Background: Remifentanil-induced secondary hyperalgesia has been documented experimentally in both animals and healthy human volunteers, but never clinically. This study tested the hypotheses that increased pain sensitivity assessed by periincisional allodynia and hyperalgesia can occur after relatively large-dose intraoperative remifentanil and that smalldose ketamine prevents this hyperalgesia. Methods: Seventy-five patients undergoing major abdominal surgery were randomly assigned to receive (1) intraoperative remifentanil at 0.05 g kg 1 min 1 (small-dose remifentanil); (2) intraoperative remifentanil at 0.40 g kg 1 min 1 (largedose remifentanil); or (3) intraoperative remifentanil at 0.40 g kg 1 min 1 and 0.5 mg/kg ketamine just after the induction, followed by an intraoperative infusion of 5 g kg 1 min 1 until skin closure and then 2 g kg 1 min 1 for 48 h (large-dose remifentanil‐ketamine). Pain scores and morphine consumption were recorded for 48 postoperative hours. Quantitative sensory tests, peak expiratory flow measures, and cognitive tests were performed at 24 and 48 h. Results: Hyperalgesia to von Frey hair stimulation adjacent to the surgical wound and morphine requirements were larger (P < 0.05) and allodynia to von Frey hair stimulation was greater (P < 0.01) in the large-dose remifentanil group compared with the other two groups, which were comparable. There were no significant differences in pain, pressure pain detection threshold with an algometer, peak flow, cognitive tests, or side effects. Conclusion: A relatively large dose of intraoperative remifentanil triggers postoperative secondary hyperalgesia. Remifentanil-induced hyperalgesia was prevented by small-dose ketamine, implicating an N-methyl-D-aspartate pain-facilitator process.

Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine

We compared the effects of coadministration of propofol and small-dose ketamine to propofol alone on respiration during monitored anesthesia care. In addition, mood, perception, and cognition in the recovery room, and pain after discharge were evaluated. In the Propofol group (n = 20), patients received propofol 38 +/- 24 microg x kg(-1) x min(-1). The Coadministration group (n = 19) received propofol 33 +/- 13 microg x kg(-1) x min(-1) and ketamine 3.7 +/- 1.5 microg x kg(-1) x min(-1). Respiration was assessed by using end-expiratory PCO(2) measurements at nasal prongs. After surgeries, mood, perception, and thought were assessed by using visual analog scales, and cognition was assessed by Mini-Mental State Examination (MMSE). Pain after discharge was assessed by a five-point rating scale in the evening for 5 days. End-expiratory PCO(2) was lower in the Coadministration group (P < 0.0001). Mood and MMSE scores were higher in the Coadministration group (P < 0.004 and P = 0.001, respectively). Pain scores and analgesic consumption after discharge were less in the Coadministration group (P = 0.0004 and P < 0.0001, respectively). We conclude that coadministration of small-dose ketamine attenuates propofol-induced hypoventilation, produces positive mood effects without perceptual changes after surgery, and may provide earlier recovery of cognition.

http://ether.stanford.edu/asc1/documents/mac.pdf

The effects of small-dose ketamine on propofol sedation: respiration, postoperative mood, perception, cognition, and pain.

Adding a small dose of ketamine to opioids may increase the analgesic effect and prevent opioid-induced hyperalgesia and acute tolerance to opioids. In this randomized, double-blinded, placebo-controlled crossover study, we investigated the effect of remifentanil combined with small concentrations o

Modulation of remifentanil-induced analgesia, hyperalgesia, and tolerance by small-dose ketamine in humans.

assigned to receive, during the postoperative period, either i.v. morphine 1 mg ml 21 or morphine with ketamine 1 mg ml 21 for each. Morphine consumption was evaluated by cumulative doses every 12 h for the three postoperative days. Postoperative respiratory disorders were assessed by spirometric evaluation and recording of nocturnal desaturation. Results. The adjunction of ketamine resulted in a significant reduction in cumulative morphine consumption as early as the 36th postoperative hour [43 (SD 18) vs 32 (14) mg, P¼0.03] with a similar visual analogue scale. In the morphine group, the percentage of time with desaturation ,90% was higher during the three nights [1.80 (0.21‐6.37) vs 0.02 (0‐0.13), P,0.001; 2.15 (0.35‐8.65) vs 0.50 (0.01‐1.30), P¼0.02; 2.46 (0.57‐5.51) vs 0.55 (0.21‐1.00), P¼0.02]. The decrease in forced expiratory volume in 1 s was less marked in the ketamine group at the first postoperative day [1.04 (0.68‐1.22) litre vs 1.21 (1.10‐0.70) litre, P¼0.039]. Conclusions. Adding small doses of ketamine to morphine in PCA devices decreases the morphine consumption and may improve respiratory disorders after thoracic surgery.

Adding ketamine to morphine for patient-controlled analgesia after thoracic surgery: influence on morphine consumption, respiratory function, and nocturnal desaturation

Ketamine is a major drug for induction of patients with hypovolemia and for general anaesthesia under primitive conditions, but also has excellent properties for more generalized use in children, adults and other fragile patients. Potential beneficial effects on cardiac ischaemia and cerebral injury is presently explored, as well as the effects of ketamine as an potent analgesic drug. Combination with propofol or midazolam for sedation provides analgesia, sleep and spontaneous ventilation. The S-isomer of ketamine has a lower incidence of psychomimetic side effects in equianalgesic doses compared with the racemate or the R-isomer alone.

Ketamine: a new look at an old drug

Background: The effects of ketamine on respiration, alone, or in combination with opioids, have not been completely clarified. Both stimulant and depressant effects have been reported, as well as attenuation of opioid-induced hypoventilation at the expense of increased oxygen consumption. These conflicting results might partly be due to dose-dependent mechanisms. We have, therefore, determined the ventilatory effects of ketamine, in combination with alfentanil, using infusions to different pseudo steady-state concentrations.



Methods: On two separate days, eight healthy male volunteers were given alfentanil as a continuous computer-controlled infusion, aiming at a plasma concentration of 50 ng  ·  mL−1. After reaching apparent steady-state for alfentanil, racemic ketamine or placebo was administered in a protocol randomised for the two days. On the ketamine days a computer-controlled infusion, aiming for escalating ketamine plasma concentrations of 50, 100 and 200 ng  ·  mL−1, was added to the alfentanil infusion. On the placebo days saline was added. Using a face-mask with an occlusion valve, respiratory parameters were measured during air-breathing and after 6 repetitive 30-s CO2 challenges.



Results: The alfentanil infusion induced hypoventilation by decreasing respiratory rate, while tidal volume and respiratory drive were unaffected. This hypoventilation was antagonised by ketamine in a concentration-dependent manner mainly through an increase in respiratory rate. The CO2 response was not affected by alfentanil or ketamine.



Conclusion: In the dose range of interest for postoperative, intensive-care and pain-clinic settings, ketamine antagonises the resting hypoventilation induced by alfentanil.

E. Götharson

Papers

Ketamine antagonises alfentanil-induced hypoventilation in healthy male volunteers.