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Anesth Analg 2001;93:116-120
© 2001 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Adding Ketamine to Morphine for Patient-Controlled Analgesia After Major Abdominal Surgery: A Double-Blinded, Randomized Controlled Trial

Mark Reeves, MB BS, FANZCA, David E. Lindholm, MB BS, FANZCA, Paul S. Myles, MB BS, MPH, MD, FCARCSI, FANZCA, Helen Fletcher, RN, and Jennifer O. Hunt, RN, BHlthSc

Department of Anaesthesia & Pain Management, Alfred Hospital; Departments of Anaesthesia, and Epidemiology & Preventive Medicine, Monash University, Australia

Address correspondence and reprint requests to David Lindholm, MB BS, Department of Anaesthesia & Pain Management, The Alfred Commercial Road, Prahran, Victoria, 3181 Australia. Address e-mail to D.Lindholm{at}alfred.org.au


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
In this double-blinded, randomized controlled trial we tested if the addition of ketamine to morphine for patient-controlled analgesia (PCA) resulted in improved analgesic efficacy and lower pain scores compared with morphine PCA alone after major abdominal surgery. Seventy-one patients were ran-domly allocated to receive either morphine 1 mg/mL (Group M) or morphine 1 mg/mL plus ketamine 1 mg/mL (Group MK) delivered via PCA after surgery. No other analgesics or regional blocks were permitted during the 48-h study period. Postoperatively there were no differences between the groups for subjective assessment of analgesic efficacy, pain scores at rest, and on movement, opioid consumption, or adverse events. Group MK patients performed worse in cognitive testing (P = 0.037). There was an increased risk of vivid dreaming in patients who received ketamine (relative risk = 1.8, 95% confidence interval 0.78–4.3). We conclude that small-dose ketamine combined with PCA morphine provides no benefit to patients undergoing major abdominal surgery.

Implications: We performed a randomized, controlled trial comparing the use of ketamine andmorphine with morphine alone to relieve pain after major abdominal surgery.Ketamine did not improve pain relief and merely increased sideeffects.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
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IV patient-controlled analgesia (PCA) with opioids is a popular method of delivering postoperative pain relief. Several adjuvant drugs are opioid sparing and/or improve analgesic efficacy (1,2). Ketamine has analgesic properties at smaller doses (3), and has enjoyed a resurgence of interest. In single-dose studies an effective plasma concentration of 100 ng/mL produced analgesia in an ischemic forearm model; however, side effects were not studied (4). Single-dose studies do not take into account the active metabolite nor-ketamine, which is inevitably present in larger concentrations in more prolonged studies. In one study (5) comparing a combination of morphine and ketamine via PCA with morphine PCA alone after microdiscectomy, pain scores were smaller in the patients who received ketamine. Opioid-related side effects were also reduced. Abdominal surgery is associated with much more postoperative pain than microdiscectomy and larger doses of opioids are needed for analgesia in the first few days after surgery. A drug that could improve pain scores and reduce the adverse effects associated with larger doses of opioids would have great clinical relevance. Postoperative administration of ketamine reduces pain after laparotomy (6). This clinical trial was designed to determine if the addition of ketamine to morphine for PCA results in subjectively increased analgesic efficacy and lower pain scores compared with morphine PCA alone after major abdominal surgery.


   Methods
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 Abstract
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 Methods
Results
 Discussion
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After hospital ethics committee approval, all patients presenting for elective major abdominal surgery involving a midline incision were identified. Patients were invited to participate if they chose PCA in preference to other forms of postoperative analgesia. After giving written, informed consent, 76 patients were randomly allocated to receive PCA consisting of either morphine 1 mg/mL (Group M) or morphine with ketamine 1 mg/mL of each (Group MK). They were stratified to two groups depending on whether they were to have upper or lower abdominal incisions, to reduce inhomogeneity between the groups.

The anesthetic technique was at the discretion of the anesthesiologist. Anesthesia consisted of IV induction with either thiopental or propofol, relaxation with cisatracurium or rocuronium and maintenance with sevoflurane or isoflurane in nitrous oxide. Intraoperative analgesia consisted of morphine plus or minus a dose of fentanyl at induction. Supplemental analgesics, such as acetaminophen, nonsteroidal antiinflammatory drugs or clonidine, and regional or local anesthetic techniques, were not allowed during the study period. Boluses of "study solution" were prescribed for administration in the postanesthesia care unit if necessary. The settings for the PCA (bolus size, lockout interval, and background infusion) were determined by the anesthesiologist. Preoperative, intraoperative and postoperative data were recorded in addition to demographic variables.

Preoperatively, baseline quality of recovery scores (7) and trail-making tests (cognitive tests of attention and perception) (8) were performed. Intraoperative data included type and duration of surgery, length and dermatomal range of incision, and total opioid dose. Postanesthesia care unit data included length of stay and total dose of study solution used. Postoperatively, 4 hourly nursing observations included pain scores at rest and on movement using an 11-point verbal rating scale, PCA use, sedation scores (0 = alert, 4 = asleep), heart rate, blood pressure, and respiratory rate. Patients were seen twice daily by the Acute Pain Service, who treated complications and adjusted the PCA as necessary without violating the protocol. Additional interventions by the Acute Pain Service were recorded. Researcher interviews were conducted at 24 h and 48 h postoperatively. Patients were asked "How effective was your medication at relieving your pain?" This five-point verbal rating scale (1 = excellent, 5 = very poor) has been shown to have discriminatory power (1). Data from the previous 24 h were also obtained for frequency of antiemetic administration, nausea scores (0 = none, 2 = severe), postoperative sleep quality (1 = much better than usual, 5 = much worse than usual), quality of recovery score, and the occurrence of adverse events (vivid dreams, nausea, hallucinations, pruritus, respiratory depression, Acute Pain Service interventions). Trail-making tests were repeated at 48 h.

Based on the results of previous studies (1,5) examining the same primary end points (subjective efficacy and pain scores), looking for a treatment effect of 25% and a power of 0.8, and accepting a type 1 error of 0.05, we planned to enroll enough patients to obtain 70 complete data sets for this effectiveness study. Missing scores were replaced using the last observation carried forward approach. Outcome measures were compared using general linear models adjusting for age, gender, site of incision, and duration of surgery. The model for pain scores also included length of incision as a covariate. The numbers of complications were compared using {chi}2 test. The risk of vivid dreams and the occurrence of hallucinations were calculated using risk ratios and their 95% confidence intervals. The null hypothesis was rejected if p<0.05. All analyses were performed using SPSS for Windows Version 9.0 (SPSS Inc., Chicago, IL).


   Results
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 Abstract
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 Methods
 Results
Discussion
 References
 
Of the 76 patients recruited, 71 had surgery and received the study medication according to the protocol; these formed the intention-to-treat population. The two groups were comparable (Table 1). There were 7 withdrawals; 4 were because of inadequate analgesia (2 in each group) and 1 a result of a protocol violation. Two patients were admitted to the intensive care unit with respiratory depression (one from each group).


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  		Table 1. Patient Demographics and Operative Data
 
Most patients rated their analgesia as good. There were no differences between the groups with respect to the primaryend points: subjective assessment of analgesic efficacy (Table 2) or pain scores (Fig. 1).


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  		Table 2. Postoperative Outcomes
 


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  		Figure 1. Pain verbal rating scale (VRS) (0 = no pain, 10 = worst pain imaginable) in patients receiving patient-controlled analgesia after major abdominal surgery. Postoperative time periods: 1 = 4 h; 2 = 8 h; 3 = 12 h; 4 = 16 h; 5 = 20 h; 6 = 24 h; 7 = 28 h; 8 = 32 h; 9 = 36 h; 10 = 40 h; 11 = 44 h; 12 = 48 h.

 
There were no statistical differences between the groups for the secondary end points except for performance of trail-making test B (see Tables 2 & 3). The overall complication rate was similar in both groups.


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  		Table 3. Incidence and Relative Risk Estimates for Vivid Dreams and Hallucinations After Major Abdominal Surgery
 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This double-blinded, randomized trial does not support the hypothesis that small-dose ketamine is a useful adjunct to morphine PCA in patients recovering from abdominal surgery. However, there is evidence that small-dose ketamine does have some clinically discernible effects, notably a decrease in cognitive function (as measured by trail-making test B). There was also an increased risk of vivid dreaming but this was not statistically significant. Thus, the ketamine dose studied was not insufficient. Larger doses of ketamine may or may not be effective, but would probably result in significant, unwanted side effects.

Trail-making tests measure visual-conceptual and visuomotor tracking. They are not specific to any disorder but are sensitive to changes in cognitive function (8,9). Test B is more difficult than test A. They are convenient to administer, reliable (9), and have been used to measure the cognitive effects of PCA with meperidine (10). The smaller group sizes for these tests reflect two factors. First, there were some logistic difficulties with recruitment that prevented 22 patients being tested (12 in Group MK and 10 in Group M) because of preoperative time constraints. Second, some patients refused to take the tests postoperatively, especially test B. Interestingly this was more frequent in Group MK than in Group M. The impact of total dose of ketamine on test performance was not analyzed in this study but has been studied in detail elsewhere (11).

Previous studies demonstrate that ketamine is analgesic (3–6) and reduces pain after laparotomy (6), yet the timing of administration, the dose used, and, probably, the type of surgery are important. Much interest has focused on the potential role of N-methyl-D-aspartate receptor antagonists in preventing central sensitization and wound hyperalgesia. Clinical trials involving IV ketamine can be broadly divided into those focusing on a preemptive effect and those using ketamine postoperatively as an analgesic.

There is support for the premise that ketamine exerts a preemptive effect in abdominal surgery (12,13), anterior cruciate ligament repair (14), and nephrectomy (15). However, a preemptive effect has not been demonstrated after mastectomy (16), nor for (R)-ketamine given before laparoscopic cholecystectomy (17); however, this may reflect the reduced potency of R(-)-ketamine on certain N-methyl-D-aspartate receptor subtypes (18). When used as a drug to induce anesthesia for cesarean delivery ketamine results in reduced postoperative morphine requirements compared with thiopental (19), yet 0.4 mg/kg given before abdominal hysterectomy is no more effective than placebo at reducing pain (20).

Ketamine appears less effective when given as a postoperative analgesic infusion. Most recently published studies in this area are negative (3,21,22). Edwards et al. (21) found that ketamine 5, 10, or 20 mg/hour did not improve the analgesia provided by morphine 1 mg/hour in elderly patients undergoing upper abdominal surgery. As in our study, these authors noted an increase in postoperative dreaming with ketamine. Owen et al. (3) found that approximately 12 mg/hour of ketamine did not provide clinically useful analgesia after abdominal surgery, although only patients in the control group had ventilatory depression. Ilkjaer et al. (22) found no benefit for ketamine 10 mg/hour over placebo after renal surgery when used in combination with epidural local anesthetic and morphine.

The study by Javery et al. (5) is unique in that much smaller doses of ketamine were used (average 1.2 mg/hour) than in other studies, and yet the effect was remarkable. In our study, the average dose of ketamine was 3.2 mg/hour for the first twenty-four hours yet we found no measurable beneficial effect. One study (23) found that 10 mg/hour of ketamine reduced morphine consumption and nausea after abdominal surgery in a study of 30 patients. They were no differences between the groups for sedation scores or the occurrence of vivid dreams. There were differences between the groups with respect to the types of surgery (11 gastrointestinal procedures in the control group versus 5 in the ketamine group). Morphine consumption over forty-eight hours was less in their study than ours (54 mg in controls, 27 mg in the ketamine group) (Table 2). These contradictory results may reflect our poor understanding of the nature and source of pain from different types of surgery. The sources and severity of pain experienced after microdiscectomy might be expected to be different than those after abdominal surgery and different again to urologic surgery. It can be speculated that opioids contribute to abdominal colic after bowel surgery and further speculated that this type of discomfort is not relieved by N-methyl-D-aspartate receptor antagonism.

Our study is the first to look at the subjective efficacy of ketamine as an analgesic and to formally assess its cognitive effects in postsurgical patients. It is also the first to use the recently validated quality of recovery score in an analgesic trial. We believe that PCA opioid consumption is an easy variable to measure but one of dubious value, and that patient satisfaction and adverse effects are more clinically relevant (1). In conclusion, this study failed to demonstrate any beneficial effect of ketamine added to morphine PCA as a postoperative analgesic after major abdominal surgery.


   Acknowledgments
 
Supported, in part, by an Alfred Hospital Research Foundation Grant, Parke Davis Pharmaceuticals and Abbott Australasia.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Plummer JL, Owen H, Isley AH, et al. Sustained-release ibuprofen as an adjunct to morphine patient-controlled analgesia. Anesth Analg 1996; 83: 92–6.[Abstract]
  2. Segal IS, Jarvis DJ, Duncan SR, et al. Clinical efficacy of oral-transdermal clonidine combinations during the postoperative period. Anesthesiology 1991; 74: 220–5.[ISI][Medline]
  3. Owen H, Reekie RM, Clements JA, et al. Analgesia from morphine and ketamine. Anaesthesia 1987; 42: 1051–6.[ISI][Medline]
  4. Clements JA, Nimmo WS. Pharmacokinetics and analgesic effect of ketamine in man. Br J Anaesth 1981; 53: 27–30.[Abstract/Free Full Text]
  5. Javery KB, Ussery TW, Steger HG, et al. Comparison of morphine and morphine with ketamine for postoperative analgesia. Can J Anaesth 1996; 43: 212–5.[Abstract/Free Full Text]
  6. Sadove M, Shulman M, Hatano S, et al. Analgesic effects of ketamine administered in subdissociative doses. Anesth Analg 1971; 50: 452–7.[Free Full Text]
  7. Myles PS, Ponsford J, Hunt J, et al. Development and psychometric testing of a quality of recovery score after general anaesthesia and surgery. Anesth Analg 1999; 88: 83–90.[Abstract/Free Full Text]
  8. Lezak MD. Neuropsychological assessment, 3rd ed. New York: Oxford University Press, 1995: 381–4.
  9. Spreen O, Strauss E. A compendium of neuropsychological tests. New York: Oxford University Press, 1991.
  10. Plummer JL, Owen H, Isley AH, et al. Morphine patient-controlled analgesia is superior to meperidine patient-controlled analgesia for postoperative pain. Anesth Analg 1997; 84: 794–9.[Abstract]
  11. Krystal JH, Karper LP, Seibyl JP, et al. Subanesthetic doses of the non-competitive NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994; 51: 199–214.[Abstract]
  12. Fu ES, Miguel R, Scharf JE. Preemptive ketamine decreases postoperative narcotic requirements in patients undergoing abdominal surgery. Anesth Analg 1997; 84: 1086–90.[Abstract]
  13. Roytblat L, Korotkoruchko A, Katz J, et al. Postoperative pain: the effect of low-dose ketamine in addition to general anesthesia. Anesth Analg 1993; 77: 1161–5.[Abstract/Free Full Text]
  14. Menigaux C, Fletcher D, Dupont X, et al. The benefits of intraoperative small-dose ketamine on postoperative pain after anterior cruciate ligament repair. Anesth Analg 2000; 90: 129–35.[Abstract/Free Full Text]
  15. Stubhaug A, Breivik H, Eide PK, et al. Mapping of punctate mechanical hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery. Acta Anaesth Scan 1997; 41: 1124–32.
  16. Adam F, Libier M, Oszustowicz T, et al. Preoperative small-dose ketamine has no preemptive analgesic effect in patients undergoing total mastectomy. Anesth Analg 1999; 89: 444–7.[Abstract/Free Full Text]
  17. Mathisen LC, Aasbo V, Raeder J. Lack of preemptive analgesic effect of (R)-ketamine in laparoscopic cholecystectomy. Acta Anaesth Scan 1999; 43: 220–4.
  18. Yamakura T, Sakimura K, Shimoji K. The stereoselective effect of ketamine isomers on heteromeric N-Methyl-D-Aspartate receptor channels. Anesth Analg 2000; 91: 225–9.[Abstract/Free Full Text]
  19. Kee WD, Khaw KS, Ma ML, et al. Postoperative analgesic requirement after cesarean section: a comparison of anesthetic induction with ketamine or thiopental. Anesth Analg 1997; 85: 1294–8.[Abstract]
  20. Dahl V, Ernoe P, Steen T, et al. Does ketamine have preemptive effects in women undergoing abdominal hysterectomy procedures? Anesth Analg 2000; 90: 1419–22.[Abstract/Free Full Text]
  21. Edwards ND, Fletcher A, Cole JR, Peacock JE. Combined infusions of morphine and ketamine for postoperative pain in elderly patients. Anaesthesia 1993; 48: 124–7.[ISI][Medline]
  22. Ilkjaer S, Nikolajsen L, Hansen TM, et al. Effect of i.v. ketamine in combination with epidural bupivacaine or epidural morphine on postoperative pain and wound tenderness after renal surgery. Br J Anaesth 1998; 81: 707–12.[Abstract/Free Full Text]
  23. Adriaenssens G, Vermeyen K, Hoffmann V, et al. Postoperative analgesia with i.v. patient-controlled morphine: effect of adding ketamine. Br J Anaesth 1999; 83: 393–6.[Abstract/Free Full Text]
Accepted for publication February 23, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press