McCartney, Colin J. L. FRCA*; Sinha, Avinash FRCA*; Katz, Joel PhD†‡§
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.
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.
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.
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.
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.
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.
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.
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 coad-minister 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.
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