Antinociceptive Agents as General Anesthetic Adjuncts: Supra-additive and Infra-additive Interactions

Abstract

The hypothesis “General anesthesia consists of producing both loss of consciousness and the inhibition of noxious stimuli reaching the brain and causing arousal” was used as a basis for the review of published data on general anesthetic interactions with antinociceptive agents: opioids, α2 adrenergic agonists, and systemic sodium channel blockers. This review is focused on a specific type of anesthetic interaction—the transformation of antinociceptive agents into general anesthetic adjuncts. The primary aim is to answer 2 questions. First, how does an antinociceptive agent transform the effect of an anesthetic in providing a certain component of anesthesia—hypnosis, immobility, or hemodynamic response to noxious stimulation? Second, does a combination of an anesthetic with an adjunct result in a simple summation of their respective effects or in a supra-additive or infra-additive interaction? The Medline database was searched for data describing the interactions of antinociceptive agents and general anesthetics. The following classes of antinociceptive agents were considered: opioids, α2 adrenergic agonists, and systemic sodium channel blockers. Drugs used in combination with antinociceptive agents were general anesthetics and benzodiazepines. The following terms related to drug interactions were used: anesthetic interactions, synergy, antagonism, isobolographic analysis, response surface analysis, and fractional analysis. The interactions of antinociceptive agents with general anesthetics result in a decrease of general anesthetic requirements, which differ for each of the components of general anesthesia: hypnosis, immobility, and hemodynamic response to noxious stimulation. Most studies of the nature of anesthetic interactions are related to opioid–general anesthetic combinations, and their conclusions usually confirm supra-additivity.

Dexmedetomidine Sedation in Dogs: Impact on Electroencephalography, Behavior, Analgesia, and Antagonism with Atipamezole

“…It has been shown that dexmedetomidine administered through CRI at doses of 0.5, 1, and 3 µg/kg/hour has antinociceptive effects when used concurrently with isoflurane and other general-anesthetic drugs [ 29 , 30 ]. A recent comprehensive review [ 31 ], encompassing both human and animal (rat) studies, highlighted the challenges associated with assessing changes in the requirements of coadministered inhaled anesthetics in the presence of alpha-2 adrenergic agonists such as clonidine and dexmedetomidine. These challenges arise from the intricate interplay between their hypnotic and antinociceptive activities [ 31 ].…”

“…A recent comprehensive review [ 31 ], encompassing both human and animal (rat) studies, highlighted the challenges associated with assessing changes in the requirements of coadministered inhaled anesthetics in the presence of alpha-2 adrenergic agonists such as clonidine and dexmedetomidine. These challenges arise from the intricate interplay between their hypnotic and antinociceptive activities [ 31 ]. The complexity is further compounded when these alpha 2 adrenergic agents are administered alone, making it challenging to achieve their target analgesic effects [ 31 ], as observed in the current study.…”

“…These challenges arise from the intricate interplay between their hypnotic and antinociceptive activities [ 31 ]. The complexity is further compounded when these alpha 2 adrenergic agents are administered alone, making it challenging to achieve their target analgesic effects [ 31 ], as observed in the current study.…”

“…This outcome underscores the premise that dexmedetomidine CRI alone, at the given dosage, produces a minimal analgesic effect. Particularly noteworthy is the understanding that true analgesia involves antinociceptive/analgesic activity which significantly contributes to the state of anesthesia/sedation by preventing nociceptive-induced arousal [ 31 ]. This emphasizes the sedative nature of dexmedetomidine and prompts reflection on its role as an anesthetic adjunct.…”

Isobolographic analysis of interactions – a pre-clinical perspective

“…The IA is a universal method in interaction analysis that can be applied in both clinical and preclinical studies, especially if the tested drugs exerted some measurable effects. At present, the IA is widely used for analysis of interactions between anticancer drugs [18-21], antiseizure medications [22-25], ototoxic drugs [26, 27], antibiotics, and antmicrobial drugs [28,29], and when evaluating the antinociceptive activity of the drugs [30][31][32][33][34][35]. Quite recently, a large-scale and fully automatic IA has been incorporated into in vitro studies for assessing the interactions between anti-cancer drugs and various radiosensitizers to accelerate the discovery of anticancer drugs [36].…”