Table 1. Incidence of respiratory depression associated with intrathecal morphine across surgical types.
Abbreviations: ND: non-significant difference in incidence of respiratory depression between comparator arms (non-significant p-value); RR: respiratory rate; ITM: intrathecal morphine; SpO2: peripheral oxygen saturation; SaO2: arterial oxygen saturation; EREM: extended-release epidural morphine; PaCO2: arterial carbon dioxide tension; ASA: American Society of Anesthesiologists
| Surgical Type | Author | Study Type | # of Patients (n) | ITM Dose | Analgesic Outcomes | Incidence of Respiratory Depression | Respiratory Depression Definition |
| Spinal | |||||||
| Araimo Morselli et al. [55] | Randomized controlled trial | 50 | 100 µg | ITM was associated with lower NRS scores, earlier mobilization, and shorter hospitalization than IV morphine. | None | SpO2 and arterial blood gas analysis | |
| Audlin et al. [87] | Retrospective review | 17 | 600 µg | No statistical difference in postoperative pain or side effects noted between ITM, IV opioids, or oral opioids. | None | - | |
| De Bie et al. [57] | Retrospective cohort study | 60 | 100 µg | ITM was associated with lower cumulative morphine consumption and VAS scores with earlier mobilization and earlier discharge compared to control. | None | - | |
| Sarwahi et al. [51] | Retrospective review | 373 | 1.5 µg/kg (avg 82.65 µg) | ITM was associated with shorter length of stay, earlier ambulation, and lower VAS scores compared to control. | None | - | |
| Wang et al. [41] | Randomized controlled trial | 92 | 200 µg | ITM was associated with lower VAS scores, PCA use, and supplemental analgesic demands with no increase in adverse effects compared to control. | None | - | |
| Yen et al. [116] | Randomized controlled trial | 32 | 3.5 µg/kg (350 µg max) | ITM resulted in lower PCA use with no difference in pain scores compared to control. | None | RR < 9 breaths/min | |
| Ziegeler et al. [86] | Randomized controlled trial | 46 | 400 µg | ITM resulted in improved VAS scores at rest 4 and 8 hours after surgery with significantly lower cumulative PCA requirements compared to control. | None | SaO2 and blood gas analysis | |
| Ibach et al. [112] | Retrospective, cross-sectional, observational study | 44 | average 369 µg | Patients experienced improved analgesia for at least 12 hours following ITM administration. | 11.4% (5 patients) | RR < 10 breaths/min | |
| Poblete et al. [85] | Prospective proof-of-concept study | 20 | 7 µg/kg (140-550 µg) | ITM for postoperative analgesia after resection of cervical and thoracic spinal cord tumors was observed to be safe and effective. | 5% (1 patient). Respiratory depression subsided quickly and without consequence or further intervention. | RR < 8 breaths/min | |
| Cohen et al. [107] | Randomized controlled trial | 71 | 7.5 µg/kg (avg 402 µg) | No difference in total morphine consumption or time until first PCA demand between EREM and ITM. EREM provided longer duration of analgesia and was associated with less opioid induced pruritus. | ND in incidence between ITM vs extended-release epidural morphine (EREM). 24% (17 patients) of ITM pts, 15% (11 patients) of EREM pts. | SpO2 < 88% | |
| Dhaliwal et al. [58] | Randomized controlled trial | 150 | 200 µg | ITM was associated with reduced postoperative opioid requirements and VAS scores compared to control. | ND in incidence between ITM vs sham saline injection. No significant differences in respiratory rates or oxygen saturation between treatment groups in the 24hrs postop. | RR < 10 breaths/min | |
| Hong et al. [61] | Retrospective review | 40 | 12 µg/kg (avg 667.2 µg) | Use of ITM in addition to routine administration of nonopioid analgesics facilitated early transition to oral analgesics, early ambulation, and early discharge compared to epidural hydromorphone. | ND in incidence between ITM vs epidural hydromorphone. 33% of patients in both groups required nasal oxygen cannulation at some point after PACU discharge, however, none required naloxone or additional treatment for hypoxemia. | SpO2 < 92% | |
| Urologic | |||||||
| Swisher et al. [66] | Retrospective case-control | 27 | 300 µg | ITM was associated with decreased opioid consumption and NRS scores compared to control. | None | - | |
| Park et al. [95] | Retrospective review | 366 | 200 µg | ITM was associated with better functional recovery of remnant kidney in living donors with favorable analgesic results on NRS. | None | - | |
| Nuri Deniz et al. [65] | Randomized controlled trial | 56 | 200 µg | ITM provided significant reduction in postoperative VAS scores, rescue analgesia, and postoperative nausea without serious adverse effects compared to control. | None | RR < 8 breaths/min | |
| Kurzova et al. [93] | Randomized controlled trial | 41 | 250 µg | ITM provided long-lasting analgesia and reduction in postoperative systemic administration of opioids compared to control. Adverse effects were comparable between groups. | None | Bradypnea or SpO2 < 90% | |
| Kim et al. [92] | Retrospective review | 272 | 200 µg | ITM was associated with lower NRS scores and cumulative opioid consumption compared to control. | None | - | |
| Kim et al. [62] | Randomized controlled trial | 45 | 300 µg | ITM was associated with lower postoperative pain on NPS with significantly lower cumulative morphine consumption compared to control. | None | At least one of the following variables: respiratory rate < 8 breaths/min, SpO2 < 90% or PaCO2 > 70 mmHg | |
| Bae et al. [43] | Randomized controlled trial | 30 | 300 µg | ITM was associated with lower NPS scores and cumulative morphine consumption compared to control. | None | At least one of the following variables: respiratory rate < 8 breaths/min, SpO2 < 90% or PaCO2 > 70 mmHg | |
| Boonmak et al. [56] | Randomized controlled trial | 80 | 300 µg | ITM was associated with lower cumulative morphine consumption and NRS scores with no significant difference in patient satisfaction with pain management compared to control. | None | - | |
| Thoracic | |||||||
| Askar et al. [44] | Randomized controlled trial | 33 | 10 µg/kg (avg 712.4 µg) | ITM was associated with lower VAS scores and morphine consumption compared to control with better preservation of respiratory function. | None | - | |
| Okbaz et al. [77] | Randomized controlled trial | 46 | 7 µg/kg (avg 429.1µg) | ITM at 10µg/kg was associated with lower postoperative morphine consumption and postoperative pain scores at 18 and 24 hours compared to ITM at 7µg/kg. | None | SpO2 < 90 on room air, RR <10 breaths/min, or Ramsay sedation scale score >3 | |
| 10 µg/kg (avg 613 µg) | |||||||
| Vijitpavan et al. [68] | Randomized controlled trial | 38 | 200 µg | ITM was associated with lower NRS scores and cumulative dose of postoperative morphine compared to control. | None | RR < 8 breaths/min | |
| Ward et al. [76] | Retrospective review | 84 | Initial injection 1000 µg, 2560 µg over 48hrs | ITM was found to be an efficacious and safe analgesic method in post-thoracotomy patients with no serious complications or sequelae at 6-month follow up. | None | RR < 8 breaths/min and/or requiring naloxone | |
| Suksompong et al. [115] | Randomized controlled trial | 40 | 200 µg | No statistical difference was found in 24-hours postoperative meperidine usage between groups. | 5% (1 patient) in 300 µg group. Pt developed respiratory acidosis with RR 10 breaths/min 44 minutes after extubation. | One patient in 300 µg group developed respiratory acidosis with RR 10 breaths/min 44 minutes after extubation | |
| 300 µg | |||||||
| Obstetric & Gynecological | |||||||
| Crowgey et al. [108] | Retrospective review | 5336 | 50-250 µg (avg 150 µg) | The upper 95% confidence limit for respirator depression was found to be 0.07%. | None | Naloxone administration for reversal of RD | |
| Karaman et al. [34] | Randomized controlled trial | 24 | 5 µg/kg (avg 344 µg) | ITM was associated with lower VAS scores, total morphine consumption, and systemic stress response compared to control. | None | RR < 10 breaths/min | |
| Bang et al. [101] | Randomized controlled trial | 68 | 200 µg | ITM was associated with lower cumulative opioid consumption and higher patient satisfaction regarding pain control compared to control. | ND in incidence between ITM and sham group – sham procedure involved 2 minutes of applied pressure with a capped needle without dural puncture. 6.1% (2 patients) of ITM group. 3% (1 patient) of sham group. | RR < 8 breaths/min or need for supplemental oxygen to maintain SpO2 92% | |
| Abdominal | |||||||
| Lee, S. et al. [114] | Prospective randomized non-inferiority trial | 55 | 300 µg | ITM 300 µg exhibited non-inferior postoperative analgesia with lower incidence of PONV compared to 400 µg. | None | RR < 8 breaths/min or SpO2 < 90% | |
| 400 µg | |||||||
| Niewiński et al. [64] | Randomized controlled trial | 36 | 400 µg | No differences in NRS scores, pain severity, cumulative opioid consumption, or early recovery was observed between ITM and IV morphine. | None | - | |
| Blay et al. [37] | Randomized controlled trial | 32 | 200 µg | ITM was associated with decreased intraoperative sufentanil, cumulative morphine consumption and VAS scores compared to control. | None | - | |
| De Pietri et al. [109] | Retrospective case control | 50 | 200 µg | ITM was associated with lower cumulative morphine consumption and VAS scores, earlier mobilization, and earlier discharge compared to control. | None | Hypercapnia or hypoxia | |
| Ko et al. [39] | Randomized controlled trial | 40 | 400 µg | ITM was associated with lower VAS scores and cumulative opioid consumption compared to control. | None | RR < 8 breaths/min | |
| Kuppusamy et al. [50] | Randomized controlled trial | 60 | 200 µg | ITM was associated with lower cumulative morphine consumption compared to control. There was no statistically significant difference in VAS scores. | None | RR < 8 breaths/min or SpO2 < 90% | |
| Beaussier et al. [45] | Randomized controlled trial | 52 | 300 µg | ITM was associated with decreased pain intensity and daily IV morphine consumption compared to control. | 7.7% (4 patients). 1 pt experienced deep sedation with respiratory depression and inhalation of gastric contents. | RR < 10 breaths/min | |
| Fares et al. [80] | Randomized controlled trial | 90 | 200 µg | Time to first analgesic request was prolonged with 500 µg and 1000 µg compared to 200 µg. Mean tramadol consumption was lower with 500 µg and 1000 µg compared to 200 µg. VAS scores were lower with 1000 µg compared to 500 µg and 200 µg. | 3.3% (1 patient) in 1000 µg group. Pt was 65 years old, frail, and ASA III. | RR < 10 breaths/min | |
| 500 µg | |||||||
| 1000 µg | |||||||
| Mittal et al. [40] | Randomized controlled trial | 60 | 200 µg | ITM was associated with lower NRS scores, cumulative fentanyl consumption, and lower total rescue analgesia compared to control. | 13.3% (4 patients) in ITM group, 3.7% (1 patient) in control group. | SpO2 < 92% | |
| Dichtwald et al. [110] | Randomized controlled trial | 49 | 4 µg/kg (avg 288 µg) | ITM was associated with lower NRS scores and reduced need for rescue analgesia compared to IV opioids. | ND in incidence between ITM vs IV remifentanil. 3% of all patients had non-life-threatening respiratory depression. | RR < 10 breaths/min and/or PaCO2 > 60 mmHg | |
| Abdominal, Urologic, or Thoracic | |||||||
| González-Santos et al. [111] | Retrospective review | 484 | 180 µg average (400 µg max) | 51.03% of patients required postoperative rescue analgesia with IV morphine with an average dose of 6.98 mg, this was significantly higher in thoracic surgery patients compared to general surgery patients or urological surgery patients. | None | RR < 10 breaths/min, Sp02 < 90%, or signs of drowsiness/sedation | |
| Cardiac | |||||||
| Dhawan et al. [55] | Randomized controlled trial | 79 | 5 µg/kg (avg 425 µg) | ITM was associated with lower cumulative morphine equivalents, VAS scores, and percent of time in severe pain compared to control. | None | Prolonged tracheal reintubation secondary to hypercarbia or escalation of respiratory support after extubation secondary to hypercarbia | |
| dos Santos et al. [73] | Randomized controlled trial | 42 | 400 µg | ITM was associated with lower VAS scores, cumulative morphine consumption, and plasma morphine concentration compared to control. | None | - | |
| Elgendy et al. [38] | Randomized controlled trial | 44 | 7 µg/kg (avg 392 µg) | ITM was associated with lower VAS scores and cumulative fentanyl consumption, and mean tramadol consumption compared to control. Time to first request for rescue analgesia was prolonged with ITM. | None | RR < 10 breaths/min | |
| Mukherjee et al. [63] | Randomized controlled trial | 61 | 1.5 µg/kg (avg 118.5 µg) | ITM was associated with decreased demand for IV opioids and VAS scores compared to IV opioids. | None | PaCO2 (limit not defined) | |
| Roediger et al [35] | Randomized controlled trial | 30 | 500 µg | ITM was associated with a 40% reduction in IV morphine and lower VAS scores at rest compared to control. | 26.7% (4 patients) in ITM group, 80% (12 patients) in control group. | RR < 10 breaths/min | |
| Breast | |||||||
| Karamese et al. [49] | Randomized controlled trial | 62 | 200 µg | ITM was associated with lower cumulative morphine consumption than control; no different was noted in pain and satisfaction scores. | None | RR< 8 breaths/min and/or SpO2 < 90% | |
| Non-surgical | |||||||
| Raffaeli et al. [102] | Randomized controlled trial | 144 | 15 µg | Patients receiving ITM all experienced clinically significant pain relief on VAS scores with reduction in values ranging from 60% - 100%; only 25% of controls showed a reduction in VAS scores of over 50%. | None | RR < 6 breaths/min | |
| 30 µg | |||||||
| 60 µg | |||||||
| 250 µg | |||||||
| Pediatric | |||||||
| Keskin et al. [113] | Retrospective observational cohort study | 100 | 5 µg/kg (300 µg max) | 96% of patients did not require rescue analgesia, sleep interruption was not observed in 97% of cases, and nurses were satisfied or very satisfied with pain management in 99% of cases. | None | RR < 18 breaths/min in patients < 10 years old; RR < 14 breaths/min in patients > 10 years old; PaCO2 above 45 mmHg |