Plantar Surgery Research Articles

Synergism between oral paracetamol and nefopam in a murine model of postoperative pain.

The use of paracetamol or nefopam for postoperative pain control is limited by the need of high doses associated with unwanted effects. Previous works suggest positive interactions between both compounds that may be exploited to obtain potentiation of antinociception. Mechanical and heat antinociception induced by oral doses of paracetamol, nefopam or their combination was studied by isobolographic analysis in a murine model of postsurgical pain. The effective doses that produced 50% antinociception (ED50 ) were calculated from the log dose-response curves for each compound. Subsequently, the effects of ED8.7 s, ED12.5 s, ED17.5 s and ED35 s of nefopam and paracetamol combined were assessed. Oral paracetamol induced dose-dependent relief of postoperative sensitivity and showed higher efficacy reducing mechanical hypersensitivity (ED50 177.3±15.4mg/kg) than heat hyperalgesia (ED50 278.6±43mg/kg). Oral nefopam induced dose-dependent antinociception with similar efficacy for mechanical and heat hypersensitivity (ED50 s 5.42±0.81 vs. 5.83±0.72). Combinations of increasing isoeffective doses revealed that combined ED17.5 s (85.76mg/kg paracetamol and 1.9mg/kg nefopam) and ED35 s (132.67mg/kg and 3.73mg/kg) showed synergistic effects leading to 75% and 90% mechanical antinociception, respectively. These mixtures were defined by interaction indexes of 0.43 and 0.41 and ratios 45:1 and 35:1 paracetamol:nefopam, respectively. The same combinations showed additive effects for the inhibition of incisional thermal hyperalgesia. This work describes a synergistic antinociceptive interaction between low doses of nefopam and paracetamol for the treatment of postoperative hypersensitivity to peripheral stimuli. The promising results obtained on reflexive nociceptive responses of young male mice subjected to plantar surgery highlight the interest of further research evaluating the effects of this mixture on the affective-motivational component of pain and in females and additional age groups. Confirmation of pain-relieving efficacy and safety of this oral combination clinically available in European and Asian countries could provide a useful tool for postsurgical pain management. Early postoperative pain is currently undertreated and has been recognized as a relevant source of chronic postsurgical pain. Oral efficient treatments could facilitate fast-track surgeries and patient recovery at home. Here, we identify in a mouse model of postoperative pain a potent synergistic oral combination consisting of low paracetamol and nefopam doses that provides relief of postsurgical hypersensitivity to mechanical and thermal stimuli. Oral multimodal paracetamol-nefopam mixtures represent a potential clinically available pharmacological strategy for the relief of incisional sensitivity and the promotion of patient recovery.

Beneficial effects of levobupivacaine regional anaesthesia on postoperative opioid induced hyperalgesia in diabetic mice.

BackgroundDiabetic neuropathy is one of the most common complications of diabetes and causes various problems in daily life. The aim of this study was to assess the effect of regional anaesthesia on post surgery opioid induced hyperalgesia in diabetic and non-diabetic mice.MethodsDiabetic and non-diabetic mice underwent plantar surgery. Levobupivacaine and sufentanil were used before surgery, for sciatic nerve block (regional anaesthesia) and analgesia, respectively. Diabetic and non-diabetic groups were each randomly assigned to three subgroups: control, no sufentanil and no levobupivacaine; sufentanil and no levobupivacaine; sufentanil and levobupivacaine. Three tests were used to assess pain behaviour: mechanical nociception; thermal nociception and guarding behaviours using a pain scale.ResultsSufentanil, alone or in combination with levobupivacaine, produced antinociceptive effects shortly after administration. Subsequently, sufentanil induced hyperalgesia in diabetic and non-diabetic mice. Opioid-induced hyperalgesia was enhanced in diabetic mice. Levobupivacaine associated to sufentanil completely prevented hyperalgesia in both groups of mice.ConclusionThe results suggest that regional anaesthesia can decrease opioid-induced hyperalgesia in diabetic as well as in non-diabetic mice. These observations may be clinically relevant for the management of diabetic patients.

Critical Role of Protease-activated Receptor 2 Activation by Mast Cell Tryptase in the Development of Postoperative Pain

Studies have indicated that nearly half of all surgical patients still have inadequate pain relief. Thus, it is crucial to understand the mechanisms involved in postoperative pain in order to better treat it. Thus, the aim of this study was to investigate the involvement of mast cell degranulation, tryptase and its substrate, the protease-activated receptor 2, in a model of postoperative pain in mice. We evaluated the effect of the compound 48/80 (to cause mast cell mediator depletion), cromoglycate or ketotifen (mast cell stabilizers), gabexate (tryptase inhibitor) or N3-methylbutyryl-N-6-aminohexanoyl-piperazine (protease-activated receptor 2 antagonist) in a postoperative pain model in mice (n = 5-10). Mast cell degranulation and tryptase activity were also evaluated in the operated tissue (n= 5-8). The pre-treatment with compound 48/80 or ketotifen was able to prevent nociception throughout the postoperative hyperalgesia course (until 5 days after surgery), whereas cromoglycate presented a shorter effect (until 1 day). Gabexate or N3-methylbutyryl-N-6-aminohexanoyl-piperazine also produced a short-lasting effect in preventing postoperative nociception. However, neither gabexate, N3-methylbutyryl-N-6-aminohexanoyl-piperazine nor cromoglycate was capable of reversing nociception when administered after incision. Surgery led to early mast cell degranulation on the incised tissue and increased tryptase activity in tissue perfusates. Cromoglycate fully prevented the tryptase release in the perfusate and the compound 48/80 substantially reduced tryptase activity in the incised tissue. Thus, the mast cell degranulation with the subsequent release of tryptase and protease-activated receptor 2 activation are potential targets for the development of novel therapies to prevent, but not reverse, postoperative pain.

Sciatic Nerve Block Fails in Preventing the Development of Late Stress-Induced Hyperalgesia When High-Dose Fentanyl Is Administered Perioperatively in Rats

: Sciatic nerve block fails in preventing the development of late stress-induced hyperalgesia (SIH) when high-dose fentanyl is administered perioperatively in rats. The aim of our study was to evaluate the effect of regional anesthesia (RA) on hyperalgesia and long-term pain vulnerability after surgery in rats exposed or not to high doses of fentanyl intraoperatively. Experiment 1 evaluated the effects of D0 RA on hyperalgesia after incision and on the variations of nociceptive threshold (NT) after non-nociceptive environmental stress (NNES) at D10. Four groups were compared: control K1 (saline in sciatic nerve catheter, no plantar surgery), I (incision: saline in sciatic nerve catheter and plantar surgery), ISSR (incision-single-shot ropivacaine: single-shot ropivacaine, plantar surgery), and IMSR (incision-multiple-shot ropivacaine: 1 shot of ropivacaine, plantar surgery, and then 3 more ropivacaine injections every 2 h). Experiment 2 evaluated the effects of D0 RA (4 injections) on NT variations after surgery (D1-D10) and after stress (D10) in rats treated with fentanyl at the time of surgery (FI and FIMSR groups). Postoperative hyperalgesia lasted for 7, 4, and 2 days for groups I, ISSR, and IMSR, respectively. Non-nociceptive environmental stress at D10 showed analgesia during stress in K1 (Dunnett, P < 0.05). Poststress area of hyperalgesia showed that I group developed greater hyperalgesia after NNES than ISSR and IMSR did (Mann-Whitney, P < 0.05). In experiment 2 in the FIMSR group, NT was significantly higher at postoperative D1 and D2 (Dunnett, P < 0.05), but no difference was shown from D3 to D10 (Dunnett, P > 0.05). Hyperalgesic indices calculated for FI and FIMSR groups after NNES at D10 did no show any significant difference (Dunnett, P > 0.05). Perioperative use of long-lasting RA reduced both acute postoperative hyperalgesia and the development of long-term pain vulnerability. However, high doses of fentanyl for intraoperative analgesia induce central sensitization that cannot be reversed by using long-lasting RA.

Involvement of mast cells in a mouse model of postoperative pain

Recent studies have indicated that nearly half of all surgical patients still have inadequate pain relief; therefore, it is becoming increasingly more important to understand the mechanisms involved in postoperative pain in order to be better treated. Previous studies have shown that incisions can cause mast cell degranulation. Thus, the aim of this study was to investigate the involvement of mast cells in a model of postoperative pain in mice. The depletion of mast cell mediators produced by pre-treatment with compound 48/80 (intraplantar (i.pl.)) widely (98 ± 23% of inhibition) and extensively (up to 96 h) prevented postoperative nociception and reduced histamine and serotonin levels (88 ± 4% and 68 ± 10%, respectively) in operated tissue. Furthermore, plantar surgery produced immense mast cell degranulation, as assessed by histology and confirmed by the increased levels of serotonin (three-fold higher) and histamine (fifteen-fold higher) in the perfused tissue, 1 h after surgery. Accordingly, pre-treatment with the mast cell membrane stabilizer cromoglycate (200 μg/paw, i.pl.) prevented mechanical allodynia (inhibition of 96 ± 21%) and an increase in histamine (44 ± 10% of inhibition) and serotonin (73 ± 5% of inhibition) levels induced by plantar surgery. Finally, local treatment with H 1 (promethazine, 100 μg/paw, i.pl.), 5-HT 3 (ondansetron, 10 μg/paw, i.pl.) or 5-HT 2A (ketanserin, 5 μg/paw, i.pl.) receptor antagonists partially decreased postoperative nociception in mice, but when co-administered together it completely reversed the mechanical allodynia in operated mice. Thus, mast cell activation mechanisms are interesting targets for the development of novel therapies to treat postoperative pain.