Alpha2 Agonists in Acute Pain Management

Review
Alpha-2 agonists in acute pain management

Albert Kam Ming Chan, Chi Wai Cheung & Yeow Kuan Chong
The University of Hong Kong, Queen Mary Hospital, Department of Anaesthesiology, Hong Kong
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Introduction Pharmacokinetics of clonidine and dexmedetomidine Pharmacodynamics of alpha-2 agonists Mechanisms leading to antinociception Clonidine and postoperative analgesia Dexmedetomidine and postoperative analgesia Expert opinion
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by HINARI on 03/27/12 For personal use only.
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Importance of the field: This review explores the significance of alpha-2 agonists used clinically in acute pain management. Areas covered in this review: Although alpha-2 agonists have been reported to have an analgesic effect, they are not commonly used clinically for acute pain management. Clinical studies on use of alpha-2 agonists for acute pain management are reviewed and discussed. A literature search was done using Medline with the keywords alpha-2 agonist, clonidine, dexmedetomidine, fadolmidine, pharmacokinetics, pharmacodynamics, postoperative analgesia, epidural, intrathecal, peripheral nerve block and various combinations with these keywords. The years 1977 -- 2009 have been included, with particular focus on clinical studies from between 1990 and 2009. What the reader will gain: This article helps to clarify the clinical use of alpha-2 agonists in acute pain management according to current, up-todate evidence. Clinically, available alpha-2 agonists, including clonidine and dexmedetomidine, are discussed in detail. Take home message: Alpha-2 agonists, especially clonidine, seem to be promising with regard to acute postoperative pain management. However, more clinical evidence on dexmedetomidine is necessary to confirm its definite role in acute postoperative pain control.
Keywords: acute pain, alpha-2 agonist, analgesia, clonidine, dexmedetomidine, fadolmidine Expert Opin. Pharmacother. (2010) 11(17):2849-2868
1.
Introduction
Since the synthesis of the first alpha-2 adrenergic receptor agonist, clonidine, in the early 1960s, numerous uses of the chemicals have been discovered -- first the antihypertensive effect [1], then drug detoxification [2] and, recently, the role in pain control and sedation [3,4]. Initially used mainly to treat hypertension, the clinical application of alpha-2 agonists has been expanded widely in the field of anesthesia. This includes adjunctive use for peri- and postoperative pain relief, sedation and anxiolysis for operative procedures as well as intensive care management, and treatment of chronic pain syndromes. Their clinical use has been even further extended to regional and neuroaxial anesthesia. One definition of acute pain is the normal, predicted physiological response to an adverse chemical, thermal or mechanical stimulus associated with surgery, trauma and acute illness [5]. Others have given definitions that related to the expected natural course [6] and opined using different defined timeframes. We explore the role of alpha-2 agonists in postoperative analgesia, the commonest type of acute pain. In this article, the underlying mechanisms and clinical uses of alpha-2 agonists in postoperative analgesia will be reviewed using clonidine, the prototype alpha-2 agonist, and dexmedetomidine, a relatively newer alpha-2 agonist that has gained popularity.
10.1517/14656566.2010.511613 2010 Informa UK, Ltd. ISSN 1465-6566 All rights reserved: reproduction in whole or in part not permitted
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Article highlights.
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Alpha-2 adrenoreceptor agonists, including clonidine and dexmedetomidine, can provide sedation, analgesia and anxiolysis in clinical practice. Even though there is compelling evidence demonstrating the postoperative analgesic effects of alpha-2 agonists, they are not very commonly used for acute pain management. Clonidine not only provides postoperative analgesia when used alone, but also improves the analgesic efficacy of local anesthetics and morphine when used regionally, although its use in epidural route is still inconclusive. Although dexmedetomidine is 8 times more specific to alpha-2 receptors than clonidine and shown to have opioid sparing effect, its analgesic benefits are still immature. Additional studies should target the analgesic benefits of dexmedetomidine in different types of surgery, in different routes of administration and in multimodal analgesia, as well as its other roles in the perioperative period. Fadolmidine, the newest alpha-2 agonist, in postoperative analgesia is yet to be determined as the drug is undergoing Phase I clinical trials at present. It is a full agonist of all subtypes of alpha-2 adrenoreceptors and does not cross the blood--brain barrier. It seems to be promising in animal studies for analgesia and may help to dissect the central and peripheral analgesic mechanisms of alpha-2 adrenoreceptor agonists.
CSF concentration is ~ 8% of the plasma concentration [11]. Dexmedetomidine is primarily metabolized into methyl and glucuronide conjugates, which are excreted mainly (95%) by the kidneys [12], while the metabolites are pharmacologically inactive [13]. Similar pharmacokinetic characteristics are found amongst the pediatric population [14].
3.
Pharmacodynamics of alpha-2 agonists
This box summarizes key points contained in the article.
Pharmacokinetics of clonidine and dexmedetomidine

2.
Clonidine is a selective agonist of alpha-2 adrenergic receptors with an alpha-2 to alpha-1 ratio of 200:1 [7]. Clonidine, when given orally, is rapidly absorbed within 30 min and has a bioavailability of 75% [7]. Clonidine can be given by oral, rectal, transdermal [8], intravenous, intrathecal and epidural routes. The pharmacokinetic variables of clonidine have been established for these routes of administration [8,9]. Clonidine crosses the blood--brain barrier and the cerebrospinal fluid (CSF) concentration is 50% of the plasma concentration [7]. It is mainly eliminated in urine in the unchanged form, and its other degradation products, mainly coming from splitting of the imidazolidine ring and hydroxylation of the phenyl ring, are pharmacologically inactive [7]. The half-life of clonidine is the same for both oral and intravenous administration, as well as single-dose and long-term treatment, at 5.2 -- 13 h [7]. Dexmedetomidine is a highly selective agonist of alpha-2 adrenergic receptor with an alpha-2 to alpha-1 ratio of 1620:1 [10], approximately 8 times more specific than clonidine to alpha-2 adrenergic receptors. Dexmedetomidine can be administered via intravenous, intramuscular, intranasal and transdermal routes. It crosses the blood--brain barrier and the
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Ahlquist in 1948 first described the alpha and beta subtypes of adrenergic receptors based on different pharmacological responses [15]. The adrenoreceptors were initially classified into alpha and beta receptors based on pharmacological characteristics. As the underlying signaling mechanism became clearer, it was found that adrenoreceptors are G-protein coupled receptors. Specifically, beta receptors are coupled to the Gs protein, which stimulates adenylyl cyclase; whereas alpha-2 receptors are coupled to the Gi and Go proteins, which inhibit and have null effect on adenylyl cyclase, respectively [16,17]. Alpha-2 adrenergic receptors have been further subclassified into alpha-2A, alpha-2B and alpha-2C based mostly on radioligand binding data [16-18]. The alpha-2A subtype is most likely to be responsible for the analgesic properties in both peripheral and central sites [19,20]. As a result of alpha-2 adrenergic activation, adenylyl cyclase activity is inhibited by the Gi protein and the plasma level of cAMP decreases. In addition to the decrease of intracellular cyclic AMP level, other effector mechanisms have also been found to follow activation of alpha-2 adrenergic receptors. Activation of potassium channels [3,4,17] (via Gi coupling and subsequently causing hyperpolarization of neuronal membrane) and inhibition of N-type voltage-sensitive calcium channels (via Go coupling with decrease calcium influx and neurotransmitter release) [3,17,21] are shown to be responsible for the analgesic effects of alpha-2 agonists.
4.
Mechanisms leading to antinociception
The analgesic properties of alpha-2 agonists are proposed to involve both peripheral and central mechanisms. Evidence of the role of alpha-2 agonists in producing antinociception peripherally stems from the fact that clonidine and other alpha-2 adrenergic agonists (St-91, in Nakamuras study) produce analgesic effects regardless of the ability to cross the blood--brain barrier [22]. The mechanism of action of alpha-2 agonists when administered peripherally remains unclear, although the receptors have been isolated from the peripheral nerves of rats [23]. However, several lines of evidence have been proposed: i) clonidine at high concentrations would cause blockade of peripheral nerve fibers, especially C-fibers [24]; ii) clonidine causes local vasoconstriction, which may result in higher concentrations of local anesthetic near the nerves and lower concentrations within the plasma [24]. However, this theory is disputed as trials have shown that, when clonidine is
Expert Opin. Pharmacother. (2010) 11(17)
Chan, Cheung & Chong
administered with a local anesthetic regionally, the plasma concentration of the local anesthetic remains the same or becomes even higher [25,26]. Another mechanistic explanation concerning the peripheral antinociceptive effect of alpha-2 adrenergic agonists lies in the phenomenon that the mu opioid receptor, the alpha-2 receptor and the A1-adenosine receptor exhibit properties of cross tolerance and dependence, as demonstrated by Aley and Levine [27]. Moreover, the authors showed that the antinociceptive action of alpha-2 agonist clonidine was blocked by mu-receptor and A1-receptor antagonists. Conversely, mureceptor-mediated and A1-receptor-mediated antinociception were both blocked by alpha-2 antagonists. By using a murine nociceptive model, Aley and Levine suggested that alpha-2 receptor-mediated antinociception is closely related to that of opioid and adenosine receptors, and that the underlying molecular mechanism of this interaction is likely to be attributed to inhibitory G-proteins. As for the central mechanism, alpha-2 adrenergic receptors are also located in the dorsal horn of the spinal cord, and it seems that alpha-2 agonists act on both pre- and postsynaptic mechanisms to produce antinociception. Local administration of clonidine i) reduces the excitability of the central terminal of primary afferent fibers [28], ii) inhibits release of substance P [29] and iii) causes hyperpolarization and a decrease in spontaneous activity of dorsal horn neurons. The supraspinal role of alpha-2 adrenergic agonists, however, remains unclear, although activation of central alpha-2 adrenoreceptors in the locus coeruleus seems to produce analgesia [30]. Whereas microinjection studies in the nucleus raphe magnus can produce antinociception [31], others argue that there is no supraspinal mechanism as direct administration of alpha-2 adrenergic agonists into brainstem conveys no antinociception [17]. Pharmacokinetic and pharmacodynamic studies support the spinal site of action as the primary location for antinociception of alpha-2 agonists, as lumbar injection of clonidine produces antinociception in the lower extremities, but not in the upper extremities of healthy volunteers, and the CSF level of clonidine corresponds to the degree of antinociception [24,32].
5.
extradural clonidine in postoperative analgesia, only to conclude that the tremendous variability in study design made it very difficult to carry out a systematic review with the data at the time. In the following sections, we review the current evidence regarding the use of clonidine in both adults and children for postoperative pain control via different routes of administration, and provide a comprehensive analysis of the available data.
Systemic clonidine in postoperative analgesia Few studies between 1990 and 2010 were identified that describe the use of parenteral clonidine (Table 2). Of these, only two were randomized, controlled-trials, both of which supported the analgesic benefits of clonidine. Bernard et al. [34] randomly assigned 50 patients postoperatively to receive either intravenous clonidine or placebo after spinal fusion. Clonidine was administered at a loading dose of 5 g/kg of clonidine during the first hour, then subsequently with a maintenance infusion of 0.3 g/kg/h. Pain scores were significantly less at all time points compared with the placebo group. Morphine requirements in the first 12 h were also reduced significantly, with a longer time to first morphine injection. De Kock et al. [35] evaluated 200 patients undergoing major abdominal surgery who were randomized to receive balanced anesthesia with intraoperative intravenous clonidine (4 g/kg over 30 min loading, followed by infusion of 2 g/kg/h until closure of peritoneum) or balanced anesthesia alone (no placebo was administered), using patient-controlled analgesia (PCA) morphine as postoperative pain control. Intraoperative administration of clonidine decreased both the rate and total demand for analgesia up to 36 h postoperatively, reduced the dose of morphine delivered via PCA and resulted in better pain scores. It was concluded that intraoperative intravenous clonidine improved the quality of postoperative morphine PCA without significant side effects. Marinangeli and colleagues demonstrated the role of clonidine in postoperative analgesia by performing a dosefinding study to evaluate the optimal dose of clonidine to be administered in the perioperative period for patients undergoing lumbar hemilaminectomy [36]. Eighty patients were randomized into four groups, receiving loading doses of 5, 3 or 2 g/kg or 0.9% NaCl respectively 30 min before end of surgery for 30 min, followed by a 0.3-g/kg/h infusion of clonidine or 0.9% NaCl. PCA morphine was given for postoperative pain relief. Total consumption of morphine was significantly less for all clonidine groups compared with placebo, and cumulative morphine dose demands were also significantly less for all clonidine groups. However, pain scores were significantly higher in the first 2 -- 5 h postoperatively in placebo and 2-g/kg groups. The highest dose of 5 g/kg provided better analgesia but adverse effects of hypotension and sedation were severe and prolonged. The group given 0.3 g/kg clonidine infusion was provided with good pain
5.1
Clonidine and postoperative analgesia
Up to 2010, there have been more than 100 publications regarding the clinical effect of clonidine in postoperative analgesia. These studies have varied greatly in study design, mode and route of administration, clinical setting, study size and outcome measures, making comparison difficult. Routes of administration that have been described for clonidine include intravenous, epidural, intrathecal, perineural, intra-articular, oral, transdermal and local infiltration, as shown in Table 1. Some researchers found that it was difficult even to perform a systemic review on one mode of administration. Armand et al. [33] performed a meta-analysis of the literature from September 1985 to 1997 concerning the role of
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Table 1. Summary of routes of administration of clonidine and dosages.

Routes/modes of administration Oral [79-83] Transdermal [85] Intravenous [34-36,42,53,63] Patient-controlled analgesia [92] Intramuscular/subcutaneous [39-41,62] Epidural [53-65] Peripheral nerve/plexus blocks [37-44] Intrathecal [45-52] Intravenous regional anaesthesia [87-91] Intraarticular [71-78] Local infiltration [84] Dosage 2 -- 5 g/kg 0.3 mg/day Loading 2 -- 8 g/kg for 20 -- 60 min Infusion 0.3 -- 2 g/kg/h 20-g bolus (5-min lockout) or 30-g bolus (15-min lockout) 150-g or 2-g/kg bolus 75 -- 800-g bolus; infusion 0.3 -- 2 g/kg/h 90 -- 150 g or 1 g/kg 15 -- 150 g 150 g 150 g or 1 g/kg 75 g or 1 g/kg
relief during the first 12 h after surgery, without significant hypotension or sedation. In summary, systemically administered clonidine indeed has an analgesic effect in the postoperative setting, and this can be attributed mainly to the central effect of this alpha-2 agonist, as CSF concentration has been shown to be 50% of plasma concentration.
Clonidine in peripheral nerve and plexus blocks Multiple studies have demonstrated the positive effects of clonidine on postoperative analgesia when used adjunctively with local anesthetics in peripheral nerve and plexus blocks. McCartney et al. [37] reviewed 27 randomized controlled trials between July 1991 and October 2006 that investigated the use of clonidine as an adjunct to local anesthesia for peripheral nerve blockade. Authors from this qualitative analysis suggested that clonidine improves the duration of analgesia when used as an adjunct to intermediate-acting local anesthetics in peripheral nerve blocks. Ppping o et al. [38] carried out a meta-analysis to evaluate clonidine as an adjuvant to local anesthetics for peripheral nerve and plexus blocks. Twenty randomized controlled trials between 1992 and 2006 were analyzed. The type of blocks included axillary plexus, ilio-inguinal-hypogastric nerve, sciaticfemoral nerve, and mid-humeral and ankle blocks, in which clonidine was added to either an intermediate- (prilocaine, mepivacaine, lidocaine) or long-acting local anesthetic (ropivacaine, bupivacaine, levobupivacaine), and comparisons were made with a control group. While clonidine doses ranged from 90 to 150 g, duration of postoperative analgesia (defined as time until first analgesic request) was significantly increased in the clonidine groups. Since McCartney et al. [37] suggested in their review that clonidine was only beneficial when used as an adjunct to intermediate-acting and not long-acting local anesthetics; sensitivity analyses with data from axillary plexus block trials were also carried out to examine this point. Ppping and colleagues found o that clonidine prolonged duration of anesthesia when added
5.2
to both intermediate- and long-acting local anesthetics, by ~ 2 -- 2.5 h. Interestingly enough, the duration of analgesia by intermediate-acting local anesthetics was increased by 56%, while duration of long-acting anesthetics was increased by only 18%. Other outcome measures such as postoperative pain intensity were not analyzed because they were infrequently reported. However, clonidine significantly increased the incidence of hypotension from 4.1 to 13.1%, bradycardia from 4.1 to 8.5% at doses ranging from 30 to 300 g and sedation from 32.4 to 55.8%. The authors concluded that clonidine, when added to both intermediate and long-acting local anesthetics for peripheral nerve or plexus block, prolongs duration of postoperative analgesia by about 2 h; they were, however, unable to demonstrate dose responsiveness for either beneficial or harmful effects. Therefore, although the peripheral mechanism of antinociception produced by clonidine has not been fully understood, the systematic reviews have clearly shown that this alpha-2 agonist has a synergistic effect when administered perineurally in adjunct with local anesthetics. A few groups went further and compared parenteral clonidine to adjunctive use of clonidine in peripheral nerve blockade, but results were quite varied. In patients receiving axillary and interscalene block with local anesthetic, 150 g of subcutaneous clonidine provided inferior pain relief compared with the same dose of clonidine used perineurally [39,40]; in another trial, no benefits in terms of postoperative analgesia were shown when 150 g of clonidine was given either intramuscularly or perineurally (via interscalene block) [41]. However, Mannion et al. [42] showed, in a randomized, controlled trial that intravenous clonidine, instead of perineural clonidine, prolonged the postoperative analgesic effect of psoas compartment block with 0.5% levobupivacaine for hip fracture surgery, as evidenced by the significant longer time interval until first request for supplementary analgesia. In view of the lack of uniformity of these study designs, it is difficult to conclude whether the analgesic effect of systemically or perineurally administered clonidine is more prominent.
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Table 2. Studies evaluating parenteral clonidine in postoperative analgesia (including comparisons with regional techniques).
No. of Dose of patients clonidine 20 2 g/kg (both routes) Postoperative Increased analgesic duration and decreased pain scores in EP group (NS) Decreased morphine consumption (S), delayed TTFA, decreased pain scores (S) in IV group Decreased rate and total demand for PCA (S), decreased morphine consumption (1st 12 h) (S), decreased pain scores (S) in IV group; similar TTFA NS Increased analgesic duration (S) for AB group; similar pain scores and analgesic requirement in all groups NS Hypotension (S) and bradycardia (S) in IV group IV > PL Drowsiness, hypotension, bradycardia similar in both groups EP = IM Timing of Postoperative administration outcome Significant adverse effects Conclusion on analgesic efficacy
Year
Authors
Comparison
1990 Bonnet [62]
IM vs EP
1991 Bernard [34]
IV vs PL
50
5 g/kg over 1 h, then 0.3 g/kg/h Postoperative
1992 De Kock [35]
IV vs control (no PL)
200
4 g/kg over 30 min, then 2 g/kg/h Intraoperative
IV > control
1992 Singelyn [40]
SC vs AB vs control
30
150 g (SC and AB routes) Preoperative
AB > SC and control
1993 De Kock [53]
IV vs EP
40
4 g/kg over Intraoperative 20 min, then 2 g/kg/h (both routes)
Sedation, hypotension, bradycardia similar in both groups
EP > IV
1995 Bernard [63]
IV vs EP
24
8 g/kg over 30 min (both routes)
Postoperative
Decreased morphine requirements (1st 6 h) (S), pain scores (1st 12 h) (S) and number of analgesic demands (S) in epidural group; similar TTFA Similar pain scores; decreased cumulative PCA clonidine (30 g boluses at 15 min lockout) (S) in epidural group Preoperative Similar analgesic duration, pain scores, morphine consumption in all 3 groups
Sedation (IV > EP)(S); hypotension and bradycardia similar in both groups
IV = EP
2001 Culebras [41]
IM vs ISB vs PL
60
150 g (IM and ISB routes)
Hypotension (S) and bradycardia (S) in IM and ISB groups; Sedation (S) (IM > ISB, PL)
IM = ISB = PL
AB: Axillary block; CL: Clonidine; EP: Epidural; IM: Intramascular; ISB: Interscalene block; IV: Intravenous; M: Morphine; NM: Not mentioned; NS: Nonsignificant; PCA: Patient-controlled analgesia; PCB: Psoas compartment block; PL: Placebo; S: Significant; SC: Subcutaneous; TTFA: Time to first analgesia.
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No. of Dose of patients clonidine 80 2, 3 or 5 g/kg over 30 min, then 0.3 g/kg/h Intraoperative Decreased consumption of morphine (S) in all clonidine groups, decreased pain scores in 3- and 5-g/kg groups in 1st 2 -- 5 h (S) Hypotension (S) and bradycardia (S) in 5 g/kg groups Timing of Postoperative administration outcome Significant adverse effects Conclusion on analgesic efficacy 3 g/kg is optimal dose Intraoperative + postoperative 4 g/kg over 20 min, then post-op PCA (20 g CL + 1 mg M bolus) Decreased pain scores (1st 12 h) (S) in CL group; decreased morphine consumption (1st 24 h) (NS) 150 g (both routes) Preoperative Similar sedation; decreased postoperative nausea and vomiting in CL group (S) Similar hypotension and bradycardia CL + M > M (1st 12 h) 40 ISB > SC 36 1 g/kg (both routes) Preoperative Decreased pain scores at 0 h (S), longer analgesic duration (S), decreased ropivacaine consumption (S) in ISB group Increased TTFA (S) in IV group; similar TTFA in PCB and control groups; similar pain scores in all groups up to 24 h Similar sedation, hypotension and bradycardia IV > PCB
Table 2. Studies evaluating parenteral clonidine in postoperative analgesia (including comparisons with regional techniques) (continued).
Year
Authors
Comparison
2002 Marinangeli [36]
IV (3 groups) vs PL
2002 Jeffs [92]
PCA (CL + M) vs 60 PCA (M)
2003 Iskandar [39]
SC vs ISB
2005 Mannion [42]
IV vs PCB vs control
AB: Axillary block; CL: Clonidine; EP: Epidural; IM: Intramascular; ISB: Interscalene block; IV: Intravenous; M: Morphine; NM: Not mentioned; NS: Nonsignificant; PCA: Patient-controlled analgesia; PCB: Psoas compartment block; PL: Placebo; S: Significant; SC: Subcutaneous; TTFA: Time to first analgesia.
In the pediatric population, there are only few trials involving clonidine as an adjunct to regional anesthesia, and the analgesic benefits are not definite in this group of patients. Kaabachi et al. [43], who studied 98 children between 1 and 12 years of age undergoing herniorrhaphy or orchidopexy, did not find any advantage in using clonidine as an adjunct to 0.25% bupivacine for ilioingionaliliohypogastric nerve block compared with local anesthetic alone. Cucchiaro et al. [44] retrospectively reviewed the addition of clonidine to local anesthetic in peripheral nerve blockade (infraclavicular, lumbar plexus, femoral, fascia iliaca, sciatic nerve block) amongst pediatric patients. Results revealed that duration of analgesia was significantly longer in the clonidine group than in the control group without significant difference in postoperative opioid consumption. The evidence concerning perineural administration of clonidine is so far inconclusive in children, as different types and volume of local anesthetic agents have been used in these studies. Moreover, efficacy of regional anesthesia is largely affected by the operators technique and accuracy. With the advent of ultrasound-guided regional techniques, the analgesic effect of adjunctive clonidine can be further elucidated.
Clonidine in intrathecal anesthesia Intrathecal clonidine has been administered alone or as an adjunct to local anesthetics or morphine in different studies. Postoperative analgesia has been shown to be effective when intrathecal clonidine is used either alone or as an adjunct to local anesthetic agents. However, when it is injected intrathecally with morphine, the results are mixed. Filios et al. [45] were the first group to describe intrathecal clonidine as a sole analgesic for pain relief after caesarean section. They carried out a randomized, controlled trial amongst 20 healthy parturients who received either 150 g of clonidine or normal saline intrathecally in the postoperative period. Time to first supplemental analgesic request was prolonged significantly and pain score reduction was also noted. The group also demonstrated that the analgesic effect of intrathecal clonidine was dose dependent in another study [46]. Subsequent studies mainly used clonidine as an adjunct to either intrathecal local anesthetic or morphine. Elia et al. [47] conducted a meta-analysis that reviewed the use of clonidine as an adjuvant to intrathecal local anesthetics. Twenty-two randomized trials between 1966 and October 2006 were identified and included. With regards to postoperative analgesia, there was a statistically significant increase in the median time (101 min) to first request for analgesia with the clonidine group (15 -- 150 g), but treatment effects were heterogenous and dose responsiveness could not be demonstrated. The authors concluded that adjunctive use of clonidine to intrathecal local anesthetics prolongs the postoperative painfree period, but the long-term analgesic profile of intrathecal clonidine remains unknown. There is only weak evidence of dose responsiveness for treatment or adverse effects.
5.3
Clonidine has also been investigated when used as an adjunct to morphine intrathecally, but the results are quite varied. Nader et al. [48] randomized 85 patients undergoing coronary artery bypass grafting to receive either intrathecal injection of 0.5 mg morphine or 100 g clonidine plus 0.5 mg morphine before induction. Patients who received clonidine had lower pain scores and opioid consumption in the first 24 h postoperatively. Andrieu et al. [49] carried out a prospective randomized study that compared postoperative analgesia for patients undergoing radical prostatectomy. Results revealed that intrathecal clonidine plus morphine significantly prolonged the time till first PCA dose compared with both intrathecal morphine alone and control groups, along with significantly decreased PCA morphine consumption compared with the control group; whereas side effects were minimal. Sites et al. [50], in another double-blinded, randomized controlled trial, showed that intrathecal clonidine and morphine decreased 24-h morphine consumption and improved the 24-h visual analogue scale (VAS) scores when compared with both intrathecal morphine alone and control, in patients undergoing spinal anesthesia with bupivacaine for total knee arthroplasty. Similar analgesic benefits were shown for postcaesarean section patients who received intrathecal injection of clonidine plus morphine [51]. By contrast, Grace et al. [52] did not find any advantage of combining intrathecal clonidine and morphine in patients undergoing hip replacement compared with morphine alone. Nevertheless, the evidence on the whole seems to point towards an improvement of analgesia with a combination of intrathecal morphine and clonidine.
Clonidine in epidural anesthesia The pharmacological benefits of clonidine in epidural anesthesia with regards to postoperative pain control have still not been clearly elucidated, and there are many conflicting accounts of its analgesic effectiveness in this mode of anesthesia. Armand et al. [33] performed a meta-analysis of studies from September 1985 to 1997 concerning the role of extradural clonidine in postoperative analgesia. The authors did an extensive search of the literature that investigated the use of extradural clonidine and found 16 articles that met the inclusion criteria of randomized, controlled, doubleblinded trials with clearly defined objectives and adequate statistical analysis. However, these studies varied greatly from mode and timing of administration of clonidine to dosage and outcome measures. For instance, clonidine was injected via various methods -- bolus injection, bolus followed by continuous infusion, bolus followed by PCA infusion; clonidine was used adjunctively with fentanyl, local anesthetics or morphine; clonidine was given on induction, before end of surgery or postoperatively. The doses ranged from 75 to 800 g for bolus injections, and from 0.3 to 2 g/kg/h for infusions. The authors commented that not even two study designs could be directly compared. Although eight of the
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trials included in this systematic review did show improvement of analgesic efficacy after major abdominal surgery when clonidine was administered epidurally either alone [53-55] or in adjunct with morphine [56,57], fentanyl [58,59] or bupivacaine plus morphine [60], variability in these studies did not allow for a conclusive meta-analysis. De Kock et al. [55] even demonstrated dose-dependent postoperative analgesia for epidural clonidine, but no other trials had comparable results. Therefore, meta-analysis of literature concerning extradural clonidine use and postoperative analgesia could not be carried out successfully owing to the great variety of study designs. What was not included in this meta-analysis was the use of clonidine as an adjunct to epidural levobupivacaine, a local anesthetic that is gaining popularity for its lower toxicity. Milligan et al. [61] demonstrated that clonidine (8.3 g/ml) in combination with 0.125% levobupivacine provided better analgesia than clonidine or levobupivacaine alone when administered as an epidural infusion postoperatively for patients undergoing total hip replacement. Studies have been conducted to compare parenteral clonidine with epidural clonidine. However, these studies did not include control groups, and showed that epidural clonidine may have greater analgesic efficacy than parenteral clonidine. Bonnet et al. [62] examined 20 patients who received a single bolus of 2 g/kg either epidurally or intramuscularly in the postoperative period. Reduction in VAS pain scores 50% was noted in 90% of epidural patients and 70% of intramuscular patients. De Kock et al. [53] compared intravenous and epidural clonidine in 40 patients undergoing intestinal surgery under general anesthesia. Patients received 4 g/kg over 20 min followed by 2 g/kg/h after induction for 12 h either epidurally or intravenously. Epidural clonidine group had reduced morphine requirements during the first 6 postoperative hours, better pain scores in the first 12 postoperative hours and fewer requests for rescue pain medications. Bernard and colleagues [63] further randomized 24 patients undergoing scoliosis surgery to receive 8 g/kg clonidine over 30 min either epidurally or intravenously at the first complaint of pain postoperatively; followed by a patient-controlled pump that delivers boluses of 30 g clonidine at 15-min lockout intervals. Pain scores were lowered after clonidine was given in both study groups, without significant difference in pain scores between the two routes of administration. Nevertheless, self-administered and cumulative dose of clonidine was significantly lower in the epidural group. It was suggested that comparable levels of analgesia could be achieved with both epidural and intravenous administration of clonidine as the sole analgesic, while epidural clonidine provided a reduction in clonidine requirement and less marked sedation. It seems that intravenous clonidine does provide postoperative analgesia, but when compared with epidural clonidine the effect is less pronounced. As the analgesic effect of epidural clonidine is largely inconclusive, as previously discussed, it is difficult to make a conclusion on the seemingly superior analgesic effects
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compared with systemic clonidine. Nevertheless, one possible explanation may be that the central action of clonidine is enhanced epidurally because of its high lipid solubility, and it can thus easily cross the blood--brain barrier into the CSF to produce a central analgesic effect. Epidural clonidine continued to be evaluated by investigators in other clinical settings. Persec et al. [64] randomized patients undergoing abdominal surgery into three groups to receive: i) epidural clonidine preoperatively, ii) epidural clonidine postoperatively or iii) saline (control). Rescue epidural morphine was given upon complaint of pain. The group receiving epidural clonidine (5 g/kg) preoperatively achieved significantly lower postoperative VAS scores at 6 and 24 h compared with the other groups and significantly less rescue epidural morphine compared with the control group. It was thus suggested that preemptive analgesia could be achieved with preoperative epidural clonidine administration. This group further characterized the benefits of preemptive analgesia with epidural clonidine in another study by measuring surrogate markers (IL-6 and procalcitonin) for surgicalinduced inflammatory response [65]. The basis is that alpha-2 agonists have been found to have anti-inflammatory effects by suppressing the production of inflammatory cytokines via a central sympatholytic action [66,67]. Moreover, preemptive analgesia could potentially prevent hyperalgesia secondary to cytokine-related central nervous system sensitization [68]. Preoperative epidural clonidine has already been previously shown, by Wu et al., to reduce IL-1RA, IL-6, IL-8, pain scores and morphine consumption postoperatively [69]. Presec et al. demonstrated that, in the postoperative period, preemptive epidural clonidine resulted in significantly lower levels of procalcitonin and IL-6, lower pain scores at rest and on movement, longer time to first administration of postoperative analgesic and also lower cumulative morphine consumption compared with epidural levobupivacaine and control groups. The correlation between suppression of inflammatory markers and pain relief could signify that the analgesic effect of clonidine is partly attributed to anti-inflammation, in addition to the proposed mechanisms with regards to alpha-2 receptor agonism as mentioned in the previous sections.
5.5
Other clinical uses of clonidine in postoperative pain relief
Clonidine has also been studied in regards to postoperative pain control via other modes of administration. It has been shown to improve postoperative analgesia when used adjunctively with local anesthetics in combined spinal-epidural anesthesia [70]. As for intra-articular injection, clonidine showed promising results for postoperative pain control when used alone [71-75] or in combination with local anesthetic [76,77]. However, studies showed varied results as to whether or not clonidine augments the analgesic effect of morphine intraarticularly [72,78]. The role of oral clonidine in postoperative analgesia is largely inconclusive [79-83]. Clonidine has even been used locally [84], transdermally [85] intraperitoneally [86]
and as adjunct to local anesthetic in intravenous regional anesthesia [87-91], but only very few trials have been identified that investigated these routes of administration. It has also been studied when used as an adjunct to intravenous PCA. Jeffs et al. [92] found that clonidine, when added to PCA morphine, improved analgesia only up to 12 h postoperatively, without significant reduction in total amount of morphine consumed. In summary, clonidine has been shown to have a definite role in postoperative pain relief when administered parenterally, and adjunctively with local anesthetics for peripheral nerve and plexus blocks as well as intrathecal anaesthesia; while the evidence on the analgesic benefits in epidural administration is largely inconclusive, even though it seems to have better analgesic effect compared with systemic clonidine.
6.
Dexmedetomidine and postoperative analgesia
Compared with clonidine, not many studies have investigated the use of dexmedetomidine in postoperative pain control as a primary outcome. Most of the literature concerning dexmedetomidine addresses the sedative properties of this alpha-2 agonist, particularly in the perioperative and intensive care unit (ICU) setting [93-97]; and through these studies, the opioid-sparing effect of dexmedetomidine has become apparent. Subsequently, postoperative pain relief is accounted for as secondary analyses by the respective authors. In recent years, more attempts have been made at investigating the postoperative analgesic effects of dexmedetomidine, but the study designs and results are quite varied. In the following section, we review current literature that concerns postoperative analgesia of dexmedetomidine in various clinical settings. A summary of routes of administration and dosage of dexmedetomidine in the studies are shown in Table 3.
6.1
Systemic dexmedetomidine in postoperative analgesia
There are a few studies that have evaluated dexmedetomidine using postoperative analgesia as a primary end point, and they vary quite a bit from study design to timing and mode of administration of this alpha-2 agonist (Table 4). For instance, Aho et al. [98] randomized women undergoing laparoscopic tubal ligation to receive either 0.2 or 0.4 g/kg of dexmedetomidine, 60 g/kg of oxycodone or 250 g/kg of diclofenac postoperatively as an intravenous bolus whenever the patient suffered moderate to severe pain. Rescue morphine was given if the study drugs were administered as three consecutive doses within 1 h or five total doses in 2 h. The higher dose of dexmedetomidine (0.4-g/kg bolus) only achieved substantial reduction in VAS scores (21%) after the third administration, but the number of patients requiring morphine (33%) was significantly lower when compared with diclofenac (83%) or lower dose of dexmedetomidine (71%). Time to first
administration of rescue morphine was also significantly longer in this group of patients. However, sedation and bradycardia were more pronounced in the 0.4-g/kg dexmedetomidine group. While it is not standard practice to administer dexmedetomidine as an intravenous bolus, the sedation caused by the repeated boluses of dexmedetomidine could have been a confounding factor for reduction in VAS pain scores or morphine requirement. Unlugenc et al. [99] also did not use a standardized technique in their prospective, randomized, double-blinded, controlled study that was designed to evaluate the effect of pre-anesthetic administration of dexmedetomidine on postoperative pain scores and morphine consumption after abdominal surgery. Patients were randomized to receive a single intravenous dose of either dexmedetomidine (1 g/kg) or 0.9% saline over 10 min before induction of anesthesia. PCA morphine was given to the patients postoperatively, and the morphine consumptions were quantified for statistical analysis. In the dexmedetomidine group, patients consumed 28% less morphine in the first 24 h compared with the control group and had lower cumulative morphine consumptions at 6, 12 and 24 h after starting PCA, despite similar pain and sedation scores. Other authors have indeed evaluated the postoperative analgesic properties of dexmedetomidine using the standard method of giving a loading dose of dexmedetomidine followed by infusion. Arain et al. [100] compared dexmedetomidine (loading dose 1 g/kg over 10 min followed by 0.4 g/kg/h) to morphine (0.08 g/kg) for postoperative pain control in patients undergoing major surgery. Patients were randomized to receive one of the study drugs 30 min before the anticipated end of surgery. Patients in the dexmedetomidine group had similar VAS pain scores compared with the morphineonly group, but required 66% less morphine (total average dose) to achieve the same level of analgesia in the postanesthesia care unit (PACU). Moreover, only 35% of patients receiving dexmedetomidine required additional pain medications in the first hour postoperatively, compared with 88% of patients in the morphine-only group. One limitation of the study was the initial loading dose of morphine (0.08 mg/kg), but the authors argued that the preselected dosing seemed to result in early postoperative pain scores equivalent to the dexmedetomidine group. Gurbet et al. [101] randomized patients undergoing total abdominal hysterectomy to receive either dexmedetomidine (loading 1 g/kg over 30 mins followed by infusion at 0.5 g/kg/h until end of surgery) or 0.9% saline (with the same infusion protocol) before induction of anesthesia. Despite similar sedation scores and VAS scores at rest and during movement, dexmedetomidine-treated patients had significantly lower mean cumulative PCA morphine consumption compared with the control group in the PACU. Cumulative morphine consumption in the ward after discharge from PACU up to 48 h postoperatively was also significantly lower.
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Table 3. Summary of routes of administration of dexmedetomidine and dosages.

Routes/modes of administration Intravenous [98-104] (i) patient-controlled analgesia [118] (ii) adjunct to epidural anaesthesia [106-108] Dosage Bolus 0.2 -- 0.4 g/kg Loading 0.5 -- 1 g/kg over 10 -- 30 min; infusion 0.2 -- 0.8 g/kg/h 5-g bolus Loading 0.5 -- 1 g/kg for 10 -- 20 min; infusion 0.3 -- 0.5 g/kg/h 0.5 g/kg over 10 min 1 g/kg 2.5 g/kg 2.5 g/kg 1 -- 1.5 g/kg 1 g/kg 1 g/kg 1 -- 2 g/kg
(iii) adjunct to spinal anaesthesia [109] (iv) intravenous regional anaesthesia [113] Buccal [117] Intramuscular [116] Intranasal [120,121] Intraarticular[119] Epidural [111] Caudal block (pediatric patients) [114,115]
Dexmedetomidine has also been studied in morbidly obese patients undergoing bariatric surgery. The theoretical advantages of the use of dexmedetomidine in such patients include the potential opioid-sparing effects and minimal respiratory depression. Feld et al. [102] carried out a pilot study amongst morbidly obese patients undergoing open gastric bypass surgery. Patients were randomized into two groups: one group to receive 0.5 g/kg fentanyl on induction followed by fentanyl infusion (0.5 g/kg/h) until end of surgery; and the other group to receive dexmedetomidine (loading dose of 0.5 g/kg over 10 min before induction, followed by infusion at 0.4 g/kg/h). The authors found that the dexmedetomidine group had significantly lower pain scores as well as significantly reduced morphine consumption in the PACU postoperatively compared with the fentanyl group. A retrospective study by Dholakia et al. [103] compared dexmedetomidine (loading dose of 1 g/kg over 10 min followed by infusion of 0.2 -- 0.7 g/kg/h until end of operation) with a control group (comprising of a similar number of patients from a different time period) in laparoscopic bariatric surgery. Pain scores were found to be similar between groups, while total morphine consumption was significantly less in the dexmedetomidine group. Tufanogullari et al. [104] further tested the dose-responsiveness of dexmedetomidine infusions on anesthetic and analgesic requirements in patients undergoing laparoscopic bariatric surgery by carrying out a blinded, randomized, controlled trial. Patients were randomized into four treatment groups in this study: 0.2, 0.4 or 0.8 g/kg/h dexmedetomidine infusions, or saline in the control group. The infusions were started before induction without a loading dose and stopped at the start of wound closure. Fentanyl boluses (25 -- 50 g i.v.) were given to control acute pain in the early postoperative period; subsequently, PCA morphine was given to the patients in the PACU. There were no significant differences in pain scores in the PACU, as well as average pain scores on postoperative days
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1, 2 and 7 among the four groups. However, fentanyl administered for control of acute pain was significantly reduced in all dexmedetomidine groups compared with control, but not when compared with each other. PCA morphine consumption also did not differ between all four treatment groups on postoperative days 1 and 2. There was also a significant reduction of mean arterial pressure during the first 45 min in the PACU for all dexmedetomidine groups, but there was no significant difference between treatment groups. Despite the apparent reduction in opioid consumption, the authors are unable to demonstrate a dose-dependent analgesic effect of dexmedetomidine, nor can they show a dose relationship for the adverse effects such as hypotension or bradycardia. The reduced morphine consumption can well be confounded by the sedative effects of dexmedetomidine, leading to similar pain scores between study groups. Since all tested doses resulted in lower opioid consumption (with no significant difference), the authors recommended the infusion rate of 0.2 g/kg/h for dexmedetomidine in bariatric surgery to minimize risk of potential adverse cardiovascular side effects. All the mentioned studies have shown that intravenous dexmedetomidine has a definite role in postoperative analgesia through reduction of opioid consumption, yet many of the reports are unable to show a significant decrease in pain scores. The implication is that dexmedetomidine may not provide sufficient pain control when administered as a sole analgesic agent, but through synergistic mechanisms via the alpha-2 adrenergic pathways, it plays a part in multimodal analgesia and is able to reduce opioid consumption -- which is particularly important in patients at risk of postoperative hypoventilation such as those who have airway diseases and those who are obese.
6.2
Dexmedetomidine as adjunct to regional anesthesia
Studies have tried to determine whether or not systemic dexmedetomidine would prolong or augment the analgesic
Table 4. Studies evaluating systemic dexmedetomidine in postoperative analgesia.

No. of patients 96 Sedation and hypotension (S) in 0.4 g/kg DEX group 0.2- or 0.4-g/kg bolus Postoperative Longer time to rescue morphine (S), decreased pain scores (S) and morphine requirement (S) in 0.4 g/kg DEX group compared with diclofenac and 0.2 g/kg DEX group Decreased morphine requirement (S), less patients requiring rescue morphine in 1st hour (S) in DEX group Decreased morphine consumption (S) in DEX group; similar pain scores Decreased morphine consumption up to 48 h post-op (S) in DEX group; similar pain scores and TTFA Decreased morphine consumption (S) and pain scores (S) in DEX group Decreased morphine consumption (S) in DEX group; similar pain scores Preoperative + intraoperative Decreased rescue fentanyl immediately post-op (S) in all DEX groups; similar pain scores and morphine consumption in all 4 groups Bradycardia (DEX > M) (S); similar sedation and MAP DEX > M Dose of dexmedetomidine Timing of administration Postoperative outcome Significant adverse effects Conclusion on analgesic efficacy 0.4 g/kg DEX = oxycodone > 0.2 g/kg DEX and diclofenac
Year
Authors
Comparison
1991
Aho [98]
DEX (2 groups) vs OXY (60 g/kg) vs DIC (250 g/kg)
2004
Arain [100]
DEX vs M (0.08 mg/kg)
34
1 g/kg over 10 min, then 0.4 g/kg/h Intraoperative
2005
Unlugenc
DEX vs PL
60
1 g/kg over 10 min Preoperative
DEX > PL
[99]
Similar sedation scores
2006
Gurbet
DEX vs PL
50
DEX > PL
[101]
1 g/kg over 30 min, then 0.5 g/kg/h Preoperative + intraoperative
Similar sedation, MAP and HR
2006
Feld [102]
DEX vs FEN (0.5-g/kg bolus, then 0.5-g/kg/h) 73 Intraoperative
20
0.5 g/kg over 10 min, then 0.4 g/kg/h Preoperative + intraoperative
Hypotension (S) and bradycardia (S) (DEX > FEN)
DEX > FEN
2007
Dholakia
DEX > control
[103]
DEX vs control (retrospective study)
1 g/kg over 10 min, then 0.2 -- 0.7 g/kg/h
Similar mean SBP and HR
2008
Tufanogullari
80
[104]
DEX (3 groups) vs PL
0.2, 0.4 or 0.8 g/kg/h
Hypotension (S) in all DEX groups in early post-op period
DEX > PL (dose-dependent analgesia not demonstrated)
DEX: Dexmedetomidine; DIC: Diclofenac; FEN: Fentanyl; HR: Heart rate; IV: Intravenous; M: Morphine; MAP: Mean arterial pressure; NS: Nonsignificant; OXY: Oxycodone; PL: Placebo; S: Significant; SBP: Systolic blood pressure; TTFA: Time to first analgesic requirement.
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effect of regional anesthesia, but the lack of standardized study designs make them difficult to compare (Table 5). Coskuner et al. [105] demonstrated that intravenous dexmedetomidine prolonged sensory blockade in epidural anesthesia with bupivacaine, but did not evaluate the effects of dexmedetomidine on postoperative analgesia. Wahlander et al. [106] studied the effects of intravenous dexmedetomidine on postoperative analgesia when used as an adjunct to epidural anesthesia after thoracic surgery. In the postoperative period, 0.125% bupivacaine was loaded epidurally followed by continuous infusion of 0.125% bupivacaine at 4 ml/h. At the same time, patients were randomized into two groups to receive either dexmedetomidine (loading dose of 0.5 g/kg over 20 min followed by infusion at 0.4 -- 0.7 g/kg/h) or saline systematically. Patients in the dexmedetomidine group required a significantly lower dose of rescue epidural fentanyl, but there was no significant difference in VAS scores or patient-controlled epidural analgesia (PCEA) use. Kida et al. [107] randomized patients undergoing gynecological surgery into four groups to receive i) systemic dexmedetomidine, ii) epidural neostigmine, iii) a combination of both or iv) control. All patients received 7 ml of 0.75% epidural ropivacaine before induction of general anesthesia, while patients randomized to receive neostigmine received an additional 0.3 mg of neostigmine epidurally. As for the patients randomized to receive dexmedetomidine, a loading dose of 1 g/kg was given intravenously over 10 min followed by a continuous infusion of 0.4 g/kg/h until end of surgery. For all patients, epidural infusion of ropivacaine was continued into the postoperative period. VAS pain scores were only significantly decreased at 24 and 72 h postoperatively for patients who were coadministered epidural neostigmine and systemic dexmedetomidine. Moreover, time to first rescue analgesic and total postoperative analgesic consumption did not differ between all groups. Authors concluded that systemic dexmedetomidine administered intraoperatively did not improve postoperative analgesia in patients undergoing lower abdominal surgery with continuous epidural infusion of ropivacaine, and combination of epidural neostigmine and systemic dexmedetomidine only conferred marginal benefit in the later recovery periods. This study mainly addresses the use of dexmedetomidine in multimodal analgesia, in which different combinations of pain medication may result in better analgesic outcome as each analgesic regulates pain control via different mechanisms and pathways. Nevertheless, concomitant use of systemic dexmedetomidine and epidural ropivacaine as well as neostigmine did not provide significant synergism as one would predict in the postoperative setting for gynecological patients. Similarly, Gomez-Vazquez et al. [108] did not find any postoperative analgesic benefit when dexmedetomidine (loading 1 g/kg over 10 min followed by 0.3 g/kg for 50 min) was compared with paracetamol in patients who received epidural anaesthesia of 2% lidocaine for arthroscopic knee surgery.
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The VAS pain scores, as well as median time to first dose of rescue analgesia, were found to be similar between groups; in fact, cumulative doses of rescue morphine were significantly higher in the dexmedetomidine group in this study. Again, not only has systemic dexmedetomidine not been shown to improve analgesia when used with epidural local anesthetic lidocaine, the morphine-sparing effect is even less pronounced than paracetamol in this group of patients receiving arthroscopic surgery under epidural anesthesia. Thus, summarizing the results from these studies, it remains inconclusive as to whether or not systemic dexmedetomidine improves or augments the effects of epidural anesthesia with local anesthetics, and the utility of this alpha-2 agonist in multimodal analgesia remains in question. As for adjunctive use to spinal anesthesia, there are very few published studies regarding the effects of systemic dexmedetomidine on postoperative analgesia. Kaya et al. [109] recently did shed light on the postoperative benefits of parenteral dexmedetomidine on intrathecal bupivacaine. They found that premedication with dexmedetomidine intravenously (0.5 g/kg over 10 min) increased the time to first request for postoperative analgesia and decreased supplementary analgesic requirements (diclofenac) in the first 24 h compared with midazolam and saline in patients receiving spinal anesthesia for transurethral resection of prostate. Unlike clonidine, dexmedetomidine has rarely been given epidurally or intrathecally, presumably because of the possible neurotoxic effects associated with epidural administration [110]. Indeed, only one recent study could be identified that used dexmededomidine (1 g/kg) as an adjunct to epidural bupivacaine [111]. Elhakim et al. evaluated the postoperative pain control in patients undergoing thoracic surgery requiring one-lung ventilation and demonstrated that adjunctive use of epidural dexmedetomidine improves postoperative analgesia by significantly lowering the pain scores and requirement for rescue paracetamol [111]. As for intrathecal dexmedetomidine, Kanazi et al. [112] investigated the effect on characteristics such as onset time and duration of sensory and motor block, but did not comment on the postoperative analgesic effect. When used as adjunct to lidocaine for intravenous regional anesthesia, dexmedetomidine resulted in significantly lower postoperative pain scores and opioid requirement [113]. Finally, addition of dexmedetomidine to bupivacaine in caudal block in pediatric patients showed promising results in terms of prolonging the duration of analgesia [114,115] and reducing the total consumption of rescue analgesic [114]. Nevertheless, in view of the paucity of evidence supporting the adjunctive use of dexmedetomidine in regional anesthesia, the role of this alpha-2 agonist in postoperative analgesia remains unclear.
Other clinical uses of dexmedetomidine The effect of dexmedetomidine on postoperative analgesia has also been studied in other modes of administration. Intramuscular dexmedetomidine had comparable analgesia
6.3
Table 5. Studies evaluating dexmedetomidine as adjunct to regional anesthesia in postoperative analgesia.

Local anesthetic Comparison No. of patients Dose of dexmedetomidine Timing of administration Postoperative outcome Significant adverse effects
Bradycardia (S) and hypotension (S)
Year
Authors
Regional technique
Conclusion on analgesic efficacy

DEX > PL
2005
Wahlander
Epidural
Bupivacaine
IV DEX vs PL
28
Postoperative
[106]
0.5 g/kg over 20 min, then 0.4 g/kg/h Decreased fentanyl requirement (S) in DEX group; similar pain scores and PCEA use Decreased pain scores (S) and fentanyl requirement (S) in IVRA DEX group 1 g/kg Preoperative
2005 Lidocaine 40 IVRA DEX vs control
Esmaoglu
IVRA DEX > control Lower MAP (S) and more sedation (S) in IVRA DEX group; similar HR Bradycardia (S) and hypertension (S)
[113]
IV regional anaesthesia
2007 Lidocaine 30 Preoperative IV DEX vs oral PCT (2 g)
Gomez-Vazquez
Epidural
DEX < PCT
[108]
1 g/kg over 10 min, then 0.3 g/kg over 50 min 1 g/kg over 10 min, then 0.4 g/kg/h Intraoperative
Increased morphine requirement (S) in DEX group; similar pain scores and TTFA Decreased pain scores in later post-op period (S) for IV DEX + EPI NEO group; similar TTFA and analgesic (butorphanol) consumption in all groups Increased TTFA (S) and decreased supplementary analgesic (diclofenac) in DEX group; similar pain scores in all groups
2008 Ropivacaine IV DEX vs EP NEO vs IV DEX + EP NEO vs control 60
Kida [107]
Epidural
Bradycardia (S) in both DEX groups; similar MAP
IV DEX + EP NEO only conferred marginal benefit

Bupivacaine IV DEX vs IV MID vs PL 75 0.5 g/kg over 10 min Preoperative Bupivacaine 60 1 g/kg Caudal DEX vs control Intraoperative (after induction) Bupivacaine 60 2 g/kg Caudal DEX vs Caudal CL (2 g/kg) vs PL EP DEX vs control 50 Intraoperative (after induction) Bupivacaine 1 g/kg intra-op; 0.2 g/kg/h post-op Intraoperative + Postoperative
2009
Kaya [109]
Intrathecal
Bradycardia and hypotension similar in all groups; sedation (S) in DEX and MID groups Decreased paracetamol requirement (S) and increased TTFA (S) in caudal DEX group Decreased pain scores (S) and increased analgesia time (S) in both caudal DEX and CL groups Decreased pain scores (S) and paracetamol requirement (S) in EPI DEX group Sedation (S) in caudal DEX group; similar hypotension and bradycardia NS
DEX > MID > PL
2009
Saadaway
Caudal DEX > control
[114]
Caudal block (pediatric)
2009
El-Hennawy
[115]
Caudal block (pediatric)
Caudal DEX = caudal CL > PL
2010
Elhakim [111]
Epidural
NS
EPI DEX > control
B: Bupivacaine; CL: Clonidine; DEX: Dexmedetomidine; EP: Epidural; HR: Heart rate; IV: Intravenous; IVRA: Intravenous regional anaesthesia; MAP: Mean arterial pressure; MID: Midazolam; NEO: Neostigmine; NS: Nonsignificant; PCEA: Patient controlled epidural analgesia; PCT: Paracetamol; PL: Placebo; S: Significant; TTFA: Time to first analgesic requirement.
2861
when used alone, or in combination with intravenous fentanyl, to a combination of intramuscular midazolam and intravenous fentanyl [116]. However, when compared with buccal administration, postoperative pain scores were higher [117]. Dexmedetomidine (5-g bolus) added to intravenous PCA morphine (1-mg bolus) for postoperative analgesia after abdominal hysterectomy was also evaluated, and it was found that dexmedetomidine significantly reduced the cumulative PCA morphine consumption and morphine-induced nausea [118]. As for intra-articular dexmedetomidine, better pain scores, longer time to first postoperative analgesic request and lower rescue diclofenac requirement were achieved in comparison with intravenous dexmedetomidine and placebo [119]. Analgesic effect of intranasal dexmedetomidine has been described only in healthy volunteers [120], and in one case series in which intranasal dexmedetomidine was administered as premedication, it was shown to be comparable to oral midazolam with regards to postoperative pain relief in pediatric burn patients [121]. No conclusion on analgesia is available so far.
7.
Expert opinion
This review has shown that there is compelling evidence demonstrating the postoperative analgesic effects of alpha-2 agonists. Although the study designs vary greatly, most trials conclude that clonidine and dexmedetomidine have a role in postoperative analgesia. Several issues can be drawn from the multitude of trials that investigated the postoperative analgesic effects of alpha-2 agonists. First of all, the well-demonstrated opioidsparing effect of alpha-2 agonists may be one of the most promising properties, particularly in those patients who are at high risk of postoperative respiratory depression (e.g., morbidly obese, chronic obstructive pulmonary disease patients). Moreover, it has already been shown that ventilatory efforts are preserved with the use of alpha-2 agonists despite occasional profound levels of sedation [122]. Thus, analgesia can be achieved without excessive use of opioids, which could increase the risk of hypoventilation in such patients. Second, following up on the sedative property of alpha-2 agonists, sedation could be a confounding factor in the assessment of postoperative analgesia. For instance, in postoperative ICU patients in whom dexmedetomidine is used for sedation, this could well be true. Most of the studies that have been reviewed either showed that there is no significant sedation in postoperative patients, or did not evaluate the sedative effects at all. Third, the adverse effects of hypotension and bradycardia are frequently mentioned and may be one of the concerns when alpha-2 agonists are used for postoperative analgesia, particularly in hemodynamically unstable patients. However, as most of these studies included ASA (American Society of Anesthesiologists) I or II patients, the authors found that
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often the adverse effects were easily remedied and did not result in devastating outcomes. There are several limitations to the studies reviewed. The sample sizes in most studies are quite small, and may not be powered to enable meaningful comparison. Longterm follow-up data (> 24 h) on the analgesic or recovery profile of postoperative patients are also lacking in most trials. The dosages used are also quite variable, as well as the timing of administration of alpha-2 agonists. One may keep in mind that the postoperative administration of alpha-2 agonists in some reports may lead to confounding results as a result of the sedative properties. For clonidine, not only does it provide postoperative analgesia when used alone, but it also improves the analgesic efficacy of local anesthetics and morphine. The evidence supporting the postoperative analgesic effect seems to be most robust when clonidine is used regionally, particularly as adjunct to peripheral nerve and plexus blocks, as well as intrathecal anesthesia, although its use in the epidural route is still inconclusive. As for dexmedetomidine, few studies have been done in recent few years to evaluate the analgesic effect in postoperative pain relief. The evidence mainly surrounds the intravenous administration of this alpha-2 agonist. When used as the sole analgesic agent, dexmedetomidine decreased morphine consumption. Interestingly, many of the studies were unable to demonstrate a decrease in pain scores, despite the apparent morphine-sparing effect of this alpha-2 agonist -the authors argue that this points to the fact that fewer supplementary analgesics are required to achieve the same level of pain relief. The results did not seem to be consistent with those of clonidine. Since dexmedetomidine is 8 times more specific to alpha-2 receptors than clonidine and it works centrally and peripherally, the analgesic effect is expected to be better, even though only 8% reaches the CSF compared with 50% for clonidine. There are several implications from this observation, including: i) the analgesic effect of alpha-2 agonists at the level of the CNS may not be as prominent as previously thought; ii) dexmedetomidine and clonidine may have different potency with regards to alpha-2 agonism in the CNS; iii) there may be other mechanisms involved that account for analgesia by alpha-2 agonists, perhaps via another receptor such as the opioid receptor as discussed by Aley and Levine [27]. To determine a mechanistic explanation for this phenomenon, studies directly comparing the analgesic effects of clonidine and dexmedetomidine should thus be carried out. There is general consensus nowadays that it is not enough for analgesics to have only opioid-sparing effects without improvement in pain relief [123]. Nevertheless, there are far fewer studies exploring postoperative pain relief of dexmedetomidine than clonidine. With future studies looking into its role in major surgery -- potential cardiovascular protection, pain relief in different routes of administration and in multimodal analgesia, potential anti-inflammatory effects,
postoperative recovery profile and effect on long-term development of chronic pain after surgery -- the analgesic benefits of dexmedetomidine, as well as its other roles in the perioperative period, can be further explored and appreciated. The role of the newest alpha-2 agonist, fadolmidine, in postoperative analgesia is yet to be determined as the drug is undergoing Phase I clinical trials. Animal studies, however, have shown promising results particularly when fadolmidine is administered intrathecally. It is a full agonist of all subtypes of alpha-2 adrenoreceptor and has greater analgesic potency compared with either clonidine or dexmedetomidine [124]. Fadolmidine has limited ability to penetrate the blood--brain barrier when given systemically [125,126]. When given intrathecally, fadolmidine seems to have less prominent sympatholytic effect compared with dexmedetomidine and clonidine, resulting in only minor effects on blood pressure and heart rate at the analgesic dose, as well as less sedation and mydriasis [124]. Given the seemingly beneficial pharamacokinetic and pharmacodynamic properties of this new alpha-2 agonist with intrathecal administration, future human studies may prove this to be a good option for postoperative analgesia with fewer adverse effects. However, at this juncture, the limited mode of administration due to its inability to enter CSF may make it less favorable than other alpha-2 agonists that can be administered systemically. Moreover, there have not been reports on any peripheral antinociceptive properties of fadolmidine yet. From a broader perspective, additional studies comparing
fadolmidine, dexmedetomidine and clonidine would surely help us answer some of the queries concerning the central and peripheral mechanisms of antinociception contributed by alpha-2 agonists, as well as clarify their roles in postoperative analgesia. In conclusion, alpha-2 agonists seem to be promising with regard to postoperative analgesia, bearing in mind the potential adverse effects of sedation, hypotension and bradycardia. Alpha-2 agonists are recommended for use as a sole analgesic agent, or as an adjunctive agent to regional techniques for postoperative pain relief, particularly clonidine. While the peripheral mechanisms of antinociception are still to be elucidated, the benefits of alpha-2 agonists as adjunct to regional anesthesia may be more fully revealed with increased accuracy with the advances in ultrasound-guided techniques. Admittedly, although the role of clonidine for postoperative pain relief is well established, the evidence supporting the analgesic benefits of dexmedetomidine is still immature. More studies should therefore be conducted to clarify its role in postoperative pain management. Fadolmidine looks promising in animal studies for analgesia, especially when administered intrathecally. Future human studies can help to explore its role in acute pain management.
Declaration of interest
The authors state no conflict of interest and have received no payment in preparation of this manuscript.
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Affiliation
Albert Kam Ming Chan1 MBBS, Chi Wai Cheung2 MBBS FHKCA FHKAM & Yeow Kuan Chong3 MBBS Author for correspondence 1 The Chinese University of Hong Kong, Prince of Wales Hospital, Department of Anaethesia and Intensive Care, Hong Kong 2 The University of Hong Kong, Queen Mary Hospital, Department of Anaesthesiology, Hong Kong, Room 424, Block K, 102 Pokfulam Road, Hong Kong Tel: +852 2255 3303; Fax: +852 2855 1654; E-mail: cheucw@hku.hk 3 Caritas Medical Centre, Accident and Emergency Department, Hong Kong
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Alpha2 Agonists in Acute Pain Management

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Alpha2 Agonists in Acute Pain Management

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Review

Alpha-2 agonists in acute pain management

Alpha-2 agonists in acute pain management

Pharmacodynamics of alpha-2 agonists

This box summarizes key points contained in the article.

Pharmacokinetics of clonidine and dexmedetomidine

Mechanisms leading to antinociception

Expert Opin. Pharmacother. (2010) 11(17)

Chan, Cheung & Chong

Clonidine and postoperative analgesia

Expert Opin. Pharmacother. (2010) 11(17)

Alpha-2 agonists in acute pain management

Table 1. Summary of routes of administration of clonidine and dosages.

Expert Opin. Pharmacother. (2010) 11(17)

1990 Bonnet [62]

1991 Bernard [34]

5 g/kg over 1 h, then 0.3 g/kg/h Postoperative

1992 De Kock [35]

IV vs control (no PL)

4 g/kg over 30 min, then 2 g/kg/h Intraoperative

1992 Singelyn [40]

150 g (SC and AB routes) Preoperative

AB > SC and control

Expert Opin. Pharmacother. (2010) 11(17)

1993 De Kock [53]

4 g/kg over Intraoperative 20 min, then 2 g/kg/h (both routes)

Sedation, hypotension, bradycardia similar in both groups

1995 Bernard [63]

8 g/kg over 30 min (both routes)

2001 Culebras [41]

150 g (IM and ISB routes)

Chan, Cheung & Chong

Alpha-2 agonists in acute pain management

2002 Marinangeli [36]

2002 Jeffs [92]

PCA (CL + M) vs 60 PCA (M)

Expert Opin. Pharmacother. (2010) 11(17)

2003 Iskandar [39]

2005 Mannion [42]

Chan, Cheung & Chong

Expert Opin. Pharmacother. (2010) 11(17)

Alpha-2 agonists in acute pain management

Other clinical uses of clonidine in postoperative pain relief

Expert Opin. Pharmacother. (2010) 11(17)

Chan, Cheung & Chong

Dexmedetomidine and postoperative analgesia

Systemic dexmedetomidine in postoperative analgesia

Expert Opin. Pharmacother. (2010) 11(17)

Alpha-2 agonists in acute pain management

Table 3. Summary of routes of administration of dexmedetomidine and dosages.

Dexmedetomidine as adjunct to regional anesthesia

Expert Opin. Pharmacother. (2010) 11(17)

Table 4. Studies evaluating systemic dexmedetomidine in postoperative analgesia.

DEX (2 groups) vs OXY (60 g/kg) vs DIC (250 g/kg)

DEX vs M (0.08 mg/kg)

1 g/kg over 10 min, then 0.4 g/kg/h Intraoperative

1 g/kg over 10 min Preoperative

Similar sedation scores

Expert Opin. Pharmacother. (2010) 11(17)

1 g/kg over 30 min, then 0.5 g/kg/h Preoperative + intraoperative

Similar sedation, MAP and HR

DEX vs FEN (0.5-g/kg bolus, then 0.5-g/kg/h) 73 Intraoperative

0.5 g/kg over 10 min, then 0.4 g/kg/h Preoperative + intraoperative