The voltage-gated sodium channel subtype NaV1.8 is expressed in the peripheral nervous system in primary afferent nociceptive C-fibers and is essential for noxious cold signaling. We utilized functional magnetic resonance imaging on NaV1.8-deficient (NaV1.8−/−) compared with wildtype (WT) mice to identify brain structures decoding noxious cold and/or heat signals. In NaV1.8−/− mice functional activity patterns, activated volumes and BOLD signal amplitudes are significantly reduced upon noxious cold stimulation whereas differences of noxious heat processing are less pronounced. Graph-theoretical analysis of the functional connectivity also shows dramatic alterations in noxious cold sensation in NaV1.8−/− mice and clearly reduced interactions between certain brain structures. In contrast, upon heat stimulation qualitatively quite the same functional connectivity pattern and consequently less prominent connectivity differences were observed between NaV1.8−/− and WT mice. Thus, the fact that NaV1.8−/− mice do not perceive nociceptive aspects of strong cooling in contrast to their WT littermates seems not only to be a pure peripheral phenomenon with diminished peripheral transmission, but also consists of upstream effects leading to altered subsequent nociceptive processing in the central nervous system and consequently altered connectivity between pain-relevant brain structures.

Acetaminophen/paracetamol is the most widely used drug of the world. At the same time, it is probably one of the most dangerous compounds in medical use, causing hundreds of deaths in all industrialized countries due to acute liver failure ( ALF ). Publications of the last 130 years found in the usual databases were analyzed. Personal contacts existed to renowned researchers having contributed to the medical use of paracetamol and its precursors as H.U. Z ollinger, S . M oeschlin, U . D ubach, J . A xelrod and others. Further information is found in earlier reviews by E ichengrün, Rodnan and B enedek, S neader, B rune; comp. references. The history of the discovery of paracetamol starts with an error (active against worms), continues with a false assumption (paracetamol is safer than phenacetin), describes the first side‐effect ‘epidemy’ (phenacetin nephropathy, drug‐induced interstitial nephritis) and ends with the discovery of second‐generation problems due to the unavoidable production of a highly toxic metabolite of paracetamol N ‐acetyl‐ p ‐benzoquinone imine ( NAPQI ) that may cause not only ALF and kidney damage but also impaired development of the fetus and the newborn child. It appears timely to reassess the risk/benefit ratio of this compound.

Der Arzneimittelkommission der deutschen Ärzteschaft (AkdÄ) wurde im Rahmen des Spontanmeldesystems eine Fallserie von revisionspflichtigen Blutungen nach elektiven gynäkologischen Eingriffen übermittelt, nachdem das Therapieregime für die perioperative Schmerzbehandlung von Diclofenac (150 mg täglich) auf Celecoxib (400 mg täglich) umgestellt worden war. Obwohl alternative Ursachen für die Blutungsereignisse nicht auszuschließen sind, könnten die dokumentierten Umstände auch auf einen möglichen kausalen Zusammenhang hinweisen. In Studien zur perioperativen Schmerzbehandlung mit Celecoxib hat sich bislang kein erhöhtes Blutungsrisiko gezeigt. Die in den gemeldeten Fällen beobachtete Blutungsneigung lässt sich pharmakologisch zunächst nicht erklären, jedoch sind bei den verwendeten hohen Dosierungen von Celecoxib und umfangreicher Begleitmedikation relative Überdosierungen durch Wechselwirkungen oder Besonderheiten im Stoffwechsel der betroffenen Patientinnen denkbar. Celecoxib ist zur Behandlung akuter postoperativer Schmerzen nicht zugelassenen, obwohl eine Reihe von Studien zu Wirksamkeit und Sicherheit bei unterschiedlichen Eingriffen durchgeführt wurden.

A series of cases of postoperative bleeding were reported to the Drug Commission of the German Medical Association (Arzneimittelkommission der deutschen Ärzteschaft, AkdÄ) within the spontaneous reporting system after the regimen for postoperative pain treatment was changed from diclofenac (150 mg per day) to celecoxib (400 mg per day). All patients underwent elective gynecological surgery and 7 out of 11 patients with postoperative bleeding required revision surgery. Although alternative causes for the hemorrhage incidents could not be excluded, the documented circumstances could have been indicative of a possible causal association. Studies on perioperative pain treatment with celecoxib had previously shown no increased risk of hemorrhage. The tendency to hemorrhage observed in the registered cases could not be pharmacologically explained; however, due to the high dosages of celecoxib and the extensive co-medications used, a relative overdosing due to drug interactions or differences in the metabolism of the affected patients was conceivable. Celecoxib is not approved for the treatment of acute postoperative pain although a number of studies were carried out on the effectiveness and safety in patients undergoing surgery.

Non-steroidal, anti-inflammatory drugs (NSAIDs, inhibitors of cyclooxygenases) are still worldwide the most intensively used remedies. These compounds are reliable therapeutics for muscle, joint, back, and traumatic pain. They cause, however, many unwanted side effects. Recently, the propensity of these compounds to cause cardiovascular diseases has been highlighted. As there are no alternatives available, attempts are made to single out those patients who are likely to develop unwanted cardiovascular drug effects when treated with NSAIDs. 2 widely used biomarkers were investigated as predictors of cardiovascular risks aggravated by the treatment with cyclooxygenase inhibitors. We here report on positive results of such evaluations employing the biomarker NTproBNP.

Correction to:Kardiovaskuläre Risiken der Therapie mit Zyklooxygenasehemmern (NSAR): Biomarker als Risikoindikatoren?Aktuelle Rheumatologie 2013; 38(01): 45-49DOI: 10.1055/s-0032-1301928

Tissue damage results in the release of inflammatory mediators, including prostaglandins, which sensitise fine nerve endings in the periphery to mechanical and thermal changes. Sensitisation of these nerve endings, or nociceptors, contributes to the phenomenon of hyperalgesia, which routinely accompanies tissue damage. It has been shown that the acidic antipyretic analgesics reduce or down-regulate the enhanced nociceptor sensitivity in damaged tissue, an effect probably attributable to inhibition of prostaglandin synthesis.

Objective: Administering cyclooxygenase-2 inhibitors preoperatively appears attractive since these drugs reduce post-operative pain, but do not increase the risk of post-operative bleeds, asthmatic attacks and stress-related gastrointestinal ulcers. In a former investigation, we could show that post-operative administration of etoricoxib reduces prostaglandin production in wound fluid, but the onset of action is variable due to delayed post-operative absorption.Methods: In this study, we investigated the preoperative administration of etoricoxib in patients undergoing hip replacement. They received 120 mg etoricoxib or placebo 2 h before surgery and 1 day after in a double-blinded, randomized, parallel group design.Results: A total of 11 patients were randomized (placebo n = 5; verum n = 6). We found high and constant levels of the drug in blood, central nervous system and wound fluid already at the end of surgery (t(max) < 2 h). This was accompanied by inhibition of prostaglandin production in the wound tissue (treatment p < 0.05), suppression of interleukin 6 increase in plasma (treatment p < 0.01), and - despite existing standard pain relief procedures - higher satisfaction with analgesics (time vs. treatment p < 0.05) and less demand for opioids (treatment p < 0.01) and intrathecal bupivacaine (treatment p = 0.05) administration.Conclusion: Administration of etoricoxib 2 h before surgery allows for an effective drug concentration in critical tissues, a reduction of the production of pro-inflammatory mediators and for better pain relief.

Introduction: Resting state or "default-mode" networks (1) refer to brain regions that are correlated and active without any external physical stimulation. These spontaneous low-frequency fluctuations of the resting brain are used to investigate functional connectivity. The “default-mode” network has been hypothesized to play an essential role in creativity, reflect particular thoughts and presents malfunctions for certain pathologies like Alzheimer's disease, autism, and schizophrenia (2). As the “default network” seems to be conserved across mammalian species, resting state functional connectivity studies were extended recently to other species, i.e. monkeys (3) and rats (4). In this study, we used, to our knowledge for the first time, functional connectivity analysis to investigate changes of cerebral resting state processing before and after heat-induced nociception in mice. We compared the resting state network of pain associated brain structures of dynorphin-overexpressing dream transgenic and wild-type mice. Dynorphin is an opioid neuropeptide which inhibits pain transmission in the spinal cord (5). The transcriptional repressor DREAM (downstream regulatory element antagonistic modulator) acts to suppress the expression of the precursor of dynorphin, prodynorphin, in the spinal cord neurons. Consequently, knocking out DREAM results in dynorphin overexpression producing a strong reduction in generalized pain behavior as well as in nociception (5) and already shown by us with fMRI (6). The selective κ-opioid receptor antagonist nor-binaltorphimine (nor-BNI) is known to reverse this reduction to wild-type levels (5,6). Material and Methods: Experiments were performed on 10 male wild-type and 8 dream transgenic mice (10-14 weeks old). Animals were anesthetized with 1.2% isoflurane in medical air. Body temperature was maintained at 37°C by warm water circulating throughout the holding cradle. The very same dream mice were measured two times with and without subcutaneous injection of nor-BNI (2 mg/kg) 24h before the fMRI experiment. Image data acquisition: fMRI experiments were performed with a 4.7 T/40 cm horizontal bore actively shielded magnet BioSpec (BRUKER, Germany). Gradient system (200 mT/m) and whole-body birdcage resonator enabled homogenous excitation. An actively RF-decoupled quadrature head coil was used as a receiver coil. Functional BOLD MRI scans were performed using a T2*-weighted single-shot gradient echo EPI sequence (22 axial slices, 64 x 64 matrix, TR= 2000 ms, k-space averaging of 2, TEef= 24.4 ms, field of view 15 x 15 mm, in-plane spatial resolution 234 x 234 μm, slice thickness 500 μm). Experimental protocol: The first 4 min of the fMRI scan without stimulation were used for resting state analysis. Afterwards a set of single thermal stimuli (45°,50°,55° and 60° ± 1°C) was applied repeatedly in 3 min 25 sec intervals for 41 min by a Peltier element on the right hindpaw. After 15 min rest another 4 min “resting state” scan was acquired. Data processing: Functional data were analyzed using our custom developed software MagnAn in IDL. After spatial smoothing in-plane using a Gaussian filter with a FWHM of 3 pixel the resting BOLD signal time courses were low-pass filtered at 0.1 Hz. Time courses were corrected for global signal fluctuations by linear regression using the global mean as regressor. Residual time courses were used for further analysis. Functional connectivity of the fMRI time courses was assessed by temporal correlating the average time course of a seed region of a given brain structure to the time courses of all other brain voxels. Seed regions were 6 voxels located around the center of mass of 162 nociception associated brain structures. The correlation coefficients obtained were FDR thresholded (q<0.05, dependent, two sided) and further analysis was restricted to those significant correlations. Registering each volume of significant correlations to a 3D version of the Paxinos rat brain atlas allowed to obtain average correlation coefficients of all 162 brain structures incorporated in that atlas for a given seed region. Consequently, full cross-correlation maps per animal were obtained as the mean correlation coefficients (r) of all 162 brain structures for all 162 seed regions. Next, these matrices were averaged over all animals per group. Connection numbers was calculated as the sum of all connections that occur in 80 % of all animals per group. Results: Resting state connectivities for wild-type increased after peripheral heat stimulation in strength and number of connections. Contrary, dream mice without nor-BNI injection, whose nociceptive sensitivity remains reduced, showed no difference in the connectivity strength or number of connections of the resting state network before and after heat stimulation indicating that the stimulation had no impact on the resting state network. Interestingly, dream mice after nor-BNI injection show highly similar networks before the heat stimulation. However, they had an increase of the number of connections (Fig.2b) as well as in connectivity strength leading to a higher r-values (Fig. 2a) after heat stimulation. The stimulation increased the efficacy of the resting state network. Further analysis may reveal structure specific effects. Additionally more significant connections can be observed in dream mice before heat stimulation compared to wild-type mice indicating an influence of this genetic modification on the resting state network. Discussion and Conclusion: Resting state networks can be demonstrated in wild-type and (transgenic) mice. They differ according to physiological (before and after nociceptive stimulation) and genetic background (dream). Especially nociceptive sensations, novel for dream mice after nor-BNI injection, increase the connectivity of pain related brain structures during rest. These results demonstrate the usefulness of non invasive fMRI in transgenic mice and molecular defined pharmacological intervention to further investigation of functional connectivity in pain research.

During the last decade there have been nearly 10,000 publications dealing with the cardiovascular risk of cyclooxygenase inhibitors and it can be concluded that the use of both selective and non-selective inhibitors is accompanied by a substantial cardiovascular risk (e.g. infarction, thromboembolic events, cardiac insufficiency and possibly stroke). As these pharmaceuticals, including paracetamol and acetylsalicylic acid, belong to the most used medications and safer alternatives are still lacking it will be the aim in the future to keep the risk connected with the therapy with these drugs limited despite the fact that the aging population will demand an increased consumption of analgesics. Choosing the right substance (e.g. selective versus non-selective, fast elimination versus slow elimination) and the correct dosage, i.e. the lowest possible dosing range, will help to keep the risk within tolerable limits. In addition biomarkers have emerged which will allow the identification of patients with a high risk of cardiovascular hepatic and gastrointestinal side effects.

Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study

www.karger.com/pha J. Ahamed, New York, N.Y., USA Jörg Ahrens, Hannover, Germany Reiko Akagi, Hiroshima, Japan Satoshi Akiba, Kyoto, Japan Y. Akiba, Los Angeles, Calif., USA Naohiko Anzai, Tochigi, Japan H. Aso, Sendai, Japan Jean Bastin, Paris, France Melvin L. Billingsley, Hershey, Pa., USA F. Boulle, Maastricht, Netherlands William Bowen, Rochester, N.Y., USA J. Breslin, Tampa, Fla., USA Keith K. Burkhart, Silver Spring, Md., USA Frederic Canini, La Tronche, France De-Liang Cao, Springfield, Ill., USA Kejiang Cao, Nanjing, China Rong Chu, Little Rock, Ark., USA George Crystal, Chicago, Ill., USA S.J. Czuczwar, Lublin, Poland Sergio De Marchi, Verona, Italy Carina Denny, Piracicaba, Brazil Le Ding, Kansas, Mo., USA Patrick D’Silva, Bangalore, India Michele Emdin, Pisa, Italy Qingfeng Fan, Philadelphia, Pa., USA J. Faridi, Stockton, Calif., USA Silvia Franchi, Milan, Italy Masanori Fujii, Kyoto, Japan M. Fujimuro, Kyoto, Japan Fenghua Fu, Yantai, China Stefano Fumagalli, Firenze, Italy Li Gan, Madison, Wis., USA Chantal Gauthier, Nantes, France Huiming Ge, Nanjing, China A. Gentilini, Firenze, Italy Lisa Giocomo, Palo Alto, Calif., USA Javier González-Maeso, New York, N.Y., USA Joseph Granchelli, Rochester, N.Y., USA Luis Granero, Valencia, Spain Xiu-Li Guo, Jinan, China E. Gussoni, Boston, Mass., USA Ki Baik Hahm, Seongnam, Korea R. Hardeland, Göttingen, Germany Noriyasu Hirasawa, Sendai, Japan Michael Holzer, Graz, Austria Martin Hönigl, Graz, Austria Lai S. Hooi, Johor Bahru, Malaysia Shigeo Horinaka, Tochigi, Japan Longshuang Huang, Chicago, Ill., USA Christian Humpel, Innsbruck, Austria Yoshimi Imura, Fujisawa, Japan N. Inagaki, Gifu, Japan Makoto Inui, Yamaguchi, Japan Keiichi Ishihara, Kyoto, Japan Yoichiro Isohama, Kumamoto, Japan Kazumi Iwata, Kyoto, Japan Yangfu Jiang, Sichuan, China Melanie S. Joy, Aurora, Colo., USA K. Kadoyama, Himeji, Japan Ira Kass, Brooklyn, N.Y., USA H. Katsuki, Kumamoto, Japan Atsufumi Kawabata, Higashiosaka, Japan Naoyuki Kawao, Osaka, Japan Zunji Ke, Shanghai, China Frieder Keller, Ulm, Germany H.R. Kim, Chungnam, Korea Yoshihisa Kitamura, Kyoto, Japan Yasuo Kizawa, Chiba, Japan T. Kobayashi, Tokyo, Japan J. Komano, Osaka, Japan Vasilios Kouloulias, Athens, Greece Toshiaki Kume, Kyoto, Japan Solene Le Douairon Lahaye, Rennes, France M-T. Lin, Tainan, Taiwan Yi-Wen Liu, Chiayi, Taiwan Zhen-Guo Liu, Columbus, Ohio, USA Pamela Lucchesi, Columbus, Ohio, USA Denisa Margina, Bucharest, Romania Xianfang Meng, Wuhan, China Francesca Menniti, Rome, Italy I. Mérida, Madrid, Spain Jing Miao, Philadelphia, Pa., USA S. Minagawa, Kyoto, Japan Keiji Miyata, Tsukuba, Japan Mizuo Miyazaki, Nagaokakyo, Japan Nobuaki Mizutani, Kobe, Japan M.J. Moshi, Dar es Salaam, Tanzania H. Motohashi, Kyoto, Japan Nariya Mukeshkumar, Jamnagar, India T. Murayama, Kanazawa, Japan H. Murota, Osaka, Japan

Background/Aim: The female gender appears to suffer from more adverse drug reactions (ADRs) than the male gender. So far, there has been no epidemiologic study analyzing gender-based differences in drug prescribing and its ADR risks. The aim of the present study was to establish a drug risk stratification adjusted to age, number of prescriptions and drug classes with respect to gender differences based on intensive data acquisition methods. Method: A prospective multicenter study was conducted in several departments in Germany and Israel (pediatrics, medicine and geriatrics) enclosing 2,371 inpatients. Results: A total of 25,532 drug prescriptions during hospitalization were evaluated. At least 1 ADR was found in 774 patients (32.6%). Drugs for the cardiovascular system, nervous system, alimentary tract and musculoskeletal system were prescribed most often in females. The following drug classes led significantly more often to ADRs in women as compared to men: alimentary tract (OR 0.5; p = 0.0002), cardiovascular system (OR 0.72; p = 0.0140), musculoskeletal system (OR 0.31; p = 0.0004) and nervous system (OR 0.62; p = 0.0023). After adjustment to age, total number of prescriptions and drug class, only anti-infectives (antibacterials) and musculoskeletal system (anti-inflammatory) drugs stand out as causing more ADRs in women. Conclusion: Antibacterials and anti-inflammatory agents cause more ADRs in females as compared to males.