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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 6  |  Issue : 3  |  Page : 371-376

Comparative study of dexmedetomidine or fentanyl as an adjuvant to epidural bupivacaine for prevention of stump and phantom pain in adult patients undergoing above-knee or below-knee amputation: a randomized prospective trial


1 Department of Anesthesia, Ain Shams University, Cairo, Egypt
2 Department of Anesthesia, Faculty of medicine, Ain Shams University, Cairo, Egypt

Date of Submission25-Nov-2018
Date of Acceptance11-Apr-2019
Date of Web Publication29-Aug-2019

Correspondence Address:
Sabah N.B Ayoub

Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/roaic.roaic_99_18

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  Abstract 

Background Phantom-limb pain is one of the most difficult-to-treat chronic pain syndromes. In this randomized prospective trial, we studied the effect of administering fentanyl or dexmedetomidine as additive to bupivacaine in epidural catheter in perioperative period to reduce acute postoperative stump and phantom pain and opioid consumption in patients undergoing unilateral above- or below-knee amputation.
Patients and methods Over 2 years, 62 patients with American Society of Anesthesiologists physical status I–II scheduled for unilateral knee amputation were analyzed. In this prospective study, two equal groups of patients randomly received dexmedetomidine or fentanyl as epidural infusion 24 h before operation and 72 h after surgery. Visual analog scale, sedation scale, patient satisfaction, incidence of phantom, and stump pain and cumulative opioid consumption over 3 days were used to compare the two groups.
Results Incidence of postoperative stump and phantom pain in group D was less significantly in comparison with group F in the first 72 h postoperatively. Moreover, after 6 months, we found the same result. Patients’ satisfaction was significantly higher in group D in comparison with group F (P˂0.01). Visual analog scale was statistically significant lower in group D than group F in the 72-h postoperative period. This led to the more use of rescue analgesic (meperidine) in group F 232±23.1 mg than group D 142.2±46.68 mg. There was a statistically significant increase in preoperative sedation score in group D. Patients in group D experienced bradycardia and hypotension significantly more than group F. However, patients in group F experienced significantly from itching than group D.
Conclusion Adding dexmedetomidine to bupivacaine as epidural infusion has been found to provide better postoperative analgesia, reduce opioid consumption, and decrease incidence of phantom and stump pain. It also improves patient satisfaction and decreases intensity of pain.

Keywords: dexmedetomidine, epidural, fentanyl, phantom pain


How to cite this article:
Ayoub SN, Hakim KY. Comparative study of dexmedetomidine or fentanyl as an adjuvant to epidural bupivacaine for prevention of stump and phantom pain in adult patients undergoing above-knee or below-knee amputation: a randomized prospective trial. Res Opin Anesth Intensive Care 2019;6:371-6

How to cite this URL:
Ayoub SN, Hakim KY. Comparative study of dexmedetomidine or fentanyl as an adjuvant to epidural bupivacaine for prevention of stump and phantom pain in adult patients undergoing above-knee or below-knee amputation: a randomized prospective trial. Res Opin Anesth Intensive Care [serial online] 2019 [cited 2019 Nov 18];6:371-6. Available from: http://www.roaic.eg.net/text.asp?2019/6/3/371/265733


  Introduction Top


Phantom-limb pain (PLP) is one of the most difficult-to-treat chronic pain syndromes. Amputation can be owing to different causes such as trauma, vascular diseases, or cancer. Diabetes mellitus is one of the most common causes of amputation [1]. Incidence of PLP in recent studies is reported to be approximately 42.2–78.8% of amputees [2]. All amputees experience phantom sensations, which may be painful or not. Different factors including site of amputation or presence of preamputation pain have been found to be correlated with the development of PLP. Painful phantom pain is extremely difficult to treat [3]. Understanding the pathophysiology of phantom pain helps in establishing different modalities of treatment. Nerve injury followed by a series of changes in peripheral and central nervous system plays a role in the incidence and maintenance of chronic phantom pain. Mirror neurons in the brain have been proposed to play a role in the generation of phantom pain [4].

Various pharmacological drugs have been used for treating phantom and stump pain such as preemptive analgesia. Mechanism of action of these drugs is through inhibiting noxious stimulus from the amputated sites and aborting neuropathic pain. Acetaminophen, NSAIDs, opioids, anticonvulsant drugs (carbamazepine, lamotrigine, and gabapentin), antidepressants (TCAs), lidocaine, mexiletine, ketamine (NMDA receptor antagonist), beta blockers, and calcitonin are most commonly used for treating neuropathic pain [5].

Perioperative regional anesthesia and perineural local anesthetic infusion are effective modalities for treating immediate postoperative stump pain but in no way are superior to the other for preventing PLP. Adding morphine, diamorphine, clonidine, or ketamine to bupivacaine in epidurals or perineural sheath was used in the prevention of phantom and stump pain [6].

Dexmedetomidine has a sedative, anxiolytic, analgesic, and antihypertensive action owing to its high selectivity to α2-adrenergic receptor, and it improves the quality of perioperative analgesia used as infusion form in reducing acute and chronic postoperative amputation pain [7].

In this randomized prospective trial, we studied the effect of administering fentanyl or dexmedetomidine as additive to bupivacaine in epidural catheter in perioperative period to reduce acute postoperative stump and phantom pain and opioid consumption in patients undergoing unilateral above- or below-knee amputation.

Patient and methods

After permission from the Institutional Review Board, written informed consent was taken from all patients after explanation of all procedural steps in Ain Shams University Hospitals. American Society of Anesthesiologists physical status I–II patients scheduled for unilateral above- or below-knee amputation owing to ischemia, infection, or trauma in the period from June 2015 to April 2017 were included. Group sample sizes of 31 in group 1 and 31 in group 2 achieved 81% power to detect a difference in postoperative stump pain between the groups proportions of 30%. The test statistic used is the two-sided Z test with pooled variance. The significance level of the test was targeted at 0.05. The significance level actually achieved by this design is 0.0521. Thirty-three patients were included in each group to replace any missing data in the study.

Patients with coagulopathy, uncontrolled diabetes, cardiac diseases, and morbid obesity; patients who refused the continuous perioperative infusion of analgesia; patients with hypersensitivity to bupivacaine, dexmedetomidine, or fentanyl; or those with excessive intraoperative blood loss more than allowable amount to every patient were excluded.

Preoperative day

Twenty-four hours before the operation, intravenous line G18 was inserted in all patients, and an infusion of 500 ml of Ringer solution was started with monitoring of heart rate and blood pressure. Epidural analgesia (Perican needle G18, catheter G 27; B. Braun, Melsungen AG, Germany) was initiated.

Cases were classified randomly (by simple randomization) into two groups.

Dexmedetomidine group

Dexmedetomidine 2 ml (200 µg) was added to 48 ml bupivacaine 0.125% in a 50-ml syringe. The rate of epidural infusion was 5 ml/h for the 24 h before surgery and 72 h postoperatively.

Fentanyl group

Fentanyl 2 ml (100 µg) was added to 48 ml bupivacaine 0.125% in a 50-ml syringe. The rate of epidural infusion was 5 ml/h for 24 h before surgery and 72 h postoperatively.

The intervention was stopped if there were adverse effects of the study medications in the two groups.

The sedation level was assessed by a modified Wilson sedation scale from 1 to 4, where 1=fully awake, 2=drowsy, 3=sleepy but arousal to commands, and 4=sleepy but arousal to physical stimulation.

Sedation scores were assessed with the start of epidural insertion and then every 6 h.

Anesthetic technique

Epidural analgesia was stopped during operation. After complete sterilization and injection of local anesthesia, all patients received spinal (L4-5 interspace) anesthesia using bupivacaine 3.5 ml 0.5% plus fentanyl 25 µg through Polymed spinal needle G25. After surgery, epidural analgesia was restarted according to the protocol of the study.

Postoperative

Drug infusion through the epidura was continued for the postoperative 72 h. The hypotension (mean arterial blood pressure decreased 20% of the baseline reading) was managed by fluid infusion, and increment doses of ephedrine (5–10 mg). The bradycardia (heart rate <60 bpm) was managed with atropine (0.02 mg/kg). If the patients had pain [visual analog scale (VAS) >4], meperidine was given. Itching was managed with naloxone. The measures included the presence of stump pain, the presence of phantom pain all over the 3 days and then after 6 months, and VAS immediately postoperative then every 6 h for 72 h. Sedation was assessed in the same timings with pain. The total dose of postoperative opioid consumption was calculated in 3 days. Patient satisfaction was measured (0=dissatisfied, 1=somewhat dissatisfied, 2=undecided, 3=somewhat satisfied, and 4=satisfied).

To follow the double-blind nature of the study, the anesthesiologist who attended the surgery and recorded the data was blind to both groups assigned.

The statistical analysis was performed using SPSS software package, version 17 (SPSS Inc., Chicago, Illinois, USA). Normally distributed numerical data are presented as mean±SD, and differences between groups were compared using the independent Student’s t test. Data not normally distributed were compared using Mann–Whitney test and are presented as median (interquartile range), and categorical variables were analyzed using the χ2 test or Fisher’s exact test and are presented as n (%). All P values are two sided. P value less than 0.05 is considered statistically significant.


  Results Top


There were no significant statistical differences between groups with respect to age, sex, weight, and American Society of Anesthesiologists. Moreover, duration, reason of amputation, and level of amputation showed no statistical difference between the studied groups ([Table 1]). Two patients in the study groups died in the follow-up period, where one of them died from myocardial infarction and the other one died from cerebral stroke. In two other patients, contact was lost with them. The rest of patients were able to complete the entire study design, and their data were included in the final analysis.
Table 1 Demographic data

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There was a statistically significant increase in preoperative sedation score in group D after 6 h of initiation of epidural analgesia ([Figure 1]). The same result was found in the 3 days postoperatively. Group D had statistically significant increase in sedation scores than group F ([Figure 2]).
Figure 1 Preoperative sedation score.

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Figure 2 Postoperative sedation score.

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VAS was statistically significant lower in group D than group F in the 72 h postoperatively ([Table 2]), which led to the more use of rescue analgesic (meperidine) in group F 232±23.1 mg than group D 142.2±46.68 mg ([Table 4]).
Table 2 Visual analog score

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Incidence of postoperative stump and phantom pain in group D was less significant in comparison with group F in the first 72 h postoperatively.

Moreover, after 6 months, we found the same results as after 72 h postoperatively ([Table 3]).
Table 3 Incidence of phantom and stump pain

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Patients’ satisfaction was significantly higher in group D in comparison with group F (P˂0.01) ([Table 4]). Regarding complications, patients in group D experienced bradycardia and hypotension significantly more than group F. However, patients in group F experienced significantly from itching than group D ([Table 5]).
Table 4 Satisfaction score and rescue analgesia

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Table 5 Complications

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  Discussion Top


PLP is defined as pain perceived by the region of the body no longer present [8]. Stump pain is described as the pain in the residual part of the amputated limb, whereas phantom sensations are the sensation of presence of body part that had been amputated [9]. Peripheral mechanisms in the form of stump and neuroma hyperactivity and central neural mechanisms such as spinal cord sensitization, changes in cortical reorganization, and cortical-motor sensory dissociation are among the theories that have gained consensus as proposed mechanisms over the recent years [10]. Perioperative use of analgesics and anesthetics is believed to prevent the noxious stimulus from the amputated limb from triggering hyperplastic changes and central neural sensitization, which may prevent the magnification of future impulses from the amputation site [11].

The present study showed that adding dexmedetomidine as an adjuvant to epidural bupivacaine 0.125% in patients undergoing above- or below-knee amputation improved patient satisfaction, decreased intensity of pain, decreased opioid consumption, and decreased incidence of phantom and stump pain in comparison with adding fentanyl. Preemptive analgesia can reduce incidence of phantom and stump pain, which usually occur after amputation [12]. This was confirmed by a lot of studies; one of them showed that adding diamorphine, clonidine, and bupivacaine to normal saline as epidural infusion in comparison with opioid injection on demand reduced the incidence of phantom and stump pain after amputation for 6 months postoperatively [13]. Another study compared preoperative epidural and intraoperative perineural anesthetic block for the prevention of postoperative stump and PLP following limb amputation. Stump pain scores were significantly higher in the first 3 days in the perineural group compared with the epidural group. Epidural is not superior to infusion of local anesthetic via a perineural catheter in preventing phantom pain, but it gives better relief of stump pain in the immediate postoperative period [14].

Dexmedetomidine is highly specific for the α2 versus the α1 receptor (200 : 1 for clonidine vs. 1600 : 1 for dexmedetomidine). It inhibits the release of norepinephrine and subsequently decreases sympathetic tone through presynaptic activation of the α2 adrenoceptors. It also attenuates the hemodynamic and neuroendocrine responses to anesthesia and surgery, leading to sedation and analgesia [15]. Various studies have investigated its role in improving neuropathic pain. Bajwa and colleagues compared dexmedetomidine with fentanyl in 102 patients undergoing lower limb surgeries. Dexmedetomidine was a better alternative to fentanyl as an epidural adjuvant with comparable stable hemodynamics, early onset of sensory block, prolonged postoperative analgesia, lower consumption of local anesthetics for epidural analgesia in postoperative period, and much better sedation levels [16]. Use of dexmedetomidine for treating phantom pain was reported by Wang and colleagues for high-risk case undergoing lower limb amputation after ischemic necrosis of the limb. This case showed that adding 1 µg/kg dexmedetomidine to ropivacaine for lumbar plexus and sciatic nerve block was a feasible and safe technique for high-risk patients for lower limb amputation surgery. This maintained hemodynamic stability with adequate sedation and intraoperative sensory block. Analgesia was maintained for 26 h after operation without the need for supplementary analgesics [17]. Disadvantages for use of dexmedetomidine in this study were excess sedation, hypotension, and bradycardia; this was because of the prolonged epidural infusion with the drug for more than 3 days.

To our knowledge, no other study used dexmedetomidine as additive to bupivacaine in epidural infusion for phantom and stump pain after lower limb amputation. This study was limited by several factors, especially the sample size. A larger number of patients might have provided power to the results. Comparison of phantom and stump pain over longer time up to 1 year after surgery was not feasible to contact with all of patients after that period. Phantom pain is a resistant symptom after amputation. It is mainly a psychiatric illness. Its incidence was explained by different mechanisms, and trials of its prevention were studied in previous studies, yet many more studies are needed to find effective treatment.


  Conclusion Top


Dexmedetomidine is an ideal adjuvant to epidural bupivacaine for preventing phantom and stump pain compared with fentanyl in patients undergoing above- or below-knee amputation. Dexmedetomidine provides a better postoperative analgesia, reduces opioid consumption, and decreases incidence of phantom and stump pain. It improved patient satisfaction and decreased intensity of pain.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Wiessman MP, Liberty IF, Segev RW, Katz T, Abu Tailakh M, Novack V. Clinical characteristics and survival of patients with diabetes mellitus following non-traumatic lower extremity amputation. Isr Med Assoc J 2015; 17:145–149.  Back to cited text no. 1
    
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Esmaoglu A, Mizrak A, Akin A, Turk Y, Boyaci A. Addition of dexmedetomidine to lidocaine for intravenous regional anaesthesia. Eur J Anaesthesiol 2005; 22:447–451.  Back to cited text no. 7
    
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Weinstein SM. Phantom limb pain and related disorders. Neurol Clin 1998; 16:919–935.  Back to cited text no. 8
    
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Jahangiri M, Bradley JWP, Jayatunga AP, Dark CH. Prevention of phantom pain after major lower limb amputation by epidural infusion of diamorphine, clonidine and bupivacaine. Ann R Coll Surg Engl 1994; 76:324–326.  Back to cited text no. 13
    
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Lambert AW, Dashfield AK, Cosgrove C, Wilkins DC, Walker AJ, Ashley S. Randomized prospective study comparing preoperative epidural and intraoperative perineural analgesia for the prevention of postoperative stump and phantom limb pain following major amputation. Reg Anesth Pain Med 2001; 26:316–321.  Back to cited text no. 14
    
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Hall JE, Uhrich TD, Barney JA, Arain SR, Ebert TJ. Sedative, amnestic and analgesic properties of small-dose dexmedetomidine infusions. Anesth Analg 2000; 90:699–705.  Back to cited text no. 15
    
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Bajwa SJS, Arora V, Kaur J, Singh A, Parmar SS. Comparative evaluation of dexmedetomidine and fentanyl for epidural analgesia in lower limb orthopedic surgeries. Saudi J Anaesth 2011; 5:365–370.  Back to cited text no. 16
    
17.
Wang C-G, Ding Y-L, Han A-P, Hu CQ, Hao S, Zhang FF. et al... Adding dexmedetomidine to ropivacaine for lumbar plexus and sciatic nerve block for amputation of lower limb in high-risk patient − a case report. Int J Clin Exp Med 2015; 8:14184–14187.  Back to cited text no. 17
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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