The pathophysiology of complex regional pain syndromes includes inflammation and central reorganisation. The treatment should be adjusted to the prevailing pathophysiology including possible psychosocial factors. Complex regional pain syndrome (CRPS) was described for the first time in the 19th century by Silas Weir Mitchell. After the exclusion of other causes, CRPS is characterised by a typical clinical constellation of pain, sensory, autonomic, motor, or trophic symptoms which can no longer be explained by the initial trauma. These symptoms spread distally and are not limited to innervation territories. If CRPS is not improved in the acute phase and becomes chronic, the visible symptoms change throughout because of the changing pathophysiology; the pain, however, remains. The diagnosis is primarily clinical, although in complex cases further technical examination mainly for exclusion of alternative diagnoses is warranted. In the initial phase, the pathophysiology is dominated by a posttraumatic inflammatory reaction by the activation of the innate and adaptive immune system. In particular, without adequate treatment, central nociceptive sensitization, reorganisation, and implicit learning processes develop, whereas the inflammation moderates. The main symptoms then include movement disorders, alternating skin temperature, sensory loss, hyperalgesia, and body perception disturbances. Psychological factors such as posttraumatic stress or pain-related fear may impact the course and the treatability of CRPS. The treatment should be ideally adjusted to the pathophysiology. Pharmacological treatment maybe particularly effective in acute stages and includes steroids, bisphosphonates, and dimethylsulfoxide cream. Common anti-neuropathic pain drugs can be recommended empirically. Intravenous long-term ketamine administration has shown efficacy in randomised controlled trials, but its repeated application is demanding and has side effects. Important components of the treatment include physio- and occupational therapy including behavioural therapy . If psychosocial comorbidities exist, patients should be appropriately treated and supported. Invasive methods should only be used in specialised centres and in carefully evaluated cases. Considering these fundamentals, CRPS often remains a chronic pain disorder but the devastating cases should become rare. The pathophysiology of complex regional pain syndrome has become clearer through research in recent years. The pathophysiology translates into clinical symptoms, which can be identified. Treatment should be individually tailored according to the predominant pathophysiology. This is outlined in this article.61 In 1901, Paul Sudeck from Hamburg, Germany, described the “acute reflex bone atrophy after inflammation and injuries of the extremities and their clinical appearances,” which corresponds to CRPS type I without nerve lesion.87 The next milestone in CRPS history was reached in 1936, when James A. Evans coined the phrase “reflex sympathetic dystrophy”, which has been used for decades.31 At a conference in Orlando, 1995, it was agreed to use the descriptive phrase “Complex Regional Pain Syndrome” to avoid claims about pathophysiology.86It took approximately 100 years to form the acronym “CRPS.” In 1864, Silas Weir Mitchell reported on patients whose disease corresponds to what we now call complex regional pain syndrome (CRPS) type II .45Complex regional pain syndrome usually develops after an injury of the extremities. The latency between the injury and the earliest CRPS diagnosis depends on the “normal” time of recovery from injury. For an uncomplicated radial fracture, a recovery of 4 to 6 weeks is typically realistic. Complicated injuries take longer to recover. Thereafter, a diagnosis of CRPS could be made . Women aged between 40 and 60 seem to be most frequently affected. The female preponderance, however, could also be an artefact because women suffer 3 times more radial fractures than men.84 Epidemiological data from 2 major studies show a CRPS incidence between 5.577 and 26.2 cases25 per 100,000 people per year. The variation may result from the use of different diagnostic criteria. It is only in the last decade that the validated “Budapest Criteria” (see below) have become generally accepted.The risk of CRPS seems to be higher for patients with complicated fractures, a rheumatological disease, or intense pain  1 week after trauma.8 Patients reporting higher levels of anxiety and pain-related fear at the beginning of therapy have worse long-term outcomes after 1 year.6Regarding the prognosis, Bean et al reported in a longitudinal study that within the first year, 70% improved, especially in the function of the extremity and the visible symptoms . However, 25% of the patients still fulfilled the Budapest Criteria and only 5% were without complaints.38  is not mentioned and neither is the fact that the signs must go beyond single-nerve innervation territories. Despite case reports, the authors doubt that CRPS of large joints, face, or trunk exists.The diagnosis of CRPS is made clinically using the diagnostic criteria of the “IASP”38 Table . It can 51; (2) Limb magnetic resonance imaging helps to exclude differential diagnoses like rheumatic diseases or infections; (3) x-rays in direct side-to-side comparison are not sensitive but can prove a patchy osteoporosis or may help to make differential diagnoses such as a pseudoarthrosis after fracture; (4) the 3-phase bone technetium scintigraphy in acute (but not chronic) CRPS has a 70% specificity and sensitivity compared to the clinical diagnostic criteria if there is evidence of an increased bone metabolism, typically in distal joints.101Instrument-based investigations might be beneficial if there are doubts concerning the differential diagnoses. (1) Repeated measurements of the skin temperature show dynamics, ie, changing temperature differences (warmer gets colder or vice versa) of >1°C57Quantitative sensory testing (QST), which has become important in academic pain medicine, is not suited to make a CRPS diagnosis because QST generally describes pain symptoms , which are not specific for any pain disorder. However, a typical QST pattern  may support a CRPS diagnosis, particularly if the distal joints, which were not directly affected by the trauma, are sensible to pressure pain.39 might be an instrument to grade the severity of CRPS and helps to monitor the course. Very low scores support considering a differential diagnosis  CRPS cases might develop shortening and fibrosis of capsules and tendons.100 In some cases, this could happen regardless of any treatment attempt. Other trophic changes can be found on the skin , the nails, and the hairs (in acute CRPS increased and in chronic CRPS decreased growth).58 The main symptom of vascular dysfunction is the oedema which can grow to dramatic extents and is always found in the acute phase.12 In chronic CRPS, patients report their own extremity often thicker than it actually is.72 Fifty percent of the patients have sudomotor disturbances, mostly a hyperhidrosis.12 All patients display a change in skin colour from reddish (“warm” CRPS) to blueish livid (“cold” CRPS).13 Skin temperature is different when comparing both sides.94 More rare are tremor, myoclonus, or fixed dystonia.93Pain is the most important symptom. It is permanent or fluctuating and most often in the deep tissue. It increases through movements and during changes in temperature; in the experience of the authors, especially in chronic and severe cases, allodynia is a hallmark.42 and striking associations to migraine.74 Associations with known gene polymorphisms have been described in smaller studies but could not be replicated in larger cohorts.44 As long as we do not have biomarkers for subgrouping, the detection of genetic factors will remain difficult. Furthermore, association studies need high numbers, but CRPS is a rare disease. MicroRNAs are “master switches” for complex inflammatory reactions and pain states because they control the translational process for several proteins at the same time. If replicated, the pattern of microRNAs in plasma exosomes for cell–cell communication might be useful to identify patients with CRPS early after a trauma.59It is heavily discussed whether there is a genetic disposition for CRPS. There are “CRPS families”58 . A trauma causes a complex immune response. In the skin, keratinocytes proliferate and produce inflammatory cytokines as part of the innate immune system.10 The cytokines  themselves proliferate connective tissue cells leading to contractures.9 Cytokines activate osteoblasts and osteoclasts, which explains the osteoporosis.98 Cytokines provoke pain and hyperalgesia through sensitization of peripheral nociceptors, and they facilitate the release of neuropeptides from nociceptors,69 which in turn are responsible for the “visible” inflammatory signs. Calcitonin gene–related peptide and substance P are released from the cytokine-sensitized nociceptors (neurogenic inflammation) and cause reddening, warmth, and edema96; substance P further promotes hair growth,71 and calcitonin gene–related peptide enhances sweating.80 Throughout the course of CRPS, most of these signs normalize, which demonstrates some change in pathophysiology.54 Recent investigations suggest a contribution of the adaptive immune system as well. The detection of agonistic serum auto-antibodies against adrenergic and cholinergic receptors renders an auto-immune component of CRPS very likely.50 Inflammation is less obvious in primarily cold CRPS, and investigations specifically for this subtype are sparse. Increased endothelin 1 and reduced nitric oxide probably contribute to the cold bluish skin.36 In preclinical studies, we found that a lack of neutral endopeptidase (reduced activity of peptidases is 1 hypothesis for a susceptibility for CRPS after trauma26) increases endothelin-1, which in turn sensitizes C-fibres.41The first step of CRPS pathophysiology is posttraumatic inflammation, mainly in “warm” CRPS, during the acute phase of the disease. Clinical observation finds signs of inflammation like redness, swelling, hyperthermia, pain, and reduced function75 Another possibility is a reflex inhibition of movement mediated by the expectation of pain.89 This results in a pathological movement pattern , which again increases the pain through eg, unphysiological muscle and joint loads.55 Other symptoms are a direct consequence of reorganisation of somatosensory function in the brain53: body midline is shifted towards the healthy side and the CRPS extremity is perceived as distorted.64 The perception of allodynia is a consequence of central  sensitization. Its presence has been verified through functional magnetic resonance imaging by activation of the “pain matrix” through painful touching of the affected but not by nonpainful touching of the unaffected hand.56 For details on functional imaging in CRPS, we refer to an upcoming review.88The next step in CRPS pathophysiology is neuronal plasticity in the CNS, which is either induced by inflammation or develops in parallel. Plasticity is important, especially for CRPS, which is treatment resistant for more than 6 to 12 months, when symptoms cannot be explained through peripheral pathophysiology alone. In part, those symptoms can be attributed to learning processes, ie, “learned non-use” because of movement-related pain avoidance.97 However, inflammatory processes fade within the first year. If visible autonomic symptoms  remain, they must have another pathophysiology, eg, sympathetic dysfunction as a consequence of central reorganisation.34 If patients with chronic CRPS think of a movement which would be painful, they activate the sympathetic nervous system.66 The skin temperature minimally changes when crossing over the hands bringing the CRPS hand into the healthy “peripersonal” space.64The significance of a sympathetic nervous system dysfunction for CRPS development has been questioned. Many of the presumably sympathetic symptoms like edema, vasodilatation, or hyperhidrosis can be explained through inflammation.2 supposedly through the inflammatory processes within the first months. This supersensitivity causes activation of the sympathetic nervous system, which is normally symmetrical, leads to asymmetrical sympathetic symptoms. The hypothesis of “sympathetically maintained pain” is similar: nociceptors in the affected limb become sensitive to catecholamines.78 The presumably sympathetic symptoms were the motivations for the use of sympathetic blocks to treat CRPS. However, meta-analyses with inconclusive findings raised doubts.67 Today, sympathetic blocks should be an exception rather than a rule for CRPS treatment.In addition, peripheral adrenoreceptors of the affected tissue develop supersensitivity50The role of the recently discovered agonistic auto-antibodies against adreno- and acetylcholine-receptors in the generation of autonomic symptoms or pain is to be clarified in future studies.7 However, it would be naive to suppose that only in CRPS, on the contrary to all other chronic pain diseases, psychosocial factors would not be involved particularly in perpetuation of pain, suffering, and reduced participation. In comparison to patients with limb pain , 38% of patients with CRPS report posttraumatic stress symptoms after life events before CRPS.85 Patients with CRPS also reported more depersonalization phenomena than limb pain controls on the 29 items Cambridge Depersonalization Scale.60 In CRPS with fixed dystonia, a somatoform movement disorder is expected in more than 25%.81 Anxiety, pain-related fears, and perceived disability are negative predictors for the treatment success after 1 year.6Depression and anxiety, which were assessed by self-reports, are not related to the development of CRPS.21 Because CRPS develops mainly after trauma, it is not surprising that many patients are involved in lawsuits or compensation claims.52 Not specifically for CRPS but for “persisting limb pain,” external attributions of responsibility for the injury, and psychological distress were predictors of significant pain 6 months after an orthopaedic trauma in a prospective study. In addition, poor recovery expectations were predictors of pain-related work disability, and being injured at work a predictor of pain severity.20 Furthermore, patients with compensation claims, greater financial worry, and actual or perceived injustice  led to an increase in the risk of failing to return to work.35 High perceived injustice was correlated to low education and prevented return to work 12 months after injury.43The research on social factors in CRPS is in its infancy. Surprisingly, it is the affluent patients, who develop CRPS more often after distal radius fracture.47 CRPS intervention studies must be interpreted with care. Nevertheless, treatment options, which were supported by an RCT, are marked by “RCT” in this review. However, the section is influenced by the authors' experiences from 25 years of CRPS care. A systematic approach would have to report mainly “no firm evidence.”68A problem of multi-faceted pathophysiology is that a “one fits all”-treatment for CRPS will probably never be available. Another big problem with CRPS therapy is that high-quality randomized controlled multicentre trials (RCTs) are missing. Most RCTs are single centre or lack an active placebo arm. Furthermore, since the publication of highly recognized negative trials for pain relief through vertebroplasty, which used an adequate control arm,(1) Medical and nonmedical pain therapy (acute and chronic phases)(2) Physiotherapy, occupational therapy and training therapy (acute and chronic phases)(3) Anti-inflammatory therapy (acute phase)(4) Psycho- and sociotherapy in a multimodal treatment setting (5) A limited number of sympathetic nerve blocks (6) Therapy of dystonia .Because of the above-mentioned constellations in CRPS pathophysiology, the following basic therapeutic principles evolve:www.dgn.org./leitlinien.html).In the following, therapeutic recommendations for CRPS are described referring also to the guidelines published by eg, the German Association for Neurology  must be demonstrated within 2 weeks. The efficacy of opioids must be strictly controlled. Otherwise, opioid-insensitive pain leads to false increase of dosage, habituation, dependence, and finally increase in pain . Opioid-insensitive pain might be frequent because of decreased central opioid receptor availability in CRPS.49There is no firm proof of efficacy in CRPS for drugs used in other chronic neuropathic pain disorders. A very moderate effect on allodynia was shown for gabapentin .82 We want to indicate that blinding must have been incomplete because of the obligate psychotropic side effects of ketamine . Accordingly, most systematic reviews and meta-analyses came to the conclusion of “low quality evidence” for ketamine.23 If treatment courses are repeated, liver and psychiatric side effects must be monitored.There might be a reduction in pain for up to 3 months after intravenous ketamine . There are 3 RCTs and many case reports. For the exact protocol, the original publication should be studied.48 SCS for the upper extremity might be problematic because of complications like dislocations of the electrodes. Equally promising seems the stimulation of dorsal root ganglia (DRG). One controlled study (RCT) has been published in which patients were treated either with DRG stimulation or with SCS.28 The devices were implanted only after positive test stimulations. The outcome of the DRG stimulation regarding pain reduction and quality of life was superior to SCS. Like in all interventions, the outcome is dependent on the surgeon's expertise. Relevant psychological comorbidities must be excluded beforehand. Otherwise, there will be further traumatization70 and reduced efficacy.16After failure of noninvasive therapies, spinal cord stimulation (SCS) seems to be an alternative to treat CRPS pain but not function in the lower extremity for up to 5 years .100 We have good experiences with the administration of high initial doses of oral glucocorticoid (100 mg prednisolone per day), which is then tapered down by 25 mg every 4 days.100 Under the assumption of an ongoing inflammation for 3 to 6 months,10 higher doses  and longer treatment courses  would make more sense but high-quality randomized controlled trials for steroids are lacking, and therefore we follow the principle of “primum non nocere.” Pathophysiologically, steroids make sense during the acute phase.Not only in our hands glucocorticoids reduce posttraumatic inflammation.18 They not only reduce osteoclast activity, but also inhibit posttraumatic inflammation.95 Alendronate is administered either orally with a high dose of 40 mg/d across 8 weeks, or intravenously with a dosage of 7.5 mg for 3 consecutive days. Clondronate is administered intravenously with a dosage of 300 mg for 10 consecutive days; pamindronate with a single dosage of 60 mg, and neridronate 4 times with 100 mg every third day. Whether bisphosphonates are a reasonable treatment only for acute or also for chronic CRPS has to be debated. Pathophysiologically, they make more sense for acute CRPS. We want to make a personal comment. In our hands, bisphosphonates seem to be of limited value in particular after steroid treatment.Bisphosphonates are drugs which are best investigated for CRPS; there are positive studies  for nearly all bisphosphonates available in the market.102In the Netherlands, the application of dimethylsulfoxide 50% as a fatty basis cream—3 times daily on the affected extremity—is a standard procedure. Dimethylsulfoxide traps free radicals, which are produced during inflammation and ischemia. Dimethylsulfoxide had a positive impact on a composite score but not specifically on pain (RCT).90 There is still a widespread misconception that patients with CRPS should avoid pain to prevent an aggravation; this is not valid. If the extremity is not moved during the inflammatory phase when a proliferation of connective tissue cells occurs, contractures follow quickly. On the contrary, painful interventions by others, against the will of the patients, eg, passive movements by therapists or less empathic physicians, should be avoided because of a loss of patients' self-control.Physical and occupational therapies accomplish reduction of pathologic movement patterns and movement limitations and train a physiologic use of the extremity. Patients should be encouraged to voluntarily use the affected extremity even if this involves a temporary increase in pain and other symptoms. The safety of such an approach has been demonstrated.15 and is a standard procedure for experienced physiotherapists. An advancement of mirror therapy is “graded motor imagery.” Initially, this includes recognition of right and left extremities on a monitor; a second step is the imagination of movements of the affected extremity, and the third step is the mirror therapy itself. Efficacy was high in single-centre studies (RCT)63 but not reproduced in an open multi-centre trial, which should usually be even more sensitive to placebo effects.46 “Pain Exposure Physical Therapy” (including passive treatments) is performed with the patients' consent, ignoring pain. Pain is not further mentioned throughout the treatment. In an open study, this approach led to an improvement of function and to an improvement of pain. This effect could not be confirmed in an RCT, drop outs were high.3 In general, meta-analyses came to the conclusion that there is still a lack of high quality studies for these components of CRPS treatment.68Mirror therapy involves learning to adapt the mirror image of the healthy extremity as the affected limb. This should reduce pain and subsequently improve movement. Mirror therapy works best with acute CRPS and CRPS after stroke 99 The authors' experiences are that patients with many psychosocial problems seem to be harder to treat. This is not due to the desire for compensation; the reason could be a deep uncertainty regarding future perspectives. This is not beneficial for an active participation in treatment.29Psychotherapeutic and sociotherapeutic methods represent an important part of multimodal pain therapy, especially if accompanying psychosocial factors or comorbidities exist .29 Graded exposure reduced pain and improved function.“Graded Exposure” (GEXP) treatment has shown good evidence for efficacy in CRPS. For this approach, a psychologist identifies and classifies fear-triggering situations . Patients are then gradually exposed to these situations by a physiotherapist. The efficacy of graded exposure in comparison to conventional rehabilitative therapy was confirmed in 1 large case series for chronic CRPS (n = 106) and a recently published small and monocentre RCT.67 because of the lack of high-quality studies. This means a definite negative assumption is also not possible. In our view and according to consensus of experts, who contributed to the German CRPS treatment guideline, a series of sympathetic blocks under strict control of the therapeutic effect (pain reduction >> 50%) throughout 5 weeks (twice a week) can be tried,4 if a test block in the beginning was successful. Such a series should be prematurely stopped if single blocks became unsuccessful, or conversely, if long-lasting therapeutic effects have been achieved. Sympathetic blocks are not first-line therapy and should only be conducted by an experienced pain therapist.A recent Cochrane analysis could not reveal evidence for the efficacy of sympathetic blocks79 However, we agree that because of the minimally invasive character, a therapeutic attempt makes sense in selected cases (Fig. 92 This treatment, however, must be performed by experienced centres and only after vigorous assessment32 including psychological factors.40 Complications like catheter dislocation or break and cerebrospinal fluid leakage with postural headaches are frequent. Firm evidence that both treatments for CRPS dystonia are successful is sparse (Fig. Botulinum toxin might be less effective for treatment of fixed dystonic posturing in CRPS than for action-related dystonia in neurology.Complex regional pain syndrome is a “visible” pain disease. During the past years, there has been significant progress in understanding the pathophysiology, which will ultimately lead to better individualized treatment. It is important to explain the pathophysiology of CRPS as good as we know and the purpose of each therapy to the patients, and to motivate them to actively participate by developing self-management strategies. Thereby, therapeutic success might become better. Whether the treatment success is sufficient to reintegrate patients back into their previous lives also depends on nonmedical factors. In any case, we urgently need multicentre RCTs, which have to be performed by closely cooperating networks.The authors have no conflict of interest to declare.The authors were supported by intramural funds of the University Medical Center Mainz to V. Dimova and the Berufsgenossenschaft für das Gesundheitswesen Mainz and the EU, FP7 under grant agreement number 602133 to F. Birklein.


NCT01546857.In recent years, gabapentin has gained popularity as an adjuvant therapy for the treatment of postoperative pain. Numerous studies have shown a decrease in pain score, even with immediate postoperative activity, which is significant for early post-op ambulation and regaining functionality sooner. However, studies have been in conclusive in patients undergoing lower extremity orthopedic surgery. For this reason, we hoped to study the effect of gabapentin on postoperative pain in patients undergoing total knee arthroplasty, total hip arthroplasty, or a hip fracture repair. This was done in the setting of ensuring adequate postoperative analgesia with regional blocks and opioid PCA, as is protocol at our institution. Given the sedative effects of gabapentin and the potential for improving postoperative sleep patterns, we also studied the drug's effect on this aspect of our patient's postoperative course. We utilized the Pittsburg Sleep Quality Index and Visual Analog Scale for pain to obtain a more objective standardized score amongst our study population. Our results indicate that gabapentin does not offer any additional relief in pain or improve sleep habits in patients who have received either a femoral or lumbar plexus block for lower extremity orthopedic surgery. This trial is registered with  Gabapensmitters  with metsmitters –6. A recsmitters . The samsmitters  in diffesmitters , and Gilsmitters . Later, smitters . They alsmitters .One of the side effects of gabapentin includes sleepiness, which may be beneficial to surgical patients in the immediate postoperative period. In a meta-analysis, Peng showed a 35% decrease in total opioid consumption in the first 24 hours postoperatively with the use of gabapentin . In healThe primary purpose of this randomized, double-blinded, placebo-controlled study was to determine whether, in the context of a lumbar plexus or femoral nerve block (depending on the surgery), a single dose of gabapentin improves self-reported measures of a patient's sleep quality in the form of a modified version of the Pittsburg Sleep Quality Index (PSQI), a subjective sleep scale. The secondary endpoint examined whether the addition of gabapentin improves postoperative pain, assessed on both postoperative days one and two.This study was submitted to approval by the IRB and, once obtained, all patients were provided with informed written consent in order to participate in the study. The patients were between 18 and 70 years old undergoing either a total knee arthroplasty, total hip arthroplasty, or a hip fracture repair. The patients selected had an ASA score between I and III. Patients were not eligible to participate in the study if they met any of the following criteria: pregnancy or breast feeding, allergy to any of the drugs to be used in the study or to aspirin and other NSAIDs (such as ibuprofen), a history of a sleep disorder (such as obstructive sleep apnea or daytime somnolence), a history of taking chronic narcotic pain medications or gabapentin, a history of rheumatoid arthritis, a psychiatric disorder, diabetes with nephropathy, a history of alcohol or illicit drug abuse, intrinsic hepatic or renal disease, the inability or unwillingness to use patient-controlled analgesia, inability to meet extubation criteria in the operating room, a history of asthma, a history of stroke or heart attack or thrombotic event within the past 3 months, lactose intolerance, or a history of cardiac surgery.Once confirmed to be eligible, the patients were recruited for the study. Demographic information was obtained in a detailed preoperative interview the morning of the surgery. Furthermore, a preoperative sleep history was obtained by using a modified version of the Pittsburgh Sleep Quality Index (PSQI), described below. Out of the 50 intended subjects, we were able to enroll only 29 patients, which were randomized into two groups: the placebo group and the gabapentin group.Both the gabapentin and placebo tablets were formulated and encapsulated by the University Hospital research pharmacist. The placebo capsules were composed of a mixture of lactose and granulose. The randomization protocol was completed solely by the research pharmacist, who was not involved in the care of the patients.Prior to surgery, all patients were given midazolam 1–3 mg intravenously to achieve anxiolysis. The patients also received a lumbar plexus block or a femoral nerve block, depending on the surgery performed, as this is the current standard of care for orthopedic patients at University Hospital in Newark. All patients received celecoxib 200 mg orally twice daily for three postoperative days. In the operating room, standard general anesthesia technique or neuraxial anesthesia was utilized. Upon extubation, the patients were transferred to the postanesthesia care unit (PACU), where baseline pain and sedation scores were obtained using the Visual Acuity Scale (VAS), the Modified Wilson Sedation Scale (WSS), and Ramsay Sedation Scale (RSS), respectively. All pain scores were assessed with subjects in the resting position. A continuous infusion of bupivacaine 0.125 mg/L was started at a rate of 10 mL/hr and continued to postoperative day 2. An IV PCA hydromorphone pump was initiated and set to deliver a 0.2 mg bolus per demand with a 5-minute lockout period without a basal infusion. If hydromorphone was unavailable PC, Morphine Sulfate was utilized and set to deliver a 1 mg bolus per demand with a 5-minute lockout. At the time of data analysis, for the subjects who received PCA Morphine, their dosages were converted to the equivalent dosage of hydromorphone. All patients were instructed to maintain their VAS pain score at less than 4 out of 10. If the VAS pain score was 5 or greater at rest on two consecutive pain assessments, the dose of intravenous PCA hydromorphone was increased to deliver a 0.3 mg bolus per demand and the PCA Morphine was increased to deliver a 1.5 mg bolus per demand.In addition to this, a single 400 mg dose of gabapentin was given at 9 pm of the procedure day and another dose was given at 9 pm on postoperative day (POD) 1. All teams involved in the care of the patient were aware not to order any additional sleep adjuvants. The following mornings, on POD1 and POD2, a questionnaire addressing the quality of sleep, hours of sleep, number of awakenings throughout the night, and contributing reasons for these awakenings  was given. Patients were also assessed for pain, sedation, and the incidence of any side effects, including nausea, vomiting, dizziness, and pruritus. In addition, all patients began an as-tolerated weight-bearing rehabilitation program for range of motion, strengthening, balance, and ambulation beginning the first day after surgery. Success in completion of the physical therapy goals of being out of bed in a chair by post-op day 1 and ambulating by post-op day 2 was determined for each group. No functionality testing was done in this study since a previous study was unable to show an association between gabapentin and improvement in function after TKA .The Pittsburg Sleep Quality Index (PSQI) , 21 is aWe also used the Visual Analog Scale for pain (VAS) as a secondary outcome. The VAS was used due to its simplicity and due to its acceptability as a generic pain measure. We asked for the highest measure of pain within the first 12 hours, on POD1 and on POD2.A total of 60 patients were intended to be enrolled in the study. However, the departure of the primary orthopedic joint replacement surgeon caused our sample size to be reduced significantly.The data compiled blindly and anonymously by the study team was transferred into a confidential study database. Data was analyzed as intent-to-treat. The investigators, with the assistance of the statistician, conducted an analysis using a two-sample Kolmogorov-Smirnov test, a two-tailed test. The primary endpoint is quality of sleep as evidenced by the modified PSQI questionnaire.Patients were recruited between years 2010 and 2011. The patients screened were undergoing either a total knee arthroplasty (TKA), total hip arthroplasty, or a hip fracture repair. A total of 36 additional patients were screened. The three most common reasons why patients were not enrolled included the following: (1) patient did not speak the English language, (2) patient had obstructive sleep apnea, and (3) patients were having a revision surgery. A total of 29 patients were used for the study.The placebo and gabapentin subject groups were comparable in terms of age, sex, and ASA status .P value was found to be 0.64. Thus, no significant differences were found on these questionnaires.Outcomes in the pre-op PSQI questionnaire and the post-op sleep questionnaire for POD1 and POD2 for the placebo and gabapentin groups can be found in Tables As previously mentioned, we used the VAS as our secondary outcome due to its simplicity and due to its acceptability as a generic pain measure. We asked for the highest measure of pain within the first 12 hours, on POD1 and on POD2. There was no significant difference in pain scores between the gabapentin and placebo groups within the first 12 hours after surgery. This result was expected, due to the effects of the peripheral blocks performed perioperatively. We also found no significant difference in pain scores between the gabapentin and placebo groups on both POD1 and POD2.This study was designed with the aim of examining whether gabapentin in the context of peripheral nerve blocks and opioid PCA would show an improvement in sleep quality. Though no specific dosage of gabapentin has been shown to be optimal, we selected to use a 400 mg preoperative dose. The present study did not find a significant difference between gabapentin and placebo groups in terms of the self-reported sleep quality questionnaire on either POD1 or POD2. Furthermore, pain scores on POD 1 and POD 2 did not differ between groups. Although the aforementioned studies and meta-analyses have shown a positive correlation between gabapentin use and reduction of postsurgical pain, it is clear that more evidence is needed to determine whether gabapentin has a positive effect on sleep quality. The results obtained from this study are unable to support the hypothesis of improved sleep quality in patients who receive gabapentin perioperatively, as opposed to patients who do not receive this adjunctive treatment.With regard to pain scores, immediate postoperative pain was minimal equally amongst both groups, which is expected with effective sciatic and femoral nerve blocks. However, even as local anesthetic effect dissipated with time, there still appeared to be no difference in pain scores on POD1 and POD2 between patients who received gabapentin and those allocated to the placebo group. The results of this study should not be generalized to alternative perioperative pain regimens  as these results were specific to our regimen. Furthermore, the power of this study, which was expected to be greater when the study was first designed, was greatly compromised due to the unexpected departure of the orthopedic surgeon performing these operations. In conclusion, a single preoperative dose of gabapentin 400 mg followed by a second dose of gabapentin 400 mg on POD1 showed no significant improvement on self-reported sleep quality or pain scores on POD1 and POD2. Future studies should consider using the same standardized version of the PSQI preoperatively and on POD1 and POD2 in order to allow for more uniform comparison between different studies.


Pain management following dental procedures, particularly pulpotomies and extraction, is of great importance in pediatric dentistry. The aim of this study was to investigate the efficacy of pre-treatment with ibuprofen on post-operative pain following pulpotomy of primary molars.  In a split mouth double-blinded randomized clinical trial, 49 children aging between 6-10 years old were given either ibuprofen or a placebo 45 min prior to the treatment. After pulpotomy and placement of a stainless steel crown (SSC), the pain level was evaluated using the Wong-Baker face visual analogue scale for up to 7 days post-treatment. McNemar and Wilcoxon tests were used for data analysis. P=0.032). However, there was no significant difference in the pain levels between placebo and ibuprofen groups at 48 and 72 h post-treatment . The number of times patients needed analgesics in ibuprofen group was significantly lower compared to that in the placebo group (P=0.008). Forty-five patients were eligible to participate in this study. Pre-medication with ibuprofen significantly reduced pain during the first 24 h post-treatment (Pre-medication with ibuprofen resulted in less pain following pulpotomy and SSC placement in primary teeth. One of the main reasons that children find dental procedures unpleasant is pain and discomfort during and after this treatment. The memory of the pain during primary experiences may prevent children from going to the dentist to receive regular check-ups and treatment even years after the first unpleasant experience .It has been reported that 37% to 95% of children may feel pain following various dental procedures, such as tooth extraction or pulpotomy and stainless steel crowns (SSC) -7. PulpoSeveral studies have reported that pre-treatment with analgesic medications significantly reduces post-operative pain after root canal treatment in adults -10. IbupParacetamol and ibuprofen are widely prescribed in children and are the most frequently used over-the-counter analgesics and antipyretics. It has been reported that single doses of ibuprofen (4-10 mg/kg) and paracetamol (7-15 mg/kg) have similar efficacy for relieving moderate to severe pain, and similar safety as analgesics or antipyretics in children. While post treatment prescription of ibuprofen (5-10 mg/kg) is more effective antipyretic than that of paracetamol (10-15 mg/kg) . Most stThis split mouth randomized clinical trial was approved by the Ethics Committee of Kerman University of Medical Sciences in Kerman, Iran (Ref No. KA/93/210) and was also registered online .The mean pain score during the first 24 h following treatment was considered the primary outcome. The sample size calculation was based on figures derived from a relevant study in Turkey [16] considering α=5% and power of 80%, to detect a significant 20% difference in pain score (SD=0.9) a sample size of 44 patients was calculated. A total number of 49 patients aged between 6 to 10 years old  who had been referred to the postgraduate clinic of the Pediatric Department at Kerman Dental School in Kerman, from October 2013 to June 2014, participated in this study.The patients’ parents were fully informed about the nature, aim and method of the study and they provided their informed consent on behalf of their children to participate in the study. The inclusion criteria were: patients aging 6-10 years old who had bilateral primary molar teeth with carious lesions, the teeth were suitable for restoration, no tenderness to percussion and no pain except after eating, teeth without symptoms, no clinical and/or radiographic signs of pulp degeneration, no sinus tract, no or minimal physiological resorption (less than two-thirds of the root length affected), and there was bleeding of the pulp at the time of cavity preparation and pulp exposure.Exclusion criteria were: any systemic diseases that contra-indicated conservative pulp therapy, or radiographic findings such as internal resorption, widening of periodontal ligament space, furcation or periapical radiolucency, and root canal calcifications.In order to carry out a double blinded study, ibuprofen and placebo elixirs were placed in similar single-dose glass bottles. The placebo had the same color, odor and taste as the ibuprofen elixir. The medication dose was calculated based on the patient’s weight. Therefore, each bottle of medication contained 4-10 mg/kg of ibuprofen, while the placebo bottle contained a strawberry-flavored starch suspension. The bottles were encoded and only the pharmacist who prepared the medications was aware of their content. Two bottles containing either ibuprofen or placebo were prepared for each patient and 45 min prior to each appointment, one of the bottles was given to the patient. The operator watched the patient to ensure that the patient drank the entire content of each bottle. After administering local anesthesia using 2% lidocaine with 1:80000 epinephrine  and placing rubber dam, a pulpotomy was performed using a sterile round bur  in a high-speed handpiece with copious water irrigation. Any remaining coronal pulp tissue was removed with a sharp spoon excavator. After all the pulp had been removed, the cavity was rinsed with 0.9% normal saline and a wet cotton pellet was applied to obtain hemostasis. If hemostasis was not achieved in both teeth, the patient was excluded from the study and a pulpectomy was performed for the tooth. Calcium-enriched mixture (CEM) cement  was used as the pulpotomy agent in the teeth with successful hemostasis. Once the material had set, a restorative glass ionomer cement  was placed over the CEM followed by final restoration using a SSC .All dental procedures including anesthesia, pulpotomy and SSC placement were performed by a second year postgraduate pediatric dentistry student. The patients’ parents were asked to complete a Wong-Baker faces pain rating scale (Wong-Baker FPRS) by asking their children how much pain they had. The pain intensity was rated for up to 7 days post-treatment. The Wong-Baker FPRS consists of a row of 6 numbered faces ranging from “no hurt” (score=0) to “hurts worst” (score=5). The pain severity scoring was outlined as follows: 0; no pain, 1-2; mild pain, 3; moderate pain, and 4-5; severe pain. The parents were also given an elixir of ibuprofen  after the treatment to be used as an analgesic in case the child had pain requiring relief. They were also asked to record the number of times the analgesic was used. The maximum use of the analgesic was one dose every 6 h and the parents were given an emergency phone number if there was any need for consultation in case of the patient had severe pain.Data were analyzed with McNemar and Wilcoxon tests and the level of significance was set at 0.05.Forty-nine patients were eligible to participate in this study ; howeverP=0.032)  (P=0.008). Furthermore, the number of the patients who used analgesics in the ibuprofen group (37.8%) was also significantly lower (62.2%) compared to the placebo group (P=0.013)  . Howeverctively) . The patP=0.013) . None ofP=0.013) .P<0.05).The results of the present study have shown that pre-treatment with ibuprofen significantly decreased post-operative pain and the need for analgesics during the first 24 h following pulpotomy and SSC placement in primary molar teeth  and CEM cement, have been used in dentistry for pulp capping, perforation repair, apical plug and root-end filling -23. BothAll previous investigations of pain control in children have focused on strategies to manage distress and discomfort following dental extractions, particularly after general anesthesia , 27, 28.Previous investigations that compared post-operative pain following extraction of primary molar teeth reported that administration of paracetamol, ibuprofen and diclofenac reduced the pain scores following primary teeth extraction in children -16, 28. However, a more recent meta-analysis has shown that ibuprofen is a more effective pain reliever compared to paracetamol which is in accordance with other study that has previously reported [30]. Paracetamol may be considered by some clinicians to be a safer analgesic than ibuprofen which is a non-steroidal anti-inflammatory drug. However, it has been reported that both medications have similar safety spectra .Therefore, in the present study ibuprofen was used as the pre-medication analgesic. Ibuprofen and paracetamol are among the most widely used analgesic compounds for treating mild to moderate dental pain. However, the results of a multicenter and double blind study in patients with postoperative dental pain has been showed that 400 mg ibuprofen provided superior analgesia over 1000 mg paracetamol that was both clinically and statistically significant. Similar efficacy for relieving moderate to severe pain, and similar safety as analgesics or antipyretics in children has been reported with single doses of ibuprofen (4-10 mg/kg) and paracetamol (7-15 mg/kg) . Therefore, in the present study ibuprofen was used as the pre-medication analgesic. Ibuprofen and paracetamol are among the most widely used analgesic compounds for treating mild to moderate dental pain. However, the results of a multicenter and double blind study in patients with postoperative dental pain has been showed that 400 mg ibuprofen provided superior analgesia over 1000 mg paracetamol that was both clinically and statistically significant. Similar efficacy for relieving moderate to severe pain, and similar safety as analgesics or antipyretics in children has been reported with single doses of ibuprofen (4-10 mg/kg) and paracetamol (7-15 mg/kg) .In a preliminary investigation, it has reported that the children pre-treated with an analgesic experienced less pain following various dental procedures . HoweverIn the present study, all children reported pain following the procedure. However, most of them had only mild pain. The reason for the more severe pain in this study compared to previous reports -7 can beIn conclusion, the present study has shown that pre-medication with ibuprofen significantly reduced the amount of post-operative pain during the first 24 h following pulpotomy and SSC placement. It has also reduced the need for using analgesics post-treatment for children undergoing these procedures.


Pain is a common symptom in cancer patients, and its control and management are complex. Despite the high concomitant use of psychotropic drugs among such patients, the association among pain, inadequate pain control, and psychotropic drug use has not been fully determined. This study examined the prevalence of cancer pain and inadequate pain control and the association with psychotropic drug use.In this cross-sectional study, we investigated 402 medical records obtained by simple random sampling of oncology patients at a hospital in northern Spain from July 2012 to July 2014. Adjusted odds ratios (ORs) were estimated together with their 95% confidence intervals (95% CIs) by unconditional logistic regression for each type of psychotropic drug .The mean patient age was 61.17 (standard deviation ± 13.14) years; 57.5% were women, 42.5% men. Pain was present in 18.4% of patients and inadequate pain control in 54.2%. We found a statistically significant association between the presence of cancer pain and anxiolytic use  and hypnotic use . Inadequate pain control was associated to a greater extent with the use of those drugs: adjusted OR for anxiolytic use, 4.74 ; adjusted OR for hypnotic use, 6.09 . By contrast, no association was found between pain and antidepressant use .The presence of pain and (to a greater extent) poor pain control were associated with increased use of certain psychotropic drugs, such as anxiolytics and hypnotics. There appeared to be no association between pain and antidepressant use. The International Association for the Study of Pain defines pain as an ‘unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’ . There iPain is thus a fundamental aspect in the treatment of cancer patients. That point was established at the 58th World Health Assembly on Cancer Prevention and Control of the World Health Organization (WHO). The assembly concluded that pain relief and palliative care should be prioritized in world cancer programmes; it urged health-care systems to establish programmes for monitoring pain control [The treatment and control of cancer pain is complex; authorities struggle to reach consensus regarding the treatment of choice ,9. The EPsychotropic drugs are commonly used in combination with analgesics in oncological patients. In a study of women with breast cancer and pain, Syrowatka et al.  reportedAround one-third of cancer patients are estimated to experience some type of mental health problem during the course of active treatment ,18. The Emotional distress in cancer patients is usually associated with pain ,24. ConsThe study protocol was approved by the Cantabria Clinical Research Ethics Committee on 29 May 2014; that was before data acquisition, which began in February 2015. The relevant authorization was also obtained in line with hospital regulations. The data were treated anonymously and confidentially under Spanish Organic Law 15/1999 of 13 December on Personal Data Protection. Because the data were analysed anonymously, it was not necessary to obtain the consent of patients to investigate their data. This study received the 16th National Nursing Research Award Valdecilla, which funds social work in Caja Cantabria (Spain). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.In this cross-sectional study, the eligibility criteria were patients aged over 18 years with oncological disease treated at the Oncology Unit of Hospital University Marqués of Valdecilla  in northern Spain between 1 July 2012 and 1 July 2014. In all, 420 Oncology Unit patients were selected by simple random sampling. We considered the medical records incomplete when information about all the variables related to pain and the use of each type of psychotropic drug was missing. We considered the records complete if they contained information about >80% of the remaining variables. If the medical records were incomplete, we withdrew the patient from the study. Of the 420 original subjects, we removed 18 patients (4.3%) in this way .P = 0.5). Under that assumption, with a 95% confidence interval for a maximum error of 5%, we estimated a sample of 400 patients. That sample size (n = 400) would have sufficient power (1 – β >80%) to detect associations ≥1.3 as significant for a 50% risk of the effect in the unexposed sample, considering an unexposed/exposed ratio of 1, using a two-tailed chi-square test with an alpha level of 0.05.To determine the sample size, we used the following criteria. With respect to prevalence, the literature is scarce, and so we calculated the sample size by assuming maximum indeterminacy , cancer treatment , and side effects of cancer treatment. The symptoms considered side effects were those established by the National Cancer Institute . S1 AppePain: presence of pain, location of pain, intensity of pain, and pain control. The presence of pain was treated dichotomously (yes/no). In patients whose pain was treated with analgesics, the type of analgesic, route of administration, and intensity of pain were recorded. The latter was measured following the recommendations of the European Society for Medical Oncology using the Visual Analogue Scale (VAS) , from 0 Use of psychotropic drugs: the use of anxiolytics, hypnotics, and antidepressants was classified dichotomously (yes/no) if a prescription for those treatments (both continuous and on demand) was reported in the patient's medical record.t test for comparisons or the Mann-Whitney U test in the case of non-normal distributions. We estimated proportions for the categorical and discrete variables by means of the Pearson chi-square test, likelihood ratio (LR) chi-square test, Wilcoxon two-sample test, and Fisher exact test as appropriate for comparisons. The use of each type of psychotropic drug was treated as a dependent variable; we performed separate analyses for anxiolytics, hypnotics, and antidepressants. Finally, we calculated a variable that included the joint use of anxiolytics and hypnotics. As a measure of association, we estimated the odds ratios (ORs) together with their 95% confidence intervals (95% CIs) by unconditional logistic regression.The data analysis included an initial descriptive analysis. Means with their standard deviation  were estimated for the continuous variables using the Student To control for confounding bias in the association between presence of pain, pain control, and use of each psychotropic drug, we predefined the potential confounders. They were as follows: age; sex; marital status; education level; having children; type of cancer (location); chemotherapy; radiotherapy; hormone therapy; biological therapy; surgery; side effects of cancer treatment; and fatigue. We calculated the adjusted ORs for all the predefined potential confounders (maximum model). Furthermore, to obtain better precision in the adjusted estimates, we predefined three additional criteria based on the simulation studies of Mickey and Greenland  and MaldP ≤0.20.Associated with the presence or absence of pain with significance levels of Associated with use of the psychotropic drug under analysis with an OR of 1.5–0.67 as criterion.Causes a major change in the OR when adjusted: a change greater than 10% with the equation (ORc-ORa)/ORa >10% was considered a criterion.For each psychotropic drug, we constructed an ad hoc optimal sub-model based on fulfilment of the above three criteria. We calculated the following: crude OR (ORc); adjusted OR (ORa) in the maximum model; and adjusted OR in the optimal sub-model.P were bilateral. All statistical analyses were performed using IBM SPSS Statistics, version 22.0.We set the alpha error at 0.05, and all P = 0.026). With respect to location, arthralgias were the most prevalent in both sexes, being reported by 31.1% of patients (n = 23). The mean pain intensity, measured by the VAS, was 5.64 (SD = 1.41) points; there were no statistically significant differences between the sexes (P = 0.621).The mean patient age was 61.17 (SD = 13.14) years; 57.5% (n = 231) were women and 42.5% (n = 171) were men. Pain was reported by 18.4%  of patients (n = 74). Pain was more prevalent in men .Among the 74 patients who reported pain, treatment was with analgesics in 72 (97.3%). With respect to the type of analgesic, strong opioids were prescribed in 41.7% (n = 30) and weak opioids in 5.6% (n = 4). Non-opioid analgesics were prescribed in 52.8% of patients (n = 38). The most common route of administration was oral, which used in 63.9% of cases (n = 46). With respect to pain control, among the 72 patients treated with analgesics, 45.8%  (n = 33) reported adequate pain control, whereas 54.2%  (n = 39) reported inadequate pain control; there were no statistically significant differences with sex (P <0.001) and hypnotics (P = 0.004) was significantly higher among the patients with pain. P ≤0.20. All these variables therefore met the first criterion for being included as confounders in the optimal models.Sex, the type of cancer (location), hormone therapy, and side effects of cancer treatment were statistically significantly associated with the presence of pain. Marital status, radiotherapy, and surgery to remove cancer were associated to a lesser degree, presenting significance levels of P trend, <0.001); ORa maximum model, 4.98 .The association of each of these variables with taking psychotropic drugs can be seen in P trend = 0.002); ORa maximum model, 7.60 . By contrast, we found no association between the presence of pain and antidepressant use: ORc, 0.95 ; ORa maximum model, 1.03 . This association was also strengthened after adjusting for all confounders in the maximum model ; ORa maximum model, 4.81 ; and ORa optimum model, 4.20 . Details appear in In our sample, 18% of patients reported cancer pain. Pain is the symptom most commonly reported by cancer patients with treatment, and it causes major suffering to patients and their families . Our finSince pain is such a widespread problem, it is particularly important to achieve effective treatment and symptom control. However, patients are often undertreated, which negatively affects their quality of life ,33. CompPain control was inadequate in more than 50% of our patients. This proportion is similar to that reported by Greco et al.  in a revIn our sample, 20% of cancer patients took some type of psychotropic drug. This result is in line with the findings of Grassi et al.  in a revAmong our patients with pain, 32.4% took anxiolytics. This figure is higher than that reported by Desplenter et al.  in a genP = 0.004).Although insomnia is often related to pain, only 12.2% of our patients with pain consumed hypnotics. That is because in the present study we investigated the use of hypnotics, not the presence of insomnia. Thus, it is possible that in our sample, many patients suffered from insomnia but were not receiving pharmacological treatment; some studies have reported a higher prevalence of insomnia in patients with pain ,39. HoweWe found that 4.1% of our patients with pain took antidepressants; that figure did not differ from the group of patients without pain. These results are much lower than those reported by Syrowatka et al. , Barry eWe found that the presence of pain and (to a greater extent) inadequate pain control were associated with a higher risk of taking anxiolytics and hypnotics, but not antidepressants. When adjusted for the optimal model, with respect to patients with no pain, the possibility (odds) of taking anxiolytics and hypnotics increased 4.74-fold and 6.09-fold, respectively, in patients with inadequate pain control. There are several explanations for this association. Lack of pain control results in poorer patient quality of life and social relationships as well as in less tolerance to cancer treatment . This siThe cross-sectional nature of our study does not permit conclusions to be drawn in the above regard. Future longitudinal studies should investigate this association in greater depth. They should determine to what extent pain leads to more psychiatric symptoms (since that is the reason for taking psychotropic drugs) and to what extent psychotropic drugs are prescribed as adjuvants in the treatment of pain, without assessing psychiatric symptoms. However, the above association suggests that if pain can be reduced—following analgesic recommendations or using interventions based on relaxation or adaptive coping strategies —the patiThe present study shows that despite the latest recommendations ,13, cancIn this study, we investigated only the presence of pain and its management and control independently of the duration. Our objective was to determine the association between pain control and psychotropic drug use. However, we believe that future studies should address any differences between acute and chronic pain.In retrospective studies based on secondary information (records), the low quality of the information—owing to either incomplete records or lack of agreement among different records—can be a major limitation. For this reason, we selected variables that could be collected homogeneously in secondary records. However, we were unable to obtain information about symptoms of stress, anxiety, depression, and sleeping problems or identify the reasons for patients having been prescribed psychotropic drugs. We only derived information about the whole oncological situation at the time of data collection; oncological processes may, though, in some cases continue for several years.The protocol in this study involved checking for discrepancies (contradictory information) individually with the physicians or nurses responsible for the patient; we conducted a sensitivity analysis by incorporating the information separately. We found 100% agreement regarding the analysed variables.One limitation of this study was that the small number of patients who took antidepressants did not enable their association for inadequate pain control to be determined with sufficient precision. One of the strengths of the study was the control of confounding bias on the associations: applying the optimal model allowed the confounding bias to be minimized with the highest possible precision in the estimates.In conclusion, we found the prevalence of pain in cancer patients to be almost 20%. Despite receiving analgesic treatment, pain was inadequately controlled in over 50% of patients. Both the presence of pain and (to a greater extent) inadequate pain control were associated with use of anxiolytics and hypnotics. This association did not appear to exist for antidepressant use.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S1 Appendix(DOCX)Click here for additional data file.


High body mass index, as well as maintaining this condition for a long period of time, are important risk factors for the development of osteoarthritis.  To determine joint pain and osteoarthritis prevalence in patients referred to bariatric surgery.  Morbidly obese patients referred to bariatric surgery responded to the visual analogue pain scale (VAS) and the WOMAC questionnaire. X-rays of the hips and knees were evaluated. The primary endpoints were self-reported joint pain and the diagnosis of osteoarthritis by clinical and radiological criteria of the American College of Rheumatology.  141 patients were interviewed (85.1% women) with a mean age of 40 years. The mean body mass index was 46. The lumbar spine and knee joint were the most commonly reported as painful (77.9% and 73.2% respectively). Prevalence of knee osteoarthritis was 63.1% and hip osteoarthritis was 40.8%. Age, mean VAS and WOMAC scores were higher in the osteoarthritic individuals. There is prevalence of 90.1% of pain symptoms in morbidly obese patients referred to bariatric surgery. The prevalence of knee osteoarthritis was 63.1% and hip osteoarthritis was 40.8% in this sample. Obese individuals have increased cardiovascular events and many other conditions, including osteoarthritis, which is strongly associated with high metabolic and inflammatory environmentsPrevalence of osteoarthritis in Brazilian adult population is 4.14% according to the only existing study on the subjectThe aim of this study was to define the prevalence of joint pain and osteoarthritis of the knees and hips of obese patients awaiting treatment of obesity through bariatric surgery.This is a prevalence study  conducted in a bariatric surgery service between July and December 2015 and was approved by the local Research Ethics Committee.Were evaluated 141 consecutive patients in preoperative assessment for bariatric surgery. Inclusion criteria were obese with BMI above 35 referred for bariatric surgery and ability to read, understand and accept the informed consent.Patients responded to visual analogue pain scale (VAS)Patients underwent radiographs of the hips (anteroposterior incidence) and knees . The radiographs were classified according to Kellgren and Lawrence classificationThe primary outcomes were presence of self-reported joint pain and diagnosis of osteoarthritis according to the clinical and radiological American College of Rheumatology criteria for knee and hip OADescriptive analysis was performed for all variables. Data was presented as mean and standard deviation (SD) for continuous variables and as absolute frequency and relative frequency for categorical variables. Kolmogorov-Smirnov test, histograms and multivariate skewness and kurtosis measures were applied to determine which variables were normally distributed. Comparisons between two continuous variables were performed using the Student-t test for independent samples and with Mann-Whitney u test when data did not meet conditions for use of parametric tests. Binary logistic regression was performed to test the association between total prevalence of OA, prevalence of knee OA and hip OA (dependent variables) and the risk factors such as age, gender, height, weight and BMI. Results were described as Odds Ratio (OR) . Chi-square test was used for categorical variables, or Fisher’s exact test when 20% or more of the table cells showed absolute count of less than five. The level of significance was set at 0.05. All reported p values are two-tailed. All analyzes were performed using IBM SPSS Statistics software .One hundred forty-one patients were analyzed. Demographic characteristics of the sample are shown in Prevalence of musculoskeletal pain in this sample of morbidly obese patients was very high. Only 14 patients (9.9%) had no complaints. The other 127 (90.1%) reported pain in one or more joints. The most common pain site was the lumbar spine, followed by the knees. Of these 127 patients with pain, 99 (77.9%) had low back pain, 33 (25.9%) dorsal pain, 33 (25.9%) cervical pain, 93 (73.2%) knee pain , 61 (48.1%) hip pain and 54 (42.5%) reported pain in the hands. Only 15 patients (11.8%) reported pain on a single joint. Moment VAS had a mean of 39.9±34.6. Last three days’s VAS was 52.4±34.1. Mean total WOMAC was 36.3±21.2. Mean WOMAC pain subscale was 7.9±4.6. Mean WOMAC stiffness subscale was 2.8±2.4. Mean WOMAC function subscale was 25.6±15.5. The result of the total WOMAC questionnaire and its subscales  are shown in Radiographs were taken in 103 patients. The other 38 patients refused or did not attend to the scheduled examination. Radiographs were classified according to the Kellgren-Lawrence scheme (K&L) by three authors. In case of disagreement, the classification given by the majority (two observers) was considered. There was no total disagreement.In these 103 patients, 80 (77.7%) had one or more joints with joint pain and radiological changes consistent with OA (K&L ≥2). The prevalence of knee OA was 63.1% (n=65) and hip OA was 40.8% (n=42).There was no difference between the prevalence of OA and gender considering any joint , only knee OA  or only hip OA . Regarding the continuous variables, comparisons between the average of the group with OA (K&L ≥2) and without OA (K&L ≤1) are shown in The age of the patients with OA was higher, as well as the WOMAC and last three days VAS levels. Associations between continuous variables as potential risk factors for developing OA tested by binary logistic regression are presented in This study found a high prevalence of joint pain, especially in the lumbar spine and knees, as well as OA in the hips and knees in a population of morbidly obese patients awaiting for bariatric surgery. This is the first Brazilian report of prevalence of pain and OA in morbidly obese population.,Aging and obesity are the two main risk factors for OA developmentIt is currently known that knee OA is strongly associated with high metabolic and inflammatory environments found in obesityThis study, as reported in the literature, found a direct relationship between age, obesity and osteoarthritis. The present analysis did not find significant statistical correlation between gender and OA, maybe be due to the low number of males in our sample. The vast majority of our subjects were female. There is increasing evidence that estrogen plays an important role in maintaining homeostasis of articular tissues. The dramatic increase in the prevalence of OA in women after menopauseSince OA is a chronic disease, prevalence measurement becomes much more important than incidence and can indicate the risk of exposure for susceptible individuals. Prevalence studies are often used for planning public health and as an initial step (baseline) to assess comorbidity control programs.,,In addition to the simple prevalence of the disease, we also obtained the algofunctional profile of the studied individuals through the application of Analogue Visual Scale of pain (VAS) and WOMAC questionnaire. We could also observe greater pain and loss of function in the OA individuals, which had almost twice the pain and loss of function expressed by a higher score on the WOMAC questionnaire. It is important to notice that even individuals without OA diagnosis presented with high WOMAC scores, which points out the functional limitation imposed by the presence of obesity. Several studies have shown an improvement of symptoms and quality of life in obese osteoarthritic subjects treated with bariatric surgeryThe main limitation of this study is that the sample is composed of individuals referred for surgical treatment of obesity in the public system. There could be some degree of selection bias since joint pain can act as a motivator to make the individual seek surgical treatment. Thus, the prevalence of joint pain and OA could be expected to be smaller in the general Brazilian obese population. To overcome such limitation it would be necessary to carry out a sampling study in the Brazilian population involving home visits, much more expensive and time consuming. Our next step will be to re-evaluate the individuals after bariatric surgery and observe any correlation between this treatment and changes in symptoms caused by osteoarthritis.There is a prevalence of 90.1% of pain symptoms in morbidly obese patients awaiting treatment with bariatric surgery. The prevalence of knee OA was 63.1% and hip OA was 40.8% in this sample.


The total Oswestry score representing quality of life improved in the aboA group compared to the placebo group (p = 0.0448). Moreover, significantly more patients reported their low back pain as “much improved” in the abobotulinum toxin A group (0.0293).Chronic low back pain is a debilitating condition with a complex and multifactorial pathophysiology. Botulinum neurotoxins (BoNTs) have strong analgesic effects, as shown in both animal models of pain and in human beings. A randomized, double-blind, placebo-controlled, parallel format study to investigate the efficacy of abobotulinum toxin A (aboA) in chronic low back pain was conducted. The study cohort consisted of 18 patients who received 100 units of aboA into each of the five lumbar extensor spinae muscles unilaterally or bilaterally , and 19 who received normal saline of the same volume. The level of pain and quality of life were assessed using the visual analogue scale (VAS) and three questionnaires including the Oswestry Low Back Pain Disability Questionnaire (OLBPDQ). Patients’ perception of improvement was recorded via patient global impression of change (PGIC). The primary outcome measure, the proportion of responders with VAS of <4 at 6 weeks, was not met, but the data was significantly in favor of aboA at 4 weeks ( Low back pain is the leading cause of disability in the United States and worldwide ,2. ChronClostridium botulinum [Botox). Randomized, class I [A multitude of pathologies including, but not limited to, chronic disc disease, lumbar spinal stenosis and osteoarthritis can be responsible for chronic low back pain, and so management is extremely challenging. Relief is often partial and side effects of analgesic and opioid medications hinder their chronic use. New and more efficacious modes of treatment for chronic low back pain are being investigated, such as the use of ultrasound and high intensity laser therapy . Botulinotulinum . BoNTs cotulinum . In addiotulinum ,12,13,14otulinum ,16, alth class I  placebo- class I ,19,20.Dysport) in chronic low back pain.In this communication, we report the result of an investigation on the effects of abobotulinum toxin A . The final analysis was performed on 37 subjects (18 aboA and 19 placebo). The mean age of participants was 49.2 years in the placebo (range 27–69) and 52.5 years (range 18–78) in the neurotoxin group. The baseline characteristics of these patients are depicted in p = 0.4470). However, more patients in the aboA group (9 out of 18) showed improvement of at least 2 grades on the VAS score compared to the placebo group (4 out of 19) at 6 weeks (p = 0.0911). Furthermore, at 4 weeks, 7 of 18 (39%) subjects in the aboA group and 4 of 19 subjects (21%) in the placebo group demonstrated a VAS score of <4 (p = 0.0084). With regard to the secondary outcomes, the total score in the Oswestry questionnaire  improved in 10 of 18 subjects (55.5%) in the aboA group, but only in 4 of 19 (22.2%) subjects in the placebo group (p = 0.0448). Eight of 18 (44.4%) subjects in the aboA group and 2 of 19 subjects in the placebo group (10.5%) expressed their pain as “much improved” in the patient global impression of change scale (PGIC), (p = 0.0293). Improvement (≥2 grades) of quality of life in the ACPA scale was reported by 5 patients in the aboA group and 1 patient in the placebo group (p = 0.0897). No significant differences between the two groups were noted in relation to the total score in the short form-36 (SF-36) scale. A summary of the results is presented in The primary outcome of this study was the proportion of responders with a visual analogue scale (VAS) of <4 at 6 weeks. At 6 weeks, 5 subjects in the toxin group and 3 subjects in the placebo group (28% and 16%) met this criterion (p = 0.6390).There were no serious side effects during the duration of the study. Three patients in the toxin group and 2 patients in placebo group developed local pain at the site of injection which lasted for a few days . Injection of BoNTs in rats has been shown to significantly reduce both neurogenic inflammation and pain induced by formalin, capsaicin, and allyl isothiocyanate (the active component of mustard oil and wasabi) along with a reduction in the local accumulation of glutamate [Botulinum neurotoxins can have an analgesic effect by acting on several pain inducing mechanisms which have been tested in animal studies. They are known to inhibit the release of a number of neurotransmitters, including acetylcholine, substance P, calcitonin gene-related peptide, bradykinin, and glutamate, from presynaptic vesicles via action on soluble lutamate ,25. In alutamate . In diablutamate . BoNT tylutamate ,29. Intrlutamate ,31.Several experiments on capsaicin-induced pain in human volunteers have demonstrated the anti-nociceptive properties of BoNTs ,32. In hp < 0.03) [p = 0.02) [Recent literature indicates that aboA can also relieve pain in human subjects. In a double-blind study of 24 patients with chronic anterior knee pain due to quadriceps imbalance, injection of 500 units of aboA into the vastus lateralis muscle reduced pain significantly (compared to placebo) at 12 weeks post-injection ( < 0.03) . In anot < 0.03) . In anot < 0.03) , injecti = 0.02) .p = 0.012). At 8 weeks, 9 of 15 (60%) in the onaA group and 2 of 16 (12.5%) in the saline group noted relief (p = 0.009). Repeat OLBPDQ at 8 weeks showed improvement in 10 of 15 (66.7%) in the onaA group vs. 3 of 16 (18.8%) in the saline group (p = 0.011). No side effects were reported. The Therapeutic and Technology Assessment Subcommittee of the American Academy of Neurology defined this study as class II, depicting possible efficacy of onaA in chronic low back pain [The efficacy of botulinum toxins in low back pain has been suggested previously by two studies. Foster et al. , in a doack pain .p < 0.005). Additionally, greater pain relief was experienced by patients in the aboA group at 8 weeks . Significant functional improvement (a minimum of two-grade improvement between baseline and post-treatment assessments) was also demonstrated in a higher number of patients receiving aboA than in the saline group  by the 8th week.In another randomized, placebo-controlled, single-blind study of 50 patients , 500 uniIn contrast to the two aforementioned studies, there was no statistically significant difference in the outcome between unilateral injection of 50 units each of onaA into the quadratus lumborum and psoas muscles of 29 subjects suffering from bilateral pain compared to saline injection into the same group of muscles on the contralateral side. Both injections reduced the pain by 1.5 grades in the VAS at two weeks on each side .p = 0.09).The mechanism(s) by which the botulinum neurotoxins can relieve low back pain is subject to discussion. In our view, it is multifactorial, being similar to the action of the toxin in other pain conditions in some, and different in others. For instance, inhibition of the pain transmitter/modulator release from peripheral nerve endings and DRG as well as reducing local inflammation are believed to be the major mechanisms of botulinum neurotoxins’ analgesic effect in post-herpetic, post-traumatic neuralgias and in painful diabetic neuropathy. These mechanisms are also at work in chronic low back pain which like any chronic pain condition involves peripheral and central sensitization of the sensory system as well as local inflammation which can develop around the nerve roots. Different mechanisms are involved on the motor side. Many patients with low back pain have increased tone in paraspinal muscles as well as painful spasms. Botulinum neurotoxins can relieve painful spasms and reduce muscle tone via blockage of acetylcholine release from neuromuscular junction. Furthermore, muscles injected by botulinum toxins often develop atrophy; and, in low back pain associated with a tight compartment (compartment syndrome), reduction of pressure may relieve pain by easing pressure against pain sensitive structures. Finally, proximity of the injected muscles (erector spinae) to the spinal cord  promotes the central analgesic effect of the toxin, albeit not yet proven. The technical design of our current study with aboA was similar to our previous study with onaA in chronic low back pain, which demonstrated favorable results . In bothWe acknowledge the limitations of our study. This is a small study and a study with a larger cohort may demonstrate different results. Causal heterogeneity of low back pain in our study cohort may also complicate the results. It is conceivable that the cause of chronic low back pain may have some influence on the magnitude of pain response to botulinum toxin treatment. Better localization of the injected muscles with newer techniques such as ultrasound (as sole technique or in addition to EMG) may help improve the results of botulinum toxin ,42. A coThis was an investigator-initiated, randomized, double-blind, parallel design, placebo-controlled study. The study was funded by Ipsen Pharmaceuticals. A sample size of 80 was selected based on an anticipation of up to 25% placebo effect and a previously reported 52% pain relief after administration of onaA in chronic low back pain . The enrAfter obtaining a thorough clinical history from the eligible subjects, a neurological examination was performed on all. Subjects were on a variety of analgesic medications before entering the study, and these medications were not changed for 30 days prior to or at any point during the study.They were then randomized into either the aboA group or the placebo group. The level of pain was assessed by the VAS and rated from 0 to 10. In addition, patients filled three questionnaires which described their level of functionality and quality of life: the American Chronic Pain Association’s (ACPA) Quality of Life Scale, the Oswestry Low Back Pain Disability Questionnaire (OLBPDQ), and the Short Form-36 (SF-36) . During Study subjects revisited the clinic again at Weeks 6, 12, and 16 during which physical examination, the VAS scores, and the three questionnaires were reassessed. In addition, during these visits, the subject’s impression of change was recorded using the Patient’s Global Impression of Change (PGIC) scale . The PGI


Pancreatic adenocarcinoma is currently the fourth-leading cause of cancer-related death. Up to 60–90% of patients with advanced disease suffer cancer-related pain, severely impacting their quality of life. Current management involves primarily pharmacotherapy with opioid narcotics and celiac plexus neurolysis; unfortunately, both approaches offer transient relief and cause undesired side-effects. High intensity focused ultrasound (HIFU) is a non-invasive thermal ablation technique that has been used to treat pancreatic cancer. This meta-analysis aims to evaluate the role of HIFU in pain palliation of advanced unresectable pancreatic adenocarcinoma.τ2, and Cochran’s Q test for heterogeneity among studies. The I2 was calculated to assess the percentage of the total variability in the different effect size estimates that can be attributed to heterogeneity among the true effects. A rank correlation test of funnel plot asymmetry was done to assess possible publication bias.An electronic search was performed in PubMed Medline database up to the end of July 2016, for unresectable pancreatic cancer pain palliation with HIFU. Pertinent studies were identified through the PubMed search engine using the following keywords: HIFU, pancreas, pancreatic cancer, pain and palliation. Additional studies were included after manual search of the selected bibliographies. Pain palliation results reported in each study were analyzed using a logit-transformed random-effects model using the inverse variance method, with the DerSimonian-Laird estimator for τ2 (variance among studies) was 0.195, and I2 (percentage of variation among studies) was 40% (95% CI: 1–64%); the Q test p-value was 0.026, indicating significant heterogeneity among studies. Among 639 patients treated with HIFU, 567 complained of pancreatic pain before the treatment and 459 patients experienced partial or complete pain relief after treatment. The random effects estimate of the proportion of patients with pain reduction was 0.81 (95% CI: 0.76–86).The meta-analysis includes a total number of 23 studies with 865 patients, 729 with pancreatic cancer. The population enrolled ranges from 3 patients in the smallest series, up to 61 in the largest study. HIFU appears to be an effective tool for pain palliation in advanced pancreatic cancer. Studies assessing treatment in patients with pancreatic adenocarcinoma are limited by factors such as small sample sizes and heterogeneity in clinical definitions and assessments. Prospective randomized and standardized studies are necessary to confirm the effectiveness of HIFU in relieving pain, and to evaluate for any potential impact on tumor control and patient survival. Pancreatic cancer incidence is increasing worldwide with 53070 new cases and 41780 deaths estimated in 2016, and is currently the fourth cause of cancer-related death [Despite advances in diagnostic methods and the development of new therapeutic approaches, the prognosis for pancreatic cancer has remained dismal over the past 40 years . The onlHigh intensity focused ultrasound (HIFU) is a non-invasive imaging-guided thermal ablation technique that uses an extracorporeal transducer to deliver ultrasound energy to induce an increase of temperature in a sharply demarcated region. Ultrasound or magnetic resonance imaging are used to assess the anatomy of the region for targeting and to provide real time feedback during ablation . HIFU haWe aim to examine the current literature on the role of HIFU in pain palliation in advanced pancreatic cancer and to compare the methodologies used for treatment, with the goal of providing a comprehensive resource of comparable data for the design of future studies.A systematic electronic search was performed using the PubMed Medline database through July 2016. The electronic system was interrogated with the following keywords: “HIFU” AND “Pancreatic cancer”, “HIFU” AND “Pain” AND “Pancreas”, “HIFU” AND “Pain” AND “Pancreatic Cancer”, “HIFU” AND “Palliation” AND “Pancreas”,” HIFU” AND “Palliation” AND “Pancreatic Cancer”. All variants of HIFU/high intensity focused ultrasound, pancreatic/pancreas, cancer/carcinoma, palliation/palliative were searched. Because some of the research published in this area was not written in English, it does not appear in PubMed; therefore, a manual search of the bibliographies of selected studies and reviews was completed to supplement the electronic search.The following exclusion criteria were applied: I) Reviews II) Studies not including pancreas III) Preclinical studies IV) Pain assessment not reported V) Reported imaging appearance or histology other than pancreatic adenocarcinoma VI) No primary pancreatic tumor VII) Studies with ≤ 2 patients VIII) Papers analyzing more than one type of malignancy in which data specific for pancreatic cancer related pain was not reported. Full-text articles were screened by SD, CM and PG. Translation of articles written in Chinese was provided by JHH. The flow of selection is described using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) model . Fig. 11Fig. 1PRτ2, and Cochran’s Q test for heterogeneity among studies. The I2 was calculated to assess the percentage of the total variability in the different effect size estimates that can be attributed to heterogeneity among the true effects . A rank correlation test of funnel plot asymmetry was done to assess possible publication bias. All statistical analyses were done with R 3.1.2 and version 4.4.0 of the “meta” package (r-project.org).A meta-analysis of 23 studies on the therapeutic effect of HIFU on pancreatic cancer, defined as the proportion of patients having no or reduced pain post-procedure, was carried out. A logit-transformed random-effects model using the inverse variance method was used, with the DerSimonian-Laird estimator for The primary electronic search identified 82 articles. Following the application of the exclusion criteria and the unavailability of one paper , 17 studThe demographic and clinical data are listed in Table Among 639 patients treated with HIFU, 567 complained of pancreatic pain before the treatment. After HIFU, 459 patients experienced a partial or complete pain relief Table . The ran2 of the included studies was 40% (95% CI: 1–64%). This result indicates that multiple effect sizes are possibly present, most probably because of the considerable variability in patients, treatments and other parameters in the publications. In fact, the Q test p-value was 0.026, confirming a significant heterogeneity among studies, as shown in Fig. p = 0.054).The IPain evaluation was heterogeneous among the studies, and the follow up periods were not consistent, with different or not specified assessment intervals. Eighteen studies used a quantitative estimate of the pain, adopting a numerical scale, VAS  or NRS  ranging from 0 to 10, with ten defined as the maximum pain experienced and 0 no pain reported. The associated use of painkillers was variably included in the definition of pain relief; although most of the patients reduced or discontinued the use of analgesic medications, it is not possible to quantify this rate due to heterogeneous reporting of the details of opioid analgesia in these papers.The tumor response was not part of the statistical analysis since there were no uniform criteria, methodology and timing of evaluation among the studies. The modality of assessment and the number of patients with a tumor response after ultrasound ablation are summarized in Table n = 38, 5.9%), followed by edema  and first and second degree skin burns . Only eight cases of severe complications were reported . , but most treatments do not require sedation or hospitalization  or the FEB-BY HIFU system  Table . Both syent from  to 7, buPost-operatively, the skin was evaluated for development of skin burns, and biochemical blood tests were used to monitor for the development of pancreatitis. Depending on the study’s design and the authors’ preferences, several imaging modalities were used immediately after HIFU and in the post-treatment period to assess ablation and tumor response.The origin of pain from pancreatic cancer is multifactorial, resulting from tumor infiltration of nerves, tumor mass compression and inflammatory reaction elicited by the malignancy , 26. TheOur study suggests that HIFU is a very effective mean of relieving pain in patients with pancreatic cancer. Despite the heterogeneity in the studies published in the literature, 81% of patients had a partial or total decrease of pain following the treatment. Case reports published in the literature, excluded from our analysis because of their small sample size, are consistent with our findings on the efficacy and safety of HIFU for pain palliation –31.Not all papers reported the duration of pain relief. The longest follow up period was reported by Wu et al., with no pain progression seen in a up to 17 months, and Anzidei et al., with pain alleviation persisting at 6 months , 32. WanThe main treatment proposed when opioids fail in pain control is currently neurolytic celiac plexus blockade (NCPB). NCPB involves percutaneous or endoscopic injection of anesthetics and neurolytic substances (Ethanol or Phenol) along the celiac plexus in order to interrupt nociceptive transmission . The actn = 1, 2.9%) and fistula formation between the tumor and the duodenum were listed as major complications  [Focused ultrasound technology appears to be an attractive alternative because it is non-invasive, provides rapid pain relief and has a high safety profile , it has 3, 8.5%) . In our In these studies, local tumor control achieved after HIFU was assessed through different imaging methods. Among 639 patients who underwent HIFU for pancreatic cancer, 455 had a positive tumor response excluding two studies not reporting this data (Table P < 0.05), but not at 12 months  [Pancreatic adenocarcinoma is relatively hypovascular and is surrounded by a thick fibrous ring that limits the penetration and diffusion of chemotherapeutic agents, accounting in part for the poor responsiveness to pharmacological treatment. Recent studies have demonstrated that HIFU may have a synergistic effect with chemotherapy, boosting the drug concentration in the tumor and reducing the systemic toxicity. The underlying mechanisms proposed are increased permeability of vascular endothelial cells and enhanced diffusion of the chemotherapeutic agent under the radiation force from the ultrasound field . Among t > 0.05) . Li X et > 0.05) .Good control of pain relief has a significant impact on the quality of life of the patient, but further studies are needed to assess the potential that this may have on survival. Survival benefit following HIFU has been previously reported in the literature. Vidal et al. observed an unexpectedly prolonged survival time for patient with stage III and stage IV pancreatic carcinoma treated with HIFU and chemotherapy, with the longest survival of 3.4 years. Moreover, the estimate of the survival was surprisingly high, with 33.5% pancreatic cancer patients still alive at 4.2 years . HIFU waThe main limitation in our study is the lack of randomized controlled trials and the considerable heterogeneity in the data reported by the single papers, which sometimes made comparison of the results not feasible. The most important differences were in the evaluation of pain, assessment of tumor response and technique used for the treatment. It was not possible for us to estimate quantitatively the reduction of pain following HIFU, as most of the papers did not use a numerical scale to assess the difference at baseline and follow up. Moreover, the timing of pain evaluation was not consistent, while precise intervals would allow an estimate of pain relief in the long term. A considerable heterogeneity was observed in the use of analgesic drugs, in terms of need of pain medications after treatment, opioid or non-opioid use, and eventual doses required. Some studies defined pain relief considering only the absolute decrease in pain, while others included the change in analgesic drugs need. Likewise, the tumor response evaluation differed in the criteria, timing and methodology used to evaluate it. A more consistent follow up time is necessary to assess longer term results and to address the potential survival benefit following HIFU. Uniformity is needed in the inclusion criteria used and in the description of the characteristics of the tumor treated  in order to make data more homogeneous and comparable.Most of the current literature reports experience with USgFUS, and few reports suggest the feasibility and safety of MRgFUS. The US guided methodology uses ultrasound for both the detection and ablation of the lesion, allowing identification of potential obstructions in the US beam pathway, such as air. USgFUS has some limitations: its contrast resolution may not be adequate to depict accurately the borders of the lesion, it lacks a real-time temperature monitoring to ensure adequate ablation, and it is operator dependent. MRgFUS is promising, because of improved tissue contrast allowing definition of the tumor and surrounding structures and because of real time MR thermometry, which allows better targeting and monitoring of the ablated region , 51, 52.Even though most of the studies were performed with US guided HIFU, standardization of energy, power and technical parameters are lacking, and still needed to obtain the best results at the minimum risk for the patient. The studies included used two different US systems; indeed, the biological effect of continuous wave HIFU can have considerable differences from the pulsed wave focused ultrasound in terms of biological effects on the tissue, interaction with other therapeutic regimens and clinical response of the patient. Not all papers specified if HIFU was applied alone or with concurrent chemotherapy/radiotherapy. In the future, these data need to be specified to better discriminate the potential of HIFU as single therapy and the effects of combination therapies on tumor response.Therefore, there is need for uniformly designed studies in order to determine the data necessary to report in each trial, in order to objectively evaluate the treatment results. A clinical registry of the results of HIFU treatment of pancreatic cancer is planned. This will provide an analytical tool useful to assess the eventual benefit of HIFU on the overall survival and pain palliation in pancreatic cancer, which is still a poorly treated aggressive tumor bearing a poor prognosis.Although the literature is heterogeneous, our study supports that High Intensity Focused Ultrasound is a potent tool for pain palliation in unresectable pancreatic cancer. The potential role of HIFU requires further well designed studies to confirm its efficacy, safety and advantages compared to other palliative techniques.