Development of Sedative Dexmedetomidine Sublingual In Situ Gels: In Vitro and In Vivo Evaluations.

Intravenous dexmedetomidine (DEX) is currently approved by the FDA for the sedation of intubated patients in intensive care units to reduce anxiety and to augment postoperative analgesia. Bradycardia and hypotension are limitations associated with the intravenous administration of DEX. In this study, DEX sublingual in situ gels were developed and assessed for their pH, gelling capacity, viscosity, mucoadhesion and in vitro drug release. The optimized gelling system demonstrated enhanced mucoadhesion, superior gelling capacity, reasonable pH and optimal rheological profile. In vivo, compared to the oral solution, the optimal sublingual gel resulted in a significant higher rate and extent of bioavailability. Although the in situ gel had comparable plasma levels to those observed following intravenous administration, significant amelioration of the systemic adverse reactions were attained. As demonstrated by the hot plate method, a sustained duration of analgesia in rats was observed after sublingual administration of DEX gel compared to the intravenously administered DEX solution. Furthermore, no changes in systolic blood pressure and heart rate were recorded in rats and rabbits, respectively, after sublingual administration of DEX. Sublingual administration of DEX in situ gel provides a promising approach for analgesia and sedation, while circumventing the reported adverse reactions associated with intravenous administration of DEX.

Effect of Dexmedetomidine Added to Modified Pectoral Block on Postoperative Pain and Stress Response in Patient Undergoing Modified Radical Mastectomy.

BACKGROUND: The most common surgical procedure for breast cancer is the modified radical mastectomy (MRM), but it is associated with significant postoperative pain. Regional anesthesia can reduce the stress response associated with surgical trauma. OBJECTIVES: Our aim is to explore the efficacy of 1 µg/kg dexmedetomedine added to an ultrasound (US)-modified pectoral (Pecs) block on postoperative pain and stress response in patients undergoing MRM. STUDY DESIGN: A randomized, double-blind, prospective study. SETTING: An academic medical center. METHODS: Sixty patients with American Society of Anesthesiologists (ASA) physical status I-II (18-60 years old and weighing 50-90 kg) scheduled for MRM were enrolled and randomly assigned into 2 groups (30 in each) to receive a preoperative US Pecs block with 30 mL of 0.25% bupivacaine only (group 1, bupivacaine group [GB]) or 30 mL of 0.25% bupivacaine plus 1 µg/kg dexmedetomidine (group II, dexmedetomidine group [GD]). The patients were followed-up 48 hours postoperatively for vital signs (heart rate [HR], noninvasive blood pressure [NIBP], respiratory rate [RR], and oxygen saturation [Sao2]), visual analog scale (VAS) scores, time to first request of rescue analgesia, total morphine consumption, and side effects. Serum levels of cortisol and prolactin were assessed at baseline and at 1 and 24 hours postoperatively. RESULTS: A significant reduction in the intraoperative HR, systolic blood pressure (SBP), and diastolic blood pressure (DBP) starting at 30 minutes until 120 minutes in the GD group compared to the GB group (P < 0.05) was observed. The VAS scores showed a statistically significant reduction in the GD group compared to the GB group, which started immediately up until 12 hours postoperatively (P < 0.05). There was a delayed time to first request of analgesia in the GD group (25.4 ± 16.4 hrs) compared to the GB group (17 ± 12 hrs) (P = 0.029), and there was a significant decrease of the total amount of morphine consumption in the GD group (9 + 3.6 mg) compared to the GB group (12 + 3.6 mg) (P = 0.001). There was a significant reduction in the mean serum cortisol and prolactin levels at 1 and 24 hours postoperative in the GD patients compared to the GB patients (P < 0.05). LIMITATIONS: This study was limited by its sample size. CONCLUSION: The addition of 1 µg/kg dexmedetomidine to an US-modified Pecs block has superior analgesia and more attenuation to stress hormone levels without serious side effects, compared to a regular Pecs block in patients who underwent MRM. KEY WORDS: Postoperative pain, dexmedetomidine, Pecs block, stress response, breast surgery.

Effect of Intrathecally Administered Ketamine, Morphine, and Their Combination Added to Bupivacaine in Patients Undergoing Major Abdominal Cancer Surgery a Randomized, Double-Blind Study.

Objective: Effective postoperative pain control reduces postoperative morbidity. In this study, we investigated the effects of intrathecal morphine, ketamine, and their combination with bupivacaine for postoperative analgesia in major abdominal cancer surgery. Study Design: Prospective, randomized, double-blind. Setting: Academic medical center. Patients and Methods: Ninety ASA I-III patients age 30 to 50 years were divided randomly into three groups: the morphine group (group M) received 10 mg of hyperbaric bupivacaine 0.5% in 2 mL volume and 0.3 mg morphine in 1 mL volume intrathecally. The ketamine group (group K) received 0.1 mg/kg ketamine in 1 mL volume instead of morphine. The morphine + ketamine group (group K + M) received both 0.3 mg morphine and 0.1 mg/kg ketamine in 1 mL volume intrathecally. Postoperative total morphine consumption, first request of analgesia, visual analog score (VAS), and side effects were recorded. Results: Total PCA morphine was significantly decreased in group M + K compared with groups M and K. Time to first request of analgesia was prolonged in groups M and M + K compared with group K (P < 0.001). VAS in group M + K was reduced from two to 24 hours, and in group M from 12 and 18 hours postoperation compared with group K, with an overall good analgesia in the three groups. Sedation was significantly higher in group M + K compared with group M until six hours postoperation. No other side effects were observed. Conclusions: Adding intrathecal ketamine 0.1 mg/kg to morphine 0.3 mg in patients who underwent major abdominal cancer surgery reduced the total postoperative morphine consumption in comparison with either drug alone, with an overall good postoperative analgesia in all groups, with no side effects apart from sedation.

Comparison Between the Effects of Intravenous Morphine, Tramadol, and Ketorolac on Stress and Immune Responses in Patients Undergoing Modified Radical Mastectomy.

OBJECTIVES: Analgesics had been suspected of impairing various immune functions either directly or indirectly. Our primary objective was to compare the effects of intravenous (IV) morphine, tramadol, and ketorolac on stress and immune responses in patients who underwent modified radical mastectomy. PATIENTS: Sixty patients randomly assigned to receive IV morphine 5 mg (group M, n=20), tramadol 100 mg (group T, n=20), or ketorolac 60 mg (group K, n=20) at the end of surgery. METHODS: Serum cortisol, prolactin were measured immediately, 40 minutes, and 24 hours postoperatively. Expressions of peripheral T lymphocytes (CD3, CD3CD4, CD3CD8) and natural killer cells (CD3, CD56) were measured as percentages of total lymphocytes by flow cytometry immediately, 90 minutes, and 24 hours postoperatively. RESULTS: After 40 minutes, cortisol level increased but prolactin decreased significantly (P=0.001), then both decreased after 24 hours (P=0.001) compared with baseline within the 3 groups. CD3, CD4, CD8, and CD56 significantly decreased at 90 minutes and 24 hours (P≤0.033) compared with baseline in the 3 groups. CD4, CD8, and CD56 significantly decreased in group M, compared with group T and K (P≤0.016) and CD3, CD8, and CD56 in group T compared with group K at 90 minutes (P≤0.024) postoperatively. After 24 hours, CD4, and CD8 decreased in group M compared with group T (P≤0.048) and CD4 and CD56 in groups M and T compared with group K (P≤0.049). CONCLUSIONS: IV morphine, tramadol, and ketorolac suppressed stress and immune responses. Ketorolac was the least immunosuppressive among the 3 drugs.

Dexmedetomidine as an adjunctive analgesic with bupivacaine in paravertebral analgesia for breast cancer surgery.

BACKGROUND: There is little systematic research on the efficacy and tolerability of the addition of adjunctive analgesic agents in paravertebral analgesia. The addition of adjunctive analgesics, such as fentanyl and clonidine, to local anesthetics has been shown to enhance the quality and duration of sensory neural blockades, and decrease the dose of local anesthetic and supplemental analgesia. OBJECTIVES: Investigation of the safety and the analgesic efficacy of adding 1 µg/kg dexmedetomidine to bupivacaine 0.25% in thoracic paravertebral blocks (PVB) in patients undergoing modified radical mastectomy. STUDY DESIGN: A randomized, double-blind trial. SETTING: Academic medical center. METHODS: Sixty American Society of Anesthesiologists physical status -I - III patients were randomly assigned to receive thoracicPVB with either 20 mL of bupivacaine 0.25% (Group B, n = 30), or 20 mL of bupivacaine 0.25% + 1 µg/kg dexmedetomidine (Group BD, n= 30). Assessment parameters included hemodynamics, sedation score, pain severity, time of first analgesics request, total analgesic consumption, and side effects in the first 48 hours. RESULTS: There was a significant reduction in pulse rate and diastolic blood pressure starting at 30 minutes in both groups, but more evidenced in group BD (P < 0.001). Intraoperative Systolic blood pressure showed a significant reduction at 30 minutes in both groups (P < 0.001) then returned to baseline level at 120 minutes in both groups. There was a significant increase in pulse rate starting 2 hours postoperative until 48 hours postoperatively in group B but only after 12 hours until 48 hours in group BD (P < 0.001). The time of the first rescue analgesic requirement was significantly prolonged in the group BD (8.16 ± 42 hours) in comparison to group B (6.48 ± 5.24 hours) (P = 0.04). The mean total consumption of intravenous tramadol rescue analgesia in the postanesthesia care unit in the firtst 48 hours postoperatively was significantly decreased in group BD (150.19 ± 76.98 mg) compared to group B (194.44 ± 63.91 mg) (P = 0.03). No significant serious adverse effects were recorded during the study. LIMITATIONS: This study is limited by its sample size. CONCLUSION: The addition of dexmedetomidine 1 µg/kg to bupivacaine 0.25% in thoracic PVB in patients undergoing modified radical mastectomy improves the quality and the duration of analgesia and also provides an analgesic sparing effect with no serious side effects.

Effect of thoracic epidural analgesia on pro-inflammatory cytokines in patients subjected to protective lung ventilation during Ivor Lewis esophagectomy.

BACKGROUND: Thoracic epidural analgesia (TEA) has a well-known effect on neurohormonal response. Attenuation of stress response by post-operative epidural analgesia has shown beneficial effects such as lower pain scores and less immunological alterations. OBJECTIVES: Investigation of the combined effects of TEA and protective lung ventilation on pro-inflammatory cytokines and patients' outcome after Ivor Lewis esophagectomy. STUDY DESIGN: A randomized controlled study. SETTING: Academic medical center. METHODS: Thirty patients of the American Society of Anesthesiologists (ASA) I and II were randomly allocated into 2 groups: G1 (n = 15) patients received general anesthesia and were mechanically ventilated with 9 mL/kg during 2 lung ventilations, reduced to 5 mL/kg and 5cm H2O positive end expiratory pressure (PEEP) during one lung ventilation (OLV) or GII) (n = 15) patients received TEA and the same general anesthesia and mechanical ventilation used in G1. Assessment parameters included hemodynamics, pain severity, total analgesic consumption, and measurement of interleukins (IL) (IL-6 and IL-8) at baseline time after anesthetic induction (TBaseline,); at the end of the abdominal stage of the operation (TAbdo,); 15 minutes after initiation and at the end of OLV (TOLV 15) and (TOLV End) respectively; one and 20 hours after the end of the surgical procedure (TPostop1 and TPostop20), respectively, and patient's outcome also recorded. RESULTS: There was a significant reduction in mean arterial blood pressure (MAP) and pulse rate in GII during the intraoperative period, at Tabdo, TOLV15, and TOLV End (P < 0.05). The mean of systolic blood pressure (SBP) values were significantly lower in GII over all 3 post-operative days (P = 0.001), and the mean diastolic blood pressure (DBP) showed a significant reduction in GII for 16 hours post-operatively (P = 0.001). The mean of heart rate values showed a significant reduction in GII over all 3 post-operative days in comparison to GI (P = 0.001). The mean resting and dynamic VAS scores were significantly reduced in GII at all time periods studied in comparison to G1 (P = 0.001). The daily PCA morphine consumption was markedly decreased in GII compared to GI in the first 3 days post-operatively (P = 0.001). There were significant reductions in blood level of IL-6 and IL-8 in GII compared to G1 over the entire study period (P < 0.05). There were no significant differences in post-operative adverse effects between the 2 groups (P > 0.05). The duration of stay in PACU was significantly decreased in GII (10 ± 2 days) compared to GI (15 ± 3 days) (P = 0.001). LIMITATIONS: This study is limited by its sample size. CONCLUSION: Our study concluded that TEA reduced the systemic pro-inflammatory response and provided optimal post-operative pain relief. Although there were no significant differences in adverse events, there was a trend towards improved outcome. Further clinical studies with larger numbers of patients are required.

Long-term antalgic effects of repetitive transcranial magnetic stimulation of motor cortex and serum beta-endorphin in patients with phantom pain.

OBJECTIVES: To assess the long-term analgesic effect of repetitive transcranial stimulation (rTMS) on chronic phantom pain using high frequency stimulation and to measure the serum beta-endorphin level pre- and post-rTMS. MATERIAL AND METHODS: The study included 27 patients with unilateral amputation; all patients had chronic phantom pain. The patients were classified into two groups. Seventeen patients received 10 minutes real rTMS over the hand area of motor cortex (20 Hz, 10 second trains, intensity 80% of motor threshold) every day for five consecutive days and 10 patients received sham stimulation. Pain was assessed using a visual analogue scale (VAS) and the Leeds assessment of neuropathic symptoms and signs (LANSS) scale, before and after the first, fifth sessions, one and two months after the last session. Quantitative determination of serum beta-endorphin before and after five sessions was measured. RESULTS: There was no significant difference between true and sham groups in the duration of illness, VAS, LANSS scores and resting motor threshold in upper and lower limb amputation at the base line. VAS and LANS scores of the patients who received real rTMS decreased more over the course of the treatment through the different points of follow-up (after five sessions, one and two months) than those who received sham stimulation. Serum beta-endorphin was increased significantly after real stimulation with no changes in patients received shame. Serum beta-endorphin showed no significant correlation to Hamilton depression, anxiety, VAS and LANS scores in true or sham groups before or after five sessions for rTMS. CONCLUSION: These results confirm that five daily sessions of rTMS over motor cortex can produce long lasting pain relief in patients with phantom pain and it might be related to an elevation of serum beta-endorphin concentration.