Chapter 8. Analgesic Adjuvants in Neuraxial Anesthesia

The ease of practice and relative predictability of neuraxial anesthesia, coupled with its potential to provide multiple benefits to patients in the perioperative period has led to its widespread popularity. Nevertheless, concern of potential failed blocks and untoward effects still limits the acceptance of these techniques. Much effort has been put forth to minimize these undesirable events and optimize the patient experience. The addition of adjuvant medications to local anesthetic preparations has been one avenue pursued to attain these goals.

As early as 1900, Matas1 was combining morphine and cocaine for subarachnoid injection. Morphine was added in an attempt to prolong the effects of cocaine and to provide sedation. It was not until the 1970s, after the demonstration of opiate receptors in the spinal cord, that neuraxial opioids again began to enter routine use as part of modern regional anesthesia. As the percentage of surgeries performed in the ambulatory setting increases, interest has shifted to finding adjuncts that will provide faster recovery without compromising anesthetic reliability. Many substances have been investigated for use in the subarachnoid and epidural space as an attempt to improve the way that we care for patients (Tables 8–1 and 8–2).

Since the identification of opioid receptors in the spinal cord, the potent analgesic effects of neuraxial opioids have been exploited to improve perioperative analgesia and reduce the supraspinal side effects of sedation and respiratory depression seen with systemic opioids. This technique is still limited by dose-dependent pruritis, nausea, and urinary retention.

Pharmacology

Whether administered in the epidural or subarachnoid space, opioids that diffuse into the spinal cord exert spinal analgesia by modulating A-δ and C fibers to decrease afferent nociceptive input.2 Both μ- and δ-receptor agonists act presynaptically by inhibiting Ca2 + influx. Postsynaptically, μ-receptor agonists increase K+ conductance and hyperpolarize ascending neurons.3 Opioids have minimal effect on dorsal root axons and somatosensory-evoked potentials.

Cardiovascular Effects

Intrathecal opioids have been shown to have a synergistic interaction with local anesthetics, which allows for enhanced analgesia without increased motor or sympathetic blockade.4 Thus neuraxial opioids are considered to maintain cardiovascular stability better than equally analgesic doses of local anesthetics. However, neuraxial opioids can reduce sympathetic outflow, via opioid receptors in the sympathetic ganglia, thereby eliciting hypotension. Furthermore, Curatolo and coworkers5 identified the addition of fentanyl to local anesthetics as a factor associated with hypotension with epidural blockade. They proposed that this reaction may be secondary to a faster onset of blockade exceeding the rate of compensatory mechanisms.

Epidural Space

Given its delayed onset, the addition of morphine to epidural anesthetics may not reduce the intraoperative requirement for volatile anesthetics.6 This is typically done in an effort to provide postoperative analgesia with prolonged effect. The use of the lipophilic opioid fentanyl intraoperatively for epidural administration can reduce requirements for volatiles more than intravenous fentanyl (more than twofold at 2 mcg/kg).7 The method of delivery of epidural fentanyl may be important for optimal effect. Ginosaur and colleagues8 have presented evidence that when epidural fentanyl is given as a bolus, it imparts segmental analgesia consistent with spinal level of action. On the other hand, if given as an infusion, the analgesia is mediated through systemic uptake and supraspinal effect. Similar findings have been reported for sufentanil and alfentanil.9

Subarachnoidal Space

Owing to its hydrophilic nature, intrathecal morphine provides highly selective, prolonged spinal analgesia, but is not typically used to augment intraoperative anesthesia.

The lipophilic opioids are more suited for intraoperative use in the intrathecal space due to their rapid onset and modest duration. Additionally, with more timely clearance from the CSF, the risk of delayed respiratory depression from these drugs is much lower than morphine. Exploiting the synergy between local anesthetics and opioids, the addition of 10 to 25 mcg fentanyl to low-dose lidocaine and bupivacaine spinal anesthetics dramatically improves anesthetic success, without delaying achievement of discharge criteria for ambulatory patients.4,10 Pruritis remains a concern with intrathecal fentanyl, especially when administered with procaine or 2-chloroprocaine.11 Furthermore, when used with the ultrashort-acting spinal anesthetic 2-chloroprocaine, fentanyl can slightly delay discharge (95 vs 104 min) as shown by Vath and Kopacz.11 Nevertheless, fentanyl remains one of the most useful analgesic adjuncts for ambulatory spinal anesthesia.

Vasoconstricting agents are commonly added to local anesthetic solutions and have a long history of clinical use. Epinephrine is by far the most commonly employed vasoconstrictor in neuraxial anesthesia for prolonging the anesthetic effect, but it can also reduce peak blood levels, provide more reliable block, and intensify anesthesia and analgesia.12–15 All of these benefits can result in a reduction in the amount of local anesthetic ncessary and consequently decrease the potential for toxicity in a given clinical situation. It had long been thought that the effects of epinephrine are solely due to its vasoconstricting effects, but we now know that it exerts presynaptic adrenergic receptor activity that directly contributes to analgesia.16

Phenylephrine is a synthetic α-adrenergic agonist typically used to prolong spinal anesthesia. Currently it is far less commonly used clinically than epinephrine.

Pharmacology

Epinephrine is an endogenous catacholamine that produces a dose-related pharmacologic profile that is linked to its affinity for various adrenergic receptors. At low doses, epinephrine stimulates β2-receptors, producing arterial vasodilation. Higher doses cause arterial vasoconstriction by stimulating α1-and α2-receptors. Vasoconstriction, and thus decreased blood flow, can reduce uptake of local anesthetics into the circulation, thus maintaining concentrations at the site of injection and reducing peak plasma concentrations. The intrinsic analgesic effects of epinephrine are exerted via stimulation of presynaptic α2-adrenoreceptors found at the terminals of primary afferents. These receptors are also found centrally on neurons in the superficial laminae of the spinal cord and several brainstem nuclei that participate in analgesic mechanisms.

Epinephrine is metabolized rapidly by monoamine oxidase (MAO) and cataechol-O-methyl transferase, resulting in the end product vanillylmandelic acid (VMA). These enzymes are present in the plasma, kidneys, and liver. They are also present in the central nervous system and show particularly high activity in the arachnoid mater.17,18 Due to the rapid inactivation of epinephrine by these enzymes, the duration of the clinical effect of epinephrine is dependent on the rate of exposure to these enzymes.

Cardiovascular Effects

With the typical dose range used for epidural anesthesia, systemic levels of epinephrine remain low. This usually produces mild vasodilation and increased heart rate and myocardial contractility. Ward and coworkers19 evaluated the cardiovascular effects of epidural blockade to T5 using lidocaine with and without epinephrine. Mean arterial pressure decreased 20% in the epinephrine group, compared with 10% in the group receiving plain lidocaine. However, the group with epinephrine also showed a 20–30% increase in cardiac output. Bonica suggested that the systemic β-adrenergic effects of epinephrine administered epidurally might prevent the potential cardiovascular collapse from epidural blockade.20 Higher than normal doses or situations that result in increased vascular uptake can result in peripheral alpha stimulation, thus increasing peripheral vascular resistance. Exceeding a total dose of 0.25 mg of epinephrine may be associated with cardiac arrhythmias.21

When phenylephrine is added to epidural solutions, the systemic absorption results in increased vascular resistance without the benefit of increased contractility or chronotropy seen with epinephrine. Bearing this is mind, anesthesiologists typically only use phenylephrine in the subarachnoid space.

Epidural Space

The typical concentration of epinephrine for epidural anesthesia is 1:200,000, or 5 mcg/mL. The commercially available premixed solutions of local anesthetics with epinephrine are more acidic in an effort to preserve the potency of the epinephrine. This lower pH will slow the onset of blockade and inhibit the vasoconstricting actions of epinephrine; therefore, adding “fresh” epinephrine to local anesthetic solutions at the time of use is preferred.

The clinical effect of epinephrine on duration of anesthesia depends on the local anesthetic used. Epinephrine is more effective at prolonging the anesthetic duration of shorter acting agents, such as lidocaine and 2-chloroprocaine. Adding 1:200,000 epinephrine to 2% lidocaine will nearly double the time to resolution of blockade.22 Agents with longer duration of action show much less prolongation of anesthesia with the addition of epinephrine. Adding epinephrine to ropivacaine will intensify the block, but will not prolong the duration of epidural anesthesia or affect plasma levels.13 This is likely due to the inherent vasoconstricting effects of ropivacaine. Other agents do show reduction of plasma levels when epinephrine is added.12,14 Epinephrine 1:200,000 will decrease plasma lidocaine and chloroprocaine levels by 20% to 30%, but will decrease plasma bupivacaine levels only by 10% to 20%. The effect of epinephrine on plasma levels of local anesthetics has long been thought to be due to constriction of the epidural venous plexus and therefore leads to reduced blood flow and slower uptake of local anesthetics. More recent evidence implies that reduced dural blood flow and increased hepatic clearance may be more important in this phenomenon.23 Its potential to prolong discharge times and delay bladder function limits the utility of adding epinephrine to epidural agents for ambulatory surgery.

Subarachnoidal Space

Both epinephrine and phenylephrine will prolong spinal anesthesia and provide a more intense and reliable block in a dose-related fashion. Epinephrine is much more commonly employed with a typical dose of 0.2 mg, although doses of 0.1 to 0.6 mg have been described. Adding 0.2 mg of epinephrine to a bupivacaine spinal anesthetic will typically increase time of regression to L2 by 25%.24,25

The use of vasoconstrictors in ambulatory spinal anesthesia is quite problematic. Adding epinephrine to spinal anesthetics will prolong motor blockade and delay the return of bladder function, thus preventing patients from achieving discharge criteria. Chiu and coworkers26 showed in volunteers that adding 0.2 mg epinephrine to 50 mg hyperbaric lidocaine prolonged surgical anesthesia (as demonstrated by tolerance of transcutaneous electrical stimulation) by 30 min, and time to void and discharge time increased by 80 min.

In clinically relevant doses intrathecal epinephrine by itself does not carry a risk of neurotoxicity. Spinal cord blood flow is well maintained in the dog and cat model in doses up to 0.5 mg.27 However, it is suggested that epinephrine may contribute to the neurotoxicity of local anesthetics and has been associated with a case report of cauda equina syndrome after single-shot lidocaine spinal anesthesia.28

Phenylephrine may increase the risk of transient neurologic symptoms as suggested by Sakura and coworkers in a study of tetracaine spinal anesthesia.29 A recent volunteer study with spinal 2-chloroprocaine reported consistent flu-like symptoms when epinephrine was added.30

Alpha2-agonists have been gaining popularity in the field of regional anesthesia. Clonidine was first injected intrathecally in humans in 1984, but other α2-agonists had been used in veterinary anesthesia for many years. Clonidine can be useful in enhancing neuraxial analgesia with a different side effect profile than opioids. A preservative-free preparation of clonidine is commercially available in the United States.

Pharmacology

Clonidine binds to α2-adrenoreceptors on primary afferent, substantia gelatinosa, and several brainstem nuclei attributed to analgesic mechanisms. Clonidine is thought to exert its effects by attenuating A-δ and C-fiber nociception and producing conduction blockade via increased potassium conductance.30,31 Clonidine has been shown to increase acetylcholine and norepinephrine in the CSF and to inhibit the release of substance P and modulate wide dynamic range neurons in the dorsal horn of the spinal cord.32 Clonidine is rather lipophilic and thus is rapidly redistributed systemically to the periphery after epidural or spinal administration.

However, neuraxially administered clonidine imparts analgesia through spinal mechanisms rather than systemic absorption as evidenced by the lack of correlation between time of analgesia and peripheral blood levels. The analgesic effects of clonidine have been shown to be reversed by yohimbine, an α2-adrenergic antagonist.33 Clonidine is an extremely stable compound and has undergone extensive testing for neurotoxicity and safety in several animal models without histopathologic or behavioral evidence of detriment.

Cardiovascular Effects

Neuraxially administered clonidine exerts hemodynamic effects through not only central means, but also peripheral action due to its rapid systemic absorption. The effect of clonidine on blood pressure is the result of potentially opposing actions at multiple sites. Neuraxially administered clonidine directly inhibits preganglionic sympathetic neurons in the spinal cord.34 When injected in the low thoracic or lumbar region, or even the cervical epidural space, the effect on blood pressure is not significantly different from intravenous injection.35 However, when given in the mid or upper thoracic epidural space, a much more profound drop in blood pressure is observed.36 This is thought to be due to the upper thoracic dermatomes supplying the heart and the relative concentration of noradrenergic innervation of sympathetic preganglionic neurons.

In the brainstem, activation of α2-adrenoreceptors of the locus ceruleus and nucleus tractus solitarius decreases sympathetic drive. Clonidine will also bind to nonadrenergic imidazoline-prefering receptors in the nucleus reticularis lateralis and impart both hypotensive and antiarrhythmogenic actions.37,38 In the periphery, clonidine activates presynaptic α2-receptors and inhibits the release of norepinephrine from the terminals of sympathetic nerves, thus promoting vasoconstriction and reducing chronotropic drive. However, at higher concentrations of circulating clonidine, the direct α2-/α1-agonist action begins to promote vasoconstriction and thus opposes the presynaptic and brainstem effects. Thus the dose–response curve for neuraxially or systemically administered clonidine is U-shaped, reflecting the central sympatholysis being offset by peripheral vasoconstriction at higher doses.39

Clonidine reduces heart rate by not only inhibiting norepinephrine release, but also through a vagomimetic effect. This, as with afterload-reducing effects, decreases myocardial oxygen demand. The resulting effect of clonidine on cardiac output varies from patient to patient depending on the predominance of either its vasoactive or chronotropic influences. The hemodynamic effect of clonidine peaks after 1 to 2 h and lasts 6–8 h after a single bolus. The addition of clinical doses clonidine to local anesthetics for neuraxial anesthesia is unlikely to increase the degree of resulting hypotension or significantly alter responsiveness to resuscitation drugs.40–43

Epidural Space

Clonidine produces segmental hypoalgesia when administered in the epidural space.35,44 Doses ranging from 100 to 900 mcg have been studied and shown to produce analgesic effects that begin about 20 min after administration and peak at around 1 h.45 The quality of analgesia produced by epidural clonidine has been said to be comparable with that from epidural morphine.46 Side effects of sedation and dry mouth are usually dose-related.

Although clonidine has been studied as a sole agent for epidural administration,47 it is typically used in combination with local anesthetics or opiates in clinical practice. When clonidine is used in combination with opiates, the analgesic effects have been shown to be additive, but not synergistic.48–51 Thus, patients require a smaller total dose of the narcotic and have a decreased incidence of oxygen desaturation with equivalent analgesia.

Adding clonidine to local anesthetics intensifies and prolongs epidural blockade and can reduce local anesthetic dose requirement.52,53 When adding clonidine to local anesthetics, the typical dose for epidural bolus administration is 150 mcg, or 2 mcg/kg.54–56 Klimscha and colleagues showed that the addition of 150 mcg of clonidine to 10 mL of 0.5% bupivacaine for epidural anesthesia in patients undergoing hip surgery increased the mean duration of anesthesia from 1.8 to 5.3 h.55 This dose is associated with decreased intraoperative anesthetic and analgesic requirements,56 reduced pain scores,54–58 increased time to first analgesic request51,54,56–58 and increased patient satisfaction.57 These benefits usually persist for around 3 h and can be achieved without increasing hemodynamic instability more than would occur from local anesthetic alone.

Subarachnoid Space

Intrathecal clonidine produces dose-dependent analgesia without the concerns of pruritis and respiratory depression seen with opioids. Malinovsky and coworkers59 investigated intrathecal clonidine, in doses of 75 to 450 mcg, as the sole anesthetic for transurethral resection of the prostate. All but two patients required general anesthesia, but prolonged analgesia was evident in all patients. The majority of the clinical use of intrathecal clonidine occurs in combination with a variety of local anesthetics, in which it produces dose-dependent prolongation of both sensory and motor blockade.60–63 Side effects of sedation, hypotension, and bradycardia are seen with intrathecal clonidine and are also dose-dependent. Less urinary retention is seen with intrathecal clonidine than with intrathecal morphine.64

Low-dose intrathecal clonidine has a promising role in ambulatory anesthesia. De Kock and coworkers65 demonstrated that the addition of 15 mcg of clonidine to 8 mg of ropivacaine for spinal anesthesia in patients undergoing knee arthroscopy increased anesthetic success from 70 to 90% without significant effect on recovery time. However, when the dose of clonidine was increased to 45 mcg, resolution of motor and sensory blockade and time to voiding increased from 170 to 215 min.

Local anesthetics are weak bases consisting of a lipophilic benzene ring linked to a hydrophilic group, usually a tertiary amine, that can exist in ionized and nonionized forms. To promote aqueous solubility, these compounds are typically prepared in the form of their hydrochloride salts resulting in an acidic solution (pH ranging from 3.4 to 6.4). Commercially available solutions containing epinephrine are prepared at an even lower pH (usually with bisulfite), ranging from 3.2 to 4.2, in efforts to preserve the epinephrine. Alkalinizing solutions to raise the pH closer to the pKa of the local anesthetic and thus increase the proportion of the nonionized form available to cross cell membranes, is thought to speed the onset of anesthesia. Although this is well demonstrated, in vitro66 studies attempting to demonstrate this in epidural anesthetics are sometimes conflicting.

Most studies show that alkalinization speeds onset of epidural blockade with lidocaine,67–72 bupivacaine,67,73,74 mepivacaine,67,75,76 and chloroprocaine77,78 by up to 10 min. Ropivacaine seems to not show faster onset with alkalinization,79 but like the other drugs, there is evidence that alkalinization can intensify epidural anesthesia and improves spread to sacral dermatomes.68,71,72,80 One noted trend is that the effects of alkalinization are greatest on solutions containing epinephrine, whether freshly added or prepackaged. This is perhaps due to pH-dependent vasoconstrictive actions of epinephrine.

It should be noted that the degree of alkalinization is limited by precipitation. Table 8–1 shows the commonly recommended amounts of sodium bicarbonate to be added to each local anesthetic solution, but all preparations should be inspected for precipitation before administration. Alternatively, the carbonate salts of local anesthetics have been shown to have more rapid onset of epidural blockade than standard hydrochloride preparations.81 However, carbonated drugs are of limited availability and may be more prone to induce hypotension with epidural administration.5

Neostigmine

The acetylcholinesterase inhibitor neostigmine has been investigated as a neuraxial analgesic adjunct due to its ability to provide analgesia without hemodynamic depression. However, enthusiasm for clinical use of neostigmine is limited by its tendency to induce nausea and delay recovery from neuraxial blockade.

Pharmacology

Intrathecal neostigmine inhibits the breakdown of acetylcholine in the spinal cord via reversible inhibition of acetylcholinesterase. Animal models have suggested that acetylcholine plays a role in spinal analgesia through stimulation of cholinergic receptors in the substantia gelatinosa and superficial laminae of the dorsal horn of the spinal cord82–84 and perhaps through stimulating nitric oxide production in the spinal cord.85 Although intrathecal injection of cholinergic agonists will stimulate all receptors of a particular class, neostigmine increases endogenous acetylcholine in a manner dependent on the tonic production of this neurotransmitter within each particular region of the spinal cord.

Cardiovascular Effects

Intrathecal neostigmine has been shown to counteract hypotension resulting from bupivacaine spinal anesthesia in rats,86 but these effects are not reproducible in human subjects.87 Volunteers receiving high doses of intrathecal neostigmine developed increased heart rate and respiratory rate—responses that have been attributed to the concomitant severe nausea and vomiting.88 Low and moderate doses are considered to have little or no cardiovascular effects.

Epidural Space

Lauretti and coworkers89 studied the analgesic effect of epidural neostigmine in doses from 1 to 4 mcg/kg added to epidural lidocaine and showed a dose-independent analgesic effect, increasing time to first analgesic request from 3.5 to 8 h. Other studies have reported similar results with doses in the range of 1 to 10 mcg/kg, without report of increased nausea,90–95 but some suggestion of sedation.94

Subarachnoid Space

Subsequent to reassuring toxologic studies in animals, Hood and colleagues88 evaluated safety, analgesic efficacy, and side effects of intrathecal neostigmine in volunteers. All doses produced analgesia without sedation, pruritis, respiratory depression, hypotension, or bradycardia; however, dose-related motor weakness, decreases in deep tendon reflexes, urinary incontinence, genitourinary stimulation, and nausea and vomiting did occur. Further studies in patients revealed similar responses of nausea and vomiting that proved to be prolonged and difficult to treat.96–100 Liu and coworkers100 showed that when added to low-dose (7.5 mg) bupivacaine spinal anesthetics, 50 mcg of neostigmine enhanced motor and sensory blockade, but delayed achievement of discharge criteria. Doses of 6.25 and 12.5 mcg did not prolong anesthesia but still elicited nausea and delayed discharge.

Ketamine

Many studies have demonstrated the involvement of Nmethyl-d-aspartate (NMDA) receptors in analgesia,101–107 central sensitization,102,103,106–108 and opioid tolerance.104,105,107 Ketamine is a noncompetitive antagonist of NMDA receptors, but also has actions at monoaminergic receptors, opioid receptors, voltage-sensitive Ca channels, muscarinic receptors, and local anesthetic actions through Na channel blockade.109 Commercially available as a racemic mixture, the S-enantiomer is far more potent at NMDA receptors.110 Animal models suggest that preservative-free ketamine lacks neurotoxicity.111

Epidural administration of ketamine at 0.5 to 1 mg/kg has been shown to reduce intraoperative112 and postoperative112–115 analgesic requirements without increased side effects. Ozyalcin and coworkers demonstrated decreased pinprick hyperalgesia and touch allodynia in thoracotomy patients receiving epidural versus intramuscular ketamine.115

Ketamine was first used intrathecally as a sole anesthetic by Bion in 1984.116 Hawksworth and coworkers reported intolerable rate of anesthetic failure and psychometric side effects at doses of 0.7 to 0.95 mg/kg.117 Other investigators found similar problems when combining with bupivacaine for spinal anesthesia.118 Further work continues to delineate potential applications for ketamine in the treatment of chronic neuropathic pain, as a preemptive analgesia, and in the modulation of opioid tolerance.119,120

Ketorolac

Eisenach and coworkers have demonstrated involvement of spinal cyclooxygenase (COX) enzymes in postoperative hypersensitivity and pain.121,122 Ketorolac tromethamine is a nonselective, but COX-1-preferring, nonsteroidal antiinflammatory drug that has been investigated in multiple animal models for intrathecal administration and has demonstrated antinociception and lack of neurotoxicity.121–128 There is evidence that ketorolac may enhance analgesic effects of intrathecal clonidine127 and have analgesic synergy with intrathecal morphine128 in rat models. A phase I safety study of preservative-free ketorolac in healthy volunteers using single bolus doses of 0.5 to 2 mg showed no immediate or delayed neurologic detriment.129 This study revealed no significant effect on blood pressure or motor function, but also showed no decrease in pain with heat stimuli. Further human investigations are underway and will it is hoped identify the clinical role of intrathecal ketorolac.

Other Agents and Future Considerations

Researchers continue to investigate various compounds in the hope of improving neuraxial anesthesia. One avenue of research is in liposomal and polymer-encapsulated compounds. Thus far, liposomal morphine is the only agent on the market and intended for single-shot epidural analgesia lasting up to 48 h. It should be noted that it must not be administered with epidural local anesthetics. Doing so can cause early and uncontrolled release of the drug.

Eisenach and coworkers are investigating the role of adenosine in spinal analgesia.130 The potential benefits appear to be in treating chronic neuropathic pain rather than for acute analgesia.

Although previous animal studies had shown inconsistent evidence of neurotoxicity,131,132 further evidence is gathering to suggest that intrathecal midazolam may be a safe and promising adjunct to spinal anesthesia.133,134 The analgesic benefits appear to be greatest when combined with intrathecal opioids,135 but the appropriate clinical role is still to be determined.

The use of analgesic adjuvants in neuraxial anesthesia has improved the care we can provide by improving the reliability and quality of neuraxial blockade, reducing local anesthetic dose and systemic plasma levels, and providing postoperative analgesia. This area continues to be a rich source of future research into the ways of optimizing ambulatory anesthesia, and potentially affecting preemptive analgesia and central sensitization.