What psychotropic drugs, including opioids (e.g. morphine, fentanyl, codeine), benzodiazepines (e.g. alprazolam, clonazepam), selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), can cause respiratory depression?

Psychotropic Drugs That Cause Respiratory Depression

Opioids and benzodiazepines are the primary psychotropic drug classes that cause clinically significant respiratory depression, with synergistic effects when combined; SSRIs and TCAs generally do not cause direct respiratory depression but certain SSRIs (particularly paroxetine) may worsen opioid-induced respiratory depression through drug interactions. 1, 2

Opioids: Primary Respiratory Depressants

All opioid agonists cause dose-dependent respiratory depression by binding to μ-opioid receptors in the central nervous system, particularly in the pre-Bötzinger complex and pons 3:

Commonly Used Opioids

• Morphine: Causes serious, life-threatening respiratory depression that can occur at any time during use, with greatest risk during initiation or dose increases 4
• Fentanyl: Produces more rapid onset of respiratory depression than morphine or heroin, depresses both respiratory rate and tidal volume, and is less responsive to naloxone reversal than other opioids 5, 6
• Meperidine: Major adverse effect is respiratory depression, particularly when combined with benzodiazepines or barbiturates 1
• Codeine: Metabolized to morphine and carries similar respiratory depression risks 1
• Hydromorphone: Carries higher risk of respiratory depression compared to fentanyl when administered neuraxially 1

Critical Risk Factors

• Dose-dependent effect: Risk significantly increases above 80-100 morphine milligram equivalents (MME) per day 7
• Timing: Respiratory depression risk is greatest within the first 24-72 hours of initiation or following dose increases 4
• Duration: With fentanyl transdermal systems, respiratory depression may persist for 17+ hours after patch removal due to continued skin absorption 5

Benzodiazepines: Synergistic Respiratory Depressants

Benzodiazepines alone typically do not cause significant respiratory depression, but when combined with opioids, they produce synergistic respiratory depression 1:

Key Evidence

• Alprazolam and clonazepam (along with other benzodiazepines like diazepam and midazolam) dramatically increase respiratory depression risk when co-administered with opioids 1
• In controlled studies, benzodiazepines alone caused no significant respiratory depression, but when combined with opioids, hypoxemia occurred in 92% of subjects and apnea in 50% 1
• The combination has a synergistic (not merely additive) effect on respiratory depression risk 1

Clinical Implications

• When both agents are necessary, administer the opioid first and carefully titrate the benzodiazepine dose 1
• The American Society of Anesthesiologists strongly agrees that adding parenteral opioids or hypnotics (including benzodiazepines) to neuraxial opioids increases respiratory depression occurrence 1

SSRIs: Indirect Risk Through Drug Interactions

SSRIs do not directly cause respiratory depression, but specific agents can worsen opioid-induced respiratory depression through pharmacokinetic interactions 2:

High-Risk SSRI

• Paroxetine: When co-administered with oxycodone, significantly increased arterial pCO₂ above oxycodone alone, with effects exceeding what would be expected from pharmacokinetic interactions alone, suggesting an additional pharmacodynamic mechanism 2

Other Considerations

• Most SSRIs do not independently cause respiratory depression
• The primary concern is drug-drug interactions that increase opioid exposure or enhance respiratory depressant effects 2

Tricyclic Antidepressants (TCAs)

The provided evidence does not document TCAs as direct causes of respiratory depression. While TCAs have significant cardiovascular and anticholinergic effects, respiratory depression is not a characteristic adverse effect of this drug class in therapeutic dosing.

Other Psychotropic Drugs With Respiratory Depression Risk

Sedative-Hypnotics

• Barbiturates: Have synergistic effect on respiratory depression when combined with opioids 1
• Zolpidem and other non-benzodiazepine hypnotics: Increase respiratory depression risk when combined with neuraxial opioids 1

Antipsychotics

• Quetiapine: Significantly increased pCO₂ when co-administered with oxycodone, primarily through pharmacokinetic interactions increasing opioid exposure 2
• Clozapine and risperidone: Studied but did not show significant respiratory depression effects at clinically relevant exposures 2

Other Agents

• Trazodone: Significantly increased pCO₂ when given with oxycodone 2
• Carisoprodol (muscle relaxant): Can contribute to respiratory depression when combined with opioids 2

Critical Clinical Warnings

High-Risk Combinations to Avoid

• Opioid + benzodiazepine: Most dangerous combination with synergistic respiratory depression 1
• Opioid + alcohol: Additive CNS depressant effects 5
• Opioid + multiple sedating agents: Exponentially increases risk 1

Monitoring Requirements

• Patients receiving combined opioid and sedative therapy require increased intensity and duration of monitoring 1
• Monitor adequacy of ventilation, oxygenation, and level of consciousness 1
• End-tidal CO₂ monitoring is more effective than clinical observation alone for detecting respiratory depression 1

Reversal Considerations

• Naloxone reverses opioid-induced respiratory depression but has shorter duration (30-45 minutes) than many opioids, requiring extended monitoring for 2+ hours 1, 3
• Fentanyl-induced respiratory depression is less responsive to naloxone than morphine-induced depression 6
• Naloxone does not reverse benzodiazepine or other non-opioid sedative effects 1