Determining the Plasma Concentration of Ketamine That Enhances Epidural Bupivacaine-and-Morphine-Induced Analgesia

Abstract

N-methyl-D-aspartate (NMDA) receptor antagonists enhance opioid-induced analgesia. The plasma concentration of ketamine, an NMDA receptor antagonist that enhances epidural morphine-and-bupivacaine-induced analgesia, is not known. We examined 24 patients with lung carcinoma or metastatic lung tumor who underwent video-assisted thoracic surgery in a placebo-controlled, double-blind manner 4 h after emergence from anesthesia. The morphine + ketamine group (n = 8) and morphine + placebo group (n = 8) received 5 mL volume of 2.5 mg morphine and 0.25% bupivacaine and the placebo + ketamine group (n = 8) received 5 mL volume of saline and 0.25% bupivacaine epidurally at the end of skin closure. Four hours after this anesthesia, in the morphine + ketamine and placebo + ketamine groups, ketamine was administered to successively maintain a stable plasma ketamine concentration of 0, 10, 20, 30, 40, and 50 ng/mL by a target-controlled infusion device, and patients assessed the levels of pain at rest, pain on coughing, somnolence (drowsiness), and nausea using a 100-mm visual analog scale (VAS). In the morphine + placebo group, a placebo (saline) was similarly administered instead of ketamine. In the morphine + ketamine group, the VAS scores for pain at rest and pain on coughing significantly decreased on ketamine administration at a plasma concentration of 20 ng/mL or larger compared with the respective baseline VAS scores (P < 0.05 each). In the placebo + ketamine group, the VAS scores for pain at rest and pain on coughing did not significantly change at any plasma concentration of ketamine as compared to the morphine + placebo group. In the morphine + ketamine group, a plasma concentration of ketamine larger than 20 ng/mL did not further reduce VAS scores for pain at rest and pain on coughing. The VAS scores for drowsiness were comparable among the three groups at any plasma concentration of ketamine. Ketamine at a plasma concentration of 20 ng/mL or larger may enhance epidural morphine-and-bupivacaine-induced analgesia. As an adjunct with epidural morphine-and-bupivacaine and considering the safety of small doses, the minimal plasma concentration of ketamine given IV may be approximately 20 ng/mL.

Low concentrations of ketamine initiate dendritic atrophy of differentiated GABAergic neurons in culture

“…Whereas anaesthesia-inducing plasma concentrations of ketamine in humans have been reported to be above 1 g/ml (Malinovsky et al, 1996;Weber et al, 2004), adequate pain relief-associated plasma levels of this anesthetics are several fold lower, situating around 20 ng/ml (Suzuki et al, 2005). Although it is ethically impossible to determine blood-brain distribution coefficient of ketamine in humans, based on experimental studies of ketamine pharmacokinetics (Edwards et al, 2002), it is thus strongly possible, as discussed above, that plasma concentrations of 20 ng/ml of ketamine result in several fold higher brain concentrations.…”

Opioid Tolerance Development: A Pharmacokinetic/Pharmacodynamic Perspective

“…The majority of studies characterized the NMDA receptor antagonists as enhancing or having no effect on analgesia, whereas a minority demonstrated attenuation of acute morphine analgesia (88)(89)(90)(91)(92)(93). One challenge in this area is the absence of consistent results identifying which opioids exhibit NMDA receptor antagonist-enhanced antinociception.…”

Morphine and MK-801 administration leads to alternative N-methyl-d-aspartate receptor 1 splicing and associated changes in reward seeking behavior and nociception on an operant orofacial assay

“…Indeed, clinical studies have demonstrated that NMDAR antagonists do not alter opioid tolerance in humans (Compton et al, 2008;Galer et al, 2005). Part of the confusion may stem from the fact that NMDAR antagonists like ketamine have been demonstrated to have an additive effect on opioid analgesia (Suzuki et al, 2005;Wadhwa et al, 2001;Weinbroum et al, 2002;Wiesenfeld-Hallin, 1998) which may have an effect on the reflex-based measures of antinociception in animal studies (Carlezon et al, 2000). In order to determine if attenuated tolerance is an artifact of reflex-based measures, we investigated the effects of the NMDAR antagonist MK-801 on morphine tolerance in a non-reflex based operant orofacial thermal pain assay.…”