Numerical Analysis of Transcranial Magnetic Stimulation Application in Patients With Orofacial Pain.

In this paper, we monitored the accuracy of non-navigated application of repetitive Transcranial Magnetic Stimulation (rTMS) in 10 patients suffering from orofacial pain by using functional magnetic resonance (fMRI), computer modeling and numerical simulation. Through a unique process, each fMRI scan was used to define a Region of Interest (ROI) where the source of the orofacial pain was located, which was to be stimulated using rTMS. For each patient, MRI scans with a spatial resolution of 0.7 mm were converted into an anatomically accurate head model. The head model including the ROI was then co-registered with a model of the stimulation coil in an electromagnetic field numerical simulator. The accuracy of rTMS application was evaluated based on the calculations of electric field intensity distribution in the ROI. The research has yielded unique insight into ROIs (with average volume 904 mm3) in patients with orofacial pain and has also extended further possibilities of human head MRI image semi-automatic segmentation. According to the calculations performed, the average ROI volume that was stimulated by an electric field with an intensity of over 80 V/m was only 4.4%, with the maximum ROI volume being 20.5%. Furthermore, a numerical study of the impact of coil rotation and translation was performed. It demonstrated a) the optimal placement of the stimulation coil can significantly increase the volume of the stimulated ROI up to 60% and b) patients with orofacial pain would need precise coil positioning with a navigation error lower than 10 mm. Due to an acceptable proccessing time of up to 6 hours, described numerical simulation opens up new options for precise rTMS treatment planning. This planning platform together with patient-specific navigated rTMS, could lead to significant increase of treatment outcomes in patients suffering from orofacial pain.

A Prospective Single-Center Study of the Effects of Repetitive Transcranial Magnetic Stimulation at 2-Week Follow-Up in 17 Patients with Chronic Orofacial Pain Diagnosed by Infrared Thermography.

BACKGROUND Infrared thermography is a diagnostic method used to monitor acute and chronic orofacial pain syndrome. Repetitive transcranial magnetic stimulation (rTMS) is a form of non-invasive brain stimulation. This prospective study from a single center aimed to investigate the effects of rTMS and used infrared thermography as a confirmatory test of orofacial pain. MATERIAL AND METHODS We used infrared thermography to examine the incidence of inflammatory changes as orofacial pain triggers. During the analysis of rTMS effects on patients with orofacial pain, we compared the decrease in pain and the thermal difference in the study group (n=17) and in the research group (n=13). RESULTS In the control group (n=13), there were no statistically significant changes. Both groups showed a significant decrease in self-reported pain. Numerical pain rating scores were significantly lower after S2 stimulation than after S1/M1 (P=0.0071) or sham (P=0.0187) stimulation. The Brief Pain Inventory scores were also lower 3 to 5 days after S2 stimulation than at the pretreatment baseline (P=0.0127 for the intensity of pain and p=0.0074 for the interference of pain), and after S1/M1 (P=0.001 and P=0.0001) and sham (P=0.0491 and P=0.0359) stimulations. CONCLUSIONS The findings from this study support the role of infrared thermography for the diagnosis of chronic orofacial pain, and showed that on the first and fifth days of rTMS therapy in the study group there was a significant reduction of the thermography findings when compared with the control group without rTMS therapy.

Indications for venous access in oncology - recommendations of national professional societies and current state in the Czech Republic.

BACKGROUND: The aim of the paper is to present the current recommendations and indications of venous access in oncology which reflect and recognize the opinions of national and international professional societies. It focuses exclusively on the indications of intravenous catheter placement for anticancer treatment, such as medium-term and long-term venous accesses. MATERIALS AND METHODS: The survey results obtained from a national questionnaire of 24 oncology centers identified the current situation in the Czech Republic. There were evaluated relevant data on the number of and the criteria for the introduction of venous accesses provided by physicians. Comparisons were made between current oncological practice and recommendations provided by evidence-based medicine. RESULTS: At each center surveyed in the Czech Republic, an average of 130 ports and 80 permanent implanted central catheters are introduced annually. The ports are increasingly indicated, with over a half of the centers surveyed introducing ports to more than 100 patients a year, with four centers introducing a total of 1,600 ports annually. In all centers, the decision for venous access is made by an oncologist. However, most procedures are performed by a doctor of another specialization, most often by a surgeon, a radiologist or an anesthesiologist. More than a half of the indications for venous access placement result from poor peripheral venous system or complications of parenteral therapy, not from comprehensive assessment prior to the initiation of the therapy. CONCLUSION: Based on our findings, we developed general indications and recommendations for venous access to cancer patients which represent the consensus of an interdisciplinary team of specialists, predominantly from the committee of professional societies - the Society for Ports and Permanent Catheters, the Working Group of Nutritional Care in Oncology of the Czech Oncological Society and the Society of Clinical Nutrition and Intensive Metabolic Care. The number of introduced venous access catheters remains insufficient to meet the needs in the Czech Republic, which necessitates increased awareness and possibilities for safe drug administration.

Transcranial Neurostimulation (rTMS, tDCS) in the Treatment of Chronic Orofacial Pain.

Although commonly seen in the clinical practice, chronic orofacial pain quite often does not have a clear unambiguous organic origin. It may be difficult to find optimal pharmacotherapy, and in many cases, this pain may become pharmacotherapy resistant. Neuromodulation, particularly with electromagnetic neurostimulation techniques, has been widely used for the treatment of different types of pharmacoresistant pain, and repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) exemplify readily available noninvasive neuromodulation methods. We have used rTMS and tDCS to treat pharmacoresistant chronic orofacial pain. rTMS uses an electromagnetic coil placed over the patient's head to induce electrical current impulses within the brain tissue, thereby modulating brain activity. In tDCS, an electrode placement location(s) must be chosen in accordance with the density and the time course of the current, mainly to prevent undesired pathological changes in the underlying tissue. Transcranial neuromodulation methods provide a nondestructive and reversible approach to treatment of severe and otherwise uncontrollable chronic orofacial pain. These methods may be curative - as a part of so called "reconstructive neurosurgery" stimulation of neural structures may be used as an alternative to surgical destruction of neural pathways.

Tapentadol in an Experimental Animal Model of Acute Orofacial Pain.

OBJECTIVE: Tapentadol exhibits a synergistic dual effect effect (MOR / NRI) -agonist effect on noradrena-line reuptake inhibition (NRI). Tapentadol is effective on pain with neuropathic characteristics, therefore we decided to use it in an experimental model of acute orofacial pain. METHODS: The Orofacial Stimulation Test, developed by Ugo Basile, measures hypersensitivity to thermal or mechanical stimulation of the trigeminal area. In the experiment, rats had to voluntarily contact a thermal or mechanical stimulator with their unshaved vibrissal pad in order to access a food reward. Twenty adult laboratory rats (average weight 345 grams) were tested. Intraperitoneal tapentadol was used in doses of 1 mg/kg and 2 mg/kg. RESULTS: The results of the pilot study indicate that intraperitoneal administration of tapentadol (2 mg/kg) increased mechanical anti-nociception in rats.

Thermovision: a new diagnostic method for orofacial pain?

BACKGROUND: Infrared thermography can be used to obtain more complete information about a patient's condition. The method can be used in various medical applications for monitoring acute and chronic orofacial pain syndrome. With this diagnostic method, thermal differences in the examined region are usually compared to the same reference region on the opposite side of the body. METHODS: Infrared quantitative thermography is a non-invasive method for contactless monitoring of dynamic thermal fields on a surface, or in this case, the human body. This method is based on detection of infrared radiation, which is naturally emitted from the surface of the body. In a pilot project with a patient having orofacial pain, changes before and after repetitive transcranial magnetic brain stimulation treatment were assessed. RESULTS: First-day measurements found significantly higher maximum, minimum, and average temperatures, before and after therapy, in the area where the patient subjectively reported pain. The fifth and final measurements, before and after therapy, found only a slight elevation of the maximum temperature of the assessed regions, relative to the same regions on the opposite side of the face. CONCLUSION: During the measurements on the fifth day, a thermal difference greater than 0.4°C was only observed relative to the minimum temperatures associated with the regions of self-reported pain before and after therapy. For validation of the effects, this method will need to be tested using a randomized, double-blind study with a larger number of patients.

[Non-opioid analgesics]. / Neopioidní analgetika.

Non-opioid analgesics are commonly used to treat mild and moderate acute and chronic pain. They can be used as monotherapy; however, they have greater efficacy in combination with weak and strong opioids. Unlike opioids, long-term use of non-steroidal anti-inflammatory drugs does not lead to physical dependence. One of the main disadvantages of the NSA is the risk of gastrointestinal side effects, especially bleeding into the digestive tract. This is increased especially in ulcerative disease and in higher doses, but also in the elderly (over 65 years), also with concomitant administration of corticosteroids, anticoagulants or other NSAIDs.

Noninvasive transcranial direct current stimulation (tDCS) for the treatment of orofacial pain.

OBJECTIVE: tDCS is a promising method for the treatment of chronic pain. Electrode placement locations must be chosen in accordance with the density and the time course of the current in order to prevent pathological changes in the underlying tissue. In order to reduce current spatial variability, more electrodes of the same polarity are placed in a circle around the second electrode of the opposite polarity. The applied current produced the greatest changes directly beneath the electrodes: the cathode reduces the excitability of cortical neurons, while the anode has the opposite effect. METHODS: Based on inclusion criteria, 10 patients with chronic orofacial pain, secondary trigeminal neuralgia after oral surgery, were enrolled and underwent both anode and cathode stimulation. Before the first session we measured pain intensity on a numeric pain rating scale and tactile and thermal stimulation were used to assess somatosensory status. tDCS was applied for five consecutive days. At the end of tDCS application, somatosensory status was assessed again. RESULTS: From our results we can conclude that the application of tDCS improves the perception of some types of pain. When we increase our sample size, we would expect confirmation not only on our positive results, but also some additional findings for explaining the pathophysiology of orofacial pain. These pathophysiological findings and explanations are very important for the application of tDCS in the treatment of orofacial pain and also for other types of neuropathic pain.

The effects of extracorporeal shock wave therapy on pain patients.

The method of shock wave therapy (ESWT) was used for the treatment of several symptoms of chronic pain. There were especially: cervical syndromes, lumbago, plantar fasciitis, achillodynia, metatarsalgia and humeral epicondylitis. We confirmed the positive effect of shock wave therapy for pain relief on these syndromes. This method is also effective in other pain syndromes. The effect of this application is very individual and therefore it is necessary to indicate differing numbers of therapeutic applications. We recommend this method as a very useful tool for completion possibilities in the treatment of chronic pain.

Common mechanisms of pain and depression: are antidepressants also analgesics?

Neither pain, nor depression exist as independent phenomena per se, they are highly subjective inner states, formed by our brain and built on the bases of our experiences, cognition and emotions. Chronic pain is associated with changes in brain physiology and anatomy. It has been suggested that the neuronal activity underlying subjective perception of chronic pain may be divergent from the activity associated with acute pain. We will discuss the possible common pathophysiological mechanism of chronic pain and depression with respect to the default mode network of the brain, neuroplasticity and the effect of antidepressants on these two pathological conditions. The default mode network of the brain has an important role in the representation of introspective mental activities and therefore can be considered as a nodal point, common for both chronic pain and depression. Neuroplasticity which involves molecular, cellular and synaptic processes modifying connectivity between neurons and neuronal circuits can also be affected by pathological states such as chronic pain or depression. We suppose that pathogenesis of depression and chronic pain shares common negative neuroplastic changes in the central nervous system (CNS). The positive impact of antidepressants would result in a reduction of these pathological cellular/molecular processes and in the amelioration of symptoms, but it may also increase survival times and quality of life of patients with chronic cancer pain.

A randomized, placebo-controlled study of a new sublingual formulation of fentanyl citrate (fentanyl ethypharm) for breakthrough pain in opioid-treated patients with cancer.

BACKGROUND: Oromucosal fentanyl is currently used for the treatment of breakthrough pain (BTP) in opioid-treated cancer patients. Ethypharm developed a sublingual formulation of fentanyl suprabioavailable to oral transmucosal fentanyl citrate with a higher early systemic exposure and a shorter Tmax. OBJECTIVES: This study evaluated the efficacy and safety profile of fentanyl Ethypharm (FE) in relieving BTP in opioid-treated cancer patients. METHODS: Opioid-treated adult cancer patients, experiencing 1 to 4 episodes of BTP per day, were included in the study. After an open-label titration period to identify an optimal dose that would provide adequate pain relief for 2 consecutive episodes of BTP with an acceptable level of adverse events, patients were randomly assigned to a double-blind, placebo-controlled, crossover period with 1 of 13 prespecified sequences of 9 tablets (6 tablets of FE of the dose identified during the open-label titration and 3 placebo). Pain intensity and pain relief were recorded at 3, 6, 10, 15, 30, and 60 minutes after study drug administration. Adverse events were recorded. The primary end point was the sum of pain intensity differences (SPID) at 30 minutes. RESULTS: The distribution of optimal dosages of FE was as follows: 133 µg, 35.9%; 267 µg, 30.8%; 400 µg, 14.1%; 533 µg, 12.8%; and 800 µg, 6.4%. In the modified intention-to-treat population (n = 73), FE significantly improved mean (SE) SPID compared with placebo at 30 minutes (75.0 [49.8] vs 52.5 [52.8]; P < 0.0001). FE significantly improved SPID, pain intensity difference, and pain relief compared with placebo from 6 to 60 minutes' postadministration. Patients with BTP who received placebo required the use of rescue medication more often than those treated with FE (38.4% vs 17.5%; P < 0.0001). A significant improvement in pain scores (>33% and >50% reductions) was also reported for BTP treated with FE. Pain scores for patients with BTP with a neuropathic component (13 patients) were lower with FE than for those receiving placebo, but the difference was not significant. AEs were of mild or moderate severity and typical of opioid drugs. CONCLUSIONS: This newly developed galenic formulation with a higher early systemic exposure and a shorter Tmax compared with oral transmucosal fentanyl citrate makes FE a particularly suitable formulation for the management of BTP in opioid-treated cancer patients due to the very rapid onset of action. FE provided significant improvement in pain intensity of BTP compared with placebo as early as 6 minutes' postadministration with a sustained effect over 60 minutes. FE was well tolerated by patients. ClinicalTrials.gov identifier: NCT 01842893.

The influence of pre-emptive analgesia on postoperative analgesia and its objective evaluation.

INTRODUCTION: The evaluation of pain intensity is still a subject of research. Mostly psychological evaluations are used. We started to conduct biochemical evaluation in animal experiments. Now we present biochemical evaluation in postoperative pain in man. MATERIAL AND METHODS: In 67 patients herniotomy was done. For pre-emptive analgesia morphine and pethidine were used and the following indicators were measured: visual analogue scale (VAS), measurement of lipid spectra, saccharides and proteins, thioredoxin, super-oxide dismutase (SOD), glutathione peroxidase (GPx) and NAD(P)H-oxidase (NOX), and free radicals using electron paramagnetic resonance (EPR). Blood samples were taken and tested: before pre-medication and intervention, 4 h after and 24 h after intervention. RESULTS: Free radicals (FR) increased in individual samples during the postoperative course in pethidine and without pre-medication. After application of morphine the FR were insignificantly reduced. Statistically significant differences were found in albumin, prealbumin, apolipoprotein A, total cholesterol, atherosclerotic index, CRP, glucose, and thioredoxin (p ≤ 0.001). A greater difference was seen in VAS values between morphine and pethidine premedications (p ≤ 0.001). CONCLUSIONS: It was proved that the biochemical markers of lipid, protein and saccharide metabolisms and free radicals as well as singlet oxygen can serve as very good indicators of the intensity of pain and nociception. In patients it was proved that pre-emptive analgesia plays an important role in reducing the intensity of postoperative pain. From the three modalities of pre-emptive analgesia morphine represents the best solution.

The effect of laparotomy on hydroxyl radicals, singlet oxygen and antioxidants measured by EPR method in the tails of rats.

OBJECTIVES: The aim of the study was to demonstrate that direct measurement of hydroxyl radicals and singlet oxygen in the tail of living rats is possible. The basic level of hydroxyl radicals and singlet oxygen were measured and the effects of antioxidants on their levels were studied in the tail of living anaesthetized rats after acute postoperative pain. Laparotomy was performed as the source of acute abdominal pain. After closure of the abdominal cavity, the animals began to awaken within 30-60 minutes. They were left to recover for 2-3 hours; then they were reanesthetized and the effect of antioxidants was measured on the numbers of hydroxyl radicals and singlet oxygen via blood in the tail. METHODS: The laparotomy was preformed under general anesthesia (Xylazin and Ketamin) using Wistar rats. After recovery and several hours of consciousness they were reanaesthetized and free radicals and singlet oxygen were measured. An antioxidant mixture (vitamins A, C, D and Selenium) was administered intramuscularly prior to the laparotomy. All measurements were done on the tail of anaesthetized animals. In this particular article, the effect of antioxidants is only reported for hydroxyl radicals. RESULTS: After laparotomy, which represented both somatic and visceral pain, hydroxyl radicals and singlet oxygen were increased. Antioxidant application prior to laparotomy decreased the numbers of hydroxyl radicals. CONCLUSION: Results are in agreement with our previous finding regarding the increase in hydroxyl free radicals and singlet oxygen following nociceptive stimulation, in this case a combination of both somatic and visceral pain. The administered antioxidants mitigated the increase. This is further confirmation that direct measurement of free radicals and singlet oxygen represents a very useful method for the biochemical evaluation of pain and nociception.

The evaluation of nociceptive intensity by using free radicals direct measurement by EPR method in the tail of anaesthetized rats.

OBJECTIVES: The aim of the study was to demonstrate the ability to measure free radicals and singlet oxygen, using EPR methods, in the tail of anaesthetized rats. The advantage of this method lies in the potential for continuous evaluation of free radicals and singlet oxygen during nociceptive processes. METHODS: Electron paramagnetic (spin) resonance (EPR/ESR) was used. DMPO and PBN as spin traps and thermal mechanical pulp (TMP) as a spin detector of singlet oxygen were used. Thirty-one adult male (Wistar) rats were used for the experiments. They were housed according to principles of good laboratory practice. The animals were stimulated for 10 minutes on 5 consecutive days by using clamps on the hind limbs. During the EPR measurement they were anaesthetized with a mixture of ketamine and xylazine. Hydroxyl and nitroxide free radicals, as well as singlet oxygen were measured. RESULTS: After nociceptive stimulation, free hydroxyl radicals were increased as well as free nitroxide radicals. Singlet oxygen was also increased after nociceptive stimulation. Antioxidants significantly decreased the increase in hydroxyl radicals after nociceptive stimulation. CONCLUSIONS: Our results confirmed an increase in free radicals and singlet oxygen after nociceptive stimulation and a reduced increase after application of antioxidants. Direct EPR methods were first used in the tail of anaesthetized rats and represent an extremely useful tool for the evaluation of pain intensity in living animals.