JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS
AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
A&A International Anesthesia Research Society
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (42)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by McCartney, C. J. L.
Right arrow Articles by Katz, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by McCartney, C. J. L.
Right arrow Articles by Katz, J.
Related Collections
Right arrow Mechanisms
Right arrow Pain
Right arrow Pharmacology

Anesth Analg 2004;98:1385-1400
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000108501.57073.38

PAIN MEDICINE

A Qualitative Systematic Review of the Role of N-Methyl-D-Aspartate Receptor Antagonists in Preventive Analgesia

Colin J. L. McCartney, FRCA*, Avinash Sinha, FRCA*, and Joel Katz, PhD{dagger},{ddagger},§

*Department of Anesthesia and Pain Management, Toronto Western Hospital and University of Toronto; {dagger}Department of Anesthesia, University of Toronto; {ddagger}Department of Anesthesia and Pain Management, Toronto General Hospital and Mount Sinai Hospital; and §Department of Psychology and School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada

Address correspondence to Colin J. L. McCartney, MB ChB, FRCA, Department of Anesthesia and Pain Management, Toronto Western Hospital, EC2-046, 399 Bathurst St., Toronto M5T2S8, ON, Canada. Address e-mail to colin.mccartney{at}uhn.on.ca Reprints will not be available from the authors.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We evaluated in a qualitative systematic review the effect of N-methyl-D-aspartate (NMDA) receptor antagonists on reducing postoperative pain and analgesic consumption beyond the clinical duration of action of the target drug (preventive analgesia). Randomized trials examining the use of an NMDA antagonist in the perioperative period were sought by using a MEDLINE (1966–2003) and EMBASE (1985–2003) search. Reference sections of relevant articles were reviewed, and additional articles were obtained if they evaluated postoperative analgesia after the administration of NMDA antagonists. The primary outcome was a reduction in pain, analgesic consumption, or both in a time period beyond five half-lives of the drug under examination. Secondary outcomes included time to first analgesic request and adverse effects. Forty articles met the inclusion criteria (24 ketamine, 12 dextromethorphan, and 4 magnesium). The evidence in favor of preventive analgesia was strongest in the case of dextromethorphan and ketamine, with 67% and 58%, respectively, of studies demonstrating a reduction in pain, analgesic consumption, or both beyond the clinical duration of action of the drug concerned. None of the four studies examining magnesium demonstrated preventive analgesia.

IMPLICATIONS: We evaluated, in a qualitative systematic review, the effect of N-methyl D-aspartate antagonists on reducing postoperative pain and analgesic consumption beyond the clinical duration of action of the target drug (preventive analgesia). Dextromethorphan and ketamine were found to have significant immediate and preventive analgesic benefit in 67% and 58% of studies, respectively.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The N-methyl-D-aspartate (NMDA) receptor is an excitatory amino acid receptor that has been implicated in the modulation of prolonged pain states in animal models (1). NMDA antagonists, such as ketamine and dextromethorphan, have been shown to be useful in the reduction of acute postoperative pain, analgesic consumption, or both when they are added to more conventional means of providing analgesia, such as opioids and nonsteroidal antiinflammatory drugs, in the perioperative period (1,2).

Intraoperative and postoperative noxious inputs may cause central sensitization, but analgesic interventions given before the noxious stimulus may attenuate or block sensitization and, hence, reduce acute pain (3). The concept of preemptive analgesia was initially put forward by Crile (4) and then by Wall (3), who suggested that the administration of opioids or local anesthetics before surgery might reduce the C-fiber-induced injury barrage associated with incision and, thereby, the intensity of postoperative pain. This first definition of preemptive analgesia did not include the imperative to compare a preoperative intervention with a postoperative intervention. This requirement, adopted shortly thereafter (5), imposed a constraint that limited the demonstration of preemptive analgesia to experimental designs with less potential for clinically significant effects. The evidence in support of preemptive analgesia by this strictest of definitions has been equivocal, and a recent systematic review of the literature examining the role of preemptive analgesia and the role of timing of analgesia demonstrated no overall benefit of this concept (6).

However, since the introduction of the term preemptive analgesia into the pain and anesthesia literature, the concept has evolved. The previously held belief that it was the surgical incision that triggered central sensitization has been expanded to include the sensitizing effects of preoperative noxious inputs and pain, as well as other noxious intraoperative and postoperative stimuli. This would suggest that the previous definition of preemptive analgesia is too restrictive (7), because an analgesic intervention given after surgical incision (e.g., during or after surgery) may also reduce central sensitization and thus decrease postoperative pain intensity. We can evaluate this possibility only by adding a control group that does not receive the analgesic intervention, a group that receives the intervention before and after surgery, or both groups. Unfortunately, many negative studies examining for a preemptive analgesic effect do not include appropriate control groups and hence may be missing an important effect.

The term preventive analgesia (8) was introduced to emphasize the fact that central sensitization is induced by noxious preoperative and postoperative inputs and has been used to describe a reduction in postoperative pain intensity, analgesic use, or both beyond the clinical duration of action of the target preventive drug (9,10). Thus, in the absence of a postincisional intervention, the finding that pain or analgesic consumption is reduced beyond the pharmacological duration of action relative to an untreated or placebo control condition is evidence of a preventive analgesic effect. Thus, the aim of preventive analgesia is to reduce central sensitization that arises from noxious inputs across the entire perioperative period and not just from those brought about by incision. The concept of preventive analgesia, therefore, has greater clinical relevance than does preemptive analgesia (8,10).

Although many drugs have demonstrated evidence of preventive analgesic benefit (9), treatments that are likely to prevent the development of central excitability may have the greatest benefit. Because antagonists at the NMDA receptor have potential for attenuating central sensitization, we conducted a systematic review of the literature to determine the extent to which NMDA antagonists have yielded preventive analgesic effects when given during the perioperative period.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
We systematically conducted a search of the MEDLINE and EMBASE databases from 1966 to April 2003 (MEDLINE) and from 1985 to April 2003 (EMBASE) by using the following key words and limiting the search strategy to English language reports in humans: "pre-emptive analgesia" or "preemptive analgesia," "pre-operative," "preoperative," "post-operative," "postoperative," "pre-incision," "preincision," "post-incision," "postincision," and "timing." These key words were then cross-referenced with the following: NMDA, ketamine, memantine, amantadine, dextromethorphan, magnesium, and methadone. Reference sections of relevant articles were reviewed, and additional articles were obtained if they evaluated postoperative analgesia after the administration of NMDA antagonists. Authors were not contacted for original data.

The criteria for assessing the quality of reports as described by Jadad et al. (11) were used, and the quality score was recorded. Studies without randomization and blinding were excluded. Therefore, the minimum score of an included study was 2, and the maximum score was 5. In addition to a randomized protocol and double-blinded assessment of pain and analgesic use, studies also had to include a report of pain or hyperalgesia by using a reliable and valid measure (e.g., visual analog scale, numeric rating scale, verbal descriptor scale, quantitative sensory testing, or pressure algometry), a report of analgesic consumption, and, for studies that assessed the effect of timing according to the definition of preventive analgesia, consumption of analgesics reported at a point in time that exceeded the duration of action of the target drug whose effect on postoperative pain was being examined. For the purposes of this review, a point in time equivalent to five half-lives of the drug under examination was taken as exceeding the clinical duration of action of the drug. This criterion, although stringent, was chosen to ensure that observed effects were not simply direct analgesic effects of residual drug. The stated half-life of each drug was determined and found to be 3 h for ketamine (12), 2–4 h for dextromethorphan (13), 20 h for methadone (14), and 5 h for ionized magnesium (15). The final criterion was the absence of methodological problems that render results ambiguous and make interpretation difficult.

A preventive analgesic effect was confirmed if pain, analgesic consumption, or both were significantly reduced (P < 0.05) five half-lives beyond the administration of the NMDA antagonist under examination or if the first analgesic request occurred beyond five half-lives of the drug concerned, and if it was significantly longer than that in the control group (P < 0.05). Positive preemptive analgesic studies in which pain, analgesic consumption, or both were reduced in a preincisional group in relation to a postincisional group and placebo control were also included. However, negative preemptive studies that did not include a placebo control group were excluded, because it could not be determined whether a preventive analgesic effect had occurred (both preincisional and postincisional groups may have received analgesic benefit, and these groups could not be contrasted with a placebo control group).

Differences in study quality (11) were analyzed with the Mann-Whitney U-test by using SPSS for Windows Version 9.0 (SPSS Inc., Chicago, IL). P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The MEDLINE and EMBASE searches identified 136 articles that examined the use of an NMDA antagonist for perioperative pain management. Forty studies fulfilled the inclusion criteria outlined previously. Ninety-six studies were excluded. The most frequent reason for exclusion (n = 53 studies) was the failure to design the study to test for a preventive analgesic effect (i.e., absence of pain and/or analgesic data beyond five half-lives of the drug). Two studies were excluded because they were negative preemptive studies with no placebo control group. Two were case reports, 4 did not examine a surgical population, and 35 were excluded because of methodological flaws. Table 1 [[16–20,21–25,26–36,37–50,51–61,62–75,76–86,87–100,101–111]]lists the studies that were excluded from the review and shows which of the inclusion criteria were not met.


View this table:
[in this window]
[in a new window]
  		Table 1. Excluded Studies by Criteria
 
Of the included studies, 24 examined the use of ketamine (112–135), 12 examined dextromethorphan (136–147), and 4 examined magnesium (148–151). A total of 2034 patients were studied, and the number of patients in the studies ranged from a minimum of 18 in a study using a crossover design (133) to a maximum of 121 patients in the largest randomized controlled trial (112). Study quality across the positive and negative studies for each drug is presented in Table 2. There were no significant differences in study quality between studies that found positive or negative outcomes for each drug.


View this table:
[in this window]
[in a new window]
  		Table 2. Study Quality Score by Drug and Positive or Negative Outcome
 
Quantitative analysis of the degree of analgesic benefit was not performed because of the variability of consistency of reporting of numerical pain and analgesic consumption data. Thirty-six (90%) of 40 studies presented data in tables together with significance levels (P values) or in other formats that allowed for assessment of the degree of benefit but did not allow for quantitative analysis. Instead, data have been presented in table format for each drug, as performed for other recent qualitative systematic reviews (152).

Twenty-four studies examined ketamine (Table 3), and 14 (58%) demonstrated a positive preemptive or preventive analgesic effect. Three studies used a preemptive design (113,115,134), and 21 studies used a preventive design. Of the 10 negative studies, 6 did not demonstrate any direct analgesic effect of the intervention. Patients enrolled in these studies underwent a variety of surgical procedures, including ambulatory and major inpatient surgery, and doses ranged from 0.15 to 1 mg/kg. There was no obvious effect of surgical type on the success of the preventive intervention, and success did not depend on the dose administered.


View this table:
[in this window]
[in a new window]
  		Table 3. Studies Examining Ketamine That Met Inclusion Criteria
 

View this table:
[in this window]
[in a new window]
  		Table 3. (Continued)
 

View this table:
[in this window]
[in a new window]
  		Table 3. (Continued)
 

View this table:
[in this window]
[in a new window]
  		Table 3. (Continued)
 

View this table:
[in this window]
[in a new window]
  		Table 3. (Continued)
 

View this table:
[in this window]
[in a new window]
  		Table 3. (Continued)
 
Ketamine was administered IV in nine positive studies and seven negative studies, epidurally or intrathecally in four positive and three negative studies, and subcutaneously in one positive study. Most studies (both positive and negative) coadministered opioids with ketamine. However, in two positive studies, an analgesic benefit was demonstrated with the NMDA antagonist alone (without coadministered opioid) (116,121).

Twenty of 24 studies documented evaluation of adverse effects, including psychomimetic effects. Twelve studies documented no adverse effects. Seven studies documented adverse effects but found no difference between treatment and control groups. One study documented psychomimetic effects related to epidural ketamine 20 mg (120).

Twelve studies examined the use of dextromethorphan (Table 4), and eight (67%) demonstrated evidence of a preemptive or preventive analgesic effect. Three studies used a preemptive (136,138,145) and nine studies used a preventive design. Of the four negative studies, two (141,142) did not demonstrate any direct effect of the analgesic intervention.


View this table:
[in this window]
[in a new window]
  		Table 4. Studies Examining Dextromethorphan That Met Inclusion Criteria
 

View this table:
[in this window]
[in a new window]
  		Table 4. (Continued)
 
Both positive and negative studies used a variety of major and minor surgical procedures, and the success of the preventive intervention did not appear to be associated with the type of surgery. Dosages varied from 0.5 mg/kg to 150 mg and did not appear to be associated with the success of the intervention. Two of the studies in the negative group (141,142) used a smaller dose by the oral route that was not associated with a direct analgesic effect. Positive studies used both oral (four studies) and IV or IM routes, whereas all four negative studies used the oral route.

All but one study coadministered an opioid for analgesia, and therefore preventive analgesia may have been related to a reduction in opioid tolerance in many studies. One study (147) that did not use a coadministered opioid demonstrated a direct analgesic effect of the dextromethorphan itself.

Adverse effects related to opioids were described in 11 of 12 studies, but no statistical difference was determined between groups. One study did not document adverse effects (147).

Four studies examined magnesium, and none demonstrated a preventive analgesic benefit (Table 5). Two of the four studies did not demonstrate a direct analgesic effect. Surgical type was limited to major abdominal or pelvic surgery, and all studies coadministered an opioid. Magnesium was administered by the IV route in all four studies. All studies documented opioid-related adverse effects but no statistical difference was found between groups.


View this table:
[in this window]
[in a new window]
  		Table 5. Studies That Examined Magnesium and Met Inclusion Criteria
 

View this table:
[in this window]
[in a new window]
  		Table 5. (Continued)
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Adherence to the narrow definition of preemptive analgesia that currently dominates the literature may have led to a large proportion of negative results. This is especially true for studies that did not include a placebo control group to control for the possibility that the presurgical and postsurgical interventions provided an equal overall benefit in reducing central sensitization (7,154). This methodological shortcoming has limited the potential clinical utility of the narrow definition because central sensitization may be induced by noxious stimuli throughout the perioperative period and not only by skin incision (7,154). The limited clinical utility of the narrow definition of preemptive analgesia was demonstrated by a recent systematic review (6).

Preventive analgesia provides a broader, more clinically relevant concept in which the administration of a drug at any point in the perioperative period and the presumed associated reduction in central sensitization may reduce pain, analgesic consumption, or both beyond the clinical activity of the target drug. The NMDA antagonists would appear to be potentially useful drugs in this regard because of their effect in reducing central hypersensitivity and wind-up-like states in humans.

The results of this systematic review showed that ketamine and dextromethorphan produced a significant preventive analgesic benefit in 58% and 67% of studies, respectively. This is in addition to the benefit that in all positive preventive studies, a direct analgesic benefit of the drug occurred in the early postoperative period. It is interesting that in a large proportion (56%) of the studies that did not find a preventive analgesic effect, a direct effect of the target drug also was absent. This strongly suggests that central sensitization was unaffected by these interventions, both immediately and in the longer term.

NMDA antagonists may reduce pain, opioid consumption, or both by two non-mutually exclusive mechanisms. The first is the more widely recognized reduction in central hypersensitivity, but NMDA antagonists have also been seen to reduce opioid tolerance in many animal and human studies. In this review, 22 ketamine and 11 dextromethorphan studies coadministered opioid analgesics with the NMDA antagonists. The analgesic benefit or reduction in opioid consumption in these studies therefore may have been due, at least in part, to a reduction of acute opioid tolerance. The other three positive studies (two ketamine and one dextromethorphan) did not coadminister opioid with the NMDA antagonist, suggesting that the reduction in pain intensity or analgesic use was due to an NMDA-mediated reduction in central sensitization brought about by the preventive analgesic intervention (although other possibilities include effects due to drug action at other receptor sites).

Many surgical procedures were included in both positive and negative studies, and there did not appear to be one specific procedure that yielded more benefit than any other. In the dextromethorphan studies, all four negative studies used the oral route, and in two of these trials at smaller doses of drug, there was no direct analgesic effect of the intervention.

It may be that dextromethorphan should be administered parenterally in a dose of at least 1 mg/kg for maximal preventive effect. A variety of doses of ketamine, from 0.15 to 1 mg/kg, were used, although the spread of doses was similar in both positive and negative studies.

Magnesium demonstrated no preventive analgesic effect in the four studies examined. It is difficult to understand why magnesium should have less effect than other drugs. It is possible either that the magnesium is removed from extracellular fluid rapidly or that the ion is specific to the NMDA receptor channel and does not influence the receptor sites to which other NMDA antagonists bind and thus reduce pain, analgesic consumption, or both. It is important to note that in two of four studies, the administration of magnesium did not demonstrate any direct benefit (pain or analgesic reduction) and that, therefore, it is unlikely to have shown effects later in time.

This is the first systematic review to attempt to evaluate the efficacy of preventive analgesia by examining the analgesic benefit five half-lives beyond analgesic administration. It was critical to select this time point because unlike with most studies of preemptive analgesia, preventive analgesia does not involve a postincisional analgesic intervention. We chose five half-lives to exclude as much as possible any direct effect of the NMDA antagonist. However, to avoid excluding most studies, we chose a point at which <5% of the plasma drug concentration would remain. We could be criticized for being overly stringent and might have chosen, for example, three half-lives. In fact, changing the criterion to three half-lives would lead to inclusion of an additional six studies: two of these were negative (one dextromethorphan and one magnesium), and four, all using ketamine, were positive. Therefore, changing the cutoff to three half-lives would actually strengthen our review for the ketamine result, slightly weaken the dextromethorphan result, and leave the magnesium result unchanged.

This systematic review was limited to English-language reports and therefore may be missing data from important studies published in other languages. However, it has been reported that language-limited reports do not lead to biased estimates of intervention effectiveness (155). If the same holds true for the field of preventive analgesia, then our exclusion of the non-English literature would be not be expected to alter our findings and conclusions.

A number of areas remain for future investigation with the NMDA antagonists. NMDA receptors have been isolated in the peripheral nervous system, and NMDA antagonists have been demonstrated to produce analgesic benefit in animals and volunteers (156–158). Further research is required to determine benefit in the clinical setting.

Many studies coadminister NMDA antagonists with opioid analgesics and may produce benefits through a reduction in opioid tolerance (159). Further research is required to determine whether NMDA antagonist-mediated analgesia is effected through reduction in opioid tolerance or whether these drugs have analgesic benefit in isolation. Future studies should also focus on design issues, such as appropriate control groups, standardization of pain assessment, and analgesic consumption data collection (10), to allow for quantitative systematic review and meta-analysis.

In most studies included in this systematic review, the perioperative administration of ketamine and dextromethorphan reduced pain, analgesic consumption, or both immediately and beyond the clinical duration of action of the drugs used preventively. The most likely mechanism is a reduction in NMDA receptor-mediated central sensitization.


   Acknowledgments
 
Joel Katz is supported by a Canada Research Chair in Health Psychology at York University, Toronto, ON, Canada.


   Footnotes
 
Presented at the Annual Meeting of the American Society of Regional Anesthesia and Pain Medicine, San Diego, CA, April, 2003.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Fisher K, Coderre TJ, Hagen NA. Targeting the N-methyl-D-aspartate receptor for chronic pain management: preclinical animal studies, recent clinical experience and future research directions. J Pain Symptom Manage 2000; 20: 358–73.[ISI][Medline]
  2. Schmid RL, Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain 1999; 82: 111–25.[ISI][Medline]
  3. Wall PD. The prevention of postoperative pain. Pain 1988; 33: 289–90.[ISI][Medline]
  4. Katz J. George Washington Crile, anoci-association, and pre-emptive analgesia. Pain 1993; 53: 243–5.[ISI][Medline]
  5. McQuay HJ. Pre-emptive analgesia. Br J Anaesth 1992; 69: 1–3.[Free Full Text]
  6. Moiniche S, Kehlet H, Dahl JB. A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief: the role of timing of analgesia. Anesthesiology 2002; 96: 725–41.[ISI][Medline]
  7. Katz J. Pre-emptive analgesia: evidence, current status and future directions. Eur J Anaesthesiol Suppl 1995; 10: 8–13.[Medline]
  8. Kissin I. Preemptive analgesia: terminology and clinical relevance. Anesth Analg 1994; 79: 809–10.[Free Full Text]
  9. Katz J, McCartney CJ. Update on pre-emptive analgesia. Curr Opin Anesthesiol 2002; 15: 435–41.
  10. Katz J. Timing of treatment and pre-emptive analgesia. In: Rice A, Warfield C, Justins D, Eccleston C, eds. Clinical pain management. Vol 1: Acute pain. London: Arnold, 2003: 113–63.
  11. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17: 1–12.[ISI][Medline]
  12. Clements JA, Nimmo WS, Grant IS. Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans. J Pharm Sci 1982; 71: 539–42.[ISI][Medline]
  13. Woodworth JR, Dennis SR, Moore L, Rotenberg KS. The polymorphic metabolism of dextromethorphan. J Clin Pharmacol 1987; 27: 139–43.[Abstract]
  14. Eap CB, Buclin T, Baumann P. Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet 2002; 41: 1153–93.[ISI][Medline]
  15. Taber EB, Tan L, Chao CR, et al. Pharmacokinetics of ionized versus total magnesium in subjects with preterm labor and preeclampsia. Am J Obstet Gynecol 2002; 186: 1017–21.[ISI][Medline]
  16. Kawana Y, Sato H, Shimada H, et al. Epidural ketamine for postoperative pain relief after gynecologic operations: a double-blind study and comparison with epidural morphine. Anesth Analg 1987; 66: 735–8.[Abstract/Free Full Text]
  17. Kucuk N, Kizilkaya M, Tokdemir M. Preoperative epidural ketamine does not have a postoperative opioid sparing effect. Anesth Analg 1998; 87: 103–6.[Abstract/Free Full Text]
  18. Ravat F, Dorne R, Baechle JP, et al. Epidural ketamine or morphine for postoperative analgesia. Anesthesiology 1987; 66: 819–22.[ISI][Medline]
  19. Vallejo MC, Romeo RC, Davis DJ, Ramanathan S. Propofol-ketamine versus propofol-fentanyl for outpatient laparoscopy: comparison of postoperative nausea, emesis, analgesia, and recovery. J Clin Anesth 2002; 14: 426–31.[ISI][Medline]
  20. Wu CT, Yeh CC, Yu JC, et al. Pre-incisional epidural ketamine, morphine and bupivacaine combined with epidural and general anaesthesia provides pre-emptive analgesia for upper abdominal surgery. Acta Anaesthesiol Scand 2000; 44: 63–8.[ISI][Medline]
  21. Yeh CC, Ho ST, Kong SS, et al. Absence of the preemptive analgesic effect of dextromethorphan in total knee replacement under epidural anesthesia. Acta Anaesthesiol Sin 2000; 38: 187–93.[Medline]
  22. Grace RF, Lesteour T, Sala T, Stewart J. A randomized comparison of low-dose ketamine and lignocaine infiltration with ketamine-diazepam anaesthesia for post partum tubal ligation in Vanuatu. Anaesth Intensive Care 2001; 29: 30–3.[ISI][Medline]
  23. Callesen T, Bech K, Andersen J, et al. Pain after primary inguinal herniorrhaphy: influence of surgical technique. J Am Coll Surg 1999; 188: 355–9.[ISI][Medline]
  24. Findlow D, Aldridge LM, Doyle E. Comparison of caudal block using bupivacaine and ketamine with ilioinguinal nerve block for orchidopexy in children. Anaesthesia 1997; 52: 1110–3.[ISI][Medline]
  25. Gourlay GK, Willis RJ, Wilson PR. Postoperative pain control with methadone: influence of supplementary methadone doses and blood concentration–response relationships. Anesthesiology 1984; 61: 19–26.[ISI][Medline]
  26. Hager H, Marhofer P, Sitzwohl C, et al. Caudal clonidine prolongs analgesia from caudal S(+)-ketamine in children. Anesth Analg 2002; 94: 1169–72.[Abstract/Free Full Text]
  27. Johnston P, Findlow D, Aldridge LM, Doyle E. The effect of ketamine on 0.25% and 0.125% bupivacaine for caudal epidural blockade in children. Paediatr Anaesth 1999; 9: 31–4.[ISI][Medline]
  28. Koinig H, Marhofer P, Krenn CG, et al. Analgesic effects of caudal and intramuscular S(+)-ketamine in children. Anesthesiology 2000; 93: 976–80.[ISI][Medline]
  29. Naguib M, Adu-Gyamfi Y, Absood GH, et al. Epidural ketamine for postoperative analgesia. Can Anaesth Soc J 1986; 33: 16–21.[ISI][Medline]
  30. Parbrook GD. Post-operative pain relief: comparison of methadone and morphine when used concurrently with nitrous-oxide analgesia. BMJ 1966; 2: 616–8.[Medline]
  31. Prieto-Alvarez P, Tello-Galindo I, Cuenca-Pena J, et al. Continuous epidural infusion of racemic methadone results in effective postoperative analgesia and low plasma concentrations. Can J Anaesth 2002; 49: 25–31.[Abstract/Free Full Text]
  32. Taura P, Fuster J, Blasi A, et al. Postoperative pain relief after hepatic resection in cirrhotic patients: the efficacy of a single small dose of ketamine plus morphine epidurally. Anesth Analg 2003; 96: 475–80.[Abstract/Free Full Text]
  33. Aggarwal A, Ganguly S, Anand VK, Patwari AK. Efficacy and safety of intravenous ketamine for sedation and analgesia during pediatric endoscopic procedures. Indian Pediatr 1998; 35: 1211–4.[Medline]
  34. Grabinski PY, Kaiko RF, Rogers AG, Houde RW. Plasma levels and analgesia following deltoid and gluteal injections of methadone and morphine. J Clin Pharmacol 1983; 23: 48–55.[Abstract]
  35. Hartvig P, Larsson E, Joachimsson PO. Postoperative analgesia and sedation following pediatric cardiac surgery using a constant infusion of ketamine. J Cardiothorac Vasc Anesth 1993; 7: 148–53.[Medline]
  36. Islas JA, Astorga J, Laredo M. Epidural ketamine for control of postoperative pain. Anesth Analg 1985; 64: 1161–2.[Abstract/Free Full Text]
  37. Ito Y, Ichiyanagi K. Post-operative pain relief with ketamine infusion. Anaesthesia 1974; 29: 222–6.[ISI][Medline]
  38. Mathisen LC, Skjelbred P, Skoglund LA, Oye I. Effect of ketamine, an NMDA receptor inhibitor, in acute and chronic orofacial pain. Pain 1995; 61: 215–20.[ISI][Medline]
  39. Nyska M, Klin B, Shapira Y, et al. Epidural methadone for preoperative analgesia in patients with proximal femoral fractures. Br Med J (Clin Res Ed) 1986; 293: 1347–8.
  40. Shir Y, Eimerl D, Magora F, et al. Plasma concentrations of methadone during postoperative patient-controlled extradural analgesia. Br J Anaesth 1990; 65: 204–9.[Abstract/Free Full Text]
  41. Welch DB, Hrynaszkiewicz A. Postoperative analgesia using epidural methadone: administration by the lumbar route for thoracic pain relief. Anaesthesia 1981; 36: 1051–4.[ISI][Medline]
  42. Cook B, Grubb DJ, Aldridge LA, Doyle E. Comparison of the effects of adrenaline, clonidine and ketamine on the duration of caudal analgesia produced by bupivacaine in children. Br J Anaesth 1995; 75: 698–701.[Abstract/Free Full Text]
  43. Schulz-Stubner S, Wettmann G, Reyle-Hahn SM, Rossaint R. Magnesium as part of balanced general anaesthesia with propofol, remifentanil and mivacurium: a double-blind, randomized prospective study in 50 patients. Eur J Anaesthesiol 2001; 18: 723–9.[ISI][Medline]
  44. Wadhwa A, Clarke D, Goodchild CS, Young D. Large-dose oral dextromethorphan as an adjunct to patient-controlled analgesia with morphine after knee surgery. Anesth Analg 2001; 92: 448–54.[Abstract/Free Full Text]
  45. Wong CS, Liaw WJ, Tung CS, et al. Ketamine potentiates analgesic effect of morphine in postoperative epidural pain control. Reg Anesth 1996; 21: 534–41.[ISI][Medline]
  46. Abdel-Ghaffar ME, Abdulatif MA, al Ghamdi A, et al. Epidural ketamine reduces post-operative epidural PCA consumption of fentanyl/bupivacaine. Can J Anaesth 1998; 45: 103–9.[Abstract/Free Full Text]
  47. 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]
  48. Javery KB, Ussery TW, Steger HG, Colclough GW. Comparison of morphine and morphine with ketamine for postoperative analgesia. Can J Anaesth 1996; 43: 212–5.[Abstract/Free Full Text]
  49. Lauretti GR, Oliveira AP, Rodrigues AM, Paccola CA. The effect of transdermal nitroglycerin on spinal S(+)-ketamine antinociception following orthopedic surgery. J Clin Anesth 2001; 13: 576–81.[ISI][Medline]
  50. Ozbek H, Bilen A, Ozcengiz D, et al. The comparison of caudal ketamine, alfentanil and ketamine plus alfentanil administration for postoperative analgesia in children. Paediatr Anaesth 2002; 12: 610–6.[ISI][Medline]
  51. Subramaniam B, Subramaniam K, Pawar DK, Sennaraj B. Preoperative epidural ketamine in combination with morphine does not have a clinically relevant intra- and postoperative opioid-sparing effect. Anesth Analg 2001; 93: 1321–6.[Abstract/Free Full Text]
  52. Tan PH, Kuo MC, Kao PF, et al. Patient-controlled epidural analgesia with morphine or morphine plus ketamine for post-operative pain relief. Eur J Anaesthesiol 1999; 16: 820–5.[ISI][Medline]
  53. 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.[Abstract/Free Full Text]
  54. Zacharias M, Hunter KM, Baker AB. Effectiveness of preoperative analgesics on postoperative dental pain: a study. Anesth Prog 1996; 43: 92–6.[Medline]
  55. Chia YY, Liu K, Liu YC, et al. Adding ketamine in a multimodal patient-controlled epidural regimen reduces postoperative pain and analgesic consumption. Anesth Analg 1998; 86: 1245–9.[Abstract]
  56. Dawson GS, Seidman P, Ramadan HH. Improved postoperative pain control in pediatric adenotonsillectomy with dextromethorphan. Laryngoscope 2001; 111: 1223–6.[ISI][Medline]
  57. Dich-Nielsen JO, Svendsen LB, Berthelsen P. Intramuscular low-dose ketamine versus pethidine for postoperative pain treatment after thoracic surgery. Acta Anaesthesiol Scand 1992; 36: 583–7.[ISI][Medline]
  58. Joachimsson PO, Hedstrand U, Eklund A. Low-dose ketamine infusion for analgesia during postoperative ventilator treatment. Acta Anaesthesiol Scand 1986; 30: 697–702.[ISI][Medline]
  59. Levanen J. Ketamine and oxycodone in the management of postoperative pain. Mil Med 2000; 165: 450–5.[ISI][Medline]
  60. Liu ST, Wu CT, Yeh CC, et al. Premedication with dextromethorphan provides posthemorrhoidectomy pain relief. Dis Colon Rectum 2000; 43: 507–10.[ISI][Medline]
  61. Marcus RJ, Victoria BA, Rushman SC, Thompson JP. Comparison of ketamine and morphine for analgesia after tonsillectomy in children. Br J Anaesth 2000; 84: 739–42.[Abstract/Free Full Text]
  62. Marhofer P, Krenn CG, Plochl W, et al. S(+)-ketamine for caudal block in paediatric anaesthesia. Br J Anaesth 2000; 84: 341–5.[Abstract/Free Full Text]
  63. Maurset A, Skoglund LA, Hustveit O, Oye I. Comparison of ketamine and pethidine in experimental and postoperative pain. Pain 1989; 36: 37–41.[ISI][Medline]
  64. Murray WB, Yankelowitz SM, le Roux M, Bester HF. Prevention of post-tonsillectomy pain with analgesic doses of ketamine. S Afr Med J 1987; 72: 839–42.[ISI][Medline]
  65. Owen H, Reekie RM, Clements JA, et al. Analgesia from morphine and ketamine: a comparison of infusions of morphine and ketamine for postoperative analgesia. Anaesthesia 1987; 42: 1051–6.[ISI][Medline]
  66. Parkhouse J, Marriott G. Postoperative analgesia with ketamine and pethidine. Anaesthesia 1977; 32: 285–9.[ISI][Medline]
  67. Reeves M, Lindholm DE, Myles PS, et al. Adding ketamine to morphine for patient-controlled analgesia after major abdominal surgery: a double-blinded, randomized controlled trial. Anesth Analg 2001; 93: 116–20.[Abstract/Free Full Text]
  68. Suzuki M, Tsueda K, Lansing PS, et al. Small-dose ketamine enhances morphine-induced analgesia after outpatient surgery. Anesth Analg 1999; 89: 98–103.[Abstract/Free Full Text]
  69. Weinbroum AA, Gorodetzky A, Nirkin A, et al. Dextromethorphan for the reduction of immediate and late postoperative pain and morphine consumption in orthopedic oncology patients: a randomized, placebo-controlled, double-blind study. Cancer 2002; 95: 1164–70.[ISI][Medline]
  70. Wong CS, Wu CT, Yu JC, et al. Preincisional dextromethorphan decreases postoperative pain and opioid requirement after modified radical mastectomy. Can J Anaesth 1999; 46: 1122–6.[Abstract/Free Full Text]
  71. Liu ST, Wu CT, Yeh CC, et al. Premedication with dextromethorphan provides posthemorrhoidectomy pain relief. Dis Colon Rectum 2000; 43: 507–10.[ISI][Medline]
  72. Berde CB, Beyer JE, Bournaki MC, et al. Comparison of morphine and methadone for prevention of postoperative pain in 3- to 7-year-old children. J Pediatr 1991; 119: 136–41.[ISI][Medline]
  73. Ilkjaer S, Nielsen PA, Bach LF, et al. The effect of dextromethorphan, alone or in combination with ibuprofen, on postoperative pain after minor gynaecological surgery. Acta Anaesthesiol Scand 2000; 44: 873–7.[ISI][Medline]
  74. Richlin DM, Reuben SS. Postoperative pain control with methadone following lower abdominal surgery. J Clin Anesth 1991; 3: 112–6.[Medline]
  75. Haynes SR, Davidson I, Allsop JR, Dutton DA. Comparison of epidural methadone with epidural diamorphine for analgesia following caesarean section. Acta Anaesthesiol Scand 1993; 37: 375–80.[ISI][Medline]
  76. Beeby D, MacIntosh KC, Bailey M, Welch DB. Postoperative analgesia for Caesarean section using epidural methadone. Anaesthesia 1984; 39: 61–3.[ISI][Medline]
  77. Chui PT, Gin T. A double-blind randomised trial comparing postoperative analgesia after perioperative loading doses of methadone or morphine. Anaesth Intensive Care 1992; 20: 46–51.[ISI][Medline]
  78. Gedney JA, Liu EH. Side-effects of epidural infusions of opioid bupivacaine mixtures. Anaesthesia 1998; 53: 1148–55.[ISI][Medline]
  79. Gourlay GK, Willis RJ, Lamberty J. A double-blind comparison of the efficacy of methadone and morphine in postoperative pain control. Anesthesiology 1986; 64: 322–7.[ISI][Medline]
  80. Jacobson L, Chabal C, Brody MC, et al. Intrathecal methadone and morphine for postoperative analgesia: a comparison of the efficacy, duration, and side effects. Anesthesiology 1989; 70: 742–6.[ISI][Medline]
  81. Wang JM, Knarr DC, Raj PP, Denson D. Continuous epidural methadone for the management of postoperative pain after lower abdominal surgery. Reg Anesth 1992; 17: 26–8.[ISI][Medline]
  82. Adriaenssens G, Vermeyen KM, Hoffmann VL, 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]
  83. 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]
  84. Jahangir SM, Islam F, Aziz L. Ketamine infusion for postoperative analgesia in asthmatics: a comparison with intermittent meperidine. Anesth Analg 1993; 76: 45–9.[Abstract/Free Full Text]
  85. Koinig H, Wallner T, Marhofer P, et al. Magnesium sulfate reduces intra- and postoperative analgesic requirements. Anesth Analg 1998; 87: 206–10.[Abstract/Free Full Text]
  86. Memis D, Turan A, Karamanlioglu B, et al. The use of magnesium sulfate to prevent pain on injection of propofol. Anesth Analg 2002; 95: 606–8.[Abstract/Free Full Text]
  87. Aspinall RL, Mayor A. A prospective randomized controlled study of the efficacy of ketamine for postoperative pain relief in children after adenotonsillectomy. Paediatr Anaesth 2001; 11: 333–6.[ISI][Medline]
  88. Buvanendran A, McCarthy RJ, Kroin JS, et al. Intrathecal magnesium prolongs fentanyl analgesia: a prospective, randomized, controlled trial. Anesth Analg 2002; 95: 661–6.[Abstract/Free Full Text]
  89. 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]
  90. Naguib M, Sharif AM, Seraj M, et al. Ketamine for caudal analgesia in children: comparison with caudal bupivacaine. Br J Anaesth 1991; 67: 559–64.[Abstract/Free Full Text]
  91. Unlugenc H, Gunduz M, Ozalevli M, Akman H. A comparative study on the analgesic effect of tramadol, tramadol plus magnesium, and tramadol plus ketamine for postoperative pain management after major abdominal surgery. Acta Anaesthesiol Scand 2002; 46: 1025–30.[ISI][Medline]
  92. 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.[ISI][Medline]
  93. Levaux C, Bonhomme V, Dewandre PY, et al. Effect of intra-operative magnesium sulphate on pain relief and patient comfort after major lumbar orthopaedic surgery. Anaesthesia 2003; 58: 131–5.[ISI][Medline]
  94. Weinbroum AA. A single small dose of postoperative ketamine provides rapid and sustained improvement in morphine analgesia in the presence of morphine-resistant pain. Anesth Analg 2003; 96: 789–95.[Abstract/Free Full Text]
  95. Lee HM, Sanders GM. Caudal ropivacaine and ketamine for postoperative analgesia in children. Anaesthesia 2000; 55: 806–10.[ISI][Medline]
  96. Cheng KI, Chu KS, Fang YR, et al. Total intravenous anesthesia using propofol and ketamine for ambulatory gynecologic laparoscopy. Kaohsiung J Med Sci 1999; 15: 536–41.[Medline]
  97. Funk W, Jakob W, Riedl T, Taeger K. Oral preanaesthetic medication for children: double-blind randomized study of a combination of midazolam and ketamine vs midazolam or ketamine alone. Br J Anaesth 2000; 84: 335–40.[Abstract/Free Full Text]
  98. Guit JB, Koning HM, Coster ML, et al. Ketamine as analgesic for total intravenous anaesthesia with propofol. Anaesthesia 1991; 46: 24–7.[ISI][Medline]
  99. Porter EJ, McQuay HJ, Bullingham RE, et al. Comparison of effects of intraoperative and postoperative methadone: acute tolerance to the postoperative dose? Br J Anaesth 1983; 55: 325–32.[Abstract/Free Full Text]
  100. Satsumae T, Yamaguchi H, Sakaguchi M, et al. Preoperative small-dose ketamine prevented tourniquet-induced arterial pressure increase in orthopedic patients under general anesthesia. Anesth Analg 2001; 92: 1286–9.[Abstract/Free Full Text]
  101. Telci L, Esen F, Akcora D, et al. Evaluation of effects of magnesium sulphate in reducing intraoperative anaesthetic requirements. Br J Anaesth 2002; 89: 594–8.[Abstract/Free Full Text]
  102. Lee IO, Kim WK, Kong MH, et al. No enhancement of sensory and motor blockade by ketamine added to ropivacaine interscalene brachial plexus blockade. Acta Anaesthesiol Scand 2002; 46: 821–6.[ISI][Medline]
  103. Matot I, Oppenheim-Eden A, Ratrot R, et al. Preoperative cardiac events in elderly patients with hip fracture randomized to epidural or conventional analgesia. Anesthesiology 2003; 98: 156–63.[ISI][Medline]
  104. Fernandez-Liesa JI, Panadero A. Use of intrathecal hyperbaric methadone in postoperative analgesia of thoracic surgery. Reg Anesth 2000; 25: 325.
  105. Persson J, Axelsson G, Hallin RG, Gustafsson L. Beneficial effects of ketamine in a chronic pain state with allodynia possibly due to central sensitization. Pain 1995; 60: 217–22.[ISI][Medline]
  106. Guirimand F, Dupont X, Brasseur L, et al. The effects of ketamine on the temporal summation (wind-up) of the R(III) nociceptive flexion reflex and pain in humans. Anesth Analg 2000; 90: 408–14.[Abstract/Free Full Text]
  107. 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.[ISI][Medline]
  108. Nikolajsen L, Gottrup H, Kristensen AG, Jensen TS. Memantine (a N-methyl-D-aspartate receptor antagonist) in the treatment of neuropathic pain after amputation or surgery: a randomized, double-blinded, cross-over study. Anesth Analg 2000; 91: 960–6.[Abstract/Free Full Text]
  109. Yang CY, Wong CS, Chang JY, Ho ST. Intrathecal ketamine reduces morphine requirements in patients with terminal cancer pain. Can J Anaesth 1996; 43: 379–83.[Abstract/Free Full Text]
  110. 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]
  111. Holthusen H, Backhaus P, Boeminghaus F, et al. Preemptive analgesia: no relevant advantage of preoperative compared with postoperative intravenous administration of morphine, ketamine, and clonidine in patients undergoing transperitoneal tumor nephrectomy. Reg Anesth Pain Med 2002; 27: 249–53.[ISI][Medline]
  112. Aida S, Yamakura T, Baba H, et al. Preemptive analgesia by intravenous low-dose ketamine and epidural morphine in gastrectomy: a randomized double-blind study. Anesthesiology 2000; 92: 1624–30.[ISI][Medline]
  113. 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.[Abstract]
  114. Dahl V, Ernoe PE, 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]
  115. Fu ES, Miguel R, Scharf JE. Preemptive ketamine decreases postoperative narcotic requirements in patients undergoing abdominal surgery. Anesth Analg 1997; 84: 1086–90.[Abstract]
  116. Himmelseher S, Ziegler-Pithamitsis D, Argiriadou H, et al. Small-dose S(+)-ketamine reduces postoperative pain when applied with ropivacaine in epidural anesthesia for total knee arthroplasty. Anesth Analg 2001; 92: 1290–5.[Abstract/Free Full Text]
  117. Huang GS, Yeh CC, Kong SS, et al. Intra-articular ketamine for pain control following arthroscopic knee surgery. Acta Anaesthesiol Sin 2000; 38: 131–6.[Medline]
  118. Jaksch W, Lang S, Reichhalter R, et al. Perioperative small-dose S(+)-ketamine has no incremental beneficial effects on postoperative pain when standard-practice opioid infusions are used. Anesth Analg 2002; 94: 981–6.[Abstract/Free Full Text]
  119. Kathirvel S, Sadhasivam S, Saxena A, et al. Effects of intrathecal ketamine added to bupivacaine for spinal anaesthesia. Anaesthesia 2000; 55: 899–904.[ISI][Medline]
  120. Kirdemir P, Ozkocak I, Demir T, Gogus N. Comparison of postoperative analgesic effects of preemptively used epidural ketamine and neostigmine. J Clin Anesth 2000; 12: 543–8.[ISI][Medline]
  121. Lauretti GR, Azevedo VM. Intravenous ketamine or fentanyl prolongs postoperative analgesia after intrathecal neostigmine. Anesth Analg 1996; 83: 766–70.[Abstract]
  122. Mathisen LC, Aasbo V, Raeder J. Lack of pre-emptive analgesic effect of (R)-ketamine in laparoscopic cholecystectomy. Acta Anaesthesiol Scand 1999; 43: 220–4.[ISI][Medline]
  123. 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]
  124. Menigaux C, Guignard B, Fletcher D, et al. Intraoperative small-dose ketamine enhances analgesia after outpatient knee arthroscopy. Anesth Analg 2001; 93: 606–12.[Abstract/Free Full Text]
  125. Mortero RF, Clark LD, Tolan MM, et al. The effects of small-dose ketamine on propofol sedation: respiration, postoperative mood, perception, cognition, and pain. Anesth Analg 2001; 92: 1465–9.[Abstract/Free Full Text]
  126. Papaziogas B, Argiriadou H, Papagiannopoulou P, et al. Preincisional intravenous low-dose ketamine and local infiltration with ropivacaine reduces postoperative pain after laparoscopic cholecystectomy. Surg Endosc 2001; 15: 1030–3.[ISI][Medline]
  127. Peat SJ, Bras P, Hanna MH. A double-blind comparison of epidural ketamine and diamorphine for postoperative analgesia. Anaesthesia 1989; 44: 555–8.[ISI]