Opioid Anesthesia

Mechanism of Action

Opioids characteristically exert their effects by interacting with various types of opioid receptors, which may result in a range of receptor responses, from inducing the most significant receptor activity to no activity.[6] Those medications that cause the most profound positive receptor response are opioid agonists. Medications inducing a partial positive response are known as partial agonists, while those inhibiting or blocking receptor response activity are described as antagonists.

Opioid Receptors and Intracellular Pathways

Although numerous subgroups exist, 3 main opioid receptors have been identified: mu, delta, and kappa.[7] The nociceptin/orphanin FQ receptor (NOP), also known as the opioid receptor-like (ORL1) receptor, is considered another opioid receptor system. Opioid receptors are G protein-coupled receptors comprised of 7 transmembrane domains that interact with G-proteins.[8] 

After the receptor and ligand interaction activate the G-protein, G alpha and G beta-gamma subunits separate and impact various intracellular pathways, including kinase cascades and various proteins. Although this receptor activation leads to many downstream effects, ion channel modulation seems to be one of the most critical immediate consequences. For instance, after receptor activation, the G alpha subunit directly alters potassium channel conductance, producing cell hyperpolarization and reduced neuronal excitability.[8] The G beta-gamma subunit appears to further contribute to this alteration in membrane potential by reducing calcium conductance.

While these opioid receptors are present in both neural and nonneural tissue, they tend to cluster in the periaqueductal grey, rostral ventral medulla, locus coeruleus, and substantia gelatinosa. Activation of opioid receptors at these structures appears to lead to the descending inhibitory signaling that interferes with the transmission of nociceptive signals, via disruption of neuron modulation by substance P, from the peripheral nervous system to the cortex.[8]

Opioid Receptor Mechanisms

Recent research has significantly advanced our understanding of opioid receptor mechanisms. The primary opioid receptor targets include μ (mu/MOP), δ (delta/DOP), and κ (kappa/KOP) receptors, all of which produce analgesic effects and are naloxone-sensitive. The NOP receptor represents another opioid receptor that is not naloxone-sensitive but has critical clinical developments underway.[9]

Modern investigations continue to confirm that opioid receptors are G protein-coupled receptors with 7 transmembrane domains that interact with G-proteins. After receptor-ligand interaction activates the G-protein, the G alpha and G beta-gamma subunits separate and influence various intracellular pathways, including kinase cascades. Current research indicates that respiratory depression caused by opioids occurs through activation of opioid receptors at sites, eg, the pre-Bötzinger complex (PBC), nucleus tractus solitarius, and KF nucleus, likely through mechanisms involving inhibition of adenylate cyclase, G protein-coupled inwardly rectifying potassium (GIRK) channels, and voltage-gated calcium channels that regulate respiration.[10] 

Research on pharmacological innovation has introduced several promising new approaches, including biased opioid receptor agonists that can potentially separate analgesic effects from respiratory depression, as well as positive allosteric modulators (PAMs) that can enhance the efficacy of endogenous opioid peptides or reduce required doses of exogenous opioids.

Administration

Opioid administration routes are diverse, including buccal, enteral, transdermal, subcutaneous, epidural, intrathecal, aerosolized, and intravenous. The primary route of administration for an opioid anesthetic is intravenous, with either repeat injections or as a continuous infusion. Mixtures of local anesthetic and opioid medication in an intrathecal or epidural approach are also useful for select cases.[2]

Perioperative anesthesia opioids include the more commonly known agents, eg, fentanyl, morphine, and hydromorphone. Less well-known and much more potent opioid medications include continuous intravenous administration of sufentanil, remifentanil, and alfentanil, mainly reserved for use during the intraoperative period.[11] Fentanyl has a rapid onset, is very potent, and is straightforward for anesthesiologists to dose; it has been the favored intraoperative opioid agent for years. Additionally, further research into the use of methadone in the perioperative environment is ongoing with the goal of further reduction in total morphine equivalent requirements and postoperative opioid requirements. 

Emerging Multimodal Approaches

Recent advances in multimodal analgesia have significantly changed perioperative pain management.Enhanced recovery after surgery (ERAS) protocols employ multimodal perioperative care pathways designed to achieve early recovery after surgical procedures by maintaining preoperative organ function and minimizing stress response following surgery. Contemporary multimodal approaches focus on nonsteroidal anti-inflammatories, acetaminophen, gabapentinoids, NMDA antagonists, alpha-2-agonists, and sodium and calcium channel blocking agents rather than opioid-centric models. 

Effective multimodal approaches now include nonopioid medications, specialized anesthesia techniques, surgical techniques, and various postoperative nonmedication strategies, eg, physical therapy, transcutaneous electrical nerve stimulation, cryotherapy, and cognitive techniques. Newer analgesics being investigated include peripheral-acting opioids, nitric oxide inhibitors, calcitonin gene-related peptide receptor antagonists, interleukin-6 receptor antagonists, and gene therapy techniques.[12]

Opioid-Free Anesthesia

Recent clinical trials have investigated opioid-free anesthesia approaches. For example, the SOFA Trial (Standard versus Opioid-Free Anesthesia) demonstrated that opioid-free anesthesia protocols improved quality of recovery after major elective surgery compared to standard anesthesia, with statistically significant benefits in recovery quality scores at 24, 48, and 72 hours.[13]Complete avoidance of intraoperative opioids remains controversial, as it doesn't necessarily ensure avoidance of postoperative opioids. While multimodal analgesia, including local or regional anesthesia, may allow OFA for selected minimally invasive surgeries, further research is needed for surgeries with high postoperative opioid requirements.

Adverse Effects

Adverse effects from opioid anesthesia are consistent with the general adverse effects of opioid use. Common adverse effects of intravenous opioid anesthetics include hypotension exacerbation, respiratory depression or apnea, bradycardia, somnolence, confusion, urinary retention, and constipation.

Other potential adverse effects include increased intracranial pressure secondary to hypercapnia, rigidity, delayed emergence, delirium, postoperative nausea and vomiting, pruritis, ileus, and the potential for the development of opioid-induced hyperalgesia (most commonly associated with remifentanil) or the development of abuse/misuse habits. The risk of adverse effects increases as the population age increases or the comorbidities of the patient increase. The risk of adverse effects of opioid use is reducible through dose reduction, opioid-sparing, or newer multimodal analgesia approaches.[1][5][14]

A rather unique adverse effect related to opioid anesthesia is a phenomenon known as opioid-induced chest wall rigidity. This skeletal muscle rigidity may involve a dopaminergic pathway within the central nervous system, resulting in chest wall stiffness, which can impair ventilation. Such cases may require high inspiratory pressures or the administration of neuromuscular blocking drugs to facilitate effective ventilation.[15][16]

Emerging Technologies for Monitoring and Prevention

Advanced monitoring technologies are becoming essential in preventing opioid-induced respiratory depression.Recent studies have compared different electronic monitoring devices (eg, pulse oximetry, capnography, and minute ventilation monitoring) to determine which are most effective at identifying patients experiencing respiratory compromise to develop algorithms for earlier detection of respiratory depression. For pediatric patients, particular caution is needed as children are not "little adults" and adult guidelines must be extrapolated carefully. Specialized monitoring protocols have been developed for children receiving opioids, especially those with risk factors (eg, obstructive sleep apnea).[17]

High Risk Factors and Patient Selection

Specific patient populations at increased risk of opioid-induced respiratory depression include obese patients, those with sleep apnea, and older adults. For these populations, opioid reduction strategies using adjuvant nonopioid analgesics (α-2 agonists, gabapentinoids, NMDA receptor antagonists) and regional/neuraxial anesthesia techniques are particularly important.

Contraindications

Avoidance of opioid use is recommended in patients who have taken a monoamine oxidase inhibitor (MAOI) within 14 days due to the increased risk of serotonin toxicity.[18] Recommendations also include caution in patients currently taking selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs).[19] Other relative contraindications include patients older than 65 due to an increased likelihood of polypharmacy with accompanying drug interactions, as well as a greater potential for cognitive impairment. Opioids increase the risk of delirium, confusion, and increased sedation, although the cause of delirium is controversial.[20] Caution is also necessary for patients with renal or hepatic impairment.[21] 

For patients with renal or hepatic disease, consideration should be taken in choosing the appropriate opioid based on the drug's rate of metabolism and excretion. Avoiding opioids is also suggested in patients with pulmonary impairment, eg, chronic obstructive pulmonary disease, due to the decreased respiratory drive caused by opioid administration. Similarly, caution is warranted in patients with increased intracranial pressure, bradyarrhythmias, or gastrointestinal obstruction due to common adverse reactions of opioid use (Please refer to the Adverse Effects section for more information on the adverse effects of opioids). 

Patients with substance use disorder may also pose a contraindication to intraoperative and perioperative opioid anesthesia and analgesia. Clinicians must carefully weigh the benefit-to-risk ratio in these patients when deciding how to best proceed with anesthesia for a given procedure.[22][14]

Monitoring

The standard of care for anesthesia monitoring is employed when using opioid anesthetics for general anesthesia or monitored anesthesia care sedation. Monitoring modalities include electrocardiogram, pulse oximetry, end-tidal CO₂, respiratory rate, ventilation volume and pressures, and blood pressure measurement. Potential opioid adverse effects that necessitate monitoring include bradycardia, hypotension, and depressed respiratory drive. Monitoring also involves assessing intraoperative nociception in response to surgical stimulation to optimize opioid dosing, using the lowest possible dose to achieve the needed effect.[23] 

Blood pressure, respiration rate, and heart rate all provide useful information when titrating optimal intraoperative dosing of opioid medications. When correlated with surgical stimulation, high heart rate, blood pressure, and respiratory rate may indicate the need for more opioid pain medication. Conversely, low or normal values in the same vital signs likely indicate no need for further opioid administration at that time.

Toxicity

In the cases of significant hypoventilation induced by opioid anesthesia or excessive levels at the end of a case, frequent stimulation may be initially necessary to maintain and encourage adequate ventilation. If the stimulation is insufficient, positive pressure ventilation or titration of intravenous naloxone can support the patient until recovery is sufficient for adequate spontaneous ventilation.

Careful titration of naloxone is necessary for adequate analgesia and the prevention of a sympathetic surge. This is why patients receiving intraoperative opioid anesthesia require constant vital sign monitoring, as outlined above, to help prevent potential toxicity.

Enhancing Healthcare Team Outcomes

Effective opioid anesthesia management requires a coordinated, interprofessional approach that leverages the unique skills and responsibilities of physicians, advanced practitioners, nurses, pharmacists, and other healthcare professionals. As the opioid epidemic continues, interprofessional communication and care coordination among healthcare team members are imperative to appropriately and safely use opioids for patient care. With proper interprofessional communication, excess quantities, as well as duplicate prescriptions, will be reduced. Unfortunately, such communication can be challenging with multiple institutes, pharmacies, and clinicians involved in the ongoing care of the same patient. Many clinicians and pharmacists have found direct communication to be less than 100% effective.[24]

Anesthesiologists must strategically balance analgesic efficacy with opioid-sparing techniques, such as multimodal analgesia and regional blocks, to reduce the risk of long-term misuse, especially in opioid-naive patients. Pharmacists play a crucial role in guiding appropriate drug selection, dose conversion, and identifying potential interactions, particularly during shortages that necessitate alternative opioid agents.[25][26][27][28] Nurses and advanced practitioners must closely monitor patients for signs of adverse effects, participate in pain assessments, and ensure adherence to postoperative pain protocols. When each team member contributes their expertise and maintains awareness of the patient's full care plan, the risk of opioid-related complications can be minimized while still ensuring adequate pain control.

Interprofessional communication is central to achieving these outcomes. Closed-loop communication systems and collaborative strategies are essential for sharing patient-specific information, such as opioid tolerance, dosing history, and comorbidities. These systems are critical in complex care settings involving multiple institutions, clinicians, and pharmacies, where the risk of duplicate or excessive prescriptions increases. When communication breaks down, the consequences can be severe, including opioid toxicity or inadequate pain management. Consistent, proactive care coordination—across preoperative, intraoperative, and postoperative phases—strengthens patient-centered care and team performance. Ultimately, fostering a culture of accountability, continuous communication, and shared responsibility across disciplines enhances patient safety and outcomes in opioid anesthesia management.