Local Anaesthetic Systemic Toxicity in Dental and Oral and Maxillofacial Surgery: Safe Dosing, Combination Agents, and Emergency Management—A Narrative Review
Safe LA administration in oral surgery requires systematic MRD calculation, application of the fractional dose rule for combined-agent appointments, attention to patient-specific risk factors, setting-appropriate emergency preparedness, and structured differential diagnosis to distinguish LAST from more common dental emergencies.
Abstract
Background/Objectives: Local anaesthetic systemic toxicity (LAST) is a rare but potentially fatal complication of dental and oral and maxillofacial surgical local anaesthesia (LA). Three amide agents are commonly used in the UK: lignocaine (lidocaine) 2% with adrenaline 1:80,000; articaine 4% with adrenaline 1:100,000 (2.2 mL cartridges); and bupivacaine 0.5%. Clinically significant discrepancies between guideline sources for maximum recommended dosages (MRDs) persist, and the additive toxicity of combined amide agents remains underappreciated. The objectives are: to provide clear, evidence-appraised MRD guidance for dental practitioners; to explain safe combination dosing using the fractional dose rule with acknowledgement of its pharmacokinetic limitations; and to outline recognition and management of LAST, including intravenous lipid emulsion (ILE) therapy, setting-stratified response, and differential diagnosis. Methods: These include the following: narrative review of MEDLINE (via PubMed), the Cochrane Library, and Embase (inception to May 2026), supplemented by key regulatory documents (British National Formulary (BNF) 91; US Food and Drug Administration (FDA) prescribing information; UK Summaries of Product Characteristics (SmPCs)); major guideline documents (American Society of Regional Anesthesia and Pain Medicine (ASRA) 2018; Association of Anaesthetists 2021; Resuscitation Council UK 2021); systematic reviews; and peer-reviewed literature, ranked by a jurisdiction-specific UK prescribing and regulatory source hierarchy. Results: BNF 91 and the FDA both support a 7 mg/kg (500 mg) MRD for lignocaine with adrenaline; in practice, the adrenaline ceiling limits administration to 6–7 cartridges (2.2 mL) regardless of the guideline followed. The principal reasons for caution when combining amide agents are; additive systemic toxicity, more complex dose calculation, absence of proven clinical benefit for concurrent mixing, unnecessary drug exposure, and incremental hypersensitivity risk—not metabolic pathway differences. The fractional dose rule is a pharmacologically justified safety heuristic with acknowledged pharmacokinetic limitations. ILE is a specific rescue therapy for severe or cardiovascular LAST; airway support and oxygenation remain the primary interventions. Patient-specific factors substantially lower the effective toxic threshold. Conclusions: Safe LA administration in oral surgery requires systematic MRD calculation, application of the fractional dose rule for combined-agent appointments, attention to patient-specific risk factors, setting-appropriate emergency preparedness, and structured differential diagnosis to distinguish LAST from more common dental emergencies.
LA solutions can elicit systemic metabolic responses, and caution is warranted when using lignocaine containing adrenaline in patients with T2DM patients, and Clinicians should consider plain LA alternatives for diabetic patients when prolonged anaesthesia or enhanced haemostasis is not essential.
Harshawardhan Kadam, CV Pattanshetti, Swapnil U. Shinde et al.· Journal of Clinical and Diag...· 0 citations
Introduction: Conscious sedation (CS) is commonly recommended in pediatric dental clinics to manage uncooperative and anxious patients. Various routes of drug administration have been introduced to achieve effective CS. Among these, the intranasal (IN) route has gained popularity in dentistry due to its non-invasive nature. However, there is currently no comprehensive thematic review analyzing the efficacy and safety of drug regimens delivered via the intranasal route alone or in combination with other administration routes. Therefore, the aim of the present review is to thematically analyze the efficacy and safety of different drug regimens used for conscious sedation delivered through the intranasal route and/or in combination with other routes. Material and Method: This scoping review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist. The protocol was prospectively registered on the Open Science Framework (OSF) prior to data extraction. Predefined inclusion criteria were developed, and five electronic databases were searched. The search identified a total of 239 articles from different databases. After evaluation and removal of duplicates, a total of 54 articles were assessed for full-text eligibility. Finally, 18 articles were included, and data extraction was performed. To develop themes the included articles were imported to the N-vivo software package. Results: Six themes and sixteen subthemes were developed. The major themes were route efficacy and behavioral outcomes, onset of action, patients’ acceptance and tolerance, special needs population, recovery and duration, safety profile and adverse events. Conclusion: Combined intranasal and oral conscious sedation is a generally safe and well-accepted approach in pediatric dentistry, but variations in recovery time, patient acceptance, and adverse events necessitate individualized sedation strategies.
Local anaesthetics are essential to regional anaesthesia but may exert neurotoxic effects on peripheral nerves under specific conditions. Although perioperative nerve injury is increasingly recognised, the contribution of local-anaesthetic neurotoxicity, the relative toxicity of different agents and concentrations, and the influence of patient-related risk factors remain incompletely defined. This evidence-based narrative review synthesises experimental and clinical data on peripheral nerve neurotoxicity associated with local anaesthetics and discusses implications for clinical practice and future research. A prospectively registered search was conducted across major biomedical databases for studies published between 1990 and 2024. Experimental evidence consistently demonstrates dose-dependent and time-dependent neurotoxicity for all clinically used local anaesthetics, characterised by ultrastructural damage, oxidative stress, mitochondrial dysfunction and activation of apoptotic and intracellular signalling pathways. Relative toxicity varies between agents and concentrations, with lidocaine and bupivacaine often appearing more potent than ropivacaine or chloroprocaine in preclinical models, while findings for articaine remain heterogeneous. Diabetic and metabolically compromised nerves exhibit increased susceptibility, supporting a 'two-hit' model of injury. In contrast, clinical evidence directly linking specific agents, concentrations or exposure durations to permanent peripheral nerve injury is limited, and such injuries are typically multifactorial. Overall, chemical neurotoxicity should be considered one component of a broader perioperative risk profile. Risk mitigation should prioritise avoidance of intraneural injection, adherence to recommended doses and cautious use of high concentrations or prolonged exposure, particularly in vulnerable nerves. Further research should integrate mechanistic and clinical outcomes while accounting for patient-level risk factors.
P. Goffin, J. Lecoq, M. Carella et al.· European Journal of Anaesthe...· 0 citations
Purpose of the review Local anesthetics remain vital to modern medicine, yet their narrow therapeutic window continues to result in complications. This review synthesizes recent literature to define the current landscape of local anesthetic-associated adverse events. Recent findings Perioperative mortality attributable to local anesthetics persists despite sustained safety initiatives and professional society recommendations. Pharmacovigilance and case data identify lidocaine (oropharyngeal, topical, and via local infiltration) as the predominant contributor to adverse outcomes, including death. Local anesthetic systemic toxicity remains an issue, with a recent shift in epidemiology: an increasing proportion of toxic events originates from surgeon- and proceduralist-administered analgesia. Anesthesiologist-controlled methods also cause toxicity via catheter-based delivery and nerve blocks in highly vascular regions. Localized toxicity in the form of high neuraxial contributes to morbidity, with recent reviews reinforcing known risk factors; whereas localized neurotoxicity appears less troublesome when managed appropriately. Summary The cumulative evidence identifies shifts in the patterns of systemic and localized toxicities. Bupivacaine-based peripheral nerve blocks no longer represent the principal cause of complications because of the advent of ultrasound guidance and lipid emulsion therapy. In contrast, high neuraxial techniques persist as a cause of morbidity, accompanied by intravenous/oropharyngeal lidocaine, proceduralist-administered local infiltration analgesia, and catheter-based delivery.
Michael R. Fettiplace· Current Opinion in Anaesthes...· 0 citations
Background: To determine the median effective dose (ED 50 ) of tegileridine for immediate postoperative analgesia following laparoscopic colorectal cancer surgery (LCRS), and to evaluate its safety profile. Methods: A modified Dixon’s up-and-down sequential method was employed, starting with an initial tegileridine dose of 15 µg/kg and a dose ratio of 1:1.1. Patients undergoing elective LCRS received a standardized multimodal analgesic background, including a transversus abdominis plane block and intraoperative sufentanil, and received intravenous tegileridine 10 minutes before the end of surgery. A blinded investigator assessed pain using the Numerical Rating Scale (NRS) at 15 and 30 minutes, and 2 hours post-extubation. Effective analgesia was defined as an NRS score ≤ 3 without rescue analgesia within 2 hours. The ED 50 was calculated using probit regression analysis. Hemodynamic variables and adverse events were documented, and safety was followed until postoperative day 2. Results: Analysis of the 40 patients revealed that the ED 50 of tegileridine for LCRS was 7.311 μg/kg (95% confidence interval [CI]: 2.044 to 9.194). Adverse events were mild and no serious adverse events were observed. In the PACU, 5/40 patients (12.5%) experienced adverse events (hypoxaemia, nausea, vomiting, and dizziness). By postoperative day 2, the cumulative incidence was 17.5% (predominantly dizziness and nausea). Conclusion: This exploratory study provides a preliminary ED 50 estimate for tegileridine in immediate post-LCRS analgesia within a multimodal regimen, with a favorable short-term safety profile. However, the wide CI limits these findings; larger studies are needed to validate dose–response relationships and better define clinically relevant effective doses.
Minna Guo, Tong Wang, Shuchi Lin et al.· Drug Design, Development and...· 0 citations
BACKGROUND
Multimodal anesthesia (MMA) is widely used to reduce opioid use and improve postoperative recovery. However, evidence for bundled MMA regimens-defined as opioids plus ≥2 adjunct analgesic modalities-has not been systematically synthesized across patient-centered outcomes.
METHODS
We performed a systematic review and meta-analysis of randomized controlled trials comparing MMA (opioids plus ≥2 adjuncts, including regional techniques and/or systemic agents such as dexmedetomidine, ketamine, intravenous lidocaine, clonidine, or magnesium) with opioid-based general anesthesia in adults undergoing elective surgery. MEDLINE, Embase, CINAHL, Web of Science, and the Cochrane Library were searched to 28 October 2025. Primary outcomes were postoperative pain, PONV, QoR-15, and pulmonary complications. Secondary outcomes included opioid consumption in Morphine Milligram Equivalent (MME) and PACU length of stay. Risk of bias was assessed with RoB 2 and certainty with GRADE. Registered in PROSPERO (CRD42024470056).
RESULTS
Twenty-one RCTs (n = 1828) were included. At 24 h, no clear effect of MMA on pain intensity was observed (10 trials, n = 785; MD -0.6, 95% CI -1.5 to 0.2; very low certainty). MMA reduced PONV incidence (4 trials, n = 352; RR 0.59, 95% CI 0.44 to 0.77; low certainty). For secondary outcomes, MMA reduced opioid consumption (10 trials, n = 915; MD -7.0 mg MME, 95% CI -12.8 to -1.3; moderate certainty), with the opioid-sparing effect persisting at 48 h (MD -14.0 mg MME) and study end (MD -16.0 mg). Data for QoR-15, PACU stay, and pulmonary complications were insufficient for pooling.
CONCLUSIONS
MMA shows no clear effect on postoperative pain at 24 h but reduces PONV incidence and opioid consumption. Evidence certainty ranges from moderate to very low. Larger, standardized trials are needed to define optimal MMA regimens and patient selection.
Stefano M Arigoni, Adina B Heitmann-Frei, Marc S. von Gernler et al.· Journal of clinical anesthes...· 0 citations