Sufentanil Sublingual Tablet System: from rationale of use to clinical practice.

The control of post-operative pain in Italy and other western countries is still suboptimal. In recent years, the Sufentanil Sublingual Tablet System (SSTS; Zalviso; AcelRx Pharmaceuticals, Redwood City, CA, USA), which is designed for patient-controlled analgesia (PCA), has entered clinical practice. SSTS enables patients to manage moderate-to-severe acute pain during the first 72 postoperative hours directly in the hospital setting. However, the role of SSTS within the current framework of options for the management of post-operative pain needs to be better established. This paper presents the position on the use of SSTS of a multidisciplinary group of Italian Experts and provides protocols for the use of this device.

Testosterone deficiency in non-cancer opioid-treated patients.

PURPOSE: The use of opioids in patients with chronic non-cancer pain is common and can be associated with opioid-induced androgen deficiency (OPIAD) in men. This review aims to evaluate the current literature regarding the prevalence, clinical consequence and management of OPIAD. METHODS: A database search was performed in Medline, Embase and Cochrane using terms such as "analgesics", "opioids" and "testosterone". Relevant literature from January 1969 to March 2018 was evaluated. RESULTS: The prevalence of patients with OPIAD ranges from 19 to 86%, depending on the criteria for diagnosis of hypogonadism. The opioid-induced suppression of gonadotropin-releasing and luteinizing hormones represents the main important pathogenetic mechanisms. OPIAD has significant negative clinical consequences on sexual function, mood, bone density and body composition. In addition, OPIAD can also impair pain control leading to hyperalgesia, which can contribute to sexual dysfunction and mood impairment. CONCLUSIONS: OPIAD is a common adverse effect of opioid treatment and contributes to sexual dysfunction, impairs pain relief and reduces overall quality of life. The evaluation of serum testosterone levels should be considered in male chronic opioid users and the decision to initiate testosterone treatment should be based on the clinical profile of individuals, in consultation with the patient.

From acute to chronic pain: tapentadol in the progressive stages of this disease entity.

OBJECTIVE: Chronic pain is now recognized as a neural disease, which results from a maladaptive functional and structural transformation process occurring over time. In its chronic phase, pain is not just a symptom but also a disease entity. Therefore, pain must be properly addressed, as many patients still report unsatisfactory pain control despite on-going treatment. The selection of the therapy - taking into account the pathophysiological mechanisms of pain - and the right timing can result in a successful analgesic outcome. This review will present the functional and structural modifications leading to chronification of pain, focusing on the role of tapentadol in this setting. MATERIALS AND METHODS: For inclusion in this review, research studies were retrieved via a keyword-based query of multiple databases (MEDLINE, Embase, Cochrane). The search was last updated in November 2016; no limitations were applied. RESULTS: Functional and structural abnormalities of the nervous system associated with pain chronification have been reported in several conditions, including osteoarthritis, chronic back pain, chronic pelvic pain and fibromyalgia. Correct identification and treatment of pain in recurrent/progressive stage is crucial to prevent chronification and related changes in neural structures. Among analgesic drugs, tapentadol, with its dual mechanism of action (opioid agonist and noradrenaline reuptake blocker), has recently resulted active in pain control at both central and spinal level. CONCLUSIONS: Tapentadol represents a suitable candidate for patients at early progressive stage of pain who have developed neuroplasticity with modification of pain pathways. The availability of different doses of tapentadol may help clinicians to tailor treatment based on the individual need of each patient, with the aim to enhance therapeutic appropriateness in the treatment of musculoskeletal and neuropathic pain.

Sublingual sufentanil, a new opportunity for the improvement of postoperative pain management in Italy.

Despite the availability of national and international guidelines, adequate postoperative pain (POP) management is still a challenge in Italy. One of the potential reasons for the high incidence of surgical patients complaining moderate to severe pain is the difficult application of the currently recommended analgesic techniques in clinical practice. In particular, morphine, the most commonly used systemic opioid in the POP treatment, has some unfavorable pharmacodynamic and pharmacokinetic characteristics for POP management, suggesting a potential relevant improvement by using different opioids. Many of sufentanil properties make it particularly suitable for POP control: a high affinity for the µ opioid receptor, the highest therapeutic index compared to any other opioid used in clinical practice and the absence of clinically relevant active metabolites. The elevated potency, together with the high lipophilicity of sufentanil, allow the preparation of a nanotablet, 3 mm of diameter and 0.75 mm of thickness, containing 15 µg of active drug. The sublingual route allows a longer time of drug plasmatic permanence in comparison to IV route, overcoming the need for continuous dosing. The patient-controlled system, considered in the present review, is preprogrammed to deliver one sublingual tablet of sufentanil with a 20-minute lockout period with a radiofrequency identification thumb tag allowing only the patient to activate the on demand button. Phase II and III studies have assessed the efficacy of this system in POP management, showing that it was considered more satisfactory than the IV PCA morphine system by both patients and nurses. The introduction of this simple and innovative system of patient-controlled analgesic administration could represent an opportunity for Italy to update the current practice in POP management.

Postoperative Pain Surveys in Italy from 2006 and 2012: (POPSI and POPSI-2).

OBJECTIVE: Despite established standards, effective treatments, and evidence-based guidelines, postoperative pain control in Italy and other parts of the world remains suboptimal. Pain control has been recognized as a fundamental human right. Effective treatments exist to control postsurgical pain. Inadequate postoperative analgesia may prolong the length of hospital stays and may adversely impact outcomes. MATERIALS AND METHODS: The same multiple-choice survey administered at the SIAARTI National Congress in Perugia in 2006 (n=588) was given at the SIAARTI National Congress in Naples, Italy in 2012 (n=635). The 2012 survey was analysed and compared to the 2006 results. RESULTS: Postoperative pain control in Italy was less than optimal in 2006 and showed no substantial improvements in 2012. Geographical distinctions were evident with certain parts of Italy offering better postoperative pain control than other. Fewer than half of hospitals represented had an active Acute Pain Service (APS) and only about 10% of postsurgical patients were managed according to evidence-based guidelines. For example, elastomeric pumps for continuous IV infusion are commonly used in Italy, although patient-controlled analgesia systems are recommended in the guidelines. The biggest obstacles to optimal postoperative pain control reported by respondents could be categorized as organizational, cultural, and economic. CONCLUSIONS: There is considerable room for improvement in postoperative pain control in Italy, specifically in the areas of clinical education, evidence-based treatments, better equipment, and implementation of active APS departments in more hospitals. Two surveys taken six years apart in Italy reveal, with striking similarity, that there are many unmet needs in postoperative pain control and that Italy still falls below European standards for postoperative pain control.

The prevention of analgesic opioids abuse: expert opinion.

Opioids are drugs of reference for the treatment of moderate to severe pain. Their proper use and a periodic assessment of the patient are crucial to prevent misuse. A multidisciplinary group suggests strategies for all stakeholders involved in the management of pain and suggests the importance of the doctor-patient relationship.

A look inside the association codeine-paracetamol: clinical pharmacology supports analgesic efficacy.

Acute and chronic pain often requires a multimodal approach. Combination therapy reduces the number of individual daily administrations and improves patient's compliance with the prescribed analgesic treatment. Despite the association codeine/paracetamol is one of the most widely used central analgesic, the exact mechanism of action, particularly of paracetamol, is still object of pharmacological research. Recent findings showed that paracetamol may act through cerebral cyclo-oxygenase, descending opioidergic inhibitory pathways, serotonin pathway, and the endocannabinoid system; while codeine activity seems to related not only to its conversion to morphine, as previously known, but also by itself and through its metabolites, such as norcodeine (NORC) and codeine-6-glucuronide (C-6-G). The addition of codeine to paracetamol significantly improves the analgesic action and reduces the number needed to treat (NNT) from 5 to 2.3-3.1. Recent warnings about the risk of its metabolism related to CYP450 and its genetic variability in general population should be mainly considered when the association is used in paediatric patients undergoing tonsillectomy and/or adenoidectomy procedures for obstructive sleep apnoea syndrome (OSAS). In adults, the association codeine/paracetamol has been shown to be effective and safe in different settings: acute pain, trauma patients, and chronic nociceptive pain.

Italian Intersociety Recommendations on pain management in the emergency setting (SIAARTI, SIMEU, SIS 118, AISD, SIARED, SICUT, IRC).

BACKGRAUND: Pain is the primary reason for admission to the Emergency Department (ED). However, the management of pain in this setting is often inadequate because of opiophagia, fear of excessive sedation, and fear of compromising an adequate clinical assessment. METHODS: An intersociety consensus conference was held in 2010 on the assessment and treatment of pain in the emergency setting. This report is the Italian Intersociety recommendations on pain management in the emergency department setting. RESULTS: The list of level A recommendations includes: 1) use of IV acetaminophen for opioid sparing properties and reduction of opioid related adverse events; 2) ketamine-midazolam combination preferred over fentanyl-midazolam fentanyl-propofol in pediatric patients; 3) boluses of ketamine IV (particularly in the population under the age of 2 years and over the age of 13) can lead to impairment of the upper airways, including the onset of laryngospasm, requiring specific expertise and skills for administration; 4) the use of ketamine increases the potential risk of psychomotor agitation, which can happen in up to 30% of adult patients (this peculiar side effect can be significantly reduced by concomitant systemic use of benzodiazepines); 5) for shoulder dislocations and fractures of the upper limbs, the performance of brachial plexus block reduces the time spent in ED compared to sedation; 6) pain relief and the use of opioids in patients with acute abdominal pain do not increase the risk of error in the diagnostic and therapeutic pathway in adults; 7) in newborns, the administration of sucrose reduces behavioural responses to blood sampling from a heel puncture; 8) in newborns, breastfeeding or formula feeding during the procedure reduces the measures of distress; 9) in pediatric patients, non-pharmacological techniques such as distraction, hypnosis and cognitive-behavioural interventions reduce procedural pain caused by the use of needles; 10) in pediatric patients, preventive application of eutectic mixtures of prilocaine and lidocaine allows arterial and venous samples to be taken in optimum conditions; 11) in pediatric patients, the combination of hypnotics (midazolam) and N2O is effective for procedural pain, but may be accompanied by loss of consciousness. CONCLUSION: The diagnostic-therapeutic pathway of pain management in emergency should be implemented, through further interdisciplinary trials, in order to improve the EBM level of specific guidelines.

[Localized neuropathic pain--5% lidocaine medicated patch as a first-line treatment and as add-on therapy: literature review and personal experience]. / Dolore neuropatico localizzato: revisione della letteratura sull'utilizzo de Lidocaina cerotto 5% come first line treatment e nostra esperienza come add-on therapy.

Localized neuropathic pain (LNP) is a type of neuropathic pain characterized by consistent and circumscribed area(s) of maximum pain, which are associated with negative or positive sensory signs and/or spontaneous symptoms typical of neuropathic pain. This description outlines the clinical features of a group of pathologies, in which a LNP can be diagnosed and for whom topical targeted treatment with 5% Lidocaine medicated plaster can be suggested. Indeed both American as well as European guidelines already suggest 5% Lidocaine medicated plaster as a first line treatment in post herpetic neuralgia and in general in the treatment of conditions such as diabetic painful polyneuropathy and post surgical pain where a LNP can be ascertain. In a daily practice of a Pain Unit however the usual case mix encompasses also other causes of LNP, most of them with a scanty pain control in spite of a ongoing polytherapy. Aims of this paper were to focus on 5% Lidocaine medicated plaster as a first line treatment in LNP and to add new insight on its possible use as add-on therapy reporting our data on a consecutive series of 42 patients affected by LNP under unsatisfactory polytherapy in which 5% Lidocaine medicated plaster was able to achieve a satisfactory pain control.

Chronic pain management in pregnancy and lactation.

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.

Change Pain: changing the approach to chronic pain.

In Italy, chronic pain has a prevalence of about 26%, a rate that warrants efforts by specialists and primary care physicians to improve its treatment. From a study of various treatment systems, it is clear that a radical change in the approach to pain pathology is needed. To this end, the Change Pain International Advisory Board*, an international panel of experts, highlighted the limits to current treatment schemes and proposed new strategies. Among the criticalities are poor or inadequate communication between physician and patient, difficulty in qualitative and quantitative measurement of pain, management of adverse effects, and the "vicious circle" generated by current therapies, often the cause of poor compliance with pain treatment or discontinuation of analgesic therapy. A further limitation to current therapeutic practice is to consider pain intensity as the sole reference parameter in its treatment. In light of these considerations, the Advisory Board has drawn up a strategy to improve outcomes of pain therapy: 1) a shared therapeutic pact between physician and patient based on efficacious communication rather than on information alone; 2) identification of defined therapeutic objectives that allow for reaching a balance between reduction of pain and occurrence of adverse effects; 3) adoption of drug therapies that respond at least in part to an approach based on the pathogenic mechanism of pain rather than on pain intensity alone.

Bone metastatic disease: taking aim at new therapeutic targets.

Conventional treatment for metastatic bone pain requires a multidisciplinary approach (medical therapy, surgery, and radiation), but is primarily palliative. Biphosphonates introduced the concept of disease-modifying therapy, by effectively reducing bone pain and skeletal related events in patients suffering from bone metastatic cancer. In the past decade, the growing knowledge of bone biology and our understanding of the molecular mechanisms at the basis of the interaction between cancer cells and bone matrix led to the identification of new therapeutic targets for innovative "smart drugs". The most investigated is the RANK/RANKL/OPG pathway, and denosumab, among novel targeted therapies, is the molecule that is in the most advanced development phase. Additional targets have been identified and potential novel therapeutic interventions, classified as inhibitors of bone resorption or stimulators of bone formation, are under preclinical and clinical evaluation. These promising targets include cathepsin K, the Src tyrosine kinases, integrins, chloride channels, the parathyroid hormone-related peptide, endotelin-1, sclerostin, and TGF-beta. Other pathways or molecules expressed by bone cells and cancer cells, such as CXCR4, GPNMB, EGF-family ligands, Wnt/DKK1, and MIP-1 alpha have recently emerged as potential targets. The aim of this review is to discuss the molecular mechanisms behind these emerging therapeutic targets in bone metastases and to give an overview of results from those in advanced clinical phases.

Determinants of patient satisfaction in postoperative pain management following hand ambulatory day-surgery.

AIM: Adequate postoperative analgesia is a prerequisite for successful ambulatory surgery and continues to be a challenge for anesthesiologists. The goal of the study was to analyze what are determinants of patients' overall satisfaction in postoperative pain management after ambulatory hand surgery. METHODS: Patients undergoing ambulatory hand surgery received oral fixed association tramadol/acetaminophen 37.5/325 mg every 6 hours during the first 48 hours after operation. Analgesic efficacy was evaluated by self-assessment of pain intensity by numeric rating scale. Patients also recorded total number of daily study analgesic tablets, frequency and severity of adverse events, sleep pain interference (SPI 0-10), number of rescue doses and patient global assessment (PGA) on a 4-grade scale. Success ratings on the PGA were considered "good" and "excellent". Preoperative pain intensity, analgesic use, and expectation were also recorded. RESULTS: One hundred and forty-three subjects were evaluated in the study. The percentage of patients who reported rating of success on the PGA was 88.8%. The most significant determinant of failure on the PGA was the presence of moderate to severe adverse events (R=-0.85). Determinants of ratings of success on PGA were adequate analgesia and SPI ≤ 4. Predictors of successful patient satisfaction were preoperative pain ≤ 4 on NRS, lack of preoperative analgesic consumption, expected pain >6 on NRS, and lower education level. Weak correlation (R=0.26) was observed between mean daily pain intensity and analgesics intake. CONCLUSION: Results indicate that the oral association tramadol/acetaminophen 37,5/325 mg is effective for the management of postoperative pain after ambulatory hand surgery. The lack of adverse events is the most important determinant of patient satisfaction, followed by the analgesic efficacy.

OROS® hydromorphone in chronic pain management: when drug delivery technology matches clinical needs.

The osmotic-controlled release oral delivery system (OROS®) is an innovative drug delivery technology that uses osmotic pressure as the driving force to deliver pharmacotherapies in many therapeutic areas. In chronic pain management requiring long-term therapy, pharmaceutical technologies that ensure the controlled release of analgesic medications are imperative. In addition, once-daily formulations ensure better patient compliance to prescribed therapies. Hydromorphone was the first opioid to be formulated as a once-daily preparation using OROS® technology. The purpose of this review is to discuss the application of OROS® technology in the field of chronic pain management and to examine clinical trial results for OROS® Hydromorphone. OROS® hydromorphone ensures the constant delivery of hydromorphone over a 24-hour period, and its pharmacokinetic profile is only minimally affected by food and alcohol. Dose-conversion studies have shown that patients with chronic pain can be easily switched from previous opioid therapies to OROS® hydromorphone without a loss of pain control. These studies support the clinical utility of the 5:1 ratio used for the conversion of oral morphine to oral OROS® hydromorphone. Furthermore, once-daily OROS® hydromorphone has been shown to be effective in patients with chronic cancer and non-cancer pain, and it provides similar pain relief to SR morphine and ER oxycodone. In chronic pain management, OROS® products can result in more stable drug concentrations, reduced dosing frequency and an improved safety profile.

[Nimesulide: 25 years later]. / Nimesulide 25 anni dopo.

The first marketing authorization for nimesulide was approved in Italy in 1985. After one quarter of a century we evaluate its peculiar characteristics compared with other NSAIDs. Nimesulide is the only NSAID related to the arylsulfonamide class and is a "COX-2 preferential NSAIDs", because despite having a prevalent effect on COX-2, has a balanced action on both cyclooxygenase. The gastrointestinal absorption is rapid and complete and explains the short onset of action. Nimesulide is rapidly distributed in the synovial fluid, where it persists longer than in the blood, thus contributing to effectiveness of the drug in pain control. From the standpoint of safety, nimesulide arises NSAIDs with lower risk of upper gastrointestinal bleeding thanks to its preferential activity on COX-2. In relation to the risk of severe hepatic reactions, the benefit/risk profile of nimesulide was considered by european regulatory authorities similar to other NSAIDs. Respecting international guidelines, the use of nimesulide in pain management, as that of other NSAIDs, must be considered as an alternative therapy when paracetamol is ineffective, or where the pain is caused or supported by an inflammatory process.

Postoperative pain treatment SIAARTI Recommendations 2010. Short version.

The aim of these recommendations is the revision of data published in 2002 in the "SIAARTI Recommendations for acute postoperative pain treatment". In this version, the SIAARTI Study Group for acute and chronic pain decided to grade evidence based on the "modified Delphi" method with 5 levels of recommendation strength. Analgesia is a fundamental right of the patient. The appropriate management of postoperative pain (POP) is known to significantly reduce perioperative morbidity, including the incidence of postoperative complications, hospital stay and costs, especially in high-risk patients (ASA III-V), those undergoing major surgery and those hospitalized in a critical unit (Level A). Therefore, the treatment of POP represents a high-priority institutional objective, as well as an integral part of the treatment plan for "perioperative disease", which includes analgesia, early mobilization, early enteral nutrition and active physiokinesitherapy (Level A). In order to improve an ACUTE PAIN SERVICE organization, we recommend: --a plan for pain management that includes adequate preoperative evaluation, pain measurement, organization of existing resources, identification and training of involved personnel in order to assure multimodal analgesia, early mobilization, early enteral nutrition and active physiokinesitherapy (Level A); --the implementation of an Acute Pain Service, a multidisciplinary structure which includes an anesthetist (team coordinator), surgeons, nurses, physiotherapists and eventually other specialists; --referring to high-quality indicators in establishing an APS and considering the following key points in its organization (Level C): --service adoption; --identifying a referring anesthetist who is on call 24 hours a day; --patient care during the night and weekend; --sharing, drafting and updating written therapeutic protocols; --continuous medical education; --systematic pain assessment; --data collection regarding the efficacy and safety of the implemented protocols; --at least one audit per year. --a preoperative evaluation, including all the necessary information for the management of postoperative analgesia (Level C); --to adequately inform the patient about the risks and benefits of drugs and procedures used to obtain the maximum efficacy from the administered treatments (Level D). We describe pharmacological and loco-regional techniques with special attention to day surgery and difficult populations. Risk management pathways must be the reference for early identification and treatment of adverse events and chronic pain development.

Postoperative pain survey in Italy (POPSI): a snapshot of current national practices.

AIM: Over the last several years, significant efforts have been directed towards improving the quality of postoperative pain management. As data are lacking on the organization and quality of these services in Italy, we surveyed current Italian practices. METHODS: A 16-item questionnaire was randomly supplied to 650 anesthesiologists attending the Italian Society of Anesthesia Analgesia Resuscitation and Intensive Care Medicine (SIAARTI) National Congress in 2006. The survey requested information concerning their current practices in analgesic techniques, use of guidelines, educational programs, availability of an Acute Pain Service (APS), and existing barriers to optimal postoperative pain management. RESULTS: Based on 588 respondents, a sample of 163 hospitals was analyzed (24.4% of Italian public hospitals); 41.7% of the surveyed hospitals had an organized APS. University and teaching hospitals had an organized APS more frequently than did other hospitals (P<0.02). Continuous intravenous analgesia using elastomeric infusion systems was the most commonly used analgesic technique, performed in 44% of the treated patients. The frequency of both intravenous patient-controlled analgesia and epidural techniques was extremely low (5% and 13%, respectively). The main reasons given for suboptimal pain relief were inadequate training of surgeons and nurses (44.3%), poor organization (29.9%), and lack of equipment (21.5%). A total of 51.2% of the respondents would like to have a dedicated anesthesiologist assigned on a daily rotational basis to postoperative pain management. CONCLUSIONS: A comparison to international survey data showed that postoperative pain management in Italy is still below the European standards. Additional efforts to overcome these hurdles and to reach an acceptable level of quality are required.

What anesthesiologists should know about paracetamol (acetaminophen).

Paracetamol is widely used in the management of acute and chronic pain. The purpose of this review is to give anesthesiologists answers to some of the most common questions about paracetamol, specifically the following questions. What is the mechanism of action of paracetamol? Is paracetamol a NSAID? Which endogenous analgesic systems are influenced by paracetamol? Are the perceived concerns about paracetamol use real? What new research is there into paracetamol-induced liver failure? Is paracetamol safe for use by patients with liver disease or those taking anticoagulants? How effective is paracetamol for the management of postoperative pain? Does paracetamol have any opioid-sparing effects? Which formula has the best analgesic efficacy? Which route of administration has the better pharmacokinetic profile? Is the concentration of paracetamol in blood or cerebrospinal fluid relevant to the analgesic effect? Which starting dose should be administrated in intravenous infusion?

Paracetamol/Tramadol association: the easy solution for mild-moderate pain.

Some authors have proposed an updating of the therapeutic recommendations for some kinds of pain, such as musculoskeletal, post-traumatic and post-surgical pain for which a multimodal approach is being increasingly considered. With regard to this, an association of analgesics belonging to different pharmacological classes becomes an important option, given that analgesic efficacy can be ensured using lower dosages of single components, improving the tolerability of the drugs. The fixed combination of paracetamol (325 mg) and tramadol (37.5 mg) has a precisely dose ratio to obtain an additive analgesic effect, improving both the analgesic efficacy, which is more stronger and complete, and the duration of the action, guaranteeing a quick analgesic effect over time. A wide international literature exists for this association. This review considers particularly 15 studies. In nine of them, all double-blind, the duration of treatment was 1-10 days and, in total, 2 537 patients were admitted, affected by acute painful flares of chronic-degenerative pathologies, trauma or subjected to surgery. The mean daily dose of paracetamol/tramadol most frequently used was 4.3-4.5 tablets/day. Rigorous studies were conducted also for chronic pain; in the 6 studies considered the duration of treatment was 4-13 weeks and a total of 1 890 patients, affected by chronic musculoskeletal pain, were admitted. The mean daily dose of paracetamol/tramadol was between 3.5 and 4.2 tablets/day, showing itself to be constant and independent of the disease considered. In conclusion, the fixed association paracetamol/tramadol is a new therapeutic option, particularly useful in mild-moderate pain where paracetamol is inadequate.