Effective amelioration of pain following spine procedures remains a fundamental challenge. Inadequate pain control is observed in approximately 57% of patients in the first 24 hours following elective spine surgery [1]. This profound pain is attributable to extensive soft tissue and muscle damage. Spine surgeries have a long-drawn-out recovery phase, and adequate pain relief contributes to a shorter hospital stay, early ambulation and recovery, and overall patient satisfaction [2,3].

Several pharmacological options exist for adequate perioperative pain management. However, each drug has its pros and cons limiting its broad applicability. Although opioids remain the cornerstone of perioperative analgesia, they produce numerous side effects, including respiratory depression, postoperative hyperalgesia, nausea, vomiting, ileus, and urinary retention [2]. A non-opioid drug that is equipotent to opioids with minimal or no side effects is yet to be discovered. The use of a combination of adjunct analgesics to alleviate pain is a viable approach. The enhanced recovery protocol following spine surgery focuses on insignificant opioid use and multi-modal analgesia to improve patient outcomes [3].

Ketamine, a non-competitive N-methyl-D-aspartate antagonist, is a suitable analgesic in subanaesthetic doses. It binds to the opiate receptors in the brain and spinal cord, inhibits the “wind-up” phenomenon and central sensitization, and reduces the development of chronic pain [4,5]. Perioperative ketamine has a consistent opioid-sparing effect, minimizes the development of tolerance, and reduces the postoperative pain scores for up to 24 hours following spine surgery [6]. Dexmedetomidine is a selective α2-receptor agonist, whose analgesic and hypnotic effects are exerted at the spinal and supraspinal levels. Furthermore, its antinociceptive effect is mediated by stimulation of α2 receptors located in the locus coeruleus. The intrinsic antinociceptive and anti-hyperalgesia properties of α2 agonists reportedly reduce postoperative opioid consumption following spine surgery [7,8].

Numerous studies have demonstrated the analgesic and opioid-sparing properties of dexmedetomidine and ketamine in spine surgeries [6–11]. However, to the best of our knowledge, no study has assessed the postoperative analgesia produced by the simultaneous, but separate, use of low-dose ketamine and dexmedetomidine (ketodex infusion) as intraoperative anesthetic adjuvants. We hypothesized that intraoperative administration of ketodex infusion would produce a significant postoperative opioid-sparing effect, reducing the requirement of anesthetic agents and postoperative rescue analgesics in patients undergoing thoracolumbar spine surgery.

This prospective, randomized, double-blind study was conducted at a tertiary hospital from March 2021 to November 2021. Consecutive adults (aged 18–60 years) of either sex who were classified as American Society of Anesthesiologists (ASA) physical status I and II and scheduled for thoracolumbar spine surgeries involving >3 vertebral levels were included in the study. Patients with sensory deficits at the level planned for surgery, severe hypertension, coronary heart disease, heart block, liver or renal disease, raised intracranial pressure, α2 agonist or β-blocker use, ASA III/IV classification, and allergy to study drugs, pregnant patients and non-consenting adults were excluded from the study.

A total of 85 patients were assessed over the study period of which 60 patients (group KD, n=30 and group F, n=30) were finally analyzed (Fig. 1). The groups were comparable in their demographic characteristics, vertebral levels involved, and duration of surgery (Table 1).

Although ketamine and dexmedetomidine are conventional anesthetics, their combination use has been seldom assessed. In the realm of neurosurgeries, ketodex has been successfully used for concurrent electrocorticography and subcortical motor evoked potential mapping [13]. The present prospective randomized study was conducted to observe the postoperative analgesia effects of intraoperative low-dose ketodex infusion and compare it with those of the more commonly used fentanyl infusion in patients undergoing thoracolumbar spine surgery.

Empirical evidence supports the individual use of ketamine and dexmedetomidine for pain control [9–11]. Sub-anesthetic doses of ketamine inhibit central nociceptive system sensitization and produce fewer psychomimetic side effects [4,5]. Dexmedetomidine acts on the dorsal horn of the spinal cord and inhibits the release of substance P and other inflammatory cytokines during tissue injury [14]. Co-administration of these drugs could provide a synergistic analgesic effect while acting at different sites.

In our study, ketodex use almost doubled the mean time to first rescue analgesia and significantly reduced the requirement of postoperative analgesics in the first 24 hours as opposed to fentanyl use. This ketodex-induced prolongation of the mean time to first rescue analgesia may be attributable to the synergistic effect of the ketodex combination. This finding is significant as ketodex use could reduce the demand for rescue opioids, thereby minimizing various opioid-related adverse effects. We found that the postoperative NRS-pain scores were significantly lower in group KD than in group F at most timepoints, except when they were comparable at the 16th and 20th postoperative hour. This could be due to the additional postoperative administration of fentanyl in group F when the NRS score was >4 after 12 hours compared to almost 22 hours in group KD.

Our results were in concordance with those of the study by Garg et al. [9], who compared ketamine and dexmedetomidine infusions for analgesia following spine surgery. Patients who were administered ketamine were pain-free for longer than those who were administered dexmedetomidine (860 minutes versus 580 minutes). Furthermore, the rescue morphine requirement was lower in the ketamine and dexmedetomidine groups than in the placebo group. Thus, it suggested that infusions of low-dose ketamine and dexmedetomidine provide agreeable postoperative analgesia with minimal side effects. Our study differed from that by Garg et al. [9] in that the study drugs were administered intraoperatively in our study; the study drugs were administered in the 24 hours postoperative period in the study by Garg et al. [9].

Mitra et al. [10] assessed the use of low-dose ketamine and dexmedetomidine as an anesthetic adjuvant in lumbar spine instrumentation surgery for postoperative analgesia. The drugs were administered intraoperatively after placing the patient in the prone position. Similar to the observations in our study, the total fentanyl administration in the first 24 hours following surgery was less in the dexmedetomidine and ketamine groups than in the saline group. They concluded that opioid consumption, pain scores, inhalational agent administration, and hospital stay were comparable with ketamine or dexmedetomidine use [10]. Both drugs have proved to be effective in reducing postoperative pain after posterior spinal fusion surgery [11]. However, ketamine and dexmedetomidine were administered separately in previous studies; they were concurrently administered in our study.

The opioid-sparing effects of low-dose ketamine (defined as a continuous intravenous administration rate of ≤20 μg/kg/min) were evaluated by Kim et al. [15] after lumbar spinal fusion surgery. After a ketamine loading dose of 0.5 mg/kg, a continuous ketamine infusion (1 or 2 μg/kg/min) was administered before the skin was incised and continued until 48 hours postoperatively. They determined that low-dose ketamine (2 μg/kg/min) significantly reduced the total amount of fentanyl administered during the 48 hours postoperative period without increasing the incidence of adverse effects [15]. These results are in concurrence with those of our study. We used the drugs as an anesthetic adjuvant, unlike in this study where the drugs were infused prior to skin incision and continued until 48 hours postoperatively. A careful look at these studies reveal the heterogeneity in the administration timeline of the study drugs (only postoperative, intraoperative, or perioperative), making explicit comparisons difficult [9–11,15].

A recent meta-analysis indicated that only postoperative or intraoperative and postoperative administration of low-dose ketamine reduces opioid consumption and prolongs the postoperative analgesia time up to 48 hours after spine surgery [4]. However, our study demonstrated that the intraoperative use of ketodex was suitable. This could be ascribed to the additional analgesic effect of dexmedetomidine in ketodex, obviating the need for postoperative infusions, which are often cumbersome. Moreover, the results of the meta-analysis cautiously interpreted considering the heterogeneous studies included, methodological quality of the included studies, and different ketamine doses used.

The intraoperative anesthetic requirement in the form of desflurane was congruent in both groups. This may be attributable to the sub-anesthetic ketodex dose used, producing inadequate hypnotic plasma levels and only decreasing the perioperative pain score. Additionally, it may have resulted in relatively higher BIS scores, which were used to guide the maintenance of anesthesia, in the ketodex group despite adequate anesthetic depth. Both ketamine and dexmedetomidine are known to interfere with BIS values, with ketamine increasing these values. Higher BIS values in the ketodex group might have provoked the overuse of desflurane to maintain a BIS value of 40–60.

The overall rescue fentanyl administration was higher in group F than in group KD in our study. The PACU stay was significantly longer in group F than in group KD (49.83±9.86 minutes versus 30.83±7.99 minutes, p<0.001). This could be explained by the unfavorable postoperative effects of opioids, which require monitoring and treatment, thereby prolonging the PACU stay. Patients in group F experienced nausea and vomiting, while only one patient in group KD suffered from mild nausea. This could be attributable to the opioid-sparing effect of the ketodex infusion; a meta-analysis of 24 trials concluded that dexmedetomidine reduces the risk of postoperative nausea and vomiting due to a reduction in the administration of perioperative opioids [16]. More patients experienced respiratory depression in group F than in group KD; patients in group KD maintained a regular RR and showed no signs of respiratory depression. One factor, which could have contributed to the higher incidence of postoperative respiratory depression in our study, was the continuation of fentanyl infusion until the last skin suture was placed. Although opioids are currently the preferred choice for intraoperative analgesia in multiple level spine surgeries, the search for a better analgesic without the side effects of opioids is ongoing.

Opioids and dexmedetomidine inhibit shivering; this was evidenced in our study by the statistically insignificant incidence of shivering among our groups. More delirium episodes were observed in group KD than in group F; however, it was statistically insignificant. This may attributed to the psychomimetic potential of ketamine used in group KD. The concurrent use of dexmedetomidine and propofol counteracts the psychomimetic effects of ketamine.

The intraoperative hemodynamics (HR, systolic BP, and MAP) were marginally lower in group KD than in group F at most timepoints. Although statistically significant, both groups had stable vital parameters without substantial fluctuations. This is desirable during spine surgeries. The marginally lower HR and MAP values in group KD may be ascribed to the sympatholytic action of the vastly potent dexmedetomidine. Although we did not measure pain using an intraoperative pain monitoring device, the lower HR and MAP scores indicate a superior analgesic efficacy that was obtained by the synchronized action of ketamine and dexmedetomidine. Rahimzadeh et al. [17] also demonstrated that dexmedetomidine significantly lowered the intraoperative BP and HR compared to remifentanil in posterior spinal fusion surgeries. A prospective randomized controlled trial compared the effects of intraoperative dexmedetomidine and lidocaine infusion on hemodynamics, fentanyl requirements, and postoperative analgesia among patients undergoing lumbar fixation surgery. Akin to our study, the MAP and HR were lower in the dexmedetomidine group than in the lidocaine group [18]. In our study, none of the patients experienced dexmedetomidine-induced bradycardia or severe hypotension; this may be imputable to the concurrent administration of ketamine, which counterbalances the parasympathetic override of dexmedetomidine.

The intraoperative trend of lower hemodynamic parameters in the ketodex group continued for 24 hours postoperatively. The better analgesia provided by the ketodex synergism and sympatholytic action of dexmedetomidine and lesser episodes of nausea, vomiting, and other adverse effects that are usually associated with opioids, could allow a pleasant PACU stay. This has led to the early discharge from PACU with minimal side effects and overall better patient satisfaction. None of the patients experienced any adverse effects of ketamine or dexmedetomidine in the perioperative period. This may be due to the low dose of the two-constituent drugs used in the ketodex infusion.

Our study had a few limitations. The sample size was small, and we had no record of the severity of preoperative pain. The attending anesthesiologist could not be blinded to the study intervention groups and thus, remains an inevitable source of bias. The ketodex and fentanyl infusion doses used in our study was dissimilar and based on doses used in previous studies and our routine perioperative protocol. The use of BIS to assess the anesthetic depth may have led to ketamine and dexmedetomidine inordinately increasing its value, leading to study protocol-driven attempts to limit it, thereby altering desflurane administration. The hemodynamic parameters (HR and MAP) were used to guide the rescue analgesic doses. Using an intraoperative pain monitoring device would have added more objectivity to this measure.

In summary, use of ketodex as an anesthetic adjuvant during spine surgeries offers a hemodynamic profile comparable to fentanyl, a commonly used opioid. Although the consumption of maintenance agents was not majorly affected, the dose of concurrently administered opioid analgesics was reduced. Postoperatively, the patients who were administered ketodex reported less pain, required minimal rescue opioids, and experienced fewer side effects leading to speedy discharge and better patient satisfaction. Thus, low-dose ketodex infusion can be a safe substitute for fentanyl infusion when employed as an anesthetic adjuvant during general anesthesia for patients undergoing thoracolumbar spine surgeries for >3 vertebral levels to achieve prolonged analgesia without any opioid-related side effects.