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Opioid-free anesthesia (OFA) has re-emerged over the past two decades as a clinically relevant strategy to address opioid-related adverse effects, including respiratory depression, postoperative nausea and vomiting (PONV), ileus, hyperalgesia, and prolonged recovery. While contemporary OFA protocols are often presented as multimodal, guideline-driven constructs, their evolution has been shaped by earlier pragmatic efforts to disentangle hypnosis, analgesia, and immobility into measurable and independently titratable components. The conceptual framework, referred to as Friedberg’s Triad[1,2] — measure the brain, preempt the pain, emetic drugs abstain [Figure 1] — illustrates a transition from experience-based practice toward quantitative, reproducible anesthetic delivery.Figure 1: Friedberg’s Triad. From: Friedberg’s triad and opioid free anesthesia in the morbidly obese patient.[ 2 ] Used with permission under CC-BY licenseClinical Constraints as a Driver of Opioid Avoidance Early implementation of OFA occurred in ambulatory office-based surgical settings with limited resources. These environments typically lacked anesthesia machines, mechanical ventilators, and scavenging systems, thereby precluding conversion from intravenous sedation to general anesthesia. Continuous spontaneous ventilation and airway patency were therefore non-negotiable clinical priorities. Monitoring capabilities were limited to pulse oximetry, non-invasive blood pressure, and electrocardiography, with oxygen delivery, manual ventilation equipment, and emergency airway devices available for rescue. Within these constraints, the use of opioids posed disproportionate risk. Even modest opioid dosing could compound sedative-induced respiratory depression, leading to loss of airway reflexes in settings without definitive ventilatory support. The need for a technique that preserved spontaneous ventilation, avoided respiratory depressants, and allowed rapid titration of hypnotic depth led to systematic exploration of non-opioid pharmacological strategies. Propofol as a Titratable Hypnotic Platform Following its introduction into North American practice in the late 1980s, propofol rapidly became the hypnotic agent of choice for procedural sedation owing to its favorable pharmacokinetic profile.[3] However, bolus dosing strategies commonly used for the induction of general anesthesia were unsuitable for office-based sedation. Rapid bolus administration frequently resulted in abrupt loss of airway tone, hypoventilation, or apnea. Incremental propofol administration was therefore adopted to achieve stable central nervous system concentrations while preserving airway reflexes. Early techniques relied on gravity-driven infusion systems using diluted propofol solutions to permit fine titration. Sedation targets were defined clinically by loss of verbal responsiveness and loss of the eyelash reflex, while maintaining spontaneous ventilation with oxygen saturation between 93% and 96% on room air. Marked interindividual variability in propofol sensitivity was observed. Some patients achieved the desired hypnotic endpoint with minimal infusion rates, whereas others required substantially higher doses. Recognizing and accommodating this variability proved essential. Incremental induction exposed patient-specific sensitivity early, allowing individualized titration and avoiding the masking effect of bolus administration.[4] This principle remains foundational in modern OFA practice. Ketamine Dissociation and the Separation of Immobility from Hypnosis Ketamine was initially reintroduced to adult practice despite its declining popularity due to concerns regarding hallucinations and dysphoria.[5] Prior evidence had demonstrated that benzodiazepines attenuated ketamine-induced psychomimetic effects,[6] but it was unclear whether propofol exerted a similar protective effect. Sequential administration—propofol-induced hypnosis followed by ketamine—allowed this question to be explored empirically. Administering ketamine only after achieving adequate hypnotic depth with propofol consistently prevented emergence hallucinations, confirming that propofol effectively blocks ketamine-related psychotropic phenomena.[7] Importantly, patients exhibited profound immobility during local anesthetic infiltration despite the absence of opioids [Figure 2]. This immobility, attributable to ketamine-induced dissociation via NMDA receptor antagonism, occurred independently of patient weight when a fixed dose of 50 mg was administered 2–3 minutes prior to local analgesia injection and surgical stimulation.Figure 2: Schematic illustration of the proposed neurophysiological mechanism underlying opioid-free anesthesia based on Friedberg’s Triad. Incremental propofol administration establishes cortical hypnosis and amnesia, while a fixed pre-stimulation dose of ketamine (50 mg administered 2–3 minutes before surgical stimulation) produces dissociation through saturation of midbrain NMDA receptors. This dissociative blockade interrupts the transmission and processing of nociceptive signals from subcortical and brainstem structures to the cerebral cortex, thereby preventing conscious perception of noxious input despite preserved spontaneous ventilation. Subsequent local or regional anesthesia abolishes peripheral nociceptive generation at the surgical site. The combined effect is immobility and analgesia without opioid administration, cortical arousal, or central nociceptive processingThis dosing strategy reliably produced 10–20 minutes of immobility across a wide range of body weights. In contrast, weight-based ketamine dosing (e.g., 0.5 mg/kg) produced variable dissociative effects and inconsistent pre-emptive analgesia. These observations suggest that effective midbrain NMDA receptor saturation may be dose-threshold rather than weight-dependent. Glycopyrrolate 0.2 mg IV should be given prior to propofol sedation to mitigate ketamine associated oral secretions that not infrequently trigger ketamine-associated laryngospasm (KAL). Though rare, KAL is a disturbing experience. Typically, laryngospasm is diagnosed by the “crowing” sound generated by incomplete vocal cord closure. KAL involves complete closure of the vocal cords – hence, no crowing noise is generated – only a cough or sneeze is in evidence. The traditional treatment of anterior jaw thrust with positive-pressure ventilation has been proven inadequate. Rapid injection of lidocaine 2 mg/kg has been shown to be effective.[8] Eliminating Antiemetic Drugs The third component of Friedberg’s Triad is also the intentional absence of prophylactic antiemetic drugs. By withholding antiemetics, PONV can be treated as an unmasked physiological outcome, allowing identification of its primary etiological drivers. Between 1992 and 1997, prospective observational data were collected from 1,264 patients undergoing opioid-free propofol–ketamine–local anesthesia.[9] The cohort predominantly consisted of female, non-smoking patients undergoing cosmetic surgery, many with a history of motion sickness or prior PONV.[10] Despite the absence of prophylactic antiemetics, the incidence of PONV was only 0.6%.[9] Notably, the observed PONV rate was far lower than predicted by consensus guidelines recommending one antiemetic per risk factor.[11] These findings suggest that opioids, rather than anesthesia itself, may represent the dominant contributor to postoperative emesis. Routine administration of antiemetic agents may therefore obscure causality and perpetuate opioid-inclusive practice without addressing the underlying mechanism. Within Friedberg’s Triad, the absence of antiemetics serves both as confirmation of effective opioid avoidance and as an objective indicator of physiological recovery following anesthesia. Measurement of Hypnosis Depth While early practice relied on clinical signs to titrate hypnosis, the introduction of processed EEG monitoring enabled objective quantification.[12] Bispectral index (BIS) monitoring revealed an important limitation: BIS values lag real-time cortical activity by 15–30 seconds. This delay initially caused apparent paradoxes, with sudden BIS increases occurring despite stable drug delivery. Resolution came through concurrent electromyography (EMG) trend analysis. EMG spikes reliably preceded BIS changes and signaled incipient arousal.[13] In spontaneously breathing, non-paralyzed patients, EMG provided actionable, forward-looking information. Absence of EMG response to local analgesia injection as well as incision following ketamine administration supported the concept of effective dissociation, nociceptive blockade, and the beginning of opioid-free pre-emptive analgesia. When EMG spikes occurred, timely incremental propofol dosing prevented cortical arousal.[14] Thus, EMG served as the “windshield,” while BIS functioned as the “rear-view mirror” of hypnotic depth [Figure 3].Figure 3: Limitations of BIS-only monitoring and the added value of real-time EMG trending. This schematic contrasts bispectral index (BIS) monitoring when interpreted in isolation with BIS combined with frontal electromyography (EMG) trending. Together, these panels illustrate that BIS alone provides retrospective information, whereas integrating EMG trending transforms processed EEG monitoring into a real-time, clinically actionable tool for optimizing hypnosis during opioid-free, spontaneously ventilated anesthesia. Recreated from: Friedberg’s Triad and opioid free anesthesia in the morbidly obese patient.[ 2 ] Used with permission under CC-BY licenseTargeting BIS values between 60 and 75 with baseline EMG corresponded to moderate-to-deep sedation, sufficient for amnesia without excessive hypnotic dosing. Over more than 4,000 propofol-only titrations using this strategy, no cases of awareness with recall were reported, underscoring the reliability of propofol as an amnestic agent when objectively measured.[14] From Qualitative Titration to Numerical Reproducibility Demand for reproducible dosing parameters led to the adoption of programmable infusion pumps. We published a case report recommending propofol infusion rates around 50 µg·kg−1·min−1, with bolus supplementation, which were refined as experience accumulated.[14] True interindividual variability spanned nearly two orders of magnitude, with some patients requiring as little as 2 µg·kg−1·min−1 and others exceeding 200 µg·kg−1·min−1. Recognition of this variability underscored the inadequacy of fixed-dosing schemes and highlighted the need for real-time physiological monitoring. Slower titration rates further improved airway stability by avoiding precipitous relaxation of upper airway musculature. Airway Preservation without Instrumentation Preservation of spontaneous ventilation is a defining feature of OFA. Bolus induction techniques commonly used in general anesthesia rapidly relax airway-supporting muscles and frequently necessitate airway instrumentation. In contrast, incremental propofol sedation avoids abrupt loss of tone, allowing most patients to maintain airway patency with minimal intervention, as seen in our published video.[15] A stepwise approach to airway support proved effective. Rhytidectomy (chin up, lateral rotation) positioning alone preserved patency in approximately one-third of patients. Shoulder elevation – easily achieved by placing an unheated 1,000 cc IV bag under the patient’s shoulders, thereby increasing the force of extension on the genioglossus – results in a patent airway and enhanced airway alignment. Nasal airways sufficed for most remaining cases, while laryngeal mask airways (LMA) were reserved for a small minority, primarily in procedures where surgical access necessitated airway security. Our previously published study demonstrated that endotracheal intubation was not required in over 6,000 cases spanning 26 years.[14] Avoidance of opioids further reduced the risk of respiratory depression, reinforcing the compatibility of OFA with spontaneous ventilation strategies. Clinical Implications and Broader Relevance The two highly reported causes of unplanned hospital admission after ambulatory surgery are pain and PONV.[16,17] In office-based environments where inpatient transfer represents a major escalation of care, avoidance of these complications is paramount. Across more than two decades of observation using an opioid-free, brain-monitored, incremental propofol–ketamine–regional analgesia pathway, no admissions for pain or PONV were recorded.[14] Alongside ambulatory surgery, the principles underpinning Friedberg’s Triad are relevant to resource-limited environments, military medicine, and mass-casualty settings. By separating hypnosis, dissociation, and analgesia into independently measurable components, anesthesia can be delivered without reliance on volatile agents, opioids, or complex infrastructure. Conclusion The evolution of opioid-free anesthesia from qualitative observation to quantitative practice illustrates the value of physiological measurement, pharmacological clarity, and deliberate separation of anesthetic components. Friedberg’s Triad offers a reproducible framework in which hypnosis is titrated with propofol, immobility is achieved through ketamine-induced dissociation, and nociception is eliminated by regional analgesia. The resulting anesthetic state minimizes pain, PONV, respiratory depression, and unplanned admissions. As contemporary anesthesia increasingly emphasizes opioid stewardship, patient-centered outcomes, and resource efficiency, these principles warrant renewed consideration and rigorous prospective evaluation. Author’s contribution Both authors similarly contribute to the conception, literature review, data synthesis, manuscript drafting, and approval of the final version. Data availability statement No new data was generated in the writing of this manuscript. Use of GenAI statement The authors declare that no generative artificial intelligence tools were used in the preparation of this manuscript. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.