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 µg/kg per injection at 15-minute intervals) resulting in a total dose of 240 µg/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.

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 alpha2delta 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 microg/kg per injection at 15-min intervals). Intraperitoneal (30, 75, 150, or 300 mg/kg) or intrathecal (300 microg) 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 alpha2delta auxiliary subunits of voltage-gated calcium channels.

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.

Protective effect of prior administration of magnesium on delayed hyperalgesia induced by fentanyl in rats.

PURPOSE: Magnesium exerts a physiological block of the ion channel on the N-methyl-D-aspartate receptor, and may therefore prevent the induction of central sensitization. The purpose of this study was to assess whether systemic magnesium can prevent long-lasting hyperalgesia induced by sc fentanyl administration in uninjured rats. METHODS: Long-lasting hyperalgesia was induced in male Sprague Dawley rats with sc fentanyl (four injections, 60 microg x kg(-1) per injection at 15-min intervals). Magnesium sulphate (100 mg x kg(-1)) was injected ip 30 min prior to the first sc fentanyl injection. Sensitivity to nociceptive stimuli (paw-pressure test) was assessed for several days after injections. RESULTS: Subcutaneous fentanyl led to delayed hyperalgesia associated with a decrease in the nociceptive threshold lasting two days (35% decrease for the maximum effect). Intraperitoneal magnesium sulphate partially but significantly (P < 0.05) prevented the delayed decrease in the nociceptive threshold following sc administration of fentanyl. CONCLUSIONS: This study shows that magnesium may prevent the delayed and prolonged hyperalgesia following fentanyl administration in rats.

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

PURPOSE: The aim of this study was to assess the effect of pre- vs postincisional low-dose iv ketamine on postoperative pain in outpatients scheduled for oral surgery under general anesthesia. METHODS: Eighty-four patients were randomly assigned to receive intravenously saline before and after surgery in Group 1, ketamine 300 microg x kg(-1) iv before and saline after surgery in Group 2, saline before and ketamine 300 microg x kg(-1) iv after surgery in Group 3. Postoperative analgesia consisted of iv proparacetamol and ketoprofen. Rescue analgesia consisted of nalbuphine 200 microg x kg(-1) iv. 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. RESULTS: There 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 microg x kg(-1) +/- 16.8, 75.9 microg x kg(-1) +/- 17.5, 66.7 microg x 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. CONCLUSIONS: There was no benefit to pre-emptive administration of ketamine 300 microg x kg(-1) iv whether administered pre- or postoperatively.

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 microg and 10 microg) 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.

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

UNLABELLED: 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 degrees -15 degrees 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. IMPLICATIONS: This new anterior approach to the sciatic nerve using the inguinal crease and femoral artery as landmarks is an easy and reliable technique.