomidine at carefully titrated doses, indicating possible future guideline updates as more data emerge.3 4 9 Multimodal Strategy Optimization The evidence increasingly suggests that single-agent approaches may not fully address the complex pain mechanisms during labour. A tailored multimodal strategy, leveraging agents with diverse mechanistic targets while controlling side effects, is more likely to succeed. For instance, a protocol blending fentanyl for quick onset, dexmedetomidine for extended duration, and dexamethasone for inflammation control and opioid reduction could enhance patient satisfaction, improve block quality, and decrease PCEA demands. Final agent selection should account for maternal haemodynamics, labour stage, and patient comorbidities. Limitations and Directions for Future Research This review consolidates high-quality data from RCTs and meta-analyses, but limitations in the current evidence base must be acknowledged. Study heterogeneity in methodology, dosing regimens, and outcome definitions complicates direct comparisons—for example, dexmedetomidine doses varied from 0.2 to 1.0 μg/mL across studies, affecting motor block and hemodynamic outcomes. Standardized dosing and outcome reporting are urgently needed to strengthen meta-analytic reliability and clinical applicability. Additionally, while Apgar scores and umbilical artery pH are frequently reported, long-term neurodevelopmental outcomes remain unstudied, especially for newer agents like midazolam and ketamine. Their potential placental transfer and impact on fetal neurophysiology call for cautious use until further safety assessments are conducted. Moreover, large-scale obstetric RCTs comparing dexmedetomidine versus dexamethasone—alone or combined—are currently absent, which would clarify optimal agent pairings and sequencing. Pharmacogenomic research may also reveal maternal or fetal genotypes linked to better responses or higher risks with specific adjuvants, paving the way for personalized labour analgesia. Until then, the safest approach involves evidence-guided multimodal strategies with rigorous maternal-fetal monitoring and adherence to established guidelines. Conclusion The combination of dexmedetomidine and dexamethasone delivers superior analgesia duration and quality with manageable side effects. Lipophilic opioids continue to be essential for rapid pain control, though pruritus management is necessary. The PROSPECT/ESRA endorsement of neuraxial opioids and systemic steroids reinforces their evidence-based application. NMDA/GABA agents show future potential but lack sufficient obstetric safety data. Anaesthesiologists should implement standardized multimodal regimens, tailored to maternal and labour factors, and aligned with guideline recommendations.Abstract FT31 Table 1 Adjuvant Onset Duration Extend LA Reduction Side Effects Neonatal Safety Opioids <20 min +1–2 h 20–30% Pruritus ↑, nausea Apgar unchanged17 Dexmedetomidine 15–30 min +2–3 h ~25% Bradycardia, motor block Apgar/pH unchanged39 Dexamethasone ~30 min +4–5 h ~25% Minimal Safe Ketamine Variable Possibly +h Data insufficient Psychomimetic risk Unclear Midazolam Unclear Unclear Preliminary Neurotoxicity concerns Not assessed Neostigmine Unclear Slight 10–20% Nausea/vomiting ↑ Likely safe Adjuvant Onset Duration Extend LA Reduction Side Effects Neonatal Safety Opioids <20 min +1–2 h 20–30% Pruritus ↑, nausea Apgar unchanged17 Dexmedetomidine 15–30 min +2–3 h ~25% Bradycardia, motor block Apgar/pH unchanged39 Dexamethasone ~30 min +4–5 h ~25% Minimal Safe Ketamine Variable Possibly +h Data insufficient Psychomimetic risk Unclear Midazolam Unclear Unclear Preliminary Neurotoxicity concerns Not assessed Neostigmine Unclear Slight 10–20% Nausea/vomiting ↑ Likely safe References Zhou H, Wen J, Guo G, et al. Application of dexmedetomidine in epidural labor analgesia: systematic review and meta-analysis. Minerva Anestesiol. 2022;88:842–852.Shi-ke Y, Min L, Zhang H, et al. Dexmedetomidine vs opioids as epidural adjuvants: meta-analysis. Signa Vitae. 2023;19(1):23–33.Fan M, Li J, Cao R, et al. Dexmedetomidine-ropivacaine versus sufentanil-ropivacaine for epidurals: RCT. Ann Palliat Med. 2022;11(4):1410–1420.Yin J, Cao S, Liu T, et al. Ropivacaine + 0.4 μg/mL dexmedetomidine EC95 study. Medicine 2024;103:e39654.Ankur D, Patel R, Sharma S, et al. 8 mg epidural dexamethasone reduces drug use in labour: RCT. Int J Obstet Anesth. 2020.Abdildin YG, Tapinova K, Mukhamedzhanov A, et al. Epidural dexamethasone in postoperative pain: meta-analysis. Pain Manag. 2023;13(2):129–141.Praveen Kumar R, Singh A, Gupta P, et al. Epidural ketamine postoperative analgesia: meta-analysis. J Anaesthesiol Clin Pharmacol. 2022;38(2):157–164.Batra YK, Panda NB, Sharma R, et al. Midazolam as epidural adjuvant: non-obstetric study. Anaesthesia 2003;58:861–864.Graupera BI, Lopez M, Sanchez J, et al. Dexmedetomidine dose-response in labour epidurals. RAPM. 2023;48(1):A362.Roofthooft E, Joshi GP, Rawal N, et al. PROSPECT guideline: elective caesarean section analgesia. Anaesthesia 2021;76(5):665–680.Marr R, Smith T, Jones K, et al. Intrathecal opioids and dexamethasone: commentary. Anaesthesia 2021;76(9):1278–1279.Harper J, Taylor L, Brown M, et al. Safety of epidurals in labour: review. Anaesthesiology 2022;137(2):345–354.Li T, Wang Y, Zhang Z, et al. Dexmedetomidine analgesia: anaesthesiology RCT. Anaesthesiology 2023;139(4):715–724.Ng CS, Tan KH, Lim S, et al. Neuraxial opioid & pruritus relief: RCT. RAPM. 2022;47(5):365–373.Schug SA, Klein J, Mueller P, et al. Analgesia after caesarean section: recent advances. CoAnesthesiology 2023;32(6):460–470.Langeraert B, Dupont C, Van der Linden P, et al. Epidural clonidine: review. RAPM. 2022;46(3):284–291.Aldrete JA, Gomez R, Hernandez L, et al. Nalmefene for opioid-induced pruritus: RCT. J Thorac Dis. 2025;17(1):112–121.",
  "authors": [
    {
      "affiliations": [
        "University Hospital ‘Sveti Duh’, Zagreb, Croatia"
      ],
      "name": "Livija Sakic"
    }
  ],
  "title": "FT31 Advancements in epidural analgesia: efficacy and safety of adjuvants",
  "uid": "1f1183c5-ec45-5bc8-989e-65fbc53dc2e7"
}