Adjuvants to local anesthetics: Current understanding and future trends

Table 1 Summary of the commonly used local anaesthetic adjuvants

Name of drug	Routes and dosages	Adverse effects	Recommendations for use	Mechanism of action
Morphine[12,22]	Intrathecal: 100-200 μg	Pruritus	Useful in neuraxial blocks
	Epidural: 1-5 mg	Nausea vomiting	Not recommended for peripheral nerve blocks
	Peripheral nerve block: 75-100 μg/kg	Respiratory failure
Fentanyl[23-26,30-35]	Intrathecal: 10-25 μg	Same adverse effects as morphine	Useful in neuraxial blocks
	Epidural: 2-4 μg/mL	Adverse effect profile slightly favourable in neuraxial use	Not recommended in neuraxial blocks due to inconsistent results
	Peripheral nerve block	Increased sedation, bradycardia and hypotension		Spinal opioid receptor
Sufentanyl[36-40]	Intrathecal: 1.5-5 μg		Efficacious in neuraxial blocks	Local action in peripheral nerve blocks
	Epidural: 0.75-1.0 μg/mL
	Not used in peripheral nerve blocks
Hydromorphone[41-44]	Intrathecal: 100 μg	Better adverse effect profile than Morphine	Useful in neuraxial blocks
	Epidural: 500-600 μg
	Not used in peripheral nerve blocks
Buprenorphine[5,45-48]	Intrathecal: 75-150 μg		Good efficacy in neuraxial and peripheral nerve block routes
	Epidural: 150-300 μg
	Peripheral nerve block: 300 μg
Tramadol[49-72]	Intrathecal: 10-50 mg	Nausea and vomiting	Present evidence supports use in epidural infusions	Weak opioid agonist actions
	Epidural: 1-2 mg/kg		Poor evidence in peripheral nerve block studies	Sodium/potassium channel blocking actions
	Peripheral nerve block: 1-5 mg/kg			Blockade of norepinephrine and serotonin uptake
Clonidine[89-121]	Intrathecal: 15-40 μg	Sedation	Good quality evidence to support use in neuraxial blocks especially at lower dosages	Activation of post junctional alpha-2 receptors in dorsal horn of spinal cord
	Epidural: 25-50 μg	Bradycardia	In 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)	Hypertension	Additional benefit in Alcohol withdrawal
		Adverse effects show association with dose
Dexmeditomidine[122-147]	Intrathecal: 5-10 μg	Sedation	Prolongation of neuraxial and peripheral nerve blocks with good efficacy of use	Mechanism similar to Clonidine
	Epidural: 1 μg/kg	Bradycardia
	Peripheral nerve block: 20-150 μg	Hypertension
		Adverse effects show association with dose
Dexamethasone[148-161]	Intrathecal: 8 mg	Adverse effects minimal	Efficacious in neuraxial blocks, however better studies required	Local action on nerve fibers
	Epidural: 4-8 mg	Advantageous to prevent ponv	Prolongs nerve blockade in PNB
	Peripheral nerve block: 1-8 mg	Troublesome paresthesias with PNB use
Midazolam[164-184]	Intrathecal: 1-2.5 mg	Sedation	Neurotoxicity is a major concern in neuraxial and peripheral nerve routes	GABAergic and opioid receptor mechanisms
	Epidural: 50 μg/kg diluted in 10 mL of saline	Respiratory depression	Not recommended for routine neuraxial and PNB use
Neostigmine[185-202]	Intrathecal: 5-10 μg to 50-150 μg	Neuraxial use associated with bradycardia, restlessness	Lower dosages recommended for neuraxial use	Enhancement of endogenous acetylcholine at nerve terminal
	Epidural: 1, 2 and 4 μg	PNB use associated with gastrointestinal adverse effects	Not recommended for PNB use (neurotoxicity in animal models)
	Peripheral nerve block-not investigated
Ketamine[203-223]		Neuraxial use associated with nausea, vomiting and hallucinations	Neuraxial use-shortens onset and duration of anesthesia	NMDA receptor antagonists shown to have local anesthetic properties
		PNB use associated with psychomimetic sequelae	Not recommended for PNB use	Cholinergic, adrenergic and 5HT mechanisms
Magnesium[224-238]	Intrathecal: 25-100 mg	Headache	Prolongs analgesia and quality of block by all perineural routes	NMDA receptor antagonism
	Epidural: 50-100 mg	Cardiovascular disturbances	However more studies required to determine minimal effective doses	Voltage gated calcium channel blockade
		Nausea vomiting	Not recommended for routine use

PNB: Peripheral nerve block; NMDA: N-methyl-D-aspartate; 5HT: % hydroxyl-tryptamine.