Epidural morphine provides analgesia without sensory, motor, or sympathetic block. Compared with systemic morphine administration, it also offers better and longer pain relief with a smaller dose and fewer side effects [1,2]. Nonetheless, side effects of epidural morphine include nausea, vomiting, pruritus, delayed respiratory depression and urinary retention [1,3]. In addition, tolerance develops after long-term administration of opioids, limiting their therapeutic efficacy. Various medications have been suggested as alternatives to opioids for pain management, because of the problems associated with tolerance and side effects.
The N-methyl-D-aspartate (NMDA) receptors are widely distributed throughout the central nervous system. Activation of NMDA receptors is essential for central sensitization after nociceptive stimulation and probably plays an important role in the generation and maintenance of persistent pain states . Several animal studies have shown that NMDA receptor antagonists produce antihyperalgesic or anti-allodynic effects and significantly increase morphine's anti-nociceptive effect [5-8]. Epidural administration of ketamine, one of the few NMDA receptor antagonists in clinical use, has been reported to potentiate morphine's analgesic effect after a single bolus injection when co-administered with an epidural injection of morphine . In the present study, we examined the efficacy of combined ketamine and morphine administration in a patient-controlled epidural analgesia (PCEA) regime. The analgesic response and side effects generated with the combined regime were compared with PCEA morphine alone for post-operative pain relief after lower abdominal surgery.
Approval by the medical ethics committee of our hospital and written, informed consent from each patient were obtained before research began. Sixty ASA physical status I-II patients admitted for lower abdominal surgical procedures were included. Patients were instructed how to use a patient-controlled analgesia (PCA) device (Abbott Pain Management Provider, Abbott Laboratories, Chicago, IL, USA) at the time of the pre-operative visit; this was reviewed with each patient before initiating PCA therapy in the post-operative care unit. Patients were encouraged to use PCA to maintain a satisfactory level of pain relief. After written consent, subjects were randomized to group I or group II. All outcome data were obtained by observers blinded to the study drug group assignment.
Before induction of anaesthesia, a lumbar epidural catheter was placed at the L3-4 or L4-5 interspace. General anaesthesia was then induced with thiopentone 5 mg kg−1 and suxamethonium 1.5 mg kg−1 was given to facilitate orotracheal intubation. Anaesthesia was maintained with inhalation of isoflurane and 50% nitrous oxide in oxygen. Atracurium 0.4 mg kg−1 was used to maintain muscle relaxation. No opioid was given during the pre-operative or intraoperative period. The patients were randomly assigned to one of the two groups in a double-blind fashion. Thirty patients in group I received a PCEA regime containing morphine 0.02% (0.2 mg mL−1). Another 30 patients in group II received a PCEA regime containing morphine 0.02% and ketamine 0.05% (0.5 mg mL−1). Upon first complaint of post-operative pain, the patients in group I received morphine 1 mg in 10 mL normal saline via an epidural catheter, and the patients of group II received morphine 1 mg plus ketamine 5 mg in 10 mL normal saline administered by syringe through the epidural catheter. Following the bolus epidural injection, the PCA device was connected to the epidural catheter and programmed to deliver 1 mL h−1 and 1 mL per bolus, with a lockout time of 10 min, and a 4-h maximum dose of 15 mL. The level of pain was assessed on a 10-point visual analogue scale (VAS; from 0=none to 10=maximum). The level of sedation was simultaneously assessed on a 4-point scale: 0=none, 1=drowsy, 2=somnolent but easily aroused, 3=asleep or somnolent and difficult to arouse. Patients were asked to evaluate their resting pain intensity using the 10-point VAS, and meanwhile, sedation levels, psychomimetic effect, and morphine-related side effects including nausea, vomiting, pruritus, and respiratory depression were assessed at 30 min and at 3, 6, 12, 18, and 24 h post-operatively. The total consumption of morphine was recorded at 24 h post-operatively. Respiratory depression was defined as a respiratory rate of less than 10 min−1. Nausea and vomiting were treated with metoclopramide 10 mg i.v. and droperidol 0.5 mg i.v., if necessary. Droperidol was given if patients still complained of nausea or vomiting 30 min after receiving i.v. metoclopramide.
The Mann-Whitney U-test was used to compare non-parametric data between the two groups. Student's t-test was used to compare normally distributed data between the two groups. Fisher's exact test was used to compare the incidence of side effects between the two groups. A value of P < 0.05 was regarded as a statistically significant difference. Data are expressed as mean±standard error of the mean.
There were no differences between the two groups with regard to age, weight and height (Table 1). Pain relief was better in group II than in group I (P < 0.05) in the first 3 h. There were no differences between the two groups in post-operative pain scores during the post-operative 3-24 h (P < 0.05, Fig. 1). The total amount of morphine administered in the first 24 h post-operatively was lower in group II (6.2±0.2 mg) than in group I (8.6±0.7 mg) (P < 0.05, Fig. 2). The number of patients complaining of adverse effects in the two groups, including nausea, vomiting, pruritus, urinary retention, respiratory depression, and psychomimetic effects is shown in Table 2. The incidence and severity of post-operative pruritus and the sedative level were similar in the two groups. Vomiting occurred more frequently in group I (26%) than in group II (13%) (P < 0.05). The respiratory rate was not less than 10 min−1 at any time in any of the patients. Urinary retention could not be assessed because indwelling catheters in the urinary bladder were left in place for approximately 24 h post-operatively.
This study compared the effectiveness of PCA in postoperative pain control between patient groups receiving epidural morphine alone or combined with low dose ketamine. PCEA with a combination of ketamine and morphine was more efficacious in providing post-operative pain relief after low abdominal surgery. The lower pain scores and fewer side effects in the patients in group II suggest that a PCEA regime of ketamine 0.5 mg h−1 plus morphine 0.2 mg h−1 has superior efficacy for post-operative analgesia compared with the regime of morphine 0.2 mg h−1 alone.
The effectiveness of epidurally-administered opioids appears to depend on their hydrophilic or the lipophilic nature. Epidural morphine, which is the prototypical hydrophilic opioid, produces excellent analgesia of long duration and an extended dermatomal activity with doses much lower than those required parenterally. It has been widely used for post-operative pain relief. The recommended dose of epidural morphine is 0.1-1.0 mg h−1 with a continuous infusion of 3-10 mL h−1. In the present study, we chose a dose of PCEA morphine of 0.2 mg h−1 with a continuous infusion of 1 mL h−1. This dose is low but within the recommended range. The lower pain score and lower morphine consumption in group II suggests that the combination of ketamine with the low dose of morphine (0.2 mg h−1) enhanced the analgesic effect of morphine and thereby reduced the dose requirement for morphine. The mechanism for the potentiation effect of ketamine on morphine analgesia is unknown and requires further investigation.
Opioid peptides have long been demonstrated to modulate the responses of glutamate and its analogues . In the rabbit spinal cord, NMDA and opioid receptors have been shown to co-exist and possibly interact in the dorsal horn [11,12]. Evidence suggests that NMDA antagonists might enhance the antinociceptive effect of opioids by interaction at the spinal cord level .
The mechanisms underlying the interaction between NMDA receptor antagonists and morphine are unclear, but may be related to a modulation of NMDA receptors by opiates. It has been reported that iontophoretically applied opiates, in addition to blocking the glutamate-induced response in dorsal horn neurones, enhances NMDA receptor-mediated neuronal responses in dorsal horn neurones and in other areas of the central nervous system [14,15]. Intracellular studies conducted on dorsal horn neurones reveal an enhancement of NMDA-evoked responses by μ-opioid agonists [16,17]. These findings led to the hypothesis that even a single morphine administration seems to elicit adaptive changes in the nervous system by activation of the NMDA receptor, leading to the attenuation of the effect of morphine . Thus, stimulation of NMDA receptors by morphine may reduce and shorten its antinociceptive effect. Blockade of NMDA receptors may therefore enhance and prolong the effect of morphine. The results of the present study support this explanation.
Recently, many reports have demonstrated the efficacy of epidural ketamine for post-operative pain control. Islas and co-workers demonstrated that epidural administration of ketamine 4 mg produced potent pain relief without narcotic-like side effects for minor surgery . The onset of analgesia was within 5-10 min and duration of pain relief averaged 4.06±1.34 h (SD). However, epidural doses of ketamine 4-10 mg lacked analgesic effects in patients undergoing major surgery [19-21]. The insufficient effect of epidural ketamine for post-operative pain indicates that the site of action might not be the spinal cord dorsal horn . There is not complete agreement concerning the effect of ketamine and the site of action. Some studies on ketamine administered epidurally have shown pain alleviation and proposed the spinal site of action as predominant [20,22]. However, a recent study found that ketamine exerts a significant effect distal to a spinal transection . The hypoanalgesic effect of ketamine is most likely a continuum ranging between no effect and total anaesthesia, depending on the state of the nociceptive system and the dose. However, clinical studies do not provide the possibility of distinguishing between different stimulus modalities, and results are related only to the pain modalities investigated . The appropriate dose during different surgery, the predominant site of action, and the benefits of the appropriate dermatomal level of insertion of the epidural catheter need to be examined. Recent evidence shows that ketamine may act by potentiating the analgesic effect of morphine and by reducing its consumption [9,25]. Chia and colleagues demonstrated that the administration of ketamine 0.4 mg mL−1 in a multimodal PCEA regime including morphine, epinephrine, and bupivacaine provided effective analgesia. In our study, the regime of co-administration of ketamine (0.5 mg mL−1) and morphine enhanced the analgesic effect of morphine and reduced the morphine demand. No difference in pain scores observed during the period of 3-24 h could be due to the pain scores being too low for comparison, nor the lack of effect of ketamine. The reduced morphine consumption proves that ketamine potentiated the analgesic effect of morphine.
The incidence of side effects was similar in both groups with the exception of vomiting. Patients in group I had a higher incidence of vomiting (26%) than those in group II (13%) (P < 0.05). The higher incidence of vomiting in group I might have been due to the higher total dose of morphine in these patients. However, the reason for the similar incidence of pruritus between groups is unclear and speculation is difficult because the pathogenesis of spinal-induced pruritus has not yet been elucidated . No serious adverse effects, such as respiratory depression or sleep deprivation were noted in either of the groups. Psychomimetic effects, one of the most troubling side effects of ketamine, were not observed in this study.
Recently, ketamine was reported to possess some neurotoxicity, which was subsequently ascribed to chlorobutanol (the preservative in commercial ketamine preparations) , while subarachnoid ketamine (with benzethonium chloride as the preservative) showed no neurotoxicity in monkeys or baboons [29,30]. A previous study  found no neurotoxic effects with continuous infusion of ketamine. In this study, ketamine 5 mg (containing 0.01 mg benzethonium chloride) was injected epidurally as a loading dose and a total of approximately, ketamine 13 mg (containing 0.026 mg benzethonium chloride) was given in maintenance doses over a 1-day period. This low dose of ketamine appeared to be quite safe and no clinically important side effects were correlated with its use. Neurological sequelae including persistent paresthesia, sensory or motor deficits, and bowel or bladder dysfunction were reviewed in the subsequent outpatient follow-up. None of the patients in this study developed short- or long-term neurological impairment or deficit during a 1-year follow-up period.
In conclusion, the results of this study show that the combination of low dose ketamine and morphine delivered via PCEA provided effective post-operative analgesia, reduced the dose of morphine needed, and thereby attenuated morphine-induced side effects. Therefore, this ketamine-potentiated regime of opioid PCA may prove to be a safe and effective means of providing post-operative analgesia. Further studies are needed to elucidate the mechanism of opioid analgesic potentiation by ketamine.
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