Adjuvants to local anesthetics: A combination wisdom

Sir,

Adjuvants are those drugs which, when co-administered with local anesthetic agents, may improve the speed of onset and duration of analgesia and counteract disadvantageous effects of local anesthetics. By adding these adjuvants, the dose of local anesthetics like bupivacaine can be reduced, thereby reducing its side effects like myocardial depression, hypotension, bradycardia, heart block, and ventricular arrhythmias. Based on “Combination Wisdom”, the use of adjuvants to local anesthetics has been promoted a lot.

A wide variety of drugs have been used for both neuraxial and peripheral nerve blocks. It is broadly divided into non-opioids and opioids, with non-opiods being epinephrine, α₂-adrenoceptor agonists (clonidine and dexmedetomidine), acetylcholine esterase inhibitors (neostigmine), adenosine, ketorolac, midazolam, magnesium, sodium bicarbonate and hyaluronidase, and opiods being lipophilic (fentanyl and sufentanyl) and hydrophilic (morphine).

Alpha₂-adrenergic agonists like clonidine have expanded the horizons of regional anesthesia. Co-administration of clonidine and local anesthetics epidurally has been used in abdominal surgeries, total knee replacement surgeries,[1,2] labor analgesia, chronic pain and cancer pain treatment.

Alpha₂-adrenoceptors are located on primary afferents of both peripheral and spinal nerve endings, on the superficial laminae of the spinal cord, and within several brainstem nuclei implicating analgesic action at peripheral, spinal, and brainstem sites in animals.[3] But evidence supports only a spinal action of clonidine in producing analgesia in humans. Clonidine also produces a minor degree of nerve conduction blockade (C-fibers) at high concentrations[4] and hence the enhancement of peripheral nerve block when added to local anesthetics.

The right balance of the drug components in combination administered through epidural route is a challenge. A single lumbar epidural bolus injection of clonidine produces analgesia in the lower, but not upper extremity, in contrast to continuous epidural infusion of clonidine for 4 hours, suggesting more extensive dermatomal distribution of analgesia with continuous infusion.[5] Epidural local anesthetics, when administered at a lumbar level, frequently cause motor blockade preventing patient's mobilization, which is important to avoid postoperative complications such as thromboembolism. Moreover, it may mask complications like epidural hematoma. Adding clonidine to bupivacaine reduces the concentration of local anesthetic agent to be administered through epidural route, thereby reducing the incidence of motor block. However, this practice may also increase side effects like hypotension caused by interaction of clonidine with bupivacaine.[6]

Doses as high as 100–150 μg/hour are required when clonidine was used alone for continuous epidural analgesia,[7] but such high doses can cause hypotension, bradycardia, and sedation. In combination with either opioids or local anesthetics, epidural clonidine has been used in single bolus dose of 75–800 μg or continuous infusion dosage of 20–50 μg/hour[8] which too can cause such side effects. Epidural clonidine and fentanyl interact in an additive or only mildly synergistic manner after bolus administration in humans.[3] Duration of analgesia ranges from 2 to 6 hours, which is similar to lipid soluble opioids but briefer than morphine; however, there is no increase in duration beyond a dose of 400 μg.[9]

Side effects commonly observed after epidural clonidine in postoperative patients are hypotension, bradycardia, sedation, and dry mouth. Clonidine produces sympatholysis and reduced blood pressure by its actions in the periphery, brainstem, and spinal cord, which is opposed by direct vasoconstriction from alpha₂-adrenergic agonists in the periphery. Epidural clonidine reduces blood pressure more when injected in the upper thoracic than in the cervical, lower thoracic or lumbar space because of direct inhibition of sympathetic preganglionic neurons in the upper thoracic dermatomes which supply the heart.

Sedation is a side effect frequently associated with the use of clonidine in postoperative analgesia, often in conjunction with opioids. Sedation after epidural administration of clonidine occurs because of systemic absorption and vascular redistribution to higher centers. Regardless of route of administration, clonidine produces dose-dependent sedation over the dose range 50–900 μg. After a large epidural bolus dose (700 μg), sedation is intense for 4–6 hours.[3] Clonidine does not produce respiratory depression like opiods but a few sporadic reports are there.[10] Blood pressure and heart rate should be monitored for at least 2 hours after bolus clonidine injection, and pulse oximetry should be considered if large boluses (>300 μg) of clonidine are to be administered.[3]

Clonidine is more potent after neuraxial than systemic administration because of spinal site of action favoring its neuraxial administration. Bernard and colleagues[11] demonstrated that clonidine is twice as potent epidurally as compared to intravenously. Epidural clonidine is a much promoted adjuvant when opiods use has to be avoided, in pain syndromes poorly responsive to opioids, and in neuropathic or sympathetically mediated pain. Newer and more specific alpha₂-adrenergic agonist, dexmedetomidine, has also been used as an epidural adjuvant and will soon gain popularity.

Over the last two decades, there has been considerable revival of interest in the use of regional anesthesia techniques for surgery and pain management. In order to counterbalance the side effects of subarachnoid block and epidural, new adjuvants to local anesthetics keep on adding to the list. Combination allows for a reduction in doses of both classes of drugs, thus lessening the likelihood of side effects attributable to each. The adjuvants added to local anesthetics “Combination Wisdom”, have brought a new era to the regional anesthesia.