Keywords
anorectal surgery - hemorrhoidectomy - nefopam - postoperative pain - opioid requirements
Introduction
Anorectal surgery consists of various procedures, varying from minor to major operations.
Even though most of them are seemingly minor operations, some can be excruciating
procedures. Several studies are trying to determine an effective analgesic technique
to control postoperative pain, but no regimen has been accepted as the best protocol.
The decision on postoperative analgesic regimens is widely based on the preference
of individual surgeons.
Nefopam, a non-opioid and non-steroidal analgesic drug, is a benzoxazocine derivative.
It was developed in the early 1970s and is known to act as an N –methyl D-aspartate
(NMDA) receptor antagonist and a monoamine reuptake inhibitor.[1]
[2] The analgesic mechanism of nefopam is the inhibition of serotonin, norepinephrine,
and dopamine reuptake. This action results in the reduction and prevention of central
sensitization, leading to decreased nociceptive responses. In addition, it has an
indirect modulating effect on NMDA receptors. Nefopam 20 mg is equianalgesic to 7-12 mg
of morphine, 50 mg of meperidine, and 10 mg of ketamine.[3]
[4]
[5] A trend toward multimodal opioid-sparing analgesia is a pivotal element in ERAS
protocols. Thus, nefopam has gained popularity as an analgesic adjunct in various
surgeries. Some recent studies have shown that nefopam can significantly reduce postoperative
opioid consumption in many surgeries, namely, laparoscopic gastrectomy, laparoscopic
cholecystectomy, breast surgery, and gynecological surgery.[6]
[7]
[8] Nevertheless, there is currently no research on nefopam as an analgesic adjunct
in anorectal surgery.
Regardless, some of the colorectal surgeons in our hospital have been prescribing
this medication for surgical pain control. We have interestingly been observing their
clinical benefits. Hence, this study aims to examine the effectiveness of nefopam
on postoperative pain control after anorectal surgeries. We hypothesized that nefopam
would reduce additional postoperative opioid requirements.
Materials and Methods
This study was approved by the Institutional Review Board of Chulalongkorn University,
Bangkok, Thailand (IRB No. 806/64) and registered with the Thai Clinical Trials Registry
(https://www.clinicaltrials.in.th/ TCTR 20220405003). We retrospectively reviewed the electronic medical records of
patients who underwent anorectal surgeries (e.g., hemorrhoidectomy, fistulotomy, fistulectomy,
sphincterotomy) from January 2019 to March 2022 from two medical centers, King Chulalongkorn
Memorial Hospital (KCMH) and Bangkok Christain Hospital (BCH). Patients 18 to 65 years
old with an American Society of Anesthesiologists physical status classification I
to III were included in the study. Written informed consent was waived by the IRB,
as this was a retrospective study. Exclusion criteria include day-case surgery, incomplete
medical record, and chronic opioid use.
Each of the patients received one of the anesthetic techniques, including spinal anesthesia
(SA), total intravenous anesthesia (TIVA), or local anesthesia (LA), as deemed appropriate
by the surgeon. This was mainly based on the patient's condition, diagnosis, and surgical
procedures. After the surgery, pain control was prescribed according to the surgeon's
preferences. They usually used multimodal analgesic regimens comprising opioids and
non-opioid analgesia. Every patient would receive oral paracetamol, as needed, in
addition to intravenous opioids for the first-line analgesic rescue therapy. Some
patients might be prescribed other analgesics such as nefopam, NSAIDs (etoricoxib),
and gabapentin if moderate to severe postoperative pain is expected.
We divided the data into two groups. The Nefopam group included patients who received
nefopam postoperatively as an adjuvant to an analgesic regimen. The conventional group
was comprised of patients who did not receive nefopam postoperatively. The primary
outcome was additional postoperative opioid consumption measured by the number of
patients who requested additional opioids for breakthrough pain in the 24-h postoperative
period. The secondary outcomes were as follows: numeric rating pain scores (NRPS)
at 6-12 h, 12-18 h, and 18-24 h postoperative period, analgesic drugs related side
effects. We did not record NRPS during the first 6-h after surgery because various
anesthetic techniques undoubtedly influenced them.
All data analysis was executed in STATA 15.1 statistical software (StataCorp LP, College
Station, TX). Continuous variables were analyzed with the independent t-test reported
as mean and standard deviation for patient demographic information and regression
analysis. All categorical variables were analyzed with the Exact probability test.
Regarding the effects of different anesthetic techniques on postoperative pain, we
did a subgroup analysis to prove its effects on the 24-h postoperative additional
opioid requirement. Also, each surgical procedures cause a different degree of tissue
trauma and postoperative pain. Among anorectal procedures, hemorrhoidectomy is renowned
as an excruciating procedure. We thereby, in addition, show subgroup analysis adjusted
to types of surgery. Furthermore, we evaluated the effects of other analgesic drugs
that were commonly prescribed to our patients.
Results
A total of 150 patients were included in this study. Three were excluded due to chronic
opioid usage and incomplete data record. Therefore, 147 patients were analyzed and
divided into the conventional group (87 patients) and the nefopam group (60 patients).
[Table 1] shows baseline demographics and clinical characteristics. There was no significant
statistical difference between the groups, except for the anesthetic techniques.
Table 1
Baseline demographics and clinical characteristics
|
Patient characteristics
|
Nefopam (n = 60)
n (%)
|
Conventional (n = 87)
n (%)
|
P-value[†]
|
|
- Age (years)
[a]
|
46.50 ± 11.65
|
44.46 ± 11.79
|
0.302[‡]
|
|
- Sex
|
|
|
0.388
|
|
Male
Female
|
40 (66.7)
|
51 (58.6)
|
–
|
|
20 (33.3)
|
36 (41.4)
|
–
|
|
- BMI (Kg/m2)
|
|
|
0.096
|
|
Underweight (BMI ≤ 18)
Normal (BMI 18-24.9)
Overweight (BMI 25-29.9)
Obese (BMI ≥ 30)
|
3 (5.0)
|
2 (2.3)
|
–
|
|
33 (55.0)
|
47 (54.0)
|
–
|
|
20 (33.3)
|
21 (24.1)
|
–
|
|
4 (6.7)
|
17 (19.5)
|
–
|
|
- ASA physical status
|
|
|
0.557
|
|
I
II
III
|
43 (71.7)
|
60 (69.0)
|
–
|
|
14 (23.3)
|
25 (28.7)
|
–
|
|
3 (5.0)
|
2 (2.3)
|
–
|
|
- Type of surgery
|
|
|
0.057
|
|
LIFT/Fistulotomy
Hemorrhoidectomy
Strictulotomy/Anoplasty
LIS/Sphincterotomy
Combined (>1 operation)
|
30 (50.0)
|
50 (57.5)
|
–
|
|
23 (38.3)
|
20 (23.0)
|
–
|
|
0 (0)
|
2 (2.3)
|
–
|
|
0 (0)
|
6 (6.9)
|
–
|
|
7 (11.7)
|
9 (10.3)
|
–
|
|
- Operation time (min)
[a]
|
60.38 ± 28.13
|
71.72 ± 30.89
|
0.023[‡]
|
|
- Anesthetic technique
|
|
|
0.009
|
|
Spinal anesthesia
Total intravenous anesthesia (TIVA)
Local anesthesia
|
29 (48.3)
|
48 (55.2)
|
–
|
|
16 (26.7)
|
7 (8.1)
|
–
|
|
15 (25.0)
|
32 (36.8)
|
–
|
|
- Intraoperative morphine use (mg)
[a]
|
2.65 ± 3.24
|
2.55 ± 2.75
|
0.843[‡]
|
Abbreviations: ASA, American Society of Anesthesiologists; BMI, body mass index.
a Data expressed as mean ± standard deviation.
† Exact probability test.
‡ Independent t-test.
Patients in the nefopam group reported lower additional opioid requirements compared
to the conventional group in all dimensions of analysis, including overall, adjusted
to anesthetic techniques and types of surgery. Nevertheless, none of the analyses
did reach a statistical significance, except for those who underwent hemorrhoidectomy
under TIVA or spinal anesthesia (P = 0.016, 60% mean difference, [Table 2]).
Table 2
Number of patients reported rescue opioid in 24-h postoperatively
|
Analgesic requirement
|
Nefopam (n = 60)
n (%)
|
Conventional (n = 87)
n (%)
|
P-value[†]
|
|
- Opioid requirement
|
26 (43.3)
|
51 (58.6)
|
0.093
|
|
- Anesthetic technique
|
|
|
|
|
Spinal anesthesia
|
12 (41.1)
|
26 (54.2)
|
0.349
|
|
Total intravenous anesthesia (TIVA)
|
6 (37.5)
|
5 (71.4)
|
0.193
|
|
Local anesthesia
|
8 (53.3)
|
20 (62.5)
|
0.751
|
|
- Type of surgery
|
|
|
|
|
LIFT/Fistulotomy
|
13 (43.3)
|
27 (54.0)
|
0.356
|
|
Hemorrhoidectomy (Overall)
|
9 (39.1)
|
13 (65.0)
|
0.090
|
|
Hemorrhoidectomy
(Spinal anesthesia or TIVA)
|
3 (23.1)
|
5 (83.3)
|
0.016
|
|
Strictulotomy/Anoplasty
|
0 (0)
|
2 (100.0)
|
–
|
|
LIS/Sphincterotomy
|
3 (50.0)
|
3 (50.0)
|
–
|
|
Combined (>1 operation)
|
4 (57.1)
|
6 (66.7)
|
0.696
|
Significant p values are in bold (p < 0.05).
† Exact probability test.
For 24-h postoperative morphine consumption, patients in the nefopam group required
a compatibly lower dose. They showed a statistically significant difference in patients
who underwent hemorrhoidectomy under TIVA or spinal anesthesia accordingly (mean difference = −3.4,
95% CI: 0.72, 6.08, [Table 3]). The dot plot graph shows that 10 of 13 patients in the nefopam group who underwent
hemorrhoidectomy under TIVA or spinal anesthesia did not require any additional morphine
postoperatively. In comparison, five of 6 patients in the conventional group did ([Fig. 1]).
Table 3
24-hr postoperative morphine consumption (mg)
|
Analgesic requirement
|
Nefopam (n = 60)
|
Conventional (n = 87)
|
Mean difference
|
95% CI of mean difference
|
|
Overall of anorectal surgery[a]
|
1.83 ± 2.65
|
2.32 ± 2.38
|
−0.48
|
−0.34, 1.31
|
|
Hemorrhoidectomy
(Spinal anesthesia or TIVA)[a]
|
0.85 ± 1.72
|
4.25 ± 3.92
|
−3.40
|
0.72, 6.08[*]
|
a Data expressed as mean ± standard deviation.
* Significance < 0.05.
Fig. 1 Dot plot graph represent 24-h postoperative morphine requirement in patients undergoing
hemorrhoidectomy under spinal anesthesia or TIVA technique.
To evaluate the interfering effects of other analgesic drugs, both groups showed no
statistical differences in NSAID-related effects ([Table 4]).
Table 4
NSAIDs effects
|
Analgesic requirement
|
NSAIDs (n = 107) n (%)
|
No NSAIDs (n = 40)
n (%)
|
P-value
|
|
Opioid requirement
|
57 (53.3)
|
20 (50.0)
|
0.853[†]
|
|
Morphine consumption[a]
|
2.11 ± 2.55
|
2.15 ± 2.38
|
0.927
|
a Data expressed as mean ± standard deviation.
† Exact probability test.
Mean numeric rating pain scores are expressed in [Table 5]. Patients in the nefopam group reported significantly lower scores in the 12-18 h
postoperative period (P = 0.009).
Table 5
Mean numeric rating pain scores
|
Mean pain scores
|
Nefopam (n = 60)
|
Conventional (n = 87)
|
P-value
|
Mean difference
|
95% CI
|
|
- At 6-12 h
[a]
|
2.68 ± 2.61
|
3.21 ± 2.14
|
0.185
|
0.524
|
−0.25, 1.30
|
|
Spinal anesthesia
|
2.97 ± 3.06
|
3.46 ± 2.44
|
0.439
|
0.493
|
−0.77, 1.75
|
|
Total intravenous anesthesia (TIVA)
|
1.44 ± 1.26
|
3.14 ± 1.68
|
0.013
|
1.705
|
0.39, 3.02
|
|
Local anesthesia
|
3.46 ± 2.39
|
2.84 ± 1.69
|
0.308
|
−0.623
|
−1.84, 0.59
|
|
- At 12-18 h
[a]
|
1.45 ± 1.59
|
2.33 ± 2.23
|
0.009
|
0.883
|
0.22, 1.54
|
|
Spinal anesthesia
|
1.48 ± 1.86
|
2.52 ± 2.69
|
0.072
|
1.038
|
−0.93, 2.17
|
|
Total intravenous anesthesia (TIVA)
|
0.88 ± 1.02
|
1.43 ± 0.98
|
0.240
|
0.554
|
−0.40, 1.51
|
|
Local anesthesia
|
2.00 ± 1.36
|
2.25 ± 1.55
|
0.595
|
0.250
|
−0.69, 1.19
|
|
- At 18 -24 h
[a]
|
1.37 ± 1.81
|
1.52 ± 1.80
|
0.620
|
0.151
|
−0.45, 0.75
|
|
Spinal anesthesia
|
1.17 ± 1.47
|
1.38 ± 1.79
|
0.609
|
0.203
|
−0.58, 0.99
|
|
Total intravenous anesthesia (TIVA)
|
1.44 ± 2.71
|
1.43 ± 1.62
|
0.994
|
−0.089
|
−2.31, 2.30
|
|
Local anesthesia
|
1.67 ± 1.23
|
1.75 ± 1.88
|
0.877
|
0.083
|
−0.99, 1.16
|
Significant p values are in bold (p < 0.05).
a Data expressed as mean ± standard deviation.
Eight of 147 patients in total experienced nausea and vomited. One patient in the
nefopam group developed the rash. Nevertheless, the groups had no significant difference
in analgesic drug-related side effects ([Table 6]).
Table 6
Analgesic drugs related side effects
|
Side effect
|
Nefopam (n = 60)
n (%)
|
Conventional (n = 87)
n (%)
|
P-value[†]
|
|
- Nausea and vomiting
|
4 (6.7)
|
4 (4.6)
|
0.716
|
|
- Rash
|
1 (1.7)
|
0 (0)
|
0.408
|
† Exact probability test.
Discussion
The results of this retrospective study established a positive trend reinforcing nefopam
as an adjunct that can reduce postoperative opioid requirements in anorectal surgery.
Although the overall comparison did not reach a statistical significance between the
groups, only the patients who underwent hemorrhoidectomy under TIVA or spinal anesthesia
and received nefopam expressed significantly less postoperative opioid requirement
(P = 0.016, mean difference = 60%), as well as postoperative morphine consumption
(mean difference: −3.4, 95%CI: 0.72, 6.08). The explanations for these outcomes are
as follows. Anorectal surgery is a wide-encompassing term covering any procedure from
simple to extensive surgery. The data in this study also included several anorectal
procedures known to result in various degrees of pain ranging from mild to severe
pain. The power of each type of surgery was seemingly low and might not be enough
to identify the significant differences. Data analysis suggested that surgeons mainly
ordered nefopam for the patients who underwent hemorrhoidectomy, LIFT, or fistulotomy
([Table 1]). More than 50% of the patients in the nefopam group who underwent hemorrhoidectomy
did not require rescue opioids postoperatively (61% for overall analysis, and 77%
for under spinal anesthesia/ TIVA, P = 0.01, mean difference = 60%, [Table 2]). To decide which anesthetic technique was suitable for each procedure, the surgeons
generally evaluated the difficulty and the severity of pathologic lesions. The lesions
that needed spinal anesthesia or TIVA seemed more complex; hence, the patients were
more likely to experience moderate or severe postoperative pain.
On the other hand, those procedures done under local anesthesia might not be as complicated;
therefore, a lower pain level was expected. Hemorrhoidectomy is renowned for being
a painful surgery. Several studies are trying to find effective techniques to relieve
post-hemorrhoidectomy pain ranging from topical analgesia (i.e., EMLA, suppository
diclofenac) to systemic analgesia.[9]
[10]
[11]
[12]
Nefopam is now widely prescribed to treat moderate to severe postoperative pain. The
current evidence proposes that nefopam can relieve postoperative pain.[6]
[7]
[8] The analgesic efficacy of nefopam depends on the initial level of pain severity.
Annmarie Hedges et al.[13] demonstrated that the effectiveness of nefopam is more apparent in patients with
moderate to severe pain than with mild pain. Interestingly, the results of our study
also confirm that assumption.
Concerning the analgesic impacts from other analgesic drugs on the primary outcome,
we analyzed the impact of NSAIDs on postoperative opioid requirements. Analysis of
the Exact probability test shows no significant difference in the 24-h postoperative
opioid requirement. 53% of the patients who received NSAIDs still required additional
postoperative opioids, slightly higher than those who did not (50%) ([Table 4]). Therefore, it could be implied that the administration of NSAIDs in this study
did not influence the nefopam effect.
The enhanced analgesic effects of nefopam were demonstrated. The mean numeric rating
pain scores (NRPS) in the conventional group were relatively higher than those in
the nefopam group ([Table 5]). For the time point beyond the first 6-h postoperative, we are concerned about
the lasting effects of spinal anesthesia. Patients in the nefopam group distinctively
experienced lower NRPS during 12-18 h postoperatively with a statistical difference
(P = 0.009). Comparably, in the study of Na HS et al., the NRPS of the nefopam group
was significantly lower than that of the control group.[6]
The common side effects of nefopam have been reported as nausea, vomiting, rash, tachycardia,
and hypertension. The incidence of these side effects herein was similar in both groups.
However, many studies expressed a lower incidence of nausea and vomiting in the nefopam
group.[14]
[15] Moreover, from this study, 6 of 8 patients who had nausea and vomiting were undergoing
local anesthesia, and another two were undergoing total intravenous anesthesia technique.
Finally, this study demonstrates that nefopam is beneficial as a part of multimodal
analgesia in major anorectal surgery.
Limitations for this retrospective observational study include a lack of controllable
factors and an insufficient number of patients in some categories, making it hard
to conclude this comparison properly. This study's power of subgroup analysis may
not be enough to detect significant differences. Our results illustrate that nefopam
can effectively reduce postoperative moderate to severe pain after anorectal procedures,
for example, hemorrhoidectomy. For further studies, we suggest conducting randomized
controlled trials with appropriate power adjustment, especially in hemorrhoidectomy
that requires anesthesia.
In conclusion, prescribing nefopam as part of the analgesic regimen in patients undergoing
major anorectal surgery reduces postoperative opioid requirements.
IRB number: IRB No. 806/64 (The Institutional Review Board of Chulalongkorn University, Bangkok,
Thailand)
Clinical trial registration number:
https://www.clinicaltrials.in.th/ TCTR 20220405003
Previous meeting/presentation: Oral presentation in the 14th International Congress of Asian society of Cardiothoracic Anesthesia (ASCA 2022)
in conjunction with the 16th Annual Scientific Meeting of the Royal College of Anesthesiologists of Thailand,
held in Chiang Mai, Thailand from 1–4 December 2022
