Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and post-surgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk in both developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the first discovery of activity-dependent synaptic plasticity in the spinal cord and the revelation that it occurs and produces pain hypersensitivity in patients. Nevertheless, discovering the genetic and environmental contributors to and objective biomarkers of central sensitization will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent and promiscuous form of pain plasticity.

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Central sensitization: implications for the diagnosis and treatment of pain.

Major surgery is still associated with undesirable sequelae such as pain, cardiopulmonary, infective and thromboembolic complications, cerebral dysfunction, nausea and gastrointestinal paralysis, fatigue and prolonged convalescence. The key pathogenic factor in postoperative morbidity, excluding failures of surgical and anaesthetic technique, is the surgical stress response with subsequent increased demands on organ function. These changes in organ function are thought to be mediated by trauma-induced endocrine metabolic changes and activation of several biological cascade systems (cytokines, complement, arachidonic acid metabolites, nitric oxide, free oxygen radicals, etc). To understand postoperative morbidity it is therefore necessary to understand the pathophysiological role of the various components of the surgical stress response and to determine if modification of such responses may improve surgical outcome. While no single technique or drug regimen has been shown to eliminate postoperative morbidity and mortality, multimodal interventions may lead to a major reduction in the undesirable sequelae of surgical injury with improved recovery and reduction in postoperative morbidity and overall costs.

Multimodal approach to control postoperative pathophysiology and rehabilitation.

Peripheral tissue damage or nerve injury often leads to pathological pain processes, such as spontaneous pain, hyperalgesia and allodynia, that persist for years or decades after all possible tissue healing has occurred. Although peripheral neural mechanisms, such as nociceptor sensitization and neuroma formation, contribute to these pathological pain processes, recent evidence indicates that changes in central neural function may also play a significant role. In this review, we examine the clinical and experimental evidence which points to a contribution of central neural plasticity to the development of pathological pain. We also assess the physiological, biochemical, cellular and molecular mechanisms that underlie plasticity induced in the central nervous system (CNS) in response to noxious peripheral stimulation. Finally, we examine theories which have been proposed to explain how injury or noxious stimulation lead to alterations in CNS function which influence subsequent pain experience.

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Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence

The study of pain in awake animals raises ethical, philosophical, and technical problems. We review the ethical standards for studying pain in animals and emphasize that there are scientific as well as moral reasons for keeping to them. Philosophically, there is the problem that pain cannot be monitored directly in animals but can only be estimated by examining their responses to nociceptive stimuli; however, such responses do not necessarily mean that there is a concomitant sensation. The types of nociceptive stimuli (electrical, thermal, mechanical, or chemical) that have been used in different pain models are reviewed with the conclusion that none is ideal, although chemical stimuli probably most closely mimic acute clinical pain. The monitored reactions are almost always motor responses ranging from spinal reflexes to complex behaviors. Most have the weakness that they may be associated with, or modulated by, other physiological functions. The main tests are critically reviewed in terms of their sensitivity, specificity, and predictiveness. Weaknesses are highlighted, including 1) that in most tests responses are monitored around a nociceptive threshold, whereas clinical pain is almost always more severe; 2) differences in the fashion whereby responses are evoked from healthy and inflamed tissues; and 3) problems in assessing threshold responses to stimuli, which continue to increase in intensity. It is concluded that although the neural basis of the most used tests is poorly understood, their use will be more profitable if pain is considered within, rather than apart from, the body's homeostatic mechanisms.

Animal Models of Nociception

reatment of postoperative pain is provided for humanitarian reasons and to alleviate nocicepT tion-induced responses, such as the endocrine metabolic response to surgery, autonomic reflexes with adverse effects on organ function, reflexes leading to muscle spasm, and other undesirable results (1). During the last decade there has been a virtual explosion in our knowledge of basic pain physiology (2,3), but the implications for clinical practice have been less substantial. The explanation for the discrepancy between the fast progress in basic pain pathophysiology and the rather slow advances in providing optimal postoperative pain treatment may be several, but one important factor may be that more than 95% of the literature on postoperative pain treatment has considered unimodal treatment. We have emphasized previously that total or optimal pain relief allowing normal function can not be achieved by a single drug or method without major strain on equipment and surveillance systems or without significant side effects (4). Therefore, we have recommended combined analgesic regimens (balanced analgesia) or a multimodal approach to the treatment of postoperative pain (4). The rationale for this strategy is achievement of sufficient analgesia due to additive or synergistic effects between different analgesics, with concomitant reduction of side effects, due to resulting lower doses of analgesics and differences in side-effect profiles. We summarize here the existing knowledge concerning the efficacy of analgesic combination therapy from postoperative pain studies. The effects on postoperative outcome are not included, because of lack of sufficient studies. We also exclude obstetric and pediatric pain, which may represent special pain entities and solutions for treatment, although they obviously share many of the problems of general postoperative pain. Primary emphasis will be placed on moderate and severe pain and the use of and need for

The value of "multimodal" or "balanced analgesia" in postoperative pain treatment.

Background: Preliminary clinical studies have suggested that gabapentin may produce analgesia and reduce the need for opioids in postoperative patients. The aim of the present study was to investigate the opioid-sparing and analgesic effects of gabapentin administered during the first 24 h after abdominal hysterectomy.



Methods:  In a randomized, double-blind study, 80 patients received oral gabapentin 1200 mg or placebo 1 h before surgery, followed by oral gabapentin 600 mg or placebo 8, 16 and 24 h after the initial dose. Patients received patient-controlled analgesia with morphine at doses of 2.5 mg with a lock-out time of 10 min for 24 h postoperatively. Pain was assessed on a visual analogue scale (VAS) at rest and during mobilization, nausea, somnolence and dizziness on a four-point verbal scale, and vomiting as present/not present at 2, 4, 22 and 24 h postoperatively.



Results:  Thirty-nine patients in the gabapentin group, and 32 patients in the placebo group completed the study. Gabapentin reduced total morphine consumption from median 63 (interquartile range 53–88) mg to 43 (28–60) mg (P < 0.001). We observed a significant inverse association between plasma levels of gabapentin at 2 h postoperatively, and morphine usage from 0 to 2 h, and from 0 to 4 h postoperatively (R2 = 0.30, P = 0.003 and R2 = 0.24 P = 0.008, respectively).



No significant differences in pain at rest or during mobilization, or in side-effects, were observed between groups.



Conclusion:  Gabapentin in a total dose of 3000 mg, administered before and during the first 24 h after abdominal hysterectomy, reduced morphine consumption with 32%, without significant effects on pain scores. No significant differences in side-effects were observed between study-groups.

Effects of gabapentin on postoperative morphine consumption and pain after abdominal hysterectomy: a randomized, double-blind trial.

The analgesic effects of an identical inguinal field block, performed before or immediately after inguinal herniorrhaphy, were evaluated in 32 healthy patients in a double-blind, randomized study. During surgery, all patients received a light general anaesthesia with thiopentone, alfentanil and nitrous oxide in oxygen. After inducation of general anaesthesia, patients were allocated randomly to receive an inguinal field block with lignocaine, either 15 min before operation or immediately after operation, after closure of the surgical wound, but before the patients were awake. Pain score on a visual analogue scale and on a verbal scale at rest, during mobilization from supine into sitting position and during cough was assessed 1, 2, 4, 6, 8 and 24 h, and 7 days after operation. No significant differences between the groups were observed in VAS scores or verbal pain scores during rest or ambulation at any time. There was no significant difference in time to first request for morphine or total morphine consumption. These results do not show pre-emptive analgesia with a conventional inguinal field block to be of clinical importance compared with a similar block administered after operation.

Effect of pre- vs postoperative inguinal field block on postoperative pain after herniorrhaphy

We have studied the effect of continuous extradural analgesia with bupivacaine and morphine, initiated before or after colonic surgery, in a double-blind, randomized study. Thirty-two patients were allocated randomly to receive an identical extradural block initiated 40 min before surgical incision (n = 16) or at closure of the surgical wound (n = 16). The extradural regimen consisted of a bolus of 7 ml of plain bupivacaine 7.5 mg ml−1 plus morphine 2 mg and continuous extradural infusion of a mixture of bupivacaine 7.5mg ml−1 plus morphine 0.05 mg ml−1, 4 ml h−1 for 2 h, followed by a continuous extradural infusion of a mixture of bupivacaine 2.5mgml−1 plus morphine 0.05 mg ml−1, 4 ml−1 h−1, continued for 72 h after operation. In addition, all patients received similar general anaesthesia. There was no significant difference in request for additional morphine and no significant differences between the groups in pain scores (visual analogue scale or verbal) during rest or ambulation at any time of measurement. These results do not suggest that timing of analgesia with a conventional extradural regimen is of major clinical importance in patients undergoing colonic surgery

Influence of timing on the effect of continuous extradural analgesia with bupivacaine and morphine after major abdominal surgery

In this randomized pilot clinical trial, the authors tested the hypothesis that using gabapentin as an add-on agent in the treatment of postoperative pain reduces the occurrence of postoperative delirium. Postoperative delirium occurred in 5/12 patients (42%) who received placebo vs 0/9 patients who received gabapentin, p = 0.045. The reduction in delirium appears to be secondary to the opioid-sparing effect of gabapentin.

Pilot clinical trial of gabapentin to decrease postoperative delirium in older patients

Ketamine reduces nociception by binding noncompetitively to the N-methyl-D-aspartate (NMDA) receptor, activation of which increases spinal hypersensitivity We studied 19 healthy, unmedicated male volunteers, aged 20-31 yr Burn injuries were produced on the medial surface of the dominant calf with a 25 x 50 mm rectangular thermode On 3 separate days, at least 1 week apart, subjects received a bolus of either ketamine 015 mg kg-1, ketamine 030 mg kg-1 or placebo, delivered by a mechanical infusion pump over 15 min The bolus was followed by continuous infusion of ketamine 015 mg kg-1 h-1, ketamine 030 mg kg-1 h-1 or placebo, respectively, for 135 min Ketamine reduced the magnitude of both primary and secondary hyperalgesia, and also pain evoked by prolonged noxious heat stimulation, in a dose-dependent manner In contrast, ketamine did not alter phasic heat pain perception (perception of transient, painful, thermal stimuli) in undamaged skin The analgesic effects of ketamine in the burn injury model are in agreement with results from experimental studies, and can be distinguished from those of local anaesthetics and opioids Side effects caused by continuous infusion of ketamine 015 and 030 mg kg-1 h-1 were frequent but clinically acceptable

J. B. Dahl

Papers

Effects of gabapentin on postoperative morphine consumption and pain after abdominal hysterectomy: a randomized, double-blind trial.

Effect of pre- vs postoperative inguinal field block on postoperative pain after herniorrhaphy

Influence of timing on the effect of continuous extradural analgesia with bupivacaine and morphine after major abdominal surgery

Pilot clinical trial of gabapentin to decrease postoperative delirium in older patients

Effect of systemic N-methyl-D-aspartate receptor antagonist (ketamine) on primary and secondary hyperalgesia in humans.