Most patients with multiple myeloma (MM) suffer from chronic pain at every stage of the natural disease process. This review focuses on the most common causes of chronic pain in MM patients: (1) pain from myeloma bone disease (MBD); (2) chemotherapy-induced peripheral neuropathy as a possible consequence of proteasome inhibitor therapy ; (3) post-herpetic neuralgia as a possible complication of varicella zoster virus reactivation because of post-transplantation immunodepression; and (4) pain in cancer survivors, with increasing numbers due to the success of antiblastic treatments, which have significantly improved overall survival and quality of life. In this review, non-pain specialists will find an overview including a detailed description of physiopathological mechanisms underlying central sensitization and pain chronification in bone pain, the rationale for the correct use of analgesics and invasive techniques in different pain syndromes, and the most recent recommendations published on these topics. The ultimate target of this review was to underlie that different types of pain can be observed in MM patients, and highlight that only after an accurate pain assessment, clinical examination, and pain classification, can pain be safely and effectively addressed by selecting the right analgesic option for the right patient. Multiple myeloma (MM) is the second most common haematological malignance after non-Hodgkin lymphoma, representing 1.8% of all new cancer cases and the 14th cause of cancer death in the US .Osteolytic bone lesions are one of the most common complications of MM, with up to 90% of patients complaining of bone pain. In one third of patients, MM is diagnosed after a bone fracture, leading to severe pain and increased morbidity and mortality . Due to Finally, the improvement in therapeutic options for MM, together with supportive care, have significantly increased the percentage of patients who survive the disease; however, they may present specific “cancer survivor” syndrome, characterized by chronic pain, fatigue, insomnia, depression, physical and psychological impairment, cognitive dysfunction, cancer-related neuropathies, and overall reduced quality of life .In this narrative review, the authors intended to offer an overview of the different pain syndromes that physicians, particularly non-pain specialists, may encounter when they manage patients with MM. The pathophysiological mechanisms of chronic pain, along with the intensity, are the basis for establishment of an appropriate analgesic plan for adequate pain relief  and for Specific cancer types, including MM, lung, prostate, breast, and kidney cancer, are commonly associated with bone metastases. Bone lesions often lead to skeletal complications, which are commonly described as skeletal-related events (SREs), including pathological fracture, the need for bone radiotherapy or bone surgery, spinal cord compression, and hypercalcemia. These complications may reduce overall survival and are accompanied by severe chronic pain, loss of mobility and social role, and significant decrease in QoL .Osteolytic bone lesions occur in 80%–90% of patients with MM, with back localization being a presenting feature in over three quarters of patients. Myeloma bone disease (MBD) is associated with a number of clinical consequences including bone pain (70%–80%), fractures (50%–60%), hypercalcemia (15%), and spinal cord compression (2%–3%) [The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines suggest a multidisciplinary approach, including all the health care professionals (HCPs) involved in the management of cancer patients . Treatme+ sensory nerve fibers (A-delta), while it does not receive innervation from larger A-beta fibers and TrkA− unmyelinated C fibers. Bones are deep structures that do not require the sensitivity of the skin to fine touch, light pressure, and brushing; therefore, they do not receive A-beta fiber innervation. Bone sensory fibers are probably silent nociceptors, which are activated only in case of trauma or injury [The adult skeleton is innervated by thinly myelinated, tropomyosin receptor kinase A (TrkA)r injury . Acute ar injury . Normal r injury .Investigating skeletal pain pathophysiology may suggest potential new targets of analgesic treatment. Future targets for analgesia in MM-induced bone pain could also include the acid-sensing channels 3 (ASIC3). Protons released during bone resorption create an acidic bone microenvironment that excites bone sensory neurons via activation of ASIC3 .Bone injury, similarly to other musculoskeletal conditions, induces peripheral and central sensitization, which amplifies the perception of pain. In particular, the neuroplasticity phenomena occurring in the dorsal horn of the spinal cord causes exaggerated pain sensation after even non-painful stimuli  or increased pain perception after even mild painful stimuli . These central nervous system functional and structural modifications are implicated in the process of pain chronification . AlthougThese finding suggest the use of a central analgesic for managing severe chronic bone pain, and the integration of adjuvants such as gabapentioids and antidepressants to manage the neuropathic component of MBD.MBD is characterized by dysregulation of the physiological bone remodeling, defined as the interaction between bone marrow, osteoclast, osteoblasts, osteocytes, and the immune cells. MM cells alter the bone marrow microenvironment and induce apoptosis in osteocytes. Additionally, growth factors such as osteopontin, released by the resorptive process, increase the growth of MM cells  and inhiManagement of MBD is always palliative, but it is essential for improving patients’ quality of life and includes antiresorptive therapies, with the aim of preventing further SREs, and radiotherapy, surgical procedures, corticosteroids, and analgesics in order to reduce the intensity of bone pain.ESMO practice guidelines on multiple myeloma strongly suggest the use of antiresorptive treatments in myeloma patients with bone disease for two years, and to eventually restart the treatment in relapsed patients . AntiresBisphosphonates (BPs) are the cornerstone of antiresorptive therapy in the management of MM. They act by inhibiting bone resorption, with a direct apoptotic effect on osteoclasts, which rapidly uptake BPs bound to the exposed mineralized bone . Bone leOral clodronate (CLO), intravenous pamidronate (PAM), and intravenous zoledronic acid (ZA) have been approved for the management of MBD. Overall evidence is weak to recommend one bone-modifying agent over another and to define the optimal duration of the treatment. The main results of randomized controlled trials (RCTs) on BPs in MBD are presented in The European Myeloma Network suggests all MM patients presenting with adequate renal function and osteolytic disease be treated with intravenous BPs . SimilarA recent Cochrane meta-analysis evaluated the role of BPs in improving overall survival in MM by analyzing 24 placebo-controlled RCTs and four RCTs versus an active comparator. The results showed that BPs may reduce pathological vertebral fractures, SREs, and pain in MM patients; however, there is only moderate evidence for their reducing mortality .In general, multiple RCTs on BPs in MM have shown a significant reduction in the incidence of SREs; however, data on their efficacy as analgesics are still lacking. The Medical Research Council (MRC) Myeloma IX trial reported a significant improvement in pain, fatigue, QoL, and physical functioning in MM patients treated with combined therapy with BPs (clodronic acid or zoledronic acid) and induction treatment .In 2018, the Food and Drug Administration (FDA) approved denosumab for the prevention of SREs in patients with MM. Denosumab is a fully human monoclonal antibody that targets RANKL, which is an essential mediator for osteoclast survival and activation. In a recent phase 3, double-blind RCT, denosumab in patients with newly diagnosed MM was been shown to be non-inferior to zoledronic acid for time to first SRE, suggesting a potential role as an alternative to BPs in the management of MBD. Overall survival and side effects were similar in the two groups, with neutropenia being the most common (15% in both groups) and pneumonia being the most serious (8% in both groups) adverse events .Denosumab is administered subcutaneously at 120 mg monthly. Of relevance could be the different impact of these two drugs on renal function, which is impaired in up to 60% of patients with MM, often limiting the use of BPs. Nephrotoxicity is, indeed, a well-known side effect of zoledronic acid, while denosumab is better tolerated in terms of significant increases of creatinine levels. No data were available in this trial on the analgesic effects of the two comparators.The number of MM patients treated with denosumab is still too limited to suggest any specific recommendation on its use and indications on how to stop. Denosumab does not show prolonged activity after discontinuation, and therefore immediate bridging with BPs is recommended .Radiotherapy (RT) alone is generally highly effective for bone pain, with a response rate higher than 85% . The resPatients with pathological vertebral fractures and without spinal cord compression should be considered for vertebroplasty. Percutaneous vertebroplasty is a minimally invasive procedure involving the injection of polymethylmethacrylate (PMMA), bone cement, into the vertebral body. Kyphoplasty is a similar procedure where an inflatable balloon is placed into the vertebral body before the injection of bone cement. Both techniques are indicated in patients with vertebral compression fractures (VCFs) and result in effective pain relief, better mobility, and improved performance status . These mThe analgesic effect of these techniques may be related to different factors. PMMA has a direct cytotoxic effect, which could cause necrosis of the tumor tissue, and has been shown to stabilize microfractures. Moreover, heat generated during the polymerization of PMMA may contribute to destruction of nerve endings in the vertebral body .The Cancer Patient Fracture Evaluation (CAFE) study was a multicenter RCT which randomized patients who had cancer and one to three painful VCFs to receive kyphoplasty or non-surgical management. Back-specific functional status at one month was significantly improved in the kyphoplasty group, with the report of a rapid onset of pain relief . HoweverCorticosteroids such as prednisone and dexamethasone are included in all major treatment regimens in MM, both in front-line treatment and for relapse/refractory disease . MoreoveAdequate pain control is of crucial importance for the quality of life of myeloma patients, and analgesics are essential in the management of BMD. Osteolytic lesions are often the first clinical symptom of MM. Even in patients where invasive treatments  are indicated, an effective analgesic treatment should be promptly started while waiting for the surgery. Moreover, most patients treated with other systemic treatments, such as bone-target agents, may require analgesic support to obtain adequate pain relief.Managing chronic pain require adequate pain assessment through accurate medical history, physical examination, review of clinical records, and further investigations. Pain should be evaluated in terms of location, onset, duration, severity, and quality. Alleviating and aggravating factors should be investigated. Impact of pain on mood, sleep, daily activities, functionality, and QoL is essential for assessment. Previous analgesics, reported adverse events, and ongoing response to treatment is a useful basis for managing pharmacological treatment. Personal characteristics, comorbidities, and concomitant medications help physicians to select the right drug for the right patient .Among non-opioids, non-steroid anti-inflammatory drugs (NSAIDs) are not recommended due to their potential nephrotoxicity, especially in MM patients where kidney function is usually affected by the disease itself and by BPs. Acetaminophen, up to 4 g daily, is a safe and well tolerated drug for mild acute and chronic pain, even in the most vulnerable patients. There is no evidence to support or refuse the use of NSAIDs or acetaminophen alone or in combination with opioids for mild to moderate cancer pain .Opioids are still the mainstay in the management of severe cancer pain. The oral route of administration should be considered as the first choice, except when oral intake is not possible. Individual titration is strongly recommended to achieve adequate analgesia without intolerable side effects. Both short-acting opioids (SAO) and long-acting opioids (LAO) can be used during titration, while transdermal formulations should be reserved for patients using a stable dose of opioid analgesics .Opioids act mainly in the central nervous system, where they modulate the ascending pain pathway. Opioids induce analgesia by binding to mu-opioid receptors (MOR) and modulating ion channel performance. They reduce pain transmission by inhibiting voltage-gated calcium channel influx in the pre-synaptic neuron (primary afferent fibre), and subsequent inhibition of the neurotransmitter release. Secondly, post-synaptically, they increase potassium conductance of the second-order sensory neuron in the spinal cord dorsal horn . They arThe analgesic effect of opioids is more evident for the nociceptive component of pain, while adjuvants may be required to manage neuropathic pain. Neuropathic pain characteristics are detected in 20% of patients with cancer ; howeverTapentadol, due to its dual mechanism of action , has been effectively used in MM patients for the management of moderate to severe pain caused by MBD, and has been shown to be well tolerated and effective for reducing the neuropathic component of pain . Its actIn MM patients, renal function may be a limiting factor in the prescription of some opioids such as codeine and morphine, which may accumulate in patients with moderate to severe renal insufficiency and may have toxic side effects. Oxycodone and hydromorphone require dosage adaptation, while buprenorphine and fentanyl are considered the first-choice opioid drugs in patients with severe kidney failure (creatinine clearance < 30 mL/min). Tapentadol does not require dosage adaptation for mild to moderate renal failure, but data on its use in end-stage renal disease are not available .Another emerging concern about chronic opioid use, particularly in MM patients, is the possible negative impact of MOR agonists on the bone density. Opioids may affect bone density via direct activity on osteoblasts or via indirect activity on the hypothalamic–pituitary–adrenal (HPA) axis . OpioidsThe pharmacokinetic properties of opioids are essential for tailoring analgesia in poly-medicated patients . For exaFrom a clinical perspective, the main problem with opioid analgesia in the presence of vertebral involvement, is that pain at rest may be easily controllable with analgesics, while pain on movement may be severe enough to limit physical activity. This type of predictable event represents a subset of a large phenomenon commonly called breakthrough cancer pain (BTcP) . BTcP isGeneral rules for the use of ROO in the management of BTcP include: (a) patients with chronic background pain (≥12 h/day during previous week), which is adequately controlled using a stable daily dose of LAO ≥ 60 mg equivalent of morphine; (b) maximum 4 episodes of BTcP per day with an intensity ≥7 on a 11 point numerical rating scale; and (c) dose selection by using titration for patients using low doses of baseline opioids and dose proportionality (1:6) for high-dose patients .The abovementioned chemotherapeutic agent bortezomib is a well-established drug for the treatment of multiple myeloma and mantle cell lymphoma. Among other side effects, bortezomib can induce a mild to moderate dose-dependent sensory neuropathy in MM patients ,67. RiskBortezomib-induced peripheral neuropathy (BIPN) is clinically characterized by neuropathic pain in fingers and toes, paraesthesias, burning dysaesthesias, numbness, and other clinical features such as (rare) sensory ataxia . Median Clinical electrophysiology has shown axonal rather than demyelinating sensory neuropathy in BIPN  with abnBortezomib is a proteasome inhibitor affecting the development of the cytoskeleton and many other aspects of cell metabolism. The details of the mechanisms resulting in BIPN are still unknown. Several studies have suggested multifactorial pathways towards nerve fiber degeneration. Bortezomib induces aerobic glycolysis in sensory neurons, which may lead to the extrusion of metabolites sensitizing primary sensory afferents, finally causing pain . One stuChemotherapy-induced neuropathic pain should be treated like any other type of cancer-related neuropathic pain. This includes a systemic medical management focusing on tricyclic antidepressants, the serotonin/norepinephrine reuptake inhibitor duloxetine, or gabapentinoids. Focal pain spots can be treated topically with lidocaine or high-dose capsaicin patches . InteresInfections are a leading cause of morbidity in MM patients, because of the immunosuppression related to anti-myeloma therapies  and to the disease itself. The introduction of novel therapies such as bortezomib, thalidomide, and lenalidomide has improved the outcomes of MM patients, but it has probably increased the incidence and the spectrum of infections . ProteasPost-herpetic neuralgia (PHN) is a potential complication after acute herpes zoster or VZV reactivation and herpetic neuralgia. PHN is a typical example of localized neuropathic pain (LNP), which is usually limited to a superficial, circumscribed, and easily identifiable area. LNP always reflects a peripheral nerve lesions which is dermatomal in distribution, does not cross the midline, and can be associated with positive sensory phenomena such as spontaneous burning pain, allodynia, and hyperalgesia .In these conditions, topical treatments, including lidocaine 5% plasters and capsaicin 8% patches may be appropriate . TopicalLidocaine 5% plaster is a first-choice drug in PHN, as a single therapy or as add-on therapy together with systemic analgesics, particularly adjuvants such as gabapentinoids and antidepressants. Lidocaine 5% shows good short- and long-term tolerability, with the most common adverse events being application site reactions . SuperfiCapsaicin is a highly selective agonist of the transient receptor potential vanilloid-1 (TRPV-1) receptor. Capsaicin 8% dermal patches are indicated for the treatment of peripheral neuropathic pain in adults either alone or in combination with other analgesics. A single 60 min application of capsaicin 8% provides prolonged pain relief in patients with PHN, with good tolerability. Transient application-site reactions such as reddening of the skin are the most common adverse events .Current guidelines on neuropathic pain suggest as first-line treatment, in monotherapy, gabapentin (1200–3600 mg daily), pregabalin (300–600 mg daily), duloxetine (60–120 mg daily), venlafaxine (150–225 mg daily), and tricyclic antidepressants (TCAs) (25–150 mg daily). When these drugs do not provide adequate analgesia, weak opioids such as tramadol are recommended. Strong opioids, despite their number needed to treat (NNT) which offer significantly better results than other systemic drugs, are not recommended in PHN because their efficacy in neuropathic pain is still under discussion, and also largely because of their potential risk of abuse, which led the US into its recent opioid crisis . AtypicaUnfortunately, RCTs for the management of cancer-related neuropathic pain are sparse, and most recommendations are extrapolated from studies on chronic non-cancer neuropathic pain syndromes. Dealing with the task of limited evidence in this context, the ESMO has recently published a cancer pain practice guideline which also addreses the management of cancer-related neuropathic pain .Since the introduction of bortezomib, thalidomide, and lenalidomide, median overall survival in patients with MM younger than 50 years was calculated to be >10 years in 2014. Since the introduction of newer drugs and combination therapies, about 70% of patients with MM now achieve complete responses and minimal residual disease (MRD) negativity .As survival time has increased with two-, three-, and four-drug combination regimens, the number of cancer survivors presenting with chronic pain has increased as well. The concept of being a “cancer survivor” is relatively new, without a consensus on its definition, but it is usually related to a patient who lives with and beyond cancer .Despite few specific data being available on patients with MM who have experienced prolonged survival , it is aApart from the above-described pain syndromes, cancer survivors may present a number of long-term symptoms, including fatigue, which is a persistent feeling of physical, emotional, or mental tiredness or exhaustion. Obstacles in treating chronic pain in these patients could be related to emotional difficulties, such as fear of recurrence, depression, anxiety, anger, and guilt. The bio-psychosocial model of chronic pain should be considered when managing cancer patients .A survey conducted on 199 cancer survivors, and examining the differences between different types of cancer, showed that MM is associated with the highest percentage (33%) of patients suffering from chronic pain, compared with the other cancer types . Moreover, women experience more pain than men, and black people experienced more disability than white. Pain was closely related to depressive symptoms and poor functioning Fatigue and pain have been identified as the two most important factors affecting quality of life in long-term MM survivors, even in stable-phase disease. About 70% of these patients were prescribed analgesics and 68% of these were on opioids. Over 50% of survivors reported neuropathic pain and were managed mainly with gabapentinoids .According to a recent survey among long-term survivors (5 years) after autologous hematopoietic cell transplantation (AHCT), 33% of MM patients reported use of medications for pain management. Worse physical and mental functioning were associated with pain and depression, which strongly affected quality of life .Graft-versus-host disease (GvHD) is a potential consequence after allogeneic hematopoietic stem cell transplantation, which occurs in 20%–50% of transplant survivors. Neuromuscular manifestations of GvHD are rare, but may cause painful conditions and have a major impact on the QoL. Muscle cramps, immune-mediated neuropathies, and myositis have been described among peripheral nervous system manifestations of GvHD . PatientExercise training is recommended in cancer survivors, while inactivity should be avoided. Exercise is a potent stimulus to endorphine production; therefore, it could improve not only mobility, but also analgesia, and probably mood .Cancer survivors should be considered vulnerable patients, particularly for mood disorders. In these subjects, prescribing long-term opioid therapy can be challenging and require continued medical education, with specific familiarity with risk-mitigation tools and current guidelines, in light of the increasing fear about opioid abuse potential .Patients affected by MM suffer from chronic, moderate-to-severe pain at every stage of the natural disease process. Pain intensity is only one of the pain characteristics affecting the type of analgesia that should be selected. Adequate pain management requires identification of the pathophysiological mechanisms at the basis of chronic pain, and classification of pain as mainly nociceptive, mainly neuropathic, or mixed pain syndromes . Central


To assess the computed tomography coronary angiography (CTCA) accuracy for demonstrating possible non-cardiovascular causes of non-acute retrosternal chest pain in patients without known coronary artery disease (CAD) and to correlate CTCA results with the patient management and relief from pain.This prospective observational study was approved by the ethical committee. Consecutive patients suffering non-acute chest pain who underwent CTCA and with not known CAD were enrolled and classified as having coronary diseases (CD) or extracardiac diseases (ECD). Association between age, sex, body mass index (BMI), cardiovascular risk factors, and type of chest pain with CD or ECD was estimated. Correlation between BMI classes and each risk factor was also calculated.p = 0.003) and hypercholesterolemia among females (p = 0.017); hypertension and hypercholesterolemia significantly correlated with age, and hypertension also with BMI. Pain was atypical in 70/106 (66%) patients. The kind of pain did not correlate with disease or gender. CTCA showed possible causes of chest pain in 69/106 (65%) patients; 32/69 (47%) having only CD, 23/69 (33%) only ECD, and 14/69 (20%) both CD and ECD. Prevalence was: hiatal hernia 35/106 (33%); significant CAD 24/106 (23%); myocardial bridging 22/106 (21%). At follow-up of 94/106 (89%) patients, 71/94 (76%) were pain-free, 14/17 (82%) significant CAD had been treated, and only one patient with non-significant CAD was treated after CTCA.A total of 106 patients  were enrolled. Hypertension was found in 71/106 (67%); smoking was significantly more frequent among males (CTCA suggested possible causes of non-acute pain in 65% of patients.CTCA can either rule in or rule out possible causes of chest pain alternative to CAD.• Clinically relevant findings were detected in 65% of patients with non-acute chest pain.• Non-cardiovascular diseases potentially explained symptoms in 35% of patients.•  The differential diagnosis of retrosternal chest pain can be difficult , 2. AngiMost patients with retrosternal chest pain consult a cardiologist. This often results in a late referral to other specialists, after a cardiac origin of the symptoms had been definitely excluded, with persistent patient discomfort for months after the first painful episode .In recent years, the use of computed tomography (CT) in the evaluation of coronary artery disease (CAD) has spread –9. CurreThe first aim of our study was to assess, in a population of patients without previous CAD history, referred to CTCA for retrosternal chest pain, the prevalence of both coronary/cardiovascular disease and non-cardiovascular diseases, and correlate them with the kind of chest pain. The second aim was to perform a clinical follow-up in order to evaluate the correlations between CTCA results, patient management, and potential relief from chest pain.typical (three criteria of NICE 2016 classification) or no-cardiac origin/atypical (one or two criteria of NICE 2016 classification)—was recorded [This prospective observational study was approved by the ethical committee and written informed consent was obtained from all patients. All consecutive patients who arrived in the Radiology Department of our hospital, between July 2010 and September 2014, to perform a CTCA for many clinical questions , and affected by retrosternal chest pain, were prospectively included. Patients with acute chest pain, directly referred to the Emergency Department, were excluded, as well as patients with known CAD. For each patient, a form with data about age, sex, body mass index (BMI), cardiovascular risk factors, and type of chest pain—recorded , 14.In all patients with a resting heart rate > 65 bpm and no contraindications, metoprolol (50–100 mg) was orally administered about 1 h before the examination to achieve a target heart rate ≤ 65 bpm. Administration of sublingual nitroglycerin (0.30 mg) was used to enhance coronary vasodilatation at the time of imaging. CTCA examinations were performed using a LightSpeed VCT , with retrospective ECG gating, end-diastolic (60–80% of the R-R cardiac cycle) craniocaudal reconstruction (carina to diaphragm), detector configuration 64 × 0.625 mm, acquisition thickness 0.625 mm, acquisition interval 0.625 mm, tube rotation time 0.4 s, tube voltage 80–120 kV (based on patient body weight), ECG-dependent tube current modulation settled to a reference of 250–700 mAs in the 60–80% RR interval, and of 250mAs for the rest of the cardiac circle (with an average effective radiation dose ≤ 15 mSv), acquisition field of view (FOV) 25 × 25 cm, standard filter kernel, and mediastinal CT window.All patients received a bolus of 85 mL of contrast material  through an antecubital vein at 5 mL/s, followed by 50 mL of saline solution at the same rate. The scan delay was determined using the bolus tracking technique, positioning a region of interest with a triggering threshold preset at 150 HU on the descending aorta at the level of the four-chamber view. Images were reconstructed with a thickness 0.625 mm and an interval of 0.4 mm, as well as contiguous 2.5 mm, with an enlarged FOV (32 cm × 32 cm) and lung and mediastinal window for the evaluation of lung parenchyma and other structures included in the acquisition volume.CTCA data sets were analyzed using a dedicated workstation . Evaluation of coronary arteries was performed by a certified radiologist (S.T.) with 8 years of experience in cardiac CT on axial, multi-planar reformatted (MPR) images, and curved planar reformatted (CPR) images along the centerline of each vessel; if necessary, maximum intensity projection (MIP) and volume rendering (VR) images were used. In the presence of calcified, non-calcified, or mixed plaques in at least one coronary segment (defined following the 17-segment modified AHA classification), coronary atherosclerosis was diagnosed and classified following the grading system recommended by the Society of Cardiovascular Computed Tomography  . We defiFollow-up was conducted either by means of telephone interviews or by reviewing the hospital medical records, such as hospital discharge letters, provocative tests, or conventional coronary angiography results, with a wide follow-up time range, mainly due to the duration of the study and different follow-up modalities. For each patient, the definitive diagnosis and treatment choice were decided by the referring cardiologist or general practitioner. Correlations between CTCA results, patient management, and relief from chest pain were analyzed.2 or Fisher’s exact test. Correlation between BMI and risk factors was estimated with Spearman’s correlation. Association between type of chest pain and presence of cardiovascular alterations was estimated using the χ2 or Fisher’s exact test. All analyses were performed using SPSS v.21  and p-values < 0.05 were considered significant.Continuous variables are expressed as mean ± standard deviation (SD), whereas categorical variables are indicated as frequencies or percentages. Association between gender, age, and risk factors, including BMI, was estimated with the χn = 48), new evidence of dilated cardiomyopathy (n = 16), symptoms and many risk factors (n = 13), discordance between two different provocative tests (n = 10), recent diagnosis of acute coronary syndrome (n = 10), and suspected coronary anomaly (n = 9).The study population included 106 patients , aged 62 ± 14 years . Indications for CTCA were: discordance between symptoms and provocative test (p = 0.043). Hypertension was the most common risk factor , while diabetes was the least frequent risk factor . Smoking habit was significantly more common among males  than among females  . More females  than males  had hypercholesterolemia (p = 0.017). The distribution of hypertension and hypercholesterolemia in the study population was significantly correlated to patient age . Moreover, a significant correlation was found between hypertension and BMI classes .Most of the study population was overweight , with a significant difference in weight between males  and females  .Thirty-four percent (36/106) of patients had typical and 66% (70/106) atypical chest pain, with no significant differences between genders (n = 3); atrial fibrillation (n = 2); multiple ventricular ectopic beats (n = 1). The heart rate was 62 ± 10 bpm . Thirty-five percent (37/106) of patients did not present any pathological findings at the CT scan, 30% (32/106) were diagnosed with only coronary disease .Almost 80% of patients (82/106) presented with normal coronary arteries or minimal/mild CAD, the majority of whom presented with atypical pain . Among patients with typical pain (36/106), 25% (9/36) had significant CAD. No significant association was demonstrated between the kind of chest pain  and any disease detected at CT (coronary Follow-up information was available for 94/106 patients (89%), with a median follow-up time of 33 months (range 7–57). In Table Ten patients had undergone a provocative test during follow-up; eight of them had negative results, one positive result , and one positive result (with percutaneous revascularization 1 year after CT).CTCA has evolved into an effective technique for the evaluation of CAD in selected patients, mainly those at low-to-intermediate cardiovascular risk , 16, 17.We investigated one relevant advantage of CT over other cardiac imaging methods, i.e., the possibility to evaluate not only the heart but also the presence of alternative causes of retrosternal chest pain , 16, 17.Many authors underlined the high prevalence of extracardiac findings at cardiac CT. Flor et al.  stated tThe comparison between our results and those of other studies is not easy. Koonce et al.  includedThe evaluation of non-cardiac structures is a key point in these patients: chest pain is common and disabling, and often persists after a normal cardiac study. Patient management is often inefficient and associated with a significant economic burden , 11. OnuAs expected, we did not find any significant association between the kind of chest pain and disease, making CTCA a problem-solving diagnostic tool , 2, 10. Notably, large discrepancies were found in the literature between the prevalence of clinically relevant findings and the number of findings that actually led to therapeutic or diagnostic interventions . Our patn = 106). However, patient selection was narrowed to only patients experiencing retrosternal chest pain, without previous CAD history. Second, the relationship between chest pain and CT findings  was not always completely clarified by our follow up. As a consequence, the attribute of clinical improvement to the treatment has some degree of uncertainty. In any case, the suspicion of non-cardiovascular disease from CT findings can be a valid aid for clinical decision-making.Our study has limitations. The first is the relatively small sample size  of only relevant non-cardiovascular findings, which need to be carefully examined by radiologists.


When suffering from chronic pain, attempts to control or avoid pain often compete with other daily activities. Engaging in one activity excludes engaging in another, equally valued activity, which is referred to as “goal conflict.” As yet, the presence and effects of goal conflicts in patients with chronic pain remain poorly understood.This study systematically mapped the presence and experience of goal conflicts in patients with fibromyalgia compared to healthy controls. A total of 40 patients and 37 controls completed a semi-structured interview in which they first reconstructed the previous day, identified conflicts experienced during that day, and classified each of the conflicting goals in one of nine goal categories. Additionally, they assessed how they experienced the previous day and the reported conflicts.Results showed that patients did not experience more goal conflicts than healthy controls, but that they did differ in the type of conflicts experienced. Compared to controls, patients reported more conflicts related to pain, and fewer conflicts involving work-related, social or pleasure-related goals. Moreover, patients experienced conflicts as more aversive and more difficult to resolve than control participants.This study provides more insight in the dynamics of goal conflict in daily life, and indicates that patients experience conflict as more aversive than controls, and that conflict between pain control (and avoidance) and other valued activities is part of the life of patients. The fear-avoidance model of chronic pain , 2012 esThere is a call for including a broad motivational context into the model: patients with chronic pain often not only want to avoid pain, but may also want to pursue other valued activities, such as socializing with friends . DiffereHere, we seek to further our understanding of goal conflict in patients with chronic pain. The main objective was exploratory in nature, and focuses on mapping the presence and experience of goal conflicts in patients with fibromyalgia and in healthy controls. Research questions were (1) do patients experience more goal conflict in daily life than healthy participants; (2) do patient and healthy participants differ in the type of conflicts they experience; (3) which goals commonly compete with pain-related goals; (4) do patients and controls differ in the experience and context of conflict; and (5) can core constructs of the fear-avoidance model or individual differences predict the number of (pain-related) goal conflicts?To this purpose, patients with fibromyalgia and matched healthy controls were invited to participate in a semi-structured interview based on the day reconstruction method (DRM)  in whichThe current study is part of the Pain-Attention-Motivation Project 1  From July 2011 to August 2014, posters were placed in the waiting room of the Multidisciplinary Pain Centre of Ghent University Hospital, and medical doctors informed patients about the possibility to participate in research. Eighty-four interested patients with fibromyalgia provided their information to be contacted for participation; (b) From August 2014 onwards, patients from the Multidisciplinary Pain Centre are asked to complete online questionnaires at intake. Upon completion of these questionnaires, participants provide their contact details for research purposes. Fourteen individuals with fibromyalgia left their contact information. In sum, both recruitment methods led to a total number of 98 individuals with fibromyalgia who could be contacted. Inclusion criteria were: being diagnosed with Fibromyalgia, fluency in the Dutch language, normal or corrected-to-normal eyesight, normal or corrected-to-normal hearing. Participants were excluded if they suffered from neurological problems , or reduced tactile sensitivity as this was relevant for another, but unrelated study of the PAM-I-project.M = 45.8, SD = 9.22). The majority of patients was married (57.5%), or cohabiting (5%). Fifteen (37.5%) patients received higher education. Only 22.5% of patients was employed, 5% was retired, and 7.5% was unemployed. The remaining patients received health insurance (17.5%) or disability (47.5%) benefits. The mean reported duration of patients’ pain was 14.5 ± 12.01 years.We contacted 90 (91.8%) of the 98 candidates until the predetermined number of 40 participants was reached. Fifty (51%) of the 90 patients did not wish to participate. Most common reasons for non-participation were distance to the faculty, time constraints, or aggravation of complaints. In total, 40 patients with fibromyalgia  participated. Patients were between 29 and 64 years of age  of these 181 candidates; 126 (69.61%) of candidates were not contacted, as they did not match the participant profile  or a sufficient number of control participants was reached. Fourteen out of 55 (23.6%) did not wish to participate. Most common reasons for non-participation were suffering from a chronic illness and lack of time. In total, 41 controls participated. Inclusion and exclusion criteria were the similar, except for the following: fulfilling the criteria for fibromyalgia of the American College of Rheumatology (ACR criteria) for fibromyalgia , and suft(75) < 1, p = 0.619, age, t(75) < 1, p = 0.957, level of education, t(75) = −1.31, p = 0.194, and in marital status, t(75) < 1; p = 0.419. However, patients were more often unemployed or receiving disability benefits than control participants, t(75) = −6.775, p < 0.0001.Control participants were matched to patient participants, as they did not significantly differ from patient participants in terms of gender, All participants provided verbal and written informed consent and were informed that participation was voluntary and could be stopped at any point in time, without negative consequences.Participants were invited for an individual appointment at Ghent University, which took approximately 3 h. Before the individual appointment, participants were asked to complete a sociodemographical information sheet  and several questionnaires. Patients additionally provided information on their pain problem, and completed questionnaires . Seventy participants filled in these questionnaires online, seven participants filled in a paper version. Questionnaires were included either for descriptive purposes , assessing inclusion and exclusion criteria , and/or exploring the predictive value of the constructs , pain catastrophizing scale (PCS), Experience of Cognitive Intrusion Pain scale (ECIP)) in the experience of goal conflict. As this study was part of a large project, a number of questionnaires were not included in the analysis of this study.During the individual appointment, participants completed a semi-structured interview based on the DRM . This seFor descriptive purposes, participants provided information on gender, age, education, employment, and marital status. Patients also provided information on the duration and treatment of their pain problem.Participants completed the Dutch version of the ACR Criteria for fibromyalgia , which cTo assess pain severity, the Graded Chronic Pain Scale GCPS;  was compI keep thinking about how much it hurts”), magnification , and helplessness . Internal consistency and validity of the PCS are shown to be good , ruminative thoughts on pain , and control by pain . The total score ranges from 0 to 60, and is obtained by summing all items. Cronbach’s α for the ECIP in this study was 0.97.The ECIP was used to measure the extent to which the experience of pain interferes with thinking when experiencing pain . The scainterested, cheerful), and 10 negative affect words . Respondents used a five-point Likert scale  to indicate the extent to which they generally experience each of the emotions. This Dutch version of the PANAS is shown to be a reliable and valid instrument  using an eleven point numerical scale . The PDI is considered a reliable and valid instrument to study pain-related disability , which contains 16 items that measure the respondent’s vigilance for painful sensations during the last 2 weeks . Each itTo assess four components—fearful appraisal of pain, cognitive anxiety, psychological anxiety, and escape and avoidance behavior—of pain-related fear, patient participants completed the Pain Anxiety Symptoms Scale PASS; . The PASParticipants completed a semi-structured interview based on the DRM of First the interviewer explained the objective and procedure of the interview to participants. Participants indicated the date and day of the previous day, as well as the time they woke up in the morning and the time they went to bed. In contrast with the original DRM—where participants independently reconstruct their previous day by means of an anonymous diary—the interviewer asked participants to verbally report on the activities they had undertaken the previous day. The interviewer prompted participants to freely report the activities of the previous day, and to take the time needed to reflect on that day and on possible key words describing these activities. Participants were asked to report on activities during the morning (from waking until noon), afternoon (noon until about 18:00), and evening (from about 18:00 until going to bed). An activity usually varied between 15 min and 2 h, and often started when someone new joined in, or when going to another location. The interviewer stressed that participants could express themselves in a way they felt comfortable, and that all information shared during the interview was confidential. After having constructed their previous day, participants were given the opportunity to review their previous day again, and add, delete or alter activities if necessary.inter-relations and goal interference are existent, none of them focus on the assessment of goal conflict in humans. Our definition of goal conflict was informed by the theoretical accounts of goal conflict by Next, possible conflicts that arose that day were assessed. Although measures focusing on goal Goal conflict is defined as the experience of indecisiveness or doubt about which of two activities to pursue. Examples of conflicts are having doubts whether ‘to study for an exam’ or ‘going out for drinks’, ‘reading a newspaper’ or ‘repairing a leaky faucet’, or ‘resting to reduce pain’ or ‘going for dinner with friends’. This definition does not incorporate ‘social conflict’, which is having a fight or an argument.”The information provided to the participants about goal conflict was the following. “In order to ensure comprehensibility, participants were asked to provide an example that fitted the definition above. Further clarification was given if needed. Participants were then asked to report the conflicts experienced during the previous day. Further information concerning these conflicts was obtained, such as the type of activities involved, the context, reasons of conflict, duration, and decision.Thirty-one out of 40 (77.5%) patients and 32 out of 37 (86.49%) controls reported at least one conflict. Nine out of 40 (22.5%) patients and five out of 37 (13.51%) controls did not report any conflicts.Interpersonal/Social: the goal is to maintain or improve contact or relationships with other people ;Intrapersonal: the goal is to maintain or improve personal qualities or personal growth ;Work/Education: the goal is related to work and/or educational purposes, and is aimed at the personal (academic) career ;Household: the goal is to pursue household activities or chores, and is aimed at maintaining or improving your household ;Leisure: the goal is to relax or to enjoy yourself, mostly the goal is to pursue activities that are aimed at things you do in your spare time ;Financial: the goal is to maintain or improve your financial status, freedom, independence, security or stability;General physical and mental health: the goal is to maintain or improve your general physical and/or mental health, for example, eating healthy food, stress reduction; with the exception of the goal to avoid, reduce or control pain;Pain control, avoidance and/or reduction: the goal is to control, avoid or reduce pain, for example, resting, avoiding movements, taking medication; andOther: if the goal does not fit in one of the other categories, this category can be selected.After having reported all conflicts, these conflicts were examined more closely. Participants were asked to classify the goal underlying each activity of goal conflicts using the following goal category system :Interpe“Imagine sitting in a restaurant and doubting between staying for a chat with your friend, or going back to work. You may want to chat with your friend because you want to invest in the relationship with your friend. This can be placed in the category ‘social/interpersonal’. You may want to go back to work because you wish to do the work you are meant to do; this can be classified in the category ‘work/education’. However, it is also possible that you wish to go back to work because you want to be a professional and hard-working person, which can be classified in the category ‘intrapersonal’. Another goal you may have, is to obtain a financial bonus; this can be placed in the category ‘financial’. Since multiple goals are present, you have to pick the one that was most applicable in that situation, for example, ‘work’.”Participants were informed that only one goal per activity could be selected. If multiple categories were fitting, participants should select the most important one. The list of the goal categories was placed in front of the participant as a reminder. The interviewer also illustrated how to classify the goals of the activities using an example:Next, participants themselves classified each activity of the conflicts. This classification allows to identify the type of goal conflict; for example: pain (control/avoidance/reduction) vs. financial. For the purposes of this study, we will refer to a pain-related goal conflict if a pain avoidance/control/reduction is identified as one of the underlying goals in a goal conflict.After the goal classification of each conflict, participants were asked to assess a maximum of three conflicts. In case more than three conflicts were reported, the conflicts were selected at random (using a randomization table). As there were two patients reporting more than three conflicts and four controls reporting more than three conflicts, there was no data collection for two conflicts in patients and eight conflicts in controls.(“How strongly did you experience this conflict?”), worry (“To what extent did you worry during this conflict?”), pain-related worry (“To what extent did you worry about pain during this conflict?”), stress (“To what extent did you feel stressed during this conflict?”), need of support (“To what extent did you need support during this conflict?”), conflict solution (“How difficult was it to solve this conflict?”) and solution satisfaction (“How satisfied were you with the solution of this conflict?”).Questions regarding goal conflict involved conflict strength positive affect, which comprises the variables happy, enthusiastic, and relaxed; and (2) negative affect, which comprises the variables sad, nervous, irritated, angry, afraid, powerless, frustrated, and helpless.Participants also rated the affect during the conflict . All questions were assessed on a seven-point scale going . We ran a principal component analysis on these 11 affect-items. The scree plot analysis revealed two factors with an eigenvalue greater than 1 explaining 74.24% of the variance. The factors created as a result of the factor analysis were (1) Statistical analyses were performed using SPSS 23.0 and Microsoft® Excel 2010. Alpha was set at 0.05.Do patients experience more goal conflict than healthy participants?Do patient and healthy participants differ in the type of conflict experienced?Which goals are most commonly conflicting with pain related goals?Do patient and healthy participants differ in the experience and context of conflict?Can core constructs of the fear-avoidance model or individual differences predict the number of (pain-related) goal conflicts?The key questions addressed in this paper are:U tests were used because the assumption of normality was violated. Patients on average reported 1.53 ± 1.13 goal conflicts (range: 0–4). The total number of conflicts reported by patient participants was 61. Nine patients did not report any conflicts. Control participants reported on average 1.87 ± 1.46 goal conflicts (range: 0–7). Five controls did not report any conflicts. The total number of conflicts reported by control participants was 69. There was no significant difference in the number of conflicts between patients and controls . The primary objective of this study was to determine the presence of goal conflict in a patient sample and in controls, and investigate whether both groups differ in the frequency of goal conflicts. For this comparison Mann–Whitney Another aim was to explore whether patients and controls differ in the type of conflicts experienced. More specifically, a motivational account of the fear-avoidance model posits that pain-avoidance goals may compete with other goals in patients with chronic pain. Therefore, we expected that patients experience more pain-related goal conflict than control participants. We assessed whether patients report certain types of conflict more often than control participants. For this purpose, we calculated the number of times that a goal category was used during the goal classification of the conflicts. This resulted in a number of endorsements for each of the nine goal categories per participant.U tests were reported because the assumption of normality was violated. Our tests revealed that on average, patients with fibromyalgia reported more pain-related goal conflicts than control participants, 0.875 ± 0.991, and 0.054 ± 0.229, respectively, U = 363, p ≤ 0.001. As shown in U = 363, p ≤ 0.001, less social-related goal conflicts, U = 534.5, p = 0.021, and less pleasure-related goal conflicts, U = 499.5, p = 0.004. Patient and control participants did not differ in the average number of health-related, finance-related, household-related, and intrapersonal-related goal conflicts, ps > 0.05.Mann–Whitney Subsequently, we identified the type of goal that participants reported to conflict with the pain-related goal . As mentioned above, patient and control participants reported 61 and 69 goal conflicts, respectively. Of the 61 goal conflicts reported by patients, 35 (57.4%) goal conflicts involved a pain-related goal, whereas only two out of 69 (2.9%) goal conflicts reported by control participants involved a pain-related goal. For patients, the pain-related goal most often conflicted with household goals (45.7%), social goals (20%), and intrapersonal goals (14.3%). Furthermore, pain-related goals conflicted with other health-related goals in 8.6% and with financial goals in 5.7% of reported conflicts. For controls, the two pain-related goal conflicts involved pleasure goals and household goals, respectively.As contextual factors might play an important role in the experience of conflict, we compared the contexts between conflicts reported by patients and conflicts reported by healthy controls. Although we did not find any differences in terms of the number of goal conflicts, we expected that patients might experience conflicts as more aversive, and might experience more difficulties in resolving their conflicts. Because the analyses on the experience of conflict were conducted on the conflict level, only participants that reported a conflict, could be included. The analyses were thus run on 61 conflicts reported by 32 controls and 59 conflicts reported by 31 patients.The context of a conflict pertains to with whom the subject was with during the conflict, where the participant was (location), whether another person caused the conflict, and how the conflict was solved. The frequency and percentage of participants per group is described in Nconflicts) and the interaction between these variables. The variables log (conflict duration), conflict strength, satisfaction, difficulty, worry, worry about pain, stress, and the positive and negative affect factors are used as outcome variables in subsequent multilevel analyses. Using ijY to represent the score of person i on experience-of-conflict measure Y (the outcome variable) for conflict j, the multilevel model can be formulated as follows:In order to investigate whether patients and controls differ in the experience of conflict, and to what extent the experience of conflict varies as a function of the number of conflicts we conducted multilevel analysis (on conflicts nested within persons). More specifically, different multilevel analyses are used to explain different measures of experience of conflict  as a function of the “dummy” variable patient , the number of conflicts  indicates how many standard deviations the average predicted Y-value increases for patients who reported an average number of conflicts compared to controls who reported an average number of conflicts. Furthermore, the regression coefficient of the number of conflicts (βnc) indicates how many standard deviations the predicted average Y-value increases when persons of the control group report one conflict more. In addition, the coefficient of the interaction (βp × nc) indicates the additional increase in the predicted average Y-value for patients compared to controls if the person reported one conflict more. Finally, as our sample is relatively small and dependent variables are not always normally distributed, standard errors for estimated parameters are calculated using bootstrapping to increase accuracy. The results of the analysis are presented in The error term εp = 0.304, SE = 0.142, p = 0.015, reported to worry more about their pain, βp = 1.11, SE = 0.123, p < 0.001, reported to be more stressed during a conflict, βp = 0.68, SE = 0.134, p < 0.001, felt more strongly that they needed support during conflicts, βp = 0.574, SE = 0.15, p < 0.001, found their conflicts more difficult to solve, βp = 0.509, SE = 0.14, p < 0.001, were less satisfied with how they solved their conflict, βp = −0.507, SE = 0.162, p < 0.001, experienced less positive feelings, βp = −0.441, SE = 0.133, p = 0.001, and more negative feelings during the conflict, βp = 0.45, SE = 0.131, p = 0.001. Furthermore, assuming an average number conflicts was reported, it took patients longer than controls to solve their conflicts, βp = 0.56, SE = 0.138, p < 0.001. This difference between patients and controls increases 0.346 if one conflict more is reported, βp × nc = 0.346, SE = 0.122, p = 0.001. Lastly, assuming an average number of reported conflicts, patients reported to experience their conflicts more strongly than controls, βp = 0.601, SE = 0.137, p < 0.001. Moreover, the size of this effect increases 0.273 if patients reported one conflict more, βp × nc = 0.273, SE = 0.119, p = 0.01. The number of conflicts did not alter the experience of conflict in either of the groups for all other outcome variables.The estimated coefficient for the patient dummy variable indicated that (for persons who reported an average number of conflicts) patients reported to worry more during conflicts, βBecause the fear-avoidance model proposes that several factors might play a role in the development of pain-related fear, avoidance, and disability , we explpain-related goal conflicts. Because only two control participants reported a pain-related goal conflict, regressions were carried out with the patient group only (N = 40). Measures assessing traits/states included were: positive and negative affect (PANAS), trait anxiety (STAI), Depression, anxiety and stress (DASS), pain catastrophizing (PCS), pain disability (PDI), hypervigilance (PVAQ), pain-related fear (PASS), and cognitive intrusions (ECIP). We also assessed individual differences in disability, years of pain onset, average pain (in a week), pain intensity, and hindrance by pain. We corrected for over- or under-dispersion using a quasi-Poisson approach. Our results indicated that the average number of pain-related goal conflicts reported by patients increased 39.6% for each increase of one standard deviation in average pain, β = 0.396 (95% CI [0.013–0.778]), Wald χ2 = 4.11, df = 1, p = 0.043, 4.3% for every standard deviation increase in anxiety (DASS), β = 0.043 (95% CI [0.002–0.082]), Wald χ2 = 4.28, df = 1, p = 0.039, and 2.5% for each increase of one standard deviation on cognitive intrusions, β = 0.025 (95% CI [0.006–0.043]), Wald χ2 = 7.011, df = 1, p = 0.008. A marginally significant increase of 3.3% and 3.1% in the average number of pain-related conflicts reported were found for an increase of one standard deviation in negative affect, β = 0.033 (95% CI [−0.001–0.067]), Wald χ2 = 3.6, df = 1, p = 0.058, and depression, β = 0.031 (95% CI [−0.002–0.064]), Wald χ2 = 3.29, df = 1, p = 0.07, respectively. None of the other individual difference variables predicted the number of pain-related goal conflicts: pain catastrophizing: β = 0.018 (95% CI [−0.011–0.047]), Wald χ2 = 1.52, df = 1, p = 0.218; positive affect: β = −0.025 (95% CI [−0.078–0.029]), Wald χ2< 1, df = 1, p = 0.365; trait anxiety: β = 0.017 (95% CI [−0.013–0.048]), Wald χ2 = 1.21, df = 1, p = 0.272; stress (DASS): β = 0.023 (95% CI [−0.011–0.056]), Wald χ2 = 1.79, df = 1, p = 0.181; pain disability: β = 0.02 (95% CI [−0.011–0.051]), Wald χ2 = 1.56, df = 1, p = 0.212; hypervigilance: β = 0.022 (95% CI [−0.006–0.050]), Wald χ2 = 2.35, df = 1, p = 0.125; pain-related fear: β = 0.010 (95% CI [−0.002–0.023]), Wald χ2 = 2.72, df = 1, p = 0.099; disability: β = −0.093 (95% CI [−0.835–0.649]), Wald χ2< 1, df = 1, p = 0.806; years of pain onset: β = −0.017 (95% CI [−0.050–0.017]), Wald χ2< 1, df = 1, p = 0.323; pain intensity: β = 0.186 (95% CI [−0.204–0.576]), Wald χ2 < 1, df = 1, p = 0.351; hindrance by pain: β = 0.244 (95% CI [−0.082–0.530]), Wald χ2 = 2.06, df = 1, p = 0.151.Poisson regressions were carried out to assess whether individual differences predicted the number of This study investigated the presence and experience of goal conflicts in patients with fibromyalgia in comparison to healthy controls. For this purpose, 40 patients with fibromyalgia and 37 healthy participants completed a semi-structured interview in which they identified experienced goal conflicts, assessed the experience of the conflict, classified each of their goals in pre-defined categories, and assessed their previous day.First, we expected patients with fibromyalgia to report more goal conflict than control participants. Both patient and control participants were readily able to report and identify goal conflict. When asked for an example, participants spontaneously reported on personal experiences. These examples often included recurring experiences—patients with fibromyalgia mostly describing conflicts between resting in order to control/reduce pain and doing household chores or going out with friends/family—or examples of great value to the participant . Nevertheless, our results revealed that patients with fibromyalgia did not spontaneously report more goal conflicts than healthy controls. This finding is not in line with the finding of Third, another aim was to study the contextual characteristics and the affective experience of the conflict. Regarding the contextual characteristics, our findings demonstrate that patients experienced most conflicts at home (86%), whereas this is less the case for control participants (58%), who also reported experiencing conflicts at work/school or when on their way; again, this may be due to the low employment rate and disability benefits of our patient sample. Both groups reported that they most often experienced a conflict when they were alone. Furthermore, despite the absence of a difference in the number of conflicts they report, patients and controls differed in how they perceive conflict. Overall, it seems that patients experienced conflicts more negatively than controls: they reported less positive and more negative feelings, worried more, felt more stress, and felt more need for support than controls. Patients also perceived their conflicts as more difficult to solve than control participants, and they reported that it took them longer to solve their conflicts. Lastly, patients were on average less satisfied with how they solved their conflicts than control participants. Interestingly, the number of conflicts a participant experienced had little to no impact on the experience of conflict. Our findings are in line with those of number of pain-related conflicts, but the characteristics of the experienced conflict. Further research is needed to investigate this hypothesis. Also of importance is that the number of outcome variables is rather large, and that they might be (strongly) related to each other. It might therefore be useful to investigate which variables are closely related and reliably reflect the impact of goal conflict. Nonetheless, our results demonstrate that expanding the fear-avoidance model with a broad motivational perspective may be fruitful. Our findings indicate that goal conflict or competition in chronic pain is related to the interpretation of a situation as catastrophic, fueled by cognitive intrusions and anxiety. Another intriguing question is whether the characteristics of pain-related conflicts differ from the characteristics of non-pain-related conflicts. This question requires an analysis of the type of goal conflict within subjects. Unfortunately, this analysis was not feasible, because only a limited number of pain and non-pain related goal conflicts was reported, resulting in insufficient power to conduct those analyses on the current dataset.The last aim of the current study was to investigate whether individual differences in disability, pain, and core constructs of the fear-avoidance model could predict differences in the amount of pain-related goal conflict. First, we found that higher average pain intensity was associated with a strong increase in the reported number of pain-related conflicts of patients. As these results are correlational in nature, this might indicate that experiencing intense pain may lead to more goal conflict, or conversely, that conflict leads to an increase in pain . The relThis study may have clinical implications. The results underscore the importance of the inclusion of goal dynamics in our understanding of chronic pain problems , and proAdditionally, it might be appropriate to screen for certain individual characteristics such as general anxiety, as these individuals might benefit more from a tailored treatment strategy, since our research suggested that these individuals might experience more pain-related goal conflicts. However, more insight is needed on which patients experience more goal interference than others, or for which patients pain-related goal conflicts weighs more on their physical and psychological well-being.Some limitations should be considered. First, we had a cross-sectional study design, and no cause-effect relationships can be discerned. Therefore, caution is warranted when interpreting the results. Second, this study is one of the first of its kind, and largely exploratory in nature. Further research is needed to replicate and extend our findings. Third, the DRM generated a large database. To assess the impact of personal characteristics , we focused on predicting the number of conflicts. However, other analyses are also possible, and we encourage the use of our database for secondary analyses. Also, a large number of (outcome) variables was collected, which may be dependent. This should be taken into account when looking at the different analyses reported here, or when performing secondary analyses. Fourth, our study sample was limited to patients with fibromyalgia. Therefore, we need to be careful in generalizing our findings to other pain syndromes.This study provides more insight in the dynamic relations between pain-related and other goals and their impact on daily life. At the same time they provide a good starting point to further study the impact of pain-related goal conflict in patients with chronic pain. It seems that goals competing for resources differ between patients and controls, with a more prominent role for pain-avoidance and -control in the lives of patients. Furthermore, our results suggest that patients experience conflict more aversively than healthy controls. However, further scientific inquiry is required to uncover the potential detrimental impact of pain-related goal conflict on daily life experience.10.7717/peerj.5272/supp-1Supplemental Information 1Click here for additional data file.10.7717/peerj.5272/supp-2Supplemental Information 2Click here for additional data file.10.7717/peerj.5272/supp-3Supplemental Information 3Click here for additional data file.10.7717/peerj.5272/supp-4Supplemental Information 4Click here for additional data file.


PPTs were significantly higher after treatment at all evaluation time points. This study indicated that MRgFUS is effective in reducing pressure pain at the site of most severe tenderness in patients with painful bone and joint diseases. Treatment response was comparable between patients with BM, L-OA, and K-OA.Local bone denervation by magnetic resonance-guided focused ultrasound (MRgFUS) is a promising tool for alleviation of pain in patients with painful bone metastasis (BM). Considering the underlying mechanism of pain alleviation, MRgFUS might be effective for various bone and joint diseases associated with local tenderness. This study was conducted to clarify the therapeutic effect of focused ultrasound in patients with various painful bone and joint diseases that are associated with local tenderness. Ten patients with BM, 11 patients with lumbar facet joint osteoarthritis (L-OA), and 19 patients with knee osteoarthritis (K-OA) were included. MRgFUS treatment was applied to the bone surface with real-time temperature monitoring at the target sites. Pain intensity was assessed using a 100 mm numerical rating scale (NRS) at various time points. Pressure pain threshold (PPT) was evaluated on the sonication area and control sites. Compared to baseline, the pain NRS scores significantly decreased in all groups 1 month after treatment, and PPT at the treated sites significantly increased in all groups 3 months after treatment. The percentage of patients who showed  Magnetic resonance-guided focused ultrasound (MRgFUS) treatment is a noninvasive technique of localized thermal ablation by precisely focusing acoustic energy at the target site . Recentlin vivo results in demyelination and neural degeneration [The pain alleviation mechanism is believed to be due to heat-induced protein denaturation that is confined to the focal region. HIFU acts on hypersensitive nerve fibers and causes denaturation of increased neurotransmitters at the target site, leading to pain alleviation. During bone irradiation with focused ultrasound, most of the energy is absorbed by the bone surface; this increases the temperature of the bone surface and the contiguous soft tissues rather than the deeper bone tissues. Therefore, the pain mitigation effect is largely attributable to degeneration of nociceptors and primary afferent sensory nerve fibers on the bone surface. This hypothesis is reinforced by evidence that unmyelinated nerve fibers are particularly vulnerable to (non-HIFU) thermal injury , and thaneration .Considering the pain alleviation mechanism resulting from local bone denervation, this treatment might be effective against pain associated with BM, as well as chronic joint pain due to osteoarthritis of the knee joint and lumbar facet joints. Based on the premise that HIFU treatment is likely to be effective against joint pain, if the bone surface is considered to be the major source of pain, we have pioneered the use of this method for treating chronic pain associated with medial K-OA.Several studies, including randomized controlled trials, have demonstrated HIFU's effectiveness for pain associated with BM ; howeverSo far, our experience with MRgFUS for BM, L-OA, and K-OA has indicated that it has high therapeutic value, although it has also raised the question of the most effective positioning of the therapy. In this regard, we hypothesize that this therapy is most effective when applied at the point of maximal tenderness.The purpose of this study was to elucidate the changes in PPT and pain induced by applying this therapy to the region of maximal tenderness in patients with three types of bone diseases.At our facility, since 2008, three clinical studies have been conducted to evaluate pain relief with the use of MRgFUS in patients with BM, L-OA, and K-OA. The subjects of the current study were retrospectively extracted from these three studies. We enrolled patients with intractable pain  score ≥4) that persisted for more than 3 months and with bone surface tenderness. Only patients who would be available for clinical evaluation at each evaluation time were included.As a result, ten patients with painful BM, 11 patients with chronic low back pain associated with L-OA, and 18 patients with chronic medial knee pain associated with K-OA were included in this study.The exclusion criteria for the three clinical trials were patients on dialysis, unstable cardiac status, severe hypertension, active uncontrolled diseases such as infection, hematological diseases, neurological diseases, severe cerebrovascular diseases, severe coagulation disorders, or use of anticoagulant/platelet drugs, mental handicaps, or psychiatric conditions that precluded adequate communication, contraindications for MR imaging due to implanted metallic devices, claustrophobia, or obesity (weight >113 kg).The inclusion criteria for BM patients were pain refractory to conventional palliative therapy, such as radiation and/or opioids, age >18 years, number of metastatic bony lesions <3, tumor diameter <8 cm, tumors located at least 1 cm away from the skin, internal organs and nerves, low risk of pathological fractures (Mirels' score ≤7) , life exThe inclusion criteria for patients with L-OA were chronic low back pain refractory to other conservative treatments for >6 months, age >65 years, number of targeted facet joints with tenderness  <2, at least 70% pain reduction achieved with diagnostic facet joint block using 1% lidocaine, and absence of radicular pain.The inclusion criteria for patients with K-OA were chronic medial knee pain refractory to other conservative treatments for >6 months, surface of the target bone at least 1 cm distant from skin, age >60 years, no severe instability of the knee joint with tenderness, and grade 3 or 4 medial knee OA according to the Kellgren–Lawrence classification .The treatment sites in patients with BM were the ilium (4 patients), sacrum (2 patients), femur (2 patients), scapula (1 patient), and pubic bone (1 patient). The sources of metastasis were prostate cancer (2 patients), myeloma (2 patients), and one case each of hepatoma, uterine cancer, lung cancer, thyroid cancer, breast cancer, and adenoid cystic carcinoma. On radiological examination of patients with BM, four patients had osteolytic lesions and the remaining had mixed and/or osteoblastic lesions, but the structure of bone surface in the treatment area of all patients was almost maintained.MRgFUS was applied to the most tender region over the metastatic tumor in the BM group, the dorsal area of the painful facet joints, which was selected based on 70% reduction of pain with the diagnostic block in the L-OA group, and the bone surface around osteophytes in the medial tibiofemoral joint in the K-OA group. Before FUS treatment, the points of tenderness around the painful area were meticulously identified. Once the most tender point was identified, the planned focal FUS treatment was to be applied exclusively at that point and the surrounding area.All procedures were performed under MRI  guidance. Two FUS systems were used: the ExAblate® 2000 system , integrated with the MRI table, was used in patients with BM and L-OA. With the ExAblate® 2000 system, the patient was made to lie recumbent with the lesion in contact with the FUS transducer embedded in the MRI table, a gel pad was placed between the transducer and the lesion, and the periphery was filled with degassed water. The ExAblate® 2100 conformal bone system  was used for K-OA patients. A ball filled with degassed water was formed on the irradiated side of the transducer in this system, and the transducer was placed in contact with the body surface and secured with a strap.The target area was determined in accordance with the disease group. For BM, the target site was the surface of bone with maximum tenderness among the areas of BM, as detected in advance by the physical examination; for K-OA, it was the bone surface at the region of maximum tenderness on the inner side of the tibiofemoral joint; for L-OA, it was the bone surface on the dorsal side of the facet joint identified in advance, where transient relief from tenderness was obtained by the diagnostic nerve block.The transducer was placed on the body with the selected target area at its center, and before initiation of treatment, it was confirmed by MRI that irradiation could be performed without a problem. The location of the transducer was also confirmed on the MRI monitor before treatment. If the location was found unsuitable, the procedure for confirmation of the suitable transducer position by MRI was repeated, while changing the placement position.After determining the target area, several parameters, including the required energy level, number of focused ultrasound energy deliveries (sonications), and the direction of the pathway of the beam, were automatically optimized.Actual views of the monitor screen when setting the irradiation path of ultrasonic waves for BM, K-OA, and L-OA are shown in Figures A sonication session lasted approximately 20 seconds and was repeated after a cooling period of >90 seconds between each sonication. Initially, low energy sonication was applied as a test to ensure safety and accuracy. Then, therapeutic sonication begun with a higher energy level was used to complete ablation.Throughout the treatment, the location of each sonication and the temperature of the tissues adjacent to the target area were monitored in real time, using proton resonance frequency shift thermometry . The tara ≥ 50% decrease in NRS scores, as recommended by the Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) [The primary outcome measure was the worst pain at the painful area indicated by NRS scores in the last 24 hours (range: 0 (no pain) to 10 cm (worst pain)). A response to treatment was defined as T-OARSI) . NRS scoPPT was defined as the first instance at which the patients perceived the pressure as slight pain. We assessed the PPT using an electronic pressure algometer at the most tender point. PPT was evaluated at the treatment site and at the corresponding contralateral, nontreated site as a control. For the measurement, the area of maximum tenderness was identified before treatment and marked as the target treatment site. Then, the direction and distance of this site from an anatomical landmark was recorded by photography, to avoid region variation during subsequent measurements. The measurement was thus performed at the same point in sequential assessments at all posttreatment time points.2 probe was used to evaluate PPTs. The measurements of PPTs were performed by two examiners (MK or HN) before treatment and at 1 week, 1 month, and 3 months after treatment. PPTs were measured four times at each evaluation point, and the average of the remaining two values, excluding the maximum and minimum values, was used for analysis.A handheld algometer  with a 1 cmt test, chi-squared test, and Fisher's exact test were used to compare demographic data and treatment responders. Pain NRS scores and PPT data are presented as the median (interquartile range). Friedman test, followed by Dunn's post hoc test, was used to evaluate the time course of pain NRS scores and PPT in each group. Friedman test, followed by Dunn's post hoc test, was used to evaluate the time course of PPT at every assessment point. Mann–Whitney's U test was used to compare the PPT between responders and nonresponders at each assessment point. A significant difference was set at p < 0.05. Statistical analysis was conducted with GraphPad Prism 7 software  for Windows .Unpaired In the BM group, 10 patients completed the treatment, while one patient withdrew due to anxiety. Assessment of pain NRS scores and PPT was completed in 10 and 8 patients, respectively. In the L-OA group, all patients completed the treatment. Assessment of pain NRS score and PPT was completed in 11 and 8 patients, respectively.In the K-OA group, 18 patients completed the treatment, while one patient could not complete the planned sonication treatment because of anxiety during the treatment. Assessment of pain NRS scores and PPT was completed in 14 and 9 patients, respectively. Total knee arthroplasty was subsequently performed in four patients who expressed a desire for the procedure because pain was not sufficiently alleviated within the first 3 months posttreatment or was more severe than expected. The patients' baseline characteristics are shown in In the BM group, the percentage of patients who responded to FUS treatment was 60% at one week, 80% at 1 month, and 80% at 3 months after treatment. The corresponding percentages in the L-OA group were 64% at one week, 64% at 1 month, and 82% at 3 months, while those in the K-OA group were 50% at one week, 78% at 1 month, and 67% at 3 months . Althougp < 0.0005), from 8 (4–9) to 3 (0–7) in the L-OA group (p < 0.0005), and from 7.5 (5–9) to 3 (1–9) in the K-OA group (p < 0.005); however, there were no significant differences between the three groups with respect to pain reduction (p < 0.005), from 273 kPa (66–427) to 487 kPa (352–858) in the L-OA group (p < 0.05), and from 156 kPa (50–249) to 246 kPa (120–427) in the K-OA group (p < 0.005) (The median NRS score (min–max) significantly decreased from 6 (4–8) at baseline to 2 (0–6) at the final follow-up in the BM group (eduction . The med< 0.005) . There w< 0.005) .Although previous studies have shown consistently good results of MRgFUS treatment for pain management in BM patients , 15, 16,Since BM is a progressive condition, the associated pain is liable to recur due to disease progression. However, in the present study, patients with BM showed significantly reduced pain for more than 3 months after treatment. There are several factors that could explain the efficacy of FUS against the pain associated with BM. First, the treatment causes denaturation of not only the sensory nerves but also the superficial part of the lesion itself. Therefore, the treatment might prevent lesion expansion to some extent. Second, pain associated with BM is not usually generated by joint motion, in contrast to that with L/K-OA. Lastly, a large proportion of patients did not have rapidly progressing tumors.L/K-OA is a chronic rather than rapidly progressive disease. The pain associated with L/K-OA usually correlates with mechanical stress. Since abnormal mechanical stress cannot be eliminated by MRgFUS treatment, pain associated with motion is liable to recur. Therefore, we hypothesized that the pain associated with L/K-OA was more likely to recur than that due to BM. However, the effect of pain relief was almost the same in all three groups in this study. There are several possible reasons for the good pain relief effect in patients with OA. First, although the pain associated with OA is caused by various mechanisms, patients with obvious localized pain at the medial knee was selected in this study. Second, patients who had severe knee and lumbar instability were excluded from the study. Lastly, denervation of sensory nerves without any damage to the joints aborts the nociceptive input without necessarily affecting the disease course.Many researchers have reported the pain relieving effect of MRgFUS on painful BM , 16. In Only one previous study by Weeks et al. has investigated the use of MRgFUS treatment in L-OA patients . In theiFurthermore, the average number of facet joints treated in their study was 4.9. In contrast, the corresponding number in our study was 1.2. Despite fewer treatment sites in our study, the therapeutic effects in both studies were equivalent. This is likely attributable to the selection of only patients who had tender points on their backs in our study. Therefore, the treatment was effective owing to the appropriate identification and treatment at the points of maximal tenderness.Only one previous study, conducted by Izumi et al. at our institution, has investigated MRgFUS treatment in K-OA patients . In our At our facility, we have treated patients with BM, L-OA, and K-OA who have tenderness. In the present study, comparing the effects in these three disease groups, we found similar therapeutic effects for all three diseases. Moreover, in the group with treatment response, PPT began to increase significantly from an early stage. In other words, in both BM and OA, focal ablation of local hypersensitive nerve fibers seems capable of effectively reducing the level of pain (NRS score) experienced by the patient.This is the first report in which the effects of MRgFUS treatment were investigated using tender sites in bone and joint diseases with various manifestations of pain. This study shows that the efficacy of the treatment in osteoarthritis is similar to that in painful BM. In addition, the response to treatment was higher than that in previous studies conducted in patients with BM and L-OA. We believe that this is attributable to meticulous detection and targeting of the most painful sites in our study. For MRgFUS treatment, it is important to select patients with tender points in the painful areas.The results in the three groups in our study shows that meticulous detection of the point with the lowest PPT as the main treatment area is likely to permit identification of the eligible lesion, thus optimizing the results.In the current study, we have only reported on the short-term results of MRgFUS, which is a limitation of the study. Future studies should evaluate the long-term outcomes of treatment. However, our study demonstrates the potential of FUS as a promising treatment for degenerative musculoskeletal diseases. Some other limitations should also be acknowledged, the most important of which is that this was a small case-series without a control group. Hence, it is difficult to rule out a placebo effect. Secondly, two types of treatment devices (ExAblate 2000 and 2100) were used in this study, which might have affected the degree of pain relief. However, we believe that this was of little consequence as temperature elevation was confirmed by MRI monitoring during treatment.This study showed that MRgFUS reduced pain when applied at the site of most severe tenderness in patients with painful bone and joint diseases. The treatment response was comparable in patients with BM, L-OA, and K-OA. MRgFUS increased the threshold of tenderness at the lesion site in all three disease groups.