Aida, S., T.Yamakura, et al., Anesthesiology 2000; 92 (6): 1624-30.

Reviewed by: R. Coombs, M.D.

Introduction: Sensory neurons at the brain level are more sensitive to peripheral inputs after activation of C fibers by a noxious stimuli, a process called central sensitization. Sensory neurons at the spinal cord level also become more sensitive to peripheral inputs after repeated stimulation of C fibers, a mechanism referred to as wind up. "Low-dose" epidural morphine exerts its effects at the spinal cord level with little or no central effects. "Low-dose" ketamine blocks NMDA receptor activation in the brain, and has no effect on spinal cord neurons. Epidural morphine and intravenous ketamine have both been given at the beginning and during a variety of surgical procedures as preemptive analgesics in an attempt to lower postoperative pain and decrease the amount of analgesic medications required to control pain in the postoperative period. Neither has been shown to be reliably successful as a preemptive analgesic. This study attempts to see if blocking both central and spinal cord sites during gastrectomy can lead to effective preemptive analgesia.

Study: All patients had an epidural placed at the T8-T9 level prior to surgery. All patients were anesthetized with Sevoflurane 1-2% in 70% Nitrous Oxide and 30% Oxygen. The patients were divided into four groups:

Group 1 – Epidural Morphine and IV Saline

Group 2 – Epidural Saline and IV Ketamine

Group 3 – Epidural Morphine and IV Ketamine

Group 4 – Epidural Saline and IV Saline

Epidural morphine was given as a bolus of .06mg./kg. 40 minutes prior to skin incision, then .02mg./kg./hr. as a continuous infusion. Ketamine was given as a bolus 1mg./kg. 10 minutes prior to skin incision, then .5mg./kg./hr. as a continuous infusion until closure. Postsurgical pain management and pain assessment was performed by a blinded observer. All patients were put on an epidural PCA with a unit dose of 0.2mg. morphine and a 15-minute lockout. There was no background infusion and no maximum dose. The cumulative dose of morphine was measured at 6, 12, 24, and 48 hours. No other analgesics were given. A blinded physician assessed spontaneous postsurgical pain intensity at rest using a visual analog scale (VAS) at 6, 12, 24, and 48 hours. Pain during movement was assessed by the VAS at 12 hours only.

Results: All patients recovered awareness within 20 minutes after skin closure and patients could use the PCA freely from this point.

-The epidural morphine group had significant reduction in postsurgical VAS scores at 24 and 48 hours. Morphine consumption in this group was significantly lower than that in the control group at 6, 12, 24, and 48 hours.

-The ketamine group VAS scores were lower than controls at 6, 12, 24, and 48 hours, and cumulative dose was lower than the control group at 6, 12, 24, and 48 hours.

-In the combination group, which received both morphine and ketamine before and during surgery, preemptive analgesia was definitive. VAS scores at rest and cumulative morphine dose were significantly the best among all groups at every time point observed.

-Assessment of pain during movement at 12 hours showed similar results. The morphine and ketamine groups both had lower morphine requirements and lower VAS scores, but the combination of morphine and ketamine again provided the greatest preemptive analgesic effect.

Comments: Studies on preemptive analgesia for lower extremity orthopedic procedures have shown definitive preemptive analgesic effects for morphine alone. Pain sensations from the lower extremities travel via spinal nerves only. The visceroperitoneal organs are innervated by the spinal nerves (T5 – T12), the vagus nerve, and phrenic nerve (C3 – C5) in the upper abdomen. All these nerves are closely associated with visceroperitoneal nociception. In upper abdominal surgery, multiple blockades of afferent nociception may be necessary for definitive analgesia.

Aftereffects of ketamine in this study appeared minimal because patients recovered awareness in 20 minutes and were able to complete the VAS at 6 hours without problem. At the dosage given in this study, a 70 kg. patient undergoing a 3-hour gastrectomy would have received an initial 70 mg. of ketamine before skin incision and a total infusion dose of 105 mg. for a total dose of 175 mg. Should we be infusing "low-dose" ketamine in combination with our epidurals for intra-abdominal surgeries? Would the fact that we usually use local anesthetics in addition to morphine in our epidurals make a difference in preemptive analgesic effects?