Published online December 13, 2004

Pre-emptive analgesia
Jrgen B. Dahl and Steen Miniche
Department of Anaesthesiology, Glostrup University Hospital, Glostrup, Denmark

Transmission of pain signals evoked by tissue damage leads to sensitization of the peripheral and central pain pathways. Pre-emptive analgesia is a treatment that is initiated before the surgical procedure in order to reduce this sensitization. Owing to this protective effect on the nociceptive system, pre-emptive analgesia has the potential to be more effective than a similar analgesic treatment initiated after surgery. Theoretically, immediate postoperative pain may be reduced and the development of chronic pain may be prevented. Although some clinical studies have demonstrated significant effects on acute postoperative pain, no major clinical benefits of pre-emptive analgesia have been documented. The only way to prevent sensitization of the nociceptive system might be to block completely any pain signal originating from the surgical wound from the time of incision until final wound healing. Other pharmacological interventions, including antihyperalgesic drugs such as NMDA-receptor antagonists and gabapentin, may interfere with the induction and maintenance of sensitization. Future studies will investigate the analgesic effect of prolonged multimodal combinations of different classes of traditional analgesics and antihyperalgesics on postoperative pain.

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The concept
Pain signals from damaged tissue are not transmitted to the central nervous system (CNS) through hard-wired pathways. In contrast, nociceptive signals, once initiated, will launch a cascade of alterations in the somatosensory system, including an increase in the responsiveness of both peripheral and central neurons. These alterations will increase the response to subsequent stimuli and thus amplify pain.1 Pre-emptive analgesia is a treatment that is initiated before and is operational during the surgical procedure in order to reduce the physiological consequences of nociceptive transmission provoked by the procedure. Owing to this protective effect on the nociceptive pathways, pre-emptive analgesia has the potential to be more effective than a similar analgesic treatment initiated after surgery. Consequently, immediate postoperative pain may be reduced and the development of chronic pain may be prevented.2
British Medical Bulletin, Vol. 71 The British Council 2004; all rights reserved

Accepted: November 3, 2004 Correspondence to: Jrgen B. Dahl, Department of Anaesthesiology, Glostrup University Hospital Ndr. Ringvej, DK-2600 Glostrup, Denmark. E-mail: jbdahl@dadlnet.dk

British Medical Bulletin 2004; 71: 1327 DOI: 10.1093/bmb/ldh030

J. B. Dahl and S. Miniche

In this article we briefly review the scientific rationale and the clinical evidence for pre-emptive analgesia. Controversies will be discussed, and suggestions for further developments and research will be addressed.

The scientific rationale

Painful or injurious (noxious) stimuli to the body are detected by the free endings of peripheral nerves (primary afferent neurons), jointly called nociceptors. The peripheral terminals of nociceptors act as transducers, converting chemical, mechanical or thermal energy at the site of the stimulus to electrical activity, which is then conducted to the dorsal horn of the CNS (Fig. 1). Nociceptors are subdivided into different groups depending on their location in various tissues and their response to different stimuli. In general, the myelinated A nociceptors are specialized for detecting mechanical and thermal injury and for triggering a rapid sharp pain response, termed first pain. The unmyelinated C nociceptors

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Fig. 1 Tissue damage initiates a number of alterations of the peripheral and the central pain pathways. At the periphery, pain-promoting substances from peripheral nerve endings and extraneural sources (neurokinins, prostaglandins, serotonin, histamine) lead to sensitization of the nociceptors, resulting in altered transduction and increased conduction of nociceptive impulses towards the CNS. The barrage of pain signals from the nociceptors on the WDR neurons leads to prolonged alterations in the responsiveness of these neurons. Signals from A and C fibres are amplified (hyperalgesia), and activity in A fibres is interpreted as pain signals (allodynia). This central sensitization may outlast the stimuli that triggered the alterations in the first place and thus turn into a pain memory.

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respond to strong mechanical, thermal and/or chemical stimuli, and they mediate a more delayed burning pain response, termed second pain. In the dorsal horn, the pain signals are transmitted from the nociceptors to secondary nociceptive neurons. Two classes of dorsal horn neurons are involved in the response to and further signalling of pain sensation: Nociceptive-specific (NS) neurons respond only to pain signals in A and C nociceptors, whereas wide-dynamic-range (WDR) neurons respond to both non-nociceptive impulses in A fibres (e.g. touch) and nociceptive impulses in A and C nociceptors (Fig. 1). A range of substances are involved in the transmission of nociceptive signals in the dorsal horn, including the excitatory amino acids aspartate and glutamate, and substance P, which acts on N-methyl-D-aspartate (NMDA) and 2-amino-3hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors. WDR neurons receive convergent input from primary afferents which supply skin, subcutaneous tissue, muscles and viscera. The activity of these neurons is determined by the convergence of excitatory and inhibitory inputs from nociceptive and non-nociceptive peripheral nerve fibres, local circuit excitatory and inhibitory neurons, and descending inputs from supraspinal sites. Depending on the severity of the injury, external stimuli that activate nociceptors and induce pain may or may not result in overt tissue damage. Activation of nociceptors without accompanying tissue damage generally results in a consistent and proportionate relationship between the stimulus and the response. Consequently, when the stimulus that caused the pain recedes, the pain disappears without leaving any trace in the nociceptive system. In contrast, stimuli associated with actual tissue damage initiate a number of alterations, or modulations, of both the peripheral and the central pain pathways. At the periphery, tissue damage results in a local inflammatory response with release of pain-promoting (algogenic) substances from peripheral nerve endings and extraneural sources (e.g. substance P, prostaglandins, serotonin, bradykinin and histamine) (Fig. 1). These mediators lead to peripheral sensitization of the nociceptors, resulting in altered transduction and increased conduction of nociceptive impulses towards the CNS. In addition, the barrage of pain signals from the nociceptors onto the NS and WDR neurons in the dorsal horn leads to prolonged alterations in the responsiveness of these neurons. Signals from A and C fibres will be amplified (hyperalgesia), and activity in A fibres will be interpreted not as touch but as pain signals by the WDR neurons (allodynia). This central sensitization may outlast the stimuli that triggered the alterations in the first place and thus become a pain memory (Fig. 1). In summary, pain associated with tissue damage results in prolonged modulation of the somatosensory system, with increased responsiveness of both peripheral and central pain pathways.1 Experimental evidence suggests that it may be possible, and indeed preferable, to prevent or
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pre-empt the neurophysiological and biochemical consequences of a noxious input to the CNS rather than to begin treatment when these consequences are already established. Accordingly, prevention of postoperative pain may be more effective than treatment.2

The clinical evidence

The idea of pain prevention was first introduced into clinical practice by Crile in 1913,3 and further developed by Wall4 and Woolf.5 Based on a large body of experimental observations which suggested that analgesic interventions were more effective if they included the period of the noxious stimuli, and not just the post-injury stage, Woolf5 suggested that simple changes in the timing of treatment can have profound effects on postoperative pain. Subsequently, these promising experimental findings were incorporated in clinical testing of the hypothesis. Because the original experimental observations suggested that timing of analgesic treatment in relation to the noxious (surgical) injury was the important issue, most studies of clinical pre-emptive analgesia have been designed to test this hypothesis. A substantial number of different analgesics or analgesic interventions have been investigated in a large number of double-blind randomized controlled trials of identical or very similar analgesic regimens initiated before versus after surgical incision, or before versus after surgical procedure. These studies include investigations of non-steroidal anti-inflammatory drugs (NSAIDs), opioids, ketamine, dextromethorphan, peripheral local anaesthetics and epidural analgesics. A recent meta-analysis summarized the results from 80 trials involving 3761 patients, of whom 1964 received pre-emptive treatment, published between 1983 and 2000.6 Reports that were included in this meta-analysis consisted of double-blind randomized comparisons of identical or nearly identical analgesic regimens initiated before versus after surgical incision/ procedure for postoperative pain relief with or without the use of a double dummy. Reports that were excluded included trials of comparisons of preoperative treatment with placebo treatment versus no treatment, and trials of comparisons of preoperative with preoperative plus postoperative treatment. A brief synopsis of the results of this meta-analysis is given below.

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Non-steroidal anti-inflammatory drugs

Twenty trials studying various odontological, abdominal and orthopaedic procedures were identified. Some aspects of postoperative pain control were improved by pre-emptive treatment in four of the 20 trials, but no
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Fig. 2 Results from a meta-analysis of 80 randomized trials with 3761 patients of whom 1964 received pre-emptive treatment.6 The figure shows the 95% confidence interval of the difference between intervention before and after incision. Numbers in parentheses are the number of trials for each intervention. No clinical benefits were demonstrated with pre-emptive analgesia. In contrast, the WMD in VAS scores with i.v. opioids was statistically significant in favour of the postoperative groups.

improvements were demonstrated in the remaining 16 trials. Quantitative analysis with the calculation of the weighted mean difference (WMD) of visual analogue scale (VAS) pain scores (0 = no pain; 10 = worst pain imaginable) between treatment groups was not significant in 14 trials (Fig. 2). Overall, the meta-analysis demonstrated no analgesic benefit for pre-emptive compared with post-incisional administration of NSAIDs.6

Intravenous opioids

Eight trials compared pre-incisional with post-incisional administration of various opioids. The surgical procedure in all studies was abdominal hysterectomy. None of the studies demonstrated significantly reduced pain scores in the pre-emptive group. In contrast, quantitative analysis of pain scores revealed that the WMD in VAS scores between study groups was statistically significant in favour of the postoperative groups (Fig. 2). It was concluded that no overall improvement in postoperative pain control was observed after pre-emptive administration of systemic opioids.6

N-methyl-D-aspartate receptor antagonists

Eight trials compared pre- versus post-incisional ketamine (six studies) or dextromethorphanin (two studies) in a variety of surgical procedures.
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The results of the review showed that the worst pain score was significantly reduced in one trial of dextromethorphan. No effect on pain scores was observed in the other seven trials. The WMD of VAS scores were not significant (Fig. 2). Supplementary analgesic consumption was significantly reduced by pre-emptive analgesia in three trials, but no significant effects were observed in the other five trials. The overall conclusion of the meta-analysis was that pre-emptive ketamine did not produce any improvement in postoperative pain control. Both studies on dextromethorphan were positive, but the data were too sparse for definitive conclusions to be drawn.6

Epidural, caudal and spinal regimens

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Eighteen trials of pre- versus post-surgically initiated epidural analgesic regimens were identified. These could be divided into trials of single-dose analgesic regimens and trials of continuous analgesic regimens extending 2472 h into the postoperative period. Furthermore, trials of caudal analgesia in children, and one trial of intrathecal anaesthesiaanalgesia were analysed.6 The single-dose epidural analgesic regimens evaluated were pre- versus post-incisional opioids (four trials), local anaesthetics (three trials), combined opioid and local anaesthetic (three trials) and a mixture of opioid and ketamine (one trial). From the quantitative meta-analysis of mean VAS pain scores it was concluded that no significant reduction by pre-emptive single-dose epidural analgesia with opioids or local anaesthetics, or a mixture of the two, could be demonstrated (Fig. 2). However, statistically significant but generally small reductions in analgesic demand were demonstrated in seven of 11 treatment arms with pre-emptive analgesia.6 Eight trials compared different pre- versus post-incisional continuous epidural regimens that extended 2472 h into the postoperative period. The regimens included various mixtures of opioid, local anaesthetic and ketamine. The results from the meta-analysis showed no overall improvement in postoperative pain relief with pre-emptive continuous epidural analgesia (Fig. 2). Finally, pre-emptive treatment was ineffective in four of five studies of caudal block and in the single study of intrathecal block.6

Peripheral local anaesthetics

Twenty trials comparing pre-emptive with post-incisional application of peripheral local anaesthetics were analysed. These were divided into trials of wound infiltration, peripheral nerve block and intraperitoneal infiltration.
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Sixteen trials compared preoperative incisional local anaesthetics with similar post-incisional administration. Quantitative analysis was possible for 14 of these trials. The WMD of VAS pain scores between treatment groups was not significant (Fig. 2). It was concluded that there was no evidence for improved pain relief with pre-emptive local anaesthetic wound infiltration compared with a similar post-incisional administration. Three trials investigated different nerve blocks but found no overall beneficial effects of the pre-emptive regimens. However, pain scores and demand for supplementary ketorolac were reduced in the pre-emptive treatment group in one trial of topical intraperitoneal bupivacaine.6
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Update on studies of pre-emptive analgesia in acute pain

A search on Medline (www.ncbi.nlm.nih.gov/PubMed/) for the period 20012004, using the search term preemptive analgesia OR pre-emptive analgesia, revealed at least 30 randomized studies of pre- versus postoperative administration of various analgesics or analgesic regimens736 that had been published since the meta-analysis performed by Miniche et al.6 A brief summary of the major endpoints of these trials is shown in Table 1. Some reductions in postoperative pain and/or analgesic requirements with pre-emptive analgesia were observed in 13 studies,719 whereas no significant differences were observed in 17 other studies.2036 In particular, the results with various NSAIDs were more positive, with six of eight studies published after 2001 showing a pre-emptive effect (Table 1) compared with only four of 20 studies published before 2001.6 There is no obvious explanation for this discrepancy. In contrast, the results from studies with local anaesthetics (epidural, infiltration, nerve blocks) are almost uniformly negative (Table 1), confirming the results of previous studies.6

Pre-emptive analgesia and chronic pain

It has been suggested that pre-emptive analgesia may reduce the risk of developing chronic postoperative pain. In the only trial to compare the effect of identical pre- versus post-incisional treatment on long-term pain, the percentage of patients with pain at 6 months postoperatively was significantly reduced.37 A study of patients undergoing limb amputation, who were allocated to pre- and intraoperative epidural blockade or to an intraoperative blockade alone, assessed the occurrence of phantom limb pain for the subsequent 12 months.38 The results showed a significant reduction in phantom limb pain 6 months postoperatively in the pre- and intraoperative group,
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Table 1 Summary of major endpoints in randomized studies of pre- versus post-surgical initiation of identical, or nearly identical analgesic regimens, published in 20012004
Reference Procedure Pre/post drug Pain scores Supplementary Comments analgesic demand

Systemic NSAIDS 7 Orthodontic 20 Tonsillectomy 8 Ankle surgery 9 Breast biopsy 10 Breast surgery 11 Knee surgery 21 Laparoscopic cholecystectomy 12 Gynaecological IV, intra-articular or epidural opioids 22 Abdominal hysterectomy 13 Knee surgery 14 Abdominal hysterectomy 23 Abdominal surgery 24 Herniorrhaphy Epidural local anaesthetic 25 Gynaecological

Ibuprofen Ketoprofen Ketorolac Tenoxicam Ketoprofen Rofecoxib Diclofenac Lornoxicam IV morphine Intra-articular morphine Epidural sufentanil Epidural fentanyl Caudal morphine Epidural ropivacaine

(Pre < post) NS Pre < post Pre < post Pre < post Pre < post NS NS

(Modest effect) NS NS Pre < post Pre < post Pre < post NS Pre < post

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Pre < post NS (Pre > post) NS NS

NS Pre < post (Pre < post) NS NS NS

(Modest effect) (Modest effect)

Pre-group received less intraoperative sufentanil Post-group received less study drug

Combined epidural local anaesthetic and opioid 15 Abdominal Epidural bupivacaine + fentanyl hysterectomy 26 Gynaecological Epidural lidocaine + fentanyl 16 Thoracic Epidural bupivacaine + fentanyl NMDA-receptor antagonists 27 Gynaecological 17 Gynaecological 18 Abdominal surgery

Pre < post NS Pre < post

NS NS

Post-group received less study drug NS Pre < post Pre < post NS NS NS NS

IV ketamine IV ketamine IM dextromethorphan

NS Pre < post (Pre < post) NS NS (Pre > post) NS NS NS NS NS NS Pre < post

(Modest effect)

Infiltration or nerve block with local anaesthetics 30 Knee surgery Intra-articular bupivacaine 31 Herniorrhaphy Field block, bupivacaine 28 Gynaecological Infiltration, port sites, lidocaine laparoscopic 29 Laparoscopic Infiltration port sites + topical cholecystectomy peritoneal bupivacaine 32 Tonsillectomy Infiltration, bupivacaine 33 Tympanomastoid Nerve block 34 Laparoscopic Infiltration, port site, cholecystectomy bupivacaine 35 Abdominal hysterectomy Skin infiltration, ropivacaine Multimodal analgesia 36 Nephrectomy 19 Knee surgery Combined i.v. morphine// ketamine/clonidine Combined ketorolac/intra-articular ropivacaine + morphine/ femoral nerve block

(Modest effect)

NS NS NS NS Pre < post

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with a non-significant similar trend 7 days and 1 year postoperatively. Unfortunately, it has not been possible to confirm these findings in subsequent controlled studies, and a recent meta-analysis concluded that there is little evidence from randomized trials to guide clinicians with treatment [of phantom limb pain].39

Overall conclusion on clinical evidence

Statistical improvements in postoperative pain relief following preemptive analgesia compared with post-incisional treatment have been demonstrated for some parameters or time points in 37 of 110 randomized trials. In a meta-analysis of 80 of these trials reported between 1983 and 2000 none of the quantitative analyses of WMD of average VAS pain scores recorded within 24 h after surgery showed significant improvement after the pre-emptive treatment.6 Results from studies published between 2001 and 2004 largely confirm the results from previous studies, allthough results with NSAIDs were more positive in the later studies. However, the overall conclusion is that pre-emptive administration of analgesics in surgical patients has not proved to confer major benefits in terms of immediate postoperative pain relief or reduced need for supplemental analgesics. On the other hand, no major deleterious effects have been identified, and optimal intraoperative analgesia may still be recommended in order to blunt surgical stress response.40 The evidence concerning the effect of pre-emptive analgesia on chronic pain states is sparse, and further research is warranted. It should be emphasized that VAS scores and other measures of pain may be influenced by side effects and other confounding variables, and may not be reliable as the sole measure in the study of pre-emptive analgesia. Furthermore, various psychosocial variables have been shown to influence pain experience of varying duration, but they have not been evaluated in studies of pre-emptive analgesia.26 Assessment of such factors may help to shed light on the processes involved in recovery from post-surgical pain.26

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The controversies
The definition of pre-emptive analgesia has varied, and this has caused confusion, misunderstanding and controversy.2,6,4143 Several papers have compared preoperative administration of analgesics with no treatment versus placebo treatment, and some of these studies have shown prolonged postoperative pain relief in patients receiving active treatment. It has been argued that the pre-emptive regimens in these studies
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had analgesic effects that outlasted the expected clinical duration of action of the agents, and it was suggested that these effects were due to a blockade of nociceptive impulses during surgery, resulting in a reduction of central sensitization (Fig. 3D). A positive result in studies designed to show that an analgesic intervention made before surgery is more effective than no intervention at all may suggest a worthwhile clinical benefit. However, these results are not evidence for or against a pre-emptive effect, since such evidence requires a control of the same intervention made at some time point after initiation of the surgical procedure.43 As emphasized previously, the concept of pre-emptive analgesia originates from experimental studies which focus on the noxious stimulus as the trigger of central sensitization. The experimental noxious stimulus has been interpreted as the surgical incision per se by some investigators, and to the entire surgical procedure by others. Consequently, some clinical trials have compared identical or very similar analgesic regimens initiated before versus after the surgical incision, whereas others have compared before versus after the surgical procedure. A number of trials have compared continuous infusion regimens initiated before the surgical incision versus after closure of the surgical wound in order to block nociceptive transmission during the entire operation with the pre-emptive regimen (Fig. 3AC). However, it is possible that none of these approaches reproduces the experimental situation. Pain can be divided by mechanism into nociceptive, inflammatory and neurogenic pain. Nociceptive pain is often regarded as the key feature of acute postoperative pain. However, in addition to incisional damage to skin and various other tissues the nociceptive barrage during surgery is followed by a protracted inflammatory state in the postoperative period, both of which may contribute to central sensitization.41,43 In contrast with experimental studies, where the nociceptive stimuli usually do not involve severe ongoing tissue damage, and where an analgesic intervention may block most of the afferent nociceptive input to the CNS (Fig. 4A), the noxious stimuli occurring during and after surgery may be insufficiently reduced by conventional analgesic methods. Consequently, the single-dose regimens or even the prolonged continuous pre-emptive infusion regimens explored in clinical studies may have been inadequate (intensity and duration) to prevent or even reduce the central neuronal alterations (Fig. 4B). Indeed, it may be difficult to prevent central sensitization in the clinical situation. There is no systematic evidence in the clinical literature to suggest that a particular pre-emptive study design (e.g. preincisional/post-incisional or pre-surgical/post-surgical) will influence a particular conclusion as to whether it supported or refuted a preemptive analgesic effect.
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Fig. 3 Different study designs employed to investigate the role of post-injury sensitization in surgical pain. (A) Some clinical trials have compared identical or very similar analgesic regimens initiated before versus after the entire surgical procedure, while (B) others have compared regimens initiated before versus after the surgical incision per se. (C) A number of trials have compared continuous infusion regimens initiated before the surgical incision versus after closure of the surgical wound in order to block nociceptive transmission during the entire operation and postoperative period with the pre-emptive regimen. (D) Several studies have compared preoperative administration of analgesics with no treatment versus placebo treatment. However, this design is not valid for demonstrating a pre-emptive effect.

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Fig. 4 Possible explanations for the lack of effects of pre-emptive analgesia in (A) experimental compared with (B) clinical studies. In experimental studies, the noxious stimuli did not involve severe ongoing tissue damage and were completely blocked by the analgesic intervention (A). Conventional clinical methods of analgesia may provide insufficient blockade during surgery, and central sensitization may be generated not only during surgery, but also in the postoperative period (B). A short-term pre-emptive regimen may not have major effects in this situation. Adapted from Kehlet H and Dahl JB (1995) Preemptive analgesia: Is it effective in clinical pain states? In Gebhart GF (ed) Progress in Pain Research and Management, Vol. 5, Visceral pain. Seattle, WA: IASP Press, 489504.

The future
Prevention of injury-induced functional alterations in the CNS by preemptive analgesia is a fascinating working hypothesis based on substantial scientific evidence. The hypothesis has attracted a great deal of attention, and has contributed to a substantial increase in our knowledge of the mechanisms of acute pain. Recent studies have focused on the central sensitization process itself rather than on pre-emptive analgesia, and a number of new pharmacological interventions have been demonstrated to interfere with the induction and maintenance of central hypersensitivity. Ketamine, dextromethorphan and gabapentin have demonstrated promising anti-hyperalgesic potential in a number of clinical trials of postoperative pain.4446 Future studies should investigate the analgesic effect of
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combinations of different classes of traditional analgesics and antihyperalgesics. Furthermore, such studies should redirect their focus from the timing of perioperative analgesia to protective analgesia,46 with the aim of preventing hypersensitivity to pain. The only way to prevent central sensitization might be to completely block any pain originating from the surgical wound from the time of incision until final wound healing. Consequently, an ideal pre-emptive, or protective, analgesic clinical trial should investigate the effect of intense and prolonged multimodal (protective) interventions versus less aggressive conventional perioperative analgesia on immediate and late postoperative pain6,46 as well as on various psychosocial variables.26
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References
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