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Evaluation of the safety and efficacy of epidural ketamine combined with morphine for postoperative analgesia after major upper abdominal surgery
Original Contributions Evaluation of the Safety and Efficacy of Epidural Ketamine Combined With Morphine for Postoperative Analgesia After Major Upper Abdominal Surgery Kathirvel Subramaniam, MD,* Balachundhar Subramaniam, MD,† Dilip K. Pawar, MD, Lakesh Kumar, MD,§ Department of Anesthesiology, All India Institute of Medical Sciences, New Delhi, India
*Senior Resident †Senior Resident ‡Additional Professor §Assistant Professor Address correspondence and reprint requests to Dr. Subramaniam, Department of Anesthesiology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215. E-mail: [email protected] Received for publication May 8, 2000; revised manuscript accepted for publication April 18, 2001.
Study Objective: To evaluate the efficacy of the combination of epidural ketamine and morphine compared with epidural morphine alone for postoperative pain relief following major upper abdominal surgery. Study design: Prospective, randomized, double-blinded study. Setting: Tertiary care referral and teaching hospital Patients: 46 ASA physical status I and II patients who underwent major upper abdominal procedures. Interventions: Patients were randomly allocated to one of the two treatment groups: patients in Group 1 received epidural morphine 50 g/kg whereas patients in Group 2 received epidural ketamine 1 mg/kg combined with 50 g/kg of morphine postoperatively. Measurements: A blinded observer using a visual analog scale (VAS) for pain assessment followed up patients for 48 hours postoperatively. Top-up dose of epidural morphine was provided when VAS was higher than 4. Analgesic requirements and side effects were compared between the two groups. Results: Only 40 patients completed the study. There were no differences between the two groups with respect to age, gender, weight, duration, or type of surgical procedure or intraoperative opioid requirements. Onset of analgesia was faster (p ⬍ 0.001) in Group 2 (11 min) than in Group 1 patients (25 min). The time for first requirement of analgesia was significantly (p ⬍ 0.01) longer (19.8 ⫾ 9.8 hours) in Group 2 patients than Group 1 (12.8 ⫾ 6.2 hours). Total number of supplemental doses of epidural morphine required in the first 48 hours postoperatively was also significantly less (p ⬍ 0.005) in Group 2 compared to Group 1. Patients in Group 2 had higher sedation scores than Group I patients for the first 2 hours postoperatively. None of the patients in either group developed hallucinations or respiratory depression. Other side effects such as pruritus, nausea, and vomiting were also similar in both groups. Conclusions: The addition of epidural ketamine 1 mg/kg to morphine 50 g/kg
Journal of Clinical Anesthesia 13:339 –344, 2001 © 2001 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
0952-8180/01/$–see front matter PII S0952-8180(01)00278-1
Original Contributions
improved analgesia after major upper abdominal surgery without increasing side effects. © 2001 by Elsevier Science Inc. Keywords: Analgesia: postoperative; analgesics: morphine, ketamine; anesthetic technique: epidural.
Introduction Epidural analgesia in the postoperative period is associated with significant reduction in pulmonary and cardiovascular morbidity, aided recovery and reduced intensive care unit stay compared to analgesics given through systemic route.1,2 Local anesthetics and opioids are used for postoperative analgesia through the epidural route. Local anesthetics produce excellent pain relief but are associated with hemodynamic instability. Epidural morphine produces antinociception through opioid receptors to reduce the primary afferent neurotransmitter release presynaptically. It also acts postsynaptically to hyperpolarize dorsal horn neurons.3 Ketamine, which is a noncompetitive antagonist of N-methyl D-aspartate (NMDA) receptors, can prevent the induction of central sensitization caused by peripheral nociception stimulation and blocks the wind-up phenomenon.4 Ketamine analgesia is also mediated by its interaction with opioid receptors.5 Ketamine can prevent action potential conduction by an effect on the sodium and potassium channels in nerve membranes and, hence, is considered to have local anesthetic properties.6 Wong et al.,7 in an experimental study of rats, showed that neither competitive nor noncompetitive NMDA antagonists had an antinociceptive effect by themselves but potentiated the antinociceptive effect of morphine and prevented the development of tolerance. Addition of ketamine to epidural morphine increased the duration of analgesia from 10 to 20 days in terminal cancer patients.8 Sandler et al.,9 after reviewing the clinical trials of epidural ketamine, suggested that epidural ketamine although not a potent analgesic alone may have an additive effect with opioids and local anesthetics. Hence, we hypothesized that the addition of the NMDA antagonist, ketamine, to epidural morphine can produce improved analgesia when compared with morphine alone.
Materials and Methods After obtaining approval from the All India Institute of Medical Sciences Institutional Ethics Committee and written informed consent, we studied 46 ASA physical status I and II adult patients of either gender undergoing major upper abdominal surgery with balanced general anesthesia. Patients with history of drug abuse, major systemic illnesses, bleeding diathesis, or neurologic dysfunction were excluded from the study. Patients were assigned to one of the two treatment groups using a table of random numbers generated by Statistical Program for Social Sciences (SPSS, Chicago, IL) version 7. A vertical 100-mm Visual Analog Scale (VAS) with endpoints marked as 0 ⫽ no pain and 10 ⫽ worst imaginable pain was used for the assessment of postoperative pain. All patients received instruction about using 340
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VAS during their preoperative visit. Patients were premedicated with diazepam 10 mg on the morning of surgery, 2 hours before the induction of anesthesia. On arrival in the operation theater (OR), an intravenous (IV) cannula was inserted. Patients were placed in the lateral position and an epidural catheter was inserted in the T12 –L1 interspace by an experienced anesthesiologist using the loss-of-resistance technique with local analgesia. Catheter advancement technique was used to confirm the catheter placement.10 With this technique, after eliciting a lack of resistance, the ability to advance a soft epidural catheter 20 cm without a stylet beyond the vertebral foramina with minimal resistance was taken as successful catheterization. After the catheter advancement technique, the catheter was withdrawn up to 17 to 18 cm and gravity drainage of cerebrospinal fluid (CSF) or blood was tested. After affixing the epidural catheter to the backs of the patients, patients were placed supine for induction of general anesthesia. Patients were induced with thiopental sodium 5 mg/kg, and the trachea was intubated with vecuronium 0.1 mg/kg IV. All patients were maintained with nitrous oxide (N2O) 66% and halothane 0.5% in 33% oxygen (O2). Intraoperative analgesia was provided with IV morphine 200 g/kg initially and supplemented with 50 g/kg of morphine, which was titrated to the clinical parameters such as increase in heart rate (HR), blood pressure (BP), and the presence of lacrimation and sweating. Continuous monitoring of electrocardiography (ECG), automatic noninvasive BP (NIBP), central venous pressure (CVP), O2 saturation (SpO2), and end-tidal carbon dioxide (ETCO2) was done using Datex Cardiocap II monitoring systems (Datex, Instrumentarium Inc., Helsinki, Finland). Residual neuromuscular block was reversed with neostigmine 50 g/kg and atropine 20 g/kg and the patients’ tracheas were extubated at the end of the surgery. Patient’s pain was assessed after extubation in the OR and later in the recovery room using VAS. When VAS scores on deep inspiration were higher than 4, they received either morphine 50 g/kg or ketamine 1 mg/kg combined with morphine 50 g/kg in 10 mL of normal saline through the epidural catheter. These patients were monitored in high-dependency recovery room for the first 12 hours postoperatively and then transferred to an inpatient ward. Postoperatively, an anesthesiologist followed-up these patients and he was blinded as to the type of study drugs being given. Time to onset of analgesia was noted. Patients with no pain relief or insufficient analgesia (VAS ⬎ 4) at 40 minutes after the study drug administration were given IV opioids and then excluded from the study. Patients were followed up at 2, 4, 8, 12, 18, 24, 30, 36, 42, and 48 hours postoperatively for pain using VAS during deep inspiration. A top-up dose of epidural morphine 50 g/kg was administered when a VAS score was higher than 4. If the patients complained of pain during the 6-hour follow-up period, the on-call anesthesia resident assessed the patients and administered top-up analgesic if required. The on-call residents were aware of the nature of the study but blinded as to the study medications being given. The duration of analgesia provided by the
Epidural morphine with ketamine: Subramaniam et al.
Table 1. Patient Characteristics, Duration of Surgery, and Intraoperative Opioid Requirements Group 1 (nⴝ20) Age (yrs) Gender (Male/Female) Weight (kg) Duration of surgery (hrs) Intraoperative morphine dose (mgs)
Group 2 (nⴝ20)
43.9 ⫾ 14.8 35.2 ⫾ 16.9 14/6 14/6 52.4 ⫾ 11.7 54 ⫾ 9.8 4.4 ⫾ 1.3 3.8 ⫾ 1.3 13.2 ⫾ 2.9 12.9 ⫾ 2.5
Note: Values expressed as means ⫾ SD.
first dose and the total number of top-up doses given in the first 48 hours were recorded. Sedation was assessed at 2, 6, 12, and 24 hours postoperatively using a 5-point scale (0 ⫽ completely awake with the eyes open, 1 ⫽ drowsy, closed eyes; 2 ⫽ asleep but responding to verbal commands; 3 ⫽ asleep but responding to touch or pain; 4 ⫽ does not respond). Patients were also questioned as to side effects such as hallucinations, pruritus, and nausea and vomiting in the first 48 hours postoperatively. Respiratory rate (RR) and the patient’s response were used to diagnose respiratory depression. If the RR was below 10 breaths/min and the patient was not verbally responsive, respiratory depression was diagnosed. If the patient was not responding and RR was above 10 breaths/min, excessive sedation was diagnosed. Values normally distributed are expressed as means ⫾ SD and values not normally distributed are expressed as medians (ranges). Age, weight, duration of surgery, intraoperative opioid requirement, and time for the first requirement of analgesia were analyzed by unpaired Student’s t-test. Time duration from extubation to the administration of the study drugs, onset of analgesia, and number of supplemental epidural morphine administrations for 48 hours were compared between the groups by Mann-Whitney U test. Sedation scores and other side effects were compared between the groups by Yate’s corrected Chi-square test or Fisher’s exact tests wherever appropriate. p values less than 0.05 were considered statistically significant. Sample size was decided based on our earlier study in which epidural morphine had a median duration of action for 10 hours if administered postincisionally.11 Prestudy power analysis determined that at least 17 patients would be necessary in each group to have 90% chance ( ⫽ 0.1) of detecting 50% absolute increase in the duration of analgesia (Epi Info 6, Centers for Disease Control, Atlanta, GA, and World Health Organization, Geneva, Switzerland).
Results Age, gender, weight, type and duration of surgery, and intraoperative morphine requirements were comparable in the two groups (Table 1). All patients underwent major upper abdominal procedures (Table 2). Three patients in each group were excluded from the study because of insufficient analgesia at 40 minutes after bolus epidural
drug administration. Median time interval between extubation and the requirement of analgesia was comparable in both the groups. Epidural analgesia was administered 10 minutes and 12.5 minutes after extubation in Group 1 and Group 2 patients, respectively. Onset of analgesia was faster in Group 2 than in Group 1 (Table 3). Patients in Group 2 required the first top-up dose of epidural morphine at 19.8 ⫾ 9.8 hours after the study drug administration. This finding was significantly longer (p ⬍ 0.01) than that seen in the Group 1 patients (12.8 ⫾ 6.2 hours). Total number of epidural morphine supplemental doses required in the first 48 hours was significantly less (p ⬍ 0.005) in Group 2 than in Group 1 (Table 3). VAS scores were maintained below 4 by administering top-up dose of epidural morphine in patients from both groups. Because analysis of VAS reflects only the top-up analgesic need indirectly, these data were not analyzed or compared statistically. Six of 20 patients (30%) in Group 2 had high sedation scores (3 or 4) versus no patients in Group 1 in the first 2 hours postoperatively (p ⬍ 0.05). There was no significant difference in sedation between the two groups beyond 2 hours observation period postoperatively. Other side effects were comparable between the two groups (Table 4). Post study power analysis was done to validate our results. Our study had 95% power to demonstrate the difference between the groups in time for first analgesic request, with the sample size of 20 in each group and type 1 error of 0.05.
Discussion In this study, epidural ketamine combined with morphine increased the time for first request of analgesia and decreased the requirement of supplemental doses of epidural morphine for 48 hours following major upper abdominal surgery. Opioid receptor activation results in phosphorylation of NMDA receptors, which activates a series of cascade leading to opioid receptor down regulation (tolerance) and hyperresponsiveness (hyperalgesia).12 The attenuation of acute tolerance and rebound hyperalgesia by the NMDA receptor antagonist, ketamine, can explain the improved analgesia in the ketamine morphine group patients. Analgesia produced by intratheTable 2. Type of Surgery Performed in Both Groups (n) Group 1 Group 2 (n ⴝ 20) (n ⴝ 20)
Surgical Procedure Transhiatal esophagectomy and gastric pull up Whipple’s procedure Pancreatico-jejunostomy Cystogastrostomy Radical nephrectomy Hemicolectomy Total proctocolectomy and ileoanal anastomosis Retroperitoneal sarcoma excision Radical gastrectomy
9
5
1 2 0 0 2 1
3 2 1 1 2 1
1 4
0 5
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Table 3. Postoperative Analgesia Data in Both the Groups
Time to study drug administration from extubation (min) Onset of analgesia (min) Epidural morphine supplements for 48 hours (n)
Group 1 (n ⴝ 20)
Group 2 (n ⴝ 20)
P-value
10 (0–45) 25 (15–35) 3 (0–4)
12.5 (0–60) 11 (5–22) 2 (0–3)
0.8686 ⬍0.0001 0.0019
Note: Values are expressed as medians (range).
cal ketamine has been reversed by naloxone in rats.13 Thus, the interaction of ketamine with opioid receptors and the resulting synergistic effects between ketamine and morphine can also explain our study findings. While studying the efficacy of multi-modal patientcontrolled epidural regimen using ketamine, morphine, bupivacaine, and adrenaline for major upper abdominal and thoracic operations, Chia et al.14 demonstrated an additive analgesic effect when ketamine was added. Caudal coadministration of ketamine and bupivacaine produced better postoperative analgesia than did bupivacaine alone in children after inguinal herniorrhaphy.15 Yanli et al.16 have shown that extradural ketamine reduces onset time and increases the height of bupivacaine block by two segments. Because these two studies denote synergistic effects between epidural ketamine and local anesthetics, the improved analgesia noticed in Chia et al.’s14 study could not specifically address the interaction between morphine and ketamine in the epidural space. In our study, we administered only morphine and ketamine without local anesthetics, and this combination increased the duration and decreased the need for supplemental analgesics over the first 48 hours postoperatively. Wong et al.17 suggested that epidural ketamine potentiated the analgesic effect of morphine in postoperative pain control after major joint replacement surgery. In their study design, all patients were pretreated with ketamine and lidocaine before surgery. This action could have influenced their results. Although clinical trials did not show encouraging results when ketamine was given alone for preemptive analgesia,18,19 Wu et al.20 and Wong et al.,21 have demonstrated that preemptive multimodal analgesia using ketamine, morphine, and local anesthetics improved postoperative analgesia compared to their postincisional administration. Our aim was to demonstrate the clinical benefits of the ketamine-morphine combination without any other confounding factors such as preemptive effect and local anesthetics. With preemptive drug administration, it would not have been possible to define the onset of analgesia. In our study, epidural ketamine potentiated the analgesic actions of morphine even without pretreatment with ketamine and/or lidocaine. The combination of low-dose ketamine (containing the preservative, benzethonium chloride) and morphine delivered via patient-controlled epidural analgesia (PCEA) has been shown by Tan et al.22 to provide effective postoperative analgesia, which reduced the requirement of morphine and its related side effects in patients undergo342
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ing lower abdominal surgery. Patients undergoing upper abdominal and thoracic surgery have more postoperative pain and organ dysfunction.23 We did not use PCEA in the study and all patients underwent major upper abdominal surgical procedures. Despite these differences in study design and site of surgery, our results were similar to Tan et al. who followed up their patients for 1 year during which no patient developed neurologic impairment. However, a recent case report of a terminally ill cancer patient who received continuous infusion of intrathecal ketamine with preservative for 3 weeks for subpial vacuolar myelopathy has been reported.24 We used preservative-free ketamine through the epidural route since preservative-free ketamine has been shown to be devoid of neurotoxic effects after both single and repeated administrations.25,26 Aida et al.,27 in a randomized, placebo-controlled study, evaluated preemptive additive analgesic effects between epidural morphine and IV ketamine, and suggested that improved analgesia was achieved because morphine affects the spinal cord segmentally and IV ketamine may block brain stem sensitization via phrenic or vagus nerve during upper abdominal surgery. The preferred route of administration and the site of action of ketamine for analgesia are still not clear. Alam et al.28 evaluated the antinociceptive effects of epidural and IV ketamine in rats and showed that both epidural and IV ketamine produced greater antinociceptive effects to visceral than to somatic stimulation, and that epidural ketamine has a low incidence of emergence reactions. Koinig et al. 29 compared the analgesic efficacy and plasma concentrations after administration of S (⫹) ketamine caudally and intramuscularly (IM) in children and showed that despite similar plasma concentrations during most of the postoperative period, caudal ketamine provided more effective analgesia than did IM ketamine. Pharmacokinetic studies have shown that epidural administration produced higher CSF levels and longer elimination half-life than did IV administration.30 Table 4. Side Effects
Side effects Pruritus Nausea and vomiting Respiratory depression Psychomimetic effects
Group 1 (n ⴝ 20)
Group 2 (n ⴝ 20)
5 3 none none
4 3 none none
Epidural morphine with ketamine: Subramaniam et al.
Weir et al.31 have observed significant sedation in patients who received extradural ketamine with bupivacaine in patients undergoing arthroscopic surgery. They explained the excessive sedation that was seen in their patients to be due to lipid solubility and extensive intravascular absorption of ketamine from epidural space. We hypothesize that the initial sedation and rapid onset of analgesia were due to systemic absorption of ketamine. The higher CSF concentration and local effects explained prolongation of analgesia. Sedation without compromise of airway reflexes or respiratory depression seen in patients from the ketamine-morphine combination group in the immediate postoperative period could be beneficial to minimize patient distress. Epidural ketamine in low doses (less than 10 mg) did not provide adequate analgesia after gynecological procedures compared with epidural morphine.32 Naguib et al.,33 in their study, increased the dosage to 30 mg and this produced satisfactory analgesia after lower abdominal surgery. In our study, the surgical procedures were major, highly invasive, and involved midline upper abdominal incision necessitating that we use a higher dose of 1 mg/kg along with morphine. The use of ketamine through the intrathecal route was associated with significant increase in central nervous system side effects.34,35 However, epidural ketamine up to 1 mg/kg has been studied and well tolerated in patients undergoing upper abdominal surgery.18,36 All patients in our study received diazepam premedication and none developed psychomimetic effects. The incidence of nausea and vomiting after epidural opioid administration ranges from 10 to 30%.37 In this study, the incidence was low (15%) and addition of ketamine was not associated with increase in the incidence of nausea and vomiting. In our experience, epidural morphine provides good quality analgesia lasting 10 to 12 hours after upper abdominal surgery. Addition of epidural ketamine shortened the onset and increased the duration of analgesia provided by epidural morphine. We administered the study drugs after patients complained of pain in the postoperative period so that the timing or dose of intraoperative opioids did not influence the study results. Median number of epidural supplements was less in the combination group (2 supplements in the morphine group vs. 3 in the ketaminemorphine group). Although a decrease of one dose in the 24-hour period may not seem to be clinically relevant, it is of tremendous significance as the duration of the morphine-ketamine combination was found to be about 19 hours or more. We recommend further large well-controlled clinical trials on this epidural drug combination before using in routine clinical practice since ketamine is still not FDA approved for epidural or spinal use.
Acknowledgements We thank Mr. Dwivedi, Associate Professor, Department of Biostatistics, All India Institute of Medical Sciences, New Delhi and Mr. Thennarasu, Assistant Professor, Department of Biostatistics, Postgraduate Institute Of Medical Education and Research (PGIMER),
Chandigarh, for their valuable help in collection and statistical analysis of the data.
References 1. Tuman KJ, McCarthy RJ, March RJ, DeLaria GA, Patel RV, Ivankovich AD: Effect of epidural anesthesia and analgesia on coagulation and outcome after major vascular surgery. Anesth Analg 1991;73:696 –704. 2. Shulman M, Sandler AN, Bradley JW, Young PS, Brebner J: Postthoracotomy pain and pulmonary function following epidural and systemic morphine. Anesthesiology 1984;61:569 –75. 3. Dickenson AH: Mechanisms of the analgesic actions of opiates and opioids: Br Med Bull 1991;47:690 –702. 4. Woolf CJ, Thompson SW: The induction and maintenance of central sensitization is dependent on N-methyl D-aspartate acid receptor activation: implication for the treatment of post-injury pain hypersensitivity states. Pain 1991;44:293–9. 5. Finck AD, Ngai SH: Opiate receptor mediation of ketamine analgesia. Anesthesiology 1982;56:291–7. 6. Collins JG: Effects of ketamine on low intensity tactile sensory input are not dependent upon a spinal site of action. Anesth Analg 1986;65:1123–9. 7. Wong CS, Cherng CH, Luk HN, Ho ST, Tung CS: Effect of NMDA receptor antagonist on inhibition of morphine tolerance in rats, binding at mu-receptors. Eur J Pharmacol 1996;297:27–33. 8. Lauretti GR, Gomes JM, Reis MP, Pereira NL: Low doses of epidural ketamine or neostigmine, but not midazolam, improve morphine analgesia in epidural terminal cancer pain therapy. J Clin Anesth 1999;11:663– 8. 9. Sandler AN, Schmid R, Katz J: Epidural ketamine for postoperative analgesia. Can J Anaesth 1998;45:99 –102. 10. El Baz, NM, Faber LP, Jensik RJ: Continuous epidural infusion of morphine for treatment of pain after thoracic surgery: a new technique. Anesth Analg 1984;63:754 – 64. 11. Subramaniam B, Pawar DK, Kashyap L: Pre-emptive analgesia with epidural morphine or morphine and bupivacaine. Anaesth Intensive Care 2000;28:392– 8. 12. Mao JR, Price DD, Mayer DJ: Mechanism of hyperalgesia and opioid tolerance: a current view of their possible interactions. Pain 1995;62:259 –74. 13. Pekoe GM, Smith DJ: The involvement of opiate and monoaminergic neuronal systems in the analgesic effects of ketamine. Pain 1982;12:57–73. 14. Chia YY, Liu K, Liu YC, Chang HC, Wong CS: Adding ketamine in a multimodal patient-controlled epidural regimen reduces postoperative pain and analgesic consumption. Anesth Analg 1998;86:1245–9. 15. Naguib M, Sharif MY, Seraj M, el Gammel M, Dawlatly KA: Ketamine for caudal analgesia in children: comparison with caudal bupivacaine. Br J Anaesth 1991;67:559 – 64. 16. Yanli Y, Eren A: The effect of extradural ketamine on onset time and sensory block in extradural anaesthesia with bupivacaine. Anaesthesia 1996;51:84 – 6. 17. Wong CS, Liaw WJ, Tung CS, Su YF, Ho ST: Ketamine potentiates analgesic effect of morphine in postoperative epidural pain control. Reg Anesth 1996;21:534 – 41. 18. Kucuk N, Kizilkaya M, Tokdemir M: Preoperative epidural ketamine does not have a postoperative opioid sparing effect. Anesth Analg 1998;87:103– 6. 19. Heinke W, Grimm D: Preemptive effects caused by co-analgesia with ketamine in gynecological laparotomies? Anaesthesiol Reanim 1999;24:60 – 4. 20. Wu CT, Yeh CC, Yu JC, et al.: Preincisional epidural ketamine, morphine and bupivacaine combined with epidural and general J. Clin. Anesth., vol. 13, August 2001
343
Original Contributions
21.
22.
23. 24.
25.
26.
27.
28.
29.
344
anaesthesia provides pre-emptive analgesia for upper abdominal surgery Acta Anaesthesiol Scand 2000;44:63– 8. Wong CS, Lu CC, Cherng CH, Ho ST: Pre-emptive analgesia with ketamine, morphine and epidural lidocaine prior to total knee replacement. Can J Anaesth 1997;44:31–7. Tan PH, Kuo MC, Kao PF, Chia YY, Liu K: Patient-controlled epidural analgesia with morphine or morphine plus ketamine for post-operative pain relief. Eur J Anaesthesiol 1999;16:820 –5. Bonica JJ: Postoperative pain. In: Bonica JJ (ed): The Management of Pain. Philadelphia: Lea & Febiger, 1990:462. Karpinski N, Dunn J, Hansen L, Masliah E: Subpial vacuolar myelopathy after intrathecal ketamine: report of a case. Pain 1997;73:103–5. Borgbjerg FM, Svensson BA, Frigast C, Gordh T Jr: Histopathology after repeated intrathecal injections of preservative free ketamine in the rabbit: a light and electron microscopic examination. Anesth Analg 1994;79:105–11. Malinovsky JM, Lepage JY, Cozain A, Mussini JM, Pinaudt M, Souron R: Is ketamine or its preservative responsible for neurotoxicity in the rabbit? Anesthesiology 1993;78:109 –15. Aida S, Yamakura T, Baba H, Taga K, Fukuda S, Shimoji K: Preemptive analgesia by intravenous low-dose ketamine and epidural morphine in gastrectomy: a randomized double-blind study. Anesthesiology 2000;92:1624 –30. Alam S, Saito Y, Kosako Y: Antinociceptive effects of epidural and intravenous ketamine to somatic and visceral stimuli in rats. Can J Anaesth 1996;43:408 –13. Koinig H, Marhofer P, Krenn CG, et al: Analgesic effects of
J. Clin. Anesth., vol. 13, August 2001
30.
31.
32.
33.
34. 35.
36.
37.
caudal and intramuscular S(⫹) ketamine in children. Anesthesiology 2000;93:976 – 80. Pedraz JL, Calvo MB, Gascon AR, et al.: Pharmacokinetics and distribution of ketamine after extradural administration to dogs. Br J Anaesth 1991;67:310 – 6. Weir PS, Fee JP: Double-blind comparison of extradural block with three bupivacaine-ketamine mixtures in knee arthroplasty. Br J Anaesth 1998;80:299 –301. Kawana Y, Sato H, Shimada H, et al: Epidural ketamine for postoperative pain relief after gynecologic operations: doubleblind study and comparison with epidural morphine. Anesth Analg 1987;66:735– 8. Naguib M, Adu-Gyamfi Y, Absood GH, Farag H, Gyasi HK: Epidural ketamine for postoperative analgesia. Can Anaesth Soc J 1986;33:16 –21. Hawksworth C, Serpell M: Intrathecal anesthesia with ketamine. Reg Anesth Pain Med 1998;23:283– 8. Kathirvel S, Sadhasivam S, Saxena A, Kannan TR, Ganjoo P: Effects of intrathecal ketamine added to bupivacaine for spinal anaesthesia. Anaesthesia 2000;55:899 –904. Choe H, Choi YS, Kim YH, et al.: Epidural morphine plus ketamine for upper abdominal surgery: improved analgesia from preincisional versus postincisional administration. Anesth Analg 1997;84:560 –3. Chung JH, Harris SN: Common side effects associated with spinal opioids and their treatment. In: Sinatra RS, Hord AH, Ginsberg B, Preble LM (eds): Acute Pain Mechanisms and Management. St. Louis: Mosby-Year Book, 1992:279 –92.
*Senior Resident †Senior Resident ‡Additional Professor §Assistant Professor Address correspondence and reprint requests to Dr. Subramaniam, Department of Anesthesiology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215. E-mail: [email protected] Received for publication May 8, 2000; revised manuscript accepted for publication April 18, 2001.
Study Objective: To evaluate the efficacy of the combination of epidural ketamine and morphine compared with epidural morphine alone for postoperative pain relief following major upper abdominal surgery. Study design: Prospective, randomized, double-blinded study. Setting: Tertiary care referral and teaching hospital Patients: 46 ASA physical status I and II patients who underwent major upper abdominal procedures. Interventions: Patients were randomly allocated to one of the two treatment groups: patients in Group 1 received epidural morphine 50 g/kg whereas patients in Group 2 received epidural ketamine 1 mg/kg combined with 50 g/kg of morphine postoperatively. Measurements: A blinded observer using a visual analog scale (VAS) for pain assessment followed up patients for 48 hours postoperatively. Top-up dose of epidural morphine was provided when VAS was higher than 4. Analgesic requirements and side effects were compared between the two groups. Results: Only 40 patients completed the study. There were no differences between the two groups with respect to age, gender, weight, duration, or type of surgical procedure or intraoperative opioid requirements. Onset of analgesia was faster (p ⬍ 0.001) in Group 2 (11 min) than in Group 1 patients (25 min). The time for first requirement of analgesia was significantly (p ⬍ 0.01) longer (19.8 ⫾ 9.8 hours) in Group 2 patients than Group 1 (12.8 ⫾ 6.2 hours). Total number of supplemental doses of epidural morphine required in the first 48 hours postoperatively was also significantly less (p ⬍ 0.005) in Group 2 compared to Group 1. Patients in Group 2 had higher sedation scores than Group I patients for the first 2 hours postoperatively. None of the patients in either group developed hallucinations or respiratory depression. Other side effects such as pruritus, nausea, and vomiting were also similar in both groups. Conclusions: The addition of epidural ketamine 1 mg/kg to morphine 50 g/kg
Journal of Clinical Anesthesia 13:339 –344, 2001 © 2001 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
0952-8180/01/$–see front matter PII S0952-8180(01)00278-1
Original Contributions
improved analgesia after major upper abdominal surgery without increasing side effects. © 2001 by Elsevier Science Inc. Keywords: Analgesia: postoperative; analgesics: morphine, ketamine; anesthetic technique: epidural.
Introduction Epidural analgesia in the postoperative period is associated with significant reduction in pulmonary and cardiovascular morbidity, aided recovery and reduced intensive care unit stay compared to analgesics given through systemic route.1,2 Local anesthetics and opioids are used for postoperative analgesia through the epidural route. Local anesthetics produce excellent pain relief but are associated with hemodynamic instability. Epidural morphine produces antinociception through opioid receptors to reduce the primary afferent neurotransmitter release presynaptically. It also acts postsynaptically to hyperpolarize dorsal horn neurons.3 Ketamine, which is a noncompetitive antagonist of N-methyl D-aspartate (NMDA) receptors, can prevent the induction of central sensitization caused by peripheral nociception stimulation and blocks the wind-up phenomenon.4 Ketamine analgesia is also mediated by its interaction with opioid receptors.5 Ketamine can prevent action potential conduction by an effect on the sodium and potassium channels in nerve membranes and, hence, is considered to have local anesthetic properties.6 Wong et al.,7 in an experimental study of rats, showed that neither competitive nor noncompetitive NMDA antagonists had an antinociceptive effect by themselves but potentiated the antinociceptive effect of morphine and prevented the development of tolerance. Addition of ketamine to epidural morphine increased the duration of analgesia from 10 to 20 days in terminal cancer patients.8 Sandler et al.,9 after reviewing the clinical trials of epidural ketamine, suggested that epidural ketamine although not a potent analgesic alone may have an additive effect with opioids and local anesthetics. Hence, we hypothesized that the addition of the NMDA antagonist, ketamine, to epidural morphine can produce improved analgesia when compared with morphine alone.
Materials and Methods After obtaining approval from the All India Institute of Medical Sciences Institutional Ethics Committee and written informed consent, we studied 46 ASA physical status I and II adult patients of either gender undergoing major upper abdominal surgery with balanced general anesthesia. Patients with history of drug abuse, major systemic illnesses, bleeding diathesis, or neurologic dysfunction were excluded from the study. Patients were assigned to one of the two treatment groups using a table of random numbers generated by Statistical Program for Social Sciences (SPSS, Chicago, IL) version 7. A vertical 100-mm Visual Analog Scale (VAS) with endpoints marked as 0 ⫽ no pain and 10 ⫽ worst imaginable pain was used for the assessment of postoperative pain. All patients received instruction about using 340
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VAS during their preoperative visit. Patients were premedicated with diazepam 10 mg on the morning of surgery, 2 hours before the induction of anesthesia. On arrival in the operation theater (OR), an intravenous (IV) cannula was inserted. Patients were placed in the lateral position and an epidural catheter was inserted in the T12 –L1 interspace by an experienced anesthesiologist using the loss-of-resistance technique with local analgesia. Catheter advancement technique was used to confirm the catheter placement.10 With this technique, after eliciting a lack of resistance, the ability to advance a soft epidural catheter 20 cm without a stylet beyond the vertebral foramina with minimal resistance was taken as successful catheterization. After the catheter advancement technique, the catheter was withdrawn up to 17 to 18 cm and gravity drainage of cerebrospinal fluid (CSF) or blood was tested. After affixing the epidural catheter to the backs of the patients, patients were placed supine for induction of general anesthesia. Patients were induced with thiopental sodium 5 mg/kg, and the trachea was intubated with vecuronium 0.1 mg/kg IV. All patients were maintained with nitrous oxide (N2O) 66% and halothane 0.5% in 33% oxygen (O2). Intraoperative analgesia was provided with IV morphine 200 g/kg initially and supplemented with 50 g/kg of morphine, which was titrated to the clinical parameters such as increase in heart rate (HR), blood pressure (BP), and the presence of lacrimation and sweating. Continuous monitoring of electrocardiography (ECG), automatic noninvasive BP (NIBP), central venous pressure (CVP), O2 saturation (SpO2), and end-tidal carbon dioxide (ETCO2) was done using Datex Cardiocap II monitoring systems (Datex, Instrumentarium Inc., Helsinki, Finland). Residual neuromuscular block was reversed with neostigmine 50 g/kg and atropine 20 g/kg and the patients’ tracheas were extubated at the end of the surgery. Patient’s pain was assessed after extubation in the OR and later in the recovery room using VAS. When VAS scores on deep inspiration were higher than 4, they received either morphine 50 g/kg or ketamine 1 mg/kg combined with morphine 50 g/kg in 10 mL of normal saline through the epidural catheter. These patients were monitored in high-dependency recovery room for the first 12 hours postoperatively and then transferred to an inpatient ward. Postoperatively, an anesthesiologist followed-up these patients and he was blinded as to the type of study drugs being given. Time to onset of analgesia was noted. Patients with no pain relief or insufficient analgesia (VAS ⬎ 4) at 40 minutes after the study drug administration were given IV opioids and then excluded from the study. Patients were followed up at 2, 4, 8, 12, 18, 24, 30, 36, 42, and 48 hours postoperatively for pain using VAS during deep inspiration. A top-up dose of epidural morphine 50 g/kg was administered when a VAS score was higher than 4. If the patients complained of pain during the 6-hour follow-up period, the on-call anesthesia resident assessed the patients and administered top-up analgesic if required. The on-call residents were aware of the nature of the study but blinded as to the study medications being given. The duration of analgesia provided by the
Epidural morphine with ketamine: Subramaniam et al.
Table 1. Patient Characteristics, Duration of Surgery, and Intraoperative Opioid Requirements Group 1 (nⴝ20) Age (yrs) Gender (Male/Female) Weight (kg) Duration of surgery (hrs) Intraoperative morphine dose (mgs)
Group 2 (nⴝ20)
43.9 ⫾ 14.8 35.2 ⫾ 16.9 14/6 14/6 52.4 ⫾ 11.7 54 ⫾ 9.8 4.4 ⫾ 1.3 3.8 ⫾ 1.3 13.2 ⫾ 2.9 12.9 ⫾ 2.5
Note: Values expressed as means ⫾ SD.
first dose and the total number of top-up doses given in the first 48 hours were recorded. Sedation was assessed at 2, 6, 12, and 24 hours postoperatively using a 5-point scale (0 ⫽ completely awake with the eyes open, 1 ⫽ drowsy, closed eyes; 2 ⫽ asleep but responding to verbal commands; 3 ⫽ asleep but responding to touch or pain; 4 ⫽ does not respond). Patients were also questioned as to side effects such as hallucinations, pruritus, and nausea and vomiting in the first 48 hours postoperatively. Respiratory rate (RR) and the patient’s response were used to diagnose respiratory depression. If the RR was below 10 breaths/min and the patient was not verbally responsive, respiratory depression was diagnosed. If the patient was not responding and RR was above 10 breaths/min, excessive sedation was diagnosed. Values normally distributed are expressed as means ⫾ SD and values not normally distributed are expressed as medians (ranges). Age, weight, duration of surgery, intraoperative opioid requirement, and time for the first requirement of analgesia were analyzed by unpaired Student’s t-test. Time duration from extubation to the administration of the study drugs, onset of analgesia, and number of supplemental epidural morphine administrations for 48 hours were compared between the groups by Mann-Whitney U test. Sedation scores and other side effects were compared between the groups by Yate’s corrected Chi-square test or Fisher’s exact tests wherever appropriate. p values less than 0.05 were considered statistically significant. Sample size was decided based on our earlier study in which epidural morphine had a median duration of action for 10 hours if administered postincisionally.11 Prestudy power analysis determined that at least 17 patients would be necessary in each group to have 90% chance ( ⫽ 0.1) of detecting 50% absolute increase in the duration of analgesia (Epi Info 6, Centers for Disease Control, Atlanta, GA, and World Health Organization, Geneva, Switzerland).
Results Age, gender, weight, type and duration of surgery, and intraoperative morphine requirements were comparable in the two groups (Table 1). All patients underwent major upper abdominal procedures (Table 2). Three patients in each group were excluded from the study because of insufficient analgesia at 40 minutes after bolus epidural
drug administration. Median time interval between extubation and the requirement of analgesia was comparable in both the groups. Epidural analgesia was administered 10 minutes and 12.5 minutes after extubation in Group 1 and Group 2 patients, respectively. Onset of analgesia was faster in Group 2 than in Group 1 (Table 3). Patients in Group 2 required the first top-up dose of epidural morphine at 19.8 ⫾ 9.8 hours after the study drug administration. This finding was significantly longer (p ⬍ 0.01) than that seen in the Group 1 patients (12.8 ⫾ 6.2 hours). Total number of epidural morphine supplemental doses required in the first 48 hours was significantly less (p ⬍ 0.005) in Group 2 than in Group 1 (Table 3). VAS scores were maintained below 4 by administering top-up dose of epidural morphine in patients from both groups. Because analysis of VAS reflects only the top-up analgesic need indirectly, these data were not analyzed or compared statistically. Six of 20 patients (30%) in Group 2 had high sedation scores (3 or 4) versus no patients in Group 1 in the first 2 hours postoperatively (p ⬍ 0.05). There was no significant difference in sedation between the two groups beyond 2 hours observation period postoperatively. Other side effects were comparable between the two groups (Table 4). Post study power analysis was done to validate our results. Our study had 95% power to demonstrate the difference between the groups in time for first analgesic request, with the sample size of 20 in each group and type 1 error of 0.05.
Discussion In this study, epidural ketamine combined with morphine increased the time for first request of analgesia and decreased the requirement of supplemental doses of epidural morphine for 48 hours following major upper abdominal surgery. Opioid receptor activation results in phosphorylation of NMDA receptors, which activates a series of cascade leading to opioid receptor down regulation (tolerance) and hyperresponsiveness (hyperalgesia).12 The attenuation of acute tolerance and rebound hyperalgesia by the NMDA receptor antagonist, ketamine, can explain the improved analgesia in the ketamine morphine group patients. Analgesia produced by intratheTable 2. Type of Surgery Performed in Both Groups (n) Group 1 Group 2 (n ⴝ 20) (n ⴝ 20)
Surgical Procedure Transhiatal esophagectomy and gastric pull up Whipple’s procedure Pancreatico-jejunostomy Cystogastrostomy Radical nephrectomy Hemicolectomy Total proctocolectomy and ileoanal anastomosis Retroperitoneal sarcoma excision Radical gastrectomy
9
5
1 2 0 0 2 1
3 2 1 1 2 1
1 4
0 5
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Table 3. Postoperative Analgesia Data in Both the Groups
Time to study drug administration from extubation (min) Onset of analgesia (min) Epidural morphine supplements for 48 hours (n)
Group 1 (n ⴝ 20)
Group 2 (n ⴝ 20)
P-value
10 (0–45) 25 (15–35) 3 (0–4)
12.5 (0–60) 11 (5–22) 2 (0–3)
0.8686 ⬍0.0001 0.0019
Note: Values are expressed as medians (range).
cal ketamine has been reversed by naloxone in rats.13 Thus, the interaction of ketamine with opioid receptors and the resulting synergistic effects between ketamine and morphine can also explain our study findings. While studying the efficacy of multi-modal patientcontrolled epidural regimen using ketamine, morphine, bupivacaine, and adrenaline for major upper abdominal and thoracic operations, Chia et al.14 demonstrated an additive analgesic effect when ketamine was added. Caudal coadministration of ketamine and bupivacaine produced better postoperative analgesia than did bupivacaine alone in children after inguinal herniorrhaphy.15 Yanli et al.16 have shown that extradural ketamine reduces onset time and increases the height of bupivacaine block by two segments. Because these two studies denote synergistic effects between epidural ketamine and local anesthetics, the improved analgesia noticed in Chia et al.’s14 study could not specifically address the interaction between morphine and ketamine in the epidural space. In our study, we administered only morphine and ketamine without local anesthetics, and this combination increased the duration and decreased the need for supplemental analgesics over the first 48 hours postoperatively. Wong et al.17 suggested that epidural ketamine potentiated the analgesic effect of morphine in postoperative pain control after major joint replacement surgery. In their study design, all patients were pretreated with ketamine and lidocaine before surgery. This action could have influenced their results. Although clinical trials did not show encouraging results when ketamine was given alone for preemptive analgesia,18,19 Wu et al.20 and Wong et al.,21 have demonstrated that preemptive multimodal analgesia using ketamine, morphine, and local anesthetics improved postoperative analgesia compared to their postincisional administration. Our aim was to demonstrate the clinical benefits of the ketamine-morphine combination without any other confounding factors such as preemptive effect and local anesthetics. With preemptive drug administration, it would not have been possible to define the onset of analgesia. In our study, epidural ketamine potentiated the analgesic actions of morphine even without pretreatment with ketamine and/or lidocaine. The combination of low-dose ketamine (containing the preservative, benzethonium chloride) and morphine delivered via patient-controlled epidural analgesia (PCEA) has been shown by Tan et al.22 to provide effective postoperative analgesia, which reduced the requirement of morphine and its related side effects in patients undergo342
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ing lower abdominal surgery. Patients undergoing upper abdominal and thoracic surgery have more postoperative pain and organ dysfunction.23 We did not use PCEA in the study and all patients underwent major upper abdominal surgical procedures. Despite these differences in study design and site of surgery, our results were similar to Tan et al. who followed up their patients for 1 year during which no patient developed neurologic impairment. However, a recent case report of a terminally ill cancer patient who received continuous infusion of intrathecal ketamine with preservative for 3 weeks for subpial vacuolar myelopathy has been reported.24 We used preservative-free ketamine through the epidural route since preservative-free ketamine has been shown to be devoid of neurotoxic effects after both single and repeated administrations.25,26 Aida et al.,27 in a randomized, placebo-controlled study, evaluated preemptive additive analgesic effects between epidural morphine and IV ketamine, and suggested that improved analgesia was achieved because morphine affects the spinal cord segmentally and IV ketamine may block brain stem sensitization via phrenic or vagus nerve during upper abdominal surgery. The preferred route of administration and the site of action of ketamine for analgesia are still not clear. Alam et al.28 evaluated the antinociceptive effects of epidural and IV ketamine in rats and showed that both epidural and IV ketamine produced greater antinociceptive effects to visceral than to somatic stimulation, and that epidural ketamine has a low incidence of emergence reactions. Koinig et al. 29 compared the analgesic efficacy and plasma concentrations after administration of S (⫹) ketamine caudally and intramuscularly (IM) in children and showed that despite similar plasma concentrations during most of the postoperative period, caudal ketamine provided more effective analgesia than did IM ketamine. Pharmacokinetic studies have shown that epidural administration produced higher CSF levels and longer elimination half-life than did IV administration.30 Table 4. Side Effects
Side effects Pruritus Nausea and vomiting Respiratory depression Psychomimetic effects
Group 1 (n ⴝ 20)
Group 2 (n ⴝ 20)
5 3 none none
4 3 none none
Epidural morphine with ketamine: Subramaniam et al.
Weir et al.31 have observed significant sedation in patients who received extradural ketamine with bupivacaine in patients undergoing arthroscopic surgery. They explained the excessive sedation that was seen in their patients to be due to lipid solubility and extensive intravascular absorption of ketamine from epidural space. We hypothesize that the initial sedation and rapid onset of analgesia were due to systemic absorption of ketamine. The higher CSF concentration and local effects explained prolongation of analgesia. Sedation without compromise of airway reflexes or respiratory depression seen in patients from the ketamine-morphine combination group in the immediate postoperative period could be beneficial to minimize patient distress. Epidural ketamine in low doses (less than 10 mg) did not provide adequate analgesia after gynecological procedures compared with epidural morphine.32 Naguib et al.,33 in their study, increased the dosage to 30 mg and this produced satisfactory analgesia after lower abdominal surgery. In our study, the surgical procedures were major, highly invasive, and involved midline upper abdominal incision necessitating that we use a higher dose of 1 mg/kg along with morphine. The use of ketamine through the intrathecal route was associated with significant increase in central nervous system side effects.34,35 However, epidural ketamine up to 1 mg/kg has been studied and well tolerated in patients undergoing upper abdominal surgery.18,36 All patients in our study received diazepam premedication and none developed psychomimetic effects. The incidence of nausea and vomiting after epidural opioid administration ranges from 10 to 30%.37 In this study, the incidence was low (15%) and addition of ketamine was not associated with increase in the incidence of nausea and vomiting. In our experience, epidural morphine provides good quality analgesia lasting 10 to 12 hours after upper abdominal surgery. Addition of epidural ketamine shortened the onset and increased the duration of analgesia provided by epidural morphine. We administered the study drugs after patients complained of pain in the postoperative period so that the timing or dose of intraoperative opioids did not influence the study results. Median number of epidural supplements was less in the combination group (2 supplements in the morphine group vs. 3 in the ketaminemorphine group). Although a decrease of one dose in the 24-hour period may not seem to be clinically relevant, it is of tremendous significance as the duration of the morphine-ketamine combination was found to be about 19 hours or more. We recommend further large well-controlled clinical trials on this epidural drug combination before using in routine clinical practice since ketamine is still not FDA approved for epidural or spinal use.
Acknowledgements We thank Mr. Dwivedi, Associate Professor, Department of Biostatistics, All India Institute of Medical Sciences, New Delhi and Mr. Thennarasu, Assistant Professor, Department of Biostatistics, Postgraduate Institute Of Medical Education and Research (PGIMER),
Chandigarh, for their valuable help in collection and statistical analysis of the data.
References 1. Tuman KJ, McCarthy RJ, March RJ, DeLaria GA, Patel RV, Ivankovich AD: Effect of epidural anesthesia and analgesia on coagulation and outcome after major vascular surgery. Anesth Analg 1991;73:696 –704. 2. Shulman M, Sandler AN, Bradley JW, Young PS, Brebner J: Postthoracotomy pain and pulmonary function following epidural and systemic morphine. Anesthesiology 1984;61:569 –75. 3. Dickenson AH: Mechanisms of the analgesic actions of opiates and opioids: Br Med Bull 1991;47:690 –702. 4. Woolf CJ, Thompson SW: The induction and maintenance of central sensitization is dependent on N-methyl D-aspartate acid receptor activation: implication for the treatment of post-injury pain hypersensitivity states. Pain 1991;44:293–9. 5. Finck AD, Ngai SH: Opiate receptor mediation of ketamine analgesia. Anesthesiology 1982;56:291–7. 6. Collins JG: Effects of ketamine on low intensity tactile sensory input are not dependent upon a spinal site of action. Anesth Analg 1986;65:1123–9. 7. Wong CS, Cherng CH, Luk HN, Ho ST, Tung CS: Effect of NMDA receptor antagonist on inhibition of morphine tolerance in rats, binding at mu-receptors. Eur J Pharmacol 1996;297:27–33. 8. Lauretti GR, Gomes JM, Reis MP, Pereira NL: Low doses of epidural ketamine or neostigmine, but not midazolam, improve morphine analgesia in epidural terminal cancer pain therapy. J Clin Anesth 1999;11:663– 8. 9. Sandler AN, Schmid R, Katz J: Epidural ketamine for postoperative analgesia. Can J Anaesth 1998;45:99 –102. 10. El Baz, NM, Faber LP, Jensik RJ: Continuous epidural infusion of morphine for treatment of pain after thoracic surgery: a new technique. Anesth Analg 1984;63:754 – 64. 11. Subramaniam B, Pawar DK, Kashyap L: Pre-emptive analgesia with epidural morphine or morphine and bupivacaine. Anaesth Intensive Care 2000;28:392– 8. 12. Mao JR, Price DD, Mayer DJ: Mechanism of hyperalgesia and opioid tolerance: a current view of their possible interactions. Pain 1995;62:259 –74. 13. Pekoe GM, Smith DJ: The involvement of opiate and monoaminergic neuronal systems in the analgesic effects of ketamine. Pain 1982;12:57–73. 14. Chia YY, Liu K, Liu YC, Chang HC, Wong CS: Adding ketamine in a multimodal patient-controlled epidural regimen reduces postoperative pain and analgesic consumption. Anesth Analg 1998;86:1245–9. 15. Naguib M, Sharif MY, Seraj M, el Gammel M, Dawlatly KA: Ketamine for caudal analgesia in children: comparison with caudal bupivacaine. Br J Anaesth 1991;67:559 – 64. 16. Yanli Y, Eren A: The effect of extradural ketamine on onset time and sensory block in extradural anaesthesia with bupivacaine. Anaesthesia 1996;51:84 – 6. 17. Wong CS, Liaw WJ, Tung CS, Su YF, Ho ST: Ketamine potentiates analgesic effect of morphine in postoperative epidural pain control. Reg Anesth 1996;21:534 – 41. 18. Kucuk N, Kizilkaya M, Tokdemir M: Preoperative epidural ketamine does not have a postoperative opioid sparing effect. Anesth Analg 1998;87:103– 6. 19. Heinke W, Grimm D: Preemptive effects caused by co-analgesia with ketamine in gynecological laparotomies? Anaesthesiol Reanim 1999;24:60 – 4. 20. Wu CT, Yeh CC, Yu JC, et al.: Preincisional epidural ketamine, morphine and bupivacaine combined with epidural and general J. Clin. Anesth., vol. 13, August 2001
343
Original Contributions
21.
22.
23. 24.
25.
26.
27.
28.
29.
344
anaesthesia provides pre-emptive analgesia for upper abdominal surgery Acta Anaesthesiol Scand 2000;44:63– 8. Wong CS, Lu CC, Cherng CH, Ho ST: Pre-emptive analgesia with ketamine, morphine and epidural lidocaine prior to total knee replacement. Can J Anaesth 1997;44:31–7. Tan PH, Kuo MC, Kao PF, Chia YY, Liu K: Patient-controlled epidural analgesia with morphine or morphine plus ketamine for post-operative pain relief. Eur J Anaesthesiol 1999;16:820 –5. Bonica JJ: Postoperative pain. In: Bonica JJ (ed): The Management of Pain. Philadelphia: Lea & Febiger, 1990:462. Karpinski N, Dunn J, Hansen L, Masliah E: Subpial vacuolar myelopathy after intrathecal ketamine: report of a case. Pain 1997;73:103–5. Borgbjerg FM, Svensson BA, Frigast C, Gordh T Jr: Histopathology after repeated intrathecal injections of preservative free ketamine in the rabbit: a light and electron microscopic examination. Anesth Analg 1994;79:105–11. Malinovsky JM, Lepage JY, Cozain A, Mussini JM, Pinaudt M, Souron R: Is ketamine or its preservative responsible for neurotoxicity in the rabbit? Anesthesiology 1993;78:109 –15. Aida S, Yamakura T, Baba H, Taga K, Fukuda S, Shimoji K: Preemptive analgesia by intravenous low-dose ketamine and epidural morphine in gastrectomy: a randomized double-blind study. Anesthesiology 2000;92:1624 –30. Alam S, Saito Y, Kosako Y: Antinociceptive effects of epidural and intravenous ketamine to somatic and visceral stimuli in rats. Can J Anaesth 1996;43:408 –13. Koinig H, Marhofer P, Krenn CG, et al: Analgesic effects of
J. Clin. Anesth., vol. 13, August 2001
30.
31.
32.
33.
34. 35.
36.
37.
caudal and intramuscular S(⫹) ketamine in children. Anesthesiology 2000;93:976 – 80. Pedraz JL, Calvo MB, Gascon AR, et al.: Pharmacokinetics and distribution of ketamine after extradural administration to dogs. Br J Anaesth 1991;67:310 – 6. Weir PS, Fee JP: Double-blind comparison of extradural block with three bupivacaine-ketamine mixtures in knee arthroplasty. Br J Anaesth 1998;80:299 –301. Kawana Y, Sato H, Shimada H, et al: Epidural ketamine for postoperative pain relief after gynecologic operations: doubleblind study and comparison with epidural morphine. Anesth Analg 1987;66:735– 8. Naguib M, Adu-Gyamfi Y, Absood GH, Farag H, Gyasi HK: Epidural ketamine for postoperative analgesia. Can Anaesth Soc J 1986;33:16 –21. Hawksworth C, Serpell M: Intrathecal anesthesia with ketamine. Reg Anesth Pain Med 1998;23:283– 8. Kathirvel S, Sadhasivam S, Saxena A, Kannan TR, Ganjoo P: Effects of intrathecal ketamine added to bupivacaine for spinal anaesthesia. Anaesthesia 2000;55:899 –904. Choe H, Choi YS, Kim YH, et al.: Epidural morphine plus ketamine for upper abdominal surgery: improved analgesia from preincisional versus postincisional administration. Anesth Analg 1997;84:560 –3. Chung JH, Harris SN: Common side effects associated with spinal opioids and their treatment. In: Sinatra RS, Hord AH, Ginsberg B, Preble LM (eds): Acute Pain Mechanisms and Management. St. Louis: Mosby-Year Book, 1992:279 –92.