Alain C. Van Elstraete

A single dose of intrathecal morphine in rats induces long-lasting hyperalgesia: the protective effect of prior administration of ketamine.

An active pronociceptive process involving N-methyl-d-aspartate (NMDA) receptor activation is initiated by opioid administration, leading to opioid-induced pain sensitivity. Experimental observations in rats have reported reduction of baseline nociceptive threshold after prolonged spinal opioid administration. In this study we sought to determine whether a single dose of intrathecal morphine can induce hyperalgesia in uninjured rats and to assess the effects of pretreatment with the NMDA-antagonist ketamine on nociceptive thresholds. Sensitivity to nociceptive stimuli (paw pressure test) was assessed for several days after an acute intrathecal injection of morphine (5 &mgr;g and 10 &mgr;g) in male Sprague-Dawley rats. The effects of subcutaneously administered NMDA-receptor antagonist ketamine (10 mg/kg) before intrathecally administered morphine were also evaluated. A single intrathecal injection of morphine led to a biphasic effect on nociception; early analgesia associated with an increase in the nociceptive threshold lasting 3-5 h was followed by delayed hyperalgesia associated with a decrease in the nociceptive threshold lasting 1-2 days. Subcutaneous ketamine did not significantly modify the early analgesic component but almost completely prevented the delayed decrease in nociceptive threshold after intrathecal administration of morphine. A single intrathecal injection of morphine in rats produces a delayed and sustained hyperalgesia linked to the development of opioid-induced pain sensitivity.

Gabapentin Prevents Delayed and Long-lasting Hyperalgesia Induced by Fentanyl in Rats

Background:Opioid-induced hyperalgesia can develop rapidly after opioid exposure. Neuropathic pain and opioid-induced hyperalgesia share common pathophysiologic mechanisms. Gabapentin is effective for the management of neuropathic pain and may therefore prevent opioid-induced hyperalgesia. This study tested the effectiveness of gabapentin for prevention of long-lasting hyperalgesia induced by acute systemic fentanyl in uninjured rats. Involvement of the &agr;2&dgr; auxiliary subunits of voltage-gated calcium channels in the prevention of opioid-induced hyperalgesia by gabapentin also was assessed. Methods:Hyperalgesia was induced in male Sprague-Dawley rats with subcutaneous fentanyl (four injections, 20, 60, or 100 &mgr;g/kg per injection at 15-min intervals). Intraperitoneal (30, 75, 150, or 300 mg/kg) or intrathecal (300 &mgr;g) gabapentin was administered 30 min before or 300 min after (intraperitoneal 150 mg/kg) the first fentanyl injection. Sensitivity to nociceptive stimuli (paw-pressure test) was assessed on the day of the experiment and for several days after injections. The effects combining gabapentin with intrathecal ruthenium red (20 ng) also were assessed. Results:Fentanyl administration was followed by an early increase (analgesia) and by a later and sustained decrease (hyperalgesia) in nociceptive thresholds. Gabapentin did not significantly modify the early analgesic component but dose-dependently prevented the delayed decrease in nociceptive threshold. Ruthenium red partially, but significantly, opposed the prevention of opioid-induced hyperalgesia by gabapentin. Conclusions:Intraperitoneal and intrathecal gabapentin prevents the development of hyperalgesia induced by acute systemic exposure to opioids. This prevention may result, at least in part, from binding of gabapentin to the &agr;2&dgr; auxiliary subunits of voltage-gated calcium channels.

New landmarks for the anterior approach to the sciatic nerve block: imaging and clinical study.

In this study, we assessed the reliability of the inguinal crease and femoral artery as anatomic landmarks for the anterior approach to the sciatic nerve and determined the optimal position of the leg during this approach. An imaging study was conducted before the clinical study. The sciatic nerve was located twice in 20 patients undergoing ankle or foot surgery, once with the leg in the neutral position and once with the leg in the externally rotated position. The patient was lying supine. A 22-gauge, 150-mm insulated b-beveled needle connected to a nerve stimulator was inserted 2.5 cm distal to the inguinal crease and 2.5 cm medial to the femoral artery and was directed posteriorly and laterally with a 10°–15° angle relative to the vertical plane. The sciatic nerve was located in all patients at a depth of 10.6 ± 1.8 cm when the leg was in the neutral position and 10.4 ± 1.5 cm when the leg was in the externally rotated position (not significant). In the neutral position and in the externally rotated position, the time needed to identify anatomic landmarks was 28 ± 15 s and 26 ± 14 s, respectively (not significant), and the time needed to locate the sciatic nerve was 79 ± 53 s and 46 ± 25 s (P < 0.006), respectively. We conclude that the inguinal crease and femoral artery are reliable and effective anatomic landmarks for the anterior approach to the sciatic nerve and that the optimal position of the leg is the externally rotated position.

Effect of preincision versus postincision infiltration with bupivacaine on postoperative pain

STUDY OBJECTIVE To compare the efficacy of preincision wound infiltration with bupivacaine to wound infiltration at the end of the operation. DESIGN A prospective, randomized, double-blind study. SETTING University medical center. PATIENTS 56 ASA status I and II women scheduled for abdominal hysterectomy were randomly assigned to one of three treatment groups. INTERVENTIONS Group 1 (control) received no local anesthetic infiltration. Group 2 received subcutaneous infiltration with 40 ml of bupivacaine 0.5% (pH 6.9) 15 minutes prior to incision. Group 3 received wound infiltration with a similar solution at the end of surgery. Anesthesia was induced with thiopental 3.0 mg/kg i.v., droperidol 50 micrograms/kg i.v., and sufentanil 0.5 microgram/kg i.v. and maintained with nitrous oxide 67% in oxygen and sufentanil 0.1 microgram/kg IV boluses as required. Postoperative pain was treated with morphine via a patient-controlled analgesia delivery system for 24 hours, followed by oral hydrocodone for 3 days. MEASUREMENTS AND MAIN RESULTS The opioid consumption was recorded for 4 days postoperatively. Pain scores were measured at 4 to 8-hour intervals using 100 mm visual analog scales. There was no difference in either the opioid analgesic requirements or the pain scores between the three study groups. CONCLUSIONS Wound infiltration, either preincision or postincision, had no clinically significant effect on the pain scores or analgesic requirements following abdominal hysterectomy.

The Median Effective Dose of Preemptive Gabapentin on Postoperative Morphine Consumption After Posterior Lumbar Spinal Fusion

BACKGROUND:A single dose of preemptive gabapentin reduces postoperative pain and postoperative analgesic consumption. However, the optimal dose of preemptive gabapentin remains to be evaluated. METHODS:In this prospective study, we defined the median effective analgesic dose using an up-and-down sequential allocation technique of preemptive gabapentin in 67 patients undergoing elective posterior lumbar spinal fusion. The efficacy of the study drug was assessed by morphine consumption during the first 24 h postoperatively. RESULTS:The median effective analgesic dose (median value and 95% confidence interval) of gabapentin was 21.7 mg/kg (19.9–23.5 mg/kg). CONCLUSION:Given the large dose of gabapentin needed, further powered studies are warranted to assess side effects.

Comparison of an ephedrine infusion with crystalloid administration for prevention of hypotension during spinal anesthesia

This study was designed to compare the efficacy of an ephedrine infusion with crystalloid administration for reducing the incidence of hypotension during spinal anesthesia. Fifty-four ASA I patients scheduled for postpartum tubal ligations under spinal anesthesia were randomly allocated to receive either 15 mL/kg of crystalloid (crystalloid group) or an ephedrine infusion (infusion group). Spinal anesthesia was performed using 70-90 mg of hyperbaric 5% lidocaine. Patients in the infusion group immediately thereafter received an ephedrine infusion at a rate of 5 mg/min for the first 2 min and then 1 mg/min for the next 18 min. The incidence of hypotension was 15/27 (55%) in the crystalloid group and 6/27 (22%) in the infusion group (P < 0.05). There was no significant difference between the groups in relation to the level of anesthesia or maximal heart rate, and hypertension did not occur in either group. We conclude that a prophylactic ephedrine infusion is effective for minimizing and managing hypotension associated with spinal anesthesia and compares favorably with crystalloid administration in this patient population in terms of efficacy and incidence of side effects.

Lack of a pre-emptive effect of low-dose ketamine on postoperative pain following oral surgery.

Objectif Le but de cette etude etait de tester ľefficacite sur la douleur postoperatoire de faibles doses iv de ketamine preoperatoires vs postoperatoires en chirurgie buccale ambulatoire.PurposeThe aim of this study was to assess the effect of pre- vs postincisional low-doseiv ketamine on postoperative pain in outpatients scheduled for oral surgery under general anesthesia.MethodsEighty-four patients were randomly assigned to receive intravenously saline before and after surgery in Group 1, ketamine 300 µg·kg-1iv before and saline after surgery in Group 2, saline before and ketamine 300 µg·kg-1iv after surgery in Group 3. Postoperative analgesia consisted ofiv proparacetamol and ketoprofen. Rescue analgesia consisted of nalbuphine 200 µg·kg-1iv. Analgesia at home consisted of oral ketoprofen, and acetaminophen with codeine as rescue analgesia. A telephone interview was conducted on the first and second postoperative days.ResultsThere were no significant differences between groups with respect to pain scores, the number of patients requiring nalbuphine in the postanesthesia care unit (PACU), (36.7%, 38.7%, and 39.5% for Groups 1, 2, and 3 respectively), or nalbuphine consumption in the PACU (66.5 µg·kg-1 ± 16.8, 75.9 µg·kg-1 ± 17.5, 66.7 µg·kg-1 ± 21.6 for Groups 1, 2, and 3 respectively). The number of rescue analgesic tablets taken at home, and time to first request for rescue analgesia, sedation scores, or side-effects were similar amongst groups. No patient required nalbuphine in the ambulatory care unit.ConclusionsThere was no benefit to pre-emptive administration of ketamine 300 µg·kg-1iv whether administered pre- or postoperatively.RésuméObjectifLe but de cette étude était de tester ľefficacité sur la douleur postopératoire de faibles doses iv de kétamine préopératoires vs postopératoires en chirurgie buccale ambulatoire.MéthodeQuatre-vingt-quatre patients étaient répartis au hasard pour recevoir par voie iv respectivement avant et après la chirurgie: une solution salée dans le Groupe 1, 300 µg·kg-1 de kétamine et une solution salée dans le Groupe 2, une solution salée et 300 µg·kg-1 de kétamine dans le Groupe 3. Ľanalgésie postopératoire était assurée systématiquement par du propara-cétamol et du kétoprofène en hospitalisation, et du kétoprofène à domicile. ľanalgésie de complément était assurée par 200 µg·kg-1 de nalbuphine en hospitalisation, et par du paracétamol-codéine po à domicile. Un interview téléphonique était effectué les premier et second jours postopératoires.RésultatsAucune différence significative n’a été retrouvée entre les groupes concernant les scores de douleur, le nombre de patients ayant reçu de la nalbuphine (36,7 %, 38,7 %, et 39,5 % respectivement pour les Groupes 1, 2 et 3), la consommation de nalbuphine (66,5 µg·kg-1 ± 16,8, 75,9 µg·kg-1 ± 17,5, 66,7 µg·kg-1 ± 21,6 respectivement pour les Groupes 1, 2 et 3), le nombre de comprimés de secours à domicile: 6 (2,13), 7 (2,20), et 7 (1,12) respectivement pour les Groupes 1, 2 et 3, la première demande ďanalgésique de secours, les scores de sédation ou les effets secondaires.ConclusionCette étude n’a démontré aucun effet préventif sur la douleur postopératoire de 300 µg·kg-1 de kétamine iv administrée avant ou après ľopération.

Nasotracheal intubation in patients with immobilized cervical spine: a comparison of tracheal tube cuff inflation and fiberoptic bronchoscopy.

Tracheal intubation may pose problems in patients with cervical spine injury (CSI).In patients without CSI, the success rate of blind nasotracheal intubation is increased by endotracheal tube (ETT) cuff inflation in the pharynx. The purpose of this study was to assess the efficacy of ETT cuff inflation in the pharynx as an aid to blind nasotracheal intubation in patients with an immobilized cervical spine. The technique was compared with fiberoptic bronchoscopy. Twenty ASA physical status I and II patients undergoing elective surgery in which the trachea was to be intubated nasally were enrolled in this prospective, randomized study. The cervical spine of each patient was immobilized. The trachea of each patient was intubated twice, once using fiberoptic bronchoscopy and once blindly using the technique of ETT cuff inflation in the pharynx. A maximum of three attempts was allowed for intubation using ETT cuff inflation. A maximum of 3 min was allowed for intubation using fiberoptic bronchoscopy. When ETT cuff inflation was used, intubation was successful in 19 of 20 patients (95%); the first attempt at intubation was successful in 14 of 20 patients (70%). Intubation was successful in 19 of 20 patients (95%) when using fiberoptic bronchoscopy. Mean times to intubate were 20.8 +/- 23 s when the ETT cuff was inflated in the pharynx and 60.1 +/- 56 s when using fiberoptic laryngoscopy (P < 0.01). We conclude that both ETT cuff inflation in the pharynx and fiberoptic bronchoscopy are valuable for nasotracheal intubation in patients with an immobilized cervical spine and that ETT cuff inflation can be used as an alternative to fiberoptic bronchoscopy in patients with CSI. Implications: We compared the technique of endotracheal tube cuff inflation in the pharynx for blind nasotracheal intubation in patients with an immobilized cervical spine with fiberoptic bronchoscopy. There was no significant difference between the success rates of the techniques. (Anesth Analg 1998;87:400-2)

The Median Effective Dose of Ketamine and Gabapentin in Opioid-Induced Hyperalgesia in Rats: An Isobolographic Analysis of Their Interaction

BACKGROUND: Ketamine and gabapentin have been shown to prevent the delayed hyperalgesia induced by short-term use of systemic opioids. The mechanism of this action is believed to be likely at the spinal level, through an antagonism of the N-methyl-d-aspartate receptors for ketamine, and through a specific binding site for gabapentin. In this study, we sought to determine the nature of the interaction of these 2 mechanistically distinct antihyperalgesic drugs in a model of opioid-induced hyperalgesia in rats. The median effective antihyperalgesic doses of each drug and of their combination were first defined, to assess the nature of the interaction using an isobolographic analysis. METHODS: Long-lasting hyperalgesia was induced in male Sprague Dawley rats with subcutaneous fentanyl (4 injections, 60 &mgr;g/kg per injection at 15-minute intervals) resulting in a total dose of 240 &mgr;g/kg. Subcutaneous ketamine, or intraperitoneal gabapentin, or their combination was administered 30 minutes before the first subcutaneous fentanyl injection. Sensitivity to nociceptive stimuli (von Frey filaments) was assessed on the day of the experiment and on the day after injections. The dose of ketamine and gabapentin received by a particular animal was determined by the response of the previous animal of the same group, using an up-and-down technique. Initial doses were 10 mg/kg and 300 mg/kg, with dose adjustment intervals of 1 mg/kg and 30 mg/kg, in the ketamine and gabapentin groups, respectively. The initial doses of ketamine and gabapentin were 5 mg/kg and 150 mg/kg, respectively, in the ketamine-gabapentin group, with the same dose adjustment intervals. Antihyperalgesic efficacy was defined as complete prevention of hyperalgesia on the day after drug injections. RESULTS: The median effective antihyperalgesic doses (median value and 95% confidence interval) of ketamine and gabapentin were 12.4 mg/kg (11.7–13.1 mg/kg) and 296.3 mg/kg (283.5–309.1 mg/kg), respectively. The median effective antihyperalgesic dose of the combination was 4.3 mg/kg (3.7–4.6 mg/kg) for ketamine and 123.9 mg/kg (111.1–136.7 mg/kg) for gabapentin. CONCLUSION: The isobolographic analysis demonstrated that the combination of the 2 drugs produces effective antihyperalgesia with a supraadditive (synergistic) action.

Are preemptive analgesic effects of ketamine linked to inadequate perioperative analgesia

We read with interest the article by Kwok et al. (1). The authors demonstrated that small dose of the N-methyl-d-aspartic acid (NMDA) receptor antagonist ketamine provides preemptive analgesia in patients undergoing gynecologic laparoscopic surgery. There are conflicting results in the literature concerning preemptive effect of ketamine. Studies have documented a preemptive effect (2–5) and others have not (6–10). The efficacy of ketamine is linked to activation of NMDA receptors of the dorsal horn of the spinal cord. In case of adequate perioperative analgesia, NMDA receptors activation is likely to be suppressed and ketamine administration useless. In the studies that have documented a preemptive effect of ketamine (2–5), the perioperative opioid analgesia is questionable and likely to have induced intraoperative activation of NMDA receptors. In the study of Kwok et al. (1) patients were administered an average total dose of 2 g/kg of fentanyl. Surgery lasted more than 60 min. Given the pharmacokinetics of fentanyl, we can wonder whether intraoperative analgesia was adequate, even in these minimally invasive surgery procedures. Inadequate analgesia might have, therefore, led to NMDA receptor activation and subsequent positive action of ketamine. The real challenge, however, in the clinical setting might not be to use the least amount of analgesic drug but to minimize long-term complications and occurrence of chronic pain syndromes. The study of Kwok et al. would have gained in interest if they had more focused on the long-term follow-up of the patients, using clinical assessment of allodynia and hyperalgesia.