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Adjuvant agents in regional anaesthesia
REGIONAL ANAESTHESIA
Adjuvant agents in regional anaesthesia
Learning objectives After reading this article, you should be able to understand the: C role of perioperative adjuvant drugs in regional anaesthesia C way in which different opioid adjuvants behave neuraxially and the influence of their relative lipophilicity C mechanism of action of clonidine and ketamine and their role as adjuvants
Sudhakar R Marri
Abstract Adjuvant agents are pharmacological drugs that, when co-administered with local anaesthetic agents, may improve the speed of onset, the quality and/or duration of analgesia. A wide range of drugs has been assessed for both neuraxial and peripheral nerve blocks. Here, we review the adjuvants used in clinical practice in the UK and also briefly mention other drugs that have been used for neuraxial administration and peripheral nerve blockade to provide perioperative analgesia.
Fentanyl has a more rapid onset and a shorter duration of action than the more hydrophilic opioids such as morphine, when administered either intrathecally or epidurally. It also has a narrower band of segmental analgesia because of rapid uptake of the drug by neural tissues. By contrast, hydrophilic morphine is less readily absorbed in to spinal cord, resulting in slower onset of analgesia and, as it moves towards the brain via CSF convection, the analgesia is spread over more dermatomes. However, late cephalad CSF spread of morphine increases the potential for subsequent brainstem binding with the potential to induce respiratory depression (although this is extremely rare in clinical practice). It also increases the risk of nausea and vomiting by stimulation of dopamine and 5-HT3 receptors in the chemoreceptor trigger zone in the area postrema of the medulla. Diamorphine is a diacetylated analogue of morphine, and has a potency of approximately 1.5e2 that of morphine. It is more lipid soluble than morphine, resulting in a faster onset of action and a slightly shorter duration of action. However, its duration of action is longer than fentanyl. Systemic reviews have shown a prolonged analgesic effect with intrathecal morphine in lower limb arthroplasty.1,2 A systematic review of post-thoracotomy analgesia concluded that a thoracic epidural infusion of local anaesthetic (LA) with an opioid provided the most consistently effective analgesia.3 A systematic qualitative review of randomized controlled trials on the analgesic efficacy of intra-articular morphine after knee arthroscopic surgery indicates that it does not work.4
Keywords Adjuvants; adrenaline; clonidine; dexamethasone; ketamine; magnesium; midazolam; neostigmine; opioids; sodium bicarbonate Royal College of Anaesthetists CPD Matrix: 1A02 3A09
Local anaesthetic agents can produce unwanted side effects such as motor and autonomic block. Their onset may be slow and have limited duration of action. At higher doses, there is a risk of cardiotoxicity and central nervous system side effects. For these reasons, other drugs are sometimes co-administered to utilize their synergistic analgesic properties and to limit the local anaesthetic dose requirement. Opioids remain by far the most commonly used adjuvants via the neuraxial route. However, an increasing number of other agents are being used clinically both for neuraxial and peripheral nerve blocks for their additive or synergistic interactions.
Opioids Opioid receptors are widely spread in the dorsal horn of the spinal cord, the periaqueductal grey and pontine reticular formation in the brain, and peripherally on distal primary afferent neurons. The effects of neuraxially administered opioids result from the composite action of: (i) direct effects on spinal cord opioid receptors, (ii) effect on cerebral opioid receptors resulting from cephalad spread via the CSF and peripheral, and (iii) central effects following vascular absorption. The relative contribution of these three mechanisms of effect is dependent on the dose, site of administration and the lipid solubility of the specific opioid. Morphine is hydrophilic (octanewater partition coefficient of 6), diamorphine (partition coefficient of 52) and fentanyl is lipophilic (partition coefficient of 813).
Adverse effects of neuraxial opioids Late-onset respiratory depression associated with the use of intrathecal morphine is extremely rare with the microgram doses used in clinical practice today. However, nausea and vomiting is common with an incidence of approximately 50%. Our own audit data has shown that prophylactic triple antiemetic therapy of cyclizine, ondansetron and dexamethasone reduces the incidence of postoperative nausea and vomiting (PONV) associated with intrathecal morphine in hip and knee replacement patients to 11%. Urinary retention and pruritus are the other specific side effects related to administration of opioids by spinal route.
a2-Adrenoceptor agonists Specific a2-adrenoceptor agonists inhibit pain transmission by binding to pre-and post-synaptic a2 receptors in the substantia gelatinosa of the dorsal horn of the spinal cord, their primary site of action. The receptors also exist in the brain where these drugs
Sudhakar R Marri MBBS FCARCSI EDRA is a Consultant Anaesthetist at City Hospital (Sandwell and West Birmingham Hospitals NHS Trust), Birmingham, UK. Conflicts of interest: His interests are regional anaesthesia and enhanced recovery.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:11
559
Ó 2012 Elsevier Ltd. All rights reserved.
REGIONAL ANAESTHESIA
can cause sedation. Cardiovascular depression from a2 agonists can occur at both brain and spinal cord sites. These two side effects limit these agents to only an adjuvant role as analgesics.
If these receptors bind adrenaline, they inhibit presynaptic transmitter release from C and Ad fibres and cause post-synaptic hyperpolarization of the substantia gelatinosa transmission cells of the spinal cord dorsal horn. Similarly, peripheral nerves may express a2-adrenoreceptors. If bound by adrenaline, these receptors activate Kþ channels and hyperpolarize the cell, which raises the firing threshold for impulse transmission, therefore potentiating the blocking action of local anaesthetics. Indirectly, adrenaline acts as an adjuvant through its effect on the local vasculature. Some local anaesthetic drugs are intrinsic vasodilators. The addition of adrenaline to the injectate can oppose this vasodilatation. This, in turn, may extend the local anaesthetic effect by reducing systemic absorption. The risk of systemic toxicity may also be reduced. When injected into epidural space, the effect of adrenaline depends on the local anaesthetic. It slows the systemic absorption of the local anaesthetic, thus extending the duration of a single-shot injection and reducing the peak plasma concentration. At least one study has shown that, when bupivacaine is combined with fentanyl and infused into the thoracic epidural space after laparotomy, the analgesia is more effective when adrenaline is added. When adrenaline is added to local anaesthetics injected around peripheral nerve, adrenaline can reduce the peak concentration and extend the duration of the block. Adrenaline can act as an indicator of an inadvertent intravascular injection and has its advocates for inclusion in local anaesthetic ‘test doses’ in epidural or peripheral nerve block. The sensitivity and specificity of developing a tachycardia from adrenaline alone is relatively low; for example, patients receiving b-adrenergic antagonists may not develop tachycardia and women in labour may become tachycardic for other reasons.
Clonidine It has been hypothesized that clonidine acts at a2-adrenergic receptors in the spinal cord to stimulate acetylcholine release, which acts at both muscarinic and nicotinic receptor subtypes for postoperative pain relief. Clonidine has been administered orally, intravenously and transdermally as adjuvant for postoperative pain relief, but it is mainly administered via intrathecal or epidural route as an adjuvant to opioids and local anaesthetic agents. It has also been added to local anaesthetic drugs intra-articularly to reduce postoperative pain following arthroscopic knee surgery. Clonidine, as an adjuvant to local anaesthetic for neuraxial blocks, extends analgesia for several hours. The increase in quality and duration of analgesia is dose-dependent. However, the adverse effects using clonidine as adjuvant, particularly hypotension, bradycardia and sedation, also tend to be doserelated (low incidence with doses of <150 mg). Sedation mainly reflects systemic absorption and does not potentiate opioidinduced respiratory depression. A recent systemic review of the intrathecal use of clonidine as an adjunct to an LA found that: (i) it prolonged the duration of the sensory blockade by approximately 1 hour and the time to first analgesic by 100 minute, (ii) it prolonged duration of motor blockade, (iii) it resulted in greater incidence of hypotension, (iv) the optimal dose for intrathecal use could not be established, but there was linear relationship between clonidine doses of between 50 and 150 mg and the time to regression of the sensory block, and (v) further work is needed to establish whether intrathecal clonidine offers an advantage over an increased dose of LA alone.5 A qualitative systematic review of the literature on clonidine and peripheral nerve block concluded that: (i) clonidine seems to prolong analgesia when added to intermediate-acting local anaesthetics for axillary and peribulbar blocks, (ii) side effects seem to be limited at doses up to 150 mg, (iii) evidence is lacking for the use of clonidine as an adjunct to local anaesthetics for continuous catheter techniques, and (iv) further research is required to examine the peripheral analgesic mechanism of clonidine.6 The use of clonidine (1 mg/kg) as adjuvant is widely accepted in paediatric anaesthesia. In caudal blocks, it doubles the duration of analgesia when compared with local anaesthetic use alone, but is sedative. It is also used to a lesser extent in obstetric anaesthesia, to improve epidural analgesia in labour.
NMDA antagonists L-Glutamate is the most important excitatory neurotransmitter in the
central nervous system. The glutamate receptors are mostly found in the post-synaptic membrane of the dorsal horn interneurons, with which primary afferent neurons interact. Blocking glutamate receptor reduces afferent stimulation of the spinal cord and therefore blocks pain transmission. Many drugs that reduce central glutamate excitation are antagonists of the N-methyl-D-aspartic acid (NMDA) subtype of glutamate receptor. The primary reason for NMDA antagonists alone to be not useful as postoperative analgesics is that they can cause side effects like hallucinations.
Ketamine Ketamine is a non-competitive antagonist at the NMDA receptor that should be administered neuraxially in a preservative-free solution to avoid neurotoxic effects. It is used as an adjuvant to opioid/local anaesthetic mixtures in the epidural space. Following major upper-abdominal surgery, an epidural ketamine/morphine combination compared with morphine alone reduces intraoperative morphine consumption and prolongs time for rescue analgesia, but there is no reduction in postoperative opioid consumption.7 When added to local anaesthetic mixtures injected into the caudal epidural space of children, ketamine extends analgesia by several hours and is more effective than clonidine. It does not cause central side effects at the recommended dose of 0.5 mg/kg.
Dexmedetomidine Dexmedetomidine is a highly selective a2-adrenoreceptor agonist than clonidine that has been used systemically mainly to provide sedation.
Adrenaline (epinephrine) Adrenaline acts as an adjuvant by its direct and indirect actions. It has direct action on a2 adrenoreceptors present in the substantia gelatinosa of the dorsal horn of the spinal cord.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:11
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Ó 2012 Elsevier Ltd. All rights reserved.
REGIONAL ANAESTHESIA
Intra-articular ketamine at 0.5 mg/kg has been shown to be analgesic for outpatient arthroscopic surgery with no resulting systemic side effects.8 The risk of psychomimetic adverse effects such as hallucinations is the main reason for many clinicians to be apprehensive in using ketamine, but using benzodiazepines as premedication prior to block, reduces the risk of these side effects.
speed the onset of the block. The theory is that an increase in the pH of the solution will increase the proportion of the drug in the non-ionized, membrane-permeant form and thus increase the intensity and duration. The results of clinical studies have not been entirely consistent, and, even where a positive effect has been demonstrated, doubt has been expressed about its clinical usefulness. There is always the risk that the pH change will cause the drug to precipitate before injection and the method has little to commend it.
Magnesium Magnesium is an NMDA receptor antagonist. Although it is not widely used as adjuvant in regional anaesthesia, it has been shown that intrathecal magnesium sulphate 50 mg prolongs spinal fentanyl analgesia in women in labour9 and lower limb surgery. When given as an adjunct to bupivacaine and fentanyl by epidural route before incision, magnesium has shown to provide pre-emptive and preventive analgesia in patients undergoing abdominal hysterectomy without any side effects.10 Magnesium sulphate is available as a preservative-free solution and the optimal dose of either epidural or intrathecal use remains to be established.
Midazolam Because of its effect on GABAA receptors, midazolam is thought to be involved in antinociception by reducing hyperexcitability.13 There are studies to support the analgesic efficacy of intrathecal midazolam. Intrathecal midazolam 2.5 mg, when used as an adjunct to bupivacaine, provides moderate prolongation of postoperative analgesia in patients undergoing orthopaedic surgery.14
Hyaluronidase Dexamethasone
The tissue enzyme hyaluronidase is popular in ophthalmology for speeding onset of local anaesthetic. Injecting unlicensed drugs or drugs with preservatives intrathecally or perineurally is not recommended as the risks of neurotoxicity are unknown. A
Dexamethasone increases the activity of inhibitory potassium channels on nociceptive C-fibres (via glucocorticoid receptors), thus decreasing their activity. A recent study concluded that (i) dexamethasone significantly prolongs the analgesic effect of plain ropivacaine and bupivacaine used as a single-injection interscalene block, (ii) although the toxicity profile of dexamethasone is promising, large studies will be necessary to demonstrate its safety for perineural use.11
REFERENCES 1 Fischer HB, Simanski CJ, Sharp C, et al. A procedure-specific systematic review and consensus recommendations for postoperative analgesia following total knee arthroplasty. Anaesthesia 2008; 63: 1105e23. 2 Fischer HB, Simanski CJ, Sharp C, et al. A procedure-specific systematic review and consensus recommendations for analgesia after total knee replacement. Anaesthesia 2005; 60: 1189e202. 3 Joshi GP, Bonnet F, Shah R, et al. A systematic review of randomized trials evaluating regional techniques for post-thoracotomy analgesia. Anaesth Analgesia 2008; 107: 1026e40. 4 Rosseland L. No evidence for analgesic effect of intra-articular morphine after knee arthroscopy: a qualitative systematic review. Reg Anesth Pain Med 2005; 30: 83e98. 5 Elia N, Culebras X, Mazza C, Sciffer E, Tramer MR. Clonidine as an adjuvant to intrathecal local naesthetics for surgery: systemic review of randomized trials. Reg Anesth Pain Med 2008; 33: 159e67. 6 McCartney C, Duggan E, Apatu E. Should we add clonidine to local anesthetic for peripheral nerve blockade? A qualitative systematic review of the literature. Reg Anesth Pain Med 2007; 32: 330e8. 7 Subramaniam K, Subramaniam B, Pawar DK, Sennaraj B. Preoperative epidural ketamine in combination with morphine does not have a clinically relevant intra- and postoperative opioid-sparing effect. Anesth Analg 2001; 93: 1321e6. 8 Dal D, Tetik O, Altunkaya H, Tetik O, Doral MN. The efficacy of intraarticular ketamine for postoperative analgesia in out patient arthroscopic surgery. Arthroscopy 2004; 20: 300e5. 9 Buvanendran A, McCarthy RJ, Kroin JS, Leong W, Perry P, Tuman KJ. Intrathecal magnesium prolongs fentanyl analgesia: a prospective, randomized, controlled trial. Anesth Analg 2002; 95: 661e6.
Acetylcholine esterase inhibitors Muscarinic receptors are present at high density in the dorsal horn. They contribute to the descending modulation of ascending nociceptive transmission. Acetylcholine may cause analgesia through direct action on spinal cholinergic muscarinic receptors M1 and M3 as well as nicotinic receptor subtypes, and indirectly through stimulation of release of the second-messenger nitric oxide in the spinal cord.
Neostigmine Neostigmine is an acetylcholinesterase inhibitor, which, if applied to the neuraxis, will increase the synaptic concentration of acetylcholine and so may induce analgesia. Commercially available neostigmine contains phenol, so it must not be administered intrathecally. Doses used in clinical studies for intrathecal administration have been 50e750 mg, with the higher doses being associated with side effects such as nausea and vomiting, bradycardia, agitation and faecal incontinence resistant to treatment. A recent meta-analysis concluded that the high incidence of significant side effects far outweighed the small improvements in analgesia, and its use could not be recommended.12
Sodium bicarbonate The alkalization of local anaesthetic solutions by the addition of sodium bicarbonate has also been employed in an attempt to
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:11
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Ó 2012 Elsevier Ltd. All rights reserved.
REGIONAL ANAESTHESIA
10 Farouk S. Pre-incisional epidural magnesium provides pre-emptive and preventive analgesia in patients undergoing abdominal hysterectomy. Br J Anaesth 2008; 101: 694e9. 11 Cummings KC, Napierkowski DE, et al. Effect of dexamethasone on the duration of interscalene nerve blocks with ropivicaine or bupivacaine. Br J Anaesth 2011; 107: 446e53. 12 Ho KM, Ismail H, Lee KC, Branch R. Use of intrathecal neostigmine as an adjunct to other spinal medications in perioperative and peripartum analgesia: a meta-analysis. Anaesth Intensive Care 2005; 33: 41e53. 13 Kohno T, Wakai A, Ataka T, Ikoma M, Yamakura T, Baba H. Actions of midazolam on excitatory transmission in dorsal horn neurons of adult rat spinal cord. Anesthesiol 2006; 104: 338e43.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:11
14 Gupta A, Prakash S, Deshpande S, Kale KS. The effects of intrathecal midazolam 2.5 mg with bupivacaine on postoperative pain relief in patients undergoing orthopaedic surgery. J Anaesth Clin Pharmacol 2008; 24: 189e92. FURTHER READING Local anaesthetics and adjuvants e future developments. Anaesthesia 2010; 65: 22e37. Neuraxial Drug Administration. A review of treatment options for anaesthesia and analgesia. CNS Drugs 2006; 20: 917e33. Useful adjuvants for postoperative pain management. A update. Best Prac Res Clin Anesthesiol 2007; 21: 31e49.
562
Ó 2012 Elsevier Ltd. All rights reserved.
Adjuvant agents in regional anaesthesia
Learning objectives After reading this article, you should be able to understand the: C role of perioperative adjuvant drugs in regional anaesthesia C way in which different opioid adjuvants behave neuraxially and the influence of their relative lipophilicity C mechanism of action of clonidine and ketamine and their role as adjuvants
Sudhakar R Marri
Abstract Adjuvant agents are pharmacological drugs that, when co-administered with local anaesthetic agents, may improve the speed of onset, the quality and/or duration of analgesia. A wide range of drugs has been assessed for both neuraxial and peripheral nerve blocks. Here, we review the adjuvants used in clinical practice in the UK and also briefly mention other drugs that have been used for neuraxial administration and peripheral nerve blockade to provide perioperative analgesia.
Fentanyl has a more rapid onset and a shorter duration of action than the more hydrophilic opioids such as morphine, when administered either intrathecally or epidurally. It also has a narrower band of segmental analgesia because of rapid uptake of the drug by neural tissues. By contrast, hydrophilic morphine is less readily absorbed in to spinal cord, resulting in slower onset of analgesia and, as it moves towards the brain via CSF convection, the analgesia is spread over more dermatomes. However, late cephalad CSF spread of morphine increases the potential for subsequent brainstem binding with the potential to induce respiratory depression (although this is extremely rare in clinical practice). It also increases the risk of nausea and vomiting by stimulation of dopamine and 5-HT3 receptors in the chemoreceptor trigger zone in the area postrema of the medulla. Diamorphine is a diacetylated analogue of morphine, and has a potency of approximately 1.5e2 that of morphine. It is more lipid soluble than morphine, resulting in a faster onset of action and a slightly shorter duration of action. However, its duration of action is longer than fentanyl. Systemic reviews have shown a prolonged analgesic effect with intrathecal morphine in lower limb arthroplasty.1,2 A systematic review of post-thoracotomy analgesia concluded that a thoracic epidural infusion of local anaesthetic (LA) with an opioid provided the most consistently effective analgesia.3 A systematic qualitative review of randomized controlled trials on the analgesic efficacy of intra-articular morphine after knee arthroscopic surgery indicates that it does not work.4
Keywords Adjuvants; adrenaline; clonidine; dexamethasone; ketamine; magnesium; midazolam; neostigmine; opioids; sodium bicarbonate Royal College of Anaesthetists CPD Matrix: 1A02 3A09
Local anaesthetic agents can produce unwanted side effects such as motor and autonomic block. Their onset may be slow and have limited duration of action. At higher doses, there is a risk of cardiotoxicity and central nervous system side effects. For these reasons, other drugs are sometimes co-administered to utilize their synergistic analgesic properties and to limit the local anaesthetic dose requirement. Opioids remain by far the most commonly used adjuvants via the neuraxial route. However, an increasing number of other agents are being used clinically both for neuraxial and peripheral nerve blocks for their additive or synergistic interactions.
Opioids Opioid receptors are widely spread in the dorsal horn of the spinal cord, the periaqueductal grey and pontine reticular formation in the brain, and peripherally on distal primary afferent neurons. The effects of neuraxially administered opioids result from the composite action of: (i) direct effects on spinal cord opioid receptors, (ii) effect on cerebral opioid receptors resulting from cephalad spread via the CSF and peripheral, and (iii) central effects following vascular absorption. The relative contribution of these three mechanisms of effect is dependent on the dose, site of administration and the lipid solubility of the specific opioid. Morphine is hydrophilic (octanewater partition coefficient of 6), diamorphine (partition coefficient of 52) and fentanyl is lipophilic (partition coefficient of 813).
Adverse effects of neuraxial opioids Late-onset respiratory depression associated with the use of intrathecal morphine is extremely rare with the microgram doses used in clinical practice today. However, nausea and vomiting is common with an incidence of approximately 50%. Our own audit data has shown that prophylactic triple antiemetic therapy of cyclizine, ondansetron and dexamethasone reduces the incidence of postoperative nausea and vomiting (PONV) associated with intrathecal morphine in hip and knee replacement patients to 11%. Urinary retention and pruritus are the other specific side effects related to administration of opioids by spinal route.
a2-Adrenoceptor agonists Specific a2-adrenoceptor agonists inhibit pain transmission by binding to pre-and post-synaptic a2 receptors in the substantia gelatinosa of the dorsal horn of the spinal cord, their primary site of action. The receptors also exist in the brain where these drugs
Sudhakar R Marri MBBS FCARCSI EDRA is a Consultant Anaesthetist at City Hospital (Sandwell and West Birmingham Hospitals NHS Trust), Birmingham, UK. Conflicts of interest: His interests are regional anaesthesia and enhanced recovery.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:11
559
Ó 2012 Elsevier Ltd. All rights reserved.
REGIONAL ANAESTHESIA
can cause sedation. Cardiovascular depression from a2 agonists can occur at both brain and spinal cord sites. These two side effects limit these agents to only an adjuvant role as analgesics.
If these receptors bind adrenaline, they inhibit presynaptic transmitter release from C and Ad fibres and cause post-synaptic hyperpolarization of the substantia gelatinosa transmission cells of the spinal cord dorsal horn. Similarly, peripheral nerves may express a2-adrenoreceptors. If bound by adrenaline, these receptors activate Kþ channels and hyperpolarize the cell, which raises the firing threshold for impulse transmission, therefore potentiating the blocking action of local anaesthetics. Indirectly, adrenaline acts as an adjuvant through its effect on the local vasculature. Some local anaesthetic drugs are intrinsic vasodilators. The addition of adrenaline to the injectate can oppose this vasodilatation. This, in turn, may extend the local anaesthetic effect by reducing systemic absorption. The risk of systemic toxicity may also be reduced. When injected into epidural space, the effect of adrenaline depends on the local anaesthetic. It slows the systemic absorption of the local anaesthetic, thus extending the duration of a single-shot injection and reducing the peak plasma concentration. At least one study has shown that, when bupivacaine is combined with fentanyl and infused into the thoracic epidural space after laparotomy, the analgesia is more effective when adrenaline is added. When adrenaline is added to local anaesthetics injected around peripheral nerve, adrenaline can reduce the peak concentration and extend the duration of the block. Adrenaline can act as an indicator of an inadvertent intravascular injection and has its advocates for inclusion in local anaesthetic ‘test doses’ in epidural or peripheral nerve block. The sensitivity and specificity of developing a tachycardia from adrenaline alone is relatively low; for example, patients receiving b-adrenergic antagonists may not develop tachycardia and women in labour may become tachycardic for other reasons.
Clonidine It has been hypothesized that clonidine acts at a2-adrenergic receptors in the spinal cord to stimulate acetylcholine release, which acts at both muscarinic and nicotinic receptor subtypes for postoperative pain relief. Clonidine has been administered orally, intravenously and transdermally as adjuvant for postoperative pain relief, but it is mainly administered via intrathecal or epidural route as an adjuvant to opioids and local anaesthetic agents. It has also been added to local anaesthetic drugs intra-articularly to reduce postoperative pain following arthroscopic knee surgery. Clonidine, as an adjuvant to local anaesthetic for neuraxial blocks, extends analgesia for several hours. The increase in quality and duration of analgesia is dose-dependent. However, the adverse effects using clonidine as adjuvant, particularly hypotension, bradycardia and sedation, also tend to be doserelated (low incidence with doses of <150 mg). Sedation mainly reflects systemic absorption and does not potentiate opioidinduced respiratory depression. A recent systemic review of the intrathecal use of clonidine as an adjunct to an LA found that: (i) it prolonged the duration of the sensory blockade by approximately 1 hour and the time to first analgesic by 100 minute, (ii) it prolonged duration of motor blockade, (iii) it resulted in greater incidence of hypotension, (iv) the optimal dose for intrathecal use could not be established, but there was linear relationship between clonidine doses of between 50 and 150 mg and the time to regression of the sensory block, and (v) further work is needed to establish whether intrathecal clonidine offers an advantage over an increased dose of LA alone.5 A qualitative systematic review of the literature on clonidine and peripheral nerve block concluded that: (i) clonidine seems to prolong analgesia when added to intermediate-acting local anaesthetics for axillary and peribulbar blocks, (ii) side effects seem to be limited at doses up to 150 mg, (iii) evidence is lacking for the use of clonidine as an adjunct to local anaesthetics for continuous catheter techniques, and (iv) further research is required to examine the peripheral analgesic mechanism of clonidine.6 The use of clonidine (1 mg/kg) as adjuvant is widely accepted in paediatric anaesthesia. In caudal blocks, it doubles the duration of analgesia when compared with local anaesthetic use alone, but is sedative. It is also used to a lesser extent in obstetric anaesthesia, to improve epidural analgesia in labour.
NMDA antagonists L-Glutamate is the most important excitatory neurotransmitter in the
central nervous system. The glutamate receptors are mostly found in the post-synaptic membrane of the dorsal horn interneurons, with which primary afferent neurons interact. Blocking glutamate receptor reduces afferent stimulation of the spinal cord and therefore blocks pain transmission. Many drugs that reduce central glutamate excitation are antagonists of the N-methyl-D-aspartic acid (NMDA) subtype of glutamate receptor. The primary reason for NMDA antagonists alone to be not useful as postoperative analgesics is that they can cause side effects like hallucinations.
Ketamine Ketamine is a non-competitive antagonist at the NMDA receptor that should be administered neuraxially in a preservative-free solution to avoid neurotoxic effects. It is used as an adjuvant to opioid/local anaesthetic mixtures in the epidural space. Following major upper-abdominal surgery, an epidural ketamine/morphine combination compared with morphine alone reduces intraoperative morphine consumption and prolongs time for rescue analgesia, but there is no reduction in postoperative opioid consumption.7 When added to local anaesthetic mixtures injected into the caudal epidural space of children, ketamine extends analgesia by several hours and is more effective than clonidine. It does not cause central side effects at the recommended dose of 0.5 mg/kg.
Dexmedetomidine Dexmedetomidine is a highly selective a2-adrenoreceptor agonist than clonidine that has been used systemically mainly to provide sedation.
Adrenaline (epinephrine) Adrenaline acts as an adjuvant by its direct and indirect actions. It has direct action on a2 adrenoreceptors present in the substantia gelatinosa of the dorsal horn of the spinal cord.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:11
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Ó 2012 Elsevier Ltd. All rights reserved.
REGIONAL ANAESTHESIA
Intra-articular ketamine at 0.5 mg/kg has been shown to be analgesic for outpatient arthroscopic surgery with no resulting systemic side effects.8 The risk of psychomimetic adverse effects such as hallucinations is the main reason for many clinicians to be apprehensive in using ketamine, but using benzodiazepines as premedication prior to block, reduces the risk of these side effects.
speed the onset of the block. The theory is that an increase in the pH of the solution will increase the proportion of the drug in the non-ionized, membrane-permeant form and thus increase the intensity and duration. The results of clinical studies have not been entirely consistent, and, even where a positive effect has been demonstrated, doubt has been expressed about its clinical usefulness. There is always the risk that the pH change will cause the drug to precipitate before injection and the method has little to commend it.
Magnesium Magnesium is an NMDA receptor antagonist. Although it is not widely used as adjuvant in regional anaesthesia, it has been shown that intrathecal magnesium sulphate 50 mg prolongs spinal fentanyl analgesia in women in labour9 and lower limb surgery. When given as an adjunct to bupivacaine and fentanyl by epidural route before incision, magnesium has shown to provide pre-emptive and preventive analgesia in patients undergoing abdominal hysterectomy without any side effects.10 Magnesium sulphate is available as a preservative-free solution and the optimal dose of either epidural or intrathecal use remains to be established.
Midazolam Because of its effect on GABAA receptors, midazolam is thought to be involved in antinociception by reducing hyperexcitability.13 There are studies to support the analgesic efficacy of intrathecal midazolam. Intrathecal midazolam 2.5 mg, when used as an adjunct to bupivacaine, provides moderate prolongation of postoperative analgesia in patients undergoing orthopaedic surgery.14
Hyaluronidase Dexamethasone
The tissue enzyme hyaluronidase is popular in ophthalmology for speeding onset of local anaesthetic. Injecting unlicensed drugs or drugs with preservatives intrathecally or perineurally is not recommended as the risks of neurotoxicity are unknown. A
Dexamethasone increases the activity of inhibitory potassium channels on nociceptive C-fibres (via glucocorticoid receptors), thus decreasing their activity. A recent study concluded that (i) dexamethasone significantly prolongs the analgesic effect of plain ropivacaine and bupivacaine used as a single-injection interscalene block, (ii) although the toxicity profile of dexamethasone is promising, large studies will be necessary to demonstrate its safety for perineural use.11
REFERENCES 1 Fischer HB, Simanski CJ, Sharp C, et al. A procedure-specific systematic review and consensus recommendations for postoperative analgesia following total knee arthroplasty. Anaesthesia 2008; 63: 1105e23. 2 Fischer HB, Simanski CJ, Sharp C, et al. A procedure-specific systematic review and consensus recommendations for analgesia after total knee replacement. Anaesthesia 2005; 60: 1189e202. 3 Joshi GP, Bonnet F, Shah R, et al. A systematic review of randomized trials evaluating regional techniques for post-thoracotomy analgesia. Anaesth Analgesia 2008; 107: 1026e40. 4 Rosseland L. No evidence for analgesic effect of intra-articular morphine after knee arthroscopy: a qualitative systematic review. Reg Anesth Pain Med 2005; 30: 83e98. 5 Elia N, Culebras X, Mazza C, Sciffer E, Tramer MR. Clonidine as an adjuvant to intrathecal local naesthetics for surgery: systemic review of randomized trials. Reg Anesth Pain Med 2008; 33: 159e67. 6 McCartney C, Duggan E, Apatu E. Should we add clonidine to local anesthetic for peripheral nerve blockade? A qualitative systematic review of the literature. Reg Anesth Pain Med 2007; 32: 330e8. 7 Subramaniam K, Subramaniam B, Pawar DK, Sennaraj B. Preoperative epidural ketamine in combination with morphine does not have a clinically relevant intra- and postoperative opioid-sparing effect. Anesth Analg 2001; 93: 1321e6. 8 Dal D, Tetik O, Altunkaya H, Tetik O, Doral MN. The efficacy of intraarticular ketamine for postoperative analgesia in out patient arthroscopic surgery. Arthroscopy 2004; 20: 300e5. 9 Buvanendran A, McCarthy RJ, Kroin JS, Leong W, Perry P, Tuman KJ. Intrathecal magnesium prolongs fentanyl analgesia: a prospective, randomized, controlled trial. Anesth Analg 2002; 95: 661e6.
Acetylcholine esterase inhibitors Muscarinic receptors are present at high density in the dorsal horn. They contribute to the descending modulation of ascending nociceptive transmission. Acetylcholine may cause analgesia through direct action on spinal cholinergic muscarinic receptors M1 and M3 as well as nicotinic receptor subtypes, and indirectly through stimulation of release of the second-messenger nitric oxide in the spinal cord.
Neostigmine Neostigmine is an acetylcholinesterase inhibitor, which, if applied to the neuraxis, will increase the synaptic concentration of acetylcholine and so may induce analgesia. Commercially available neostigmine contains phenol, so it must not be administered intrathecally. Doses used in clinical studies for intrathecal administration have been 50e750 mg, with the higher doses being associated with side effects such as nausea and vomiting, bradycardia, agitation and faecal incontinence resistant to treatment. A recent meta-analysis concluded that the high incidence of significant side effects far outweighed the small improvements in analgesia, and its use could not be recommended.12
Sodium bicarbonate The alkalization of local anaesthetic solutions by the addition of sodium bicarbonate has also been employed in an attempt to
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:11
561
Ó 2012 Elsevier Ltd. All rights reserved.
REGIONAL ANAESTHESIA
10 Farouk S. Pre-incisional epidural magnesium provides pre-emptive and preventive analgesia in patients undergoing abdominal hysterectomy. Br J Anaesth 2008; 101: 694e9. 11 Cummings KC, Napierkowski DE, et al. Effect of dexamethasone on the duration of interscalene nerve blocks with ropivicaine or bupivacaine. Br J Anaesth 2011; 107: 446e53. 12 Ho KM, Ismail H, Lee KC, Branch R. Use of intrathecal neostigmine as an adjunct to other spinal medications in perioperative and peripartum analgesia: a meta-analysis. Anaesth Intensive Care 2005; 33: 41e53. 13 Kohno T, Wakai A, Ataka T, Ikoma M, Yamakura T, Baba H. Actions of midazolam on excitatory transmission in dorsal horn neurons of adult rat spinal cord. Anesthesiol 2006; 104: 338e43.
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14 Gupta A, Prakash S, Deshpande S, Kale KS. The effects of intrathecal midazolam 2.5 mg with bupivacaine on postoperative pain relief in patients undergoing orthopaedic surgery. J Anaesth Clin Pharmacol 2008; 24: 189e92. FURTHER READING Local anaesthetics and adjuvants e future developments. Anaesthesia 2010; 65: 22e37. Neuraxial Drug Administration. A review of treatment options for anaesthesia and analgesia. CNS Drugs 2006; 20: 917e33. Useful adjuvants for postoperative pain management. A update. Best Prac Res Clin Anesthesiol 2007; 21: 31e49.
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