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Elisa Mura,1 Stefano Govoni,1 Marco Racchi,1 Valeria Carossa,1 Guglielmina Nadia Ranzani,2 Massimo Allegri,3,4 Ron HN van Schaik5 1Department of Drug Sciences, Centre of Excellence in Applied Biology, University of Pavia, Pavia, Italy; 2Department of Biology and Biotechnology, University of Pavia, Pavia, Italy; 3Pain Therapy Service, Foundation IRCCS San Matteo Hospital, Pavia, Italy; 4Department of Clinical, Surgical Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy; 5Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands Abstract: The 118A>G single nucleotide polymorphism (SNP) in the µ-opioid receptor (OPRM1) gene has been the most described variant in pharmacogenetic studies regarding opioid drugs. Despite evidence for an altered biological function encoded by this variant, this knowledge is not yet utilized clinically. The aim of the present review was to collect and discuss the available information on the 118A>G SNP in the OPRM1 gene, at the molecular level and in its clinical manifestations. In vitro biochemical and molecular assays have shown that the variant receptor has higher binding affinity for ß-endorphins, that it has altered signal transduction cascade, and that it has a lower expression compared with wild-type OPRM1. Studies using animal models for 118A>G have revealed a double effect of the variant receptor, with an apparent gain of function with respect to the response to endogenous opioids but a loss of function with exogenous administered opioid drugs. Although patients with this variant have shown a lower pain threshold and a higher drug consumption in order to achieve the analgesic effect, clinical experiences have demonstrated that patients carrying the variant allele are not affected by the increased opioid consumption in terms of side effects. Keywords: µ-opioid receptor, opioids, pharmacogenetics, pain, analgesia

The aim of this study was to evaluate the efficacy of omalizumab in the treatment of Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS), evaluated by visual analogue score for pain and urgency- frequency, O’Leary-Sant IC symptom and problem index questionnaire, Pain Urgency Frequency questionnaire and Patient Global Assessment questionnaire. Four female patients with a diagnosis of IC/BPS were included in the study, with an age between 20 and 39 years. In the first patient the subjective final evaluation was of a marked improvement. The second patient had a moderate improvement of the subjective final evaluation. The third patient considered her overall clinical situation to have slightly improved after treatment. One 32-year-old patient, with multiple allergies, discontinued treatment after 3 months and could not complete the study due to side effects. Omalizumab was subcutaneously administered to patients with IC/PBS; it induced both a subjective and objective improvement of symptoms in 2 patients enrolled in the study.

The chemical structures of morphine and its metabolites are closely related to the clinical effects of drugs (analgesia and side-effects) and to their capability to cross the Blood Brain Barrier (BBB). Morphine-6-glucuronide (M6G) and Morphine-3-glucuronide (M3G) are both highly hydrophilic, but only M6G can penetrate the BBB; accordingly, M6G is considered a more attractive analgesic than the parent drug and the M3G. Several hypotheses have been made to explain these differences. In this review we will discuss recent advances in the field, considering brain disposition of M6G, UDP-glucoronosyltransferases (UGT) involved in morphine metabolism, UGT interindividual variability and transport proteins.

Recently, many trials have been published to validate different techniques in peripheral regional anesthesia, but it is important to understand why and when we have to choose a specific technique and which advantages are offered by each of them. We performed a review of the clinical trials from the last three years (January 2007-September 2009), finding 644 articles on this topic. Even if many clinical trials underline a better efficacy of ultrasound (US) rather than peripheral nerve stimulators (PNSs), it could be important to confirm these results with trials having larger sample sizes and to compare US to percutaneous electric guidance (PEG) and/or sequential electrical nerve stimulation (SENS) techniques rather than peripheral nerve stimulation. Finally, even if it is well recognized that peripheral regional anesthesia is a safe technique, it is important to underline how the "new" techniques can guarantee a further improvement in the safety and effectiveness of regional anesthesia.

We organized a training program for oral fiber optic intubation (FOI) under conscious sedation. The efficacy of the program was evaluated by comparing the performances of experts and novices.The training procedure was divided into two sessions: a theoretical session on difficult airways, the fiber optic bronchoscope (FOB), remifentanil, topical anesthesia and patient interactions; and a session involving simulations of the FOI technique on dummies. For in vivo FOI, we enrolled patients requiring orotracheal intubation for elective surgery. Electrocardiograms, mean arterial pressure was railroaded over the fiberscope, and tracheal intubati6 and 7) FOIs, respectively, joined the study. To reach ±23 bpm, P=0.02), and RR was decreased (from 16±3 to 12±4 bpm, P0.05). No differences were recorded between the experts and less-experienced anesthesiologists. The average duration of FOI was 3.3±2.0 min for experts and 4.2±2.4 min for novices (P=0.03). Procedures were successful in both groups, with patients in each group being equally satisfied with the procedures.This study highlights the importance of a structured FOI training program, demonstrating that it is possible to learn to perform FOI proficiently by practicing on dummies.

Ample evidence is now available showing the analgesic efficacy of a local anaesthetic-opioid combination to control postoperative pain. This retrospective study aimed to analyze any improvement in the ability of sufentanyl, a highly lipophilic opioid, and morphine, a poorly lipophilic opioid, to control postoperative pain at rest and in motion when combined with ropivacaine 0.2%.In this retrospective study, 171 patients who underwent major abdominal or urological surgery were evaluated. The therapeutic protocol provided for continuous epidural perfusion (5 mL/h) of ropivacaine 0.2% + morphine 0.03 mg/mL or ropivacaine 0.2% + sufentanyl 0.75 mug/mL for 48 h. Pain at rest (numeric rate scale, NRS) and in motion (NRSm) was evaluated by means of the NRS upon waking and at 3, 6, 12, 24, 36, and 48 hs, providing for the administration of a rescue dose if NRS4. The overall analgesic effect was evaluated by comparing the area under the NRS curve (AUC) of both treatments using the Mann Whitney U test. Any differences between treatments in terms of NRS and NRSm in time were evaluated using ordinal logistic regression. To compare the frequency of patients who reported NRS4 at least once during the follow-up period, logistic regression was used. Finally, the frequency of patients who required at least one additional drug or reported side effects was compared using Fisher's exact test.While both groups showed a comparable overall analgesic effect, the baseline values of NRS and NRSm were lower for the sufentanyl group (P0.001), perhaps as a result of its quicker onset due to higher lipophilicity. No statistically significant difference was observed in the frequency of patients requiring administration of an additional analgesic drug (P=0.136) or in the incidence of complications (P=0.799).Both protocols providing a combination of a local anaesthetic and an opioid demonstrated an excellent safety and efficacy profile. The differing lipophilicity of the opioids did not cause any clinically or statistically significant differences in terms of efficacy or safety, other than a reduced onset time of sufentanyl, ensuring better pain control upon waking. We therefore believe that morphine should be the standard opioid for neuraxial use, although these results must be confirmed in the setting of a randomized controlled clinical trial.

When peripheral neuropathic pain affects a specific, clearly demarcated area of the body, it may be described as localized neuropathic pain (LNP). Examples include postherpetic neuralgia and painful diabetic neuropathy, as well as post-surgical and post-traumatic pain. These conditions may respond to topical treatment, i.e., pharmaceutical agents acting locally on the peripheral nervous system, and the topical route offers advantages over systemic administration. Notably, only a small fraction of the dose reaches the systemic circulation, thereby reducing the risk of systemic adverse effects, drug-drug interactions and overdose. From the patient's perspective, the analgesic agent is easily applied to the most painful area(s). The 5% lidocaine-medicated plaster has been used for several years to treat LNP and is registered in approximately 50 countries. Many clinical guidelines recommend this treatment modality as a first-line option for treating LNP, particularly in frail and/or elderly patients and those receiving multiple medications, because the benefit-to-risk ratios are far better than those of systemic analgesics. However, some guidelines make only a weak recommendation for its use. This paper considers the positioning of the 5% lidocaine-medicated plaster in international treatment guidelines and how they may be influenced by the specific criteria used in developing them, such as the methodology employed by randomized, placebo-controlled trials. It then examines the body of evidence supporting use of the plaster in some prevalent LNP conditions. Common themes that emerge from clinical studies are: (1) the excellent tolerability and safety of the plaster, which can increase patients' adherence to treatment, (2) continued efficacy over long-term treatment, and (3) significant reduction in the size of the painful area. On this basis, it is felt that the 5% lidocaine-medicated plaster should be more strongly recommended for treating LNP, either as one component of a multimodal approach or as monotherapy.

During pregnancy most of women will experience some kind of pain, either as a result of a pre-existing condition (low back pain, headache, fibromyalgia, and rheumatoid arthritis) or as a direct consequence of pregnancy (weight gain, postural changes, pelvic floor dysfunction, hormonal factors). However, chronic pain management during pregnancy and lactation remains a challenge for clinicians and pregnant women are at risk of undertreatment for painful conditions, because of fear about use of drugs during pregnancy. Few analgesic drugs have been demonstrated to be absolutely contraindicated during pregnancy and breastfeeding, but studies in pregnant women are not available for most of pain medications. The aim of this paper is to review the safety profile in pregnancy or lactation of the commonly prescribed pain medications and non-pharmacological treatments. In addition to the conventional classifications from the Food and Drug Administration and the American Academy of Paediatrics, authors analyzed the currently available clinical data from literature.

In recent years, increasing attention has been focused on the treatment of acute and chronic pain with a considerable number of publications about it. Nevertheless all the attention focused on it, the evidence of pain treatments is still unfolding, and occasionally conflicting. Hence it is still necessary that we point out our research efforts in trying to obtain a better understand of pathophysiology of pain and of real efficacy and safety of acute and chronic pain treatments. Our goal with this review is to summarize the latest research trends and the most advanced therapeutic standards for pain syndromes described in the literature, the discussion will be divided in four main topics, as these topics were treated during the SIMPAR (Study In Multidisciplinary PAin Research) meeting, held on December 2010 in Pavia: pathophysiology of pain, acute postoperative pain, opioids and pain, and chronic pain (Failed Back Surgery Syndrome). In the chapter of pathophysiology of pain we analyzed how to obtain a more personalized treatment through the study of the genetic and neurophysiological characteristics of patients and how to select the right local anesthetic according to anatomic and metabolizing patterns of patients. In acute postoperative pain we focalized our attention on the evidence supporting the use of continuous peripheral nerve blocks in the treatment of postoperative pain and in the prevention of chronic persistent post-operative pain, with a special attention in preventing side effects of regional anesthesia. We also reviewed the current evidence about the use of new very interesting modality to control postoperative pain after laparoscopy: pre-emptive nebulization of local anesthetic in abdominal cavity. As opioids are currently widely used to control chronic oncologic and non-oncologic pain, in this review we analyzed the level of evidence for their use, how to manage them better and psychological factors that can affect their success and/or determine addiction. Finally, we summarized the current evidence about Failed Back Surgery Syndrome focalizing our attention both in diagnosing it correctly and treating this syndrome with specific knowledge of the anatomic space that we have to approach and applying the possible treatments depending on pain pathophysiology and patient characteristics. In conclusion, it is important to try to personalize even better the therapy of patients with acute and chronic pain through a more accurate knowledge of anatomy, pathophysiology of pain, pharmacokinetic of pain drugs and of new device/therapies available.