Analgesic effect of dexmedetomidine in colorectal cancer patients undergoing laparoscopic surgery

Despite remarkable developments in minimally invasive surgical techniques and understanding of pain mechanisms, postoperative pain remains a serious issue.¹ Surgical tissue and neural damage activate nociceptive neurons, leading to peripheral and central sensitization.² Acute postoperative pain mostly revolves within one week; however, in approximately 10% of all surgeries, acute postoperative pain persists beyond the usual tissue healing time and transits into persistent postoperative pain.² The presence and intensity of intraoperative pain comprise the most important determinants of persistent postoperative pain.^2,3 Therefore, multimodal analgesic management is needed to attenuate nociceptor sensitization and decrease postoperative pain.^4,5 Opioids have been considered the gold standard of acute postoperative pain management for decades.³ They provide balanced anesthesia and analgesia by blunting the hemodynamic response to surgical stimuli.⁶ However, opioid monotherapy is limited due to adverse events (respiratory depression, oversedation, and rapid development of tolerance).⁷ Therefore, opioid-sparing analgesia is a critical component of acute and chronic pain management to enhance analgesic efficacy and eliminate adverse effects. Large numbers of non-opioids, such as nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, or alpha-2 agonist, have improved analgesic properties.⁸

Dexmedetomidine (DEX), a highly selective and potent agonist of alpha-2 adrenoreceptors, acts on neuropathic pain modulation.^9,10 It has sedative, sympatholytic, and analgesic effect.¹¹ Dexmedetomidine inhibits norepinephrine release from synaptic neurons via alpha-2 receptors in rostral pons and central pain modification by enhancing the inhibitory descending pain pathway.^11,12 Reportedly, DEX diminishes the catecholamine levels by decreasing the sympathetic nervous system activity and provide hemodynamic stability during surgery.¹³ Dexmedetomidine has been used as a sub-anesthetic and anxiolytic agent; however, of late, DEX has been found to have an antinociceptive effect, thus broadening its usage in acute and chronic pain conditions. Perioperative administration of DEX has been shown to have superior analgesic and opioid-sparing effects in several surgeries.^14-17 In laparoscopic hysterectomy, intraoperative DEX showed decreased postoperative pain and improved bowel function.^11,18 In spinal fusion surgery, intraoperative DEX did not decrease postoperative pain and opioid consumption.¹¹ Nonetheless, the analgesic efficacy of DEX is still unclear due to different surgical and pain characteristics. In laparoscopic colon surgery, the enhanced recovery after surgery (ERAS) guideline recommends multimodal analgesia using opioids and non-opioids (NSAIDs or paracetamol).^19,20 Published studies regarding DEX in colorectal surgery focused on cognitive dysfunction, cardiovascular stability, or cerebral protection effect; however, these studies are insufficient to determine the analgesic efficacy of DEX. Therefore, the aim of this syudy was to evaluate the efficacy of intraoperative DEX on postoperative pain in colorectal cancer surgery.

Methods

We retrospectively examined the electronic medical records of colorectal cancer patients who underwent laparoscopic surgery between October 2020 and May 2021 at Samsung Medical Center, Seoul, Korea. The patients were aged 27-87 years. The inclusion criteria were as follow: I) patients who were diagnosed with malignant tumors in the colon or rectum; and II) who have undergone elective laparoscopic colectomy or anterior resection.²¹ The exclusion criteria were as follow: I) non-elective surgery; II) metastatic cancer surgery; III) open or conversion to open surgery; IV) insufficient follow-up data; V) intensive care unit discharge after surgery; VI) inability to express pain intensity; and VII) usage of any of the analgesics (NSAIDs, acetaminophen, or dexamethasone) during anesthesia.²¹ This study was carried out according to the guidelines of the Declaration of Helsinki. It was approved by the Institutional Review Board of Samsung Medical Center, Seoul, Korea, (SMC 2021-07-089) and registered with the Clinical Research Information Service of the Korea National Institute of Health, (ref: KCT0006382). Since this was a retrospective review of medical records, patient consent was waived.

The patients were not premedicated preoperatively. In the operating room, standard monitoring for anesthesia was carried out, including oxygen saturation, electrocardiography, end-tidal carbon dioxide (CO2), bispectral index (BIS), oxygen reserve index, and non-invasive blood pressure. Anesthesia was induced with 40 mg of 2% lidocaine, 2 mg/kg of 2% propofol, 0.5-1.0 μg/kg of fentanyl, 0.05 mg/kg of midazolam, and 0.6-0.8 mg/kg of rocuronium intravenously. At anesthetic induction, 0.5-1.0 μg/kg/hour of DEX (Precedex^®, Hospira, Lake Forest, IL, USA) was administered without a bolus dose, and continued until the end of anesthesia. Endotracheal intubation was carried out after approximately 3-5 minutes of mask ventilation and loss of all 4 twitches by train-of-4 stimulation of the ulnar nerve. After endotracheal intubation, anesthesia was maintained with 1.5-2.0 vol% sevoflurane and a bolus injection of 0.5-1.0 μg/kg fentanyl to maintain hemodynamic parameters within 20% of baseline values and BIS at 30-60. The lungs were ventilated with 50% oxygen with air. This was adjusted to maintain an end-tidal CO2 level of 30-40 mmHg. Intraoperative fluid was managed considering blood pressure, heart rate, and hemoglobin level. The temperature was maintained within normal ranges using a warm blanket. All surgeries were carried out by specialized surgeons who followed standardized procedures for colorectal cancer.²² At the end of the surgery, patients received intravenous patient-controlled analgesia (PCA) pump (Automed3200^®, Ace Medical, South Korea), which delivered 10-20 μg/kg of fentanyl in normal saline (100 ml) at a basal infusion rate of 0.5 ml/hour and bolus of 1 ml. At the end of the anesthesia, the patients were administered 4 mg/kg of sugammadex or 0.03 mg/kg of pyridostigmine and 0.002 mg/kg of glycopyrrolate intravenously. After extubation, the patients were transferred to the post-anesthesia care unit (PACU). They received a further bolus of intravenous fentanyl at 0.5 μg/kg when the reported scores on a numeric rating scale (NRS: 0=no pain to 10=absolutely intolerable pain) were greater than 3. After discharge from the PACU, postoperative intravenous opioids (fentanyl, pethidine, or hydromorphone) and oral opioids (oxycodone or tapentadol) were administered in the general ward according to the attending physician’s decision.

The primary endpoints were postoperative pain and opioid consumption. The pain scores were checked at PACU arrival, PACU discharge, and postoperative day (POD) 1, 2, and 3. Opioid consumption was recorded by conversion to fentanyl units throughout POD 1, 2, and 3.²² The secondary endpoint was the incidence of postoperative complications.

Results

Of the enrolled 190 patients, 31 were ruled out due to exclusion criteria. Thus, data were evaluated for 159 patients. Patients were divided into 2 groups based on whether they received DEX infusion intraoperatively; patients who received DEX infusion during anesthesia comprised the DEX group (n=74) and those who did not receive DEX infusion comprised the non-DEX group (n=85). The demographic and clinical data are summarized in Table 1. In the DEX group, the mean dose of infused DEX was 70.6±24.5 μg. The intraoperative fentanyl dose was significantly lower in the DEX group (p=0.008). Details regarding intraoperative hemodynamics are shown in Table 2. Compared to the non-DEX group, the mean arterial pressure was significantly lower in the DEX group at T4 (p<0.001) and T5 (p=0.003) and the heart rate was significantly lower at T3 (p<0.001), T4 (p<0.001), and T5 (p=0.001). Moreover, the BIS (p=0.016) and oxygen reserve index (p=0.030) were significantly lower in the DEX group at T4; however, no between-group differences were observed at other time points. Oxygen saturation was not different between the groups. The MAC of sevoflurane was significantly lower in the DEX group at T2 (p=0.002) and T3 (p<0.001). The GEE analysis revealed significant between-group differences in the mean arterial pressure (p<0.001) and heart rate (p<0.001) over time (from T0-5). There were no significant differences in the BIS and MAC of sevoflurane over time between both groups. Table 3 shows the postoperative pain scores. We found that the NRS scores at PACU admission (p<0.001) and discharge (p=0.027) were significantly lower in the DEX group; however, the NRS scores throughout POD 1-3 were not significantly different between the groups. Table 4 shows the postoperative data. The fentanyl dose during PACU admission was significantly lower in the DEX group (p<0.001). From POD 1-3, the fentanyl dose was not different between the groups. Postoperatively, the discontinuation day of PCA, time to pass flatus, and length of hospital stay were not different between the groups. Table 5 shows the postoperative complications. The incidence was not different between the groups.

Discussion

In this study, we aimed to evaluate the analgesic effectiveness of intraoperative DEX in colorectal cancer patients undergoing laparoscopic surgery. Dexmedetomidine had intraoperative analgesia as indicated by the lower mean arterial pressure, heart rate, and MAC of sevoflurane, as well as the reduced fentanyl consumption by 18.5%. Postoperatively, it induced analgesia based on lowered pain scores and a 43.8% reduction in fentanyl consumption during PACU admission. After PACU discharge, pain scores and opioid consumptions were not different on POD 1, 2, and 3 between both groups. Notably, the incidence of postoperative nausea/vomiting, dizziness, itching, and headache was not different between both groups. Continuous DEX infusion reduced intraoperative pain, but not postoperative pain. We hypothesize that although intraoperative DEX has an analgesic effect, the short half-time of DEX or dose of DEX is insufficient to sustain the analgesic effect for postoperative pain.²³ Therefore, continuous multimodal analgesia is required to achieve prolonged analgesia after surgery.⁸ Furthermore, postoperative pain after colorectal surgery has a mixed character (nociceptive, visceral, and neuropathic pain); since the pelvic cavity is a limited space, there is an increased risk of damage to the pelvic nerve plexus during surgery.^22,24 These multiple sources of pain may induce more severe pain compared to other laparoscopic surgeries; therefore, intraoperative DEX infusion induce postoperative analgesia not lasting over 24 hours.

The ERAS recommendations included the combined use of non-opioid analgesics with opioids.⁵ However, the application of various analgesic protocols has shown different results regarding postoperative pain management.^7,19,20,25 Dexmedetomidine has previously been administered intravenously for sedation and analgesia during critical illness and surgical procedures.²⁶ It induces analgesia by releasing centrally acting enkephalin-like substance, inhibits the release of substance P at the level of the dorsal root neuron, and prevents norepinephrine release at nerve endings.¹¹ Dexmedetomidine has anti-inflammatory properties indicated by the reduced secretion of inflammatory factors and decreased inhibition of immunity, leading to reduced opioid consumption.²⁷ It was shown to have a rapid distribution corresponding to a half-time of 6 minutes, followed by a 2-hour terminal half-time and 4 hours context sensitive half-time after a prolonged 8 hours infusion.^12,28 The adverse effects of DEX include hypotension, hypertension, nausea, bradycardia, atrial fibrillation, and hypoxia.²⁸ When DEX is infused at a higher bolus dose, it triggers tachycardia and hypertension. Therefore, further studies are warranted to determine the optimal dose of DEX. Several studies have reported improved analgesia when DEX was used as an adjuvant to anesthetic agents via various routes (intravenous, nasal, oral, intramuscular, intraperitoneal, and interfascial plane).^12,28 In laparoscopic colon cancer surgery, 0.5-1.5 μg/kg DEX was administered with ropivacaine for transversus abdominis plane block during anesthesia, and it showed improved postoperative pain compared with a placebo group.²⁹ Intravenous DEX combined with sufentanil showed significantly decreased pain score until post-operative 48 hours after colon cancer surgery.³⁰ Intravenous analgesic regimens of DEX administration for adults recommend 0.25-0.5 μg/kg for the loading bolus and 0.2-1.0 μg/kg/hour for continuous injection.^12,31 A comparison of continuous injection of DEX with or without a loading dose showed no differences in 24 hours postoperative opioid consumption after abdominal surgery.^12,32 In our study, we infused DEX corresponding to 0.5-1.0 μg/kg/hour continuously and stopped the infusion at the end of anesthesia; we observed that the analgesic effect was significant until PACU discharge. Considering the sedative effects of DEX and the importance of early ambulation after surgery, other analgesics or interventions are required to prolong analgesia postoperatively.