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EDITORIAL
Year : 2014  |  Volume : 58  |  Issue : 6  |  Page : 681-683  

Alpha 2 agonists in regional anaesthesia practice: Efficient yet safe?


1 Section Editor (Critical Care), IJA; Department of Anaesthesiology and Critical Care, Jawaharlal Institute of Postgraduate Medical Education and Research, Institute of National Importance, Pondicherry, India
2 Department of Anaesthesiology and Critical Care, Jawaharlal Institute of Postgraduate Medical Education and Research, Institute of National Importance, Pondicherry, India

Date of Web Publication17-Dec-2014

Correspondence Address:
Kundra Pankaj
Section Editor (Critical Care), IJA; Department of Anaesthesiology and Critical Care, Jawaharlal Institute of Postgraduate Medical Education and Research, Institute of National Importance, Pondicherry
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-5049.147127

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How to cite this article:
Pankaj K, Rajan P S. Alpha 2 agonists in regional anaesthesia practice: Efficient yet safe?. Indian J Anaesth 2014;58:681-3

How to cite this URL:
Pankaj K, Rajan P S. Alpha 2 agonists in regional anaesthesia practice: Efficient yet safe?. Indian J Anaesth [serial online] 2014 [cited 2019 Dec 15];58:681-3. Available from: http://www.ijaweb.org/text.asp?2014/58/6/681/147127

Clonidine and dexmedetomidine, partial and selective alpha 2 agonists respectively are being studied and used in regional anaesthesia practice as adjuvant to local anaesthetic (LA) agents for a long period of time. Widespread presence of alpha 2 receptors in the brain, spinal lamina and peripheral nerves and their role in pain modulation explains the analgesic and LA sparing action of these agents. Despite their potential analgesic benefits it is prudent to analyse their systemic as well as neuronal safety issues in the current era of safe anaesthesia practice.

Clonidine has been used as an epidural analgesic for cancer pain relief from 1980. [1] Development of preservative free clonidine and its proven safety for neuraxial use in animal studies [2],[3],[4] have popularised its use as an adjuvant to LA agents in neuraxial [5],[6] and peripheral nerve and plexus blocks. [7],[8] Clonidine was used as adjuvant to LA agents via oral, [9],[10] intravenous, [11] neuraxial and perineural routes to study its beneficial effect on prolonging sensory or motor block and postoperative analgesia by various regional anaesthetic techniques. Route of administration of clonidine as an adjuvant to LA agents has its own relevance in practice. Oral clonidine premedication did not prolong analgesia after hernia surgery [9] and the postoperative analgesic duration was similar to oral diazepam premedication in elderly patients undergoing ocular surgeries under peribulbar block [10] indicating minimal effect of oral clonidine in prolonging LA agents action. However, neuraxial clonidine with bupivacaine triples the duration of spinal anaesthesia (5.3 h vs. 1.8 h) in patients undergoing hip surgery and caudal clonidine prolonged the time to require first analgesic by six hours in anorectal surgery. [12] Although there was no evidence of neurotoxicity in humans, the current concern of using clonidine in regional anaesthesia is related to its haemodynamic and undesired sedative side effects. In a recent review and meta-analysis of perineural use of clonidine along with LA agents, clonidine prolonged mean duration of analgesia and motor blockade by about two hours and was associated with high incidence of hypotension (OR: 3.61; 95% CI: 1.52-8.55, number needed to harm [NNH] =11), fainting (OR: 5.07; 95% CI: 1.20-21.4, NNH = 5) with unclear dose responsiveness for beneficial or harmful effects. [13]

Dexmedetomidine, a more selective alpha 2 agonist used for many years in veterinary anaesthesia practice [14] is also studied in humans for its safety and efficacy through intravenous and combined use with LA agents as an adjunct to neuraxial and perineurally administered LA agents. A meta-analysis evaluating the effect of intravenous dexmedetomidine on spinal anaesthesia characteristics found that the duration of sensory block and motor block was prolonged by 37% and 17% respectively. The time to first analgesic request was increased by at least 53%. This was associated with 3.4-fold increase in transient bradycardia incidents without significant hypotension and sedation. [15] Another meta-analysis analysing the effects of intrathecal and intravenous dexmedetomidine in spinal anaesthesia found high incidence of bradycardia requiring atropine (OR: 7.55; 95% CI: 2.76-20.63) with significant prolongation of motor and sensory block duration. [16] Similarly a review and meta-analysis on facilitatory effect of perineurally administered dexmedetomidine along with LA agents concluded that it prolonged mean sensory block by 284 minutes with 7% incidence of reversible bradycardia. (17] In spite of unclear dose responsiveness for either harmful or beneficial effect, when these agents are used in the lowest effective dose, the systemic side effects seem to be minimal without affecting the benefits. Low and equipotent dose of clonidine (30 μg) and dexmedetomidine (3 μg) along with 12 mg of bupivacaine significantly improved the onset of motor blockade and prolonged the motor and sensory block regression when compared to bupivacaine alone in spinal anaesthesia without any significant hypotension. [17] The available evidences clearly show a differential block pattern while adding these agents as adjuvants to LA agents. Clonidine prolonged sensory block preferentially when compared to dexmedetomidine which prolonged both sensory and motor block duration. Prolonged motor block may delay early ambulation and discharge or may result in patient fall. [18]

United States Food and Drug Administration and Drug Controller General of India (DCGI) approved dexmedetomidine for short term sedation of mechanically ventilated patients and for ICU sedation. [19],[20] Off-label clinical and investigational use of dexmedetomidine is reported in literature for perineural and neuraxial administration. If the physicians use a product for an indication other than the approved purpose they have the responsibility to be well informed about the product and its use with firm scientific rationale. It does not require the submission of an Investigational New Drug (IND) or Investigational Device Exemption (IDE) application if it is used for practice of medicine. Investigational use of approved marketed products needs submission to IND or IDE if it involves change in the route of administration or dosage level, use in subject population or other factors that significantly increases the risk. [21] The studies concerning peripheral and intrathecal usage of dexmedetomidine as an adjuvant to LA agents are mostly from middle eastern countries. A recent review on this subject questions the policies of institutional review boards and editorial boards. [17]

Neurotoxicity of perineurally administered dexmedetomidine is unclear. Demyelination of oligodentrocytes has been reported when injected epidurally. [22] However, other studies in animals demonstrated neuro protective effect of intravenous dexmedetomidine against cerebral ischemic events. [23],[24] Although human studies of perineural dexmedetomidine show no evidence of neurological deficit, the safety data on the use of dexmedetomidine in perineural and neuraxial administration is limited and do not support its use in routine clinical practice. [17] Investigational use of perineural or neuraxial dexmedetomidine without approval from DCGI may place the investigator, the institute and the review board at risk of medical malpractice litigations if there are drug related adverse events. Till the safety of perineural and neuraxial dexmedetomidine is clearly proven by further approved studies it is safe to avoid its use in neuraxial and perineural routes.

To conclude, for the safe regional anaesthesia practice in patients receiving alpha 2 agonists as adjuvants to LA agents, one should monitor for bradycardia and hypotension, possible excess sedation and subsequent fall in haemoglobin saturation. Till regulatory board approved and well powered safety studies for the use of perineural dexmedetomidine are available, it is safe to restrict its use in regional anaesthesia practice as an intravenous adjuvant to LA agents for its beneficial sedative and analgesic properties without respiratory depression.

 
   References Top

1.
Tamsen A, Gordh T. Epidural clonidine produces analgesia. Lancet 1984;2:231-2.  Back to cited text no. 1
    
2.
Eisenach JC, Grice SC. Epidural clonidine does not decrease blood pressure or spinal cord blood flow in awake sheep. Anesthesiology 1988;68:335-40.  Back to cited text no. 2
    
3.
Yaksh TL, Rathbun M, Jage J, Mirzai T, Grafe M, Hiles RA. Pharmacology and toxicology of chronically infused epidural clonidine.HCl in dogs. Fundam Appl Toxicol 1994;23:319-35.  Back to cited text no. 3
    
4.
Gordh T Jr, Post C, Olsson Y. Evaluation of the toxicity of subarachnoid clonidine, guanfacine, and a substance P-antagonist on rat spinal cord and nerve roots: Light and electron microscopic observations after chronic intrathecal administration. Anesth Analg 1986;65:1303-11.  Back to cited text no. 4
[PUBMED]    
5.
Forster JG, Rosenberg PH. Small dose clonidine mixed with low dose ropivacaine and fentanyl for epidural analgesia after total knee arthroplasty. Br J Anaesth 2004;93:670-7.  Back to cited text no. 5
    
6.
Thakur A, Bharadwaj M, Kaur K, Dureja J, Hooda S, Taxak S. Intrathecal clonidine as an adjuvant to hyperbaric bupivacaine in patients undergoing inguinal herniorraphy: A randomised double-blinded study. J Anaesthesiol Clin Pharmacol 2013;29:66-70.  Back to cited text no. 6
[PUBMED]  Medknow Journal  
7.
Casati A, Magistris L, Fanelli G, Beccaria P, Cappelleri G, Aldegheri G, et al. Small-dose clonidine prolongs postoperative analgesia after sciatic-femoral nerve block with 0.75% ropivacaine for foot surgery. Anesth Analg 2000;91:388-92.  Back to cited text no. 7
    
8.
Hutschala D, Mascher H, Schmetterer L, Klimscha W, Fleck T, Eichler HG, et al. Clonidine added to bupivacaine enhances and prolongs analgesia after brachial plexus block via a local mechanism in healthy volunteers. Eur J Anaesthesiol 2004;21:198-204.  Back to cited text no. 8
    
9.
Ezri T, Szmuk P, Shklar B, Katz J, Geva D. Oral clonidine premedication does not prolong analgesia after herniorrhaphy under subarachnoid anesthesia. J Clin Anesth 1998;10:474-81.  Back to cited text no. 9
    
10.
Kumar A, Bose S, Bhattacharya A, Tandon OP, Kundra P. Oral clonidine premedication for elderly patients undergoing intraocular surgery. Acta Anaesthesiol Scand 1992;36:159-64.  Back to cited text no. 10
    
11.
Bernard JM, Kick O, Bonnet F. Comparison of intravenous and epidural clonidine for postoperative patient-controlled analgesia. Anesth Analg 1995;81:706-12.  Back to cited text no. 11
    
12.
Eisenach JC, De Kock M, Klimscha W. Alpha (2)-adrenergic agonists for regional anesthesia. A clinical review of clonidine (1984-1995). Anesthesiology 1996;85:655-74.  Back to cited text no. 12
    
13.
Pöpping DM, Elia N, Marret E, Wenk M, Tramèr MR. Clonidine as an adjuvant to local anesthetics for peripheral nerve and plexus blocks: A meta-analysis of randomized trials. Anesthesiology 2009;111:406-15.  Back to cited text no. 13
    
14.
Sinclair MD. A review of the physiological effects of alpha2-agonists related to the clinical use of medetomidine in small animal practice. Can Vet J 2003;44:885-97.  Back to cited text no. 14
    
15.
Abdallah FW, Abrishami A, Brull R. The facilitatory effects of intravenous dexmedetomidine on the duration of spinal anesthesia: A systematic review and meta-analysis. Anesth Analg 2013;117:271-8.  Back to cited text no. 15
    
16.
Niu XY, Ding XB, Guo T, Chen MH, Fu SK, Li Q. Effects of intravenous and intrathecal dexmedetomidine in spinal anesthesia: A meta-analysis. CNS Neurosci Ther 2013;19:897-904.  Back to cited text no. 16
    
17.
Kanazi GE, Aouad MT, Jabbour-Khoury SI, Al Jazzar MD, Alameddine MM, Al-Yaman R, et al. Effect of low-dose dexmedetomidine or clonidine on the characteristics of bupivacaine spinal block. Acta Anaesthesiol Scand 2006;50:222-7.  Back to cited text no. 17
    
18.
Abdallah FW, Brull R. Facilitatory effects of perineural dexmedetomidine on neuraxial and peripheral nerve block: A systematic review and meta-analysis. Br J Anaesth 2013;110:915-25.  Back to cited text no. 18
    
19.
US Food and Drug Administration. Precedex (dexmedetomidine hydrochloride) prescribing information October 2010. Available from: http://www.accessdata.fda.gov/drugsaftdadocs/label/2010/021038s017ibl.pdf. [Last accessed on 2014 Dec 01].  Back to cited text no. 19
    
20.
Central Drugs Standard Control Organization. Approved drug list; 29/May/2009. Available from: http://www.cdsco.nic.in/.[Last accessed on 2014 Dec 01].  Back to cited text no. 20
    
21.
Off label and investigational use of marketed drugs, biologics and medical devices- information sheet. Available from: http://www.fda.gov/regulatoryInformation/Guidelinces/ucm126486.htm. [Last accessed on 2014 Dec 01].  Back to cited text no. 21
    
22.
Konakci S, Adanir T, Yilmaz G, Rezanko T. The efficacy and neurotoxicity of dexmedetomidine administered via the epidural route. Eur J Anaesthesiol 2008;25:403-9.  Back to cited text no. 22
    
23.
Degos V, Charpentier TL, Chhor V, Brissaud O, Lebon S, Schwendimann L, et al. Neuroprotective effects of dexmedetomidine against glutamate agonist-induced neuronal cell death are related to increased astrocyte brain-derived neurotrophic factor expression. Anesthesiology 2013;118:1123-32.  Back to cited text no. 23
    
24.
Ma D, Hossain M, Rajakumaraswamy N, Arshad M, Sanders RD, Franks NP, et al. Dexmedetomidine produces its neuroprotective effect via the alpha 2A-adrenoceptor subtype. Eur J Pharmacol 2004;502:87-97.  Back to cited text no. 24
    



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