Int
J Med Sci 2015;
12(8):644-649. doi:10.7150/ijms.11828
Research
Paper
A Randomized Clinical Trial of Nefopam
versus Ketorolac Combined With Oxycodone in Patient-Controlled Analgesia after
Gynecologic Surgery
Boo-Young
Hwang, Jae-Young Kwon 
, Do-Won Lee, Eunsoo Kim, Tae-Kyun Kim, Hae-Kyu Kim.
, Do-Won Lee, Eunsoo Kim, Tae-Kyun Kim, Hae-Kyu Kim.Abstract
Objectives:
Nefopam is a centrally-acting non-opioid
analgesic, which has no effect on bleeding time and platelet aggregation. There
has been no study about nefopam and oxycodone combination for postoperative
analgesia. In this study, we present efficacy and side effects of
nefopam/oxycodone compared with ketorolac/oxycodone in patient-controlled
analgesia (PCA) after gynecologic surgery.
Methods:
120 patients undergoing gynecologic surgery
were divided randomly into two groups: Nefopam group treated with oxycodone 1
mg and nefopam 1 mg bolus; and Ketorolac group treated with oxycodone 1 mg and
ketorolac 1.5 mg bolus. After the operation, a blinded observer assessed the
pain with a numeric rating scale (NRS), infused PCA dose and sedation score at
1, 4, 24, and 48 h, nausea, vomiting, headache, shivering, pruritus and
delirium at 6, 24 and 48 h, and satisfaction at 48 h after the operation.
Results:
Nefopam group showed less nausea than Ketorolac
group within 6 h after the operation. There were no significant differences in
demographic data and other complications between both groups. At 48 h after
operation, satisfaction and the infused PCA volumes of Nefopam group (34.0±
19.7 ml) showed no significant differences compared to Ketorolac group (30.7±
18.4 ml, P-value= 0.46).
Conclusion:
Nefopam showed a similar efficacy and lower
incidence of nausea within 6 h after the operation to that of ketorolac in PCA.
Nefopam may be a useful analgesic drug for the opioid-based PCA after
gynecologic surgery. Further evaluation of accurate equivalent dose of nefopam
as well as pharmacokinetics of bolus administration is required.
Keywords:
Gynecologic surgery, Nefopam, Oxycodone, Patient-controlled analgesia,
Postoperative pain
Introduction
Postoperative
pain can induce postoperative complications such as atelectasis, hypertension,
delirium, prolonged hospital stay, and decreased satisfaction of patients.
Patient-controlled analgesia (PCA) has been known to decrease pain intensity
and postoperative complications more effectively than conventional opioid
analgesia [1].
Non-steroidal anti-inflammatory drugs (NSAIDs) have been used in combination
with opioids such as fentanyl, morphine, or oxycodone for PCA since they have
been known to reduce opioid consumption and opioid-related side effects [2]. However,
NSAIDs may affect platelet function which increase bleeding tendency, and
induce gastrointestinal side-effects [3,4]. Nefopam
is a centrally acting analgesic which has been used in many countries since the
mid-1970s [5]. Manoir et
al. [6] suggested
that bolus administration of nefopam (every 4 h for 24 h) showed a significant
morphine-sparing effect without major side-effects. Even solitary administration
of nefopam in PCA provided postoperative analgesia in cardiac surgery [7]. There are
no contraindication to combine nefopam and ketorolac. However, we focused that
nefopam could be a substitute for NSAIDs in patients who are contraindications
and have a difficulty in using NSAIDs. Despite many studies on effects of
nefopam, knowledge about nefopam/oxycodone combination for postoperative
analgesia is lacking. Therefore, here we investigate the efficacy and side
effects of nefopam in comparison with ketorolac in oxycodone PCA after
gynecologic surgery.
Methods
Study design and Ethics approval
A
prospective, randomized and double blind study was conducted at the Department
of Anesthesia and Pain Medicine at Pusan National University Hospital, Korea
from June to September 2014. This study was approved by the Institutional
Review Board for Human Experiments at Pusan University Hospital Medical
Research Institute and registered with Clinical Research Information Service
which conforms to the World Health Organization International Clinical Trials
Registry Platform (WHO-ICTRP); KCT0001236. All patients were provided informed
consent.
120
patients, who were admitted for elective gynecologic surgery, ASA class I or
II, and aged 18 to 65 years old, were assessed. Patients, who do not qualify
for or do not prefer treatment of opioids or NSAIDs, or who have psychological
disorder, chronic pain disorder or preoperative administration of drugs
including opioids, antidepressants, gabapentin, pregabalin, and carbamazepine,
were excluded. Patients, who cannot use numerical rating scale (NRS), who have
increased intracranial pressure, renal failure, hepatic failure, or in pregnancy,
were also excluded. 105 patients were enrolled in this study.
Treatment
Patients
were divided randomly into two groups using online statistical program “www.randomization.com”:
Nefopam group (nefopam 1 mg and oxycodone 1 mg per 1 ml in PCA, n = 52)
and Ketorolac group (ketorolac 1.5 mg and oxycodone 1 mg per 1 ml in PCA, n=
53). The randomized number were divided into two groups, and we had a random
number table before patients were confirmed. Patients were received randomized
number in sequence. They were separated into two groups. All patients and
anesthesia doctors who participated in the study did not know about in which
group patients were during anesthesia and postoperative visit for pain
assessment. Anesthesia was standardized. Glycopyrrolate 0.2 mg was
intramuscularly injected to all the patients 30 min before induction of
anesthesia. After the patient arrived in the operating room, baseline heart
rate, mean arterial blood pressure, and oxygen saturation were measured using a
patient monitor. Bispectral index (BIS, XP version 4.1; Aspect Medical Systems,
Newton, MA, USA) monitoring was used to measure the depth of anesthesia.
Propofol 2 mg/kg i.v., rocuronium 0.6 mg/kg i.v., and remifentanil 0.5 μg/kg/ min
i.v. were administered for the induction, and remifentanil and desflurane were
used for maintenance. Remifentanil was adjusted to maintain systolic arterial
pressure within 20% of baseline value. An antiemetic (ondansetron 8 mg i.v.)
was administered 30 min before the end of surgery. During subcutaneous suture,
loading dose of analgesics (nefopam 20 mg and oxycodone 5 mg in Nefopam group,
ketorolac 30 mg and oxycodone 5 mg in Ketorolac group) was infused slowly.
After the operation, pyridostigmine 10 mg i.v. and glycopyrrolate 0.4 mg i.v.
were administered, and patients were transferred to post-anesthesia care unit,
and stayed until Aldrete score was greater than 8. Patients received pain
control via PCA device (GemStar Infusion System, Hospira, IL, USA) with a bolus
dose of 1 ml, a lock-out interval of 6 min, and a 4 hours limit of 40 ml.
Nurses in anesthesiology department prepared the drugs for PCA according to the
group. Anesthesia doctors did not know patient's group during anesthesia and
postoperative visit for pain assessment.
Assessment
After
the operation, a blinded observer assessed the pain using a numeric rating
scale (NRS) at rest, infused PCA dose, Ramsay sedation scale at 1, 4, 24, and
48 h. If a patient complained the pain above NRS 5, we recommended the patient
to press the button. There were no other rescue medications. The Ramsay
sedation scale was applied to assess the sedation level: 1 = anxious, agitated,
or restless; 2 = cooperative, oriented, and tranquil; 3 = responds to command;
4 = brisk response to a light glabellar tap or loud auditory stimulus; 5 =
sluggish response to a light glabellar tap or loud auditory stimulus; and 6 =
no response to the stimuli. Side-effects such as nausea, vomiting, headache,
shivering, pruritus, and delirium were assessed at 6, 24, and 48 h, and
satisfaction at 48 h after the operation. Nausea was classified into three
grades: 1 = mild; 2 = moderate; and 3 = severe. If patients complained nausea
above grade 2, 4 mg i.v. ondansetron was administered. Vomiting was graded into
two grades: 1 = <4 times of vomiting; 2 = ≥4 times of vomiting. Patients
were asked to rank their satisfaction according to the following scale: 1 =
very unsatisfactory; 2 = unsatisfactory; 3 = neutral; 4 = satisfactory; and 5 =
very satisfactory.
Statistical analysis
The
estimated sample size was 50 subjects in each group which was calculated from β-risk
of 80% at an α-level of 0.05 for detecting a difference in cumulative
PCA dose (29 ml vs. 33 ml) of at least 4 ml at 48 h after the operation with
the standard deviation of 8.0 for each group in the preliminary test. 120
patients were assessed for study considering 20% as exclusion rate. Data are
expressed as mean ± SD. The demographic data were compared using the Student's
t-test. Preoperative diagnoses, procedures and the incidence of side-effects
was compared between two groups using the chi-square test and Mann-Whitney
test. The cumulative PCA dose, blood loss and the sedation scores were compared
using Mann-Whitney test. The NRS were compared using two-way repeated measures
ANOVA. The satisfaction scores of two groups were compared using the chi-square
test. A probability of < 0.05 was considered to be significant. SPSS (21.0
IBM statistics data editor SPSS Inc., Chicago, IL, USA) was used for all
statistical analyses.
Results
Six
patients in Ketorolac group and five patients in Nefopam group were excluded
and discontinued earlier due to early discharge or intractable nausea. There
were no differences in weight, height, age, operation time, preoperative
diagnoses, procedure, blood loss, total remifentanil infusion dose, previous
emesis history, smoking history, change of hemoglobin and the incidence of
transfusion between both groups (Table 1). Nefopam
group showed less nausea in 6 h after the operation (P-value = 0.04).
There were no significant differences in nausea after 6 h after the operation,
vomiting, headache, shivering, pruritus, delirium, and satisfaction between the
two groups (Table 2, Table 3). There
were no significant differences in NRS and accumulated PCA dose between both
groups. At 48 h after operation, the infused PCA volume of Nefopam group (34.0
± 19.72ml) was not significantly different from that of Ketorolac group (30.7 ±
18.39 ml, P-value = 0.457). Both groups showed a decrease in pain as
time. Ramsay sedation scale of Nefopam group was also not significantly
different from that of Ketorolac group.
Table
1
Demographic
Data.
|
Nefopam
|
Ketorolac
|
P-value
|
||
|
Weight
(kg)
|
58.4
(6.9)
|
58.36
(9.3)
|
0.05
|
|
|
Height
(cm)
|
159.33
(5.4)
|
158.21
(5.4)
|
0.44
|
|
|
Age
(yrs.)
|
43.25
(11.5)
|
41.81
(13.3)
|
0.24
|
|
|
Operation
time (min)
|
127
(42.0)
|
125.6
(41.6)
|
0.79
|
|
|
Preoperative
diagnoses
|
||||
|
Ovarian
mass
|
26
|
21
|
0.29
|
|
|
Myoma
|
26
|
32
|
||
|
Type
of surgery (laparoscopy/laparotomy)
|
31
/ 21
|
29
/ 24
|
0.61
|
|
|
Laparoscopic
ovarian cystectomy
|
26
|
21
|
0.51
|
|
|
Total
laparoscopic hysterectomy
|
5
|
8
|
||
|
Total
abdominal hysterectomy
|
13
|
18
|
||
|
Abdominal
myomectomy |
8
|
6
|
||
|
Blood
loss (ml)
|
351.4
(270.4)
|
281.9
(260.7)
|
0.19
|
|
|
Total
infused remifentanil dose (mcg)
|
489.5
(323.6)
|
427
(209.6)
|
0.07
|
|
|
History
of motion sickness or PONV (n)
|
2
|
4
|
0.33
|
|
|
Smoking
history (n)
|
0
|
2
|
0.22
|
|
|
Change
of Hb (mg/dl)
(POD1 Hb - POD2 Hb) |
1.3
(0.9)
|
1.2
(1.0)
|
0.76
|
|
|
Postoperative
transfusion (n)
|
1
|
2
|
1.00
|
|
There
are no differences in weight, height, age, operation time, preoperative
diagnoses, procedures, blood loss, total infusion dose of remifentanil, history
of motion sickness, smoking, change of hemoglobin (Hb) and the incidence of
transfusion between both groups. Data are expressed as mean value and standard
deviation (SD).
Table
2
Side
Effects of Patient-Controlled Analgesia.
|
Nefopam
|
Ketorolac
|
Total
|
P-value
|
|||
|
Nausea
|
<
6 hours
|
1
|
11
|
19
|
30
|
0.04
|
|
2
|
2
|
4
|
6
|
|||
|
3
|
0
|
1
|
1
|
|||
|
6-24
hours
|
1
|
7
|
12
|
19
|
0.31
|
|
|
2
|
2
|
1
|
3
|
|||
|
3
|
1
|
1
|
2
|
|||
|
>24
hours
|
1
|
2
|
1
|
3
|
1.00
|
|
|
2
|
2
|
2
|
4
|
|||
|
Vomiting
|
1
|
0
|
1
|
1
|
1.00
|
|
|
2
|
0
|
1
|
1
|
|||
|
Headache
|
2
|
3
|
5
|
0.67
|
||
|
Shivering
|
3
|
4
|
7
|
0.72
|
||
|
Pruritus
|
1
|
3
|
4
|
0.36
|
||
|
Delirium
|
0
|
0
|
0
|
1.00
|
Nefopam
group shows lesser nausea in 6 hours after the operation. There are no
significant differences in nausea after 6 hours after the operation, vomiting,
headache, shivering, pruritus and delirium between groups.
Table
3
Satisfaction
of Patients on Patient-Controlled Analgesia.
|
Nefopam
|
Ketorolac
|
P-value
|
|
|
Very
satisfied
|
16
(34)
|
8
(17)
|
0.14
|
|
Somewhat
satisfied
|
24
(51.1)
|
28
(59.6)
|
|
|
Neither
satisfied nor dissatisfied
|
7
(14.9)
|
9(19.1)
|
|
|
Somewhat
dissatisfied
|
0
(0)
|
2
(4.3)
|
|
|
Very
dissatisfied
|
0
(0)
|
0
(0)
|
There
is no significant difference on satisfaction between both groups.
Study
flow chart with individual causes of study interruptions and dropouts. The flow
chart of this study was according to the CONSORT Statement. There was no
significant difference on rate of dropouts between both groups. (P-value
= 0.78)
The
NRS of pain intensity was assessed at 1, 4, 24 and 48 h after the operation.
There is no significant difference between both groups. Both groups show a
decrease in pain as the time passed. Data are expressed as mean ± SD.
The
accumulated PCA dose was assessed at 1, 4, 24 and 48 h after the operation.
There is no significant difference between both groups. Data are expressed as
mean ± SD.
Ramsey
sedation scale was assessed at 1, 4, 24 and 48 h after the operation. There is
no significant difference between both groups. Data are expressed as mean ± SD.
Discussion
Many
medical centers have applied opioids, NSAIDs, antiemetics and other analgesics
for i.v. PCA. Opioids are effective analgesics for the management of
postoperative pain, but the use of opioids has been limited by adverse effects
such as postoperative bowel ileus, drowsiness, nausea, vomiting, constipation,
urinary retention, shivering, acute tolerance, respiratory depression, and
delirium. Gynecologic surgery is known to induce severe nausea. In the previous
study, we observed that oxycodone PCA induces more nausea than fentanyl PCA in
acute period after the operation. To reduce an opioid consumption, it is
necessary to carry on further studies on adjuvant analgesics.
There
have been a lot of alternative ways to manage postoperative pain including
analgesic adjuvants such as capsaicin, ketamine, gabapentin, dexmedetomidine,
and transformed mode in PCA. NSAIDs have been known to increase the efficiency
and decrease the opioid-related adverse effects in opioid-based PCA. However,
NSAIDs have limitations as PCA adjuvants. First, NSAIDs may cause digestive
ulcer and bleeding. Second, NSAIDs are the drugs most commonly involved in
hypersensitivity drug reactions. Third, NSAIDs are cleared from blood stream by
kidney, but patients over 65 years old or with renal insufficiency may have a
kidney injury. Patients who have cardiovascular risk are also known to be
assessed carefully before the treatment with NSAIDs. Therefore, alternative
adjuvant analgesics are still required. Nefopam showed significant opioid-sparing
effects in combination with morphine PCA after orthopedic surgery. The
combination of nefopam and paracetamol provided synergistic analgesic effects
on mild and moderate pain surgery. There have also been several studies about
the analgesic effects of nefopam on neuropathic pain. Nefopam is a centrally
acting benzoxazocine analgesic, and is a cyclized analogue of diphenhydramine.
Nefopam could be related neurologic side effects such as delirium, confusion
and seizure in old age. But this study excluded patients who have psychological
disorder, old age, or preoperative administration of drugs that have an effect
on patient's neurology. There was no complication such as delirium in the
current study.
We
compared the efficacy and side-effects of nefopam/oxycodone and
ketorolac/oxycodone combination. However, we did not consider the
pharmacokinetic factors of drugs, and they have a different onset time and
duration. Therefore, we cannot confirm the accurate efficacy and potency of
both analgesics at the same time. Further evaluation of accurate equivalent
dose of ketorolac and nefopam as well as pharmacokinetics of bolus
administration is required. It could be effective method if NSAIDs, nefopam and
opioid are combined while patients are not contraindications and do not have
any risk of NSAIDs-related side effects. If we have a further evaluation for
pharmacologic interactions and metabolism of both drugs, it could be a good
study for opioid minization in PCA.
This
study showed that nefopam has a comparable analgesic effect in the pain
management after gynecologic surgery as compared to ketorolac. The frequency of
nausea within 6 h after the operation in Nefopam group was lower than that in
Ketorolac group. Considering that many patients discontinue PCA due to severe
nausea, application of nefopam for oxycodone-based PCA would be great advantage
for postoperative pain management. Nefopam would be an adequate substitute for
NSAIDs, especially in high risk patients using NSAIDs or opioid alone.
Conflicts of Interest
The
authors declare that there are no conflicts of interest.
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