Preemptive analgesia II: recent advances and current trends

PURPOSE: This two-part review summarizes the current knowledge of physiological mechanisms, pharmacological modalities and controversial issues surrounding preemptive analgesia. SOURCE: Articles from 1966 to present were obtained from the MEDLINE databases. Search terms included analgesia, preemptive; neurotransmitters; pain, postoperative; hyperalgesia; sensitization, central nervous system; pathways, nociception; anesthetic techniques; analgesics, agents. Principal findings: In Part I of this review article, techniques and agents that attenuate or prevent central and peripheral sensitization were reviewed. In Part II, the conditions required for effective preemptive techniques are evaluated. Specifically, preemptive analgesia may be defined as an antinociceptive treatment that prevents establishment of altered central processing of afferent input from sites of injury. The most important conditions for establishment of effective preemptive analgesia are the establishment of an effective level of antinociception before injury, and the continuation of this effective analgesic level well into the post-injury period to prevent central sensitization during the inflammatory phase. Although single-agent therapy may attenuate the central nociceptive processing, multi-modal therapy is more effective, and may be associated with fewer side effects compared with the high-dose, single-agent therapy. CONCLUSION: The variable patient characteristics and timing of preemptive analgesia in relation to surgical noxious input require individualization of the technique(s) chosen. Multi-modal analgesic techniques appear more effective.     

Preemptive analgesia in foot and ankle surgery

Central neuroplasticity, or changes in CNS processing due to surgical nociception. can amplify postoperative pain. As a result, a hyperalgesic state called wind-up can occur, having debilitating effects on postoperative patients. Preemptive analgesia works to prevent this process and results in a more positive surgical experience. Inhibition of afferent pain pathways by use of local anesthetic blocks, altered perception of pain with opioid use, and inhibition of pain pathways by NMDA receptor antagonists are examples of preemptive analgesia. Using a combination of preemptive modalities and addressing patients' perceptions can aid in interrupting pathologic pain cycles. Positive and modest results have been obtained from animal and human preemptive trials, yet basic pathophysiology demonstrates the validity and importance of preemptive analgesia. Future studies are needed to test effective blockade of afferent input while controlling perception, hyperalgesia, and NMDA receptor activity. The Agency for Health Care Policy and Research now recommends a multifaceted approach to postoperative pain. The goal in pain management is to inhibit destructive pain pathways, maintain intraoperative analgesia, and prevent central sensitization. Preliminary results of multimodal preemptive analgesia trials continue to be promising.     

Review article: Preventive analgesia: quo vadimus?

The classic definition of preemptive analgesia requires 2 groups of patients to receive identical treatment before or after incision or surgery. The only difference between the 2 groups is the timing of administration of the drug relative to incision. The constraint to include a postincision or postsurgical treatment group is methodologically appealing, because in the presence of a positive result, it provides a window of time within which the observed effect occurred, and thus points to possible mechanisms underlying the effect: the classic view assumes that the intraoperative nociceptive barrage contributes to a greater extent to postoperative pain than does the postoperative nociceptive barrage. However, this view is too restrictive and narrow, in part because we know that sensitization is induced by factors other than the peripheral nociceptive barrage associated with incision and subsequent noxious intraoperative events. A broader approach to the prevention of postoperative pain has evolved that aims to minimize the deleterious immediate and long-term effects of noxious perioperative afferent input. The focus of preventive analgesia is not on the relative timing of analgesic or anesthetic interventions, but on attenuating the impact of the peripheral nociceptive barrage associated with noxious preoperative, intraoperative, and/or postoperative stimuli. These stimuli induce peripheral and central sensitization, which increase postoperative pain intensity and analgesic requirements. Preventing sensitization will reduce pain and analgesic requirements. Preventive analgesia is demonstrated when postoperative pain and/or analgesic use are reduced beyond the duration of action of the target drug, which we have defined as 5.5 half-lives of the target drug. This requirement ensures that the observed effects are not direct analgesic effects. In this article, we briefly review the history of preemptive analgesia and relate it to the broader concept of preventive analgesia. We highlight clinical trial designs and examples from the literature that distinguish preventive analgesia from preemptive analgesia and conclude with suggestions for future research.     

Strategies for postoperative pain management

Despite advances in our understanding of the neurobiology of nociception, postoperative pain continues to be undertreated. There are many modalities that may provide effective postoperative analgesia, including systemic (e.g. opioids, non-steroidal anti-inflammatory agents) and regional analgesic options. The particular modality or modalities utilized for a particular patient will depend on the risk-benefit profile and patient preferences. Ideally, analgesic options should be incorporated into a multimodal approach to facilitate patient recovery after surgery.     

Do we need preemptive analgesia for the treatment of postoperative pain?

Preemptive analgesia means that an analgesic intervention is started before the noxious stimulus arises in order to block peripheral and central nociception. This afferent blockade of nociceptive impulses is maintained throughout the intra-operative and post-operative period. The goals of preemptive analgesia are, first, to decrease acute pain after tissue injury, second, to prevent pain-related pathologic modulation of the central nervous system, and third, to inhibit the persistence of postoperative pain and the development of chronic pain. So far, the promising results from animal models have not been translated into clinical practice. Therefore, clinicians should rely on conventional anaesthetic and analgesic methods with proven efficacy, i.e. a multimodal approach including the combination of strong opioids, non-opioid analgesics, and peripheral or neuraxial local anaesthetics that act at different sites of the pain pathways.     

Preemptive analgesia or balanced periemptive analgesia?

"Preemptive analgesia" means that analgesia given before the painful stimulus prevents or reduces subsequent pain. The concept of preemptive analgesia originates from basic science and experimental studies. However, in some clinical studies preemptive effect is not always present. The authors think that it happens for: differences among experimental models and clinical reality, wrong use of some pharmacological knowledges, some methodological errors in clinical research. The authors analyze these factors and review in a critical manner clinical studies on preemptive analgesia. In some operations, only one administration of an analgesic drug, before surgery, is not sufficient to produce an evident preemptive effect. Postoperative pain can be reduced making a pharmacological treatment before surgery, for the whole time of painful stimulus. For this reason, the term "preemptive analgesia", like "analgesia given before surgery" is not adequate. The authors suggest that the concept of prevention of postoperative pain is well defined by the term of "balanced periemptive analgesia"; it is a new approach that use many modalities of analgesia in different times to prevent and control painful stimulus for the whole time of its origin: before and/or during operation and, if necessary, in the postoperative period for the residual pain.     

Preemptive ketamine during general anesthesia for postoperative analgesia in patients undergoing laparoscopic cholecystectomy

AIM: Preemptive analgesia is currently in use in the management of postoperative pain and no more under search. The administration of ketamine as intraoperative analgesic agent is well-known since a long time; the analgesic properties of this drug are related to its actions as a non-competitive N-methyl-D-aspartate receptors antagonist; these receptors present an excitatory function on pain transmission and this binding seems to prevent or reverse the central sensitisation of every kind of pain, including postoperative pain. In literature, the use of this anesthetic for the preemptive analgesia in the management of postoperative pain is controversial; for this reason the aim of our study was the clinical evaluation of preemptive perioperative analgesia with low-doses ketamine. METHODS: This trial involved 40 patients undergoing laparoscopic cholecystectomy, with the same surgical operator; postoperative analgesia was performed with the intraoperative administration of ketamine (0.7 mg/kg) or tramadol (15 mg/kg). A randomized, double-blind study was performed; after an inhalatory/analgesic general anesthesia (sevofluorane + remifentanyl) the postoperative-pain control was clinically evaluated through algometric measurements (Visual Analog Scale, Verbal Rating Scale, Pain Intensity Difference); supplemental doses of tramadol were administered if required, also to quantify the adequacy of analgesia, and adverse effects were evaluated. RESULTS: The results show that preemptive intraoperative analgesia with ketamine produces a good analgesia at the awakening, despite low duration (approximately 1 hour), and upgrades the analgesic effect of tramadol in the postoperative period. Among the adverse effects, some (for example nausea) were related to the administration of both analgesics and to the kind of surgery, others (hallucinosis, nystagmus, photophobia, psychomotor excitation, psychotic symptoms) were due to ketamine, and others (respiratory depression and hypotension) could be related to tramadol. Although the adverse effects due to ketamine are more numerous than those related to tramadol, the second could potentially be more dangerous. CONCLUSION: Our study suggests that preemptive low-doses ketamine is able to produce an adequate postoperative analgesia and increases the analgesic effect of tramadol; furthermore, ketamine adverse effects could be reduced by intraoperative administration of benzodiazepines and/or antiemetic drugs, or by the association of ketamine and a peripheral analgesic (ketorolac).     

The effectiveness of preemptive analgesia varies according to the type of surgery: a randomized, double-blind study.

The reliability of preemptive analgesia is controversial. Its effectiveness may vary among anatomical areas or surgical types. We evaluated preemptive analgesia by epidural morphine in six surgery types in a randomized, double-blind manner. Pain intensity was rated using a visual analog scale, a verbal report, and a measurement of postsurgical morphine consumption. Preemptive analgesia was effective in limb surgery and mastectomy, but ineffective for gastrectomy, hysterectomy, herniorrhaphy, and appendectomy. Relief of postsurgical pain in hemiorrhaphy was more rapid than that in the other surgery types. Preemptive analgesia was effective in limb surgery and mastectomy, but not in surgeries involving laparotomy, regardless of whether the surgery was major (gastrectomy and hysterectomy) or minor (herniorrhaphy and appendectomy). These results suggest that viscero-peritoneal nociception is involved in postsurgical pain. The abdominal viscera and peritoneum are innervated both heterosegmentally (in duplicate or triplicate by the vagus and/or phrenic nerves) and segmentally (by the spinal nerves). Therefore, supraspinal and/or cervical spinal neurons might be sensitized, despite the blockade of the segmental nerves with epidural morphine. The rapid retreat of the pain after hemiorrhaphy suggests that central sensitization remits soon after minor surgery, but that in appendicitis, it may be protracted by additional noxious stimuli, such as infection. IMPLICATIONS: Epidural preemptive analgesia was reliably effective in limb and breast surgeries but ineffective in abdominal surgery, suggesting involvement of the brainstem and cervical spinal cord via the vagus and phlenic nerves.     

Analgesic agents for the postoperative period. Nonopioids.

For many reasons, nonopioid analgesics have proven to be of immense benefit in postoperative pain relief. Consideration of the limitations and side effects of opioids confirms the need for alternative, complementary analgesics. The current understanding of pain pathophysiology recognizes that many tissue and neuronal factors and changes are invoked by tissue damage, producing peripheral and central sensitization, and some of these may be modulated by the use of NSAIDs, NMDA antagonists, and local anesthetic agents. If successful preemptive analgesic techniques are developed, they will likely include the use of NSAIDs and perhaps NMDA antagonists. Nonopioids are of benefit in multimodal analgesia and allow acute rehabilitation of surgical patients. Acetaminophen, NSAIDs, alpha 2-antagonists, and NMDA antagonists are in routine use as components of multimodal analgesia, in combination with opioids or local anesthetic techniques. Tramadol is interesting because it has nonopioid and opioid actions that can be attributed to the two isomers found in the racemic mixture. Spinal neostigmine and the use of adenosine represent completely different mechanisms of nonopioid analgesia being investigated. Nonopioids, including lidocaine, ketamine, the anticonvulsants, and the antidepressants, are necessary for the treatment of patients with the difficult clinical problem of neuropathic pain that can present in the postoperative period.     

Management of postoperative pain and emesis

As more extensive and painful surgical procedures (e.g., laparoscopic cholecystectomy, laminectomy, knee and shoulder reconstruction, hysterectomy) are being performed on an outpatient basis, the availability of sophisticated postoperative analgesic regimens are necessary to optimize the benefits of day-case surgery for both the patient and the health care provider. However, outcome studies are needed to evaluate the effects of these newer therapeutic approaches with respect to postoperative side effects, cost and important recovery variables. Recent studies suggest that factors other than painper se must be controlled in order to reduce postoperative morbidity and facilitate the recovery process. Not surprisingly, the anaesthetic technique can influence the analgesic requirements and the likelihood of emesis in the early postoperative period. Although opioid analgesics will continue to play an important role, the adjunctive use of both local anaesthetic agents and NSAIDs will probably assume an even greater role in the future. Use of drug combinations (e.g., opioids with local anaesthetics, alpha2 agonists and/or NSAIDs) may provide for improved analgesia with fewer opioid-related side effects than narcotic analgesics alone. Finally, safer and simpler analgesic delivery systems are needed to improve our ability to provide cost-effective pain relief after day-case surgery in the future. In conclusion, as a result of our enhanced understanding of the mechanisms of acute pain and the physiological basis of nociception, the provision of “stress free” anaesthesia with minimal postoperative discomfort is now possible for most patients undergoing ambulatory surgical procedures. The aim of any analgesic technique should not only be to lower the pain scores but also to facilitate earlier mobilization and to reduce perioperative complications, in particular PONY In future, clinicians should be able to effectively treat postoperative pain using a combination of “balanced,” “preemptive,” and “peripheral” analgesia techniques without producing emetic sequelae.     

Update zur präemptiven Analgesie

Background

Wall created the term preemptive analgesia in 1988 and in doing so set in motion a movement to prevent acute and chronic postsurgical pain. The concept of preemptive analgesia implies the administration of analgesic drugs or an intervention before a surgical procedure. A preemptive analgesic approach can comprise non-steroidal anti-inflammatory drugs (NSAID) and cyclo-oxygenase-2 inhibitors (coxibs) used to decrease the production of prostaglandins, local anesthetics (e.g. epidural) to reduce nociceptive input to the spinal cord as well as opioids, N-methyl-D-aspartate (NMDA) antagonists, antidepressants and anticonvulsants, all of which have an inhibitory influence on the central nervous system.

Aim

The aim of this article is to present the current possibilities and limits of preoperative pain therapy.

Material and methods

Since 2002 several meta-analyses on the effectiveness of preemptive analgesia have been published which came to varying conclusions on the supportive use of preemptive analgesia. The S3 guidelines on current perioperative pain management developed by the German Interdisciplinary Association for Pain Management (DIVS) specify the preemptive analgesic interventions found to be effective and will be discussed in detail in this article. Furthermore, the results of a current meta-analysis which follows the principle of preventive analgesia will be presented and which have not yet been considered in the S3 guidelines.

Results

Preemptive analgesia can reduce acute postoperative pain; however, minimizing the development of chronic pain conditions can only be successful in combination with intraoperative and postoperative pain therapy as well as social and psychological support when indicated (preventive analgesia).

Conclusion

Reduction of chronic postoperative pain is an important medical function which is also justified from socioeconomic perspectives. Future studies should combine several procedures for perioperative pain therapy in order to do justice to the multifactorial aspects of pain chronification and should also be planned over a sufficiently long observation time period.     

Lack of secondary hyperalgesia and central sensitization in an acute sheep model

BACKGROUND AND OBJECTIVES: We aimed to determine the following in an experimental acute pain model in sheep: (1) whether multimodal analgesia with intravenous fentanyl and ketorolac was more effective than fentanyl alone; (2) whether secondary hyperalgesia (central sensitization) occurred in adjacent (foreleg) dermatomes after thoracic surgery; (3) whether ketorolac used preemptively influenced the development of secondary hyperalgesia after surgery. METHODS: Changes in primary nociception were measured by increases to tolerated pressure, applied to the foreleg by a blunt pin, before foreleg withdrawal occurred. Changes to breath-to-breath interval and estimated end-tidal CO2 were used as indices of respiratory effects. Study 1 (n = 6) compared the paired responses to acute nociception after ketorolac (90 mg) or saline (control) pretreatment, followed by fentanyl (graded, 0 mg to 1.5 mg). Study 2 (n = 6) used a cross-over of ketorolac (90 mg) or saline (control) 24 hours and 1 hour, respectively, before a standardized thoracotomy incision, followed by antinociceptive testing with ketorolac (90 mg) and fentanyl (0.6 mg) daily over 4 days. RESULTS: In study 1, fentanyl produced naloxone-antagonizable antinociception and respiratory depression. Ketorolac did not affect fentanyl antinociception, except for prolonging antinociception at the highest dose; it did not affect the respiratory effects. In study 2, preemptive ketorolac had no effect on the postoperative antinociceptive or respiratory effects of fentanyl. The pharmacokinetics of fentanyl were unaltered by ketorolac. CONCLUSIONS: The results obtained in this acute pain model found no significant evidence of a fentanyl-ketorolac interaction, of central sensitization as shown by secondary hyperalgesia, or of a preemptive analgesic effect.     

The efficacy of preemptive analgesia for acute postoperative pain management: a meta-analysis

Whether preemptive analgesic interventions are more effective than conventional regimens in managing acute postoperative pain remains controversial. We systematically searched for randomized controlled trials that specifically compared preoperative analgesic interventions with similar postoperative analgesic interventions via the same route. The retrieved reports were stratified according to five types of analgesic interventions: epidural analgesia, local anesthetic wound infiltration, systemic N-methyl-d-aspartic acid (NMDA) receptor antagonists, systemic nonsteroidal antiinflammatory drugs (NSAIDs), and systemic opioids. The primary outcome measures analyzed were the pain intensity scores, supplemental analgesic consumption, and time to first analgesic consumption. Sixty-six studies with data from 3261 patients were analyzed. Data were combined by using a fixed-effect model, and the effect size index (ES) used was the standardized mean difference. When the data from all three outcome measures were combined, the ES was most pronounced for preemptive administration of epidural analgesia (ES, 0.38; 95% confidence interval [CI], 0.28-0.47), local anesthetic wound infiltration (ES, 0.29; 95% CI, 0.17-0.40), and NSAID administration (ES, 0.39; 95% CI, 0.27-0.48). Whereas preemptive epidural analgesia resulted in consistent improvements in all three outcome variables, preemptive local anesthetic wound infiltration and NSAID administration improved analgesic consumption and time to first rescue analgesic request, but not postoperative pain scores. The least proof of efficacy was found in the case of systemic NMDA antagonist (ES, 0.09; 95% CI, -0.03 to 0.22) and opioid (ES, -0.10; 95% CI, -0.26 to 0.07) administration, and the results remain equivocal.     

The effects on postoperative oral surgery pain by varying NSAID administration times: comparison on effect of preemptive analgesia.

OBJECTIVE: Many studies on the efficacy of preemptive analgesia have been processed in different ways. But the value of preemptive analgesia is still controversial. The goal of this study was to compare analgesic effects of a nonsteroidal anti-inflammatory drug (NSAID) for oral surgical pain according to 3 different administration times. STUDY DESIGN: Using a randomized, parallel-group, single-center, and active-controlled test design, this study was conducted with 80 healthy patients undergoing a surgical removal of an impacted mandibular third molar requiring bone removal. The oral NSAID was first administered 1 hour preoperatively, or 1 hour postoperatively, or no scheduled administration pre- or postsurgery. Whenever patients felt at least moderate pain (score > or =5 on a 10-point scale) after surgery, they were instructed to take the same drug. Pain intensities and times to the first and second onsets of postoperative pain from the end of surgery were assessed for 24 hours. RESULTS: Of the 80 enrolled subjects in this study, 25 patients were assigned to the preemptive group, 26 to the posttreatment group, and 29 to the no-treatment group. The demographic distribution and duration of surgery in the 3 groups were statistically similar. The mean time to first onset of postoperative pain was significantly prolonged in the posttreatment group (277.2 minutes, P < .05) compared to the preemptive group (158.4 minutes) and the no-treatment group (196.5 minutes). The mean time to second onset of postoperative pain was not significantly different among the 3 groups. No significant statistical difference was found among the mean pain intensities at the first and second onsets of postoperative pain in the 3 groups. CONCLUSIONS: In this small selected group of subjects and limited study design, the analgesic effects of NSAID administered preoperatively were no longer effective for postoperative pain. The results in this population imply that scheduled postoperative analgesics before pain development are adequate for postoperative analgesia without preoperative administration.     

Anatomy,physiology and pharmacology of pain

Although there is an anatomical framework that is involved in pain processing, this system is not ‘hard wired’ but undergoes changes affecting the sensitivity and the ‘gain’ of nociception. Peripheral sensitization contributes to increasing afferent barrage to the spinal cord. It is mediated by many diverse elements, including nerve and immune cells, in a complex array of algogenic products. Numerous receptors and ion channels are involved. Continuing increased input into the spinal cord causes further changes of central sensitization. The glutamate receptor, N-methyl-d-aspartate (NMDA) is pivotal to these processes. The NMDA receptor is therefore a potential target for analgesic therapy. Visceral pain shares the features of the pain mechanisms described in this article, but there are some anatomical, physiological and biochemical differences to somatic pain. Damage to nerves causes changes in excitability, which induce similar peripheral and central sensitization processes that contribute to neuropathic pain. Knowledge of all these processes identifies not only a rationale for standard pain treatments but also novel potential analgesic targets. However, these systems display complex interactions and, rather than targeting a single moiety, a multi-mechanistic approach to analgesia is required.     

Post-thoracotomy analgesia and perioperative outcome.

Post-thoracotomy pain is the most severe form of pain after surgery and is continuously exacerbated by ventilatory function. Due to the multiplicity of nociceptive inputs from the chest wall, thoracic viscera, diaphragm and postoperative chest tubes, postoperative pain may be difficult to control with single modalities. The aim is excellent analgesia with function i.e. normal ventilation and rapid mobilisation. A variety of agents and techniques have been shown to be effective analgesics with varying degrees of functional success. These include systemic opioids, NSAIDS and ketamine, regional analgesia (including epidural, spinal, paravetebral, intercostal and intrapleural techniques) and cryoanalgesia. The most popular and probably most effective technique at the present time is thoracic epidural analgesia using a combination of different local anesthetic agents and opioids. There are few data indicating any influence on outcome of different postthoracotomy analgesic techniques. Improvement in outcome requires a co-ordinated approach from all caregivers using the best possible analgesic techniques.     

Preemptive analgesia by intravenous low-dose ketamine and epidural morphine in gastrectomy: a randomized double-blind study

BACKGROUND: Morphine and ketamine may prevent central sensitization during surgery and result in preemptive analgesia. The reliability of preemptive analgesia, however, is controversial. METHODS: Gastrectomy patients were given preemptive analgesia consisting of epidural morphine, intravenous low-dose ketamine, and combinations of these in a randomized, double-blind manner. Postsurgical pain intensity was rated by a visual analog scale, a categoric pain evaluation, and cumulative morphine consumption. RESULTS: Preemptive analgesia by epidural morphine and by intravenous low-dose ketamine were significantly effective but not definitive. With epidural morphine, a significant reduction in visual analog scale scores at rest was observed at 24 and 48 h, and morphine consumption was significantly lower at 6 and 12 h, compared with control values. With intravenous ketamine, visual analog scale scores at rest and morphine consumption were significantly lower at 6, 12, 24, and 48 h than those in control subjects. The combination of epidural morphine and intravenous ketamine provided definitive preemptive analgesia: Visual analog scale scores at rest and morphine consumption were significantly the lowest at 6, 12, 24, and 48 h, and the visual analog scale score during movement and the categoric pain score also were significantly the lowest among the groups. CONCLUSION: The results suggest that for definitive preemptive analgesia, blockade of opioid and N-methyl-d-aspartate receptors is necessary for upper abdominal surgery such as gastrectomy; singly, either treatment provided significant, but not definitive, postsurgical pain relief. Epidural morphine may affect the spinal cord segmentally, whereas intravenous ketamine may block brain stem sensitization via the vagus nerve during upper abdominal surgery.     

Preemptive Analgesia by Intravenous Low-dose Ketamine and Epidural Morphine in Gastrectomy: A Randomized Double-blind Study

Background: Morphine and ketamine may prevent central sensitization during surgery and result in preemptive analgesia. The reliability of preemptive analgesia, however, is controversial.

Methods: Gastrectomy patients were given preemptive analgesia consisting of epidural morphine, intravenous low-dose ketamine, and combinations of these in a randomized, double-blind manner. Postsurgical pain intensity was rated by a visual analog scale, a categoric pain evaluation, and cumulative morphine consumption.

Results: Preemptive analgesia by epidural morphine and by intravenous low-dose ketamine were significantly effective but not definitive. With epidural morphine, a significant reduction in visual analog scale scores at rest was observed at 24 and 48 h, and morphine consumption was significantly lower at 6 and 12 h, compared with control values. With intravenous ketamine, visual analog scale scores at rest and morphine consumption were significantly lower at 6, 12, 24, and 48 h than those in control subjects. The combination of epidural morphine and intravenous ketamine provided definitive preemptive analgesia: Visual analog scale scores at rest and morphine consumption were significantly the lowest at 6, 12, 24, and 48 h, and the visual analog scale score during movement and the categoric pain score also were significantly the lowest among the groups.     

Intraoperative Epidural Analgesia Combined with Ketamine Provides Effective Preventive Analgesia in Patients Undergoing Major Digestive Surgery

Background: As a broader definition of preemptive analgesia, preventive analgesia aims to prevent the sensitization of central nervous system, hence the development of pathologic pain after tissular injury. To demonstrate benefits from preventive treatment, objective measurement of postoperative pain such as wound hyperalgesia and persistent pain should be evaluated. The current study assessed the role and timing of epidural analgesia in this context.

Methods: In a randomized, double-blinded trial, 85 patients scheduled to undergo neoplastic colonic resection were included. All the patients received a thoracic epidural catheter, systemic ketamine at a antihyperalgesic dose, and general anesthesia. Continuous infusion of analgesics belonging to the same class was administered by either intravenous or epidural route before incision until 72 h after surgery. Patients were allocated to four groups to receive intraoperative intravenous lidocaine-sufentanil-clonidine or epidural bupivacaine-sufentanil-clonidine followed postoperatively by either intravenous (lidocaine-morphine-clonidine) or epidural (bupivacaine-sufentanil-clonidine) patient-controlled analgesia. Postoperative pain scores (visual analog scale), analgesic consumption, wound area of punctuate hyperalgesia, residual pain, and analgesics needed from 2 weeks until 12 months were recorded.

Results: Analgesic requirements, visual analog scale scores, and area of hyperalgesia were significantly higher in the intravenous treatment group (intravenous-intravenous), and more patients reported residual pain from 2 weeks until 1 yr (28%). Although postoperative pain measurements did not differ, postoperative epidural treatment (intravenous-epidural) was less effective to prevent residual pain at 1 yr (11%; P = 0.2 with intravenous-intravenous group) than intraoperative one (epidural-epidural and epidural-intravenous groups) (0%; P = 0.01 with intravenous-intravenous group).     

Prophylactic Use of Epidural Mepivacaine/Morphine, Systemic Diclofenac, and Metamizole Reduces Postoperative Morphine Consumption after Major Abdominal Surgery

Background: Surgical trauma induces nociceptive sensitization leading to amplification and prolongation of postoperative pain. While preemptive analgesic treatment with numerous agents has been successful in experimental animals, results of human studies remain conflicting. The authors used a multimodal approach for preemptive analgesia before abdominal surgery: diclofenac and metamizole inhibit prostaglandin synthesis, thus influencing peripheral sensitization; epidural local anesthetics induce conduction block, epidural opioids inhibit nociceptive synaptic transmission, and metamizole induces descending inhibition. The interaction of these drugs might suppress spinal nociceptive sensitization and postoperative analgesic demand.

Methods: One hundred forty-two patients scheduled for major abdominal surgery were randomly assigned to one of three groups and studied prospectively. Epidural catheters in groups 1 and 2 were placed at interspaces T8-T10, the position of the catheter was confirmed by epidurography, and sensory testing after administration of 5 ml mepivacaine 1%. Group 1 received 75 mg intramuscular diclofenac, 1000 mg intravenous metamizole, 5.3+/-1 mg epidural morphine, and 15-20 ml mepivacaine 1% 85+/-41 min before skin incision. Epidural analgesia was maintained by injections of 0.1 ml *symbol* kg sup -1 *symbol* h sup -1 mepivacaine 1%. Group 2 patients received the balanced analgesia regimen before wound closure (221+/-86 min after skin incision). Group 3 patients did not receive any study substances. General anesthesia was induced with 5 mg/kg thiopental and 2 micro gram/kg fentanyl and maintained with enflurane and nitrous oxide. Postoperative analgesia consisted of patient-controlled intravenous morphine over 5 days.

Results: Median visual analog scale pain intensities were < 3 cm and did not differ among the groups. Morphine consumption per hour on postoperative day 2 was 0.8+/-0.1 mg/h (group 1) < 1.2+/- 0.1 mg/h (group 2) = 1.1+/-0.1 mg/h (group 3) and cumulative morphine consumption (in mg) on the morning of day 5 was 95+/-9 (group 1) < 111+/-11 (group 2) < 137+/-10 (group 3).