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The Effect of Dexmedetomidine on the Acute Pain After Cardiothoracic Surgeries: A Systematic Review

Abstract

Introduction:

Acute post-operative pain remains a troublesome complication of cardiothoracic surgeries. Several randomized controlled trials have examined the efficacy of dexmedetomidine as a single or as an adjuvant agent before, during and after surgery. However, no evidence-based conclusion has been reached regarding the advantages of dexmedetomidine over the other analgesics.

Objective:

To review the effect of dexmedetomidine on acute post-thoracotomy/sternotomy pain.

Methods:

Medline, SCOPUS, Web of Science, and Cochrane databases were used to search for randomized controlled trials that investigated the analgesia effect of dexmedetomidine on post-thoracotomy/sternotomy pain in adults' patients. The outcomes were postoperative pain intensity or incidence, postoperative analgesia duration, and the number of postoperative analgesic requirements.

Results:

From 1789 citations, 12 trials including 804 subjects met the inclusion criteria. Most studies showed that pain score was significantly lower in the dexmedetomidine group up to 24 hours after surgery. Two studies reported the significant lower postoperative analgesia requirements and one study reported the significant lower incidence of acute pain after surgery in dexmedetomidine group. Ten studies found that the total consumption of narcotics was significantly lower in the dexmedetomidine group. The most reported complications of dexmedetomidine were nausea/vomiting, bradycardia and hypotension.

Conclusion:

Dexmedetomidine can be used as a safe and efficient analgesic agent for reducing the postoperative pain and analgesic requirements up to 24 hours after cardiothoracic surgeries. However, further well-designed trials are needed to find the optimal dosage, route, time, and duration of dexmedetomidine administration.

Keywords:
Pain, Postoperative; Thoracic Surgery; Cardiovascular Surgical Procedures; Thoracotomy; Sternotomy; Adrenergic Alpha-2 Receptor Agonists; Dexmedetomidine; Analgesia

Abbreviations, acronyms & symbols CABG = Coronary artery bypass graft CTS = Cardiothoracic surgeries DEX = Dexmedetomidine FDA = Food and Drug Administration ICU = Intensive care unit NRS = Numerical rating scales PCIA = Patient controlled intravenous analgesia POP = Postoperative pain RCTs = Randomized controlled trials SUF = Sufentanil VAS = Visual analogue scale VRS = Verbal rating scales

INTRODUCTION

Acute pain is one of the intense complications after cardiothoracic surgeries (CTS), which can delay patients' recovery and may increase patients' morbidity and mortality[11 Attri JP, Kaur R, Kaur H, Makhni R. Post thoracotomy pain management: a review of current available modalities. Northern J ISA. 2016;1(1):7-10.]. Acute pain after CTS has been determined as a main risk factor in the pathogenesis of numerous postoperative side effects such as respiratory failure[22 Rodriguez-Aldrete D, Candiotti KA, Janakiraman R, Rodriguez-Blanco YF. Trends and new evidence in the management of acute and chronic post-thoracotomy pain: an overview of the literature from 2005 to 2015. J Cardiothorac Vasc Anesth. 2016;30(3):762-72.,33 Gerner P. Post-thoracotomy pain management problems. Anesthesiol Clin. 2008;26(2):355-vii.]. Inadequately controlling the postoperative pain (POP) increase the risk of pulmonary complications due to the diaphragmatic dysfunction and incapability of patients to take large-volume breaths[44 Gottschalk A, Cohen SP, Yang S, Ochroch E. Preventing and treating pain after thoracic surgery. Anesthesiology. 2006;104(3):594-600.]. Consequently, effective pain management can play a vital role in reducing patients discomfort and, therefore, it should be a prerequisite for promoting respiratory and cardiac function of patients undergoing CTS[55 Komatsu T, Sowa T, Takahashi K, Fujinaga T. Paravertebral block as a promising analgesic modality for managing post-thoracotomy pain. Ann Thorac Cardiovasc Surg. 2014;20(2):113-6.,66 Maxwell C, Nicoara A. New developments in the treatment of acute pain after thoracic surgery. Curr Opin Anaesthesiol. 2014;27(1):6-11.].

In last decades, several pharmacological and nonpharmacological interventions have been developed to reduce acute POP including opioids, paravertebral and epidural infusion of local anesthetics, sedatives, nerve blockades, intrapleural analgesia, nerve stimulation, ketamine, gabapentinoids, selective COX-2 inhibitors, nonsteroidal anti-inflammatory drugs, alpha2- agonists, and aromatherapy[22 Rodriguez-Aldrete D, Candiotti KA, Janakiraman R, Rodriguez-Blanco YF. Trends and new evidence in the management of acute and chronic post-thoracotomy pain: an overview of the literature from 2005 to 2015. J Cardiothorac Vasc Anesth. 2016;30(3):762-72.,77 Heidari Gorji MA, Ashrastaghi OG, Habibi V, Charati JY, Ebrahimzadeh MA, Ayasi M. The effectiveness of lavender essence on strernotomy related pain intensity after coronary artery bypass grafting. Adv Biomed Res. 2015;4:127.]. However, the effectiveness and efficacy of those interventions are variable among studies. Many of those interventions, particularly opioids, have several side effects that can impair cardiac and respiratory function following surgery[11 Attri JP, Kaur R, Kaur H, Makhni R. Post thoracotomy pain management: a review of current available modalities. Northern J ISA. 2016;1(1):7-10.,22 Rodriguez-Aldrete D, Candiotti KA, Janakiraman R, Rodriguez-Blanco YF. Trends and new evidence in the management of acute and chronic post-thoracotomy pain: an overview of the literature from 2005 to 2015. J Cardiothorac Vasc Anesth. 2016;30(3):762-72.]. In addition, the benefits of thoracic epidural analgesia as a gold standard for controlling POP have been questioned because of higher risk of severe cardiovascular complications[88 Rice DC, Cata JP, Mena GE, Rodriguez-Restrepo A, Correa AM, Mehran RJ. Posterior intercostal nerve block with liposomal bupivacaine: an alternative to thoracic epidural analgesia. Ann Thorac Surg. 2015;99(6):1953-60.]. Hence, acute pain management continues to be a challenge in CTS.

Recently, some opioid-sparing analgesics such as dexmedetomidine (DEX) have demonstrated a promising opportunity to decrease the postoperative complications particularly impairment of respiratory function[99 Peng K, Liu HY, Wu SR, Cheng H, Ji FH. Effects of combining dexmedetomidine and opioids for postoperative intravenous patient-controlled analgesia: a systematic review and meta-analysis. Clin J Pain. 2015;31(12):1097-104.,1010 Fan W, Yang H, Sun Y, Zhang J, Li G, Zheng Y, et al. Comparison of the pro-postoperative analgesia of intraoperative dexmedetomidine with and without loading dose following general anesthesia: a prospective, randomized, controlled clinical trial. Medicine (Baltimore). 2017;96(7):e6106.]. DEX has been recommended for sedating agitated patients in the intensive care unit (ICU)[1111 Barr J, Fraser GL, Puntillo K, Ely EW, Gélinas C, Dasta JF, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1):263-306.], because it does not depress the respiratory and cognitive dysfunctions[99 Peng K, Liu HY, Wu SR, Cheng H, Ji FH. Effects of combining dexmedetomidine and opioids for postoperative intravenous patient-controlled analgesia: a systematic review and meta-analysis. Clin J Pain. 2015;31(12):1097-104.,1212 Wu HH, Wang HT, Jin JJ, Cui GB, Zhou KC, Chen Y, et al. Does dexmedetomidine as a neuraxial adjuvant facilitate better anesthesia and analgesia? A systematic review and meta-analysis. PLoS One. 2014;9(3):e93114.].

Several randomized controlled trials (RCTs) have examined the efficacy of DEX on POP after CTS. However, a clear advantage of DEX over other analgesics has not been evident so far. Therefore, the aim of this study was to review the effectiveness of DEX for reducing the acute post-thoracotomy/sternotomy pain in comparison with other analgesics.

METHODS

This systematic review was accomplished in accordance to the PRISMA: the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines[1313 Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8(5):336-41.]. Our PICOS research question was formulated as follows: (P) patients undergoing thoracotomy or sternotomy; (I) dexmedetomidine; (C) placebo or other analgesic drug; (O) postoperative pain; (S) trial.

Eligibility Criteria

Inclusion criteria were: (1) Study designed with RCT; (2) Patients undergoing thoracotomies or sternotomy; (3) Study with at least two groups that compared perioperative (preoperative, intraoperative, or postoperative) administration of DEX with other analgesic agents or placebo; (4) DEX with different routes, dosage, frequency, and duration of administration; (5) POP should be one of the study outcomes.

Conference proceedings, abstracts, letters, and commentaries were excluded. In addition, quasi-randomized trials, nonrandomized trials, studies not published in English and animal trials were excluded.

Outcomes Measurement

Primary outcomes were (1) POP intensity measured by visual analogue scale (VAS) or verbal or numerical rating scales (VRS or NRS) or POP incidence; (2) number of postoperative narcotic and/or analgesic requirements; (3) postoperative analgesia duration. Secondary outcomes were: (1) number of DEX-associated major adverse events.

Information Sources

A predefined Medline-based strategy was developed to search the following databases (Appendix 1 APPENDIX A Keywords for PubMed ("adrenergic alpha-2 receptor agonists"[MeSH Terms] OR dexmedetomidine[Title/Abstract]) AND ("pain"[MeSH Terms] OR pain[Title/Abstract] OR analgesia[Title/Abstract] OR analgesic[Title/Abstract]) AND (Clinical Trial[ptyp] AND "humans"[MeSH Terms] AND English[lang]) AND (Clinical Trial[ptyp] AND "humans"[MeSH Terms] AND English[lang]) =294 SCOPUS (2017-June-15) TITLE-ABS-KEY ( dexmedetomidine ) OR TITLE-ABS-KEY ( "adrenergic alpha 2 receptor agonist" ) AND TITLE-ABS-KEY ( pain ) AND ( LIMIT-TO ( DOCTYPE , "ar" ) OR LIMIT-TO ( DOCTYPE , "ip" ) ) AND ( LIMIT-TO ( EXACTKEYWORD , "Human" ) OR LIMIT-TO ( EXACTKEYWORD , "Humans" ) ) AND ( LIMIT-TO ( LANGUAGE , "English" ) ) AND ( LIMIT-TO ( SRCTYPE , "j" ) )=701 ISI (2017-June-15) (TS=(dexmedetomidine AND pain)) AND LANGUAGE: (English) AND DOCUMENT TYPES: (Article)=617 Indexes=SCI-EXPANDED, SSCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years Cochrane (2017-June-17) #1 MeSH descriptor: [Pain] explode all trees #2 MeSH descriptor: [Adrenergic alpha-2 Receptor Agonists] explode all trees #3 MeSH descriptor: [Dexmedetomidine] explode all trees #4 (#1 and #2) or (#1 and #4) in Trials= 165 ): Medline via PubMed, SCOPUS, Institute for Scientific Information (ISI) Web of Science, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. Reference sections of the included trials, published meta-analyses, and pertinent review articles were hand searched to find additional articles.

Search Strategy

Both subject headings and free-text terms were used in searching the databases. The search strategy contained two components: (1) dexmedetomidine OR adrenergic alpha-2 receptor agonists; (2) pain OR analgesia. These two components were combined using the Boolean operator, "AND", to obtain any link between them. We searched the databases without publication date restriction from the inception of each database until June 12, 2017.

Study Selection and Data Collection Process

Two authors (FHK-HS) searched the databases using search strategy (n=1789). They independently screened the titles and abstracts of retrieved studies against the predetermined inclusion criteria for selecting relevant articles (1221 title rejected straightaway because of duplicate or irrelevant study. Reasons for excluding an article were documented. The full-text of potentially relevant articles, which met the inclusion criteria, was reviewed for comprehensive assessment against the inclusion criteria. Disagreement about study selection was resolved by discussion and consensus with the third author (VH). In cases that additional data was required, the corresponding author of the study was contacted. Each included study was independently evaluated by three authors (VH-FHK-HS) for content. Then, data extraction table was completed by relevant data of studies that met the inclusion criteria. None of the review authors (VH-FHK-HS) was blinded to reference details during the study selection process.

Assessing Risk of Bias

The methodological quality of the selected studies was independently evaluated by two authors (VH-FHK) using the Cochrane Collaboration's tool for assessing risk of bias (Table 1). As recommended by tool developer[2626 Higgins J, Green S. Cochrane handbook for systematic reviews of interventions: the Cochrane Collaboration; 2011 [updated March 2011; cited 2017 June]. 5.1.0: Available from: http://handbook.cochrane.org.
http://handbook.cochrane.org...
], we did not determine the total quality score for each domain, however, in interpreting the results, the limitations of each study were considered.

Table 1
Cochrane Collaboration's tool for assessing risk of bias.

RESULTS

Study Selection

From 1789 citations identified through database searches, 124 articles were examined in more detail. Twelve studies met the inclusion criteria[1414 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.

15 Dutta V, Kumar B, Jayant A, Mishra AK. Effect of continuous paravertebral dexmedetomidine administration on intraoperative anesthetic drug requirement and post-thoracotomy pain syndrome after thoracotomy: a randomized controlled trial. J Cardiothorac Vasc Anesth. 2017;31(1):159-165.

16 Jabbary Moghaddam M, Barkhori A, Mirkheshti A, Hashemian M, Amir Mohajerani S. The effect of pre-emptive dexmedetomidine on the incidence of post-thoracotomy pain syndrome in patients undergoing coronary artery bypass grafting. Anesth Pain Med. 2016;6(3):e36344.

17 Cai X, Zhang P, Lu S, Zhang Z, Yu A, Liu D, et al. Effects of intraoperative dexmedetomidine on postoperative pain in highly nicotine-dependent patients after thoracic surgery: a prospective, randomized, controlled trial. Medicine (Baltimore). 2016;95(22):e3814.

18 Priye S, Jagannath S, Singh D, Shivaprakash S, Reddy DP. Dexmedetomidine as an adjunct in postoperative analgesia following cardiac surgery: a randomized, double-blind study. Saudi J Anaesth. 2015;9(4):353-8.

19 Ren C, Zhang X, Liu Z, Li C, Zhang Z, Qi F, et al. Effect of intraoperative and postoperative infusion of dexmedetomidine on the quality of postoperative analgesia in highly nicotine-dependent patients after thoracic surgery: a consort-prospective, randomized, controlled trial. Medicine (Baltimore). 2015;94(32):e1329.

20 Ramsay MA, Newman KB, Leeper B, Hamman BL, Hebeler RF Jr, Henry AC, et al. Dexmedetomidine infusion for analgesia up to 48 hours after lung surgery performed by lateral thoracotomy. Proc (Bayl Univ Med Cent). 2014;27(1):3-10.

21 Abdel-Meguid ME. Dexmedetomidine as anesthetic adjunct for fast tracking and pain control in off-pump coronary artery bypass. Saudi J Anaesth. 2013;7(1):6-8.

22 Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M. Effect of epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilation. Acta Anaesthesiol Scand. 2010;54(6):703-9.

23 Ghandi I, Alavi SM, Babaee T, Ghadrdoost B, Bakhshandeh H, Ziyaeifard M, et al. The analgesic effect of morphine and dexmedetomidine intravenous patient-controlled analgesia method to control pain after open cardiac surgery: a randomized control trial. Arch Crit Care Med. 2015;1(3):e6453.

24 Wahlander S, Frumento RJ, Wagener G, Saldana-Ferretti B, Joshi RR, Playford HR, et al. A prospective, double-blind, randomized, placebo-controlled study of dexmedetomidine as an adjunct to epidural analgesia after thoracic surgery. J Cardiothorac Vasc Anesth. 2005;19(5):630-5.
-2525 Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 1999;54(12):1136-42.]. The total number of subjects was 804 (DEX, n=419; Control, n=385). Sample sizes ranged from 14 to 54 subjects for each group. The number of patients undergoing general surgery from the total sample size in one study was excluded[2525 Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 1999;54(12):1136-42.]. The flow chart to select the final 12 trials is detailed in Figure 1.

Fig. 1
PRISMA flow diagram of search strategy and study selection.

Study Characteristics

All twelve trials were RCT with two parallel groups, except for one study that consist of two groups with different dosages of DEX and a third control group[1919 Ren C, Zhang X, Liu Z, Li C, Zhang Z, Qi F, et al. Effect of intraoperative and postoperative infusion of dexmedetomidine on the quality of postoperative analgesia in highly nicotine-dependent patients after thoracic surgery: a consort-prospective, randomized, controlled trial. Medicine (Baltimore). 2015;94(32):e1329.]. Among the 12 RCTs, the VAS was the most frequently used scale to determine the intensity of POP. Eight studies used the VAS[1414 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.,1515 Dutta V, Kumar B, Jayant A, Mishra AK. Effect of continuous paravertebral dexmedetomidine administration on intraoperative anesthetic drug requirement and post-thoracotomy pain syndrome after thoracotomy: a randomized controlled trial. J Cardiothorac Vasc Anesth. 2017;31(1):159-165.,1818 Priye S, Jagannath S, Singh D, Shivaprakash S, Reddy DP. Dexmedetomidine as an adjunct in postoperative analgesia following cardiac surgery: a randomized, double-blind study. Saudi J Anaesth. 2015;9(4):353-8.,2020 Ramsay MA, Newman KB, Leeper B, Hamman BL, Hebeler RF Jr, Henry AC, et al. Dexmedetomidine infusion for analgesia up to 48 hours after lung surgery performed by lateral thoracotomy. Proc (Bayl Univ Med Cent). 2014;27(1):3-10.,2121 Abdel-Meguid ME. Dexmedetomidine as anesthetic adjunct for fast tracking and pain control in off-pump coronary artery bypass. Saudi J Anaesth. 2013;7(1):6-8.,2323 Ghandi I, Alavi SM, Babaee T, Ghadrdoost B, Bakhshandeh H, Ziyaeifard M, et al. The analgesic effect of morphine and dexmedetomidine intravenous patient-controlled analgesia method to control pain after open cardiac surgery: a randomized control trial. Arch Crit Care Med. 2015;1(3):e6453.

24 Wahlander S, Frumento RJ, Wagener G, Saldana-Ferretti B, Joshi RR, Playford HR, et al. A prospective, double-blind, randomized, placebo-controlled study of dexmedetomidine as an adjunct to epidural analgesia after thoracic surgery. J Cardiothorac Vasc Anesth. 2005;19(5):630-5.
-2525 Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 1999;54(12):1136-42.], three used the NRS[1616 Jabbary Moghaddam M, Barkhori A, Mirkheshti A, Hashemian M, Amir Mohajerani S. The effect of pre-emptive dexmedetomidine on the incidence of post-thoracotomy pain syndrome in patients undergoing coronary artery bypass grafting. Anesth Pain Med. 2016;6(3):e36344.,1717 Cai X, Zhang P, Lu S, Zhang Z, Yu A, Liu D, et al. Effects of intraoperative dexmedetomidine on postoperative pain in highly nicotine-dependent patients after thoracic surgery: a prospective, randomized, controlled trial. Medicine (Baltimore). 2016;95(22):e3814.,1919 Ren C, Zhang X, Liu Z, Li C, Zhang Z, Qi F, et al. Effect of intraoperative and postoperative infusion of dexmedetomidine on the quality of postoperative analgesia in highly nicotine-dependent patients after thoracic surgery: a consort-prospective, randomized, controlled trial. Medicine (Baltimore). 2015;94(32):e1329.] and one of them used the VRS[2222 Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M. Effect of epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilation. Acta Anaesthesiol Scand. 2010;54(6):703-9.].

Patients' mean age among all trials was 55.89 years (range between 34.4 and 67.7 years). Trials included a total number of 566 (70.4%) male and 228 (28.4%) female, for the last 110 subjects. An error in reported data in one study was found[1414 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.] (Table 1) and one study did not report the male/female ratio. Generally, the number of male patients was greater than female.

No statistically significant difference was found between the DEX and control groups regarding the baseline characteristics of patients in all included studies. Table 2 depicts the details for perioperative data and anesthesia techniques.

Table 2
Preoperative data, monitoring and anesthesia.

Types of surgery were thoracic surgery (n=425)[1414 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.,1515 Dutta V, Kumar B, Jayant A, Mishra AK. Effect of continuous paravertebral dexmedetomidine administration on intraoperative anesthetic drug requirement and post-thoracotomy pain syndrome after thoracotomy: a randomized controlled trial. J Cardiothorac Vasc Anesth. 2017;31(1):159-165.,1717 Cai X, Zhang P, Lu S, Zhang Z, Yu A, Liu D, et al. Effects of intraoperative dexmedetomidine on postoperative pain in highly nicotine-dependent patients after thoracic surgery: a prospective, randomized, controlled trial. Medicine (Baltimore). 2016;95(22):e3814.,1919 Ren C, Zhang X, Liu Z, Li C, Zhang Z, Qi F, et al. Effect of intraoperative and postoperative infusion of dexmedetomidine on the quality of postoperative analgesia in highly nicotine-dependent patients after thoracic surgery: a consort-prospective, randomized, controlled trial. Medicine (Baltimore). 2015;94(32):e1329.,2020 Ramsay MA, Newman KB, Leeper B, Hamman BL, Hebeler RF Jr, Henry AC, et al. Dexmedetomidine infusion for analgesia up to 48 hours after lung surgery performed by lateral thoracotomy. Proc (Bayl Univ Med Cent). 2014;27(1):3-10.,2222 Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M. Effect of epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilation. Acta Anaesthesiol Scand. 2010;54(6):703-9.,2424 Wahlander S, Frumento RJ, Wagener G, Saldana-Ferretti B, Joshi RR, Playford HR, et al. A prospective, double-blind, randomized, placebo-controlled study of dexmedetomidine as an adjunct to epidural analgesia after thoracic surgery. J Cardiothorac Vasc Anesth. 2005;19(5):630-5.] and cardiac surgery (n=379)[1616 Jabbary Moghaddam M, Barkhori A, Mirkheshti A, Hashemian M, Amir Mohajerani S. The effect of pre-emptive dexmedetomidine on the incidence of post-thoracotomy pain syndrome in patients undergoing coronary artery bypass grafting. Anesth Pain Med. 2016;6(3):e36344.,1818 Priye S, Jagannath S, Singh D, Shivaprakash S, Reddy DP. Dexmedetomidine as an adjunct in postoperative analgesia following cardiac surgery: a randomized, double-blind study. Saudi J Anaesth. 2015;9(4):353-8.,2121 Abdel-Meguid ME. Dexmedetomidine as anesthetic adjunct for fast tracking and pain control in off-pump coronary artery bypass. Saudi J Anaesth. 2013;7(1):6-8.,2323 Ghandi I, Alavi SM, Babaee T, Ghadrdoost B, Bakhshandeh H, Ziyaeifard M, et al. The analgesic effect of morphine and dexmedetomidine intravenous patient-controlled analgesia method to control pain after open cardiac surgery: a randomized control trial. Arch Crit Care Med. 2015;1(3):e6453.,2525 Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 1999;54(12):1136-42.]. As depicted in Table 3, only eight studies including 466 subjects reported their surgeries as elective. Subcategories of thoracotomy operations were esophageal neoplasia resection (n=200), lobectomy (n=77), pneumonectomy (n=26), mediastinal mass or cancer (n=24), pneumothorax (n=7), cyst excision (n=5), decortication (n=4), and bullectomy (n=1), pleurectomy (n=14), other non-categorized major open thoracotomy surgeries (n=67). Subcategories of cardiac surgery were on-pump coronary artery bypass bypass graft (CABG), off-pump CABG, valve surgery, and atrial septal defect closure. We could not determine the exact number of patients in each subcategory of cardiac surgery because some studies did not report the number of patients in each category.

Table 3
Characteristics of included trials.

Outcomes Among the Trials

The reviewed trials reported several outcomes. Only the outcomes pertinent to our review were described. The primary or secondary outcomes of included studies were sufentanil (SUF) consumption[1414 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.,1717 Cai X, Zhang P, Lu S, Zhang Z, Yu A, Liu D, et al. Effects of intraoperative dexmedetomidine on postoperative pain in highly nicotine-dependent patients after thoracic surgery: a prospective, randomized, controlled trial. Medicine (Baltimore). 2016;95(22):e3814.,1919 Ren C, Zhang X, Liu Z, Li C, Zhang Z, Qi F, et al. Effect of intraoperative and postoperative infusion of dexmedetomidine on the quality of postoperative analgesia in highly nicotine-dependent patients after thoracic surgery: a consort-prospective, randomized, controlled trial. Medicine (Baltimore). 2015;94(32):e1329.], the mean of pain intensity[1414 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.,1515 Dutta V, Kumar B, Jayant A, Mishra AK. Effect of continuous paravertebral dexmedetomidine administration on intraoperative anesthetic drug requirement and post-thoracotomy pain syndrome after thoracotomy: a randomized controlled trial. J Cardiothorac Vasc Anesth. 2017;31(1):159-165.,1717 Cai X, Zhang P, Lu S, Zhang Z, Yu A, Liu D, et al. Effects of intraoperative dexmedetomidine on postoperative pain in highly nicotine-dependent patients after thoracic surgery: a prospective, randomized, controlled trial. Medicine (Baltimore). 2016;95(22):e3814.

18 Priye S, Jagannath S, Singh D, Shivaprakash S, Reddy DP. Dexmedetomidine as an adjunct in postoperative analgesia following cardiac surgery: a randomized, double-blind study. Saudi J Anaesth. 2015;9(4):353-8.

19 Ren C, Zhang X, Liu Z, Li C, Zhang Z, Qi F, et al. Effect of intraoperative and postoperative infusion of dexmedetomidine on the quality of postoperative analgesia in highly nicotine-dependent patients after thoracic surgery: a consort-prospective, randomized, controlled trial. Medicine (Baltimore). 2015;94(32):e1329.
-2020 Ramsay MA, Newman KB, Leeper B, Hamman BL, Hebeler RF Jr, Henry AC, et al. Dexmedetomidine infusion for analgesia up to 48 hours after lung surgery performed by lateral thoracotomy. Proc (Bayl Univ Med Cent). 2014;27(1):3-10.,2222 Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M. Effect of epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilation. Acta Anaesthesiol Scand. 2010;54(6):703-9.,2323 Ghandi I, Alavi SM, Babaee T, Ghadrdoost B, Bakhshandeh H, Ziyaeifard M, et al. The analgesic effect of morphine and dexmedetomidine intravenous patient-controlled analgesia method to control pain after open cardiac surgery: a randomized control trial. Arch Crit Care Med. 2015;1(3):e6453.], the median of POP[2121 Abdel-Meguid ME. Dexmedetomidine as anesthetic adjunct for fast tracking and pain control in off-pump coronary artery bypass. Saudi J Anaesth. 2013;7(1):6-8.], the number of patient controlled intravenous analgesia (PCIA) self-administer[1414 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.], the number of opioid injection[1414 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.,2020 Ramsay MA, Newman KB, Leeper B, Hamman BL, Hebeler RF Jr, Henry AC, et al. Dexmedetomidine infusion for analgesia up to 48 hours after lung surgery performed by lateral thoracotomy. Proc (Bayl Univ Med Cent). 2014;27(1):3-10.], morphine consumption[1515 Dutta V, Kumar B, Jayant A, Mishra AK. Effect of continuous paravertebral dexmedetomidine administration on intraoperative anesthetic drug requirement and post-thoracotomy pain syndrome after thoracotomy: a randomized controlled trial. J Cardiothorac Vasc Anesth. 2017;31(1):159-165.,2121 Abdel-Meguid ME. Dexmedetomidine as anesthetic adjunct for fast tracking and pain control in off-pump coronary artery bypass. Saudi J Anaesth. 2013;7(1):6-8.,2323 Ghandi I, Alavi SM, Babaee T, Ghadrdoost B, Bakhshandeh H, Ziyaeifard M, et al. The analgesic effect of morphine and dexmedetomidine intravenous patient-controlled analgesia method to control pain after open cardiac surgery: a randomized control trial. Arch Crit Care Med. 2015;1(3):e6453.,2525 Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 1999;54(12):1136-42.], the number of intraoperative anesthetic drug requirements[1515 Dutta V, Kumar B, Jayant A, Mishra AK. Effect of continuous paravertebral dexmedetomidine administration on intraoperative anesthetic drug requirement and post-thoracotomy pain syndrome after thoracotomy: a randomized controlled trial. J Cardiothorac Vasc Anesth. 2017;31(1):159-165.], fentanyl consumption[1818 Priye S, Jagannath S, Singh D, Shivaprakash S, Reddy DP. Dexmedetomidine as an adjunct in postoperative analgesia following cardiac surgery: a randomized, double-blind study. Saudi J Anaesth. 2015;9(4):353-8.,2424 Wahlander S, Frumento RJ, Wagener G, Saldana-Ferretti B, Joshi RR, Playford HR, et al. A prospective, double-blind, randomized, placebo-controlled study of dexmedetomidine as an adjunct to epidural analgesia after thoracic surgery. J Cardiothorac Vasc Anesth. 2005;19(5):630-5.], postoperative analgesic requirements[2222 Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M. Effect of epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilation. Acta Anaesthesiol Scand. 2010;54(6):703-9.], need for additional epidural bupivacaine[2424 Wahlander S, Frumento RJ, Wagener G, Saldana-Ferretti B, Joshi RR, Playford HR, et al. A prospective, double-blind, randomized, placebo-controlled study of dexmedetomidine as an adjunct to epidural analgesia after thoracic surgery. J Cardiothorac Vasc Anesth. 2005;19(5):630-5.], and the incidence of POP[1616 Jabbary Moghaddam M, Barkhori A, Mirkheshti A, Hashemian M, Amir Mohajerani S. The effect of pre-emptive dexmedetomidine on the incidence of post-thoracotomy pain syndrome in patients undergoing coronary artery bypass grafting. Anesth Pain Med. 2016;6(3):e36344.]. The pain was evaluated from one to 72 hours after the operation. Table 3 depicts the additional details for characteristics of included trials.

Table 4 briefly shows a list of the preliminary findings of this review.

Table 4
The most relevant preliminary findings of our review.

The DEX Administration Protocol

Table 5 summarized the protocol of DEX administration among trials. Five studies[1515 Dutta V, Kumar B, Jayant A, Mishra AK. Effect of continuous paravertebral dexmedetomidine administration on intraoperative anesthetic drug requirement and post-thoracotomy pain syndrome after thoracotomy: a randomized controlled trial. J Cardiothorac Vasc Anesth. 2017;31(1):159-165.

16 Jabbary Moghaddam M, Barkhori A, Mirkheshti A, Hashemian M, Amir Mohajerani S. The effect of pre-emptive dexmedetomidine on the incidence of post-thoracotomy pain syndrome in patients undergoing coronary artery bypass grafting. Anesth Pain Med. 2016;6(3):e36344.
-1717 Cai X, Zhang P, Lu S, Zhang Z, Yu A, Liu D, et al. Effects of intraoperative dexmedetomidine on postoperative pain in highly nicotine-dependent patients after thoracic surgery: a prospective, randomized, controlled trial. Medicine (Baltimore). 2016;95(22):e3814.,2121 Abdel-Meguid ME. Dexmedetomidine as anesthetic adjunct for fast tracking and pain control in off-pump coronary artery bypass. Saudi J Anaesth. 2013;7(1):6-8.,2222 Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M. Effect of epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilation. Acta Anaesthesiol Scand. 2010;54(6):703-9.] used DEX in the intraoperative period while seven studies[1414 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.,1818 Priye S, Jagannath S, Singh D, Shivaprakash S, Reddy DP. Dexmedetomidine as an adjunct in postoperative analgesia following cardiac surgery: a randomized, double-blind study. Saudi J Anaesth. 2015;9(4):353-8.

19 Ren C, Zhang X, Liu Z, Li C, Zhang Z, Qi F, et al. Effect of intraoperative and postoperative infusion of dexmedetomidine on the quality of postoperative analgesia in highly nicotine-dependent patients after thoracic surgery: a consort-prospective, randomized, controlled trial. Medicine (Baltimore). 2015;94(32):e1329.
-2020 Ramsay MA, Newman KB, Leeper B, Hamman BL, Hebeler RF Jr, Henry AC, et al. Dexmedetomidine infusion for analgesia up to 48 hours after lung surgery performed by lateral thoracotomy. Proc (Bayl Univ Med Cent). 2014;27(1):3-10.,2323 Ghandi I, Alavi SM, Babaee T, Ghadrdoost B, Bakhshandeh H, Ziyaeifard M, et al. The analgesic effect of morphine and dexmedetomidine intravenous patient-controlled analgesia method to control pain after open cardiac surgery: a randomized control trial. Arch Crit Care Med. 2015;1(3):e6453.

24 Wahlander S, Frumento RJ, Wagener G, Saldana-Ferretti B, Joshi RR, Playford HR, et al. A prospective, double-blind, randomized, placebo-controlled study of dexmedetomidine as an adjunct to epidural analgesia after thoracic surgery. J Cardiothorac Vasc Anesth. 2005;19(5):630-5.
-2525 Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 1999;54(12):1136-42.] used DEX in the postoperative period. Dosage for the intravenous infusion ranged from 0.02 to 0.7 mcg/kg/h and for the epidural catheter was 1.0 mcg/kg[1515 Dutta V, Kumar B, Jayant A, Mishra AK. Effect of continuous paravertebral dexmedetomidine administration on intraoperative anesthetic drug requirement and post-thoracotomy pain syndrome after thoracotomy: a randomized controlled trial. J Cardiothorac Vasc Anesth. 2017;31(1):159-165.,2222 Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M. Effect of epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilation. Acta Anaesthesiol Scand. 2010;54(6):703-9.]. Two studies added the DEX to the patient-controlled intravenous analgesia (PCIA) pump (dosage ranged from 0.2 to 4 mcg/kg)[1414 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.,2323 Ghandi I, Alavi SM, Babaee T, Ghadrdoost B, Bakhshandeh H, Ziyaeifard M, et al. The analgesic effect of morphine and dexmedetomidine intravenous patient-controlled analgesia method to control pain after open cardiac surgery: a randomized control trial. Arch Crit Care Med. 2015;1(3):e6453.]. The duration of DEX administration among the trials was varied and ranged from one to 72 hours.

Table 5
Protocol for DEX administration in the DEX group.

Interventions for Control Group

Different comparators with DEX were placebo (normal saline) in 9 study arms[1414 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.

15 Dutta V, Kumar B, Jayant A, Mishra AK. Effect of continuous paravertebral dexmedetomidine administration on intraoperative anesthetic drug requirement and post-thoracotomy pain syndrome after thoracotomy: a randomized controlled trial. J Cardiothorac Vasc Anesth. 2017;31(1):159-165.

16 Jabbary Moghaddam M, Barkhori A, Mirkheshti A, Hashemian M, Amir Mohajerani S. The effect of pre-emptive dexmedetomidine on the incidence of post-thoracotomy pain syndrome in patients undergoing coronary artery bypass grafting. Anesth Pain Med. 2016;6(3):e36344.

17 Cai X, Zhang P, Lu S, Zhang Z, Yu A, Liu D, et al. Effects of intraoperative dexmedetomidine on postoperative pain in highly nicotine-dependent patients after thoracic surgery: a prospective, randomized, controlled trial. Medicine (Baltimore). 2016;95(22):e3814.
-1818 Priye S, Jagannath S, Singh D, Shivaprakash S, Reddy DP. Dexmedetomidine as an adjunct in postoperative analgesia following cardiac surgery: a randomized, double-blind study. Saudi J Anaesth. 2015;9(4):353-8.,2020 Ramsay MA, Newman KB, Leeper B, Hamman BL, Hebeler RF Jr, Henry AC, et al. Dexmedetomidine infusion for analgesia up to 48 hours after lung surgery performed by lateral thoracotomy. Proc (Bayl Univ Med Cent). 2014;27(1):3-10.,2121 Abdel-Meguid ME. Dexmedetomidine as anesthetic adjunct for fast tracking and pain control in off-pump coronary artery bypass. Saudi J Anaesth. 2013;7(1):6-8.,2424 Wahlander S, Frumento RJ, Wagener G, Saldana-Ferretti B, Joshi RR, Playford HR, et al. A prospective, double-blind, randomized, placebo-controlled study of dexmedetomidine as an adjunct to epidural analgesia after thoracic surgery. J Cardiothorac Vasc Anesth. 2005;19(5):630-5.,2525 Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 1999;54(12):1136-42.], different dosages of DEX with SUF 0.02 mcg/kg/h in 1 arm[1919 Ren C, Zhang X, Liu Z, Li C, Zhang Z, Qi F, et al. Effect of intraoperative and postoperative infusion of dexmedetomidine on the quality of postoperative analgesia in highly nicotine-dependent patients after thoracic surgery: a consort-prospective, randomized, controlled trial. Medicine (Baltimore). 2015;94(32):e1329.], morphine in 1 arm[2323 Ghandi I, Alavi SM, Babaee T, Ghadrdoost B, Bakhshandeh H, Ziyaeifard M, et al. The analgesic effect of morphine and dexmedetomidine intravenous patient-controlled analgesia method to control pain after open cardiac surgery: a randomized control trial. Arch Crit Care Med. 2015;1(3):e6453.] and bupivacaine in 1 arm[2222 Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M. Effect of epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilation. Acta Anaesthesiol Scand. 2010;54(6):703-9.].

DEX versus Placebo

Nine trials compared DEX with placebo. Intraoperative administration of DEX was compared with placebo (normal saline) in four trials[1515 Dutta V, Kumar B, Jayant A, Mishra AK. Effect of continuous paravertebral dexmedetomidine administration on intraoperative anesthetic drug requirement and post-thoracotomy pain syndrome after thoracotomy: a randomized controlled trial. J Cardiothorac Vasc Anesth. 2017;31(1):159-165.,1616 Jabbary Moghaddam M, Barkhori A, Mirkheshti A, Hashemian M, Amir Mohajerani S. The effect of pre-emptive dexmedetomidine on the incidence of post-thoracotomy pain syndrome in patients undergoing coronary artery bypass grafting. Anesth Pain Med. 2016;6(3):e36344.,1717 Cai X, Zhang P, Lu S, Zhang Z, Yu A, Liu D, et al. Effects of intraoperative dexmedetomidine on postoperative pain in highly nicotine-dependent patients after thoracic surgery: a prospective, randomized, controlled trial. Medicine (Baltimore). 2016;95(22):e3814.,2121 Abdel-Meguid ME. Dexmedetomidine as anesthetic adjunct for fast tracking and pain control in off-pump coronary artery bypass. Saudi J Anaesth. 2013;7(1):6-8.], while postoperative administration of DEX was compared with placebo (normal saline) in five trials[1414 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.,1818 Priye S, Jagannath S, Singh D, Shivaprakash S, Reddy DP. Dexmedetomidine as an adjunct in postoperative analgesia following cardiac surgery: a randomized, double-blind study. Saudi J Anaesth. 2015;9(4):353-8.,2020 Ramsay MA, Newman KB, Leeper B, Hamman BL, Hebeler RF Jr, Henry AC, et al. Dexmedetomidine infusion for analgesia up to 48 hours after lung surgery performed by lateral thoracotomy. Proc (Bayl Univ Med Cent). 2014;27(1):3-10.,2424 Wahlander S, Frumento RJ, Wagener G, Saldana-Ferretti B, Joshi RR, Playford HR, et al. A prospective, double-blind, randomized, placebo-controlled study of dexmedetomidine as an adjunct to epidural analgesia after thoracic surgery. J Cardiothorac Vasc Anesth. 2005;19(5):630-5.,2525 Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 1999;54(12):1136-42.]. All of these nine trials showed significant lower POP scores in the DEX group. In general, intra- and postoperative administration of DEX could reduce the pain intensity score after surgery in comparison with placebo.

DEX versus Morphine

In comparison with morphine (0.2 mg via PCIA), administration of DEX 4 mcg/kg/h via PCIA could improve the pain control during the first 12 hours after surgery and decrease intravenous morphine consumption during ICU stay[2323 Ghandi I, Alavi SM, Babaee T, Ghadrdoost B, Bakhshandeh H, Ziyaeifard M, et al. The analgesic effect of morphine and dexmedetomidine intravenous patient-controlled analgesia method to control pain after open cardiac surgery: a randomized control trial. Arch Crit Care Med. 2015;1(3):e6453.].

DEX Addition to Bupivacaine

One study compared the addition of DEX (1 mcg/kg) to epidural bupivacaine 0.5% with epidural bupivacaine 0.5% and found that epidural use of DEX could decrease the anesthetic requirements and improve postoperative analgesia[2222 Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M. Effect of epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilation. Acta Anaesthesiol Scand. 2010;54(6):703-9.].

Main Outcomes

Post-Operative Pain Intensity or Incidence

Nine trials reported the POP scores at different time points[1414 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.,1515 Dutta V, Kumar B, Jayant A, Mishra AK. Effect of continuous paravertebral dexmedetomidine administration on intraoperative anesthetic drug requirement and post-thoracotomy pain syndrome after thoracotomy: a randomized controlled trial. J Cardiothorac Vasc Anesth. 2017;31(1):159-165.,1717 Cai X, Zhang P, Lu S, Zhang Z, Yu A, Liu D, et al. Effects of intraoperative dexmedetomidine on postoperative pain in highly nicotine-dependent patients after thoracic surgery: a prospective, randomized, controlled trial. Medicine (Baltimore). 2016;95(22):e3814.

18 Priye S, Jagannath S, Singh D, Shivaprakash S, Reddy DP. Dexmedetomidine as an adjunct in postoperative analgesia following cardiac surgery: a randomized, double-blind study. Saudi J Anaesth. 2015;9(4):353-8.

19 Ren C, Zhang X, Liu Z, Li C, Zhang Z, Qi F, et al. Effect of intraoperative and postoperative infusion of dexmedetomidine on the quality of postoperative analgesia in highly nicotine-dependent patients after thoracic surgery: a consort-prospective, randomized, controlled trial. Medicine (Baltimore). 2015;94(32):e1329.

20 Ramsay MA, Newman KB, Leeper B, Hamman BL, Hebeler RF Jr, Henry AC, et al. Dexmedetomidine infusion for analgesia up to 48 hours after lung surgery performed by lateral thoracotomy. Proc (Bayl Univ Med Cent). 2014;27(1):3-10.

21 Abdel-Meguid ME. Dexmedetomidine as anesthetic adjunct for fast tracking and pain control in off-pump coronary artery bypass. Saudi J Anaesth. 2013;7(1):6-8.

22 Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M. Effect of epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilation. Acta Anaesthesiol Scand. 2010;54(6):703-9.
-2323 Ghandi I, Alavi SM, Babaee T, Ghadrdoost B, Bakhshandeh H, Ziyaeifard M, et al. The analgesic effect of morphine and dexmedetomidine intravenous patient-controlled analgesia method to control pain after open cardiac surgery: a randomized control trial. Arch Crit Care Med. 2015;1(3):e6453.]. Table 6 shows the POP scores at different time points, which were significantly lower in the DEX group. Only one trial[1414 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.] showed a significant lower pain intensity 36 hours after surgery in the DEX group. The incidence of POP in the DEX group was significantly lower in the DEX group when DEX was administered intraoperatively via IV route[1616 Jabbary Moghaddam M, Barkhori A, Mirkheshti A, Hashemian M, Amir Mohajerani S. The effect of pre-emptive dexmedetomidine on the incidence of post-thoracotomy pain syndrome in patients undergoing coronary artery bypass grafting. Anesth Pain Med. 2016;6(3):e36344.]. The median of POP was significantly lower at all time points up to 24 hours in DEX group when DEX was administered intraoperatively via IV route[2121 Abdel-Meguid ME. Dexmedetomidine as anesthetic adjunct for fast tracking and pain control in off-pump coronary artery bypass. Saudi J Anaesth. 2013;7(1):6-8.]. The POP scores and morphine consumption were significantly lower in the DEX group when DEX was used intraoperatively via epidural catheter[1515 Dutta V, Kumar B, Jayant A, Mishra AK. Effect of continuous paravertebral dexmedetomidine administration on intraoperative anesthetic drug requirement and post-thoracotomy pain syndrome after thoracotomy: a randomized controlled trial. J Cardiothorac Vasc Anesth. 2017;31(1):159-165.]. In all of the trials, no significant difference was found between groups 48 and 72 hours after surgery in terms of POP scores. In general, DEX probably is able to reduce the pain intensity score after CTS up to 24 hours.

Table 6
Significant lower pain score at different time points after surgery.

The Post-Operative Narcotics and/or Analgesic Requirements

Ten studies[1414 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.,1515 Dutta V, Kumar B, Jayant A, Mishra AK. Effect of continuous paravertebral dexmedetomidine administration on intraoperative anesthetic drug requirement and post-thoracotomy pain syndrome after thoracotomy: a randomized controlled trial. J Cardiothorac Vasc Anesth. 2017;31(1):159-165.,1717 Cai X, Zhang P, Lu S, Zhang Z, Yu A, Liu D, et al. Effects of intraoperative dexmedetomidine on postoperative pain in highly nicotine-dependent patients after thoracic surgery: a prospective, randomized, controlled trial. Medicine (Baltimore). 2016;95(22):e3814.,1919 Ren C, Zhang X, Liu Z, Li C, Zhang Z, Qi F, et al. Effect of intraoperative and postoperative infusion of dexmedetomidine on the quality of postoperative analgesia in highly nicotine-dependent patients after thoracic surgery: a consort-prospective, randomized, controlled trial. Medicine (Baltimore). 2015;94(32):e1329.

20 Ramsay MA, Newman KB, Leeper B, Hamman BL, Hebeler RF Jr, Henry AC, et al. Dexmedetomidine infusion for analgesia up to 48 hours after lung surgery performed by lateral thoracotomy. Proc (Bayl Univ Med Cent). 2014;27(1):3-10.

21 Abdel-Meguid ME. Dexmedetomidine as anesthetic adjunct for fast tracking and pain control in off-pump coronary artery bypass. Saudi J Anaesth. 2013;7(1):6-8.

22 Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M. Effect of epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilation. Acta Anaesthesiol Scand. 2010;54(6):703-9.

23 Ghandi I, Alavi SM, Babaee T, Ghadrdoost B, Bakhshandeh H, Ziyaeifard M, et al. The analgesic effect of morphine and dexmedetomidine intravenous patient-controlled analgesia method to control pain after open cardiac surgery: a randomized control trial. Arch Crit Care Med. 2015;1(3):e6453.

24 Wahlander S, Frumento RJ, Wagener G, Saldana-Ferretti B, Joshi RR, Playford HR, et al. A prospective, double-blind, randomized, placebo-controlled study of dexmedetomidine as an adjunct to epidural analgesia after thoracic surgery. J Cardiothorac Vasc Anesth. 2005;19(5):630-5.
-2525 Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 1999;54(12):1136-42.] found that the total consumption of narcotics was significantly lower in the DEX group. The requirement for postoperative rescue sedation and analgesia in DEX group was significantly lower when DEX was administered postoperatively via intravenous route[2424 Wahlander S, Frumento RJ, Wagener G, Saldana-Ferretti B, Joshi RR, Playford HR, et al. A prospective, double-blind, randomized, placebo-controlled study of dexmedetomidine as an adjunct to epidural analgesia after thoracic surgery. J Cardiothorac Vasc Anesth. 2005;19(5):630-5.,2525 Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 1999;54(12):1136-42.]. One study compared the addition of different dosage of DEX (0.02 and 0.04 mcg/kg/h) to SUF with SUF 0.02 mcg/kg/h. The addition of DEX 0.04 mcg/kg/h to SUF could improve the analgesic effect of SUF and decrease the total dosage of SUF during the first 72 hours after surgery[1919 Ren C, Zhang X, Liu Z, Li C, Zhang Z, Qi F, et al. Effect of intraoperative and postoperative infusion of dexmedetomidine on the quality of postoperative analgesia in highly nicotine-dependent patients after thoracic surgery: a consort-prospective, randomized, controlled trial. Medicine (Baltimore). 2015;94(32):e1329.]. In general, DEX administration probably is able to reduce the requirements for supplemental narcotic, rescue sedation and analgesia in the postoperative period for up to 24 hours.

DEX Adverse Events

Only six trials (n=206) have reported the adverse events of DEX administration. In all of those trials, DEX was administered postoperatively through intravenous injection or using PCIA. As depicted in Table 7, the differences between two groups regarding the adverse events were not statistically significant, except for the occurrence of atelectasis, which was significantly higher in the control group (OR 0.400, CI 95%: 0.177-0.904). Because of incomplete report of some trials, the adverse events rate was not comparable among patients who received DEX intraoperatively and postoperatively. Therefore, the duration and timing of DEX administration (short vs. prolonged) on the incident of adverse events was not evaluated.

Table 7
The comparison of adverse events between DEX and Control groups.

The most reported complications of DEX were nausea/vomiting[1717 Cai X, Zhang P, Lu S, Zhang Z, Yu A, Liu D, et al. Effects of intraoperative dexmedetomidine on postoperative pain in highly nicotine-dependent patients after thoracic surgery: a prospective, randomized, controlled trial. Medicine (Baltimore). 2016;95(22):e3814.,1919 Ren C, Zhang X, Liu Z, Li C, Zhang Z, Qi F, et al. Effect of intraoperative and postoperative infusion of dexmedetomidine on the quality of postoperative analgesia in highly nicotine-dependent patients after thoracic surgery: a consort-prospective, randomized, controlled trial. Medicine (Baltimore). 2015;94(32):e1329.,2020 Ramsay MA, Newman KB, Leeper B, Hamman BL, Hebeler RF Jr, Henry AC, et al. Dexmedetomidine infusion for analgesia up to 48 hours after lung surgery performed by lateral thoracotomy. Proc (Bayl Univ Med Cent). 2014;27(1):3-10.,2323 Ghandi I, Alavi SM, Babaee T, Ghadrdoost B, Bakhshandeh H, Ziyaeifard M, et al. The analgesic effect of morphine and dexmedetomidine intravenous patient-controlled analgesia method to control pain after open cardiac surgery: a randomized control trial. Arch Crit Care Med. 2015;1(3):e6453.,2525 Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 1999;54(12):1136-42.], bradycardia[1414 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.,1515 Dutta V, Kumar B, Jayant A, Mishra AK. Effect of continuous paravertebral dexmedetomidine administration on intraoperative anesthetic drug requirement and post-thoracotomy pain syndrome after thoracotomy: a randomized controlled trial. J Cardiothorac Vasc Anesth. 2017;31(1):159-165.,1717 Cai X, Zhang P, Lu S, Zhang Z, Yu A, Liu D, et al. Effects of intraoperative dexmedetomidine on postoperative pain in highly nicotine-dependent patients after thoracic surgery: a prospective, randomized, controlled trial. Medicine (Baltimore). 2016;95(22):e3814.,2525 Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 1999;54(12):1136-42.] and hypotension[1414 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.,1515 Dutta V, Kumar B, Jayant A, Mishra AK. Effect of continuous paravertebral dexmedetomidine administration on intraoperative anesthetic drug requirement and post-thoracotomy pain syndrome after thoracotomy: a randomized controlled trial. J Cardiothorac Vasc Anesth. 2017;31(1):159-165.,2020 Ramsay MA, Newman KB, Leeper B, Hamman BL, Hebeler RF Jr, Henry AC, et al. Dexmedetomidine infusion for analgesia up to 48 hours after lung surgery performed by lateral thoracotomy. Proc (Bayl Univ Med Cent). 2014;27(1):3-10.,2424 Wahlander S, Frumento RJ, Wagener G, Saldana-Ferretti B, Joshi RR, Playford HR, et al. A prospective, double-blind, randomized, placebo-controlled study of dexmedetomidine as an adjunct to epidural analgesia after thoracic surgery. J Cardiothorac Vasc Anesth. 2005;19(5):630-5.,2525 Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 1999;54(12):1136-42.]. Two studies did not report DEX complications[1616 Jabbary Moghaddam M, Barkhori A, Mirkheshti A, Hashemian M, Amir Mohajerani S. The effect of pre-emptive dexmedetomidine on the incidence of post-thoracotomy pain syndrome in patients undergoing coronary artery bypass grafting. Anesth Pain Med. 2016;6(3):e36344.,2121 Abdel-Meguid ME. Dexmedetomidine as anesthetic adjunct for fast tracking and pain control in off-pump coronary artery bypass. Saudi J Anaesth. 2013;7(1):6-8.] and four studies reported no statistically significant complications between groups[1818 Priye S, Jagannath S, Singh D, Shivaprakash S, Reddy DP. Dexmedetomidine as an adjunct in postoperative analgesia following cardiac surgery: a randomized, double-blind study. Saudi J Anaesth. 2015;9(4):353-8.,1919 Ren C, Zhang X, Liu Z, Li C, Zhang Z, Qi F, et al. Effect of intraoperative and postoperative infusion of dexmedetomidine on the quality of postoperative analgesia in highly nicotine-dependent patients after thoracic surgery: a consort-prospective, randomized, controlled trial. Medicine (Baltimore). 2015;94(32):e1329.,2222 Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M. Effect of epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilation. Acta Anaesthesiol Scand. 2010;54(6):703-9.,2323 Ghandi I, Alavi SM, Babaee T, Ghadrdoost B, Bakhshandeh H, Ziyaeifard M, et al. The analgesic effect of morphine and dexmedetomidine intravenous patient-controlled analgesia method to control pain after open cardiac surgery: a randomized control trial. Arch Crit Care Med. 2015;1(3):e6453.]. One of the included trials reported four events of respiratory depression in the DEX group[1414 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.].

Other Outcomes

The clinical efficacy of DEX on the ICU length of stay was only reported by one study, which showed that ICU stay was significantly shorter in the DEX group than in the control group (2 and 3 days, respectively)[2222 Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M. Effect of epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilation. Acta Anaesthesiol Scand. 2010;54(6):703-9.]. DEX efficacy on the time spent on the ventilator was not reported by any of the included trials. In addition, the information regarding the number of patients who admitted to the ICU after surgery and the duration of ICU stay were not clearly reported across the reviewed trials.

Dealing with Missing Data

In four cases, we contacted the corresponding author to request further information regarding random sequence generation, allocation concealment, additional blinding details, and type of surgery without success and in one case the contact address was not retrievable.

DISCUSSION

Pain management after CTS is an important issue for clinicians because POP can significantly impair the cardiovascular and respiratory function. The present study, including 12 RCTs, reviewed the effectiveness of DEX in reducing POP. Regardless of the methodological quality of included studies, the overall results are relatively consistent among studies. Approximately all included studies were methodologically homogenous; however, they were different in the sample size, use of analgesic and anesthetic agent, number of measured outcomes, study population, route and timing of DEX administration and type of surgery.

Findings from our review suggest that, compared with normal saline as a placebo, DEX probably is able to reduce the pain intensity score, the number of narcotic consumption and analgesic requirements up to 24 hours. However, due to the low to medium quality of reviewed trials, further studies are warranted to confirm or refute our findings.

Our finding may have noteworthy implications for pain management of adults' patients undergoing CTS, particularly in the first 24 hours after surgery. It is necessary to mention that the use of DEX beyond 24 hours may be associated with a dose-related increase in adverse events and for this reason, the Food and Drug Administration (FDA) has not recommended the use of DEX for more than 24 hours[2727 Popat K, Purugganan R, Malik I. Off-label uses of dexmedetomidine. Adv Anesthesia. 2006;24(Suppl C):177-92.,2828 Keating GM. Dexmedetomidine: a review of its use for sedation in the intensive care setting. Drugs. 2015;75(10):1119-30.]. However, the safe use of this drug has been reported from 24 hours to more than a week[2828 Keating GM. Dexmedetomidine: a review of its use for sedation in the intensive care setting. Drugs. 2015;75(10):1119-30.,2929 Panzer O, Moitra V, Sladen RN. Pharmacology of sedative-analgesic agents: dexmedetomidine, remifentanil, ketamine, volatile anesthetics, and the role of peripheral mu antagonists. Crit Care Clin. 2009;25(3):451-69.].

In the present review, the detailed comparison of the results of the included trials was not possible due to differences in intervention protocol and outcomes measurement. Additionally, five of 12 trials[2020 Ramsay MA, Newman KB, Leeper B, Hamman BL, Hebeler RF Jr, Henry AC, et al. Dexmedetomidine infusion for analgesia up to 48 hours after lung surgery performed by lateral thoracotomy. Proc (Bayl Univ Med Cent). 2014;27(1):3-10.

21 Abdel-Meguid ME. Dexmedetomidine as anesthetic adjunct for fast tracking and pain control in off-pump coronary artery bypass. Saudi J Anaesth. 2013;7(1):6-8.

22 Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M. Effect of epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilation. Acta Anaesthesiol Scand. 2010;54(6):703-9.
-2323 Ghandi I, Alavi SM, Babaee T, Ghadrdoost B, Bakhshandeh H, Ziyaeifard M, et al. The analgesic effect of morphine and dexmedetomidine intravenous patient-controlled analgesia method to control pain after open cardiac surgery: a randomized control trial. Arch Crit Care Med. 2015;1(3):e6453.,2525 Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 1999;54(12):1136-42.] were likely underpowered for the outcomes, since they did not power the sample size. Therefore, the optimal dosage, timing, and route of DEX administration remain to be elucidated in future studies.

Previous studies have revealed that the most effective dosage of DEX for maximum POP reduction is a loading dose of 1 mcg/kg, which is followed by a continuous infusion of 0.5-1 mcg/kg/h[3030 Schnabel A, Meyer-Frießem CH, Reichl SU, Zahn PK, Pogatzki-Zahn EM. Is intraoperative dexmedetomidine a new option for postoperative pain treatment? A meta-analysis of randomized controlled trials. Pain. 2013;154(7):1140-9.]. In our review, the dosage for the intravenous infusion were ranged from 0.02 to 0.7 mcg/kg/h and only two studies[1717 Cai X, Zhang P, Lu S, Zhang Z, Yu A, Liu D, et al. Effects of intraoperative dexmedetomidine on postoperative pain in highly nicotine-dependent patients after thoracic surgery: a prospective, randomized, controlled trial. Medicine (Baltimore). 2016;95(22):e3814.,2525 Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 1999;54(12):1136-42.] infused DEX at maximum POP reduction dose. We also found that a limited number of studies suggested a scientific justification of the rationale for choosing a dose.

The common adverse events of DEX are hypotension at low blood concentrations, hypertension at high blood concentrations, bradycardia and nausea[2929 Panzer O, Moitra V, Sladen RN. Pharmacology of sedative-analgesic agents: dexmedetomidine, remifentanil, ketamine, volatile anesthetics, and the role of peripheral mu antagonists. Crit Care Clin. 2009;25(3):451-69.]. Most of these side effects occur at infusion of 0.2-0.7 mcg/kg/h without a bolus dose[2828 Keating GM. Dexmedetomidine: a review of its use for sedation in the intensive care setting. Drugs. 2015;75(10):1119-30.,3131 Constantin JM, Momon A, Mantz J, Payen JF, De Jonghe B, Perbet S, et al. Efficacy and safety of sedation with dexmedetomidine in critical care patients: a meta-analysis of randomized controlled trials. Anaesth Crit Care Pain Med. 2016;35(1):7-15.]. In our review, the occurrence of respiratory depression was low and reported only in one trials[1414 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.], which is consistent with previous studies[1111 Barr J, Fraser GL, Puntillo K, Ely EW, Gélinas C, Dasta JF, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1):263-306.,2828 Keating GM. Dexmedetomidine: a review of its use for sedation in the intensive care setting. Drugs. 2015;75(10):1119-30.,3131 Constantin JM, Momon A, Mantz J, Payen JF, De Jonghe B, Perbet S, et al. Efficacy and safety of sedation with dexmedetomidine in critical care patients: a meta-analysis of randomized controlled trials. Anaesth Crit Care Pain Med. 2016;35(1):7-15.]. Previous study showed that respiratory suppression does not even occur at DEX plasma levels up to 8.0 ng/mL and only there is a risk of over-sedation[3232 Ebert TJ, Hall JE, Barney JA, Uhrich TD, Colinco MD. The effects of increasing plasma concentrations of dexmedetomidine in humans. Anesthesiology. 2000;93(2):382-94.].

DEX possesses analgesic and opioid-sparing effects in the ICU patients[3333 Hall JE, Uhrich TD, Barney JA, Arain SR, Ebert TJ. Sedative, amnestic, and analgesic properties of small-dose dexmedetomidine infusions. Anesth Analg. 2000;90(3):699-705.]. DEX, a shorter-acting and highly selective presynaptic alpha-2-receptor agonist, also possesses pharmacologic sedative, hypnotic, anti-anxious, sympatholytic and analgesic properties[2828 Keating GM. Dexmedetomidine: a review of its use for sedation in the intensive care setting. Drugs. 2015;75(10):1119-30.]. Its analgesic and opioid-sparing effects are dose-dependent and trigger at spinal cord sites as well as through non-spinal mechanisms[2929 Panzer O, Moitra V, Sladen RN. Pharmacology of sedative-analgesic agents: dexmedetomidine, remifentanil, ketamine, volatile anesthetics, and the role of peripheral mu antagonists. Crit Care Clin. 2009;25(3):451-69.]. It has been suggested that alpha-2A receptors activation, inhibition of the C and A delta fibers signals conduction, and the local release of encephalin are the underlying non-spinal mechanisms of DEX to provide anti-nociception effects[3434 Yoshitomi T, Kohjitani A, Maeda S, Higuchi H, Shimada M, Miyawaki T. Dexmedetomidine enhances the local anesthetic action of lidocaine via an alpha-2A adrenoceptor. Anesth Analg. 2008;107(1):96-101.]. In terms of pharmacokinetics, its action starts about 15 minutes after intravenous injection and its peak concentration is achieved within an hour of continuous intravenous infusion. Appropriate pharmacodynamic effects of DEX are revealed between the plasma concentration of 0.5 and 1.2 ng/ml.

Several strategies have been introduced for POP management[3535 Bottiger BA, Esper SA, Stafford-Smith M. Pain management strategies for thoracotomy and thoracic pain syndromes. Semin Cardiothorac Vasc Anesth. 2014;18(1):45-56.]. It is believed that multimodal analgesic approaches combining different analgesic agents with different mechanisms of action can maximize pain relief while minimize the opioid consumption and thus can limit the opioid-induced side effects[66 Maxwell C, Nicoara A. New developments in the treatment of acute pain after thoracic surgery. Curr Opin Anaesthesiol. 2014;27(1):6-11.,3636 Devin CJ, McGirt MJ. Best evidence in multimodal pain management in spine surgery and means of assessing postoperative pain and functional outcomes. J Clin Neurosci. 2015;22(6):930-8.]. As a method of limiting opioid-induced adverse events, therefore, multimodal POP management has the potential to decrease morbidity and mortality after surgery[3535 Bottiger BA, Esper SA, Stafford-Smith M. Pain management strategies for thoracotomy and thoracic pain syndromes. Semin Cardiothorac Vasc Anesth. 2014;18(1):45-56.]. Consequently, it is expected that the sedative, anesthetic, analgesic, and cardiorespiratory effects of DEX may enhance with concomitant administration with other anesthetic, sedative and analgesic medications[2828 Keating GM. Dexmedetomidine: a review of its use for sedation in the intensive care setting. Drugs. 2015;75(10):1119-30.]. In our review, regardless of the route of administration, three studies used the multimodal approaches and found a reduction in the narcotic consumption and supplemental analgesics requirements[1414 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.,1717 Cai X, Zhang P, Lu S, Zhang Z, Yu A, Liu D, et al. Effects of intraoperative dexmedetomidine on postoperative pain in highly nicotine-dependent patients after thoracic surgery: a prospective, randomized, controlled trial. Medicine (Baltimore). 2016;95(22):e3814.,1919 Ren C, Zhang X, Liu Z, Li C, Zhang Z, Qi F, et al. Effect of intraoperative and postoperative infusion of dexmedetomidine on the quality of postoperative analgesia in highly nicotine-dependent patients after thoracic surgery: a consort-prospective, randomized, controlled trial. Medicine (Baltimore). 2015;94(32):e1329.]. In addition, two studies found that the addition of DEX to morphine can reduce the opioid consumption[2020 Ramsay MA, Newman KB, Leeper B, Hamman BL, Hebeler RF Jr, Henry AC, et al. Dexmedetomidine infusion for analgesia up to 48 hours after lung surgery performed by lateral thoracotomy. Proc (Bayl Univ Med Cent). 2014;27(1):3-10.,2121 Abdel-Meguid ME. Dexmedetomidine as anesthetic adjunct for fast tracking and pain control in off-pump coronary artery bypass. Saudi J Anaesth. 2013;7(1):6-8.], the risk of respiratory depression[2020 Ramsay MA, Newman KB, Leeper B, Hamman BL, Hebeler RF Jr, Henry AC, et al. Dexmedetomidine infusion for analgesia up to 48 hours after lung surgery performed by lateral thoracotomy. Proc (Bayl Univ Med Cent). 2014;27(1):3-10.] and the time of extubation[2121 Abdel-Meguid ME. Dexmedetomidine as anesthetic adjunct for fast tracking and pain control in off-pump coronary artery bypass. Saudi J Anaesth. 2013;7(1):6-8.]. One study found that epidural use of DEX plus bupivacaine 0.5% plus fentanyl can decrease the anesthetic requirements and provides effective post-operative analgesia[2222 Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M. Effect of epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilation. Acta Anaesthesiol Scand. 2010;54(6):703-9.]. It should be noted that the peridural (epidural) form of DEX has not been officially approved by any drug administrations around the world. However, in many clinical practices, the off-label form of DEX has been used in various scenarios in the operating room including thoracic epidural anesthesia, regional anesthesia block, intubation, monitored anesthesia care sedation, cardiothoracic surgery, and neurosurgery. The United States FDA has only approved the form of intravenous injection of DEX[2727 Popat K, Purugganan R, Malik I. Off-label uses of dexmedetomidine. Adv Anesthesia. 2006;24(Suppl C):177-92.].

As the findings of our review suggest, several advantages may encourage clinicians to use DEX over other agents for POP reduction. First, DEX does not interfere with respiratory function and has predictable and stable hemodynamic responses. Second, because of its synergistic effects with narcotics and sedatives, DEX can be used to reduce the total dosage of those drugs. Third, DEX has anxiolytic and sedative properties that may improve POP control. Forth, DEX can be used as an adjuvant to local anesthesia; hence, it can improve postoperative analgesia, and reduce the opioid requirement. Fifth, technically, the use of intravenous DEX is easier that paravertebral or peridural route in terms of equipment, skill, and side effects.

These advantages are consistent with the finding of several reviews that have emphasized the analgesic effects of DEX on POP in different sample of patients and surgeries. Schnabel et al.[3030 Schnabel A, Meyer-Frießem CH, Reichl SU, Zahn PK, Pogatzki-Zahn EM. Is intraoperative dexmedetomidine a new option for postoperative pain treatment? A meta-analysis of randomized controlled trials. Pain. 2013;154(7):1140-9.] found that the IV administration of DEX compared with placebo or opioids reduces acute POP and opioid consumption, as well as declines the risk of opioid-related adverse events in patients undergoing non-thoracotomy surgeries. Peng et al.[99 Peng K, Liu HY, Wu SR, Cheng H, Ji FH. Effects of combining dexmedetomidine and opioids for postoperative intravenous patient-controlled analgesia: a systematic review and meta-analysis. Clin J Pain. 2015;31(12):1097-104.] found that postoperative PCIA protocols containing opioid-DEX combination have beneficial effects for reducing the POP intensity, postoperative morphine-equivalent consumption and the adverse events. Liu et al.[3737 Liu Y, Liang F, Liu X, Shao X, Jiang N, Gan X. Dexmedetomidine reduces perioperative opioid consumption and postoperative pain intensity in neurosurgery: a meta-analysis. J Neurosurg Anesthesiol. 2018;30(2):146-55.] reviewed the efficacy of DEX on perioperative opioid consumption and POP intensity of patients undergoing neurosurgery and found that DEX could reduce opioid consumption and POP intensity. Bellon et al.[3838 Bellon M, Le Bot A, Michelet D, Hilly J, Maesani M, Brasher C, et al. Efficacy of intraoperative dexmedetomidine compared with placebo for postoperative pain management: a meta-analysis of published studies. Pain Ther. 2016;5(1):63-80.] found that the intraoperative administration of DEX could reduce postoperative opioids consumption and POP intensity in children undergoing surgery.

There are also some studies demonstrating that administration of DEX cannot reduce POP. Jessen Lundorf et al.[3939 Jessen Lundorf L, Korvenius Nedergaard H, Moller AM. Perioperative dexmedetomidine for acute pain after abdominal surgery in adults. Cochrane Database Syst Rev. 2016;2:CD010358.] concluded that perioperative administration of DEX in comparison with placebo seems to have some opioid-sparing effect with no important differences in POP in adult patients undergoing abdominal surgery. Tan and Ho[4040 Tan JA, Ho KM. Use of dexmedetomidine as a sedative and analgesic agent in critically ill adult patients: a meta-analysis. Intensive Care Med. 2010;36(6):926-39.] showed that DEX might reduce the length of ICU stay and duration of mechanical ventilation, but increases the risk of bradycardia and hypotension in critically ill adult patients.

Limitations

This systematic review has some limitations. First, we did not judge regarding the quality of each trials and risk of bias due to the limit number of retrieved trials; however, we used the Cochrane risk assessment tool to demonstrate any risk of bias at each domain. Second, due to the considerable heterogeneity between studies, we could not perform meta-analysis to evaluate statistically the efficacy of DEX over the other analgesic agents. Third, due to the lack of reported data in some of the trials, difference in DEX doses, and different times of administration, we could not synthesis the results based on the subgroups. Forth, the outcome of pain was incompletely measured and reported in some trials; hence, we could not critically appraise the outcome of those trials. Fifth, we cannot compare the DEX group with control group regarding the POP scores based on the type of surgery because the number of patients in subcategories of cardiac surgery was reported incompletely.

CONCLUSION

In comparison with placebo or other analgesic agents, the use of DEX after CTS is associated with a lower POP intensity, a lower number of post-operative analgesic requirements and a lower number of adverse events, particularly respiratory depression. Thus, DEX can be used as a safe and efficient analgesic agent for reducing the POP up to 24 hours. Overall, data published to date regarding the use of DEX after CTS suggest a marginal clinical benefit. Further well-designed studies with powered sample size are needed to find the optimal dosage, route, time, and duration of administration as well as the best choice of adjuvant analgesia to DEX for reducing POP.

Authors' roles & responsibilities VH Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; final approval of the version to be published FHK Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; final approval of the version to be published HS Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; final approval of the version to be published
  • This study was carried out at Mazandaran University of Medical Sciences, Sari, Iran.
  • No financial support.

APPENDIX A

Keywords for PubMed

("adrenergic alpha-2 receptor agonists"[MeSH Terms] OR dexmedetomidine[Title/Abstract]) AND ("pain"[MeSH Terms] OR pain[Title/Abstract] OR analgesia[Title/Abstract] OR analgesic[Title/Abstract]) AND (Clinical Trial[ptyp] AND "humans"[MeSH Terms] AND English[lang]) AND (Clinical Trial[ptyp] AND "humans"[MeSH Terms] AND English[lang]) =294

SCOPUS (2017-June-15)

TITLE-ABS-KEY ( dexmedetomidine ) OR TITLE-ABS-KEY ( "adrenergic alpha 2 receptor agonist" ) AND TITLE-ABS-KEY ( pain ) AND ( LIMIT-TO ( DOCTYPE , "ar" ) OR LIMIT-TO ( DOCTYPE , "ip" ) ) AND ( LIMIT-TO ( EXACTKEYWORD , "Human" ) OR LIMIT-TO ( EXACTKEYWORD , "Humans" ) ) AND ( LIMIT-TO ( LANGUAGE , "English" ) ) AND ( LIMIT-TO ( SRCTYPE , "j" ) )=701

ISI (2017-June-15)

(TS=(dexmedetomidine AND pain)) AND LANGUAGE: (English) AND DOCUMENT TYPES: (Article)=617

Indexes=SCI-EXPANDED, SSCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years

Cochrane (2017-June-17)

#1 MeSH descriptor: [Pain] explode all trees

#2 MeSH descriptor: [Adrenergic alpha-2 Receptor Agonists] explode all trees

#3 MeSH descriptor: [Dexmedetomidine] explode all trees

#4 (#1 and #2) or (#1 and #4) in Trials= 165

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Publication Dates

  • Publication in this collection
    Jul-Aug 2018

History

  • Received
    24 Dec 2017
  • Accepted
    08 Mar 2018
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