Evidence in combining the Adjuvants to Local anesthetics

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Information about Evidence in combining the Adjuvants to Local anesthetics
Health & Medicine

Published on February 20, 2014

Author: drmmprao1

Source: slideshare.net

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Prof. Mridul M. Panditrao has added another of his very important, useful and in vogue topic to his collection. This is his well acclaimed andwell received faculty lecture at recently concluded International conference on Pain... ISSPCON 2014, at Mumbai/ Bombay from 6th to 9th Feb. 2014.

Evidence in Combining Adjuvants To Local anesthetics !

Prof. Mridul M. Panditrao Consultant Department of Anesthesiology & Critical Care Public Hospital Authority’s Rand Memorial Hospital Freeport, Grand Bahama, Commonwealth of The Bahamas

That’s one small step for a man, one giant leap for mankind! Neil Armstrong July 20th ,1969

History of Local Anesthetic Agents (LAAs) • Karl Koller: (1884) Cocaine drops • A major milestone! • Parenteral route → toxic effects and death →serious introspection • Einhorn :( 1904) Procaine : resurgence of local anesthesia, • high incidence of anaphylaxis • Lidocaine (1943) & Bupivacaine (1963): introduction of amides. • changed the practice of local/regional anesthesia, • ensured flexibility, adaptability and safety of LAAs.

Amides: Paradoxical Properties 1. The onset, peak and total duration of action: • Lidocaine • • • • • faster onset & better distribution shorter duration of action unsuitable for prolonged surgeries/post operative analgesia so continuous catheter techniques But increases dose and toxicity • Bupivacaine, Mepivacaine & Ropivacine • longer duration of action • delayed onset and patchy block

LAAs 2. Systemic toxicity: • Directly proportional to the dose, concentration, volume and the vascularity of tissue injected. 3. Efficacy, penetrability and depth of block: • Larger molecules • Bupivacaine, mepivacaine have limited penetrability across the myelin sheath; incomplete block.

Modifications to LAAs • Mixing of the LAAs • Improving the pKa by trying to change pH: • Increase penetrability across the tissue planes/ neurilemma • Decreasing absorption/removal • Addition of various unrelated agents (non LAAs) to the mixture. • These are what we call “Adjuvants”.

ADJUVANTS? • Origin from French/ Latin; from Latin adjuvans, present participle of adjuvare - to aid or more at aid A pharmacological agent which is added to a drug to increase or aid its efficacy or one that helps or facilitates as: • a : an ingredient (as in a prescription or a solution) that modifies the action of the principal ingredient • b : something (as a drug or method) that enhances the effectiveness of medical treatment. Logically, anything which will increase efficacy and potency is an adjuvant! www.thefreedictionary.com/adjuvant, www.merriam-webster.com/dictionary/adjuvant

An “Ideal Adjuvant ?” There are certain characteristics/ properties which are desirable and needed in a drug, to be labelled as an “Ideal Adjuvant” • Physical • Pharmacological • Pharmacodynamic • Pharmacokinetic • Miscellaneous

An “Ideal Adjuvant” Physical characteristics: • Easy solubility: preferably in water • Easy miscibility: No precipitation on mixing with LAA solution • Non irritability: when injected • Increase the pH of resulting mixture & portion of active form of LAA • Higher lipid solubility • Longer shelf life: Be stable so no need of stabilizers/ preservatives.

An “Ideal Adjuvant” Pharmacological properties: Pharmacodynamics: • Enhance onset of action, • Maintain rapid and steady peak of action • Prolong the duration of action • Have no inherent, any other systemic effects/ side-effects • Not only enhance the efficacy of LAAs, but have its own inherent LAA like activity • Have a higher potency, so that requirement of dose is minimal • Should be completely devoid of any systemic toxicity

An “Ideal Adjuvant” Pharmacological properties: Pharmacokinetics: • Minimal systemic absorption • High protein binding • Rapid redistribution • Rapid plasma clearance Rapid metabolism • Non active Metabolites • Simple non hepatic/ non renal dependent excretion

An “Ideal Adjuvant” Miscellaneous properties: • Should be economical • Should be freely available/ non-scheduled drug • Should not require any specific conditions for the storage Co-incidentally there is no single drug which can fulfill all these properties!!!!!!

ADJUVANTS Mechanisms of Action: • To decrease the uptake at the site of injection: • Change of pH/ pKa: • To Increase baricity: • To increase shelf life and sterility: • To form the water soluble complexes at the site: • To increase the penetrability across the tissue planes: • To prolong the duration of analgesia, both intra/ post-operative

ADJUVANTS 1. Decreasing the uptake at the site of injection: Vasoconstrictors • Braun - Cocaine(1903) • Adrenaline is pre-added to the marketed preparations, as 1: 100,000 to 200,000 concentrations. • Adrenaline - Inherent analgesic action • Direct stimulation of alpha-2 adrenoreceptors • Decreasing presynaptic release of neuro-transmitter from C- and A δ- fibres in the substantia gelatinosa of the dorsal horn. •Collier C. Additives to Local Anaesthetics. www.csaol.cn/img/Hypertextbook/a/c5.htm •Wiles, M. D. and Nathanson, M. H. Local anaesthetics and adjuvants – future developments. Anaesthesia, 2010; 65: 22–37.

2. Change of pH/ pKa: Sodium Bicarbonate • Bignon (1892) – Made Cocaine alkaline • ↑ pH ↑ Lipid soluble molecules ↑ Penetrability • pH:3.2-6.5 :: pKa 7.5 - 9.0 = <3% non-ionized free base : crosses nerve sheaths and membranes • pH - less acidic (closer to the pKa) – more non-ionized form present Onset of nerve-block will be more rapid • Conflicting evidence • increased efficacy by addition of 8.4% NaHCO3 (Tackley RM, Coe AJ. & Capogna G, Constantino P, Muratori A ) • while some refuting the fact (Stevens RA, Chester WL, & Benhamou D, Labaille T, et al.) Becker DE, Reed KL. Essentials of Local Anesthetic Pharmacology. AnesthProg. 2006 Fall; 53(3): 98–109 Tackley RM, Coe AJ. Alkalinised bupivacaine and adrenaline for epidural Caesarean section. Anaesthesia 1988; 43:1019-1021 Capogna G, Constantino P, Muratori A et al. The addition of bicarbonate improves the quality of intraoperative analgesia of lidocaine-fentanyl epidural anesthesia for cesarean section. Regional Anesthesia 1992 ;17:S32. Stevens RA, Chester WL, et al . The effect of pH adjustment of 0.5% bupivacaine on the latency of epidural anesthesia. Regional Anesthesia 1989; 14:236- 239. Benhamou D, Labaille T, Bonhomme L, Perrachon N. Alkalinisation of epidural 0.5% bupivacaine for cesarean section. Regional Anesthesia 1989 14:240-243.

3. To Increase baricity: Dextrose (3% - 5%) • Especially for neuraxial block • Easy control/level of the block • Density of the block • Lesser sympathetic blockade/side-effects/ complications • Ropivacaine - Isobaric form - minimal side effects Thus obviating addition of dextrose to the final preparation.

4. To increase shelf life and sterility: Stabilizers – Sodium metabisulphite (0.1%) Preservatives/Anti-microbials – Methyl/Propyl paraben • “Local anesthetic hypersentivity/Allergic’’ reactions* • “Xilocaine/Lidocaine sensitivity Test ???????” • Opaque polypropylene bottles rather than Translucent glass •*Aldrete JA, Johnson DA. Evaluation of intracutaneous testing for investigation of allergy to local anesthetic agents. Anesthesia and Analgesia 1970 49:173

5. To form the water soluble complexes at the site : Dextran To prolong the duration of action of the sensory blockade • Mechanism of action is not known: • dextrans may form water-soluble complexes with LAAs • remain at the site of injection longer than the unbound drug • due to an increase in viscosity with reduced diffusion of the complex • Alternatively, the addition of dextran makes more alkalinisation, which may contribute to the prolongation of action Conflicting results……. Fallen in serious disrepute/abandoned!!! •Aberg G, Friberger P, Sydnes G. Studies on the duration of local anaesthesia: a possible mechanism for the prolonging effect of dextran on the duration of infiltration anaesthesia. ActaPharmacologicaetToxicologica 1978; 42: 88–92. •Covino BG. Pharmacology of local anaesthetic agents. British Journal of Anaesthesia 1986; 58: 701–16.

6. To increase the penetrability across the tissue planes: Hyaluronidase • Especially in the peripheral, regional and superficial nerve blocks. • Nerves/ roots/trunks/ cords are enclosed in the fascial sheaths/ septae. • Transported across these structures for the better penetrability. • break the hyaluronic acid in the tissues • Increase the tissue permeability • Improve penetrability - Spread evenly and in the deeper plains • Dose of 7.5 IU/mL added to the local anesthetic improves peribulbar block15 •Kallio H, Paloheimo M, Maunuksela EL. Hyaluronidase as an adjuvant in bupivacaine-lidocaine mixture for retrobulbar/peribulbar block.AnesthAnalg. 2000;91(4):934-7.

7. To prolong the duration of peri-operative analgesia * • By acting at the one or all 4 important phenomena i. Transduction: By acting on nociceptors: peripheral, central ii. Transmission: By acting at the fibers: Aδ and C (periphery as well as near the neuraxis) iii. Modulation: By acting on neuromodulators iv. Perception: By acting at the central sites of perception. • *Mridul Panditrao. Pain and Its Physiological considerations. In Principles of Anaesthesia, Eds, Deshpande S et al. Paras, Hyderabad, India. 1st edition.2007:181-190

Classes 1. Opioids Hydrophilic opioids - Morphine, Diamorphine Lipophilic opioids - Fentanyl, Alfentanil, Sufentanil 2. Alpha2 (α2) stimulants: Clonidine, Dexmedetomidine 3. GABA receptor agonists: GABA A receptor agonist - Midazolam GABA B receptor agonist – Baclophen 4. NMDA receptor antagonist: Ketamine

Classes 5. Neostigmine: Cholinesterase inhibitor (CHEI) 6. Tramadol 7. Glucocorticoids: Dexamethasone 8. NSAIDs 9. Magnesium 10. Neuro-Muscular Blocking Drugs 11. Dextrans 12. Adenosine

Opioids • Neuraxial use – 1979 • Site of action initially assumed to be brain. • Proven to be global: multisystemic • Mechanism of action: Neuraxially • Analgesia - alone or as Adjuvants to local anesthetics. • Act on opioid receptors - distributed throughout the CNS • areas governing the perception like post central gyrus • Stimulating neuro-modulation like limbic system, peri-aqueductal and peri-ventricular grey matter, median raphe nucleus magnus • descending pathways on the periaqueductal grey matter and rostral ventromedial medulla •Behar M, Magora F, Olshwang D, Davidson JT. Epidural morphine in treatment of pain. Lancet 1979; 1: 527–9. • Wang JK, Nauss LA, Thomas JE. Pain relief by intrathecally applied morphine in man. Anesthesiology 1979; 50: 149–51.

Opioids * • G protein coupled receptors - µ, κ, σ, and δ families • Endodogenous ligands - Endorphins (endogenous morphines), pentapeptides called enkephalins and dynorphin. • Action by • Directly acting on the opioid receptors of the CNS. • They may also inhibit release of other excitatory neurotransmitters. • Varying degrees of effectivity. • Dose - safely decreased even up to 25% of the systemic dose. • Side-effects/Toxicity reduced proportionately. Opioids are and will remain the mainstay as adjuvants neuraxially in the peri-operative analgesia protocols •Zhou Hy, Chen SR, Chen H, Pan HL. Opioid-induced long-term potentiation in the spinal cord is a pre synaptic event. J Neurosci; 2010; 30 (12): 4460-6 •Salomaki TE, Latinen JO, NuutinenLS . A randomized double blind comparison of epidural versus intravenous fentanyl infusion and analgesia after thoracotomy. Anesthesiology ;1991;75 : 790 •Cohen S, Pantuck CB, Amar D, Burley E,Pantuck EJ. The primary action of epidural fentanyl after caesarian delivery is via a spinal mechanism. Anesth Analg ;2002;94 (3):674-9 •Loper KA, Ready LB. Epidural morphine after anterior cruciate ligament repair : A comparison with patient-controlled intravenous morphine. Anesth Analg; 1989;68:350

α2 Adrenergic Stimulants : Dexmedetomidine • “Novel” Mechanism of Analgesia and Sedation of Dexmedetomidine • Two unique mechanisms for producing analgesia: • Prevention of transmission of pain impulse by the way of hyper polarization (mediated through G1 protein controlled „gating „ mechanism). • Regulation of calcium channels (mediated through G0 protein controlled, N type voltage gated channels). • Neither the nerve/terminal is allowed to get stimulated, nor can it transmit/ propagate the signal forwards. • Supra-spinal and Spinal level. • Peripheral α2 adreno receptors may regulate the analgesic effect • Supra-spinal effects - modulation of descending noradrenergic pathway from Locus Ceruleus. • These pathways and central opioidal pathways have a common output in this area. •Nelson LE. The alpha 2 adrenoceptor agonist dexmedetomidine converges on an endogenous sleep promoting pathway to exert its sedative effects. Anesthesiology 2003; 98:428-436 •Hunter JC, Fontana DJ, Hedley LR et al. Assessment of the role of alpha 2 adrenoceptor subtypes in anti nociceptive , sedative and hypothermic action of dexmedetomidine in transgenic mice Br J Pharmacol1997; 122: 1339-1344 •Venn RM, Bradshaw CJ, Spencer R et al. Preliminary UK experience of dexmedetomidine, a novel agent for post operative sedation in intensive care unit. Anaesthesia 1999; 54: 11361142

MECHANISM: CLINICAL CNS EFFECTS • Spinal: Spinal cord • Binding to receptors analgesia At Substantia gelatinosa (Lamina II) • Closing the gate at the dorsal horn to stimuli coming from Aδ and C fibers • Inhibit release of nociceptive humoral transmitters like Substance P release of substance P 2 •Kuraishi Y, Hirota N, Sato Y, et al Noradrenergic inhibition of the release of Substance P from the primary afferents in the rabbit spinal cord dorsal horn. Brain res.1985; 309: 177- 182 •Nakamura M, Fereira SM. Peripheral analgesic action of clonidine: Mediation of endogenous enkephalin like substances. Eur J Pharmacol. 1988:146: 223-228 •Venn RM, Bell J, Ground R. Respiratory effects of dexmedetomidine in the surgical patients requiring intensive care. Crit care 2000; 43: 302-308 •Roberts L Dexmedetomidine J Pharm Soc. Wis. November/December 2003; 47-52

Clonidine • Useful adjuvant for brachial plexus blockade • Acting by peripherally mediated mechanisms • In the dose of 150 µg it appears to be very effective •McCartney CJL, Duggan E, Apatu E. Should we add clonidine to local anesthetic for peripheral nerve bockade? A qualitative systematic review of the literature. Reg Anesth Pain Med. 2007;32:330–338. •Iskandar H, Guillaume E, Dixmerias F, Binje B, Rakotondriamihary S, Thiebaut R, et al. The enhancement of sensory blockade by clonidine selectively added to mepivacaine after midhumeral block. AnesthAnalg. 2001;93:771–775. •Singelyn FJ, Gouverneur J-M, Robert A. A minimum dose of clonidine added to mepivacaine prolongs the duration of anesthesia and analgesia after axillary brachial plexus block. AnesthAnalg. 1996;83:1046–1050.

GABA Areceptor agonists : Midazolam • Benzodiazepine receptors found in Substantia Gelatinosa cells • Facilitates the inhibitory action of the γ-aminobutyric acid (GABA). • Activation of spinal δ opioid receptors • Neuraxial addition of 1–2 mg Midazolam - potentiates the analgesic effects of intrathecal Bupivacaine for 2–6 h. • Supraclavicular brachial block - Midazolam 50 μg/kg improved postoperative pain scores and decreased analgesic requirements for up to 24 h •Goodchild CS, Guo Z, Musgreave A, Gent JP. Antinociception by intrathecal midazolam involves endogenous neurotransmitters acting at spinal cord delta opioid receptors. British Journal of Anaesthesia 1996; 77: 758–63. •Kim MH, Lee YM. Intrathecal midazolam increases the analgesic effects of spinal blockade with bupivacaine in patients undergoing haemorrhoidectomy. British Journal of Anaesthesia 2001; 86: 77–9. •Valentine JM, Lyons G, Bellamy MC. The effect of intrathecal midazolam on post-operative pain. European Journal of Anaesthesiology 1996; 13: 589–93. •Jarbo K, Batra YK, Panda NB. Brachial plexus block with midazolam and bupivacaine improves analgesia. Canadian Journal of Anesthesia 2005; 52: 822–6. •Ho KM, Ismail H. Use of intrathecal midazolam to improve perioperative analgesia : a meta analysis. Anaesth Intensive Care 2008; 36(3): 365-73

GABAB agonists: Baclophen • Decreases the painful spasticity and dystonia secondary to cerebral palsy and spastic post traumatic spinal cord injury •Jagatsinh Y. Intrathecalbaclofen : Its effect on symptoms and activities of daily living in severe spasticity due to spinal cord injuries: A pilot study. Indian J Orthop ;2009. 43(1):46-49 •Cox RF , Collins MA . the effects of benzodiazepines on human opioid receptor binding and function. AnaesthAnalg 2001; 93 (2) : 354-8.

NMDA antagonists • Ketamine : A drug full of paradox, which even today is a mystery to us. • „Sole neuraxial agent‟ – Bion (1984) • Combined with LAAs - administered by various blocks. • Multiple sites of actions • Primarily - Acts as a non-competitive antagonist of the NMDA receptor through interaction with the phencyclidine receptor. • Effects on sodium and calcium channels, and nicotinic, muscarinic and opioid receptors • Sole drug for intrathecal administration - doses of 50-100 mg • 30mg added to Bupivacaine epidurally •BionJF .Intrathecal ketamine for war surgery.A preliminary study under field conditions. Anaesthesia ;1984; 39 : 1023-28 •Schmid RL, Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain 1999; 82: 111–25. •Mohamed Naguib, Yaw Adu-Gyamfi, Gamil H Absood, HeshamFarag, Henry K Gyasi. Epidural ketamine for postoperative analgesia. Can AnaesthSoc J ;1986; 33 : 16-21

Neostigmine • Acetyl Cholinesterase inhibitor (AChE Inhibitor) • Reversal agent. • Introduced intra/ extra thecally - Increase the central descending, inhibitory tonus of cerebral cholinergic pathways via muscarinic receptors, especially acting on SG cells, via muscarinic receptors. •Krukowski J, Hood D, Eisenach J, Mallak K, Parker R. Intrathecal neostigmine for post-cesarean section analgesia: dose response. Anesthesia & Analgesia 1997; 84: 1269–75.

Tramadol • Selective weak agonist of µ-receptors • Prevents reuptake of noradrenaline • Increases release both serotonin and noradrenaline release • Acts at descending pathways by increasing their inhibitory activity, causing transmission of nociception at the spinal level • Use in peripheral blocks still cannot be vouched for because of lack of reliabile trials proving its efficacy via that route. •Robaux S, Blunt C, Viel E, Cuvillon P, Nouguier P, Dautel G, Boileaus GF, Bouaziz H Tramadol added to 1.5% mepivacaine for axillary brachial plexus block improvespostoperative analgesia dose-dependently. AnesthAnalg 2004; 98:1172–7

Dexamethasone • Anti-inflammatory properties - Intra Venous Regional Anesthesia • Study: Dose of 8 mg Dexamethasone when added to Lidocaine to prolong axillary brachial plexus blockade, resulted in a significant increase in duration of sensory and motor blocks. • Cummings et al found addition of Dexamethasone to Ropivacaine as well as Bupivacaine administered via inter scalene block prolonged the duration of effect of both the LAAs, but more pronounced of that of Ropivacaine •Movafegh A, Razazian M, Hajimaohamadi F, Meysamie A. Dexamethasone added to lidocaine prolongs axillary brachial plexus blockade. AnesthAnalg. 2006; 102: 263–7 •Cummings KC, Napierkowski DE, Parra-Sanchez I, Kurz A, Dalton JE, BremsJJ, SesslerDI.Effect of dexamethasone on the duration of interscalene nerve blocks with ropivacaine or bupivacaine. BJA .107: 446-453.

NSAIDs • Adjuncts in IVRA. • Lornoxicam 8 mg used with lidocaine – Faster onsets of motor and sensory blocks with improvement in postoperative analgesia. • Improvement in postoperative analgesia with • Ketorolac (20–60 mg) • Tenoxicam (20 mg) • Lysine acetylsalicylate (90 mg) •Sen S, Ugur B, Aydin ON, Ogurlu M, Gezer E, Savk O. The analgesic effect of lornoxicam when added to lidocaine for intravenous regional anaesthesia. British Journal of Anaesthesia 2006; 97: 408–13. • Steinberg R, Reuben S, Gardner G. The dose-response relationship of ketorolac as a ccomponent of intravenous regional anesthesia with lidocaine. Anesthesia & Analgesia 1998; 86: 791–3. •Jankovic RJ, Visnjic MM, Milic DJ, Stojanovic MP, Djordjevic DR, Pavlovic MS. Does the addition of ketorolac and dexamethasone to lidocaine intravenous regional anesthesia improve postoperative analgesia and tourniquet tolerance for ambulatory hand surgery? Minerva Anestesiologica 2008; 74: 521–7. •Jones NC, Pugh SC. The addition of tenoxicam to prilocaine for intravenous regional anaesthesia. Anaesthesia 1996; 51: 446–8. •Corpataux J, Van Gessel E, Donald F, Forster A, Gamulin Z. Effect on postoperative analgesia of small-dose lysine acetylsalicylate added to prilocaine during intravenous regional anesthesia. Anesthesia & Analgesia 1997; 84: 1081–5. • Lee IO, Seo Y. The effects of intrathecal cyclooxygenase-1, cyclooxygenase-2, or nonselective inhibitors on pain behavior and spinal Fos-like immunoreactivity. Anesthesia & Analgesia 2008; 106: 972–7.

Magnesium • NMDA antagonistic action - Noncompetitive type • effective LAA adjuvant when given intrathecally and epidurally. • Still a dispute about the optimum dose of magnesium •Ault B, Evans RH, Francis AA, Oakes DJ, Watkins JC. Selective depression of excitatory amino acid induced depolarizations by magnesium ions in isolated spinal cord preparations. Journal of Physiology 1980; 307: 413–28. •Ozalevli M, Cetin TO, Unlugenc H, Guler T, Isik G. The effect of adding intrathecal magnesium sulphate to bupivacaine-fentanyl spinal anaesthesia. ActaAnaesthesiologicaScandinavica 2005; 49: 1514–19 •Arcioni R, Palmisani S, Tigano S, et al. Combined intrathecal and epidural magnesium sulfate supplementation of spinal anesthesia to reduce post-operative analgesic requirements: a prospective, randomized, double-blind, controlled trial in patients undergoing major orthopedic surgery. ActaAnaesthesiologicaScandinavica 2007; 51: 482–9. •Farouk S. Pre-incisional epidural magnesium provides pre-emptive and preventive analgesia in patients undergoing abdominal hysterectomy. British Journal of Anaesthesia 2008; 101: 694–9. •Buvanendran A, McCarthy RJ, Kroin JS, Leong W, Perry P, Tuman KJ. Intrathecal magnesium prolongs fentanyl analgesia: a prospective, randomized, controlled trial. Anesthesia & Analgesia 2002; 95: 661–6.

Neuro Muscular Blocking Drugs • Muscle relaxants - Peribulbar blocks, IVRA • Vecuronium (0.5 mg) added to lidocaine with adrenaline or Bupivacaine and Hyaluronidase • Shown to provide better ocular and eyelid akinesia • Atracurium (5 mg) to a Lidocaine and Bupivacaine mixture • more rapid ocular akinesia • Atracurium (2 mg) and Cisatracurium (0.01 mg.kg−1) to Lidocaine and Prilocaine for IVRA • better intra-operative analgesia and easier forearm fracture reduction with no adverse side effects •Reah G, Bodenham AR, Braithwaite P, Esmond J, Menage MJ. Peribulbar anaesthesia using a mixture of local anaesthetic and vecuronium. Anaesthesia 1998; 53: 551–4. •Küçükyavuz Z, Arici MK. Effects of atracurium added to local anesthetics on akinesia in peribulbar block. Regional Anesthesia and Pain Medicine 2002; 27: 487–90. •Elhakim M, Sadek RA. Addition of atracurium to lidocaine for intravenous regional anaesthesia. ActaAnaesthesiologicaScandinavica 1994; 38: 542–4. •Esmaoglu A, Akin A, Mizrak A, Turk Y, Boyaci A. Addition of cisatracurium to lidocaine for intravenous regional anesthesia. Journal of Clinical Anesthesia 2006; 18: 194–7. 6 •McGlone R, Heyes F, Harris P. The use of muscle relaxant to supplement local anaesthetics for Bier’s blocks. Archives of Emergency Medicine 1988; 5: 79–85.

Adenosine • Via spinal Adenosine A1 receptors - SG cells (Lamina II of Rexed) • Anti-inflammatory activity • Transient side effects - fainting, palpitations, headache, transient atrioventricular block and severe bronchospasm • Conflicting evidence shown in two trials: • Use of intrathecal Adenosine (0.5–1.0 mg) in patients undergoing hysterectomy made no difference to pain scores or postoperative analgesic consumption • In brachial plexus block in the dose of 10 mg used as an adjuvant to a Prilocaine and Lidocaine mixture, there was no difference to the onset or offset of sensory blockade, and did not extend the duration of analgesia •Cronstein BN. Adenosine, an endogenous anti-inflammatory agent. Journal of Applied Physiology 1994; 76: 5–13. •Gan TJ, Habib AS. Adenosine as a non-opioid analgesic in the perioperative setting. Anesthesia & Analgesia 2007; 105: 487–94.

Recent Advances Ziconotide • Calcium (Ca++) channel antagonist • N type voltage dependent calcium channels - dorsal horn of the spinal cord, cerebral cortex, and neurohyophysis • Both nociceptive and neuropathic pain. • Intrathecal doses start at 2.4 mcg/day (0.1 mcg/hr)- titrated to patient response • Increased up to 2.4 mcg/day at intervals no more than two to three times per week until a recommended maximum of 19.2 mcg/day (0.8 mcg/hr) is reached • Adverse effects - memory loss, dizziness, nystagmus, impaired speech, ataxia, and confusion

Recent Advances • Calcitonin: • The analgesic action found to be comparable to that of fentanyl given epidurally • Side effects - nausea and vomiting • Epidural and intrathecal dose: 100 IU • Cyclooxygenase Inhibitor - Ketorolac • Gabapentin • Inhibits Glutamate release at dorsal horn - Voltage gated calcium channels • Not yet FDA approved, a human phase II clinical trial is in progress. • Experimental Drugs: Octreotide, Rresiniferatoxin, Xen 2174, CGX1160 and P-Saporin I are still in their experimental stages. The detailed coverage of these is beyond the scope of present review.

Conclusion • Quest for an “Ideal Local Anesthetic Agent” • The requirement of Adjuvants to LAAs is a real time ground reality and a challenging concept. • Almost every drug in an Anesthesiologists‟ armamentarium has a potential to be included in this group. • There is a need of imaginative planning, thorough execution and innovative analysis, while designing and carrying out various Randomized controlled Trials.

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