The innate repair receptor (IRR) is a heteromer of the erythropoietin receptor and the β-common (CD131) receptor, which simultaneously activates anti-inflammatory and tissue repair pathways. Experimental data suggest that after peripheral nerve injury, the IRR is upregulated in the spinal cord and modulates the neurogenic inflammatory response. The recently introduced selective IRR agonist ARA290 is an 11-amino acid peptide initially tested in animal models of neuropathy. After sciatic nerve injury, ARA290 produced a rapid and long-term relief of mechanical and cold allodynia in normal mice, but not in animals with a β-common receptor knockout phenotype. In humans, ARA290 has been evaluated in patients with small fiber neuropathy associated with sarcoidosis or type 2 diabetes (T2D) mellitus. In patients with sarcoidosis, ARA290 significantly improved neuropathic and autonomic symptoms, as well as quality of life as assessed by the small fiber neuropathy screening list questionnaire. In addition, ARA290 treatment for 28 days initiated a regrowth of small nerve fibers in the cornea, but not in the epidermis. In patients with T2D, the results were similar to those observed in patients with sarcoidosis along with an improved metabolic profile. In both populations, ARA290 lacked significant adverse effects. These experimental and clinical studies show that ARA290 effectively reprograms a proinflammatory, tissue-damaging milieu into one of healing and tissue repair. Further clinical trials with long-term treatment and follow-up are needed to assess the full potential of IRR activation by ARA290 as a disease-modifying therapy in neuropathy of various etiologies. Furthermore, current pharmacotherapies come with severe side effects that reduce patient compliance, which consequently is an additional cause of failed therapy.Although our knowledge of the pathophysiology of neuropathic pain, ie, pain caused by a lesion of the somatosensory nervous system, has increased significantly over the last decades, it remains difficult to control the chronic pain condition, which affects many patients. Neuropathic pain is observed in a large variety of disorders that vary from metabolic and infectious disorders, which affect the small, afferent sensory nerve fibers , to diseases of the central nervous system . Patients with neuropathic pain share a spectrum of clinical symptoms, irrespective of the underlying disease, including spontaneous  pain, allodynia (increased sensitivity to nonnoxious stimuli such as intolerance of bed sheets), and hyperalgesia (increased sensitivity to noxious stimuli). In addition, patients with neuropathic pain often display symptoms of anxiety, depression, sleep disturbance, and social isolation, all further reducing their quality of life. Although multiple therapeutic options are available, only a minority of patients (30%-50%) achieve moderate to adequate pain relief with an average reduction in pain score of 30% to 50%.53 Inflammation is thought to be caused by nerve damage and to maintain resulting painful symptoms, eventually resulting in peripheral and/or central sensitization with persistent allodynia and hyperalgesia. For example, there is ample evidence from animal studies that peripheral nerve injury triggers a spinal inflammatory response with the release from nociceptive spinal neurons of proinflammatory molecules, such as fractalkine, chemokine (C-C motif) ligand-2 (CCL2), and tumor necrosis factor (TNF-α), which results in the invasion of resident macrophages  and monocytes from peripheral blood toward the spinal cord level of the peripheral nerve lesion site.58 Consequently, at that location, microglial cells increase in number and along with astrocytes show signs of heightened reactivity .48 Importantly, the inflammatory response is not restricted to the level of the nerve injury but also moves in a cranial and caudal direction with concomitant symptoms of spreading mechanical allodynia.59 In addition, there is evidence of contralateral dissemination of the inflammatory response.44 Although the neuroinflammatory response may eventually subside, neuroplastic changes occur in pain sensory and modulatory networks which cause the persistence of symptoms. These findings of neurogenic inflammation are mirrored by one case report in a deceased patient who had suffered from long-standing complex regional pain syndrome.18 His autopsy revealed heightened spinal cord glial activity. The body of evidence that is described above strongly suggests that inhibition of the activated inflammatory cells in the spinal cord may be an important mechanism to relieve neuropathic symptoms. Evidence for this is found in the observation that drugs, which stabilize activated microglial cells, such as ketamine, local anesthetics, or minocycline, reduce mechanical allodynia after experimental damage to large peripheral nerves.61 The effect of ketamine on neuropathic pain has previously been ascribed to its exclusive effect at the N-methyl-d-aspartate (NMDA) receptor. However, we recently showed that ketamine reduces the production of inflammatory molecules within the spinal cord after sciatic nerve injury with a concomitant decrease in mechanical allodynia.49 These effects were unrelated to NMDA receptor antagonism .An important feature of neuropathic pain is the occurrence of peripheral and/or central inflammation.ity Fig. . In addi13 This process involves the release of reactive oxygen species, vascular thrombosis, and edema formation and the mobilization of additional inflammatory cells. To balance this destructive process, dampen the inflammatory process, and counteract collateral damage (apoptosis of nearby nonaffected cells), anti-inflammatory molecules are upregulated in response to the tissue injury, one of the most important ones being the cytokine erythropoietin (EPO).6 Note that the local synthesis and release of EPO after tissue injury is distinct from its endocrine effect on the hematopoietic system, which is related to the release of low concentrations of EPO by the kidney. Furthermore, locally produced EPO is chemically distinct from renal EPO, because of a reduced degree of sialylation, which acts to significantly reduce its half-life. Erythropoietin acts through the erythropoietin homodimer receptor (EPOR2) on erythrocyte precursor cells in the bone marrow with high affinity to modulate the production of mature red blood cells; activation of the EPOR2 inhibits apoptosis of red cell precursor cells. In contrast, the paracrine/autocrine EPO-induced tissue-protective effects are mediated through activation of the innate repair receptor (IRR), which is a member of the Type 1 cytokine receptor family.6 The IRR is a heteromeric receptor that comprises β-common (CD131) and EPO receptor subunits  and the subsequent release of proinflammatory cytokines , which are aimed at the isolation and destruction of toxins, pathogens, and damaged tissue.ptor EPOR on eryth8 Recovery was absent in homozygous βCR knockout mice (βCR−/−), ie, mice lacking the IRR, indicative of the molecular mechanism of action of EPO. Exogenous EPO is also effective in animal models of painful neuropathy with a rapid recovery of sensory functions and reduction of allodynia.35 However, clinical studies indicate that the use of recombinant EPO is associated with serious side effects, such as arterial and venous thrombosis, hypertension, stroke, and myocardial infarction.15 Hence, the use of exogenous EPO has not been pursued seriously in clinical studies requiring extended dosing.A number of studies confirmed the tissue-protective role of exogenously administered EPO in experimental models of renal, cardiac, retinal, and neural damage  is an 11-amino acid linear peptide with a molecular weight of 1257 Da (Pyr-Glu-Glu-Leu-Glu-Arg-Ala-Leu-Asn-Ser-Ser-OH) that was designed to separate EPO's hematopoietic and thrombotic effects from its anti-inflammatory effects. ARA290 mimics the configuration in space of the B-helix of the EPO molecule, which interacts with the IRR.9 The pharmacokinetics of ARA290 in humans shows an elimination half-life of ∼20 minutes after subcutaneous administration and just 2 minutes after an intravenous injection.43 Similar observations were made in animal studies and suggest that ARA290 rapidly reaches its target site and activates a master switch (the IRR), which subsequently initiates a cascade of events ultimately resulting in clinical effects.27 ARA290 may activate IRRs within the central nervous system , as well as at peripheral sites.To overcome the hematopoietic and thrombotic effects of EPO, several nonhematopoietic IRR-activating analogues have been developed such as carbamylated EPO, and ARA290, also known as pyroglutamate helix B surface peptide.Cooperation between Anthony Cerami, Michael Brines, and the Experimental Pain Research Group of the Department of Anesthesiology at Leiden University Medical Center has led to a series of experimental and clinical studies on ARA290's effect in neuropathy.rhEPO) improved sensory nerve function in streptozotocin-induced diabetic neuropathy.4 Erythropoietin reduced allodynia and improved motor function in rodents after L5 spinal nerve transection, dorsal root ganglion crush injury, and chronic constriction injury.34 Importantly, signs of spinal inflammation were reduced by systemic administration of rhEPO resulting in less reactive glial cells and decreased release of TNF-α, interleukin-1β, and NF-κB activation in the spinal cord and at supraspinal sites. Also, peripheral effects are observed after rhEpo with the reduction of intraepidermal nerve loss in diabetic neuropathy and reduced Schwann cell TNF-α expression in chronic constriction injury.11 In contrast, in a rat neuritis model, ARA290 prevented the development of mechanical allodynia but did not reduce TNF-α mRNA production in the affected nerve, suggestive of a central effect of ARA290.45 In addition, ARA290 has been shown to promote repair of small autonomic nerve fibers within sympathetic ganglia in a mouse model of diabetic neuropathy.47Erythropoietin improves neuropathic pain symptoms in a variety of experimental neuropathic pain models. Recombinant human EPO  due to nerve injury was attenuated by ARA290 ,50 suggestive of an effect of ARA290 on the inflammatory response which involved both microglia and astrocytes.We tested ARA290 in the spared nerve injury (SNI) model in mice and rats.50 Additional experiments in mice lacking the IRR showed that ketamine-induced reduced behavioral responses to acute noxious stimuli  were retained; however, ketamine was without effect on SNI-induced allodynia. We relate the antinociceptive effects of ketamine to its actions on NMDA receptor antagonism and consequently inhibition of glutamate-dependent pain signaling and possibly also to its effects on mu-opioid receptors. These same NMDA receptors seem to be unimportant for the effects of ketamine in SNI neuropathy. Like ARA290, ketamine is a potent anti-inflammatory agent and has been shown to reduce TNF-α in a murine laparoscopic model.52 Whether ketamine directly interacts with the IRR remains unknown at present, but it is clear that ketamine analgesia in SNI-induced chronic allodynia is dependent on a pathway, which involves the IRR.We additionally tested the effect of subanesthetic concentrations of ketamine in our SNI model and observed that ketamine reduced mechanical allodynia as well as neuropathy-related inflammatory markers and NMDA receptor subunits in a similar manner compared with ARA290.60 This ion channel is a key modulator of neuroinflammation and nociception, and therefore, the beneficial effects of IRR activation likely depends at least in part on dampening TRPV1 activity of small intraepidermal nerve endings and on central effects.Recently, it has been shown that ARA290 inhibits capsaicin-evoked TRPV1 channel activity in dorsal root and trigeminal ganglion cells and relieves capsaicin-induced mechanical allodynia in mice.The administration of ARA290 to humans followed as a logical step considering the positive results of the animal experiments. Clinical studies were performed after approval from the Leiden University Medical Center Institutional Review Board . Protocols were registered in the publicly available Netherlands Trial Register . For all clinical studies, oral written informed consent was obtained from participants before study enrollment.43 All patients were diagnosed with small fiber neuropathy (SFN) and had pain symptoms as well as signs of autonomic nerve fiber loss. All patients received 3 intravenous injections with ARA290 over one week . No relevant adverse events were noted. Pain relief was maximal on the day of the third injection with a 25% reduction in pain score in patients with T2D (baseline score: 7.0) and 40% in patients with sarcoidosis (baseline score: 7.1). These results without apparent significant adverse effects prompted us to perform a series of placebo-controlled double-blind trials to assess the effect of ARA290 on SFN-related symptoms in patients with sarcoidosis.Initially, an open-label proof-of-concept and safety study was performed in a small number of sarcoidosis (n = 10) and type 2 diabetes (T2D) mellitus (n = 10) patients with moderate to severe neuropathy pain .33 Although any organ may be affected, in more than 90% of cases the lungs are involved. Pain in sarcoidosis is often related to SFN, which selectively affects thinly myelinated Aδ- and unmyelinated C-nerve fibers.28 Because these small fibers subserve both sensory and autonomous function, symptoms include neuropathic pain and autonomic dysfunction. Autonomic symptoms include orthostatic dizziness, dry eyes, facial flushing, incontinence for urine, sexual dysfunction, hypo/hyperhidrosis, and restless leg syndrome among others.Sarcoidosis is a multiorgan inflammatory illness, which is characterized by noncaseating granulomas.29 Both studies were small proof-of-concept phase 2 trials in a total of 60 patients of which 33 patients received active treatment. All patients had a confirmed diagnosis of sarcoidosis with painful SFN. In the first study (n = 22), patients were treated for 1 month with intravenous ARA290 2 mg administered 3 times weekly, with 3-month follow-up.29 Main endpoints were (1) pain intensity scores from the Brief Pain Inventory (BPI) questionnaire; (2) the score on the Small Fiber Neuropathy Screening List (SFNSL),30 a validated Dutch questionnaire for assessment of SFN in sarcoidosis. The SFNSL reports on pain-related and autonomic symptoms; and (3) quality-of-life scores from the RAND-36 questionnaire. Although pain intensity scores were similarly reduced by 2.1  and 2.3 points  in both treatment arms, ARA290 produced greater effects in the 2 dimensions of the SFNSL at week 4 of treatment with additionally a greater responder rate . Also, the quality of life improved significantly by ARA290 treatment. No safety issues were detected.In 3 randomized controlled trials, the efficacy of ARA290 was evaluated against a placebo control. The data of the first 2 studies have been analyzed and published.16 subcutaneous ARA290 4 mg was administered daily for 4 weeks with a 3-month follow-up. The focus of this trial was on the effect of ARA290 on small fiber morphology as measured from skin biopsies and corneal confocal microscopy and functional capacity as assessed by the 6-min walk test. Corneal confocal microscopy is a relatively new technique used to quantify the morphology of small fibers (predominantly the unmyelinated C-fibers) in Bowman layer of the cornea.31 Corneal confocal microscopy allows determination of corneal nerve fiber area, corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), and corneal nerve fiber branching density. The cornea may be especially sensitive to changes in the small nerve fibers of the human body as it has the highest density of small nerve fibers than all other tissues. For example, compared with the skin, the nerve fiber density is approximately 600 times higher. The corneal nerve fibers originate from the ophthalmic branch of the trigeminal nerve, and the fibers run parallel to the surface. Hence, visualization of these with a confocal microscope is relatively easy. An example of a healthy individual and patient with SFN is given in Figure 55 We recently showed in patients with sarcoidosis that CNFD and CNFL are reduced compared with normal and inversely correlate with the degree to which pain interferes with daily activities (assessed by the Brief Pain Inventory questionnaire).10 In addition, CNFL correlated with intraepidermal nerve density of the distal  limb after corrections were made for age, gender, and height.In the second phase 2 trial with acronym NERVARA (n = 38),16 These data are important for 2 reasons. First, ARA290 initiates a rapid regrowth of small nerve fibers in the cornea, which is a sign of tissue healing and restoration as earlier observed in experimental studies. Second, the corneal nerve fibers seem to be more sensitive to regeneration than skin fibers, and consequently, the cornea is the more appropriate location to assess not only the state of small fiber pathology but also assess the effect of treatment. Moreover, the technique is simple and noninvasive and may be repeated frequently without causing damage.The results of the NERVARA trial indicate a significant increase in corneal nerve fiber area by 14% within the 4-week treatment period  without affecting proximal and distal limb intraepidermal nerve fiber densities.Functional capacity as evaluated by the 6-minute walk test was reduced by approximately 30% in the sarcoidosis patients with SFN compared with normal age and gender-matched controls. After 28 days of ARA290 administration, 50% of patients receiving ARA290 could walk at least 25 m more, compared with only 12% in placebo-treated patients. Additional results of the NERVARA trial included an improvement of SFN symptoms as assessed by the SFNSL questionnaire with an ameliorating effect in the 2 queried domains, pain and autonomic symptoms. The results of these 2 small-randomized placebo-controlled trials are promising and indicate that the tissue-restorative peptide ARA290 produces improvement in neuropathic pain and autonomic symptoms, quality of life, and exercise capacity, and initiates the process of nerve fiber regeneration in the cornea. Larger trials are needed to further strengthen the evidence of a role of ARA290 in the long-term treatment of neuropathic pain.7 Forty-eight T2D patients with moderate to severe SFN-induced chronic pain were treated with daily subcutaneous injections of ARA290 4 mg or placebo for 28 days. The results of the trial were similar to those obtained earlier in sarcoidosis patients with improvements in neuropathic symptoms, an increase in CNFD in patients with an initial reduction in CNFD. Furthermore, an improvement in HbA1C and lipid profiles during ARA290 treatment as well as during the 56-day follow-up was observed. These data extend the findings in patients with sarcoidosis and indicate that in addition to a positive effect of IRR activation on neuropathic pain, the peptide improves the metabolic profile in patients with T2D (see also The data from one additional randomized controlled trial on ARA290 have recently become available.see also , which mSelective activation of the IRR using engineered molecules offers the potential to decrease tissue damage while simultaneously augmenting repair over a wide range of disease processes. The small peptide ARA290, modeled from the 3-dimensional structure of EPO, has shown efficacy in preclinical models of disease, including neuropathy, without associated adverse effects. In these models, ARA290 has been shown to reprogram a proinflammatory, tissue-damaging milieu into one of healing and repair. The favorable effects of ARA290 administration to patients with neuropathic pain coupled with observed increases in small nerve fiber density, as assessed by examination of the cornea, are consistent with disease modification. However, to date, clinical observations have been limited to only 28 days of treatment. Only longer duration clinical trials with extended follow-up will provide the critical data with which to assess the full potential of IRR activation as a disease-modifying therapy.Leiden University received financial support from ARAIM Pharmaceuticals, Inc, to perform experimental and clinical studies on ARA290. M. Brines and A. Cerami are employees of ARAIM Pharmaceuticals, Inc, which is innate repair receptor agonists for clinical use. The other authors report no conflicts of interest to declare.


The objective of this cross-sectional, noninterventional, 6-month observational study was to assess the adequacy of pain management in patients with cancer admitted to the Oncology Department of Guru Gobind Singh Medical College in Faridkot, India.A total of 348 patients with cancer were recruited for evaluation of the prevalence of inadequate cancer pain management using the Brief Pain Inventory Pain Management Index.The current study included 127 males (36.5%) and 221 females (63.5%). The most prevalent cancer type was genitourinary; 268 patients (77%) had inadequately managed pain. A significant correlation was observed between poorly managed pain and age groups, analgesic used, and body mass index.Our observation of inadequate pain management among 77% of patients indicates that pain management was insufficient in three quarters of the patients in this study. Accumulating data regarding the inadequacy of cancer pain management is crucial to improve symptom management. Better management of pain not only alleviates pain symptoms but also increases the quality of life for patients with cancer. However, pain is the most regular symptom of advanced cancer, increasing the emotional and physical challenges of patients.8The undertreatment of cancer pain is a well-known fact internationally, despite the existence of numerous guidelines for cancer pain management and wide-ranging consensus among health care professionals that 90% of patients with cancer can attain adequate pain relief with analgesics. Inadequate pain relief may depressingly impact a patient’s life. Health care providers, the patient’s family, and society play an important role in supporting patients who experience pain.9 The guidelines contain suggestions about the type of analgesic that can be prescribed for pain that is normally mild, moderate, or severe. Mild pain should be managed with a nonsteroidal anti-inflammatory drug or acetaminophen. Weak opioids  should be prescribed for moderate-level pain, and a strong opioid  should be prescribed for severe pain.10The WHO developed guidelines for the treatment of cancer pain in 1986 (revised in 1996) that were aimed at decreasing the prevalence of inadequate analgesia.12 Strictly following the WHO’s three-step analgesic treatment ladder is the best guideline in this regard.9 The situation is poor in developing countries such as India, where numerous challenges in optimum pain management have been described, such as a lack of reporting, poor communication, and misconceptions on the part of the patient and the health care staff regarding strong opioid use.13Gauging the adequacy of pain management in cancer research is distinctly different from merely assessing pain intensity or pain relief because inadequacy is a predictor of functional impairment.14 The Pain Management Index (PMI) is a well-validated technique used to assess the adequacy of pain management on the basis of the WHO and Agency for Health Care Policy and Research guidelines; it is said to be a conservative measure and was developed by Cleeland et al15 for patients with cancer in 1994. To assess the adequacy of pain management in patients with cancer, we designed a study to estimate the prevalence of inadequately managed cancer pain by calculating PMI scores.Liberal use of opioids is always suggested for patients with advanced-stage cancer, but a conservative approach to opioid use may result in the undertreatment of cancer pain. With proper use of the WHO analgesic ladder, approximately 88% of patients reportedly obtain reasonable pain relief.This was a cross-sectional, 6-month, noninterventional, prospective study conducted from January to July 2015 in the Oncology Department of Guru Gobind Singh Medical College, Faridkot, Punjab, India. A total of 348 patients with cancer participated in the study. All participants provided formal written consent, and ethical clearance was obtained from the institutional ethical review board. Patients were included in the study if they were diagnosed with cancer, were visiting the institution to receive chemotherapy, and agreed to participate. The exclusion criteria included a history of other chronic disease, such as diabetes or heart disease, and any known mental problem or being treated with psychotropic drugs.16Patients were interviewed, and sociodemographic variables, medical history, medication history, number of drugs prescribed , current diagnosis, and current medication information were collected on a case record sheet. Data on the PMI score, pain severity, pain interference with daily life, and adequacy of analgesic use were collected, along with the Brief Pain Inventory (BPI) score and visual analog scales to evaluate pain and its impact on daily function. The PMI score is a simple index that usually indicates how well the reported level of pain is managed by the analgesics prescribed. A pain score of 0 was defined as an absence of pain, 1 as mild pain, 2 as moderate pain, and 3 as severe pain. The BPI pain score categorization is 0 for an absence of pain, 1 to 4 for mild pain, 5 to 6 for moderate pain, and 7 to 10 for severe pain.17 The PMI calculation was then determined by subtracting the worst pain score from the analgesic score. Patients with negative PMI scores were classified as receiving inadequate analgesic treatment for their cancer pain.A patient’s analgesic score on the PMI was calculated according to the type of analgesic prescribed by the physician. No prescribed analgesic was scored as 0, a nonopioid medication  was scored as 1, a weak opioid  was 2, and a strong opioid  as 3.2 test). All P values ≤ .05 were considered significant.Baseline distinctiveness  was summarized by descriptive statistics. Frequency, mean, percentages, and standard deviation were calculated wherever appropriate. Analyses to determine the association of patients’ adequately or inadequately managed pain with their age, sex, occupation, family history, duration, and cancer type were performed with appropriate statistical tests  were male and 221 (63.5%) were female. The mean age ± standard deviation was 52.12 ± 12.35 years . The leading age group in the total study population was 40 to 50 years of age. The most prevalent cancer type was genitourinary, diagnosed in 100 patients (28.7%), which included cervical, prostate, ovarian, endometrial, and testicular cancer, followed by breast cancer in 80 patients (23%) and head and neck cancer in 71 patients (20.4%). The most common occupation was housewife . A small number of patients  presented with a positive family history of cancer .Among the 348 patients, 268 (77%) had inadequate pain management/analgesia use, and 80 (23%) had better control of pain, as listed in The following groups had poor pain control: patients from 40 to 50 years of age (91.2%), males (81.9%) compared with females (74.21%), patients with genitourinary cancer (81%), patients taking nonsteroidal anti-inflammatory drugs (86.8%), and patients with higher BMI (obese), as listed in BPI scores were used to assess patients’ painful experiences as a result of cancer . AccordiA high prevalence of inadequate pain management (77%) was found in our study population of 348 patients with cancer. The most important observation was that no strong opioids were prescribed to any of the patients in this study. In accordance with our experience, the majority of participants were concerned about their pain, regardless of the cause, stage of disease, treatment modality, or prognosis. For this reason, pain symptoms must be prevented, treated as a priority, and considered an independent part of cancer management.18 in which approximately 29% to 48% of patients were inadequately treated for their pain symptoms.This study examined the prevalence of inadequate analgesic treatment of patients with different types of cancer. Among the 348 patients in the study, approximately 77% were poorly managed or were undertreated for pain, which is a much higher proportion than that shown in the study by Kirou-Mauro et al,15 A US study by Cleeland et al12 found that 42% of patients were undermedicated. A European study showed that 57.5% of patients were undermedicated for cancer pain.19 Compared with developed countries, the prevalence of undermedication is higher in Asian countries. In China, a study by Wang et al20 showed that 67% of patients were undermedicated for cancer pain. A study in South Africa by Beck and Falkson21 reported that only 21% of patients with cancer had achieved 100% pain relief. A Canadian study by Vuong et al22 reported that 33.3% of patients reported inadequate pain management, and 106 of 354 patients reported severe pain despite taking strong opioids. In India, however, the proportion of inadequately managed pain was 79%, as reported by Saxena et al.23Few studies from developed countries have shown a lower number of undermedicated patients or patients whose pain was inadequately managed compared with the present study. A meta-analysis of 26 studies on undertreatment revealed that 43% of patients with cancer presented with a negative PMI.24 Furthermore, in many developing countries, morphine and other analgesics are not available or are not in regular supply, they might be expensive, or physicians are reluctant to prescribe them and patients are reluctant to use them because of known adverse effects and concern about addiction.The reason behind this disparity in cancer pain management between developed and underdeveloped countries is mainly that the affluent population of developed countries has relatively easy access to health care and required prescription drugs, and a culture exists in which taking pain medications is not perceived negatively.25 found higher analgesic consumption rates among female participants. A study by Bernabei et al26 reported that the high level of well-managed pain in female patients with cancer may be attributed to their better knowledge about pain and pain management than men. In the current study, a higher BMI was related to poor pain control. A study by Stone et al27 showed a positive correlation between obesity and pain; explanations for this association include the effects of leptin and other hormones associated with excess fat and physiologic and psychologic factors associated with obesity, among others.This study showed that female patients (25.8%) had better pain management than did male patients (18.1%). Simone et al28 in the United States developed a standard in 2001 that established new requirements for the assessment and management of cancer pain, including the patient’s right to appropriate assessment and management, follow-up, staff competency in pain management, policies supporting appropriate prescriptions, education of patients, and monitoring of appropriateness and effectiveness of pain management. All health care institutions providing cancer care must address this standard to provide better pain management.The Joint Commission on Accreditation of Healthcare OrganizationsIn conclusion, the prevalence of inadequate pain management among 77% of the patients in our study was far too high and demonstrated that pain management was insufficient in more than three quarters of the patients. The undertreatment of pain-related cancer occurs worldwide and may fluctuate, depending on socioeconomic status, the patient’s culture, access to a doctor, the patient's inability to communicate the intensity of his or her pain, the reluctance of physicians to prescribe opioids, and patients’ reluctance to use opioids because of their known adverse events. Accumulating data regarding the inadequacy of cancer pain management is crucial to improve symptom management. We believe this study highlights the importance of cancer pain management and encourages providers to investigate the true status of cancer pain management. It also emphasizes the need for better education about pain and its control in the curricula of medical professionals. The systematic recording of pain intensity and follow-up of patients with cancer, regardless of the phase of the disease, should be routinely practiced in cancer wards. A better management approach will not only alleviate the pain symptoms but will also increase the patient’s quality of life.


In osteoarthritis (OA) clinical trials, a pain measure that is most sensitive to change is considered optimal. We compared sensitivity to change of patient‐reported pain outcomes, including a patient‐preference measure (where the patient nominates an activity that aggravates their pain).NA), as well as completing questions on overall knee pain and the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were also calculated from the KOOS. Standardized changes in each outcome were generated between treatment and control after 6 weeks intervention in the BRACE trial, and 1–2 weeks following intervention in the steroid trial.We used data from 2 trials of patients with confirmed (American College of Rheumatology criteria) knee OA: a trial of brace treatment for patellofemoral OA, and a trial of intraarticular steroids in knee OA. Both trials reported an improvement in pain following treatment. Participants rated pain on a 100‐mm visual analog scale (VAS), in the activity that caused them the most knee pain (VASNA produced standardized changes following treatment that were at least as large as other pain outcomes. In the BRACE trial, the between‐groups standardized change with the VASNA was −0.63, compared with the KOOS pain subscale change of −0.33, and pain in the last week VAS change of −0.56. In the steroid study, within‐group change following treatment in the VASNA was −0.60, compared to the last week VAS change of −0.51, and KOOS pain subscale change of −0.58.The VASPain on nominated activity appears to be at least as, and in some cases more, sensitive to change than the KOOS/WOMAC questionnaire. Pain is an outcome that is of particular interest to researchers in osteoarthritis (OA); it is highly clinically relevant and relatively easy to measure. For these reasons, pain is one outcome commonly collected in OA trials. The most commonly used outcome measure is the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Box 1To our knowledge, this article is the first to assess the sensitivity of a patient‐preference outcome measure, assessing pain in patients with knee osteoarthritis (OA).NA]) is only one simple question.We find that the sensitivity of this novel outcome is at least comparable, if not marginally superior to, the Knee Injury and Osteoarthritis Outcome Score and the Western Ontario and McMaster Universities Osteoarthritis Index. This is particularly useful, as the novel outcome .The VASSelf‐reported pain is often assessed via a single‐item index, e.g., a numerical rating scale (NRS) from 0–10 that rates pain in the last 24 hours. Alternatively, multi‐item questionnaires, such as the WOMAC and Knee Injury and Osteoarthritis Outcome Score (KOOS), can be used; these measures ask several questions on various aspects of pain in order to calculate a composite overall pain score. The questions used in multi‐item measures are typically fixed and inflexible between patients. This rigidity in wording allows the individual patient scores to be compared easily between patients, since they all answer the same question(s). However, there are limitations caused by fixing the question wording in this way. In a multi‐item measure, asking many correlated questions  in an attempt to provide a more comprehensive assessment gathers much more data. However, this is offset by the fact that 1) these questionnaires take longer to administer than a single‐item measure, and 2) there is a risk that many items may be irrelevant to the patient. In theory, irrelevant items will change less following an intervention than more salient ones, and therefore the sensitivity of a tool to detect change will be moderated by the relevancy of the questions asked.NA).Of single‐item approaches to assessing outcome in OA, an approach that allows for individual variability could be used. Such approaches might ask subjects, for example, to nominate an activity that most aggravates their pain, and then provides a rating score within that context (“Please indicate how much pain you have in that activity”). Current examples of such patient‐preference measures include the McMaster Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR) Comparisons of outcomes in trials in OA with regards to sensitivity to change To this end, we sought to characterize and compare pain self‐report outcomes, using data from 2 clinical trials in patients with OA that reported a statistically significant positive change in 1 or more pain outcomes, in an attempt to establish whether there was a difference between single‐ and multi‐item questionnaires, and particularly, whether a patient‐preference approach performed well with respect to sensitivity to change.Data from 2 interventional clinical trials on patients with knee OA were used in this analysis. In both trials, eligible subjects had to meet American College of Rheumatology criteria for knee OA The TASK (Targeting Synovitis Knee Osteoarthritis) trial (ISRCTN 07329370) was an open‐label trial of persons with painful knee OA monitoring response to intraarticular methylprednisolone. Participants were assessed just prior to treatment and approximately 1 week later last week) and pain during an activity nominated by the patient to be the most aggravating for their knee pain (VASNA). The TASK trial participants were additionally asked to score a patient global assessment on a 100‐mm VAS . All VAS scores ranged from 0–100 , where 0 indicated no pain at all and 100 indicated pain as bad as the patient could possibly imagine. Both trials have reported a positive effect  on pain outcomes.Patients were asked to complete the KOOS questionnaire, as well as 2 single‐item, 100‐mm VAS that rated pain in 2 situations: pain in the last week  to be made between the outcomes. In contrast, the more commonly used approach of simply deriving effect sizes for each outcome (Cohen's D) only allows comparison of the magnitude of effect sizes without formal statistical tests.Changes in standardized scores were calculated between the treatment and control groups in the BRACE trial at the 6‐week followup visit. The TASK trial featured an open‐label design without a control group; so the changes in standardized scores for this trial were calculated for the treatment group alone, assessing the change between the baseline and first followup visit after the intervention was applied.NA, VASlast week, KOOS pain subscale, KOOS symptoms subscale, KOOS activities of daily living subscale, WOMAC pain subscale, WOMAC stiffness subscale, or the WOMAC function subscale, coded as dummy variables) as a predictor variable. The KOOS sport and recreation and quality of life subscales were excluded from analyses, since many participants in both trials left more than 2 items blank (often more), precluding them from being scored in accordance with the KOOS user guide . We used participant identifier as the panel variable for the random‐effects model. For the BRACE trial analysis, we also included a predictor variable for treatment group, and an interaction effect between the treatment group and the outcome type.The initial aim was to compare the magnitude of changes in each outcome. We used random‐effects panel linear regression, with the standardized score at the followup visit as the outcome , the standardized score at the baseline visit as a covariate, and outcome type , x = standardized score at baseline, βjk = outcome × treatment group interaction, μ = model intercept, ui = subject‐level random effect, and Wij = error.Where i = patient, j = outcome  (coded as dummy variables), k = treatment, The random‐effects model for the TASK data is as follows:yij = standardized score at the postinjection followup visit, Xij1 = standardized score at baseline, Xij2 = outcome type  (coded as dummy variables), ui = subject, μ = model intercept, and Wij = error.Where The nominated painful activities reported by participants were collected in the form of a free‐text field. We split patients into subgroups based on their nominated activity “themes,” and attempted to match these to WOMAC/KOOS items to better understand the overlap between patient‐preference choices and these instruments.Statistical analysis was undertaken using Stata (version 13.1). We used a significance level of 5% in all statistical tests.Baseline characteristics of patients from the BRACE and TASK trial were generally similar Table . PatientNA had the greatest standardized change following treatment in the BRACE study (−0.63) for the between groups analysis  .Comparing the postintervention standardized differences across the different outcomes, the VASs Figure . Knee pa) Figure . SubsequNA and change in function in these items when the direction of stair travel matched . Another frequently nominated painful set of activities was squatting and kneeling, which again is not covered by the KOOS/WOMAC. Five additional themes nominated by participants were clearly not covered by the KOOS or WOMAC, and together these themes made up 30.2% of the BRACE participants’ nominated activities, and 19.0% of the activities of TASK patients  . The premise behind these methodologies NA, is to include a free‐text item that allows participants to vary the context of a question. All participants will still score pain throughout the trial, but it allows the participant to give an individualized response on pain in a framework (activity) appropriate and relevant to their situation. Allowing a question to be individualized by the patient may increase sensitivity to change, without adding information on other, less relevant activities.An alternative approach, used by the VASAsking a single question has other advantages than simply sensitivity/precision. While the activity themes reported in both trials were broadly similar, the proportions in which they were reported differed largely, with BRACE trial participants citing stairs or inclines much more often than those in the TASK trial. This is an unsurprising finding, given that the BRACE trial's inclusion criteria selected persons with patellofemoral OA, whereas the TASK inclusion/exclusion criteria allowed participants with more mixed disease. It also suggests that using fixed instruments like the WOMAC and KOOS for patellofemoral OA is likely to compromise sensitivity to change, whereas this choice may be more reasonable in trials of knee OA in general.There are a number of possible advantages to this more bottom‐up approach of involving patients’ perspectives directly in outcome measures in OA, as opposed to the top‐down method of the researcher deciding which questions are best for the patient. It includes more of a patient's view directly in the study. Furthermore, it provides additional data alongside a simple pain score, as patients also provide qualitative data on the sorts of activities that are painful to them, i.e., activities that might not otherwise have been considered. For example, we found many patients in both the BRACE and TASK trials appear to find either going up or going downstairs alone more aggravating to their pain, which contrasts with many pain questionnaires that ignore the direction of stair travel. A potential drawback to this approach is that while it aims to maximize sensitivity to detect a treatment effect, by selecting questions for activities that are most painful, it risks ignoring those activities that are most important to the patient's activities of daily living.last week) versus the WOMAC/KOOS pain scale. For the patellofemoral OA trial, the VASlast week was more sensitive to change than the KOOS/WOMAC, but that was not the case for the TASK study. The difference in VASlast week responsiveness between TASK and BRACE is an interesting finding, and the reasons for this observation are unclear. One possible explanation for this difference could be the different samples used in each of the trials. The TASK trial was comprised of subjects with mixed OA , unlike BRACE, which selected patients with patellofemoral OA only. The KOOS and WOMAC were specifically designed for use in mixed disease contexts, and it may be that the patellofemoral patients are not captured quite as well, hence the difference between the 2 trials. Given that the other outcomes are fairly consistent between BRACE and TASK, another possible explanation is linked to the focus of BRACE on patellofemoral OA versus TASK, which recruited a more general group of patients with painful knee OA. Our data do not permit us to conclude which of these alternative choices is likely to be consistently more sensitive to change in OA trials. Others have reported that a global pain question in a fixed timeframe is more sensitive to change than the WOMAC pain subscale Our analysis also included as a by‐product an examination of the comparative sensitivity to change of a global knee pain question  reasonably sure that a true treatment effect has occurred. It is difficult to selectively search for OA trials that are 1) positive, i.e., observed a true pain reduction, 2) in a mixture of OA subpopulations, and 3) collected data and reported on multiple collinear outcomes. Our study is at least informative in part, since our analysis used one trial focused on patellofemoral OA and the other unselected knee OA patients.Arthritis Care & Research web site at http://onlinelibrary.wiley.com/doi/10.1002/acr.22823/abstract). This is not an unexpected finding, given that all measures should theoretically measure the same construct , and should therefore have at least similar effect sizes. Given the similarity of these measures, it would require either large differences in effects, or large sample sizes to establish differences in outcomes. The trials we analyzed were neither designed nor powered to observe such small differences between outcome measures, and therefore the likelihood of observing truly significant differences was unfortunately lacking. In the future, we would recommend performing this type of analysis in larger real‐world trials. Another potential limitation is that use of a single question focused on pain with 1 activity may compromise content validity, the evaluation of all of the impacts of a disease.The analysis approach we used allowed us to test for differences between outcomes. While we did observe some statistically significant differences between outcomes, no one outcome was clearly superior in both trials in terms of sensitivity to change  has a large pain effect, and 2) is very long term; these are not uncommon properties of OA trials.If a patient nominates an activity in which pain is ameliorated completely following treatment, then that activity experiences floor effects, especially in a long‐term study. For example, a treatment that fully cures pain from sitting to standing after initial application would register no change at the subsequent followup, highlighting the importance of the activity that the patient selects. In a similar vein, in longer‐term followup, activities that were selected by participants at baseline may become less relevant as the pattern of disability changes. Allowing the patient to alter the selected activity should it reach the minimal score is complex, particularly if patients select an activity that is not in the same “dimension.” For example, a patient nominates “pain when getting up from sitting,” then improves in the trial, and then switches to “pain when doing exercise classes.” These 2 activities are acceptable on their own, at each visit, but it is unclear how comparable they are on a unidimensional scale, which is a limitation of the proposed flexible approach. CAT methods sidestep this issue through prior calibration of item‐bank questions to ensure that they all measure 1 common metric. A drawback of the VASNA uses a visual analog score to collect continuous data on pain. Some groups have reported that participants find VAS difficult to understand, leading to decreased response rates when compared to a Likert scale or NRS NA could be applied using an NRS , which would have the advantages of both sensitivity and increased response rates.The VASIn conclusion, we suggest that in knee OA studies patient‐preference instruments may offer sensitivity to change and the opportunity to detect treatment effects that might be missed by conventional fixed instruments. Our work needs to be corroborated in other studies.All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Mr. Parkes had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.Study conception and design. Parkes, Felson.Acquisition of data. Callaghan, O'Neill, Forsythe.Analysis and interpretation of data. Parkes, Lunt, Felson.Supplementary MaterialsClick here for additional data file.


This 1-year prospective cohort study aimed to compare the changes in clinical symptoms and functional disability between patients with coexisting patellofemoral (PF) and tibiofemoral (TF) osteoarthritis (OA) and those with isolated TFOA.Seventy-two patients with medial knee OA were enrolled. Knee pain and functional disability were assessed at baseline and at 1-year follow-up using the Japanese Knee Osteoarthritis Measure (JKOM) and a visual analog scale (VAS). We performed two-way analysis of covariance for the clinical outcome variables to examine, time (baseline and follow-up), group (coexisting PFOA and isolated TFOA), and time-group interaction effects. Furthermore, we conducted post-hoc exploratory analysis to address the possibility that dividing patients according to location of PFOA  may identify a distinct subgroup with different changes in clinical outcomes at 1-year follow-up.P = 0.012) and VAS (P = 0.033), adjusted for age, sex, and body mass index. Patients with coexisting PFOA have stable moderate level knee pain and functional disability throughout the year which is significantly worse than that in those with isolated TFOA. Post-hoc subgroup analysis demonstrated that change of knee pain likely varied with location of PFOA. Patients with isolated lateral PFOA had mild/moderate level knee pain, and their VAS scores were likely to improve, whereas those with mixed PFOA exhibited stable to worsening moderate/severe knee pain.We detected group effects only in scores of the JKOM pain subscale  contains supplementary material, which is available to authorized users. Osteoarthritis (OA) of the knee is a common chronic and degenerative disease and a major cause of knee pain and functional disability worldwide . GeneralAlthough patellofemoral (PF) OA remains an under recognized type of knee OA, patients with PFOA have been recently considered a subgroup different from patients with tibiofemoral (TF) OA . Duncan These studies suggest that patients with coexisting PFOA may have a natural course of the disease different from that in patients with isolated TFOA and may exhibit worsening clinical symptoms and functional disability over time. However, previous studies that investigated coexisting PFOA had a cross-sectional design , 13. A lAs described in the previous study , 143 patMethods for baseline radiographic evaluation of severity of OA of the TF and PF joints determination were described in detail elsewhere . In brieSeverity of self-reported knee pain was evaluated individually at baseline and 1-year follow-up, using a visual analog scale (VAS) and the “pain and stiffness” subcategory of the Japanese Knee Osteoarthritis Measure (JKOM) in person-specific assessments. The VAS score was interpreted as no pain (VAS ≤ 10 mm), mild pain (10 mm < VAS ≤ 30 mm), moderate pain (30 mm < VAS ≤ 60 mm), or severe pain (VAS > 60 mm) based on previous studies . The JKOSecondary outcomes included the other JKOM subcategories  evaluated at both baseline and 1-year follow-up. The JKOM subcategory “activities of daily living” is a self-reported physical functional assessment reflecting daily activities such as stair use, bending, standing up from a sitting position, walking, shopping, taking off socks, and performing light and heavy household duties.Data on age, sex, and height were self-reported by the patients. Weight was measured on a scale, with the participants wearing their clothes but not their shoes. Body mass index (BMI) was calculated by dividing the weight by the square of height.t-test for parametric continuous variables, Mann-Whitney U test for nonparametric continuous variables, or chi-square/Fisher’s exact tests for dichotomous/categorical variables. Next, we performed two-way repeated analysis of covariance (ANCOVA) for clinical outcome variables (JKOM and VAS scores) to assess the interaction between time (baseline and 1-year follow-up) and group (coexisting PFOA and isolated TFOA) adjusted for age (continuous), sex, and BMI (continuous) and further adjusted for TF joint K/L grade (continuous). As age, sex, BMI, and TF joint K/L grade were likely to affect the clinical outcome of OA [To minimize bias produced by similarities between the right and left knees of the same patient , only onme of OA , 20 and P-values <0.05 were considered to indicate statistical significance.To verify the possibility that dividing patients according to location of PFOA may identify a distinct subgroup with different trajectories of clinical outcomes at 1-year follow-up, we performed explorative subgroup analysis of the relationships between location of PFOA  and outcome variables by using subsamples of patients with coexisting PFOA. We performed a two-way repeated ANCOVA for the clinical outcome variables to assess the interaction between time (baseline and 1-year follow-up) and group  adjusted for age, sex, BMI, and further adjusted for TF joint K/L grade, with post-hoc pairwise comparisons. Furthermore, we calculated the percentage of patients having unacceptable symptoms representing a clinically relevant treatment target, defined as a VAS score above 30 mm , 34, 35,Our final sample included 72 patients/knees (response rate: 50.3%) with a K/L grade ≥2 primarily for the medial compartment. Patients who failed to complete the study were unable to be contacted or declined to be followed for non-specific reasons. Baseline characteristics were compared between completers and non-completers Table , and no Two-way repeated ANCOVA revealed no significant time-group interactions at any outcome variables, and only the group main effect was confirmed for all the outcome variables adjusted for age, sex, and BMI Table . FurtherP-value = 0.012) and VAS score . Nevertheless, clinical symptoms in patients with isolated lateral PFOA were likely to decrease during the 1-year follow-up . In contrast, clinical symptoms in patients with mixed PFOA were moderate/severe and stable or worsening throughout the year . Additionally, a multiple comparison revealed that “pain and stiffness” and VAS scores in patients with mixed PFOA were significantly higher than in those with isolated lateral PFOA when adjusted for age, sex, and BMI . Moreover, patients with mixed PFOA had consistently worse scores in the other JKOM subcategories and total JKOM score. When TF joint K/L grade was further adjusted for in the two-way repeated ANCOVA model, all the main group effects were attenuated (data not shown).Explorative subgroup analysis stratified for the patients with coexisting PFOA showed that pain trajectory depended on the location of PFOA Table . Two-wayP-value = 0.015), but not in those with isolated medial  and mixed  PFOA. Importantly, more than 65% of patients with mixed PFOA had consistently unacceptable symptoms throughout the year (change: from 65.1% to 73.9%).Individual pain trajectories Fig.  revealedThere is growing evidence that coexisting PFOA in patients with knee OA is common , and thiRecently, Nicholls et al. characterized distinct trajectories of knee pain using latent class growth curve modeling analysis, showing that patients labeled “mild, non-progressive,” “moderate,” or “severe, non-improving” constituted stable subgroups of two independent large datasets . Other sPrevious longitudinal studies of clinical symptom progression suggested heterogeneous outcomes in patients with knee OA, with knee pain improving in only some patients –5. In thInterestingly, the improvement in clinical symptoms in patients with isolated lateral PFOA may not be accompanied by significant functional improvement Table . This maOur study has several limitations to be noted. It is unknown whether the clinical symptoms and functional disability at the 1-year follow-up were affected by a bias due to missing values during this period. Therefore, follow-up losses need to be minimized to exactly characterize pain and functional changes in patients with coexisting PFOA. However, there were no significant differences between patients who completed the follow-up study and those who did not in baseline characteristics, which might indicate that data are missing at random. We confirmed that baseline knee pain intensity, which is a previously reported prognostic factor for worsening pain and disability , did notClinical symptoms and functional disability in patients with coexisting PFOA were overall stable rather than worsening at the 1-year follow-up. This indicates that patients with coexisting PFOA may be a clinically severe disease subgroup. Additionally, subgroup analysis revealed that patients with isolated lateral PFOA had mild/moderate knee pain, and their VAS scores were likely to improve, whereas those with mixed PFOA exhibited stable to worsening moderate/severe knee pain. This suggests that patients with coexisting PFOA might have heterogeneous clinical outcomes, and presence of mixed PFOA might be an indicator of severe clinical knee OA.


To examine whether hypoesthesia and chronic pain are related in patients with MS.  Sixty-seven MS patients with pain and 80 persons without MS were included. Sensory functioning was tested by bedside neurological examination. Touch, joint position , temperature sense, and pain  were tested. Pain intensity was measured by the Colored Analogue Scale (CAS Intensity) and the Faces Pain Scale (FPS); pain affect was also measured by CAS Affect and Number of Words Chosen-Affective (NWC-A). Mood was assessed with the SCL-90 anxiety and depression subscales and the Beck Depression Inventory (BDI).  A significant negative relationship was found between pain intensity and the function of the dorsal column-medial lemniscal pathway, but not with the spinothalamic tract.  In addition to the already known relation between hyperesthesia and pain, hypoesthesia for touch and joint position also seems to be related to chronic pain in MS patients. Chronic pain is a common symptom in multiple sclerosis (MS) . Betweendecline in sensory functions, for example, hypoesthesia to touch [A lesion in the brain or spinal cord may express itself in sensory disturbances. It is well known that MS is characterized by sensory disturbances reflected in both hyper- and hypoesthesia . Hyperesto touch –11. The to touch . Compareto touch . HoweverCompared with the role of the spinothalamic pathway in pain, little is known about the role of the dorsal column-medial lemniscal pathway in chronic pain in MS . In examThe cumulative goal of the present study was thus to examine a possible relationship between chronic pain intensity and affect, and a decline in sensory functioning in patients with MS. Such a relationship may be clinically relevant as it implies that the presence of chronic pain in MS may be reflected by both hypo- and hyperesthesia. This study hypothesizes that, depending on the types of sensory dysfunction, that is, temperature, pain, light touch, and position sense, hypoesthesia may also be indicative of chronic pain intensity, pain affect, or both.The present cross-sectional study was part of a larger study examining the relationship between pain and cognition in patients with multiple sclerosis , 17.From the larger study, we included in the present study 67 MS patients who suffered from chronic pain. MS patients were recruited from a center, specialized in MS and other neurodegenerative disorders in the Netherlands, or enrolled from the personal environment of the researchers. In each case, an official diagnosis of MS was made by a neurologist, according to the criteria of Poser or McDonald criteria , 19. We Both the MS patients and the control participants were screened for education. Education was divided into five categories: elementary school not finished (score = 1), elementary school (score = 2), lower secondary school (score = 3), higher secondary school (score = 4), and higher vocational training for 18+/university (score = 5).Both groups suffered from arthrosis/rheumatoid arthritis, musculoskeletal disorders (e.g. neck-shoulder pain), migraine, osteoporosis, and peripheral neuropathic pain. Peripheral neuropathic pain was due to metatarsalgia, carpal tunnel syndrome, low back pain with irradiation, and meralgia paresthetica. Probably, our participants did not suffer from central neuropathic pain reflected in an absence of allodynia. Chronic pain was defined as pain occurred during a period of 3 months or longer .Within the scope of the present study, we listed analgesics  and medication that might be related to sensory disturbances: sedatives , antipsychotics , antidepressives , anxiolytics , and neurological disorders .Comorbidities that might cause sensory disturbances, that is, diabetes, transient ischemic attack (TIA), migraine, and epilepsy, were listed (for a full list of comorbidities see ).Participants (patients and controls) were excluded if they had a history of neoplasms, cerebral traumata, alcoholism, normal pressure hydrocephalus, disorders of the central nervous system other than MS, or disturbances of consciousness.The local medical ethical committee gave their approval for the present study . The patients were asked to give oral and written consent after they had been extensively informed about the aim and procedure of the study. After permission, the neuropsychological, the sensory function, and the pain perception tests were obtained. The patients were able to discontinue their participation at any time during the current study.Sensory function was tested by a bedside neurological examination. In particular, it was tested whether the sensory function of the MS patient was normal (score = 2) or decreased (score = 1) on two levels: dorsal column-medial lemniscal function (by testing joint position and touch) and function of the spinothalamic cortical pathway (by testing temperature sense and pain). The classification from Svendsen and colleagues was used to assess the spinothalamic cortical pathway and dorsal column-medial lemniscal pathway .This pathway mediates fine touch and joint position. Fine touch was tested by applying a cotton wool on the dorsal side of the right and left hand, forearm, and upper arm. Joint position was tested by passively stretching or bending one finger of the patient. The patient was asked which finger has been stretched or bended. Three fingers of each hand were moved. Fine touch or joint position were considered to be disturbed if the participant failed, by giving one or more incorrect answers, to indicate whether they were touched or gave an incorrect answer concerning the position of the joint. During all of these tests the patients kept their eyes closed .This pathway mediates pain and temperature. Pain was tested by applying a pinprick with a needle with either a sharp or blunt end on the dorsal side of the participant's right and left hand, forearm, and upper arm. Temperature sense was evaluated by making a distinction between warm and cold. The investigator touches the dorsal side of the right and left hand, forearm, and upper arm with a small plastic bottle filled with either cold or hot water. The patient kept their eyes closed during the test. If the participant gave one or more incorrect answers, sensory function was considered to be disturbed .Two CAS scales were applied: one measures the intensity of pain (CAS Intensity) and the other measures the affective/emotional components of pain (CAS Affect) . The CASThis is the affective part of the McGill Pain Questionnaire (Dutch version) and is composed of 5 groups . Each grThis scale consists of seven different faces with different expressions. Each face represents an increased feeling of pain , 25. TheTwo pain domains were composed: (1) pain intensity, which is composed of the CAS Intensity and the FPS, and (2) pain affect, which is composed of CAS Affect and the NWCA. The MS patients were asked to indicate their level of pain during the last week. This way of measuring the level of pain is reliable, according to a study of Forouzanfar and colleagues .The extent to which patients were suffering from pain is presented in the Results section.As pain may be associated with depression and anxiety , three qThe scores of these three scales were first converted into z-scores. Subsequently, a reliability analysis resulted in a Cronbach's alpha of 0.84. Next, we made a composite domain score “mood.”The pain scales  and sensory tests  were administered in one session. First, the pain scales were conducted from the patient, after which the sensory functions were assessed.t-tests, and Mann–Whitney U tests were applied to analyze data between groups. As some cells had a low cell count, statistical significance was established by means of Fischer's exact tests (two-tailed). The relationships between chronic pain, the dorsal column-lemniscal pathway, and the spinothalamic tract were analyzed by hierarchical linear regression analyses: one model predicting pain intensity and one predicting pain affect. In the first step, mood was added as a predictor; in the second step, the dorsal column-medial lemniscal pathway; and in the third step, the spinothalamic tract was entered. Adjusted R2 and R2 are reported as measures of model fit and ΔR2 as a measure of the effect of sensory functioning  on pain while controlling for mood. The level of significance was set at p < 0.05.We used the SPSS-PC program for the data analyses. Chi-square tests, t (145) = 1.46; p=0.15).The mean age of the MS patients  did not differ significantly from the mean age of the control group  .The distribution of gender within the group of MS patients is as follows: 66.2% women and 33.8% men. Within the control group, the distribution of gender was 66.3% women and 33.8% men  = 0.55; p < 0.59).The mean level of education of the MS patients is 3.57 (SD = 0.76). The mean level of education of the control group was 3.50 .With respect to depression and anxiety, MS patients showed significant higher scores than the controls .23.9% of the MS patients had decreased sensibility to touch. Disturbances in joint position were found in 25.8% of the MS patients. Both sensory functions were significantly more disturbed in MS patients than in the control group  and a group of patients without sensory disturbances. We were interested whether, compared to MS patients without sensory disturbances, those with sensory disturbances suffered more from comorbidities that might have caused those sensory disturbances. As can be seen in U tests show that MS patients suffer significantly more from pain intensity and pain affect, compared to controls  were examined by means of chi-square test and Fisher's exact test. The results show that concerning analgesics, only cannabis differed significantly between both groups; MS patients with sensory disturbances used significantly more cannabis than those without sensory disturbances. No significant differences between both groups were observed concerning the other medications that might be related to sensory disturbances . Adding the functioning of the dorsal column-medial lemniscal pathway explained an additional 10% of variance in pain intensity (Model 2). There was no significant change in explained variance in pain intensity, after adding the function of the spinothalamic tract (Model 3) .The results of a hierarchical regression analysis show a significant relationship between mood and pain affect, explaining 9% of the variance in pain affect (Model 1). No significant relationships were found between pain affect and the function of the dorsal column-medial lemniscal pathway (Model 2) and between pain affect and the function of the spinothalamic tract (Model 3) .The goal of the present study was to examine a possible relationship between hypoesthesia and chronic pain in MS patients. The main finding relates to our observation of a significant negative relationship between pain intensity and hyposensitivity concerning light touch and joint position  . This fiThe rationale is that chronic pain, known to be present in MS , may be The main finding yielded related questions. One of these include whether MS patients with sensory disturbances differed from those without sensory disturbances concerning comorbidities that might provoke sensory disturbances. This appeared not to be the case . A similCompared with controls, the use of baclofen, paracetamol, and cannabis was significantly higher in our MS patients . The higOur finding concerning the relationship between hypoesthesia and pain intensity in MS patients may be clinically relevant. In cases of hyperesthesia, a patient may respond quite vividly to light touch, for example, due to a considerable increase in pain , even whsymptoms instead of major depressive disorders [Our results further show that compared with controls, MS patients had higher scores on scales measuring mood, more specifically depression and anxiety . The relisorders . We obseisorders . Feisteiisorders  emphasizisorders . They alisorders .The present study has several limitations. Firstly, we were unable to perform quantitative sensory testing (QST) to examine sensory function in MS patients in an objective way. This is because our study was based partly on Svendsen and colleagues' study , which eβ fibers  or by laser-evoked potentials that are transmitted by Aδ fibers (nociceptive) [In addition to QST, a neurophysiological examination in a study on pain in MS could be conducted, for example, by measuring somatosensory-evoked potentials that are transmitted by thick-myelinated Aceptive) .Another limitation of the present study is that we did not observe central neuropathic pain in our patients. Central neuropathic pain might occur in 50% of the MS patients . Althougwithout chronic pain in the present study. Such a control group would have been appropriate to examine the clinical and neuropathological characteristics of MS patients who do suffer from chronic pain.A final limitation is that we did not include an MS group could be an indication of chronic pain in MS patients.The present study indicated a negative relationship between hypoesthesia, for light touch and joint position, and pain intensity in MS patients who suffer from chronic pain. As a consequence, the clinician should be aware of the fact that, although hypoesthesia need not per se be related to chronic pain, it


Patients with low familial support may also benefit from PTSD screening and referral but further study is needed.Individuals with chronic pain often have psychiatric disorders, such as depression and posttraumatic stress disorder (PTSD), which can affect their intimate relationship satisfaction and stability. Little is known about the nature of support stemming from chronic pain patients’ intimate relationships, and therefore, this study sought to: (1) use cluster modeling to construct specific intimate relationship groups based on types of support patients receive, and (2) determine if there is a relationship between support type and PTSD, chronic pain, anxiety, and depression. Ward’s method of cluster analysis in Stata was used to create groups based on the level of informational, affirmation, confident, emotional, and fun support received from chronic pain patients’ most intimate relationship. Three types of support were identified: high , high emotional/low instrumental , and unstable . Types 1 and 3 included more family members , than type 2 (77%). Type 2 patients experienced more trauma (Mean = 9.4 ± 1.7 vs. 7.5 ± 0.88 for types 1 and 3) and were significantly more likely to have PTSD (X Chronic pain is one of the most common symptoms treated by primary care physicians (PCPs) in the United States. With an estimated 126.1 million adults suffering from some type of chronic pain in the past three months . A numbeMeanwhile, large multi-site studies, like the Adverse Childhood Experiences study, have shown how childhood exposure to traumatic events is associated with a marked and graded increased risk of future health problems. Kaiser Permanente healthcare member patients exposed to four or more childhood traumas engaged in riskier health behaviors  and had more negative health and mental health outcomes  . FurtherGiven that trauma-exposed chronic pain patients often have limited functioning due to their pain and a higher burden of chronic disease, they may need to rely more heavily on their social support networks  and clinicians . For clinicians, the quality of patients’ social support networks are of significant concern; these network members encourage or discourage healthy or unhealthy behaviors and may support compliance with, and utilization of, healthcare. The inability to relate to an intimate partner may also more broadly define the patient’s relationships in general, including the patient-healthcare provider relationship. That is, patients with PTSD who are unable to trust, have high levels of irritability, and anger easily, have difficulties with impulse control , and may(1)What types of social support and social stressors exist for trauma-exposed chronic pain patients in their most intimate relationships?(2)Do some trauma-exposed chronic pain patients experience more social support and stressors than other trauma-exposed patients within their relationships?(3)Is the quality of these relationships significantly related to other outcomes of traumatized chronic pain patients, including level of pain, anxiety, PTSD and depression?To better understand both chronic pain patients and their social support networks, we conducted detailed, semi-structured interviews with 41 chronic pain patients. In doing so, we sought to answer the following research questions:Forty-one patients were recruited from four primary care clinics affiliated with a large regional hospital system in St. Louis, Missouri to participate in detailed, semi-structured interviews. Together, the four sites service patients and families from diverse socioeconomic, ethnic/racial, and urban/rural backgrounds. Inclusion criteria for the sample included being over the age of 18, a current patient at one of the four clinics, and a diagnosis of chronic pain (lasting three months or longer). Exclusion criteria included individuals who cannot speak English and who lacked the cognitive capacity to provide consent, who did not have a chronic pain condition, and who had not been exposed to a DSM 5 qualifying traumatic event. Cognitive capacity was determined by a review of the electronic medical record, and if the interviewer detected possible cognitive defects, the Mini-Mental Status Exam (cutoff = 27) was administered .After participants agreed to participate in the study, a trained research assistant interviewed participants about their close social networks. Study participants were then asked to complete a self-administered survey that assesses sociodemographic, health, and mental health characteristics. All of the interviews were conducted by master’s level professional research assistants with a background in either social work or public health. Research assistants read the survey questions to participants with reading difficulties and recorded their responses. This study was approved by the internal review board at Saint Louis University School of Medicine (IRB Number 22321).Adapted from the Social Convoy Model ,13, reseHealth and mental health characteristics included both physical (level of pain) and mental health . Level of pain was assessed using a 1–10 scale with 10 being the worst pain ever experienced and 1 being no pain. We utilized the Patient Health Questionnaire (PHQ-9) to assess symptoms of depression and the Beck Anxiety Inventory—Primary Care (BAI-PC) to assess symptoms of anxiety. The psychometric properties of both instruments are well established , cutoff ≥ 15) ,  were used.Complete patient PCP and chart data was extracted to Stata v. 13.0 (Stata Inc.)  and demoParticipants were mostly female (61.0%) and had a mean age of 52.9 (SD = 12.7). About half of the participants were White (51.2%) and the other half African American 48.8%; . Thirty One hundred percent of participants had experienced a potentially traumatic event with the number of events ranging from 1 to 19. Reported traumatic events included combat (2.4%), assault by stranger (46%), assault by someone known (63%), sexual assault by a stranger (20%), sexual assault by known someone (29%), life threatening accident (56%), natural disasters (27%), life threatening illness (44%), torture (12%), kidnapping (20%), and incest (27%). the mean number of traumatic events was 7.9 . About 27% of the sample had a probable diagnosis of PTSD, 24% had depression and 59% had anxiety. Mean pain score was 5.1 (SD = 2.1).Analysis identified three clusters of social support. These types included Type 1: High support overall, Type 2 high emotional/instrumental support and Type 3 unstable support. Type 1, in which 100% of its members experienced instrumental, informational, affirmation, confident, emotional, and fun support from their most intimate relationships see . Type 1 Type 2 had the most non-familial individuals as their most intimate relationship (33%). These relationships had high levels of informational (100%) and affirmation support (100%), and most of them provided confidant (78%) and emotional support (89%). Nearly one quarter (22%) of the most intimate relationships in type 2 were considered quite stressful or extremely stressful. These relationships were less trusting than type 1 with 22% trusting their most intimate relationship not at all or a little bit. Nevertheless, type 2 participants did not find the person who was in the intimate relationship with them to be critical or disapproving of them, did not experience too many demands from this person nor this person to be verbally aggressive , but some found it challenging (22%) to measure up to the expectations of their most intimate relationship.Type 3 had social support networks more biological/familial in nature than type 2 with only 7% stating that their most intimate relationship was with a friend, roommate, or other person. Type 3 individuals received unstable support across the board with only 45% having instrumental support (slightly higher than type 2), 13% having informational support, 27% affirmation support, 47% confidant support, 53% emotional support, and 40% fun support. Type 3 was the only group to experience verbal aggression from their most intimate relationship . This higher tendency toward verbal aggression was also reflected within other relationship stressors: 53% of this group thought their most intimate relationship made their life quite a bit more or extremely stressful; 40% did not trust their most intimate relationship; 74% thought that their most intimate relationship was too critical or disapproving of them; 53% thought that they did not measure up; and, 40% thought that this relationship was too demanding. Open-ended responses in Demographic factors were explored across each of the three social support subtypes. Type 3 was older than the other groups (mean age 57.0 (SD = 3.4) vs. mean age 47.7 (SD = 4.5) type 2, mean age 51.8 (SD = 2.8) type 1). More males were in types 2 and 3. Type 1 members were more likely to be married than other groups (52.9% vs. 33.3% types 2 and 3) and to be employed (35% vs. 11.1% types 2 and 3), while type 3 members tended to have a higher income. Fewer African Americans had type 1 subtype relationships than Whites.2 = 7.91, p < 0.05. The level of pain among subtypes was similar with 5.2 (SD = 0.6) type 1, 5.4 (SD = 0.8) type 2 and 4.8 (SD = 0.5) type 3. Although non-significant, individuals with type 2 intimate relationships were more likely to have anxiety (77.8% vs. 52.8% for types 1 and 3) and depression (44.4% vs. 18.8% for types 1 and 3).Type 2 reported experiencing more potentially traumatic events (mean 9.4 (SD = 1.7) vs. mean 7.5 (SD = 0.9) for types 1 and 3 and was significantly more likely to have PTSD (55.6% vs. 33.3% type 3 and 5.9% type 1)  was associated with higher trauma exposure and PTSD. They also tended to be comprised of individuals who were non-familial (friends or other types of relationships) but there was no significant relationship between familial relations and intimate relationship clusters.Studies show that individuals with chronic pain are more likely than other groups to rely on their most intimate relationships to play a caregiving role . CaregivChronic pain patients exposed to potentially traumatic events do benefit from high levels of social support . They exClinicians should consider chronic pain patients’ sense of equity within intimate relationships. Part of treating chronic pain patients is related to restoring a sense of equity with their intimate relationships by involving their intimate relationships in determining ways in which the patient can reduce their benefits (rely less on caregiver), do more things for the caregiver or do things differently for the caregiver. When significant traumatic events and PTSD has increased the chronic pain patients’ level of irritability, anger, and willingness to engage in intimacy, then PTSD screening and additional cognitive therapies like cognitive processing therapy for couples with mental health professionals should be considered.Several limitations were present in this study. First, the sample size is very low and is concentrated in a Midwestern city where the majority of residents were either White or African American. Because of limitations related to power, we were not able to use more sophisticated statistical methods to assess the role of potential confounding factors, such as income, health conditions, etc. Thus, results-related clusters of social support should be interpreted with caution. These results are preliminary and could change if additional subjects were added to the existing dataset. Nevertheless, this study is novel because it is one of the first to determine the qualities of chronic pain patients’ intimate relationships. Chronic pain patients need individuals to provide caregiving and tend to be more likely to have trauma exposure and PTSD, which puts additional stresses on these relationships. Therefore, an exploratory study of the most intimate social support networks is useful for understanding chronic pain patients needs and determining whether to integrate social support arrangements into treatment planning. Future studies utilizing larger samples from a more diverse geographic locations could build on these findings. Future studies could also use qualitative methodology to derive a better understanding of relationship problems of chronic pain patients with and without trauma exposure.In this study, we constructed three clusters of intimate relationship social support among trauma-exposed chronic pain patients. We found that a significant proportion had very supportive intimate relationship social networks. However, the other two groups experienced varying degrees of stress in their relations plus less instrumental support. Clinicians should ask chronic pain patients with known trauma about the status of their social support networks in order to determine whether they are receiving appropriate support to enhance functioning, health behavior and future chronic pain outcomes.


Chronic pain occurs in 20–30% of patients after hernia surgery. As a consequence of this chronic pain, almost one third of patients have limitations in daily activities. Frequency and severity of this pain varies with different techniques of hernia repair. The objective of this study was to compare polypropylene suture and skin staples for securing mesh in uncomplicated ventral hernioplasty in terms of acute and chronic postoperative pain and to compare the time taken for mesh fixation between polypropylene sutures and skin stapler in ventral hernioplasty.This study was conducted in Surgery Department of Dow University Hospital, Dow University of Health Sciences, Ojha Campus and included 53 patients from Jan 2015 to Dec 2016, after taking informed consent. All patients were operated under general anesthesia by the same surgical team. Patients were randomized into two groups; in one group mesh fixed with 2/0 polypropylene suture while in other group mesh stapler was used. Time taken to apply mesh was noted in minutes from laying the mesh over anterior rectus sheath to completion of fixation by either method. The severity of post-operative pain was measured with VAS (1-10) after one week, one month and after one year after surgery. Data was analysed using SPSS version 17.Patient characteristics and operative outcome were similar in the two groups and statistically non-significant in both. Early postoperative pain was more after suture fixation but it was not statistically significant. Mean ± SD pain score was after one week 3.47±2.7 after sutures while 2.91±1.88 after stapler. After four weeks, 0.40±0.49 after suture while 0.35±0.48 after stapler fixation. In both study groups 30–34% of the patients felt some pain in follow-up after one year. Severity of pain was 0.60±0.62 after suture while 1.65±1.94 after stapler fixation which is statistically significant as well (p<0.007). Mean operative time was 15.33±6.33 minutes for suture fixation while 1.56±0.41 minutes for fixation by staples, p-value < 0.001.The method of fixation does not appear to cause significant difference in early post-operative pain but chronic pain is more after stapler fixation of mesh. However, operative time was reduced significantly in staple fixation group as compared to suture fixation group Ventral hernia is the bulging of part of the contents of the abdominal cavity through the musculoaponeurotic covering of the anterior abdominal wall. Ventral hernias include incisional hernia  and umbilical and epigastric hernias (10%) of hernias).9The rationale of our study is to evaluate a method of mesh fixation for ventral hernia repair. Mesh fixation in ventral hernioplasty by skin staples is hypothesized to decrease chronic pain after hernia repair. Mesh fixation in ventral hernioplasty by skin staplers will take shorter time than by sutures. Less operative time will decrease infection rate. Less mesh handling in experimental group will again decrease operative time. More knots of suture material are expected to cause more acute and chronic pain in comparison to skin staples.This randomized control study was conducted in Surgery Department of Dow University Hospital, Dow University of Health Sciences, Ojha Campus and included 53 patients from Jan 2015 to Dec 2016. The sample size was calculated by OpenEpi calculator. The mean pain score difference between two fixation techniques was taken as 0.7 .All patients after fulfilling the inclusion and exclusion criteria were verbally explained the procedure of mesh fixation in control and experimental groups. Written consent forms in English and Urdu were provided to the patients and collected after one week in the pre-operative outpatient clinic. Patients agreeing to be included in the study were randomized into two groups: group A in whom mesh was fixed with polypropylene suture and group B in which mesh was fixed with rotatable head skin stapler by Ethicon Johnson & Johnson.All patients were operated under general anaesthesia. After dissection and opening the hernia sac, contents were reduced and repair with polypropylene suture no 1 was done. Tailored 15 × 15 cm mesh was used according to the size of hernia gap. Onlay meshplasty was done in group A with polypropylene suture no 2/0 and in group B with staples. Time taken to apply mesh was noted in minutes from laying the mesh over anterior rectus sheath to completion of fixation by either method. The severity of pain was measured with Visual Analogue Score (1 to 10) after one week, one month and one year of operation. All data was entered in Proforma.All statistical analysis was performed using SPSS software version 17. Description of study variables were reported using descriptive statistics; mean and standard deviations were reported for continuous variables like age, BMI and operative time; and frequency and percentages were reported for categorical variables including sex, hernia site and size, hospital stay, and fixation techniques (outcome variable). Normality for continuous variables was assessed using Shapiro-Wilk Test . To assess the association between fixation techniques and all study variables Chi-square analyses for categorical variables and independent t-test for continuous variables were performed, for non-normal continuous variable Mann-Whitney test statistic was used. Association between Visual Analogue Score (VAS) and fixation techniques at different time periods was also assessed using Mann-Whitney nonparametric test, and all results were reported as p-values. Significant criteria was used as p-value <0.05.A total of 53 patients were included in the study that met inclusion and exclusion criteria, all selected individuals were randomly assigned to both fixation technique groups. After discharge, individuals were followed up at outpatient department at time period of one week, fourth weeks and one year.Mean age of participants was (44.55±8.74), mean BMI (30.04±5.05), and females were dominant as compared to males (84.9% vs. 15.1%). Patients with suture fixation were 56.6% (n=30), and with staple fixation technique were 43.4% (n=23). Incisional and Paraumbilical hernia site were found more common.Clinical and operative characteristics of patients according to fixation technique areshown in Postoperative pain scores in both fixation groups at different assessment periods were reported in Ventral hernia is a common condition accounting for about 150,000 hernia repairs being done in USA every year.We found significant differences in mean BMI of both groups , however mean age was not different significantly in the two comparative groups . This was not consistent with the recent studies of Beldi G et al. done in 2011 and of Wessenaar E et al. done in 2010, as both studies have shown similar demographic parameters.In our study there was a significant difference in operative time between the two study groups with a p-value of <0.001, suture fixation 15.33±6.33) had a higher operative time as compared to staple fixation (1.56±0.41). This finding was consistent with three other studies of Dhillon RS et al., Khan AA et al. and Sheikh FA et al. done in 2008, 2014 and 2013 respectively..33±6.33 13We have studied postoperative pain scores at one week, four weeks and one year in both groups. At first week pain was more severe after suture fixation than staple fixation but the difference was statistically nonsignificant. However chronic postoperative pain was more severe among patients of staple fixation group as compared to suture fixation with p-value of 0.007. These findings were not consistent with some studies as it has been reported that there is no significant difference in chronic pain after meshplasty between the study groups in the studies of Sheikh FA et al., Kitamura RK et al., Beldi G et al., Wessenaar E et al. and Colak E et al.14In a study done by Chatzimavroudis G et al. in 2017 it was concluded that none of the evaluated fixation method proved to be ideal.16The method of mesh fixation does not appear to cause any significant difference in early post-operative pain after meshplasty of open ventral hernia repair but chronic pain is more after stapler fixation of mesh. However operative time was reduced significantly in staple fixation group as compared to suture fixation group.NS: Did statistical analysis, manuscript writing, revising critically, editing and final approval of manuscript.FJ: Conceived, designed, did data collection, editing, revising critically and final approval of manuscript.MJ and IZ: Helps in data collection and final approval of the manuscript for publication.