Zhu et al.

BMC Anesthesiology (2020) 20:101

https://doi.org/10.1186/s12871-020-01027-5

RESEARCH ARTICLE Open Access

Comparison of ED95 of Butorphanol and

Sufentanil for gastrointestinal endoscopy
sedation: a randomized controlled trial
Xiaona Zhu, Limei Chen, Shuang Zheng and Linmin Pan*

Abstract
Background: Butorphanol, a synthetic opioid partial agonist analgesic, has been widely used to control
perioperative pain. However, the ideal dose and availability of butorphanol for gastrointestinal (GI) endoscopy are
not well known. The aim of this study was to evaluated the 95% effective dose (ED95) of butorphanol and
sufentanil in GI endoscopy and compared their clinical efficacy, especially regarding the recovery time.
Methods: The study was divided into two parts. For the first part, voluntary patients who needed GI endoscopy
anesthesia were recruited to measure the ED95 of butorphanol and sufentanil needed to achieve successful
sedation before GI endoscopy using the sequential method (the Dixon up-and-down method). The second part
was a double-blind, randomized study. Two hundred cases of painless GI endoscopy patients were randomly
divided into two groups (n = 100), including group B (butorphanol at the ED95 dose) and group S (sufentanil at the
ED95 dose). Propofol was infused intravenously as the sedative in both groups. The recovery time, visual analogue
scale (VAS) score, hand grip strength, fatigue severity scores, incidence of nausea and vomiting, and incidence of
dizziness were recorded.
Results: The ED95 of butorphanol for painless GI endoscopy was 9.07 μg/kg (95% confidence interval: 7.81–
19.66 μg/kg). The ED95 of sufentanil was 0.1 μg/kg (95% CI, 0.079–0.422 μg/kg). Both butorphanol and sufentanil
provided a good analgesic effect for GI endoscopy. However, the recovery time for butorphanol was significantly
shorter than that for sufentanil (P < 0.05, group B vs. group S:21.26 ± 7.70 vs. 24.03 ± 7.80 min).
Conclusions: Butorphanol at 9.07 μg/kg was more effective than sufentanil for GI endoscopy sedation and notably
reduced the recovery time.
Trial registration: Chinese Clinical Trail Registry (Registration number # ChiCTR1900022780; Date of Registration on
April 25rd, 2019).
Keywords: Butorphanol, Sufentanil, Gastrointestinal endoscopy, Sedation

Background been used as a standard method for the diagnosis of

The morbidity from gastric and intestinal cancer is esophageal, gastroduodenal, and colorectal disease.
ranked second and fifth highest for cancers in China, re- However, unbearable abdominal pain can be caused by
spectively [1]. Gastrointestinal (GI) examination has the distension and traction of viscera during GI endos-
copy, eventually resulting in poor conditions for obser-
* Correspondence: [email protected]
vation and severe arrhythmia [2]. Presently, sedative
Department of Anesthesiology, the First Affiliated Hospital, Wenzhou Medical drugs combined with analgesics are typically used to al-
University, Shangcai village, Nanbaixiang town, Ouhai District, Wenzhou City leviate pain and nervousness during GI endoscopy.
325000, Zhejiang Province, China

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Zhu et al. BMC Anesthesiology (2020) 20:101 Page 2 of 7

Currently, opioid μ receptor agonists, such as sufenta- comparison of the clinical efficacy of butorphanol with
nil and fentanyl, are the most commonly used analgesics. the efficacy of the equivalent sufentanil.
The stomach and intestine are mainly innervated by the
sympathetic and parasympathetic nervous systems [3] ED95 of butorphanol and sufentanil
and the kappa receptor agonist is found at higher con- All patients underwent routine GI preparation before
centrations in the spinal cord thus is involved in reliev- endoscopy, fasting from solids for 8 h and liquids for 2 h
ing visceral pain [4]. Butorphanol is a kappa receptor before the operation. The anesthesia machine was
agonist, which has the advantages of light respiratory de- inspected, and intravenous access was established. Before
pression, stable hemodynamics, a rapid onset, and a inducting anesthesia in the outpatient operating room,
moderate effective duration [5], and it may be a more standard monitoring was applied, including for non-
suitable intraoperative and postoperative analgesic for invasive blood pressure (BP), electrocardiogram (ECG),
painless GI endoscopy. and oxygen saturation (SpO2), and the patients were
Butorphanol is a more effective analgesic than mor- placed in the left lateral position. All the patients re-
phine, while its respiratory depression is as low as 1/5 ceived 3 L per minute supplemental oxygen via nasal in-
that of morphine [6]. At present, butorphanol can be halation and were asked to hold the facial mask
safely applied as a maternal analgesic, especially for themselves.
pregnant women with pre-eclampsia and chronic hyper- Butorphanol (Batch number: 190411BP, Jiangsu Hen-
tension, it dose not cause severe fluctuations in blood grui Pharmaceutical Co., Ltd.) or sufentanil (Batch num-
pressure [7]. Butorphanol has also been used in outpa- ber: 3018511505, Yichang Humanwell Pharmaceutical
tients undergoing laparoscopic tubal sterilization in the Co., Ltd.) was slowly injected intravenously. Given the 3
early stage [8], although the analgesic dose has not been min onset time, propofol (Batch number: 1811236
standardized [9, 10]. It is imperative that the optimal Beijing Fresenius Kabi Pharmaceutical Co., Ltd.) was ad-
butorphanol dose that produces analgesia and minimizes ministrated intravenously at a constant speed until the
side effects during outpatient sedation is found. patient lost consciousness and dropped the hand-held
The objective of this study was to detect the ED50, mask, followed by a continuous intravenous infusion at
ED95, and 95% confidence intervals for butorphanol a rate of 50–150 μg•kg− 1•min− 1.The bispectral index
using the sequential method and to compared these to (BIS) was monitored (BIS Complete Monitoring System,
the ED95 dose of sufentanil to assess the feasibility and Covidien), and a controlled BIS value of between 50 and
superiority of butorphanol in GI endoscopy. 60 was maintained by adjusting propofol speed. Then,
the endoscopy was begun (operated by the same gastro-
Methods enterologist). If the patient showed “failed sedation” (def-
This clinical study was approved by the Hospital Ethics inition of failed sedation: occurrence of gag reflex [11],
Committee of the First Affiliated Hospital of Wenzhou coughing, or body movement during esophagogastro-
Medical University and was registered in the Clinical Trial duodenoscopy, or body movement during colonoscopy)
Registration Center of China (ChiCTR1900022780). In- during the GI endoscopy, an additional propofol dose of
formed consent was obtained from all individual partici- 0.5–1 mg/kg was administered. Once the SpO2 fell to
pants included in the study. This study adhered to 90%, assisted ventilation with oxygen via a facial mask
CONSORT guidelines. was applied. If the heart rate dropped below 45 beats per
This study was based on the medical records of ASA minute, atropine (0.5 mg) was applied. If the mean arter-
I-II patients aged 18 to 65 who underwent an outpatient ial pressure was less than 50 mmHg, ephedrine 5–10 mg
GI endoscopy (diagnostic esophagogastroduodenoscopy was administered. After surgery, the patients were trans-
and colonoscopy, without therapeutic procedures), who ported to the postanesthesia care unit (PACU) to rest
required anesthesia and an operation of no more than and recover.
30 min in duration at the endoscopy center from May to
July 2019. Patients were excluded from the study based Dixon up-and-down method
on the following criteria: not willing or able to finish the The dose of butorphanol administered to each patient
whole study; acute upper respiratory tract infection; was determined by the Dixon up-and-down method
hepatitis and renal failure; habitual sedative or analgesic [12]. According to geometric progression, the dose gra-
use; analgesic use for acute pain; chronic fatigue syn- dient was divided into six steps: 12.00, 10.00, 8.33, 6.94,
drome; low potassium; myasthenia gravis; psychiatric 5.79, and 4.82 μg/kg. In a preliminary experiment, the
disease; and allergy to butorphanol, sufentanil, or ED95 of butorphanol for “successful sedation” (definition
propofol. of successful sedation: without gag reflex, coughing, or
This study was divided into two parts: (1) determin- body movement in esophagogastroduodenoscopy and
ation of the ED95 of butorphanol and sufentanil; (2) body movement in colonoscopy) with propofol in
Zhu et al. BMC Anesthesiology (2020) 20:101 Page 3 of 7

outpatient GI endoscopy was 9.8 μg/kg. Therefore, the sedation, fatigue severity scores (assessed with an 11-
first patient was prescribed a dose of 10.00 μg/kg. The point (0–10) scale [15] 15 min after awakening time),
dose grade was increased or decreased using the up- VAS score of abdominal pain (15 min after awakening
down method based on the failure or success of the sed- time), value of hand grip strength before and 15 min
ation in the previous patient. This process was repeated after operation (assessed using an electronic hand dyna-
until there were nine cross-over pairs [13] (i.e., one suc- mometer [EH101, Camry Co. Zhongshan, China]), the
cessful sedation, followed by one failed sedation). incidence of nausea and vomiting, and dizziness after
The dose of sufentanil given to each patient was also awakening.
determined by the Dixon up-and-down method. Accord-
ing to geometric progression, the dose gradient was di- Statistical analysis
vided into six steps: 0.12, 0.1, 0.083, 0.069, 0.058, and SPSS statistical software (IBM Corporation, version 19)
0.048 μg/kg. In the preliminary experiment, the ED95 of was used for statistical analyses. The median effective
sufentanil for “successful sedation” with propofol in out- dose (ED50), ED95, and the 95% confidence intervals (CI)
patient GI endoscopy was 0.085 μg/kg. Thus, the first of butorphanol and sufentanil were determined by bin-
patient was prescribed a dose of 0.083 μg/kg. The follow- ary regression (probit) [16].
ing process was similar to that used for testing the ED95 The sample size in part two was evaluated by PASS
of butorphanol. 11.0. The primary indicator was recovery time. The pre-
experimental measurements showed that the recovery
Comparison with sufentanil time was 22.12 ± 7.9 min in the butorphanol group and
Groups 25.57 ± 8.1 min in the sufentanil group. A sample size of
Two hundred cases of painless GI endoscopy patients 93 in each group was determined to be required for a β
were recruited. The patients were randomly divided into value of 0.10 and an α value of 0.05. Considering the loss
two groups: the butorphanol group (group B, n = 100) of data and the number of patients who could not be
and the sufentanil group (group S, n = 100). interviewed after endoscopy, 100 patients were selected
in each group to ensure that the experiment had a large
Anesthesia methods enough sample size.
This part of the study was double-blind and randomized. Normally distributed data were analyzed with the
The patients were grouped according to the envelope mean ± standard deviation, and a two independent sam-
method. The dispensing nurse dispensed the drugs ac- ple t-test was used to evaluate the differences between
cording to the directions of the anesthetist. The pre- the two groups. The non-parametric data were analysed
operative preparation and anesthesia methods were the using the median (Q1, Q3) or ratio, and a non-
same as in the first part of the study and were performed parametric test was used to evaluate the differences be-
by the anesthetist. The ED95 dose of butorphanol tween the two groups. The complication rates were
(9.07 μg/kg) was administered to group B. The ED95 compared using a four-square table Chi-squared test. A
doses of sufentanil (0.1 μg/kg) was administered to group P-value < 0.05 was considered to be statistically
S. The ED95 doses of butorphanol and sufentanil were significant.
estimated in the first part of the study. Postoperative in-
dications in the PACU were evaluated and recorded by Results
another postoperative observer who was blinded to the The data of 30 patients were screened in the first part of
group division. the study. One patient was excluded due to poor GI prep-
aration, thus 29 cases remained. The individual responses
Efficacy measurements and variables to butorphanol assessed using Dixon’s up-and-down
The primary outcome in this study was the recovery method are shown in Fig. 1. The ED50 of butorphanol for
time, which represented the time from completion of inhibiting body movement during painless GI endoscopy
the examination and to the patient’s departure from the was 6.58 μg/kg (95% CI, 5.57–7.49 μg/kg), and the ED95 of
PACU. The standards for hospital discharge were our butorphanol was 9.07 μg/kg (95% CI, 7.81–19.66 μg/kg)
outpatient operational standards [14] (including vital for the same procedure. A total of 37 patients were in-
signs, pain, orientation, dizziness, and walking). The sec- cluded in the second part of the study. The individual re-
ondary outcomes included the demographic and medical sponses to sufentanil assessed using Dixon’s up-and-down
data, i.e., the incidence of respiratory depression (re- method are shown in Fig. 2. The ED50 of sufentanil for
spiratory rate < 10 beats/min or SpO2 < 90% in nasal inhibiting body movement during painless GI endoscopy
catheter oxygenation with 3 L/min), the incidence of cir- was 0.060 μg/kg (95% CI, 0.048–0.073 μg/kg) and the
culatory inhibition (MAP < 50 mmHg or HR < 45 beats ED95 of sufentanil was 0.100 μg/kg (95% CI, 0.079–
/min), dosage of propofol, the incidence of failed 0.422 μg/kg) for the same procedure. No significant
Zhu et al. BMC Anesthesiology (2020) 20:101 Page 4 of 7

Fig. 1 Responses (successful sedation) of 29 consecutive patients who received butorphanol as an analgesic during GI endoscopy

circulatory or respiratory depression occurred during the dizziness (P = 0.205), and propofol dosage (P = 0.171).
operation. Compared to group S, group B showed lower fatigue se-
A total of 200 patients were recruited to completed verity scores (P = 0.001) and better postoperative hand
the second part of the study, and their data were ana- grip strength (P < 0.001). Furthermore, the recovery time
lyzed to produce the final results (n = 100 per group). for group B was significantly shorter than for group S
The characteristics of the enrolled subjects are shown in (P = 0.012). The incidence of nausea and vomiting for
Table 1. There were no significant differences between group B was significantly lower than for group S (P =
the two groups regarding patient age-gender compos- 0.014), as shown in Table 2.
ition, SBP (Systolic Blood Pressure), heart rate, weight,
height, BMI, GI endoscopy operation time, preoperative Discussion
hand grip strength, and ASA (American Society of Anes- In our study, the ED50 of butorphanol for inhibiting
thesiologists) grade composition (P > 0.05). body movement in painless GI endoscopy was 6.58 μg/
There were no statistically significant differences in the kg, (95%CI: 5.57–7.49 μg/kg) and the ED95 was 9.07 μg/
incidences of respiratory depression (P = 0.469), circula- kg (95%CI: 7.81–19.66 μg/kg). The ED50 for inhibiting
tory inhibition (P = 0.489), failed sedation (P = 0.352), body movement of sufentanil in painless GI endoscopy

Fig. 2 Responses (successful sedation) of 37 consecutive patients who received sufentanil as an analgesic during GI endoscopy
Zhu et al. BMC Anesthesiology (2020) 20:101 Page 5 of 7

Table 1 General comparison between group S and group B With a published in vitro affinity for opioid receptors
S group(n = 100) B group(n = 100) of 1:4:25 (mu: delta: kappa), butorphanol has been
Weight, kg 63 ± 11 64 ± 10 known to act on kappa-opioid receptors of the upper
Sex (male, female) (60, 40) (63, 37)
spinal cord to inhibit nociceptive stimulus conduction
[5]. Ozaki et al. demonstrated that kappa-, but not mu-
SBP, mmHg 128 ± 15 130 ± 21
or delta-, opioid receptor agonists modulate visceral sen-
Heat rate, beats/min 69 ± 17 77 ± 13 sations conveyed by the vagal afferent fibers innervating
Height, cm 165 ± 8 166 ± 8 the stomach [17]. Soichiro et al. reported that
BMI, kg/m2 23.3 ± 3.0 23.4 ± 2.8 butorphanol-induced visceral chemical antinociception
Operation time, min 14.4 ± 4.9 14.6 ± 4.9 was entirely blocked by pretreatment with a kappa-
Preoperative hand grip strength, kg 42.9 ± 9.5 44.4 ± 8.9
opioid receptor antagonist [18]. Kappa receptor shows
absent related to respiratory depression, nausea, and
ASA classification, I/II 60/40 66/34
vomiting. The mu receptor has strong effects on respira-
ASA American Society of Anesthesiologists ASA physical status classification.
Normally distributed statistics dates were mean ± SD, and a two independent
tory depression and is associated with nausea and vomit-
sample t-test was used to evaluate the differences between the two groups. ing [19]. Our experimental results are consistent with
Sex and ASA classification were ratio and were compared by χ2 test. There previous findings; they also confirm that butorphanol is
were no significant differences between the two groups (P > 0.05)
less likely to cause nausea and vomiting and show that
butorphanol resulted in a lower postoperative VAS score
was 0.060 μg/kg (95% CI, 0.048–0.073 μg/kg) and the than the pure mu-opioid receptor agonist sufentanil at the
ED95 was 0.100 μg/kg (95% CI, 0.079–0.422 μg/kg). In ED95 dose. The most likely reason for this is the difference
the second part of our study, the primary indicator (re- between the kappa and mu receptors. In addition, the
covery time) in group B was significantly shorter than doses of butorphanol and sufentanil used in our study
that in group S. Compared to group S, the VAS score, were low, thus led to a low incidence of respiratory de-
fatigue severity score, incidence of postoperative nausea pression and did not result in a significant difference be-
and vomiting were lower in group B. tween them. The duration of the analgesic effect of
A sequential method was used to accurately select the butorphanol is about 4 h. Although the average examin-
optimal doses of butorphanol and sufentanil for GI en- ation time of painless GI endoscopy is not that long, the
doscopy. An advantage of this method is that it can be patient still needs excellent analgesia after waking up. Pre-
used to evaluate the efficacy of drugs using fewer cases myslFalt et al. reported that, with an intravenous injection
over a short time. The ED95 values of butorphanol and of 2 mg midazolam after routine air-inflated GI endos-
sufentanil were 9.07 μg/kg and 0.1 μg/kg, respectively, copy, 1% of patients still reported abdominal pain and 2%
which were close to the doses used in the first patients of patients had flatulence during the 3 h and 30 min after
in whom we administered the drugs (10 and 0.83 μg/kg, the procedure had finished [20]. It is essential to have ex-
respectively). In our study, we confirmed that there was cellent analgesia during this period, and butorphanol is a
no difference in the incidences of successful sedation suitable choice.
using the ED95 of butorphanol and sufentanil during GI Postoperative fatigue influences the emotional and
endoscopy. mental state of the patients after surgery and affects

Table 2 Comparison of the indicators between group S and group B

S group(n = 100) B group(n = 100) P value
Incidence of respiratory depression 11% 8% 0.469
Incidence of circulatory inhibition 12% 9% 0.489
Dosage of propofol, mg 222.6 ± 38.4 215.0 ± 39.7 0.171
Incidence of failed sedation 7% 4% 0.352
VAS score 2 (1,3) 2 (1,2) 0.001*
Fatigue severity scores 2.18 ± 1.30 1.66 ± 0.87 0.001*
Postoperative grip strength, kg 31.8 ± 6.8 35.5 ± 7.7 0.000*
Incidence of nausea and vomiting 7% 0 0.014*
Incidence of dizzness 6% 11% 0.205
Recovery time, min 24.03 ± 7.80 21.26 ± 7.70 0.012*
The VAS scores are the median (Q1, Q3). The Mann-Whitney U-test was used to evaluate the differences. Normally distributed statistics dates were mean ± SD, and
a two independent sample t-test was used to evaluate the differences. Ratios were compared by χ2 test.* P < 0.05
Zhu et al. BMC Anesthesiology (2020) 20:101 Page 6 of 7

their recovery [21]. Sufentanil is the classic analgesic Availability of data and materials
drug used for painless GI endoscopy. However, during The datasets during and analyzed during the current study are available
from the corresponding author on reasonable requests.
its clinical in our study, several patients experienced fa-
tigue phenomenon lasting more than 1 h. In C11- labeled Ethics approval and consent to participate
positron emission tomography, it was found that exer- The Ethics Committee at the First Affiliated Hospital of Wenzhou Medical
University approved this prospective trial, and the trial was registered at the
cise can evoke and be related to changes in μ receptors Chinese Clinical Trial Registry (ChiCTR1900022780, 2019). Before study entry,
in most of the limbic system, and deactivation of the μ all subjects reviewed and signed an informed consent document explaining
receptor is the main reason for fatigue [22]. There was a the study procedures and potential risks.
strong correlation between grip strength and fatigue,
Consent for publication
after adjustment for age and height, that was independ- Not applicable.
ent of physical activity levels [23, 24]. Butorphanol re-
sulted in less fatigue than sufentanil according to both Competing interests
Xiaona Zhu, Limei Chen, Shuang Zheng, and Linmin Pan declare no
subjective and objective indicators. We speculated that competing interests.
butorphanol can reduce visceral pain in GI endoscopy,
as it targets the kappa receptor and decreases deactiva- Received: 5 February 2020 Accepted: 27 April 2020
tion of the μ receptor, thereby reducing postoperative
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