AANA Journal Course—α2-Adrenergic Receptor Agonist, an ...

www.aana.com/aanajournalonline AANA Journal December 2021 Vol. 89, No. 6 529

AANA Journal Courseαα2-Adrenergic Receptor Agonist, an Attractive but Underused ERAS Component in Improving Fast-Track Recovery and Surgical OutcomesSarah Jingying Zhang, PhD, CRNAGloria Lai, MSN, CRNACharles A. Griffis, PhD, CRNA, FAANAMichelle Schiltz, MSN, CRNA Edwin N. Aroke, PhD, CRNA, FAAN

ObjectivesAt the conclusion of this course, the learner will be able to:

1. Describe the unique analgesic properties of α2-agonists and their mechanism of action.

2. Discuss the current evidence-based practice of α2-agonists in acute pain management in the periop-erative setting.

3. Delineate the benefits of α2-agonists in improved surgical pain management outcomes.

4. Describe the application of α2-agonists in opioid and nonopioid withdrawal management.

5. Review the potential side effects of administration of α2-agonists in the perioperative setting.

IntroductionEnhanced Recovery After Surgery (ERAS) protocols are widely used evidence-based pathways designed to improve clinical outcomes and decrease opioid consump-tion, postoperative complications, length of stay, and healthcare costs.1 These ERAS protocols are pathways for complex procedures with multiple individual com-ponents (interventions) spanning the preoperative, in-traoperative, and postoperative phases.1 Multimodal pain management is an essential component of the ERAS pro-tocol. Studies have shown that suboptimal implementa-tion of the ERAS protocol can results in inadequate post-operative management.1 Poorly controlled postoperative pain may delay recovery after surgery, prolong duration of stay, decrease satisfaction with care, decrease quality

Enhanced Recovery After Surgery (ERAS) protocols have been implemented in many institutions to atten-uate the stress of surgery and facilitate early recovery. Careful selection of multimodal analgesic medica-tion plays an essential role in achieving the goals of ERAS protocols. Clonidine and dexmedetomidine are α2-adrenergic receptor (α2-AR) agonists that can greatly enhance various ERAS components owing to their unique pharmacologic properties: antinocicep-tion, anxiolysis, anti-inflammation, and renal protec-tion. The α2-AR agonists exert supraspinal and spinal antinociceptive effects by potentiating descending pain modulatory pathways and inhibiting peripheral C fibers. These antinociceptive effects of α2-AR ago-nists are independent of opioid receptors and result in analgesic synergy with opioid agonists. Several meta-analyses and systematic reviews have reported

that α2-AR agonists decrease opioid consumption and side effects in adult and pediatric surgical patients. Given the wide distribution of α2-ARs in the body, α2-AR agonists have been associated with a reduc-tion in anxiety, perioperative stress, inflammation, postoperative nausea and vomiting, shivering, and cognitive dysfunction. This course describes the basic and applied pharmacology of the α2-AR agonists and provides emerging evidence to support their utility in acute pain management and ERAS protocols. Periop-erative administration of α2-AR agonists can enhance pain management, decrease adverse effects, and pro-mote surgical recovery.

Keywords: α2-agonists, anesthesiology, Enhanced Recovery After Surgery, multimodal analgesia, postop-erative pain management.

The AANA Journal Course is published in each issue of the AANA Journal. Each article includes objectives for the reader and sources for additional reading. A 5-question open-book exam for each course is published on the CRNA Knowledge Network and will remain live on the site for a period of 3 years. One Class A CE credit can be earned by passing the examination (a score of 80% or greater) and completing the evaluation. Journal Courses released after September 1, 2020 are free to AANA members as a benefit of membership. For details, go to https://knowledgenetwork.aana.com/home.

530 AANA Journal December 2021 Vol. 89, No. 6 www.aana.com/aanajournalonline

of life, and increase healthcare costs. Even in procedures with high compliance to ERAS protocols, postoperative pain management remains insufficient. The reason for the suboptimal pain management is unclear but may be related to high opioid use.1

Traditional opioids remain the mainstay for treating perioperative pain but are associated with undesirable side effects and complications, including increased incidence of respiratory depression, postoperative nausea and vom-iting (PONV), opioid-induced hyperalgesia (OIH), cogni-tive impairment, and immunomodulation.1,2 Increased doses of opioids intraoperatively are associated with increased opioid consumption during the postoperative period.2 Also, the use of prescription opioids has been blamed for the ongoing opioid epidemic. As the opioid crisis spreads, dexmedetomidine and clonidine have gained popularity in the detoxification in opioid-depen-dent patients.3 Furthermore, addition of α2-adrenergic receptor (α2-AR) agonists to opioid therapy has been used successfully to treat intractable acute pain, particu-larly when conventional opioid therapy alone is ineffec-tive in the perioperative setting.4,5 Factors that increase postoperative opioid consumption include preoperative anxiety, increased inflammatory response to the trauma of surgery, and history of opioid misuse/abuse, among others. Recently, α2-AR agonists have been recognized as valuable adjuncts to the ERAS component owing to their unique analgesic properties, including antinociception, anti-inflammation, and antihyperalgesia.6-8 Despite their recognized role in multimodal analgesic regimens, α2-AR agonists are underused in many ERAS programs.

In this Journal course, we discuss the basic and applied pharmacology of α2-AR agonist drugs. Specifically, we discuss the role of dexmedetomidine and clonidine in postoperative pain management, antinociception, anx-iolysis, modulation of inflammation, and management of patients with opioid dependence. We also discuss the role of these drugs in the reduction of opioid consump-tion and opioid-related side effects such as PONV.

Overview of Physiologic Properties of αα2-Adrenergic Receptors Traditionally, adrenergic receptors have been classified into α- and β-receptors based on physiologic interactions between the receptors and endogenous catecholamines (eg, norepinephrine).9 The α-receptors are further clas-sified into α1 and α2 receptors, which are located in pre-synaptic and postsynaptic membranes.10 Studies using knockout rats have further differentiated α2 receptors into 3 subtypes, α2A, α2B, and α2C, which are located throughout the human body.9,11 All 3 subtypes of α2-ARs are G-coupled protein receptors regulated by guanine nucleotide. Specifically, α2-ARs are coupled to the Gi and Go proteins, which elicit an inhibitory effect or null effect via cyclic adenosine monophosphate (cAMP).9

Activation of the Go-coupled receptor leads to a reduc-tion in cAMP levels that results in hyperpolarization of the neuronal membrane and decreased adrenergic responses. It has also been suggested that Gi protein-induced hyperpolarization is regulated by voltage-gated potassium and calcium channels, which prevents the initiation of an action potential (Figure).9,12

In the central nervous system (CNS), activation of α2A-AR produce sedative and analgesic effects via de-creasing release of neurotransmitters and inhibiting N-type voltage-sensitive calcium channels.10 The attenu-ated sympathetic nociception and outflow leads to mod-ulation of pain pathways. Stimulation of α2B-AR mediates gastric mucosal protective action, whereas activation of the α2C subtype may be involved in stress-dependent de-pression and other psychiatric illnesses such as attention deficit hyperactivity disorder.9,10 In the periphery, α2A subtypes also play a crucial role in analgesia.

Pharmacologic Properties of αα2-Agonists: Clonidine and DexmedetomidineClonidine binds to α1 and α2 receptors with an α2 to α1 receptor ratio of 200:1. Because of its quick absorption and high bioavailability, clonidine can be administered via oral, rectal, transdermal, parenteral, intrathecal, and epidural routes.13 For instance, orally administered clonidine is absorbed within 30 minutes, and its bio-availability approaches 75%. In addition, clonidine is lipophilic and readily crosses the blood-brain barrier. Studies have shown that the concentration of clonidine in cerebrospinal fluid is approximately 50% of the concen-tration in plasma.13 Given the widespread availability of α2-ARs, clonidine can exert pharmacologic effects in the CNS and peripheral nervous system (PNS).11 It is chiefly eliminated in urine in the unchanged form and has an elimination half-life of 12 to 16 hours. The long duration of action of clonidine makes it an excellent adjunct in pain management.13 However, sudden cessation of long-term clonidine use should be avoided, as it is associated with rebound hypertension, which usually occurs about 20 hours from the last dose.11

Compared with clonidine, dexmedetomidine is a more selective α2-AR agonist with an α2 to α1 affinity ratio of 1,620:1.9,10 Dexmedetomidine can be admin-istered via intravenous, intramuscular, intranasal, and transdermal routes.4,14 Its elimination half-life is roughly 2 to 3 hours. Dexmedetomidine is not as lipophilic as clonidine. Hence, when given intravenously, only ap-proximately 8% of the medication will reach the CSF.10 Dexmedetomidine is metabolized by hepatic cytochrome P450 and glucuronidation enzymes into pharmacologi-cally inactive conjugates by the liver and excreted by the kidney.6,9 Because of its high affinity for the α2-AR, dexmedetomidine inhibits neuronal activity in the CNS (brain and spinal cord), resulting in sedation, anxiolysis,


analgesia, hypotension, and bradycardia.9 One of the major advantages of dexmedetomidine over other seda-tive and analgesic medications is that it produces pro-found calmness with minimal respiratory depression.15 As a result, its perioperative use can optimize one of the major goals of ERAS, safe and efficacious postoperative pain management, which deserves further consideration.

Unique Analgesic Effects of αα2-AgonistsFor decades, the role of α2-AR activation on nociception has been the center of intense study. Although a detailed description of the mechanism of pain is beyond the scope of this article, a quick review of the essential events in-volved in pain are germane to understanding the role of α2-adrenergic agonists. Acute and chronic painful stimuli undergo 3 fundamental processes: transduction, transmis-sion, and modulation. Specialized ion-gated channels in free nerve endings (eg, voltage-gated sodium channels, transient receptor potentials, and acid-sensing ion chan-nels) play a critical role in the activation of afferent un-myelinated C and myelinated Aδ fibers, which transmit nociceptive signals to the CNS. Afferent C fibers and Aδ fibers transmit noxious stimuli from the peripheral to the dorsal horn of the spinal cord, from where they are projected to higher brain centers (supraspinal areas) via the spinothalamic and spinoreticular tracts.16 Then, 2 su-praspinal pathways transmit physical discriminatory and motivational or emotional aspects of pain to the somato-sensory cortex.16 These ascending pain pathways can be

modulated by descending pathways via the periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) in the midbrain. In the descending tracts, the signal from the insular cortex, hypothalamus, and amygdala can modulate pain by inhibiting the PAG-RVM-dorsal horn pathway.17,18 Several neurotransmitters and receptors involved in pain modulation such as cannabinoids, endogenous opioids, sympathomimetics, and α2-ARs are significantly expressed in the PAG-RVM-dorsal horn pathways.18

The α2-ARs are widely distributed along the pain pathways in the CNS and PNS.10,11 In the CNS, the α2-ARs in the locus caeruleus (LC) and dorsal horn of the spinal cord play an important role in pain modula-tion and antinociception.17 Presynaptic activation of the α2-AR in the LC inhibits calcium ion influx, and reduces norepinephrine release.11,19 Presynaptic activation of α2-ARs has also been shown to inhibit adenyl cyclase, in turn, decreasing the level of cAMP, causing hyperpolar-ization of noradrenergic neurons.9,10 In the dorsal horn, activation of α2-Gi protein-coupled receptors causes hy-perpolarization, reduces the release of substance P, and inhibits spontaneous activity of nociceptive neurons.9,20 Overall, activation of the sympathetic nervous system (SNS) affects nociception in 2 principal and opposing mechanisms, implying a balance determining even-tual response outcome. First, the sympathetic activation potentiates the release of nociceptive chemical media-tors such as substance P. Second, activation of the α2-receptors in the LC and dorsal horn, activates descending

Figure. Schematic of proposed effector mechanisms of α-2 adrenergic receptors. α-2-ARs are G-coupled protein receptors regulated by guanine nucleotide. Specifically, α-2-ARs are coupled to Gi and Go proteins which elicit an inhibitory effect or null effect via cyclic adenosine monophosphate (cAMP). Activation of Go coupled receptor leads to a reduction in cAMP levels that result in hyperpolarization of neuronal membrane, and decreased adrenergic response. Gi protein-induced hyperpolarization is regulated by voltage-gated potassium and calcium channels, which prevents the initiation of an action potential.


modulatory pathways by inhibiting norepinephrine and substance P release.4,11,16,17

αα2-Agonist and Analgesia/AntinociceptionClonidine and dexmedetomidine-induced activation of α2-ARs mediate antinociception and analgesia in the CNS and PNS. Supraspinal activation of the α2-ARs decreases sympathetic outflow with resultant analgesia.6 It has been suggested that activation of α2-ARs by dexmedetomidine diminishes presynaptic calcium entry via voltage-gated calcium channels and inhibits exocytosis of neurotrans-mitters. Specifically, presynaptic inhibition of the release of norepinephrine in the LC prevents pain transmission and enhances pain modulation.6,9 Other investigators have suggested that the analgesic effects of α2-AR ago-nists result from the activation of the Gi protein-coupled inhibition of cAMP, which decreases adrenergic cellular response and nociception. Also, the activation of Gi protein-gated potassium channels results in membrane hyperpolarization, which prevents the initiation of an action potential.9,12 Neuraxial administration of α2-AR agonists has shown that hyperpolarization of nociceptive neurons inhibits the firing of the nociceptors and prevents the release of substance P from the substantia gelatinosa, resulting in analgesia.6,9 Given that the descending inhibi-tory pathways are mediated by α2-ARs in the superficial laminae and spinal cord, activation of these receptors by α2-AR agonists may reduce nociceptive inputs and promote analgesia.12,19

In the PNS, preclinical studies have suggested that high doses of clonidine may induce antinociception by block-ing nociceptive C fibers.12 Others have suggested that its peripheral antinociceptive effects may be related to the vasoconstriction, or activation of peripheral μ-opioid and adenosine receptors.12 To date, the exact mechanism of peripheral antinociception of α2-ARs remains to be elu-cidated. In the sections that follow, we discuss the role of α2-AR agonists in antinociception, the synergistic anal-gesic effect of α2-AR agonists with opioids, hyperalgesia, and postoperative pain management.

αα2-Agonists in Acute Postoperative Pain ManagementDespite their recognized analgesic and antinociceptive effects, α2-AR agonists are underused in acute postop-erative pain management. As mentioned earlier, α2-AR agonists can enhance the analgesic effect of opioids, decrease anxiolysis, and prevent hyperalgesia, among other effects. The role of clonidine and dexmedetomi-dine in acute postoperative pain management has been extensively reported in the literature.5,21-28 Multiple sys-tematic reviews and meta-analyses have shown that intra-thecal administration of clonidine and dexmedetomidine reduces the onset of sensory loss, extends the duration of spinal analgesia, and decreases postoperative opioid

consumption.21,24,29 Similarly, epidural administration of clonidine and dexmedetomidine hastens onset of analge-sia, prolongs duration of analgesia, and decreases adverse events.24 There is no significant difference in analgesic effect between dexmedetomidine and clonidine.24 For patients undergoing knee arthroscopy, intra-articular administration of clonidine decreased postoperative pain, at least mildly.22,23 Similarly, systemic administration of α2-AR agonist drugs decreased pain and opioid consump-tion in patients undergoing noncardiac surgery.5 More recently, the safety, efficacy, and analgesic benefits of clonidine have been documented in pediatric ophthalmic surgery.27 Like clonidine, the postoperative analgesic ef-ficacy of dexmedetomidine has been documented in sys-tematic reviews and meta-analysis of adult and pediatric patients who underwent various surgical procedures.14,26 The Table summarizes the commonly administered dose of α2-AR agonists by route of administration.

Analgesic Synergy Between Opioid Recep-tors and αα2 Adrenoreceptor ActivitySynergistic drug interactions occur when the administra-tion of 2 or more drugs result in an enhanced potency and/or efficacy that is greater than the sum of the effect of each drug alone. Multiple studies have documented that co-administration of α2-AR agonists and opioids results in greater analgesia and/or antinociception than the administration of either drug alone.29,30 The molecu-lar mechanism of the synergy between α2-AR agonists and opioids is not fully understood. However, the wide expression of α2-AR receptor subtypes (α2A, α2B, α2C, and α2D) and opioid receptors (μ, δ, and κ) in pain pathways suggests that various receptor subtypes are involved in analgesia synergy.29 Using mutant knock-out mice and moxonidine, an α2-specific imidazoline, Fairbanks and colleagues20 found that α2C-ARs contrib-ute to antinociception in the spinal cord and synergy with opioids. Other authors have suggested that the in-teraction between δ-opioid receptors and α2A-AR subtype are responsible for analgesia and synergy.31 Results of animal studies have documented enhanced antinocicep-tive effects and decreased opioid consumption when clonidine or dexmedetomidine is co-administered with opioids, either intrathecally or systemically.

In a randomized controlled trial (RCT), Lin et al32 re-ported that the addition of dexmedetomidine to PCA with morphine demonstrated significant reduction of morphine consumption with fewer PONV incidents. Other investiga-tors have compared the effect of combining α2-AR agonists with opioids against single therapy and documented a lower opioid requirement to obtain adequate analgesia.33 Although additional studies are needed to examine the molecular mechanism of the α2-AR-agonist–opioid synergy, co-admin-istration of both drugs does reduce opioid requirements, thus reducing potential opioid-related adverse effects.


Effect of αα2-Agonists in Reducing HyperalgesiaTissue damage such as surgical incision, bruise, or scrape is usually followed by pain that is proportional to the nature of the injury. However, in some instances, the tissue surrounding an injury exhibits exaggerated sensi-tivity and responsiveness to painful stimuli. Hyperalgesia describes a phenomenon characterized by heightened painful perception of a stimulus that usually causes pain (primary hyperalgesia) and pain perception of tissue near the site of injury that would not usually be painful (secondary hyperalgesia). Like pain, hyperalgesia is medi-ated by sensitization of nociceptive neurons through the dorsal horn of the spinal cord. Sensitization and associ-ated primary and secondary hyperalgesia are caused by the release of various substances, including bradykinin, histamine, prostaglandins, leukotrienes, serotonin, and potassium ions, among others. Another type of hyperalge-sia that is commonly encountered in anesthesia practice, OIH, follows long-term or rapid administration of potent opioids such as remifentanil, morphine, and fentanyl.

Clonidine and dexmedetomidine have been shown to reduce OIH. A double-blinded RCT of healthy volunteers found that co-administration of clonidine and remifentanil significantly reduced OIH compared with remifentanil alone.8 Similarly, an RCT of patients who underwent laparoscopic-assisted vaginal hyster-ectomy found that compared with morphine alone, co-administration of morphine and dexmedetomidine significantly decreased postoperative opioid require-ment and OIH.34 More recently, a double-blinded RCT of patients who underwent thyroidectomy found that administration of both low-dose (0.2 μg/kg) and high-dose (0.6 μg/kg) dexmedetomidine significantly decreased postoperative pain and remifentanil-induced hyperalgesia. Interestingly, they also reported a small

but significant sex-related difference in the influence of dexmedetomidine.35

Anxiety and Pain PerceptionThere is a bidirectional relationship between acute and chronic pain and anxiety such that chronic pain can lead to anxiety, and anxiety can heighten the perception of pain.36 For instance, focusing full attention on painful stimuli worsens pain perception, whereas shifting atten-tion from the painful stimuli to another activity such as soothing music has been shown to decrease perception. Findings of functional magnetic resonance studies have shown that the pain of migraine was associated with an increase in functional connectivity in brain areas that regulate mood and pain, including the LC, caudate, hy-pothalamus, and parahippocampus gyrus.37

Preoperative anxiety and catastrophizing behavior has been shown to predict the development of chronic post-operative pain. Multiple systematic reviews and meta-analyses found that preoperative anxiety and associated catastrophizing behaviors correlate with acute postsurgi-cal pain.15,38 This positive relationship between preop-erative anxiety and postoperative pain has been shown in patients undergoing cardiac and noncardiac surgery.39,40

A systematic review and meta-analysis found that dex-medetomidine not only provided superior anxiolysis over midazolam and ketamine but also decreased postoperative pain among children undergoing surgery.39 Results of an RCT found that among children undergoing same-day surgery for hernia repair, a preoperative infusion dose of dexmedetomidine provided better anxiolysis compared with midazolam.40 In a double-blinded RCT, Ghai and colleagues41 compared intranasal dexmedetomidine vs oral midazolam in children undergoing CT imaging; dexmedetomidine provided superior anxiolysis compared

Table. Commonly Administered Doses of αα2-AgonistsAbbreviation: PONV, postoperative nausea and vomiting.aPediatric dose

Route of Commonly administered dose administration Dexmedetomidine Clonidine Comments

Spinal28,31,35 2.5-10 µg 30-150 μg or 1 µg/kg No significant difference between low dose (<75 μg) and high dose (>75 μg) of clonidine.

Epidural31,32 0.5-1.5 µg/kg Bolus: 75-400 µg No significant difference in onset and duration Infusion:10-40 µg/h between equipotent doses of dexmedetomidine

and clonidine.

Intravenous10 0.2-0.5 µg/kg/h 2-5 μg/kg Significant reduction in PONV

Intra-articular29,30 100 µg or 1 µg/kg 1 µg/kg No significant hypotension reported with intra-articular use. Significant reduction in PONV

Intranasal33 1-2 µg/kg Limited number of studies with intranasal administration

Transdermal 5 mg

Oral34 0.4 mg/kga 150-300 µg or 2-5 µg/kg 2-4 µg/kga


with midazolam. Similarly, premedication with clonidine has been shown to be more effective at decreasing anxiety and postoperative pain compared with midazolam.42

Role of αα2-Agonists in Other ERAS ComponentsBesides optimal pain management, other goals of ERAS protocols include organ protection and decreased periop-erative stress.1 The stress of surgery activates the release of neuroinflammatory hormones such as cortisol, inter-leukins, and cytokines. These hormones and inflamma-tory mediators increase the patient’s risk of postoperative complications such as infections, cognitive dysfunction, atrial fibrillation, poor wound healing, and multiorgan dysfunction.43 α2-AR agonists modulate perioperative stress and immune response in surgical patients through the hypothalamic-pituitary-adrenal axis and anti-inflam-matory pathways.43,44

αα2-Adrenoreceptor Agonists Modulate Immuno-inflammatory ResponsesThe body’s response to stress involves an intricate inter-play among the immune, endocrine, and nervous systems. Surgical procedures induce stress that is characterized by substantial activation of the SNS and by catecholamine release. High levels of catecholamines result in immune suppression by inhibiting the proliferative function of lymphocytes. It is also associated with the stimulation of macrophages and tumor necrosis factor (TNF).43 These inflammatory responses are regulated by the CNS, and as mentioned earlier, clonidine and dexmedetomidine can decrease the release of catecholamines.9,17 Thus, activa-tion of α2-ARs can exert anti-inflammatory effects by mediating the release of catecholamines and stress hor-mones. A recent systematic review and meta-analysis by Wang et al43 found that perioperative administration of dexmedetomidine attenuates surgical stress and inflam-mation, and enhances immune function. Specifically, dexmedetomidine significantly decreased the concentra-tions of interleukin 6 (IL-6), IL-1β, IL-8, TNF-α, and C-reactive protein and increased the level of IL-10 in surgical patients postoperatively.43 Thus, perioperative use of dexmedetomidine may preserve immune func-tions, which are critical for postoperative wound healing, recovery, and organ protection.

αα2-Adrenoreceptor Agonists Protect Renal FunctionAcute kidney injury (AKI) is a known complication of some major surgical procedures such as vascular, cardiac, and liver procedures.45 Renal ischemia or re-perfusion injury is a leading cause of AKI. Authors of some studies reported that certain types of anesthesia and surgical stress deleteriously affected renal func-tion, whereas other investigators showed that some

anesthetic drugs may exert protective effects to reduce AKI via anti-inflammatory, antinecrotic, and antiapop-totic effects.45 Activation of α2-ARs in the kidney has been associated with increased secretion of sodium and water.9 In a meta-analysis, Liu et al45 demonstrated that administration of dexmedetomidine in cardiac surgery provides renal protection by attenuating the response of sympathetic activity and exerting anti-inflammatory effects. In patients who underwent noncardiac surgery, perioperative administration of α2-AR agonists increased urine output; however, other renal protective effects were inconsistent.46 Thus, it is reasonable to conclude that in high-risk patients who are prone to renal injury, α2-AR agonists may be beneficial in preserving renal function. More studies are needed to examine their effect on renal function and renal protection.

αα2-Agonists and Postoperative Nausea and VomitingNausea and/or vomiting is one of the most common complaints after an operation. Common risk factors for PONV include opioid use, stress, and anxiety. As earlier discussed, α2-AR agonists can decrease both periop-erative opioid requirements and anxiety.5,39,42 Results of multiple studies have shown that both clonidine and dex-medetomidine are effective in reducing PONV in adults as well as in pediatric populations.5,39 A systematic review and meta-analysis that included approximately 1,000 pediatric patients who underwent ophthalmic surgery reported that clonidine lowered the incidence of PONV up to 24 hours postoperatively. Interestingly, the use of clonidine was not associated with any significant adverse hemodynamic effects.27 Although the exact antiemetic mechanism of α2-AR agonist drugs remains unknown, it has been proposed that their antiemetic effects may be related to a reduction in release of catecholamines and adrenergic response.13 Also, it may be related to the decreased opioid consumption associated with the use of α2-AR agonists.5 Overall, the use of α2-agonists into the ERAS protocol brings additional benefits to patients who are likely to experience PONV.

Effect of αα2-Agonists on Opiate Addiction and Nonopioid AddictionUndoubtedly, opioid dependence is a major healthcare and societal problem in the United States. Patients un-dergoing surgery may experience opioid withdrawal symptoms for several reasons. α2-AR agonists attenuate withdrawal symptoms in both opiate and nonopioid ad-diction.3,11,47 In opioid withdrawal, unrestrained adren-ergic activity increases anxiety, irritability, insomnia, and hyperactivity, resulting in large part from SNS activation. Withdrawal symptoms are positively correlated with the level of norepinephrine released in the plasma. α2-AR ag-onists such as clonidine and dexmedetomidine have been


widely used to successfully reduce the release of norepi-nephrine, thereby mitigating stress and anxiety, associ-ated with alcohol and opioid withdrawal symptoms.3,47 Thus, sympatholytic properties of α2-AR agonists make the use of these drugs attractive for the management of withdrawal symptoms.

Authors of a 2016 Cochrane review concluded that the rate of successful opioid withdrawal was similar between α2-AR agonists and methadone. Following the admin-istration of α2-AR agonists, the signs and symptoms of opioid withdrawal resolved earlier than with a reduction of methadone dose.47 Others reported similar results when clonidine was compared with buprenorphine.48 Jain et al48 investigated the most effective dose of cloni-dine for detoxification of opioid-dependent patients. They compared low-dose (0.2-0.4 mg/d) and high-dose (0.5-0.8 mg/d) clonidine administered to patients over 14 days of detoxification. Both low and high doses of clonidine were successful in decreasing opioid crav-ings. However, the higher-dose group reported more side effects such as dry mouth and hypotension.48

Dexmedetomidine has been used not only in adults but also in the pediatric population to facilitate opioid and benzodiazepine withdrawal symptoms.3,48

Side Effects of αα2-AgonistsLong-term treatments with α2-AR agonists have proved to be safe, yet side effects of drowsiness, dizziness, and pos-tural hypotension remain common.13 In the perioperative period, the most common side effects of α2-AR agonists are hypotension and bradycardia.9,11 Although the inci-dence of symptomatic bradycardia is low, caution must be used during administration of α2-AR agonists to patients with atrial-ventricular (AV) nodal dysfunction.4,10 The antidromotropic effects of α2-AR agonists may depress conduction through the AV node and prolong the PR in-terval.9,25 Also, patients with renal insufficiency must be closely monitored when treated with α2-AR agonists.13,25 The α2-AR agonists may produce hypotension by reduc-ing adrenergic activity in the LC and nucleus tractus solitarii.10 Because of hypotension and sedation, patients treated with α2-AR agonists require more frequent post-operative monitoring.11,15 Perioperative maintenance of clonidine is warranted to avoid rebound hypertension and to prevent sympathetic hyperactivity in patients with long-term clonidine administration.

ConclusionOptimal perioperative pain management, anxiolysis, im-munomodulation, and prevention of postoperative com-plications such as PONV are essential components of ERAS. Current ERAS protocols are complex multistep pro-cesses, yet postoperative pain continues to be a problem.1 As part of a multimodal analgesic regimen, the synergistic combination of α2-AR agonists and opioids may improve

postoperative pain control while simultaneously enhanc-ing other goals of ERAS protocols. The ongoing opioid epidemic calls for the need to develop novel nonopioid analgesic medications. Highly selective α2-AR agonists remain a viable avenue that investigators can explore. Like most medications, α2-AR agonists are not indicated for all patients and circumstances. As a result, providers should always exercise sound clinical judgment when administer-ing these drugs. The unique properties of α2-AR agonists make them well suited for inclusion in perioperative mul-timodal analgesia and ERAS protocols.

REFERENCES 1. Joshi GP, Kehlet H. Postoperative pain management in the era of

ERAS: an overview. Best Pract Res Clin Anaesthesiol. 2019;33(3):259-267. doi:10.1016/j.bpa.2019.07.016

2. Chia YY, Liu K, Wang JJ, Kuo MC, Ho ST. Intraoperative high dose fentanyl induces postoperative fentanyl tolerance. Can J Anesth. 1999;46(9):872. doi:10.1007/BF03012978

3. Oschman A, McCabe T, Kuhn RJ. Dexmedetomidine for opioid and benzodiazepine withdrawal in pediatric patients. Am J Health Syst Pharm. 2011;68(13):1233-1238. doi:10.2146/ajhp100257

4. Nguyen V, Tiemann D, Park E, Salehi A. Alpha-2 agonists. Anesthesiol Clin. 2017;35(2):233-245. doi:10.1016/j.anclin.2017.01.009

5. Blaudszun G, Lysakowski C, Elia N, Tramer MR. Effect of periop-erative systemic α2 agonists on postoperative morphine consumption and pain intensity: systematic review and meta-analysis of ran-domized controlled trials. Anesthesiology. 2012;116(6):1312-1322. doi:10.1097/ALN.0b013e31825681cb

6. Zhang X, Bai X. New therapeutic uses for an alpha2 adrenergic recep-tor agonist—dexmedetomidine in pain management. Neuroscience Lett. 2014;561:7-12. doi:10.1016/j.neulet.2013.12.039

7. Dong W, Chen MH, Yang YH, et al. The effect of dexmedetomidine on expressions of inflammatory factors in patients with radical resec-tion of gastric cancer. Eur Rev Med Pharmacol Sci. 2017;21(15):3510-3515.

8. Koppert W, Sittl R, Scheuber K, Alsheimer M, Schmelz M, Schuttler J. Differential modulation of remifentanil-induced analgesia and postin-fusion hyperalgesia by S-ketamine and clonidine in humans. Anes-thesiology. 2003;99(1):152-159. doi:10.1097/00000542-200307000-00025

9. Gertler R, Brown HC, Mitchell DH, Silvius EN. Dexmedetomi-dine: a novel sedative-analgesic agent. Bayl Univ Med Cent Proc. 2001;14(1):13-21. doi:10.1080/08998280.2001.11927725

10. Smith H, Elliott J. Alpha(2) receptors and agonists in pain management. Curr Opin Anaesthesiol. 2001;14(5):513-518. doi:10.1097/00001503-200110000-00009

11. Giovannitti JA Jr, Thoms SM, Crawford JJ. Alpha-2 adrenergic recep-tor agonists: a review of current clinical applications. Anesth Prog. 2015;62(1):31-39. doi:10.2344/0003-3006-62.1.31

12. Chan AK, Cheung CW, Chong YK. Alpha-2 agonists in acute pain management. Expert Opin Pharmacother. 2010;11(17):2849-2868. doi:10.1517/14656566.2010.511613

13. Neil MJ. Clonidine: clinical pharmacology and therapeutic use in pain management. Curr Clin Pharmacol. 2011;6(4):280-287. doi:10.2174/157488411798375886

14. Bellon M, Le Bot A, Michelet D, et al. Efficacy of intraoperative dexmedetomidine compared with placebo for postoperative pain management: a meta-analysis of published studies. Pain Ther. 2016;5(1):63-80. doi:10.1007/s40122-016-0045-2

15. Chieng YJ, Chan WC, Klainin-Yobas P, He HG. Perioperative anxiety and postoperative pain in children and adolescents undergoing elec-tive surgical procedures: a quantitative systematic review. J Adv Nurs. 2014;70(2):243-255.


16. Szabadi E. Modulation of physiological reflexes by pain: role of the locus coeruleus. Front Integr Neurosci. 2012;6(94). doi:10.3389/fnint.2012.00094

17. Llorca-Torralba M, Borges G, Neto F, Mico JA, Berrocoso E. Norad-renergic locus coeruleus pathways in pain modulation. Neuroscience. 2016;338:93-113. doi:10.1016/j.neuroscience.2016.05.057

18. Ossipov MH, Morimura K, Porreca F. Descending pain modula-tion and chronification of pain. Curr Opin Support Palliat Care. 2014;8(2):143-151. doi:10.1097/SPC.0000000000000055

19. Koga K, Yamada A, Song Q, et al. Ascending noradrenergic excitation from the locus coeruleus to the anterior cingulate cortex. Mol Brain. 2020;13(1):49. doi:10.1186/s13041-020-00586-5

20. Fairbanks CA, Stone LS, Kitto KF, Nguyen HO, Posthumus IJ, Wilcox GL. α2C-adrenergic receptors mediate spinal analgesia and adrenergic-opioid synergy. J Pharmacol Exp Ther. 2002;300(1):282-290. doi:10.1124/jpet.300.1.282

21. Engelman E, Marsala C. Efficacy of adding clonidine to intrathecal morphine in acute postoperative pain: meta-analysis. Br J Anaesth. 2013;110(1):21-27. doi:10.1093/bja/aes344

22. Sun R, Zhao W, Hao Q, et al. Intra-articular clonidine for post-operative analgesia following arthroscopic knee surgery: a system-atic review and meta-analysis. Knee Surg Sports Traumatol Arthrosc. 2014;22(9):2076-2084. doi:10.1007/s00167-013-2615-8

23. Perritt E, Wallace H, Singh S, Banerjee A. Effect of intra-articular alpha-agonists on post-operative outcomes following arthroscopic knee surgery: a systematic review and meta-analysis. Egypt J Anaesth. 2017;33(2):195-201. doi:10.1016/j.egja.2017.02.004

24. Allen TK, Mishriky BM, Klinger RY, Habib AS. The impact of neur-axial clonidine on postoperative analgesia and perioperative adverse effects in women having elective caesarean section—a system-atic review and meta-analysis. Br J Anaesth. 2018;120(2):228-240. doi:10.1016/j.bja.2017.11.085

25. Zhang X, Wang D, Shi M, Luo YG. Efficacy and safety of dexmedeto-midine as an adjuvant in epidural analgesia and anesthesia: a system-atic review and meta-analysis of randomized controlled trials. Clin Drug Invest. 2017;37(4):343-354. doi:10.1007/s40261-016-0477-9

26. Schnabel A, Reichl SU, Poepping DM, Kranke P, Pogatzki-Zahn EM, Zahn PK. Efficacy and safety of intraoperative dexmedetomidine for acute postoperative pain in children: a meta-analysis of randomized controlled trials. Pediatr Anesth. 2013;23(2):170-179. doi:10.1111/pan.12030

27. Hsu YP, Chu KC, Bai CH, Huang CJ, Chen C, Hsu CW. Safety and efficacy of clonidine on postoperative vomiting and pain in pediatric ophthalmic surgery: a systematic review and meta-analysis. Pediatr Anesth. 2019;29(10):1011-1023. doi:10.1111/pan.13712

28. Rajan R, Gosavi S, Dhakate V, Ninave S. A comparative study of equi-potent doses of intrathecal clonidine and dexmedetomidine on char-acteristics of bupivacaine spinal anesthesia. J Datta Meghe Inst Med Sci Univ. 2018;13(1):4-8. doi:10.4103/jdmimsu.jdmimsu_59_18

29. Whizar-Lugo VM. Topics in Spinal Anaesthesia. InTech; 2014.

30. Chabot-Dore AJ, Schuster DJ, Stone LS, Wilcox GL. Analgesic synergy between opioid and α2-adrenoceptors. Br J Pharmacol. 2015;172(2):388-402. doi:10.1111/bph.12695

31. Chabot-Dore AJ, Millecamps M, Stone LS. The delta-opioid receptor is sufficient, but not necessary, for spinal opioid-adrenergic analgesic synergy. J Pharmacol Exp Ther. 2013;347(3):773-780. doi:10.1124/jpet.113.206581

32. Eisenach JC, D’Angelo R, Taylor C, Hood DD. An isobolographic study of epidural clonidine and fentanyl after cesarean section. Anesth Analg. 1994;79(2):285-290. doi:10.1213/00000539-199408000-00014

33. Paech MJ, Pavy TJ, Orlikowski CE, et al. Postcesarean analgesia with spinal morphine, clonidine, or their combination. Anesth Analg. 2004;98(5):1460-1466. doi:10.1213/01.ane.0000111208.08867.3c

34. Lee C, Kim YD, Kim JN. Antihyperalgesic effects of dexmedetomidine on high-dose remifentanil-induced hyperalgesia. Korean J Anesthesiol. 2013;64(4):301-307. doi:10.4097/kjae.2013.64.4.301

35. Qiu H, Sun Z, Shadhiya F, et al. The influence of dexmedetomidine

on remifentanil-induced hyperalgesia and the sex differences. Exp Ther Med. 2018;16(4):3596-3602. doi:10.3892/etm.2018.6641

36. Koga K, Descalzi G, Chen T, et al. Coexistence of two forms of LTP in ACC provides a synaptic mechanism for the interactions between anxiety and chronic pain. Neuron. 2015;85(2):377-389. doi:10.1016/j.neuron.2014.12.021

37. Moulton EA, Becerra L, Johnson A, Burstein R, Borsook D. Altered hypothalamic functional connectivity with autonomic circuits and the locus coeruleus in migraine. PloS One. 2014;9(4):e95508. doi:10.1371/journal.pone.0095508

38. Sobol-Kwapinska M, Ba̧ bel P, Plotek W, Stelcer B. Psychological correlates of acute postsurgical pain: a systematic review and meta-analysis. Eur J Pain. 2016;20(10):1573-1586. doi:10.1002/ejp.886

39. Peng K, Wu SR, Ji FH, Li J. Premedication with dexmedetomidine in pediatric patients: a systematic review and meta-analysis. Clinics. 2014;69(11):777-786. doi:10.6061/clinics/2014(11)12

40. Du Z, Zhang XY, Qu SQ, et al. The comparison of dexmedetomidine and midazolam premedication on postoperative anxiety in children for hernia repair surgery: a randomized controlled trial. Pediatr Anesth. 2019;29(8):843-849. doi:10.1111/pan.13667

41. Ghai B, Jain K, Saxena AK, Bhatia N, Sodhi KS. Comparison of oral midazolam with intranasal dexmedetomidine premedication for children undergoing ct imaging: a randomized, double-blind, and controlled study. Paediatr Anaesth. 2017;27(1):37-44. doi:10.1111/pan.13010

42. Dahmani S, Brasher C, Stany I, et al. Premedication with clonidine is superior to benzodiazepines. A meta analysis of published studies. Acta Anaesthesiol Scand. 2010;54(4):397-402. doi:10.1111/j.1399-6576.2009.02207.x

43. Wang K, Wu M, Xu J, et al. Effects of dexmedetomidine on periop-erative stress, inflammation, and immune function: systematic review and meta-analysis. Br J Anaesth. 2019;123(6):777-794. doi:10.1016/j.bja.2019.07.027

44. Chavez-Valdez R, Kovell L, Ahlawat R, McLemore GL, Wills-Karp M, Gauda EB. Opioids and clonidine modulate cytokine production and opioid receptor expression in neonatal immune cells. J Perinatol. 2013;33(5):374-382. doi:10.1038/jp.2012.124

45. Liu Y, Sheng B, Wang S, Lu F, Zhen J, Chen W. Dexmedetomidine prevents acute kidney injury after adult cardiac surgery: a meta-anal-ysis of randomized controlled trials. BMC Anesthesiol. 2018;18(1):7. doi:10.1186/s12871-018-0472-1

46. Peng K, Ji FH, Liu HY, Zhang J, Chen QC, Jiang YH. Effects of periop-erative dexmedetomidine on postoperative mortality and morbidity: a systematic review and meta-analysis. Clin Ther. 2019;41(1):138-154.e4. doi:10.1016/j.clinthera.2018.10.022

47. Gowing L, Farrell M, Ali R, White JM. Alpha 2-adrenergic agonists for the management of opioid withdrawal. Cochrane Database Syst Rev. 2016;2016(5):CD002024. doi:10.1002/14651858.CD002024.pub5

48. Jain N, Chavan B, Sidana A, Das S. Efficacy of buprenorphine and clonidine in opioid detoxification: a hospital-based study. Indian J Psychiatry. 2018;60(3):292-299. doi:10.4103/psychiatry.IndianJPsy-chiatry_381_17

AUTHORSSarah Jingying Zhang, PhD, CRNA, is an assistant professor of nursing, Pro-gram of Nurse Anesthesiology, University of South Florida, Tampa, Florida; adjunct assistant professor of nursing, Program of Nurse Anesthesia, Samuel Merritt University, Oakland, California. Email: [email protected].

Gloria Lai, MSN, CRNA is a staff CRNA, Department of Anesthesiol-ogy, University of California Davis, Davis California. E-mail: [email protected].

Charles A. Griffis, PhD, CRNA, FAANA, is a clinical instructor of anesthesiology, Program of Nurse Anesthesia, University of Southern Cali-fornia, Los Angeles, California. E-mail: [email protected].

Michelle Schiltz, MSN, CRNA, is staff CRNA, Department of Anes-thesiology, Kaiser Permanente-South Sacramento Medical Center, Sacra-mento, California. Email: [email protected].


Edwin N. Aroke, PhD, CRNA, FAAN, is an associate professor of nurs-ing, Nurse Anesthesia Program, University of Alabama at Birmingham, Birmingham, Alabama. Email: [email protected].

DISCLOSURESName: Sarah Jingying Zhang, PhD, CRNA

Contribution: This author made significant contributions to the concep-tion, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author.

Disclosures: Partly supported by the Department of Anesthesiology, Uni-versity of Minnesota.

Name: Gloria Lai, MSN, CRNA


Disclosures: None.

Name: Charles A. Griffis, PhD, CRNA, FAANA


Disclosures: None.

Name: Michelle Schiltz, MSN, CRNA


Disclosures: None.

Name: Edwin N. Aroke, PhD, CRNA, FAAN


Disclosures: Supported by an Administrative Supplement from the National Institutes of Health/National Institute of Mental Health (grant 3R01MD010441-03S1).

The authors did not discuss off-label use within the article. Disclosure statements are available for viewing upon request.

AANA Journal Course—α2-Adrenergic Receptor Agonist, an ...

Documents

Transcript of AANA Journal Course—α2-Adrenergic Receptor Agonist, an ...