To compare the efficacy and side effects of patient-controlled intravenous analgesia (PCIA) with hydromorphone, sufentanil, and oxycodone on the management of advanced cancer patients with pain.  Patients allocated to receive PCIA between January 2015 and December 2016 were chosen for this study. After reviewing medical records, we verified if hydromorphone, sufentanil, or oxycodone for PCIA could equally provide effective pain relief. A numeric rating scale (NRS) of cancer pain was applied before PCIA, at 4 hours after PCIA, and at the discontinuation of PCIA. Secondary, the incidence of clinical side effects attributed to PCIA was observed. n=30), sufentanil (n=34), and oxycodone (n=21) was used for cancer pain management. PCIA successfully improved pain control in 97.6% of the patients. The most common side effects were constipation (11.8%), nausea (8.2%), and sedation (5.9%). Drug addiction, delirium, or respiratory depression associated with PCIA was not reported in this case series study. No significant intergroup difference was observed in NRS at any of the abovementioned time points. There was no significant difference of analgesic effect among the hydromorphone, sufentanil, or oxycodone.  A total of 85 medical records were reviewed. PCIA with hydromorphone ( PCIA provided timely, safe, and satisfactory analgesia for advanced cancer patients with pain and may be useful for titration of opioids, management of severe breakthrough pain, and conversion to oral analgesia. There was no significant difference of analgesic effect and side effect among the hydromorphone, sufentanil, and oxycodone. With the increasing number of cancer patients, cancer pain has grown up to be a major public health problem all over the world. Despite recent advances in diagnosis and treatment, cancer pain continues to present a significant challenge to cope with. The World Health Organization (WHO) analgesic ladder is now the preferred protocol of choice all over the world. In clinical practice, this protocol works effectively and is prompt in controlling mild-to-moderate cancer pain initially.As the disease progresses, alternate routes of administration are frequently used for advanced cancer patients with pain. Although primarily used in the treatment of acute postoperative pain, PCIA has been applied to advanced cancer patients with pain which allows the patient to individualize therapy by self-administrating predetermined doses of opioid analgesics. It was shown that PCIA can decrease the delayed opioid administration from the time requested, accompanied by rapidity and ease of dose titration and adaptability to the variable analgesic dosing needs . AnotherThe goal of this study was to retrospectively review the safety and the analgesic efficacy of hydromorphone, sufentanil, and oxycodone by PCIA in advanced cancer patients with pain.The study was approved by the ethics committee of the First Affiliated Hospital, School of Medicine, Zhejiang University. Patients who used PCIA for cancer pain management with sufentanil, hydromorphone, and oxycodone between January 2015 and December 2016 at the First Affiliated Hospital of the School of Medicine, Zhejiang University, were recruited in the retrospective cohort study. Criteria for exclusion include patient chart not available, discontinuation of PCIA therapy for more than 4 hours, and data not available. A total of 85 patients were identified and collected.Information gathered from their electronic medical record included general demographic data, cancer diagnosis, date of PCIA pump used, 11-point (0 to 10) NRS before and after PCIA, times of breakthrough pain, the medications placed in the pump for basal and patient-controlled dosing, and opioid medications before and after pump placement.Hospitalized cancer patients are usually treated by oncologists according to the National Comprehensive Cancer Network (NCCN) guidelines for opioid prescription. Whenever adequate pain control was not achieved with an amount of daily morphine equivalents ≥ 120 mg, they should get help from the department of pain medicine.The decision criteria to install a PCIA were that the patient presented with severe breakthrough pain requiring at least five daily doses of systemic opioid rescue medication, unable to take oral medication, or pain control still not satisfied after oral drug titration in the last 24 h. The patient should not have a history of drug or alcohol abuse.When using different forms of opioid drugs, the opioid equivalence dosage was compared using oral morphine equivalent dose –5. The aDiscontinuation of therapy criteria is that pain was satisfactorily controlled for at least 24 hours or patients have clinical complications such as respiratory depression.When the patient received PCIA as a supplementary rescue technique, their usual systemic medication was still using according to the NCCN guideline-based analgesic administration . After tPain relief was defined as comfortable with subtotal pain relief with desired no increase of morphine dose. After pain relief, the patient took oral oxycodone or fentanyl transdermal patch equal to the intravenous requirement .During the PCIA utilizing, a nurse assessed the baseline blood pressure, heart and respiratory rates, level of consciousness, pain score, and any other adverse effects.Our primary outcome was to verify if different PCIA opioid-based solutions could effectively provide pain relief in cancer patients. In addition, the incidence of clinical side effects associated with PCIA therapy, including respiratory depression, drowsiness, constipation, and delirium was also observed.t-test, the chi-square test, or the Mann–Whitney U test was utilized to group variables. P value less than 0.05 was considered significant.Data were collected and analyzed using SPSS version 16.0 for Windows . Continuous variables were presented as means ± standard deviation, and categorical data were shown as numbers and percentages. The independent sample n=30), sufentanil (n=34), and oxycodone (n=21) was used for cancer pain management. Depending upon the discontinuation criteria for PCIA established, success after PCIA prescription occurred in all of the patients except two patients. PCIA successfully improved pain control in 97.6% of the patients. Baseline characteristics of the patients are shown in A total of 92 patients' records were included in this retrospective study. Screening of medical records was the first step to select eligible patients. Five were excluded due to missing data. PCIA failed in the remaining 2 patients, and intrathecal drug (morphine) delivery system was implanted for treatment of patients with intractable pain . PCIA wiA comparison of NRS score was showed before PCIA, at 4 hours after PCIA, and at the discontinuation of PCIA. Mean NRS score before PCIA in group hydromorphone, group sufentanil, and group oxycodone was 5.0 ± 1.1, 4.9 ± 1.0, and 5.3 ± 1.1. At 4 hours after PCIA, these decreased to 2.3 ± 0.8, 2.0 ± 1.0, and 2.2 ± 0.7. When PCIA is discontinued, these decreased to 1.9 ± 0.7, 1.7 ± 0.7, and 2.0 ± 0.6, respectively. No significant intergroup difference was observed in NRS at any of the abovementioned time points .PCIA therapy was employed for an average length of 5.9 ± 4 days. The most common side effects were constipation (11.8%), nausea (8.2%), and sedation (5.9%). Drug addiction, delirium, or respiratory depression originated in PCIA was not reported in this case series study . There wThe vast majority of advanced cancer patients with pain can obtain satisfactory control by following the WHO analgesic ladder with morphine sustained-release tablets, fentanyl transdermal system, and other noninvasive drug treatments . HoweverApplication of PCIA can maintain the blood drug concentration near the lowest effective plasma concentration. The pharmacological characteristics of PCIA allowed for determining the treatment on needs of the patients. In addition, the effective blood concentration to maintain a stable and minimum effective quantity eliminates the difference to avoid the risk of drug overdose or insufficient. Compared to the conventional analgesic therapy, the PCIA is well accepted as a helpful and effective technique by the cancer patient with being able to control the pain themselves and the minimum delay between request for analgesia and pain relief –11.The breakthrough pain was defined as a rapid onset, short duration, moderate-to-severe intensity, and frequent occurrence. The typical duration of an episode is 15–30 minutes. The frequency of pain episodes can vary from a single time to several times daily or weekly , 13. WitAn obvious advantage is that PCIA can avoid delays in the administration of analgesics and benefits for patients suffering from frequent breakthrough pain episodes. PCIA has the advantages of immediately releasing the drug whenever the patient demands in low doses, short intervals, short duration of effect, and easy titration of opioids. Another one is that PCIA can ease of dose titration and adaptability to patients need to analgesics .μ receptors which exert potent analgesic effects but also be coupled with adverse effects like nausea, vomiting, constipation, itching, and respiratory depression [Hydromorphone, sufentanil, and oxycodone are opioid analgesics currently widely used in cancer pain. They are primarily an agonist at pression , 15. TheOur experience suggests that hydromorphone, sufentanil, and oxycodone provides a good safety profile and represents an effective analgesic drug in cancer patient. All cancer patients treated with hydromorphone, sufentanil, and oxycodone of PCIA enjoyed satisfactory analgesia. The pain intensity score and times of breakthrough pain recorded during the treatment with PCIA indicated significant pain relief when compared to the starting time and remained stable for the entire time of treatment.This study suffered from the limitations of any retrospective design. Some data records were not retrieved. Most detailed pain characteristics data such as movement related, light-dark intervals and sleep quality as was not in a position to be collected. In addition, the data of the effect of PCIA on anxiety, depression, and quality of life were insufficiency. Regardless of the fact that PCIA resulted in shorter length of hospital stay allowing to be available for other patients, the cost of drug and pump increases. The economic aspect of the use of PCIA is a worthwhile topic for further exploration.In conclusion, PCIA, providing timely, safe, and satisfactory analgesia for advanced cancer patients with pain, may be useful for treating breakthrough pain and titration of opioid to aid weaning to oral analgesia. There was no significant difference of analgesic effect and side effect among the hydromorphone, sufentanil, and oxycodone. Clinicians should be familiar with the benefits and potential risks of PCIA with many kinds of opioids. More prospective, randomized controlled trials of clinical safety and efficacy of PCIA with opioid should be examined in advanced cancer patients with pain.


Pain is one of the most disabling symptoms of Gaucher disease. It is referred by the majority of Gaucher patients and often persists despite long-term enzyme replacement treatment. It has been mainly considered as nociceptive pain secondary to skeletal involvement but it is described even in the absence of bone disease without a clear explanation. In the last years an increasing number of reports have described the presence of neurological manifestation in Gaucher type 1 patients, including subclinical large fibre neuropathy. In our Gaucher clinic we have observed the recurrence of painful symptoms in a group of type 1 Gaucher patients even after a long-term enzyme replacement therapy.A cross-sectional study was designed to investigate the pathophysiology of pain in a cohort of 25 Gaucher patients . Twenty-two patients received enzyme replacement therapy for a period of time ranging from 10 to >20 years, while three were new diagnosis. Pain was classified as bone or neurologic related on the basis of anamnestic data, clinical and electrophysilogical examinations. Intensity and quality of pain were recorded by Douleur Neuropathique en 4 questionnaire and Neuropathic Pain Symptom Inventory. Neuroalgological evaluation, quantitative sensory testing, nerve conduction studies and evaluation of epidermal nerve fibres density were performed. Comorbidities for peripheral neuropathy were excluded.errata sensation (burning instead of cold), paradoxical heat sensation and mechanic hypoesthesia; three patients showed pressure pain hyperalgesia. Epidermal denervation was present in 19 patients, 12 of them with non-length dependent pattern.Thirteen patients complained of pain suggestive of neuropathic origin with proximal patchy distribution, six manifested severe pain paroxysmal, nine pinprick hypoesthesia and 17 thermal hypoesthesia. At quantitative sensory testing, all of them showed high cold thresholds with continuum Gaucher phenotype, and provide a new interpretation of pain origin that should be considered for an appropriate disease management and to avoid unnecessary dose escalations of enzyme therapy.These results confirm the role of peripheral neuropathy in Gaucher pain and demonstrate that skin denervation is as a constitutive feature of the disorder. In addition, they further confirm the existence of a  Based oGD1 form . In accoGD1 form –9. In paA relevant manifestation of GD is pain, usually related to skeletal involvement , 10. In However, we have recently observed pain recurrence or sensory dysesthesias with neuropathic features in a group of GD1 patients who had received long-term ERT (up to >20 years). Neuropathic pain is considered consequent to a primary lesion in somatosensory nervous system, in particular to the damage of small nerve fibers , 14. HowThis is a cross-sectional study that enrolled 25 GD1 patients  followed for 10 to >20 years by the Regional Coordinator Centre for Rare Diseases of the Academic Medical Centre Hospital (AMCH) of Udine. Twenty-nine GD1 patients who came to the annual follow-up visit from 1st April 2016 to 31st December 2016 were asked to participate in the study, regardless of the presence of painful symptoms. Twenty-five patients accepted to participate and signed the informed consent. The study was approved by the Ethical Committee of the Regione Friuli Venezia Giulia.GBA gene. Twenty-two patients received alglucerase/imiglucerase therapy or substrate reduction therapy (SRT) with miglustat (1 patient) for a mean of 15.0 (±6.4) years, while 3 patients were naïve for any treatment.The diagnosis of Gaucher disease was based on the assessment of residual leukocytes β-glucosidase activity and the molecular analysis of the The follow-up protocol included: yearly clinical examination, laboratory tests  and bi-annual imaging study . Therapy efficacy was evaluated by Zimran-severity score index (Zimran-SSI).Other causes of somatic and/or autonomic neuropathy were excluded: diabetes mellitus; renal, liver or thyroid dysfunction; HIV, HCV; hematological diseases; connective tissue diseases; malignancies; vitamin B12 deficiency; hereditary neuropathy; exposure to neurotoxic drugs; alcohol abuse; causes of monoclonal gammopathy not GD related.Anamnestic data on the presence of recurrent or chronic dull pain,  as well as on the presence of bone crisis were collected through patients’ diary consultation and direct interrogation. In presence of a positive feedback, pain was classified as of bone origin.Neurological examination included extensive sensory evaluation according to the European Federation Neurological Society (EFNS) Guideline , 16. IntSensory and motor nerve conduction studies (NCS) were performed using surface recording electrodes and standard placement. Compound muscle action potential (CMAP), motor nerve conduction velocity (MCV), distal motor latency (DL) and F wave latencies were recorded for median, ulnar, peroneal, and tibial nerves. Sensory nerve conduction velocity (SNCV) and sensory nerve action potential (SNAP) were assessed for median, ulnar, lateral femoral-cutaneous and sural nerves.QST was performed using calibrated device and standard procedure , 20. WarThe mechanical detection threshold (MDT) was measured with a standardized set of modified von Frey hairs, from 0.26mN to 490mN using the method of limits making 5 threshold determination in the same sites of thermal thresholds determination. The VDT was performed with a graded Rydel-Seiffer tuning fork  placed over the head of homerous, scapula, ulnar styloid process and internal malleolus. The pressure pain threshold (PPT) was performed with a pressure gauge device , able to exert forces up to 20 kg/cm2 with increasing ramp of 50 kPa/s. The PPT was determined with three series of ascending stimulus intensities, each applied as a slowly increasing ramp of 50 kPa/s. We created profiles of sensory changes using the Z-transformation of QST in order to obtain a Z-score , 20.Patients underwent a 3-mm punch skin biopsy at the distal site of the leg and proximal thigh following a standardized protocol . SpecimeP values <0.05 were considered statistically significant. IENF density was considered abnormal when it was below the 5th percentile of the normative database [Shapiro-Wilks statistic was used to test the normal distribution of variables. Clinical data, neurophysiologic measures and skin biopsy findings were compared by using the χ2 or Fischer exact tests, and the Mann-Whitney U-Test for comparisons of means. Data were reported as means and standard deviation (SD) when normally distributed, and median with 25 to 75% quartiles  when not normally distributed. database . Findingdatabase , whereasdatabase  and withPatients’ demographic characteristics and a summary of therapeutic outcomes are reported in Table GBA gene showed the presence of the common N370S mutation in 21 patients (four homozygous and 17 compound heterozygous) while different mutations were identified in four patients, Table p < 0.01) and a progressive normalization of laboratory parameters: mean Hb value increased from 11.9 to 14.3 g/dl (p = <0.01) while platelets count increased from 155.7 × 103/mm3 to 214.3 × 103/mm3 (p = <0.05). Elevated serum levels of IgG were present in ten patients  at T0 and persisted in two of them (patients 7 and 8) at Tx, with a mean value decreasing from 1632.5 to 1164.5 g/dl (p = <0.01).At T0, β-glucosidase activity was significantly reduced in all patients (data not shown), while the molecular analysis of the Bone mineral density showed a mean Z-score of −1.0 at T0 that increased to −0.26 at last visit. Only three patients  had a Z-score in the range of osteoporosis  that after ERT normalized in patients 7 and remained pathological in the other 2 (8 and 20): −2.0 and -2.8 respectively.Zimran-SSI was calculated in 21 patients both a T0 and Tx, showing a reduction to the milder severity group (score 0–10) in all of them.Due to the severe osteoporosis, patient 20 received exclusive SRT with miglustat for 3 years, then he switched to combined SRT/ERT for 1 year and finally switched to ERT exclusively. He never complained of bone crisis or symptoms secondary to miglustat treatment .Data of patients’ therapy duration, genotyping and pain history are reported in Table cold pain with proximal distribution, in six with paroxysmal cold sensation. Among them: eight had referred bone pain at T0 , three developed pain over time  and two were new diagnosed patients, naïve to any treatment (patients 16 and 24). At NRS, pain intensity resulted >4/10 in all. Only one patient (17) experienced a severe chronic pain (mean NRS of 8) with pins paroxysmal (NRS of 10), Table However, at Tx a group of 13 patients  referred the presence of painful symptoms, described as a persistent Clinical evaluation showed pinprick hypoesthesia at lower limb, usually in patchy fashion, in nine patients , in two of them (patients 8 and 18) with a stocking pattern involving also the hands, Fig. In all 13 patients with chronic pain at Tx, the DN4 score was ≥4/10, Table errata sensation (burning or pins instead of cold), presence of paradoxycal heat sensation (PHS) and mechanical hypoestesia (MDT), Table Seventeen patients performed the multimodal QST, Fig. GBA genotype was observed.Skin biopsy performed in 21 patients, showed abnormal IENF density in 19 of them , Table Despite affecting a considerable number of patients and representing one of the most disabling symptoms, pain per se has been poorly studied in GD. It has been generally associated with skeletal involvement, particularly with its most severe form, the bone crisis , 24. Mornon-neural tissue, and is due to the activation of nociceptors by several noxius stimuli such as chemical mediators release or mechanical stress [Muscoskeletal pain is defined by the presence of acute or chronic pain that arises from actual or threatened damage to l stress . The skel stress .The persistence of pain symptoms in several patients after long-term ERT, even after they had reached the therapeutic goals , with moIn our cohort ERT showed to be effective in controlling bone involvement and bone pain in nine out of the 13 who presented bone pain at T0. Only a group of four patients showed a persistence of attenuated joint pain during treatment . However, an evolution of painful symptoms was observed after long-time ERT, with the presence of pain features suggestive of neuropathic origin with a quite stereotypical pattern of sensory profile in 13 patients. Four of them belonged to the group in which bone pain was resolved in course of ERT , 3 were patients with persisting bone symptoms , 4 were previously asymptomatic  and 2 were new diagnosed (patients: 16 and 24). The pattern mostly showed thermal-hypoesthesia affecting lower limbs with prevalent involvement of cold than warm perception, similar to pain features observed in Fabry patients , 32.These functional data were confirmed by histopathology, showing the presence of IENF denervation in 19/21 patients, both symptomatic and asymptomatic ones. Interestingly a denervation pattern was observed also in the three naïve asymptomatic patients , excluding a correlation with ERT.constitutive role of peripheral neuropathy in GD. Most interesting, we found a high prevalence of a non-length dependent degeneration of somatic IENF, suggesting the primary involvement of dorsal root ganglion (DRG) neurons.The presence of SFN in asymptomatic patients, strongly suggests a 2+ levels associated with the functional up-regulation of voltage-activated Ca2+ channels in DRG neurons [2+-dependent excitability of nociceptors a possible mechanism. In addition, a direct effect of lipid accumulation on small nerve fibers damage has been hypothesized, since Ca2+ influx promoted by lyso-Gb3 may cause Ca2+-dependent excitotoxicity [The presence of a severe SFN is a well-known feature in Fabry disease and has recently been described also in a patient affected by Pompe disease –35. Desp neurons  These datoxicity .2+ release from ryanodine-sensitive intracellular stores can induce neuronal cell death [Whether a similar mechanism plays a role in painful perception in Gaucher patients needs to be investigated. However, it has been well documented that increased levels of glucosyceramide, the main lipid accumulating in GD, leads to an overactivation of the endoplasmic reticulum (ER) calcium channel, the ryanodine receptor, with the consequent increase of agonist-inducted Ca2+ release from this compartment , 39. Furll death . In lighconstitutive feature of the disease in GD. This result stresses the concept of the existence of a phenotypic continuum already evidenced by previous studies [The results of our study suggest that SNF is a  studies . Therefo


On the basis of six meta-analyses, the guidelines of the European Hernia Society (EHS) recommend laparo-endoscopic recurrent repair following previous open inguinal hernia operation and, likewise, open repair following previous laparo-endoscopic operation. So far no data are available on implementation of the guidelines or for comparison of outcomes. Besides, there are no studies for comparison of outcomes for compliance versus non-compliance with the guidelines.In total, 4812 patients with elective unilateral recurrent inguinal hernia repair in men were enrolled between September 1, 2009, and September 17, 2014, in the Herniamed Registry. Only patients with 1-year follow-up were included.p = 0.004) and pain on exertion . Comparison of laparo-endoscopic and open recurrent repair in settings of compliance versus non-compliance with the guidelines showed a higher incidence of perioperative complications and re-recurrences for recurrent repairs that did not comply with the guidelines.Out of the 2482 laparo-endoscopic recurrent repair operations 90.5% of patients, and out of the 2330 open recurrent repair procedures only 38.5% of patients, were operated on in accordance with the guidelines of the EHS. Besides, on compliance with the guidelines multivariable analysis demonstrated for laparo-endoscopic recurrent repair a significantly lower risk of pain at rest (OR 0.643 ; The EHS guidelines for recurrent inguinal hernia repair are not yet being observed to the extent required. Non-compliance with the guidelines is associated with higher perioperative complication rates and higher risk of re-recurrence. Even on compliance with the guidelines, the risk of pain at rest and pain on exertion is higher after open recurrent repair than after laparo-endoscopic repair. Patients who underwent laparo-endoscopic repair experienced significantly less chronic pain . Patients of the laparo-endoscopic group had a significantly earlier return to normal daily activities . Operative time was significantly longer in laparo-endoscopic operations  [p = 0.039) [Compared with primary inguinal hernia operations, both open and laparo-endoscopic recurrent repair procedures are associated with a higher rate of perioperative complications, re-recurrences and chronic pain , 2. Six = 0.039) .On the basis of the meta-analyses, the European Hernia Society recommends laparo-endoscopic inguinal hernia repair of recurrent hernias after conventional open repair , 23 and This present analysis of data from the Herniamed Hernia Registry  now inveThe Herniamed Registry is a multicenter, Internet-based hernia registry  into whiIn total, 4812 patients were enrolled between September 1, 2009, and August 31, 2013 , ASA classification  as well as EHS classification  [The demographic and surgery-related parameters included age (years), BMI (kg/m= >3 cm)  and geneThe dependent variables were intra- and postoperative complication rates, number of reoperations due to complications as well as the 1-year results .p value ≤0.05 represents a significant result. To discern differences between the groups in unadjusted analyses, Fisher’s exact test was used for categorical outcome variables and the robust t-test (Satterthwaite) for continuous variables.All analyses were performed with the software 9.2  and intentionally calculated to a full significance level of 5%, i.e., they were not corrected in respect of multiple tests, and each To rule out any confounding of data caused by different patient characteristics, the results of unadjusted analyses were verified via multivariable analyses in which, in addition to laparo-endoscopic or open operation, other influence parameters were simultaneously reviewed.2) the five-point OR estimate were given. Results were presented in tabular form, sorted by descending impact.To identify influence factors in multivariable analyses, the binary logistic regression model for dichotomous outcome variables was used. Estimates for odds ratio (OR) and the corresponding 95% confidence interval based on the Wald test were given. For influence variables with more than two categories, one of the latter forms was used in each case as reference category. For age (years) the 10-year OR estimate and for BMI  patients following the open suture technique for n = 718/2482 (28.9%) after open mesh repair, and for n = 233/2482 (9.4%) following laparo-endoscopic primary mesh repair (unknown 0.1%).n = 1011/2330 (43.4%) patients following previous open suture repair, for n = 897/2330 (38.5%) patients following laparo-endoscopic mesh repair and for 412/2330 (17.7%) patients after open mesh repair of the primary inguinal hernia (unknown 0.4%).Open recurrent repair was performed for Accordingly, in the laparo-endoscopic recurrent repair group 90.5%, and in the open recurrent repair group 38.5%, of patients were operated on in compliance with the guidelines of the international hernia societies.2.Is there a difference in the outcome of open versus laparo-endoscopic recurrent inguinal hernia repair in compliance with the guidelines?This analysis is based on n = 2246 laparo-endoscopic recurrent inguinal hernia repair operations following previous open primary operation and n = 897 open recurrent inguinal hernia repair operations following previous laparo-endoscopic primary repair (Table ir Table . Unadjusir Table . No diffir Table . Non-adjp = 0.002). Only medial EHS localization impacted the postoperative complication rate. Medial EHS classification reduced the risk of postoperative complications . But there was no evidence of the surgical technique having impacted the postoperative complication rate. The multivariable analysis results of pain at rest are presented in Table p < 0.001). Here, the BMI proved to be the strongest influence factor (p = 0.001). A five-point higher BMI increased the risk of pain at rest . On the other hand, laparo-endoscopic operation  and larger defect size  significantly reduced the risk of pain at rest. The multivariable analysis results of pain on exertion are given in Table p < 0.001). These were highly significantly affected by age and hernia defect size (p < 0.001). A higher age  as well as larger hernias  reduced the risk of pain on exertion. Likewise, laparo-endoscopic operations  compared with open operations reduced the risk for onset of pain on exertion. Similarly, lateral EHS classification reduced the risk  of pain on exertion. However, the risk was increased in association with a five-point higher BMI . The multivariable analysis results of chronic pain requiring treatment are presented in Table p = 0.005). Here, only the BMI proved to be a significant influence factor (p = 0.014). A five-point higher BM increased the rate of pain requiring treatment . However, there was no evidence of the surgical technique having impacted the rate of pain requiring treatment. For multivariable analysis of intraoperative complications, complication-related reoperations and recurrence on 1-year follow-up, it was not possible to calculate any model because of the paucity of relevant cases. The results of the model that explored the variables influencing onset of postoperative complications are illustrated in Table 0.213; 0.57; p = 0How do the outcomes of laparo-endoscopic recurrent inguinal hernia repair differ on compliance versus non-compliance with the guidelines?In the laparo-endoscopic recurrent operation group, the recurrent operation was performed for n = 233/2482 (9.4%) patients following laparo-endoscopic primary mesh repair, i.e., not in compliance with the guidelines of the international hernia societies (Table n = 2246/2482 (90.6%) patients who were operated on in compliance with the guidelines, with laparo-endoscopic procedure for recurrent repair following previous open primary inguinal hernia operation (Table p = 0.019) and postoperative complications  as well as a lower re-recurrence risk . The postoperative complications were impacted, in particular, by the procedures conducted in accordance with the guidelines (p = 0.001). When the guidelines were observed, the risk of onset of postoperative complications declined . Besides, the defect size had a significant effect on the postoperative complication risk. Larger hernia defects  were associated with a higher complication risk.The multivariable analysis results for the postoperative complications are presented in Table 3b.How do the outcomes of open recurrent inguinal hernia repair differ on compliance versus non-compliance with the guidelines? In the open recurrent repair group, only n = 897/2.320 (38.5%) of operations were performed following previous primary laparo-endoscopic inguinal hernia repair, i.e., according to the guidelines. Conduct of open recurrent repair following previous suture procedure for the primary inguinal hernia repair  and after mesh procedure  was not in compliance with the guidelines  versus non-compliance with the guidelines .es Table . Below ap = 0.021) and complication-related reoperation  as well as a lower re-recurrence risk . On the other hand, there was an increase in the risk of pain at rest  and on exertion .The multivariable analysis results of variables influencing onset of postoperative complications are given in Table p = 0.003) having a higher risk of postoperative complications. There was no evidence that repair as per the guidelines impacted the postoperative complications.The postoperative complications were only affected by age, with older patients . Here, the hernia defect size proved to be the strongest influence factor (p = 0.006). A larger recurrent hernia  reduced the risk of pain at rest.The multivariable analysis results for pain at rest are presented in Table p = 0.016) and BMI (p = 0.019) had a significant influence on pain at rest. Repair as per the guidelines  as well as a five-point higher BMI  increased the risk of pain at rest.Likewise, repair as per the guidelines  and medium-sized (1.5–3 cm) hernias Table .Table 20p < 0.001). These were significantly influenced by the hernia defect size (p = 0.002), repair as per the guidelines (p = 0.010), BMI (p = 0.023), age (p = 0.027) and scrotal EHS classification (p = 0.036). A higher age , larger hernias  as well as scrotal EHS classification  reduced the risk of pain on exertion. Conversely, there was a higher risk of pain for repair as per the guidelines  and for a five-point larger BMI . Likewise, for pain on exertion the risk was attributable, in particular, to small-sized (<1.5 cm) and medium-sized (1.5–3 cm) recurrent hernias  and also a smaller number of laparo-endoscopic (9.4%) recurrent repair procedures were not performed in accordance with the recommendations of the guidelines, the question arises as to how the outcomes compare with the respective repair procedures carried out in compliance with the guidelines.If recurrent repair is conducted as per the guidelines, laparo-endoscopic repair is associated with fewer intraoperative and postoperative complications and with a lower re-recurrence rate. No difference was found for the pain rates. Multivariable analysis demonstrated especially for the postoperative complications the impact of repair as per the guidelines.Comparison of open recurrent repair conducted on compliance versus non-compliance with the guidelines revealed fewer postoperative complications and complication-related reoperation rates as well as a lower re-recurrence rate following repair as per the guidelines. On the other hand, the risk of pain at rest and on exertion was higher on compliance with the guidelines. Multivariable analysis revealed that the postoperative complications were only affected by age but not by the use of a repair procedure in accordance with the guidelines. Matters were different for pain at rest and pain on exertion. For the latter, multivariable analysis confirmed that repair as per the guidelines exerted a significantly negative effect on onset of pain at rest and pain on exertion. However, multivariable analysis as well as an additional analysis demonstrated that a small defect size had the greatest impact on the risk of pain at rest and pain on exertion. Likewise, a higher BMI negatively impacted the risk of pain at rest and pain on exertion. Although recommended in the guidelines, patients with a small defect size and a higher BMI have a higher risk of pain at rest and exertion following open repair of a recurrence after a previous laparo-endoscopic inguinal hernia repair. Therefore, sufficient diagnostic work-up of a small recurrence as cause of groin pain is mandatory.In summary, it can be stated that in the Herniamed Registry (1) 90% of the laparo-endoscopic and only 40% of open recurrent inguinal hernia repair operations are carried out in accordance with the EHS guidelines; (2) comparison of laparo-endoscopic with open recurrent repair conducted in accordance with the guidelines demonstrated that open recurrent repair as per the guidelines was associated with a higher risk of pain at rest and pain on exertion on 1-year follow-up; and (3) finally, comparison of recurrent repair procedures on compliance versus non-compliance with the guidelines showed that both laparo-endoscopic and open repair operations that did not comply with the guidelines presented a higher risk of perioperative complications and re-recurrences. As such, the recommendations set out in the EHS guidelines should be implemented, but considering the specific circumstances of a given patient.


Danish patients with musculoskeletal disorders are commonly referred for primary care physiotherapy treatment but little is known about their general health status, pain diagnoses, clinical course and prognosis.The objectives of this study were to 1) describe the clinical course of patients with musculoskeletal disorders referred to physiotherapy, 2) identify predictors associated with a satisfactory outcome, and 3) determine the influence of the primary pain site diagnosis relative to those predictors.n = 2,706) newly referred because of musculoskeletal pain to 30 physiotherapy practices from January 2012 to May 2012. Data were collected via a web-based questionnaire 1–2 days prior to the first physiotherapy consultation and at 6 weeks, 3 and 6 months, from clinical records , and from national registry data. The main outcome was the Patient Acceptable Symptom State. Potential predictors were analysed using backwards step-wise selection during longitudinal Generalised Estimating Equation regression modelling. To assess the influence of pain site on these associations, primary pain site diagnosis was added to the model.This was a prospective cohort study of patients . The percentage of patients reporting their symptoms as acceptable was 32% at 6 weeks, 43% at 3 months and 52% at 6 months. A higher probability of satisfactory outcome was associated with place of residence, being retired, no compensation claim, less frequent pain, shorter duration of pain, lower levels of disability and fear avoidance, better mental health and being a non-smoker. Primary pain site diagnosis had little influence on these associations, and was not predictive of a satisfactory outcome.Only half of the patients rated their symptoms as acceptable at 6 months. Although satisfactory outcome was difficult to predict at an individual patient level, there were a number of prognostic factors that were associated with this outcome. These factors should be considered when developing generic prediction tools to assess the probability of satisfactory outcome in musculoskeletal physiotherapy patients, because the site of pain did not affect that prognostic association.The online version of this article (doi:10.1186/s12891-017-1487-3) contains supplementary material, which is available to authorized users. Musculoskeletal disorders are a common cause of ill-health, with substantial personal, community and societal consequences , 2. In DIdentifying prognostic factors and subgroups of patients who respond best to physiotherapy interventions is considered an important research priority , 7. TherCommonly used outcome measures in musculoskeletal pain prognostic studies have been improvement in pain, improvement in function or various definitions of ‘disabling pain’, but there are reasons why outcome measures that tap into broader aspects of recovery might be suitable alternative measures of outcome. The first reason is that the relationship between pain and function is strongly influenced by psychosocial attributes, such as coping, catastrophisation, pain beliefs and pain self-efficacy . SecondlThe Patient Acceptable Symptom State (PASS) is measured using a question that assesses the level of symptoms beyond which patients consider themselves well and, while it was originally developed for patients with rheumatic disorders , 18, it In addition, most prognostic factor research in musculoskeletal pain has been centred on people with pain in specific anatomical pain sites  –10. HoweTherefore, the three objectives of the study were to: 1) describe the clinical management and course of Danish patients referred to physiotherapy due to musculoskeletal pain, on the outcomes of pain intensity, disability (activity limitation), sick leave and whether they perceived their symptoms as acceptable at follow-up (satisfactory outcome), 2) identify predictors associated with satisfactory outcome, and 3) investigate the influence of primary pain site diagnosis on the strength of those associations. [This was a prospective cohort study conducted in primary-care physiotherapy practices in Denmark. Denmark is divided into five geographical regions, with each region administering its own public hospitals and primary health care services, including physiotherapy practices. A total of 30 physiotherapy practices in four regions  participated in the study. Each physiotherapist was requested to collect completed questionnaires and clinical data on newly referred patients with musculoskeletal disorders in the period from January 2012 to May 2012. Consecutive patients were invited to participate if they fulfilled the following inclusion criteria: aged 18 years or above, able to understand Danish well enough to self-complete the questionnaires, not referred for home treatment, and not having received physiotherapy treatment for the same problem in the preceding 3 months. All participants signed written informed consent forms and the study was approved by the Danish Data Protection Agency (No. 2007-58-0010). As treatment was not affected by participation in the study, under Danish law, this study did not need ethics approval www.fysdb.dk). Patients who agreed to participate in the study were asked to complete on-line questionnaires 1–2 days prior to the first physiotherapy consultation (baseline) and at 6 weeks, 3 and 6 months follow up. Participants were notified by e-mail when the follow-up questionnaires were available for completion. The questionnaires included items about education, weight, height, smoking, and physical activity, as previously used in other Danish population-based surveys [Questionnaire and clinical data were collected using an existing web-based clinical database  that was not specific to only one body region. The SEQ assesses pain, disability, and sleep disturbance in three separate modules: SEQ-pain , SEQ-disnd edition (ICPC-2) system [At the initial physiotherapy consultation, the patients’ primary musculoskeletal pain site diagnosis was recorded using the International Classification for Primary Care 2) system , which i) system . Prior tSociodemographic factors which included sex, age, educational level , vocational and training, medium level (3–4 years), higher level (>4 years), and other), geographical region (i.e. the physiotherapy practice’s location in one of four regions), information on health-related income support received (classified into none (no record of transfer payments), temporary , permanent , flex-job (which is an income subsidised job due to limited work capacity) or age retirement). These definitions have been used to quantify social and economic consequences of health-related disability in other prospective cohort studies [private health insurance, any ongoing compensation claim (litigation) for their current pain condition, or previous claim was obtained; studies , 41. FurPain and Function were measured by the SEQ pain and disability modules, which included (i) items on duration of pain , frequency of pain  and pain medication , pain location and number of pain sites (shown on a pain chart), pain intensity in body regions scored on a numerical rating scale , (ii) a subscale of pain during activity consisting of 12 items , and (iii) a subscale of disability consisting of 12 items  covering activities of daily living in three sections, namely, the upper, lower and spinal body regions, that were converted into a sum score 0–100, where 0 represented no pain/no difficulties;Psychological factors included (i) three questions on fear of physical activity in leisure and work activities, each scored on a 0 to 10 numeric scale  and added to become a sum score (0–30), (ii) one question on ability to cope and deal with pain  from the MSPQ [sleep problems and influence of sleep problems in daytime activity scored on a 0 to10 numeric scale  converted into a sum score 0–100 [well-being scored on a 5-point Likert scale from the MH-5 [the MSPQ , 42,  measured by a single-item question adapted from the original question designed for rheumatology patients , 18, thaceptable  has beenceptable  and acroceptable .Descriptive statistics  were used to report the clinical course. We calculated the number of missing values, follow-up response rates, and differences in baseline characteristics between responders and non-responders at each time point and across administrative regions. For each time point, pain and disability scores, the percentages of patients being on temporary health-related benefits, and the proportion of participants who perceived their symptoms as acceptable (PASS), were calculated and change over time was analysed by longitudinal linear mixed models for continuous variables and Generalised Estimating Equation (GEE) models for categorical variables .p-value was removed from the model until all remaining variables had a p-value below 0.05. Then the variable primary symptom diagnosis (ICPC-2 classification) was added to the model and the models were compared. To explore if the significance level would affect the inclusion of variables, sensitivity analysis was performed by repeating the stepwise backward regression analysis using a p-value below 0.2 to retain variables. In addition, the possible influence of further sub-grouping symptom diagnosis was explored by reclassifying neck and low back patients into those with or without radiating pain. All statistical analyses were performed using Stata Version 13 .Analysis of predictors for satisfactory outcomes was performed by multivariable regression modelling (GEE). Consideration of the number of variables to include in multivariable model building was based on the rule-of-thumb that a least 10 cases per variable were needed to avoid over-fitting the model , 48. Inip < 0.05).The flow of participants within the study is shown in Fig. The distribution of the primary pain site diagnosis (ICPC-2 classification) is presented in Fig. On average, patient improvement at the 6-month follow-up was 2.9  on their pain intensity scores and 9.7 (95% CI 8.9 to 10.5) on their disability scores. The prevalence of being on temporary health-related benefits was reduced from 12% at baseline to 8% at the 6-month follow up - a total reduction of 4.1% (95% CI 3.0% to 5.3%) - when excluding patients who retired or received permanent health-related income support. The percentages of patients perceiving their symptoms as acceptable increased from 32% at 6 weeks to 43% at 3 months and 52% at 6 months – an estimated difference of 19.1% (95% CI 16.3% to 21.7%) On average, patients who perceived their symptoms as acceptable had significantly better pain and disability scores at the three follow up time points than those patients who did not perceive their symptoms as acceptable, mean difference 1.8 (95% CI 1.7 to 2.0) for pain intensity and 7.2 (95% CI 6.4 to 8.0) for disability.Table This study evaluated the clinical course, treatment, prevalence of satisfactory outcome, and predictors of satisfactory outcome in musculoskeletal physiotherapy patients, including the possible influence of a primary pain site diagnosis on those predictors. Over the 6-month follow-up period, statistically significant and clinically relevant improvements were observed across outcomes; however, in keeping with the recurrent and fluctuating nature of many musculoskeletal conditions, only 52% of patients rated their symptoms as acceptable at 6 months. A higher probability of satisfactory outcome was associated with geographic region, being retired, no compensation claim, less frequent pain, shorter duration of pain, lower levels of disability, lower levels of fear avoidance, better mental health and being a non-smoker. Primary pain site diagnosis had little impact on the strength of these associations and did not add any significant predictive ability.Our study included a large consecutive cohort of patients who were recruited from many physiotherapy practices and therefore the results are likely to reflect primary care musculoskeletal problems as they present to Danish physiotherapists. Information from several data sources was combined  allowing the inclusion of a broad variety of variables to describe the clinical course and to identify predictors of outcome.A limitation of this study is that 33% of the patients invited to participate declined the offer and another 12% had to be excluded due to incomplete data and for other reasons. This modest participation rate may have affected the generalisability of our findings, although it also reflects the general difficulty of recruiting consecutive cohorts of patients from routine clinical practice. Such non-participation rates are common in large population studies and there is evidence from other Danish studies that the estimated associations between variables may not necessarily be biased by non-participation , 50. In It could also be argued that diagnostic pain site labelling according to the ICPC-2 system is too broad for musculoskeletal pain conditions, but repeating the analyses after reclassifying neck and low back patients into those with or without radiating pain did not change our results. While no consensus exists on the best method to build models using candidate predictors, some have argued that backward elimination method that we used is the preferred method . Also, wThe distribution of gender, age, duration of symptoms and primary pain site diagnoses in our study, is similar to that found in a previous Danish study of patients referred to physiotherapy , as wellIn our study, a number of predictors associated with satisfactory outcome were identified from diverse health domains. Duration of symptoms, disability levels and psychological factors have consistently been found to be associated with subsequent outcomes in multiple prognostic studies in primary care , 9, 19. Socio-demographic variables that predicted outcome, included compensation claim, geographic region and health-related income support. Having an ongoing compensation claim can be stressful and is a predictor of outcome in secondary care neck and back patients , 65. AltPrimary pain site diagnosis had little impact on the prediction of outcome. The prognosis of patients did not differ across the primary pain site diagnosis from that of patients who were classified with non-specific muscular symptoms and limited function. These results are supported by those from cohort studies in the USA, showing anatomical pain sites did not influence the predictive value of psychological factors, such as fear avoidance beliefs and depressive symptoms, in patients seeking physiotherapy treatment for musculoskeletal pain , 68. TraAmong Danish musculoskeletal physiotherapy patients, only one in two perceived their symptoms as acceptable at 6 months, despite the average improvement being above the threshold for clinically important change. A number of predictors of satisfactory outcome were identified, which appear to be prognostic regardless of primary pain site diagnosis and which may have a role in generic prediction models for physiotherapy patients with musculoskeletal pain. While clearly there is a role for studies of single-site musculoskeletal pain, our results also support the need for more research that offers insights into the drivers of recovery regardless of pain site and provides generic tools to assist the management of musculoskeletal pain, whether it be single-site or multi-site.


Supplemental Digital Content is Available in the Text.An 8-week treatment with 1800 mg of Gralise decreased the severity of postmastectomy pain syndrome and the degree of sleep impairment and catastrophizing behavior. Chronic pain is a common and debilitating complication following breast surgery. One of the most challenging for treatment is the neuropathic pain condition, postmastectomy pain syndrome (PMPS). Gabapentin is a pharmacotherapy for neuropathic pain disorders; however, its once-daily, gastroretentive formulation, Gralise, has not been evaluated in PMPS.To evaluate the safety and effectiveness of Gralise in patients with moderate-to-severe PMPS.The primary effectiveness endpoint was a change in the worst pain intensity score from baseline to completion of 8 weeks of Gralise therapy. The secondary endpoints included the change in mood, coping behavior, sleep, and function. Sensitivity to experimental stimuli was tested before and after treatment via quantitative sensory testing. The incidence and type of adverse event were used to evaluate the safety and tolerability of Gralise.Twenty-one patients with confirmed moderate-to-severe PMPS were enrolled. Nineteen of 21 (90.5%) patients completed the 8-week treatment with Gralise. A significant positive change was found in pain intensity, pain impact, and sleep. There was no change in sensory testing scores. Of total, 63.16% of patients reported reduction in present pain, 78.95% in average pain, 89.47% in worst pain, and 84.21% in overall pain severity at posttreatment visit. No significant adverse effects were noted in the study.Variation in type of breast surgery, small sample size, lack of placebo control.There was a significant improvement in pain and sleep, and Gralise was well tolerated in patients with PMPS. Further investigation is warranted. Food and Drug Administration (FDA) for patients with postherpetic neuralgia.11Gralise is a once-daily, gastroretentive formulation of gabapentin that gradually releases gabapentin over a 24-hour period to the optimal site of absorption, the proximal small intestine. Among other advantages, this gradual release reduces the chance of saturating intestinal uptake3 no studies have been conducted using Gralise, and its safety and efficacy profiles have not been investigated in breast cancer survivors with chronic pain. Therefore, the purpose of this study was to determine whether Gralise has a potential as a safe, tolerable, and effective treatment for PMPS and how it affects pain-related traits. In the large observational epidemiological study, we identified patients who underwent breast surgery and reported moderate-to-severe pain at 6 months or later postoperatively.6 We hypothesized that Gralise would reduce their pain intensity, increase sensitivity thresholds for painful stimulation, and improve mood, sleep, coping behavior, and overall pain impact scores. This study aimed to inform future randomized clinical trials with Gralise on phenotyping strategies for comprehensive evaluation of PMPS and related traits.Despite some positive evidence of PMPS relief with gabapentin,27 After the 2-week period, patients received a stable dose of 1800 mg/d for an additional 8 weeks. At the end of the 8 weeks, Gralise was gradually discontinued over 1 week , and stored according to the manufacture's guidelines. At the first visit, subjects were dispensed a 2-week titration package, 8-week maintenance package, and 1-week discontinuing package supply of Gralise. Treatment was initiated at a dose of 300 mg/d and increased over a 2-week period to a total daily dose of 1800 mg/d. As recommended by manufacturers and previously described, 1800 mg/d is the clinically effective regimen.6 In Belfer's original study, these patients were screened for postmastectomy pain at least 6 months following their surgery, and the average postoperative screening time was 38.3 months.6 Patients' pain quality was described using 3 instruments, The Brief Pain Inventory, The Short Form McGill Pain Questionnaire and the Breast Cancer Pain Questionnaire (BCPQ), as well as the pain burden index, as described previously, were calculated for each subject.6 Twenty-one patients amongst the 611 were selected to participate in this study based on the presence and scale of current postmastectomy pain, presence of neuropathic pain symptoms, overall health, history of pain management, and availability for this trial. These patients had all reported moderate-to-severe pain  at the time of their initial screening and were included in this study if they reported current pain level ≥4/10 at follow-up, to ensure that their pain had not decreased spontaneously over the several year span. Medical charts were reviewed for creatinine levels, history of kidney disease, and list of pain medications. Full demographic, clinical, and medical data from eRecords were available for each patient.The subject cohort was selected from Belfer's database of over 600 postmastectomy patients for whom pain and related psychosocial traits were previously obtained and described.28 Patients were required to have pain level ≥4/10 at present time, which was first determined via phone interview and then confirmed at visit 1. Patients were excluded from this study if they were pregnant or breastfeeding, had any known allergy to gabapentin, had a history of gabapentin dose-limiting tolerance or lack of efficacy at doses of ≥1200 mg/d or pregabalin at doses of >300 mg/d, had any current pain management (such as treatment with duloxetine or opioids) and creatinine clearance <60 mL/L.Women 18 years or older who underwent total or partial unilateral mastectomy due to a breast cancer diagnosis and suffered from moderate-to-severe PMPS were eligible for the study. Moderate-to-severe PMPS was defined as shooting, pressing, burning, or pricking pain in the remaining breast, chest wall, armpit, and/or arm, persisted from the time of breast surgery and sometimes accompanied by tingling and/or numbness (as per BCPQ descriptors). Pain intensity score cutoff was ≥4/10 on the NRS, which was reported as a clinically significant level affecting patients' daily activities and quality of life.http://links.lww.com/PR9/A4). At the first clinic visit to the Pain Sensory Lab at the Magee Women's Hospital, confirmation of eligibility was determined via a neuropathic pain assessment by a chronic pain expert .23 All patients recruited to this study were confirmed as having PMPS with both specific pain descriptions as per BCPQ and specific sensory tests . Serum creatinine levels were obtained through local laboratories. Signed informed consent was attained before study procedures from each subject. Once the quantitative sensory testing (QST) session and study questionnaires were completed during the first visit, the patient was given a Gralise supply and scheduled for a future second visit. The clinical coordinator contacted the study subject the following day to confirm that the first dose was taken. For the next 10 weeks, the patient was called weekly, and pain and adverse event (AE) data were collected via structured phone interview. If patients did not self-report drug-related side effects, patients were asked about the presence of AEs commonly observed with gabapentin treatment. During the second visit , the subject completed the same surveys and underwent the same QST procedures as the first visit (baseline). A follow-up telephone call addressing any AEs was conducted at week 12 (7 days after treatment completion). The duration of the subject's participation in the study was 15 weeks (after eligibility determination), which included the 3-week washout period, 2-week titration-up period, 8-week treatment period, 1 week titration-down period, and 1 week follow-up period.Patients were contacted by the clinical coordinator and invited to participate in the study. There were a total of 2 clinic visits and 10 telephone visits . The Brief Pain Inventory (BPI)38 was used to characterize pain. The location, intensity (measured by the NRS), duration, frequency and quality of pain, and pain-related functional limitations were recorded. Primary endpoint was a change in the worst pain level over a 24-hour period. Anxiety, symptoms of depression, and sleep disturbances were assessed using short-form instruments from the National Institutes of Health roadmap initiative, Patient-Reported Outcome Measurement Information System (PROMIS).12 These instruments have been calibrated on more than 20,000 subjects and have been extensively validated in studies comparing results with established scales.30 Catastrophic thinking associated with pain was quantified via the Pain Catastrophizing Scale.40 This scale has been validated in patients with chronic pain.An extensive phenotyping of pain and comorbid traits was achieved through validated questionnaires and QST  with a flat round transducer (probe area 0.785 cm2) applied bilaterally at the trapezius muscle and on the dorsal aspect of the proximal forearm over the extensor muscle compartment. Pressure was increased at a steady rate of approximately 1 kg/s until the subject perceived the pressure first as painful (indicating the patient's threshold) and then unbearable (suprathreshold sensitivity or tolerance), and the pressure in kilograms was recorded.Sensitivity to painful stimulation was assessed by measuring both mechanical (pressure) and thermal (cold pressor) pain thresholds and tolerance, as described previously.Cold pain sensitivity was determined via immersion of the right hand in a circulating cold water bath maintained at 4°C for 30 seconds. This was repeated 3 times, with 2 minutes in between immersions. The third immersion lasted until the subject reached the pain tolerance (or a 3-minute maximum), and the time in seconds was recorded. The intensity of cold pain was rated using the NRS at the midpoint of and 30 seconds after each test. All procedures were performed by the clinical coordinator and a trained clinical volunteer under Belfer's supervision, and the questionnaires were self-administered under the supervision of the study staff. All data were entered into a web-based database in real time.The mean change in patient reported worst pain level measured over 24 hours with NRS (via the BPI instrument) from baseline (visit 1) to week 10 .The mean change in patient reported levels of present and average pain, mood, coping behavior, sleep, and function, as well as in pain sensitivity scores  from baseline to week 10.t tests in IBM SPSS Statistics 22.0. Differences between baseline and posttreatment values of >30% for psychosocial variables and pain sensitivity scores, and a difference of 1.5 to 2 points on the NRS for pain intensity were considered clinically significant. A probability of <0.05 was considered statistically significant. This proof-of-concept pilot study aimed to collect the data for power and sample size calculations for future larger-scale clinical trials.All continuous variables were normally distributed, and the mean values and SDs were calculated. To assess the change in PMPS and PMPS-related outcomes from baseline to the end of treatment, the pretreatment and posttreatment mean scores were compared using paired sample P = 0.0001). The subjects' average pain intensity showed a decrease of pain at a mean level of 4.6 (SD = 1.9) before treatment started to 2.2 (SD = 1.8) on the NRS at the end of 8 weeks of treatment. The mean difference of subjects' average pain intensity ratings between baseline and the end of the study was 2.4 (SD = 2.7) (P = 0.001). Of the 19 subjects who completed the treatment, 12 (63.2%) reported significant reduction in present pain , 15 (79.0%) reported significantly lower average pain , 15 (79.0%) reported significantly lower worst pain , and 16 (84.2%) reported significantly lower overall pain severity  at posttreatment visit  and included in Table R2 = 0.56).All study participants were women of Caucasian origin. The mean age of the 21 patients was 55.2 (SD = 6.5) years old at the baseline. The mean body mass index was 27.5 (SD = 4.9). Table P = 0.002) compared with their survey answers pretreatment, 38.89% of patients reported feeling less stressed, and 61.1% of patients reported having greater feelings of control. There was also a significant improvement in sleep variables after Gralise treatment compared with baseline. Of total, 61.9% of patients reported significantly improved sleep demonstrated by a decrease in restless sleep, a decrease in difficulty sleeping, and a decrease in trouble staying asleep , while 27.8% of patients reported better sleep quality at the end of Gralise treatment, demonstrated by feeling more satisfied with sleep, feeling that sleep was more refreshing, and feeling that they got enough sleep. Posttreatment catastrophizing scores were also significantly lower . However, Gralise was not noted to have a significant effect on anxiety or depressive symptoms .Additional objectives for this study were to assess if there were any changes in the impact of pain on daily activities, mood, coping behavior, and sleep patterns. Compared with baseline, 73.7% of patients reported significantly lower impact of their pain on daily functioning at the posttreatment visit  and right arms (P = 0.3). Likewise, there was no difference in pressure threshold (P = 0.51) or tolerance on the left arm (P = 0.3) and right arm (P = 0.59) between pretreatment and posttreatment measurements. There was a trend towards higher tolerance  to ice-cold water when comparing baseline to posttreatment scores (P = 0.09). All the psychological factor data are displayed and summarized in supplemental Figure 2s (available at http://links.lww.com/PR9/A4) and Table The secondary effectiveness endpoint used QST to assess if Gralise therapy improved patients' sensitivity to mechanical and thermal experimental stimulation. There was no difference between pretreatment and posttreatment scores in patients' average pressure thresholds on both the left P = 0. and righhttp://links.lww.com/PR9/A4). Patients were categorized as having marked, mild or unchanged/worse pain relief and also none, not significant, or significant side effects. None of the patients in the study had the significant side effects of diarrhea, vomiting, nausea, or weight gain that are reported in previous gabapentin trials, suggesting better tolerability of Gralise compared with gabapentin.The safety and tolerability were evaluated by the incidence of AEs reported while on Gralise therapy. No severe AEs were noted. Of the total 21 patients enrolled in the study, only 1 patient (61 years old) withdrew from the study on week 2 due to AEs . There were a total of 5 AEs: fatigue, dizziness, dry mouth, sleeplessness, and itchiness. All AEs were mild and did not require treatment. Fourteen patients reported at least 1 of these events. Of total, 42.9% (9/21) of the patients reported fatigue, 33.3% (7/21) reported dizziness in the morning, 4.8% (1/21) reported dry mouth, and 9.5% (2/21) reported sleeplessness. Among the 14 patients with the before mentioned side effects, 7 patients reported 2 or more. All side effects, with the exception of itchiness, subsided by week 7 of the study. One patient (4.5%) reported itchiness that lasted from week 3 to week 12. At the end of the 12 weeks, patients were asked to report their general impression of their degree of pain relief; these results were compared simultaneously with patient reports of side effects from the Gralise therapy -δ site of voltage-dependent calcium channels and modulates the influx of calcium, with a resulting reduction in excitatory neurotransmitter release. Gabapentin  has been used for the management of pain related to postherpetic neuralgiaam), when patients are sleeping. Consequently, patients report a lower rate of dizziness and sedation relative to immediate release of gabapentin and pregabalin.19 Indeed, fatigue and dizziness observed in our study had mild symptoms, resolved spontaneously by week 7 of treatment, and were not accompanied by other AEs commonly observed in gabapentin trials, such as diarrhea, vomiting, nausea, or weight gain. Therefore, this pilot study indicates better tolerability of Gralise compared with nongastroretentive gabapentin that should be confirmed in follow-up studies.Gastroretentive gabapentin, Gralise, is a unique extended-release, once-daily formulation of gabapentin that provides both efficacy and increased tolerability. It was developed using AcuForm technology, a polymer-based drug delivery system that retains the tablet in the stomach and upper gastrointestinal tract for a sustained period. When administered with a meal, the tablet swells and remains in the stomach for up to 15 hours, releasing the drug gradually for absorption by the small intestine. The starting dose is typically 300 mg/d once daily and increased over 2 weeks to a target dose of 1800 mg/d. When administered with an evening meal, the peak dose occurs in the early morning  with a threshold score for inclusion in the study41 would facilitate the recruitment of patients with a neuropathic component to their postmastectomy pain and further enrich the study population. Finally, evaluation of long-term effects of Gralise (beyond 8 weeks of treatment) in the future prospective studies will help to determine its ultimate value for pain management in patients with persistent and severe PMPS.Breast cancer is the most common cancer in women worldwide. Partial or total mastectomy is the most common treatment choice in patients with breast cancer. Furthermore, with recent advances in breast cancer risk assessment and prediction, bilateral prophylactic mastectomy has become the most common risk-reducing surgery in high-risk women. Therefore, the rates of preventive mastectomy are on the rise.This study, for the first time, found that an 8-week treatment with 1800 mg of Gralise significantly decreased the severity of PMPS and improved patients' sleep and catastrophizing traits associated with PMPS. The positive findings from this study suggest that Gralise may expand treatment options for PMPS; however, the possibility that pain reduction experienced by patients is, in part, due to a placebo response cannot be ruled out. Future studies would require a placebo control and use of a noninferiority trial with gabapentin. Data from this study may lead to large-scale trials on the efficacy of Gralise in comparison with other pain medicine for chronic neuropathic pain relief and functional improvement in breast cancer survivors.The authors have no conflicts of interest to declare.This study was supported by the Investigator-Initiated Research grant , internal funds of the Department of Anesthesiology, and the Clinical and Translational Science Institute (CTSI) at the University of Pittsburgh, Pittsburgh, PA.Appendix Ahttp://links.lww.com/PR9/A4.Supplemental Digital Content associated with this article can be found online at


Inter-patient variability in response to opioids is well known but a comprehensive definition of its pathophysiological mechanism is still lacking and, more importantly, no studies have focused on children. The STOP Pain project aimed to evaluate the risk factors that contribute to clinical response and adverse drug reactions to opioids by means of a systematic review and a clinical investigation on paediatric oncological patients.We conducted a systematic literature search in EMBASE and PubMed up to the 24th of November 2016 following Cochrane Handbook and PRISMA guidelines. Two independent reviewers screened titles and abstracts along with full-text papers; disagreements were resolved by discussion with two other independent reviewers. We used a data extraction form to provide details of the included studies, and conducted quality assessment using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies.Young age, lung or gastrointestinal cancer, neuropathic or breakthrough pain and anxiety or sleep disturbance were associated to a worse response to opioid analgesia. No clear association was identified in literature regarding gender, ethnicity, weight, presence of metastases, biochemical or hematological factors. Studies in children were lacking. Between June 2011 and April 2014, the Italian STOP Pain project enrolled 87 paediatric cancer patients under treatment with opioids .Future studies on cancer pain should be designed with consideration for the highlighted factors to enhance our understanding of opioid non-response and safety. Studies in children are mandatory.CRD42017057740.The online version of this article (10.1186/s12885-018-4478-3) contains supplementary material, which is available to authorized users. UGT) [OPRM1) [Worldwide incidence of childhood cancer is about 160,000 new cases/year with 90,000 deaths/year under 15 years of age . ChildreUGT)  and phar [OPRM1)  on opioi [OPRM1) . Further [OPRM1) . TherefoFor these reasons, in 2010 we designed a longitudinal study focused only on paediatric cancer patients, called STOP Pain (Suitable Treatment for Oncologic Paediatric Pain) to continue recruitment for the regional study in an attempt to get as homogeneous a sample as possible, i.e. patients from the same population (with cancer pain) and treated in a homogeneous way. The main objectives of the project are to conduct a comprehensive literature review of the association between inter-individual opioid responsiveness, socio-demographic and medical factors and to evaluate the risk factors that contribute to response/non-response and adverse drug reactions to opioids in a sample of paediatric oncological patients.This review was performed in accordance with the Cochrane Handbook and the Prisma Statement for Systematic Reviews  and it wA systematic PUBMED and EMBASE search for any study evaluating opioid non-response and safety among cancer patients was performed up to the 24th of November 2016. Four themes  were combined by using the Boolean operator “and”  independently reviewed titles and abstracts, and selected articles. Any disagreements was resolved through discussion and consensus with two other independent reviewers (EL and VM).Patients included were cancer patientsDrugs involved were opioidsOutcomes evaluated were opioid non-response and safety  for cancer-related pain relief between June 2011 and April 2014. The institutional review board of Meyer Children’s Hospital approved the study.Two structured questionnaires were administered to the enrolled children or their parents after obtaining written informed consent. The first questionnaire included demographic information , medical history, concomitant illnesses and lifestyle of the children. Data concerning cancer diagnosis and evolution of the disease were collected from medical records. Data on health conditions as well as other parameters potentially predictive of high or low treatment responsiveness were collected carefully with the aim of adjusting for any confounding variables and/or effect modifiers. The second questionnaire included demographic information on parents and family environment.An Individual Case Report Form (CRF) recorded all data. Unique Patient Code anonymized the patient before the matching with genetic data. Peripheral blood or mouth swab (when possible) were collected after patient recruitment. DNA was isolated using EZ1 Extractor (Qiagen) and standard commercial kits. DNA concentration and purity was then measured with NanoDrop 2000 (Thermo Scientific) and stored at − 20 °C. Genotyping was carried out using the Taqman assay . Taqman probes were designed and synthesized by Applied Biosystems, who also provided standard PCR profile and reaction conditions. PCR plates were read on a 7500 Fast Real Time PCR system (Applied Biosystems).IV ME = oral oxycodone*2/3 = IV tramadol*10 = oral tramadol*30 = oral codeine *30 = IV fentanyl/100. When the direct conversion factor to IV ME was not available, the dosage was first converted to oral morphine equivalents and then to IV ME (3:1). Data are presented as mean and standard deviation.Opioid dosing was standardized through the conversion to intravenous (IV) morphine equivalents (ME) according to the following opioid equi-analgesic calculation : IV ME =24h) and total dose (mg/kg) of IV ME (Dosetot).We considered the following two outcomes regarding dose: dose (mg/kg) of IV ME administered during the first 24 h of treatment  was compiled by children of older age (> 6 yrs). Wong & Baker FACES Pain Rating Scale was administered to children between 4 and 6 years of age as an alternative outcome measure. When self-reporting of pain was not possible, such as in children who had difficulty verbalizing the presence or intensity of pain, the FLACC scale was used. Nurses administered the scales for pain intensity to patients at the first examination, repeating the procedure eight-hourly for intra-individual pain intensity evaluation.to); difference between pain intensity after 24 h of treatment and PIto (∆ VAS); time to reach the lowest possible pain intensity (Timetot).We considered the following three outcomes regarding pain intensity: pain intensity before treatment , central nervous system effects , and all adverse effects .We checked data for consistency and completeness by tabulating the variables of interest. We compared differences for mean values of continuous response variables by one-way ANOVA and differences for percentages of categorical variables by chi-square test.The PUMBED and EMBASE search produced 9847 records. A review of titles and abstracts resulted in the selection of 336 records of original studies, among which 72 met the inclusion criteria. Figure The characteristics of 74 studies included in this review –91 are r using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies [For the included studies, the assessment of methodological quality was performed  Studies . Items 1Given the high number of factors considered, we decided to report only the results on associations investigated in more than three studies and found in 39 studies including more than 50 subjects and published after 2000 Table . With reCancer diagnosis, biochemical parameters, cognition, metastases location, psychological distress, and sleep disturbances were the clinical factors studied, with high heterogeneity of specific measures investigated and no clear association with outcomes. However, patients with lung cancer or mesothelioma (three out of 16 studies) or gastrointestinal cancer (two studies) had a worse response (direct association), as did patients with anxiety (two studies), or sleep disturbance (two out of four studies).Pain-related factors were investigated and two studies reported a direct association between breakthrough cancer pain and worse response (i.e. subjects with breakthrough pain had a worse response), while one study reported no association. Similarly, two studies reported a direct association with incidental pain while two others found no association.High heterogeneity emerged for measures of pain intensity and with regard to pain pathophysiology  with no clear association, although four out of 11 studies reported a direct association between the presence of neuropathic pain and opioid non-response.Finally, analgesic drugs, adjuvants and other drugs were often studied as possible factors associated with non-response but contrasting results were reported.Results on predictive factors of opioid safety are shown in Table Compared to younger patients, older ones reported a lower rate of myoclonus, urinary hesitancy, dry mouth, and nausea. No notable relationship was found between gender and itch, myoclonus, nausea, urinary hesitancy and constipation nor between age and anorexia, itch, nausea, constipation, confusion, or drowsiness, whereas anorexia and dry mouth were more common in female patients and constipation, dry mouth, and hallucinations were more frequent in older patients in only one study. We found no relationship between most clinical factors  and the occurrence of adverse events although constipation was related to low glomerular filtration rate (GFR), comorbidity and terminal stage, as well as to confusion and drowsiness. The presence of neuropathic or somatic pain was related to the onset of confusion and dry mouth; while visceral pain was associated with a high frequency of dry mouth and gastrointestinal symptoms.No significant differences in side effects were observed regarding anorexia, somnolence, nausea, vomiting, constipation, dry mouth, and emesis despite high opioid doses. However, an inverse association was found between opioid dose and dry mouth, while one study reported a direct association with urinary hesitancy. One study found a direct association between the length of opioid therapy and concomitant use of more than two opioids and the onset of constipation; nevertheless, the association was denied in another study. A direct relationship was found between opioid switching, dysuria, and constipation.Validation of the Prisma checklist for the systematic review is reported in Additional file n = 6), terminally ill patients (n = 9), early discharge (n = 7), hospitalization in sterile room (n = 7), non-Italian speaking parents (n = 25).One hundred twenty-nine (75 + 54) patients met the inclusion criteria and resulted eligible for the study. Informed consent was requested from parents of 54 children but they were not included in the study for the following reasons: refusals .2 . Cancer diagnoses were mainly leukemia and lymphoma (39.08), sarcoma (20.69%) or osteosarcoma (19.54%), in 26.44% of cases with metastases, with oral cavity (49.43%) or skeletal (16.09%) pain. Patients were treated with morphine (68.97%), tramadol (21.84%), oxycodone (2.30%), codeine (2.30%) and more than one opioid (4.60%) for the achievement of pain relief. Table Table ABCB1 (ATP binding cassette subfamily B member 1), COMT (catechol-O-methyltransferase), IL6 and IL8 (interleukin 6 and 8), KCNJ6 , NR1I2 (nuclear receptor subfamily 1 group I member 2), OPRM1 , TNF-α (tumor necrosis factor α) and UGT2B7 . For SNP selection, high priority was given to those SNPs for which functional alteration data were available in the literature and the minor allele frequency is above 15% in the Caucasian population.The aim of the present study was to investigate patient’s genetic predisposing trait  to opioid responsiveness and safety profile. The investigated genes were The large inter-individual variability in response to opioid analgesia and high prevalence of adverse events associated with their use underline the clinical importance of being able to predict who will or will not respond to opioid treatment.According to our review, opioid non-response is associated with age in that older patients had a better response (inverse association). This result can be found in the majority of studies that show that elderly patients present an increased sensitivity to opioids . Indeed,We also found that patients with lung or gastrointestinal cancer had a worse response to opioid analgesia (direct association). Most surveys on cancer pain have not assessed the effect of primary diagnosis on the incidence, intensity, and treatment of cancer pain since the assessment of these effects is often complicated by the existence of multiple medical problems. The current evidence emerging mainly from studies conducted in palliative care units suggests that somatic pain is associated with lung, head and neck, breast, and prostate cancer, while visceral pain is associated with colorectal, gastric, liver, pancreatic, and uterine cancer . MoreovePatients with anxiety or sleep disturbance had a worse response (direct association). Psychological distress is often assessed by patients themselves via several health-related quality of life tools and in particular the EORTC QLQ-C30 , a test able to assess many psychological parameters, including major depression, anxiety, or hostility that can make treatment more difficult . UntreatPatients with neuropathic or breakthrough pain had a worse response (direct association). Breakthrough pain, including incidental pain, is a transient exacerbation of pain that occurs either spontaneously or in relation to a specific predictable or unpredictable trigger . NeuropaNo clear association was found between the use of other drugs and opioid non-response. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids is recommended in combination with weak or low dose opioids. Therefore, their usage may be directly linked to non-response because of poor treatment. On the other hand, proton pump inhibitors and laxatives might be prescribed to relieve adverse effects induced by high dose opioids. The use of these drugs may enhance response when concomitantly prescribed with high dose or strong opioids.While some preliminary data were available, the relationship between non-response and cancer site, presence and location of metastases, and cognition was not defined.In light of these results, we strongly suggest that future studies on cancer pain be designed with the specific aim of enhancing our understanding of opioid non-response and safety. Further information could be obtained through individual patient data meta-analysis, however it could be burdensome per se and problematic due to the low quality of original papers as well as the heterogeneity of the definition of “non-response” reported in the studies conducted up to now.Moreover, the use of morphine dose to define drug response might be questionable. In our opinion, more efforts should be made to include proper treatment response evaluations, which can assess the real decrease in pain intensity through use of validated instruments, and not only through drug dose as a proxy. Further efforts should be made to precisely and routinely measure cancer pain in the strictest and most reliable manner available. This issue could be properly approached by clinicians according to Evidence Based Medicine parameters and not, as often still happens, according to their personal beliefs, hospital tradition or to unreliable self-reporting instruments.A comprehensive and robust systematic review in accordance with Cochrane Handbook and PRISMA guidelines.Search of two electronic database and assessment of the methodological quality of the included studies.All reviewing and data extraction was carried out by one author and double-checked by a second author; two other independent reviewers discussed and resolved any disagreement.Evaluation of a broad range of risk factors contributing to clinical response and adverse drug reactions to opioids.Definition of “non-response” reported in the studies included in the systematic review was heterogeneous.In an effort to overcome the above mentioned problems, a longitudinal, nation-wide, paediatric study was planned by the Department of Neuroscience, Psychology, Drug Research and Children’s Health of the University of Florence, Italy and Anna Meyer Children’s University Hospital  entitled “STOP Pain - Suitable Treatment for Oncologic Paediatric Pain”.In particular, the study uses more than one outcome to evaluate opioid responsiveness in terms of both opioid dosage and pain intensity assessment. This point raises the challenge of selecting a proper outcome measure of pain since it is a subjective experience that might be quite difficult to quantify . In 2010Moreover, since children suffer from different types of cancer pain, the fact we did not characterize the nature of such pain  could represent another point of weakness of our study. Nevertheless, in some disease conditions, as well as in cancer, patients may have mixed pain consisting of somatic, visceral and neuropathic pain all at the same time or each separately at different times . ClinicaIn any case, planning of multicentric studies is pivotal to reach the appropriate sample size to address multiple comparison problems and capture minor genetic effects.It is our hope that the design of larger studies will consider the factors highlighted in the present work to enhance the understanding of opioid non-response and safety. And finally, we wish to underscore the necessity for studies on children in this field.Additional file 1:BMC Cancer.doc, Full Search Strategy. (DOCX 17 kb)Additional file 2:BMC Cancer.doc, Characteristics of the 74 studies included in the review. (RTF 506 kb)Additional file 3:BMC Cancer.doc, Criteria for the quality assessment of the included studies in the review. (DOCX 62 kb)Additional file 4:BMC Cancer.doc, The assessment of methodological quality for the included studies in the review. (DOC 174 kb)Additional file 5:BMC Cancer.doc, PRISMA Checklist for the current review. (DOC 58 kb)