Int J Clin Exp Med 2019;12(12):13651-13658 www.ijcem.com /ISSN:1940-5901/IJCEM0102240

Original Article A comparison of dezocine and dexmedetomidine with NSAIDs in burn wound dressing change procedures: a prospective, double-blind, randomized clinical trial

Le Li1, Pei Zhao2, Ran Zhao3

1Department of Orthopedic , Qilu Hospital of Shandong University, Jinan, Shandong, China; 2Department of Cardiac Center, Huaihe Hospital of Henan University, Kaifeng, Henan, China; 3Department of Burns and Recon- structive Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China Received September 12, 2019; Accepted November 8, 2019; Epub December 15, 2019; Published December 30, 2019

Abstract: Aim: To compare the effect of dezocine and dexmedetomidine with NSAIDs in burn wound dress- ing change procedures. Methods: A total of sixty adult burn patients from 2018/10/01 to 2019/04/30 in Shandong Provincial Hospital, China, were enrolled. At each dressing change procedure time, each patient randomly received one group of drugs from three dosage regimens: A (dezocine + dexmedetomidine); B (dezocine + placebo); C (flur- biprofen + placebo). Before the wound care procedure, the vital signs (BP, HR, SpO2), the Present Pain Index (PPI) (0-10), and the Willingness of Dressing Change (WDC) (-5-5) were recorded. During the process, HR, Other-evaluated

Pain Index (OEPI) (0-4), and the procedure duration (min) were recorded. Afterwards, the BP, HR, SpO2, VAS scores (0, 10, 30, 60, 120 min), and the side effects were recorded. Results: The background pain (PPI) was statistically undifferentiated among the groups. However, the patients’ WDC was significantly higher in groups A (1.1) and B (1.3) compared to group C (-0.7). Moreover, during the procedures, the OEPI was significantly lower in groups A (1.6) and B (1.6) than in group C (2.0). As to the vital signs, the elevations of Bp (-9.4±1.1 mmHg, 6.9±1.0 mmHg and 14.3±2.2 mmHg) and HR (-0.3±1.2 bpm, 10.1±1.4 bpm and 7.6±2.4 bpm), as well as the decreases in SpO2 (-0.2±0.2%, -0.8±0.2%, and -1.6±0.4%) were much smaller in group A. The VAS scores of the five time points after- wards showed a clear decreasing trend, but there were no significant inter-group differences. Inappetence (16.0%) was the most common undesirable symptom, which was undifferentiated between the groups, but somnolence was found to be significantly higher in group A (8.6%). Conclusion: Compared to , dezocine reduced pain dur- ing the wound care procedures and improved the patients’ willingness beforehand. Dexmedetomidine decreased the hemodynamic fluctuations but didn’t show any adjuvant analgesic effect.

Keywords: Sedative, , analgesic, dressing change, registered trial, pain relieving

Introduction tiple drug regimens have been recommended [4-7]. However, in China, most effective analge- Pain is the most unpleasant feeling for burn sics, like and derivatives, patients throughout the curing, healing and cannot be used without monitoring by an anes- rehabilitation processes. Acute sharp pain can thetist. Due to the serious national shortage of cause multiple immediate physical reactions, anesthetists, the pain management of Chinese like wound bleeding, hypertension, tachycar- burn patients is largely insufficient [8]. Thus, as dia, and tachypnea, etc. [1]. Repetitive uncon- the biggest provincial burn center, we keep try- trolled pain can also lead to psychological reac- ing to explore new analgesic regimens that are tions like anxiety, , depression, etc., both available and effective in non-ICU burn and can even raise the long-term incidence of wards. suicide [2, 3]. As a κ- and μ-antagonist to opioid recep- Dressing change, an essential care procedure tors, dezocine has a strong analgesic effect, a for burn patients, always comes with unbear- relatively low addictive effect, and few able pain. Pharmacological treatment is the pri- effects of dysphoria and [9]. In mary approach to managing it, and various mul- addition, dexmedetomidine, a highly selective Pain management of wound care procedures

org.cn (ChiCTR-OPh-160089- 68). Sixty patients were en- rolled and a written informed consent was signed by every participant.

Study design

This study was a prospective, double-blind, randomized clini- cal trial. Three drug regimens of A (dezocine and dexmede- tomidine), B (dezocine and sa- line), and C (flurbiprofen and saline) were designed.

Inclusion and exclusion crite- ria

Only hospitalized adult patients (aged 18 to 60) with fresh (less than 48 hours after injury) burn wounds of 10% to 40% TBSA (total body surface area) could be enrolled. The exclu- sion criteria included: HR < 70/ min, BP < 90/60 mmHg, aller- gic to opioid drugs, history of craniocerebral diseases, cho- ledocholithiasis, arrhythmia, Figure 1. Flowchart of the three dosage regimens. hypoxia, or chronic respiratory disease, expected surgery or agonist of α2-adrenrgic receptors, has a strong discharge within a week. Also, the study of par- antiadrenergic sedative effect, a weak analge- ticipants with a residual wound of less than 5% sic effect, and it avoids the risk of respiratory TBSA would be terminated. depression [10]. Published studies have report- ed it can enhance the analgesic effect of opi- Random method oids and decrease the respiratory and gastroin- A table of 100 rows and 100 columns was testinal side effects by reducing the consu- designed, which respectively represented the mption of [11]. Flurbiprofen is a typical patients’ enrollment numbers and the dressing intravenous NSAID, commonly used to relieve changing times. The table was filled with a ran- acute pain. domized sequence of 1, 2 and 3, respectively indicating the designed three drug regimens of We designed this prospective double-blind ran- A, B, and C. This table was blinded to both the domized clinical study to objectively compare clinicians and patients. the analgesic effects of dezocine, dexmedeto- midine, and flurbiprofen in burn wound care Regimens and dosages (Figure 1) procedures. In regimen A, dezocine (5 mg) and dexmedeto- Methods midine (1.0 mgkg-1) were given at 15 min be- fore the procedure, and during the procedure, Preparations dezocine (5 mg) and dexmedetomidine (1.0 mgkg-1h-1) were continuously given. In regimen We conducted this study from 10/01/2018 to B, only dezocine was given before (5 mg) and 04/30/2019, after receiving approval from our during (5 mg) the procedure. In regimen C, flur- institutional ethics review board. This study biprofen was given before (50 mg) and during was previously registered at http://www.chictr. (50 mg) the procedure.

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Table 1. Records of this study Items Units or Explanations Twenty minutes before dressing change BP (Blood pressure) mmHg HR (Heart rate) bpm

SpO2 (Oxygen saturation) % PPI (Present Pain Index) Eleven degrees (0-10): From absolute painless (0) to extremely painful (10). Immediately before dressing change WDC (Willingness of Dressing change) Eleven degrees (-5-5): From extremely unwilling (-5) to extremely willing (5). During dressing change HR (Heart rate) bpm OEPI (Other-evaluated Pain Index) Five degrees (0-4): Little (0, eased, peaceful), slight (1, frown, teeth gritting, slight dodge), moderate (2, incontrollable sound, intentional dodge), severe (3, yelling, cry, refuse to cooperate) and extremely severe (4, faint or other symptoms forcing dressing-change to stop). Duration min Immediately after dressing change (0 min) BP (Blood pressure) mmHg HR (Heart rate) bpm

SpO2 (Surplus pulse of Oxygen) % VAS (Visual analogue scale) pain score mm/100 mm Four time points after dressing change (10, 30, 60, 120 min) VAS (Visual analogue scale) pain score mm/100 mm Undesirable symptoms Headache, dizziness, nausea, vomiting, somnolence, inappetence, hallucina- tion, bradycardia, asthma, disorientation and uroschesis, etc.

Records (Table 1) PPI, from 0 (absolutely painless) to 10 (extr- emely painful). Vital signs: The vital signs of blood pressure (BP), heart rate (HR), and oxygen saturation At the moment immediately before entering the dressing room, the patients were asked to (SpO2) were recorded at two time points: twenty minutes before (t0) and immediately after (t1) score the WDC, reflecting their psychological the procedure. burden of the upcoming wound care proce- dures, from -5 (extremely unwilling) to 5 (ex- The mean blood pressure (mBP) was calculated tremely willing). through a formula (α), from the systolic pres- sure (sBP) and the diastolic pressure (dBP). Other-evaluated Pain Index (OEPI): To evaluate the pain during the procedures objectively, we mBP = dBP + (sBP-dBP)/3 (α) designed the OEPI, scored by an objective observer, based on patients’ facial expressions To evaluate the changes of BP, HR, and SpO 2 and physical reactions. We categorized the before and after the dressing change, three pain into one of five degrees (0-4): little (eased, new variables of ΔBP, ΔHR, and ΔSpO were 2 peaceful), slight (frown, teeth gritting, slight used, which were calculated through the for- dodge), moderate (incontrollable sound, inten- mula (β, γ, and δ) below. tional dodge), severe (yelling, crying, refusing to ΔBP = mBP - mBP (β) cooperate), extremely severe (fainting or other (t1) (t0) symptoms stopping the procedure), which were

ΔHR = HR(t1) - HR(t0) (γ) scored as 0 to 4, respectively.

ΔSpO2 = SpO2(t1) - SpO2(t0) (δ) Duration of the procedure: The duration of the dressing change procedure was recorded. Present Pain Index (PPI) and Willingness of Dressing Change (WDC): To evaluate the Visual analogue score (VAS) for pain: At the background pain, at 20 min before the proce- time points of 0 min (t1), 10 min (t2), 30 min dure, the patients were asked to score their (t3), 60 min (t4) and 120 min (t5) after their

13653 Int J Clin Exp Med 2019;12(12):13651-13658 Pain management of wound care procedures

Table 2. Basic information of the participants while the ranked data (PPI, WDC, OEPI) were Item Results analyzed using a Kruskal-Wallis test, a non- parametric test. A P value less than 0.05 indi- Number 60 cated a significant difference among the Male/Female 33/27 groups. Age 34.9±9.3 (y) BMI 23.5±3.7 (kg/m2) Results Burnt surface area 26.6±7.4 (%TBSA) Times of dressing change 7.3±2.2 Demographics and wound information (Tables 2, 3) Total person-time of dressing change 438 We observed total of 438 dressing change pro- Table 3. Information on the burn wounds cedures in 60 patients (33 males and 27 females) in this study, 7.3±2.2 procedures per Items Number Percentage (%) patient. Of these patients, the mean age was Wound Depth 34.9±9.3 y, the BMI was 23.5±3.7 kg/m2, and First to second degree 4 6.7 the mean burnt surface area was 26.6±7.4% Second degree 22 36.7 TBSA. Second to third degree 32 53.3 About 90% of the wounds were only or mainly Fourth degree 2 3.3 partial burns. More than half of the patients Location were injured at the back, trunk, or the upper or Back 42 70.0 lower limbs. About half of the cases were Trunk 34 56.7 caused by flames, and about one fourth were Head 12 20.0 related to scalds. Upper limb 32 53.3 Lower limb 34 56.7 Comparison of the PPI, WDC and OEPI (Figure 2A) Causes Explosion 10 16.7 Before the procedure began, the PPIs (Present Flame 28 46.6 Pain Index, 0-10) of groups A, B, and C were Scald 16 26.7 2.5, 3.0, and 2.4, respectively, and no signifi- Chemical fluid 4 6.7 cant difference was found among their rank Electricity 2 3.3 means (103.7, 123.6, 104.5) through the Kruskal-Wallis test (P=0.058). procedures, the patients were asked to de- Before entering the dressing changing room, scribe their pain by choosing a point on a 100 the patients’ WDC (Willingness of Dressing mm line, and the length of the line’s left part Change, -5-5) was found to be significantly was recorded as the VAS score. higher in groups A (1.1) and B (1.3) compared to group C (-0.7), and the p value was 0.000 as Undesirable symptoms: Within two hours after determined by the Kruskal-Wallis test (rank the procedure, multiple possible undesirable means: 129.1, 135.5, 65.8). symptoms were checked and recorded, includ- ing headache, dizziness, nausea, vomiting, so- During the dressing change procedure, the mnolence, inappetence, , brady- OEPI (Other-Evaluated Pain Index, 0-4) was cardia, asthma, disorientation, and uroschesis, significantly lower in groups A (1.6) and B (1.6) etc. compared to group C (2.0), and the p value was 0.002 as determined by the Kruskal-Wallis test Statistical analysis (rank means: 96.7, 101.4, 127.6).

All the primary data were recorded on printed Comparison of the ΔBP, ΔHR and ΔSpO2 (Fig- case report forms, which were then organized ure 2B) using Microsoft EXCEL and statistically ana- lyzed using SPSS 19.0. The measurement data Compared to the basal level, after the dressing

(BP, HR, SpO2, duration, VAS) were analyzed changing procedures, the BP of groups A, B, using a one-way analysis of variance (ANOVA), and C increased -9.4±1.1 mmHg, 6.9±1.0

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SpO2 in group C, compared to groups A and B (P=0.000).

VAS score after the dressing change (Figure 2C)

The VAS scores of five time points (t1-t5) after the proce- dures showed a clear decreas- ing trend along with time.

Specifically, the VAS(t2), VAS(t3),

and VAS(t4) of group B were sig- nificantly lower than those of group C.

Undesirable symptoms (Table 4)

The most common symptom was inappetence (16.0%), wh- ich was undifferentiated am- ong the groups. The second most common symptom was somnolence (8.6%), which was found to be significantly higher in group A. No other symptoms occurred surpassed 5.0% or showed a difference among the groups.

The relationship between ΔHR and the duration of the dress- ing change (Figure 3)

Since the dexmedetomidine was given to each patient at 1.0 ug/kg-1h-1, the duration of Figure 2. A. The PPI (Present Pain Index), WDC (Willingness of Dressing the procedure was positively Change), and OEPI (Other-Evaluated Pain Index) of the three groups. B. correlated with the total Changes in the vital signs (HR, Bp, and SpO ) before and after the proce- 2 infused dosage. To evaluate dures. C. The mean VAS pain scores of the three groups at five time points whether or not the anti-adren- after the dressing change. *: P value less than 0.05. ergic effects of dexmedetomi- dine were dose-dependent, we mmHg, and 14.3±2.2 mmHg, respectively, and analyzed the relationship between ΔHR and the the ΔBP of group A was significantly lower than length of time of the procedure with regimen A, it was in groups B and C (P=0.000). but no correlation was found (R2=0.001, P=0.961 > 0.05). Similarly, the ΔHR was -0.3±1.2 bpm in group A, 10.1±1.4 bpm in group B, and 7.6±2.4 bpm Discussion in group C, and the value of group A was signifi- cantly lower than those of groups B and C This trial was designed to explore a practical (P=0.000). and safe analgesic regimen for burn patients. We chose dezocine and dexmedetomidine

In addition, the ΔSpO2 of groups A, B, and C was based on their pharmacological effects and on -0.2±0.2%, -0.8±0.2%, and -1.6±0.4%, respec- published studies about them [9, 12]. However, tively, and there was a significant decrease of what we actually found was partly unexpected.

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Table 4. Occurrence of the undesirable symp- been proven, evidently. Therefore, for a relative- toms ly long period, we should maintain a cautious Items Percentage (%) attitude towards this drug, in order to monitor its long-term, systemic outcomes. headache 1.8 dizziness 2.3 Since dezocine has been widely used to relieve nausea 5.0 post-operative pain, cancer-related pain, and vomiting 0.0 pain related to clinical procedures [16-18], it somnolence 8.6*A seems an ideal analgesic for burn wound care inappetence 16.0 procedures. However, in our research, the hallucination 0.0 patients’ OEPIs were still slight to moderate after 10 mg of dezocine was given (groups A bradycardia 1.8 and B, mean score: 1.6), but it was mostly mod- asthma 2.7 erate (mean score: 2.0) in the placebo group disorientation 0.0 (C). To solve this problem, we would design uroschesis 0.0 future studies to explore more drug combina- Total: 438 person-time. *AThe occurrence of this item was tion possibilities. significantly higher in group A. Surprisingly, a previous infusion of dezocine (5 mg) could significantly increase patients’ will- First, we found dezocine to be an effective ingness to undergo the upcoming procedure. pain-reliever for the burn patients, reducing We think the possible explanations include: 1) their pain levels both during and after the Dezocine can decrease the background pain, dressing change. Moreover, a previous dezo- leading to a higher level of tolerance to upcom- cine infusion (15 min) can significantly improve ing pain; 2) Dezocine can react with opioid the patients’ willingness for a dressing change. receptors, which might bring a feeling of eupho- However, dexmedetomidine showed no adju- ria, and lessen fear and aversion. Other studies vant analgesic effect, but it can reduce elevat- have reported a similar stress-reduction effect ed Bp and HR and reduce tissue hypoxia (SpO2) of dezocine during abortion procedures [19]. during wound care procedures. About dexmedetomidine About dezocine Pharmacologically, dexmedetomidine should Dezocine is a mixed agonist-antagonist opioid, exhibit analgesic effects by reducing the secre- a full κ-receptor agonist and a partial μ-receptor tion of norepinephrine at the spinal level. agonist, and it is now the number one opioid Actually, lots of studies have reported its adju- painkiller prescribed in China, accounting for vant analgesic effects on other , like about 44% of the national opioid analgesics bupivacaine, fentanyl, flurbiprofen, etc. [20- market [13]. Dezocine is not classified as a 22]. However, in this study, no significant better controlled substance by the World Health Or- analgesic effect was seen in group A (dezocine ganization, and it is listed as a Category II psy- + dexmedetomidine), compared to group B chotropic drug in both China and the United (dezocine). The possible explanations include: States. Compared with other analgesics avail- 1) There is a ceiling effect of the drugs’ pain- able, dezocine has a more favorable tolerability, relieving ability, so the adjuvant analgesic effect including less respiratory depression, fewer could only be seen at a rather low dose of other gastrointestinal symptoms, and less cough and analgesics (like dezocine at 5 mg); 2) Dex- itch [9, 14, 15]. medetomidine could only reduce the consump- tion of other analgesics, but it cannot enhance Dezocine was first introduced to the market in their pain-relieving ability. More studies could 1990 by -Ayerst (now Pfizer) to treat peri- be performed in the future to verify the two operative pain. However, without giving a spe- hypotheses. cific reason, the manufacturer voluntarily with- drew it from the market in 2000 (http://www. Peri-operational physiological reactions were fda.gov/ohrms/dockets/98fr/091300c.htm) common, usually bringing hemodynamic fluctu- [13]. The FDA reported a possible side effect of ations [23]. For patients with chronic hyperten- cardiac toxicity of dezocine, but this has not sion, the dressing change procedure was a

13656 Int J Clin Exp Med 2019;12(12):13651-13658 Pain management of wound care procedures

the wound exudates, etc. [27], all of which cannot be previ- ously designed, possibly in- creasing the intra-group differ- ences, and relatively reducing the inter-group differences.

Conclusion

Compared to flurbiprofen, de- zocine can reduce the pain of wound care procedures and improve patients’ willingness to undergo the procedures beforehand. Dexmedetomidine can decrease the fluctuations Figure 3. No correlation was found between the procedure’s duration and of BP, HR and SaO but doesn’t ΔHR in group A, indicating the HR-reducing effect of dexmedetomidine was 2 not dose-dependent. show an adjuvant analgesic effect. definite dangerous scene of acute cardio-cere- Acknowledgements brovascular events. Dexmedetomidine has un- specific targeted effects to heart and blood This study was supported by a grant from the vessels, mostly seen as side effects to be pre- Shandong Provincial Natural Science Fund vented [24]. However, in our trial, we found it (ZR2016HB46), China. could significantly reduce the increases in HR and Bp, avoiding tissue hypoxia, which actually Disclosure of conflict of interest reduces the risk of acute cardio-cerebrovascu- None. lar events. Also, based on our analysis (Figure 3), the HR decrease was not dose-dependent, Address correspondence to: Ran Zhao, Department indicating that it would be safe even when the of Burns and Reconstructive Surgery, Shandong wound care procedure was quite long. It should Provincial Hospital Affiliated to Shandong Univer- be noticed that the dexmedetomidine could sity, 324 Jingwu Road, Jinan 250021, Shandong, cause about a 10 mmHg’s Bp drop, so it is inap- China. Tel: +86-0531-68778158; E-mail: zhaoran- propriate for patients with the potential for [email protected] shock. In other studies [25, 26], dexmedetomi- dine also showed a significant reducing effect References to Bp and HR. [1] de Castro RJ, Leal PC and Sakata RK. Pain Although dexmedetomidine is now mostly used management in burn patients. Braz J Anesthe- in ICUs and operating rooms, it has a high siol 2013; 63: 149-153. potential to be used in non-ICU wards, covering [2] James DL and Jowza M. Principles of burn pain the elderly and children [10]. This drug has management. Clin Plast Surg 2017; 44: 737- been the subject of much research recently, 747. but its intravenous use in general wards has [3] Retrouvey H and Shahrokhi S. Pain and the thermally injured patient-a review of current not been sufficiently studied [12]. Our research therapies. J Burn Care Res 2015; 36: 315- reports on the safety of using dexmedetomi- 323. dine without monitoring facilities. [4] Upton D and Andrews A. The impact of stress at dressing change in patients with burns: a Limitations review of the literature on pain and itching. Wounds 2014; 26: 77-82. In this study, we didn’t design groups of differ- [5] Bell C and McCarthy G. The assessment and ent drug doses, failing to reveal the relationship treatment of wound pain at dressing change. between the drug dosage and the clinical Br J Nurs 2010; 19: S4, S6, S8 passim. effects. Besides, the pain related to the dress- [6] Myers R, Lozenski J, Wyatt M, Peña M, Northrop ing change process was largely dependent on K, Bhavsar D and Kovac A. Sedation and anal- the skills of the clinicians, the type of dressings, gesia for dressing change: a survey of Ameri-

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