Intrathecal Morphine Enhances Postoperative Analgesia and Recovery in Robotic-Assisted Laparoscopic Partial Nephrectomy: A Retrospective Study of 272 Patients

Introduction

Renal cell carcinoma (RCC) is a rare cancer worldwide [1]. However, its incidence has increased, especially in East Asian countries, owing to drastic changes in diet and the development of early detection and diagnostic imaging. Surgical resection is the standard approach for treating localized renal tumors [2].

During the last few decades, partial nephrectomy using laparoscopy has been increasingly used to reduce surgical stress and promote postoperative recovery as compared to open surgery [3]. Moreover, robot-assisted laparoscopic partial nephrectomy (RAPN) has several clinical benefits over laparoscopy, such as a shorter learning curve and more ergonomic features [4].

However, RAPN can induce acute incisional, peritoneal, visceral, and referred pains [5]. Severe postoperative pain often impairs functional recovery and quality of life and increases morbidity and healthcare costs [6]. Notably, effective analgesic administration to lower acute pain intensity or prevent its occurrence has the potential to prevent the development of persistent pain [7]. Therefore, concerns regarding acute pain control in laparoscopic or robotic surgery have renewed [8].

An analgesic approach for abdominal surgery should modulate diverse pathways evoking pain [9]. Intrathecal morphine (ITM) administration has been in clinical use for pain management following various abdominal surgeries [10]. Moreover, the preference for minimally invasive surgery has resulted in an increasing interest in ITM or abdominal wall blocks in place of epidural analgesia [11]. Bae et al reported that ITM decreased postoperative pain scores and opioid requirements after robot-assisted laparoscopic prostatectomy [12]. In addition, the clinical benefits of ITM within an enhanced recovery protocol after surgery were also demonstrated [13]. Although several opioid-related complications increased, ITM facilitated faster postoperative recovery and enhanced pain control.

Recently, a retrospective study by Meineke et al demonstrated that acute pain treatment modality comprising preoperative ITM (200–300 μg depending on the age and renal function), and postoperative non-opioids significantly reduced postoperative opioid uses [5]. However, the independent effects of ITM on analgesia and recovery after RAPN have not been thoroughly assessed. Therefore, our retrospective study aimed to evaluate the efficacy of ITM for postoperative pain control and overall recovery in the patients who underwent RAPN at our institute.

Material and Methods

ETHICAL CONSIDERATIONS AND STUDY POPULATION:

The Institutional Review Board and Ethics Committee of Seoul St. Mary’s Hospital approved this retrospective study (approval number: KC23RISI0525) on July 21, 2023, and waived the requirement for informed consent.

All data were retrospectively collected from the electronic medical records of patients who underwent RAPN for renal tumors at the Department of Urology, Seoul St. Mary’s Hospital, from January 2020 to December 2021. The inclusion criterion for this study was planned RAPN during this period. The exclusion criteria were as follows: 1) age <19 years or >75 years; 2) American Society of Anesthesiologists Physical Status (ASA-PS) ≥3; 3) cases with open conversion; 4) combined operation; and/or 5) reoperation until postoperative day (POD) 1.

ANESTHESIA AND SURGERY:

After arrival at the operating room, the patient was monitored using routine devices, including a noninvasive blood pressure cuff, a three-lead electrocardiogram, and a pulse oximeter. Intravenous (IV) propofol (1.5–2 mg/kg, Fresenius Kabi, Bad Homburg, Germany) and rocuronium (0.8–1 mg/kg, Merck Sharp and Dohme Corp., Kenilworth, NJ, USA) were infused to induce anesthesia. For balanced general anesthesia, 5–6% inhaled desflurane (Baxter, Deerfield, IL, USA) with 0.01–0.1 μg/kg/min of IV remifentanil (Hanlim Pharm. Co., Ltd., Seoul, Republic of Korea) was administered, targeting a Bispectral Index™ (Medtronic, Minneapolis, MN, USA) between 20 and 60. During surgery, IV fluid was infused at 2–4 mL/kg/h with additional volumes for blood loss. To maintain the intraoperative blood pressure, 4 mg of ephedrine (Daewon Pharm. Co., Ltd., Seoul, Republic of Korea) was administered when the systolic blood pressure was reduced to <80 mmHg, although an intravascular volume deficit was not suspected. At the end of the surgery, neuromuscular blockade was recovered with 4 mg/kg of Sugammadex (Merck Sharp and Dohme Corp., Kenilworth, NJ, USA) under ventilation with 100% oxygen supplementation.

After the induction of general anesthesia, expert urologists installed and operated the da Vinci surgical system (Intuitive Surgical, Inc., Sunnyvale, CA, USA) following the manufacturer’s instructions. After sterile draping of the surgical field with povidone, trocars were inserted. Under kidney traction, the perirenal fat was carefully dissected. After pedicle exposure, mannitol (0.5 mg/kg) was administered intravenously and laparoscopic bulldog clamps were applied to clamp renal vessels. Subsequently, the tumor mass was removed. The excised kidney was sutured with a wound-closure V-Loc device (Medtronic, Minneapolis, MN, USA). The sliding-clip renorrhaphy was applied using Hem-o-lok clips (Teleflex Medical, Research Triangle Park, NC, USA) to exert pressure on the parenchyma for hemostasis. The bulldog clamps were then removed, while Surgicel (Ethicon Endo-Surgery, Somerville, NJ, USA) and fibrin glue (Tisseel; Baxter Healthcare, Deerfield, IL, USA) were applied around the operative site. A laparoscopic surgical bag was inserted for tumor retrieval and removed through the port site. A single Jackson-Pratt drain was inserted into the flexure of the ascending colon. The peritoneum, subcutaneous tissue, and skin were sutured after the bleeding was controlled.

ANALGESIC MANAGEMENT:

Intrathecal analgesia was introduced at our institute using 200 μg of morphine for pain control after RAPN in January 2021. For preoperative ITM, the patients were positioned in the lateral decubitus or sitting position right before general anesthesia induction, the skin over the lumbar region was cleaned with chlorhexidine and draped, a 25-gauge Quincke-type spinal needle (TAE-CHANG Industrial Co., Ltd., Chungcheongnam-do, Republic of Korea) was inserted between the lumbar vertebrae 3 and 4, or 4 and 5, and 200 μg (0.2 mL) of morphine (BCWORLD Pharm. Co., Ltd., Seoul, Republic of Korea) mixed with normal saline (1 mL) was administered after confirmation of clear cerebrospinal fluid.

Moreover, IV patient-controlled analgesia (PCA) was initiated at the end of surgery for all patients. According to the analgesic protocol established in January 2020, the PCA regimen included 1000 μg of fentanyl (Dai Han Pharm. Co., Ltd., Seoul, Republic of Korea) and 0.3 mg of ramosetron (Boryung Co., Ltd., Seoul, Republic of Korea) mixed with 100 ml of normal saline administered at a basal infusion rate of 1 mL/h, a bolus injection volume of 1 mL, and a lockout time of 10 min (AutoMed 3200, Acemedical, Seoul, Republic of Korea). In cases of continued moderate pain, pain intensity ≥4 on a numeric rating scale (NRS), despite the use of PCA boluses or acute severe pain (pain intensity ≥7 on NRS), IV rescue analgesics were administered at the discretion of the attending physicians; 50 μg of fentanyl in the post-anesthetic care unit (PACU) and 50 mg of tramadol (YUHAN, Seoul, Republic of Korea) in the ward. In patients aged >75 years or with ASA-PS ≥III, the doses of PCA and rescue analgesics were determined at the attending staff’s discretion.

The implementation of ITM allowed us to divide the patients who underwent RAPN from January 2020 to December 2021 into 2 groups according to the analgesic measures they received: the ITM group (intrathecal morphine and IV-PCA) and the control group (IV-PCA alone).

ASSESSMENT OF ANALGESIA AND RECOVERY FINDINGS:

Using an NRS of an 11-point numeric scale (0=no pain and 10=worst pain ever possible), pain assessment was performed in all patients at arrival in the PACU (0 h) and 3, 6, 12, and 24 h after surgery in the ward by the attending nurses [14]. The cumulative doses of PCA and rescue opioids were also monitored until 24 h after surgery.

The Quality of Recovery-15 (QoR-15) questionnaire was developed to assess the recovery quality after general anesthesia [15]. It is a self-report outcome questionnaire consisting of the following 5 subscales: physical comfort (5 items), emotional state (4 items), psychological support (2 items), physical independence (2 items), and pain (2 items). The QoR-15 items are rated on an 11-point Likert scale with 10 being the best score for positive questions and 0 being the best score for negative questions. The total global QoR-15 score ranges from 0 to 150, with higher scores indicating better recovery. The Korean version of the QoR-15 (QoR-15K) questionnaire, which was created based on the cultural and linguistic adaptation of self-reporting measures, has been extensively validated in Korean patients [16].

At our institute, the QoR-15K score was measured by the attending physician on the evening of the first postoperative day and recorded. During the study period, approximately 80% of the patients who underwent RAPN completed the QoR-15K questionnaire.

CLINICAL VARIABLES AND STUDY OUTCOMES:

Demographic data included age, sex, body mass index (BMI), ASA-PS classification, underlying disease, and history of abdominal surgery. Intraoperative data included case length, type of surgical approach, remifentanil dose, fluid infusion, urine output, and estimated blood loss. Postoperative data included hospital stay, surgical complications assessed by Clavien-Dindo classification, and episodes of postoperative nausea and vomiting (PONV) requiring antiemetics within 24 h after surgery. Moreover, a pulse oximeter measurement of ≤93% at the PACU discharge was considered postoperative hypoxia.

The primary endpoint of this study was the incidence of moderate-to-severe pain, which was defined by 24-h average NRS pain score ≥4, because a treatment threshold of NRS pain score ≥4 has been employed to identify patients with moderate-to-severe pain intensity [17]. The 24-h average NRS pain score was determined by dividing the sum of the weighted pain scores, which was calculated by multiplying the average of adjacent pain observations by the duration of time between the observations, by 24 [18]. Secondary outcomes were NRS pain scores, cumulative opioid requirements, postoperative complications within 24 h after surgery, and the QoR-15K score on POD 1. Cumulative opioid requirements were calculated by adding the doses of IV PCA and rescue opioids, expressed as morphine equivalents (mg).

STATISTICAL ANALYSIS:

We assessed the normality of continuous data using the Shapiro-Wilk test. Categorical variables are presented as frequencies (%), and the χ² test or Fisher’s exact test was used to compare, as appropriate. Continuous variables are presented as means (standard deviations) or medians (interquartile range), and Student’s t-test or the Mann-Whitney U test was used for comparison, as appropriate. All statistical tests were two-sided, and a P value <0.05 was considered statistically significant. Statistical analyses were performed using SPSS Statistics software (version 24.0; IBM Corp., Armonk, NY, USA).

Results

COMPARISON OF PREOPERATIVE AND INTRAOPERATIVE FINDINGS BETWEEN THE ITM AND CONTROL GROUPS:

Overall, 301 patients underwent RAPN at our institute from January 2020 to December 2021. Among them, 14 patients were older than 75 years, ASA-PS was ≥3 in 10 patients, and 1 case with open conversion, 3 cases of combined operation, and 1 case of reoperation until POD 1 were observed. Of the remaining 272 patients, 137 underwent RAPN after January 2021 when the ITM-based analgesic protocol was implemented. Among them, intrathecal analgesia was not performed in 2 patients due to their refusal. Therefore, 135 patients were classified in the ITM group; the control group comprised 137 patients who did not receive ITM (Figure 1).

Table 1 presents the preoperative and intraoperative findings of the 2 groups. Preoperative albumin level was significantly different between the 2 groups (4.7 vs 4.5 g/dL, P=0.001); however, the difference was not clinically meaningful. In addition, the ITM group had significantly less intraoperative remifentanil dose than the control group (2.9 vs 3.7 μg/kg/h, P<0.001). No other demographic or surgical variables differed between the 2 groups.

COMPARISON OF POSTOPERATIVE ANALGESIC FINDINGS BETWEEN THE ITM AND CONTROL GROUPS:

As presented in Table 2, the incidence of moderate-to-severe pain was significantly lower in the ITM group than in the control group (36.3% vs 61.3%, P<0.001), and the NRS pain scores were significantly lower in the ITM group than that in the control group at 0, 3, 6, 12, and 24 h after surgery (4 vs 5, P<0.001; 4 vs 5, P=0.001; 4 vs 5, P<0.001; 3 vs 4, P<0.001; 3 vs 4, P<0.001, respectively). Cumulative opioid requirements were also significantly lower in the ITM group than those in the control group at 3, 12, 24 h after the surgery (8.5 vs 12.6, P<0.001; 19.3 vs 36.0, P<0.001; 26.8 vs 49.3, P<0.001, respectively).

COMPARISON OF POSTOPERATIVE RECOVERY FINDINGS BETWEEN THE ITM AND CONTROL GROUPS:

As presented in Table 3, PONV occurred significantly more in the ITM group (27.4% vs 13.1%, P=0.003) as compared to the control group. The other postoperative findings did not differ between the 2 groups. No serious complications related to the ITM, such as persistent respiratory depression, post-dural puncture headache, or infection, were observed.

Figure 2 presents the QoR-15K score on POD 1, which was significantly higher in the ITM group than that in the control group (129 vs 120, P=0.003). Among the subscales, the ITM group had significantly higher scores for physical comfort, emotional state, and pain (43 vs 41, P=0.019; 35 vs 33, P=0.022; and 17 vs 13, P<0.001, respectively).

Discussion

In our study, the ITM group exhibited a lower incidence of moderate-to-severe pain than the control group. The pain scores and opioid requirements also differed between the 2 groups until 24 h after surgery. Moreover, the ITM group had a significantly higher QoR-15K score on POD 1 than the control group. However, the incidence of PONV was significantly higher in the ITM group, while the other postoperative findings were similar between the groups.

The findings indicating that ITM significantly reduced postoperative opioid requirements are consistent with those in a prior study by Meineke et al [5]. In addition, we demonstrated the independent effect of ITM on postoperative pain control and overall recovery by comprehensive assessments involving NRS pain scores, QoR-15K scores, and complications in a larger population.

Robot-assisted surgery has benefits, such as smaller incisions, less tissue retraction, and less muscle stretching [19]. However, multiple stimuli during surgery trigger perioperative pain – trocar placement and abdominal wall extraction cause incisional pain, pneumoperitoneum using carbon dioxide irritates the peritoneum, and diaphragmatic stretching is associated with referred pain [20]. Moreover, patients requiring urinary catheterization after surgery often experience catheter-related bladder discomfort (CRBD), another perioperative factor associated with pain [21]. The aggravation of CRBD symptoms also results in negative effects on the overall quality of recovery. Thus, the analgesic measures for RAPN should be selected based on these factors.

Thoracic epidural analgesia using local anesthetics and opioids is a conventional analgesic method used for abdominal surgery [22]. However, its use is no longer recommended, especially after laparoscopic surgery, owing to its adverse effects, including hypotension and motor blockade [23]. Moreover, postoperative nursing care is required after epidurals, making it work-intensive. Therefore, the use of thoracic epidurals in enhanced recovery protocols for major abdominal surgeries is questionable [24].

Among the abdominal wall blocks, the transversus abdominis plane block has become the most popular analgesic approach for surgeries involving the anterolateral abdominal wall. Its efficacy has been demonstrated in various types of abdominal surgeries [25]. However, the transversus abdominis plane block only controls parietal pain, and the efficacy of prolonged analgesia is inconsistent [26]. Therefore, it is not considered as a standalone analgesic method [27].

However, spinal analgesia with opioids provides ‘true analgesia’ [28]. Its action is exerted on both the somatic and visceral pathways through spinal opioid receptors [29]. Intrathecal administration of hydrophilic opioids requires a smaller volume of distribution and has slower diffusion when compared to intravenous infusion. Therefore, hydrophilic opioids have a longer duration of action with higher potency when administered via the intrathecal routes. Thus, effective analgesia lasting up to 24 h postoperatively can be achieved using a single spinal morphine injection [30].

ITM improved patients’ perception of early postoperative recovery, as shown by the significant difference in the QoR-15K score observed between the groups on POD 1 [31]. The reduced pain scores and opioid requirements after surgery in the ITM group led to an enhanced quality of recovery. These findings are consistent with those of recent studies on robot-assisted laparoscopic prostatectomies [32,33]. In the study by Koning et al, intrathecal administration of morphine with bupivacaine reduced postoperative morphine uses, lowered pain scores, and resulted in negative effects on the QoR-15 score, as our prior study indicated.

On the other hand, Russo et al demonstrated that low-dose ITM prevented CRBD by reducing bladder spasms [21]. Although the incidence and severity of CRBD were not investigated in our study, the alleviated bladder discomfort in the ITM group probably led to enhanced postoperative analgesia as compared to that in the control group.

Furthermore, ITM played a preventive analgesic role through preoperative administration [34]. Ideally, analgesia should be preemptively provided before surgical stimuli and continued throughout the intraoperative and postoperative periods. Preoperative ITM reduces the intraoperative nociceptive responses activated by both the parietal and visceral pathways during laparoscopic surgery and provides prolonged postoperative analgesia. Due to attenuated surgical stimuli, the ITM group probably required fewer doses of remifentanil during surgery than that in the control group.

The optimal ITM dose depends on specific surgical procedures [35]. Although <100 μg of morphine is sufficient to provide adequate pain control after cesarian section, >500 μg of morphine is needed for analgesia after extensive surgeries including major abdominal surgery or thoracotomy [30]. As >300 μg of morphine significantly increases the incidences of nausea, vomiting, pruritus, and urinary retention, the balance between the benefits of improved analgesia and risks of adverse effects in higher doses should be considered. On the other hand, our regimen of intrathecal analgesia did not involve co-administration of bupivacaine with morphine owing to its short effective duration [36]. Thus, our study examined the efficacy of intrathecal analgesia using 200 μg morphine without bupivacaine in RAPN, and the results agree with those of prior studies in robot-assisted urologic surgeries with similar intrathecal doses [5,21]. Although the incidence of PONV was significantly increased in the ITM group, it did not decrease the patient’s perception of recovery, and all events were treated successfully with antiemetic use.

Nonetheless, our study has several limitations. First, the nature of the retrospective single center study limits the generalizability of the results. Information bias may have been inherent in this study. Second, we analyzed patients who underwent RAPN at a single institute. The efficacy of ITM should be examined in other perioperative settings using various analgesic protocols. Third, the dose-dependent effect of ITM on increasing PONV occurrence while preserving analgesic potency was not assessed because the same dose of morphine was administered to patients who received ITM during the study period. Lastly, the evaluation of delayed respiratory depression was limited because routine pulse oximeter measurements were not performed in the ward; nevertheless, the incidence of delayed respiratory depression resulting from low-dose morphine is usually low [37]. Future prospective studies in various clinical settings are required to address these limitations.

Conclusions

Intrathecal analgesia using 200 μg of morphine provided superior pain control during the early period following RAPN, with reduced postoperative opioid requirements. Moreover, ITM improved patient satisfaction with recovery. The optimal dose of ITM for enhancing analgesia and recovery with minimal adverse effects should be validated in future studies.