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Methylphenidate hydrochloride (MPH/Ritalin) is a stimulant used for off-label management of cancer-related fatigue and sedation; however, its use in pain treatment is still relatively rare. This study 1) compares the antinociceptive effect of MPH and its combination with morphine (MOR) in adult male Wistar rats after a single administration of MPH, MOR or their combination, and 2) compares the analgesic effects of opioids and Ritalin combined therapy with opioid monotherapy in patients with cancer pain. To objectively assess physical activity during a three-week monitoring period, patients were equipped with Actiwatch Score Actigraph. Patients performed daily evaluations of pain intensity and frequency, and the extent to which pain interfered with their daily life. Our research with rats supports the evidence that MPH in lower doses has the ability to enhance the analgesic properties of morphine when the two drugs are used in combination. Results from the patient arm of our study found that short-term treatment had no significant effect on intensity or frequency of pain, however it decreased the overall burden of pain; the combined treatment of opioid and Ritalin also showed anti-sedation effects and resulted in mild improvement in one of our patient’s quality of life.

This review, which summarizes our findings concerning the long-term effects of pre-, peri- and postnatal factors affecting development, nociception and sensorimotor functions, focuses on three areas: 1) perinatal factors influencing nociception in adult rats were examined in rats with hippocampal lesions, after the administration of stress influencing and psychostimulant drugs (dexamethasone, indomethacine and methamphetamine); 2) the effect of pre- and early postnatal methamphetamine administration was shown to impair the development of sensorimotor functions tested in rat pups throughout the preweaning period; 3) the effect of extensive dorsal rhizotomy of the brachial plexus during the early postnatal period was studied with respect to neuropathic pain development and sensorimotor functions. The present study indicates that prenatal or neonatal stress, as well as various drugs, may disturb the development of the nociceptive system and cause long-term behavioral changes persisting to adulthood and that some types of neuropathic pain cannot be induced during the first two postnatal weeks at all. A mature nervous system is required for the development of the described pathological behaviors.

Repetitive transcranial magnetic stimulation (rTMS) is non-invasive neuromodulation method. We applied rTMS for the treatment of farmacoresistant chronic orofacial pain. We compared the effect of 10 Hz and 20 Hz stimulation. The study included 23 patients for 20 Hz stimulation and 36 patients for 10 Hz stimulation with pharmacotherapy resistant chronic facial pain aged 33-65 years with pain duration of at least 6 months. Monitoring of treatment effects was performed within 15 minutes of each rTMS application (days 1-5) and finally stimulation (active vs. sham coil). If compared with data with 10 Hz rTMS study (n=36) and with 20 Hz rTMS (n=23) trials using a parallel design. Only the results obtained in a series of five rTMS treatments in the first step (active n=24, sham n=12), that 20 Hz frequency rTMS using a higher intensity (95 % of motor threshold) to be equally effective relative to VAS (Visual analogue scale) and QST (quantitative sensory testing). In conclusions, the better results with the relief of orofacial pain were obtained with 20 Hz stimulation if compared with 10 Hz stimulation. It was proved with subjective (VAS) and objective evaluation (QST). rTMS can be used in the treatment of chronic intractable pain.

The main neuromodulatory methods using neurostimulation principles are described. It concerns peripheral nerve stimulation (PNS), spinal cord stimulation (SCS), deep brain stimulation (DBS), motor cortex stimulation (MSC), and repetitive transcranial magnetic stimulation (rTMS). For each method the history, pathophysiology, the principles for use and the associated diagnoses are mentioned. Special attention is focused on the most common neuromodulatory invasive methods like SCS and MCS and non-invasive methods such as rTMS. In addition to the positive effects, side effects and complications are described and discussed in detail. In conclusion, neuromodulatory (neurostimulatory) techniques are highly recommended for the treatment of different types of pharmacoresistant pain.

Background: To compare the number of severe periprocedural bleeding complications from the total number of bleeding complications associated with diagnostic selective coronary an­giography or percutaneous coronary intervention (PCI) when using different classifications (TIMI, GUSTO, PLATO, BARC) and to relate these classifications to real hemodynamic status of evaluated patients. Methods: We analyzed data from 106 patients who underwent invasive procedure for ischemic heart disease (selective coronary angiography/PCI) and suffered from any type of bleeding complication. Results: The number of bleeding according to impacts on hemodynamic status and consequent treatment shows that 54.7% of all bleedings did not need any specific therapy. Bleeding leading to death, hemorrhagic shock, hemodynamic instability, administration of blood transfusion, surgical procedure and local treatment occurred in 6.6%, 1.9%, 5.7%, 14.2%, 2.8%, and 14.2%, respectively. The results comparing bleeding classifications demonstrate that the rate of severe bleeding complications may increase up to 4 times when different classifications are used on the same group of patients (TIMI 9.4%, GUSTO 15.1%, PLATO 39.2% and BARC 35.9%). The power of association between severe bleeding determined by these classifications and real hemodynamic compromise using Kendall’s tau-c correlation is –0.4106 (95% CI –0.599 to –0.222), –0.5355 (95% CI –0.718 to –0.353), –0.5513 (95% CI –0.729 to –0.374) and –0.7552 (95% CI –0.897 to –0.612) for TIMI, GUSTO, PLATO and BARC, respectively. Conclusions: The data show significant dependence of percentage of severe periprocedural bleeding complications on selected classification. The strongest association between severe bleeding and real hemodynamic status was found for BARC classification as this classification seems to be promising for future general use.

Drug abuse of pregnant women is a growing problem. The effect of prenatal drug exposure may have devastating effect on development of the offsprings that may be long-term or even permanent. One of the most common drug abused by pregnant women is methamphetamine (MA), which is also the most frequently abused illicit drug in the Czech Republic. Our previous studies demonstrated that prenatal MA exposure alters behavior, cognition, pain and seizures in adult rats in sex-specific manner. Our most recent studies demonstrate that prenatal MA exposure makes adult rats more sensitive to acute injection of the same or related drugs than their controls. The aim of the present study was to examine the effect of prenatal MA exposure on drug-seeking behavior of adult male rats tested in the Conditioned place preference (CPP). Adult male rats were divided to: prenatally MA-exposed (5 mg/kg daily for the entire prenatal period), prenatally saline-exposed (1 ml/kg of physiological saline) and controls (without maternal injections). The following drugs were used in the CPP test in adulthood: MA (5 mg/kg), amphetamine (5 mg/kg), cocaine (5 and 10 mg/kg), morphine (5 mg/kg), MDMA (5 mg/kg) and THC (2 mg/kg). Our data demonstrated that prenatally MA-exposed rats displayed higher amphetamine-seeking behavior than both controls. MA as well as morphine induced drug-seeking behavior of adult male rats, however this effect did not differ based on the prenatal MA exposure. In contrast, prenatal MA exposure induced rather tolerance to cocaine than sensitization after the conditioning in the CPP. MDMA and THC did not induce significant effects. Even though the present data did not fully confirmed our hypotheses, future studies are planned to test the drug-seeking behavior also in self-administration test.

The aim of the present study was to compare the response to acute application of several drugs in adult male and female rats prenatally exposed to methamphetamine (MA). Spontaneous locomotor activity and exploratory behavior of adult male and female rats prenatally exposed to MA (5 mg/kg) or saline were tested in a Laboras apparatus (Metris B.V., Netherlands) for 1 h. Challenge dose of the examined drug [amphetamine – 5 mg/kg; cocaine – 5mg/kg; MDMA (3,4-methylenedioxymethamphetamine) – 5 mg/kg; morphine – 5 mg/kg; THC (delta9-tetrahydrocannabinol) – 2 mg/kg] or saline was injected prior to testing. Our data demonstrate that prenatal MA exposure did not affect behavior in male rats with cocaine or morphine treatment, but increased locomotion and exploration in females. Application of amphetamine and MDMA in adulthood increased activity in both sexes, while cocaine and THC only in female rats. Morphine, on the other hand, decreased the activity in the Laboras test in both sexes. As far as sex and estrous cycle is concerned, the present study shows that males were generally less active than females and also females in proestrus-estrus phase of the estrous cycle were more active than females in diestrus. In conclusion, the present study shows that the prenatal MA exposure does not induce general sensitization but affects the sensitivity to drugs dependently to mechanism of drug action and with respect to gonadal hormones.

We have recently demonstrated that selective inducible nitric oxide (NO) synthase (iNOS) inhibition with 1400W attenuated the hemodynamic and metabolic alterations affiliated with hyperdynamic porcine endotoxemia. In contrast to endotoxemia, limited evidence is available to document a relationship between NO and organ dysfunction in large animal bacteremic models. Therefore, using the same experimental setup, we investigated the role of selective iNOS blockade in porcine bacteremia induced and maintained for 24 h with a continuous infusion of live Pseudomonas aeruginosa. After 12 h of sepsis, animals received either vehicle (Control, n = 8) or continuous infusion of selective iNOS inhibitor, L-N6-(1-iminoethyl)-lysine (L-NIL; n = 8). Measurements were performed before, and 12, 18, and 24 h after P. aeruginosa infusion. L-NIL inhibited sepsis-induced increase in plasma nitrate/nitrite concentrations and prevented hypotension without affecting cardiac output. Despite comparable hepatosplanchnic macrocirculation, L-NIL blunted the progressive deterioration in ileal mucosal microcirculation and prevented mucosal acidosis. L-NIL largely attenuated mesenteric and hepatic venous acidosis, significantly improved P. aeruginosa-induced impairment of hepatosplanchnic redox state, and mitigated the decline in liver lactate clearance. Furthermore, the administration of L-NIL reduced the hepatocellular injury and prevented the development of renal dysfunction. Finally, treatment with L-NIL significantly attenuated the formation of 8-isoprostane concentrations, a direct marker of lipid peroxidation. Thus, selective iNOS inhibition with L-NIL prevented live bacteria from causing key features of metabolic derangements in porcine hyperdynamic sepsis. Underlying mechanisms probably include reduced oxidative stress with improved microcirculatory perfusion and restoration of cellular respiration.

Theta burst stimulation (TBS) is a modified form of high-frequency repetitive transcranial magnetic stimulation (rTMS) with promising effect in chronic pain. The aim of our double-blind, sham-controlled, parallel-group, randomized study was to assess an efficacy of intermittent TBS (iTBS) in the treatment of patients with chronic orofacial pain. Nineteen patients (twelve females) with chronic orofacial pain were prospectively included and randomly assigned to single session of an active (iTBS) or sham (intermediate TBS; imTBS) stimulation delivered to the primary motor cortex (M1) contralateral to painful side. The primary outcome was pain relief assessed using a visual analogue scale (VAS) after stimulation and at the end of two-week follow- up. The secondary outcomes were changes in the quantitative sensory testing (QST). QST set the threshold for thermal and tactile (touch) sensation in the affected facial area. Intermittent TBS, compared with the sham, showed significant improvement in VAS after stimulation, but not at the end of two-week follow-up. Regarding the secondary outcomes (QST), we failed to find any significant difference between iTBS and sham. Our findings demonstrate that iTBS of M1 transiently provides transient and modest subjective pain relief in chronic orofacial pain.