Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. Aug 16, 2017; 5(8): 307-323
Published online Aug 16, 2017. doi: 10.12998/wjcc.v5.i8.307
Adjuvants to local anesthetics: Current understanding and future trends
Amlan Swain, Deb Sanjay Nag, Seelora Sahu, Devi Prasad Samaddar
Amlan Swain, Deb Sanjay Nag, Seelora Sahu, Devi Prasad Samaddar, Department of Anaesthesia and Critical Care, Tata Main Hospital, Jamshedpur 831001, India
Author contributions: All the authors contributed to the manuscript.
Conflict-of-interest statement: The authors declare no conflicts of interest regarding this manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Deb Sanjay Nag, Department of Anaesthesia and Critical Care, Tata Main Hospital, C Road West, Northern Town, Bistupur, Jamshedpur 831001, India. ds.nag@tatasteel.com
Telephone: +91-943-1166582 Fax: +91-657-2224559
Received: February 5, 2017
Peer-review started: February 7, 2017
First decision: April 18, 2017
Revised: May 3, 2017
Accepted: May 18, 2017
Article in press: May 19, 2017
Published online: August 16, 2017


Although beneficial in acute and chronic pain management, the use of local anaesthetics is limited by its duration of action and the dose dependent adverse effects on the cardiac and central nervous system. Adjuvants or additives are often used with local anaesthetics for its synergistic effect by prolonging the duration of sensory-motor block and limiting the cumulative dose requirement of local anaesthetics. The armamentarium of local anesthetic adjuvants have evolved over time from classical opioids to a wide array of drugs spanning several groups and varying mechanisms of action. A large array of opioids ranging from morphine, fentanyl and sufentanyl to hydromorphone, buprenorphine and tramadol has been used with varying success. However, their use has been limited by their adverse effect like respiratory depression, nausea, vomiting and pruritus, especially with its neuraxial use. Epinephrine potentiates the local anesthetics by its antinociceptive properties mediated by alpha-2 adrenoreceptor activation along with its vasoconstrictive properties limiting the systemic absorption of local anesthetics. Alpha 2 adrenoreceptor antagonists like clonidine and dexmedetomidine are one of the most widely used class of local anesthetic adjuvants. Other drugs like steroids (dexamethasone), anti-inflammatory agents (parecoxib and lornoxicam), midazolam, ketamine, magnesium sulfate and neostigmine have also been used with mixed success. The concern regarding the safety profile of these adjuvants is due to its potential neurotoxicity and neurological complications which necessitate further research in this direction. Current research is directed towards a search for agents and techniques which would prolong local anaesthetic action without its deleterious effects. This includes novel approaches like use of charged molecules to produce local anaesthetic action (tonicaine and n butyl tetracaine), new age delivery mechanisms for prolonged bioavailability (liposomal, microspheres and cyclodextrin systems) and further studies with other drugs (adenosine, neuromuscular blockers, dextrans).

Key Words: Local anesthetics, Adjuvants, Neurotoxicity, Opioids, Ketamine, Midazolam, Alpha-2 adrenoreceptor antagonists

Core tip: The use of local anaesthetics in acute and chronic pain is limited by its duration of action and the dose dependent adverse effects. Adjuvants or additives are often used with local anaesthetics for its synergistic effect by prolonging the duration of sensory-motor block and limiting its cumulative dose requirement. Various drugs like opioids, epinephrine, alpha-2 adrenergic antagonists, steroids, anti-inflammatory drugs, midazolam, ketamine, magnesium sulfate and neostigmine have been used to potentiate the effect of local anesthetics. Due its potential adverse effects, current research is exploring newer drugs and delivery mechanisms to prolong the duration of action of local anesthetics.


From time immemorial, alleviation of acute and chronic pain has continued to perplex medical professionals. The early success of pharmacologic endeavors in pain mitigation involved extensive use of opioids. Although reasonably successful, it was often associated with systemic complications like nausea, vomiting, respiratory depression, sedation, delayed recovery of bowel functions and hyperalgesia. In an effort to reduce the need and adverse effects of systemic opioids, the perineural (intrathecal, epidural or peripheral nerve blocks) use of local anesthetics have gradually evolved over time.

Although beneficial in acute and chronic pain management, local anaesthetics do have the potential to produce deleterious effects like cardiac arrhythmias, central nervous system depression, seizures, respiratory depression, hypertension and allergic reactions[1-4]. By prolonging the duration of sensory-motor block and limiting the cumulative dose requirement of local anaesthetics, co-administration of adjuvants has the potential to improve efficacy of perineural blocks and decrease local anaesthetic toxicity. The terms, local anaesthetic “adjuvants” or “additives”, have often been used interchangeably. They contribute in their own special manner to potentiate the analgesic effect of the local anaesthetics[5]. The armamentarium of local anesthetic adjuvants have evolved over time from classical opioids to a wide array of drugs spanning several groups and varying mechanisms of action.

The aim of this editorial is to have a comprehensive look at the various local anesthetic adjuvants which have been studied till date, ascertain the evidence for their safety and efficacy in perineural use, discuss various novel approaches in local anesthetic usage and highlight the present lacuna in knowledge for directing future research on the subject.


Opioids are the most frequently used local anesthetic adjuvants and their use in neuraxial blocks have evolved over the last 50 years[6]. The opioids potentiate anti-nociception of local anesthetics by G protein coupled receptor mechanisms by causing hyperpolarisation of the afferent sensory neurons[7]. The dose, site of injection, lipophilicity and the acid-base milieu of the site of drug deposition determine the extent of efficacy of the block[8,9].

Morphine: Use of preservative free morphine with or without local anesthetics has been used extensively in neuraxial blocks across all age groups[10,11]. Intrathecal Morphine in the dose range of 100-200 μg has exhibited good analgesic efficacy, especially in obstetric and orthopedic subsets[12,13]. Similarly epidural morphine has also been used over a wide dose range (1-5 mg) and has exhibited efficacy in diverse population subsets[14-17]. The hydrophilic nature of neuraxial Morphine results in cephalad spread, thereby increasing the area of analgesia. However the adverse effect of its use in neuraxial blocks includes respiratory depression (early and late), nausea, vomiting, pruritus and urinary retention. Specifically, there is evidence to suggest that intrathecal morphine administration of doses lower than 100 μg results in lesser adverse effects in elderly patients[13]. The use of Morphine in peripheral nerve blocks is presently not recommended as studies have failed to show any advantage over intravenous (IV) and intramuscular (IM) routes. Their adverse effects persist irrespective of the route of administration[18-22].

Fentanyl: Intrathecal fentanyl in the dose range of 10-25 μg has also been shown to prolong the duration and extent of sensory block with a favorable adverse effect profile in comparison to morphine[23-25]. However, epidural fentanyl does not necessarily follow the same pattern and a higher incidence of adverse effects have been observed with its use[26]. The addition of epinephrine 2 μg/mL to neuraxial local anesthetic-fentanyl mixtures has also been investigated. However, it was demonstrated that thoracic neuraxial instillation resulted in lesser nausea but its lumbar neuraxial administration didn’t reduce any opioid related adverse effects[27-29]. Numerous studies have however failed to conclusively prove the efficacy of fentanyl as an adjuvant in peripheral nerve blocks[30-35].

Sufentanyl: Intrathecal sufentanyl in the dose of 5 μg as an adjuvant to local anesthetics has shown good efficacy, however, for lesser adverse effects, the dose range needs to be lower (around 1.5 μg)[36,37]. The epidural dose of sufentanyl is 0.75-1 μg/mL and has been shown to be strikingly effective in ameliorating pain in various patient subsets[38-40].

Other opioids: Hydromorphone and Buprenorphine: Hydromorphone has been shown be an efficacious adjuvant in both intrathecal and epidural routes at the dosages of 100 μg and 500-600 μg respectively[41,42]. It is preferred in patients with renal insufficiency and had a better adverse effect profile when compared to morphine[43,44].

Buprenorphine has also been used in intrathecal (75-150 μg) and epidural routes (150-300 μg) with reasonable efficacy[5,45]. Additionally, it has also shown good efficacy when used in a dose of 0.3 mg as an adjuvant to peripheral nerve blocks[46-48].

Tramadol: Tramadol is a weak opioid agonist having sodium and potassium channel blocking actions as well as ancillary actions such as blockage of uptake of norepinephrine and serotonin[49-51]. Intrathecal tramadol in doses ranging from 10-50 mg has been in used different subsets with varying success[52-57].

Epidural tramadol in doses of 1-2 mg/kg presented itself as an attractive alternative to morphine for postoperative analgesia without any respiratory depressant effect[58]. Epidural tramadol has given good results for amelioration of pain in various patient subsets ranging from obstetric patients and abdominal surgeries to pediatric patients for lower abdominal procedures[59-63].

The incidence of nausea and vomiting remains a concern. However, incidence was less with lower doses. Other adverse effects like itching and sedation are less frequent[58,62]. Tramadol when used as an adjuvant in peripheral nerve blocks has shown conflicting and contradictory results with an unknown safety profile[64-67]. A couple of studies have shown Tramadol to increase the analgesic efficacy[64,66]. However, there have been other studies which have shown limited or no benefit of Tramadol when used as an adjuvant to local anesthetics for peripheral nerve blocks[65,68-72]. Hence, except for postoperative epidural infusions, present day anesthesia practice does not recommend routine use of Tramadol as a local anesthetic adjuvant.

Adverse effects of neuraxial opioids: The troublesome adverse effects of neuraxial opioids include pruritus, nausea, vomiting and respiratory failure, especially in elderly patients. This has prompted studies to determine the upper safe limit of administration of these drugs. The effects are more profound when the drug is deposited in the intrathecal space resulting in recommendations to reduce intrathecal dosage to avoid respiratory depression[73]. The pruritus produced by neuraxial opioids is dose dependent and responds well to Naloxone 200 μg and Ondansetron 4-8 mg[24,37,74].


Epinephrine is one of the oldest additives to local anesthetic solutions with a recommended dosing of 0.5-1.0 μg/kg in a concentration of 5-10 μg/mL[75,76]. In addition to its vasoconstrictive actions, it also seems to have intrinsic antinociceptive properties mediated by alpha-2 adrenoreceptor activation[77]. A matter of concern with the use of continuous infusion of neuraxial epinephrine has been the association of severe neurologic complications as well as evidence of intrinsic neurotoxicity attributed to epinephrine[78-82]. Its use in neuraxial anesthesia is limited to being used as an additive to caudal Bupivacaine administration and for the detection of inadvertent intra vascular placement of epidural and other perineural catheters[83,84]. In peripheral nerve blocks, Epinephrine has shown certain analgesic benefits with short and intermediate acting local anesthetic such as lidocaine, but similar effects have not been observed with long acting local anesthetic such as Bupivacaine and Ropivacaine[85,86]. The effect of Epinephrine in peripheral blocks seems to be largely dependent on its vasoconstrictive action as perineural Epinephrine alone doesn’t seem to cause any sensory or motor block[82,87,88].

Epinephrine has however had a significant role in preventing inadvertent intravascular administration of local anesthetic solutions; however the recent surge in routine use of ultrasonography in nerve blocks has made such use largely redundant. There is significant evidence indicating potential neurotoxicity with the perineural use of Epinephrine, especially in patients with diabetes mellitus, hypertension and in smokers[80,87]. Current recommendations allow use of epinephrine in peripheral blocks only when ultrasonography is not available or where needle tip and local anesthetic spread are not visualized[85].

Alpha 2 adrenoreceptor antagonists

Alpha 2 adrenoreceptor antagonists (Clonidine, Dexmedetomidine) are one of the most widely used class of local anesthetic adjuvants which give satisfactory effect in neuraxial and peripheral blocks.

Clonidine: Clonidine is an imidazole derivative with selective partial agonist properties which inhibits nociceptive impulses by activation of postjunctional alpha-2 adrenoreceptor in the dorsal horn of spinal cord[89]. In neuraxial blocks, it has a local effect on blockage of sympathetic outflow while in peripheral nerve blocks it prolongs duration of analgesia by hyperpolarisation of cyclic nucleotide gated cation channels[87,90].

Clonidine was first used in 1984 in epidural blocks[91]. Epidural clonidine in doses of 25-50 μg/h has been found to have beneficial effects in various study populations like spine instrumentation and orthopedic procedures[92-96]. Caudal administration of clonidine in pediatric age groups has also exhibited significant prolongation of the duration of analgesia with minimal cardiorespiratory perturbations[97-99]. Intrathecal administration of clonidine has evolved in terms of dosing from the initial phases of higher doses (150 μg) to routine use of lesser doses (15-40 μg) in present day practice to avoid its cardiovascular adverse effects. Intrathecal Clonidine supplementation of local anesthetic solutions result in increased segmental spread of sensory block, delayed regression of such blocks and decrease the failure rate and analgesic supplementation required in various surgical subsets[100-103]. It has also peculiarly shown benefits in alcoholics undergoing surgery by preventing postoperative alcohol withdrawal symptoms[104]. Use of clonidine in neuraxial blocks had been plagued by the adverse effects like sedation, bradycardia and hypotension, thus necessitating a gradual evolution to present day recommendations of lower dosages[93,105,106].

There have been a plethora of studies investigating efficacy of Clonidine as a local anesthetic adjuvant and results have shown varying outcomes[107-112]. A meta analysis by Pöpping et al[113] demonstrated prolongation of peripheral nerve block duration by 2 h when clonidine was used as an adjuvant. McCartney et al[114] analyzed 27 well designed studies (15 positive, 12 negative) and found that clonidine prolonged peripheral nerve blockade best in amalgamation with intermediate acting local anesthetics such as mepivacaine and lidocaine. Lesser potentiation was observed with bupivacaine and levobupivacaine while ropivacaine produced the most disappointing results. Interestingly upper extremity blocks fared better in comparison to the lower extremity blocks when clonidine was used as an adjuvant[114]. The extensive studies by McCartney and Pöpping presented convincing evidence suggesting significant association of increased doses with hemodynamic manifestations such as hypotension and bradycardia. Hence a dose of 0.5 μg/kg with a maximum of 150 μg is the recommended maximum dose of clonidine for use as an adjuvant in peripheral blocks[113,114]. Subsequently there has been evidence suggesting that clonidine as an adjuvant is beneficial in popliteal sciatic block and in specific circumstances such as axillary blocks in patients with chronic renal failure and patients undergoing paronychia surgery (analgesia in infected tissue)[115,116]. The heterogeneity of results, especially in routine brachial plexus blocks, suggest that until further well directed research shows unequivocal evidence to advocate the use of Clonidine as an adjuvant to local anesthetic, it cannot be routinely recommended for perineural use[117-120].

Dexmedetomidine: Dexmedetomidine is a 7 times more selective alpha-2 receptor agonist in comparison to clonidine and has a similar mechanism of blocking hyperpolarisation activated cation channels[121,122].

Intrathecal (5-10 μg) and epidural dexmedetomidine (1 μg/kg) as an adjuvant to isobaric bupivacaine or in combination with commonly used local anaesthetics (like ropivacaine) have been investigated for its analgesic efficacy in various patient subsets[123-129]. A meta-analysis on intrathecal dexmedetomidine has shown that its use has been associated with prolonged duration of block and improved post-operative analgesia without any associated hypotension or other adverse events, especially when used at doses less than 5 μg[130]. A qualitative review and meta-analysis on the role of dexmedetomidine in neuraxial blocks had concluded that it is a favorable local anesthetic adjuvant providing prolonged anesthesia and analgesia and decrease the need for rescue analgesics; however, it is often associated with a higher incidence of bradycardia[131]. Comparative evaluation of dexmedetomidine and clonidine has revealed the superiority of dexmedetomidine when used as an adjuvant for epidural or intrathecal administration[132,133].

Since 2004, when it was first used as a local anaesthetic adjuvant in IV regional anaesthesia, the use of dexmedetomidine in peripheral nerve blocks have evolved with burgeoning evidence of considerable utility in such situations[134]. There have been multiple studies claiming increased effectiveness of use of dexmedetomidine and this has been consolidated in a meta-analysis examining the effectiveness of dexmedetomidine as a peripheral nerve block adjuvant[135].

The meta-analysis examined primarily brachial plexus blocks at doses of 0.75 μg/kg, 1.0 μg/kg, 30 μg and 100 μg and found significant prolongation of motor block and reduced requirement of rescue analgesics[135]. The studies in this review did not reveal any increase in the incidence of hypotension as a significant adverse effect. However, reversible bradycardia was observed in less than 10% of the patients. Sensory block prolongation was not statistically significant[135].

Subsequently, there have been studies in supraclavicular, interscalene, cervical plexus and ulnar nerve blocks where dexmedetomidine has been shown to increase quality and duration of analgesia of commonly used local anaesthetics like ropivacaine and bupivacaine[136-141]. An interesting study found that dexmedetomidine fared significantly better than clonidine when used as a adjuvant in supraclavicular blocks[142]. Neuro-toxicity of dexmedetomidine, especially when used in perineural spaces is a valid concern. Surprisingly, preliminary evidence seems to suggest that dexmedetomidine has potential for neuro-protection, especially when compared with lidocaine and bupivacaine[143,144].

Hence current evidence seems to suggest that dexmedetomidine is effective when used as an adjuvant in peripheral nerve blocks in doses of 1 μg/kg. The adverse affect profile seems to be acceptable with known complications such as hypotension and bradycardia which are responsive to conventional therapies[145].


Dexamethasone: Dexamethasone is a potent anti-inflammatory agent which has been investigated in the last decade for its role as an adjuvant to local anaesthetics in neuraxial as well as peripheral nerve blocks.

The mechanisms by which steroids potentiate the analgesic effects seem to be different from its intrinsic anti-inflammatory mechanism[146,147]. There is also evidence to show that the local action on nerve fibres and systemic effects, both potentiate dexamethasone’s analgesic properties[148,149].

A study examined the effect of intrathecal dexamethasone in a dose of 8 mg (preservative free) with standard doses of hyperbaric bupivacaine 0.5% in orthopedic surgeries. It was shown to significantly prolong the duration of sensory block in spinal anaesthesia without any significant adverse effects[150].

Epidural dexamethasone in dose range of 4-8 mg has also been investigated for its analgesic efficacy and a recent meta-analysis has looked at its effectiveness[151]. The meta-analysis showed the advantages of the use of dexamethasone as an adjuvant to epidural local anaesthetics. However, it also highlighted the need of further well powered studies to establish its safety in terms of neurological complications[151].

Dexamethasone in a dose range of 1, 2, 4 and 8 mg has largely shown to be efficacious as a local anaesthetic adjuvant in a variety of blocks such as supraclavicular and inter-scalene brachial plexus block, ankle block and TAP block[152-155]. In fact, a meta-analysis exploring the use of dexamethasone as an adjuvant in brachial plexus block has found it to significantly prolong the duration of block of conventional local anaesthetic solutions[156]. A recent study by Liu et al[157] demonstrated that perineural dexamethasone (1, 2 and 4 mg) prolonged the duration of analgesia and motor blockade of bupivacaine in patients receiving supraclavicular brachial plexus nerve block for ambulatory shoulder surgery. This effect was despite the fact that most patients in the study population as well as control group received intravenous dexamethasone as well, hence refuting the assumption that perineural dexamethasone produced analgesia because of systemic absorption[157]. However, in some studies the use of perineural dexamethasone has not produced desirable results and it continues to be debated whether the analgesia produced by dexamethasone is related to its systemic effects[158-160].

Other anti-inflammatory agents

Other than dexamethasone, there have been very few studies on anti-inflammatory agents as perineural local anesthetic adjuvants. Neurotoxicity of neuraxial or perineural non-steroidal anti-inflammatory drugs (NSAIDs) as adjuvants has been a major concern. Although there are studies showing prolongation of the effect of local anaesthetics with epidural instillation of Parecoxib and Lornoxicam[161,162], the use of epidural Lornoxicam has also shown “histopathological signs of neurotoxicity”. There is very little research evidence available on the use of anti-inflammatory medications in peripheral nerve blocks and further studies are warranted. Until new evidence comes up, their use cannot be recommended for neuraxial and peripheral nerve blocks.

Other drugs

Midazolam: Neuraxial midazolam acts on the benzodiazepine receptors on the gray matter of the spinal cord, the highest concentration of which is found on the lamina II of the dorsal horn. The analgesic effect of neuraxial midazolam is caused by the spinal suppression of sensory functions and its anti-nociceptive effect mediated by GABAergic and opioid receptor mechanisms[163-168].

Intrathecal midazolam in a dose of 1-2.5 mg has been shown to be effective in providing prolonged post-operative analgesia without significant adverse effects in adults undergoing orthopedic, urological and lower abdominal surgeries, parturients undergoing caesarean sections and children undergoing urologic procedures[169-178]. Prochazka reported the safe use of intrathecal midazolam as a useful adjuvant for prolongation of analgesia in 775 patients over a period of 10 years[179].

Studies have found that epidural midazolam in doses of 50 μg/kg potentiates the effect of bupivacaine in patients undergoing upper abdominal surgery[180]. Similarly, it has also been found to potentiate the effect of caudal epidural bupivacaine by increasing the time to first analgesic requirement and decreasing the need for post-operative analgesia in children undergoing inguinal herniotomy[181].

Neurotoxicity of intrathecal and epidural midazolam in animal models has been a concern[182-184]. However, its use in a cohort study in 1100 patients by Tucker et al[185] conclusively proved that neuraxial midazolam is not associated with any adverse neurological or bladder-bowel symptoms in conventional therapeutic doses. Midazolam is not currently recommended for use in peripheral nerve blocks[145].

Neostigmine: Intrathecal neostigmine has been found to cause analgesia by muscarinic receptor mediated mechanisms[186-188]. Studies have reported its usage in the dose of 5-10 μg to as high as 50-150 μg in the intrathecal route with increased doses showing greater association with nausea and vomiting, bradycardia, agitation and restlessness[189-196].

Epidural neostigmine in the doses of 1 μg, 2 μg and 4 μg have also been investigated and have been found to be efficacious local anaesthetic adjuvants[197,198]. Studies on the use of neostigmine as a peripheral nerve block adjuvant have been very few and have exhibited very little clinical prolongation of anaesthesia and have shown to be associated with troublesome gastrointestinal adverse effects. Currently its use in peripheral nerve blocks is not recommended[199].

Neurotoxicity of perineural neostigmine remains a concern, especially because animal studies have shown mixed results and human studies have essentially found the adverse effect to be related to its dose, with doses less than 50 μg not being associated with any adverse effects[200-203].

Ketamine: Ketamine, a NMDA receptor antagonist has been explored for its local anesthetic properties[204]. Preservative free forms of ketamine are recommended for neuraxial use because of the evidence of neurotoxicity due to its preservative[205]. Ketamine has been shown to exert analgesic effects by epidural, caudal and spinal routes by a multitude of mechanisms involving N-methyl-D-aspartate (NMDA), Cholinergic, adrenergic and 5-hydroxytryptamine receptors or 5-HT receptors[206-213].

Intrathecal and epidural ketamine has been studied most commonly in patients undergoing caesarean section, prostate surgeries and orthopedic procedures. It has been found to potentiate the effect of local anaesthetics by shortening the onset of sensory and motor block, but simultaneously decreasing the duration and extent of motor block[214-219]. This effect profile of intrathecal ketamine (early onset and decreased duration of action) has led to its use in day care surgeries wherein the early return of full motor power could be advantageous[220].

Caudal ketamine in a dose of 0.5 mg/kg has been studied in children undergoing lower abdominal surgeries and has prolonged the duration of analgesia without significant adverse effects[221]. A systematic review of caudal ketamine use concluded that though efficacious, there are uncertainties related to its neurotoxicity[222]. The association of neuraxial ketamine use with troublesome adverse effects which seems to be a dose dependant phenomenon with lower doses associated with lesser systemic effects[219,223].

Use of ketamine in peripheral nerve blocks has shown it to be associated with unacceptably high incidence of adverse affects such as psychotomimetic sequelae (hallucinations, drowsiness, nausea) without any increase of block duration. Currently, ketamine is not recommended for use in peripheral nerve blocks[224].

Magnesium sulfate: Magnesium sulfate is an NMDA receptor antagonist and inhibitor of voltage gated calcium channel. It had been investigated for its analgesic properties in a variety of clinical scenarios and routes of administration[225]. It had been shown to reduce the postoperative analgesic requirements in a variety of cases.

Intrathecal administration of magnesium sulfate has been shown to suppress nociceptive impulses in neuropathic pain and potentiates opioid anti-nociception in animal studies[226,227]. In humans, profound motor and sensory block for up to 3-27 h was reported in orthopedic, general surgery and gynecological procedures[228]. The duration of spinal opioid analgesia in patients requesting analgesia for labor was significantly prolonged by co-administration of magnesium sulfate with no effect on motor block, sensory block or the incidence of adverse effects like pruritus[229]. Magnesium sulfate has been used in doses of 25-100 mg along with opioids (fentanyl/sufentanyl) with or without local anaesthetic agents (lidocaine, bupivacaine, levobupivacaine and ropivacaine)[225].

A rapid onset of sensory block has been reported with epidural administration of magnesium sulfate as an adjuvant to local anaesthetic agents in thoracic and orthopedic surgeries with a lower incidence of post-operative shivering, nausea and vomiting[230-232]. A faster onset of action, longer duration of actions and reduced breakthrough pain with no change in adverse effects or fetal outcome was observed when magnesium sulfate was used as an adjuvant in labor analgesia[233].

Magnesium sulfate has been used as an adjuvant to local anaesthetics in interscalene and supraclavicular brachial plexus block, axillary block, femoral nerve block and popliteal nerve block. It has shown to increase the duration of analgesia without any adverse effects[234-237].

The adverse effects of neuraxial use of magnesium sulfate has been reported in isolated cases and are restricted to bradycardia, hypotension, sedation, headache, disorientation or periumbilical burning pain[238,239].

Animal studies were the first to report neurological complications and pain at injection site in a dose dependant manner, especially at dose more than 2-3 mg/kg[240]. Although neurodegenerative changes on intrathecal administration of magnesium sulfate into the rat spine have been reported[241], histological evidence of direct neuronal injury is lacking in canine models, thus suggesting that the neurological injury associated with the use of magnesium sulfate in neuraxial blocks may be species specific[242,243]. The lack of well defined neurotoxicity studies for the use of magnesium sulfate precludes any recommendation for its use as an adjuvant to local anaesthetic agents[145].


There has been an ongoing search for agents and techniques which would prolong local anaesthetic action without its deleterious effects, primarily systemic toxicity and neurotoxicity. Butyl-amino-benzoate is an ester local anaesthetic agent, which though not strictly an adjuvant, has shown to provide pain relief for up-to 14 wk by novel mechanisms such as blockade of sodium and potassium channels[244-247].

Another novel approach has been to use charged molecules to produce local anaesthetic action, as with tonicaine and n butyl tetracaine[248-251]. Although onset is slow because of the time required to penetrate neuronal membranes, the duration of action is prolonged because of charge properties. However, more human trials are required before these novel local anesthetics can be used in routine clinical practice.

Recent advancement in the world of perineural local anaesthetic use has been the progress in new age delivery mechanisms such as liposomal, microspheres and cyclodextrin systems. Liposomes are microscopic lipid vesicles ranging in size from 0.02-40 μm which have the advantage of acting as a reservoir of drug with low bioavailability resulting in prolonged analgesic effects without systemic toxicity[252-254]. Liposomal local anesthetics have been used in multiple routes[255,256] and had shown prolonged analgesia with less motor block in various populations[257-259]. However there are concerns about their potential toxicity because of the compounds, their metabolites and breakdown of the liposomal core[260]. Microspheres and cyclodextrins are also alternatives drug delivery systems which have shown initial promises in animal models[149,261-264].

Among other adjuvants, adenosine showed initial promise because of its analgesia mediated at the spinal adenosine receptors and inherent anti-inflammatory actions without any neurotoxicity in initial animal studies[265-267]. However human studies using intrathecal adenosine (0.5-1.0 mg) as well as its use as an adjuvant to local anaesthetic solutions in peripheral nerve blocks have shown no additional benefit[268-270]. Dextrans, a complex branched polysaccharides derived from sucrose, had been hypothesized to form water soluble complexes with local anesthetics and thereby prolonging the duration of analgesia by sustained action at the store of its deposition, as well as by altering the local pH favorably[271,272]. Human studies on the use of dextrans as a local anaesthetic adjuvant have been mixed, some showing advantage and others being inconclusive and there remains a need for further high powered studies[273-276].

Neuromuscular blocking drugs have also been explored as local anaesthetic adjuncts and have shown promising results in peri-bulbar blocks and intravenous regional anaesthesia with good results[277-281]. However there have been concerns of such use being associated with local anesthetic toxicity and prolonged motor blockade[282].

A summary of commonly used local anaesthetic adjuvants is given in Table 1.

Table 1 Summary of the commonly used local anaesthetic adjuvants.
Name of drugRoutes and dosagesAdverse effectsRecommendations for useMechanism of action
Morphine[12,22]Intrathecal: 100-200 μgPruritusUseful in neuraxial blocks
Epidural: 1-5 mgNausea vomitingNot recommended for peripheral nerve blocks
Peripheral nerve block: 75-100 μg/kgRespiratory failure
Fentanyl[23-26,30-35]Intrathecal: 10-25 μgSame adverse effects as morphineUseful in neuraxial blocks
Epidural: 2-4 μg/mLAdverse effect profile slightly favourable in neuraxial useNot recommended in neuraxial blocks due to inconsistent results
Peripheral nerve blockIncreased sedation, bradycardia and hypotensionSpinal opioid receptor
Sufentanyl[36-40]Intrathecal: 1.5-5 μgEfficacious in neuraxial blocksLocal action in peripheral nerve blocks
Epidural: 0.75-1.0 μg/mL
Not used in peripheral nerve blocks
Hydromorphone[41-44]Intrathecal: 100 μgBetter adverse effect profile than MorphineUseful in neuraxial blocks
Epidural: 500-600 μg
Not used in peripheral nerve blocks
Buprenorphine[5,45-48]Intrathecal: 75-150 μgGood efficacy in neuraxial and peripheral nerve block routes
Epidural: 150-300 μg
Peripheral nerve block: 300 μg
Tramadol[49-72]Intrathecal: 10-50 mgNausea and vomitingPresent evidence supports use in epidural infusionsWeak opioid agonist actions
Epidural: 1-2 mg/kgPoor evidence in peripheral nerve block studiesSodium/potassium channel blocking actions
Peripheral nerve block: 1-5 mg/kgBlockade of norepinephrine and serotonin uptake
Clonidine[89-121]Intrathecal: 15-40 μgSedationGood quality evidence to support use in neuraxial blocks especially at lower dosagesActivation of post junctional alpha-2 receptors in dorsal horn of spinal cord
Epidural: 25-50 μgBradycardiaIn PNB prolongs block with Bupivacaine but poor efficacy with Ropivacaine and levobupivacaine
Peripheral nerve block: 0.5-5 μg/kg (150 μg is the maximum allowed dose in PNB)HypertensionAdditional benefit in Alcohol withdrawal
Adverse effects show association with dose
Dexmeditomidine[122-147]Intrathecal: 5-10 μgSedationProlongation of neuraxial and peripheral nerve blocks with good efficacy of useMechanism similar to Clonidine
Epidural: 1 μg/kgBradycardia
Peripheral nerve block: 20-150 μgHypertension
Adverse effects show association with dose
Dexamethasone[148-161]Intrathecal: 8 mgAdverse effects minimalEfficacious in neuraxial blocks, however better studies requiredLocal action on nerve fibers
Epidural: 4-8 mgAdvantageous to prevent ponvProlongs nerve blockade in PNB
Peripheral nerve block: 1-8 mgTroublesome paresthesias with PNB use
Midazolam[164-184]Intrathecal: 1-2.5 mgSedationNeurotoxicity is a major concern in neuraxial and peripheral nerve routesGABAergic and opioid receptor mechanisms
Epidural: 50 μg/kg diluted in 10 mL of salineRespiratory depressionNot recommended for routine neuraxial and PNB use
Neostigmine[185-202]Intrathecal: 5-10 μg to 50-150 μgNeuraxial use associated with bradycardia, restlessnessLower dosages recommended for neuraxial useEnhancement of endogenous acetylcholine at nerve terminal
Epidural: 1, 2 and 4 μgPNB use associated with gastrointestinal adverse effectsNot recommended for PNB use (neurotoxicity in animal models)
Peripheral nerve block-not investigated
Ketamine[203-223]Neuraxial use associated with nausea, vomiting and hallucinationsNeuraxial use-shortens onset and duration of anesthesiaNMDA receptor antagonists shown to have local anesthetic properties
PNB use associated with psychomimetic sequelaeNot recommended for PNB useCholinergic, adrenergic and 5HT mechanisms
Magnesium[224-238]Intrathecal: 25-100 mgHeadacheProlongs analgesia and quality of block by all perineural routesNMDA receptor antagonism
Epidural: 50-100 mgCardiovascular disturbancesHowever more studies required to determine minimal effective dosesVoltage gated calcium channel blockade
Nausea vomitingNot recommended for routine use

Adjuvant to local anesthetics is an evolving and exciting field of anesthesia practice with new technology promising to improve patient satisfaction and safety. While opioids continue to be the most commonly used local anesthetic adjuvant in clinical practice, alpha-2 receptor antagonists, especially dexmedetomidine, has been shown to potentiate the effect of local anaesthetics with an acceptable safety profile. Use of adjuvants to local anesthetic should take into consideration the available evidence and the advocated safe dose ranges, its effective routes of administration, the adverse effect profile of use of such adjuncts as well as preparedness to manage life threatening complications such as Local Anesthesia Systemic Toxicity (LAST). Its users should be aware of its neurotoxicity potential following perineural use and watch for its clinical implications. Search for newer molecules and techniques allowing for lesser perineural doses of local anesthetic, enhanced analgesic effect and improved safety profile are expected to guide further studies in future to fill up the present lacuna in evidence about the use of adjuvant for local anaesthetics.


Manuscript source: Invited manuscript

Specialty type: Medicine, research and experimental

Country of origin: India

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1.  Borgeat A, Aguirre J. Update on local anesthetics. Curr Opin Anaesthesiol. 2010;23:466-471.  [PubMed]  [DOI]
2.  Gunter JB. Benefit and risks of local anesthetics in infants and children. Paediatr Drugs. 2002;4:649-672.  [PubMed]  [DOI]
3.  Elvir-Lazo OL, White PF. The role of multimodal analgesia in pain management after ambulatory surgery. Curr Opin Anaesthesiol. 2010;23:697-703.  [PubMed]  [DOI]
4.  Kehlet H, White PF. Optimizing anesthesia for inguinal herniorrhaphy: general, regional, or local anesthesia? Anesth Analg. 2001;93:1367-1369.  [PubMed]  [DOI]
5.  Anderson CTM. Adjuvants in Regional and Neuraxial Anesthesia: An Update. In Paediatric Anaesthesiology [Internet]; 2013 March 14-17; Las Vegas, NV. Society for Pediatric Anesthesia and the American Academy of Pediatrics Section on Anesthesiology and Pain Medicine.  Available from: http://www2.pedsanesthesia.org/meetings/2013winter/syllabus/submissions/sig-pain/CAnderson.pdf.  [PubMed]  [DOI]
6.  Wang JK, Nauss LA, Thomas JE. Pain relief by intrathecally applied morphine in man. Anesthesiology. 1979;50:149-151.  [PubMed]  [DOI]
7.  Busch-Dienstfertig M, Stein C. Opioid receptors and opioid peptide-producing leukocytes in inflammatory pain--basic and therapeutic aspects. Brain Behav Immun. 2010;24:683-694.  [PubMed]  [DOI]
8.  Stein C, Millan MJ, Shippenberg TS, Peter K, Herz A. Peripheral opioid receptors mediating antinociception in inflammation. Evidence for involvement of mu, delta and kappa receptors. J Pharmacol Exp Ther. 1989;248:1269-1275.  [PubMed]  [DOI]
9.  Tegeder I, Meier S, Burian M, Schmidt H, Geisslinger G, Lötsch J. Peripheral opioid analgesia in experimental human pain models. Brain. 2003;126:1092-1102.  [PubMed]  [DOI]
10.  Henneberg SW, Hole P, Madsen de Haas I, Jensen PJ. Epidural morphine for postoperative pain relief in children. Acta Anaesthesiol Scand. 1993;37:664-667.  [PubMed]  [DOI]
11.  Krane EJ, Jacobson LE, Lynn AM, Parrot C, Tyler DC. Caudal morphine for postoperative analgesia in children: a comparison with caudal bupivacaine and intravenous morphine. Anesth Analg. 1987;66:647-653.  [PubMed]  [DOI]
12.  Karaman S, Kocabas S, Uyar M, Hayzaran S, Firat V. The effects of sufentanil or morphine added to hyperbaric bupivacaine in spinal anaesthesia for caesarean section. Eur J Anaesthesiol. 2006;23:285-291.  [PubMed]  [DOI]
13.  Murphy PM, Stack D, Kinirons B, Laffey JG. Optimizing the dose of intrathecal morphine in older patients undergoing hip arthroplasty. Anesth Analg. 2003;97:1709-1715.  [PubMed]  [DOI]
14.  Axelsson K, Johanzon E, Essving P, Weckström J, Ekbäck G. Postoperative extradural analgesia with morphine and ropivacaine. A double-blind comparison between placebo and ropivacaine 10 mg/h or 16 mg/h. Acta Anaesthesiol Scand. 2005;49:1191-1199.  [PubMed]  [DOI]
15.  Pham Dang C, Delécrin J, Péréon Y, Falconi I, Passuti N, Malinge M, Pinaud M. Epidural analgesia after scoliosis surgery: electrophysiologic and clinical assessment of the effects of bupivacaine 0.125% plus morphine versus ropivacaine 0.2% plus morphine. J Clin Anesth. 2008;20:17-24.  [PubMed]  [DOI]
16.  Bonnet MP, Mignon A, Mazoit JX, Ozier Y, Marret E. Analgesic efficacy and adverse effects of epidural morphine compared to parenteral opioids after elective caesarean section: a systematic review. Eur J Pain. 2010;14:894.e1-894.e9.  [PubMed]  [DOI]
17.  Singh SI, Rehou S, Marmai KL, Jones PM. The efficacy of 2 doses of epidural morphine for postcesarean delivery analgesia: a randomized noninferiority trial. Anesth Analg. 2013;117:677-685.  [PubMed]  [DOI]
18.  Bazin JE, Massoni C, Bruelle P, Fenies V, Groslier D, Schoeffler P. The addition of opioids to local anaesthetics in brachial plexus block: the comparative effects of morphine, buprenorphine and sufentanil. Anaesthesia. 1997;52:858-862.  [PubMed]  [DOI]
19.  Bourke DL, Furman WR. Improved postoperative analgesia with morphine added to axillary block solution. J Clin Anesth. 1993;5:114-117.  [PubMed]  [DOI]
20.  Flory N, Van-Gessel E, Donald F, Hoffmeyer P, Gamulin Z. Does the addition of morphine to brachial plexus block improve analgesia after shoulder surgery? Br J Anaesth. 1995;75:23-26.  [PubMed]  [DOI]
21.  Sternlo JE, Hägerdal M. Perineuronal morphine in intercostal block. Anaesthesia. 1992;47:613-615.  [PubMed]  [DOI]
22.  Racz H, Gunning K, Della Santa D, Forster A. Evaluation of the effect of perineuronal morphine on the quality of postoperative analgesia after axillary plexus block: a randomized double-blind study. Anesth Analg. 1991;72:769-772.  [PubMed]  [DOI]
23.  Liu S, Chiu AA, Carpenter RL, Mulroy MF, Allen HW, Neal JM, Pollock JE. Fentanyl prolongs lidocaine spinal anesthesia without prolonging recovery. Anesth Analg. 1995;80:730-734.  [PubMed]  [DOI]
24.  Varrassi G, Celleno D, Capogna G, Costantino P, Emanuelli M, Sebastiani M, Pesce AF, Niv D. Ventilatory effects of subarachnoid fentanyl in the elderly. Anaesthesia. 1992;47:558-562.  [PubMed]  [DOI]
25.  Korhonen AM, Valanne JV, Jokela RM, Ravaska P, Korttila K. Intrathecal hyperbaric bupivacaine 3 mg + fentanyl 10 microg for outpatient knee arthroscopy with tourniquet. Acta Anaesthesiol Scand. 2003;47:342-346.  [PubMed]  [DOI]
26.  Finucane BT, Ganapathy S, Carli F, Pridham JN, Ong BY, Shukla RC, Kristoffersson AH, Huizar KM, Nevin K, Ahlén KG; Canadian Ropivacaine Research Group. Prolonged epidural infusions of ropivacaine (2 mg/mL) after colonic surgery: the impact of adding fentanyl. Anesth Analg. 2001;92:1276-1285.  [PubMed]  [DOI]
27.  Niemi G, Breivik H. Epinephrine markedly improves thoracic epidural analgesia produced by a small-dose infusion of ropivacaine, fentanyl, and epinephrine after major thoracic or abdominal surgery: a randomized, double-blinded crossover study with and without epinephrine. Anesth Analg. 2002;94:1598-1605, table of contents.  [PubMed]  [DOI]
28.  Förster JG, Niemi TT, Aromaa U, Neuvonen PJ, Seppälä TA, Rosenberg PH. Epinephrine added to a lumbar epidural infusion of a small-dose ropivacaine-fentanyl mixture after arterial bypass surgery of the lower extremities. Acta Anaesthesiol Scand. 2003;47:1106-1113.  [PubMed]  [DOI]
29.  Förster JG, Lumme HM, Palkama VJ, Rosenberg PH, Pitkänen MT. Epinephrine 4 microg/mL added to a low-dose mixture of ropivacaine and fentanyl for lumbar epidural analgesia after total knee arthroplasty. Anesth Analg. 2008;106:301-304, table of contents.  [PubMed]  [DOI]
30.  Nishikawa K, Kanaya N, Nakayama M, Igarashi M, Tsunoda K, Namiki A. Fentanyl improves analgesia but prolongs the onset of axillary brachial plexus block by peripheral mechanism. Anesth Analg. 2000;91:384-387.  [PubMed]  [DOI]
31.  Fanelli G, Casati A, Magistris L, Berti M, Albertin A, Scarioni M, Torri G. Fentanyl does not improve the nerve block characteristics of axillary brachial plexus anaesthesia performed with ropivacaine. Acta Anaesthesiol Scand. 2001;45:590-594.  [PubMed]  [DOI]
32.  Fletcher D, Kuhlman G, Samii K. Addition of fentanyl to 1.5% lidocaine does not increase the success of axillary plexus block. Reg Anesth. 1994;19:183-188.  [PubMed]  [DOI]
33.  Kardash K, Schools A, Concepcion M. Effects of brachial plexus fentanyl on supraclavicular block. A randomized, double-blind study. Reg Anesth. 1995;20:311-315.  [PubMed]  [DOI]
34.  Magistris L, Casati A, Albertin A, Deni F, Danelli G, Borghi B, Fanelli G. Combined sciatic-femoral nerve block with 0.75% ropivacaine: effects of adding a systemically inactive dose of fentanyl. Eur J Anaesthesiol. 2000;17:348-353.  [PubMed]  [DOI]
35.  Moharari R, Sadeghi J, Khajavi M, Davari M, Mojtahedzadeh M. Fentanyl supplement expedites the onset time of sensory and motor blocking in interscalene lidocaine anesthesia. Daru. 2010;18:298-302.  [PubMed]  [DOI]
36.  Olofsson C, Nygårds EB, Bjersten AB, Hessling A. Low-dose bupivacaine with sufentanil prevents hypotension after spinal anesthesia for hip repair in elderly patients. Acta Anaesthesiol Scand. 2004;48:1240-1244.  [PubMed]  [DOI]
37.  Demiraran Y, Ozdemir I, Kocaman B, Yucel O. Intrathecal sufentanil (1.5 microg) added to hyperbaric bupivacaine (0.5%) for elective cesarean section provides adequate analgesia without need for pruritus therapy. J Anesth. 2006;20:274-278.  [PubMed]  [DOI]
38.  Kampe S, Weigand C, Kaufmann J, Klimek M, König DP, Lynch J. Postoperative analgesia with no motor block by continuous epidural infusion of ropivacaine 0.1% and sufentanil after total hip replacement. Anesth Analg. 1999;89:395-398.  [PubMed]  [DOI]
39.  Kampe S, Diefenbach C, Kanis B, Auweiler M, Kiencke P, Cranfield K. Epidural combination of ropivacaine with sufentanil for postoperative analgesia after total knee replacement: a pilot study. Eur J Anaesthesiol. 2002;19:666-671.  [PubMed]  [DOI]
40.  De Cosmo G, Congedo E, Lai C, Sgreccia M, Amato A, Beccia G, Aceto P. Ropivacaine vs. levobupivacaine combined with sufentanil for epidural analgesia after lung surgery. Eur J Anaesthesiol. 2008;25:1020-1025.  [PubMed]  [DOI]
41.  Rauch E. Intrathecal hydromorphone for postoperative analgesia after cesarean delivery: a retrospective study. AANA J. 2012;80:S25-S32.  [PubMed]  [DOI]
42.  Halpern SH, Arellano R, Preston R, Carstoniu J, O’Leary G, Roger S, Sandler A. Epidural morphine vs hydromorphone in post-caesarean section patients. Can J Anaesth. 1996;43:595-598.  [PubMed]  [DOI]
43.  Hong D, Flood P, Diaz G. The side effects of morphine and hydromorphone patient-controlled analgesia. Anesth Analg. 2008;107:1384-1389.  [PubMed]  [DOI]
44.  Srinivasagam K, Chandrasekaran A. Intrathecal Buprenorphine, Clonidine and Fentanyl as Adjuvants To 0.5% Hyperbaric Bupivacaine In Lower Abdominal Surgeries: A Prospective, Randomized And Comparative Study. IOSR JDMS. 2016;15:25-30.  [PubMed]  [DOI]
45.  Ipe S, Korula S, Varma S, George GM, Abraham SP, Koshy LR. A comparative study of intrathecal and epidural buprenorphine using combined spinal-epidural technique for caesarean section. Indian J Anaesth. 2010;54:205-209.  [PubMed]  [DOI]
46.  Candido KD, Franco CD, Khan MA, Winnie AP, Raja DS. Buprenorphine added to the local anesthetic for brachial plexus block to provide postoperative analgesia in outpatients. Reg Anesth Pain Med. 2001;26:352-356.  [PubMed]  [DOI]
47.  Candido KD, Winnie AP, Ghaleb AH, Fattouh MW, Franco CD. Buprenorphine added to the local anesthetic for axillary brachial plexus block prolongs postoperative analgesia. Reg Anesth Pain Med. 2002;27:162-167.  [PubMed]  [DOI]
48.  Viel EJ, Eledjam JJ, De La Coussaye JE, D’Athis F. Brachial plexus block with opioids for postoperative pain relief: comparison between buprenorphine and morphine. Reg Anesth. 1989;14:274-278.  [PubMed]  [DOI]
49.  Wilder-Smith CH, Wilder-Smith OH, Farschtschian M, Naji P. Preoperative adjuvant epidural tramadol: the effect of different doses on postoperative analgesia and pain processing. Acta Anaesthesiol Scand. 1998;42:299-305.  [PubMed]  [DOI]
50.  Güven M, Mert T, Günay I. Effects of tramadol on nerve action potentials in rat: comparisons with benzocaine and lidocaine. Int J Neurosci. 2005;115:339-349.  [PubMed]  [DOI]
51.  Sousa AM, Ashmawi HA, Costa LS, Posso IP, Slullitel A. Percutaneous sciatic nerve block with tramadol induces analgesia and motor blockade in two animal pain models. Braz J Med Biol Res. 2012;45:147-152.  [PubMed]  [DOI]
52.  Alhashemi JA, Kaki AM. Effect of intrathecal tramadol administration on postoperative pain after transurethral resection of prostate. Br J Anaesth. 2003;91:536-540.  [PubMed]  [DOI]
53.  Chakraborty S, Chakrabarti J, Bhattacharya D. Intrathecal tramadol added to bupivacaine as spinal anesthetic increases analgesic effect of the spinal blockade after major gynecological surgeries. Indian J Pharmacol. 2008;40:180-182.  [PubMed]  [DOI]
54.  Parthasarathy S, Ravishankar M. Single dose intrathecal tramadol in the management of post appendicectomy pain. J Anaesthesiol Clin Pharmacol. 2002;18:419-422.  [PubMed]  [DOI]
55.  Jung JI, Kang PS. The effect of intrathecal tramadol and clonidine on saddle block with heavy bupivacaine. Korean J Anesthesiol. 1999;37:227-232.  [PubMed]  [DOI]
56.  Mostafa MG, Mohamad MF, Farrag WSH. Which has greater analgesic effect: intrathecal nalbuphine or intrathecal tramadol? J Am Sci. 2011;7:480-484.  [PubMed]  [DOI]
57.  Subedi A, Biswas BK, Tripathi M, Bhattarai BK, Pokharel K. Analgesic effects of intrathecal tramadol in patients undergoing caesarean section: a randomised, double-blind study. Int J Obstet Anesth. 2013;22:316-321.  [PubMed]  [DOI]
58.  Baraka A, Jabbour S, Ghabash M, Nader A, Khoury G, Sibai A. A comparison of epidural tramadol and epidural morphine for postoperative analgesia. Can J Anaesth. 1993;40:308-313.  [PubMed]  [DOI]
59.  Prakash S, Tyagi R, Gogia AR, Singh R, Prakash S. Efficacy of three doses of tramadol with bupivacaine for caudal analgesia in paediatric inguinal herniotomy. Br J Anaesth. 2006;97:385-388.  [PubMed]  [DOI]
60.  Chrubasik J, Warth L, Wust H, Zindler M. Analgesic potency of epidural tramadol after abdominal surgery. Pain. 1987;30:S154.  [PubMed]  [DOI]
61.  Gunduz M, Ozcengiz D, Ozbek H, Isik G. A comparison of single dose caudal tramadol, tramadol plus bupivacaine and bupivacaine administration for postoperative analgesia in children. Paediatr Anaesth. 2001;11:323-326.  [PubMed]  [DOI]
62.  Delilkan AE, Vijayan R. Epidural tramadol for postoperative pain relief. Anaesthesia. 1993;48:328-331.  [PubMed]  [DOI]
63.  Singh AP, Singh D, Singh Y, Jain G. Postoperative analgesic efficacy of epidural tramadol as adjutant to ropivacaine in adult upper abdominal surgeries. Anesth Essays Res. 2015;9:369-373.  [PubMed]  [DOI]
64.  Alemanno F, Ghisi D, Fanelli A, Faliva A, Pergolotti B, Bizzarri F, Fanelli G. Tramadol and 0.5% levobupivacaine for single-shot interscalene block: effects on postoperative analgesia in patients undergoing shoulder arthroplasty. Minerva Anestesiol. 2012;78:291-296.  [PubMed]  [DOI]
65.  Mannion S, O’Callaghan S, Murphy DB, Shorten GD. Tramadol as adjunct to psoas compartment block with levobupivacaine 0.5%: a randomized double-blinded study. Br J Anaesth. 2005;94:352-356.  [PubMed]  [DOI]
66.  Kaabachi O, Ouezini R, Koubaa W, Ghrab B, Zargouni A, Ben Abdelaziz A. Tramadol as an adjuvant to lidocaine for axillary brachial plexus block. Anesth Analg. 2009;108:367-370.  [PubMed]  [DOI]
67.  Neal JM, Gerancher JC, Hebl JR, Ilfeld BM, McCartney CJ, Franco CD, Hogan QH. Upper extremity regional anesthesia: essentials of our current understanding, 2008. Reg Anesth Pain Med. 2009;34:134-170.  [PubMed]  [DOI]
68.  Sarsu S, Mizrak A, Karakurum G. Tramadol use for axillary brachial plexus blockade. J Surg Res. 2011;165:e23-e27.  [PubMed]  [DOI]
69.  Robaux S, Blunt C, Viel E, Cuvillon P, Nouguier P, Dautel G, Boileau S, Girard F, Bouaziz H. Tramadol added to 1.5% mepivacaine for axillary brachial plexus block improves postoperative analgesia dose-dependently. Anesth Analg. 2004;98:1172-1177, table of contents.  [PubMed]  [DOI]
70.  Kapral S, Gollmann G, Waltl B, Likar R, Sladen RN, Weinstabl C, Lehofer F. Tramadol added to mepivacaine prolongs the duration of an axillary brachial plexus blockade. Anesth Analg. 1999;88:853-856.  [PubMed]  [DOI]
71.  Kesimci E, Izdes S, Gozdemir M, Kanbak O. Tramadol does not prolong the effect of ropivacaine 7.5 mg/ml for axillary brachial plexus block. Acta Anaesthesiol Scand. 2007;51:736-741.  [PubMed]  [DOI]
72.  Omar AM, Mansour MA, Abdelwahab HH, Aboushanab OH. Role of ketamine and tramadol as adjuncts to bupivacaine 0.5% in paravertebral block for breast surgery: A randomized double-blind study. Egypt J Anaesth. 2011;27:101-105.  [PubMed]  [DOI]
73.  Fournier R, Gamulin Z, Van Gessel E. Respiratory depression after 5 micrograms of intrathecal sufentanil. Anesth Analg. 1998;87:1377-1378.  [PubMed]  [DOI]
74.  Pirat A, Tuncay SF, Torgay A, Candan S, Arslan G. Ondansetron, orally disintegrating tablets versus intravenous injection for prevention of intrathecal morphine-induced nausea, vomiting, and pruritus in young males. Anesth Analg. 2005;101:1330-1336.  [PubMed]  [DOI]
75.  Jöhr M, Berger TM. Caudal blocks. Paediatr Anaesth. 2012;22:44-50.  [PubMed]  [DOI]
76.  Braun H. Ueber die bedeutung des ephinephrine fur die chirurgie. Munch Med Wschr. 1903;50:352-353.  [PubMed]  [DOI]
77.  Collins JG, Kitahata LM, Matsumoto M, Homma E, Suzukawa M. Spinally administered epinephrine suppresses noxiously evoked activity of WDR neurons in the dorsal horn of the spinal cord. Anesthesiology. 1984;60:269-275.  [PubMed]  [DOI]
78.  Meyer MJ, Krane EJ, Goldschneider KR, Klein NJ. Case report: neurological complications associated with epidural analgesia in children: a report of 4 cases of ambiguous etiologies. Anesth Analg. 2012;115:1365-1370.  [PubMed]  [DOI]
79.  Hashimoto K, Hampl KF, Nakamura Y, Bollen AW, Feiner J, Drasner K. Epinephrine increases the neurotoxic potential of intrathecally administered lidocaine in the rat. Anesthesiology. 2001;94:876-881.  [PubMed]  [DOI]
80.  Myers RR, Heckman HM. Effects of local anesthesia on nerve blood flow: studies using lidocaine with and without epinephrine. Anesthesiology. 1989;71:757-762.  [PubMed]  [DOI]
81.  Kroin JS, Buvanendran A, Williams DK, Wagenaar B, Moric M, Tuman KJ, Kerns JM. Local anesthetic sciatic nerve block and nerve fiber damage in diabetic rats. Reg Anesth Pain Med. 2010;35:343-350.  [PubMed]  [DOI]
82.  Neal JM. Effects of epinephrine in local anesthetics on the central and peripheral nervous systems: Neurotoxicity and neural blood flow. Reg Anesth Pain Med. 2003;28:124-134.  [PubMed]  [DOI]
83.  Tobias JD. Caudal epidural block: a review of test dosing and recognition of systemic injection in children. Anesth Analg. 2001;93:1156-1161.  [PubMed]  [DOI]
84.  Förster JG, Rosenberg PH. Clinically useful adjuvants in regional anaesthesia. Curr Opin Anaesthesiol. 2003;16:477-486.  [PubMed]  [DOI]
85.  Brummett CM, Williams BA. Additives to local anesthetics for peripheral nerve blockade. Int Anesthesiol Clin. 2011;49:104-116.  [PubMed]  [DOI]
86.  Welch MB, Brummett CM, Welch TD, Tremper KK, Shanks AM, Guglani P, Mashour GA. Perioperative peripheral nerve injuries: a retrospective study of 380,680 cases during a 10-year period at a single institution. Anesthesiology. 2009;111:490-497.  [PubMed]  [DOI]
87.  Kroin JS, Buvanendran A, Beck DR, Topic JE, Watts DE, Tuman KJ. Clonidine prolongation of lidocaine analgesia after sciatic nerve block in rats Is mediated via the hyperpolarization-activated cation current, not by alpha-adrenoreceptors. Anesthesiology. 2004;101:488-494.  [PubMed]  [DOI]
88.  Hickey R, Blanchard J, Hoffman J, Sjovall J, Ramamurthy S. Plasma concentrations of ropivacaine given with or without epinephrine for brachial plexus block. Can J Anaesth. 1990;37:878-882.  [PubMed]  [DOI]
89.  Eisenach JC, De Kock M, Klimscha W. alpha(2)-adrenergic agonists for regional anesthesia. A clinical review of clonidine (1984-1995). Anesthesiology. 1996;85:655-674.  [PubMed]  [DOI]
90.  Saxena AK, Arya SK. Current concepts in neuraxial administrationof opioids and non-opioids: an overviewand future perspectives. Indian J Anaesth. 2004;48:13-24.  [PubMed]  [DOI]
91.  Tamsen A, Gordh T. Epidural clonidine produces analgesia. Lancet. 1984;2:231-232.  [PubMed]  [DOI]
92.  Rockemann MG, Seeling W, Brinkmann A, Goertz AW, Hauber N, Junge J, Georgieff M. Analgesic and hemodynamic effects of epidural clonidine, clonidine/morphine, and morphine after pancreatic surgery--a double-blind study. Anesth Analg. 1995;80:869-874.  [PubMed]  [DOI]
93.  Klimscha W, Chiari A, Krafft P, Plattner O, Taslimi R, Mayer N, Weinstabl C, Schneider B, Zimpfer M. Hemodynamic and analgesic effects of clonidine added repetitively to continuous epidural and spinal blocks. Anesth Analg. 1995;80:322-327.  [PubMed]  [DOI]
94.  Dobrydnjov I, Axelsson K, Gupta A, Lundin A, Holmström B, Granath B. Improved analgesia with clonidine when added to local anesthetic during combined spinal-epidural anesthesia for hip arthroplasty: a double-blind, randomized and placebo-controlled study. Acta Anaesthesiol Scand. 2005;49:538-545.  [PubMed]  [DOI]
95.  Milligan KR, Convery PN, Weir P, Quinn P, Connolly D. The efficacy and safety of epidural infusions of levobupivacaine with and without clonidine for postoperative pain relief in patients undergoing total hip replacement. Anesth Analg. 2000;91:393-397.  [PubMed]  [DOI]
96.  Farmery AD, Wilson-MacDonald J. The analgesic effect of epidural clonidine after spinal surgery: a randomized placebo-controlled trial. Anesth Analg. 2009;108:631-634.  [PubMed]  [DOI]
97.  Laha A, Ghosh S, Das H. Comparison of caudal analgesia between ropivacaine and ropivacaine with clonidine in children: A randomized controlled trial. Saudi J Anaesth. 2012;6:197-200.  [PubMed]  [DOI]
98.  Breschan C, Krumpholz R, Likar R, Kraschl R, Schalk HV. Can a dose of 2microg.kg(-1) caudal clonidine cause respiratory depression in neonates? Paediatr Anaesth. 1999;9:81-83.  [PubMed]  [DOI]
99.  Klimscha W, Chiari A, Michalek-Sauberer A, Wildling E, Lerche A, Lorber C, Brinkmann H, Semsroth M. The efficacy and safety of a clonidine/bupivacaine combination in caudal blockade for pediatric hernia repair. Anesth Analg. 1998;86:54-61.  [PubMed]  [DOI]
100.  Dobrydnjov I, Axelsson K, Samarütel J, Holmström B. Postoperative pain relief following intrathecal bupivacaine combined with intrathecal or oral clonidine. Acta Anaesthesiol Scand. 2002;46:806-814.  [PubMed]  [DOI]
101.  De Kock M, Gautier P, Fanard L, Hody JL, Lavand’homme P. Intrathecal ropivacaine and clonidine for ambulatory knee arthroscopy: a dose-response study. Anesthesiology. 2001;94:574-578.  [PubMed]  [DOI]
102.  Dobrydnjov I, Axelsson K, Thörn SE, Matthiesen P, Klockhoff H, Holmström B, Gupta A. Clonidine combined with small-dose bupivacaine during spinal anesthesia for inguinal herniorrhaphy: a randomized double-blinded study. Anesth Analg. 2003;96:1496-1503, table of contents.  [PubMed]  [DOI]
103.  Davis BR, Kopacz DJ. Spinal 2-chloroprocaine: the effect of added clonidine. Anesth Analg. 2005;100:559-565.  [PubMed]  [DOI]
104.  Dobrydnjov I, Axelsson K, Berggren L, Samarütel J, Holmström B. Intrathecal and oral clonidine as prophylaxis for postoperative alcohol withdrawal syndrome: a randomized double-blinded study. Anesth Analg. 2004;98:738-744, table of contents.  [PubMed]  [DOI]
105.  Niemi L. Effects of intrathecal clonidine on duration of bupivacaine spinal anaesthesia, haemodynamics, and postoperative analgesia in patients undergoing knee arthroscopy. Acta Anaesthesiol Scand. 1994;38:724-728.  [PubMed]  [DOI]
106.  Filos KS, Goudas LC, Patroni O, Polyzou V. Hemodynamic and analgesic profile after intrathecal clonidine in humans. A dose-response study. Anesthesiology. 1994;81:591-601; discussion 27A-28A.  [PubMed]  [DOI]
107.  Beaussier M, Weickmans H, Abdelhalim Z, Lienhart A. Inguinal herniorrhaphy under monitored anesthesia care with ilioinguinal-iliohypogastric block: the impact of adding clonidine to ropivacaine. Anesth Analg. 2005;101:1659-1662.  [PubMed]  [DOI]
108.  Büttner J, Ott B, Klose R. [The effect of adding clonidine to mepivacaine. Axillary brachial plexus blockade]. Anaesthesist. 1992;41:548-554.  [PubMed]  [DOI]
109.  Duma A, Urbanek B, Sitzwohl C, Kreiger A, Zimpfer M, Kapral S. Clonidine as an adjuvant to local anaesthetic axillary brachial plexus block: a randomized, controlled study. Br J Anaesth. 2005;94:112-116.  [PubMed]  [DOI]
110.  Helayel PE, Kroth L, Boos GL, Jahns MT, Oliveira Filho GR. [Effects of intramuscular and perineural clonidine on sciatic nerve block with 0.5% ropivacaine]. Rev Bras Anestesiol. 2005;55:483-490.  [PubMed]  [DOI]
111.  Iohom G, Machmachi A, Diarra DP, Khatouf M, Boileau S, Dap F, Boini S, Mertes PM, Bouaziz H. The effects of clonidine added to mepivacaine for paronychia surgery under axillary brachial plexus block. Anesth Analg. 2005;100:1179-1183.  [PubMed]  [DOI]
112.  Iskandar H, Guillaume E, Dixmérias F, Binje B, Rakotondriamihary S, Thiebaut R, Maurette P. The enhancement of sensory blockade by clonidine selectively added to mepivacaine after midhumeral block. Anesth Analg. 2001;93:771-775.  [PubMed]  [DOI]
113.  Pöpping DM, Elia N, Marret E, Wenk M, Tramèr MR. Clonidine as an adjuvant to local anesthetics for peripheral nerve and plexus blocks: a meta-analysis of randomized trials. Anesthesiology. 2009;111:406-415.  [PubMed]  [DOI]
114.  McCartney CJ, 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;32:330-338.  [PubMed]  [DOI]
115.  YaDeau JT, LaSala VR, Paroli L, Kahn RL, Jules-Elysée KM, Levine DS, Wukovits BL, Lipnitsky JY. Clonidine and analgesic duration after popliteal fossa nerve blockade: randomized, double-blind, placebo-controlled study. Anesth Analg. 2008;106:1916-1920.  [PubMed]  [DOI]
116.  Adnan T, Elif AA, Ayşe K, Gülnaz A. Clonidine as an adjuvant for lidocaine in axillary brachial plexus block in patients with chronic renal failure. Acta Anaesthesiol Scand. 2005;49:563-568.  [PubMed]  [DOI]
117.  Fournier R, Faust A, Chassot O, Gamulin Z. Perineural clonidine does not prolong levobupivacaine 0.5% after sciatic nerve block using the Labat approach in foot and ankle surgery. Reg Anesth Pain Med. 2012;37:521-524.  [PubMed]  [DOI]
118.  Jaiswal R, Bansal T, Mehta S, Ahlawat G. A study to evaluate the effect of adding Clonidine to Ropivacaine for axillary plexus blockade. Asian J Pharm Clin Res. 2013;6:165-168.  [PubMed]  [DOI]
119.  Molnar RR, Davies MJ, Scott DA, Silbert BS, Mooney PH. Comparison of clonidine and epinephrine in lidocaine for cervical plexus block. Reg Anesth. 1997;22:137-142.  [PubMed]  [DOI]
120.  Trivedi V, Patel N. A comparative clinical study of injection clonidine versus midazolam in supraclavicular brachial plexus block for sedation and postoperative analgesia: a study of 60 cases. J Indian Med Assoc. 2010;108:563-567.  [PubMed]  [DOI]
121.  Kamibayashi T, Maze M. Clinical uses of alpha2 -adrenergic agonists. Anesthesiology. 2000;93:1345-1349.  [PubMed]  [DOI]
122.  Brummett CM, Hong EK, Janda AM, Amodeo FS, Lydic R. Perineural dexmedetomidine added to ropivacaine for sciatic nerve block in rats prolongs the duration of analgesia by blocking the hyperpolarization-activated cation current. Anesthesiology. 2011;115:836-843.  [PubMed]  [DOI]
123.  Al-Mustafa MM, Abu-Halaweh SA, Aloweidi AS, Murshidi MM, Ammari BA, Awwad ZM, Al-Edwan GM, Ramsay MA. Effect of dexmedetomidine added to spinal bupivacaine for urological procedures. Saud Med J. 2009;30:365-370.  [PubMed]  [DOI]
124.  Kanazi GE, Aouad MT, Jabbour-Khoury SI, Al Jazzar MD, Alameddine MM, Al-Yaman R, Bulbul M, Baraka AS. Effect of low-dose dexmedetomidine or clonidine on the characteristics of bupivacaine spinal block. Acta Anaesthesiol Scand. 2006;50:222-227.  [PubMed]  [DOI]
125.  Shaikh SI, Mahesh SB. The efficacy and safety of epidural dexmedetomidine and clonidine with bupivacaine in patients undergoing lower limb orthopedic surgeries. J Anaesthesiol Clin Pharmacol. 2016;32:203-209.  [PubMed]  [DOI]
126.  Hong JY, Kim WO, Yoon Y, Choi Y, Kim SH, Kil HK. Effects of intravenous dexmedetomidine on low-dose bupivacaine spinal anaesthesia in elderly patients. Acta Anaesthesiol Scand. 2012;56:382-387.  [PubMed]  [DOI]
127.  Al-Mustafa MM, Badran IZ, Abu-Ali HM, Al-Barazangi BA, Massad IM, Al-Ghanem SM. Intravenous dexmedetomidine prolongs bupivacaine spinal analgesia. Middle East J Anaesthesiol. 2009;20:225-231.  [PubMed]  [DOI]
128.  Solanki SL, Bharti N, Batra YK, Jain A, Kumar P, Nikhar SA. The analgesic effect of intrathecal dexmedetomidine or clonidine, with bupivacaine, in trauma patients undergoing lower limb surgery: a randomised, double-blind study. Anaesth Intensive Care. 2013;41:51-56.  [PubMed]  [DOI]
129.  Ghanem S, Massad IM, Mustafa MM, Al-Zaben KR, Qudaisat IY, Qatawneh AM, Al-Reza SM, Ali HM, AI-Khazarji SM, Ibraheem QUDAISAT. Effect of adding dexmedetomidine versus fentanyl to intrathecal bupivacaine on spinal block characteristics in gynecological procedures: A double blind controlled study. Am J Appl Sci. 2009;6:882-887.  [PubMed]  [DOI]
130.  Niu XY, Ding XB, Guo T, Chen MH, Fu SK, Li Q. Effects of intravenous and intrathecal dexmedetomidine in spinal anesthesia: a meta-analysis. CNS Neurosci Ther. 2013;19:897-904.  [PubMed]  [DOI]
131.  Wu HH, Wang HT, Jin JJ, Cui GB, Zhou KC, Chen Y, Chen GZ, Dong YL, Wang W. Does dexmedetomidine as a neuraxial adjuvant facilitate better anesthesia and analgesia? A systematic review and meta-analysis. PLoS One. 2014;9:e93114.  [PubMed]  [DOI]
132.  Bajwa SJ, Bajwa SK, Kaur J, Singh G, Arora V, Gupta S, Kulshrestha A, Singh A, Parmar S, Singh A. Dexmedetomidine and clonidine in epidural anaesthesia: A comparative evaluation. Indian J Anaesth. 2011;55:116-121.  [PubMed]  [DOI]
133.  Mahendru V, Tewari A, Katyal S, Grewal A, Singh MR, Katyal R. A comparison of intrathecal dexmedetomidine, clonidine, and fentanyl as adjuvants to hyperbaric bupivacaine for lower limb surgery: A double blind controlled study. J Anaesthesiol Clin Pharmacol. 2013;29:496-502.  [PubMed]  [DOI]
134.  Memiş D, Turan A, Karamanlioğlu B, Pamukçu Z, Kurt I. Adding dexmedetomidine to lidocaine for intravenous regional anesthesia. Anesth Analg. 2004;98:835-840, table of contents.  [PubMed]  [DOI]
135.  Abdallah FW, Brull R. Facilitatory effects of perineural dexmedetomidine on neuraxial and peripheral nerve block: a systematic review and meta-analysis. Br J Anaesth. 2013;110:915-925.  [PubMed]  [DOI]
136.  Agarwal S, Aggarwal R, Gupta P. Dexmedetomidine prolongs the effect of bupivacaine in supraclavicular brachial plexus block. J Anaesthesiol Clin Pharmacol. 2014;30:36-40.  [PubMed]  [DOI]
137.  Fritsch G, Danninger T, Allerberger K, Tsodikov A, Felder TK, Kapeller M, Gerner P, Brummett CM. Dexmedetomidine added to ropivacaine extends the duration of interscalene brachial plexus blocks for elective shoulder surgery when compared with ropivacaine alone: a single-center, prospective, triple-blind, randomized controlled trial. Reg Anesth Pain Med. 2014;39:37-47.  [PubMed]  [DOI]
138.  Lin YN, Li Q, Yang RM, Mao ZX, Liu JC. Addition of dexmedetomidine to ropivacaine improves cervical plexus block. Acta Anaesthesiol Taiwan. 2013;51:63-66.  [PubMed]  [DOI]
139.  Marhofer D, Kettner SC, Marhofer P, Pils S, Weber M, Zeitlinger M. Dexmedetomidine as an adjuvant to ropivacaine prolongs peripheral nerve block: a volunteer study. Br J Anaesth. 2013;110:438-442.  [PubMed]  [DOI]
140.  Rancourt MP, Albert NT, Côté M, Létourneau DR, Bernard PM. Posterior tibial nerve sensory blockade duration prolonged by adding dexmedetomidine to ropivacaine. Anesth Analg. 2012;115:958-962.  [PubMed]  [DOI]
141.  Song JH, Shim HY, Lee TJ, Jung JK, Cha YD, Lee DI, Kim GW, Han JU. Comparison of dexmedetomidine and epinephrine as an adjuvant to 1% mepivacaine in brachial plexus block. Korean J Anesthesiol. 2014;66:283-289.  [PubMed]  [DOI]
142.  Swami SS, Keniya VM, Ladi SD, Rao R. Comparison of dexmedetomidine and clonidine (α2 agonist drugs) as an adjuvant to local anaesthesia in supraclavicular brachial plexus block: A randomised double-blind prospective study. Indian J Anaesth. 2012;56:243-249.  [PubMed]  [DOI]
143.  Zhang H, Zhou F, Li C, Kong M, Liu H, Zhang P, Zhang S, Cao J, Zhang L, Ma H. Molecular mechanisms underlying the analgesic property of intrathecal dexmedetomidine and its neurotoxicity evaluation: an in vivo and in vitro experimental study. PLoS One. 2013;8:e55556.  [PubMed]  [DOI]
144.  Tüfek A, Kaya S, Tokgöz O, Firat U, Evliyaoğlu O, Çelik F, Karaman H. The protective effect of dexmedetomidine on bupivacaine-induced sciatic nerve inflammation is mediated by mast cells. Clin Invest Med. 2013;36:E95-102.  [PubMed]  [DOI]
145.  Kirksey MA, Haskins SC, Cheng J, Liu SS. Local Anesthetic Peripheral Nerve Block Adjuvants for Prolongation of Analgesia: A Systematic Qualitative Review. PLoS One. 2015;10:e0137312.  [PubMed]  [DOI]
146.  McCormack K. The spinal actions of nonsteroidal anti-inflammatory drugs and the dissociation between their anti-inflammatory and analgesic effects. Drugs. 1994;47 Suppl 5:28-45; discussion 46-47.  [PubMed]  [DOI]
147.  Ahlgren SC, Wang JF, Levine JD. C-fiber mechanical stimulus-response functions are different in inflammatory versus neuropathic hyperalgesia in the rat. Neuroscience. 1997;76:285-290.  [PubMed]  [DOI]
148.  Baxendale BR, Vater M, Lavery KM. Dexamethasone reduces pain and swelling following extraction of third molar teeth. Anaesthesia. 1993;48:961-964.  [PubMed]  [DOI]
149.  Kopacz DJ, Lacouture PG, Wu D, Nandy P, Swanton R, Landau C. The dose response and effects of dexamethasone on bupivacaine microcapsules for intercostal blockade (T9 to T11) in healthy volunteers. Anesth Analg. 2003;96:576-582, table of contents.  [PubMed]  [DOI]
150.  Bani-Hashem N, Hassan-Nasab B, Pour EA, Maleh PA, Nabavi A, Jabbari A. Addition of intrathecal Dexamethasone to Bupivacaine for spinal anesthesia in orthopedic surgery. Saudi J Anaesth. 2011;5:382-386.  [PubMed]  [DOI]
151.  Jebaraj B, Khanna P, Baidya DK, Maitra S. Efficacy of epidural local anesthetic and dexamethasone in providing postoperative analgesia: A meta-analysis. Saudi J Anaesth. 2016;10:322-327.  [PubMed]  [DOI]
152.  Biradar PA, Kaimar P, Gopalakrishna K. Effect of dexamethasone added to lidocaine in supraclavicular brachial plexus block: A prospective, randomised, double-blind study. Indian J Anaesth. 2013;57:180-184.  [PubMed]  [DOI]
153.  Ammar AS, Mahmoud KM. Effect of adding dexamethasone to bupivacaine on transversus abdominis plane block for abdominal hysterectomy: A prospective randomized controlled trial. Saudi J Anaesth. 2012;6:229-233.  [PubMed]  [DOI]
154.  Rasmussen SB, Saied NN, Bowens C Jr, Mercaldo ND, Schildcrout JS, Malchow RJ. Duration of upper and lower extremity peripheral nerve blockade is prolonged with dexamethasone when added to ropivacaine: a retrospective database analysis. Pain Med. 2013;14:1239-1247.  [PubMed]  [DOI]
155.  Saritas A, Sabuncu C. Comparison of clinical effects of prilocaine, dexamethasone added to prilocaine and levobupivacaine on brachial plexus block. J Pak Med Assoc. 2014;64:433-436.  [PubMed]  [DOI]
156.  Choi S, Rodseth R, McCartney CJ. Effects of dexamethasone as a local anaesthetic adjuvant for brachial plexus block: a systematic review and meta-analysis of randomized trials. Br J Anaesth. 2014;112:427-439.  [PubMed]  [DOI]
157.  Liu J, Richman KA, Grodofsky SR, Bhatt S, Huffman GR, Kelly JD 4th, Glaser DL, Elkassabany N. Is there a dose response of dexamethasone as adjuvant for supraclavicular brachial plexus nerve block? A prospective randomized double-blinded clinical study. J Clin Anesth. 2015;27:237-242.  [PubMed]  [DOI]
158.  Fredrickson Fanzca MJ, Danesh-Clough TK, White R. Adjuvant dexamethasone for bupivacaine sciatic and ankle blocks: results from 2 randomized placebo-controlled trials. Reg Anesth Pain Med. 2013;38:300-307.  [PubMed]  [DOI]
159.  Desmet M, Braems H, Reynvoet M, Plasschaert S, Van Cauwelaert J, Pottel H, Carlier S, Missant C, Van de Velde M. I.V. and perineural dexamethasone are equivalent in increasing the analgesic duration of a single-shot interscalene block with ropivacaine for shoulder surgery: a prospective, randomized, placebo-controlled study. Br J Anaesth. 2013;111:445-452.  [PubMed]  [DOI]
160.  Rahangdale R, Kendall MC, McCarthy RJ, Tureanu L, Doty R Jr, Weingart A, De Oliveira GS Jr. The effects of perineural versus intravenous dexamethasone on sciatic nerve blockade outcomes: a randomized, double-blind, placebo-controlled study. Anesth Analg. 2014;118:1113-1119.  [PubMed]  [DOI]
161.  Kim YH, Lee PB, Park J, Lim YJ, Kim YC, Lee SC, Ahn W. The neurological safety of epidural parecoxib in rats. Neurotoxicology. 2011;32:864-870.  [PubMed]  [DOI]
162.  Canduz B, Aktug H, Mavioğlu O, Erkin Y, Yilmaz O, Uyanikgil Y, Korkmaz H, Baka M. Epidural lornoxicam administration -- innocent. J Clin Neurosci. 2007;14:968-974.  [PubMed]  [DOI]
163.  Goodchild CS, Guo Z, Musgreave A, Gent JP. Antinociception by intrathecal midazolam involves endogenous neurotransmitters acting at spinal cord delta opioid receptors. Br J Anaesth. 1996;77:758-763.  [PubMed]  [DOI]
164.  Müller H, Gerlach H, Boldt J, Börner U, Hild P, Oehler KU, Zierski J, Hempelmann G. [Spasticity treatment with spinal morphine or midazolam. In vitro experiments, animal studies and clinical studies on compatibility and effectiveness]. Anaesthesist. 1986;35:306-316.  [PubMed]  [DOI]
165.  Goodchild CS, Noble J. The effects of intrathecal midazolam on sympathetic nervous system reflexes in man-a pilot study. Brit J Clin Pharmaco. 1987;23:279-285.  [PubMed]  [DOI]
166.  Serrao JM, Gent JP, Goodchild CS. Naloxone antagonizes the spinal analgesic effects of midazolam. Brit J Clin Pharmaco. 1989;62:233-234.  [PubMed]  [DOI]
167.  Waldvogel HJ, Faull RL, Jansen KL, Dragunow M, Richards JG, Mohler H, Streit P. GABA, GABA receptors and benzodiazepine receptors in the human spinal cord: an autoradiographic and immunohistochemical study at the light and electron microscopic levels. Neuroscience. 1990;39:361-385.  [PubMed]  [DOI]
168.  Edwards M, Serrao JM, Gent JP, Goodchild CS. On the mechanism by which midazolam causes spinally mediated analgesia. Anesthesiology. 1990;73:273-277.  [PubMed]  [DOI]
169.  Güleç S, Büyükkidan B, Oral N, Ozcan N, Tanriverdi B. Comparison of caudal bupivacaine, bupivacaine-morphine and bupivacaine-midazolam mixtures for post-operative analgesia in children. Eur J Anaesthesiol. 1998;15:161-165.  [PubMed]  [DOI]
170.  Batra YK, Jain K, Chari P, Dhillon MS, Shaheen B, Reddy GM. Addition of intrathecal midazolam to bupivacaine produces better post-operative analgesia without prolonging recovery. Int J Clin Pharmacol Ther. 1999;37:519-523.  [PubMed]  [DOI]
171.  Kim MH, Lee YM. Intrathecal midazolam increases the analgesic effects of spinal blockade with bupivacaine in patients undergoing haemorrhoidectomy. Br J Anaesth. 2001;86:77-79.  [PubMed]  [DOI]
172.  Sen A, Rudra A, Sarkar SK, Biswas B. Intrathecal midazolam for postoperative pain relief in caesarean section delivery. J Indian Med Assoc. 2001;99:683-684, 686.  [PubMed]  [DOI]
173.  Mahajan R, Batra YK, Grover VK, Kajal J. A comparative study of caudal bupivacaine and midazolam-bupivacaine mixture for post-operative analgesia in children undergoing genitourinary surgery. Int J Clin Pharmacol Ther. 2001;39:116-120.  [PubMed]  [DOI]
174.  Shah FR, Halbe AR, Panchal ID, Goodchild CS. Improvement in postoperative pain relief by the addition of midazolam to an intrathecal injection of buprenorphine and bupivacaine. Eur J Anaesthesiol. 2003;20:904-910.  [PubMed]  [DOI]
175.  Bharti N, Madan R, Mohanty PR, Kaul HL. Intrathecal midazolam added to bupivacaine improves the duration and quality of spinal anaesthesia. Acta Anaesthesiol Scand. 2003;47:1101-1105.  [PubMed]  [DOI]
176.  Yegin A, Sanli S, Dosemeci L, Kayacan N, Akbas M, Karsli B. The analgesic and sedative effects of intrathecal midazolam in perianal surgery. Eur J Anaesthesiol. 2004;21:658-662.  [PubMed]  [DOI]
177.  Prakash S, Joshi N, Gogia AR, Prakash S, Singh R. Analgesic efficacy of two doses of intrathecal midazolam with bupivacaine in patients undergoing cesarean delivery. Reg Anesth Pain Med. 2006;31:221-226.  [PubMed]  [DOI]
178.  Gupta A, Prakash S, Deshpande S, Kale KS. The effect of intrathecal midazolam 2.5mg with bupivacaine on postoperative pain relief in patients undergoing orthopaedic surgery. J Clin Anaesth Pharmacol. 2008;24:189-192.  [PubMed]  [DOI]
179.  Prochazka J. 775 intrathecal midazolam as an analgesic-10 years experience. Eur J Pain. 2006;10:S202.  [PubMed]  [DOI]
180.  Nishiyama T. The post-operative analgesic action of midazolam following epidural administration. Eur J Anaesthesiol. 1995;12:369-374.  [PubMed]  [DOI]
181.  Naguib M, el Gammal M, Elhattab YS, Seraj M. Midazolam for caudal analgesia in children: comparison with caudal bupivacaine. Can J Anaesth. 1995;42:758-764.  [PubMed]  [DOI]
182.  Malinovsky JM, Cozian A, Lepage JY, Mussini JM, Pinaud M, Souron R. Ketamine and midazolam neurotoxicity in the rabbit. Anesthesiology. 1991;75:91-97.  [PubMed]  [DOI]
183.  Svensson BA, Welin M, Gordh T, Westman J. Chronic subarachnoid midazolam (Dormicum) in the rat. Morphologic evidence of spinal cord neurotoxicity. Reg Anesth. 1995;20:426-434.  [PubMed]  [DOI]
184.  Bozkurt P, Tunali Y, Kaya G, Okar I. Histological changes following epidural injection of midazolam in the neonatal rabbit. Paediatr Anaesth. 1997;7:385-389.  [PubMed]  [DOI]
185.  Tucker AP, Lai C, Nadeson R, Goodchild CS. Intrathecal midazolam I: a cohort study investigating safety. Anesth Analg. 2004;98:1512-1520, table of contents.  [PubMed]  [DOI]
186.  Yaksh TL, Dirksen R, Harty GJ. Antinociceptive effects of intrathecally injected cholinomimetic drugs in the rat and cat. Eur J Pharmacol. 1985;117:81-88.  [PubMed]  [DOI]
187.  Hood DD, Mallak KA, James RL, Tuttle R, Eisenach JC. Enhancement of analgesia from systemic opioid in humans by spinal cholinesterase inhibition. J Pharmacol Exp Ther. 1997;282:86-92.  [PubMed]  [DOI]
188.  Klamt JG, Garcia LV, Prado WA. Analgesic and adverse effects of a low dose of intrathecally administered hyperbaric neostigmine alone or combined with morphine in patients submitted to spinal anaesthesia: pilot studies. Anaesthesia. 1999;54:27-31.  [PubMed]  [DOI]
189.  Almeida RA, Lauretti GR, Mattos AL. Antinociceptive effect of low-dose intrathecal neostigmine combined with intrathecal morphine following gynecologic surgery. Anesthesiology. 2003;98:495-498.  [PubMed]  [DOI]
190.  Lauretti GR, Hood DD, Eisenach JC, Pfeifer BL. A multi-center study of intrathecal neostigmine for analgesia following vaginal hysterectomy. Anesthesiology. 1998;89:913-918.  [PubMed]  [DOI]
191.  Krukowski JA, Hood DD, Eisenach JC, Mallak KA, Parker RL. Intrathecal neostigmine for post-cesarean section analgesia: dose response. Anesth Analg. 1997;84:1269-1275.  [PubMed]  [DOI]
192.  Owen MD, Ozsaraç O, Sahin S, Uçkunkaya N, Kaplan N, Magunaci I. Low-dose clonidine and neostigmine prolong the duration of intrathecal bupivacaine-fentanyl for labor analgesia. Anesthesiology. 2000;92:361-366.  [PubMed]  [DOI]
193.  Lauretti GR, Reis MP, Prado WA, Klamt JG. Dose-response study of intrathecal morphine versus intrathecal neostigmine, their combination, or placebo for postoperative analgesia in patients undergoing anterior and posterior vaginoplasty. Anesth Analg. 1996;82:1182-1187.  [PubMed]  [DOI]
194.  Tan P-H, Kuo J-H, Liu K, Hung C-C, Tsai TC, Deng TY. Efficacy of intrathecal neostigmine for the relief of postinguinal hemiorrhaphy pain. Acta Anaesthesiol Scand. 2000;44:1056-1060.  [PubMed]  [DOI]
195.  Tan PH, Chia YY, Lo Y, Liu K, Yang LC, Lee TH. Intrathecal bupivacaine with morphine or neostigmine for postoperative analgesia after total knee replacement surgery. Can J Anaesth. 2001;48:551-556.  [PubMed]  [DOI]
196.  Lauretti GR, de Oliveira R, Reis MP, Juliâo MC, Pereira NL. Study of three different doses of epidural neostigmine coadministered with lidocaine for postoperative analgesia. Anesthesiology. 1999;90:1534-1538.  [PubMed]  [DOI]
197.  Roelants F, Lavand’homme PM. Epidural neostigmine combined with sufentanil provides balanced and selective analgesia in early labor. Anesthesiology. 2004;101:439-444.  [PubMed]  [DOI]
198.  Omais M, Lauretti GR, Paccola CA. Epidural morphine and neostigmine for postoperative analgesia after orthopedic surgery. Anesth Analg. 2002;95:1698-1701, table of contents.  [PubMed]  [DOI]
199.  Bouaziz H, Paqueron X, Bur ML, Merle M, Laxenaire MC, Benhamou D. No enhancement of sensory and motor blockade by neostigmine added to mepivacaine axillary plexus block. Anesthesiology. 1999;91:78-83.  [PubMed]  [DOI]
200.  Werdehausen R, Braun S, Hermanns H, Kremer D, Küry P, Hollmann MW, Bauer I, Stevens MF. The influence of adjuvants used in regional anesthesia on lidocaine-induced neurotoxicity in vitro. Reg Anesth Pain Med. 2011;36:436-443.  [PubMed]  [DOI]
201.  Demirel E, Ugur HC, Dolgun H, Kahilogullari G, Sargon ME, Egemen N, Kecik Y. The neurotoxic effects of intrathecal midazolam and neostigmine in rabbits. Anaesth Intensive Care. 2006;34:218-223.  [PubMed]  [DOI]
202.  Yaksh TL, Grafe MR, Malkmus S, Rathbun ML, Eisenach JC. Studies on the safety of chronically administered intrathecal neostigmine methylsulfate in rats and dogs. Anesthesiology. 1995;82:412-427.  [PubMed]  [DOI]
203.  Hood DD, Eisenach JC, Tuttle R. Phase I safety assessment of intrathecal neostigmine methylsulfate in humans. Anesthesiology. 1995;82:331-343.  [PubMed]  [DOI]
204.  Weber WV, Jawalekar KS, Jawalekar SR. The effect of ketamine on nerve conduction in isolated sciatic nerves of the toad. Neurosci Lett. 1975;1:115-120.  [PubMed]  [DOI]
205.  Karpinski N, Dunn J, Hansen L, Masliah E. Subpial vacuolar myelopathy after intrathecal ketamine: report of a case. Pain. 1997;73:103-105.  [PubMed]  [DOI]
206.  Hawksworth C, Serpell M. Intrathecal anesthesia with ketamine. Reg Anesth Pain Med. 1998;23:283-288.  [PubMed]  [DOI]
207.  Islas JA, Astorga J, Laredo M. Epidural ketamine for control of postoperative pain. Anesth Analg. 1985;64:1161-1162.  [PubMed]  [DOI]
208.  Finck AD, Ngai SH. Opiate receptor mediation of ketamine analgesia. Anesthesiology. 1982;56:291-297.  [PubMed]  [DOI]
209.  Pekoe GM, Smith DJ. Ketamine analgesia. Mediation by biogenic amine and endogenous opiate processes. Anesthesiology. 1979;51:S36.  [PubMed]  [DOI]
210.  White PF, Way WL, Trevor AJ. Ketamine--its pharmacology and therapeutic uses. Anesthesiology. 1982;56:119-136.  [PubMed]  [DOI]
211.  Way WL, Trevor AJ. Pharmacology of intravenous non-narcotic anesthetics. Text book of Anesthesiology. New York: Churchill Livingstone 1986; 813-817.  [PubMed]  [DOI]
212.  Peat SJ, Bras P, Hanna MH. A double-blind comparison of epidural ketamine and diamorphine for postoperative analgesia. Anaesthesia. 1989;44:555-558.  [PubMed]  [DOI]
213.  Gantenbein M, Abat C, Attolini L, Pisano P, Emperaire N, Bruguerolle B. Ketamine effects on bupivacaine local anaesthetic activity and pharmacokinetics of bupivacaine in mice. Life Sci. 1997;61:2027-2033.  [PubMed]  [DOI]
214.  Kathirvel S, Sadhasivam S, Saxena A, Kannan TR, Ganjoo P. Effects of intrathecal ketamine added to bupivacaine for spinal anaesthesia. Anaesthesia. 2000;55:899-904.  [PubMed]  [DOI]
215.  Togal T, Demirbilek S, Koroglu A, Yapici E, Ersoy O. Effects of S(+) ketamine added to bupivacaine for spinal anaesthesia for prostate surgery in elderly patients. Eur J Anaesthesiol. 2004;21:193-197.  [PubMed]  [DOI]
216.  Yanli Y, Eren A. The effect of extradural ketamine on onset time and sensory block in extradural anaesthesia with bupivacaine. Anaesthesia. 1996;51:84-86.  [PubMed]  [DOI]
217.  Khezri MB, Ghasemi J, Mohammadi N. Evaluation of the analgesic effect of ketamine as an additive to intrathecal bupivacaine in patients undergoing cesarean section. Acta Anaesthesiol Taiwan. 2013;51:155-160.  [PubMed]  [DOI]
218.  Patel I, Ghandhi R, Shah A, Bhatt M, Suther A. Comparative study of bupivacaine vs bupivacaine and ketamine (intrathecally) during intraoperative and post-operative analgesia in non PIH cesarean section. Natl J Med Res. 2011;1:71-75.  [PubMed]  [DOI]
219.  Weir PS, Fee JP. Double-blind comparison of extradural block with three bupivacaine-ketamine mixtures in knee arthroplasty. Br J Anaesth. 1998;80:299-301.  [PubMed]  [DOI]
220.  Kamal MM, El-Fawy D. The effect of adding ketamine to bupivacaine in spinal anesthesia in day-case surgery. Ain-Shams J Anaesthesiol. 2014;7:530-533.  [PubMed]  [DOI]
221.  Nafiu OO, Kolawole IK, Salam RA, Elegbe EO. Comparison of caudal ketamine with or without bupivacaine in pediatric subumbilical surgery. J Natl Med Assoc. 2007;99:670-673.  [PubMed]  [DOI]
222.  Schnabel A, Poepping DM, Kranke P, Zahn PK, Pogatzki-Zahn EM. Efficacy and adverse effects of ketamine as an additive for paediatric caudal anaesthesia: a quantitative systematic review of randomized controlled trials. Br J Anaesth. 2011;107:601-611.  [PubMed]  [DOI]
223.  Bion JF. Intrathecal ketamine for war surgery. A preliminary study under field conditions. Anaesthesia. 1984;39:1023-1028.  [PubMed]  [DOI]
224.  Lee IO, Kim WK, Kong MH, Lee MK, Kim NS, Choi YS, Lim SH. No enhancement of sensory and motor blockade by ketamine added to ropivacaine interscalene brachial plexus blockade. Acta Anaesthesiol Scand. 2002;46:821-826.  [PubMed]  [DOI]
225.  Morrison AP, Hunter JM, Halpern SH, Banerjee A. Effect of intrathecal magnesium in the presence or absence of local anaesthetic with and without lipophilic opioids: a systematic review and meta-analysis. Br J Anaesth. 2013;110:702-712.  [PubMed]  [DOI]
226.  Xiao WH, Bennett GJ. Magnesium suppresses neuropathic pain responses in rats via a spinal site of action. Brain Res. 1994;666:168-172.  [PubMed]  [DOI]
227.  Kroin JS, McCarthy RJ, Von Roenn N, Schwab B, Tuman KJ, Ivankovich AD. Magnesium sulfate potentiates morphine antinociception at the spinal level. Anesth Analg. 2000;90:913-917.  [PubMed]  [DOI]
228.  Haubold HA, Meltzer SJ. Spinal anesthesia by magnesium sulfate. J Am Med Assoc. 1906;46:647-650.  [PubMed]  [DOI]
229.  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;95:661-666, table of contents.  [PubMed]  [DOI]
230.  Kogler J, Perić M, Hrabač P, Bekavac-MišAk V, Karaman-Ilić M. Effects of epidural magnesium sulphate on intraoperative sufentanil and postoperative analgesic requirements in thoracic surgery patients. Signa Vitae. 2016;11:56-73.  [PubMed]  [DOI]
231.  Gunduz A, Bilir A, Gulec S. Magnesium added to prilocaine prolongs the duration of axillary plexus block. Reg Anesth Pain Med. 2006;31:233-236.  [PubMed]  [DOI]
232.  Bilir A, Gulec S, Erkan A, Ozcelik A. Epidural magnesium reduces postoperative analgesic requirement. Br J Anaesth. 2007;98:519-523.  [PubMed]  [DOI]
233.  Hasanein R, El-sayed W, Khalil M. The value of epidural magnesium sulfate as an adjuvant to bupivacaine and fentanyl for labor analgesia. Egyptian Journal of Anaesthesia. 2013;219-224.  [PubMed]  [DOI]
234.  Abdelfatah AM, Elshaer AN. The effect of adding magnesium sulfate to lidocaine in an interscalene plexus block for shoulder arthroscopic acromioplasty. Ain-Shams J Anaesthesiol. 2014;7:59-64.  [PubMed]  [DOI]
235.  El Sayed AA. The effect of adding magnesium to bupivacaine for popliteal nerve block on anesthesia and postoperative analgesia in achilles tendon repair patients: a randomized double-blinded study. Ain-Shams J Anaesthesiol. 2016;9:409-415.  [PubMed]  [DOI]
236.  Khairnar P, Agarwal M, Verma UC, Kumar R. Comparative efficacy of ropivacaine and levobupivacaine in combined femoral and lateral femoral cutaneous nerve block with adjuvant magnesium for post-operative analgesia. Indian J Anaesth. 2016;60:584-589.  [PubMed]  [DOI]
237.  Mukherjee K, Das A, Basunia SR, Dutta S, Mandal P, Mukherjee A. Evaluation of Magnesium as an adjuvant in Ropivacaine-induced supraclavicular brachial plexus block: A prospective, double-blinded randomized controlled study. J Res Pharm Pract. 2014;3:123-129.  [PubMed]  [DOI]
238.  Goodman EJ, Haas AJ, Kantor GS. Inadvertent administration of magnesium sulfate through the epidural catheter: report and analysis of a drug error. Int J Obstet Anesth. 2006;15:63-67.  [PubMed]  [DOI]
239.  Dror A, Henriksen E. Accidental epidural magnesium sulfate injection. Anesth Analg. 1987;66:1020-1021.  [PubMed]  [DOI]
240.  Saeki H, Matsumoto M, Kaneko S, Tsuruta S, Cui YJ, Ohtake K, Ishida K, Sakabe T. Is intrathecal magnesium sulfate safe and protective against ischemic spinal cord injury in rabbits? Anesth Analg. 2004;99:1805-1812, table of contents.  [PubMed]  [DOI]
241.  Levent O, Handan S, Dilsen O, Aysun P, Taner A, Bayazit D. Neurotoxic effects of intrathecal magnesium sulphate. Rev Bras Anestesiol. 2013;63:144-148.  [PubMed]  [DOI]
242.  Chanimov M, Cohen ML, Grinspun Y, Herbert M, Reif R, Kaufman I, Bahar M. Neurotoxicity after spinal anaesthesia induced by serial intrathecal injections of magnesium sulphate. An experimental study in a rat model. Anaesthesia. 1997;52:223-228.  [PubMed]  [DOI]
243.  Simpson JI, Eide TR, Schiff GA, Clagnaz JF, Hossain I, Tverskoy A, Koski G. Intrathecal magnesium sulfate protects the spinal cord from ischemic injury during thoracic aortic cross-clamping. Anesthesiology. 1994;81:1493-1499; discussion 26A-27A.  [PubMed]  [DOI]
244.  Shulman M, Lubenow TR, Nath HA, Blazek W, McCarthy RJ, Ivankovich AD. Nerve blocks with 5% butamben suspension for the treatment of chronic pain syndromes. Reg Anesth Pain Med. 1998;23:395-401.  [PubMed]  [DOI]
245.  Shulman M, Harris JE, Lubenow TR, Nath HA, Ivankovich AD. Comparison of epidural butamben to celiac plexus neurolytic block for the treatment of the pain of pancreatic cancer. Clin J Pain. 2000;16:304-309.  [PubMed]  [DOI]
246.  Korsten HH, Ackerman EW, Grouls RJ, van Zundert AA, Boon WF, Bal F, Crommelin MA, Ribot JG, Hoefsloot F, Slooff JL. Long-lasting epidural sensory blockade by n-butyl-p-aminobenzoate in the terminally ill intractable cancer pain patient. Anesthesiology. 1991;75:950-960.  [PubMed]  [DOI]
247.  Van den Berg RJ, Wang Z, Grouls RJ, Korsten HH. The local anesthetic, n-butyl-p-aminobenzoate, reduces rat sensory neuron excitability by differential actions on fast and slow Na+ current components. Eur J Pharmacol. 1996;316:87-95.  [PubMed]  [DOI]
248.  Gerner P, Nakamura T, Quan CF, Anthony DC, Wang GK. Spinal tonicaine: potency and differential blockade of sensory and motor functions. Anesthesiology. 2000;92:1350-1360.  [PubMed]  [DOI]
249.  Wang GK, Quan C, Vladimirov M, Mok WM, Thalhammer JG. Quaternary ammonium derivative of lidocaine as a long-acting local anesthetic. Anesthesiology. 1995;83:1293-1301.  [PubMed]  [DOI]
250.  Khan MA, Gerner P, Sudoh Y, Wang GK. Use of a charged lidocaine derivative, tonicaine, for prolonged infiltration anesthesia. Reg Anesth Pain Med. 2002;27:173-179.  [PubMed]  [DOI]
251.  Wang GK, Vladimirov M, Quan C, Mok WM, Thalhammer JG, Anthony DC. N-butyl tetracaine as a neurolytic agent for ultralong sciatic nerve block. Anesthesiology. 1996;85:1386-1394.  [PubMed]  [DOI]
252.  Mashimo T, Uchida I, Pak M, Shibata A, Nishimura S, Inagaki Y, Yoshiya I. Prolongation of canine epidural anesthesia by liposome encapsulation of lidocaine. Anesth Analg. 1992;74:827-834.  [PubMed]  [DOI]
253.  Grant GJ, Piskoun B, Bansinath M. Analgesic duration and kinetics of liposomal bupivacaine after subcutaneous injection in mice. Clin Exp Pharmacol Physiol. 2003;30:966-968.  [PubMed]  [DOI]
254.  de Araujo DR, Cereda CM, Brunetto GB, Pinto LM, Santana MH, de Paula E. Encapsulation of mepivacaine prolongs the analgesia provided by sciatic nerve blockade in mice. Can J Anaesth. 2004;51:566-572.  [PubMed]  [DOI]
255.  Gesztes A, Mezei M. Topical anesthesia of the skin by liposome-encapsulated tetracaine. Anesth Analg. 1988;67:1079-1081.  [PubMed]  [DOI]
256.  Franz-Montan M, Silva AL, Cogo K, Bergamaschi Cde C, Volpato MC, Ranali J, de Paula E, Groppo FC. Liposome-encapsulated ropivacaine for topical anesthesia of human oral mucosa. Anesth Analg. 2007;104:1528-1531, table of contents.  [PubMed]  [DOI]
257.  Gambling D, Hughes T, Martin G, Horton W, Manvelian G. A comparison of Depodur, a novel, single-dose extended-release epidural morphine, with standard epidural morphine for pain relief after lower abdominal surgery. Anesth Analg. 2005;100:1065-1074.  [PubMed]  [DOI]
258.  Viscusi ER, Martin G, Hartrick CT, Singla N, Manvelian G; EREM Study Group. Forty-eight hours of postoperative pain relief after total hip arthroplasty with a novel, extended-release epidural morphine formulation. Anesthesiology. 2005;102:1014-1022.  [PubMed]  [DOI]
259.  Carvalho B, Riley E, Cohen SE, Gambling D, Palmer C, Huffnagle HJ, Polley L, Muir H, Segal S, Lihou C. Single-dose, sustained-release epidural morphine in the management of postoperative pain after elective cesarean delivery: results of a multicenter randomized controlled study. Anesth Analg. 2005;100:1150-1158.  [PubMed]  [DOI]
260.  Grant SA. The Holy Grail: long-acting local anaesthetics and liposomes. Best Pract Res Clin Anaesthesiol. 2002;16:345-352.  [PubMed]  [DOI]
261.  Karashima K, Taniguchi M, Nakamura T, Takasaki M, Matsuo K, Irikura M, Irie T. Prolongation of intrathecal and sciatic nerve blocks using a complex of levobupivacaine with maltosyl-beta-cyclodextrin in rats. Anesth Analg. 2007;104:1121-1128, tables of contents.  [PubMed]  [DOI]
262.  Dräger C, Benziger D, Gao F, Berde CB. Prolonged intercostal nerve blockade in sheep using controlled-release of bupivacaine and dexamethasone from polymer microspheres. Anesthesiology. 1998;89:969-979.  [PubMed]  [DOI]
263.  Curley J, Castillo J, Hotz J, Uezono M, Hernandez S, Lim JO, Tigner J, Chasin M, Langer R, Berde C. Prolonged regional nerve blockade. Injectable biodegradable bupivacaine/polyester microspheres. Anesthesiology. 1996;84:1401-1410.  [PubMed]  [DOI]
264.  Pedersen JL, Lillesø J, Hammer NA, Werner MU, Holte K, Lacouture PG, Kehlet H. Bupivacaine in microcapsules prolongs analgesia after subcutaneous infiltration in humans: a dose-finding study. Anesth Analg. 2004;99:912-918, table of contents.  [PubMed]  [DOI]
265.  Reeve AJ, Dickenson AH. The roles of spinal adenosine receptors in the control of acute and more persistent nociceptive responses of dorsal horn neurones in the anaesthetized rat. Br J Pharmacol. 1995;116:2221-2228.  [PubMed]  [DOI]
266.  Cronstein BN. Adenosine, an endogenous anti-inflammatory agent. J Appl Physiol (1985). 1994;76:5-13.  [PubMed]  [DOI]
267.  Rane K, Karlsten R, Sollevi A, Gordh T Jr, Svensson BA. Spinal cord morphology after chronic intrathecal administration of adenosine in the rat. Acta Anaesthesiol Scand. 1999;43:1035-1040.  [PubMed]  [DOI]
268.  Rane K, Sollevi A, Segerdahl M. Intrathecal adenosine administration in abdominal hysterectomy lacks analgesic effect. Acta Anaesthesiol Scand. 2000;44:868-872.  [PubMed]  [DOI]
269.  Sharma M, Mohta M, Chawla R. Efficacy of intrathecal adenosine for postoperative pain relief. Eur J Anaesthesiol. 2006;23:449-453.  [PubMed]  [DOI]
270.  Apan A, Basar H, Ozcan S, Buyukkocak U. Combination of adenosine with prilocaine and lignocaine for brachial plexus block does not prolong postoperative analgesia. Anaesth Intensive Care. 2003;31:648-652.  [PubMed]  [DOI]
271.  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. Acta Pharmacol Toxicol (Copenh). 1978;42:88-92.  [PubMed]  [DOI]
272.  Covino BG. Pharmacology of local anaesthetic agents. Br J Anaesth. 1986;58:701-716.  [PubMed]  [DOI]
273.  Kaplan JA, Miller ED Jr, gallagher EG Jr. Postoperative analgesia for thoracotomy patients. Anesth Analg. 1975;54:773-777.  [PubMed]  [DOI]
274.  Simpson PJ, Hughes DR, Long DH. Prolonged local analgesia for inguinal herniorrhaphy with bupivacaine and dextran. Ann R Coll Surg Engl. 1982;64:243-246.  [PubMed]  [DOI]
275.  Armstrong DN, Kingsnorth AN. Local anaesthesia in inguinal herniorrhaphy: influence of dextran and saline solutions on duration of action of bupivacaine. Ann R Coll Surg Engl. 1986;68:207-208.  [PubMed]  [DOI]
276.  Kingsnorth AN, Wijesinha SS, Grixti CJ. Evaluation of dextran with local anaesthesia for short-stay inguinal herniorraphy. Ann R Coll Surg Engl. 1979;61:456-458.  [PubMed]  [DOI]
277.  Reah G, Bodenham AR, Braithwaite P, Esmond J, Menage MJ. Peribulbar anaesthesia using a mixture of local anaesthetic and vecuronium. Anaesthesia. 1998;53:551-554.  [PubMed]  [DOI]
278.  Küçükyavuz Z, Arici MK. Effects of atracurium added to local anesthetics on akinesia in peribulbar block. Reg Anesth Pain Med. 2002;27:487-490.  [PubMed]  [DOI]
279.  Elhakim M, Sadek RA. Addition of atracurium to lidocaine for intravenous regional anaesthesia. Acta Anaesthesiol Scand. 1994;38:542-544.  [PubMed]  [DOI]
280.  Esmaoglu A, Akin A, Mizrak A, Turk Y, Boyaci A. Addition of cisatracurium to lidocaine for intravenous regional anesthesia. J Clin Anesth. 2006;18:194-197.  [PubMed]  [DOI]
281.  McGlone R, Heyes F, Harris P. The use of muscle relaxant to supplement local anaesthetics for Bier’s blocks. Arch Emerg Med. 1988;5:79-85.  [PubMed]  [DOI]
282.  Torrance JM, Lewer BM, Galletly DC. Low-dose mivacurium supplementation of prilocaine i.v. regional anaesthesia. Br J Anaesth. 1997;78:222-223.  [PubMed]  [DOI]