Intrathecal Morphine for Analgesia in Minimally Invasive Cardiac Surgery

A Randomized, Placebo-controlled, Double-blinded Clinical Trial

Richa Dhawan, M.D., M.P.H.; Danisa Daubenspeck, D.O.; Kristen E. Wroblewski, M.S.; John-Henry Harrison, M.D.; Mackenzie McCrorey, M.S.P.A.C.; Husam H. Balkhy, M.D., Mark A. Chaney, M.D.


Anesthesiology. 2021;135(5):864-876. 

In This Article


This randomized, placebo-controlled, double-blinded, clinical investigation indicates that intrathecal morphine provides significant analgesia for the initial 48 postoperative hours in patients undergoing robotic totally endoscopic CABG. Significant reductions in postoperative morphine consumption, postoperative pain scores (rest, cough), and subjective pain scores (Revised American Pain Society Outcome Questionnaire) were demonstrated with minimal side effects. Thus, the technique may prove useful in patients undergoing minimally invasive cardiac surgery in the current enhanced recovery after surgery era.

Over the last 70 yr, cardiac surgery has progressed from sternotomy and universal use of CPB to minimal exposure via small thoracic incisions and avoidance of CPB (Table 7).[16] This shift is reflected in anesthetic technique, with early use of large-dose IV opioids and delayed extubation to current practices of minimal IV opioids and early extubation. The trend toward minimally invasive cardiac surgery, along with increased utilization of enhanced recovery after surgery protocols, has led to an explosion of reports of regional techniques in patients undergoing a wide range of cardiac surgeries. Specific clinical advantages/disadvantages of each technique are beyond the scope of this manuscript yet have been recently summarized.[17–25] Advancements in ultrasound-guided techniques have led to an increased use of fascial plane blocks. Major unresolved issues regarding these techniques involve simplicity (easily performed in a busy clinical environment), reliability of postoperative analgesia, time period of analgesia produced (single shot vs. catheters), and side effect profile/safety.

There is tremendous interest in regional techniques as part of a multimodal pain strategy. An ideal regional approach to the cardiac surgical patient should take into consideration the myriad sources of pain, including tissue retraction, artery dissection, body positioning, chest tubes, incision, and inflammation from surgical trauma. Unique challenges are associated with regional techniques in minimally invasive cardiac surgery. Erector spinae and paravertebral blocks are limited by high failure rate, potential adverse events in the setting of heparinization (hematoma), hemodynamic effects (epidural spread/sympatholysis), short duration of analgesia, and reports of local anesthetic toxicity.[26–28] Fascial plane blocks have limited analgesic coverage, with beneficial analgesic effects limited to the upper anterolateral, lateral, and parasternal chest wall, respectively. In contrast, intrathecal morphine offers a simple, reliable, and safe modality of providing analgesia to multiple sources of pain in patients undergoing any type of minimally invasive cardiac surgery. Not without risk, postdural headache, failed spinal, and rare instances of spinal hematoma have been reported. In our clinical trial, besides three failed spinals, we did not observe any other issues associated with a neuraxial technique.

Application of intrathecal morphine during cardiac surgery was initially reported in 1980,[29] with subsequent small randomized controlled trials demonstrating decreased use of postoperative opioids and enhanced analgesia in patients receiving intrathecal morphine.[30] The first clinical trial investigating the potential benefits of intrathecal morphine in fast-track cardiac surgery in 1997 randomized 40 patients to receive either intrathecal morphine (10 mcg/kg) or intrathecal placebo before induction.[31] Time to extubation was significantly prolonged in patients who received intrathecal morphine compared to placebo controls, with postoperative IV morphine use equivalent between groups. A follow-up study also found that four patients receiving intrathecal morphine had prolonged respiratory depression.[32] The authors concluded that although intrathecal morphine can produce reliable postoperative analgesia, its use in the setting of fast-track cardiac surgery (via median sternotomy) may potentially delay tracheal extubation.[31,32] Given these findings with larger doses, our investigation used a dose of intrathecal morphine (5 mcg/kg) that would potentially enhance postoperative analgesia without impacting early extubation. Also consistent with other studies on pain relief in cardiac surgery, morphine equivalent was chosen as a primary outcome in our clinical trial.

In the early 2000s, others continued to explore potential clinical benefits of intrathecal morphine in patients undergoing cardiac surgery, without reliable success. In 2009, three large reviews/meta-analyses focusing on use of intrathecal morphine in patients undergoing cardiac surgery concluded that this practice provides postoperative analgesia with only questionable potential clinical benefits (decreased extubation time, improved pulmonary function) and is associated with clinically important pruritus and potential respiratory depression.[33–35] One set of authors felt the technique should be abandoned.[35] The vast majority (if not all) of the clinical studies assessed by these three reviews/meta-analyses possess major methodologic design problems (small, retrospective, and others). However, two studies hint that intrathecal morphine may be uniquely beneficial in patients undergoing minimally invasive cardiac surgery, yet one is small (22 patients) and retrospective,[36] and the other is not blinded,[37] limiting interpretation of the results. Based on this set of previously published work, intrathecal morphine in cardiac surgery has been relatively disregarded. However, the results of our study contribute to understanding the clinical efficacy and side-effect profile of intrathecal morphine in minimally invasive cardiac surgery and support its routine use in clinical practice.

The analgesic and adverse effects of intrathecal morphine are dose-dependent. Dose-response studies of intrathecal morphine in cardiac cases are limited. A large meta-analysis of randomized trials reported use of various doses of intrathecal morphine in cardiac surgery (0.5 mg to 4 mg, weight-based 1.5 mcg/kg to 10 mcg/kg).[38] Noncardiac surgery dose-response studies indicate that respiratory depression (increased PaCO2) can be significant with doses greater than 1 mg, with no additional analgesic benefit.[39,40] Our clinical trial indicates that low-dose intrathecal morphine resulted in significantly decreased pain scores for 48 h with rest and cough. Furthermore, when assessing the four clinically important opioid-related side effects of nausea/vomiting, pruritus, urinary retention, and respiratory depression,[41] only nausea was significantly increased by this dose.

How important is pain after cardiac surgery? While the quality of postoperative analgesia has never been directly linked to decreased morbidity/mortality,[42,43] it is clearly important in the current era of enhanced recovery after surgery and plays an important role in patient satisfaction.[7,8,44] Several pertinent clinical questions still remain for future investigational trials. The role of intrathecal morphine needs to be defined as it pertains to enhanced recovery after surgery, achieving an "opioid-free/sparing" postoperative recovery, and patient satisfaction. Future trials should determine optimal intrathecal morphine dose for clinically important analgesia without cumbersome effects of nausea and pruritus. This technique may aid in attaining an "opioid-sparing" hospital course, a recent concern/goal of anesthesiologists and patients.[45–48] Can intrathecal morphine in combination with fascial plane blocks provide an "opioid-sparing" postoperative recovery in minimally invasive cardiac surgery? Additionally, any purported hemodynamic benefits of intrathecal morphine in minimally invasive cardiac surgery are yet to be elucidated.

There are several limitations of our clinical trial. First, high-risk patients were excluded from enrollment. Patients with obstructive sleep apnea and morbid obesity were excluded due to the possibility of increased postoperative mechanical ventilation. A change in these exclusion criteria may potentially increase observed opioid-related respiratory depression. Second, the optimal dose of intrathecal morphine is unknown and not determined; however, based on previous studies, a dose was chosen to optimize analgesia with minimal side effects. Third, due to drug shortages, patients were transitioned from fentanyl (administered by nursing, possible less patient use) to PCA morphine (administered directly by the patient, possible increased use) during the study. This strategy was necessary; however, it may have decreased the observed difference between groups and effect size estimates. Fourth, because interim analysis indicated that the primary objective was met with fewer than anticipated patients, the study was stopped early by our IRB. Without consideration of multiplicity adjustments, there is potential for inflation of a type I error. Using an even stricter alpha adjustment of 0.002 (Haybittle–Peto) at interim analysis would still have led to the same conclusions about the primary outcome (morphine equivalent) and pain scores. Fifth, we excluded some randomized participants from the primary analysis, possibly introducing bias into the treatment effect estimates. Although our analysis is per-protocol, we conducted an analysis for the primary outcome using all available data, leading to the same conclusions. Finally, only short-term postoperative pain was assessed.

In conclusion, this clinical investigation reveals that 5 mcg/kg intrathecal morphine, when administered to patients before induction of anesthesia for totally endoscopic CABG, provides significant postoperative analgesia and decreased use of opioids for 48 h with minimal side effects. Thus, intrathecal morphine may prove useful in patients undergoing a wide variety of minimally invasive cardiac surgeries in the current enhanced recovery after surgery era.