ROUND TABLE I BASIC SCIENCE AND PATHOPHYSIOLOGY OF PAIN ZINC AND Zn- METALLOPROTEINS IN PAIN MODULATION Vasiliki Kalfakakou Unit of Environmental Physiology, Laboratory of Physiology, Medical Faculty, University of Ioannina. Greece. e-mail: vkalfaka@cc.uoi.gr Zinc homeostasis is regulated by the metal response element-binding transcription factor-1 (MTF1) which initiates gene expression for zinc transporters (ZnTs, ZIPs) and metallothioneins (MTs), in response to various cell stresses.( Jackson K.A,2008). Zinc protects nerve cells from reactive oxygen species (ROS) either by forming the active center of antioxidant enzymes, such as superoxide dismutase (SOD) or by initiating, as a labile ion, anti-stress pathways ,such as the metal-responsive genes activation.(Cousins R.G ,2011). The metal holds also protective properties against local anesthetics’ cell toxicity ,such as ropivacaine induced apoptosis in human keratinocytes (Kontargiris E,2004) The metal regulates the total excitability, neurotransmission and synaptic plasticity of neuronal cells (Zhang Y,2000). Nitric oxide (NO), a potent neurotransmitter, interacts to MTs leading to Zn release, thus NO –signaling turns to Zn- signaling (Bardethe S.C,2003). Zinc is a signaling factor in the synaptic bodies, selectively released with glutamate by the cranial nerves (Frederickson C.J ,2005). Synaptic vessels of zincergic dorsal route ganglion (DRG) neurons are detected with high zinc concentrations. Metal liberation regulates substance (SP) release and the function of a vast number of receptors and ionic channels .Calcitonin gene related peptide (CGRP) and SP are simultaneously released by a number of DRG neurons, after Zn signaling, suggesting that Zn acts as a pain modulator. Neutral endopeptidase (NEP) a Zn–metalloenzyme which degrades endogenous opioids and SP, is downregulated by ropivacaine and modulated by zinc.(Kontargiris E,2012). Zinc (Zn) a key element in neuronal function and pain modulation is a highly promising agent in algos management.
THE ROLE OF GLIA IN PAIN Craig T. Hartrick, MD, FIPP Professor, Biomedical Sciences and Anesthesiology Oakland University William Beaumont School of Medicine Rochester, Michigan, USA
It is increasingly appreciated that altered central immune signaling plays an important role in a number of processes relevant to pain and pain management. Altered neuroimmune status contributes to elevated neuronal excitability, reduced effectiveness of analgesics, and perhaps even the propensity to develop persistent and chronic pain states. Advances in understanding the pathophysiology of central immune signaling have provided insights into analgesic tolerance, opioidinduced hyperalgesia, and allodynia. While a number of immunocompetent cells contribute to central immune signaling, including oligodendrocytes, endothelial cells of the blood-brain barrier, peripheral immune cells of the central nervous system, and neurons themselves, this discussion will be limited to the glial cells: astrocytes and microglia. Further, these immune signaling processes are complex; this presentation will focus on the elaboration of the cytokine interleukin-1beta and the characterization of interleukin-1 receptor antagonist genotypes as they relate to the development of chronic allodynic states. Following injury microglia may develop and maintain a primed phenotype, reacting more rapidly and exuberantly with subsequent stimulation. The genetic predisposition for this response, as well as the development of chronic pain, has been investigated. Data from patients with preexisting complex regional pain syndrome [1], a preclinical immune-mediated neuropathic pain model [2], and a recent prospective clinical study examining the development of allodynia following injury [3] will be presented. 1. Hartrick CT: Increased production of nitric oxide stimulated by interferon-gamma from peripheral blood monocytes in patients with complex regional pain syndrome. Neuroscience Letters 2002;323:75-77. 2. Zitron I, Hartrick CT: Sciatic Inflammatory Neuritis: a non-surgical technique. Journal of Neuropathic Pain and Symptom Palliation. 2005;1(4):3-12. 3. Hartrick CT, Wendell D, Pestano C, et al. CRPS following arthroscopic shoulder surgery associated with IL1-ra genotype. ASA Abstracts. 2013; A2017.
OPIOID HYPERALGESIA: MYTH OR REALITY? Prof. A. Borgeat, MD, Dept. of Anesthesiology, Orthopedic University Hospital Balgrist, Zurich, Switzerland Opioids are the cornerstone therapy for alleviating moderate to severe pain. Whereas opioids have long been used for alleviating acute and cancer-related pain, they recently have gained significant popularity for the treatment of chronic non-malignant pain. Common concerns regarding the use of opioids are the potential for detrimental side effects, physical dependence, and addiction. However, recent research suggests that opioids may yet cause another problem, often referred to as opioidinduced hyperalgesia (OIH). Patients receiving opioids to control their pain somewhat paradoxically may become more sensitive to pain as a direct result of opioid therapy. That is, the use of opioids may be a double-edged sword. They provide straight analgesic and anti hyperalgesic effects initially, but subsequently are associated with the expression of hyperalgesia likely reflecting upregulation of compensatory pronociceptive pathways The presence of hyperalgesia has a major impact on primary and secondary pain processing by the brain, with these changes having the potential to be both adaptive and maladaptive. These alterations may be detrimental in the early postoperative period for a number of reasons. First, hyperalgesia tends to increase the amount of pain the patient experiences – an unwanted outcome of itself – because of greater amplification of given noxious inputs. Second, more pain typically means more patient stress in the postoperative period, with the possibility of negative consequences for a variety of complications and outcomes. Finally, abnormal persistence of nervous system sensitization subsequent to nociception, i.e., excitatory neuroplasticity expressed as hyperalgesia and increased pain, is now considered a major candidate mechanism for the development of chronic pain (1,2) The reliable diagnosis of hyperalgesia is difficult based on clinical symptoms alone. The very definition of hyperalgesia – more pain accompanying a given stimulus - makes it clear that its detection is based on construction and comparison of stimulus-response curves before and after nociception or drug application. Therefore, the systematic diagnosis and quantification of hyperalgesia requires the formal, serial determination of stimulus dose response curves under standardized conditions, a process termed quantitative sensory testing (QST). If postoperative hyperalgesia is not diagnosed, it will not be subject to targeted treatment, which fact may – as will be discussed below – be a contributing factor to the lack of substantive progress in postoperative analgesia mentioned above (3). The circumstances under which opioid-induced hyperalgesia may occur are not entirely understood but may include high doses, long-term treatment, or abrupt changes in concentrations. Recent observations on changes in neurotransmitter release following acute and chronic exposure to opioids provide potential solutions to comprehension of opioid induced hyperalgesia (4). Opioids do not excite descending fibres directly but disinhibit them by inhibiting spontaneous GABA release from local GABAergic interneurones. Rebound adenylyl cyclase activity in withdrawal may be the fundamental step in eliciting the withdrawal behaviour. Neuropathic pain and opioid induced hyperalgesia have common pathophysiologic mechanisms. Among these neural mechanisms, the central glutaminergic system plays a pivotal role and N-methyl-d-aspartate (NMDA) receptor has been shown to be critical in the cellular mechanism of opioid-induced pain sensitivity. Perioperative opioids may increase postoperative pain and opioid requirements (5) References 1. Perkins FM, Kehlet H. Chronic pain as an outcome of surgery. A review of predictive factors. Anesthesiology 2000;93:1123-33. 2. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000;288:17659. 3. Macrae WA. Chronic pain after surgery. Br J Anaesth 2001;87:88-98. 4. Celerier E, Gonzalez JR, Maldonado R et al. Opioid-induced hyperalgesia in a murine model of postoperative pain: role of nitric oxide generated from the inducible nitric oxide synthase. Anesthesiology 2006;104:546-55. 5. Guignard B, Bossard AE, Coste C et al. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology 2000;93:409-17.
ROUND TABLE II CHRONIC PAIN: MANAGEMENT OUTCOMES & ECONOMICS MEDICAL MANAGEMENT OF CHRONIC BACK PAIN: QUO VADIS: ARE THERE ALTERNATIVES FOR INTERVENTIONAL PAIN MANAGEMENT? Jan Van Zundert, MD, PhD, FIPP. Department of anesthesiology and multidisciplinary pain center. Ziekenhuis Oost-Limburg, Genk. Belgium The life time prevalence of an episode of acute low back pain (LBP) is close to 100%. The majority of the episodes have no long lasting influence. Although earlier publications suggest that only approximately 10% of those patients develop a chronic problem1, a recent systematic review of the literature has demonstrated that 1 year after the diagnosis still 65% of the patients report pain. 2. Consequently, there is a high demand for effective and safe treatment options for chronic low back pain. A multimodal pathology requires an interdisciplinary approach A well designed diagnostic process, with the objective to identify as much as possible the structure that causes the pain, in order to facilitate the treatment that is target specific. Secondly a thorough assessment of the patient’s clinical, psychological and socio economic situation. Those factors may interfere with the pain perception and the global coping facilities of the patient. Pharmacological treatment has the goal to reduce pain and allow physical exercise to improve functionality. The different analgesics are recommended, according to the WHO pain ladder and coanalgesics should be used as appropriate. Pain rehabilitation programs, such as operant behavioral treatment have documented efficacy. These programs may consist of: graded activity training, a method to restore better function for patients who have reduced their level of physical activities; time-contingent medications and activity pacing. 3 Cognitive behavioral therapy can be included in the multidisciplinary pain management, especially when emotional distress, including fear for movement, plays a role in the development and maintenance of chronic pain. 4 It is imperative that the different care givers communicate between each other. The real meaning of interdisciplinary is that the patient is managed by a team where different specialties are available. Therefore the role of interventional pain management techniques should be seen in the global perspective of seeking the best treatment plan for the specific patient. Interventional pain management techniques may rarely be used isolated, most often they are part of the global treatment plan. Those techniques are target specific, and treatment outcome largely depend on the correct patient selection. The two most prevalent sub diagnoses are: pain originating from the lumbar facet joints and lumbar radicular pain. 5 Radiofrequency treatment of the medial branch of the dorsal ramus has evidence for efficacy in the management of lumbar facet joint pain. For the management of lumbar radicular pain the use radiofrequency adjacent to the dorsal root ganglion was demonstrated not to be better than placebo. Recently more evidence is becoming available in favor of the use of pulsed radiofrequency adjacent to the lumbar dorsal root ganglion. The findings of the different studies as well as the outcome of the animal research suggests that there are potentially ways to improve the treatment outcome. 6, 7 Opioids have gained in interest for the management of chronic (non-cancer) pain and although controlled studies showed that single doses or short intravenous infusion of opioids controls various pain syndromes, including neuropathic pain, the benefit of long term use and the relation between efficacy and dose is still questioned.8 The publication of a population based nested case control study regarding the use of opioid in non-malignant pain used the running title “Less in more”, because they found that there was a clear association between opioid dose and opioid related mortality. 9 There is, up till now, no golden bullet for the management of chronic low back pain.
References 1. Spitzer W, Le Blanc F. Scientific approach to the assessment and management of activityrelated spinal disorders. Report of the Quebec Task Force on Spinal disorders. Spine.1987; Suppl:1217. 2. Itz CJ, Geurts JW, van Kleef M, Nelemans P. Clinical course of non-specific low back pain: a systematic review of prospective cohort studies set in primary care. Eur J Pain.2013; 17:5-15. 3. Gatzounis R, Schrooten MG, Crombez G, Vlaeyen JW. Operant learning theory in pain and chronic pain rehabilitation. Curr Pain Headache Rep.2012; 16:117-126. 4. Nicholas MK, Linton SJ, Watson PJ, Main CJ, Decade of the Flags" Working G. Early identification and management of psychological risk factors ("yellow flags") in patients with low back pain: a reappraisal. Physical therapy.2011; 91:737-753. 5. Linton SJ, Maher CG, Van Zundert J. Low Back Pain: Basic Mechanisms, Treatment, and Management. In: IASP, ed. 14th World Congress on Pain Vol. Milan, Italy: IASP; 2012. 6. Van Boxem K, Cheng J, Patijn J, van Kleef M, Lataster A, Mekhail N, Van Zundert J. 11. Lumbosacral radicular pain. Pain practice : the official journal of World Institute of Pain.2010; 10:339358. 7. van Kleef M, Vanelderen P, Cohen SP, Lataster A, Van Zundert J, Mekhail N. 12. Pain Originating from the Lumbar Facet Joints. Pain practice : the official journal of World Institute of Pain.2010. 8. Ballantyne JC, Mao J. Opioid therapy for chronic pain. The New England journal of medicine.2003; 349:1943-1953. 9. Gomes T, Mamdani MM, Dhalla IA, Paterson JM, Juurlink DN. Opioid dose and drug-related mortality in patients with nonmalignant pain. Arch Intern Med.2011; 171:686-691.
IMPROVEMENT OF PAIN OUTCOMES BY BETTER PATIENT SELECTION AND DIAGNOSTIC PROGRAMS Kris C.P. Vissers, MD, PhD, FIPP. Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Nijmegen, Netherlands Already in 1977 Engel 1 described the need for a new medical model, referring to the potential multifactorial components of chronic pain. Dansie and Turk 2 in their recent review on the assessment of patients with chronic pain stressed the importance of evaluating the whole person in pain and not just the pain on itself. These authors indicate that chronic pain has a high impact on the patient, his proxies and society. Moreover; in 1998 a consensus meeting formulated a plea for a better mechanism based diagnosis of pain syndromes. 3 In fact the authors of this editorial stressed the need for a better understanding of the underlying pain mechanisms to allow targeted drug development and administration. In general, guidelines suggest to identify whether the pain of a patient is nociceptive, neuropathic or mixed. More and more these guidelines even advice to look for specific signs and symptoms of pain representing the underlying mechanisms of pain generation. This approach induces a better understanding of pain and resulted in specific recommendations for a mechanism based treatment of e.g. neuropathic pain. 4 This was confirmed by recent research that aims to individualize the selection of drugs for neuropathic pain by examining the potential coupling of a given drug's mechanism of action with the patient's pain modulation pattern.5 Several instruments have been developed and validated to identify neuropathic pain. Besides, when needed, more sophisticated investigations can help identifying the type of neuropathic pain, such as nerve conduction studies that may give an indication of changes in amplitude or conduction velocity, and somatosensory evoked potential studies that may indicate dysfunction of the somatosensory pathways. 6 Quantitative Sensory Testing (QST) analyzes perception in response to external stimuli of controlled intensity, and may be used for quantifying hyperalgesia and allodynia in painful neuropathic syndromes.7 Additionally, a simple cold water bucket test can identify problems with the descending inhibitory pain control which is very prevalent in neuropathic pain syndromes. The diagnostic process for patients suffering chronic pain, starts with an extensive history taking. The patient’s description of the symptoms may point towards more pronounced neuropathic or nociceptive pain. Instruments have been developed that help identifying neuropathic pain. 8 When a more target specific treatment is envisioned care should be taken to identify the underlying cause and mechanism of pain generation. A first triage can be made based on the clinical symptoms, which can be fine-tuned further by a targeted clinical examination. Medical imaging may be useful to confirm or reject degenerative changes, herniated disc, or other abnormalities. The presence of degeneration is however, not equivalent to the cause of the pain. Because a high percentage of patients are asymptomatic despite clear degenerative disease. Diagnostic test block(s) with local anesthetics on specific nerve struc tures are used to identify the conducting nerve structure that causes the pain. Prior to envisioning interventional treatment such as radiofrequency treatment the causative level should definitely be confirmed with such a positive diagnostic block. A recently published hypothesis-generating prospective study, shows that the perturbations to the sensory processing system from effective diagnostic blocks affect the tonic inhibitory system in a positive manner.9 These diagnostic programs should first aim at a patients’ triage, thus avoiding leading them into a painstaking trajectory of trial and error. However, a balance between the expected gain in specificity and the burden for the patient should be made. As long as we do not have a golden standard for the diagnosis, the degree of invasiveness of the diagnostic interventions should equally be balanced by the degree of invasiveness and the potential side effects of the planned therapeutic intervention. Careful standardized long-term follow up is therefore mandatory and should be extensively documented and researched in order to identify effective and useful treatments and stop ineffective treatments. The use of outcome indicators can be helpful in these evaluation programs.
1. Engel GL. The need for a new medical model: a challenge for biomedicine. Science. 1977;196:129-136.
2. Dansie EJ, Turk DC. Assessment of patients with chronic pain. British journal of anaesthesia. 2013;111:19-25. 3. Woolf CJ, Bennett GJ, Doherty M, Dubner R, Kidd B, Koltzenburg M, et al. Towards a mechanism-based classification of pain? Pain. 1998;77:227-229. 4. Jongen JL, Hans G, Benzon HT, Huygen F, Hartrick CT. Neuropathic Pain and Pharmacological Treatment. Pain practice : the official journal of World Institute of Pain. 2013. 5. Yarnitsky D, Granot M, Nahman-Averbuch H, Khamaisi M, Granovsky Y. Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy. Pain. 2012;153:1193-1198. 6. Pergolizzi J, Ahlbeck K, Aldington D, Alon E, Coluzzi F, Dahan A, et al. The development of chronic pain: physiological CHANGE necessitates a multidisciplinary approach to treatment. Curr Med Res Opin. 2013. 7. Rolke R, Baron R, Maier C, Tolle TR, Treede RD, Beyer A, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain. 2006;123:231-243. 8. Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology. 2008;70:16301635. 9. Chua NH, Vissers KC, Arendt-Nielsen L, Wilder-Smith OH. Do diagnostic blocks have beneficial effects on pain processing? Regional anesthesia and pain medicine. 2011;36:317-321.
CAN WE SAVE MONEY IN PAIN MANAGEMENT Eli Alon, MD, Zurich Switzerland Pain is an unpleasant sensory and emotional experience, associated with actual or potential tissue damage, or described in terms of such injury. Acute pain is a self limiting process and may reasonably be considered as a symptom of disease or injury. Chronic and recurrent pain affects dominantly the whole life of the suffering person and often his family and is a specific healthcare problem, a disease of its own right. A wide range of treatment is available for chronic pain, nevertheless, this presents a major challenge. Usually it is possible to alleviate pain only partially but sometimes even totally. In order to achieve a maximum pain relief it is often necessary to use an interdisciplinary model. Physician and patient should have both realistic treatment goals. Chronic pain is often very late diagnosed or incorrectly treated, this leads to high costs for the whole economy. The European Pain Federation EFIC sensitizes politicians who are becoming aware of this. It is possible to save money prescribing cheaper generic drugs. Sometimes even the apparently expensive interdisciplinary (multi-modal) or interventional pain management present a good way for saving money. Naturally money may be saved when using individual and professional pain treatment the ability to work, at least partially, is increased. Absences from workplace can also be reduced by prevention of back pain. Likewise, an improvement in the quality of life influences positively the working capacity.
ROUND TABLE III ACUTE PAIN WHICH ANALGESIA TECHNIQUES AFFECT POSTOPERATIVE OUTCOME? Narinder Rawal MD PhD Department of Anaesthesiology and Intensive Care University Hospital Örebro, Sweden Postoperative outcome is influenced by multiple factors including a) patient factors such as ASA risk status and life-style issues such as smoking and excessive alcohol intake b) surgical factors such as surgery by a skillful,high-volume surgeon in a high-volume hospital for that particular surgery c) organizational issues such as pre-set recovery goals, fast-track enhanced recovery protocols and early postoperative mobilization routines and d) choice of anaesthesia (general or regional) and analgesia techniques. Patient perspective and postoperative outcome After surgery, the delay in postoperative functional status is influenced by induced organ dysfunction, postoperative pain, nausea and vomiting (PONV),difficulty in early mobilization, sleep disturbance (in upto 30% patients), fatigue, abnormal eating habits and side effects of opioids. In recent years the role of surgical and anaesthesia/analgesia techniques in the occurrence of persistent postoperative pain has received much attention. The incidence of this complex and multifactorial problem can vary from about 15% (inguinal hernia) to 50% (mastectomy, thoracotomy) or more ( lower limb amputation). All of these are important outcomes from the patient perspective. Role of analgesic techniques Although opioids remain the mainstay of postoperative pain management and i.v opioid PCA is one of the most common and effective modalities worldwide, this technique does not reduce postoperative morbidity or hospital stay. Indeed it is generally accepted that opioids should be avoided as far as possible because of their well-known adverse effects such as nausea, vomiting, sedation, delayed gastrointestinal motility, sleep disturbance, respiratory depression. This has led to the increasing acceptance of balanced analgesia (multimodal analgesia) techniques which involve the use of a combination of non-opioids with different mechanisms of action. This is believed to provide good analgesia while reducing the risks of opioid side effects. However, in the literature a confusing variety of drug combinations have been used, there is a need for a consensus regarding the best combination for multimodal analgesia (1).The most commonly used combination is paracetamol, NSAID´s and wound infiltration using a long-acting local anaesthetic. This, along with gabapentin/pregabalin has been recommended by the American Society of Anesthesiologists guidelines on postoperative pain management (2) The best outcome results, in terms of morbidity and hospital stay, are seen after regional anaesthesia techniques particularly when used in combination with enhanced recovery protocols. Regional techniques allow early postoperative mobilization without the opioid adverse effects mentioned above. The choice of regional technique will depend on the type of surgery. Epidural technique is a well-established method that has been regarded as the gold standard in postoperative pain management. However, newer, evidence-based outcome data show that the benefits are not as impressive as previously believed. Consequently, the use of epidural technique is decreasing. Some reduction in cardiovascular and pulmonary complications has been reported in high-risk patients undergoing major abdominal or thoracic surgery but these benefits are seen only after thoracic epidural and only when local anaesthetics are administered in the catheter. In clinical practice most anaesthesiologists use a combination of opioid and local anaesthetic, the outcome after such combinations is unclear (3). Thus, the PROSPECT group that gives out procedurespecific,evidence-based recommendations for postoperative pain management, no longer recommends epidural technique for procedures such as breast surgery, lap.cholecystectomy,
lap.colon resection, abdominal hysterectomy, hip replacement, knee replacement and abdominal prostatectomy because the group believes that the risks of epidural technique outweigh the possible benefits ( www.postoppain.org). There is increasing evidence that less invasive regional analgesic techniques are as effective as epidural technique. These include paravertebral block for thoracotomy, femoral block for total hip and knee arthroplasty, wound catheter infusions for caesarean delivery, and local infiltration analgesia (LIA) techniques for lower limb joint arthroplasty (3) Infiltration techniques with and without catheters are simple,safe,and effective for many but not all procedures. They can be used alone or as part of a balanced, multimodal analgesic pain management regimen. References 1. Rawal N. Local Infiltration Analgesia and other multicomponent techniques to improve postoperative outcome- Are we comparing oranges and apples? Reg anesth Pain Med 2011;36:417420 2.Practice guidelines for acute pain management in the perioperative setting. An updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology 2012;116:248-273 3. Rawal N. Epidural technique for postoperative pain. Gold standard no more? Reg Anesth Pain Med 2012;37:310-317
POSTOPERATIVE PAIN MEDICATION REQUIREMENTS IN PATIENTS UNDERGOING MULTIPORT AND SINGLE SITE ROBOTIC PROCEDURES Konstantinidis K, Hiridis S, Chrysoheris P, Antonakopoulos F, Hiridis P, Georgiou M. Division of General, Laparoscopic, Bariatric and Robotic Surgery, ATHENS MEDICAL CENTER PURPOSE: Robotics have been introduced in surgery since year 2000 in order to overcome certain limitations of conventional laparoscopy. There are few retrospective and prospective studies suggesting further reduction of postoperative pain and pain medication use after robotic compared to conventional laparoscopic procedures. Interestingly, a recent study showed that the amount of intraoperative fentanyl analgesia does not appear to correlate with postoperative pain. Our experience is presented in this paper. METHODS: From September 2006 till July 2013 we have performed 860 robotic procedures in 703 patients. Using this technology we managed to reduce pneumoperitoneum pressures (<=10mmHg), while adequate exposure is maintained by the powerful mechanical retraction of the abdominal wall and solid organs. Since 2011 we have performed 170 cholecystectomies using the novel Single Site Robotic platform. This technology further reduced need for postoperative pain control by minimizing number of incisions to a single infraumbilical one. RESULTS: All robotic cases were offered pain control management that varied from simple NSAID coverage to intravenous (IV) and/or epidural patient-controlled analgesia (PCA) postoperatively. From the 170 single-site cholecystectomy cases, only 5 had a prolonged (more than 24hr) stay for reasons other than postoperative pain; the rest was discharged within 24hr postoperatively. We recorded patient’s perceptions of pain using the McCaffery-Pasero scale (0-10). These recordings were the following : on admission 2 ± 2 (range 0 – 8), attributed to their underlying pathology, 6hr postoperatively: 2.2 ± 1.51 (range 0 – 6), on discharge: 0.57± 0.98 (range 0 – 3) and during follow up (at 15 days): 0.06± 0.5 (range 0 – 1). CONCLUSIONS: Use of robotics is associated with significantly lower postoperative pain and pain medication requirements compared to conventional laparoscopy. This effect has largely been attributed to lower pneumoperitoneum pressures often used in robotics. Need for postoperative pain control is significantly lower in single site robotic cases showing a clear correlation of postoperative pain and number of ports used.
ENHANCING THE NURSING ROLE IN PAIN MANAGEMENT Felicia Cox Lead Nurse in Pain Management, Head of Pain Services Royal Brompton & Harefield NHS Foundation Trust London, United Kingdom Chair: Royal College of Nursing Pain and Palliative Care Forum Co-opted member: British Pain Society Council Editor: British Journal of Pain Nurse members of any Pain Management Service can make a positive contribution to patient care and outcomes The continued development of the nursing role since 1990, underpinned by advanced patient assessment modules, postgraduate prescribing courses and specialist higher degrees in Pain Management has expanded the number of clinical settings in which nurses lead patient care. Nurse specialists working at advanced practice level in the United Kingdom contribute to interdisciplinary effective pain management and clinical research in acute and chronic settings. Examples of nurse led interventions include: Outpatient clinics for neuropathic pain Chronic pain clinics in primary care Femoral nerve blocks for fractured neck of femur in the emergency room Epidural management for postoperative pain in ward settings including bolus delivery Postoperative ketamine to reduce acute pain associated with thoracotomy and the development of persistent pain Development of Interprofessional pain education at Master’s level (Carr et al 2010) The expert nurse working at this advanced level has four core functions: Expert practitioner Professional leadership & consultancy Education, training & development Service development & research This presentation will describe the educational requirements to develop a clinical nurse specialist into an advanced practitioner and how this role can drive patient centred care and make positive changes to clinical practice and patient outcomes. References: Carr E, Layzell M, Christensen M (2010) Advancing Nursing Practice in Pain Management. Oxford, Wiley-Blackwell
ROUND TABLE IV NEUROMODULATION PRESENT AND FUTURE OF INTERVENTIONAL PAIN SPECIALTY R. Ruiz Lopez ΚΡΑΤΑΜΕ ΜΙΑ ΣΕΛΙΔΑ
NEW CONCEPTS IN RF AND PULSED RF Prof. Serdar Erdine, MD,FIPP, Istanbul Pain Center, Istanbul Turkey Physicians have almost 60 years of experience using radiofrequency to create controlled, reproducible thermal lesions in the central and peripheral nervous system for the treatment of chronic pain. There are two main types of radiofrequency ,the conventional radiofrequency lesioning introduced in 1960’s and pulsed radiofrequency introduced in 1990’s. During conventional radiofrequency strong electric fields and current densities near the uninsulated tip of radiofrequency electrodes induce tissue heating, and the resulting thermal distribution is influenced by heat-conduction and blood-flow dynamics.Conventional radiofrequency lesioning has been widely used as percutaneous cordotomy, trigeminal –gasserian ganglion ablation,medial branch of the facet joints, dorsal root ganglion. On the other hand irrespective of the heat produced, a radiofrequency current was therapeutic because of electrical effects it had on the target nerve,” which gave rise to another mode of applying RF current. It was believed that a therapeutic electrical effect could be delivered without heating the nerve and therefore without coagulating it. This is achieved with brief bursts of RF energy separated by relatively long pauses between bursts to allow heat to dissipate in the target tissue, and became the theoretical basis of what is currently known as pulsed radiofrequency. Emerging evidence from physical modeling, electron microscopy, electrophysiological measurement, and biological assay characterize biological effects of pulsed RF on nerves that may explain PRF's clinical effect. In recent years pulsed rf has been used for a wide range of pain syndromes with several effects. Pulsed RF is an attractive procedure for especially those who have limited clinical experience or technical skill in percutaneous interventions is the purported reduction or avoidance of side effects and complications associated with thermal RF.A procedure with fair to reasonable short-term outcomes may look attractive. Only when long-term follow-up is conducted does the true effectiveness, or lack there of, emerge. If pulsed radiofrequency is misrepresented as the same procedure or an equivalent alternative to thermal radiofrequency, the inferior outcomes of the former may likely be misattributed to the latter.
COMPLICATIONS OF NEUROMODULATION S. Ozyalcin ΚΡΑΤΑΜΕ ΜΙΑ ΣΕΛΙΔΑ
ROUND TABLE V CANCER PAIN AND PALLIATIVE CARE CANCER PAIN: IMPROVEMENT PROGRAMS FOR CANCER PAIN K.C.P. Vissers Palliation of hindering symptoms is the right of each citizen. However, palliative care is too often reserved for patients with a limited life expectancy. Also the diagnosis and management of cancer pain is still poorly documented and promoted. A few decencies ago, the diagnosis cancer usually meant an imminent death. Hence all efforts were concentrated on the cancer treatment and prolongation of life. Nowadays, several types of cancer can be cured, which changes the scope of the treatment: besides the eradication of the cancer attention should be paid to the patient’s comfort. Unfortunately results of a population based study show that 55% of patients with cancer suffered pain during the week preceding the study. Analgesic treatment was inadequate in 44% of the patients.1 Several factors may contribute to this poor performance in pain management of patients with cancer. Patient’s and physician’s reluctance to use strong analgesic treatment is frequently quoted but also the patient’s fear to mention pain or increased pain. A national survey illustrated that patients who are currently managed for cancer are rarely asked if they have pain and how they rate their pain intensity. In the knowledge that a base value is absolutely needed to assess the effect of the treatment, the observation that the pain score is not noted is at least worrying with regard to the treatment follow-up. Guidelines for the diagnosis and management of cancer pain have as primary objective to provide clinicians with easy accessible information. A review of the different existing European guidelines for cancer pain could only withhold 9 out of 54 guidelines based on quality norms. Within these 9 guidelines that fulfilled the criteria, there were surprisingly few overlapping references. The studies used for the recommendations regarding diagnosis and treatment of neuropathic pain in patients with cancer, were often performed in patients with neuropathic pain without cancer, or patients with pain and cancer, without making the subdivision between nociceptive and neuropathic pain. 2, 3 Pain in patients with cancer is complex. Assessment should consider the different aspects of the pain, its generators and the pain perception by the patients and his proxies. A multidisciplinary assessment and consultation with a pain physician should be made available to all patients with cancer pain. The first line treatment of cancer pain can be oriented to the tumor itself, either curative or palliative anti-cancer treatment have an important role in the management of cancer pain. This treatment may be associated with pharmacological analgesic treatment, according to the WHO pain ladder. Depending on the type of pain, co-analgesics may be used. The interventional pain management techniques such as cervical cordotomy, celiac plexus block, and hypogastric plexus block should be envisioned during the multidisciplinary discussion of the patient’s case. Psychological aspects of the cancer diagnosis, the reduced functionality and activities of daily living as well as the dependence on assistance from care givers form a considerable component of the patient’s pain experience. Psychological and spiritual counseling are indispensable components of the pain management program. It has been demonstrated that physical activity is avoided in cancer patients, this may lead to reduced muscle strength, and compromised cardiac function. Maintaining and stimulating physical exercise improves the physical condition, the cardiac function as well as the general feeling of well-being. The WHO pain ladder has initiated the recognition for accurate management of cancer pain. Since its publication in 1986, the survival rate of cancer has seriously increased. A better understanding of the different aspects of cancer pain have changed the perception of the need of patients with cancer. A close collaboration between oncologists, pain therapists, rehabilitation specialists, psychologists and spiritual counselors is required to improve the patient’s quality of life. 1. van den Beuken-van Everdingen MH, de Rijke JM, Kessels AG, Schouten HC, van Kleef M, Patijn J. High prevalence of pain in patients with cancer in a large population-based study in The Netherlands. Pain. 2007;132:312-320. 2. Piano V, Verhagen S, Schalkwijk A, Burgers J, Kress H, Treede RD, et al. Diagnosing neuropathic pain in patients with cancer: comparative analysis of recommendations in national
guidelines from European countries. Pain practice : the official journal of World Institute of Pain. 2013;13:433-439. 3. Piano V, Verhagen S, Schalkwijk A, Hekster Y, Kress H, Lanteri-Minet M, et al. Treatment for Neuropathic Pain in Patients with Cancer: Comparative Analysis of Recommendations in National Clinical Practice Guidelines from European Countries. Pain practice : the official journal of World Institute of Pain. 2013.
EARLY INCLUSION OF PALLIATIVE CARE INTO ONCOLOGY CARE Snezana M Bosnjak Institute for oncology and radiology of Serbia, Belgrade, Serbia Pain management, supportive and palliative care are one of ten elements of quality cancer care according to ASCO -ESMO Consensus (2006). In 2003 ESMO stated “ since the goals of medical oncology extend beyond the reduction of tumor burden and the deferral of death to incorporate a qualitative dimension there is need for a continuum in patient care in which both primary therapies and supportive and palliative interventions are tailored to the clinical circumstances of the patient (ESMO, 2003). ASCO promote integration of palliative care into oncology by defining palliative cancer care as : “ the integration into cancer care of therapies that address the multiple issues that cause suffering for patients and their families and impact their life quality” (ASCO, 2009). According to ASCO, palliative cancer care is about relieving suffering of the cancer experience and should be provided throughout the course of a patient’s illness, regardless of stage, with or without anticancer treatment. A growing body of literature has shown improvement in quality of life, symptoms, patient/family satisfaction with care, decreased futile care and even survival in patients with metastatic cancer when palliative care is provided in conjunction with anti-cancer treatment. The ASCO has recently published a provisional clinical opinion on the topic (ASCO 2012) and the Panel’s expert consensus was that combined standard oncology care and palliative care should be considered early in the course of illness for any patient with metastatic cancer and/or high symptom burden. Key tasks of palliative care provision in the cancer center include the screening of cancer patients to identify patients with needs, and the provision of real time palliative care interventions as part of routine cancer care. The competence of palliative care is needed to improve communication, symptom assessment and management, prognostication as well as decision making and goal setting in oncology. Traditionally, the oncology has focused on the development and implementation of anticancer therapies. But, the progress in oncology should also be judged by the way we are able to support patients and families to live with the disease and cope with its treatment.
OPIOIDS AND CANCER OPIOIDS AND CANCER BIOLOGY: PRECLINICAL EVIDENCE Eleni Moka, MD, PhD, MSc, Consultant Anaesthesiologist Heraklion, Crete, Greece Cancer incidence continues to increase, despite considerable investment in prevention. Additionally, with improved oncological treatments, more people are living with, or being cured of, cancer, and many of these will have disease or treatment–related chronic pain, requiring analgesia. Currently, there is much interest in how opioids may impact on cancer biology (especially cancer recurrence and metastases) and consequently on survival. There are at least two areas of particular interest: first, how these drugs used during cancer surgery may impact long–term survival, and secondly, how both endogenous and exogenous opioids may modulate cancer biology. It is essential to understand the possible mechanisms and potential interactions, so that patients may be given the best chance of pain–free survival. Multiple laboratory and animal studies are converging with some human research to suggest that opioid drugs and the body's natural opioids may play a role in the growth and spread of cancer. Over the last decade, clinical studies have hinted that opioids, used mostly after cancer surgery, may promote the growth or recurrence of tumors, but information has been mixed. Recent data feature research papers that attack the problem from different angles—using epidemiology, human genetics, and animal models—along with extensive reviews exploring potential mechanisms by which opioid signaling may impact cancer. Among the opioids used during the perioperative period or long after, morphine has raised most of the concerns regarding its putative effects on cancer. Indeed, morphine has been found to affect many cellular and cell signaling pathways involved in cancer genesis and possibly causing tumor growth. Though it has been largely supported the that μ–opioid receptor (MOR) activity and cancer progression or survival are linked, it is clear that much more information, initially resulting from experimental studies, will be needed to clarify and settle the longstanding question of what, if any, effects the clinical use of opioids has on cancer outcomes. There is no doubt that opioids are good analgesics and are routinely used for perioperative analgesia and cancer pain control. However, there is still conflicting evidence of how opioids may impact on the cancer itself, with a variety of mechanisms postulated—some potentially useful in disease control, with others being detrimental. These mechanisms are complex and likely multifactorial. Opioids may affect both the immune response and cellular pathways that are key to cancer cell survival and spread both acutely and in the longer term. The host immune system, the tumour itself (including type, stage and site), and the interaction between them are all important in determining cancer outcome. There have been a range of studies on the effects of opioids on cell–mediated immunity and/or natural killer cell function, that is, their impact on host defenses. The balance between cancer cell proliferation and apoptosis and the ability of surviving cancer cells to invade other tissues and to migrate to distant host sites influence the impact of cancer on a patient. Opioids directly affect cancer cell proliferation, apoptosis, invasion and migration, impair immune responses, increase angiogenesis, promote local inflammation and may even act directly on tumor cells to encourage their growth and spread, thus actively affecting these procedures. It is plausible that the inevitable stress response to primary cancer surgery allied to the transient immune suppression induced by opioids, or their direct effects on cancer cells themselves may create conditions conducive to cancer cell survival and spread, at least in the immediate perioperative period. In addition, scientists have looked for genetic evidence for a role of the opioid system in cancer progression. Nevertheless, in vivo and in vitro experimental studies (cell & tissue cultures, live animal models) have yielded conflicting results, with opioids either inhibiting or promoting cancer cell growth and with reviews summarizing the range of studies that have investigated opioid effects on tumour growth, some of which may be via a direct effect on opioid receptors and others which may involve intracellular modification of other systems, such as the vascular endothelial growth factor receptors. This is complicated further by the fact that type of opioid, route and duration of administration, and dose may all be relevant factors. There is evidence for a biphasic effect of opioids, with chronic high– dose opioids suppressing tumour growth in rodent models, whereas single– or low–dose opioids, typical of perioperative use, may promote tumour growth. Changes in opioid receptors have also been studied, in particular, the μ–opioid receptor (MOR). An up–regulation of MOR has been found in
some types of non–small cell lung cancer, with in vitro and in vivo rodent studies, showing that MOR overexpression may result in increased tumour growth and metastases. As a result, MOR could become a therapeutic target for new cancer drugs. Some authors report that MOR overexpression in human non-small cell lung cancer cells increased cell migration, proliferation, and metastatic behavior. The effects appeared to be mediated by Akt and mTOR, two serine/threonine kinases involved in cancer progression. When cells were injected into immune-deficient mice, the resulting primary tumors grew more quickly from cells in which MOR was overexpressed, and a marker of lung metastasis was 20-fold higher. Importantly, the effects of opioid drugs were not investigated in these experiments. The results to date raise the possibility that blocking MOR may have therapeutic value in cancer. Interestingly, the use of a peripheral MOR antagonist, methylnaltrexone, is being tested in patients to treat metastatic breast cancer and glioma, and seemed to prevent increased tumour growth, as did silencing MOR expression using knock out techniques. While opioids may affect cancer cells, cancer treatments may also bolster opioid actions: Recently, researchers reported that morphine–induced signaling through the platelet–derived growth factor receptor–β (PDGFR-β) drives opioid tolerance, which was reversed in rats by the PDGFR kinase inhibitor and cancer drug imatinib. From all this, one thing is clear: Teasing apart the complicated relationships among the opioid system, cancer, and its treatment will require more work, both in the lab as well as in the clinic. Opioids alter endothelial barrier integrity and facilitate angiogenesis and MORs may play a special role in the surgical setting, as there is evidence of a direct effect on barrier function, potentially allowing seeding of tumors during oncologic surgery. In addition, an oncogenic effect of opioids has been demonstrated in a series of molecular, cellular and animal studies over the previous years. As there has been little alternative to the use of µ-opiates in surgery, chronic pain and palliative care, it has been virtually impossible to study this phenomenon in humans until the introduction of peripheral acting µ-opiate antagonists. Their introduction into clinical practice provides a possible mechanism for investigating the effects of exogenous and endogenous opioids on tumor growth and recurrence in humans and should be explored in the surgical and cancer setting. Whether these results can be extended into the therapy of human malignancy remains to be determined. However, multiple observations do suggest that further study of MOR as a potential target for therapeutic intervention and/or MOR antagonists as a potential therapeutic strategy is merited. Literature 1. Panagiotou S, Bakogeorgou E, Papakonstanti E, et al. Opioid agonists modify breast cancer cell proliferation by blocking cells to the G2/M phase of the cycle: involvement of cytoskeletal elements. J Cell Biochem, 1999; 73: 204 – 211. 2. Afsharimani B, Cabot P, Parat MO. Morphine and tumor growth and metastasis. Cancer Metastasis Rev, 2011; 30: 225 –238. 3. Ecimovic P, Murray D, Doran P, McDonald J, Lambert DG, Buggy DJ. Direct effect of morphine on breast cancer cell function in vitro: role of the NET1 gene. Br J Anaesth, 2011; 107: 916 – 923. 4. Singleton PA, Moss J. Effect of perioperative opioids on cancer recurrence: a hypothesis. Future Oncol 2010; 6: 1237–42 5. Gottschalk A, Sharma S, Ford J, Durieux ME, Tiouririne M. Review article: the role of the perioperative period in recurrence after cancer surgery. Anesth Analg 2010; 110: 1636 – 1643. 6. Lennon FE, Moss J, Singleton PA. The mu-opioid receptor in cancer progression: is there a direct effect? Anesthesiology 2012; 116: 940 – 945. 7. Lennon FE, Mirzapoiazova T, Mambetsariev B, Salgia R, Moss J, Singleton PA. Overexpression of the mu-opioid receptor in human non-small cell lung cancer promotes Akt and mTOR activation, tumor growth, and metastasis. Anesthesiology 2012; 116: 857 – 867. 8. Mathew B, Lennon FE, Siegler J, et al. The novel role of the mu opioid receptor in lung cancer progression: a laboratory investigation. Anesth Analg 2011; 112: 558 – 567. 9. Bortsov AV, Millikan RC, Belfer I, Boortz-Marx RL, Arora H, McLean SA. mu-Opioid receptor gene A118G polymorphism predicts survival in patients with breast cancer. Anesthesiology 2012; 116: 896 – 902. 10. Colvin LA, Fallon MT, Buggy DJ. Cancer Biology, amnalgesics and anaesthetics: Is there a Link? Br J Anaesth 2012; 109: 140 – 143.
11. Parat MO. Morphine and Metastasis: From Bench to Bediside. Morphine & Metastasis, 2013: pages 1 â&#x20AC;&#x201C; 13. 12. Shilling AM, Tiouririne M. Perioperative Morphine and Cancer Recurrence. Morphine & Metastasis, 2013: pages 123 â&#x20AC;&#x201C; 142.
PERIOPERATIVE OPIOIDS AND CANCER GROWTH I. Siafaka Assoc. Professor of Anesthesia and Pain Therapy, Aretaieio University Hospital, Medical School University of Athens, Greece Opioids and in particular morphine, have long been the mainstay of treatment of cancer pain and are important modality for the prevention of perioperative pain. In addition to their use in the treatment of pain, opioids appear to be important in the regulation of neoplastic tissue. Laboratory data on the effects of morphine on cancer are contradictory, ranging from tumor promoting to antitumor effect (1). Suppression of imunne system by morphine is an additional complication (2).There are no data directly implicating opioids in cancer genesis in humans, but animal data strongly suggest that they may contribute to cancer recurrence in the clinical setting (3). Many perioperative factors, during cancer surgery, have been shown to contribute to the dissemination of the tumor : surgery itself, stress, inflammation, pain, anesthetic drugs, opioids, blood transfusion etc (4). The type of anesthesia and analgesia chosen in cancer patient, could then be crucial and influence the evolution of the disease.Regional anesthesia/analgesia is expected to reduce the cancer recurrence via attenuating the surgical stress and reducing the amount of general anesthesia and opioid analgesia perioperatively (5). Recently W.K. Chen et al. (6) performed a meta-analysis of 5 prospective and 11 retrospective studies to test the hypothesis that : cancer patients who had surgery with epidural anesthesia /analgesia would have better outcome (overall survival of recurrence free survival) than those who have general anesthesia/opioid analgesia.The authors suggest that epidural anesthesia/analgesia might be associated with improved overall survival in patients with operable cancer undergoing surgery (especially in colorectal cancer) but it does not support an association between epidural anesthesia and cancer control. Perioperative pain management is of high significance, especially in cancer patients. Failure to proper control perioperative pain results in an exacerbated and prolonged stress response, which increases the risk of tumor spread in the postoperative period. Therefore if morphine analgesia is to be avoided in be perioperative period in cancer surgery patients, effective strategies should be adopted to effectively control perioperatve pain. These include : a) the use of regional anesthesia/analgesia, b) the coadministration with morphine of a peripheral opioid antagonist, or alternate analgesic interventions (7). The possibility that perioperative management may alter the rate or incidence of cancer recurrence is very exciting, but much more research is needed. References : 1. 2. 3. 4. 5. 6. 7.
Gach K. et al the role of morphine in regulation of cancer cell growth. Naunyn Schmiedebergs Atch Pharmacol 2011 ; 384 : 221 – 230 Sacerdote P et al. The effect of tramadol an morphine on immune responses and pain after surgery in cancer patients. Anesth Analg. 2000 ; 90 : 1411 – 1414 Afsharimani B et al. Morphine and tumor growth and metastasis. Cancer Metastasis Rev 2011 ; 30 : 225-238 Gottschalk A et al. The role of the perioperative period in Recurrence after Cancer Surgery. Anesth Analg 2010 ; 110 (6) : 1636 – 1643 Exadaktylos AK et al. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology 2006 ; 105 : 660 – 664 Chen W.K. et al . The effect of anesthetic technique on survival in human cancers. A Metaanalysis of Retrospective and Prospective Studies. PLos 2013 ; 8 (2) e56540 Afsharimani B et al. Morphine use in cancer surgery. Frontiers in Pharmacology 2011 ; 2 (46) : 1-8
MISCELLANEOUS IS HYPERALGESIA ANOTHER TYPE OF NEUROPATHIC PAIN? Menelaos Karanikolas, MD, MPH Department of Anesthesiology Washington University School of Medicine St. Louis, Missouri, USA Definitions Hyperalgesia: increased sensitivity to pain or enhanced intensity of pain sensation (Mirriam Webster Dictionary) Opioid-induced Hyperalgesia (OIH): State of increased sensitivity to pain induced by opioid exposure (Angst et al, Anesthesiology, 20013 & Chu et al, Pain, 2012). Whether or not OIH actually exists is still a matter of debate (see earlier lecture by Dr Borgeat in this Meeting), currently available evidence suggests that OIH is an unintended consequence of opioid therapy, and is a real entity with important clinical implications (Angst, Anesthesiology, 2006). Neuropathic Pain: pain arising as direct consequence of a lesion or disease affecting the somatosensory system (Geber et al, Am J Med 2009). Is Hyperalgesia another type of neuropathic pain? 1. Yes, in terms of pathophysiology:. Although the mechanism of opioid-induced hyperalgesia has not been completely elucidated, an endogenous pain facilitatory system involving the NMDA receptor has been implicated (Mao et al, Pain, 1995). In addition, administration of NMDA-receptor antagonist may prevent the development of opioid-induced hyperalgesia (Joly V et al, Anesthesiology, 2005). These pathophysiologic features are also encountered in other types of neuropathic pain. 2. Yes, in terms of clinical features: mechanical hyperalgesia surrounding the wound in postoperative patients suggests a component of central sensitization (Dirks et al, Anesthesiology, 2002). 3. Probably, In terms of therapeutic approach: Hyperalgesia is regarded as one of several manifestations of neuropathic pain. Treatment includes addressing the cause of neuropathic pain, when feasible. In cases where the mechanism of neuropathic pain is unclear, or is known but cannot be addressed, then symptom management includes interventions such as medications,
Conclusion: Hyperalgesia is increased sensitivity to pain or enhanced pain sensation, and opioid-induced hyperalgesia (OIH) is a state of increased sensitivity to pain secondary to opioid exposure. The pathophysiology of hyperalgesia is not fully understood, and is subject of ongoing investigation. However, the clinical features, presentation and available experience with different treatment options suggest that hyperalgesia in general, and opioid-induced hyperalgesia in particular are, in fact, types of neuropathic pain, and should probably treated as such. References: Angst et al, Short-term infusion of the Îź-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal, Pain 106 (1-2), 49-57, 2003 Angst et al, Opioid-induced Hyperalgesia: A Qualitative Systematic Review, Anesthesiology 104 (3), 570-587, 2005 Chu et al, Modulation of remifentanil-induced postinfusion hyperalgesia by the b-blocker propranolol in hymans. Pain 153 (2012) 974-981 Dirks et al, Mechanisms of Postoperative Pain: Clinical Indications for a Contribution of Central Neuronal Sensitization, Anesthesiology 97(6), 1591-1596, 2002 Geber et al, Revised definition of neuropathic pain and its grading system: an open case series illustrating its use in clinical practice. Am J Med 2009 Oct;122(10 Suppl):S3-12
Joly V, et al, Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with small dose Ketamine. Anesthesiology 105 (1), 147-155, 2005 Mao J, Price DD, Mayer DJ, Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain 63 (3), 259-274, 1995
THROMBOPROFYLAXIS IN CANCER Arnaoutoglou Eleni Thrombosis is the second most common cause of death in cancer patients. Venous thromboembolism (VTE) in cancer is also associated with a high rate of recurrence, bleeding, and worsened quality of life. Risk factors for cancer-associated VTE are cancer-related (risk increased with brain, pancreatic, stomach, kidney, ovarian, lung cancer and hematologic malignancies, with higher stage and during first 3-6 months since diagnosis), treatment-related (chemotherapy, antiangiogenesis agents, hormonal therapy, radiation therapy, surgery > 60 minutes, erythropoiesis-stimulating agents, transfusions, indwelling venous access), patient-related (increased age, ethnicity -risk increased in African Americans-, comorbidities-infection, renal and pulmonary disease, arterial thromboembolism, VTE history, inherited prothrombotic mutations-,obesity, hospitalization or major surgery) and biomarkers (platelet count > 350,000/ÎźL, leukocyte count > 11,000/ÎźL, hemoglobin < 10 g/dL). Guidelines for VTE and cancer patients from different medical societies (ASCO, ASH, ISTH, ESMO) recommend that most hospitalized patients with cancer require thromboprophylaxis throughout hospitalization. Thromboprophylaxis is not routinely recommended for outpatients with cancer. Based on limited RCT data it may be considered on a case-by-case basis in highly selected outpatients with solid tumors receiving chemotherapy. Consideration of such therapy should be accompanied by a discussion with the patient about the uncertainty concerning benefits and harms, as well as dose and duration of prophylaxis in this setting. Patients with multiple myeloma receiving antiangiogenesis agents with chemotherapy and/or dexamethasone should receive prophylaxis with either aspirin or LMWH for lower-risk patients and LMWH for higher-risk patients. Patients undergoing major cancer surgery should receive prophylaxis, starting before surgery and continuing for at least 7 to 10 days. Mechanical methods may be added to pharmacologic thromboprophylaxis, but should not be used as monotherapy for VTE prevention unless pharmacologic methods are contraindicated because of active bleeding or high bleeding risk. A combined regimen of pharmacologic and mechanical prophylaxis may improve efficacy, especially in the highest-risk patients. Extending prophylaxis up to 4 weeks should be considered postoperatively for patients undergoing major abdominal or pelvic surgery for cancer who have high-risk features such as restricted mobility, obesity, history of VTE. In lower risk surgical settings, the decision on appropriate duration of thromboprophylaxis should be made on a case-by-case basis considering the individual patient. LMWHs represent the preferred therapeutic option for VTE prophylaxis and treatment. Their use may be associated with improved survival in cancer, although this issue requires further study. Patients with cancer should be periodically assessed for VTE risk. A risk model for identifying cancer patients at highest risk for VTE has recently been developed. Despite the significant burden imposed by VTE and the availability of effective anticoagulant therapies, many oncology patients do not receive appropriate VTE prophylaxis as recommended by practice guidelines. Improved adherence to guidelines could substantially reduce morbidity, decrease resource use, enhance quality of life, and improve survival in these patients. Oncology professionals should provide patient education about the signs and symptoms of VTE.
INTERVENTIONAL TECHNIQUES COOLED RF APPLICATIONS IN CHRONIC PAIN N. Mekhail ΚΡΑΤΑΜΕ ΜΙΑ ΣΕΛΙΔΑ????
OROFACIAL PAIN Ph. Mavrocordatos ΚΡΑΤΑΜΕ ΜΙΑ ΣΕΛΙΔΑ ???????
LECTURES LECTURE I EDUCATION & PAIN MANAGEMENT Prithvi P. Raj, M.D. FIPP Adequate education of physicians, who practice pain management, has become a common discussion among the leading pain physicians all over the world. I will discuss the most important issues to consider for education of pain physicians. Significant points to consider are: 1: What is the present status of pain management globally? Persuasive epidemiologic evidence, mainly drawn from developed nations, has proven that chronic pain is a widespread public health issue. Community-based surveys find that 15%â&#x20AC;&#x201C;25% of adults suffer from chronic pain at any given time, a figure that increases to 50% in those older than 65 yrs. In one of the largest survey studies of pain, 18% of American respondents who rated their pain as severe or unbearable had not visited any health care professional because they did not think that anyone could relieve their suffering. 2: Why is adequate pain management important? The concept of pain management as a human right recently gained momentum. Under-treatment of pain is poor medical practice that results in many adverse effects. Chronic pain is linked with a constellation of maladaptive physical, psychological, family, and social consequences, and can be regarded as a disease entity per se. The US Food and Drug Administration and the WHO emphasize patient-reported outcomes in evaluating many therapies or health-related interventions. Pain, especially chronic pain, is a key patient-reported outcome whose poor control undermines quality of life and whose physical, psychological, social, and economic ramifications evolve, overlap, and compound one another. 3: Why is adequate physician education and training for pain management important? Physicians must employ a multidisciplinary approach to evaluating, diagnosing, treating, and rehabilitating pain problems. This requires that they rely on knowledge from multiple disciplines and also understand the complexity of pain. This is what makes pain medicine unique in relation to other medical specialties. 4: What efforts are being undertaken to improve medical education of pain physicians? Several organizations have developed pain curricula. For example, I n1995 the International Association for the Study of Pain (IASP) created the Core Curriculum for Professional Education in Pain, and it has recently been updated. This comprehensive approach to pain covers such diverse topics as anatomy and physiology, ethical standards in pain management and research, and multidisciplinary pain management. The Guidelines for Schools of Anesthesia and Hospitals Providing Advanced Training in Pain Management for Anesthetists of the Royal College of Anesthetists has endorsed this Core Curriculum. 5: How can we create a universal curriculum generally agreed by global pain societies, academic institutions and governmental agencies? Pain is a global problem that requires an international solution Reform will require an integrated approach to address the problem of under-treated pain at all levels: 1. Education for health undergraduates and graduates, including adult health professionals, 2. Adoption of universal pain management standards by professional bodies, 3. Promotion of legislative reform, 4. Promotion of pain control programs in all nations, irrespective of resources, 5. Continuing activism of the WHO in collaboration with the foremost international pain relief organizations. This lecture will explore these points and the global impact of an improved medical education of pain physicians. Suggested Reading Raj PP. Measures to establish an effective credentialing for pain physicians. Paper presented at The American Society of International Pain Physicians, March 2003.
Shumway JM: 2001. Outcomes (competency)-based curriculum and assessment: Presentation to the West Virginia University School of Medicine Curriculum Committee, West Virginia University School of Medicine. Morgantown, West Virginia, November 12, 2001. Benzon HT, Rathmell JP, Huntoon MA: New ACGME requirements for fellowship training in pain medicine. APS Bulletin. 17(3) (2007)
LECTURE II CRPS EVIDENCE BASED. WHAT’S NEW? R. Rauck ΚΡΑΤΑΜΕ ΜΙΑ ΣΕΛΙΔΑ
LECTURE III RESEARCH CONTACT AND MISCONDUCT Eriphili Argyra Assoc. Professor of Anaesthesia, Medical Faculty, National and Kapodistrian University of Athens eargyra@med.uoa.gr ΣΑΣ ΣΤΕΛΝΩ ΧΩΡΙΣΤΑ ΤΟ ΚΕΙΜΕΝΟ
Satellite Lectures ORAL TRANSMUCOSAL FENTANYL CITRATE AND BREAKTHROUGH PAIN S. Poulopoulou ΚΡΑΤΑΜΕ ΜΙΑ ΣΕΛΙΔΑ ????
EFFICACY AND TOLERABILITY OF TRANSDERMAL BUPRENORPHINE G. Varrassi*, F. Marinangeli** * General Manager AUSL Teramo, Italy ** University of L’Aquila, Department of Anesthesia and Pain Medicine, L’Aquila, Italy The cornerstone of treatment for moderate to severe pain is classical opioid therapy. The WHO Pain Analgesic Ladder recommends weak opioids for Step 2 and strong opioids for Step 3 in the management of chronic pain1, even if this recommendation has been criticized2. Classical opioid therapy is considered to have shortcomings; specifically, in providing sustained analgesic efficacy over long periods, reliable efficacy in difficult-to-treat pain syndromes, and acceptable levels of tolerability. Balancing adequate pain relief with minimal side effects is difficult, and sometimes impossible. Difficult-to-treat pain syndromes are essentially those where the pain is neuropathic in origin or has a neuropathic component. Examples include diabetic peripheral neuropathy, postherpetic neuralgia and mixed cancer pain. Especially in this case, the use of opioid analgesics has gained interest because of their effectiveness in nociceptive and neuropathic pain. Buprenorphine has unique properties. It is a partial agonist at the m-opioid receptor and an antagonist at the k-opioid receptor, with high binding affinity at both sites. The high affinity on opioid receptor may account for intense and prolonged analgesia 3. This drug has been used for many years for all routes of administration, oral, intravenous, intramuscular, intra-articular4, trans dermal, and at the moment is well perceived as an effective and well-tolerated drug, both for acute and chronic pain. In the treatment of chronic pain, transdermal buprenorphine demonstrated good analgesic efficacy in a wide range of adult patients with cancer and no-cancer musculoskeletal pain. The efficacy in nociceptive cancer pain is supported by numerous studies. Gatti et al.5 demonstrated that a low-dose opioid treatment with transdermal buprenorphine is also a safe longterm analgesic for patients experiencing chronic musculoskeletal pain of moderate-to-severe intensity. A study funded by the Procacci Foundation demonstrated an efficacy of transdermal buprenorphine at least similar to diclofenac6. The results of treatment of central neurophatic pain syndromes with buprenorphine are encouraging, suggesting that it might represent a valid alternative to standard approaches for central neuropathic pain7. The safety and tolerability of a drug is reduced when the patient is in poor condition. Management of pain in terminally-ill patients is often made more difficult by the unforeseeable kinetics of medications caused by progressive kidney and liver dysfunction. In addition, the management of opioids may prove difficult on account of the presence of active metabolites, which may bring feared side effects. A case report highlights how in a terminally ill patient with significant liver, kidney and multi-organ failure, the use of strong opiates, and specifically of transdermal and intravenous buprenorphine, makes possible to keep severe pain under control, with little incidence of side effects. In the final, pre-agonic phase of illness, in which there is no possibility of feedback from the patient, the use of the transdermal medication ensures an ethical treatment of the suffering subject8. The affinity of buprenorphine for the µ receptor can be exploited for specific problems related to neoplastic disease, such as itching. In this regard, the study of a case report in a patient with cholestatic pruritus came to very interesting conclusions. The association of transdermal buprenorphine and naloxone has allowed to reduce this disagreeable symptom in the terminal phase of life9. In conclusion, trans dermal buprenorphine, during these years of very extensive use in clinical settings, has demonstrated a high standard of safety and tolerability, such as to become a comparison drug for chronic cancer and non-cancer pain. References 1. World Health Organisation. Cancer pain relief with a guide to opioid availability. 2nd ed. Geneva: World Health Organization; 1996 2. Marinangeli F, Ciccozzi A, Leonoardis M, Aloisio L, Mazzei A, Paladini A, et al. Use of strong opioids in advanced cancer pain: a randomized trial. J Pain Symptom Manage 2004; 27: 409– 16. 3. Boas RA, Villiger JW. Clinical actions of fentanyl and buprenorphine: the significance of receptor binding. Br J Anesth 1985; 57: 192-6
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G Varrassi, F Marinangeli, A Ciccozzi, G Iovinelli, G Facchetti, A Ciccone. Intra-articular buprenorphine after knee arthroscopy. A randomised, prospective, double-blind study. Acta Anaesth Scand 1999; 43: 51-55 Gatti A, Dauri M, Leonardis F, Longo G, Marinangeli F, Mammuccari M, Sabato AF. Transdermal buprenorphine in non-oncological moderate-to-severe chronic pain. Clin Drug Investig 2010; 30: 31-8 Pregabalin-transdermal buprenorphine versus pregabalin-diclofenac in peripheral neuropathic pain: a randomized, multicenter study (In press). Guetti C, Angeletti C, Marinangeli F, Ciccozzi A, Baldascino G, Paladini A, Varrassi G. Transdermal buprenorphine for central neuropathic pain: clinical reports. Pain Pract 2011; 11: 446 -52 Ciccozzi A, Angeletti C, Baldascino G, Petrucci E, Bonetti C, De Santis S, Paladini A, Varrassi G, Marinangeli F. High dose of buprenorphine in terminally ill patient with liver failure: efficacy and tolerability. J Opioid Manage 2012; 8: 253-259 Marinangeli F, Guetti C, Angeletti C, Bonetti C, Paladini A, Piroli A, Varrassi G. Intravenous naloxone plus transdermal buprenorphine in cancer pain associated with intractable cholestatic pruritus. J Pain Symptom Manage. 2009; 38: 5-8
THE ROLE OF OXYCODONE IN CHRONIC PAIN I. Siafaka Assoc. Professor of Anesthesia and Pain Therapy, Aretaieio University Hospital, Medical School University of Athens, Greece Oxycodone is a semisynthetic opioid, that is increasingly used for the treatment of acute, cancer and chronic non cancer pain. Although oxycodone had been synthesized almost 100 years ago, its pharmacology has been poorly characterized until recently (1).Oxycodone is a fairly selective μ-opioid receptor agonist, having many similarities to morphine, but it has also properties, that set it apart from morphine. It has a faster onset of action, which is likely to be related to its cerebral accumulation and possible active influx transport through the blood-brain barrier.Unlike morphine, it has good oral bioavailability and a larger duration of action and it may have somewhat less side effects than morphine. Unlike morphine, oxycodone is mainly metabolized by CYP enzymes, so it is more prone to drug interactions compared with morphine. Many problems, such as addiction and increased incidence of fatal intoxication, associated with inappropriate prescribing of opioids have been related to ocycodone (2). The analgesic efficacy of oxycodone has been studied in different types of pain. Controlled –release formulations of oxycodone have become very popular in cancer pain (3). Recent systematic reviews suggest that oral morphine, oxycodone and hydromorphone have similar efficacy and toxicity in cancer patients (4). Oxycodone use has also increased in the management of chronic non cancer pain. Oxycodone is effective also in neuropathic pain, when compared with antidepressants or anticonvulsants and may be more effective in the treatment of visceral pain than morphine (5). Oxycodone demonstrates an increased analgesic effect as the dose is increased, without a ceiling effect. Administration of oxycodone 10 mg every 4 hours in patients with cancer pain, did not result in drug accumulation. A low dose oxycodone/paracetamol combination is available in USA as Percocet and in Italy as Depalgos, with oxycodone at different dosages (5, 10, 20 mg) and paracetamol at a low dose (325 mg). Recently oxycodone /paracetamol combination is approved by Greek National Organisation of Medicines for use in Greece.The oral fixed –dose combination of oxycodone and paracetamol immediate-release formulation, has a sinergistic mechanism of action, that is useful for moderate to severe pain and for non responders to NSAIDs or paracetamol alone. This combination offers several advantages : lower individual drug doses can be used, opioid –sparing effect and a good efficacy and tolerability profile. Efficacy and safety of this fixed-dose combination were assessed in a wide range of clinical settings : in patients with osteoarthritis or chronic musculoskeletal pain, for chronic pain in elderly patients, for cancer related pain (6) and for neuropathic pain, in the latter case usually given in combination with an NSAID or other drugs (7). By activating multiple pain-inhibitory pathways,combination analgesics can provide more effective pain relief for a broader spectrum of pain,and might also reduce adverse drug reactions. References : 1. Olkkola KT and Hagelberg NM. Oxycodone : new <old>drug. Current Opinion in Anesthesiology 2009; 22 : 459-462 2. Olkkola KT et al. Does the pharmacology of oxycodone justify its increasing use as an analgesic? Trends in Pharmacological sciences 2013 ; 34 (4) 206 - 214 3. King S J et al. A systematic review of oxycodone in the management of cancer pain. Palliative Medicine 2011 ; 25 : 454 - 470 4. Caraceni A et al. is oral morphine still the first choice opioid for moderate to severe cancer pain? A systematic review within the European Palliative Care Research Collaborative guidelines project. Palliative Medicine. 2011 ; 25 : 402 - 409 5. Kalso E et al. Opioids in chronic non cancer pain : systematic review of efficacy and safety. Pain 2004 ; 112 : 372 - 380 6. Sima L et al Efficacy of oxycodone/paracetamol for patients with bone-cancer pain : a multicenter, randomized, double-blinded, placebo – controlled trial. Journal of Clinical Pharmacy and Therapeutics, 2012 ; 37 : 27-31
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Gatti A et al Oxycodone/Paracetamol. A low dose Synergic Combination Useful in different types of Pain. Clin Drug Investing 2010 ; 30 suppl 2 : 3-14