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Thanks to the progress in early diagnosis and treatment of cancer, the life expectancy of cancer patients has now increased. Patients are, therefore, more likely to experience their individual cancer pain as a chronic pain. As a consequence, long-term treatment of cancer-related pain and oncological therapy-related pain are a major need for all patients and a challenge to all healthcare professionals. Tapentadol is a centrally acting analgesic drug characterized by two synergistic mechanisms of action, since it acts at the µ-opioid receptor (MOR) and inhibits noradrenalin re-uptake (NRI). Therefore, tapentadol has been considered the first of a new class of drugs, MOR-NRI. Tapentadol has been tested in different populations of cancer patients (opioid-naive and -pretreated), such as those with pain of mixed etiology, patients with pain from hematological malignancies and patients experiencing pain conditions due to anticancer treatment. According to available evidence, tapentadol prolonged release was well tolerated and effective in cancer pain patients. In randomized, double-blind and active-controlled trials it proved non-inferior to standard opioids like morphine or oxycodone in the management of moderate-to-severe cancer pain, both in opioid-naive and in opioid-pretreated patients. The good analgesic efficacy may be partly due to the action of tapentadol on neuropathic pain components. Together with the low rate of gastrointestinal adverse effects and the overall favorable safety profile, tapentadol can be considered a good option in cancer pain patients, who can suffer frequently from nausea, vomiting, constipation or other events that further reduce their quality of life.

Neuropathic pain (NP) is an enormous burden for patients, caregivers and society. NP is a pain state that may develop after injury of the peripheral or central nervous system because of a wide range of diseases and traumas. A NP symptom component can be found also in several types of chronic pain. Many NP patients are substantially disabled for years. Due to its chronicity, severity and unpredictability, NP is difficult to treat. Tapentadol is a central-acting oral analgesic with combined opioid and noradrenergic properties, which make it potentially suitable for a wide range of pain conditions, particularly whenever a NP component is present or cannot be excluded. In randomized controlled trials, tapentadol has proved to be effective in relieving NP in diabetic peripheral neuropathy and in chronic low back pain. In observational studies, tapentadol reduced NP in chemotherapy-induced peripheral neuropathies, blood and solid cancers, and the NP component in neck pain and Parkinson's disease. This narrative review aims to provide clinicians with a broad overview of tapentadol effects on NP.

Objective: This study reports the pharmacokinetics, tolerability, and safety of an intranasal fentanyl spray (INFS) in patients with cancer and breakthrough pain (BTP). Design: A randomized, open-label, two-period, crossover trial. Patients: Nineteen adult patients (mean 57.8 years) with BTP, receiving opioid treatment for chronic background pain, from clinical departments in Austria, France, and Norway entered and completed the study. Intervention: Patients were randomly assigned to receive one of six INFS dose sequences: 50/100, 100/50, 50/200, 200/50, 100/200, and 200/100 μg. INFS was administered as a single dose in one nostril. Each dose was separated by a minimum of 48 hours. Main outcome measure: Plasma fentanyl concentrations were measured by high-performance liquid chromatography and tandem mass spectrometry from blood samples obtained at 0 (predose) and frequently up to 300 minutes after INFS administration. Blood pressure, peripheral oxygen saturation, and respiratory rate were assessed eight times during each of the two treatment periods. Results: Mean fentanyl plasma concentrations increased in a dose-dependent manner, peaking for all fentanyl doses 9-15 minutes after INFS administration. Median Tmax values were 15, 12, and 15 minutes for the 50, 100, and 200 μg doses of INFS, respectively. Mean (SD) values for Cmax were 351 (±226), 595 (±400), and 1195 (±700) pg/mL, respectively, indicating dose-proportionality. Six patients (31.6 percent) experienced adverse events during the treatment period, the majority being mild in severity. Conclusion: INFS at doses of 50, 100, and 200 μg showed a short Tmax and was well tolerated in patients with cancer. These results support INFS use in patients with cancer suffering from BTP.

Different neuroplastic processes can occur along the nociceptive pathways and may be important in the transition from acute to chronic pain and for diagnosis and development of optimal management strategies. The neuroplastic processes may result in gain (sensitisation) or loss (desensitisation) of function in relation to the incoming nociceptive signals. Such processes play important roles in chronic pain, and although the clinical manifestations differ across condition processes, they share some common mechanistic features. The fundamental understanding and quantitative assessment of particularly some of the central sensitisation mechanisms can be translated from preclinical studies into the clinic. The clinical perspectives are implementation of such novel information into diagnostics, mechanistic phenotyping, prevention, personalised treatment, and drug development. The aims of this paper are to introduce and discuss (1) some common fundamental central pain mechanisms, (2) how they may translate into the clinical signs and symptoms across different chronic pain conditions, (3) how to evaluate gain and loss of function using quantitative pain assessment tools, and (4) the implications for optimising prevention and management of pain. The chronic pain conditions selected for the paper are neuropathic pain in general, musculoskeletal pain (chronic low back pain and osteoarthritic pain in particular), and visceral pain (irritable bowel syndrome in particular). The translational mechanisms addressed are local and widespread sensitisation, central summation, and descending pain modulation.SIGNIFICANCE: Central sensitisation is an important manifestation involved in many different chronic pain conditions. Central sensitisation can be different to assess and evaluate as the manifestations vary from pain condition to pain condition. Understanding central sensitisation may promote better profiling and diagnosis of pain patients and development of new regimes for mechanism based therapy. Some of the mechanisms underlying central sensitisation can be translated from animals to humans providing new options in development of therapies and profiling drugs under development.

After decades of worldwide use of paracetamol/acetaminophen as a popular and apparently safe prescription and over-the-counter medicine, the future role of this poorly understood analgesic has been seriously questioned by recent concerns about prenatal, cardiovascular (CV) and hepatic safety, and also about its analgesic efficacy. At the same time the usefulness of codeine in combination products has come under debate.Based on a PubMed database literature search on the terms efficacy, safety, paracetamol, acetaminophen, codeine and their combinations up to and including June 2016, this clinical update reviews the current evidence of the benefit and risks of oral paracetamol alone and with codeine for mild-to-moderate pain in adults, and compares the respective efficacy and safety profiles with those of nonsteroidal anti-inflammatory drugs (NSAIDs).Whereas there is a clear strong association of NSAID use and gastrointestinal (GI) and CV morbidity and mortality, evidence for paracetamol with and without codeine supports the recommended use even in most vulnerable individuals, such as the elderly, pregnant women, alcoholics, and compromised GI and CV patients. The controversies and widespread misconceptions about the complex hepatic metabolism and potential hepatotoxicity have been corrected by recent reviews, and paracetamol remains the first-line nonopioid analgesic in patients with liver diseases if notes of caution are applied.Due to its safety and tolerability profile paracetamol remained a first-line treatment in many international guidelines. Alone and with codeine it is a safe and effective option in adults, whilst NSAIDs are obviously less safe as alternatives, given the risk of potentially fatal GI and CV adverse effects.

Background A recent randomized-withdrawal, active- and placebo-controlled, double-blind phase 3 study showed that tapentadol prolonged release (PR) was effective and well tolerated for managing moderate to severe, chronic malignant tumour-related pain in patients who were opioid naive or dissatisfied with current treatment (Pain Physician, 2014, 17, 329–343). This post hoc, subgroup analysis evaluated the efficacy and tolerability of tapentadol PR in patients who previously received and were dissatisfied with tramadol for any reason and who had a pain intensity ≥5 (11-point numerical rating scale) before converting directly to tapentadol PR. Methods In the original study, eligible patients had been randomized (2:1) and titrated to their optimal dose of tapentadol PR (100–250 mg bid) or morphine sulphate-controlled release (40–100 mg bid) over 2 weeks. The present report focuses on results during the titration period for a subgroup of patients randomized to tapentadol PR after having been on tramadol treatment prior to randomization in the study (n = 129). Results for this subgroup are compared with results for all 338 patients who received tapentadol PR during titration (overall tapentadol PR group). Results Responder rates (responders: completed titration, mean pain intensity

Chronic pain affects a large proportion of the population, imposing significant individual distress and a considerable burden on society, yet treatment is not always instituted and/or adequate. Comprehensive multidisciplinary management based on the biopsychosocial model of pain has been shown to be clinically effective and cost-efficient, but is not widely available. A literature review of stakeholder groups revealed many reasons for this, including: i) many patients believe healthcare professionals lack relevant knowledge, and consultations are rushed, ii) general practitioners consider that pain management has a low priority and is under-resourced, iii) pain specialists cite non-adherence to evidence-based treatment, sub-optimal prescribing, and chronic pain not being regarded as a disease in its own right, iv) nurses', pharmacists' and physiotherapists' skills are not fully utilized, and v) psychological therapy is employed infrequently and often too late. Many of the issues relating to physicians could be addressed by improving medical training, both at undergraduate and postgraduate levels - for example, by making pain medicine a compulsory core subject of the undergraduate medical curriculum. This would improve physician/patient communication, increase the use of standardized pain assessment tools, and allow more patients to participate in treatment decisions. Patient care would also benefit from improved training for other multidisciplinary team members; for example, nurses could provide counseling and follow-up support, psychologists offer coping skills training, and physiotherapists have a greater role in rehabilitation. Equally important measures include the widespread adoption of a patient-centered approach, chronic pain being recognized as a disease in its own right, and the development of universal guidelines for managing chronic non-cancer pain. Perhaps the greatest barrier to improvement is lack of political will at both national and international level. Some powerful initiatives and collaborations are currently lobbying policy-making bodies to raise standards and reduce unnecessary pain - it is vital they continue.

This open-label study evaluated the effects of fentanyl buccal tablet (FBT) on functioning and mood in cancer patients with breakthrough cancer pain (BTcP). Opioid-tolerant patients in seven European countries with up to four BTcP episodes/day received FBT doses (100–800 μg) identified during open-label titration to treat up to eight BTcP episodes during an open-label treatment period. In countries where FBT was not commercially available, patients could enter an open-label continuation phase. Functionality and satisfaction assessments included change from baseline to the end of the treatment period in the modified Brief Pain Inventory (BPI-7S) seven-item interference subscale, patient’s global assessment of satisfaction and ease of use, and Patient’s Global Impression of Change (PGIC). Safety was also assessed. Of 330 randomized patients, 218 completed the treatment period and 88 entered the continuation phase. Median background pain intensity was 4.0 (mild) throughout the study. After the treatment period, mean (SD) global modified BPI-7S score improved from 39.7 (15.9) at baseline to 31.6 (16.8) for a mean change of −8.6 (95 % confidence interval CI −10.5, −6.7; P

Chronic low back pain: Chronic pain is the most common cause for people to utilize healthcare resources and has a considerable impact upon patients’ lives. The most prevalent chronic pain condition is chronic low back pain (CLBP). CLBP may be nociceptive or neuropathic, or may incorporate both components. The presence of a neuropathic component is associated with more intense pain of longer duration, and a higher prevalence of co-morbidities. However, many physicians’ knowledge of chronic pain mechanisms is currently limited and there are no universally accepted treatment guidelines, so the condition is not particularly well managed. Diagnosis: Diagnosis should begin with a focused medical history and physical examination, to exclude serious spinal pathology that may require evaluation by an appropriate specialist. Most patients have non-specific CLBP, which cannot be attributed to a particular cause. It is important to try and establish whether a neuropathic component is present, by combining the findings of physical and neurological examinations with the patient's history. This may prove difficult, however, even when using screening instruments. Multimodal management: The multifactorial nature of CLBP indicates that the most logical treatment approach is multimodal: i.e. integrated multidisciplinary therapy with co-ordinated somatic and psychotherapeutic elements. As both nociceptive and neuropathic components may be present, combining analgesic agents with different mechanisms of action is a rational treatment modality. Individually tailored combination therapy can improve analgesia whilst reducing the doses of constituent agents, thereby lessening the incidence of side effects. Conclusions: This paper outlines the development of CLBP and the underlying mechanisms involved, as well as providing information on diagnosis and the use of a wide range of pharmaceutical agents in managing the condition (including NSAIDs, COX-2 inhibitors, tricyclic antidepressants, opioids and anticonvulsants), supplemented by appropriate non-pharmacological measures such as exercise programs, manual therapies, behavioral therapies, interventional pain management and traction. Surgery may be appropriate in carefully selected patients.

Background Fentanyl buccal tablet (FBT), a rapid onset opioid used to treat breakthrough cancer pain, must be titrated to an effective dose that provides adequate analgesia and minimizes undesirable events. This open-label, randomized study compared the percentage of patients achieving an effective dose of FBT when starting titration at 100 or 200 μg. Methods Opioid-tolerant patients with chronic cancer-related pain who experienced up to four breakthrough pain episodes daily were randomized to a starting dose of 100 or 200 μg for the titration period. The dose was increased until an effective dose (100, 200, 400, 600 or 800 μg) providing adequate analgesia with acceptable adverse events was achieved. Patients achieving an effective dose entered a treatment period during which they treated up to eight breakthrough pain episodes with their effective dose. Results A total of 442 patients from 135 sites in seven European countries were screened. Non-inferiority was established with the percentage of patients achieving an effective dose starting titration at 200 μg (81.4%) compared with the 100-μg (75.2%) starting dose. The most common effective doses of FBT were 200 μg (39.6%) and 400 μg (26.9%). No new safety concerns were identified with use of FBT at doses up to 800 μg per episode. Conclusions This study involving a real clinical practice setting showed a similar percentage of patients safely achieving an effective dose by titration starting with 100 versus 200 μg of FBT.

Background: Tapentadol prolonged release (PR) is effective and well tolerated for chronic osteoarthritis, low back, and diabetic peripheral neuropathic pain. Objectives: To evaluate the efficacy and tolerability of tapentadol PR compared with placebo and morphine controlled release (CR) for managing moderate to severe chronic malignant tumor-related pain. Study Design: Randomized-withdrawal, parallel group, active- and placebo-controlled, double-blind phase 3 study (NCT00472303). Setting: Primary, secondary, and tertiary care settings in 16 countries. Methods: Eligible patients (pain intensity ≥ 5 [11-point numerical rating scale] on prior analgesics) were randomized (2:1) and titrated to their optimal dose of tapentadol PR (100 – 250 mg bid) or morphine sulfate CR (40 – 100 mg bid) over 2 weeks. Morphine sulfate immediate release 10 mg was permitted as needed for rescue medication (no maximum dose). Patients who completed titration and, during the last 3 days of titration, had mean pain intensity < 5 (based on twice-daily ratings) and mean rescue medication use ≤ 20 mg/day continued into a 4-week maintenance period; patients who received morphine CR during titration continued taking morphine CR, and those who received tapentadol PR were re-randomized (1:1) to tapentadol PR or placebo bid. Response during maintenance (primary efficacy endpoint) was defined as having: 1) completed the maintenance period, 2) a mean pain intensity < 5 during maintenance, and 3) used an average of ≤ 20 mg/day of rescue medication during maintenance. Response at the end of titration was defined similarly, with pain intensity and rescue medication averages based on the last 3 days of titration. Results: Of 622 patients screened, 496 were randomized, treated during titration, and evaluable for safety; 327 were re-randomized, treated during maintenance, and evaluable for safety; and 325 were evaluable for efficacy. The adjusted responder rate estimate during maintenance (logistic regression adjusting for treatment group, pooled center, and pain intensity at start of maintenance) was significantly higher with tapentadol PR (64.3%) than with placebo (47.1%; odds ratio (OR), 2.02 [95% confidence interval (CI), 1.12 – 3.65]; P = 0.02). Based on responder rates at the end of titration, tapentadol PR (76.0% [174/229]) was non-inferior to morphine CR (83.0% [83/100]). The lower limit of the 95% CI for the between-groups difference (−15.5%) was within the pre-specified 20% non-inferiority margin. During titration, incidences of treatment-emergent adverse events (TEAEs) were 50.0% (169/338) with tapentadol PR and 63.9% (101/158) with morphine CR; incidences of nausea, vomiting, and dry mouth were lower with tapentadol PR than with morphine CR. During maintenance, incidences of TEAEs were 56.3% (63/112), 62.3% (66/106), and 62.4% (68/109) with placebo, tapentadol PR, and morphine CR, respectively. Limitations: Statistical comparisons between tapentadol PR and morphine CR were limited to descriptive statistics during the maintenance period because of the pre-selection of responders to tapentadol PR or morphine CR during titration. Conclusions: Results obtained during maintenance indicate that tapentadol PR (100 – 250 mg bid) is effective compared with placebo for managing moderate to severe chronic malignant tumor-related pain. Based on results obtained during titration, tapentadol PR provides comparable efficacy to that of morphine sulfate CR (40 – 100 mg bid), but is associated with better gastrointestinal tolerability. Key words: Tapentadol PR, cancer pain, tumor-related pain, malignant pain, chronic pain, morphine CR, non-inferiority, efficacy, tolerability

UNLABELLED: Poorly controlled pain is a global public health issue. The personal, familial and societal costs are immeasurable. Only a minority of European patients have access to a comprehensive specialist pain clinic. More commonly the responsibility for chronic pain management and initiating opioid therapy rests with the primary care physician and other non-specialist opioid prescribers. There is much confusing and conflicting information available to non-specialist prescribers regarding opioid therapy and a great deal of unjustified fear is generated. Opioid therapy should only be initiated by competent clinicians as part of a multi-faceted treatment programme in circumstances where more simple measures have failed. Throughout, all patients must be kept under close clinical surveillance. As with any other medical therapy, if the treatment fails to yield the desired results and/or the patient is additionally burdened by an unacceptable level of adverse effects, the overall management strategy must be reviewed and revised. No responsible clinician will wish to pursue a failed treatment strategy or persist with an ineffective and burdensome treatment. In a considered attempt to empower and inform non-specialist opioid prescribers, EFIC convened a European group of experts, drawn from a diverse range of basic science and relevant clinical disciplines, to prepare a position paper on appropriate opioid use in chronic pain. The expert panel reviewed the available literature and harnessed the experience of many years of clinical practice to produce these series of recommendations. Its success will be judged on the extent to which it contributes to an improved pain management experience for chronic pain patients across Europe. SIGNIFICANCE: This position paper provides expert recommendations for primary care physicians and other non- specialist healthcare professionals in Europe, particularly those who do not have ready access to specialists in pain medicine, on the safe and appropriate use of opioid medications as part of a multi-faceted approach to pain management, in properly selected and supervised patients. ispartof: European Journal of Pain vol:21 issue:1 pages:3-19 ispartof: location:England status: published

This open-label, phase 3b study evaluated the effectiveness and tolerability of tapentadol prolonged release and tapentadol immediate release (for acute pain episodes) for severe, chronic low back pain with or without a neuropathic pain component that was inadequately managed in patients taking World Health Organization (WHO) Step I or II analgesics or who were not regularly treated with analgesics.Average baseline pain intensity was greater than 5 (11-point numerical rating scale-3 [NRS-3; 3-day average pain intensity]) with WHO Step I or II analgesics and greater than 6 with no regular analgesic regimen. WHO Step II analgesics were discontinued before starting study treatment; WHO Step I analgesics or co-analgesics were continued at the same dose. Patients received tapentadol prolonged release (50-250 mg bid) during a 5-week titration and 7-week maintenance period. Tapentadol immediate release was permitted for acute pain episodes (tapentadol prolonged release and immediate release maximum combined dose, ≤500 mg/day). The painDETECT questionnaire was used to define subsets of patients based on the probability of a neuropathic pain component to their low back pain as 'negative', 'unclear', or 'positive'.NCT00983385.The primary endpoint was the change from baseline to week 6 in average pain intensity (NRS-3), using the last observation carried forward to impute missing scores.In the painDETECT negative (n = 49) and unclear/positive (n = 126) subsets, respectively, mean (SD) changes in pain intensity from baseline to week 6 were -2.4 (2.18) and -3.0 (2.07; both p 0.0001). Among patients who had not received prior WHO Step II treatment, lower doses of tapentadol prolonged release were generally required with increasing likelihood of a neuropathic pain component. Based on the painDETECT questionnaire and the Neuropathic Pain Symptom Inventory (NPSI), tapentadol prolonged release treatment was also associated with significant improvements in neuropathic pain symptoms, with decreases in the number of pain attacks and the duration of spontaneous pain in the last 24 hours in patients with low back pain with a neuropathic pain component (painDETECT unclear or positive score at baseline or screening). The most common treatment-emergent adverse events (incidence ≥10%, n = 176) were nausea, dizziness, headache, dry mouth, fatigue, constipation, diarrhea, nasopharyngitis, and somnolence.Tapentadol prolonged release was well tolerated and effective for managing severe, chronic low back pain with or without a neuropathic pain component.

Malignant hyperthermia (MH) is a potentially lethal genetic disorder in response to volatile anesthetics and depolarizing muscle relaxants. To support the claim that a novel genetic variant causes MH, it is necessary to demonstrate that it has significant effects on the sensitivity of the ryanodine receptor (RYR1) calcium channel. In this study we focused on 2 Austrian families with strong MH disposition and new RYR1 variants.We sequenced the entire coding region of the RYR1 from 2 Austrian MH individuals. Genotype-phenotype segregation and evolutionary conservation of the variants were considered. On a functional level, Ca(2+) release experiments with fura-2-acetoxymethyl ester were performed in cultured skeletal muscle cells derived from individuals carrying the new variants and compared with control cells from nonsusceptible individuals. Caffeine, 4-chloro-m-cresole (4-CmC), and halothane were used as specific Ca(2+) releasing agents.The variant p.A612P in family A segregated with an MH-susceptible phenotype and cells showed an increased sensitivity for all Ca(2+)-releasing substances tested. In family B, 2 variants (p.R2458H/p.R3348C) were identified. While p.R2458H and p.R2458H/p.R3348C segregated with an MH-susceptible diagnosis, p.R3348C alone showed an MH equivocal diagnosis. Ca(2+)-release experiments showed that exchanges of these highly conserved amino acids increased the sensitivities for the substances tested (except 4-CmC with p.R2458H and p.R3348C) when compared with the MH-negative control group.Our results suggest that these variants are new causative MH variants.

Introduction About 4% of the population suffer from daily or near daily headache, which in most cases evolved from an episodic type of headache. The impact of psychological factors on this process is unknown. It seems reasonable to assume, that besides somatic and social conditions psychological factors like pain-related coping and cognition play an important role, as has been shown for other pain conditions. Methods We performed a cross sectional study on pain coping behaviour in 211 patients with migraine and tension type headache. Pain-related cognition and coping was investigated using the Kiel Pain Inventory. Prevalence of depression, medication intake and headache characteristics were analysed in regard to chronicity of headache. Results Overall pain intensity was high in the patient sample. The level of depression increased with headache frequency. Dysfunctional coping, characterized by fear and avoidance is frequently used by headache patients. As in low back pain, also endurance is highly prevalent. Other features known to be associated with chronic headache, like depression and medication overuse, could be confirmed. Discussion Dysfunctional coping was seen with high prevalence in the entire patient sample (66%). Against our hypothesis, it was not confined to chronic forms of headache. In respect to our data, we discuss the role of avoidance and endurance coping in headache and its possible role in chronicity.

The treatment of breakthrough pain (BTP) in cancer patients is often sub-optimal. Normal-release oral opioid formulations have a slow onset of action, such that the episode of pain has often spontaneously subsided by the time the opioid starts to work. Other oral formulations, such as oral transmucosal fentanyl citrate (OTFC), may be associated with administration problems in many cancer patients who have salivary gland dysfunction or mucositis. Thus, there is the need for a treatment that matches a typical BTP episode and that is easy to use. Intranasal fentanyl spray (INFS) has been developed as a new route of administration with a fast onset of action. INFS has been investigated in four key clinical studies involving cancer patients with BTP. Pharmacokinetic analysis has shown a dose response for maximal plasma concentrations ( C max ) of fentanyl and a short venous time to maximum plasma concentration ( T max ). A dose-ranging efficacy study demonstrated a significant improvement in pain intensity difference (PID) over placebo from as early as 10 min post-administration. A later titrated-dose efficacy study supported these findings. In a head-to-head comparative trial between INFS and OTFC, significantly more patients achieved a faster onset of ‘meaningful’ pain relief with INFS than with OTFC, with INFS producing a significantly greater PID as early as 5 min post-dosing. Furthermore, a significantly higher proportion of patients preferred INFS over OTFC. In all clinical studies, including a 10-month follow-up, INFS was well tolerated. INFS should be considered a significant advance for the management of BTP.

Aim The pharmacokinetic profiles of the two commercially available transdermal fentanyl patches Matrifen (100 microg/h) and Durogesic DTrans (100 microg/h), used to manage severe chronic pain, were compared regarding their systemic exposure, rate of absorption, and safety. Methods Transdermal matrix fentanyl patches [Matrifen or Durogesic DTrans (100 microg/h)] were applied for 72 h to 30 healthy male subjects in a randomized, four-period (two replicated treatment sequences), crossover study; 28 subjects completed the study. The pharmacokinetic parameters of fentanyl were determined for 144 h after application using plasma samples. Safety of the patches (adverse events) and performance (adhesion, skin irritation, residual fentanyl content in the patch) were evaluated. Results The plasma concentration-time curves of Matrifen (Test) and Durogesic DTrans (Reference) were similar. The geometric least square means of the Test/Reference ratio (90% confidence intervals [CI]) were within the range of 80-125%, demonstrating bioequivalence of Matrifen and Durogesic DTrans: AUC(0-tlast) 92.5 (CI 88.7-96.4), AUC(0-inf) 91.7 (CI 88.0-95.7), and C(max) 98.3 (CI 92.9-104.1). After 72 h application, Matrifen had a more efficient utilization of fentanyl (mean+/-SD 82.3+/-9.43%) than Durogesic DTrans (52.3+/-12.8%), with substantially lower residual fentanyl in patch after use. The pharmacokinetic parameters showed lower intra- and inter-subject variability for Matrifen than for Durogesic DTrans patch. Conclusions Despite different technologies, the transdermal fentanyl patches Matrifen and Durogesic DTrans are bioequivalent. Compared with Durogesic DTrans, the Matrifen patch had lower initial and lower residual fentanyl content, as well as lower intra- and inter-subject variability, allowing reproducible drug delivery and reliable analgesia.

Stimulation of primary afferent neurons offers a new approach for the control of localized chronic pain. We describe the results with a new neurostimulation technique, subcutaneous target stimulation (STS), for the treatment of chronic focal noncancer pain. STS applies permanent electrical stimulation directly at the painful area via a percutaneous-placed subcutaneous lead. We reported the

Administering drugs into the intrathecal space is becoming more popular in the treatment of patients with intractable pain or intolerable side effects of systemic analgesic treatments. Although morphine and ziconotide are the only intrathecal analgesics currently approved by regulatory authorities in the U.S. (Food and Drug Administration) and Europe (national-level approval by individual countries for morphine and European Agency for the Evaluation of Medicinal Products approval for ziconotide), a wide variety of opioid and non-opioid drugs are being used in this way. There is no official guidance concerning the selection of these drugs or their use in combinations and a paucity of efficacy and safety data from randomized controlled trials. The polyanalgesic initiative aims to summarize the current knowledge and to facilitate rational choices of intrathecal drug and drug combinations for the management of chronic pain. The most recent polyanalgesic consensus recommendations were published in 2007. In this review, we shall examine these recommendations, which are tailored toward those practicing intrathecal analgesia in the U.S., and discuss how they should be implemented in Europe, where the healthcare systems and regulations of the medical authorities are different.

Background Cannabinoid-induced analgesia was shown in animal studies of acute inflammatory and neuropathic pain. In humans, controlled clinical trials with Delta-tetrahydrocannabinol or other cannabinoids demonstrated analgesic efficacy in chronic pain syndromes, whereas the data in acute pain were less conclusive. Therefore, the aim of this study was to investigate the effects of oral cannabis extract in two different human models of acute inflammatory pain and hyperalgesia. Methods The authors conducted a double-blind, crossover study in 18 healthy female volunteers. Capsules containing Delta-tetrahydrocannabinol-standardized cannabis extract or active placebo were orally administered. A circular sunburn spot was induced at one upper leg. Heat and electrical pain thresholds were determined at the erythema, the area of secondary hyperalgesia, and the contralateral leg. Intradermal capsaicin-evoked pain and areas of flare and secondary hyperalgesia were measured. Primary outcome parameters were heat pain thresholds in the sunburn erythema and the capsaicin-evoked area of secondary hyperalgesia. Secondary measures were electrical pain thresholds, sunburn-induced secondary hyperalgesia, and capsaicin-induced pain. Results Cannabis extract did not affect heat pain thresholds in the sunburn model. Electrical thresholds (250 Hz) were significantly lower compared with baseline and placebo. In the capsaicin model, the area of secondary hyperalgesia, flare, and spontaneous pain were not altered. Conclusion To conclude, no analgesic or antihyperalgesic activity of cannabis extract was found in the experiments. Moreover, the results even point to the development of a hyperalgesic state under cannabinoids. Together with previous data, the current results suggest that cannabinoids are not effective analgesics for the treatment of acute nociceptive pain in humans.

Malignant hyperthermia is a rare, potentially life threatening pharmacogenetic disorder triggered by volatile anaesthetics and depolarizing muscle relaxants. The clinical picture comprises rhabdomyolysis, metabolic and respiratory acidosis, and hyperthermia. Carnitine palmitoyltransferase II deficiency is a metabolic myopathy affecting the transport of fatty acids into the mitochondria, leading to impaired energy supply under stressful conditions resulting in muscle weakness and rhabdomyolysis. It was postulated in a previous study that some patients with the MH phenotype have a carnitine palmitoyltransferase deficiency. To investigate a potential association, we tested 18 individuals with proven MH susceptibility for impairment of carnitine palmitoyltransferase enzyme activity in muscle. Enzyme activity was normal in all individuals tested indicating no impairment of the CPT system in this sample of malignant hyperthermia susceptible individuals. Thus our data do not support the hypothesis that susceptibility to malignant hyperthermia has an effect on the carnitine palmitoyltransferase enzyme system.

This article summarizes the outcome from an international consensus meeting, which took place in Vienna on 4 November 2014.The aim of the meeting was to provide the state of the art on the pathophysiology and treatment of acute pain with special emphasis on nimesulide, a non-steroidal anti-inflammatory drug (NSAID) indicated for the treatment of acute pain and primary dysmenorrhea. Besides the data on the mechanisms of acute inflammatory pain and on the efficacy and safety of nimesulide in patients affected by different forms of acute pain, the clinical experience of attending experts was discussed based on selected case reports.The members of this consensus group recognized that nimesulide is a NSAID highly effective in the treatment of several painful situations with an acute inflammatory component including primary dysmenorrhea. Although safety concerns regarding nimesulide have emerged in recent years, both robust new epidemiological data and clinical experience confirm a positive benefit/risk profile of nimesulide in the treatment of several forms of acute pain.The members of this international consensus group concluded that nimesulide, when used appropriately, remains a particularly valuable and safe option for the treatment of several conditions characterized by the presence of acute inflammatory pain because of the rapid onset of the analgesic action, and the positive evidence-based benefit/risk profile.

OBJECTIVES: Unrelieved pain is a substantial public health concern necessitating improvements in medical education. The Advancing the Provision of Pain Education and Learning (APPEAL) study aimed to determine current levels and methods of undergraduate pain medicine education in Europe. DESIGN AND METHODS: Using a cross-sectional design, publicly available curriculum information was sought from all medical schools in 15 representative European countries in 2012-2013. Descriptive analyses were performed on: the provision of pain teaching in dedicated pain modules, other modules or within the broader curriculum; whether pain teaching was compulsory or elective; the number of hours/credits spent teaching pain; pain topics; and teaching and assessment methods. RESULTS: Curriculum elements were publicly available from 242 of 249 identified schools (97%). In 55% (133/242) of schools, pain was taught only within compulsory non-pain-specific modules. The next most common approaches were for pain teaching to be provided wholly or in part via a dedicated pain module (74/242; 31%) or via a vertical or integrated approach to teaching through the broader curriculum, rather than within any specific module (17/242; 7%). The curricula of 17/242 schools (7%) showed no evidence of any pain teaching. Dedicated pain modules were most common in France (27/31 schools; 87%). Excluding France, only 22% (47/211 schools) provided a dedicated pain module and in only 9% (18/211) was this compulsory. Overall, the median number of hours spent teaching pain was 12.0 (range 4-56.0 h; IQR: 12.0) for compulsory dedicated pain modules and 9.0 (range 1.0-60.0 h; IQR: 10.5) for other compulsory (non-pain specific) modules. Pain medicine was principally taught in classrooms and assessed by conventional examinations. There was substantial international variation throughout. CONCLUSIONS: Documented pain teaching in many European medical schools falls far short of what might be expected given the prevalence and public health burden of pain. The project was funded by Mundipharma International Ltd.

Opioid analgesics are important therapeutic options for chronic non-cancer pain (CNCP), recognized as a major public health issue with high social and economic burden. The increasing therapeutic opioid use for CNCP, misuse and abuse of prescription opioids have become matters of severe concern in USA. The recent position paper of the American Academy of Neurology (AAN) about the use of opioids in USA expresses growing alarms about opioid misuse/abuse, and has alerted physicians worldwide to rethink about their prescription practice. Current US practice in opioid prescription has been associated with morbidity and mortality of epidemic proportions: over 100,000 people directly or indirectly died from prescribed opioids in USA in the last twenty years, reaching 16,651 deaths in 2010. The actually alarming data from US have initiated pain physicians and researchers to re-evaluate their prescribing policies and attitudes for long-term treatment of non-cancer patients with opioids. In this position paper it is explained that any change in clinical behavior should not be based on an uncritical generalization of the US data that do not reflect the European situation. The primary objective of pain physicians remains to adequately treat chronic pain. Opioids are and will continue to remain an essential part of the "armamentarium against pain"; physicians should use them in the best way, i.e. after thorough diagnosis, assessment of alternative therapeutic options in the context of a multimodal treatment concept, and with repeated careful re-evaluations of the proper indication by a close long-term follow-up of any chronic opioid patient.

BACKGROUND: The aim of this study was to compare the efficacy and side effects of gabapentin, amitriptyline, and their combination in women with chronic pelvic pain. METHODS: In this open-label, prospective, randomized trial, 56 women with chronic pelvic pain were investigated with a two-year follow-up at the Vienna Medical University Hospital. If pain intensity assessed by a visual analog scale (VAS) was 5 or more (0, no pain; 10, maximal pain), despite analgesic therapy using the nonopioid drug metamizol together with weak opioids, patients were randomized to receive gabapentin (n = 20), amitriptyline (n = 20), or a combination of both drugs (n = 16). Doses of gabapentin and amitriptyline were increased to maximum daily doses of 3600 mg and 150 mg, respectively, until sufficient pain relief or the occurrence of side effects. VAS and side effects were evaluated before treatment and at 1, 3, 6, 12 and 24 months afterwards. RESULTS: All patients experienced significant pain relief during the observation period. However, after 6, 12 and 24 months, pain relief was significantly better in patients receiving gabapentin either alone or in combination with amitriptyline than in patients receiving monotherapy with amitriptyline (gabapentin: 0 months, 7.7 ± 1.5; 6 months, 1.6 ± 0.9; 12 months, 1.5 ± 0.9; 24 months, 1.9 ± 0.9; amitriptyline: 0 months, 7.3 ± 1.5; 6 months, 2.2 ± 1.6; 12 months, 2.2 ± 1.6; 24 months; 3.4 ± 0.9; amitriptyline-gabapentin: 0 months, 7.6 ± 0.8; 6 months, 1.3 ± 0.9; 12 months, 1.7 ± 1.0; 24 months, 2.3 ± 0.9). Side effects were lower in the gabapentin group than in the two other groups, the difference reaching statistical significance after three months (P < 0.05). CONCLUSION: Gabapentin alone or in combination with amitriptyline is better than amitriptyline alone in the treatment of female chronic pelvic pain.

In 1986 the World Health Organization (WHO) released guidelines for cancer pain relief. Since then, several controlled studies on effectiveness and practicability of these guidelines have been published. Various authors described inadequate use of these guidelines. We analysed, whether the pain medication of 160 cancer patients referred to the anesthesiological pain clinic at the university hospital of Vienna corresponded to the WHO guidelines or not. Adequacy of pain treatment was assessed using the pain management index (PMI). Multiple criteria were chosen to assess the conformity of the treatment with the guidelines. Furthermore we studied the effect of a strict use of the WHO guidelines in these patients. The average pain intensity of the referred patients was 75 mm (VAS). Negative PMI scores, indicating inadequate pain therapy, were found in 39 % of cases. A violation of the rules was found in 38% of the therapy schedules. Pain medication was then modified by switching to fixed time intervals, escalation of the steps of the WHO ladder, increasing the dosage or treating neuropathic pain with adjuvant drugs. Two weeks later the average pain score of the patients was reduced to 27 mm (VAS). At that time 72% of the patients quoted an adequate reduction of pain. Inadequate knowledge or disregard of the WHO guidelines for cancer pain relief are common and result in unnecessary and prolonged suffering in these patients.

In many European countries the use of opioids for long-term treatment of nonmalignant pain has dramatically increased during the last decade in order to improve the patient's quality of life, to allow an active social life and the return to work. In modern society, driving is regarded as an essential activity of daily living. Since opioids are centrally acting drugs that may interfere with the ability of safely driving a motor vehicle, the question arises of whether or not and on which conditions patients under continuous opioid medication may be considered fit to drive. In this article the evidence from recent studies of opioid effects on driving ability of patients is reviewed. Based on these data, the prerequisites and restrictions for driving under chronic opioid medication are outlined and practical guidelines are proposed.

Cannabinoids have been shown to affect various immune functions. To date, almost no data exist on PMN, which provide the first line antimicrobial defense. The objective of the present study was to investigate the effects of the synthetic dibenzopyrane ligand CP55 940, the endogenous cannabinoid anandamide and methanandamide on the "respiratory burst" of isolated human PMN in vitro. After preincubation with high micromolar concentrations of CP55 940, fMLP-stimulated PMN showed a reduction in superoxide production, whereas the spontaneous burst activity of resting PMN remained unaffected. This inhibitory effect of CP55 940 was not CB-receptor-mediated. In contrast, anandamide and methanandamide did not alter the oxidative microbicidal PMN function.

Malignant hyperthermia (MH) is an inherited skeletal muscle disorder triggered by commonly used anesthetics. Mutated ryanodine receptors have been identified as molecular targets. The sensitivity of myotubes from individuals classified by the in vitro contracture test as MH susceptible (MHS), normal (MHN), and equivocal (MHEH) was assessed for the Ca 2+ -releasing activity of 4-chloro-m-cresol (4-CmC) and caffeine. In this study, we sought to determine whether 4-CmC can differentiate the MH status of an individual on the basis of the release of intracellular Ca 2+ , particularly in regard to MHEH diagnosis. Intracellular Ca 2+ concentration was determined photometrically with Fura2. Regions of the ryanodine receptor 1 harboring most of the described MH mutations were sequenced from MHS and MHEH cells. One MH mutation (Gly2434Arg) was found in one MHS individual. Results of the caffeine-induced Ca 2+ release in MHS and MHN cells correlated well with the in vitro contracture test results. MHS cells showed a higher sensitivity against caffeine and, to a lesser extent, against 4-CmC. Cells of MHEH individuals showed low sensitivities against both caffeine and 4-CmC, comparable to those of the MHN group. Therefore, with myotubes, caffeine was able to discriminate between MHS and MHN cells, but both caffeine and 4-CmC failed to detect MHEH cells.

Acupuncture is an established adjuvant analgesic modality for the treatment of chronic pain. Electrical stimulation of acupuncture points is considered to increase acupuncture analgesia. In this prospective, randomized, double-blind, controlled study we tested the hypothesis that auricular electroacupuncture (EA) relieves pain more effectively than conventional manual auricular acupuncture (CO) in chronic low back pain patients with insufficient pain relief (visual analogue scale [VAS]or = 5) treated with standardized analgesic therapy. Disposable acupuncture needles were inserted in the auricular acupuncture points 29, 40, and 55 of the dominant side and connected to a newly developed battery-powered miniaturized stimulator worn behind the ear. Patients were randomized into group EA (n = 31) with continuous low-frequency auricular EA (1 Hz biphasic constant current of 2 mA) and group CO (n = 30) without electrical stimulation (sham-electroacupuncture). Treatment was performed once weekly for 6 wk, and in each group needles were withdrawn 48 h after insertion. During the study period and a 3-mo follow-up, patients were asked to complete the McGill questionnaire. Psychological well being, activity level, quality of sleep, and pain intensity were assessed by means of VAS; moreover, analgesic drug consumption was documented. Pain relief was significantly better in group EA during the study and the follow-up period as compared with group CO. Similarly, psychological well-being, activity, and sleep were significantly improved in group EA versus group CO, the consumption of analgesic rescue medication was less, and more patients returned to full-time employment. Neuropathic pain in particular improved in patients treated with EA. There were no adverse side effects. These results are the first to demonstrate that continuous EA stimulation of auricular acupuncture points improves the treatment of chronic low back pain in an outpatient population.Continuous electrical stimulation of auricular acupuncture points using the new point stimulation device P-stim significantly decreases pain intensity and improves psychological well-being, activity, and sleep in chronic low back pain patients.

In this prospective, randomised and double-blind clinical study the analgesic efficacy of a continuous infusion of tramadol combined with the non-opioid dipyrone (metamizol) was compared with tramadol alone or with placebo during first 24 h postoperatively. Ninety patients were allocated to the three study groups. In group 1, patients received 600 mg tramadol with 2.5 mg droperidol (DHB); in group 2, 600 mg tramadol together with 4.0 g dipyrone and 2.5 mg DHB; and in group 3, only 2.5 mg DHB. Additionally, a patient-controlled analgesia (PCA) device with morphine was provided to each patient as a rescue in the case of insufficient pain relief. Pain at rest and during movement was measured with a visual analogue scale (VAS, 0–10) during the study time. Side effects and vital parameters were also recorded. After the 24 h study period, a significant pain relief was observed in all three groups. The consumption of morphine via PCA, however, was significantly lower in group 2 (tramadol/dipyrone) than in the tramadol or the placebo group, and also the patients in group 1 (tramadol) had received significantly less morphine than those in the placebo group. Our data suggest a significantly superior analgesic efficacy of a continuous infusion of tramadol combined with dipyrone compared to an infusion of tramadol alone or placebo.

The aim of this study was to compare thermal and current sensory testing stimuli with respect to opioid responsiveness.Eighteen healthy volunteers were randomized in a placebo-controlled, double-blind crossover study to receive an infusion of remifentanil 0.08 micro g kg(-1) min(-1) or saline for 40 min. Test procedures included determination of pain perception thresholds (PPT) and pain tolerance thresholds (PTT) to heat, cold, and current at 5, 250 and 2000 Hz, at baseline and at the end of the infusion.Both current at 5 Hz (PPT 3.69 (SD 2.48) mA vs 2.01 (1.52) mA; PTT 6.42 (2.79) mA vs 3.63 (2.31) mA; P0.001) and 250 Hz (PPT 4.31 (2.42) mA vs 2.89 (1.57) mA; PTT 7.08 (2.68) mA vs 4.81 (2.42) mA; P0.001) and heat (PPT 47.4 (2.7) degrees C vs 45.2 (3) degrees C; PTT 51.1 (1.8) degrees C vs 49.7 (1.8) degrees C; P0.05) detected a significant analgesic effect of remifentanil compared with placebo. No analgesic effect was shown on cold or current at 2000 Hz. The magnitude of responsiveness of current stimuli at 5 Hz and 250 Hz was superior to heat stimuli.Both current (5 and 250 Hz) and heat sensory testing detected a significant analgesic effect of a remifentanil infusion compared with saline. There was more response to current testing.

The development of acute opioid tolerance in humans remains controversial. We tested the hypothesis that continuous remifentanil infusion leads to rapid development of opioid tolerance. Twenty healthy male volunteers were enrolled onto a randomized, placebo-controlled, double-blinded, cross-over design study to receive a 3 h continuous infusion of remifentanil (0.08 microg x kg(-1) x min(-1)) or saline. Test procedures included determination of pain perception thresholds and pain tolerance thresholds to heat and cold and neuroselective sine wave constant current at 5 Hz and 250 Hz. Test procedures were performed at baseline and then repeated at 25, 55, 85, 115, and 160 min (heat/cold) and at 35, 65, 95, 125, and 170 min (electrical current) during infusion. No significant decrease of the pain threshold devolutions between 55 and 180 min after the start of infusion of remifentanil could be detected. In conclusion, no development of acute opioid tolerance was observed during constant remifentanil infusion of 3 h in volunteers.The opioid remifentanil was applied to 20 volunteers at a constant concentration for 3 h while pain thresholds to temperature and current were repeatedly assessed. Our aim was to study whether thresholds decrease over time because of the rapid development of opioid tolerance. No development of rapid opioid tolerance was observed.

Background We assessed the role of ester hydrolysis as an additional degradation mechanism to Hofmann elimination in the breakdown of cisatracurium and atracurium. Methods Cisatracurium and atracurium were incubated in phosphate buffer (pH 7.4, 37°C) with and without the addition of carboxylesterase. Control measurements with an added esterase inhibitor were performed separately. Cisatracurium/atracurium and their degradation products, laudanosine and monoquaternary acid, were analysed using high-pressure liquid chromatography. Results Degradation of cisatracurium and atracurium proceeded exponentially, and after addition of carboxylesterase, no significant differences in the degradation rates were found. Neither an increase in carboxylesterase activity nor the addition of esterase inhibitor showed any effect. However, areas under the peaks of the chromatogram representing monoquaternary acid increased during incubation with esterase. Conclusion The rate-limiting step in the degradation of cisatracurium/atracurium is Hofmann elimination. Ester hydrolysis is involved in the second degradation step that forms monoquaternary acid, but its contribution to the total elimination rate is negligible.

Tapentadol prolonged release (PR) is effective and well tolerated for chronic osteoarthritis, low back, and diabetic peripheral neuropathic pain.To evaluate the efficacy and tolerability of tapentadol PR compared with placebo and morphine controlled release (CR) for managing moderate to severe chronic malignant tumor-related pain.Randomized-withdrawal, parallel group, active- and placebo-controlled, double-blind phase 3 study (NCT00472303).Primary, secondary, and tertiary care settings in 16 countries.Eligible patients (pain intensity ≥ 5 [11-point numerical rating scale] on prior analgesics) were randomized (2:1) and titrated to their optimal dose of tapentadol PR (100-250 mg bid) or morphine sulfate CR (40-100 mg bid) over 2 weeks. Morphine sulfate immediate release 10 mg was permitted as needed for rescue medication (no maximum dose). Patients who completed titration and, during the last 3 days of titration, had mean pain intensity5 (based on twice-daily ratings) and mean rescue medication use = 20 mg/day continued into a 4-week maintenance period; patients who received morphine CR during titration continued taking morphine CR, and those who received tapentadol PR were re-randomized (1:1) to tapentadol PR or placebo bid. Response during maintenance (primary efficacy endpoint) was defined as having: (1) completed the maintenance period, (2) a mean pain intensity5 during maintenance, and (3) used an average of = 20 mg/day of rescue medication during maintenance. Response at the end of titration was defined similarly, with pain intensity and rescue medication averages based on the last 3 days of titration.Of 622 patients screened, 496 were randomized, treated during titration, and evaluable for safety; 327 were re-randomized, treated during maintenance, and evaluable for safety; and 325 were evaluable for efficacy. The adjusted responder rate estimate during maintenance (logistic regression adjusting for treatment group, pooled center, and pain intensity at start of maintenance) was significantly higher with tapentadol PR (64.3%) than with placebo (47.1%; odds ratio (OR), 2.02 [95% confidence interval (CI), 1.12 - 3.65]; P = 0.02). Based on responder rates at the end of titration, tapentadol PR (76.0% [174/229]) was non-inferior to morphine CR (83.0% [83/100]). The lower limit of the 95% CI for the between-groups difference (-15.5%) was within the pre-specified 20% non-inferiority margin. During titration, incidences of treatment-emergent adverse events (TEAEs) were 50.0% (169/338) with tapentadol PR and 63.9% (101/158) with morphine CR; incidences of nausea, vomiting, and dry mouth were lower with tapentadol PR than with morphine CR. During maintenance, incidences of TEAEs were 56.3% (63/112), 62.3% (66/106), and 62.4% (68/109) with placebo, tapentadol PR, and morphine CR, respectively.Statistical comparisons between tapentadol PR and morphine CR were limited to descriptive statistics during the maintenance period because of the pre-selection of responders to tapentadol PR or morphine CR during titration.Results obtained during maintenance indicate that tapentadol PR (100-250 mg bid) is effective compared with placebo for managing moderate to severe chronic malignant tumor-related pain. Based on results obtained during titration, tapentadol PR provides comparable efficacy to that of morphine sulfate CR (40-100 mg bid), but is associated with better gastrointestinal tolerability.

Remifentanil offers a wide range of clinical uses and has been successfully combined with general anesthetics. However, there are few human experimental studies demonstrating the analgesic property of remifentanil. It was our aim to determine the analgesic effect of remifentanil with regard to dose-dependent increments in a human model of heat pain threshold assessment. Twenty healthy volunteers were randomized in a double-blinded cross-over design to receive an infusion of remifentanil or saline. The stepped infusion was increased every 5 min by 0.01 microg. kg(-1). min(-1) up to 0.17 microg. kg(-1). min(-1)and terminated in case of defined safety limits. Thermal sensory testing of the heat pain threshold was performed every 5 min at the left forearm. The dose-response relationship and the effective dose for at least 50% of the subjects (ED(50)) were determined. Remifentanil led to a clear dose-dependent increase of the heat pain threshold differing significantly from placebo (P0.0007). The ED(50) of remifentanil equals 0.05 microg. kg(-1). min(-1) (first quartile 0.025 microg. kg(-1). min(-1) and third quartile 0.06 microg. kg(-1). min(-1)) in this experimental setting. In conclusion, an opioid-mediated analgesic effect of remifentanil was determined in a human heat pain threshold model. The dose of 0.05 microg. kg(-1). min(-1) is an effective and safe increment in healthy volunteers.

Dihydropyridines (DHPs) are widely used antihypertensive drugs and inhibit excitation-contraction (E-C) coupling in vascular smooth muscle and in myocardial cells by antagonizing L-type Ca2+ channels (DHP receptors). However, contradictory reports exist about the interaction of the DHP with the skeletal muscle isoform of the DHP receptor and E-C coupling in skeletal muscle cells. Using the intracellular fluorescent Ca2+ indicator fura-2, an increase in [Ca2+]i was observed after extracellular application of nifedipine to cultured human skeletal muscle cells. The rise in [Ca2+]i was dose dependent with a calculated EC50 of 614 +/- 96 nM nifedipine and a maximum increment in [Ca2+]i of 80 +/- 3.2 nM. Similar values were obtained with nitrendipine. This effect of DHPs was restricted to differentiated skeletal muscle cells and was not seen in non-differentiated cells or in PC12 cells. In spite of the observed increase in [Ca2+]i, whole-cell patch clamp experiments revealed that 10 microM nifedipine abolished inward Ba2+ currents through L-type Ca2+ channels completely. Similar to nifedipine, (+/-)Bay K 8644, an agonist of the L-type Ca2+ channel, also increased [Ca2+]i. This effect could not be enhanced by further addition of nifedipine, suggesting that both DHPs act via a common signalling pathway. Based on the specific mechanism of the skeletal muscle E-C coupling, we propose the stabilization of a conformational state of the DHP receptor by DHPs, which is sufficient to activate the ryanodine receptor.

To evaluate the efficacy of a commercial immunoglobulin (Ig) A- and IgM-enriched immunoglobulin preparation containing high antibody titers against various human pathogens in the prevention of postoperative infections in anergic patients undergoing cardiac surgery.A single-center, prospective, double-blind, randomized study comparing the effect of a polyvalent intravenous human immunoglobulin (IVIG) preparation vs. placebo. LOCATION OF THE STUDY: Institute of Anesthesiology and Department of Thoracic and Cardiovascular Surgery, University Hospital, Wurzburg, Germany.A total of 515 patients awaiting elective open-heart surgery with the aid of cardiopulmonary bypass were tested for their in vivo immune response to intradermally administered recall antigens. Forty patients who were preoperatively shown to be anergic in this skin test, and therefore at high risk of developing serious postoperative infections, were selected from this group. Twenty patients with normal immune responses, and thus having a normal risk of infection, were randomly selected from the same patient group to serve as an immunoreactive control group.After obtaining approval from the local institutional review board and informed consent from patients, the 40 anergic patients were randomized and assigned either to the IVIG group (n = 19), to receive a commercially available human IgA- and IgM-enriched immunoglobulin preparation (dose, 20 g), or to the placebo group (n = 21), to receive physiologic saline. These treatments were started 4 hrs after surgery as a 400-mL continuous infusion over a period of 53 hrs. Patients were observed for the development of postoperative infection for the next 2 wks. Group comparisons were made using repeated-measures analysis of variance and Fisher's exact test. A p value.05 was considered statistically significantPostoperative infections were detected in nine of 21 patients (43%) in the placebo group but in only one of 19 patients (5%) in the IVIG-treated group (p = .007; Fisher's exact test). Three of the 20 patients (15%) with normal immune response who received standard postoperative treatment developed postoperative infections.A commercially available IgA- and IgM-enriched intravenous immunoglobulin preparation administered immediately after cardiac surgery significantly reduced the incidence of postoperative infections in preoperatively anergic patients.

Contains fulltext : 133909.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Neuropathic pain is a common symptom, present in 39% of the patients with cancer pain. Treating this type of pain is challenging, as this patient group is often frail and has comorbidities which increase the risk of side events and hence influences their quality of life. Clinical practice guidelines (CPGs) can be helpful for clinicians, especially when scientific evidence is uncertain or weak. In this study, we focused on the quality of the review of the literature used in treatment recommendations in the selected European CPGs. METHODS: In a previous study, 9 CPGs from European countries that contained at least one paragraph on treatment for neuropathic pain in cancer were included. Recommendations with their grade (according SIGN 55 classification) and supporting literature (first author, patients' population, year and type of publication) were compared between CPGs. RESULTS: In all CPGs, amitriptylin was mentioned as the drug of first choice. Six guidelines proposed also gabapentinoids. Only 30 of the 163 citations (18%) were based on studies in patients with cancer. Seven CPGs did not argue the indirect evidence due to extrapolation of study results from non-cancer to patients with cancer. CONCLUSION: The majority of guideline development groups extrapolated their results from non-cancer publications to formulate recommendations. Consequently, these guidelines fail to address important issues such as altered kinetics and side effect profiles in these patients. We recommend creating specific recommendations by an international expert group for the treatment for neuropathic pain in patients with cancer supported by targeted research in patients with cancer.

Patients on chronic anticonvulsant therapy are relatively resistant to some nondepolarizing neuromuscular blockers. Because of the controversial reports on atracurium, the purpose of the present study was to determine the effect of long-term carbamazepine treatment on the neuromuscular block produced by this muscle relaxant.Eighteen otherwise healthy individuals scheduled for neurosurgical interventions were studied. Eight patients had received carbamazepine for an average of 41 weeks (range 4-156 weeks) prior to surgery. Ten patients without carbamazepine exposure served as controls. After premedication with oral diazepam, anaesthesia was induced with fentanyl and thiopental and maintained with nitrous oxide and isoflurane in oxygen. Atracurium was given for neuromuscular blockade and the evoked electromyogram (EMG) was recorded with a Datex Monitor NMT.The lag time, the onset time, the duration 10%, 25%, 50%, 75% and the interval 25-75% did not differ between the groups.Our results with atracurium differ from previous data demonstrating an influence of carbamazepine therapy on the pharmacokinetics and/or pharmacodynamics of other non-depolarizing muscle relaxants. As documented in this study, atracurium produces adequate neuromuscular block in patients chronically exposed to carbamazepine. Chronic carbamazepine therapy does not influence the onset time and duration of action of atracurium-induced neuromuscular block.

Das Phenzyklidin-Derivat Ketamin nimmt auch 30 Jahre nach seiner klinischen Einfuhrung eine Sonderstellung unter intravenosen Anasthetika ein. Seiner besonderen Wirkung wurde auch mit dem Begriff der „dissoziativen Anasthesie” Rechnung getragen, deren neuropharmakologische Grundlage jedoch nicht ausreichend geklart ist. Neue methodische Moglichkeiten und die Verfugbarkeit der reinen Ketaminenantiomere haben jedoch in den letzten Jahren Erkenntnisse gewinnen lassen, die in dieser Ubersicht mit ihrer Relevanz fur die analgetische, anasthetische und neuroprotektive Wirkung von Ketamin bewertet werden sollen. Ketamin scheint sehr spezifisch mit einer kleinen Gruppe ligandengesteuerter Ionenkanale (Klasse-1-Rezeptoren) zu interagieren, wobei an der zentralen Rolle des NMDA-Rezeptorkanals fur Analgesie, Amnesie, Anasthesie und psychotomimetische Wirkungen kein Zweifel besteht. Zusatzlich tragen κ-Opiatrezeptoren, monoaminerge und cholinerge Wirkungen bei. Neu ist die klinisch bedeutsame Interaktion mit muskarinischen Rezeptoren und non-NMDA-Rezeptorkanalen. Mit Ausnahme der L-Typ-Kalziumkanale spielen spannungsgesteuerte Ionenkanale, soweit bisher untersucht, fur klinische Wirkungen nur eine untergeordnete Rolle. Die Beeinflussung von L-Typ-Kalziumkanalen, non-NMDA und NMDA-Rezeptorkanalen sowie des NO-cGMP-Systems stellen auserdem eine rationale Basis fur die neuroprotektive Wirksamkeit von Ketamin dar.

Pain continues to be underdiagnosed and undertreated in Europe. A lack of training in pain medicine among clinicians has been identified as a barrier to optimal pain management. Except for clinicians entering specialized training in pain medicine or a related field, inadequate or nonexistent pain management training is the norm in Europe. A multidisciplinary group of experts, including representatives from the European Federation of IASP (International Association for the Study of Pain) Chapters (EFIC), is launching a pan-European initiative aimed at raising the profile and importance of undergraduate pain education.