Original Article

Intrathecal Morphine for Colorectal Cancer Surgery: Immediate Postoperative and Post-Discharge Outcomes

Please cite this article as follows: Strugnell N, Young J, Williams E, Riedel B. Intrathecal morphine for colorectal cancer surgery: immediate postoperative and post-discharge outcomes. Avicenna J Pharm Res. 2022; 3(2):63-68. doi:10.34172/ajpr.1079

Introduction

In Australia, colorectal cancer is the fourth most commonly diagnosed cancer and the cause of the second most cancer-related deaths (1). Surgery is at the forefront of the management of colorectal cancer, and optimal analgesia is required to reduce postoperative complications, enable earlier hospital discharge, and facilitate timely return to adjuvant therapy (2). Following colorectal cancer surgery, systemic opioids are commonly used for postoperative analgesia. However, the postoperative use of opioids may be associated with adverse effects such as nausea and vomiting, respiratory depression, and postoperative ileus, which may slow postoperative recovery and prolong hospital length of stay (3).

Intrathecal morphine (ITM) is of interest because it may have extended opioid-sparing effects, providing an alternative to systemic opioids with the provision of adequate postoperative analgesia and the potential for reduced side effects. The proposed mechanism of action of ITM is through direct access to G-protein linked pre- and post-synaptic opioid receptors in the dorsal horn, binding and reducing nociceptive transmission (4). ITM is also thought to increase adenosine concentration in the cerebrospinal fluid, reducing both neural activity and release of gamma-aminobutyric acid, and thereby reducing nociceptive transmission (5). ITM provides effective analgesia with a favourable side effect profile. This is demonstrated by a randomised control trial which recommended intrathecal analgesia as the mode of choice in laparoscopic surgery compared to epidural and patient-controlled analgesia (PCA) (6).

In a retrospective study investigating the efficacy of ITM analgesia in patients who underwent laparoscopy or laparotomy procedures for colorectal cancer, a reduction in oral morphine equivalent dose was reported after 24 hours and reduced sedation after 48 hours for those who received ITM (7). However, acute postoperative outcomes such as postoperative ileus, time to mobilisation, and postoperative pruritus were not explored in that study nor were longer term post-discharge outcomes.

There is increasing interest in the longer-term effects of neuraxial techniques, including ITM, for the prevention of chronic postsurgical pain and cancer recurrence. ITM has been associated with the reduced incidence of chronic postsurgical pain after open abdominal surgeries through blocking afferent pain fibre transmission and thereby preventing the induction of central sensitisation (8,9). A meta-analysis study suggested an association between neuraxial techniques, including ITM, and the reduced recurrence of various cancers, including colorectal cancer (10). Proposed direct and indirect mechanisms include the reduction of immunosuppression and angiogenesis through reduced exposure to systemic opioid administration and the attenuation of the surgical stress response through the suppression of the hypothalamic-pituitary-adrenal axis and the reduction of the suppression of natural killer (NK) cells (10-16).

The aim of this study was to focus on the immediate postoperative outcomes of pruritus, postoperative ileus, time to mobilisation, post-discharge outcomes of chronic postoperative pain, and long-term opioid consumption. Cancer recurrence was analysed as an exploratory endpoint. We considered the hypothesis that ITM may reduce the time to mobilisation, the incidence of postoperative ileus, chronic pain, and long-term opioid use.

Materials and Methods

This retrospective study reviewed a single institution experience (July 2014 – June 2018) in adult patients who had colorectal cancer surgery with an inpatient stay, were administered either ITM with PCA or PCA alone, and were followed up postoperatively by the Acute and Persistent Pain Service at Peter MacCallum Cancer Centre. Data were gathered retrospectively from both hospital’s paper-based and electronic medical records.

Outcome Measures

The outcomes of this study included immediate postoperative and post-discharge outcome measures. Immediate postoperative outcomes included pruritus, time to mobilisation, and postoperative ileus. Time to mobilisation (standing or ambulating) was recorded as the number of days from the operation (day 0) until documented in the medical, nursing, or physiotherapy records.

Post-discharge outcomes included the incidence of chronic pain and long-term opioid use. Chronic postoperative pain was recorded as positive if ongoing pain was identified in outpatient clinic notes three, six, and twelve months after the surgery. Long-term opioid consumption was calculated based on doses of opioid medications recorded in outpatient clinic notes and pharmacy records, accounting for medications being administered before the operation. Chronic pain and opioid use data were not recorded beyond the time of any subsequent surgeries that patients underwent. For the exploratory endpoint of cancer recurrence, outpatient clinic notes and/or medical records from subsequent admissions were extracted for a period with data collected during three years post-operative. Cancer recurrence was not recorded following surgeries with non-curative intent.

Statistical Analysis

Data on patient demographics were presented descriptively. The IBM Statistical Package for Social Sciences (SPSS) was used for statistical analysis. Differences between ITM and PCA groups were assessed using the Mann-Whitney U Test with statistical significance at P < 0.05.

Results

Overall, 260 patients that met the inclusion criteria and were selected for analysis, including 160 patients in the ITM group and 100 patients in the PCA group. Patient demographics were similar between the two cohorts where the median age was 64 for both groups, and 55.6% and 55.0% were males in the ITM and PCA groups, respectively. In both cohorts, 52% and 48% of patients underwent open laparotomy and laparoscopy procedures, respectively. The most common colorectal procedure was anterior resection performed on 64 patients (26%), while colectomy was performed on 49 patients (19%), and 27 patients (10%) underwent hyperthermic intraperitoneal chemotherapy (HIPEC)/pelvic exenteration. A summary of patient demographics is reported in Table 1.

Immediate Postoperative Outcomes

The ITM group had increased pruritus, a similar time to mobilisation, and a similar incidence of postoperative ileus (ITM 20.0% vs. PCA 23.0%, P = 0.57) compared to the PCA group. Table 2 lists a summary of immediate postoperative outcomes The trend was similar in both laparoscopy and laparotomy subgroups (Appendix 1 and 2).

Post-discharge Outcomes

In the ITM group, 3.5% and 3.1% of patients had chronic pain at three months and six months, respectively. In contrast, 7.0% and 5.0% of patients had chronic pain at three and six months, respectively, in the PCA group. Similarly, 7.7% and 9.9% of the ITM group were on long-term opioids at three and six months, respectively, compared to 10.5% and 12.5% of the PCA group. At twelve months, 4.9% in the ITM group and 4.4% in the PCA group reported ongoing pain, and 11.4% of the ITM group and 7.2% of the PCA group were on long-term opioids. There were no statistically significant differences between the groups. These outcomes are summarized in Table 3. In the laparoscopy subgroup, there were no consistent trends, with a similar incidence of chronic pain and opioid use at three and six months between the ITM and PCA groups (Appendix 1). In the laparotomy subgroup, there was a trend towards less chronic pain at three and six months in the ITM group, however the opioid use was not consistent with this (Appendix 2). Cancer recurrence was 37.8% for the ITM group compared to 36.0% for the PCA group (Supplementary file 1).

Discussion

In this retrospective study, ITM with PCA did not demonstrate statistically significant benefits compared to PCA alone in reducing the incidence of postoperative ileus, chronic pain, and opioid use at three and six months. There was no difference noted in time to mobilisation, and pruritus was more common in the ITM group. For the exploratory endpoint of cancer recurrence, the ITM group had a similar recurrence in comparison to PCA.

Postoperative ileus is a common complication of colorectal surgery and can have a significant impact on a patient’s recovery and often impacts the length of hospital stay (17). Opioids are known to perpetuate postoperative ileus through the activation of central, and predominantly, peripheral mu-opioid receptors, leading to the inhibition of gut motility (18). Therefore, ITM may reduce the incidence of postoperative ileus through the reduction of exposure to systemic opioids and blocking sympathetic neural pathways which, when overstimulated, inhibit bowel motility (18). This is supported in the literature, with one randomised control trial, showing an improvement in bowel function with ITM compared with both PCA and epidural analgesia (6).However, other studies comparing ITM with PCA have not reported an improvement in the incidence of ileus in colorectal surgery, and this may be due to the complex and multifactorial causes of ileus, including reduced mobilisation and bowel handling during surgery (19,20).Our study findings suggested that ITM represented no statistically significant reduction in postoperative ileus compared to PCA. The trend toward reduction may, however, warrant further investigation within an adequately powered prospective study.

Some studies indicated that ITM may reduce the risk of chronic pain in open abdominal surgeries (8,9). Peripheral and central sensitisation caused by prolonged afferent nociceptive input is considered a key mechanism in the development of chronic post-surgical pain (21,22). The prolonged firing of nociceptive afferents may lead to long-term structural changes in the dorsal horn, reducing pain thresholds and amplifying pain responses (21,22). Chronic post-surgical pain may therefore be reduced by adequately controlling acute postoperative pain. In this study, chronic pain trended towards being was lower in the ITM group at three (ITM 3.5% vs. PCA 7.0%) and six (ITM 3.1% vs. PCA 5.0%) months but not at twelve months (ITM 4.9% vs. PCA 4.4%). In patients who underwent laparotomies, 5.8% and 5.1% of the ITM group had chronic pain at three and six months, respectively, whereas 11.1% and 9.8% of the PCA group had chronic pain over the same timeframes (Appendix 3). Overall, the trend was similar for long-term opioid use with a trend towards a small benefit at three (ITM 7.7% vs. PCA 10.5%) and six (ITM 9.9% vs. PCA 12.5%) months but not at twelve months (ITM 11.4% vs. PCA 7.2%). Chronic pain and opioid use at twelve months may have been influenced by the development of pain conditions not related to surgery, including the advanced cancer stage.The association between intrathecal analgesia and cancer recurrence is increasingly being investigated in the literature (23).Two in vivo studies have demonstrated a reduction in cancer recurrence with ITM alongside general anaesthesia in comparison to general anaesthesia alone (24,25). One proposed mechanism is through reducing total systemic opioid administration since high-dose opiates have been shown in vitro to exhibit the pro-angiogenic characteristics of tumours through the transactivation of vascular endothelial growth factor and promote metastatic progression (13-15). Another proposed mechanism is that ITM may reduce the surgical stress response and suppress the hypothalamic-pituitary-adrenal axis to reduce immunosuppressive cortisol release and preserve the activity of NK cells (16). In this study, cancer recurrence at three years was 37.8% in the ITM group compared to 36.0% in the PCA group.

Being a retrospective study at a single institution, this research had inherent limitations. Different surgical techniques, length of follow-ups, neoadjuvant therapy, cancer type, grade, and staging were unable to be controlled in this study. Other confounding factors included patient and anaesthetist preferences for analgesia, limitations on the consistency of data collection, and difficulty in distinguishing between postoperative pain and other pain syndromes. On the other hand, this study adds to the literature surrounding the safety and efficacy of ITM in the colorectal cancer setting. The moderate sample size with the presence of a control group and years of follow-up documentation through hospital medical records allowed the research team to understand the trends of postoperative and post-discharge outcomes in this setting. This study finding represented no statistically significant associations for these outcomes, thus prospective research is warranted to further elucidate the impact of ITM.

Conclusion

There is growing interest in ITM based on its good quality postoperative analgesia, reduced systemic opioid requirements, and its potential to improve immediate postoperative and post-discharge outcomes. In the current study, in the colorectal setting, the ITM group suggested a reduction in postoperative ileus, chronic pain, and opioid use at three and six months that warrants further study with larger, adequately powered prospective studies.

Authors’ Contribution

Conceptualization: Jamie Young, Bernhard Riedel, Elizabeth Williams.

Data analysis: Nathan Strugnell, Jamie Young.

Data handling: Nathan Strugnell, Elizabeth Williams.

Data presentation: Nathan Strugnell.

Experiments design: Jamie Young, Elizabeth Williams.

Project administration: Jamie Young, Elizabeth Williams.

Supervision: Jamie Young, Bernhard Riedel, Elizabeth Williams.

Writing–original draft: Nathan Strugnell, Jamie Young.

Writing–review & editing: Nathan Strugnell, Jamie Young, Prof Bernhard Riedel.

Competing Interests

The authors declare that they have no conflicts of interests.

Funding

Nil.

Supplementary File

Appendix

Appendix

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