Opioid-Induced Ventilatory Impairment

• Opioids have multiple negative impacts on respiratory function which can potentially lead to severe respiratory depression:
• Depression of the respiratory centre in the brainstem, disrupting the generation of the normal respiratory rhythm and reducing alveolar minute ventilation
• Reduced oropharyngeal muscle tone, resulting in upper airway obstruction
• Negatively affect both central and peripheral chemoreflex loops
• Depression of the hypothalamus, leading to sedation via increased arousal thresholds
• These effects are primarily related to MOP receptor agonism within the respiratory network (pons, medulla) and carotid bodies (peripheral chemoreceptors)

• Follows a stereotypical pattern
1. Irregular breathing
2. Periodic or cyclic breathing
3. Gasping
4. Full cessation (i.e. apnoea)
• In some cases abrupt apnoea occurs without other warning signs
• Apnoea leads to asphyxia (low arterial oxygen tension but high arterial carbon dioxide tension) and potentially cardiac arrest

• Opioids affect multiple areas influencing control of ventilation:
• The pre-Botzinger complex (medulla) which is essential for respiratory rhythm generation
• Parabrachial complex (the Killiker-Fuse and parabrachial nuclei), which sustains upper airway patency, integrates sensory input from chemoreceptors and adjusts ventilation in response to arterial oxygen and carbon dioxide levels
• Phrenic pre-motor and motor neurons; a direct effect at high opioid doses which depresses phrenic motor output

Adapted from Opioid-induced respiratory depression (BJA Education, 2024)

• The HCVR (i.e. response to inhaled carbon dioxide) is a sensitive measure of the effects of opioids
• In the absence of opioids, a the HCVR graph (of steady-state PCO₂ vs. ventilation) is 'hockey-stick' shaped
• The flat part of the curve demonstrates CO₂-insensitive ventilation, i.e. baseline ventilation before a 'ventilatory recruitment threshold' is reached
• The linear, increasing part of the curve is the HCVR; it is described by both a slope (i.e. gradient) and an apnoeic threshold


• Opioids effect the HCVR graph by:
• A (slow) decrease in baseline ventilation
• Shifting the curve to the right i.e. higher levels of PCO₂ are required to trigger the ventilatory recruitment threshold
• A reduction in the gradient of the HCVR i.e. less potent ventilatory response in the presence of opioids

• Data from the PRODIGY study demonstrated that among post-operative patients receiving potent opioids the risk of at least one OIVI event was 46%
• This lead to the creation of the PRODIGY risk-prediction tool
• Such factors include:
• Advanced age
• Male gender
• Opioid naive patient
• Known sleep-disordered breathing or high STOP-BANG score
• Co-existing heart failure
• High-risk patients have a 6x higher risk (odds ratio) of respiratory depression compared to low-risk patients


• Other risk factors not included in the PRODIGY score include:
• Pathologies which may influence respiratory function e.g. obesity, respiratory diseases, neurological diseases
• Pathologies which may influence opioid pharmacokinetics e.g. renal impairment, genetic variations in opioid metabolism
• Diabetes mellitus
• Many patients who develop OIVI have no identifiable risk factors and all patients receiving opioids post-operatively must be considered to be at risk

• Chronic opioid users have a four-fold decrease in opioid sensitivity to respiratory depression compared with opioid-naïve patients
• However:
• OIVI tolerance develops more slowly than analgesic tolerance, potentially putting said patients at higher risk
• Individuals with opioid tolerance will use higher opioid doses, increasing risk of overdose
• Opioid tolerance is dynamic and may decrease during a period of abstinence (e.g. inpatient stay)

• Opioids can be classified by their affinity for the MOP receptor
• Based on the affinity constant Ki, they can be grouped as:
• High affinity (Ki<1) e.g. buprenorphine, sufentanil, carfentanil
• Intermediate affinity (Ki 1-25) e.g. fentanyl, methadone, hydromorphone
• Low affinity (Ki >25) e.g. oxycodone, codeine
• In general, opioids with a higher MOP receptor affinity display both:
• Greater respiratory depression
• Greater resistance to displacement from the receptor by antagonists such as naloxone
• However, overall the dose of opioid delivered (rather than intrinsic MOP receptor affinity) is the factor which most determines the consequent effects on ventilation

• Use age-adjusted opioid doses initially to accommodate increased risk in elderly patients
• Avoid opioid infusions
• Avoid using more than one opioid or formulation
• Use immediate-release opioids, not modified-release or long-acting formulations
• Avoid co-administering sedatives e.g. gabapentinoids, benzodiazepines
• Use standardised order sets which link opioid prescribing to monitoring and actions to take in cases of over-sedation/OIVI

• Use multi-modal opioid-sparing analgesic approaches, including on discharge
• Titrate opioid delivery to functional outcomes rather than unidimensional pain scores
• Measure sedation scores in all patients and respond appropriately

• Education about OIVI recognition and management for healthcare professionals
• Education for patients and carers about avoiding sedatives, reducing opioids after discharge and recognising symptoms of OIVI

• Harm from OIVI is preventable in the majority of cases with early detection and management
• Recommendations include:
• Sedation levels, which are the most reliable clinical marker of OIVI
• Continuous CO₂ monitoring e.g. capnography, although is commonly limited to higher-acuity settings and may not correlate well with P_aCO₂
• Routine use of pulse oximetry, although hypoxaemia is a very late sign of hypoventilation, especially if the patient is receiving supplemental oxygen
• Respiratory rate, although it is poorly reliable as a surrogate marker of OIVI/P_aCO₂

• The non-selective opioid antagonist naloxone is the first-line treatment for pharmacological reversal of OIVI (and other opioid toxicity)
• It works well for perioperative OIVI because in this patient cohort the concentration of opioid molecules at the receptors is usually only just above the threshold for respiratory depression
• Therefore low, incremental doses (up to 400μg) of naloxone can restore respiratory activity without compromising analgesia
• The relative short duration of action of naloxone compared to long-acting opioids, or large doses of short-acting opioids, may lead to failure of treatment (20-50%) and re-narcotisation
• Other issues with naloxone include:
• Triggering opioid withdrawal in those using long-term opioids either medically or as part of an opioid use disorder
• Limited ability to displace high-affinity opioids, or high-dose intermediate affinity opioids, from the MOP receptor unless large doses are given
• Compromised efficacy if there are non-opioid respiratory depressants exerting an effect too e.g. benzodiazepines, anti-depressants, gabapentinoids, alcohol

• Long-acting opioid receptor antagonists e.g. nalmefene, methocinnamox; useful for OIVI from overdose in the context of opioid use disorder but less useful for perioperative practice


• Potassium channel blockers, which stimulate the carotid bodies into mimicking the physiological response to hypoxia e.g. doxapram, ENA-001


• Drugs which stimulate the central respiratory network, exciting the respiratory rhythm generator e.g. ketamine, AMPAR-receptor agonists (a.k.a ampakines) e.g. CX717