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Timing of treatment and preemptive analgesia


Definitions and terminology 114 Summary and conclusions 127

Search strategies and criteria for including studies 116 References 128
Literature review 116 Appendix 135
Recommendations for future research 125

The management of acute postoperative pain has been ral sensitization or hyperexcitability that amplifies sub-
dominated by an outdated conceptualization of pain. I sequent input from the wound and leads to heightened
Pain is viewed as the endproduct of a passive transmis- postoperative pain. By interrupting the transmission of
sion system that faithfully transmits a peripheral signal noxious perioperative inputs to the spinal cord at various
to the spinal cord and on up to a pain center in the brain. points in time throughout the perioperative period, a pre-
This view has led to an approach to managing postopera- ventive approach can significantly reduce the induction
tive pain that does not provide adequate control of pain, of central sensitization, resulting in reduced pain inten-
in part because it focuses on treating the patient only after sity and lower analgesic requirements.
the pain is well entrenched. Patients are transported to The goal of this chapter is to critically review the lit-
the recovery room after surgery, often in agonizing pain, erature that examines the effect of the timing of adminis-
where they then receive incremental doses of opioids in tration of a variety of analgesic and anesthetic agents on
an effort to reduce already established pain. However, postoperative pain and analgesic consumption. The first
basic science and clinical data show that brief, noxious section provides a brief review of the history and recent
inputs or frank injury due to C-fiber activation (e.g. cut- progress in preemptive analgesia, followed by a descrip-
ting tissue, nerve, and bone) induce long-lasting changes tion of the targets of a preemptive analgesic approach,
in central neural function that persist after the offending and the definitions of preemptive and preventive anal-
stimulus has been removed or the injury has healed. 2 The gesia used in the present review. Experimental designs
recognition that the processes involved in pain percep- are outlined that distinguish preemptive and preven-
tion involve a dynamic interplay between peripheral and tive analgesia. The second section describes the criteria
central mechanisms is inconsistent with the Simplistic used for including studies in the present review and the
notion that pain results from transmission of impulses experimental designs and treatment combinations that
aiong a straight through pathway from the site of injury have been used in clinical studies that alter the timing
to the brain. of administration of analgesic agents. In the third sec-
The practice of treating pain only after it has been tion, the outcomes of the identified studies are reviewed
established is slowly being supplanted by a preventive according to the target agent(s) administered, the timing
approach that aims to block transmission of noxious of administration relative to incision, route and dose of
inputs before, during, and after surgery. The idea behind administration, and use of additional analgeSiC agents
this approach is not simply that it reduces nociception in the perioperative period. Outcomes are described in
and stress during surgery - although these are obviously terms of the presence or absence or a preemptive or pre-
worthwhile goals. The hypothesis is that the transmission ventive effect. The final section concludes with recom-
of noxious afferent input from the periphery (e.g. arising mendations for future research. Throughout the chapter,
from preoperative pain, incision, noxious intraoperative an attempt is made to highlight the enormous variability
events, and postoperative inflammation and ectopia) to present in many aspects of the clinical studies.
the spinal cord induces a prolonged state of central neu-
DEFINITIONS AND TERMINOLOGY Targets of preemptive and preventive

From a conceptual point of view, the perioperative period

History and recent progress in preemptive can be divided into three fairly distinct phases: preopera-
analgesia tive, intraoperative, and postoperative (Fig. 7.1). The roles
of specific factors within these three phases (as well as the
The possibility that pain after surgery might be amplified interaction between factors) contribute to the develop-
by the noxious events induced by surgical incision was ment of acute postoperative pain. These factors include:
initially put forward by Crile3 and more recently by Wall, 4 (1) preoperative noxious inputs and pain, (2) noxious
who coined the term "preemptive preoperative analge- intraoperative inputs ariSing from the cutting of skin,
sia." Wall suggested that administration of opioids and/or muscle, nerve and bone, wound retraction, etc., and (3)
local anesthetics before surgery might reduce the central postoperative noxious inputs, including those arising
(spinal) neural effects of the C-fiber-induced injury bar- from the inflammatory response and ectopiC neural activ-
rage associated with incision and thereby reduce postop- ity in the case of postsurgical nerve injury. Each of these
erative pain intensity. factors can contribute to both peripheral and central sen-
Since then it has been documented that, although gen- sitization and each is a legitimate target for a preventive
eral anesthesia may attenuate the transmission of nox- approach. The relative contribution of these three factors
ious afferent information from the periphery to the spinal to acute postoperative pain is dependent on the surgi-
cord and brain, it does not block it. 5.6 Moreover, it appears cal procedure, extent and nature of tissue damage, dura-
that systemic opioids may not provide a sufficiently dense tion of surgery, timing of treatments relative to incision,
blockade of spinal nociceptive neurons to prevent central pharmacological activity of the agent(s) used preopera-
sensitization.) The clinical Significance of these findings tively, presence or absence of additional analgeSia intra-
for patients that receive general anesthesia during surgery operatively, nature of postoperative analgesia, and a host
is that, while they are unconscious, the processes leading of other variables. Minimizing the negative impact of as
to sensitization of dorsal horn neurons are unaffected by many of these factors in the three phases will increase the
the general anesthesia or routine doses of opioids. This likelihood of preventing the induction and maintenance
sets the stage for increased postsurgical pain and an of peripheral and central sensitization. Preventing sensi-
increased requirement for analgesics. tization will reduce pain and analgesic requirements.
Notably absent from this first definition of preemp- Figure 7.1 depicts the eight possible treatment com-
tive analgesia was the imperative to compare a preop- binations of administering or not administering analge-
erative intervention with a postoperative intervention 8 sics across the three peri operative phases (preoperative,
This requirement, adopted shortly thereafter, imposed a intraoperative, and postoperative). The preoperative
constraint that limited the demonstration of preemptive period encompasses interventions that begin days before
analgesia to a narrow set of experimental designs with lit- surgery up to those administered just minutes before skin
tle potential for clinically significant effects. The almost incision. The intraoperative period includes interven-
exclusive focus on this narrow definition of preemptive tions started immediately after incision up to those ini-
analgesia had the unintended effect of diverting attention tiated just prior to the end of surgery (i.e. skin closure).
away from certain clinically Significant findings (e.g. from The postoperative period includes interventions started
studies that compared a preoperative intervention with a immediately after the end of surgery and may extend for
placebo-controlled condition) because they did not con- days thereafter. Variability in the timing of administration
form to what had become the accepted definition of pre- of analgesic agents is greatest in the pre- and postopera-
emptive analgesia. tive periods (e.g. from days to minutes), but even within
Since its introduction into the pain and anesthesia lit- the intraoperative period there is considerable potential
eratures' the concept of preemptive analgesia has evolved, for differences among studies as to when a postincisional
based in part on confirmatory and contradictory evi- intervention is administered (e.g. from minutes to hours).
dence from clinical studies, new developments in basic The eight treatment combinations give rise to 28 different
science, and critical thought. This evolution has led to two-group deSigns.
progress in our understanding of the mechanisms that
contribute to acute postoperative pain. The suggestion
Defining preemptive and preventive
that surgical incision triggered central sensitization has
been expanded to include the sensitizing effects of pre-
operative noxious inputs and pain, other noxious intra-
There has been substantial debate over the appropriate
operative stimuli, as well as postoperative inflammatory
definition of preemptive analgesia. 8- 18 This has led to a
mediators and ectopic neural activity.
variety of different terms and considerable confusion
over what constitutes a preemptive analgesic effect.
Perioperative period Figure 7 _1 Schematic representation
Treatment showing the presence (+) or absence
combination Preoperative Intraoperative: Postoperative (-) of analgesic or local anesthetic
administration during the three
------. - - - perioperative phases of surgery
(preoperative, intraoperative, and
postoperative). The administration or
+ - - nonadministration of analgesics during
the three perioperative phases yields
3 ------. - + - eight different treatment combinations.

4 ------. - - +

5 ------. + + -
6 ----- ... + - +

7 ------. - + +

8 ------. + + +

Time Incision End of surgery

For historical purposes, and to avoid further confu- ventive analgesia to refer to results from designs that do
sion, I will use the term preemptive analgesia to refer to not incorporate a postincision or postsurgical interven-
evidence (Le. reduced pain and/or analgesic consump- tion (e.g. treatment combination 1;2 or 1;8 in Fig. 7.1), or,
tion) that preoperative treatment is more effective than if they do, the pre- and post-treatments are not admin-
the identical treatment administered after incision or sur- istered in an identical manner (e.g. differences in dose
gery (e.g. treatment combinations 2;3 or 2;4 in Fig. 7.1). or route). A preventive analgeSiC effect is demonstrated
According to this definition, the only difference between when postoperative pain and/or analgesic consumption
the groups is the timing of administration of the phar- is reduced relative to another treatment, a placebo treat-
macological agent relative to incision B . 14 As it turns out, ment' or no treatment as long as the effect is observed
the requirement that the groups be treated identically at a point in time that exceeds the expected duration of
with the exception of timing is rarely achieved because action of the target agent. Thus, in the absence of a post-
it necessitates treating the two groups differently with treatment condition, the finding that pain or analgesic
respect to other potentially important anesthetic factors consumption is reduced relative to an untreated or pla-
that may unwittingly influence the outcome of the study. cebo-controlled condition is evidence of a preventive
Given identical analgesia, it may not be desirable or even analgesic effect; such a design, however, does not provide
safe to ensure that the groups are treated similarly with information about the factors underlying the effect or the
respect to other anesthetic agents. time frame within which the effect occurred.
As previously noted, this definition of preemptive Demonstration of a preventive effect does not require
analgesia is too restrictive and narrow. 13.14.19 Demonstrat- that an intervention be initiated before surgery; the tim-
ing that presurgical treatment with analgesics, but not a ing of treatment may be during the procedure (e.g. treat-
placebo, lessens pain and decreases postoperative analge- ment combination 1;3 in Fig. 7.1) or even after surgery
sic requirements at a time when the agents are no longer (e.g. treatment combination 1;4 in Fig. 7.1). For example,
clinically active7.2° suggests that some aspect of postoper- a preventive effect would be demonstrated if postopera-
ative pain can be prevented [although the mechanism(s) tive administration of a local anesthetic but not a placebo
for this effect and the time frame within which the effect (in the context of an unchecked injury barrage from inci-
occurs remain obscure]. Thus, I will use the term pre- sion and other intraoperative events) resulted in reduced
postoperative pain and analgesic consumption after the had an effect that was not significantly different from the
effects of the local anesthetic wore ofFlZi.B4Thus. the aim control condition. Also listed is the frequency of studies
of preemptive and preventive analgesia is to prevent or reporting effects opposite to that predicted.
minimize central sensitization brought about by noxious
preoperative, intraoperative, and postoperative stimuli.
INCLUDING STUDIES Timing of administration of local
A PubMed® database search was conducted from
Table A7.1 describes the 59 studies that were found to
December 1987 to January 2001 using the following key-
have examined the timing of administration of local
words and limiting the search strategy to English lan-
anesthetic agents relative to incision. A variety of surgi-
guage publications using human subjects: pre-emptive or
cal procedures has been studied, including third molar
preemptive anaigesia, preempts, pre-operative, preopera- extraction,14**:15.1S**.77 tonsillectomy,1B**-80.S1.82**.83 thy-
tive, post-operative, postoperative, pre-incision, preinci-
roid surgery,84**.8S** cholecystectomy,86.88 laparoscopic
sion, post-incision, postincision, timing. The reference surgery,89**-91.92,93**,94** inguinal hernia repair,11**.22**,
sections of the relevant articles were reviewed and addi- 95,90**.97**.98.99**·101.102**,103 appendectomy, !G7-I09 circumci-
tional articles were obtained if they evaluated the ques-
sion,104 hypospadias repair, 106** major abdornihal~gyne­
tion of timing of analgesic administration. cological surgery, 110-113.114**.115** cesarean section, 116**-119
The following criteria were used to select empirical
lower abdominal surgery, 120** laparotomy, 121 lumbar dis-
studies for review in the present
kectomy,122** arthroscopic knee surgery,123 posterolat-
1 Randomized. eral thoracotomy,124** hemorrhoidectomy,125.116 breast
2 Double-blind assessments of pain and analgesic use. biopsy,127 strabismus surgery,liB and hand and forearm
3 Report of pain using a reliable and valid measure. surgery. 129
4 Report of analgesic consumption. The most frequent designs compared preoperative
5 For studies that assess the effect of timing accord- administration of a local anesthetic with a placebo or
ing to the preventive definition outlined above, mea- another active agent (I.e. evaluation of preventive effects).
sures of pain and analgesic consumption reported at The next most commonly used designs compared preop-
a point in time that exceeds the duration of action of erative administration of a local anesthetic with the same
the target agent whose effect on postoperative pain agent administered intraoperatively, postoperatively, or
is being examined. This criterion was included to both preoperatively and postoperatively (Tables 7.2 and
ensure that the observed effects are not simply anal- 7.3). Local anesthetics were administered by cutaneous,
gesic effects. subcutaneous, and fascial infiltration, wound infiltration,
6 The fmal criterion was the absence of design flaws, topical spray, nerve blocks, and by the epidural and spi-
methodological problems, or confounds that render nal routes.
interpretation of the results ambiguous. Across these various factors, there is a significant
difference in outcome between studies that evaluate
Table 7.1 contains the studies that were excluded from
preemptive compared with preventive effects of local
review and shows which one or more of the six inclusion
anesthetics (Table 7.3). Specifically, there is a greater
criteria were not met.
proportion of positive preventive effects than
The results of the PubMed® search and subsequent
would be expected by chance alone. Seventy percent
review of identified articles resulted in 148 clinical stud-
(16/23) of the preemptive effects evaluated using local
ies that met the above inclusion criteria. Table 7.2 shows
anesthetics do not show a superiority of pre- versus
the various experimental designs and the frequency with
postincisionailsurgical administration, whereas 30% do.
which they were used across the 148 studies and specifi-
On the other hand, 65% of the comparisons examining
cally for the different classes of analgesic and anesthetic
preventive analgesia show significant preventive effects
agents. For each design, the table also shows whether
(beyond the duration of action of agents used). Taken
the effect being evaluated is preemptive or preventive
together, these data support the idea that, for the majority
as defined above. The enormous variability in timing of
of studies, blocking noxious intraoperative factors inter-
treatment is evident from the fact that 29 different designs
feres to the same degree with the development of central
have been implemented. Table 7.3 summarizes the out-
sensitization as does blocking posteroperative factors
comes of the studies reviewed below according to the
(I.e. these factors contribute equally to central sensitiza-
target agent administered. Positive studies are those that
tion) , indicating that there is a benefit to the postopera-
report a significant preemptive or preventive effect (I.e.
tive blockade. What we do not know is the extent to which
reduced pain or analgesic consumption or both). Nega-
these factors contribute independently (I.e. additively) to
tive studies are those for which the timing of treatment

Table 7.1 Studies excluded from review in the present

chapter for failing to meet one or more criteria"
Reference Year Criterion not met Reference Year Criterion not met
Local anesthetics 54 1998 DB
23 1983 P 55 1998 OF
24 1984 R. DB, P 56 1998 R
25 1990 P 57 1999 DA
26 1990 p, DF 58 2001 DB
27 1991 DF
28 1991 R, DB
29 1991 A 59 1991 DA
30 1992 P 60 1991 DA
31 1994 R,DB 61 1992 DA
32 1995 OF 62 1992 R,DB
33 1996 OF 63 1999 DA
34 1996 A,DA 64 2000 A, DA
35 1996 P N-Methyl-D-aspartate antagonists
36 1996 DB, p, DF 65 1999 P
37 1998 R
38 1998 DA local anesthetics and opioids
39 1998 A 66 1988 DB
40 1999 A 67 1992 R
41 2000 DB 68 1993 P, DA
69 1998 P,A
Nonsteroidal anti-inflammatory drugs
42 1986 DA Multimodal analgesia
43 1987 DA 70 1994 R. DB
44 1987 OF 71 1996 A
45 1988 DA 72 1999 R, DB
46 1990 DA 73 2000 DB
47 1991 DA a. R, randomized; DB, double-blind assessments; P, report of pain
48 1991 DA, DF using a reliable and valid measure; A, report of analgesic con-
49 1994 DF sumption; DA, for studies that assess the effect of timing using
50 1994 DA the definition of preventive analgesia outlined in the chapter,
51 1996 DF measures of pain, and analgesic consumption reported at a point
52 1996 DA, DF in time that exceeds the duration of action of the target agent;
1997 OF, absence of design flaw, methodological problem, or con-
53 R
found that renders interpretation of the results ambiguous_

central sensitization This can only be ascertained by preoperative saline or a no treatment control condition.
incorporating appropriate control conditions (e_g. treat- The two studies that falled to find preventive effects may
ment combinations 1 and/or 8) into the classical tviO- be explained by use of either a topical lidocalne (ligno-
group model of preemptive analgesia. caine) spray along with two nonsteroidal anti-inflamma-
tory drugs (NSAIDs)81 or too small a dose ofbupivacaine
Tonsillectomy (2mlO.2S%).83
In general, the magnitude and duration of the pre-
Seven studies examined the efficacy of preoperative topi-
ventive effects are impressive and clinically Significant,
cal anesthesia or a local anesthetic infiltration in reducing
especially considering that patients received only a single
pain and analgesic consumption after tonsillectomy.18~
preoperative infiltration. Pain, either at rest or at rest and
83.130 Three studies81 -83 evaluated both preemptive and
after swallowing, was found to be significantly less intense
preventive analgesic effects: the remaining studies eval-
than the control group for up to 8-10 days aftertonsilIec-
uated only preventive effects. Overall, significant pre- tomy_J8**·79**.80.**130**
ventive analgesic effects were found five of the seven
studies.?s***.130** Significant preemptive analgesic
Laparoscopic surgery
effects were not observed, suggesting that preoperative
and postoperative blockade are equally effective in mini- Six studies examined the effects of timing of intraperi-
mizing postoperative central sensitization. This conclu- toneallocal anesthetic spray or infiltration by preventive
sion seems defensible given that all but two studies 81.83 anaigesia,89**,90**.92.94** or both preventive and preemp-
showed Significant preventive effects when the preop- tive analgesia,91**.93** for Japaroscopic surgery, including
erative local anesthetic infiltration was compared with cholecystectomy, tubal ligation, and diagnostic gyneco-
Table 7.2 Variety and frequency of experimental designs used to evaluate the timing of administration of different classes of analgesic agents relative to incision

Design Preemptive and! Treatment combination local NMDA LAs and Total number
number or preventive (Fig. 7.1) anesthetics Opioids NSAIDs antagonists opioids Multimodal of studies
PV 1;2 14 3 4 10 1 2 34
2 PE and PV 1;2;3 6 2 4 13
3 PE and PV 1;2;3;5 1
4 PE and PV 1;2;3;6 1
5 PE and PV 1;2;4 3 4
6 PE and PV 1;2;7;8 1
7 PV 1;3 7 8
8 PV 1;3;5 1 1
9 PV 1;4 3 3
10 PV 1;5 2 4 2 8
11 PV 1;8 1 1
12 PV 2 1 2 1 4
13 PE 2;3 7 10 4 2 24
14 PE 2;4 7 2 1 10
15 PE and PV 2;4;6 1 1 2
16 PE or PV 2;5 1 4
17 PE 2;6 4 5
18 PE 2;7 1
19 PV 3;5 2
20 PV 4
21 PV 4;5
22 PV 4;6 2
23 PE and PV 4;6;7 1 1
24 PE or PV 4;8 2 6 9
25 PV 5 1
26 PV 5;8 1
27 PE and PV 6;8 1
28 PE or PV 7;8 2 3
29 PV 8 1 1
Total 59 21 20 24 19 5 148
Each design (column 1) is defined in terms of specific treatment combinations (column 3) depicted in Fig. 7.1. Each design is also described as evaluating preemptive and/or preventive effects.
PE, preemptive; PV, preventive; NSAIDs, nonsteroidal anti-inflammatory drugs; NMDA, N·methyl-o·aspartate; LAs, local anesthetics.
Table 7.3 Summary of studies according to target agent administered

Number Preemptive effects Preventive effects Opposite Total no.

Agent(s) ofstudi~ Positive Negative Positive Negative effects effects
loca I anesthetics· 59 7 (10.1) 16 (23.2) 26 (37.7) 14 (20.3) 6 (8.7) 69 (100)
Opioids 21 4 (16.7) 5 (20.8) 9 (37.5) 3 (12.5) 3 (12.5) 24 (100)
NSAlDs 20 1 (4.2) 10 (41.7) 3 (12.5) 8 (33.3) 2 (8.3) 24 (100)
NMDA antagonists 24 4 (12.9) 6 (19.4) 15 (48.4) 5 (16.1) 1 (3.2) 31 (100)
LAs and opioids 19 3 (14.3) 4 (19.0) 7 (33.3) 6 (28.6) 1 (4.8) 21 (100)
Multimodal 5 1 (14.3) 0(0) 2 (28.6) 3 (42.9) 1 (14.3) 7 (100)
Total b 148 20 (11.4) 41 (23.3) 62 (35.2) 39 (22.2) 14 (7.9) 176 (100)
Table shows the total number of studies, and number (%) with positive and negative preemptive and preventive effects. Also shown is the num·
ber (%) of studies reporting effects opposite to those predicted and the total number of effects (positive, negative, and opposite), The total num·
ber of effects exceeds the number of studies because some studies were designed to evaluate both preemptive and preventive effects, See text
for definition of preemptive and preventive effects,
NSAIDs, nonsteroidal anti·inflammatory drugs; NMDA, N·methyl·D-aspartate; LAs, local anesthetics,
a, p= 0,01 for the number of positive preventive effects by Fisher's exact test.
b, P= 0,0001 for the number of positive preventive effects by chi·squared test.

logical procedures, Only one study did not coadmin- surgery; pain while walking about was significantly lower
ister opioids during surgeryB2 All but one 92 of up to day 5 after surgery, and by 10 only 10% of the
these studies showed a significant reduction in pain and! pretreated patients reported paln compared with approx-
or morphine consumption that long outlasted the dura- imately 50% of the control group,101**
tion of of the preoperatively administered local The two studies21 **,22** that examined preventive
anesthetic agent (Le, from 24 h to 48 h after surgery) B9**- postoperative effects compared local anesthetic blockade
91.93**.94** Preoperative plus postoperative local anesthesia of postoperative noxious inputs with a placebo and a no
was significantly more efficacious in reducing postopera- treatment control condition (Le. treatment combination
tive pain than 91** postoperative90**,91** or 1;3 in Fig. 7.1) in the context of an unchecked injury bar-
no supporting recent suggestions rage from incision and subsequent intraoperative events,
that prolonged blockade may maximize the preventive Both studies found a preventive effect 24 h after surgery;
effects of local anesthesia, 13.19 pain at rest,21**,22** after movement,21** and in response
to pressure applied at the wound 21 ** were Significantly
Inguinal hernia repair lower in the group administered the local anesthetic
blockade after surgery than in the placebo or untreated
Twelve studies evaluated timing of local anesthetic block-
groups, Also, significantly lower doses of postopera-
ade with lidocaine or bupivacaine for inguinal hernia
tive analgesics were found in the treated groups, These
repair using a field block,98,loo aerosol spray,11** infiltra-
results suggest that postoperative noxious inputs from
tion,96**99** ilioinguinal nerve block/2M spinal/caudal
the wound contribute to central sensitization (increased
anesthesia,9s**,lQ3105 or a combination of two or more
pain, hyperalgesia) independent of the central sensitizing
techniques 9s **97Iolloz** (two studies io3 ,io5 also included
effects of incision and subsequent noxious intraoperative
patients undergoing other surgical procedures including
events, The results also support the argument that "nega-
circumcision and orchiopexy),
tive" studies of preemptive (e,g. treatment com-
Timing of administration varied considerably, with
bination 2;3 in Fig, 7.1) may be due to the relative efficacy
some studies preemptive analgesia in the nar-
of postoperative blockade and not the inefficacy of pre-
rowest sense, others evaluating preventive
operative blockade. They also point to the importance of
nr<>,-,n,>r<llc,,,,, effects using various treatment combina-
implementing appropriate control conditions in studies
tions, and still others evaluating preventive
of preemptive analgesia (e,g. treatment combination 1
postoperative effects.
and/or 8 in Fig. 7.1) to allow for an unambiguous inter"
Only one of' the five studies evaluating preemptive
pretation of the results. 13
analgesia was significant; however, the effect was small
Taken together, these studies suggest that, for inguinal
and limited to lower opioid consumption in favor of the
hernia repair, the contribution of postoperative noxious
pretreated group 6h after surgery only.99** Of the five
inputs to central sensitization (and hence postoperative
studies to evaluate preventive effects, three
pain and opioid consumption) is greater than that of nox-
showed remarkably and prolonged reductions in
ious inputs ariSing from incision, This is supported by the
pain and analgesic consumption in favor of the pretreated
absence of any large preemptive effects and the presence
groups between and 10 days96*~,101** after sur-
of Significant preventive effects, most notable among
gery. The effects were found in a recent study that
these are the preventive postoperative effects,
provided thorough blockade before, during, and after
Cesarean section and abdominal gynecological 132**.136.137**.138.141-143**,145.146**.149** repeated bolus
surgery doses,l**.1J3 or as a bolus dose followed by a continuous
infusion. 7. 149 ** With two exceptions,146**.I41** all studies
All four of the studies that evaluated the preventive effects
using epidural opioids have administered a single bolus
of a preoperative ilioinguinal nerve block using bupiva-
caine for women undergoing cesarean section (C-sec-
Time of administration before skin incision is not
tion) found significant effects between 24 and 48 h after
specified in all studies. For the intravenous (LV.) route,
surgery.116**-119 Six studies were found in which a pre-
most studies indicate administration is at induction of
emptive or preventive approach was evaluated in women
the general anesthesia or between 10 and 30 min before
undergoing major abdominal gynecological surgery.HO-
skin incision. Opioids administered by the epidural route
115 The timing relative to incision, routes of administra-
have been given bet\veen 30 and 60 min before induction
tion. and use of additional analgesics varied considerably.
of the general anesthetic. The timing of treatment before
Only two of the six studies found evidence for a preven-
surgery ranges between 30 min and 2h presurgery for the
tive effect lI4**1 15** There were no preemptive effects.
intramuscular (Lm,) route and 1h before surgery for the
intrathecal route.
There is considerable variability in the timing of the
Of the 69 effects that were tested (in the 59 trials), approx- second intervention for studies evaluating preemptive
imately 48% were significant. A greater proportion of pre- effects. The second intervention was administered intra-
ventive than preemptive (10%) effects (Table 7.3) operatively as early as at the start of skin incision l45 or
were found to be signifIcant, consistent with the expec- 1 min after incision. 136 Not surprisingly, neither stUdy
tation that a postincisional or postsurgical intervention demonstrated a preemptive effect. The absence of dif-
should attenuate, to some extent, the course of postop- ferences between the groups in postoperative morphine
erative central sensitization. Local anesthetic infiltration consumption and pain at 24 h may be confirmation, in the
before tonsillectomy or inguinal hernia repair appears clinical setting, of basic science findings that high-inten-
to produce clinically significant reductions in pain and sity noxious stimulation of C-fiber affetents located in
analgesic consumption that long outlast the duration of skin is conSiderably less effective in inducing prolonged
action of the local anesthetics; in the case of tonsillec- central facilitation than stimulation of afferents located in
tomy, the effects are particularly prolonged. deep tissue. 151 Since the opioid was administered a1 skin
incision 145 or 1min after incision l36 in the postincisional
group, it is unlikely that damage had heen done to deeper
Timing of administration of opioid tissues which contain the C-fiber afferents responsible for
analgesics inducing long-lasting central neural hyperexcitability.
The absence of significant preemptive effects raises
Table A7.2 shows the 21 studies that were found to have the issue of the time-course of postincisional central
examined the effects of altering the timing of administra- sensitization and whether the neural hyperexcitability
tion of a variety of opioids, including alfentanil, fentanyl, can be prevented by an early postincisional treatment.
morphine, meperidine (pethidine). sufentanil, tram ado!, Electrophysiological studies in rats have shown that sec-
and the morphine metabolite morphine 6-glucuronide ond-phase formalin responses of dorsal horn nociceptive
(M6G). The studies are almost evenly divided between neurons are inhibited to the same degree when a J1 opi-
designs comparing preoperative administration with a oid agonist is administered intrathecally before or shortly
placebo or an active agent (I.e. evaluation of preventive (I.e. 9min) after formalin injury.lsz However. pteinjury
effects) and those evaluating preoperative administration administration is significantly more effective at inhibit-
against the same agent administered intraoperatively. ing second-phase responses than late 30 min) post in-
postoperatively. or both preoperatively and postopera- jury administration. One implication of these findings for
tively (Le. preemptive effects; see Tables 7.2 and 7.3). clinical studies is that administration of J1 opioid agonists
The effects of opioids have been studied on a variety of may be equally effective before and after incision until a
surgical procedures that differ widely in duration, extent, windup-like state has developed, but, once established,
and nature of damage to tissue, bone, and nerve. These higher doses may be reqUired post surgery to proVide the
include abdominal hysterectomy,7**.13Z**13W6.137**- same degree of postoperative pain relief. It is likely that
139,141.143**.145 back surgery, ;42,144** major abdominal sur- central sensitization had not fully developed by the time
gery,134** neurosurgical procedures,149** orthopedic of the second intervention,136.145 suggesting that the pre-
surgery,140.147**.148** postepisiotomy pain, 135** third emptive analgesic potential of the opioid was missed by
molar extraction, ISO thoracotomy,131** and a variety of virtue of too early a postincisional intervention.
other surgical procedures. 146** The remaining studies administered the second inter-
Routes of administration include oral, intramuscular, vention between lOmin l33 and 15min I31 **.I43** after
intravenous, epidural, and intrathecal. Intravenous opi- incision, later during the procedure,141 at the time of clo-
oids have been administered as a single bolus dose, l3l**. sure 132 **.146**.147** or at the end or surgery.I44**.150 Two
studies administered three interventions. the third occur- Two-group studies that did not find Significant differ-
ring intraoperatively' 38 or 10 h after surgery.14D ences in pain and analgeSiC consumption between pre-
Significant effects were observed in eight and postincision groups are difficult to interpret because
studies. significant preemptive of the absence of an appropriate control group (e.g. treat-
effects in three studies, IJIH.143**.I44** and both preemp- ment combination 1 in Fig, 7.1). The negative results may
tive and preventive effects in one study'12*'" for a total of point to the relative efficacy of postincisional or postop-
13 (54%) significant effects (1able 7.3). Overall. the mag- erative blockade and not the inefficacy of preoperative
nitude of the significant effects ranges from smalF**· blockade. Other explanations for the negative findings
131**.132**.137**.143**.149** to moderate. with maximum include the possibility that preoperative administration
mean intergroup differences in visual analog scale (VAS) of opioid analgesics contributes to establishing acute opi-
pain scores (lOO-mm scale) at rest between lOmm and oid tolerance and opioid-induced hyperalgesia. Taken
20 mm at 24 h 144** to 48 h134**.131**.146**.147** after surgery. together. the findings that coadministration of low-dose
In two studies. 146**.141** differences in VAS pain scores of NMDA antagoniSts (see section on Timing of admin-
approximately 15 mm in favor of the pretreated group istration of NMDA receptor antagoniSts) and low-dose
were accompanied by a mean difference of between 3 and opioid antagonists reduce or reverse the development
4 mg epidural morphine. increasing the overall magni- of acute opioid tolerance and opioid-induced hyperalge-
tude of the preventive effects. sia l55 raise the possibility of increasing the magnitude of
Two recent lines of basic research are relevant to the the preventive and preemptive analgesic effects of opioids
efforts to prevent central sensitization by the preoperative in the clinical setting,
administration of opioids. First, there is a growing body
of evidence suggesting that opioid administration may
lead to the development of acute opioid tolerance 153,1 54 Timing of administration of NMDA receptor
and opioid-induced facilitation of nOCiceptive process- antagonists
ing, 155157 thereby increasing the requirements for postop-
erative analgesia and enhancing postoperative pain, The A variety of agents that have an antagonistic action at the
effects of opioid agonist-induced hyperalgesia are oper- NMDA receptor are clinically available, including aman-
ating at cross-purposes to the effects, thereby tadine, dextromethorphan, ketamine. ketobemidone,
reducing the overall magnitude of the preventive and memantine, and methadone, At the present time. preven-
preemptive effects of these tive or preemptive arlalgesic effects have been investigated
Second. basic science 158 clinical l59 studies indicate using ketamine or dextromethorphan but not the other
that coadministration of opioid and low-dose NMDA antagonists, Although ketamine hydrochloride 161
opioid antagonists (e.g. naloxone. naltrexone) actually and dextromethorphan 162 act on a variety of receptor sys-
enhance opioid analgesia. in part by reducing acute opi- tems, their NMDA channel-blocking properties quickly
oid tolerance. ISO In two recent clinical studies, Aida et became the focus of intense research once this receptor-
al. 14S **.141** administered epidural morphine or saline ion channel complex was discovered to playa critical role
before surgery followed by Lv, naloxone (O.OOBmg/kg) in the induction and maintenance of central sensitization
after skin closure in order to "erase the aftereffects of the and pathological pain. 163.1M The major mechanism pro-
morphine." Both studies reported significant preventive posed to underlie the reduced opioid consumption and
effects [reduced pain and lower epidural patient-con- pain in studies of preemptive analgesic effect is the pre-
trolled analgesia (peA) requirements] that extended up vention (or reversal) of NMDA-mediated sensitization of
to 48 h after surgery. These data raise the pos- spinal cord dorsal horn neurons.19.165 The NMDA channel
Sibility that the relatively large preventive effects observed blockers dextromethorphan and ketamine are of particu-
in these studies I46 **,141** may be due to the combined lar interest, therefore. in testing the hypothesis that their
actions of morphine and naloxone in preventing acute administration before surgery reduces pain and analge-
tolerance, sic consumption compared with saline administration or
In summary, of the 24 effects tested in the 21 stud- their administration after incision.
ies reviewed, approXimately 38% and 21% showed TableA7.3 shows the 24 studies that were found to have
nilkant preventive and effects respectively, used ketamine (n = 14) or dextromethorphan 10).
Thus, a total 59% of the effects tested showed that pain The most frequent deSigns have compared preoperative
and/or analgeSiC consumption were reduced by altering administration of dextromethorphan or ketamine with a
the timing of administration of opioid analgesics rela- placebo or an active agent (I.e. evaluation of preventive
tive to incision or after the analgesic effect of the opioid effects), The next most commonly used designs compare
had worn off. The lower pain and opioid-spar- preoperative administration of dextromethorphan or
ing effect were observed in large part between 24 and 48 h ketamine with the same agent administered intraopera-
after administration of the opioid used to prevent tively. postoperatively. or both preoperatively and postop-
or preempt pain, eratively (Table 7.2).
Ketamine with epidural morphine plus Lv. saline or epidural saline
plus Lv. ketamine. The magnitude of the effect of epidural
The timing of ketamine administration relative to inci-
morphine appeared to equal that of Lv. ketamine alone.
sion has been studied on a variety of surgical proce-
The exact time of administration before skin inci-
dures including abdominal hysterectomy,20**.112,173**.177
abdominal surgery,169**.171 arthroscopy,178** cesarean sion is not specified in all studies, but it appears to be
3-10 min for the Lv. route and 20-30min for the epidu-
section,168** cholecystectomy,166** gastrectomy, 167**.176**
ral route. Timing of preoperative administration is often
laparoscopic cholecystectomy, 175 mastectomy, 174 and total
specified relative to induction rather than incision. There
knee replacement. 170** There is usually no rationale given
is understandably more variability in the time of admin-
for the patient population studied in spite of the fact
istration postincision for studies evaluating preemptive
that important differences clearly exist among the vari-
effects or for studies in which the groups are not given
ous surgical procedures that may have a bearing on the
the same dose of ketamine during the first and second
outcome of the results duration of procedure rela-
intervention. The exact time after incision is not always
tive to that of the target agent, extent (deep vs. superficial)
specified; instead, it is equally common to report admin-
and nature (nerve, muscle, viscera) of tissue damage and
istration relative to a fixed surgical event (e.g. removal
of specimen, wound closure). Because of this and inter-
Ketamine has been administered via the intra-
venous 20**·166**.168**.16S**.I71.IH.175.177.17S** and epidu- study differences in the duration of the various surgical
ral 167 **,170**.171.173**.I'I6** routes. Intravenous ketamine has procedures. an accurate estimate of the interval between
the first and second intervention cannot be calculated.
been administered as a single bolus dose,166**.168**.lH.l75.
However, the timing of the second intervention occurred
177.l78** repeated bolus doses,172 or as a bolus dose fol-
between 20 and 30min postincision,17o**.m.m** at c10-
lowed by a continuous infusionl°**.169** for the duration sure,169**.17I.174,175.177,178** or at end of surgery.l16** Some
of the surgical procedure. Intravenous bolus doses of ket-
studies administered more than two interventions. 170.175
amine have ranged from 0.15 mg/kgupto 2.0mg/kg, with
Significant preventive effects were observed in seven
the majority between 0.4 mg/kg and 1.0 mglkg Lv. studies,2U**.166**.168**.16S**.173**.17S**.17B** significant pre-
There is somewhat less variability in the dose of ket-
emptive effects in one study,167** and both preemptive
amine administered by the epidural route. The five stud-
and preventive effects in one study.170** The significant
ies of epidural ketamine administered a single bolus
effects were primarily observed as an analgesia- or opi-
dose of 30 mg 173 ** or 60 mg, 167**.171 repeated bolus doses
oid-sparing effect with the treated groups receiving or
between 10 and 20 mg, 170** or a bolus dose of 1.0 mg/kg
self-administering Significantly lower doses of postop-
followed by a continuous infusion of 0.5 mg/kg/h until
erative analgesia than the untreated or placebo-treated
groups. In two studies, the preemptive l1u *,* or preven-
The surgical procedures were performed under gen-
tive I70 **.176** effects involved both reduced pain intensity
eral anesthesia in all but one of the studies. the exception
and reduced opioid requirements, and in one study the
being a positive study of patients undergoing total knee
effect was a reduction in postoperative hyperalgesia. IO *"
replacement with a combination of epidural lidocaine,
The majority of the significant effects were observed
morphine. and ketamine. 110**
between 24 hand 48 h after surgery.
Certain studies have combined ketamine with other
agents, including acetaminophen (paracetamol), 175 mor-
phine I67 ** or morphine and lidocaine, 170 making it diffi-
cultto separate the effect ofketamine from that of the other Surgical procedures include laparotomy,IB8 tonsillec-
agents on postoperative pain and analgesic consumption. tomy,179**.IBI !ower I80** or upper l86 ** abdominal surgery,
In seven studies, an opioid I66 **.IGS**.173**.174177,17S** or an hysterectomy,184 laparoscopic cholecystectomy,183**.187**
opioid plus an NSAIDI75 (preceded by preoperative local mastectomy,182** and hemorrhoidectomy,185** Of the
anesthetic infiltration) were administered as premedica- 10 studies, one 1BO** examined preemptive effects, ei
tion or at induction of the general anesthesia. ght I79 **.181.18Z**.184**-188 examined preventive effects,
Of the five studies that administered ketamine without and one study examined both preemptive and preven-
opioids, three showed a preventive effect up to 2days after tive effects. 183** Dextromethorphan has been admin-
surgery20**.169**.116** and two showed no effect of preop- istered by the oral,179.181.184**.187,188 Lm .. 182 **.183**.I8S**.
erative ketamine. but these latter studies did not include 186** and LV.I80** routes. Oral and i.m. preparations have
an appropriate control condition (Le. treatment combi- been administered in a single dose ranging from 10 mg
nation 1 in Fig. 7.1). Thus, ketamine appears to produce a to 150mg. Intravenous dextromethorphan was admin-
preventive effect when administered alone. The coadmin- istered in one study as a slow infusion of 5 mg/kg over
istration of ketamine with an opioid appears to produce a 3D-min interval starting 30min before induction of
greater effects than that of morphine alone or ketamine the general anesthetic. 180** Time of administration for
alone. as illustrated by Aida et aJ.,l76** who found that the oral route has been at least 60 min before the start of
epidural morphine plus Lv. ketamine produced a preven- surgery. Time of administration for the Lm. route uni-
tive effect at 24 hand 48 h after surgery when compared formly has been 30 min before incision. Time of postin-
cisional administration of dextromethorphan was after This question was addressed by Abdel-Ghaffar et
removal of the specimen l83 ** and at skin c1osure.1 8o** a1., 173** who used the treatment combination 1;2;3 in Fig.
General anesthesia was administered for all but one pro- 7.l. Cumulative postoperative morphine consumption
cedure, the exception being hemorrhoidectomy per- 24 h after surgery was reduced by approximately 40%
formed under lidocaine infiltration. 185 ** Intravenous among patients given epidural ketamine (30 mg) before
morphine,188 Lv. fentanyl ,180**.182**.183** Lv. morphine or after incision when compared with a control group that
and p.r. acetaminophen,181 and Lv. fentanyl and Lv. Iido- received epidural saline before and after incision (Le. no
caine I86 ** were administered either as a premedication or ketamine). Consistent with the results of Kucuk et ai., 111
during surgery as a supplement to the general anesthetic. preincisional ketamine was no better than postincisional
Only two studies did not administer an analgesic agent as ketamine in preempting postoperative pain. Importantly,
premedication or during surgery. 119**.185 a clinically significant opioid-sparing effect was found in
The outcomes of the studies examining the timing of both the preincisional and postincisional groups when
administration of dextromethorphan are similar to those compared with the placebo-controlled group, pointing to
of ketamine. Significant preventive effects were observed the importance of a proper control condition.
in six studies,6s**119**.ls2**.185-ls7** Significant preemptive
effects in one studylsD** and both preemptive and preven- Summary
tive effects in one study. 183** Effects were observed at least
Taken together, the results of the studies that have exam-
24 h after administration of dextromethorphan and, with
ined the timing of administration of ketamine or dextro-
three exceptions,6s.18o**.182** consisted of a reduction both
methorphan have proved most successful in terms of the
in analgesics administered and in pain at rest and/or after
total percentage of studies showing significant preven-
movement. One study reported significantly lower pain
tive or preemptive effects. As shown in Table 7.3, approx-
intensity and analgesic consumption for 7 days after bilat-
imately 61 % of studies have reported that administration
era tonsillectomy following a single dose of 45 mg dex-
of ketamine or dextromethorphan before surgery (com-
tromethorphan. 119 **
pared with after surgery or a placebo-controlled condi-
Design considerations: importance of control tion) results in significantly lower pain intensity and/or
conditions reduced analgesic requirements after the duration of
action of the NMDA antagonists has worn off.
As noted above, negative results of two-group studies
The preponderance of positive studies of preemptive
pose a problem in interpretation because of the absence
ketamine and dextromethorphan may be due not only to
of an appropriate control group (e.g. treatment combina-
the ability of these agents to block the neural processes
tion 1 or 8 in Fig. 7.1). This problem is illustrated in two
underlying central sensitization l61 but also, in a related
recent studies of epidural ketamine m .113 ** Using a two-
vein, to their ability to attenuate the development of acute
group design (treatment combination 2;3 in Fig. 7.1),
opioid tolerancel53.154 and reverse opioid-induced facilita-
preincisional epidural ketamine (60mg) was compared
tion of nociceptive processing.156.151 As reviewed above,
with postincisional epidural ketamine (60mg) without
opioids were administered (as premedication, during
finding the anticipated reduction in postoperative pain
surgery, or as part of the preemptive intervention) in all
and analgesic consumption in favor of the preincisional
but six of the studies. Preoperative administration of ket-
group; preincisional ketamine was no better than postin-
amine or dextromethorphan may have prevented acute
cisional ketamine in preempting postoperative pain. 111
opioid tolerance, opioid-facilitated activation of NMDA
Since there is no good rationale for a postincisional treat-
processes, and opioid-induced hyperalgesia relative to
ment in the clinical setting (Le. one would not adminis-
the control group, leading to a reduction in postoperative
ter epidural ketamine near the end of surgery without
opioid requirements and postoperative pain intensity in
also having used the epidural route preoperatively), the
the preoperatively treated groups.
impression that negative studies such as this one give is
that neither preincisional nor postincisional treatment is
clinically useful.
Timing of administration of nonsteroidal
However, as previously argued, preincisional and
anti-inflammatory drugs
postincisional noxious stimuli make separate contribu-
tions to central sensitization. 13 It is conceivable that in
The analgesic effects of NSAIDs have been attributed to
the study by Kucuk et a1. l1l pre- and postincisional nox-
their peripheral anti-inflammatory actions in inhibiting
ious stimuli contributed equally to postoperative pain
the synthesis of prostaglandins through the inactiva-
intensity so that administration of ketamine reduced
tion of cyclo-oxygenase. 189 This effect is an indirect one
(the respective pre- and postincisional contributions to
in that prostaglandins themselves do not produce pain
central sensitization and) postoperative pain when given
but sensitize receptors at the site of injury to a variety of
before or after incision. This possibility raises the ques-
neurochemicals (e.g. bradykinin, serotonin, substance P,
tion of how the pre- and postincisional groups would
calcitonin gene-related peptide). Thus, at least insofar as
have fared had they been compared with a group that did
their peripheral effects are concerned, NSAIDs are more
not receive ketamine at all.
accurately anti hyperalgesic than analgesic in action. effects I92 **.i9'1**.200** were observed at. or up to. 24 h after
Observations that the anti-inflammatory and analgesic surgery and consisted of small differences in pain and/or
effects of NSAIDs could be dissociated raised the pos- opioid consumption in favor of the pretreated group.
sibility of a central site of action for these agents. IH9 The In general, the ability to demonstrate preventive or
spinal effects of NSAIDs are not as well documented, but preemptive analgesic effects using NSAIDs (vs. opioids
include the possibility of a nonanti-inflammatory analge- or local anesthetics) is made more difficult by the fact
sic action brought about by the inhibition of cyclo-oxy- that these agents do not block nociceptive processing or
genase in the spinal cord and a consequent reduction in nerve conduction. As a consequence. clinical studies are
spinal NMDA-mediated events. 189.190 inevitably confounded by the coadministration of sys-
When administered prior to injury, opioid agonists temic opioids and/or a local anesthetic infiltration to all
and local anesthetics prevent central sensitization by patients in order to provide sufficient analgeSia or anes-
attenuating nociceptive processing and blocking nerve thesia during the surgical procedure. This would have the
conduction respectively. In contrast, NSAIDs may pre- unintended effect of reducing pain in the control group,
vent central sensitization by attenuating the inflamma- thus minimizing the intergroup differences in pain and
tory response, thereby reducing peripheral sensitization analgesic consumption.
and its effects on spinal nociceptive processing. In addi- The coadministration of these agents before, during,
tion to this indirect peripheral effect, the direct cen- and after surgery makes it difficult to assess, in a clinical
tral actions of NSAIDs may also contribute to reduCing setting, the degree to which NSAIDs, per se, contribute to
central sensitization by preventing spinal prostanoid preventive or preemptive analgeSiC effects. Nevertheless. it
synthesis. thus reducing pre- and postsynaptic release appears that from a clinical perspective NSAID treatment
of neurotransmitter (e.g. neuropeptides and excitatory does not produce meaningful preemptive or preventive
amino aCids) from primary afferent terminals and spi- analgesic effects on pain or analgesic consumption over
nal interneurons. The net effect of both actions would and above those of the analgesic and anesthetic agents
be to prevent or attenuate development of a hyperexcit- routinely administered during the perioperative period.
able state in spinal cord dorsal horn neurons. In terms of
the patient's experience of pain after surgery, this would
translate into less intense pain and a reduced requirement Timing of administration of local
for postoperative analgesicS. anesthetics and opioid analgesics in
Table A7A shows the 20 studies that were found to combination
have examined the preemptive or preventive effects of
an NSAID alone or in combination with a local anes- Table A7.5 contains a description of the 19 studies that
thetic. Studies of patients undergoing oral surgery such examined the effects of timing of administration of a
as third molar extractionI91.193.194**. or pulpec- local anesthetic and an opioid. As shown in Table 7.2.
tomyt92** were among the earliest to be conducted. More designs assessing preventive analgesia212.m.2I£~219.221-214
recently. other procedures have been studied, includ- are considerably more frequent than preemptive anal-
abdominal hysterectomy.203.205.209 orthopedic sur- gesia. 21 Two studies examined both preventive
gery.2DO**.201**.102.206.20UIO and laparoscopy.197 Routes of and preemptive effects. 215.22o
administration include oral. rectal. Lm., and Lv. A variety Effects of timing have been evaluated on a variety
of NSAIDs has been used. including the propionic acids. of surgical procedures, including abdominal hysterec-
acetic acids. oxicams. and acetaminophen, these differing tomy,21G amputation,ZZI antireflux repair.217 arthroscopic
in the extent oftheir anti-inflammatory activity, analgesic knee surgery, 22Q** cesarean section."1** colonic surgery, 111
effects. antipyretic actions. and pharmacokinetics. hernia repair. 215** lower back surgery.211** posterolateral
Of the 20 studies conducted to date, seven evaluated thoracotomy,1I7 radical prostatectomy.216**.224 third molar
preventive effects, nine evaluated preemptive effects, and extraction,Zl9 tonsiliectomy,2lS total knee arthroplasty,214
four both preventive and preemptive effects (Table 7.2). and upper abdominal surgery,ZI3**.218.123.22S**
Overall, significant effects (i.e. preemptive or preventive) All but two of the studies115.119 used the epidural or spi-
were found in 4 out of the 20 studies (20%): there was one nal route, either alone or in combination with a second
preemptive analgesic effect10I ** and three preventive eff- route (e.g. intra-articular. 110** infiltration212**).
ects. 192 **.I94**.200** Among the studies evaluating preemptive analgesia,
Not only is the proportion of positive studies small. seven administered a postoperative continuous epidural
but the magnitude of the effects. when present, is modest infusion of a local anesthetic and an opioid to both the
at best. The only study20I** to report a preemptive effect preoperative and postsurgical groups. The continuous
found that cumulative Lv. PCA morphine consump- infusion was maintained postoperatiively for 2 days217 to
tion was lower in the presurgery than in the postsur- 3 days11 1.213**.114.2IS.221.211 after surgery. Not surprisingly, six
gery group up to 6 h after surgery but not later. This effect of the seven showed no effect, and only one 213 ** reported
amounted to a mean morphine-sparing effect of approxi- a very small difference in analgesic consumption in favor
mately 1mldh over the first 6 h after surgerv. Preventive of the preoperative grouP.
These studies do not permit an unbiased test of the erative administration of Lv. morphine, i.rn. diclofenac,
preemptive analgesia hypothesis because continuous and intercostal nerve blocks with bupivacaine resulted in
postoperative epidural infusion would be expected to Significantly reduced pain on movement of about 20mm
attenuate the development of central sensitization in both on a VAS from 12 h to 48 h after posterolateral thoracot-
groups and minimize any group differences due to the 0my. Interestingly, this study was similar in patient popu-
timing of administration. Studies that examine the tim- lation, agents used, and route of administration {of two of
of treatment must allow patients to demonstrate their the to the study by Kavanagh et ai.,23D but oppo-
level of pain either directly, through verbal report (e.g. site in effect. In that study, the placebo-treated group self-
VAS pain scores). or indirectly, through their consump- administered Significantly less PCA morphine at 48 h
tion of postoperative analgesics. However, if the post- than the group treated with preoperative intercostal bupi-
operative analgesic regimen is fixed (i.e. not titrated to vacaine nerve blocks, Lm. morphine and perphenazine,
patient need, as with a continuous epidural infusion) and and p.r. indomethacin.
effective (pain levels are low), it may not be possible to
detect whether the afferent barrage produced by the sur-
gical trauma had a prolonged central effect. RECOMMENDATIONS FOR FUTURE RESEARCH
Overall, seven studies (33%) showed a significant pre-
ventive effect21z **.213**.216**.22Q**.22z**.z24** and three (14%)
showed a significant preemptive effect220**.11S**.228,,* Relationship between preexisting pain and
(Table 7.3). The effects vary in magnitude from minor timing of analgesic administration
reductions in postoperative analgesic consumption 213** to
clinically Significant reductions in pain and/or analgesic Recent evidence suggests that, in the presence of presur-
consumption lasting for 4-5 days after surgeryP4**.Z2B** gical pain, preoperative administration of analgesics does
In one notable study, the incidence of pain 9weeks after not lead to the anticipated lessening of postoperative
surgery was significantly lower among patients who had pain or analgesic consumption, perhaps because central
received preoperative epidural fentanyl or bupivacaine sensitization has already been established. Postopera-
than among a saline control group. 224** tive pain and analgesic consumption were Significantly
reduced by pre- and intraoperative epidural morphine
but not saline for patients who did not report presurgical
Timing of administration of multimodal pain. 147 ** However, among patients with presurgical pain.
analgesia pre- and intraoperative epidural morphine was no more
effective than saline. It is not clear whether the absence
The rationale for a preoperative multimodal approach of a difference in phantom limb pain or stump pain after
to postoperative pain management is to capitalize on the amputation between groups treated with preoperative
combined actions of a variety of classes of analgesic and and intraoperative epidural morphine and bupivacaine
anesthetic agents at different receptor sites in reducing versus saline 221 also relates to the presence of preamputa-
peripheral and central sensitization. z2g tion pain and the possibility that central sensitization had
Five studies evaluated the effects of timing of adminis- already been established before the preoperative treat-
tration of a combination of a local anesthetic, opioid, and ment. Future studies should report presence (and dura-
an NSAID230.231**.13z**.13l.234** (Table A7.6). Surgical pro- tion) or absence of presurgical pain.
cedures include lateral thoracotomy,23o.231**.234** abdomi-
nal surgery,232** and third molar extraction. 233 Not only
are the study designs quite varied, with only one evalu- Offsetting the competing effects of
ating the effects of the same interventions before and preventive opioid analgesia and opioid-
after surgery (Le. preemptive analgesia),m** but routes induced tolerance/hyperalgesia
of administration for a given class of agent also differ, as
do the durations of action of agents within and between As noted above, recent basic scientific evidence points
classes. to the possibility that, under certain circumstances, pre-
In general, the magnitude of the significant effects are operative administration of opioid analgesics may con-
surprisingly small given the combined use of three agents. tribute to the establishment of acute opioid tolerance l53
For example, in the by Rockemann et a1.,232** the and opioid-induced hyperalgesia.117.13s The mechanisms
PCA morphine-sparing of a combined preopera- underlying the reduced pain and opioid consumption
tive regimen of thoracic epidural mepivicaine and mor- brought about by preemptive opioid analgesia, and the
phine, Lv. metamizole, and Lrn. diclofenac did not appear increased pain and opioid consumption underlying acute
to exceed that observed by Katz et ai.,131H who compared opioid tolerance and opioid-induced hyperalgesia, con-
preincisional with postincisional lumbar epidural fen- cern competing processes involVing the NMDA recep-
tanyl. The possible exception is the study by Doyle and tor-ion channel complex. These findings have important
Bowler,234** who found that preoperative but not postop- implications for the conduct of clinical studies evaluating
the preeemptive and preventive effects of opioid analge- Measures of pain
sics since the main outcome measures (pain and opioid
consumption) will be directly affected by the mechanisms The most appropriate pain measurement instruments are
underlying these competing neural processes. The net patient-rated pain scales that have demonstrated reliabil-
effect of this competition is to attenuate (or even reverse) ity and validity (e.g. VAS, numeric rating scale, McGill
the desired preemptive and preventive effects. Coadmin- Pain Questionnaire).237 Measurement of pain with the
istration of opioids and low-dose NMDA antagonists or patient in a resting position is reported by almost all stud-
low-dose opioid antagonists has been found to inter- ies. However, the measurement of hyperalgesia is impor"
fere with the development of acute opioid tolerancels4.236 tant. The simplest and most clinically significant test of
and opioid-induced hyperalgesia. 155 A mechanism-based mechanical hyperalgesia is to have the patient perform
approach to postoperative pain management involving a standardized movement after surgery (e.g. sitting up
coadministration of these agents would be expected to from a lying position, inspirational spirometry) and rate
facilitate the preventive and preemptive analgesic effects the intenSity of the pain that ensues. More sophisticated
of opioids in patients undergoing major surgery. measures of primary and secondary mechanical hyper-
algesia include pressure algometry applied either on or
Recommendations to improve the quality near the wound dressing1o.81.238 or on the side of the body
of studies contralateral to the incision,230 measurement of thresh-
olds to electrical stimulation,141.172 temperature,181 and
use of von Frey filaments at a distance from the wound
Design considerations to determine the extent of secondary mechanical hyper-
The importance of including a standard treatment con- algesia. Baseline (preoperative) measures are
trol group in studies that aim to evaluate the effects of the important as is testing at a control site (e.g. a nonif\jured
timing of administration of drugs relative to incision was body part) to rule out a generalized effect due to factors
illustrated by example in the section on NMDA antago- such as anXiety, anticipatory pain, or a response bias.
nists, but the problem is not limited to this class of agents
(e.g. see Molliex et al. B2 ). Two-group studies that do find Measures of analgeSiC consumption
significant differences in postoperative pain or analgesic
consumption between pre- and postincision groups are The degree of pain that a patient experiences in the post-
inherently flawed because of the absence of an appropri- operative setting is in part a function of postoperative
ate control group (e.g. treatment combination I andlor 8 analgesic consumption. Use of patient -controlled analge-
in Fig. 7.1). The negative results may point to the relative sia (either Lv. or epidural) as a modality for postoperative
efficacy of postincisional or postoperative blockade and pain management has dominated the literature on pre-
not the inefficacy of preoperative blockade. emptive and preventive analgeSia. This is largely because
The preponderance of positive preventive studies over PCA is now the gold standard for postoperative pain
positive preemptive studies (Table 7.3) is understandable management at most institutions worldwide. Analgesic
when one considers that both preincisional and postin- consumption is usually the primary outcome measure
cisional or postsurgical noxious inputs contribute to because patients self-administer the agent to achieve a
postoperative central sensitization. The degree to which relatively constant pain level. However, ftom the point of
noxious inputs contribute during each of these phases is view of demonstrating preemptive or preventive analge-
probably dependent on a host of factors. The continued sia, analgeSiC consumption is not the most ideal measure
use of incomplete designs that consist of preincisional because the main hypothesis deals with pain and hyper-
and postincisional or postsurgical conditions (e.g. treat- algesia. Allowing pain to fluctuate by holding constant
ment combination 2;3 or 2;4 in 7.1) without a true the level of postoperative analgesics administered would
placebo condition (e.g. treatment combination 1 in Fig. be a more direct test of the hypothesis,zo.96 but this is not
7.1) or a complete blockade condition (e.g. treatment always feasible or ethical given the evolving standards of
combination 8 in Fig. 7.1) will hinder progress in OUf pain management practice.
understanding of preemptive analgesia. This is because Cumulative analgesic consumption at the end of the
negative results leave us with no idea of the significance study is a common measure, but report of a single value
of the preoperative or postoperative intervention relative may not provide information that is specific enough to
to a group that receives no treatment or total blockade. pinpoint the nature of the effect (analgeSiC or preven-
Adhering to the narrow definition of preemptive anal- tion of central sensitization) or exactly when it occurs.
gesia currently accepted by many in the field will perpet- The latter point may not be relevant if a postincision
uate problems of interpretation and will not lead to the control group is employed. It may be especially relevant
evolution and progress that is needed to move us beyond in studies that evaluate the preventive effect of a preop-
the current state of confusion. Inclusion of appropri- erative intervention (I.e. when comparing it with a pla-
ate control conditions is essential if we are to advance cebo) since it is likely that the largest difference in PCA
our knowledge about the factors that contribute to acute consumption between treated and untreated groups will
Dostooerative oain.
occur at the time of peak effect of the target agent used the proportion of significant preemptive effects (Table
preventively. Report of a single value of cumulative anal- 7.3). Sixty-two percent of the preventive effects reported
gesic consumption at the end of the study may be mis- showed Significant benefits associated with analgesic or
leading depending on the pattern of consumption over local anesthetic administration that extended beyond the
time. For example, if a difference in analgesic consump- clinical duration of action of these agents. These results
tion occurs within the first few hours after surgery (but suggest that central sensitization can be minimized by a
not thereafter), when the effects of the analgesics used preventive approach aimed at blocking noxious stimuli
preventively are still active, then this is an analgesic effect. during the preoperative, intraoperative, and/or postop-
Likewise, report of a single value for cumulative analge- erative periods.
sic consumption at the end of the study may result in fail- The proportion of significant preemptive effects also
ure to detect the presence of group differences at earlier appears to be than that expected by chance alone.
time points. Unless cumulative analgesic consumption Although only 20 (33%) of the 61 preemptive effects that
is reported at multiple times across the study period, an were reviewed found preoperative administration of
analgesic effect may be misinterpreted as a preemptive or analgesics or local anesthetics to result in significantly
preventive effect or either effect may be missed. Another lower pain and/or analgesic consumption than adminis-
approach that circumvents this problem is to calculate tration of the same agent(s) after incision or surgery, this
analgesic consumption within intervals bounded by the percentage is conSiderably greater than the conventional
times when pain is assessed.7.l1DI3U18 This method has the type I error rate of 5% that would be expected if pre- and
advantage of specifying an interval within which an opi- postoperative interventions did not differ in their efficacy.
aid-sparing effect has occurred. The finding that the proportion of Significant preventive
Time from end of surgery to first request for anal- effects is greater than the proportion of preemptive effects
gesics has been used as an indication of effi- is consistent with the suggestion that for most preemptive
cacy. 54.65.Bl.Bl.98126.144.150.l68.173.lBl.185.1B6.205.206.m This is a valid studies postincisional or postoperative administration is
measure of the duration of analgesia providing (1) the as efficacious as preincisional administration. The enor-
timing of administration of pre- and intraoperative anal- mous variability between studies is one factor that likely
gesia is the same for all treatment groups and (2) pain contributes to the equivocal results when studies of pre-
scores do not differ at the time of first request for anal- emptive analgesia are considered.
gesia. However, the time interval between end of surgery Nevertheless, even though the majority of studies
and first analgesic request is not meaningful when the show that there is little additional benefit to preopera-
main intervention that distinguishes groups is the tim- tive administration of analgesic agents over postoperative
ing of administration of a target analgesic relative administration, there is a clear advantage to adding local
to incision. 24o Since the study groups are designed to dif- anesthetic blockade to general anesthesia under certain
fer with respect to the timing of administration of a tar- conditions. For example, local anesthetic administration
get agent, nonsignificant intergroup differencel38.141 in the before tonsillectomy or inguinal hernia repair appears to
time from end of surgery to the time of first request for produce clinically Significant reductions in postopera-
analgesics is difficult to interpret A more meaningful tive pain that long outlast the duration of local anesthetic
measure would be time from administration of the target blockade.
agent to the first for analgesia. But even this mea- Timing of administration of opioids, with or without
sure is not recommended because it can be influenced local anesthetics, is less conclusive, possibly because of
by analgesic and anesthetic agents administered during the competing processes associated with acute opioid tol-
surgery, some of which may differ between the groups erance and opioid-induced hyperalgesia. There appears
directly as a function of the target agent used preemp- to be little evidence that the timing of administration of
tively or preventively. NSAIDs produces preemptive or preventive effects. Given
Finally, some studies report the number of patients the small number of studies of multimodal analgesia and
requiring rescue analgesics i02. the relatively large variability in the routes of administra-
or the number of supplemental doses of analgesics tion, agents, timing, and patient populations, there are
administered.99115119210 These measures lack the sensi- insufficient data to generate a reliable conclusion on the
tivity of cumulative analgesic consumption or analge- efficacy of the timing of administration of local anesthet"
sics administered within specified intervals. It should be ics, opioids, and NSAIDs. Administration of the NMDA
noted that no study included for review in this chapter antagonists ketamine or dextromethorphan before sur-
used these latter methods as the sole measure of analge- gery resulted in significantly lower pain intensity and/or
sic efficacy. reduced analgesic requirements in approximately 61 % of
the effects tested.
SUMMARY AND CONCLUSIONS The distinction between preventive and preemptive
analgesia is an important one from the clinical perspec-
tive. Demonstration of preventive analgesia allows for
Overall, across the classes of agents reviewed, the pro-
a more stringent test of the extent to which postopera-
portion of preventive effects is greater than
tive central sensitization is dampened than does a find- 14. Kissin I. Preemptive analgesia. Why its effect is not
ing of preemptive analgesia. This is because preventive always obvious. Anesthesiology 1996; 84: 1015-19,
analgesia requires pain and/or analgesic consumption to 15. Penning JP. Pre-emptive analgesia: what does it mean
be reduced at a point in time after the duration of action to the clinical anaesthetist? Can J Anaesth 1996; 43:
of the analgesic agent used preventively. Otherwise. the 97-101.
effects are analgesic. The results reviewed above indicate 16. Dionne R. Preemptive vs preventive analgesia: which
that preventive effects are more frequent than preemptive approach improves clinical outcomes? Compendium
effects, and in general they are of greater magnitude. It Continuing Educ Dent 2000; 21: 48, 51-4, 56.
is ironic then that some of the most clinically important .17. Dahl JB, Kehlet H. The value of pre-emptive analgesia
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Acknowledgment The author is supported by an Inves- pain. Dan Med Bull 1994; 41: 434-42.
tigator Award from the Canadian Institutes of Health • 19. Kissin I. Preemptive analgesia. Anesthesiology 2000;
Research. 93: 1138-43.
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225. Kundra p, Deepalakshmi K, Ravishankar M. Preemptive APPENDIX
caudal bupivacaine and morphine for postoperative
analgesia in children. Anesth Analg 1998; 87: 52-6.
The appendix tables are on the following pages.
226. Richards JT, Read JR, Chambers WA. Epidural anaesthe-
Table A7.1 Studies examining the timing of local anesthetic administration relative to incision

Group: Nature and time after

Procedure .Treatment preincision Timing of surgery of. preventive
Reference (number of combination drug/post- Timing of preincision postincision Systemic or preemptive analgesic
(year) patients) (Fig. 7.1' incision drug Route and dose intervention intervention analgesics· effect
74 (1989) Third molar 1;2 GA plus: Infiltration After induction. before NA No Preventive effect - yes
extraction G1: BUP/NA Gl. 8 ml 0.5% BUP incision on postoperation day 1
(n=70) G2: PRI/NA G2: 8 ml 3% PRI Pain: G1 =G2<3
G3: 0/NA Analgesics: Gl = G2 < G3
75 (1997) Third molar 2;3 GA plus: Nerve block Before incision After removal of No Preemptive effect no
extraction 51: 0/BUP 2 ml 0.5% BUP per nerve ('" 10 min after nerve tooth
(n=38) 52: BUP/0 block)
76 (1997) Third molar 1;2 GA plus: Intraoral injection At least 5 min before NA NS Preventive effect - yes at
extraction G1: BUP + EPI/NA 56 mg 0.5% BUP + induction 48 h postoperation
(n=48) G2: SAl+ EPI/NA 1:200,000 EPI Pain: G1 <G2
Analgesics: Gl < G2
77 (1998) Third molar 2;3 GA plus: Nerve block After induction After removal of TEN Lv. 20mg Preemptive effect - no
extraction 51: 0/BUP 2 ml 0.5% BUP per nerve ('" 10 min after nerve tooth ALF Lv. 2 mg
(n= 32) S2: BUP/0 block), before incision
78 (1989) Tonsillectomy 1;2 G1: GA only/NA Topical spray Immediately before NA G1: FEN Lv. dose Preventive effect
(n= 38) G2: lID+EPIINA 30-40mg LID operation NS - yes on days 5 and 8
Infiltration of postoperation
peritonsillar tissues Pain: G2<G1
20-30 ml of 5 mg!ml No; ready for work!
LID 5 fLg/ml EPI school: G2 > G1
79 (1991) Tonsillectomy 1;2 GA plus: Infiltration of 5 min before incision NA No Preventive effect
(n=14) G1: BUP + EPI/NA peritonsillar tissues - yes up to day 10
G2: SALINA 3-5 ml 0.25% BUP + postoperation
1 :200.000 EPI Pain at rest: Gl < G2
Pain on swallowing:
Gl <G2
80 (1993) Tonsillectomyandlor 1;2 GA plus: Infiltration of 5 min before incision NA NS Preventive effect
adenoidectomy G1: BUP + EPI/NA peritonsillar tissues yes up to day 10
(n=22) G2: SAL + EPI/NA 0.25% BUP + 1 :200.000 postoperation
EPI dose NS Pain at rest: G1 < G2
Pain on swallowing:
Gl <G2
Time to swallow: G1 < G2
81 (1995) Tonsillectomy 1;2;3 GA plus: Topical spray of tonsillar 3 min before incision After removal of KETi.m. Preemptive effect - no
(n=75) G1: lID/0 areas tonsils 1 mg/kg Preventive effect - no
G2: 0/l1D 4 mg/kg 10% II D aeroso I DIC p.r. 2 mg/kg
G3: 0/0 spray
130 (1996) Tonsillectomy 1;2 GA plus: Infiltration of tonsils and 7 min before surgery NA ACE p.r. Preventive effect - yes
(n=19) G1: BUPINA peritonsillar muscles 1,500mg at days 4,6, 7, and 9
G2: SALINA 15 ml 0.25% BUP FEN i.v. 250 [1g postoperation
Pain: G1 < G2
82 (1996) Tonsillectomy 1;2;4 GA plus: Infiltration of After induction, 5 min After surgery, FEN i.v. 3 ~lg/kg Preemptive effect - no
(n=68) G1: BUP + EPI/0 peritonsillar tissues before surgery before awakened Preventive effect - yes at
G2: SAL + EPI/0 6-9 ml 0.25% BUP + from GA 17 h postoperation
G3: 0/BUP + EPI 1 :200,000 EPI Pain: G1 = G3 < G2
83 (2000) Tonsi lIectomy 1;2;4 GA plus: Peritonsillar infiltration 5 min before tonsillar After completion MORi.m. Preemptive effect - no
(n=30) G1: SALl0 2 ml 0.25% BUP excision of the procedure 0.07mg/kg Preventive effect - no
G2: BUP/0 Pain: G1 > G2 at 4 h
G3: 0/BUP postoperation
84 (1994) Thyroidectomy 1;4 GA plus: Infiltration of surgical NA At end of surgery FEN i.v. Preventive effect - yes at
(n=40) G1: NA/BUP edges of wound G1: 3.72 [1g/kg 24 h postoperation
G2: NA/0 10ml 0.5% BUP G2: 3.81 [1g/kg Pain: G1 < G2
Analgesics: G1 < G2
85 (1999) Thyroid surgery 1;2;3 GA plus: Infiltration of skin 5 min prior to surgery Prior to skin FEN i.v. Preemptive effect - yes
(n=62) G1: lID/0 10m11% LID closure ",2 [1g/kg Preventive effect - yes
G2: 0/l1D Both at 24 h
G3: SALl0 postoperation
Pain: G1 < G2 < G3
Analgesics: G1 = G2 < G3
86 (1991) Cholecystectomy 1;3 GA plus: G1 and G3: infiltration NA At time of closure FEN or MPE Preventive effect - no
(n=80) G1: NA/BUP into peritoneal, fascial, dose NS
G2: NA/BUP and subcutaneous layers
G3: NA/SAL 40 ml 0.25% BUP
G4: NAISAL G2andG4:
topical into wound
40 ml 0.25% BUP
87 (1994) ChOlecystectomy 1;2 GA plus: Infiltration of cutis, 15 min before incision NA MPE i.m. 75- Preventive effect - no,
(n=69) G1: ROP/NA subcutis, and fascia 100mg but at 74 h postoperation
G2: ROP/NA G1: 70 ml 0.25% ROP FEN Lv. dose NS analgesics: G1 < G3
G3: SALINA G2: 70ml 0.125% ROP (p= 0.051)
88 (1995) Cholecystectomy 4;8 GA plus: Interpleural block Bolus 20-25 min before G2: bolus in ALF Lv. Preemptive effect - no
(n=30) G1: BUP/BUP Bolus 20 ml 0.5% BUP incision followed by recovery room G1: 13.6 [1g/kg
G2: SAL/BUP followed by infusion of infusion for 24 h in G1 followed by G2: 39.2 [1g/kg
7 ml/h 0.25% BUP infusion for 24 h
Table A7.1 Continued

Group: Nature and time after

Procedure Treatment preincision Ti1111 n9of surgery of preventive
Reference (number of combination drug/post~ Timing of. preincision postineision Systemic or preemptive analgesic
(year) patients) (Fig. 7.1) incision drug Route and dose intervention intervention analgesics' effect
89 (1991) Laparoscopy 1;2 GA plus: Intraperitoneal After creation of NA ALF Lv. 15 lAg/kg Preventive effect yes
G1: IO/NA infiltration pncumoperitoneum up to 48 h postoperation
G2: SAUNA G3: 80 ml 0.5% LID + Pain: G3 G4<G1 =G2
G3: LID + EPI!NA 1 :320.000 EPI
G4: BUP + EPI/NA G4: BOml 0.125%
BUP + 1 :800.000 EPI
90 (1994) Laparoscopic 1;3;5 GA plus: Peritoneal topical spray After creation of At end of FEN i.v. 5 ~lg/kg Preventive effect - yes at
cholecystectomy G1: SAUSAl 20ml 0.5% BUP + pneumoperitoneum, operation 24 h postoperation
(n=421 G2: SAUBUP + EPI 1 :200,000 EPI 10 min before surgery Pain: G3 < G2 < Gl
G3: BUP EPI! Analgesics: G3 <: G2 < G1
91 (1996) laparoscopic 1;2;3;5 GA plus: Peritoneal topical spray After creation of At end of FEN Lv. Preemptive effect - yes
cholecystectomy Gl: SAUSAl 20ml 0.5% BUP + pncumoperitoneum, operation 0.15mg/kg at 24 h postoperation
(n= 120) G2: SAUBUP + EPI 1 :200,000 EPI 10 min before surgery Pain: G4<G2
G3: BUP + EPI! Analgesics: G4 < G2
BUP+EPI Preventive effect - yes at
G4: BUP + [PI/SAL 24 h postoperation
Pain: G3 G4<G2<:G1
G3 = G4 < G2 < G1
92 (1997) laparoscop ic 1;5 GA plus: Intraperitoneal After creation of At end of No Preventive effect - no
cholecystectomy Gl: BUP/BUP infiltration pneumoperitoneum operation Pain: G1 <G2 up to Bh
(n=80j G2: SAUSAL 15ml 0.5% BUP postoperation
Analgesics: G1 < G2 up to
4 h postoperation
93 (1998) Diagnostic 1;2;3 G1: BUP/SAl Infiltration of skin and 5 min prior to incision Immediately FEN i.v. 2 ~lg/kg Preemptive effect - yes
laparoscopy or G2: SAUBUP fascia for trocar placement before closure Preventive effect - yes
laparoscopic tubal G3: SAUSAL 10 ml 0.5% BUP Both at 24h
ligation postoperation:
(n= 57) MPQ: Gl <G2 G3
TFA: G1 >G2 G3
94 (2000) Laparoscopic 1;2 GA plus: Infiltration into 15 min before incision NA MPE i.m. 50mg Preventive effect yes
gynecological G1: BUP/NA cutaneous, subcutaneous, Pain: G1 <G2 at 10h
surgery G2: SAUNA and subfascial tissues postoperation
(n=2B) 20 ml 0.25% BUP Analgesics: G1 < G2 at
24 h postoperation
95 (1982) Inguinal hernia 1;2 GA plus: Infiltration of operative Immediately before NA FEN Lv. NS Preventive effect
repair G1: LlD/NA field and IINB operation - opposite
(n=117) G2: 0/NA SOml 0.5-1% LID Analgesics: G1 > G2
21 (1988) Inguinal hernia 1;3 GA plus: Aerosol spray of NA Before closure NS Preventive effect yes at
repair G1: NAiLID cutaneous and 24 h postoperation
(n=30) G2: NAiPLA subcutaneous surface or Pain: G1 <G2=G3
G3: NA/0 wound 200 mg LI D Pain on movement:
G1 <G2=G3
Pain to pressure:
G1 <G2=G3
Analgesia: Gl < G2 G3
22 (1989) Inguinal hernia 1;3 GA plus: IINB NA Before dos! ng the PAP Preventive effect yes at
repair G1: NA/BUP 10ml 0.5% BUP external oblique MPE 24 h postoperation
(n=60) G2: NAl0 aponeurosis dose NS Pain: G1 <G2
Analgesics: G1 < G2 at
96 (1990) Inguinal 1;2 G1: GA only/NA G2: Infiltration 40 ml G2: 5 min before NA No Preventive effect
herniorrhaphy G2: GA + BUP/NA 0.25% BUP incision - yes up to day 10
(n=36) G3: BUPINA G3: spinal 12.5 mg 0.5% G3: NS postoperation
BUP Pain at rest: G2 G3 <G1
Pain on movement:
Pain to pressure:
97 (1990) Inguinal 2 Spinal LID plus: Spinal LID 5% Spinal NS NA No Preventive effect - yes
herniorrhaphy G1: BUP/NA G1: 72mg Nerve block NS up to 48 h postoperation
(n=45) G2: 0/NA G2: 74mg Pain: G1 <G2
IINB Analgesics: G1 < G2
10ml 0.5% BUP
98 (1992) Herniorrhaphy 2;4 GA plus: Inguinal field block 15 min before operation After closure but ALF Lv. 10 Ilg/kg Preemptive effect - no
(n=32) G1: LID + EPI/0 55 mll% LID + EPI before awake and 0.5 JA.g/kgl
G2: 0/L1D + EPI min
99 (1992) Inguinal herniotomy 2;3 GA plus: Infiltration of surgical 5 min before incision Immediately No Preemptive effect - yes
(n=37) Gl: LlD!0 area before skin at 6 h postoperation
G2: 0/L1D 40m11% LID closure Analgesics: G1 < G2
100 (1992) Inguinal 2;3 GA plus: Inguinal field block with After induction, before Before closure of FEN i. v. 1 UQ/kQ Preventive effect - no
herniorrhaphy Gl: BUP/0 BUP incision wound layers
(n=50) G2: 0/BUP Gl: 40 ml 0.25%
G2: 10ml 0.5%
Table A1.1 Continued

Group: Nature and time after

Procedure Treatment preincision Timing of surgery of preventive
Reference (number of combination drug/post. Timing of preincision postincision Systemic or preemptive analgesic
(year) patients) (Fig. 1.1) incision drug Route and dose intervention intervention analgesics' effect
101 (1996) Inguinal 2;4 GA plus: Infiltration Before start of surgery After surgery but No Preemptive effect no
hernioplasty G1: BUPISAL sUbcutaneously plus tlNB before end of
(n=54) G2: SAUBUP 2.5 mg/ml. 1 mg/kg BUP anesthesia
102 (2000)" Inguinal hernia 1;8 GA plus: Infiltration of proposed 1.5 h before skin Intraoperative! NS Preventive effect - yes
repair Gl: BUP/BUP/BUPI incision site and field incision after wound % pain on walking:
(n=70) BUP block of iliohypogastric closure/6 h after G1 < G2 up to day 10
G2: SAUSAL/SAL/SAL and ilioinguinal nerves preoperative field postoperation
1 ml/kg BUP 0.25% block Analgesics: Gl < G2 up to
intraoperative infiltration day 2 postoperation
0.8 ml/kg BUP
subcutaneous wound
0.2 ml/kg BUP
subcutaneous wound
1 ml/kg BUP
103 (1990) Hernia repair. 2;4 GA plus: Caudal block After induction before After completion NS Preemptive effect - no
orchiopexy, Gl: BUP/0 0.5 mllkg 0.25% surgery of surgery before
hydrocelectomy G2: 0/BUP emergence
104 (1994) Circumcision 2;4 GA plus: Caudal block 30 min before surgery Immediately after No Preemptive effect - no
(n=25) Gl: LlD/0 0.5ml/kg 1% surgery
G2: 0/L1D
105 (1997) Herniorraphy, 2;4 GA plus: Caudal After induction, before After surgery, No Preemptive effect - no
orchiopexy. G1: BUP + EPII0 0.6 ml/kg 0.25% + incision prior to
circumcision G2: 0/BUP + EPI 1:200,000 emergence
106 (1997) Hypospadias repair 2;4;6 GA plus: Penile block Immediately before Immediately after No Preemptive effect no
(n=98) Gl. BUP/0 Gl, G2: 0.5 mllkg 0.5% incision surgery before Preventive effect - yes
G2: 0/BUP BUP emerging from GA up to 24 h postoperation
G3: BUP/BUP G3: 0.25ml/kg 0.5% BUP Pain: G3 <G2
Analgesics: G3 < G2
107 (1994) Appendectomy 1;2;3 GA plus: Infiltration of skin and 3 min before incision At wound closure FEN Lv. Preemptive effect - no
(n=90) G1: LID + EPII0 subcutaneous tissue G1: 118ftg Preventive effect - no
G2: eJ/LID EPI 15 mll.S% + 1 :200.000 G2: 141 ft9
G3: 0/0 G3: 116 ftg
108 (1997) Appendectomy 1;5 GA plus: Infiltration of skin and Immediately before At wound closure NS Preventive effect - no
(n=60) G1: LID + BUPI subcutaneous tissues incision
lID+BUP 1% LID +0.5% BUP 10ml
G3: 0/0
109 (1997) Appendectomy l;Z GA plus: Infiltration After induction, before NA FEN Preventive effect
(n=43) Gl: LID + BUP/NA dose NS incision "minimal doses" - no but on days 3-5
GZ: SALINA postoperation
Analgesia: G1 < G2
(P=0.07, two-tailed)
110 (1992) Gynecological 1;3 GA pius: Aerosol spray of NA After closure of FEN Lv. 0.1 mg Preventive effect - no
laparotomy G1: NA/LiD subcutaneous tissue fascia
(n = 24) G2: NAt0 200mg LID
111(1993) Abdominal 2;3 GA plus: Lumbar epidural 15 min before start of 15 min before MOR i.m. 7.5- Preemptive effect - no
hysterectomy G1: BUP + EPI/0 15ml 0.5% BUP+ surgery waking at end of 10mg
(n = 36) G2: 0/BUP + EPI 1:200,000 EPI operation
112 (1995) Abdominal 1;2;3 GA plus: Infiltration of incision 15 min before incision At end of surgery SUF Lv. Preemptive effect - no
hysterectomy G1: 0/0 40ml 0.5% BUP + 5 f-tg/ml before skin suture G1: 92 f-tg Preventive effect - no
(n = 56) G2: BUP + EPI/0 EPI G2: 94 i-!g
G3: 0/BUP + EPI G3: 96i-!g
113 (1996) Total abdominal 2;4 GA plus: Spinal Before induction At end of MORLm. Preemptive effect
hysterectomy G1: BUP/0 3ml 0.5% BUP operation. prior to 0.15 mg/kg - opposite at 12 h
(n=38) G2: 0/BUP extubation postoperation
Lv. PCA: G1 > G2
114 (1996) Hysterectomy or 1;2 G1: BUPINA Spinal After loss of sensation NA No Preventive effect - yes
myomectomy G2: GA only/NA 3ml 0.5% BUP to pinprick at T8, before up to 24 h postoperation
(n=60) incision Pain at rest: G1 < GZ
Pain on cough: G1 < G2
Lv. PCA: G1 < G2
115 (1996) Hysterectomy 1;2 GA+plus: Infiltration of surgical 5 min before incision NA PIR p.L 40mg Preventive effect
(n=50) G1: BUPINA area FEN i.v. 0.3 mg - yes up to day 3
G2: SAUNA 40 ml 0.25% BUP BPR i.m. 0.3 mg postoperation
Analgesics: G1 < G2
116 (1988) Cesarean section 1;3 GA plus: BiiateralllNB NA At end of surgery FEN Lv. 100i-!g Preventive effect - yes
(n=26) Gl:NAlBUP 10ml 0.5% BUP before reversal up to 24 h postoperation
G2: NAISAL Pain: G1 < G2
Analgesics: Gl < G2
Table A1.1 Continued

Group: Nature and time after

Procedure Treatment preincision Timing of surgery of preventive
Reference (number of combination drug/post- Timing of preincision postincision Systemic or preemptive analgesic
(year) patients) (Fig. 7.1) incision drug Route and dose intervention intervention analgesics' effect
117 (1991) Cesarean section 1;3 GA plus: Infiltration of NA After closure of MOR Lv. 5- Preventive effect - yes at
(n=Z8) Gl: NA/BUP subcutaneous tissues peritoneum 10mg 24 h postoperation
G2: NA/SAL 0.4ml/kg 0.5% BUP i.v. PCA: Gl < G2
118 (1994) Cesarean section 1;2;3 GA plus: Gl: bilateralllNB 10ml Before surgery NS FEN i.v. lO0i-l.g Preventive effect - yes
(n=62) G1: BUP/0 0.5% on each side Pain: Gl < G3 up to 24 h
G2: 0/BUP G2: wound infiltration postoperation
G3: 0/0 20 ml 0.5% BUP Analgesics: Gl < G2 at
20 h postoperation
119 (1996) Cesarean section 2;5 Preoperative spi na I Spinal 15ml plus: IINB after spinal but Immediately after NS Preemptive effect - yes
(n=46) BUP plus: IINB before incision C·seelion at 24-48 h postoperation
Gl: BUP + EPI/0 10 ml 0.5% BUP + Pain at rest: G1 < G2
G2: 0/BUP + EPI 1:200,000 EPI Pain on movement:
G3: 0/0 G1 <G2
Preventive effect
opposite at 24-48 h
Pain at rest: G2 > G3 = G1
Pain on movement:
G2>G3 G1
120 (1994) Lower abdominal 2;3 GA plus: Lumbar epidural 35 min before incision 30min after No Preemptive effect yes
surgery Gl: BUP/SAL 15 ml 0.5% BUP incision MPQ: Gl < G2 at 24h and
(n=42) G2: SAUBUP 72 h postoperation
Lv. PCA: Gl < G2 up to
121 (1997) Laparotomy 2;3 GA plus: Infiltration of midline 5 min before incision Immediately FEN i.v. NS Preemptive effect
(n=200) Gl: BUP/0 incision before skin - opposite at 24 h
G2: 0/BUP 40ml 0.25% BUP closure postoperation
Pain: G1 >G2
122 (1993) Lumbar diskectomy 1;3 GA plus: Infiltration of wound and NA Immediately MOR Lv. 0.1 mgl Preventive effect - yes at
(n=60) Gl: NAiBUP subcutaneous tissues before wound kg 24 h postoperation
G2: NAl0 20ml 0.5% BUP closure Incidence of severe pain:
Gl <G2
Lv. PCA: Gl < G2
123 (1999)' Arthroscop it knee 4;6 GA plus: Femoral three-in-one Three-in-one block Intra-articular and FEN Lv. 1.5 !-!gl Preventive effect no
surgery Gl: ROP/ROP/ROP nerve block before surgical incision peri-incisional kg
44) G2: SAl/ROP/SAL 40ml 0.2% ROP ROP at end of
Intra-articular instillation surgery
30 ml 0.2% ROP
Peri-incisional infiltration
20 ml 0.2% ROP
124 (1999) Posterolateral 4;8 GA plus: Thoracic epidural Bolus 20 min before Bolus at NS Preemptive effect
thoracotomy Gl: MEP/MEP MEP 4 mll.5% bolus incision followed by completion - yes up to 3 days and at
(n= 70) G2: 0/MEP followed by 4 ml/h 72-h infusion of operation 6 months postoperation
infusion followed by 72-h Pain: Gl <G2
125 (1990) Hemorrhoidectomy 1;4 GA plus: Perianal infiltration NA Postoperative No Preventive effect - no
(n=40) Gl: NAIBUP + EPI 1.5 mg/kg 0.5% BUP +
G2: NA/EPI 1 :200,000 EPI
126 (1993) Hemorrhoidectomy 1;4 GA plus: Infiltration Before excision After excision NS Preventive effect
(n=30) Gl: EPI/BUP 1 :200,000 EPI opposite
G2: EPI/SAL 20ml 0.5% BUP Pain: Gl > G2 up to
2 days postoperation
127 (2000) Breast biopsy 2;6 GA plus: Infiltration TEN at induction, BUP After skin closure, AlF Lv. 5l-!g/kg Preemptive effect - no
(n= 74) Gl: TEN + BUP/0 10ml 0.5% BUP 5 min before incision while still
G2: TEN/BUP i.v. anesthetized
128 (1998) Strabismus surgery 1;2;4 GA plus: G2: retrobulbar block 10 min before surgery At conclusion of NS Preventive effect - no
(n=30) Gl: 0/0 2mI0.5%BUP surgery
G2: BUP/0 G3: subcoi]unctival
G3: 0/BUP ii]ection 0.25 ml 0.5%
129 (2000) Hand and forearm 2;4 GA plus: Axillary block 20 min before incision After surgery No Preemptive effect
surgery Gl: BUP/0 2 mg/kg 0.25% BUP (15min before the - opposite at 24 h
(no:S5) G2: 0/BUP end of GA) postoperation
Cumulative pain: G1 > G2
G1 >G2
a. Administered to all patients as premedication or during surgery.
b. This study has four interventions, the second occurring intraoperatively, the third at the end of surgery, and the fourth 6h after preoperative field block.
c. This study has three interventions, the second and third occurring at the end of surgery.
ACE, acetaminophen (paracetamol); ALF, alfentanil; BPR, buprenorphine; BUP. bupivacaine; Die diclofenac; i.v. peA. intravenous patient-controlled analgesia; EPI, epinephrine (adrenaline); FEN, fentanyl; GA, gen-
eral anesthesia; IINB, ilioinguinal and iliohypogastric nerve block; i.m., intramuscular; i.v., intravenous; KET. ketamine; KTO, ketorolac; LID. lidocaine (lignocaine); MEP. mepivacaine: MPE, meperidine (pethidine);
MPQ McGill Pain Questionnaire; MOR, morphine; NA, not applicable; NS, not stated; PAP, papaveretum; PIR. piroxicam; p.r., per rectum; PRI. prilocaine; ROP, ropivacaine; Sl and 52, first and second sides of body
in studies using patients as their own controls (i.e. within-subject design); SAL, saline; SUF. 5ufentanil; TEN, tenoxicam; 0. nothing administered.
Table A7.2 Studies examining the effects of riming of opioid administration relative to incision

Procedure Treatment Group: Timing of Timing of

Reference (number of combination preincision drug! preincision postincision Systemic Nature and time after surgery of
(year) patients) (Fig. 7.1) postincision drug Route and dose intervention intervention opioid' preventive or preemptive analgesic effect .
131 (1992) Posterolatera I 2;3 GA plus: Lumbar epidural 30 min before 15 min after No Preemptive effect yes
thoracotomy G1: FEN/SAL 4IA!l/kg FEN incision incision Pain: G1 < G2 at 6 h postoperation
(n= 30) G2: SALIFEN Lv. PCA: G1 < G2 between 12h and 24h
132 (1993) Abdominal 2;3 GA plus: G1: Lm. 10mg G1: 1 h Closure of No Preemptive effect - yes at 24 h
hysterectomy G1: MOR/0 MOR preoperation peritoneum postoperation
(n=60) G2: MORl0 G2: i.v. 10mg G2: at induction Lv. PCA: G2 < G3
G3: 0/MOR MOR Preventive effect - yes at 24 h postoperation
G3: Lv. 10mg Relative pain thresholds: G3 > G1 = G2
MOR Preemptive effect opposite at 48 h
Pain on movement: G2 > G3
133 (1994) Abdominal 2;3 GA plus: Lv. One bolus at 10min after No Preventive effect - no
hysterectomy Gl: ALF/MOR Gl: 7.5 lAg/kg ALF induction and incision
(n= 60) G2: 0/ALF + MOR per bolus one bolus 90s
G2: 15 lAg/kg ALF before incision
0.2 mg/kg MOR
134 (1994) Major abdominal 1;2 GA plus: Lumbar epidural Before induction NA FEN i.v. Preventive effect - yes up to 72 h
G1: MORINA 5mg MOR Gl 4651lg postoperation
G2: 0/NA G2: 9831lg Pain: Gl <G2
i.v. PCA: Gl < G2
135 (1994) Postepisiotomy 4 G1: MOR/SAL + SAL lumbar epidural After episiotomy Onset of episiotomy No Preventive effect - yes
pain G2: SALIMOR + ACE 2mgMOR repair pain Pain: G1 < G2
136 (1994) Abdominal 2;3 GA plus: i.v. At induction 1 min after incision No Preventive effect opposite at 24 h
hysterectomy G1: ALF/SAL + MOR 40 Ilg/kg ALF 10 min before postoperation
G2: SALIALF + MOR 0.1 mg/kg MOR incision Pain at rest: Gl > G2
137 (1995) Abdominal 2;5 GA plus: i.v. At induction Closure of No Preventive effect - yes at 48 h postoperation
hysterectomy G1: MOR/MOR G1: 10mg/dose peritoneum Pain on movement: G2 < G1
(n=49) G2: MOR/0 MOR
G2: 20mg MOR
138 (1995)b Abdominal 2;3 GA plus: i.v. 5 min before After incision of No Preemptive effect - no
hysterectomy G1: FEN/SAUSAl G1-G3: 10 [Ig/kg induction peritoneum/after
85) G2: SAUFEN/SAL FEN removal of uterus
G3: SAUSAUFEN G4-G5: 1 ;.tg/kg
139 (1996) Abdominal 1;2 GA plus: p.o. q12hfor42h 2 h before surgery FEN Lv. Preventive effect - no
hysterectomy G1: MOR/PLA 30mg/dose MOR before surgery 1
(n=51) G2: PLAIMOR
140 (1996)' Total knee 1;2;7;8 Spinal BUP plus: Spinal 1 h before Immediately after NA Preemptive effect - no
arthroplasty G1: MORI 3ml 0.5% BUP operation the operation/10 h Preventive effect - opposite at 16 h
(n= 41) MOR+MOR first intervention after the operation postoperation
G2: SAlIMOR + MOR Lm. Pain: G3 > G4
G3: MOR/SAL + SAL 0.14mg/kg MOR
G4: SAlISAlISAL second
4mg MOR
3mg MOR
7 (1996) Abdominal 1;5 GA plus: i.v. Bolus at NA No Preventive effect - yes up to 12 h
hysterectomy G1: 0/NA G2: 30 [Ig/kg induction postoperation
(n=45) G2: ALF/NA followed by 10- followed by IAA: G3 < Gl = G2
G3: AlF/NA 20iJ,g/kg AlF hourly boluses
G3: 100 lAg/kg in G2 and
followed by 1- intraoperative
2 [lg/kg/min ALF infusion in G3
141 (1996) Abdominal 2;3 GA plus: Lv. 5 min before Ligation of round No Preemptive effect - no
hysterectomy G1: SUF/SAL 1 [lg/kg SUF induction ligaments
(n=39) G2: SAlISUF
142 (1996) Back surgery 1;2 GA plus: Lv. 5min before NA No Preventive effect - no but
G1: FEN/NA 3 [lg/kg FEN induction sensory thresholds: G1 > G2
150 (1997) Third molar 2;3 GA plus: Lm. 1-2h before Immediately after FEN Lv. Preemptive effect - no
extraction G1: MPE/SAl 50mg MPE surgery surgery 1.5
143 (1997) Abdominal 2;3 GA plus: Lv. 15 min before 15 min after No Preemptive effect yes from 48 h to 72 h
hysterectomy Gl: AlF/0 70 [lg/kg ALF incision incision postoperation
38) G2: 0/ALF Lv. PCA: G1 < G2
lable A7.Z Continued

Procedure Treatment Group: Timing of Timing of

Reference (number of combination preincision drug/ preincision postincision Systemic Nature and time after surgery of
(year) patients) (Fig. 7.1) postincision drug Route and dose intervention intervention opioid· preventive or preemptive analgesic effect
144 (1997) lumbar 2;3 GA plus: lumbar epidural 60min before End of surgery MOR i.v. Preemptive effect - yes up to 24 h post
laminectomy Gl: MOR/SAL 3mg MOR surgery 0.1 mg/kg operation
(n=30) GZ: SAUMOR Pain: Gl <G2
Analgesics: Gl < GZ
TFA: Gl >G2
145 (1998) Abdominal 2;3 GA plus: Lv. At induction, At start of skin No Preemptive effect - no
hysterectomy Gl: MORISAL 0.3 mg/kg MOR 30 min before incision
(n=60) GZ: SAUMOR incision
146 (1999) limb surgery, 1;5 GA plus: Epidural Bolus 40min After skin closure NS Preventive effect - yes up to 48 h post
radical Gl: MOR/NAl bolus of 0.06 mgl before incision operation for limb surgery and mastectomy
mastectomy, G2: SAUSAL kg MOR followed followed by Pain: Gl <G2
gastrectomy, by 0.02 mg/kg/h intraoperative E-PCA: Gl < G2
hysterectomy, MOR infusion infusion until end
appendectomy Lv. of surgery
(n= 268) 0.008 mg/kg NAL
147 (2000) Orthopedic 1;5 GA plus: Cervical or Bolus 40min After skin closure NS Preventive effect - yes up to 48 h post
surgery: Removal surgery lumbar epidural before incision operation only among the group of patients
removal (n=59); Gl: MOR/NAl bolus of 0.06 mg/ followed by without preoperative pain Ii.e. removal
fracture (n", 56); G2: SAl/SAL kg MOR followed intraoperative surgery)
arthritis (n = 58) Fracture surgery by 0.02 mg/kg/h infusion until end Pain at rest: Gl < G2
G3: MOR/NAL MOR infusion of surgery Pain on movement: G1 < G2 at 12 h post
64: SAL/SAL Lv. operation
Arthritis surgery 0.008 maIko NAL E-PCA: G1 < G2
148 (2000) Open knee 1;3 GA plus: i.v. NA At beginning of ALF i.v. Preventive effect - yes up to 24 h post
Gl: NAIMOR G1: 0.15mg/kg wound closure 20-30 fA.g1 operation
(n",,37) G2: NA/M6G MOR kg Lv. PCA: Gl < G2, Gl < G3, G2", G3
G3: NA/SAL G2: 0.1 mg/kg
149 (2000) 1;5 GA plus: Lv. Bolus beginning NA No Preventive effect yes at 4 hand 8 h post
neurosurgical Gl' TRAINA G1: 1 mg/kg bolus at induction operation
procedures G2: TRAINA TRA and for G2 and Pain: G3 G2 < G1
(n=42) G3: FEN/NA G2: 0.5 mg/kg G3 continuous
bolus followed infusion
by 150 fJ.g/kg/h throughout the
continuous operation
infusion TRA
G3: 2 fJ.g/kgih
infusion FEN
a. Opioid, other than the target intervefltion, administered to all patients as a premedication or during surgery.
b. This study has three interventions, the third occurring after removal of the uterus.
c. This study has three interventions, the third occurring 10 h after the operation
ALF, alfentanil; BUP, bupivacaine; E-PCA, epidural patient-controlled analgesia; FEN, fentanyl; IAA, integrated analgesic assessment; Lv., intravenous; Lm., intramuscular; M6G, morphine-6-glucuronide; MOR,
morphine; NAL, naloxone; ACE, acetaminophen (paracetamol); MPE, meperidine (pethidine); PLA, placebo; p.o., per os; NA, not applicable; NS, not stated; SAL, saline; SUF, sufentani1; IRA, tramadol; TfA, time to
first analgesic request; 0, nothing administered.
Table A7.3 Studies examining the effects of timing of administration of the NMDA receptor antagonists ketamine or dextromethorphan relative to incision

Nature and time after

Procedure Treatment Group: Timing of Timing of surgery of preventive
Reference (number of combination pre incision drug! preincision postincision Systemic or preemptive analge·
(year) patients) (Fig. 7.1) postincision drug Route and dose intervention intervention analgesics· sic effect
166 (1993) Cl1olecystectomy 1;2 GA plus: i.v. Smin before NA FEN i.v. Preventive effect - yes
(n=22) G1: KETINA 0.5 mg/kg KET incision 2 lAg/kg at 24 h post operation
G2: SALINA AnalgesiCS: G1 < G2
20 (1994) Transabdominal 1;5 GA plus: Lv. Bolus at NA No Preventive effect
hysterectomy G1: KH/NA G1: 2 mg/kg KET bolus induction - yes up to 4811 post
(n=27) G2: FEN/NA followed by 20 lAg/kg! followed by operation
G3: 0/NA min infusion infusion until Hypera Iges ia:
G2: 51lg/kg FEN bolus end of surgery G1 =G2<G3
Followed by
kg/min infusion
167 (1997) Radical subtotal 2;3 GA plus: Thoracic epidural Before After removal No Preemptive effect - yes
gastrectomy G1: MOR + KET/SAl 2mgMOR induction of specimen at 48 h post operation
(n=60) G2: SALIMOR + KET 60mg KET Analgesics: G1 < G2
168 (1991) Cesarean section 1;2 GA plus: i.v. Induction NA MOR Lv. 0.15 Preventive effect
(n=40) G1: KETINA 1 mg/kg KET mg/kg - yes up to 2411 post
G2: THIINA operation
Lv. PCA: G1 < G2
169 (1997) Abdominal surgery 3;5 GA plus: Lv. Bolus at After wound No Preventive effect
(n=40) G1: KET/el G1: 0.5 mg!kg KET induction closure - yes up to day 2 post
G2: 0/KET bolus followed by followed by operation
10 ~lg/kg/min infusion infusion until i.v. PCA: G1 < G2
G2: 0.5 mg/kg KET closure
170 (1997)b Total knee 7;8 G1: UD+MOR+KETI Lumbar epidural 30 min before 30min after No Preemptive effect yes
replacement UD/UD+MOR KET First intervention incision incision/at at 72 h post operation
(n=45) G2: LlDI 15m12% LID end of Pain: G1 <G2
LID + MOR + KEr/ 1.5mg MOR surgery and Incident pain: G1 < G2
UD+MOR+KET 20mg KET q12h i.v. PCA: G1 < G2
G3: GA + SAl/MOR + KETI Second intervention Preventive effect
UD+MOR+KET 10m12%UD - yes up to 72 h post
1.5mg MOR operation
20mg KET Pain: G1 <G3
Tl1ird intervention Incident pain: G1 < G3
10ml 0.32% LID i.v. PCA: G1 < G2 < G3
10mg KET
171 (1998) Upper abdominal 2;3 GA plus: Thoracic epidural 20 min before Closure of No Preemptive effect - no
surgery G1: KETINA 60mg KET induction parietal
(n=98) G2: NAIKET peritoneum
172 (1998) Abdominal 5 GA plus: Lv. 3min before 25min after No Preventive effect
hysterectomy Gl: FEN/FEN Gl: 1.5 j-tg/kg FEN and induction. incision and - no but on day 5 post
45) G2: KET/KET 0.75 j-tg/kg q 30min 5 min before q 30min operation
G3: MAG/MAG G2: 0.5 mg/kg KET and incision until 45min Pain: Gl = G3 < G2
0.25 mg/kg q 30 min before end of (P = 0.054)
G3: 20 mg/kg MAG and surgery
q 30 min
173 (1998) Total abdominal 1;2;3 GA plus: lumbar epidural Before 20min after ALF i.v. Preemptive effect - no
hysterectomy G1: KET/SAL 30mg KET induction. incision Gl: 5.1 mg Preventive effect
(n=61) G2: SAUKET incision G2: 2.5mg - yes up to 24 h post
G3: SAUSAl G3: 4.0mg operation
E-PCA: Gl < G2 G3
174 (1999) Total mastectomy 2;3 GA plus: i.v. 5min before At skin SUF Lv. Preemptive effect - no
(n= 128) G1: KETlSAl 0.15mg/kg KET incision closure Gl:19.9j-tg
G2: SAl/KET G2: 20.4""g
175 (1999)' Laparoscopic 6;8 Preoperative BUP Infiltration Lv. KET 3- Lv. KET KTO Lv. Preemptive effect - no
cholecystectomy infiltration of incision BUP dose NS 10min before at skin 30mg Preventive effect - no
(n= 60) lines plus GA plus: Lv. incision closurelACE FEN Lv.
Gl: (R)-KHlSAUACE 1.0mg/kg (R)-KET on arrival 1.5-2.0 j-tg/kg
G2: SAU(R)-KETIACE p.L in recovery ALF
G3: SAUSAUACE 1.000mgACE room 0.5-1.0mg
176 (2000) Gastrectomy 1;5 GA plus: Thoracic epidural Epidural Immediately No Preventive effect - yes
(n=121) G1: MOR (epidural) + SAL 0.06 mg/kg MOR bolus 40min priorto after surgery MOllement pain:
(Lv.)/NAL (i.v.) followed by 0.02 mgl skin incision G2 < G4 at 12h post
G2: SAL (epidural) + KET kg/h infusion followed by operation
(Lv.) i.lI. infusion until Rest pain:
G3: MOR First intervention skin closure G3 < G1 = G2 < G4 at
(epidural) + KET (LII.)I 1.0mg/kg KET bolus Lv.10min 24 hand 48 h post
NAl (i.v.) followed by 0.5 mgt prior to skin operation
G4: SAL (epidural) + SAL kg/h infusion incision E·PCA:
Ii. v.)/SAL (I. v.) Second intervention followed by G3 <G1 G2 <G4 at
0.008 mg/kg NAL infusion until 24 hand 48 h post
bolus skin closure operation
Table A7.3 Continued

Nature and time after

Procedure Treatment Group: Timing of Timing of surgery of preventive
Reference (number of combination preincision drug! pre incision postincision Systemic or preemptive analge-
jyear) patients) (Fig. 7.1) postincision drug Route and dose intervention intervention analgesics' sic effect
177 (2000) Abdominal 1;2;3 GA plus: i.v. Smin before At end of skin ALF Lv. 15~tgl Preemptive effect - no
hysterectomy Gl' SAL/SAL 0.4 mg/kg KET skin incision closure kg Preventive effect
(n=99) G2: KETISAL - opposite at 60 min
G3: SAL/KET Post operation
pain: G3 < Gl = G2
178 (2000) Arthroscopic 1;2;3 GA plus: Lv. 10 min after After skin SUF Lv. Preemptive effect - no
anterior cruciate Gl: KET/SAl 0.15 mg/kg KET induction closure 0.5-0.6I-tg/kg Preventive effect - yes
ligament repair G2: SALIKET before at 24 hand 48 h post
(n=45) G3: SAL/SAL tourniquet operation
inflation Lv. PCA: Gl = G2 < G3
188 (1998) Laparotomy 1;2 GA plus: p.o. Night before NA MORi.v. Preventive effect - no
(n=37) G1: DEX/NA 60mg/dose DEX and 1 h before Gl:13mg
G2: PlAlNA surgery G2: 17mg
179 (1998) Bilateral 1;2 GA plus: p.o. 60 min before NA No Preventive effect
tonsillectomy Gl: DEX/NA G1: 30mg DEX arrival in OR - yes up to day 7 post
(n=36) G2: DEl(fNA G2: 45mg DEX operation
G3: PLA/NA Pain at rest: G2 < G3
Pain on swallowing:
G2<G1 =G3
Analgesics: G1 = G2 < G3
180 (1999) Lower abdominal 2;3 GA plus: i.v. 30 min before During skin FEN Lv. Preemptive effect
surgery Gl: DEX/SAL 5mg/kg DEX induction over closure 3l-tg/kg - yes up to day 2 post
(n=60) G2: SAL/DEX 30min operation
Lv. peA: Gl < G2
181 (1999) Adenotonsillectomy 1;2 GA plus: p.o. 60 min before NA MOR Lv. Preventive effect - no
(n=60) G1: DEX/NA G1: 0.5 mg/kg DEX start of surgery 0.075mg/kg
G2: DEX/NA G2: 1.0mg/kg DEX ACE p.r.
G3: PLA/NA 25-35mg/kg
182 (1999) Modified radical 1;2 GA plus: Lm. 30 min before NA FEN Lv. Preventive effect - yes
mastectomy G1: DEX + CPM/NA 40mg DEX incision 2l-tg/kg at 48 h post operation
(n=60) G2: CPM/NA 20mgCPM Analaesics: Gl < G2
183 (1999) Laparoscopic 1;2;3 GA plus: Lm. 30 min before Removal of FEN Lv. Preemptive effect - yes
cholecystectomy Gl: DEX + CPM/0 Gl and G2: 40 mg incision gall bladder 2IAg/kg Preventive effect - yes
(n=90) G2: 0/DEX + CPM DEX + 20mg CPM Both at 48 h post
G3: CPM/0 G3: 20mg CPM operation
Pain: Gl <G2 G3
Gl <G2=G3
184 (2000) Total abdominal 1 ;2 GA plus: p.o. 1 h before NA FEN i.v. Preventive effect no
hysterectomy Gl: DEXINA 150mg DEX surgery OAmg Lv. PCA: Gl < G2 from 0
(n=50) G2: PlAiNA to 4 h post operation
185 (2000) Hemorrhoidectomy 1;2 G1: LID + EPI + CPM/NA Infiltration Infiltration NS NA No Preventive effect - yes
(n=60) G2: UD + EPI + DEX + 10ml 2% LID + 0.4 mg Lm. injection at 48 h post operation
CPM/NA EPI in 30 ml SAL 30 min before Worst pain: G2 < Gl
Lm. skin incision Analgesics: G2 < Gl
40mg DEX
186 (2000) Upper abdominal 1;2 GA plus: i.m. 30 min before NA FEN Lv. 21A91 Preventive effect
surgery Gl: CPM/NA G2: lOmg intramuscular kg yes up to 3 days post
(n=60) G2: DEX + CPM/NA G3: 20mg incision LID Lv. operation
G3: DEX + CPMINA G4: 40mg 1.5mg/kg Cough pain: G4<Gl,
G4: DEX + CPM/NA G2,G3
Lv. PCA: G4 < Gl
181 (2001) laparoscopic 1;2 GA plus: p.o. 90min before NA FEN Lv. Preventive effect - yes
Cholecystectomy Gl: DEX/NA Gl: 90mg the operation 2.51A9 /kg at 24 h post operation
or inguinal G2: PlAiNA Pain: Gl < G2
hernioplasty Analgesics: G1 < G2

a. Administered to all patients as a premedication or during surgery.

b. This study has more than three interventions, the third occurring at the end of surgery and q 12 h thereafter.
c. This study has three interventions, the third occurring on arrival in the recovery room.
ACE, acetaminophen (paracetamol); AlF. alfentanil; BUP, bupivacaine; CPM. chlorpheniramine maleate; DEX, dextromethorphan; E-PCA. epidural patient-controlled analgesia; EPI, epinephrine (adrenaline); FEN,
fentanyl; GA, general anesthesia; Lm., intramuscular; Lv., intravenous; KET, ketamine; KTO. ketorolac; LID, lidocaine (lignocaine); MAG. magnesium; MOR, morphine; NA, not applicable; NS, not stated; NAl, nalox-
one; OR, operating room; PLA, placebo; p.o., per os; p.r., per rectum; SAL, saline; sur, 5ufentanif; THI, thiopentone; 0, nothing administered.
Table A7.4 Studies examining the effects of timing of NSAlDs relative to incision

Nature and time

Treatment Group: Timing of Timing of after surgery of pre-
Reference Procedure (num- combination preincision drug! preincision postim:ision ventive or preemp-
(year) ber of patients) (Fig. 7.1) postincision drug Routes and doses intervention intervention Systemic opioid' tive analgesic effect
191 (1983) Third molar 2;6 Preoperative LID + EPI Infiltration p.o. After surgery NS Preemptive effect - no
extraction infiltration plus: 1.8ml medications (time NS)
(n=50) 51: ACE/PLA LID + 12.5 !-tg/ml before surgery
52: PLNACE EPI (time NS)
1,000mg ACE
192 (1987) 1;2;3;6 Preoperative LID + [PI Infiltration p.o. 3 h after first No Preemptive effect - no
(n= 120) infiltration plus: 2% LID 1:100,000 medications dose of FLU or Preventive effect - yes
Gl: FLUIFLU EPI 30 min before PLA at 24 h post operation
G2: FLUIPlA p.o. surgery, Pain: Gl G3<G4
G3: PlAlFLU 100 mg FLU/dose 15 min before
G4: PLAIPLA infiltration
193 (1989) Third molar 2;6 Preoperative Infiltration p.o. 30min after No Preemptive effect - no
extraction infiltration ± i.v. sedation agent and dose N5 medications surgery
(n=20) plus: p.o, 30 min before
51: DlF/PLA 1,OOOmg DIF surgery
194 (1990) Third molar 1;2 GA plus: iv in 18ml Immediately NA NS Preventive effect
extraction Gl: DICINA Gl: 1 mg/kg DIC after - yes on day 1 post
(n= 160) G2: DICINA G3: 1 !-tg/kg FEN induction, operation
G3: FEN/NA i.m.in3ml before surgery Pain: Gl < G3, Gl < G4
G4: SAUNA G2: 1 mg/kg DIC Analgesics: Gl < G3,
G4:5AL G1 <G4
195 (1990) Third molar 2;6 Preoperative Infiltration p.o. 30 min after No Preemptive effect - no
extraction infiltration ± i.v. sedation 2% LID + 1 :100,000 medications completion of
(n=36) plus: EPI 30 min before surgery
S1: NAP/PlA p.o. surgery
196 (1990) Third molar 2 Preoperative infiltration Infiltration p.o. NA No Preventive effect - no
extraction plus: 2% LID + 1 :80,000 medications
(n~44) 51: FEB INA EPI 2h before
52: PlAlNA p,o. surgery
450 mg FEB
197 (1992) Laparoscop it 1;2 GA plus: p.r. 2 h before NA FEN Lv. Preventive effect no
sterilization G1: IND/NA ZOOmg IND surgery 1.5
(n=56) GZ: PLAINA
198 (199Z) Third molar 2 Preoperative infiltration Infiltration 20min before NA No Preventive effect - no
extraction plus: 20mg/ml operation
(n= 150) G1: DIC + PLA/NA LID + 12.5 [tg/ml
G3: PLA + PLA/NA p.o.
Gl: 150mg DIC
G2: 150 mg DIC
199 (1993) Thoracotomy 4;6 GA plus: p.r. IND night IND after MOR Preemptive effect - no
(n= 50) G1: IND/IND+PAP ZOOmg IND first before surgery completion of 10-20mg
G2: 0/1ND + PAP dose and 100 mg and b.i.d. surgery and
thereafter thereafter b.i.d. thereafter
Lv. infusion PAP infusion
PAP dose NS started after
surgery for 48 h
200 (1994) Minor orthopedic 1;2;4 GA plus: Route NS 1 h before Immediately No Preemptive effect - no
surgery G1: NAP/PLA 1,100mg NAP surgery after surgery Preventive effect - yes
(n= 180) G2: PLA/NAP at 24 h post operation
G3: PLA/PLA Pain: NS
G1 G2<G3
201 (1995) Total hip 1;2;3 GA plus: i.v. After arrival At skin closure FEN i.v. Preemptive effect
replacement G1: KI~/SAL 60mg KTO in OR before G1: 225 lAg yes up to 6 h post
(n=60) GZ: SAL/KTO induction G2: 242 1A-9 operation
G3: SAUSAL G3: Z18 lAg i.v. PCA: G1 < GZ
Preventive effect no
20Z (1995) Knee arthroscopy 2;5 GA plus: Lm. After At end of ALF i.v. Preventive effect - no
(n=60) G1: PIR/BUP 20mg PIR induction, procedure, lOlAg/kg
G2: PIR/0 infiltration of before surgery before
incisions + intra- application of
articular injection dressing
20 ml 0.25% BUP
203 (1995) Abdominal 1;2;3 GA plus: i.v. infusion Between Between skin ALF Lv. Preemptive effect - no
hysterectomy G1: KTO/SAl 10mg KTO in 50ml induction and closure and 30!!g/kg Preventive effect - no
(n=90) G2: SAUKTO 0.9% SAL skin incision recovery ward followed by
G3: SAUSAL 40 IAglkg/h
Table A1.4 Continued
Nature and time
Treatment Group: Timing of Timing of after surgery of pre-
Reference Procedure (nurn- combination preincision drugl preincision postincision ventive or preemp-
(year) ber of patients) (Fig. 1.1) postincision drug Routes and doses intervention intervention Systemic apioid" tive analgesic effect
204 (1996) Third molar 2;6 Preoperative LI D + EPI Infiltration p.o. p.o. NS Preemptive eHect - no
extraction infiltration plus: 2% + 1: 100,000 medications medications at
(n=21) 51: DIC/PLA p.o. 1 h before the end of the
S2: PLA/DIC 100mg DIC surgery operation
205 Abdominal 2;7 GA plus: Thoracic epidural 30 min before 30min after No Preemptive effect
(1996)b hysterectomy G1; BUP + DIC/0/0 20 ml 0.5% BUP incision incision/ - opposite up to 12 h
G2: 0/BUP/DIC p.r. immediately post operation
100mg DIC after surgery Lv. PCA: Gl > G2
206 (1996) Minor orthopedic 2;4 GA plus: i.v. 30 min before On arrival in No Preemptive effect - no
procedures Gl: KTO/PlA 30mg surgery PACU
(n=60) G2: PlA/KTO
207 (1999) Knee arthroscopy 1;2 GA plus: i.v. 1 h before GA NA AlF i.v. Preventive effect no
(n= 100) Gl: PRO/NA 30mg/kg PRO 10p.g/kg
G2:TEN/NA 0.5 mg/kg TEN
208 (2000) Laparoscopic 2;4 GA pius: i.v. In OR before At completion FEN Lv. Preemptive effect
gynecological Gl: KTO/SAL 30mg KTO surgery of surgery 1-2p.g/kg - opposite up to 24 h
procedures G2: SAUKTO post operation
(n=51) Pain: G1 > G2
209 (2000) Total abdominal 1;2 GA plus: Lv. 10 min before NA FEN Lv. Preventive effect no
surgery Gl: TEN/NA G1: 20mg induction of 5
(n=45) G2:TEN/NA G2: 40mg GA
210 (2001) Knee arthroscopy 2;4;6 GA plus: p.o. 1h 30min post No Preemptive effect - no
(n= 121) Gl: DIC/PLA Gl: 50mg preoperation operation
G2: PLAlDIC G2: 50mg
G3: DIG/DIC G3: 25
a. Administered to all patients as a premedication or during surgery.
b. This study has three interventions, the third occurring immediately after surgery.
AlF, alfentanil; BUr>, bupivacaine; DIC, diclofenac; DlF, diflunisal; E-PCA, epidural patient-controlled analgesia; EPI, epinephrine (adrenaline); FEB, fenbufen; FEN, fentanyl: FlU, flubiprofen; GA, general anesthe-
sia; Lm., intramuscular; IND, indomethacin: Lv., intravenous; KTO, ketorolac; LID, lidocaine (lignocaine); MOR, morphine; NA, not applicable; NAP, naproxen sodium; NS, not stated; OR, operating room; PACU,
postanesthetic care unit; PAP. papaveretum; ACE, acetaminophen (paracetamol); PIR, piroxicam; PlA. placebo; p.o" per os; p.r" per rectum; PRO, propacetamol; SAL. saline; 51 and S2, first and second sides of
body in studies using patients as their own controls: 0, nothing administered.
Table A7.5 Studies examining the effects of timing of administration of a combination of a local anesthetic and opioid as the target treatments

Nature and time

after surgery of
Procedure Treatment Group: Timing of Timing of preventive or pre-
Reference (number of combination pre incision drug' preincision postincision Systemic emptive analgesic
(year) patients) (Fig. 7.1) postincision drug Route and dose intervention intervention opioid" effect
211 (1992) Colonic surgery 4;8 GA plus: Thoracic epidural Gl: bolus 40 min G2: bolus at FEN Lv. Preemptive effect
(n= 32) G1: BUP + MORI bolus dose before incision wound closure 0.l-O.2mg no
BUP+MOR 7ml7.5mg/ml followed by followed by first
G2: 0/BUP+MOR BUP+2mg MOR first infusion for infusion for 2 h
First infusion 2 h followed by followed by second
4ml/h 7.5mg/ml second infusion infusion for 72 h
BUP + 0.05 ma/ml for 72 h
Second infusion
4 ml/h 2.5 mg/ml
BUP + 0.05 mg/ml
212 (1993) Cesarean 5;8 S1: BUP + SUF/BUP lumbar epidural Before section Infiltration of No Preventive effect
section S2: BUP+ SUF/SAl infusion of 0.1% wound edge at -yes at 24h
(n=28) BUP+S time of closure Pain: G1 < G2
SUF at 10-12mllh
followed by bolus of
0.25% BUP
wound infiltration
1 ml/cm 0.25% BUP
213 (1994) Upper 8 GA plus: Thoracic epidural Epidural before Epidural infusion ALF i.v. Preventive effect
abdominal G1: (BUP + MOR) + BUPI bolus 9 ml 0.5% induction; started 30min 1 mg - yes at 24 and 4Bh
surgery (BUP+MOR) BUP+2mgMOR infiltration after after initial bolus Analgesics: G1 < G2
(n~49) G2: (BUP + MOR) + 01 followed by infusion induction, before and continued
(BUP+MOR) of 4 ml/h 0.25% surgery for 72h post
BUP + 0.2 mg/h MOR operation
infiltration of
skin, SUbcutis, and
subfascial area
40 ml 0.25% BUP
Table A7.5 Continued

Nature and time

after surgery of
Procedure Treatment Group: Timing of Timing of preventive or pre-
Reference (number of combination preincision drug! preincision postincision Systemic emptive analgesic
(yearl patients) CFig.7.1) postincision drug Route and dose intervention intervention opioid' effect
214 (1994) Total knee 4;8 GA plus: Lumbar epidural Gl: bolus 30min G2: bolus at fEN i.v. Preemptive effect
arthroplasty G1: BUP + MORI bolus dose before incision wound closure O.3mg -no
(n;32) BUP+MOR 16m17.5mg/ml followed by first followed by first
G2: 0/BUP + MOR BUP+2mg MOR infusion for 24 h infusion for 24 h
First infusion followed by followed by second
4ml/h 1.25mg/ml second infusion infusion for 24 h
BUP + 0.05 mg/ml for 24h
Second infusion
4 ml/h 0.625 mg/ml
BUP + 0.05 mg/ml
215 (1994)' Tonsillectomy 4;6;7 GA plus: Infiltration of After induction, BUP after removal No Preemptive effect
(n=35) Gl: BUP/0/FEN tonsillar tissues Smin before of tonsils in G21 -no
G2: 0/BUP/FEN 4 ml 0.25% BUP incision FEN at end of the Preventive effect
G3: SALl0/FEN i.v. operation - no
1 f,lg!kg fEN
216 (1994) Radical 4;8 G1: BUP (no GAl/FEN lumbar epidural G1: before During skin closure G2: fEN Lv. Preventive effect
prostatectomy G2: GA + BUP/FEN BUP incision 1-2 fAg/kg -yes
(n=96) G3: GA only/FEN Gl: bolus of 0.25 mil G2: bolus after G3: MOR i.v. Pain: Gl < G3 on day
kg 0.5% followed by induction 0.2mg/kg 1 post operation
0.1 ml/kg/h 0.125% ('" 20 min before E-PCA: G1 <G2=G3
infusion incision) followed on days 2 and 3 post
G2: bolus of 0.2 mil by infusion until operation
kg 0.5% followed by skin closure
0.1 ml/kg/h 0.125%
217 (1996)' Posterolateral 7;8 GA plus: Thoracic epidural 30 min before 15 min after ALF i.v. Preventive effect
thoracotomy G1: BUP + EPI/SALIFEN/ 8ml 0.5% BUP + 1: incision incision/at end of bolus + no
(n= 45) BUP + EPI + FEN 200,000 EPI operation/infusion infusion
G2: SALIBUP + EPI/FEN! 50f,lg FEN started in recovery G1: 12.5mg
BUP + EPI + FEN 2 ml/h 0.125% room for 48h G2:
G3: SAL/SAl/FEN! BUP + 1 :400,000 G3: 10.8mg
BUP + EPI + FEN [PI + 6 ~lg!ml FEN
218 (1996)d Upper 7;8 GA plus: Thoracic epidural BUR + MEP bolus MEP boluses No Preventive effect
abdominal G1: BUR + MEP/MEP/01 First/third after induction, during surgeryl - no
surgery BUR+MEP intervention 15min before BUR+MEP
(n=40) G2: 0/MEP/BUR + MEPI bolus of 0.1 mg incision bolus after the
BUR+MEP BUR+SmI1.5% MEP end of
Second intervention continuous
1.5% MEP infusion of
intermittent boluses MEP + BUR started
Fourth intervention after extubation
1.7 mg/h infusion and maintained
of 40mll.5% for 3 days
MEP + 0.3 mg BUR
219 (1996) Third molar 2 GA plus: Inferior alveolar 5 min before NA No Preventive effect
extraction Sl: LID + EPI + MOR/NA nerve block and surgery no
(n=36) 52: SAL + MOR/NA infiltration
2m12% BUP+
1 :200,000 EPI
0.15 mg/kg MOR
220 (1997) Arthroscopic 2;5 Spinal with BUP plus: Spinal Spinal before 10min before No Preventive effect
knee surgery Gl: 0/MOR 0.7-1.0mI1% BUP surgery release of thigh - yes up to 24 h post
(n=80) G2: MOR/0 intra-articular 10min before tourniquet operation
G3: 0/MOR Gl and G2: 2 mg intra-articular Pain: Gl =G2 =G3 =
G4: MOR/0 MOR lavage and G4<G7
G5: 0/BUP G3 and G4: 5 mg surgery
G7: 0/NaCI G5: 20ml 0.25% BUP
G6: 2mg
MOR + 20 ml 0.25%
220 (1997) Arthroscopy- 1;2;3 GA plus: Intra-articular 10 min before 10min before FEN Lv. Preemptive effect
assisted anterior Gl: 0/MOR (20ml) intra-articular release of thigh 2 J.!g/kg - yes at 24 h post
crudate G2: 0/MOR Gl: 2mg MOR lavage and tourniquet operation
ligament G3: MOR/e G2 and G3: 5 mg surgery Analgesics: G2 < G3
reconstruction G4: 0/BUP MOR Preventive effect
(n=60) G5: e/MOR + BUP G4: 0.25% BUP - yes at 24 h post
G6: 0/NaCI G5: 2mg operation
MOR + 0.25% BUP Pain: G3<G6
Analgesics: G2 < G6,
Table A1.5 Continued
Nature and time
after surgery of
Procedure Treatment Group: Timing of Timing of preventive or pre·
Reference (number of combination preincision drugl preincision postincision Systemic emptive analgesic
(year) patients) (Fig. 1.1) postincision drug Route and dose intervention intervention opioid' effect
221 (1997) Lower limb 4;8 GA plus: Lumbar epidural Bolus18h Second infusion FEN Lv. Preventive effect
amputation Gl: MOR + BUPI bolus dose before operation started after 25-100 ~tg no
(n=50) MOR BUP 2mg MOR+ 5-10ml followed by first surgery and boluses
G2: SALIMOR + BUP 0.5% BUP infusion until end maintained for
First infusion of anesthesia 2-3 days
0.16-0.28 mg/h
MOR + 4-7 ml 0.25%
Second infusion
3-7mllh 0.25%
BUP + bolus doses
of 2-8 mg MOR 2-4
222 (1997) Bilateral lumbar 1;2 GA plus: Caudal epidural After induction, NA NS Preventive effect
laminotomy Gl: BUR + BUPINA 0.1 mg BPR +20ml 10min before - yes up to day 5
(n=60); G2: 0/NA 0.25% BUP incision post operation
lumbar fusion Pain: Gl <G2
(n= 50) in laminectomy
patients with a
decrease in blood
pressure after
caudal injection
223 (1997) Upper 4;5 GA plus: Thoracic epidural Bolus 65min In recovery room No Preventive effect
abdominal Gl: BUP + SUF/0 Gl: 0.2 ml/kg 0.25% before incision (316 min after opposite on days
G2: 0/BUP + sur BUP + 1 f!g/kg SUF followed by incision) 1.4 and 5 post
followed by 0.1 mil intraoperative operation
kg sur 100 I-Lg in BUP boluses q 60min E-PCA: Gl > G2
0.25% 50 ml q 60 min
G2: 0.2 mllkg 0.25%
BUP + 1 ua/ka SUF
224 (1998) Radical 4;8 GA plus: Lumbar epidural Bolus prior Bolus at beginning FEN Lv. Preventive effect
retropubic G1: 0/MOR + LID G2: FEN 20 ml 4 ~gl to induction of fascial closure G1: 39~g - yes up to day 4
prostatectomy G2: FEN/MOR + LID kg followed by 13 ml followed by G2: 75ftg post operation
(n= 100) G3: BUP + EPI/MOR + LID 0.75~g/kg FEN q 2h boluses q 2 h G3: 43 ftg Pain at rest: G3 < Gl
G3: 20ml 0.5% until fascial E-PCA: G3 < G1
BUP + 1 :200,000 EPI closure Incidence pain-
followed by 13ml free: G2 '" G3 > Gl
BUP+EPI q 2h at 9.5weeks post
Gl-G3: 5mg operation
225 (1998) Hernia repair 2;3 GA plus: Caudal After induction. After surgery No Preemptive effect
(n=60) G1: BUP + MOR/0 0.66 ml/kg 0.25% 15 min before yes
G2: 0/BUP + MOR BUP + 0.02 mg/kg surgery Pain: G1 < G2 up to
MOR 8 h post operation
Analgesics: G1 < G2
at 24h post
TFA: Gl > G2
226 (1998) Abdominal 2;3 GA pius: Lumbar epidural After induction 15 min before skin No Preemptive effect
hysterectomy G1: SAL/BUP + FEN 15mI0.5%BUP+50 closure -no
(n=50) G2: BUP + FEN/SAL fAg FEN
221 (2000) Nissin antireflux 4;8 GA plus: Thoracic epidural Bolus 30-45 min After skin closure FEN Lv. at Preventive effect
repair G1: MEP + MORI Gl: 7-13m120mgl before incision continuous induction -no
(n= 26) BUP+MOR m12% MEP+4mg followed by infusion for 3 days 100-300 ~g
G2: 0/BUP + MOR MOR followed by continuous FEN Lv.
continuous infusion infusion until during
of 6-10ml/h 2% after skin closure surgery
MEP/continuous Gl: 325 ~g
infusion of 4 ml/h G2: 568fAg
BUP + 0.125 mg/mt
G2: continuous
infusion of 4 ml/h
2.5 mg/ml 0.25%
BUP + 0.125 mg/ml
Table A7.5 Continued

Nature and time

afteuurgery of
Procedure Treatment Group: Timing of Timing of preventive or pre-
Reference (number of combination preincision drugl preincision postincision Systemic emptive analgesic
(year) patients) (Fig. 7.1) postincision drug Route and dose intervention intervention opioid' effeel
228 (2000) Upper 2;4 GA plus: Lumbar epidural 20 min before At end of surgical MORLv. Preemptive effect
abdominal or Gl: MOR/SAL Gl/G3: 10m150j.tgl induction procedure 0.1 yes up to 5 days
thoracic surgery G2: MOR + BUP/SAL kgMOR postoperation
(n=80) G3: SAL/MOR G2/G4: 10ml50l-tgl EPI analgesia:
G4: SAL/MOR + BUP kg MOR + 10mg 0.1% GZ<G4, G2<Gl,
BUP Gl =G3
a. Administered to all patients as a premedication or during surgery.
b. This study has three interventions, the third occurring at the end of the operation.
c. This study has four interventions. the third occurring at the end of the operation and the fourth in the recovery room.
d. This study has four interventions, the third occurring after the end of surgery and the fourth after extubation.
ALE alfentanil; BUP, bupivacaine; BUR, buprenorphine; E-PCA. epidural patient-controlled analgesia; EPI. epinephrine (adrenaline); FEN. fentanyl; GA. general anesthesia; i.v.. intravenous; LID. lidocaine (ligno-
caine); MEP. mepivacaine; MOR. morphine; NA. not applicable; NS, not stated; S1 and 52, first and second sides in stUdies using patients as their own controls; SAL, saline; SUF. sufentanil; TFA. time to first analge·
sic request; 0. nothing administered.
Table A7.6 Studies examining the timing of administration of local anesthetics, opioids, and NSAlDs as the target treatments

Treatment Group: Timing of Timing of Nature and time after sur-

Reference Procedure (nurn- combination preincision drugl preincision postincision Systemic gery of preventive or pre-
(year) ber of patients) (Fig. 7.1) postincision drug Routes and doses intervention intervention opioid· emptive analgesic effect
230 (1994) Posterolatera I 1;2 GA plus: Lm. Lm. and p.r. NA FEN Lv. Preventive effect opposite
thoracoto my Gl: MOR+PER+IND+BUP Gl: 0.15mg/kg medications 1 iJ-g/kg at 24 h post operation
(n=30) + EPI/NA MOR + 0.3 mg/kg 60 min before i.v. PCA: Gl > G2
G2: MID PLA+SAlINA PER surgery;
G2: 0.5 mg/kg intercostal
MID blocks after
p.r. induction
Gl: 100mg INO
intercostal blocks
G1: 15ml 0.5%
BUP + 1:200.000 EPI
G2: 15ml SAL
231 (1994) Thoracotomy 4;8 GA plus: Paravertebral 1 h before After surgery FEN i.v. Preventive effect - yes on
(n=56) Gl: DIC + MOR + BUPI blockade surgery DIG q 12h MaR 3 J.L9/kg day 1 post operation
DIG + MOR + BUP 10ml 0.5% BUP NS ICNB for 48 h Pain: G1 + G3 + G5 +G7 < G2
G2: DIG MaRl p.r. +G4+G6+G8
DIG + MOR + BUP 100mg DIG
G3: MOR + BUPI i.m.
DIG + MOR + BUP 10m9 MOR
G5: DIG + BUPI 0.1 ml/kg/h 0.5%
DIG + MOR + BUP BUP postoperatlon
G8: 0/DIG + MOR + BUP
Table A7.6 Continued
Treatment Group: Timing of Timing of Nature and time after sur-
Reference Protedure(num- combination preincision drug! preincision post incision Systemic gery of preventive or pre-
(year) ber of patients) (Fig. 7.1) postincision drug Routes and doses intervention intervention opioid' emptive analgesic effect
232 (1996) Abdominal surgery 3;5 GA plus: Thoracic epidural 85 min before - 60 min before fEN Lv. Preventive effect - yes on
(n=142) G1: G1: 0.2 ml/kg 1% skin incision end of surgery 2 j.!g/kg days 1-2 post operation
MEP + MOR + MET + DIC/l2l MEP and 75 j.!g/kg followed (221 min after E·PCA: G1 = G2 < G3;
G2: 01 MOR followed by by epidural start of surgery) days 3-4 postoperation
MEP + MOR + MET + DIG 0.1 ml/kg 1% MEP q bolus doses E-PCA: Gl < G2 < G3
G3: 0/0 60min intraoperatively
G2: 0.2ml/kg 1% q 60min
MEP and 75
1,000mg MET
75mg DIC
233 (1996) Third molar 1;2 GA plus: p.o. p.o. NA ALf Lv. Preventive effect - no
extraction Gl: PLA + TEN + LID + EPI! Gl: PLA medications 1Oll9/kg
(n= 40) NA G2: 100mg DIC 60-90 min
G2: DIG + TEN + LID + EPI! G3: 10mg MTH before surgery
NA i.v. Lv. TEN soon
G3: MTH + TEN + LID + EPI/ 20mgTEN after induction,
NA infiltration before surgery
8-10 ml 2% LID + 1: infiltration
100,000 EPI after induction,
Smin before
234 (1998) Posterolateral 2;3 GA plus: Lv. <: 20 min before At end of No Preemptive effect
thoracotomy Gl: MOR + DIG + BUP/PLA 10mgMOR start of surgery surgery.20min yes from 12-48h post
(n=30j G2: PLA/MOR + OIG + BUP Lm. before end of operation
75mg ole anesthesia Pain on movement: G1 < G2
intercostal blocks
40 ml 0.5% BUP
a. Administered to all patients as a premedication or during surgery.
ALF. alfentanil; BUP, bupivacaine; Die. diclofenac; E-PCA, epidural patient-controlled analgesia; FEN. fentanyl; GA, general anesthesia; Lm .. intramuscular; IND. indomethacin; ICNB. intercostal nerve block; i.v..
intravenous: LID. lidocaine (lignocaine); MEP. mepivacaine; MET. metamizole; MTH. methadone; MID. midazolam; MOR, morphine; NA, not applicable; NS, not stated: p.o .. per os; PER. perphenazine: PlA. pla-
cebo; p.r.. per rectum; SAL, saline; TEN, tenoxicam; 0. nothing administered.