, Volume 71, Issue 14, pp 1807–1819 | Cite as

Neuraxial Morphine and Respiratory Depression

Finding the Right Balance
  • Pervez Sultan
  • Maria Cristina Gutierrez
  • Brendan Carvalho
Leading Article


Morphine is a drug commonly administered via the epidural or intrathecal route, and is regarded by many as the ‘gold-standard’ single-dose neuraxial opioid due to its postoperative analgesic efficacy and prolonged duration of action. However, respiratory depression is a recognized side effect of neuraxial morphine administered in the perioperative setting. We conducted an extensive review of articles published since 1945 that examine respiratory depression or failure associated with perioperative intrathecal or epidural morphine use.

Respiratory depression was previously thought to result from the interaction of opioid in the cerebrospinal fluid with ventral medullary opioid receptors. More recently, the preBötzinger complex located in the medulla has been identified as the site responsible for the decrease in respiratory rate following systemic administration of opioids. Neurons in the preBötzinger complex expressing neurokinin-1 receptors are selectively inhibited by opioids, and therefore are the mediators of opioid-induced respiratory depression.

Epidural, intrathecal and plasma pharmacokinetics of opioids are complex, vary between neuraxial compartments, and can even differ within the epidural space itself depending upon level of insertion. Caution should be exercised when prescribing systemic opioids (intravenous or oral) in addition to neuraxial morphine as this can compound the potential for early or delayed respiratory depression.

There is a wide range of incidences for respiratory depression following neuraxial morphine in a perioperative setting. Disparity of definitions used for the diagnosis of respiratory depression in the literature precludes identification of the exact incidence of this rare event.

The optimal neuraxial opioid dose is a balance between the conflicting demands of providing optimal analgesia while minimizing dose-related adverse effects. Dose-response studies show that neuraxial morphine appears to have an analgesic efficacy ‘ceiling’. The optimal ‘single-shot’ intrathecal dose appears to be 0.075–0.15mg and the ideal ‘single-shot’ epidural morphine dose is 2.5–3.75mg. Analgesic efficacy studies have not been adequately powered to show differences in the incidence of clinically significant respiratory depression. Opioid antagonists such as naloxone to prevent or treat opioid-induced respiratory depression have a number of limitations. Researchers have recently focused on non-opioid drugs such as serotonin receptor agonists. Early evidence suggests that ampakine (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid [AMPA]) receptor modulators may be effective at reducing opioid-induced respiratory depression while maintaining analgesia. Sodium/proton exchanger type 3 (NHE3) inhibitors, which act centrally on respiratory pathways, also warrant further study.


Morphine Respiratory Depression Analgesic Efficacy Epidural Morphine Intrathecal Morphine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



No sources of funding were used in the preparation of this review. Brendan Carvalho reports receiving funding from EKR Therapeutics as principal investigator for study conduct (DepoDur™), and Epimed International, Inc. for research efforts. Drs Sultan and Gutierrez report no conflicts of interest that are directly relevant to the content of this review.


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Copyright information

© Adis Data Information BV 2011

Authors and Affiliations

  • Pervez Sultan
    • 1
  • Maria Cristina Gutierrez
    • 1
  • Brendan Carvalho
    • 1
  1. 1.Stanford University School of MedicineStanfordUSA

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