Diagnosing and treating refractory cancer pain have become standardized and effective procedures with guidance from the Expert Consensus on Refractory Cancer Pain released in 2017 by the Committee of Rehabilitation and Palliative Care of China. Doxorubicin has been used for perineural injection in the treatment of chronic non-cancer pain owing to its retrograde sensory ganglion resection effect. Our study reports a new fourth-ladder treatment for cancer pain: CT-guided paravertebral doxorubicin injection for patients with refractory cancer pain caused by paraspinal metastasis.A 48-year-old female and a 47-year-old male patients suffered from refractory cancer pain over the past months. They had both undergone surgical tumor resection, chemotherapy, and precision radiotherapy but result in limited analgesic effect. The daily oral morphine dosage was around 60 to 100 mg and rescue analgesic methods had been used at the time.Refractory cancer pain in 2 patients with renal cancer and hepatobiliary adenocarcinoma.The patients both received computed tomography (CT)-guided 1 mL of 0.5% doxorubicin paravertebral injection at each affected nerve root segments.The Visual Analog Scale and Douleur Neuropathique four Questions were used for 6-month follow-up, and the analgesic requirement was also recorded. The patients enjoyed satisfactory analgesia for up to 6 months without adverse reaction. In addition, the oral opioid analgesic doses were significantly reduced after the neurolytic block.The CT-guided paravertebral doxorubicin injection was an effective fourth-step analgesic interventional technology that allowed our 2 patients with refractory cancer pain to maintain satisfactory analgesia. This analgesia method taken at an appropriate stage, according to the latest analgesic concept, results in good analgesia and opioid use reduction. Also, with the imaging guidance, only a small amount of neurolytic agent is needed to achieve analgesia in a precise and safe way. The fourth-step analgesia techniques include neurolytic block, patient-controlled analgesia, and implantable drug delivery systems, listed as the main methods for refractory cancer pain management. The four-step analgesic concept allows pain practitioners to skip the steps in the treatment of cancer pain, or to choose a 2-way path starting from a high step and returning back to a low step according to the pain condition.Refractory cancer pain presents diagnostic, management, and social challenges. In 2017, the Committee of Rehabilitation and Palliative Care of China published the first Expert Consensus for Refractory Cancer Pain. In this consensus, refractory cancer pain is defined as “medium or severe pain caused by cancer or other related factors during anti-cancer treatment that cannot be effectively relieved after 1 to 2 weeks of standardized medication, and/or whose treatment causes intolerable side effects”.,4 In clinical practice, doxorubicin injections are mainly used for neuropathic pain. Reports indicated that para neural injection of doxorubicin could effectively relieve pain in patients with trigeminal, intercostal, or post-herpetic neuralgias (PHN).–7 However, few reports have used doxorubicin injection as a the fourth-step analgesia method to control refractory cancer pain. In another study, we investigated 1050 patients with cancer and found that the incidence of neuropathic pain was about 36.2% among them, and it increased to 73.3% among those with pain. Postoperative nerve injury, rib or paravertebral metastases, and tumor invasion are common causes of somatic neuropathic pain in cancer patients. Therefore, we hypothesized that target doxorubicin injection can also relieve somatic neuropathic pain in those patients. In our report, 2 patients with paravertebral metastases underwent computed tomography (CT)-guided paravertebral doxorubicin injection according to the four-step analgesia model; beneficial therapeutic effects were obtained in both patients and the amount of opioid analgesics used was reduced.Doxorubicin has been used as a neurolytic agent for para neural injection based on its retrograde sensory ganglion resection effects.22.1A 48-year-old woman was admitted to our hospital for refractory cancer pain at the left side of the lower back caused by renal cancer. She was initially diagnosed as having “invasive urothelial carcinoma of the kidney” and had undergone left nephroureterectomy 1 year before. However, 6 months after the operation, she felt pain in the left lower back and a CT examination revealed a metastasis in the ipsilateral paravertebral space at T12  by CT scanning, and marked the puncture site under infrared positioning. We advanced a 22-G needle toward the target via CT guidance, and injected 1 mL of iohexol (Omnipaque) followed by negative aspiration. After confirming the contrast spread into the target intervertebral foramen, we injected 1% lidocaine in 3 mL to test the effect. The patient reported pain relief without any discomfort during the 10-minute observation period; thus, we injected 1 mL of 0.5% doxorubicin into the intervertebral foramen. We withdrew the needle while injecting a small amount of normal saline . After 10 minutes, the patient reported pain relief and we proceeded to slowly inject 1 mL of 0.5% doxorubicin into the 2 sites . The pregabalin was reduced to 150 mg/day, and the use of oxycodone was stopped. In the second month after the operation, the patient received a course of chemotherapy for the cervical lymph node metastasis. The patient felt pain again  in the right lateral position at the 4th month, and we increased the pregabalin to 300 mg/day, which effectively controlled the pain.3 and the agent can now be used as a neurolytic agent for neurotomy. In that report, the authors described the clinical use of 1% to 2% doxorubicin to treat patients with trigeminal and PHN, and the patients achieved significantly sustained pain relief and were able to go back to work. Based on the initial pain treatment experience with doxorubicin, the agent has been applied to treat conditions such as trigeminal and PHN and other chronic pains. In the early PHN treatment reports, the effective rate for the doxorubicin injection was about 67.7%, and this number has improved with the application of visualization technologies. Studies have reported significant reductions in postoperative VAS scores and increased patient-related quality of life and sleep time with paravertebral doxorubicin injections under the guidance of C-arm or CT.,11,12 For cancer pain treatment, one report showed a 0.5-mg doxorubicin injection for the brachial plexus under CT guidance resulted in pain improvement without damage to the motor function of the upper limb and neck. In our cases, we used 0.5% doxorubicin for intervertebral foramen injections in 2 patients with refractory cancer pain. Both of them reported rapid pain reduction in the target areas, and achieved the best pain belief during 2 weeks and 1 month after injection. The analgesic effects lasted up to 4 to 5 months with a decrease in analgesics usage and daily life improvement.Paravertebral doxorubicin injection for analgesia is not an experimental procedure that is commonly used in clinical practice; this technique is mainly used for patients with neuropathic pain in several pain management centers. Kato et al first reported the clinical application of doxorubicin for the treatment of neuropathic pain in the early 1990s,,15 Unlike ethanol and phenol, doxorubicin can selectively conduct neuronal degeneration through retrograde axoplasmic transport to the dorsal root ganglia after para neural injection, while the motor roots might be well preserved. After nerve injection, doxorubicin accumulates in the ganglion and preferentially localizes in the cells nuclei and nucleoli, causing neuronal destruction by inducing chromatin condensation, nuclear eccentricity, and nuclear membrane disappearance.,18 In addition, doxorubicin can also cause structural changes on the nuclear pore complex, leading to protein synthesis disorders and ultimately destroying the sensory neurons. We noted that these findings are mainly based on the in vivo results obtained from animal models; thus, we are always cautious in the application of doxorubicin injection to our patients. To avoid any possible motor impairment, doxorubicin should not be injected into motor nerves such as brachial plexus and sciatic nerve. In addition, both the thoracic and abdominal musculatures take part in respiratory movements. It is necessary to minimize the number of target segments when administering paravertebral injection. In our patients, the pain intensity and its characteristics improved significantly after paravertebral 0.5% doxorubicin injections according to VAS and DN4 evaluations, and we did not observe any motor dysfunction or other adverse reactions in our patients.Ethanol and phenol are the 2 most common neurolytic agents presently used as neurolytic blocks, and both demonstrate a non-selectively destructive effect in Wallerian degeneration.The amount of opioid used daily by a patient should not be used as a measure to decide whether the patient should receive minimally invasive analgesia; instead, the overall evaluation should confirm the presence of refractory cancer pain. According to the latest expert consensus, the diagnosis can be made when the following criteria are met:1)pain scores remain ≥ 4 points and/or breakthrough pain occurs ≥ 3 times/day;2)the pain cannot be relieved after 1 to 2 weeks of guideline recommend opioids and/or adjuvant analgesic treatment, and/or the treatments are causing intolerable side effects.We diagnosed the 2 patients in our report as presenting refractory cancer pain before simply increasing the opioids doses. Following these recommendations, the refractory cancer pain can be detected early, and minimally invasive analgesia should be introduced, especially when conventional analgesia strategies fail to reach satisfactory outcomes. In our report, the prognosis was favorable and the pain in patients was alleviated after they were administered paravertebral injection. Thus, they no longer needed any opioids during the following months. In addition, some patients are unable to tolerate opioid-related adverse effects  and are forced to suspend the medication, resulting in inadequate analgesia. These situations prompted the advanced fourth-step on the World Health Organization analgesic ladder, which includes mainly interventional therapies. In patients with refractory cancer pain, guidelines recommend the application of fourth-step intervention approaches, including epidural infusion, nerve block, neurolytic blockade, radiotherapy, and surgery.,24 However, the indication for intervention approaches is unclear and varies in different clinical practices due to lacking definitions and diagnostic criteria for refractory cancer pain. Therefore, some patients are not optimally treated. The Expert Consensus on Refractory Cancer Pain, which regulates the diagnosis and treatment of refractory cancer pain, has reduced the magnitude of this problem. In our patients, we detected the refractory cancer pain after 1 to 2 weeks of failed attempted opioid rotation by guideline criteria in both cases, so we applied the neurolytic techniques early, which resulted in favorable analgesic effects. We did not conduct a controlled study for the paravertebral cancer pain because of less number of cases and ethical considerations, which are inevitably limitations of this report. In addition, the anti-tumor therapy and tumor progression during the perioperative period may also affect the evaluation of the analgesic effect of doxorubicin injection, which may be worthy of further study in refractory cancer pain management.Interventional pain management approaches have been important components of multimodal analgesia, and the timing of interventional treatment is a key factor for prognosis. Approximately 20% of patients with cancer pain fail to achieve significant relief from the three-step analgesic ladder.Conceptualization: Jie Tian, Kexian Zhang.Resources: Qing Zhong.Writing – original draft: Fan Lu.Writing – review & editing: Jie Tian, Kexian Zhang.


To investigate the effect of intravenous regional anesthesia with single-cuff forearm tourniquet and hematoma block on intraoperative and postoperative pain intensity of patients with distal radial bone fracture.-1 lidocaine (D group) or a single-cuff forearm tourniquet intravenous regional anesthesia with 1.5 mg.kg-1 lidocaine and a hematoma block with 10 mL 0.5% bupivacaine (S group). Pain intensity score of numerical rating scale (NRS) was measured hourly for 6 hours, then every two hours till 12th hour and every 4 hours until 24th postoperative hour. Total morphine consumption in the first 24 hours after surgery, its side effects and the patients’ global satisfaction were assessed in each group.In this randomized clinical trial, a total number of 52 patients with distal radius fractures were randomly assigned to receive either a traditional Bier block with 3 mg.kgp=0.13). Pain intensity score of NRS both during recovery room and surgical ward stay was less in S group compared to D group .Mean total morphine consumption during the first 24 hours after surgery was 11.68±7.88 mg in group D and 7.12±4.42 mg in group S (Intravenous regional anesthesia with single cuff forearm tourniquet and hematoma block compared to the traditional Bier block reduced intraoperative and postoperative pain intensity more effectively in patients with distal fracture of the radius bone and also reduced morphine consumption during the first 24 hours after surgery. According to the American Society of Anesthesiologists practice guideline, over 80% of patients who undergo surgical procedures experience acute postoperative pain and around 75% of those with postoperative pain report the severity as moderate, severe, or extreme. The advantages of optimal pain management are well recognized. Nevertheless, treatment of postoperative pain keeps on being a major challenge and deficient postoperative pain relief remains disturbingly frequent . SeveralStudies have argued whether this kind of fracture should be treated by conservative or operative methods. Choosing a management method depends on many factors, however closed reduction and percutaneous pinning is one of the most common surgical techniques. By the guidance of radiological imaging this procedure can be accomplished either under general or regional anesthesia. Bier block, a frequently used regional technique, is effective, safe and reliable, with minimal reported complications. However, limited time of tourniquet tolerance by patients and the rapid onset of postoperative pain shortly after tourniquet deflation can be considered as disadvantages of this anesthetic technique . An ideaIn this study, we decided to investigate if this dose reduction can provide the possibility of applying a second regional block for postoperative pain relieve in patients with distal radius fracture, using this modification of intravenous regional anesthesia (Bier block with a forearm tourniquet), combined with another regional technique namely, hematoma block. The aim of this study was to determine the effect of hematoma block  combined with Bier block in intraoperative and postoperative analgesia of distal radius fracture fixation surgery. Study population G6PD) deficiency, history of uncontrolled convulsion, local infection or open wound in the affected upper limb, chronic use of pain-killers or opioid dependency, patient refusal, kidney or liver insufficiencies, inability to learn pain numerical rating scale or PCA pump usage, very obese or very lean patients (BMI less than 18.5 or more than 30) and history of hypersensitivity to the study drugs. This study was a parallel, double-blind, randomized controlled clinical trial with trial registry number of IRCT201604223213N4, in which 52 patients aged 18 to 70 years, with ASA 1 or 2 and candidates of closed reduction and percutaneous pinning of distal radius fracture were enrolled. The patients were selected from those who referred to Shahid Chamran Hospital, affiliated with Shiraz University of Medical Sciences in Shiraz, Iran. The study was approved by ethical committee of the university and written consent was obtained from participants (IR.SUMS.Med.RED.1394.91). Exclusion criteria were peripheral neuropathy (e.g. caused by diabetes), sickle cell anemia, peripheral vascular disease like Raynaud's disease, glucose-6-phosphate dehydrogenase  pump and to response numerical rating scale (NRS) pain assessment tool in which zero indicated no pain and 10 the worst pain one can imagine. After establishment of the standard monitoring devices  and an intravenous line in patient’s intact hand, a distal vein at injured limb was also cannulated by a 22-gauge angiocatheter. Follow-up and outcome measurement Pain intensity score of NRS during initial traction for reduction of radial bone was evaluated and recorded. Time to first patients complain of tourniquet pain (initiated from the inflation time) was also recorded. Any time during operation, if patient reported a pain intensity of more than 4 , a 50 µg bolus dose of fentanyl was intravenously administered. If pain persisted, the same fentanyl doses would be repeated up to 3 µg.kg-1 or until patient’s respiratory rate dropped to less than 10 breaths/min. Unless this measure could relieve patient’s pain, general anesthesia would be induced and participant was excluded from the study citing the cause. At the end of surgery, tourniquet inflation time was recorded and the patient was transferred to the recovery room. Time to first request of patient for analgesic (beginning from tourniquet release) was measured and recorded. In recovery room, severity of pain was assessed and reported using NRS scale every 15 minutes. If the value was between 4 to 7, one mg morphine sulfate would be injected intravenously every 5 minutes, while patient’s vital signs were monitored. NRS score of 8 or more was treated by 2 mg morphine, bolus doses every 5 minute until it dropped below 8 in which case it was managed like the previous situation, until the pain intensity diminished to less than 4. The total dose of morphine administered in recovery room was recorded. During the recovery room stay, any signs or symptoms related to systemic toxicity of local anesthetic medication  was assessed and recorded. After patient transferred to surgical ward, a PCA pump loaded with a 20 ml syringe containing 0.5 mg/mL morphine solution prepared and connected to patient’s intravenous (IV) line. The pump setup was as bolus dose of 2 mL (1 mg morphine), lockout interval of 7 minutes, 4 hours’ limitation of 60 ml (30 mg morphine) and without any baseline infusion. During first 24 hours after surgical procedure, the patient’s pain was evaluated hourly for 6 hours, then every 2 hours for next 6 hours and every 4 hours; thereafter by means of NRS. The morphine side effects  were sought and recorded every 4 hours. Any time during these predetermined visits or between them, if patient experienced a pain with severity of more than 4, this was treated as mentioned for dealing pain in recovery room. The total amount of morphine consumed (the amount of drug administered through the pump plus extra doses injected by pain nurses) in the first postoperative 24 hours was calculated and recorded. Finally, overall patient’s satisfaction regarding intra- and post-operative pain control was evaluated with a 5-point scale . Statistical analysis Sample size was calculated based on the results of a pilot study in which 20 patients were randomly allocated in two limbs of the study. Analysis of the collected data showed results to be statistically significant with α=0.05 and β=0.80, and to recruit a total number of 28 patients (14 subjects in each group). To increase the power of the study and to compensate for any possible dropouts, 52 patients were included. To determine the normality of quantitative data, Kolmogorov-Smirnov test was used and quantitative data such as age with normal distribution were compared with Student t-test. Variables without normal distribution such as pain intensity during bone traction and reduction, the onset of tourniquet pain, the amount of fentanyl and morphine required, and the first time each patient asked for pain-killer medication were compared between the two groups with Mann-Whitney U test. Qualitative variables including sex, complication of drugs and patient’s satisfaction were analyzed by Chi-square test. ANOVA repeated measurement test was used to compare the mean pain intensity values of NRS and total amount of morphine between and within two groups and also was used to analyze the interaction between time and group. Data analysis was performed by SPSS software . The significance level was considered less than 0.05. The present study was performed on 52 patients with distal radius fracture scheduled for closed reduction and percutaneous pinning. Overall, 45 patients completed the study, 20 patients in group D and 25 patients in group S (p=0.002). The median value of morphine injected in recovery room was 4 mg (IQR=2-5) for group D, and 0.5 mg (IQR=0–2) in group S (p<0.0001). p=0.016). The difference was also significant considering the effect of time (p=0.001) and also interaction between time and groups (p=0.004). One patient in group D was excluded because of unawareness of recovery room staff of the study protocol, which meperidine instead of morphine was prescribed. The changes in pain intensity of NRS in recovery room have been illustrated in p=0.02). The effect of time in each group in consecutive measurements was significant (p=0.001). However, the interaction between time and group was not significant (p=0.3).p=0.013). p=0.42).Mean values (±SD) of totally administered morphine during the first 24 hours after operation, including recovery bolus doses, the amount injected by PCA pump plus the doses administered by nurse staffs compared with independent t-test was 11.68±7.88 mg in group D and 4.7±42.12 mg in group S  . Abdel-g’s study , 13. Hon’s study . Although the sample size was small, there was no report of systemic toxicity of local anesthetic drugs and also that of morphine sulfate in the present study. So it seems that the major limitations of the study were first the sample size which could not address the drug complications and second, the ill-designed method of the patients’ blindness, since they could feel the location of the upper extremity tourniquets.In conclusion, the results of the current study indicates that using hematoma block in combination with single cuff forearm tourniquet in intravenous regional anesthesia could be effectively used in closed fixation of distal radial bone fractures with more prolonged postoperative pain alleviation and less rescue pain-killer medication request. Therefore, the technique could be suggested in situations in which there is a concern about the risk of using concomitant drugs for relief of postoperative pain like obstructive sleep apnea (OSA) or hypersensitivity to sedative effects of opioids. None declared.


External Beam Radiotherapy (EBRT) allows remarkable pain control in patients with skeletal metastases. We performed a Bayesian network meta-analysis comparing the most commonly used radiotherapy regimens for palliative management in patients with skeletal metastases. The main online databases were accessed in October 2020. All randomized clinical trials evaluating the irradiation of painful bone metastases were considered. The following irradiation patterns were analysed and included in the present network meta-analysis: 8 Gy- and 10 Gy/single fraction, 20 Gy/5 fractions, 30 Gy/10 fractions. The Bayesian hierarchical random-effect model analysis was adopted in all comparisons. The Log Odds-Ratio (LOR) statistical method for dichotomic data was adopted for analysis. Data from 3595 patients were analysed. The mean follow-up was 9.5 (1 to 28) months. The cumulative mean age was 63.3 ± 2.9. 40.61% (1461 of 3595 patients) were female. The 8Gy/single fraction protocol detected reduced rate of “no pain response” (LOR 3.39), greater rate of “pain response” (LOR-5.88) and complete pain remission (LOR-7.05) compared to the other dose patterns. The 8Gy group detected a lower rate of pathological fractures (LOR 1.16), spinal cord compression (LOR 1.31) and re-irradiation (LOR 2.97) compared to the other dose patterns. Palliative 8Gy/single fraction radiotherapy for skeletal metastases shows outstanding results in terms of pain control, re-irradiations, pathological fractures and spinal cord compression, with no differences in terms of survivorship compared to the other multiple dose patterns.Level of evidence: I, Bayesian network meta-analysis of RCTs. Metastatic disease is a common source of bone pain . Bone meP (population): skeletal metastases;I (intervention): palliative radiotherapy;vs 20Gy vs 30Gy;C (comparison): 8Gy O (outcomes): pain scores and medications, further therapies, side effects, survivorship.The present Bayesian network meta-analysis was performed according to the PRISMA extension statement for reporting of systematic reviews incorporating network meta-analysis of health care interventions . To guidTwo authors  independently performed the literature search in October 2020. The databases accessed were Pubmed, Google Scholar, Scopus. The following keywords were used alone and in combination: metastasis, skeletal, bone, radiotherapy, irradiation, Gray, survivorship, pain, treatment, fractures, spinal cord compression, cancer, 8Gy, 20Gy, 30Gy. The same authors independently screened the resulting articles. If title and subsequent abstract matched the topic, the full-text article was accessed. The bibliographies of the studies of interest were also reviewed by hand.All randomized clinical trials evaluating irradiation of painful bone metastases were considered for analysis. Only articles of level I evidence according to the Oxford Centre of Evidenced-Based Medicine  were incTwo authors  independently extracted data from the included articles. The following variables were collected: author and year of publication, follow-up duration, number of treated patients and respective mean age and gender. Furthermore, the inclusion and exclusion criteria were reported along with the site of the primary tumour and localization of metastases. Concerning the treatment, we collected data regarding irradiation site and doses, pre- and post-treatment pain scores and medication, further therapies, side effects and survivorship.The statistical analysis was performed by the main author (FM). To analyse patient baseline comparability, the analysis of variance (ANOVA) test was performed, with values of P > 0.1 considered satisfactory. The endpoint pain medication consumption relates to the percentage of patients using that drug. For analytical statistics, the STATA Software/MP  was used. The Bayesian hierarchical random-effect model analysis was adopted in all comparisons. A reference value was set in all comparisons. The Log Odds-Ratio (LOR) and standard error (SE) statistical method for dichotomic data was adopted for analysis. The edge plot was performed to evaluate contribution of direct and indirect comparisons among the networks. To verify transitivity among studies, the overall inconsistency was evaluated through the equation for global linearity via the Wald test. Values of P > 0.05 could not reject the null hypothesis, and the consistency assumption could be accepted at the overall level of each treatment. The overall estimated effect of the comparisons and ranking for each endpoint was evaluated through the interval plot. Both the confidence interval (CI) and percentile interval (PrI) was set at 95%. Funnel plots were performed to evaluate the risk of publication bias among the studies.The literature search resulted in 188 publications, of which 41 were duplicates. A further 82 articles were excluded because not matching the eligibility criteria: not randomized trial or poor level of evidence (45); concerning different doses or fractionations and radiotherapeutic protocols (23); language limitation (1), uncertain results (3), other (10). Another 45 articles were rejected for not reporting quantitative data under the outcomes of interest. Finally, 15 randomized clinical trials were eligible for analysis in the present study  months. The cumulative mean age was 63.3 ± 2.9. 40.61% (1461 of 3595 patients) were female. The ANOVA test evidenced no differences regarding age or sex of patients among the studies at baseline (P > 0.5). Demographic data are shown in Table  to 28 moPain medication consumption was not analysed in the 20Gy group because of lack of quantitative data. Administration of pain medication was notably reduced post-treatment in the 8Gy and 30Gy groups. No administration of pain medication improved to + 19.50% and + 21.83% in the 8Gy and 30Gy groups, respectively, while the use of nonsteroidal anti-inflammatory drugs (NSAID) was reduced to − 13.92% and − 8.65%. Overall consumption of weak narcotics was reduced to − 3.33% and − 8.50% in the 8Gy and 30Gy groups, respectively. The intake of strong narcotics was reduced to − 18.25% in the 8Gy group, while in the 30Gy group an increase to +3.80% was detected during last follow-up. The mean survival was 7.93 ± 1.87 months in the 8Gy group, 6.65 ± 2.62 months in the 20Gy group, and 8.71 ± 0.8 months in the 30Gy treatment group. Pain medication consumption and survivorship are shown in Table The endpoint “no pain response” scored lower in the 8Gy group . The endpoint “complete pain remission” scored better in the 8Gy group . The 8Gy group demonstrated a better pain response to the therapy . The equation for global linearity via the Wald test detected no statically significant inconsistency (P > 0.5). Results of the network comparisons concerning pain control are shown in Fig. The 8Gy group showed a lower rate of pathological fractures compared to the other groups . In the 8Gy group there was a significant lower rate of spinal cord compression compared to the other groups . In terms of reduced re-irradiation, the the 8Gy group detected reduced rate compared to the other cohorts . The equation for global linearity via the Wald test detected no statically significant inconsistency (P > 0.5). Results of the network comparisons concerning complications are shown in Fig. This Bayesian network meta-analysis showed that a single dose of 8Gy/one fraction radiation therapy is superior to multiple doses (20Gy and 30Gy) in terms of palliative control of pain in patients with skeletal metastases. Further, the 8Gy/one fraction protocol showed lower rate re-irradiation and complications, such as spinal cord compression and fractures. No differences in survivorship between the different dose patterns was detected.The palliative 8Gy radiotherapy group performed better overall. Administration of pain medication was significantly lower in the 8Gy group compared to the 30Gy group. The network analysis reported a statistically significant lower risk of pathological fracture and spinal cord compression in the 8Gy group compared to the 20Gy and 30Gy groups. Partial and overall pain recurrence were remarkably lower in the 8Gy group compared to both 20Gy and 30Gy groups. Furthermore, the 8Gy group reported the lowest rate of non-response among patients. Concerning the endpoint of re-irradiation, no statistical significance was detected between the regimens studied in the present report. Of note, one single fractionation of radiation offers greater patient and caregiver convenience.seed-and-soil theory hypothesize that, given several cytokines and growth factors, bone tissue (the soil) can provide an optimal field for the metastases (the seed) [The he seed) . The prohe seed) , 21. Thihe seed) , 22. Bonhe seed) . Howeverhe seed) . Bisphoshe seed) . Bisphoshe seed) , 27. Bishe seed) , non-smahe seed) , 30. Thehe seed) . Denosumhe seed) . Furtherhe seed) . Howeverhe seed) . Externahe seed) . Chow ethe seed)  reportedhe seed) . Intereshe seed) . Radiatihe seed)  found a Regarding surgical intervention, an impending or frank pathological fracture from bone metastases is a classical indication for internal fixation. Surgery is also indicated when metastases cause spinal cord involvement or peripheral nerve compression. Two retrospective cohort studies evaluated the outcome of prophylactic surgical fixation of impending fractures , 37. FixMajor points of strength of this Bayesian network meta-analysis are the comprehensive nature of the literature search and the strict eligibility criteria for study inclusion. Several different palliative fractionation schedules and doses  have been described . Lack ofPalliative 8Gy/single fraction radiotherapy for skeletal metastases showed superior results compared to the other regimens. Consumption of pain medication was notably lower in the 8Gy group compared to the 30Gy group. The 8Gy/single fraction demonstrated superiority to the other multiple dose patterns (20Gy and 30Gy) in controlling pain. Pathological fractures and spinal cord compressions occurred significantly less often in the 8Gy group compared to 20Gy and 30Gy groups, along with a reduce rate of re-irradiation. Furthermore, the 8Gy group reported the lowest rate of non-response among patients. No differences in survivorship among the dose patterns was detected.


Chronic unspecific back pain (cBP) is often associated with depressive symptoms, negative body perception, and abnormal interoception. Given the general failure of surgery in cBP, treatment guidelines focus on conservative therapies. Neurophysiological evidence indicates that C-tactile fibers associated with the oxytonergic system can be activated by slow superficial stroking of the skin in the back, shoulder, neck, and dorsal limb areas. We hypothesize that, through recruitment of C-tactile fibers, psycho-regulatory massage therapy (PRMT) can reduce pain in patients with cBP. In our study, 66 patients were randomized to PRMT or CMT  over a 12-week period and tested by questionnaires regarding pain , depression (BDI-II = Beck depression inventory), and disability (ODI = Oswestry Disability Index). In all outcome measures, patients receiving PRMT improved significantly more than did those receiving CMT. The mean values of the HSAL sensory subscale decreased by −51.5% in the PRMT group compared to −6.7% in the CMT group. Depressive symptoms were reduced by −55.69% (PRMT) and −3.1% (CMT), respectively. The results suggest that the superiority of PRMT over CMT may rely on its ability to activate the C-tactile fibers of superficial skin layers, recruiting the oxytonergic system. Chronic back pain (cBP) has a leading position worldwide in disease-related disability and loss of quality of life . It reprIn the 1980s, Groddek and Dogs integrated massage therapy as a form of body therapy into the treatment of chronic pain to gain direct access to the patient’s emotions via their skin and its nervous system, thus facilitating positive body perception and cognitive-behavioral treatment ,16. BergBased on these considerations, we hypothesize that pain experience and depressive symptoms can be reduced and physical capacity can be improved by gentle massage that is optimized to activate C-tactile skin afferents. The aim of this study is to examine the effect of both classical and psycho-regulatory massage in patients with cBP on pain experience, depressive symptoms, and physical capacity. The study was conducted as a double-blind RCT. The study is registered in the German Registry for Clinical Studies (DRKS00006876), and the protocol was approved by the ethics committee of the University of Halle , Germany (Nr. 2014-22). The eligibility criteria and baseline data were assessed prior to randomization. The inclusion and exclusion criteria can be found in Clear diagnosis of chronic pain is difficult, since 90% of the diagnoses do not reveal any apparent clinical findings ,31; thusn = 16 did not meet eligibility criteria, n = 3 stated that the number of interventions was too high, n = 11 were not comfortable with the nudity required for massage therapy, n = 8 found that the questionnaires were too complicated, and n = 3 did not want to use massage oil. Overall, n = 66 patients were randomized into either the intervention or control group using hidden lots covered in envelopes. One patient was excluded prior to the first treatment due to acute illness; 61 patients completed the treatment. Two patients in each treatment group discontinued the treatments without giving any reason . The design of effect parameters differed between the intervention and control groups in terms of pressure, speed, direction, and rhythm [Interventions took place in the physiotherapy practice operated by the principle investigator (SB). The outpatient setting was chosen to maximize external validity. The intervention group received psycho-regulatory massage therapy (PRMT) and the control group received classical massage therapy (CMT). Patients were blinded towards the type of massage they received. However, they were aware of the study’s aim to compare the two types of massage. Data analysis was blind towards a patient’s treatment method. All therapists employed in the practice participated in the study , a multi-dimensional questionnaire for pain experience in adults with acute or chronic pain. The HSAL consists of 37 adjectives, 21 of those describing the affective experience of pain (pain suffering + pain anxiety) and 16 describing the sensory experience of pain (pain rhythm + pain acuity). Each item can be answered on a scale from 0  to 6 (completely correct), and the answers are added up to create a total score  . The HSA0–8no depression;9–13minimal depression;14–19mild depression;20–28moderate depression;29–63severe depression .Depressiveness was measured using the Beck Depression Inventory (BDI-II), scaling 0–3 for each item; the maximum overall score is 63 points ,40. The The clinical relevance of the respective changes in depression was assessed according to the criteria of Hiroe et al. . Accordi0–2minimal disability  are mostly possible, often no therapy necessary, activation of life is enough);21–40moderate disability ;41–60severe disability ;61–80crippled ;81–100bedridden or the patient exaggerates ,48.Quality of life was measured using the Oswestry Disability Index (ODI), a self-rating questionnaire about disability in patients with back pain . The quen = 33. Block randomization was carried out with a block size of 10 by an independent statistician from University of Halle, Saale (Germany).For sample size calculation on the basis of overall pain experience as the primary outcome, alpha was set to 5%, statistical power should be at least 90% (SD 2.0), and the drop-out rate was expected to be 20%, resulting in a group size of p-values below 0.05. To test the effect of sessions, we applied the Friedmann ANOVA test separately for CMT and PRMT. In case of significance, we used the Wilcoxon test for paired samples. According to the total of six comparisons, we used Bonferroni correction, resulting in a p-value of 0.008 as the threshold for significance.Given the ordinal data type of all questionnaires ) that were, in at least one session, not normally distributed, as tested with the Kolmogorov–Smirnov test, we applied the Wilcoxon rank-sum test for two independent samples to analyze group differences (CMT vs. PRMT) at baseline (T0) and to test the magnitude of change from baseline to the T1, T2, and T3 time points . A significant difference (two-tailed test) was accepted at The results of the non-parametric comparison using the Wilcoxon rank-sum test for two independent samples are summarized in p = 0.56), weak significance for HSAL-Affective that failed to reach the significance criterion in any of the six comparisons, and an absence of significance for HSAL-Sensory (p = 0.127). In contrast, all HSAL parameters were statistically significant for the effect of treatment session in PRMT (p < 0.001). Post hoc Wilcoxon testing revealed significant decreases in all HSAL parameters for comparisons T3 vs. T0, T4 vs. T0, T3 vs. T2, and T4 vs. T2 .HSAL total, affective, and sensory scores for pain: The total scores and the affective and sensory subscores of HSAL were significantly smaller in the T2 and T3 sessions in the PRMT group compared to the CMT group. No difference appeared in session T1. The Friedmann ANOVA yielded a non-significant effect of treatment session for CMT in HSAL-Total (p = 0.03); however, no post hoc comparison reached the Bonferroni-corrected threshold criterion. In contrast, PRMT had a significant effect of session with statistically significant post hoc Wilcoxon testing in all six comparisons (p < 0.001): T0 vs. T1, T0 vs. T2, T0 vs. T3, T1 vs. T2, T1 vs. T3, and T2 vs. T3. Thus, the BDI-II score continuously decreased over the three months of treatment. Overall, the severity of depression decreased by 55.69% with PRMT, from a moderate to minimal level of severity on average [BDI-II score for depression: PRMT reduced the intensity of depression more than CMT already during T1, but more strongly during sessions T2 and T3. The Friedman ANOVA resulted in a significant session effect in CMT ( average . Under Cp = 0.56). In contrast, there was a significant change in ODI (%) by PRMT (p < 0.001) with significant post hoc differences in all comparisons, except for T3 vs. T2. ODI (%) score for disability: The progression of improvement in functional status achieved by PRMT in comparison to CMT is quite similar to that for depression. A weak, yet significantly better improvement in PRMT than in CMT occurred in T1, but much greater treatment differences appeared in T2 and T3. The Friedmann ANOVA showed non-significant change by CMT (The primary aim of this study was to examine the effect of two forms of massage therapy in patients with chronic back pain (cBP). According to the general consensus about pain as a multidimensional experience ,50 pain Models from neuro-biological research might explain the positive effects of massage and the role of their specific techniques. Studies using microneurography have indicated the existence of low-threshold slowly conducting C-fibers in superficial skin layers that are predominantly activated by soft and low-velocity (3 cm/s) stroking stimuli . In contBoehme et al. compared patients suffering from fibromyalgia with healthy controls by using functional magnetic resonance imaging (fMRI) imaging of brain activity in response to selective C-tactile stimuli and additionally analyzed the voxel-based morphometry in areas of the limbic cortex . They obCraig  and DevuSeveral studies have shown an interaction of C-tactile afferents with the oxytonergic system in reducing pain and improving body perception ,54,55. PThe results on depression severity in our study, as measured by the BDI-II questionnaire, lend further strong support for the importance of C-tactile stimulation underlying the superior efficacy of PRMT over CMT. In the PRMT group, improvements on the BDI-II correspond to a moderate clinical effect . In contThere are limitations of our study. Since this study was conducted in the outpatient setting of a physiotherapy practice, the level of treatment standardization was low. Factors such as the patient’s daily routine; sleep, waking, and eating rhythm; and time of intervention were not standardized to increase external validity. Treatment prescription was done by private orthopedic surgeons and general practitioners using the ICD-10 codes M54 and F45, which qualified the patients for study inclusion. There might have been variability among doctors in the use of these diagnoses. Yet, no patient had indication of specific back diseases causing their pain. Use of the term “somatoform” might be debatable, and it differs between the DSM  and ICD classifications. During the update to DSM-5, the class of “somatoform disorders” was changed to “somatic symptom disorder”, whereas the term is still used in the ICD-10. Furthermore, patients were allowed to use their pain medication as usual and receive other therapies, introducing a certain risk of bias to our results. Future studies could examine how the use of analgesics can be reduced by PRMT. Standard regulations of health care insurances allow 20 to 30 min of treatment duration for CMT, but 60 min for PRMT, because the latter involves a whole-body massage. Thus, longer treatment sessions might have contributed to the superiority of PRMT over CMT. The follow-up period of our study was three months, to increase comparability with other studies . HoweverOur results indicate that psycho-regulatory massage therapy (PRMT) is more effective than classical massage therapy (CMT) in reducing pain and depression and enhancing physical capacity and activity in patients suffering from chronic unspecific back pain. Unlike CMT, PRMT characterizes a massage technique by which the therapist applies soft and slow strokes upon the skin of the back, neck, shoulders, and upper arms that specifically activate C-tactile fibers. Future studies should examine the importance of individual differences of co-morbidity with depression in patients suffering from chronic unspecific back pain for the superiority of PRMT over CMT. This knowledge would improve the selection of individualized physical therapy options for these patients.


To compare intra-articular (IA) knee injections of a cross-linked high-molecular-weight hyaluronic acid (HMW-HA) with a linear low-molecular weight HA (LMW-HA) in terms of pain and functional improvement among knee osteoarthritis (OA) patients.In this single-blinded RCT, the patients were randomly divided into two groups for HA injections. The first group received an HMW-HA (Arthromac) injection, while the other received three weekly LMW-HA  injections. Pain and function were assessed using the outcome measures including WOMAC, Lequesne and VAS indices, once prior to injection, as well as 2 and 6 months after injections.p < 0.001). There was no significant superiority between the two therapeutic protocols according to our outcome measures at any time-point of follow-up. The only except was about the improvement in WOMAC stiffness subscale that was significantly higher in LMW-HA group compared to HMW-HA (p = 0.021). Moreover, no significant difference was observed in minor complications and injection-induced pain scores between the two groups.A total of 90 patients were included. There was no significant difference in baseline characteristics including age and sex between the two groups. Our analysis showed that total WOMAC, Lequesne and VAS mean scores remarkably improved at both follow-up time-points compared to the baseline measurements (This study proved that a single HMW-HA injection is as effective as multiple injections of LMW-HA counterparts in periods of 2 and 6 months follow-up.www.irct.ir) with the trial registration number IRCT20130523013442N24 and registration date 2018-07-13.This study protocol was registered in Iranian database of RCTs (IRCT;  Osteoarthritis (OA) has been known to be the most common articular disease . The preTreatments of knee are not considered to be a disease-modifying therapy . medicatHA plays a role in traumatic energy dissipation and lubrication . IA-HA iDifferences exist in concentration, molecular weight, source of HA , dosage , expected duration of effects, cross linkage and added formulations . Based oThe aim of current trial was to compare the efficacy and safety of the single cross-linked HMW injection versus triple injection of low-molecular-weight IA-HA among knee OA patients in terms of function and pain improvement during a six-month period.2, mal-alignment as genu varum or valgum greater than 20°, any knee trauma or intra-articular injection during the last 6 months, prior hypersensitivity reaction to avian products or egg protein.In this RCT 90 patients aged between 45 and 75 years suffering from knee OA symptoms lasting for at least 3 months were included. Knee OA was classified according to Kellgren and Laurence score (KLS) . Only suwww.irct.ir) with the trial registration number IRCT20130523013442N24 and registration date 2018-07-13. Besides, the Ethics Committee of Shahid Beheshti University of Medical Sciences was in charge of approving this study (No: IR.SBMU.MSP.REC.1396.899). A written informed consent was obtained; moreover, a physiatrist described the methodology, probable advantages and disadvantages of HA injections for every participant.This study protocol was also registered in Iranian database of RCTs  was administered as a single intra-articular knee injection for 44 participants. HMW-HA solution was provided in a 3 mL prefilled syringe . In the second group, 46 subjects received a low-molecular weight HA (molecular weight 500–730 kDa)  as three weekly sessions of IA injection. LMW-HA was provided in a 2 mL prefilled syringe . All injection were performed by an expert physiatrist who had 15 years of experience in intra articular injections. The physician who injected HAs was not blinded. Rather, the assessor physicians who were three senior residents remained unaware to patients’ group till the end.Our patients did not receive any anti-inflammatory or analgesic agents since 2 weeks before the first injection known as washout period. Prior to injection, routine skin cleansing with the aid of povidone-iodine was performed. Twenty-two gauge (22G) needles through lateral midpatellar approach for knee intra-articular injections were used to administer HMW-HA and LMW-HA in a sterile manner. Upon completion of injections, the participants were requested to flex and extend their knees 10 times. Next, the patients of both groups rested briefly, after which they were given a written protocol of exercises and recommendations to be performed at home. A period of 24–48 h rest along with 20-mintue cold therapy 3 times a day and restricted weight-bearing over knee joints were strongly suggested. The exercise therapy protocol comprised of isometric strengthening workouts that gradually progressed to closed-chain isotonic exercises. Hamstring stretching and muscles strengthening  were executed three times a day, each time lasting 15 s and repeating 5 times. All patients were followed-up for 8 and 24 weeks after the therapy using visual analog scale (VAS), Lequesne index, and Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire. VAS, WOMAC, and Lequesne indices were employed to investigate the patients’ function and pain at three time-points; once at the baseline and two other times at the 2nd and 6th month after the injections –41. MoreP < 0.05.Final data before and after the treatment were imported and analyzed in SPSS v.22. Normality of the data was evaluated using Shapiro–Wilk’s test. Qualitative variables were expressed as frequency and percent. Chi square test was applied to analyze the differences of these qualitative parameters between the two groups. Also, the paired t-test and independent t-test were used to compare mean values within and between the two groups, respectively. In case of non-parametric data, we utilized Friedman and Mann-Whitney U tests, respectively. Statistical significance value was set at Among 158 patients with knee OA as candidates for IA-HA injection, 68 patients were excluded from the study. Ninety subjects who met our criteria were randomized to the HMW-HA (44 patients) and LMW-HA (46 patients) groups and received IA-HA in a manner demonstrated in Fig. p < 0.001). there was no significant difference between the LMW-HA and the HMW-HA groups based on three subscales of Lequesne index. Our analysis revealed a similar pattern in VAS mean values. In WOMAC subscale there was no superiority between two groups with one exception in WOMAC stiffness subscale at 2 months follow-up (Table P = 0.021). Furthermore, success rates [defined as ≥30% decrease from baseline scores in WOMAC, Lequesne and VAS have been presented in Table Changes in WOMAC, Lequesne index and VAS mean values in each group have been demonstrated in Table up Table . When coP = 0.378). The mean value of injection-induced pain was 2.64 and 1.9 in HMW-HA and LMW-HA groups, respectively (P = 0.286). Fortunately, no systemic adverse event or major complication such as septic arthritis was reported in the present RCT.Eventually, the frequency of minor complications and injection-induced pain have also been showed in Table Based on results of this study clinical improvement with a single cross-linked HMW-HA injection could be relatively equal to that of triple injection of a linear LMW-HA, within the periods of two and 6 months follow-up. Moreover, a comparison between the two groups indicates that there exists no statistically significant superiority. An exception was the improvement of WOMAC stiffness subscale which was significantly higher in LMW-HA group in 2 months.Altman  review wSimilarly, Diracoglu et al.  evaluateAnother study by Estades-Rubio et al. , evaluatIn the meta-analysis conducted by Concoff et al. , the effIn our study, the rate of minor complications and injection-induced pain was not statistically different between two HA products. In Bannuru’s meta-analysis , none ofAn advantage of this research is employing various outcome measures for evaluating patients’ symptoms including WOMAC subscales, Lequesne and VAS indices. The washout period was considered in this study. The fact that the physician was not blind in this study, is an important limitation. Due to ethical issues, it was not possible to do second and third sham injections in HMW-HA group. Rather, all assessors in this study were completely blinded. It would be better to enroll a higher number of patients in the future studies. Although our follow-up was for 6 months, yet longer follow-up time can be suggested. As the last limitation to be mentioned, no economic analysis was conducted in our trial.Both HMW IA-HA and LMW IA-HA caused significant functional improvement and pain relief; however, there was no significant difference between HMW IA-HA versus three weekly LMW IA-HA in terms of pain relief and function improvement in knee osteoarthritis patients in 6 months of follow-ups. This study revealed that a single HMW-HA injection is as effective as multiple injections of LMW-HA counterparts in periods of 2 and 6 months. Further research into the subject probably sheds lights on choosing the more suited protocol of HA injections.Additional file 1. CONSORT 2010 checklist.


Pain is a frequent, yet inadequately explored challenge in patients with systemic sclerosis (SSc). This study aimed to conduct an extensive pain assessment, examining pain chronification and its association with disease manifestations.Consecutive SSc patients attending their annual assessment were included. SSc-specific features were addressed as defined by the European Scleroderma Trials and Research (EUSTAR) guidelines. Pain analysis included intensity, localization, treatment, chronification grade according to the Mainz Pain Staging System (MPSS), general well-being using the Marburg questionnaire on habitual health findings (MFHW) and symptoms of anxiety and depression using the Hospital Anxiety and Depression Scale (HADS).p = 0.01); those patients also showed worse HADS and MFHW scores. Regarding pain chronification, 34.8% were in stage I according to the MPSS, 45.2% in stage II and 20.0% in stage III. There was no significant correlation between chronification grade and disease severity, but advanced chronification was significantly more frequent in patients with low back pain (p = 0.024). It was also significantly associated with pathological HADS scores (p < 0.0001) and linked with decreased well-being and higher use of analgesics.One hundred forty-seven SSc patients completed a pain questionnaire, and 118/147 patients reporting pain were included in the analysis. Median pain intensity was 4/10 on a numeric rating scale (NRS). The most frequent major pain localizations were hand and lower back. Low back pain as the main pain manifestation was significantly more frequent in patients with very early SSc (Our study implies that also non-disease-specific symptoms such as low back pain need to be considered in SSc patients, especially in early disease. Since low back pain seems to be associated with higher grades of pain chronification and psychological problems, our study underlines the importance of preventing pain chronification in order to enhance the quality of life. Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease. The pathophysiology is not yet fully understood but includes vascular and fibrotic changes. Endothelial, fibroblast and immune system dysregulation results in vasculopathy, immune cell activation, collagen accumulation and the presence of autoantibodies. Clinical manifestations are heterogeneous; frequent manifestations are Raynaud’s phenomenon and digital ulcers, skin fibrosis and joint involvement. Various symptoms may result from organ involvement of the gastrointestinal tract, lungs, heart or kidneys , 2.Pain is a frequent symptom in SSc patients and can have various causes. It may for example derive from vasospasms, digital ulcerations, synovitis, joint contractures or gastrointestinal dysmotility. Despite the fact that it is an important concern for these patients, there is only very limited data available about pain in SSc –6. Pain Despite SSc being a chronic and non-curable disease, chronification of pain has not been addressed in SSc. Chronic pain is an important issue in the general population with a prevalence between 10 and 44% . A largeTo assess pain chronification, the Mainz Pain Staging System (MPSS) is frequently used, showing good validity in patients with different pain diagnoses –29. ThisIn this study, we conducted a detailed pain analysis in order to learn more about the associations between pain characteristics, chronification and disease manifestations in patients with SSc.Consecutive patients with SSc attending the annual assessment programme at the Department of Rheumatology of the University Hospital Zurich were recruited for this study. All patients were part of the local European Scleroderma Trials and Research (EUSTAR) registry .Patients who reported no pain at all, patients with the annual clinical assessment more than ± 3 months apart from the pain assessment and patients with rheumatoid arthritis overlap, potentially influencing pain symptoms particularly in the hands, were excluded from the analysis.We used fulfilment of the different classification criteria as a measure of disease severity and assigned the patients to three groups: patients who fulfilled both the 1980 American College of Rheumatology (ACR) 1980 criteria  for SSc All patients included in this study had signed informed consent. The study had been approved by the Cantonal Ethics Committee (BASEC-Nr 2017-02115).Information on disease-related symptoms such as skin, joint and organ involvement was retrieved from the EUSTAR database and compared amongst the three groups “established”, “mild” and “very early” for patient characteristics. Clinical manifestations and organ involvement are defined according to EUSTAR standards . DiseaseHand function was assessed with the Cochin Hand Function Scale (CHFS), which was found to be a valid and reliable tool in patients with SSc , 38. It In this study, the German pain questionnaire was used, which was confirmed to be a valid and reliable tool for pain assessment . The quePsychological factors were assessed using the Hospital Anxiety and Depression Scale (HADS), which was shown to be a good screening instrument for anxiety and depressive symptoms in patients with non-psychiatric illnesses . This scThe Marburg questionnaire on habitual health findings (MFHW)  was usedU test was used for two groups and the Jonckheere-Terpstra test was used for more than two groups. A p value smaller than 0.05 was considered significant.For statistical analysis, IBM SPSS Statistics, version 2.5, was used. For nominal data, frequencies were calculated, and chi-square test or Fisher’s exact test was used for comparison. For ordinal or continuous data, means with standard deviation (SD) were calculated in case of normative distribution; otherwise, medians with first and third quartiles were calculated. For comparison of ordinal or continuous variables, the Mann-Whitney p = 0.006, and 40.0% vs. 17.2%, p < 0.001, respectively), joint contractures  and subcutaneous calcinosis of the hand  were significantly more frequent in the “established” group than in the “mild” group. In the “very early” group, digital ulcers and subcutaneous calcinosis were not present.Altogether 147 SSc patients completed the questionnaires. Nineteen patients were excluded due to lack of pain, eight because the clinical assessment was more than ± 3 months apart from the pain assessment, one due to overlap with rheumatoid arthritis and one because the patient did not have SSc. Thus, 118/147 (80.1%) patients reporting pain could be included in this study. Their clinical characteristics are summarized in Table p = 0.199). The most frequent localizations patients reported as major pain were the hands and back, mainly referring to the lumbar spine. Further frequent pain localizations were the feet and additional joints of the lower extremity, showing no significant difference between the groups.Results for the pain analysis for the three groups “established”, “mild” and “very early” are displayed in Table p = 0.150). Table p = 0.001) than other patients; the same applied for patients who reported hand pain in general (p < 0.001). Patients reporting main pain localized in the hands had more frequently digital ulcers (p = 0.008), joint contractures (p = 0.003) and tendon friction rubs (p = 0.013) than other patients. Similarly, in patients with hand pain, the median pain intensity was higher when painful digital ischemia  or joint contractures (p = 0.019) were present.As expected for SSc patients, the hands were one of the most frequent localizations of pain. Hand pain in general was reported by approximately 80% of the patients in all three groups. As shown in Table p = 0.196) . As shown in Table Low back as main pain was more frequent in the group “very early” with 27.3% compared to 17.2% in “mild” and 12.3% in “established” (p = 0.024); in stage III, more than a third of all patients reported low back pain as their major pain, and approximately 60% reported low back pain in general  were in stage I, 52/115 (45.2%) in stage II and 23/115 (20.0%) in stage III according to the MPSS. Contrary to our expectations, the proportion of patients with higher pain chronification stages did not increase with higher disease severity  as well as depression (p < 0.001) and with pathologically low scores for well-being as assessed by the MFHW (p = 0.004). From patients in MPSS stage III, 42.9% showed a positive HADS anxiety score and 28.6% a positive HADS depression score; almost 40% showed pathological scores for well-being  patients with completed assessments showed a positive HADS score for anxiety, and 12 out of 106 (11.3%) patients had a positive HADS score for depression. As shown in Table .8% patieOur study confirmed that pain is a central problem in SSc patients. The mean pain intensity was moderate, yet two thirds of the patients showed pain chronification. One in five patients met the highest stage of chronification. Higher grades of pain chronification were associated with higher HADS scores and higher usage of analgesics including strong opioids. The observation that patients with advanced pain chronification more frequently use medication, including opioids, has previously been shown during the validation of the MPSS . ContrarIn our study, 87% of the patients reported pain, which is very similar to a large descriptive study about pain in SSc that showed 83% of the patients were suffering from pain . Two smaRegarding pain chronification, our results show similar , 46 or lBack pain is a widespread complaint in the general population; a large multiregional survey in Germany showed a 1-year prevalence of 75% , an inveA recent study about chronic pain in rheumatic diseases has shown a positive effect of multimodal pain therapy on the patient’s pain-related impairment as well as physical and mental well-being . HoweverOur study has several limitations. For some sub-analyses, there were missing data and the sample size was rather small. Due to the cross-sectional study design, no statements on long-term changes in the assessed symptoms can be made. Further, we did not record the source of hand pain; therefore, we could not differentiate between pain caused by ulcers, Raynaud’s phenomenon, arthritis or other symptoms. We also did not have additional information on the specific cause and associated morphological changes of the lower back pain in the patients, which needs to be addressed in further studies. In addition, we were not able to distinguish between nociceptive and neuropathic pain, since no validated screening instrument for neuropathic pain was used in the questionnaire. Furthermore, there was no data on the presence of fibromyalgia as a potential confounder for pain chronification available in our database. The fact that we included patients diagnosed with SSc that did not yet fulfil any classification criteria may be beneficial, since very early disease stages are considered in the study, though it makes our patient sample less comparable to previous publications, where usually the 1980 ACR classification criteria had to be fulfilled as an inclusion criterion. However, our study is of importance because it is—according to our knowledge—the first to conduct such an extensive pain analysis in patients with SSc, including frequency of pain localizations and the grading of pain chronification.It remains unclear why low back pain is more frequent in the early stages of the disease in this study. A possible explanation might be the fact that with disease deterioration, other SSc-related pain symptoms such as hand pain gain priority. As selection bias cannot be ruled out, further studies examining the prevalence of back pain in SSc patients will be needed. However, our analysis has shown that back pain is a very severe problem in patients with SSc, as it is in the general population.Taken together, our study has important implications for the clinical care of SSc patients. To improve treatment and quality of life, early pain assessments should be conducted in order to detect or prevent pain chronification and associated psychological problems. Our study showed that low back pain is a major driver of pain in patients with very early disease. It is associated with higher pain chronification, depression and anxiety and has therefore major impact on well-being particularly in this patient group. It therefore needs particular attention in the care of patients with very early SSc.


Radiofrequency of the Gasserian ganglion can be used for ophthalmic herpetic neuralgia (OHN), but it is associated with complications. This study aimed to use the supraorbital nerve for computed tomography- (CT-) guided radiofrequency thermocoagulation to treat refractory OHN.  This was a retrospective case series study of patients with simple or combined OHN treated at our hospital between 06/2012 and 06/2018. The numerical rating score (NRS), spontaneous pain, allodynia, gabapentin dosage, paracetamol/oxycodone dosage, patient global impression of change (PGIC) score, Barrow numbness score, postoperative 360-day recurrence rate, and complications were recorded before the operation and at 1, 30, 90, 180, and 360 days after the operation. P < 0.001). Compared with 1 day after the operation, numbness was decreased at 30, 90, 180, and 360 days after the operation (P < 0.001). Compared with baseline, the number of patients with allodynia at each time point after the operation was decreased (P < 0.001), but without a difference for spontaneous pain (P=0.407). No subjects showed drooping eyelid, corneal ulcers, eyeball damage, decreased vision, and other severe complications.  Compared with baseline, the NRS was decreased, and PGIC was increased at postoperative 1, 30, 90, 180, and 360 days, and the gabapentin and paracetamol oxycodone doses at postoperative 30, 90, 180, and 360 days were decreased (all  CT-guided supraorbital nerve radiofrequency thermocoagulation for the treatment of OHN can effectively relieve pain and reduce the dose of analgesics, without any serious complication. This study suggests that this technique is feasible and applicable to clinical practice. Herpes zoster (HZ) is one of the clinical syndromes associated with the reactivation of latent varicella-zoster virus (VZV). HZ typically occurs years after primary VZV infection (varicella or chickenpox) –4. The aCumulative trigeminal nerves  can cause head and facial HZ, of which herpes zoster ophthalmicus (HZO) is the most common, which can account for 10%–20% of patients with HZ , 8. HZO Radiofrequency (RF) is a reliable method for the treatment of neuropathic pain in patients who are refractory to conservative treatments. RF is divided into pulsed radiofrequency (neuromodulation) and radiofrequency thermocoagulation (neurolytic impairment). Pulsed radiofrequency has an unclear analgesia mechanism. Clinically, for the treatment of refractory herpetic neuralgia, a single-pulse radiofrequency has a short effective duration, and repeated operations are often necessary to prolong the curative effect, which will increase the patients' burden . MeanwhiThe aim of this retrospective study was to examine whether the use of another target, i.e., the supraorbital nerve, showed benefits for computed tomography- (CT-) guided radiofrequency thermocoagulation for the management of refractory ophthalmic herpetic neuralgia. The results could provide another option for the management of refractory ophthalmic herpetic neuralgia.This was a retrospective case series study of patients with simple or combined HZO treated at the pain department of our hospital between June 2012 and June 2018. The procedure was approved by the hospital in 2011 (#2011–037). The data were from a prospectively maintained database using Haitai 3.0 software. The data themselves were extracted from the charts after 2018. The study was approved by the ethics committee of our hospital. The need for individual consent was waived by the committee.The inclusion criteria were as follows: (1) diagnosed with HZO , and theAll operations were performed by the same surgeon, who was a chief physician who had been engaged in the diagnosis and treatment of pain for 20 years. The patient was placed supine on the operating table in the CT treatment room, comfortably fixed, with eyes closed. ECG was monitored routinely, and oxygen inhalation was given. The supraorbital foramen (notch) was identified using CT. When a complete supraorbital foramen (notch) could be seen, the CT layer was selected as the puncture layer, the puncture path was designed, and the puncture point was marked. After routine disinfection and draping, a radiofrequency puncture needle (length of 50 mm and inner diameter of 0.7 mm), exposed end of 2 mm , was punctured vertically along the puncture path to the supraorbital orifice or the notch bottom  under thThe patients continued to take oral gabapentin . The dose for patients with NRS 1–3 points was halved, while it could be doubled in patients with NRS 4–6 points; each increase or decrease lasted for more than 1 week. Patients with NRS >6 points were rescued with paracetamol oxycodone tablets , no more than four tablets/day.Before the operation and at 1, 30, 90, 180, and 360 days after the operation, the following data were recorded routinely: NRS, occurrence of spontaneous pain, occurrence of allodynia, gabapentin dosage, paracetamol/oxycodone dosage, the patient global impression of change (PGIC) score , the Bart-test. Data with a skewed distribution were expressed as medians ; comparison between pretreatment and posttreatment data was conducted using the Friedman rank-sum test, and multiple comparisons were made using the Wilcoxon rank-sum test. Categorical data were analyzed using the Pearson chi-square test. Two-sided P values <0.05 were considered statistically significant.Statistical analyses were performed using SPSS 16.0 . Continuous data were first tested with the Kolmogorov–Smirnov normality test. Data in line with a normal distribution were expressed as means ± standard deviations, and comparison between pre- and posttreatment data was conducted using repeated-measures ANOVA and the post hoc paired Thirty-six patients among eighty patients with HZO completed the radiofrequency thermocoagulation intervention. Five patients were lost to follow-up, and 31 patients were finally analyzed in the study. Their characteristics are listed in χ2=80.37, χ2=55.53, χ2=38.00, and χ2=47.32; all P < 0.001). The differences in gabapentin and paracetamol oxycodone doses at postoperative 1 day were not statistically significant . Compared with 1 day after the operation, numbness was decreased at 30, 90, 180, and 360 days after the operation .The last follow-up was on September 1, 2019. The NRS, gabapentin dosage, paracetamol/oxycodone dosage, PGIC before and after the operation, and postoperative numbness are shown in χ2=46.25, P < 0.001), while the number of patients with spontaneous pain at each time point after the operation did not show a significant difference . In addition, there were no significant differences between the number of patients with allodynia and the number of patients with spontaneous pain before operation , but the number of patients with spontaneous pain at each time point after the operation was higher than the number of patients with allodynia .The number of patients with allodynia and spontaneous pain is shown in At 360 days after the operation, four patients (13%) had recurrences, but they were treated at other hospitals, and the details are unknown. Twenty-nine (94%) patients had varying degrees of subcutaneous swelling at the supraorbital area within 1 week of surgery, but no patients showed drooping eyelid, corneal ulcers, eyeball damage, decreased vision, and other severe complications. After 1 week without special treatment, they returned to normal on their own.Radiofrequency of the Gasserian ganglion can be used for ophthalmic herpetic neuralgia, but it is associated with risks and complications –17. ThisThe Gasserian ganglion, which is a concentration site of primary sensory neuron bodies in the head and face, is the ideal target for radiofrequency thermocoagulation in the treatment of refractory ophthalmic herpetic neuralgia –17. RadiThe ophthalmic nerve erupts from the skull via the supraorbital fissure and is immediately branched into the lacrimal, nasociliary, and frontal nerves . The nasβ fibers sprout from the deep lamellar to lamellar I and lamellar II in the spinal dorsal horn after nerve injury and occupies the upward pain pathway of the Aβ and C fibers [Among the 31 patients, the pain score decreased significantly after radiofrequency thermocoagulation, and the relief of allodynia was significantly better than that of spontaneous pain. Spontaneous pain is considered to be caused by central sensitization . This tyC fibers , which bC fibers . Since tWith the relief of pain after radiofrequency, the doses of analgesics such as gabapentin and paracetamol oxycodone after the operation could be decreased accordingly. In the present study, there was no significant change in the doses at postoperative 1 day, which may be related to pain and discomfort due to subepithelial swelling in the supraorbital area after thermocoagulation. Meanwhile, PGIC, as an indicator that effectively reflects the therapeutic effect, was improved postoperatively compared with baseline (after nerve block), indicating that the treatment is effective.Numbness is an unpleasant sensory experience and is also a cause for the low acceptance of nerve impairment methods . In the This retrospective study has some limitations. The sample size was small. There was no control group. In addition, the patients combined with HZ in the supratrochlear nerve were excluded, but some cases might have been missed since there is a somatic overlap between both nerves. Therefore, further research and observations are needed.In conclusion, radiofrequency thermocoagulation of the supraorbital nerve is a feasible method for treating ophthalmic herpetic neuralgia, without serious complications. This could be a suitable method for the management of ophthalmic herpetic neuralgia.


No Arabic or its dialect questionnaire is available to evaluate the anterior knee pain in the Saudi Arabian religious population. This study aims to translate, adapt, and psychometrically validate the Knee Injury and Osteoarthritis Outcome Score (KOOS-PF) Patellofemoral scale in the Arabic language in Saudi Arabic dialect.Translation has been done as per standard guidelines. The questionnaire was administered to 95 patients to determine the psychometric properties including on two different occasions, with a 48-hour gap in-between; to ensure that their answers were reliable; 84 patients (88.4% compliance rate) responded for test and retest reliability, ceiling-floor effects, validity and other psychometric criteria.Cronbach’s alpha  and test–retest reliability was good and excellent . None of the items showed >30% floor or ceiling effect and the minimal detectable change was within the acceptable range (<30%). The KOOS-PF subscale showed a moderate correlation (−0.568) with pain-visual analog scale for its construct validity.The Arabic dialect of KOOS-PFis reliable and valid to be used to evaluate isolated knee pain of patellofemoral origin in Muslim patients in Saudi Arabia. The knee joint is composed of three compartments; patellofemoral joint (PFJ), a subgroup of the knee joint is also affected with arthritis together with tibiofemoral joint (TFJ) arthritis (Knee osteoarthritis (OA) is one among the ten disabling diseases affecting the mobility to 80% and activities of daily living to 25% (rthritis . One stuhttp://www.koos.nu/).Diffuse pain at the anteromedial aspect of the patella is a characteristic of PFJ arthritis that can be seen while running, squatting, ascending and descending stairs . Among ahttp://www.koos.nu/). KOOS-PF measurement properties are well-validated along with adequate structural validity and patient responsiveness  and Arabic is one among them. To better serve Saudi Arab patients with patellofemoral pain syndrome, the original language KOOS-PF questionnaire need to be validated psychometrically in Saudi Arabia. This would allow better evaluations to be carried out because patients can better express their symptoms in their native language.Assessment of range of motion, muscle atrophy comes under objective examination. In terms of subjective evaluation, a well-translated, cross-culturally adapted and psychometrically validated questionnaire would provide a piece of comprehensive symptomatic information to the evaluator. Since TFJ and PFJ arthritis differ symptomatically and the target population is different as sports individuals commonly come across PFJ arthritis, a separate disease-specific KOOS-PF subscale was evolved from the KOOS long-form to subjectively evaluate the PFJ arthritis . KOOS-PF contains 11 questions out of which one is for symptom; nine for pain and one about quality of life. The exact phrase of questions is PF1. How severe is your knee stiffness after exercise? PF2. How often do you experience knee pain after stopping activity? PF3. How often does pain limit your activity? PF4. Rising from sitting (including getting out of the car). PF5. Kneeling PF6. Squatting PF7. Heavy household activities (including carrying and lifting) PF8. Hopping/jumping PF9. Running/jogging PF10. After sport and recreational activities PF11. Have you modified your sport or recreational activities due to your knee pain? Each question contains 5 options never to always (less disability to maximum disability); according to guidelines from the main developers of the KOOS, it is mandatory to mention the direction of scoring the data for better interpretation of results where the highest obtained values indicate no symptoms and lowest were the extreme symptoms. The method of scoring should be to calculate the mean score of the 11 items and divide by the maximum possible score for each item , using the formula 100–[(mean score PF1-PF11)/4 * 100] (http://www.koos.nu/).The present validation process has been approved and with the permission from the original developer (dated 29/08/2018) of the instrument, University of Southern Denmark, Denmark. The process of translation of Arabic abstract can be found on the website . “How often do you experience knee pain after stopping activity/prayer?”; item No. PF3 “How often does pain limit your activity/prostrating, kneel sitting?”; item No. PF4 “Rising from sitting” ; item No. PF5. “Kneeling” (during prayers); item No.PF6 “Squatting” (during prayers); item No.PF10. (pain) “After sport and recreational activities”, prayers/ ‘Sujud’,‘Rakaa”. The word ‘Salat’ refers to prayer added to item No.PF11. “Have you modified your sport or recreational activities and Salat (prayers) due to your knee pain?” After the subjects were convinced with the items, a final draft evolved as a complete pre-testing questionnaire (stage V). After all the above stages, the measurement properties were measured in target individuals with chronic anterior knee pain.The present study has followed the A total of 95 male subjects with anterior knee pain were selected in the present study. The inclusion criteria were patients aged between 32 to 66 years as the patellofemoral pain affects the young and middle-aged  commonlyPatients were selected through a convenient sampling technique from the outpatient departments of three different hospitals in and around Al Majmaah city, KSA who were diagnosed by an Orthopedic surgeon, from 1st November 2019 to 31st January 2020. Patients who were eligible with the inclusion criteria were asked to participate in the study. All included patients were provided with informed written consent; they were then asked to complete the translated Arabic questionnaire on two different occasions, with a 48-hour gap in-between; to ensure that their answers were reliable. The questionnaire was explained to all patients with mention of its 11 items of KOOS-PF related to their anterior knee pain. Patients were given the questionnaire soon after the diagnosis of their knee condition. Among the 95 subjects who were asked to come back after 48 h to refill the questionnaire, 84 patients (88.4% compliance rate) responded. I chose the 48-hour time gap to avoid measuring the effects of prescribed drugs on pain; as well as to prevent recall bias in questionnaire administration. Subjective pain was measured using the numeric visual analog scale (VAS). The psychometric measurement properties of the translated version such as internal consistency, test-retest reliability, floor-ceiling effect, inter-item correlation, the percentage of agreement and construct validity were done using IBM-SPSS statistical (Version 24.0) software.Cronbach’s Alpha (average correlation) psychometric statistical test was performed to measure the internal consistency of all the items of the questionnaire based on the initial data. Good internal consistency of the subscale was considered between 0.7 to 0.9, item will be removed if a value is less than 0.7 and excellent if the value is greater than 0.9 .The Intraclass correlation coefficient (ICC) (single measure) was measured to see the difference between the first and second (Test and retest) self-rated form for its reliability calculated with 95% confidence interval . The twoThis matrix within the subscale should be between 0.3 –0.8; anything less than 0.3 and more than 0.8 should be considered as redundant hence removed .PooledThe percentage of the agreement was calculated in two ways, coefficient of variance (CV) in percentage  and miniThe construct validity was assessed at obtaining baseline data through Spearman correlations to check the relationship between the KOOS-PF scale and with the numeric visual analog scale (VAS). Standard values of more than 0.70 were considered strong, between 0.70–0.50 moderate and less than 0.50 weak for Correlation coefficients .The floor and ceiling effects were evaluated for the items of the KOOS-PF questionnaire. The obtained scores are statistically acceptable when less than 15% of the participants reporting the lowest or highest possible score . CeilingWhen the correlation analysis was done between all the items of the KOOS-PF subscale, all the values were found below 0.8. Minimum inter-item correlation found between PF3 and PF11 (0.318) whereas, the maximum inter-item correlation found between PF2 and PF8 (0.784). None exceeded the standard value of 0.8 which indicates a good inter-item relationship .VAS has a moderate correlation with the KOOS-PF items (−0.568).The validated Arabic KOOS-PF and its psychometric properties shows that it has high internal consistency, high test-retest reliability, acceptable floor and ceiling effect, the inter-item correlation matrix is within the acceptable range item-total correlation is in acceptable range, and moderate construct validity with VAS. All these findings encourage one to use this questionnaire in patellofemoral joint pain patients, particularly during repeated praying activity. There is no questionnaire available to date to assess the patellofemoral pain syndrome in Arabic patients.KOOS-PF results are in line with the results of the Arabic version of full-length KOOS in which the internal consistency of pain construct Cronbach’s alpha was 0.87  whereas The average measure of the Intraclass correlation coefficient (ICC) of Arabic KOOS-PF was 0.959 which indicates an excellent test and re-test reliability. KOOS-PF intraclass correlation coefficient (ICC) was higher than the original KOOS-PF (0.86) . The IntVisual analog scale (VAS) has a moderate correlation with the KOOS-PF items (−0.568). The correlation >0.5 is acceptable as per the psychometric properties . The lonThe strength of this study is the only available Saudi dialect of Arabic questionnaire to evaluate the patellofemoral pain syndrome in the Saudi Arabian Muslim populace, which is well adapted based on the religious practice.Duration between test and retest for reliability is too short but the author decided to use short interval to avoid any analgesic effect of the drug. Author used only the male subjects in the validation process as the male therapists are not allowed to treat/evaluate female patients in the hospitals of Saudi Arabia hence, the results may not apply to female patients. Future studies should attempt to measure this property in Saudi female patients. No validation studies of KOOS-PF have been done either in any other Arabic dialect or language other than the original English KOOS-PF version to support the results. The responsiveness property was not measured and intends to measure in the future by the same author.The Knee injury and Osteoarthritis Outcome Score (KOOS-PF) Patello Femoral questionnaire has obtained acceptable measurement properties, hence is sufficiently reliable, valid and free of the ceiling and floor effects to be used to evaluate the patellofemoral problems in Saudi Arabian anterior knee pain patients.10.7717/peerj.9323/supp-1Supplemental Information 1Click here for additional data file.10.7717/peerj.9323/supp-2Supplemental Information 2Click here for additional data file.