# Abstract

 

## Background Duloxetine, Etoricoxib and opioid are of the commonly administered drugs in Lumbar laminectomy. The aim of this study is to assess the effect of perioperative use of Duloxetine in combination with Etoricoxib on postoperative pain and opioid requirements. 

## Methods One hundred twenty patients with ASA physical status were enrolled with age between 18 and 70 years. Patients were divided randomly into four groups of 30 patients: group P received placebo, group E received etoricoxib 120 mg, group D received duloxetine 60 mg and group D/E received duloxetine 60 mg capsules and etoricoxib 120 mg; 1 h before surgery and 24 h after. 

## Results Neither Duloxetine nor etoricoxib individually had effect on pain with movement, while their combination revealed a significant reduction in pain scores over the entire postoperative period at rest and on movement. Etoricoxib showed a significant decrease in pain at all times at rest when compared with group P, while it showed significant pain decrease only at 0, 2 and 4 h when compared with group D. On the other hand duloxetine alone showed significant decrease in pain at rest at 24 h and 48 h when compared with group P. ConcerningMorphine requirement after 24 h.; it wassignificantly lower in the D/E group in comparison with groups P, E and D. It should be noted also that there was a significant decrease morphine requirement in both groups E and D. 

## Conclusion The perioperative administration of the combination of etoricoxib and duloxetine improved analgesia and reduced opioid consumption without significant side effects. 

## Trial registration [ ISRCTN48329522](#). 17 June 2017 # Results From November 1, 2015 to March 1, 2017, 131 consecutive patients who met the inclusion criteria were allocated for the study (Fig. [1](#)). Eleven patients refused to participate. Therefore, 120 patients were randomized and included in the study. Characteristics of patients and surgical procedures for each group (Table [ 1](#)) showed no significant differences between the groups. <figure> <p><img src="" /></p> <figcaption>Flow diagram for participant</figcaption> </figure> ::::table-wrap

::: caption
Characteristics of patients and surgical procedures in the four groups
:::

______________________________________________________________________

Group Group (P) Group (E) Group (D) Group (D/E) *P* value
Variable (*n* = 30) (*n* = 30) (*n* = 30) (*n* = 30)

______________________________________________________________________

Age (years) 46.50 ± 8.74 45.26 ± 7.50 48.36 ± 9.80 47.50 ± 10.14 0.455

Male/Female (n) 15/15 17/13 18/12 16/14 0.471

Weight (kg) 81.23 ± 13.24 82.53 ± 12.90 80.60 ± 13.37 78.83 ± 16.78 0.794

Height (cm) 167.46 ± 8.50 165.53 ± 7.71 165.40 ± 8.21 165.00 ± 9.63 0.478

ASA (n)

I 18 18 17 15 0.36

II 7 6 9 10 0.42

III 5 6 4 5 0.23



## Duration of surgery (min) 109.9 ± 10.8 115.7 ± 9.8 113.2 ± 13.7 117.8 ± 9.7 0.65

Data are presented as Mean ± SD or number (n)

Placebo group (P), Etoricoxib group (E), Duloxetine group (D),
Duloxetine/Etoricoxib group (D/E). Data were analyzed using ANOVA test
with post hoc test (Bonferroni) and chi square test:::: 

## The morphine requirement The time to first rescue analgesic was significantly prolonged in (D/E)when compared with group D, group E and group P.There was a significant prolongation when groups E and D were compared with group P respectively with no significant difference between group E and group D (Fig. [2](#)). <figure> <p><img src="" /></p> <figcaption>Time to morphine administration after surgery in the four groups as Mean(SD). Placebo group (P), etoricoxib (E), Duloxetine (D), Duloxetine/etoricoxib (D/E). a: when compared with P group. b: when compared with E group. c: when compared with D group. d: when compared with E/D group</figcaption> </figure> The morphine requirement at 24 h was statistically different between the four groups. . There were significantly increased morphine requirements in the P group compared with E, D and D/E groups and significantly increased in E and D groups respectively when compared with D/E group with no significant difference between group E and group D (Fig. [3](#)). At 48 h, total morphine requirement were still significantly increased in the P group compared with all groups with significant increases in both E and D groups when compared with D/E group with no significant difference between group E and group D (Fig. [4](#)). But it was still significantly lower in the three groups at 48 h post-surgery when compared with those required at24 h. <figure> <p><img src="" /></p> <figcaption>Morphine requirements at 24 h in the four groups as mean (SD). Placebo group (P), etoricoxib (E), Duloxetine (D), Duloxetine/etoricoxib (D/E). a: when compared with P group. b: when compared with E group. c: when compared with D group. d: when compared with E/D group</figcaption> </figure> <figure> <p><img src="" /></p> <figcaption>Morphine requirements at 48 h in the four groups as mean (SD). Placebo group (P), etoricoxib (E), Duloxetine (D), Duloxetine/etoricoxib (D/E). a: when compared with P group. b: when compared with E group. c: when compared with D group. d: when compared with E/D group</figcaption> </figure> 

## The pain score With regard to pain scores at rest all time points, the duloxetine/etoricoxib (D/E) group had significantly lower pain scores when compared to placebo group P, while when it compared to etoricoxib group E, also when compared D/E with duloxetine group D (Table [2](#)). ::::table-wrap
::: caption
Pain scores (NRS) at rest in the four groups
:::

______________________________________________________________________

Group Group (P) Group (E) Group (D) Group (D/E) *P* value
Variable (*n* = 30) (*n* = 30) (*n* = 30) (*n*  = 30)

______________________________________________________________________

At 0 h 5 (4-5.25)^bd^ 4 (3-4) ^acd^ 4 (3-5) ^bd^ 3 (3-4) ^abc^ 0.0001

At 2 h 4 (3-5)bd 3 (3-4) ^acd^ 4 (3-5) ^bd^ 3 (3-3)^abc^ 0.0001

At 4 h 4 (3-5) ^bd^ 3 (3-4) ^acd^ 3 (3-4) ^bd^ 2 (2-3)^abc^ 0.0001

At 6 h 3 (3-4) ^bd^ 3 (2-4) ^ad^ 2.5 (2-3)^d^ 2 (1-3) ^abc^ 0.0001

At 12 h 3 (3-3) ^bd^ 3 (2-3) ^ad^ 3 (2-3)^d^ 2.5 (1-3) ^abc^ 0.0001

At 24 h 3 (2-3) ^bcd^ 2(2-3) ^ad^ 2.5 (2-3) ^ad^ 2 (1-2)^abc^ 0.0001



## At 48 h 3 (2-3) ^bcd^ 2 (2-3) ^ad^ 2 (2-3) ^ad^ 2 (0.75-2)^abc^ 0.0001

Placebo group (P), Etoricoxib (E), Duloxetine (D), Duloxetine/Etoricoxib
(D/E)

Data are presented as median (interquartile range). Data were analyzed
by Mann--Whitney U-test and kruksal-wallis test and *P* \< 0.05 is
considered significant

a: when compared with P group

b: when compared with E group

c: when compared with D group

d: when compared with D/E group:::: The pain score in group E was significantly decreased at most time periods when compared to group P at 0, 2 and 4 h at rest when compared with group D. The pain score in group D was significantly decrease at 24 and 48 h compared to group P (Table [2](#) ). While on movement pain was significantly decreased in D/E at all times when compared togroup P and when it compared to group E and when it compared to group D with no significant difference between other groups on movement (Table [3](#)). ::::table-wrap
::: caption
Pain scores (NRS) on movement in the four groups
:::

______________________________________________________________________

Group Group (P) Group (E) Group (D) Group (D/E) *P* value
Variable (*n* = 30) (*n* = 30) (*n* = 30) (*n*  = 30)

______________________________________________________________________

0 h 5 (5-6.25) ^d^ 5 (5-6) ^d^ 5 (5-6) ^d^ 5 (4.5.25) ^abc^ 0.013

After 2 h 5 (5-6) ^d^ 5 (4-6) ^d^ 5 (5-6) ^d^ 5 (4-5) ^abc^ 0.002

After 4 h 4 (4-5) ^d^ 4 (4-5) ^d^ 4 (4-5) ^d^ 4 (3-4) ^abc^ 0.019

After 6 h 4 (3-5) ^d^ 4 (3-5) ^d^ 4 (4-5) ^d^ 4 (3-4) ^abc^ 0.007

After 12 h 4 (3-5) ^d^ 4 (3-4) ^d^ 4 (3-4.25) ^d^ 3 (3-4) ^abc^ 0.030

After 24 h 4 (3-5) ^d^ 4 (3-4.25) ^d^ 4 (3-4) ^d^ 3 (2.75-4) ^abc^ 0.059



## After 48 h 3.5 (3-4) ^d^ 3 (3-4) ^d^ 3.5 (3-4) ^d^ 3 (2.75-4) ^abc^ 0.049

Placebo group (P), Etoricoxib (E), Duloxetine (D), Duloxetine/Etoricoxib
(D/E)

Data are presented as median (interquartile range). Data were analyzed
by Mann--Whitney U-test and kruksal-wallis test and *P* \< 0.05 is
considered significant. a: when compared with P group

b: when compared with E group

c: when compared with D group

d: when compared with D/E group:::: 

## Patients' satisfaction The percentage of patients' satisfaction (excellent) shows significant differences between the four groups at 24 h (Table [4](#)) with no significant differences between the three groups at 48 h. ::::table-wrap
::: caption
Patient's satisfaction in the four groups at 24 h
:::

______________________________________________________________________

Group Group(P) Group(E) Group(D) Group(D/E) p
Patient satisfaction (*n* = 30) (*n* = 30) (*n* = 30) (*n* = 30)

______________________________________________________________________

ExEellent 9 (30%) 12(40%) 11(36.7%) 21 (63.3%)\* 0.004

Good 9(30%) 10(33.3%) 9(30%) 5(23.3%) 0.237

Fair 8(26.7%) 5 (16.5%) 6(20%) 2(6.7%) 0.069



## Poor 4(13.3%) 3(10%) 3(10%) 2(6.7%) 0.933

Data are presented as number (%). Data were analyzed using chi square.
Placebo group (P), Etoricoxib (E), Duloxetine (D), Duloxetine/Etoricoxib
(D/E). *P* \< 0.05 is considered significant

\**P* = 0.016 when compare with P:::: The most common adverse effect expected by patients in the study was nausea and vomiting grades III and IV. There was a significant increase in percentage of patients in group P (43.3%) when compared with group D/E (16.6%) and who reported nausea and vomiting. All complained patients responded to i.v.ondansetron. No statistically significant differences were noted between groups with regard to adverse effects (Table [5](#)). ::::table-wrap
::: caption
Side effects in the four groups
:::

______________________________________________________________________

Group Group(P) Group(E) Group(D) Group(D/E) p
Side effect (*n* = 30) (*n* = 30) (*n* = 30) (*n* = 30)

______________________________________________________________________

PONV (%) 13 (43.3%)\* 7 (23.3%) 7 (23.3%) 5 (16.6%) 0.027
IIII&IV

Somnolence 1 (3.3%) 1 (3.3%) 2 (6.7%) 3 (10%) 0.225

Pruritus 5 (16.7%) 4 (13.3%) 3 (10%) 3 (10%) 0.390

Dizziness 1 (3.3%) 2 (6.7%) 4 (13.3%) 3 (10%) 0.239



## Headache 6 (20%) 3 (10%) 5 (16.7%) 4 (13.3%) 0.907

Data are presented as number (%). Data were analyzed using chi square
test and fisher's exact test. Placebo group (P), Etoricoxib (E),
Duloxetine (D), Duloxetine/Etoricoxib (D/E). *P* \< 0.05 is considered
significant. \**P* = 0.024 when compare P and D/E::::


Extracted trial result:
Outcome: time to first rescue analgesic (continuous)
Intervention: duloxetine 60 and etoricoxib 120mg (group D/E)
Comparator: Placebo group (P)
Intervention group size: 30
Comparator group size: 30
Notes: found in fig2