Neuraxial Morphine: A review of Mechanism of Action and Respiratory Depression
Article Sidebar
Published:
Aug 28, 2020
Keywords:
Neuraxial analgesia, Morphine, Opioids, Respiratory depression
Main Article Content
Abstract
Neuraxial morphine have been used as the mainstay for moderate to severe acute pain due to its postoperative analgesia efficacy and prolonged duration of action. However, the awareness remains about their potential adverse effects on ventilation. Opioid induced respiratory depression results from the interaction of opioid in the cerebrospinal fluid with ventral medullary opioid receptors and preBotzinger complex, which located in the medulla. Even though the incidence of opioid induced respiratory depression was identified as a rare event around 0-23% during a perioperative setting. Risks are often higher in patients with extreme age, obesity or having cardiopulmonary disease. Therefore, identification of patients at increased risk of respiratory depression is recommended by focused history and physical examination. The optimal neuraxial opioid dose should be used to achieve optimal analgesia while minimizing dose-related adverse effects. Doseresponse studies show that neuraxial morphine appears to have an analgesic efficacy “ceiling”. The optimal single shot intrathecal morphine appears to be 0.075-0.15 mg and the ideal single shot epidural morphine dose is 2.5-3.75 mg. Moreover, the detection of respiratory depression is crucial after giving neuraxial opioids in order to early detection and management of respiratory depression.
Article Details
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Review articles
References
1. Apfelbaum JL, Chen C, Mehta SS,etal. Postoperative pain
experience: results from a national survey suggest
postoperative paincontinues to beundermanaged. Anesth
Analg 2003;97:534-40.
2. Pert CB, Snyder SH. Opiate receptor: demonstration in
nervous tissue. Science1973;179:1011-4.
3. Wang JK, NaussLA,Thomas JE. Painrelief by intrathecally
applied morphinein man. Anesthesiology1979;50:149-51.
4. Behar M, Olshwang D, Magora F, et al. Epidural morphine
intreatmentof pain.Lancet1979;313:527-9.
5. DeSousa KA, Chandran R. Intrathecal morphine for
postoperativeanalgesia: Current trends.World J Anesthesiol
2014;3:191-202.
6. DahlJB,JeppesenIS,Jorgensen H,etal. Intraoperativeand
postoperative analgesic efficacy and adverse effects of
intrathecalopioidsin patientsundergoing cesareansection
with spinal anesthesia: a qualitative and quantitative
systematic review of randomized controlled trials.
Anesthesiology1999;91:1919-27.
7. Cohen SE, Woods WA.Theroleofepidural morphineinthe
postcesarean patient: efficacy and effects on bonding.
Anesthesiology1983;58:500-4.
8. Rosaeg OP, Lui AC, Cicutti NJ, et al. Peri-operative
multimodal pain therapy for caesarean section: analgesia
and fitness for discharge. CanJ Anesth1997;44:803-9.
9. StoeltingRK. Intrathecalmorphine-anunderusedcombination
for postoperative pain management. Anesth Analg 1989;
68:707-9.
10. Bujedo BM. Spinal opioid bioavailability in postoperative
pain. Pain Pract2014;14:350-64.
11. Bernards CM, Shen DD, Sterling ES, et al. Epidural,
cerebrospinalfluid,and plasma pharmacokineticsofepidural
opioids(part1): differencesamong opioids. Anesthesiology
2003;99:455-65.
12. Bernards CM, Hill HF. Physical and chemical properties of
drug molecules governing their diffusionthroughthespinal
meninges. Anesthesiology1992;77:750-6.
13. Weddel SJ, Ritter RR. Serum levels following epidural
administration of morphine and correlation with relief of
postsurgical pain. Anesthesiology1981;54:210-4.
14. Moulin DE, Inturrisi CE, Foley KM. Cerebrospinal fluid
pharmacokineticsof intrathecalmorphinesulfateand D-Ala2-
D-Leu5-enkephalin. Annalsofneurology1986;20:218-22.
15. Hanna MH, Peat SJ, Woodham M, et al. Analgesic efficacy
and CSF pharmacokinetics of intrathecal morphine6-glucuronide: comparison with morphine. Br J Anaesth
1990;64:547-50.
16. Davies GK, Tolhurst-Cleaver CL, James TL. Respiratory
depression after intrathecal narcotics. Anaesthesia 1980;
35:1080-3.
17. Nordberg G, HednerT, Mellstrand T,etal. Pharmacokinetic
aspects of intrathecal morphine analgesia. Anesthesiology
1984;60:448-54.
18. Sjostrom S,Tamsen A, Persson MP,etal. Pharmacokinetics
of intrathecal morphine and meperidine in humans.
Anesthesiology1987;67:889-95.
19. Gourlay GK, Cherry DA, Cousins MJ. Cephalad migrationof
morphinein CSFfollowing lumbarepiduraladministrationin
patients withcancer pain. Pain1985;23:317-26.
20. IonescuTI,Taverne RH, Drost RH,etal. Epidural morphine
anesthesia for abdominal aortic surgery-pharmacokinetics.
Reg Anesth1989;14:107-14.
21. Bellanca L, Latteri MT, Latteri S, et al. Plasma and CSF
morphine concentrations after i.m. and epidural
administration. Pharmacol Res Commun1985;17:189-96.
22. Sultan P, Gutierrez MC, Carvalho B. Neuraxial morphineand
respiratory depression: finding the right balance. Drugs
2011;71:1807-19.
23. Macintyre PE, Loadsman JA, Scott DA. Opioids, ventilation
and acute pain management. Anaesth Intensive Care
2011;39:545-58.
24. Hurle MA, Mediavilla A, Florez J. Morphine, pentobarbital
and naloxoneintheventral medullarychemosensitiveareas:
differential respiratory and cardiovascular effects.
J Pharmacol Exp Ther1982;220:642-7.
25. Mueller RA,Lundberg DB, Breese GR, HednerJ, HednerT,
Jonason J. The neuropharmacology of respiratory control.
Pharmacol Rev1982;34:255-85.
26. Pokorski M, Grieb P, Wideman J. Opiate system influences
central respiratorychemosensors. Brain Res1981;211:221-6.
27. Li Y, van den Pol AN. Mu-opioid receptor-mediated
depression of the hypothalamic hypocretin/orexin arousal
system. J Neurosci2008;28:2814-9.
28. Sieker HO, Hickam JB. Carbon dioxide intoxication: the
clinical syndrome, its etiology and management with
particular reference to the use of mechanical respirators.
Medicine1956;35:389-423.
29. Overdyk FJ, Hillman DR. Opioid modeling of central
respiratory drive must take upper airway obstruction into
account. Anesthesiology2011;114:219-20.
30. LoadsmanJA, Hillman DR. Anaesthesiaand sleep apnoea.
Br J Anaesth2001;86:254-66.
31. Gustafsson LL, Schildt B, Jacobsen K. Adverse effects of
extradural and intrathecal opiates: report of a nationwide
survey in Sweden1982. Br J Anaesth1998;81:86-93.
32. Stenseth R, Sellevold O, Breivik H. Epidural morphine for
postoperative pain: experience with 1085 patients. Acta
Anaesthesiol Scand 1985;29:148-56.
33. Koren G, Sandler AN, Klein J, et al. Relationship between
the pharmacokinetics and the analgesic and respiratory
pharmacodynamics of epidural sufentanil. Clin Pharmacol
Ther1989;46:458-62.
34. Brockway MS, Noble DW, Sharwood-Smith GH, et al.
Profound respiratory depression after extradural fentanyl.
Br J Anaesth1990;64:243-5.
35. Bujedo BM. Recommendations for spinal opioids clinical
practiceinthe managementof postoperative pain.J Anesth
Clin Res2013;2.
36. Bailey PL, Rhondeau S, Schafer PG, et al. Dose-response
pharmacologyof intrathecal morphineinhumanvolunteers.
Anesthesiology1993;79:49-59.
37. Kafer ER, Brown JT, Scott D, et al. Biphasic depression of
ventilatory responses to CO2 following epidural morphine.
Anesthesiology1983;58:418-27.
38. HorlockerTT, Burton AW, Connis RT,etal. Practice guidelines
for the prevention, detection,andmanagementof respiratory
depressionassociated withneuraxialopioid administration.
Anesthesiology2009;110:218-30.
39. Gehling M, Tryba M. Risks and side-effects of intrathecal
morphinecombined withspinalanaesthesia:ameta-analysis.
Anaesthesia2009;64:643-51.
40. Meylan N, Elia N, Lysakowski C, et al. Benefit and risk of
intrathecal morphine without local anaesthetic in patients
undergoing major surgery: meta-analysis of randomized
trials. Br J Anaesth2009;102:156-67.
41. Shapiro A, Zohar E, Zaslansky R, et al. The frequency and
timing of respiratory depression in 1524 postoperative
patients treated withsystemicorneuraxial morphine. J Clin
Anesth2005;17:537-42.
42. Duale C, Frey C, Bolandard F, et al. Epidural versus
intrathecal morphine for postoperative analgesia after
Caesareansection. Br J Anaesth2003;91:690-4.
43. Sarvela J, Halonen P, Soikkeli A, et al. A double-blinded,
randomized comparisonof intrathecaland epiduralmorphine
forelectivecesarean delivery. Anesth Analg 2002;95:436-40.
44. Ng K, Parsons J, Cyna AM, et al. Spinal versus epidural
anaesthesiaforcaesareansection.CDSR 2004(2):Cd003765.
45. Abouleish E, Rawal N, Rashad MN. The addition of 0.2 mg
subarachnoid morphine to hyperbaric bupivacaine for
cesarean delivery: a prospective study of 856 cases. Reg
Anesth1991;16:137-40.
46. Ladha KS, Kato R, Tsen LC, et al. A prospective study of
post-cesarean deliveryhypoxiaafter spinalanesthesia with
intrathecal morphine 150 mg. Int J Obstet Anesth 2017;32:
48-53.
47. Crowgey TR, Dominguez JE, Peterson-Layne C, et al. A
retrospective assessment of the incidence of respiratory
depression after neuraxial morphine administration for
postcesarean delivery analgesia. Anesth Analg 2013;117:
1368-70.
48. Fuller JG, McMorland GH, Douglas MJ, et al. Epidural
morphine for analgesia after caesarean section: a report of
4880 patients. CanJ Anaesth1990;37:636-40.
49. Kato R, Shimamoto H, Terui K, et al. Delayed respiratory
depression associated with 0.15 mg intrathecal morphine
for cesarean section: a review of 1915 cases. J Anesth
2008;22:112-6.
50. Gwirtz KH, Young JV, Byers RS,etal.Thesafetyand efficacy
of intrathecalopioid analgesiaforacute postoperative pain:
seven years’ experience with 5969 surgical patients at
Indiana University Hospital. Anesth Analg 1999;88:599-604.
51. Flisberg P, Rudin A, Linner R, et al. Pain relief and safety
after major surgery. A prospective study of epidural and
intravenous analgesia in 2696 patients. Acta Anaesthesiol
Scand 2003;47:457-65.
52. Rygnestad T, Borchgrevink PC, Eide E. Postoperative
epidural infusion of morphine and bupivacaine is safe on
surgical wards. Organisation of the treatment, effects and
side-effectsin2000consecutive patients. Acta Anaesthesiol
Scand 1997;41:868-76.
53. Tsui SL, Irwin MG, Wong CM,etal. Anauditof thesafetyof
anacute painservice. Anaesthesia1997;52:1042-7.
54. Frassanito L, Vergari A, Zanghi F, et al. Post-operative
analgesia following total knee arthroplasty: comparison of
low-dose intrathecal morphine and single-shot ultrasoundguided femoral nerve block: a randomized, single blinded,
controlled study. Eur Rev Med Pharmacol Sci 2010;14:
589-96.
55. Duman A, Apiliogullari S, Balasar M,etal. Comparisonof50
mg and 25 mg dosesof intrathecalmorphineon postoperative
analgesicrequirementsin patientsundergoing transurethral
resection of the prostate with intrathecal anesthesia. J Clin
Anesth2010;22:329-33.
56. Sharawi N, Carvalho B, Habib AS,etal. A Systematicreview
evaluating neuraxial morphineand diamorphine-associated
respiratory depressionaftercesarean delivery. Anesth Analg
2018;127:1385-95.
57. Lee LA, Caplan RA, Stephens LS, et al. Postoperative
opioid-induced respiratory depression: a closed claims
analysis. Anesthesiology2015;122:659-65.
58. Gupta K, Nagappa M, Prasad A, et al. Risk factors for
opioid-induced respiratory depression in surgical patients:
a systematic review and meta-analyses. BMJ Open
2018;8:e024086.
59. Pleym H, Spigset O, Kharasch ED,etal. Gender differences
in drug effects: implications for anesthesiologists. Acta
Anaesthesiol Scand 2003;47:241-59.
60. Gupta K, Prasad A, Nagappa M, et al. Risk factors for
opioid-induced respiratory depressionand failuretorescue:
areview. Curr Opin Anaesthesiol2018;31:110-9.
61. Uchiyama A, Nakano S, Ueyama H, et al. Low dose
intrathecal morphine and pain relief following caesarean
section. Int J Obstet Anesth1994;3:87-91.
62. Sultan P, Halpern SH, Pushpanathan E, et al. The Effect of
intrathecal morphine dose on outcomes after elective
cesarean delivery: A Meta-Analysis. Anesth Analg 2016;123:
154-64.
63. Hein A, Rosblad P, Gillis-Haegerstrand C, et al. Low dose
intrathecalmorphineeffectson post-hysterectomy pain:arandomized placebo-controlled study. Acta Anaesthesiol Scand
2012;56:102-9.
64. Meco BC, Bermede O, Vural C, et al. A comparison of two
different dosesof morphineadded tospinal bupivacainefor
inguinalherniarepair. Braz J Anesthesiol2016;66:140-4.
65. Murphy PM, Stack D, Kinirons B, et al. Optimizing the dose
of intrathecal morphine in older patients undergoing hip
arthroplasty. Anesth Analg 2003;97:1709-15.
66. Slappendel R, Weber EW, Dirksen R, et al. Optimization of
the dose of intrathecal morphine in total hip surgery:
a dose-finding study. Anesth Analg 1999;88:822-6.
67. Hassett P, Ansari B, Gnanamoorthy P, et al. Determination
of the efficacy and side-effect profile of lower doses of
intrathecal morphine in patients undergoing total knee
arthroplasty. Anesthesiology2008;8:5.
68. Palmer CM, Nogami WM, Van Maren G,etal. Postcesarean
epidural morphine: a dose-response study. Anesth Analg
2000;90:887-91.
69. Lanz E, Kehrberger E, Theiss D. Epidural morphine:
a clinical double-blind study of dosage. Anesth Analg
1985;64:786-91.
70. BauchatJR,Weiniger CF, Sultan P,etal. Societyfor Obstetric
Anesthesia and Perinatology consensus statement:
monitoring recommendations for prevention and detection
of respiratory depression associated with administration of
neuraxial morphineforcesarean deliveryanalgesia. Anesth
Analg 2019;129:458-74.
experience: results from a national survey suggest
postoperative paincontinues to beundermanaged. Anesth
Analg 2003;97:534-40.
2. Pert CB, Snyder SH. Opiate receptor: demonstration in
nervous tissue. Science1973;179:1011-4.
3. Wang JK, NaussLA,Thomas JE. Painrelief by intrathecally
applied morphinein man. Anesthesiology1979;50:149-51.
4. Behar M, Olshwang D, Magora F, et al. Epidural morphine
intreatmentof pain.Lancet1979;313:527-9.
5. DeSousa KA, Chandran R. Intrathecal morphine for
postoperativeanalgesia: Current trends.World J Anesthesiol
2014;3:191-202.
6. DahlJB,JeppesenIS,Jorgensen H,etal. Intraoperativeand
postoperative analgesic efficacy and adverse effects of
intrathecalopioidsin patientsundergoing cesareansection
with spinal anesthesia: a qualitative and quantitative
systematic review of randomized controlled trials.
Anesthesiology1999;91:1919-27.
7. Cohen SE, Woods WA.Theroleofepidural morphineinthe
postcesarean patient: efficacy and effects on bonding.
Anesthesiology1983;58:500-4.
8. Rosaeg OP, Lui AC, Cicutti NJ, et al. Peri-operative
multimodal pain therapy for caesarean section: analgesia
and fitness for discharge. CanJ Anesth1997;44:803-9.
9. StoeltingRK. Intrathecalmorphine-anunderusedcombination
for postoperative pain management. Anesth Analg 1989;
68:707-9.
10. Bujedo BM. Spinal opioid bioavailability in postoperative
pain. Pain Pract2014;14:350-64.
11. Bernards CM, Shen DD, Sterling ES, et al. Epidural,
cerebrospinalfluid,and plasma pharmacokineticsofepidural
opioids(part1): differencesamong opioids. Anesthesiology
2003;99:455-65.
12. Bernards CM, Hill HF. Physical and chemical properties of
drug molecules governing their diffusionthroughthespinal
meninges. Anesthesiology1992;77:750-6.
13. Weddel SJ, Ritter RR. Serum levels following epidural
administration of morphine and correlation with relief of
postsurgical pain. Anesthesiology1981;54:210-4.
14. Moulin DE, Inturrisi CE, Foley KM. Cerebrospinal fluid
pharmacokineticsof intrathecalmorphinesulfateand D-Ala2-
D-Leu5-enkephalin. Annalsofneurology1986;20:218-22.
15. Hanna MH, Peat SJ, Woodham M, et al. Analgesic efficacy
and CSF pharmacokinetics of intrathecal morphine6-glucuronide: comparison with morphine. Br J Anaesth
1990;64:547-50.
16. Davies GK, Tolhurst-Cleaver CL, James TL. Respiratory
depression after intrathecal narcotics. Anaesthesia 1980;
35:1080-3.
17. Nordberg G, HednerT, Mellstrand T,etal. Pharmacokinetic
aspects of intrathecal morphine analgesia. Anesthesiology
1984;60:448-54.
18. Sjostrom S,Tamsen A, Persson MP,etal. Pharmacokinetics
of intrathecal morphine and meperidine in humans.
Anesthesiology1987;67:889-95.
19. Gourlay GK, Cherry DA, Cousins MJ. Cephalad migrationof
morphinein CSFfollowing lumbarepiduraladministrationin
patients withcancer pain. Pain1985;23:317-26.
20. IonescuTI,Taverne RH, Drost RH,etal. Epidural morphine
anesthesia for abdominal aortic surgery-pharmacokinetics.
Reg Anesth1989;14:107-14.
21. Bellanca L, Latteri MT, Latteri S, et al. Plasma and CSF
morphine concentrations after i.m. and epidural
administration. Pharmacol Res Commun1985;17:189-96.
22. Sultan P, Gutierrez MC, Carvalho B. Neuraxial morphineand
respiratory depression: finding the right balance. Drugs
2011;71:1807-19.
23. Macintyre PE, Loadsman JA, Scott DA. Opioids, ventilation
and acute pain management. Anaesth Intensive Care
2011;39:545-58.
24. Hurle MA, Mediavilla A, Florez J. Morphine, pentobarbital
and naloxoneintheventral medullarychemosensitiveareas:
differential respiratory and cardiovascular effects.
J Pharmacol Exp Ther1982;220:642-7.
25. Mueller RA,Lundberg DB, Breese GR, HednerJ, HednerT,
Jonason J. The neuropharmacology of respiratory control.
Pharmacol Rev1982;34:255-85.
26. Pokorski M, Grieb P, Wideman J. Opiate system influences
central respiratorychemosensors. Brain Res1981;211:221-6.
27. Li Y, van den Pol AN. Mu-opioid receptor-mediated
depression of the hypothalamic hypocretin/orexin arousal
system. J Neurosci2008;28:2814-9.
28. Sieker HO, Hickam JB. Carbon dioxide intoxication: the
clinical syndrome, its etiology and management with
particular reference to the use of mechanical respirators.
Medicine1956;35:389-423.
29. Overdyk FJ, Hillman DR. Opioid modeling of central
respiratory drive must take upper airway obstruction into
account. Anesthesiology2011;114:219-20.
30. LoadsmanJA, Hillman DR. Anaesthesiaand sleep apnoea.
Br J Anaesth2001;86:254-66.
31. Gustafsson LL, Schildt B, Jacobsen K. Adverse effects of
extradural and intrathecal opiates: report of a nationwide
survey in Sweden1982. Br J Anaesth1998;81:86-93.
32. Stenseth R, Sellevold O, Breivik H. Epidural morphine for
postoperative pain: experience with 1085 patients. Acta
Anaesthesiol Scand 1985;29:148-56.
33. Koren G, Sandler AN, Klein J, et al. Relationship between
the pharmacokinetics and the analgesic and respiratory
pharmacodynamics of epidural sufentanil. Clin Pharmacol
Ther1989;46:458-62.
34. Brockway MS, Noble DW, Sharwood-Smith GH, et al.
Profound respiratory depression after extradural fentanyl.
Br J Anaesth1990;64:243-5.
35. Bujedo BM. Recommendations for spinal opioids clinical
practiceinthe managementof postoperative pain.J Anesth
Clin Res2013;2.
36. Bailey PL, Rhondeau S, Schafer PG, et al. Dose-response
pharmacologyof intrathecal morphineinhumanvolunteers.
Anesthesiology1993;79:49-59.
37. Kafer ER, Brown JT, Scott D, et al. Biphasic depression of
ventilatory responses to CO2 following epidural morphine.
Anesthesiology1983;58:418-27.
38. HorlockerTT, Burton AW, Connis RT,etal. Practice guidelines
for the prevention, detection,andmanagementof respiratory
depressionassociated withneuraxialopioid administration.
Anesthesiology2009;110:218-30.
39. Gehling M, Tryba M. Risks and side-effects of intrathecal
morphinecombined withspinalanaesthesia:ameta-analysis.
Anaesthesia2009;64:643-51.
40. Meylan N, Elia N, Lysakowski C, et al. Benefit and risk of
intrathecal morphine without local anaesthetic in patients
undergoing major surgery: meta-analysis of randomized
trials. Br J Anaesth2009;102:156-67.
41. Shapiro A, Zohar E, Zaslansky R, et al. The frequency and
timing of respiratory depression in 1524 postoperative
patients treated withsystemicorneuraxial morphine. J Clin
Anesth2005;17:537-42.
42. Duale C, Frey C, Bolandard F, et al. Epidural versus
intrathecal morphine for postoperative analgesia after
Caesareansection. Br J Anaesth2003;91:690-4.
43. Sarvela J, Halonen P, Soikkeli A, et al. A double-blinded,
randomized comparisonof intrathecaland epiduralmorphine
forelectivecesarean delivery. Anesth Analg 2002;95:436-40.
44. Ng K, Parsons J, Cyna AM, et al. Spinal versus epidural
anaesthesiaforcaesareansection.CDSR 2004(2):Cd003765.
45. Abouleish E, Rawal N, Rashad MN. The addition of 0.2 mg
subarachnoid morphine to hyperbaric bupivacaine for
cesarean delivery: a prospective study of 856 cases. Reg
Anesth1991;16:137-40.
46. Ladha KS, Kato R, Tsen LC, et al. A prospective study of
post-cesarean deliveryhypoxiaafter spinalanesthesia with
intrathecal morphine 150 mg. Int J Obstet Anesth 2017;32:
48-53.
47. Crowgey TR, Dominguez JE, Peterson-Layne C, et al. A
retrospective assessment of the incidence of respiratory
depression after neuraxial morphine administration for
postcesarean delivery analgesia. Anesth Analg 2013;117:
1368-70.
48. Fuller JG, McMorland GH, Douglas MJ, et al. Epidural
morphine for analgesia after caesarean section: a report of
4880 patients. CanJ Anaesth1990;37:636-40.
49. Kato R, Shimamoto H, Terui K, et al. Delayed respiratory
depression associated with 0.15 mg intrathecal morphine
for cesarean section: a review of 1915 cases. J Anesth
2008;22:112-6.
50. Gwirtz KH, Young JV, Byers RS,etal.Thesafetyand efficacy
of intrathecalopioid analgesiaforacute postoperative pain:
seven years’ experience with 5969 surgical patients at
Indiana University Hospital. Anesth Analg 1999;88:599-604.
51. Flisberg P, Rudin A, Linner R, et al. Pain relief and safety
after major surgery. A prospective study of epidural and
intravenous analgesia in 2696 patients. Acta Anaesthesiol
Scand 2003;47:457-65.
52. Rygnestad T, Borchgrevink PC, Eide E. Postoperative
epidural infusion of morphine and bupivacaine is safe on
surgical wards. Organisation of the treatment, effects and
side-effectsin2000consecutive patients. Acta Anaesthesiol
Scand 1997;41:868-76.
53. Tsui SL, Irwin MG, Wong CM,etal. Anauditof thesafetyof
anacute painservice. Anaesthesia1997;52:1042-7.
54. Frassanito L, Vergari A, Zanghi F, et al. Post-operative
analgesia following total knee arthroplasty: comparison of
low-dose intrathecal morphine and single-shot ultrasoundguided femoral nerve block: a randomized, single blinded,
controlled study. Eur Rev Med Pharmacol Sci 2010;14:
589-96.
55. Duman A, Apiliogullari S, Balasar M,etal. Comparisonof50
mg and 25 mg dosesof intrathecalmorphineon postoperative
analgesicrequirementsin patientsundergoing transurethral
resection of the prostate with intrathecal anesthesia. J Clin
Anesth2010;22:329-33.
56. Sharawi N, Carvalho B, Habib AS,etal. A Systematicreview
evaluating neuraxial morphineand diamorphine-associated
respiratory depressionaftercesarean delivery. Anesth Analg
2018;127:1385-95.
57. Lee LA, Caplan RA, Stephens LS, et al. Postoperative
opioid-induced respiratory depression: a closed claims
analysis. Anesthesiology2015;122:659-65.
58. Gupta K, Nagappa M, Prasad A, et al. Risk factors for
opioid-induced respiratory depression in surgical patients:
a systematic review and meta-analyses. BMJ Open
2018;8:e024086.
59. Pleym H, Spigset O, Kharasch ED,etal. Gender differences
in drug effects: implications for anesthesiologists. Acta
Anaesthesiol Scand 2003;47:241-59.
60. Gupta K, Prasad A, Nagappa M, et al. Risk factors for
opioid-induced respiratory depressionand failuretorescue:
areview. Curr Opin Anaesthesiol2018;31:110-9.
61. Uchiyama A, Nakano S, Ueyama H, et al. Low dose
intrathecal morphine and pain relief following caesarean
section. Int J Obstet Anesth1994;3:87-91.
62. Sultan P, Halpern SH, Pushpanathan E, et al. The Effect of
intrathecal morphine dose on outcomes after elective
cesarean delivery: A Meta-Analysis. Anesth Analg 2016;123:
154-64.
63. Hein A, Rosblad P, Gillis-Haegerstrand C, et al. Low dose
intrathecalmorphineeffectson post-hysterectomy pain:arandomized placebo-controlled study. Acta Anaesthesiol Scand
2012;56:102-9.
64. Meco BC, Bermede O, Vural C, et al. A comparison of two
different dosesof morphineadded tospinal bupivacainefor
inguinalherniarepair. Braz J Anesthesiol2016;66:140-4.
65. Murphy PM, Stack D, Kinirons B, et al. Optimizing the dose
of intrathecal morphine in older patients undergoing hip
arthroplasty. Anesth Analg 2003;97:1709-15.
66. Slappendel R, Weber EW, Dirksen R, et al. Optimization of
the dose of intrathecal morphine in total hip surgery:
a dose-finding study. Anesth Analg 1999;88:822-6.
67. Hassett P, Ansari B, Gnanamoorthy P, et al. Determination
of the efficacy and side-effect profile of lower doses of
intrathecal morphine in patients undergoing total knee
arthroplasty. Anesthesiology2008;8:5.
68. Palmer CM, Nogami WM, Van Maren G,etal. Postcesarean
epidural morphine: a dose-response study. Anesth Analg
2000;90:887-91.
69. Lanz E, Kehrberger E, Theiss D. Epidural morphine:
a clinical double-blind study of dosage. Anesth Analg
1985;64:786-91.
70. BauchatJR,Weiniger CF, Sultan P,etal. Societyfor Obstetric
Anesthesia and Perinatology consensus statement:
monitoring recommendations for prevention and detection
of respiratory depression associated with administration of
neuraxial morphineforcesarean deliveryanalgesia. Anesth
Analg 2019;129:458-74.