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British Medical Bulletin 2004; 71: 13–27 British Medical Bulletin, Vol. 71 © The British Council 2004; all rights reserved

DOI: 10.1093/bmb/ldh030

Pre-emptive analgesia

Jørgen B. Dahl and Steen Møiniche

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.

The concept

Pain signals from damaged tissue are not transmitted to the centralnervous system (CNS) through ‘hard-wired’ pathways. In contrast,nociceptive signals, once initiated, will launch a cascade of alterations inthe somatosensory system, including an increase in the responsiveness of both peripheral and central neurons. These alterations will increase theresponse to subsequent stimuli and thus amplify pain.1

Pre-emptive analgesia is a treatment that is initiated before and is opera-tional during the surgical procedure in order to reduce the physiologicalconsequences of nociceptive transmission provoked by the procedure.Owing to this ‘protective’ effect on the nociceptive pathways, pre-emptiveanalgesia has the potential to be more effective than a similar analgesictreatment initiated after surgery. Consequently, immediate postoperativepain may be reduced and the development of chronic pain may beprevented.2

Accepted:

November 3, 2004

Correspondence to:

Jørgen B. Dahl,

Department of

Anaesthesiology,

Glostrup University

Hospital Ndr. Ringvej,

DK-2600 Glostrup,

Denmark. E-mail:

[email protected]

Published online December 13, 2004



J. B. Dahl and S. Møiniche

14 British Medical Bulletin 2004;71

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

The scientific rationale

Painful or injurious (noxious) stimuli to the body are detected by the freeendings of peripheral nerves (primary afferent neurons), jointly callednociceptors. The peripheral terminals of nociceptors act as transducers,converting chemical, mechanical or thermal energy at the site of thestimulus to electrical activity, which is then conducted to the dorsal hornof the CNS (Fig. 1). Nociceptors are subdivided into different groupsdepending on their location in various tissues and their response to differ-ent stimuli. In general, the myelinated Aδ nociceptors are specialized fordetecting mechanical and thermal injury and for triggering a rapid sharppain response, termed ‘first pain’. The unmyelinated C nociceptors

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

Aδ and C fibres are amplified (hyperalgesia), and activity in Aβ fibres is interpreted as pain

signals (allodynia). This central sensitization may outlast the stimuli that triggered the alter-

ations in the first place and thus turn into a ‘pain memory’.




British Medical Bulletin 2004;71 15

respond to strong mechanical, thermal and/or chemical stimuli, and theymediate a more delayed burning pain response, termed ‘second pain’.

In the dorsal horn, the pain signals are transmitted from the nociceptorsto secondary nociceptive neurons. Two classes of dorsal horn neurons areinvolved in the response to and further signalling of pain sensation:

Nociceptive-specific (NS) neurons respond only to pain signals in Aδ andC nociceptors, whereas wide-dynamic-range (WDR) neurons respond toboth non-nociceptive impulses in Aβ fibres (e.g. touch) and nociceptiveimpulses in Aδ and C nociceptors (Fig. 1). A range of substances areinvolved in the transmission of nociceptive signals in the dorsal horn,including the excitatory amino acids aspartate and glutamate, and sub-stance P, which acts on N -methyl-D-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors.

WDR neurons receive convergent input from primary afferents whichsupply skin, subcutaneous tissue, muscles and viscera. The activity of these neurons is determined by the convergence of excitatory and inhibi-tory inputs from nociceptive and non-nociceptive peripheral nervefibres, local circuit excitatory and inhibitory neurons, and descendinginputs from supraspinal sites.

Depending on the severity of the injury, external stimuli that activate noci-ceptors and induce pain may or may not result in overt tissue damage. Acti-vation of nociceptors without accompanying tissue damage generally resultsin a consistent and proportionate relationship between the stimulus and theresponse. Consequently, when the stimulus that caused the pain recedes, thepain 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 thecentral pain pathways. At the periphery, tissue damage results in a localinflammatory 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, result-ing in altered transduction and increased conduction of nociceptiveimpulses towards the CNS. In addition, the barrage of pain signals fromthe nociceptors onto the NS and WDR neurons in the dorsal horn leads toprolonged alterations in the responsiveness of these neurons. Signals from

Aδ and C fibres will be amplified (hyperalgesia), and activity in Aβ fibreswill be interpreted not as touch but as pain signals by the WDR neurons(allodynia). This central sensitization may outlast the stimuli that triggeredthe alterations in the first place and thus become a ‘pain memory’ (Fig. 1).

In summary, pain associated with tissue damage results in prolongedmodulation of the somatosensory system, with increased responsivenessof both peripheral and central pain pathways.1 Experimental evidencesuggests that it may be possible, and indeed preferable, to prevent or





‘pre-empt’ the neurophysiological and biochemical consequences of anoxious input to the CNS rather than to begin treatment when theseconsequences are already established. Accordingly, prevention of post-operative pain may be more effective than treatment.2

The clinical evidence

The idea of pain prevention was first introduced into clinical practice byCrile in 1913,3 and further developed by Wall4 and Woolf.5 Based on alarge body of experimental observations which suggested that analgesicinterventions were more effective if they included the period of the nox-ious stimuli, and not just the post-injury stage, Woolf 5 suggested that‘simple changes in the timing of treatment can have profound effects onpostoperative pain’.

Subsequently, these promising experimental findings were incorpo-rated in clinical testing of the hypothesis. Because the original experi-mental observations suggested that timing of analgesic treatment inrelation to the noxious (surgical) injury was the important issue, moststudies of clinical pre-emptive analgesia have been designed to test thishypothesis. A substantial number of different analgesics or analgesicinterventions have been investigated in a large number of double-blindrandomized controlled trials of identical or very similar analgesic regi-mens initiated before versus after surgical incision, or before versus aftersurgical procedure. These studies include investigations of non-steroidalanti-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, publishedbetween 1983 and 2000.6 Reports that were included in this meta-analysisconsisted of double-blind randomized comparisons of identical or nearlyidentical analgesic regimens initiated before versus after surgical incision/ procedure for postoperative pain relief with or without the use of a doubledummy. Reports that were excluded included trials of comparisons of pre-operative treatment with placebo treatment versus no treatment, and trialsof comparisons of preoperative with preoperative plus postoperative treat-

ment. A brief synopsis of the results of this meta-analysis is given below.

Non-steroidal anti-inflammatory drugs

Twenty trials studying various odontological, abdominal and orthopaedicprocedures were identified. Some aspects of postoperative pain controlwere improved by pre-emptive treatment in four of the 20 trials, but no





improvements were demonstrated in the remaining 16 trials. Quantitativeanalysis with the calculation of the weighted mean difference (WMD) of visual analogue scale (VAS) pain scores (0 = no pain; 10 = worst painimaginable) 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 hys-terectomy. None of the studies demonstrated significantly reduced painscores in the pre-emptive group. In contrast, quantitative analysis of painscores revealed that the WMD in VAS scores between study groups wasstatistically significant in favour of the postoperative groups (Fig. 2). It

was concluded that no overall improvement in postoperative pain controlwas 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.

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.





The results of the review showed that the ‘worst pain score’ was signifi-cantly reduced in one trial of dextromethorphan. No effect on painscores was observed in the other seven trials. The WMD of VAS scoreswere not significant (Fig. 2). Supplementary analgesic consumption wassignificantly reduced by pre-emptive analgesia in three trials, but no

significant effects were observed in the other five trials. The overallconclusion of the meta-analysis was that pre-emptive ketamine did notproduce any improvement in postoperative pain control. Both studies ondextromethorphan were positive, but the data were too sparse for defin-itive conclusions to be drawn.6

Epidural, caudal and spinal regimens

Eighteen trials of pre- versus post-surgically initiated epidural analgesicregimens were identified. These could be divided into trials of single-dose

analgesic regimens and trials of continuous analgesic regimens extending24–72 h into the postoperative period. Furthermore, trials of caudalanalgesia in children, and one trial of intrathecal anaesthesia–analgesiawere analysed.6

The single-dose epidural analgesic regimens evaluated were pre- versuspost-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 bypre-emptive single-dose epidural analgesia with opioids or local anaesthetics,

or a mixture of the two, could be demonstrated (Fig. 2). However, statisti-cally significant but generally small reductions in analgesic demand weredemonstrated in seven of 11 treatment arms with pre-emptive analgesia.6

Eight trials compared different pre- versus post-incisional continuousepidural regimens that extended 24–72 h into the postoperative period.The regimens included various mixtures of opioid, local anaesthetic andketamine. The results from the meta-analysis showed no overall improve-ment in postoperative pain relief with pre-emptive continuous epiduralanalgesia (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 applicationof peripheral local anaesthetics were analysed. These were divided intotrials of wound infiltration, peripheral nerve block and intraperitonealinfiltration.





Sixteen trials compared preoperative incisional local anaestheticswith similar post-incisional administration. Quantitative analysis waspossible for 14 of these trials. The WMD of VAS pain scores betweentreatment groups was not significant (Fig. 2). It was concluded thatthere was no evidence for improved pain relief with pre-emptive local

anaesthetic wound infiltration compared with a similar post-incisionaladministration.

Three trials investigated different nerve blocks but found no overallbeneficial effects of the pre-emptive regimens. However, pain scores anddemand for supplementary ketorolac were reduced in the pre-emptivetreatment group in one trial of topical intraperitoneal bupivacaine.6

Update on studies of pre-emptive analgesia in acute pain

A search on Medline (www.ncbi.nlm.nih.gov/PubMed/) for the period

2001–2004, using the search term ‘preemptive analgesia OR pre-emptiveanalgesia’, revealed at least 30 randomized studies of pre- versus postop-erative administration of various analgesics or analgesic regimens7–36 thathad been published since the meta-analysis performed by Møinicheet al .6 A brief summary of the major endpoints of these trials is shown inTable 1. Some reductions in postoperative pain and/or analgesic require-ments with pre-emptive analgesia were observed in 13 studies,7–19

whereas no significant differences were observed in 17 other studies.20–36

In particular, the results with various NSAIDs were more positive, withsix 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, theresults from studies with local anaesthetics (epidural, infiltration, nerveblocks) are almost uniformly negative (Table 1), confirming the resultsof 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-termpain, the percentage of patients with pain at 6 months postoperativelywas significantly reduced.37

A study of patients undergoing limb amputation, who were allocated topre- and intraoperative epidural blockade or to an intraoperative blockadealone, assessed the occurrence of phantom limb pain for the subsequent 12months.38 The results showed a significant reduction in phantom limbpain 6 months postoperatively in the pre- and intraoperative group,





Table 1 Summary of major endpoints in randomized studies of pre- versus post-surgical initiation of identical, or

nearly identical analgesic regimens, published in 2001–2004

Reference Procedure Pre/post drug Pain scores Supplementary

analgesic

demand

Comments

Systemic NSAIDS

7 Orthodontic Ibuprofen (Pre < post) (Modest effect)

20 Tonsillectomy Ketoprofen NS NS

8 Ankle surgery Ketorolac Pre < post NS

9 Breast biopsy Tenoxicam Pre < post Pre < post

10 Breast surgery Ketoprofen Pre < post Pre < post

11 Knee surgery Rofecoxib Pre < post Pre < post

21 Laparoscopic

cholecystectomy

Diclofenac NS NS

12 Gynaecological Lornoxicam NS Pre < post

IV, intra-articular or epidural opioids

22 Abdominal hysterectomy IV morphine NS

13 Knee surgery Intra-articular morphine Pre < post Pre < post

14 Abdominal hysterectomy Epidural sufentanil NS (Pre < post) (Modest effect)

23 Abdominal surgery Epidural fentanyl (Pre > post) NS (Modest effect)

24 Herniorrhaphy Caudal morphine NS NS

Epidural local anaesthetic

25 Gynaecological Epidural ropivacaine NS NS Pre-group received less

intraoperative sufentanil

Combined epidural local anaesthetic and opioid

15 Abdominal

hysterectomy

Epidural bupivacaine + fentanyl Pre < post NS Post-group received less

study drug

26 Gynaecological Epidural lidocaine +

fentanyl

NS NS

16 Thoracic Epidural bupivacaine + fentanyl Pre < post Post-group received less

study drug

NMDA-receptor antagonists27 Gynaecological IV ketamine NS NS

17 Gynaecological IV ketamine Pre < post Pre < post

18 Abdominal surgery IM dextromethorphan (Pre < post) Pre < post (Modest effect)

Infiltration or nerve block with local anaesthetics

30 Knee surgery Intra-articular bupivacaine NS NS

31 Herniorrhaphy Field block, bupivacaine NS NS

28 Gynaecological

laparoscopic

Infiltration, port sites, lidocaine (Pre > post) NS (Modest effect)

29 Laparoscopic

cholecystectomy

Infiltration port sites + topical

peritoneal bupivacaine

NS NS

32 Tonsillectomy Infiltration, bupivacaine NS

33 Tympanomastoid Nerve block NS NS

34 Laparoscopiccholecystectomy

Infiltration, port site,bupivacaine

NS NS

35 Abdominal hysterectomy Skin infiltration, ropivacaine NS NS

Multimodal analgesia

36 Nephrectomy Combined i.v. morphine//

ketamine/clonidine

NS NS

19 Knee surgery Combined ketorolac/intra-articular

ropivacaine + morphine/

femoral nerve block

Pre < post Pre < post





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

Overall conclusion on clinical evidence

Statistical improvements in postoperative pain relief following pre-emptive analgesia compared with post-incisional treatment have beendemonstrated for some parameters or time points in 37 of 110 rand-omized trials. In a meta-analysis of 80 of these trials reported between1983 and 2000 none of the quantitative analyses of WMD of averageVAS pain scores recorded within 24 h after surgery showed significantimprovement after the pre-emptive treatment.6 Results from studies

published between 2001 and 2004 largely confirm the results fromprevious studies, allthough results with NSAIDs were more positive inthe later studies. However, the overall conclusion is that pre-emptiveadministration of analgesics in surgical patients has not proved to confermajor benefits in terms of immediate postoperative pain relief orreduced need for supplemental analgesics. On the other hand, no majordeleterious effects have been identified, and optimal intraoperative anal-gesia may still be recommended in order to blunt surgical stressresponse.40 The evidence concerning the effect of pre-emptive analgesiaon chronic pain states is sparse, and further research is warranted.

It should be emphasized that VAS scores and other measures of painmay be influenced by side effects and other confounding variables, andmay not be reliable as the sole measure in the study of pre-emptive anal-gesia. Furthermore, various psychosocial variables have been shown toinfluence pain experience of varying duration, but they have not beenevaluated in studies of pre-emptive analgesia.26 Assessment of suchfactors ‘may help to shed light on the processes involved in recoveryfrom post-surgical pain’.26

The controversies

The definition of pre-emptive analgesia has varied, and this has causedconfusion, misunderstanding and controversy.2,6,41–43 Several papershave compared preoperative administration of analgesics with no treat-ment versus placebo treatment, and some of these studies have shownprolonged postoperative pain relief in patients receiving active treat-ment. It has been argued that the ‘pre-emptive’ regimens in these studies





had analgesic effects that outlasted the expected clinical duration of action of the agents, and it was suggested that these effects were dueto a blockade of nociceptive impulses during surgery, resulting in areduction of central sensitization (Fig. 3D). A positive result in studiesdesigned to show that an analgesic intervention made before surgery is

more effective than no intervention at all may suggest a worthwhileclinical benefit. However, these results are not evidence for or against apre-emptive effect, since such evidence requires a control of the sameintervention made at some time point after initiation of the surgicalprocedure.43

As emphasized previously, the concept of pre-emptive analgesia origi-nates from experimental studies which focus on the noxious stimulus asthe trigger of central sensitization. The experimental noxious stimulushas been interpreted as the surgical incision per se by some investigators,and to the entire surgical procedure by others. Consequently, someclinical trials have compared identical or very similar analgesic regimensinitiated before versus after the surgical incision, whereas others havecompared before versus after the surgical procedure. A number of trialshave compared continuous infusion regimens initiated before the surgicalincision versus after closure of the surgical wound in order to blocknociceptive transmission during the entire operation with the pre-emptiveregimen (Fig. 3A–C).

However, it is possible that none of these approaches reproduces theexperimental situation. Pain can be divided by mechanism into nocicep-tive, inflammatory and neurogenic pain. Nociceptive pain is oftenregarded as the key feature of acute postoperative pain. However, in

addition to incisional damage to skin and various other tissues the noci-ceptive barrage during surgery is followed by a protracted inflamma-tory state in the postoperative period, both of which may contribute tocentral sensitization.41,43 In contrast with experimental studies, wherethe nociceptive stimuli usually do not involve severe ongoing tissuedamage, and where an analgesic intervention may block most of theafferent nociceptive input to the CNS (Fig. 4A), the noxious stimulioccurring during and after surgery may be insufficiently reduced byconventional analgesic methods. Consequently, the single-dose regimensor even the prolonged continuous pre-emptive infusion regimens

explored in clinical studies may have been inadequate (intensity andduration) to prevent or even reduce the central neuronal alterations(Fig. 4B). Indeed, it may be difficult to prevent central sensitization inthe clinical situation. There is no systematic evidence in the clinicalliterature to suggest that a particular pre-emptive study design (e.g. pre-incisional/post-incisional or pre-surgical/post-surgical) will influence aparticular conclusion as to whether it supported or refuted a ‘pre-emptive’ analgesic effect.





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 numberof trials have compared continuous infusion regimens initiated before the surgical incision

versus after closure of the surgical wound in order to block nociceptive transmission duringthe 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.

A

B

C

D





The future

Prevention of injury-induced functional alterations in the CNS by pre-emptive analgesia is a fascinating working hypothesis based on substantialscientific evidence. The hypothesis has attracted a great deal of attention,

and has contributed to a substantial increase in our knowledge of themechanisms of acute pain. Recent studies have focused on the centralsensitization process itself rather than on pre-emptive analgesia, and anumber of ‘new’ pharmacological interventions have been demonstratedto interfere with the induction and maintenance of central hypersensitivity.Ketamine, dextromethorphan and gabapentin have demonstrated promis-ing anti-hyperalgesic potential in a number of clinical trials of postop-erative pain.44–46 Future studies should investigate the analgesic effect of

Fig. 4 Possible explanations for the lack of effects of pre-emptive analgesia in (A) experi-

mental 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 block-

ade 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 Manage-

ment , Vol. 5, Visceral pain. Seattle, WA: IASP Press, 489–504.

A B





combinations of different classes of ‘traditional’ analgesics and ‘antihy-peralgesics’. Furthermore, such studies should redirect their focus fromthe timing of perioperative analgesia to protective analgesia,46 with theaim of preventing hypersensitivity to pain. The only way to prevent cen-tral 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 clinicaltrial should investigate the effect of intense and prolonged multimodal(protective) interventions versus less aggressive conventional periopera-tive analgesia on immediate and late postoperative pain6,46 as well as onvarious psychosocial variables.26

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