Preemptive analgesia I: physiological pathways and pharmacological modalities

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: The physiological basis of preemptive analgesia is complex and involves modification of the pain pathways. The pharmacological modalities available may modify the physiological responses at various levels. Effective preemptive analgesic techniques require multi-modal interception of nociceptive input, increasing threshold for nociception, and blocking or decreasing nociceptor receptor activation. Although the literature is controversial regarding the effectiveness of preemptive analgesia, some general recommendations can be helpful in guiding clinical care. Regional anesthesia induced prior to surgical trauma and continued well into the postoperative period is effective in attenuating peripheral and central sensitization. Pharmacologic agents such as NSAIDs (non-steroidal anti-inflammatory drugs) opioids, and NMDA (N-methyl-D-aspartate) - and alpha-2-receptor antagonists, especially when used in combination, act synergistically to decrease postoperative pain. CONCLUSION: The variable patient characteristics and timing of preemptive analgesia in relation to surgical noxious input requires individualization of the technique(s) chosen. Multi-modal analgesic techniques appear most 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.     

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.     

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).     

Preemptive Analgesic Effects of Steroid Anesthesia with Alphaxalone in the Rat Formalin Test: Evidence for Differential GABA sub A Receptor Modulation in Persistent Nociception

Background: The role of preemptive treatment with volatile and intravenous anesthetics has been examined in previous studies using the rat formalin test. Evidence describing analgesic properties of the gamma-amino butyric acid-ergic (GABAergic) steroid anesthetics, such as alphaxalone, suggest that they may suppress the development of central sensitization to pain. This study examined the preemptive effects of alphaxalone in comparison with other GABAergic anesthetics, propofol and pentobarbital.

Methods: The pain behavior of rats was evaluated (using the previously validated weighted scores method of behavioral rating) 15-60 min after subcutaneous hind paw injection of 50 micro liter 1.5% formalin. In each trial, anesthetics and their respective vehicles were administered by tail-vein injection either 0.5-10 min before or 5 min after, formalin injection. When analgesic effects were observed with any of these agents, further studies were conducted with a GABAA receptor antagonist in an attempt to confirm a specific receptor-mediated action of the agent.

Results: Alphaxalone pretreatment produced transient analgesia in the early part of phase 2, which was not observed in rats posttreated with alphaxalone. The analgesic effect of alphaxalone was antagonized by picrotoxin, as well. Neither pentobarbital nor propofol showed any analgesic effects at the doses used in our study.     

Preventing the development of chronic pain after orthopaedic surgery with preventive multimodal analgesic techniques

The prevalences of complex regional pain syndrome, phantom limb pain, chronic donor-site pain, and persistent pain following total joint arthroplasty are alarmingly high. Central nervous system plasticity that occurs in response to tissue injury may contribute to the development of persistent postoperative pain. Many researchers have focused on methods to prevent central neuroplastic changes from occurring through the utilization of preemptive or preventive multimodal analgesic techniques. Multimodal analgesia allows a reduction in the doses of individual drugs for postoperative pain and thus a lower prevalence of opioid-related adverse events. The rationale for this strategy is the achievement of sufficient analgesia due to the additive effects of, or the synergistic effects between, different analgesics. Effective multimodal analgesic techniques include the use of nonsteroidal anti-inflammatory drugs, local anesthetics, alpha-2 agonists, ketamine, alpha(2)-delta ligands, and opioids.     

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). CONCLUSION: Combined with an antihyperalgesic dose of ketamine, intraoperative epidural analgesia provides effective preventive analgesia after major digestive surgery.     

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.     

A new method of preemptive analgesia in laparoscopic cholecystectomy

Background: Although laparoscopic cholecystectomy (LC) results in less pain then open cholecystectomy, it is not a pain-free procedure. The aim of this study was to test a new method of preemptive analgesia.Methods: By simple randomization 60 patients were assigned to two groups (30 in each group). Group A, the placebo group, received 200 ml of 0.9% saline, and group B received 5 mg/kg of a local anesthetic solution (ropivacaine) in 200 ml of 0.9% saline. Local anesthetic or placebo solution were administer before creation of the pneumoperitoneum. Results: Pain intensity, as rated by visual analog and verbal rating scales, and stress response data were significantly less in the group receiving ropivacaine than in the placebo group. No patients in treatment group received an additional dose of analgesic, whereas two patients in placebo group needed an additional analgesic. Conclusions: Our results support the clinical validity of preemptive analgesia, but the timing of intraperitoneal administration of local anesthetic is very important. Only application before creation of the pneumoperitoneum may preempt every neuronal central sensitization.     

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.     

Update on preemptive analgesia

Perioperative pain remains prevalent and poorly treated. Apart from its impact on the rate and unpleasantness of recovery from surgery, pain often remains as a residual aftereffect of surgery even though tissue healing appears complete. A growing appreciation for the underlying neurobiology of pain has identified mechanisms that can enhance the intensity of perioperative pain and even lead to more prolonged painful conditions. An essential observation is that tissue injury and the resulting nociceptor barrage initiates a cascade of events that can indelibly alter pain perception. Preemptive analgesia is the concept of initiating analgesic therapy before the onset of the noxious stimulus so as to prevent the nociceptor barrage and its consequences. However, preemptive analgesia, though firmly grounded in the neurobiology of pain, has yet to realize its anticipated clinical potential. As data accumulates, it has become clear that clinical studies emulating those from the laboratory and designed around a relatively narrow definition of preemptive analgesia have been largely unsupportive of its use. Nevertheless, preemptive analgesic interventions that recognize the intensity, duration, and somatotopic extent of major surgery can help reduce perioperative pain and its longer-term sequelae.     

围术期镇痛对术后炎症反应的影响

手术创伤后局部组织损伤产生炎症介质,包括PGs,细胞因子等,它们释放人血产生全身炎症反应,炎症介质还可产生疼痛或痛觉增敏。围术期镇痛应该采用多种药物、方法的多模式镇痛,其中局麻药硬膜外镇痛具有较重要的作用,结合阿片类镇痛药、NSAIDs、超前镇痛等,通过抑制交感活化及炎症介质产生等机制对减轻术后炎症反应,促进术后恢复及结局改善具有重要意义。     

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).     

Preemptive analgesia: no relevant advantage of preoperative compared with postoperative intravenous administration of morphine,ketamine, and clonidine in patients undergoing transperitoneal tumor nephrectomy

BACKGROUND AND OBJECTIVES: Preemptive analgesia often failed in the clinical arena because application of a single intravenously applied drug may not prevent nociceptive input and spinal pain processing sufficiently. We therefore used an intravenous (IV), multireceptor approach and tested the preemptive analgesic effect of the antinociceptive drugs morphine, ketamine, and clonidine given before or immediately after surgery. METHODS: A double-blind, randomized, prospective study was performed in 30 patients undergoing transperitoneal tumor nephrectomy (via median laparotomy). Standard general anesthesia procedure without opioids was used. After induction, patients were randomly allocated to receive 150 microg x kg(-1) of morphine, 150 microg x kg(-1) of ketamine, and 5 microg x kg(-1) of clonidine intravenously via a motor-driven pump within 15 minutes, either before or immediately after surgery. Patient-controlled analgesia (PCA) with the opioid piritramide (IV) was used for postoperative analgesia. Postoperative pain at rest and during induced cough was quantified by analgesic requirement and pain scores (visual analog scale [VAS]) within 48 hours. RESULTS: There was no significant difference in analgesic requirement of piritramide and pain scores at rest or during induced cough. CONCLUSIONS: In contrast to encouraging observations on the combination of antinociceptive drugs, the multireceptor approach tested here failed to exert a clinically relevant effect.     

超前镇痛的相关研究进展

超前镇痛是通过防止外周和中枢敏化来降低伤害性刺激引起的痛觉过敏和痛觉异常的一种镇痛方法.现介绍超前镇痛的机制、临床常用方法及药物,并展望超前镇痛亟待解决的问题.     

超前镇痛的相关研究进展

超前镇痛是通过防止外周和中枢敏化来降低伤害性刺激引起的痛觉过敏和痛觉异常的一种镇痛方法.现介绍超前镇痛的机制、临床常用方法及药物,并展望超前镇痛亟待解决的问题.     

超前镇痛的相关研究进展

超前镇痛是通过防止外周和中枢敏化来降低伤害性刺激引起的痛觉过敏和痛觉异常的一种镇痛方法.现介绍超前镇痛的机制、临床常用方法及药物,并展望超前镇痛亟待解决的问题.