In the title of their review, Katz et al.1 used the expression “Quo Vadimus?” (where are we going?) instead of Peter's familiar question to Jesus, “Quo Vadis?” (where are you going?). The change in wording probably symbolizes another transformation in the authors' review topic: “preventive analgesia” instead of more common “preemptive analgesia.” This change is well justified2–4 and excellently described in the review.
The narrow view on preemptive analgesia is so entrenched that the only way to widen its restrictive limits is to use another term, preventive analgesia. Dahl and Kehlet4 also suggested that “the term preemptive analgesia should be abandoned and replaced by the term preventive analgesia.” The alternative approach is to regard preemptive analgesia as a component of preventive analgesia related specifically to the sensitization induced only during surgical intervention. However, the danger of such an approach is that if clinical value of preemptive analgesia (with its narrow time limits) is not obvious in each specific situation, the benefits of prevention (preemption) of sensitization caused by surgery (but not limited to the time of operation) will be rejected without adequate assessment.
There are 2 major problems in the blueprint shared by many studies on preventive analgesia. One of them is related to experimental study design. The authors of the review deal effectively with this problem by describing appropriate designs of study groups with various treatment combinations based on 3 perioperative periods. In situations in which the clinical value of preventive analgesia is under question (for a specific treatment and a specific surgery), the design should maximize possible clinical benefit and therefore embrace all components of preventive analgesia (treatment combinations 1 vs 8 in Fig. 1 of Katz et al.'s review1). For analysis of the contributions of different components of preventive analgesia, other designs presented in the review can be used. For example, the treatment combinations 1 vs 4 can reveal the preventive effect of a target analgesic agent when administered only postoperatively. This is illustrated by the study5 in which a bolus of ropivacaine versus saline was followed by a 48-hour infusion of ropivacaine (also versus saline) administered into the iliac crest bone graft harvest site (after incision and graft harvest); the treatment reduced pain on movement 3 months after surgery.
The second major problem in studies assessing clinical value of preventive analgesia is the absence of appropriate balance between control of bias, on one hand, and treatment integrity, on the other (Table 1). Bias control is a very important element in the assessment of clinical studies. In the past, it was regarded as the primary indicator of study quality.6 With the proliferation of correctly performed randomized controlled trials, the role of bias control in rating clinical studies should be balanced by other considerations, especially when quality threshold is used as a criterion for inclusion of a study in a meta-analysis. In studies of preventive (preemptive) analgesia, this is very important. In these studies, another factor is of primary importance, treatment integrity, because the adequacy of treatment is often not controlled for (for example, completeness of neural blockade, degree, and duration). As a result, on the basis of perfect control of bias, a study without adequate treatment (and therefore, with negative outcome) can be included in the meta-analysis and thus provides the wrong influence on the final outcome. Both factors (Table 1) should be balanced in the assessment of clinical studies on preventive analgesia. As an example of appropriate treatment integrity in a study on preemptive analgesia, I cite the paper by Gottschalk et al.7 In patients scheduled for radical prostatectomy, they administered epidural bupivacaine or epidural fentanyl before induction of general anesthesia and throughout the surgery, and compared the pain outcomes with those of patients receiving similar treatment initiated at the fascial closure. Sufficiency of epidural blockade was verified by measurement of the sensory level (at least the 4th thoracic dermatome) before induction of general anesthesia and also in the postanesthesia care unit. Patients who did not have a T4 sensory level were excluded from the study; in addition, the patient's response to injury was assessed by measuring plasma cortisol levels. The authors reported that the patients who received epidural bupivacaine or epidural fentanyl before surgical incision (preemptive analgesia group) experienced less pain while they were hospitalized (visual analog scale was one-third lower; P = 0.007). At 9.5 weeks, 86% of the patients who received preemptive analgesia were pain free in comparison with only 47% of the control patients; P = 0.004). The authors concluded that even in the presence of aggressive postoperative pain management, preemptive epidural analgesia decreases postoperative pain during hospitalization and long after discharge.
One of the authors of this review demonstrated previously8 that preventive analgesia can be revealed when postoperative pain or analgesic use are reduced beyond the duration of action of the studied agent, which he has defined as 5.5 half-lives of the agent. This is an appropriate time interval; it constitutes half of what is recommended for a time interval between the 2 treatment periods in the crossover study design.
In conclusion, there should be a reassessment of the clinical value of preemptive analgesia based on the more inclusive term preventive analgesia. Such a reassessment should rest on the adequate control of treatment integrity, including treatment during all phases of perioperative period (not just the period of surgical intervention).
1. Katz J, Clarke H, Seltzer Z. Preventive analgesia: Quo vadimus?Anesth Analg 2011;113:1242–53
2. Kissin I. Preemptive analgesia: terminology and clinical relevance. Anesth Analg 1994;79:809–10
3. Katz J, McCartney CJL. Current status of preemptive analgesia. Curr Opin Anaesthesiol 2002;15:435–41
4. Dahl JB, Kehlet H. Preventive analgesia. Curr Opin Anesthesiol 2011;24:331–8
5. Blumenthal S, Dullenkopf A, Rentsch K, Borgeat A. Continuous infusion of ropivacaine for pain relief after iliac crest bone grafting for shoulder surgery. Anesthesiology 2005;102:392–7
6. McQuay HJ, Moore RA. An Evidence-Based Resource for Pain Relief. Oxford: Oxford University Press, 1998:10
7. Gottschalk A, Smith DS, Jobes DR, Kennedy SK, Lally SE, Noble VE, Grugan KF, Selfert HA, Cheung A. Preemptive epidural analgesia and recovery from radical prostatectomy: a randomized controlled trial. JAMA 1998;279:1076–82
8. Katz J, Clarke H. Preventive analgesia and beyond. Current status, evidence, and future directions. In: Macintyre PE, Rowbotham DJ, Howard R eds. Clinical Pain Management: Acute Pain. 2nd ed. London: Hodder Arnold Ltd., 2008:154–98