Preoperative Gabapentin for Pain Control: A Randomized, Placebo-controlled Clinical Trial in Patients Undergoing Inguinal Hernioplasty.

PURPOSE: The perioperative use of gabapentin has been suggested to reduce postoperative pain and opioid consumption. However, there is a variation in clinical practice, the type of surgery and the administration time seem to be distinct between the available studies. We assess whether gabapentin administered before surgery reduces postoperative pain in patients who have undergone inguinal hernioplasty. DESIGN: This is a double-blind, randomized, and placebo-controlled trial. METHODS: Seventy-seven patients scheduled for inguinal hernioplasty were randomized in two groups to receive gabapentin (900 mg) or placebo in the perioperative period. The primary outcome was analgesia measured by visual analog scale up to 30 days after surgery. The secondary outcomes such as morphine consumption, nausea, headache, and sedation have been also described. FINDINGS: Patients who received gabapentin had lower postoperative pain scores compared to the control group, P < .001. The postoperative morphine use was significantly lower in the gabapentin (5.3%) versus placebo group (74.4%), P < .001. No significant difference between groups was observed for the occurrence of adverse events. CONCLUSIONS: The perioperative administration of gabapentin was effective in reducing postoperative pain and had an important effect in decreasing morphine use. Together, our data reveal a long-lasting opioid-sparing effect of gabapentin in patients who underwent inguinal hernioplasty.

Preclinical study in a postoperative pain model to investigate the action of ketamine, lidocaine, and ascorbic acid in reversing fentanyl-induced, non-glutamate-dependent hyperalgesia.

Introduction: Opioid-induced hyperalgesia (OIH) is a paradoxical phenomenon in which exposure to opioids can increase sensitivity to painful stimuli. Currently, several drugs have been used in an attempt to prevent OIH. We design this study to address the effect of preemptive treatment with ketamine, lidocaine, and ascorbic acid in a rat preclinical model of perioperative opioid-induced hyperalgesia. Methods: To reproduce OIH in a model of postoperative pain, rats received successive doses of fentanyl subcutaneously and underwent an incision in the paw. In an attempt to prevent OIH, ketamine, lidocaine, and ascorbic acid were administered before treatment with fentanyl. The von Frey test and the hot-plate test were used to evaluate mechanical allodynia and thermal hyperalgesia, respectively, with a follow-up period from 1 hour up to 7 days after surgery. Spinal cord nerve terminals (synaptosomes) were used to assess glutamate release under our experimental conditions. Results: Consecutive fentanyl injections increased the postoperative pain as indicated by increased thermal hyperalgesia and allodynia 48 hours after incision. Ketamine, lidocaine, and the combination of ketamine + lidocaine were able to prevent thermal hyperalgesia but not mechanical allodynia. Ascorbic acid did not prevent the hyperalgesia induced by fentanyl. We found no correlation between spinal glutamate release and the pharmacological treatments. Conclusion: Fentanyl induced a hyperalgesic effect that last few days in a postoperative model of pain. Hyperalgesic effect was not totally inhibited by ketamine and lidocaine in rats. Increased glutamate release was not the main molecular mechanism of fentanyl-induced hyperalgesia.

Isobolographic analysis reveals antinociceptive synergism between Phα1ß recombinant toxin and morphine in a model of cancer pain in C57BL/6J mice.

BACKGROUND: Phoneutria nigriventer venom contains Phα1ß. This toxin and its recombinant form have a remarkable analgesic potential that is associated with blockage of voltage-gated calcium channels and TRPA1 receptors. Although morphine is a mainstay drug to treat moderate and severe pain related to cancer, it has serious and dose-limiting side effects. Combining recombinant Phα1ß and morphine to treat pain is an interesting approach that has been gaining attention. Therefore, a quantitative and reliable method to establish the strength of the antinociceptive interaction between these two substances is necessary. The present study was designed to investigate the nature of the functional antinociceptive (analgesic) interaction between Phα1ß recombinant toxin and morphine in a model of cancer pain. METHODS: Melanoma was produced by intraplantar inoculation of B16-F10 cells into the right paw of C57BL/6J mice. Von Frey filaments measured the paw-withdrawal threshold after intrathecal administration of morphine, recombinant Phα1ß, and their combination. Thermal hyperalgesia was assessed using Hargreaves apparatus. The degree of interaction was evaluated using isobolographic analysis. Spontaneous and forced motor performance was assessed with the open-field and rotarod tests, respectively. RESULTS: Co-administration of recombinant Phα1ß and morphine synergistically reverses the melanoma-induced mechanical hyperalgesia. The potency of the mixture, measured as the effective dose to reach 50% of maximum possible effect (MPE) in ameliorating mechanical hyperalgesia, was about twice fold higher than expected if the interaction between morphine and recombinant Phα1ß was merely additive. Treatment with the combination at doses necessary to reach 50% of MPE caused no spontaneous nor forced motor alterations. CONCLUSION: The combinatorial use of recombinant Phα1ß and morphine allows significant and effective dose reduction of both agents, which has translational potential for opioid-sparing approaches in pain management related to cancer.

Ketamine potentiates TRPV1 receptor signaling in the peripheral nociceptive pathways.

TRPV1 is a cation channel expressed in peripheral nociceptive pathways and its activation can trigger nociception signals to the brain. Ketamine is an intravenous anesthetic routinely used for anesthesia induction and with potent analgesic activity. Despite its proven depressant action on peripheral sensory pathways, the relationship between ketamine and TRPV1 receptors is still unclear. In this study, we evaluated the effect of ketamine injected peripherally in a rat model of spontaneous pain induced by capsaicin. We also investigated the effect of ketamine on Ca2+ transients in cultured dorsal root ganglia (DRG) neurons and HEK293 cells expressing the TRPV1 receptor (HEK-TRPV1 cells). Intraplantar administration of ketamine caused an unexpected increase in nocifensive behavior induced by capsaicin. Incubation of HEK-TRPV1 cells with 10 µM ketamine increased TRPV1 and PKCє phosphorylation. Ketamine potentiated capsaicin-induced Ca2+ transients in HEK-TRPV1 cells and DRG neurons. Ketamine also prevented TRPV1 receptor desensitization induced by successive applications of capsaicin. єV1-2, a PKCє inhibitor, reduced potentiation of capsaicin-induced Ca2+ transients by ketamine. Taken together, our data indicate that ketamine potentiates TRPV1 receptor sensitivity to capsaicin through a mechanism dependent on PKCє activity.

Isobolographic analysis reveals antinociceptive synergism between Ph1 recombinant toxin and morphine in a model of cancer pain in C57BL/6J mice

Abstract Background: Phoneutria nigriventer venom contains Ph1. This toxin and its recombinant form have a remarkable analgesic potential that is associated with blockage of voltage-gated calcium channels and TRPA1 receptors. Although morphine is a mainstay drug to treat moderate and severe pain related to cancer, it has serious and dose-limiting side effects. Combining recombinant Ph1 and morphine to treat pain is an interesting approach that has been gaining attention. Therefore, a quantitative and reliable method to establish the strength of the antinociceptive interaction between these two substances is necessary. The present study was designed to investigate the nature of the functional antinociceptive (analgesic) interaction between Ph1 recombinant toxin and morphine in a model of cancer pain. Methods: Melanoma was produced by intraplantar inoculation of B16-F10 cells into the right paw of C57BL/6J mice. Von Frey filaments measured the paw-withdrawal threshold after intrathecal administration of morphine, recombinant Ph1, and their combination. Thermal hyperalgesia was assessed using Hargreaves apparatus. The degree of interaction was evaluated using isobolographic analysis. Spontaneous and forced motor performance was assessed with the open-field and rotarod tests, respectively. Results: Co-administration of recombinant Ph1 and morphine synergistically reverses the melanoma-induced mechanical hyperalgesia. The potency of the mixture, measured as the effective dose to reach 50% of maximum possible effect (MPE) in ameliorating mechanical hyperalgesia, was about twice fold higher than expected if the interaction between morphine and recombinant Ph1 was merely additive. Treatment with the combination at doses necessary to reach 50% of MPE caused no spontaneous nor forced motor alterations. Conclusion: The combinatorial use of recombinant Ph1 and morphine allows significant and effective dose reduction of both agents, which has translational potential for opioid-sparing approaches in pain management related to cancer.