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Anesthesiology:
Clinical Concepts and Commentary

Preemptive Analgesia

Kissin, Igor M.D., Ph.D.*
Section Editor(s): Weiskopf, Richard B. Editor

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Kissin, Igor M.D., Ph.D.*
Section Editor(s): Weiskopf, Richard B. Editor

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PREEMPTIVE analgesia is an antinociceptive treatment that prevents establishment of altered processing of afferent input, which amplifies postoperative pain. The concept of preemptive analgesia was formulated by Crile 1 at the beginning of the previous century on the basis of clinical observations. Crile advocated the use of regional blocks in addition to general anesthesia to prevent intraoperative nociception and the formation of painful scars caused by changes in the central nervous system during surgery. The revival of this idea was associated with a series of animal studies started by Woolf. 2
Several years ago, views on the concept of preemptive analgesia were summarized by a statement that evidence for the concept derived from experimental studies is overwhelmingly convincing; however, results of clinical studies regarding the value of preemptive analgesia are controversial. 3 For the past several years, many new studies on preemptive analgesia were published and summarized in several reviews. 4–8 Although these clinical studies did not significantly change the ratio of negative versus positive outcomes of preemptive treatments, there was a clear change in opinion: that it was essential to consider the inflammatory injury.
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Terms and Definitions

Terms Commonly Used in Studies on Preemptive Analgesia
Central sensitization—persistent postinjury changes in the central nervous system that result in pain hypersensitivity
Central hyperexcitability—exaggerated and prolonged responsiveness of neurons to normal afferent input after tissue damage
Preincisional treatment—treatment that starts before an initial surgical incision
Postincisional treatment—treatment that starts immediately after the end of operation
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Adequacy of Preemptive Treatment Has Two Basic Requirements
The two basic requirements for adequacy of preemptive treatment are as follows:
verification of the effectiveness of the direct pharmacologic effect of a treatment, for example, by measuring the degree of a difference between control and treatment groups in the initial nociceptive response (plasma β-endorphin or cortisol level), by verification of the sufficiency of a neural blockade, etc.
extension of an antinociceptive treatment into the initial postoperative period, when generation of nociceptive stimuli by the inflammatory process may be very intensive for 12 to 48 h, depending on the type of surgery.
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Definitions of Preemptive Analgesia
Three different definitions have been used as the basis for the recent clinical trials. Preemptive analgesia has been defined as treatment that: (1) starts before surgery; (2) prevents the establishment of central sensitization caused by incisional injury (covers only the period of surgery); and (3) prevents the establishment of central sensitization caused by incisional and inflammatory injuries (covers the period of surgery and the initial postoperative period).
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Definition of Preemptive Anesthesia Is the Major Source of Controversy Regarding Its Clinical Relevance

Definitions of preemptive analgesia are far from being uniform. The first definition (1) presented above is an erroneous definition that can lead to a false conclusion in a clinical trial. It does not reflect both basic requirements for the adequacy of preemptive analgesia. “Preemptive” means “preventive,” not simply “before” incision. There should be proof that an intervention provides at least its direct effect. An insufficient afferent block cannot be preemptive, even if it is administered before the incision. The second definition (2) represents preemptive analgesia only in a narrow sense because it excludes central sensitization caused by inflammatory injury that occurs in the initial postoperative period. Those authors who believe that preemptive analgesia is not clinically relevant usually base their studies on this definition. With the narrow definition of preemptive analgesia, the difference in the outcome measure of an antinociceptive intervention made before and at the end of surgery is evidence of a preemptive effect.
Those who think preemptive analgesia has promise for the effective treatment of postoperative pain (including myself) support the broad definition (3). They define it as treatment that prevents establishment of central sensitization caused by incisional and inflammatory injuries; it starts before incision and covers both the period of surgery and the initial postoperative period. The balance between incisional injury and inflammatory injury depends on the nature of surgery; with certain conditions, inflammatory injury can be a very dominant factor. 9,10
Preemptive analgesia prevents (or reduces) pathologic pain that is different from physiologic pain in several aspects: It is excessive (in intensity and spread) and can be activated by low-intensity stimuli (allodynia, hyperalgesia) and hyperpathia.
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Animal Studies

The first study on preemptive analgesia was published by Woolf and Wall 11 in 1986. In a model of central hyperexcitability produced by electrical stimulation of C-fibers and recorded in rat dorsal horn neurons, they showed that the amount of systemically administered morphine needed to prevent the development of hyperexcitability was much less than the amount needed to reverse it after the establishment of hyperexcitability. Animal studies on preemptive analgesia have been extensively reviewed elsewhere. 9 It is interesting that the most impressive evidence of the preemptive effect was obtained with inflammatory models of central sensitization. In a rat model involving a brief surgical incision at the plantar hind paw, there was no difference between preincisional and postincisional treatment with intrathecal bupivacaine or intrathecal morphine. 12 Surgery-induced central sensitization has two phases: incisional and inflammatory (reaction to the damaged tissue). It is possible to suggest that with inflammatory injury playing the dominant role, antinociceptive protection provided by preemptive treatment should extend well into the postoperative period to cover the inflammatory phase. Otherwise it is ineffective, as in the rat paw incisional model.
New experimental evidence indicates that, even for short periods of time, both central mechanisms and afferent input are needed to maintain pain hypersensitivity. 13 Contrary to previous studies with various formalin models of pain hypersensitivity in rats, Taylor et al.14 found that if the paw is anesthetized with a local anesthetic 15 minutes after formalin injection, the signs ofhypersensitivity disappear relatively rapidly. If the peripheral afferent input is responsible for maintenance of central sensitization, the established postoperative pain hypersensitivity can be reversed by the blockade of afferent input if it is sufficiently prolonged. This response was demonstrated in a study with carrageenan-induced inflammation in rats: Hyperalgesia (usually lasting >5 d) was permanently reversed by a prolonged (10–12 h) nerve block but not with a block lasting less than 1 h. 15
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Human Studies: Preincisional versus Postincisional Treatment

Table 1
Table 1
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Studies comparing preincisional with postincisional treatment failed to provide convincing evidence for the value of preemptive analgesia. The conclusions of recent reviews of the studies using such an approach are presented in table 1. Many studies could not find differences between treatments. If statistically significant positive effects were reported, they were of relatively small magnitude. Most significant advantages were reported with ketamine. One of the most important factors in the failure to demonstrate clinical significance of preemptive analgesia with preincisional versus postincisional treatment trials is the exclusion from such comparison of the results of central sensitization caused by inflammatory injury that occurs after surgery.
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Human Studies with Neural Blockade

Fig. 1
Fig. 1
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Figure 1 represents studies with peripheral nerve block. All of the studies with randomization and double-blinding that were criteria specific for preemptive analgesia (verification of block sufficiency and degree of initial difference in nociceptive response between control and preemptive groups) are presented in this figure. Clinical significance of the effect was defined as statistically significant difference between control and treatment groups in postoperative pain intensity and/or analgesic consumption that persisted for 24 h or more (see legend to fig. 1). Of six studies, a clinically significant outcome was observed in five. The three studies with a higher specific quality score than the others (see legend to fig. 1) all had a very good outcome. The figure demonstrates that clinically meaningful effects can be observed when the degree of nociceptive blockade is confirmed and the block is extended into the initial postoperative period.
The important role of sufficiency in the degree of afferent blockade was evident in the studies on preemptive analgesia with epidural anesthesia. Shir et al.16 compared three groups of patients undergoing radical prostatectomy with general, epidural, or combined epidural and general anesthesia. The authors concluded that complete intraoperative blockade is fundamental for observing a preemptive effect. 16
Another study with well-controlled sufficiency of epidural anesthesia in patients undergoing radical prostatectomy also reported positive results. Gottschalk et al.17 administered epidural bupivacaine or epidural fentanyl before induction of general anesthesia and throughout the surgery, and compared the pain outcomes with those of similar treatment initiated at the fascial closure. Sufficiency of epidural blockade was verified by measurement of the sensory level (at least the fourth 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 [VAS] was one-third less;P = 0.007). At 9.5 weeks, 86% of the patients who received preemptive analgesia were pain-free compared 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. 17
As indicated above, block of sufficient duration is another requirement for positive clinical outcome of preemptive treatment. Kehlet stated that a key question in this respect is whether the term preemptive analgesia has been used correctly, since it ideally implies prevention of the development of central hyperexcitability, even if it occurs after surgery; a local anesthetic should be applied preoperatively and as a continuous postoperative administration. 7 In patients undergoing total knee arthroplasty, Mφiniche et al.18 compared the effect of epidural bupivacaine–morphine anesthesia followed by continuous epidural analgesia postoperatively with that of general anesthesia followed by a conventional intramuscular opioid and acetaminophen regimen (control group) in patients undergoing knee or hip arthroplasty. After the cessation of the epidural regimen, the preemptive group received less morphine than did the control group for another 4 days. However, the authors did not observe any important improvements in convalescence and hospital stay. Findings regarding the reduction of convalescence time with prolonged epidural bupivacaine have been reported in other studies. 19,20
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Preemptive Effect versus Combined Effect on Central Sensitization

Fig. 2
Fig. 2
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Fig. 3
Fig. 3
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The prevention of postoperative pain hypersensitivity should not be narrowed by exclusively focusing on the preemptive effect. The approach should be wider and centered on central sensitization in general (fig. 2). Incontrast to conventional perioperative analgesia, this approach is centered only on “pathological,” not “physiological,” pain. Some pharmacologic agents that do not have any effect on acute “physiological” pain, however, can change the course of central sensitization and thus influence “pathological” pain. N-methyl-d-aspartate (NMDA) receptor antagonists seem to have such properties. The reversal of the established hyperalgesia with the use of glutamate receptor antagonists has been reported in several animal studies. However, clinical studies have not been performed. Reversal of pain hypersensitivity can be accelerated with neural blockade if it is complete and of sufficient duration (fig. 3). Thus, two ways for reversal of central sensitization can be used: direct effect (potentially with glutamate receptor antagonists) or indirect acceleration of the reversal process by blockade of afferent input that maintains sensitization. I suggest that when various approaches attenuating central sensitization are used in combination, the probability of meaningful clinical benefits is increased.
How long could the preemptive effect last (after the block resolution)? For example, Gottschalk et al.17 observed the results of preemptive analgesia 9 weeks after its administration. If the pain hypersensitivity does not last well beyond block resolution, the treatment would not be different from simple perioperative analgesia directed at physiologic pain. Figure 3 helps to assess conditions necessary for prolonged prevention of pathologic pain after neural blockade that preempts or reverses hypersensitivity.
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Conclusion

When preemptive analgesia was studied by comparing preincisional versus postincisional treatment groups, many authors found no difference in the pain outcome, while some reported statistically significant but clinically modest benefits with preincisional analgesia. It is clear that the above approach is too simple to overcome multiple problems posed by the complexities of central sensitization and the technical difficulties of clinical studies. However, some of the previous positive clinical studies in combination with basic science results are probably sufficient to indicate that preemptive analgesia is a valid phenomenon. The question is how to demonstrate the maximal clinical benefits that can be obtained with the use of preemptive treatment. It is clear that this cannot be done simply by comparing preincisional versus postincisional treatment groups. Two conditions for clinical study are especially important: (1) providing effective suppression of the afferent input with sufficient duration of such treatment (that covers the initial postoperative period), and (2) combined treatment approaches aimed at: preemptive treatment, maintenance of the obtained effect, and reversal of central sensitization (in the case of an incomplete preemptive effect). A narrow definition of preemptive analgesia leads to a belief that this concept is clinically meaningless. Preemptive analgesia continues to have promise for the effective treatment of postoperative pain. Evaluation of the true importance of preemptive analgesia will have to await further research with new, more comprehensive approaches.
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References

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Lingual nerve damage after mandibular third molar surgery: A randomized clinical trial
Amorim, AC; Vasconcelos, BCD; Silva, EDO; da Silva, LCF
Journal of Oral and Maxillofacial Surgery, 63(): 1443-1446.
10.1016/j.joms.2005.06.012
CrossRef
Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontics
The effects on postoperative oral surgery pain by varying NSAID administration times: Comparison on effect of preemptive analgesia
Jung, YS; Kim, MK; Um, YJ; Park, HS; Lee, EW; Kang, JW
Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontics, 100(5): 559-563.
10.1016/j.tripleo.2005.02.065
CrossRef
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
Lack of a pre-emptive effect of low-dose ketamine on postoperative pain following oral surgery
Lebrun, T; Van Elstraete, AC; Sandefo, I; Polin, B; Pierre-Louis, L
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 53(2): 146-152.

Canadian Veterinary Journal-Revue Veterinaire Canadienne
Perioperative use of analgesics in dogs and cats by Canadian veterinarians in 2001
Hewson, CJ; Dohoo, IR; Lemke, KA
Canadian Veterinary Journal-Revue Veterinaire Canadienne, 47(4): 352-359.

Clinical Orthopaedics and Related Research
Multimodal analgesia without routine parenteral narcotics for total hip arthroplasty
Maheshwari, AV; Boutary, M; Yun, AG; Sirianni, LE; Dorr, LD
Clinical Orthopaedics and Related Research, (): 231-238.
10.1097/01.blo.0000246545.72445.c4
CrossRef
Journal of Clinical Nursing
Using a patient-controlled analgesia multimedia intervention for improving analgesia quality
Yeh, ML; Yang, HJ; Chen, HH; Tsou, MY
Journal of Clinical Nursing, 16(): 2039-2046.
10.1111/j.1365-2702.2006.01770.x
CrossRef
Journal of Endodontics
Evaluation of pretreatment analgesia and endodontic treatment for postoperative endodontic pain
Attar, S; Bowles, WR; Baisden, MK; Hodges, JS; McClanahan, SB
Journal of Endodontics, 34(6): 652-655.
10.1016/j.joen.2008.02.017
CrossRef
Veterinary Medicine
Preemptive analgesia: Managing pain before it begins
Shafford, HL; Lascelles, BDX; Hellyer, PW
Veterinary Medicine, 96(6): 478-+.

Drugs
What is the role of NSAIDs in pre-emptive analgesia?
Ochroch, EA; Mardini, IA; Gottschalk, A
Drugs, 63(): 2709-2723.

British Journal of Oral & Maxillofacial Surgery
A double-blind randomised controlled clinical trial of the effect of preoperative ibuprofen, diclofenac, paracetamol with codeine and placebo tablets for relief of postoperative pain after removal of impacted third molars
Joshi, A; Parara, E; Macfarlane, TV
British Journal of Oral & Maxillofacial Surgery, 42(4): 299-306.
10.1016/j.bioms.2004.02.004
CrossRef
Polish Journal of Pharmacology
Influence of pre-operative ketoprofen administration (preemptive analgesia) on analgesic requirement and the level of prostaglandins in the early postoperative period
Wnek, W; Zajaczkowska, R; Wordliczek, J; Dobrogowski, J; Korbut, R
Polish Journal of Pharmacology, 56(5): 547-552.

Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
Preemptive gabapentin decreases postoperative pain after lumbar discoidectomy
Pandey, CK; Sahay, S; Gupta, D; Ambesh, SP; Singh, RB; Raza, M; Singh, U; Singh, PK
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 51(): 986-989.

Anesthesia and Analgesia
The efficacy of preemptive analgesia for acute postoperative pain management: A meta-analysis
Ong, CKS; Lirk, P; Seymour, RA; Jenkins, BJ
Anesthesia and Analgesia, 100(3): 757-773.
10.1213/01.ANE.0000144428.98767.0E
CrossRef
New Zealand Veterinary Journal
Current attitudes to, and use of, peri-operative analgesia in dogs and cats by veterinarians in New Zealand
Williams, VM; Lascelles, BDX; Robson, MC
New Zealand Veterinary Journal, 53(3): 193-202.

Anesthesia and Analgesia
The short-lasting analgesia and long-term antihyperalgesic effect of intrathecal clonidine in patients undergoing colonic surgery
De Kock, M; Lavand'homme, P; Waterloos, H
Anesthesia and Analgesia, 101(2): 566-572.
10.1213/01.ANE.0000157121.71808.04
CrossRef
Auris Nasus Larynx
Pre-emptive analgesia for removal of nasal packing: A double-blind placebo controlled study
Yilmazer, C; Sener, M; Yilmaz, I; Erkan, AN; Cagici, CA; Donmez, A; Arslan, G; Ozluoglu, LN
Auris Nasus Larynx, 34(4): 471-475.
10.1016/j.anl.2006.11.013
CrossRef
Annales Francaises D Anesthesie Et De Reanimation
Administration of ketamine during induction and maintenance of anaesthesia in postoperative pain prevention Clinical trial in oncology
Colombani, S; Kabbani, Y; Mathoulin-Pelissier, S; Gekiere, JP; Dixmerias, F; Monnin, D; Lakdja, F
Annales Francaises D Anesthesie Et De Reanimation, 27(3): 202-207.
10.1016/j.annfar.2007.11.025
CrossRef
Pain
Effect of plantar local anesthetic injection on dorsal horn neuron activity and pain behaviors caused by incision
Pogatzki, EM; Vandermeulen, EP; Brennan, TJ
Pain, 97(): 151-161.
PII S0304-3959(02)00014-3
CrossRef
Anesthesia and Analgesia
Cyclooxygenase inhibition for postoperative analgesia
McCrory, CR; Lindahl, SGE
Anesthesia and Analgesia, 95(1): 169-176.
10.1213/01.ANE.0000018525.78635.8C
CrossRef
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
Prophylactic ip injection of bupivacaine and/or morphine does not improve postoperative analgesia after laparoscopic gynecologic surgery
Keita, H; Benifla, JL; Le Bouar, V; Porcher, R; Wachowska, B; Bedairia, K; Mantz, J; Desmonts, JM
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 50(4): 362-367.

Jama-Journal of the American Medical Association
Effects of perioperative administration of a selective cyclooxygenase 2 inhibitor on pain management and recovery of function after knee replacement - A randomized controlled trial
Buvanendran, A; Kroin, JS; Tuman, KJ; Lubenow, TR; Elmofty, D; Moric, M; Rosenberg, AG
Jama-Journal of the American Medical Association, 290(): 2411-2418.

Pain
Pre-emptive analgesia using intravenous fentanyl plus low-dose ketamine for radical prostatectomy under general anesthesia does not produce short-term or long-term reductions in pain or analgesic use
Katz, J; Schmid, R; Snijdelaar, DG; Coderre, TJ; McCartney, CJL; Wowk, A
Pain, 110(3): 707-718.
10.1016/j.pain.2004.05.011
CrossRef
Veterinary Anaesthesia and Analgesia
Systemic lidocaine infusion as an analgesic for intraocular surgery in dogs: a pilot study
Smith, LJ; Bentley, E; Shih, A; Miller, PE
Veterinary Anaesthesia and Analgesia, 31(1): 53-63.

Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontics
A prospective randomized crossover study of the preemptive analgesic effect of nitrous oxide in oral surgery
Ong, KS; Seymour, RA; Tan, JML
Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontics, 98(6): 637-642.
10.1016/j.tripleo.2004.02.078
CrossRef
Anesthesia and Analgesia
Development of acute opioid tolerance during infusion of remifentanil for pediatric scoliosis surgery
Crawford, MW; Hickey, C; Zaarour, C; Howard, A; Naser, B
Anesthesia and Analgesia, 102(6): 1662-1667.
10.1213/01.ane.0000216036.95705.c2
CrossRef
Journal of Clinical Anesthesia
Multimodal analgesia for radical prostatectomy provides better analgesia and shortens hospital stay
Ben-David, B; Swanson, J; Nelson, JB; Chelly, JE
Journal of Clinical Anesthesia, 19(4): 264-268.
10.1016/j.jclinane.2006.12.003
CrossRef
Clinical Orthopaedics and Related Research
The emotional state of the patient after total hip and knee arthroplasty
Dorr, LD; Chao, L
Clinical Orthopaedics and Related Research, (): 7-12.
10.1097/BLO.0b013e318149296c
CrossRef
West Indian Medical Journal
Effect of meloxicam on postoperative pain relief after inguinal hernia repair with local anaesthesia
Kurukahvecioglu, O; Karamercan, A; Ege, B; Koksal, H; Anadol, Z; Tezel, E; Ersoy, E
West Indian Medical Journal, 56(6): 530-533.

Anesthesia and Analgesia
Attenuation of pain in a randomized trial by suppression of peripheral nociceptive activity in the immediate postoperative period
Gordon, SM; Brahim, JS; Dubner, R; McCullagh, LM; Sang, C; Dionne, RA
Anesthesia and Analgesia, 95(5): 1351-1357.
10.1213/01.ANE.0000033210.87385.AD
CrossRef
Polish Journal of Pharmacology
Influence of pre- or intraoperational use of tramadol (preemptive or preventive analgesia) on tramadol requirement in the early postoperative period
Wordliczek, J; Banach, M; Garlicki, J; Wordliczek, JJ; Dobrogowski, J
Polish Journal of Pharmacology, 54(6): 693-697.

Anesthesia and Analgesia
Acute pain management revisited
Rowlingson, JC
Anesthesia and Analgesia, 96(3): 87-95.

Anesthesia and Analgesia
The effect of epidural clonidine on perioperative cytokine response, postoperative pain, and bowel function in patients undergoing colorectal surgery
Wu, CT; Jao, SW; Borel, CO; Yeh, CC; Li, CY; Lu, CH; Wong, CS
Anesthesia and Analgesia, 99(2): 502-509.
10.1213/01.ANE.0000117146.46373.51
CrossRef
Current Medicinal Chemistry
Novel insights and therapeutical applications in the field of inhibitors of COX-2
Kiefer, W; Dannhardt, G
Current Medicinal Chemistry, 11(): 3147-3161.

Tijdschrift Voor Diergeneeskunde
Recent developments in pet anaesthesia
Akkerdaas, LC
Tijdschrift Voor Diergeneeskunde, 133(): 1048-1054.

Anasthesiologie & Intensivmedizin
Spinal mechanisms of postoperative pain
Zahn, PK
Anasthesiologie & Intensivmedizin, 47(): 517-527.

Regional Anesthesia and Pain Medicine
Long-Lasting Analgesic Effects of Intraoperative Thoracic Epidural With Bupivacaine for Liver Resection
Mondor, ME; Massicotte, L; Beaulieu, D; Roy, JD; Lapointe, R; Dagenais, M; Roy, A
Regional Anesthesia and Pain Medicine, 35(1): 51-56.
10.1097/AAP.0b013e3181c6f8f2
CrossRef
Drug Development Research
Therapeutic Na+ channel blockers beneficial for pain syndromes
Wang, GK; Strichartz, GR
Drug Development Research, 54(3): 154-158.

Brazilian Journal of Medical and Biological Research
Presurgical ketoprofen, but not morphine, dipyrone, diclofenac or tenoxicam, preempts post-incisional mechanical allodynia in rats
Prado, WA; Pontes, RMC
Brazilian Journal of Medical and Biological Research, 35(1): 111-119.

Anesthesia and Analgesia
The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance
Laulin, JP; Maurette, P; Corcuff, JB; Rivat, C; Chauvin, M; Simonnet, G
Anesthesia and Analgesia, 94(5): 1263-1269.

International Journal of Oral and Maxillofacial Surgery
A comparison of pre-emptive analgesic efficacy of diflunisal and lornoxicam for postoperative pain management: a prospective, randomized, single-blind, crossover study
Pektas, ZO; Sener, M; Bayram, B; Eroglu, T; Bozdogan, N; Donmez, A; Arslan, G; Uckan, S
International Journal of Oral and Maxillofacial Surgery, 36(2): 123-127.
10.1016/j.ijom.2006.10.005
CrossRef
Pharmacological Reports
Comparison of the analgesic efficacy of preemptive and preventive tramadol after lumpectomy
Shen, XF; Wang, FZ; Xu, SQ; Ma, L; Liu, YS; Feng, SW; Wang, WG; Zhao, QS; Li, XH; Zhao, LP; Yao, XQ; Qu, J; Xie, B; Wang, HP; Yuan, HM; Cao, Y; Sun, YY; Wang, W; Guo, LM; Song, ZS; Wang, Z; Guan, XN
Pharmacological Reports, 60(3): 415-421.

Anesthesia and Analgesia
Prolonged differential wound hyperalgesia after an interval of unilateral epidural blockade during lower abdominal surgery
Gottschalk, A; Frank, SM
Anesthesia and Analgesia, 100(5): 1411-1413.
10.1213/01.ANE.0000150608.78242.1A
CrossRef
Pain
Heat hyperalgesia after incision requires TRPV1 and is distinct from pure inflammatory pain
Pogatzki-Zahn, EM; Shimizu, I; Caterina, M; Raja, SN
Pain, 115(3): 296-307.
10.1016/j.pain.2005.03.010
CrossRef
Brain Research
Effects of surgical stress on brain prostaglandin E-2 production and on the pituitary-adrenal axis: Attenuation by preemptive analgesia and by central amygdala lesion
Shavit, Y; Weidenfeld, J; DeKeyser, FG; Fish, G; Wolf, G; Mayburd, E; Meerson, Y; Beilin, B
Brain Research, 1047(1): 10-17.
10.1016/j.brainres.2005.04.003
CrossRef
Journal of Clinical Anesthesia
Improved postoperative analgesia with coadministration of preoperative epidural ketamine and midazolam
Wang, X; Xie, H; Wang, GL
Journal of Clinical Anesthesia, 18(8): 563-569.
10.1016/j.clinane.2006.03.023
CrossRef
Brazilian Journal of Medical and Biological Research
Comparison of pre- versus post-incision administration of intraplantar indomethacin and MK886 in a rat model of postoperative pain
Gaspar, AF; Prado, WA
Brazilian Journal of Medical and Biological Research, 40(8): 1141-1147.

West Indian Medical Journal
Paediatric day surgery: Revisiting the University Hospital of the West Indies experience
Scarlett, M; Crawford-Sykes, A; Thomas, M; Duncan, ND
West Indian Medical Journal, 56(4): 320-325.

Orthodontics & Craniofacial Research
Tenoxicam controls pain without altering orthodontic movement of maxillary canines
Arantes, GM; Arantes, VMN; Ashmawi, HA; Posso, IP
Orthodontics & Craniofacial Research, 12(1): 14-19.
10.1111/j.1601-6343.2008.01432.x
CrossRef
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
Adenylate cyclase inhibition attenuates neuropathic pain but lacks pre-emptive effects in rats
Liou, JT; Liu, FC; Mao, CC; Hsin, ST; Lui, PW
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 56(): 763-769.
10.1007/s12630-009-9149-z
CrossRef
Annales Francaises D Anesthesie Et De Reanimation
Pupillary dilatation monitoring to evaluate acute remifentanil tolerance in cardiac surgery
Coquin, J; Tafer, N; Mazerolles, M; Pouquet, O; Pfeiff, R; Richebe, P; Janvier, G
Annales Francaises D Anesthesie Et De Reanimation, 28(): 930-935.
10.1016/j.annfar.2009.07.073
CrossRef
Regional Anesthesia and Pain Medicine
Study design to demonstrate clinical value of preemptive analgesia: Is the commonly used approach valid?
Kissin, I
Regional Anesthesia and Pain Medicine, 27(3): 242-244.
10.1053/rapm.2002.31936
CrossRef
Ophthalmic Surgery Lasers & Imaging
Preemptive sub-Tenon's anesthesia for Pars Plana Vitrectomy under general anesthesia: Is it effective?
Smiddy, WE; Gayer, S
Ophthalmic Surgery Lasers & Imaging, 39(5): 438.

British Journal of Anaesthesia
Pre-incisional epidural magnesium provides pre-emptive and preventive analgesia in patients undergoing abdominal hysterectomy
Farouk, S
British Journal of Anaesthesia, 101(5): 694-699.
10.1093/bja/aen274
CrossRef
Journal of Korean Academy of Nursing
The Effects of Preemptive Analgesia of Morphine and Ketorolac on Postoperative Pain, Cortisol, O-2 Saturation and Heart Rate
Seo, YJ; Yoon, H
Journal of Korean Academy of Nursing, 38(5): 720-729.
10.4040/jkan.2008.38.5.720
CrossRef
Journal of Neuroimmune Pharmacology
Postoperative Pain Management and Proinflammatory Cytokines: Animal and Human Studies
Shavit, Y; Fridel, K; Beilin, B
Journal of Neuroimmune Pharmacology, 1(4): 443-451.
10.1007/s11481-006-9043-1
CrossRef
British Journal of Anaesthesia
Low dose of S(+)-ketamine prevents long-term potentiation in pain pathways under strong opioid analgesia in the rat spinal cord in vivo
Benrath, J; Brechtel, C; Sandkuhler, J
British Journal of Anaesthesia, 95(4): 518-523.
10.1093/bja/aei215
CrossRef
Anesthesia and Analgesia
The efficacy of thoracic epidural neostigmine infusion after thoracotomy
Chia, YY; Chang, TH; Liu, K; Chang, HC; Ko, NH; Wang, YM
Anesthesia and Analgesia, 102(1): 201-208.
10.1213/01.ane.0000184812.94185.b3
CrossRef
American Journal of Health-System Pharmacy
Postoperative pain management: A practical review, part 1
Strassels, SA; McNicol, E; Suleman, R
American Journal of Health-System Pharmacy, 62(): 1904-1916.
10.2146/ajhp040490.p1
CrossRef
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
Pain relief and functional status after vaginal hysterectomy: intrathecal versus general anesthesia
Sprung, J; Sanders, MS; Warner, ME; Gebhart, JB; Stanhope, CR; Jankowski, CJ; Liedl, L; Schroeder, DR; Brown, DR; Warner, DO
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 53(7): 690-700.

Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
Intravenous flurbiprofen axetil accelerates restoration of bowel function after colorectal surgery
Xu, YJ; Tan, ZM; Chen, JW; Lou, FF; Chen, W
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 55(7): 414-422.

Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
Preemptive analgesia II: recent advances and current trends
Kelly, DJ; Ahmad, M; Brull, SJ
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 48(): 1091-1101.

Otolaryngology-Head and Neck Surgery
Preliminary findings for preemptive analgesia with inhaled morphine: Efficacy in septoplasty and septorhinoplasty cases
Onal, SA; Keles, E; Toprak, GC; Demirel, I; Alpay, HC; Avci, L
Otolaryngology-Head and Neck Surgery, 135(1): 85-89.
10.1016/j.otohns.2006.02.012
CrossRef
Ophthalmology
Preoperative sub-Tenon's capsule injection of ropivacaine in conjunction with general anesthesia in retinal detachment surgery
Bergman, L; Backmark, I; Ones, H; von Euler, C; Olivestedt, G; Kvanta, A; Steen, B; Seregard, S; Nilsson, B; Berglin, L
Ophthalmology, 114(): 2055-2060.
10.1016/j.ophtha.2006.12.031
CrossRef
Proceedings of the 7Th Biennial Congress Asian & Oceanic Society of Regional Anesthesia & Pain Medicine
Preemptive analgesia in children
Verghese, ST
Proceedings of the 7Th Biennial Congress Asian & Oceanic Society of Regional Anesthesia & Pain Medicine, (): 155-162.

Anesthesia and Analgesia
Scalp nerve blocks decrease the severity of pain after craniotomy
Nguyen, A; Girard, F; Boudreault, D; Fugere, F; Ruel, M; Moumdjian, R; Bouthilier, A; Caron, JL; Bojanowski, MW; Girard, DC
Anesthesia and Analgesia, 93(5): 1272-1276.

Journal of the American College of Surgeons
Pain control in outpatient surgery
Schecter, WP; Bongard, FS; Gainor, BJ; Weltz, DL; Horn, JK
Journal of the American College of Surgeons, 195(1): 95-104.
PII S1075-7515(02)01148-1
CrossRef
Molecular Pain
Pre-injury administration of morphine prevents development of neuropathic hyperalgesia through activation of descending monoaminergic mechanisms in the spinal cord in mice
Rashid, MH; Ueda, H
Molecular Pain, 1(): -.
ARTN 19
CrossRef
Anesthesia and Analgesia
Improvement of pain treatment after major abdominal surgery by intravenous S(+)-ketamine
Argiriadou, H; Himmelseher, S; Papagiannopoulou, P; Georgiou, M; Kanakoudis, F; Giala, M; Kochs, E
Anesthesia and Analgesia, 98(5): 1413-1418.
10.1213/01.ANE.0000111204.31815.2D
CrossRef
Anesthesia and Analgesia
Preincisional dextromethorphan combined with thoracic epidural anesthesia and analgesia improves postoperative pain and bowel function in patients undergoing colonic surgery
Yeh, CC; Jao, SW; Huh, BK; Wong, CS; Yang, CP; White, WD; Wu, CT
Anesthesia and Analgesia, 100(5): 1384-1389.
10.1213/01.ANE.0000148687.51613.B5
CrossRef
Singapore Medical Journal
Incidence of phantom limb phenomena after lower limb amputations in a Singapore tertiary hospital
Sin, EIL; Thong, SY; Poon, KH
Singapore Medical Journal, 54(2): 75-81.

Journal of Clinical Anesthesia
Effect of preemptive and preventive acetaminophen on postoperative pain score: a randomized, double-blind trial of patients undergoing lower extremity surgery
Khalili, G; Janghorbani, M; Saryazdi, H; Emaminejad, A
Journal of Clinical Anesthesia, 25(3): 188-192.
10.1016/j.jclinane.2012.09.004
CrossRef
European Review for Medical and Pharmacological Sciences
Comparison of the effects of preoperative and intraoperative intravenous application of dexketoprofen on postoperative analgesia in septorhinoplasty patients: randomised double blind clinical trial
Ozer, AB; Erhan, OL; Keles, E; Demirel, I; Bestas, A; Gunduz, G
European Review for Medical and Pharmacological Sciences, 16(): 1828-1833.

Pferdeheilkunde
Experiences with the local retrobulbar anesthesia in ophthalmologic surgery of the standing horse
Toth, J; Hollerrieder, J
Pferdeheilkunde, 29(1): 21-26.

Veterinary Clinics of North America-Food Animal Practice
A Review of Analgesic Compounds Used in Food Animals in the United States
Coetzee, JF
Veterinary Clinics of North America-Food Animal Practice, 29(1): 11-+.
10.1016/j.cvfa.2012.11.008
CrossRef
Anesthesiology
Effects of Preemptive Analgesia on Pain and Cytokine Production in the Postoperative Period
Beilin, B; Bessler, H; Mayburd, E; Smirnov, G; Dekel, A; Yardeni, I; Shavit, Y
Anesthesiology, 98(1): 151-155.

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Anesthesiology
Preemptive Analgesia: What Do We Do Now?
Gottschalk, A; Ochroch, E
Anesthesiology, 98(1): 280-281.

Anesthesiology
Fentanyl Enhancement of Carrageenan-induced Long-lasting Hyperalgesia in Rats: Prevention by the N-methyl-d-aspartate Receptor Antagonist Ketamine
Rivat, C; Laulin, J; Corcuff, J; Célèrier, E; Pain, L; Simonnet, G
Anesthesiology, 96(2): 381-391.

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Anesthesiology
A Qualitative and Quantitative Systematic Review of Preemptive Analgesia for Postoperative Pain Relief: The Role of Timing of Analgesia
Møiniche, S; Kehlet, H; Dahl, JB
Anesthesiology, 96(3): 725-741.

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Anesthesiology
Postoperative Morphine Use and Hyperalgesia Are Reduced by Preoperative but Not Intraoperative Epidural Analgesia: Implications for Preemptive Analgesia and the Prevention of Central Sensitization
Katz, J; Cohen, L; Schmid, R; Chan, VW; Wowk, A
Anesthesiology, 98(6): 1449-1460.

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Anesthesiology
Mechanical Pain Hypersensitivity after Incisional Surgery Is Enhanced in Rats Subjected to Neonatal Peripheral Inflammation: Effects of N-Methyl-d-aspartate Receptor Antagonists
Chu, Y; Chan, K; Tsou, M; Lin, S; Hsieh, Y; Tao, Y
Anesthesiology, 106(6): 1204-1212.
10.1097/01.anes.0000267604.40258.d1
PDF (944) | CrossRef
Anesthesiology
Reduction of Postincisional Allodynia by Subcutaneous Bupivacaine: Findings with a New Model in the Hairy Skin of the Rat
Duarte, AM; Pospisilova, E; Reilly, E; Mujenda, F; Hamaya, Y; Strichartz, GR
Anesthesiology, 103(1): 113-125.

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Anesthesiology
Intraoperative Epidural Analgesia Combined with Ketamine Provides Effective Preventive Analgesia in Patients Undergoing Major Digestive Surgery
Lavand’homme, P; De Kock, M; Waterloos, H
Anesthesiology, 103(4): 813-820.

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The Clinical Journal of Pain
Catastrophizing: A Risk Factor For Postsurgical Pain
Pavlin, DJ; Sullivan, MJ; Freund, PR; Roesen, K
The Clinical Journal of Pain, 21(1): 83-90.

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The Clinical Journal of Pain
An Overview of Neuropathic Pain: Syndromes, Symptoms, Signs, and Several Mechanisms
Dworkin, RH
The Clinical Journal of Pain, 18(6): 343-349.

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European Journal of Anaesthesiology (EJA)
Does perioperative administration of rofecoxib improve analgesia after spine, breast and orthopaedic surgery?
Riest, G; Peters, J; Weiss, M; Pospiech, J; Hoffmann, O; Neuhäuser, M; Beiderlinden, M; Eikermann, M
European Journal of Anaesthesiology (EJA), 23(3): 219-226.
10.1017/S026502150500222X
PDF (235) | CrossRef
European Journal of Anaesthesiology (EJA)
Efficacy of intrathecal adenosine for postoperative pain relief
Sharma, M; Mohta, M; Chawla, R
European Journal of Anaesthesiology (EJA), 23(6): 449-453.
10.1017/S0265021506000342
PDF (68) | CrossRef
European Journal of Anaesthesiology (EJA)
The persisting analgesic effect of low‐dose intravenous ketamine after spinal anaesthesia for Caesarean section
Sen, S; Ozmert, G; Aydin, ON; Baran, N; Calskan, E
European Journal of Anaesthesiology (EJA), 22(7): 518-523.
10.1017/S026502150500089X
PDF (217) | CrossRef
European Journal of Anaesthesiology (EJA)
Anaesthesia for the professional singer
Errando, CL
European Journal of Anaesthesiology (EJA), 19(9): 687.

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Journal of Neurosurgical Anesthesiology
Preincision 0.25% Bupivacaine Scalp Infiltration and Postcraniotomy Pain A Randomized Double‐Blind, Placebo‐Controlled Study
Biswas, BK; Bithal, PK
Journal of Neurosurgical Anesthesiology, 15(3): 234-239.

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Ophthalmic Plastic & Reconstructive Surgery
Effect of Preemptive Retrobulbar Analgesia on Perioperative Hemodynamics and Postoperative Pain After Enucleation
Yeatts, RP; Doneyhue, W; Scuderi, PE; Brasington, CR; James, R
Ophthalmic Plastic & Reconstructive Surgery, 20(3): 226-231.

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Plastic and Reconstructive Surgery
Outpatient Abdominoplasty Facilitated by Rib Blocks
Michaels, BM; Eko, FN
Plastic and Reconstructive Surgery, 124(2): 635-642.
10.1097/PRS.0b013e3181addbd7
PDF (608) | CrossRef
Retina
PREEMPTIVE ANALGESIA IN RHEGMATOGENOUS RETINAL DETACHMENT SURGERY: Is It Effective?
MAHFOUZ, AM; NABAWI, KS
Retina, 22(5): 602-606.

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Keywords:
Central sensitization; neural blockade; pain management; postoperative pain.

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