Effect of Transcranial Direct Current Brain Stimulation of the Motor Cortex on Chemotherapy-Induced Nausea and Vomiting in Female Patients with Breast Cancer.

OBJECTIVE: Chemotherapy-induced nausea and vomiting (CINV) is an adverse outcome associated with chemotherapy and is sometimes difficult to manage. This study aimed to examine the impact of a single session of transcranial direct current brain stimulation (tDCS; 2 mA) over the motor cortex for 20 minutes before chemotherapy in patients receiving a highly emetogenic chemotherapy. STUDY DESIGN: Prospective randomized double-blind sham-controlled study. SETTING: Academic medical center. METHOD: Sixty patients with breast cancer who were scheduled for chemotherapy treatment were selected and allocated randomly into two equal groups: a stimulation group and a sham group. tDCS was implemented over the primary motor area (M1) (2 mA) for 20 minutes. Patients' nausea was measured by a cumulative index of nausea, a visual analog scale for nausea (VAS-N), episodes of vomiting, and the Edmonton Symptoms Assessment Scale (ESAS) to assess symptoms like pain, malaise, and sense of well-being. Evaluation was done before stimulation and every 24 hours for 72 hours after the end of infusion of chemotherapy. RESULTS: The tDCS group showed a reduction in the cumulative index of nausea (P < 0.001, F = 50), the VAS-N (P < 0.001, F = 52), the ESAS malaise score (P < 0.001, F = 37.6), and the sense of well-being score (P < 0.001, F = 25) vs the sham group. Six patients (20%) in the tDCS group required rescue antiemtic therapy vs 14 patients (46.7%) in the sham group (P < 0.028). CONCLUSION: A single session of M1 tDCS is suggested as an effective adjuvant therapy to control CINV in female patients suffering from breast cancer and receiving highly emetogenic chemotherapy. Corroboratory studies are needed.

Preemptive Stem Cells Ameliorate Neuropathic Pain in Rats: A Central Component of Preemptive Analgesia.

The present study aims to investigate the efficacy of intravenously injected mesenchymal stem cells (MSCs) in treating neuropathic pain either before or after its induction by a chronic constriction injury (CCI) model. Rats were divided into four groups: control group, neuropathic group, and treated groups (pre and postinduction) with i.v. mononuclear cells (106 cell/mL). For these rats, experimental testing for both thermal and mechanical hyperalgesia was evaluated. The cerebral cortex of the rats was dissected, and immunohistochemical analysis using anti-proliferating cell nuclear antigen (PCNA), CD117, nestin, and glial fibrillary acidic protein was performed. Our results showed that a single injection of MSCs (either preemptive/or post-CCI) produced equipotent effects on allodynia, mechanical hyperalgesia, and thermal response. Immunohistochemical analysis showed that the stem cells have reached the cerebral cortex. The injected group with MSCs before CCI showing few stem cells expressed PCNA, CD117, and nestin in the cerebral cortex. The group injected with MSCs after CCI, showing numerous recently proliferated CD117-, nestin-, PCNA-positive stem cells in the cerebral cortex. In conclusion, our findings demonstrate that the most probable effect of i.v. stem cells is the central anti-inflammatory effect, which opens concerns about how stem cells circulating in systemic administration to reach the site of injury.

Reactive Astrogliosis in an Experimental Model of Fibromyalgia: Effect of Dexmedetomidine.

To our knowledge, this is the first study which investigates the induction of neuroinflammation in rats using an acidic-saline model of fibromyalgia. It is well known that the hippocampus has a fundamental role in pain perception, and astrocytes play a crucial role in pain signaling. Our aim is to evaluate the ability of dexmedetomidine to attenuate the inflammatory responses induced in astrocytes. In a group of healthy rats, induction of chronic muscle pain by intramuscular injection of 100 µL of acidic saline on days 0 and 5 resulted in peripheral sensitization (measured using the von Frey test) and significant (p < 0.05) increases in IL-1ß (160.2 ± 1.1 to 335.2 ± 1.8), IL-6 (100.1 ± 1.4 to 202.4 ± 1.1), and TNF-α (60.0 ± 0.7 to 115.5 ± 1). Light and electron microscopy revealed degenerative changes in the hippocampus and reactive astrogliosis. Immunohistochemistry showed increased expression of glial fibrillary acid protein and inducible nitric oxide synthase. Surprisingly, treatment with a single dose of an α2-adrenergic agonist, dexmedetomidine (5 µg/kg i.p.), attenuated these changes. This trial suggests that dexmedetomidine possibly directly acts on astrocytes, and a peripheral action is also suggested.

Effect of Transcranial Direct Current Stimulation of the Motor Cortex on Visceral Pain in Patients with Hepatocellular Carcinoma.

Objective: Hepatocellular carcinoma (HCC) is frequently associated with visceral pain. Transcranial direct current stimulation (tDCS) has been proven to reduce chronic pain; however, its effectiveness in malignant visceral pain is unknown. This study aimed to investigate the effects of tDCS in patients with visceral pain due to HCC. Design: This is a randomized, sham-controlled, double-blind, prospective study. Forty patients with visceral pain due to HCC were enrolled and randomly assigned into two groups: a real and a sham group; tDCS was applied over the primary motor area (M1) for 10 consecutive days (2 mA, 30 minutes). Patient's pain was evaluated by visual analog scale (VAS) and verbal descriptor scale (VDS) and for depression by Hamilton rating scale (HAM-D). Evaluation was done at prestimulation, after the first, fifth, and 10th sessions, and one month after the end of stimulation sessions. Results: Real tDCS showed a reduction of VDS (P = 0.001, F = 4.01) and VAS (P = 0.001, F = 6.817) for HAM-D (P = 0.012, F = 5,077); the effect started from the fifth session and continued to one month after stimulation, while in the sham group the effect persisted for five days only. Percentage reduction in all scales in the real group after the 10th session was as follows: VDS P = 0.008, VAS P = 0.001, HAM-D = 0.001; for one month after the end of stimulation, it was as follows: VDS P = 0.001, VAS P = 0.037, HAM-D = 0.002. Conclusions: tDCS proved to be an effective and clinically relevant therapeutic strategy for visceral pain due to HCC.

Effects of transcranial direct current stimulation on pain, mood and serum endorphin level in the treatment of fibromyalgia: A double blinded, randomized clinical trial.

BACKGROUND: Recent studies have shown that novel neuro-modulating techniques can have pain-relieving effects in the treatment of chronic pain. The aim of this work is to evaluate the effects of transcranial direct current stimulation (tDCS) in relieving fibromyalgia pain and its relation with beta-endorphin changes. MATERIAL AND METHODS: Forty eligible patients with primary fibromyalgia were randomized to receive real anodal tDCS or sham tDCS of the left motor cortex (M1) daily for 10 days. Each patient was evaluated using widespread pain index (WPI), symptom severity of fibromyalgia (SS), visual analogue scale (VAS), and determination of pain threshold as a primary outcome. Hamilton depression and anxiety scales (HAM-D and HAM-A) and estimation of serum beta-endorphin level pre and post-sessions were used as secondary outcome. All rating scales were conducted at the baseline, after the 5th, 10th session, 15 days and 1 month after the end of the sessions. RESULTS: Eighteen patients from each group completed the follow-up schedule with no significant difference between them regarding the duration of illness or the baseline scales. A significant TIME × GROUP interaction for each rating scale (WPI, SS, VAS, pain threshold, HAM-A, HAM-D) indicated that the effect of treatment differed in the two groups with higher improvement in the experimental scores of the patients in the real tDCS group (P = 0.001 for WPI, SS, VAS, pain threshold, and 0.002, 0.03 for HAM-A, HAM-D respectively). Negative correlations between changes in serum beta-endorphin level and the changes in different rating scales were found (P = 0.003, 0.003, 0.05, 0.002, 0002 for WPI, SS, VAS, HAM-A, and HAM-D respectively). CONCLUSION: Ten sessions of real tDCS over M1 can induce pain relief and mood improvement in patients with fibromyalgia, which were found to be related to changes in serum endorphin levels. ClinicalTrials.gov Identifier: NCT02704611.

The effects of dexmedetomidine alone and in combination with tramadol or amitriptyline in a neuropathic pain model.

BACKGROUND: Interactions between the sympathetic and somatic nervous system play an essential role in the pathophysiologic mechanisms of neuropathic pain. The α2-adrenoceptor agonists produce effective antinociception, but sedation is an important adverse effect. Multidrug therapy is potentially valuable to decrease side effects. OBJECTIVE: The aim of the present study was to investigate the possible antinociceptive effect of dexmedetomidine, an α2-adrenoceptor agonist, and its combination with front-line treatment of neuropathic pain, i.e., amitriptyline or tramadol, in a chronic constriction injury (CCI) model of the sciatic nerve in rats. STUDY DESIGN: Controlled animal study. METHODS: Following unilateral ligation of the left sciatic nerve, the effect of intraperitoneal (i.p.) dexmedetomidine (5 ug/kg), tramadol (5 mg/kg), and amitriptyline (30 mg/kg) on mechanical allodynia (measured by electrical von Frey apparatus) and hyperalgesia (measured by Randall and Selitto test) was studied. RESULTS: The sham-operated rats and un-operated hind paw (right paw) press normally on the floor reproduced by a weighted pain score of 0. Behavioral and mechanical tests confirmed the development of neuropathic pain after CCI. All individual drugs and dexmedetomidine combination with either tramadol or amitriptyline were effective in reducing mechanical allodynia and hyperalgesia. Dexmedetomidine, amitriptyline, tramadol, amitriptyline+dexmedetomidine, and tramadol+dexmedetomidine combination did not produce any sedation/motor impairment (P > 0.05). LIMITATIONS: Although the combination of these drugs improved the CCI model of neuropathic pain in this study, an additional interpretation of the underlying mechanism(s) will be needed to confirm these findings. CONCLUSION: The combination of these drugs appears to be more effective in increasing the pain threshold after peripheral nerve injury, when compared with the administration of either of amitriptyline or tramadol alone and should be considered as a possible alternative to decrease side effects of individual drug therapy.

Comparative evaluation of the effect of tricyclic antidepressants on inducible nitric oxide synthase expression in neuropathic pain model.

The analgesic effect of acute i.p. administration of amitriptyline (norepinepherine and serotonin reuptake inhibitor), clomipramine (serotonin reuptake inhibitor) and desipramine (norepinepherine reuptake inhibitor) was studied in chronic constriction injury (CCI) model of sciatic nerve in rats and mRNA and protein expression of inducible nitric oxide synthase (iNOS) were also investigated. Acute treatment with amitriptyline and clomipramine produced antinociceptive effects after sciatic nerve injury and blockade of norepinephrine reuptake using desipramine did not demonstrate antinociceptive effects. The antinociceptive effect of amitriptyline, not clomipramine, was augmented by the selective iNOS inhibitor, aminoguanidine. Amitriptyline inhibited iNOS mRNA and protein expression in cerebellum and hippocampus. However, desipramine altered neither iNOS expression at mRNA level nor at post-transcriptional level. Based on our experimental findings, we conclude that the analgesic effect of the dual norepinepherine and serotonin reuptake inhibitor, amitriptyline, is partially due to inhibition of central iNOS.

The effect of rectal ozone on the portal vein oxygenation and pharmacokinetics of propranolol in liver cirrhosis (a preliminary human study).

AIM: The aim of this study was to investigate the effect of rectal ozone on portal vein oxygenation and the pharmacokinetic changes of propranolol in patients with liver cirrhosis. METHODS: Fifteen patients with liver cirrhosis were included They were given a fixed oral dose of propranolol 80mg on the morning of day 1 after overnight fasting. Blood samples were collected at fixed time intervals for 24h. Patients were given 12 sessions of rectal ozone of 300ml of 40% ozone/oxygen mixture. On day 14 another oral dose of 80mg propranolol was given and blood samples were collected as on day 1. Plasma concentrations of propranolol were measured by HPLC. Portal vein oxygen tension and saturation were measured before and after rectal ozone. RESULTS: Plasma concentrations of propranolol were reduced after ozone therapy with pronounced decreases in the maximum plasma concentration and the area under the plasma concentration-time curve. The changes were consistent with a decrease in propranolol bioavailability. There was a decrease in the elimination half-life and mean residence time. Portal vein oxygenation significantly increased after rectal ozone. CONCLUSIONS: The changes in the pharmacokinetics of propranolol probably reflect an increase in the rate and extent of its metabolism resulting from improved portal vein oxygenation attributable to the ozone therapy. The present work highlights that ozone can be an alternative medical measure to improve portal vein oxygenation in liver cirrhosis.

Pharmacokinetics of oral tramadol in patients with liver cancer.

BACKGROUND: There are no studies reported on pharmacokinetics of opioids in patients with hepatocellular carcinoma, the fifth most common cancer in the world. METHODS: The authors have studied the pharmacokinetic profile of oral tramadol (50 mg) capsule in 20 patients with liver carcinoma (10 with primary carcinoma on top of chronic hepatitis C and 10 with secondary metastatic liver malignancy as a result of other primary) compared with 10 healthy controls. Plasma tramadol concentrations were measured in venous samples at intervals up to 12 hours by high-pressure liquid chromatography. Allpharmacokinetic variables were evaluated using one-compartment model. RESULTS: Tramadol bioavailability showed a substantial increase in patients with primary liver cancer and secondary metastatic than that of control (98 percent, 75 percent, and 68 percent, respectively). The area under the serum concentration-time curve increased significantly in patients with primary and metastatic cancer of liver than in control [1,933 microg/h/L (SD = 41), 1,327 microg/h/L (SD = 51), 1,138.5 microg/h/L (SD = 31), respectively]. Also, a significant difference in Cmax and Tmax was found between patients with malignant liver and control. Reduced clearance and impaired elimination was significantly observed in patients with liver carcinoma than control. Clearance was reduced to 50 percent of control, and elimination halflife increased up to three folds in patients with primary liver carcinoma than that of control. Satisfactory pain relief with minimal side effects was observed all over study period. CONCLUSION: It is recommended to lengthen the dose interval of oral tramadol, if it is to be used in patients with liver cancer for analgesic purposes, to 50 mg every 12 hours as it is proved to be effective and safe.

Complete primary repair of bladder exstrophy: initial experience with 33 cases.

PURPOSE: We evaluated our initial experience with complete primary repair of bladder exstrophy in 33 children. MATERIALS AND METHODS: Between 1998 and 2001, 33 children with classic bladder exstrophy were treated with 1-stage primary repair for the first time in all except 4, who had undergone previous failed initial bladder closure. Our series included 26 boys and 7 girls with a mean age of 2 months (range 3 weeks to 14 months). The bladder was closed in continuity with the urethra and complete penile disassembly was used for epispadias repair. Anterior transverse innominate osteotomy was performed in all cases. Combined general and caudal anaesthesia were applied in all cases with an indwelling epidural caudal catheter in 7. RESULTS: Median followup was 42 months (range 24 to 62). Enterocystoplasty was needed in 3 cases during primary repair of a small bladder plate. Wound dehiscence was not recorded. Bladder neck fistula was reported in 2 children, while urethral fistula was recorded in 1 boy. Abdominal ultrasound detected no hydronephrosis in all except 3 patients. Voiding cystourethrogram showed vesicoureteral reflux in 6 patients. No loss of renal function or febrile urinary tract infection was recorded. A dry interval of 3 hours or greater was reported in 24 children (72.7%), while 9 who were incontinent of urine after failed toilet training needed other procedures to achieve continence. CONCLUSIONS: Complete primary repair with penile disassembly provides a good approach to achieve this purpose without the need for bladder neck reconstruction in some cases. Selection of the proper surgical technique together with adjunctive procedures such as osteotomy and a pain-free early postoperative period can maximize the chance of successful exstrophy repair.