Journal of Clinical Anesthesia (2015) 27, 658–664

Original Contribution

Effect of postoperative analgesia on acute

and persistent postherniotomy pain:
a randomized study☆,☆☆
Dario Bugada MD h,⁎, Patricia Lavand'homme MD, PhD b , Andrea Luigi Ambrosoli MD c ,
Catherine Klersy MD f , Antonio Braschi MD (Professor) a,e , Guido Fanelli MD (Professor) d ,
Gloria M.R. Saccani Jotti MD (Professor) g , Massimo Allegri MD d , on behalf of SIMPAR group
Marco Baciarello MD 3 , Silvia Bettinelli MD 1 , Lorenzo Cobianchi MD, PHD 4,5,
Manuela De Gregori PHD 6 , Maria Di Matteo MD 1 , Silvia Guarisco MD 1 , Pavla Krizova MD 2 ,
Fabio Marangoni MD 2 , Cristina E. Minella MD 6 , Thekla Niebel MD, PHD 1 ,
Andrea Peloso MD, PHD 5 , Francesca Repetti MD 1,2
1
Department of Anesthesia and Intensive Care, Foundation IRCCS Policlinico San Matteo, P.le Golgi 19, 27100, Pavia, Italy
2
Day Surgery Unit, Azienda Ospedaliera Ospedale di Circolo e Fondazione Macchi, Polo Universitario, Via Lazio, Varese, Italy
3
Department of Anesthesia, Intensive Care and Pain Therapy, University of Parma, Viale Gramsci, 14-43126, Parma, Italy
4
Department of Surgical, Medical, Diagnostic and Pediatric Science, University of Pavia, P.le Golgi 19, 27100, Pavia, Italy
5
Department of Surgery, Foundation IRCCS Policlinico San Matteo, P.le Golgi 19, 27100, Pavia, Italy
6
Pain Therapy Service, Foundation IRCCS Policlinico San Matteo, P.le Golgi 19, 27100, Pavia, Italy
a
Department of Anesthesia and Intensive Care, Foundation IRCCS Policlinico San Matteo, P.le Golgi 19, 27100, Pavia, Italy
b
Department of Anesthesia and Perioperative Medicine, Catholic University of Louvain, St Luc Hospital, 10 Ave Hippocrate,
1200 Brussels, Belgium
c
Day Surgery Unit, Azienda Ospedaliera Ospedale di Circolo e Fondazione Macchi, Polo Universitario, Via Lazio, Varese, Italy
d
Department of Anesthesia, Intensive Care and Pain Therapy, University of Parma, Viale Gramsci, 14-43126, Parma, Italy
e
Department of Surgical, Medical, Diagnostic and Pediatric Science, University of Pavia, P.le Golgi 19, 27100, Pavia, Italy
f
Service of Biometry & Statistics, Foundation IRCCS Policlinico San Matteo, P.le Golgi 19, 27100, Pavia, Italy
g
Department of Biomedical, Biotechnological & Translational Sciences, Faculty of Medicine, University of Parma, Parma, Italy
h
Department of Surgical Sciences, University of Parma, Parma, Italy

Received 22 December 2014; revised 9 April 2015; accepted 9 June 2015

☆
The trial was registered on clinicaltrials.gov (NCT01345162; principal investigator, Massimo Allegri) and European Union Drug Regulating Authorities
Clinical Trials (EUDRACT) (2009-011-856-23).
☆☆
Full protocol accessible at Bioethics Committee Secretariat–Istituto Di Ricerca e Cura a Carattere Scientifico (IRCCS) Foundation Policlinico S Matteo, Pavia, Italy
(e-mail: comitato.bioetica@smatteo.pv.it).
* Corresponding author at: Servizio di Anestesia e Rianimazione 1, IRCCS Policlinico S Matteo, P.le Golgi 19, 27100 Pavia, Italy. Tel.: + 39 0382 502627;
fax: + 39 0382 502226.
E-mail addresses: dariobugada@gmail.com (D. Bugada), Patricia.Lavandhomme@uclouvain.be (P. Lavand'homme), andrealuigi.ambrosoli@gmail.com
(A.L. Ambrosoli), klersy@smatteo.pv.it (C. Klersy), a.braschi@smatteo.pv.it (A. Braschi), gfanelli@parmanesthesia.com (G. Fanelli), gloria.saccani@unipr.it
(G.M.R.S. Jotti), massimo.allegri@unipv.it (M. Allegri).

http://dx.doi.org/10.1016/j.jclinane.2015.06.008
0952-8180/© 2015 Elsevier Inc. All rights reserved.
Acute and chronic postherniotomy pain 659

Keywords: Abstract
Hernia surgery; Study objective: The study objective is to identify differences in postoperative pain management
Inflammation; according to different analgesic treatments, targeting 2 main pathways involved in pain perception.
Persistent pain; Design: The design is a randomized, parallel groups, open-label study.
Postherniotomy pain; Setting: The setting is in an operating room, postoperative recovery area, and surgical ward.
Postoperative pain Patients: There are 200 patients undergoing open inguinal hernia repair (IHR) with tension-free
technique (mesh repair).
Interventions: The intervention is a randomization to receive ketorolac (group K) or tramadol (group T)
for 3 days after surgery.
MeasurementsThe measurements are differences in analgesic efficacy (numeric rating scale [NRS]) in the
postoperative (up to 5 days) period, chronic pain incidence (1 and 3 months), side effects, and complications.
Main results: We found no differences in analgesic efficacy (NRS value ≥ 4 in the first 96 hours: 26% in
group K vs 32% in group T, P = .43); the proportion of patients with NRS ≥4 was similar in both groups, and
the time trajectories were not significantly different (P for interaction = .24). Side effects were higher (12% vs
6%) in the tramadol group, although not significantly (P = .14), with a case of bleeding in the ketorolac group
and higher incidence of constipation in tramadol group. One patient in each group developed chronic pain.
Conclusions: Ketorolac or weak opioids are equally effective on acute pain and on persistent postsurgical
pain development after IHR, and drug choice should be based on their potential side effects and patient's
comorbidities. Further studies are needed to standardize the most rational approach to prevent persistent
postsurgical pain after IHR.
© 2015 Elsevier Inc. All rights reserved.

1. Introduction approaches, one focusing on inflammation, the other

Inguinal hernia repair (IHR) is a common surgical
intervention performed worldwide [1]. In Italy, the health
ministry registered 75,392 procedures in 2010 [2]. Despite
minimal postoperative morbidity, PPSP is still the most
common and serious long-term problem after IHR and able
to influence patients' quality of life [3-5].
The incidence of PPSP after IHR is reported to be
approximately 10% [6], but because hernia surgery is very
common, a large number of individuals may be affected.
Persistent postsurgical pain (PPSP) is a complex condition in
which inflammatory, nociceptive, and neuropathic components
are involved [7,8]. Among risk factors for PPSP, the severity of
acute postoperative pain is often mentioned; individuals prone to
experience intense postoperative pain may be the ones most
vulnerable to PPSP [9,10]. Despite this, postoperative analgesia
remains a challenge; 30% of the patients report severe pain
within the first 24 hours, a prevalence that has remained
unchanged for almost 10 years [11].
Multimodal analgesia is recommended for postoperative
analgesia after hernia repair [12], but no studies have fixed
the issue on whether inflammation or descending inhibitory
pathways should be preferentially targeted for a more
effective acute pain relief and to avoid PPSP.
In this prospective, multicenter single-blind randomized
clinical trial, we aimed to determine which analgesic
treatment is most effective both in controlling acute
postoperative pain and in reducing PPSP occurrence at 1
and 3 months after inguinal hernia repair (IHR); the 2
treatments are paradigmatic of 2 different pathophysiological
focusing on pain modulation through activation of central
descending inhibitory activity. Thereby, the 2 treatment
groups involved a 3-day administration of either a nonste-
roidal anti-inflammatory drug (NSAID), ketorolac, or of a
weak opioid combining a central descending inhibitory
activity, tramadol. Our secondary aim was to verify any
difference in terms of side effects, surgical complications,
use of rescue medications, functional activity, and chronic
pain incidence.
2. Methods
2.1. Patients' enrollment
After ethical committee approval from the 2 hospitals
involved in the study (IRCCS Policlinico S Matteo, Pavia,
Italy, and Ospedale di Circolo–Fondazione Macchi, Varese,
Italy), the trial was registered on clinicaltrials.gov
(NCT01345162; principal investigator, Massimo Allegri)
and EUDRACT (2009-011-856-23). The study was designed
according to Consolidated Standards Of Reporting Trials
(CONSORT) guidelines [13]. All the patients enrolled in the
study signed an informed consent. No changes in methods
were made after the trial was started.
Adult patients scheduled for monolateral IHR with
anterior approach (open, non-videolaparoscopic approach)
and tension-free technique (mesh repair), with type 2, 3A,
and 3B inguinal hernia (according to Nyhus 1993 classifi-
cation) [14]; ≥ 18 years; and with American Society of
660
Anesthesiologists I or II status were included in the study.
Exclusion criteria were American Society of Anesthesiologists
status III and IV; emergency surgery and postsurgical admission
to intensive care unit; type 1, 3C, and 4 inguinal hernia
(according to Nyhus 1993 classification) [14]; laparoscopic
surgery; cognitive or psychiatric disorders; and allergy to the
study drugs. Finally, the use of opioids and/or NSAIDs in the 5
days before surgery was also an exclusion criterion.
On the day of surgery, a research assistant confirmed
patient eligibility and did consent patients together with the
attending anesthesiologist.
Group allocation was conducted with a computer-generated
randomization sequence to 2 different treatment groups; group
allocation was known only by the anesthesiologist and by
the patient after surgery. Another blinded research assistant
collected all clinical parameters after surgery.
2.2. Clinical procedures
Surgical anesthesia was left to the discretion of the
anesthesiologist who was in charge of the patient; general
anesthesia, spinal anesthesia, or local anesthesia with field
infiltration were provided. General anesthesia was realized with
total intravenous (IV) anesthesia induced with propofol, 2 mg/kg
and remifentanyl, 0.15-0.25 μg/kg per minute and maintained
with propofol, 4-8 mg/kg per hour and remifentanyl. A laryngeal
mask was positioned to assure airway control. Spinal anesthesia
was realized by subarachnoid injection of hyperbaric bupiva-
caine, 0.5% (dose of 12.5-15 mg); any subdural adjuvant/
narcotic was not used, according to our clinical practice for 1-day
surgery procedures. Local anesthesia was performed with
ropivacaine, 0.2% (maximum, 10 mL) and lidocaine, 2%
(maximum, 10 mL) before surgery. Before the end of the
procedure, all the patients received ketorolac, 30 mg intrave-
nously and tramadol, 100 mg (50 mg if weighing b 50 kg). After
surgery, patients were treated as follows according to the
randomization process.
Patients in group K received ketorolac, 30 mg IV every 8
hours for the first 24 hours and then, after discharge, ketorolac 10
mg per os every 8 hours for 3 days, with proper gastroprotective
prophylaxis. Patients in group T received tramadol 100 mg IV
(50 mg if weighing b 50 kg) every 8 hours for the first 24 hours
after surgery and then, after discharge, an association tramadol,
37.5 mg/paracetamol 325 mg (Patrol) per os every 8 hours.
Rescue analgesia was provided with paracetamol 1000
mg (intravenously in the day of surgery, per os from the first
day after surgery) in both treatment groups. Use of other
narcotics in the postoperative period was considered as
additional criterion for exclusion.
2.3. Data collection
Data collected included patient's age, sex, body mass
index (BMI), the type of hernia, surgical technique, and
anesthesia technique.
D. Bugada et al.
All the patients were evaluated at the end of the surgery at
Post-anesthrsia care unit (PACU) arrival (T0) and then at 6, 12,
and 24 hours after the intraoperative bolus of ketorolac and
tramadol. Pain intensity was assessed using an 11-point
numeric rating scale (NRS) (0 “no pain” to 10 “worst possible
pain”). Pain was measured at rest (NRS) and when moving
(mNRS), that is, deep inspiration and coughing (dynamic pain).
The patients were sent home with a pain diary to complete
from day 1 until day 5 and were asked to record details of
pain, possible side effects associated with the analgesic
treatment, and resumption of normal functional activity.
On day 5 postsurgery, all the patients came back for a surgical
examination. Pain scores at rest and during movement were
assessed, together with the need for rescue analgesics. Surgical
complications (infection, surgical bleeding, abnormalities in
wound healing, and re-intervention) and any side effect
potentially associated with the analgesic treatment were recorded.
At 1 and 3 months from surgery, a phone interview was
performed to ask the patients if they complain pain in the area of
surgery (PPSP, according to international association for the
study of pain (IASP) definition)[15]. If present, a visit to the pain
center was scheduled for a more precise evaluation of the patient
as well as prescription of a more adapted treatment. Pain intensity
at rest and with mobilization were assessed, and a surgical
evaluation was carried out to eliminate any surgical complication
as the main cause of pain persistence (wound healing problem,
infection, prosthesis' reaction, and hernia recurrence).
2.4. Study design and end points
This is a randomized, parallel group, open-label study, with
blind evaluator. Treatment allocation was based on a computer-
generated sequence of treatments randomly permuted in blocks
of varying size. Concealment was obtained with the use of
opaque envelopes. The primary end point was to determine the
differences in the analgesic efficacy of the 2 treatments about
acute postoperative pain. The primary outcome measure was the
proportion of patients with the highest NRS ≥4 (from day 0-4).
The secondary end points were to verify any difference in terms
of side effects, surgical complications, use of rescue medications,
functional activity (measured as differences in mNRS values),
and incidence of chronic pain at 1 and 3 months. Secondary
outcome measures were the proportion of patients witn
mNRS≥4 within 4 days, the proportion of patients with surgical
complication, the proportion of patients who used rescue
medication, the proportion of patients with side effects, and the
proportion of patients with NRS≥4 or mNRS≥4 at 1 and 3
months as well as the actual NRS and mNRS values over time.
2.5. Sample size calculation
We based the sample size calculation on data from a pilot
study (unpublished) held in our institution (Policlinico S Matteo,
Pavia, Italy) about pain control using the 2 study drugs; we
hypothesized that the proportion of patients with NRS ≥4
Acute and chronic postherniotomy pain
would be 35% in group K at 96 hours after surgery and that it
would decrease to 15% in group T. We calculated that a Fisher
exact test with a 0.050 two-sided significance level would have
84% power to detect such a difference between these 2 groups,
when the sample size in each group is 90. Assuming a drop-out
percentage of 10%, approximately 100 patients per group were
planned to be enrolled in the study. nQuery Advisor version 4
(Statistical Solutions, Cork, IRL) was used for computation.
2.6. Statistical analysis
Data were summarized within groups as mean and SD for
continuous variables and counts and percentage for categorical
variables. Normality of the distribution was assessed graphically
with a Q-Q plot. For the primary analysis of the primary end
point, the proportion of patients with the highest (within 4 days)
NRS ≥4 was compared with the Fisher exact test; the difference
in proportions and 95% confidence interval (CI) was computed.
In a second analysis of the primary end point, we compared
the maximum value of NRS within 4 days by means of the
Mann-Whitney U test and the pain trajectory over time
(proportion of patients with NRS ≥4) with a logistic model
for repeated measures, including the interaction of treatment arm
and time and calculation of Huber-White robust SEs to account
for intrapatient correlation of measures. For the secondary end
points, the same methods as for the primary end point were used
to compare proportions and trajectories over time, respectively.
Stata 13 (StatCorp, College Station, TX) was used for
computation. A 2-sided P value b .05 was considered
statistically significant.
3. Results
3.1. Demographics
Two hundred patients were enrolled in the present study
(100 in each hospital) from March 2010 to May 2012. Two
patients in group K and 4 patients within group T were
excluded from the final analysis due to protocol violations
(they did not accept the prescribed therapy or stopped it
before the third day after surgery). Ninety-eight patients in
group K and 96 within group T were included in the final
analysis (see Fig. 1, flow chart). Baseline characteristics are
comparable as shown in Table 1. Particularly, the distribu-
tion of types of anesthesia and the surgical classification of
hernias [16] was similar between groups.
3.2. Analysis of the primary end point
Both analgesic treatments provided postoperative pain
control comparable with what previously demonstrated by
relevant literature [17] as demonstrated by the relative low
percentage of patients with an NRS value ≥ 4 of 26.5% and
32.3% in the ketorolac and tramadol groups, respectively
661
Fig. 1 Study flow chart.
(Table 2), with a nonsignificant difference in proportions
marginally favoring tramadol by 6% (95% CI, −7% to 19%; P =
.43). Furthermore, mean values of the highest NRS recorded
within 4 days were very low (around 2.5) and similar in both
groups (Table 2). As shown in Figure 2, the proportion of
patients with NRS ≥4 was similar in both groups up to 24 hours
and tended to be higher in the tramadol group afterward,
although, overall, the time trajectories were not significantly
different between groups (P for interaction = .24).
3.3. Analysis of the secondary end points
The comparisons of the treatment groups for the
secondary end points are summarized in Table 2. The return
to normal activity as measured by the proportion of patients
with highest movement NRS ≥ 4 within 4 days as well as by
the highest movement NRS was highly similar between the 2
groups, whereas the time trajectory followed the same
pattern as for the rest NRS (P for interaction = .38) as shown
in Figure 3. No surgical complications were recorded. The
use of rescue medication slightly favored the tramadol group
(5% vs 8%), although not significantly (P = .57). Registered
side effects included reactive hydrocele, bleeding, dyspepsia
and/or heartburn, nausea and/or vomiting, constipation,
dizziness, headache, hypotension, choking, and paresthesia.
Some of the patients developed N 1 side effect; we therefore
decided to make a sum of them and consider the number of
patients experiencing side effects in each group and then
compare the 2 groups. They were higher (12% vs 6%) in the
tramadol group, although not significantly (risk difference,
6%; 95% CI, − 2% to 14%; P = .14). We registered 6 cases of
constipation in the tramadol group vs 1 case in the ketorolac
group, whereas a case of bleeding (anal rhagade bleeding)
and 2 cases of gastric symptoms were registered in the
ketorolac group.
Only 1 patient developed chronic pain in each group as
shown by the proportions at 1 and 3 months in Table 2. For
662 D. Bugada et al.

Table 1 Demographic data Among risk factors to develop PPSP, acute pain and
Group Group postoperative analgesia effectiveness [6,9] as well as the
ketorolac tramadol surgical technique [16,20,21] have been identified. To date,
the severity of acute pain, that is, the failure of postoperative
(n = 98) (n = 96)
pain management seems to be an important risk factor for
Male, n (%) 93 (95%) 87 (91%) PPSP [6,10]. Unfortunately, postoperative pain management
Age (y) 57 ± 15 57 ± 15 remains challenging even after minor procedures [17];
BMI (kg/m2) 25 ± 2.4 25 ± 2.9 efforts toward an improvement in pain relief should be
Surgery duration (min) 57 ± 23 62 ± 24 pursued to both improve the quality of care in the immediate
Type of anesthesia, n (%)
postoperative period and to prevent PPSP occurrence.
General 24 (24%) 23 (24%)
Spinal 41 (42%) 48 (50%) In our study, we compared the efficacy on both acute
Local infiltration 33 (34%) 25 (26%) postoperative pain and PPSP of 2 drugs, which are
Proinflammatory status a, n (%) 8 (8%) 10 (10%) paradigmatic of 2 different pathophysiological approaches;
Obesity (BMI N 25), n (%) 39 (40%) 44 (46%) ketorolac is a NSAID with balanced analgesic (through
Preoperative NLR, n (%) 2.29 ± 0.91 2.31 ± 0.98 cyclooxygenase (COX)-1 inhibition) and anti-inflammatory
Anxious-depressive disorder, 8 (8%) 9 (9%) effect (through a COX-2 inhibition) being extensively used
n (%) in clinical practice; animal studies have highlighted the
Hypertension, n (%) 25 (26%) 23 (24%) potential role of NSAIDs to prevent hyperalgesia, with an
Abbreviation: NLR, neutrophil-to-lymphocyte ratio. action based on inhibiting inflammatory mediators' release
Continuous variables are shown as mean ± SD. both at peripheral and spinal level [22]. Tramadol is a weak
a
Proinflammatory condition included patients with irritable bowel opioid combining an action on μ-opioid receptor and a central
syndrome, migraine, rheumatologic diseases, and Crohn disease.
descending inhibitory activity that could theoretically reduce
pain chronicization. To date, no studies have elucidated the
further considerations, we mention that when we considered all
higher effectiveness (if any) of 1 of these 2 approaches, neither
patients who reported long-term pain (presence/absence of pain,
in providing analgesia in the immediate postoperative period,
regardless of NRS values), incidence of local pain was 39% (n =
nor in preventing the development of PPSP.
38) in group K and 46% (n = 44) in group T (P = .32) at 1 month,
Regarding the primary end point, no differences in
whereas 29% (n = 28) of patients mentioned local pain in group
analgesic efficacy were found between the 2 treatments,
K and 20% (n = 19) in group T (P = .15) at 3 months.
which were meanwhile associated with a low request for
rescue analgesics; although a slight trend for lower pain
values is observed over time with ketorolac (Figs. 2 and 3),
4. Discussion this difference was only apparent and not statistically
significant. Surprisingly, patients with uncontrolled pain
Persistent postsurgical pain is a pain syndrome that can also were less in group K than in group T (26.5% vs 32.3%; risk
occur after minor surgery, such as hernia repair. Inguinal hernia difference, 5.8; 95% CI, − 7.0 to 18.6; P = .43), with a
repair can be associated with severe pain scores [18,19], and difference between groups of 5.8% instead of the expected
even if PPSP incidence is approximately 10%, the huge number 20%, confirming that despite any trend observed in pain
of these surgical procedures performed yearly produces a large control, the difference between the 2 treatmemts in terms of
amount of patients developing chronic pain. uneffective pain control is minimal and not clinically

Table 2 Primary and secondary end points—comparison between groups

Primary end point Group ketorolac Group tramadol Difference (95% CI) P
Maximum NRS ≥ 4, n (%) 26 (26.5%) 31 (32.3%) 5.8% (− 7.0 to 18.6) .43
Maximum NRS, mean (SD) 2.62 (1.90) 2.74 (2.04) 0.14 (− 0.44 to 0.67) .99
Secondary end points
Maximum mNRS ≥ 4, n (%) 47 (48.0%) 49 (49.0%) 1.0% (− 13.0 to 15.1) 1.00
Maximum mNRS, mean (SD) 3.68 (2.14) 3.92 (2.34) 0.23 (− 0.40 to 0.87) .65
Surgical complications, n (%) 0 0 – –
Rescue medication, n (%) 8 (8.2%) 5 (5.2%) − 2.9% (− 10.0 to 4.0) .57
Side effects, n (%) 6 (6.1%) 12 (12.5%) 6.4% (− 1.8 to 14.5) .14
NRS ≥ 4 at 1 mo, n (%) 1 (1.0%) 1 (1.1%) 0.0% (− 2.8 to 2.9) 1.00
mNRS ≥ 4 at 1 mo, n (%) 5 (5.1%) 2 (2.2%) − 2.9% (− 8.2 to 2.3) .44
NRS ≥ 4 at 3 mo, n (%) 0 0 – –
mNRS ≥ 4 at 3 mo, n (%) 1 (1.0%) 1 (1.1%) 0.0% (− 2.8 to 2.9) 1.00
Acute and chronic postherniotomy pain 663

.4 central antihyperalgesic action [22]. Specific NSAIDs'

K-NAIDS T-TRAM
contribution to this action and biochemical mechanism is
still to be determined; no clear data are available to state
Proportion of NRS>=4

.3 which NSAID is more effective in preventing hyperalgesia,

.2
.1
0 powerful central hyperalgesic action may be pursued by
0 3 6 12 24 48 60 72 84 96
Hours since surgery
Fig. 2 Distribution over time of mean NRS at rest over time in the
first 96 hours after surgery. A trend for better pain control with
ketorolac is noted without any statistically significant difference.
significant. Otherwise, it is noteworthy that a not negligible
percentage of patients had a not optimal pain control (26.5%
vs 32.3%); this supports once again the evidence that
postoperative pain relief remains an issue, even after minor
procedures, and further improvements are needed to ensure a
high-quality patients' care [17].
No statistical differences in terms of total percentage of
patients experiencing side effects existed; however, if we
thoroughly consider side effects (higher incidence of consti-
pation in the tramadol group; bleeding and gastric symptoms
limited to the ketorolac group), our study confirms the
well-known (reported in informative leaflets) side effects
associated with opioids (nausea/vomiting, constipation, dizzi-
ness, and hypotension) or NSAIDs (bleeding, gastric symp-
toms), suggesting that drug choice should be mainly guided by
risk of associated side effects and on patient's comorbidities.
Otherwise, recent findings highlighted the widespread
effects of NSAIDs, with an increasing knowledge about the
K-NAIDS
.5
Proportion of mNRS>=4
but it has been proposed that selective COX-2 action and
high central biodisposition (due to higher ability to pass
through the blood-brain barrier) are the key factors for higher
effectiveness. Further trials should probably investigate the
role of different NSAIDs according to their COX selectivity
and their chemical properties; in our study, we did not
demonstrated any effect on PPSP incidence, but a more
using a more COX-2 selective, centrally acting NSAID.
108 120 132
Regarding secondary end points (PPSP), no differences
were noted between groups, nor at 1 nor at 3 months;
comparisons on the efficacy of each treatment remain
difficult because of the low incidence of PPSP. Persistent
postsurgical pain incidence has a great variability (from
5%-35%) in literature, with a mean reported incidence of
10% [6]; our study conflicts with previous data, showing a
lower incidence of PPSP. Noteworthy, in the current study,
we considered only patients experiencing persistent NRS
values ≥ 4; incidence of PPSP is higher if we consider any
patient presenting pain, regardless of NRS value. This
consideration suggests, in our opinion, a need for less
heterogeneity among future trials about PPSP definition.
Otherwise, the low incidence of PPSP might be associated with
the effective postoperative pain relief observed in our
population, in which a prolonged analgesic plan (up to 3 days)
was provided. These findings, once confirmed, could further
support the concept of prolonged pain treament even after minor
procedures (up to 3 days after patients' discharge) and already
starting intraoperatively with a combination of NSAID-weak
opioid, to target the 2 main pathophysiological pathways
involved in pain perception and continuation.
Finally, risk factors for chronic pain are still matter of
debate, and although the ineffective acute pain control is
considered the most striking risk factor, systemic proinflam-
matory status has been advocated as an important determi-
T-TRAM
nant in PPSP development [9]. Evidence exists about a
higher cytokine activation in vitro [23] in patients with

.4 higher BMI (known to be a proinflammatory condition),

suggesting that basal inflammation is a risk factor for
.3 stronger postoperative inflammatory reaction. No conclusive
data are available about the association between this
.2 inflammatory reaction and pain intensity [23], but our results
could have been potentially influenced by a poor stratifica-
.1 tion of our population according to basal inflammation (as
we did not consider only patients with/without a preexisting
0
inflammatory condition). Further studies are needed to
0 36 12 24 48 60 72 84 96 108 120 132
understand the role of basal inflammation in acute and
Hours since surgery chronic pain development and to clarify wheter NSAIDs are
more effective than other drugs in this specific subtype of
Fig. 3 Distribution over time of mean mNRS over time in the patients, arguing that the effect of NSAIDs and potentially all
first 96 hours after surgery. A trend for better pain control with other anti-inflammatory techniques may depend of systemic
ketorolac is noted without any statistically significant difference. inflammation level.
664
The present study has some limitations. Because our
primary aim was to identify the superiority of targeting 1
between the 2 pain pathways, our main concern was to
provide a basal homogeneous anti-inflammatory and de-
scending inhibitory activity to all patients; we then tried to
give all the patients with a standard analgesic treatment
before the end of surgery (acting both on inflammation and
descending inhibitory system), further analyzing the effects
of continuation of each treatment. Furthermore, because we
have pursued this approach, we escaped from abovemen-
tioned clinical recommendations from procedure specific
postoperative pain management (PROSPECT) group [12]
because a weak opioid was used as first-line therapy (and
not a rescue analgesia). This choice was driven by the aim
of providing patients with a continuous action on a specific
pain pathway with tramadol or ketorolac, leaving paracet-
amol as rescue medication. This approach, in our opinion,
could help focusing more on the type of physiological
pathway involved in pain development, rather than on the
effect of different anesthetic techniques. Despite this, the
lack of standardization in the type of anesthesia (general,
spinal, and field block) could be questionable; we think,
however, to have overcome this concern because data
show a good stratification of study population, with no
statistical differences between the 2 groups in terms of
anesthesia, and subgroup analysis did not have evidence of
any difference in primary outcome between patients
receiving general, spinal, or field block anesthesia. Finally,
the heterogeneity in the type of anesthesia helps in
depicting the real situation found by clinicians in clinical
practice because despite recommendations, not all of the
patients (and all of the hernias) can be treated with the same
type of anesthesia/analgesia.
In conclusion, our study demonstrated that NSAIDs
or weak opioids have the same effectiveness in acute
pain relief after open IHR, and both treatments are associated
to low incidence of PPSP. The choice between them
should be driven by their potential side effects, but
further studies focusing on different NSAIDs and patient's
basal inflammatory status are suggested to get to an
individualized therapy and to improve perioperative and
long-term outcome.
Acknowledgment
This study was supported by a grant from IRCCS
Foundation Policlinico S Matteo.
We thank Alfa Wassermann for providing acetaminophen-
tramadol combination (Patrol) for home therapy after
patients' discharge.
D. Bugada et al.
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