To investigate changes in nonspecific genitourinary discomfort or pain (GUDP) before and after holmium laser enucleation of prostate (HoLEP). GUDP associated with lower urinary tract symptoms (LUTS) is a common complaint among benign prostatic hyperplasia (BPH) patients, but very little is known about this clinical entity.From February 2010 to August 2011, 100 HoLEP patients with complete clinical data at a single institution were enrolled in the study to analyze the degree of GUDP with a visual analog scale (VAS) from 0 to 10 points at baseline and at 3 and 6 months postoperatively, and to investigate any relationships between GUDP and urodynamics, uroflowmetry, and scores from the International Prostate Symptom Score (IPSS) questionnaire.Fifty-six patients had LUTS only, while the remaining 44 had both LUTS and GUDP. Pain was located in the suprapubic (42.0%), perineal/penile (33.0%), back (17.0%), and perianal (8.0%) regions. During the post-operative period, at six months, the VAS, IPSS, peak flow rate and post-void residual volume had improved significantly in 44 GUDP patients (p<0.010). GUDP had completely resolved in 40 (90.9%) patients and had decreased in four (9.1%) patients, while seven (12.5%) patients developed GUDP with voiding in the urethral and perineal areas by the third month postoperatively. When compared to patients with complete resolution, those with persistent GUDP were found to have a significantly higher preoperative presence of bladder outlet obstruction (BOO) as an independent risk factor .Both GUDP and LUTS improved significantly after HoLEP. Patients with significant preoperative BOO tended to have persistent GUDP after surgery. In recent decades, benign prostatic hyperplasia (BPH) has become increasingly prevalent. Among symptoms other than lower urinary tract symptoms (LUTS) suggestive of BPH, patients often present with complaints of painful urination or discomfort in various nonspecific areas. Several reports have shown that approximately 7.7% to 40% of BPH patients suffer from bothersome genitourinary symptoms, such as discomfort or pain (GUDP), related to voiding Genitourinary pain can be manifested in several urological pathologies, such as bladder pain syndrome (BPS), chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), and overactive bladder (OAB). In clinical practice, clinicians frequently encounter patients with BPH who complain not only of LUTS, but also of pain or discomfort in the suprapubic/lower abdomen and the urethral, scrotal, perineal, or penile areas For those patients with BPH refractory to medical therapy, it has been suggested that surgery, such as transurethral prostactectomy (TURP) and other types of prostatectomy, may improve voiding functions and may also decrease bothersome symptoms of discomfort and pain All study protocols were performed according to ethical guidelines of the “World Medical Association Declaration of Helsinki–Ethical Principles for Medical Research Involving Human Subjects”. The prospective study was approved by the institutional review board at Seoul National University Hospital (No. H1301-016-454). All the written informed consents from the patients were obtained.Clinical records of 144 consecutive refractory BPH patients from February 2010 to October 2011 were reviewed from the institutional prospectively collected BPH database registry. Among the patients in the registry, patients were included for ages over 50 years with complaints of LUTS. The exclusion criteria were as follows: presence of genitourinary cancer, previous genitourinary surgery history, urethral stricture, urinary calculi, urinary tract infection, congenital genitourinary anomaly, primary renal disease, interstitial cystitis/bladder pain syndrome, other neurodegenerative disorders, and those who declined to either respond to the questionnaires or to participate in this study.All patients underwent the baseline evaluation which included the following components: a general medical history/physical examination for LUTS/BPH including digital rectal examination, International Prostate Symptom Score (IPSS), urinalysis, urine culture in the presence of pyuria, serum creatinine, serum prostate-specific antigen (PSA), transrectal ultrasonography (TRUS), and multichannel video urodynamic study  to help distinguish obstruction and overactivity of bladder components of the LUTS. In every patient, digital rectal examination was performed to identify suspicious nodules suggestive of malignancy, with TRUS-guided prostate biopsy reserved for those suspected of having prostate cancer. There were no patients with cystoscopic abnormality suggesting interstitial cystitis on preoperative cystoscopy.All surgical procedures were performed by one urologist (SJO) who experienced more than 100 HoLEP operations at the time of starting this study in the routine manner, as described in a previous publication All of the patients were asked to rate GUDP with the visual analog scale (VAS) from 0 (no pain) to 10 (worst pain possible) points and to fill out IPSS questionnaire to evaluate LUTS at baseline and at 3 and 6 months post operation. Additionally, patients were instructed to self-assess pain separately from sexual activity, to exclude ejaculation-related discomfort or pain.The demographics of patients (LUTS and pain are not demographics) including LUTS (IPSS) and pain (VAS) were analyzed using the Chi-square, paired t, Spearman and Fischer’s exact tests for the correlation between pain and other parameters. Multivariate logistic regression analyses were performed to evaluate significant univariate variables influencing pain. Variables with a 5% level of significance were accepted. All analyses were performed using SPSS for Windows version 18, .2. The mean PSA was 4.3 (±3.9) ng/dL, with total prostate volume of 67.3 (±24.5) mL. Urine cultures were all negative. Additional patient demographics and perioperative variables are summarized in Among a total of 144 patients identified, available clinical data was complete for 100 patients. The mean age of these 100 patients was 68.0 (±5.2) years, with a mean body mass index of 23.7 (±4.2) kg/cmAmong the 100 patients, 56 (56.0%) had LUTS alone, and the remaining 44 (44.0%) patients had LUTS and GUDP . The locPostoperatively, at six months, the VAS (0.2±0.8), IPSS (5.1±5.1), Qmax (24.6±11.5 ml/sec) and PVR (17.6±26.5 ml) showed significant improvement in 44 GUDP patients p<0.010, . GUDP haMost cases of GUDP were resolved in patients with severe or moderate pain (>5 on VAS) after HoLEP. The four (9.1%) patients with persistent postoperative GUDP complained of discomfort or pain in either the urethral or perineal areas. Among the 56 patients without preoperative GUDP, seven (12.5%) patients developed new mild postoperative pain (less than three on VAS), and these patients associated their pain with voiding in the urethral and perineal areas.When compared to patients without preoperative GUDP, those with preoperative GUDP did not have significantly different clinical parameters, with the exception of smaller volumes of prostate and of transitional zones (GUDP group 62.1/34.3 ml ±32.7/24.6 ml vs. no GUDP group 75.5/44.9 ml ±31.6/25.0 ml). However, neither of these parameters was significant in multivariate analysis .When compared with patients with complete resolution of GUDP (n = 40), those with persistent GUDP (n = 4) had significantly lower PSA levels, larger maximal bladder capacity, larger volume for bladder sensation (strong desire), higher bladder compliance, and higher prevalence of bladder outlet obstruction (BOO) at baseline p<0.05, . Multiva10. Pain or discomfort among patients with either BPS or CP/CPPS was reported at a mean baseline VAS of greater than 5 The nature of GUDP in this study population is uncertain. Patients with LUTS/BPH were reported to experience symptoms of nonspecific, vague pelvic discomfort or pain. In some patients, symptoms are transiently associated with micturition, while in others, symptoms are persistent. Because these symptoms are not well characterized, the same set of symptoms can be misdiagnosed as either BPS or CP/CPPS. The nature of pain in patients with BPS is characterized by chronic, recurrent extreme pelvic pain or pressure accompanied with LUTS, which is related to the degree of bladder filling LUTS-related pelvic pain and discomfort might be caused by BPH, and surgery might help to reduce pain and discomfort. A few reports have shown that surgery not only improved the LUTS, but also improved pain at nonspecific areas related to the bladder and urethra The baseline demographics of enrolled patients demonstrated that GUDP was less severe relative to either BPS or CPPS (baseline VAS 3.2±1.6). Most of the preoperative GUDP scale (95.4%) was of the moderate level (<7 on VAS), and HoLEP reduced GUDP to a mild level 89.0%, . In thosIPSS scores, uroflowmetry, and VAS were improved postoperatively in an inter-related manner, as reported in a similar study In spite of the small number of patients to evaluate the relationship between IPSS and urodynamic findings, the first finding of a better response in voiding symptoms in IPSS might be explained by the relationship between BOO and GUDP, which was proven as an independent risk factor found among other significant variables  such that the removed prostatic volumes were less than 10 gm. These patients reported satisfactory improvement in LUTS and complete resolution of GUDP following HoLEP.Among the various manifestations of GUDP included in this study, the back pain of seven (15.9%) patients was the only pain or discomfort arising from outside of the pelvic area that was relieved following HoLEP. Those patients did not have any symptom or signs of pyelonephritis or urinary stones at baseline evaluation before surgery. The seven patients with back pain experienced complete relief from GUDP symptoms in the back or flank areas after relieving the BOO with HoLEP. The exact pathophysiological mechanisms associated with both BOO and back pain are still unknown. However, we propose that any abnormal conditions of the prostate can cause diffuse dull pain or discomfort in the back area, which is commonly observed in chronic nonbacterial prostatitis.This study investigated the relationship between GUDP and LUTS using VAS to assess pain and IPSS questionnaires to demonstrate a close interrelationship among patients with BPH before and after prostatectomy. The study is among the first research efforts to characterize pain before and after HoLEP and to determine the significance of BOO as it relates to GUDP. However, this study has some limitations to consider. First, this was a relatively short-term, follow-up study with small numbers of patients. Therefore, a prospective long-term, follow-up study with a larger number of patients and a randomized control is needed, especially to evaluate persistent or de novo GUDP patients. Second, to further characterize GUDP in relation to LUTS, more specific and thorough evaluations are necessary to assess GUDP in greater detail. Third, the enrolled patients did not receive specific diagnostic evaluations for CP/CPPS, and there was no further acknowledgment of the likely role of CP/CPPS, such as lower urinary tract localization tests in prostate-specific specimens to exclude CP or laboratory studies on expressed prostatic secretions and post-prostatic massage urine. Therefore, future study with thoroughly acknowledged CP patients among BPH patients could be planned in order to differentiate CP patients’ GUDP from other patients following prostatectomy.This study demonstrated that both LUTS and GUDP improved significantly following prostatectomy, and that preoperative BOO may be responsible for GUDP.


The plasma levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), antioxidant superoxide dismutase (SOD), and the lipid peroxidation product malondialdehyde (MDA) were detected at baseline and after 2, 4, and 24 h of drug administration. The VAS pain scores and OAAS scores were significantly lower for patients in group D compared to group M. The plasma levels of TNF-α, IL-6, and MDA were significantly lower in group D patients than those in group M at 2 h and 4 h. In group M, SOD levels decreased as compared to group D at 2 h and 4 h. The plasma levels of TNF-α, IL-6, and MDA were positively correlated with VAS pain scores while SOD negatively correlated with VAS pain scores. Therefore, DEX appears to provide better sedation during office-based artificial tooth implantation. DEX offers better postoperative analgesia via anti-inflammatory and antioxidation pathway.The aim of the study was to determine whether or not dexmedetomidine- (DEX-) based intravenous infusion in dental implantation can provide better sedation and postoperative analgesia via suppressing postoperative inflammation and oxidative stress. Sixty patients were randomly assigned to receive either DEX (group D) or midazolam (group M). Recorded variables were vital sign (SBP/HR/RPP/SpO Dental implants are considered one of the most common and popular treatment options for edentulous patients in modern dentistry. However, dental implantation remains significantly associated with pain and high levels of anxiety , 2. Implα2-adrenergic receptor, selectively binds to presynaptic α2 adrenergic receptors norepinephrine release, resulting in a reduction of postsynaptic adrenergic activity [α, SOD, and MDA to reflect inflammatory and oxidation conditions in vivo.DEX, a selective agonist of activity . DEX is activity , in polyactivity , during activity , and in activity  and lapaactivity . DEX alsactivity  and ischactivity . Our resIt has been proposed that irrespective of the characteristic of the pain, whether it is sharp, dull, aching, burning, stabbing, numbing, or tingling, all pains arise from inflammation and the inflammatory response . Our stuSixty patients enrolled in this project either have previously used DEX, midazolam, paracetamol, and other nonsteroidal anti-inflammatory drugs or had no known allergy to these drugs. All patients provided written informed consent. The patients were of American Society of Anesthesiology (ASA) physical status I or II, between 19 and 60 years old, and with mandibular teeth defect . The patients were to have 3 dental implants to be placed and flap and bone graft were to be performed during surgery. Patients were excluded if they had a clinical history or electrocardiographic evidence of heart block, ischemic heart disease, asthma, sleep apnea syndrome, impaired liver or renal function, known psychiatric illness, diabetes, facial pain, psychological problems, smoking history, or chronic use of sedative or analgesic drugs or opioids. Also excluded were those who refused to participate, were pregnant, or presented with preoperative inflammation at the site of surgery.The 60 patients were randomly divided into two treatment groups using a computer-generated random list. Patients were infused either with midazolam and fentanyl (group M) or with DEX and fentanyl (group D). Each patient had an intravenous cannula inserted. Investigators who were not directly involved in the care of the patient prepared the infusions, while the dental surgeon, anesthetist, and the patients were blinded to the group allocation and drugs given.μg/kg) and fentanyl (0.001 mg/kg) in 20 mL of normal saline for 10 min and then a continuous infusion of DEX (1.0 μg/kg/h) until the end of the surgery. Patients in group M received midazolam (0.05 mg/kg) and fentanyl (0.001 mg/kg) in 20 mL of normal saline for 10 min, followed by a continuous infusion of midazolam (0.05 mg/kg/h) until the end of the surgery. Ten minutes after the start of the loading dose, local anesthesia was provided with 4% hydrochloric articaine and 1/100000 adrenaline, administered by qualified dental surgeons. Surgeons then performed the standard surgical procedure during which patients were provided with a mouth prop to help keep the mouth open when required. At the end of the operation, patients were kept in the recovery area 4 h after drug administration. Patients were prescribed one analgesic tablet containing 500 mg of paracetamol and then oral amoxicillin capsule 500 mg three times a day and ornidazole capsule 500 mg twice a day until 7 days after surgery.Patients in group D received DEX (1.0 α), antioxidant enzyme superoxide dismutase (SOD), and serum levels of lipid peroxidation product (MDA).Venous blood samples (3.0 mL each) were drawn at 0, 2, 4, and 24 hours after drug administration for the measurement of plasma cytokines. Plasma samples were immediately separated by centrifugation at 3,000 rpm for 10 min at 4°C and then divided into aliquots and stored at −80°C for subsequent assays by highly sensitive enzyme-linked immunosorbent assays (ELISA) kits to detect the proinflammatory cytokine ; Interleukin-6 Human ELISA Kit .The production lot numbers and manufacturer of ELISA kits are SOD Human ELISA Kit ; MDA Human ELISA Kit ; TNF-2) were recorded at 15 min intervals until 4 h after the start of drug infusion. Sedation levels were assessed using observer's assessment of alertness/sedation scale (OAAS). The patients evaluated their level of pain subjectively using a VAS ruler, with zero representing no pain and 10 the worst pain the patient had ever experienced.All indices were recorded before initiating sedation  and then at 15 min intervals until 4 h after the start of drug infusion. Systolic blood pressure (SBP), heart rate (HR), rate-pressure product (RPP), breathing rate (RR), and saturation of pulse oxygen . P values of <0.05 were considered statistically significant.All variables were tested for normal distribution using the Shapiro-Wilk test. The data are expressed as the mean ± standard deviation (SD), median and interquartile range (IQR), or number. The OAAS and VAS scores were analyzed using the Kruskal-Wallis test. SpOSixty patients were recruited. The patient characteristics and operation data of both groups are shown in 2, RR, and RPP at different time points in each group. The SBP, HR, and RPP of group D became significantly lower than those of group M 30–45 min after drug administration and remained so for the rest of the study. There was no difference in SpO2 or RR between groups D and M.P < 0.05 group D versus group M)  , indicat Figures .α, and IL-6 at 2, 4 after drug administration are shown in α and IL-6 content  secretion after endotoxin injection and that DEX reduced the mortality rate in endotoxemia-induced shock rat models in a dose-dependent manner. In addition, several studies [α-naphthylthiourea-induced acute lung injury. Compared to group M, our results showed that DEX exhibited potent activity in inhibiting TNF-α and IL-6 in dental surgery, particularly 4 h after drug administration. Although studies have shown the regulatory effects of DEX on inflammatory reactions, the exact mechanisms responsible for these actions are not well understood.It is known that an increase in the level of proinflammatory cytokines, including TNF-l trials , 31 have studies –34 have α is a major proinflammatory cytokine produced not only in the immune system but also in the peripheral and central nervous system, especially under the pathological conditions [α is also known for its substantial role in periodontitis [α in the pathogenesis of pain including neuropathic pain [α, IL-6 content were positively correlated at 2, 4 h after drug administration. This suggests that postoperative pain may be caused by acute inflammation and that reducing inflammation cytokine release should have played an important role in DEX mediated reduction of postoperative pain in patients undergoing implant surgery.TNF-nditions . TNF-α idontitis . Increashic pain , 38 and hic pain , 39. IL-hic pain  and medihic pain . Followihic pain . In samphic pain , 44. Col2−) is critical for sensitization of spinal neurons and persistent pain [SOD has strong antioxidant and physical activity and serves as a major free radical scavenger of body . MDA, thent pain , 50. Antα increased the levels of superoxide anion and MDA and then induced oxidative stress and cell toxicity [α in inducing human vascular endothelial cell apoptosis [α and MDA, SOD content were correlated closely. While correlation relationship does not necessarily indicate a causal relationship, the findings of our current study provide mechanistic clues for future in-depth study to elucidate the mechanism of dexmedetomidine in clinical settings.An exaggerated inflammatory response to tissue injury, ischemia, and reperfusion injuries can all result in excessive production of free radicals . Free ratoxicity , 55. A spoptosis . Our resOur study demonstrates that DEX appears to provide better sedation, postoperative analgesia than traditional medicine midazolam during office-based artificial tooth implantation. Further, our findings provide evidence to suggest that reduction of postoperative inflammatory and oxidative stress plays important role in DEX postoperative analgesic effects, although detailed mechanism needs further study.


Although many cross-sectional studies have demonstrated the association between cancer pain and psychospiritual distress, the time-dependent relationship has not been fully explored. For that reason, this study aims to investigate the time-dependent relationship between psychospiritual distress and cancer pain management in advanced cancer patients.improved versus not improved groups).This is a prospective observational study. Two hundred thirty-seven advanced cancer patients were recruited from a palliative care unit in Taiwan. Demographic and clinical data were retrieved at admission. Pain and psychospiritual distress  were assessed upon admission and one week later, by using a “Symptom Reporting Form”. Patients were divided into two groups according to the pain status one week post-admission  patients were assigned to the not improved group. There were no differences in the psychospiritual variables between groups upon admission. In overall patients, all psychospiritual variables improved one week post-admission, but the improvement of depression and family/social support in the not improved group was not significant. Consistent with this, for depression scores, there was a statistically significant pain group x time interaction effect detected, meaning that the pain group effect on depression scores was dependent on time.One hundred sixty-three (68.8 %) patients were assigned to the We demonstrated a time-dependent relationship between depression and pain management in advanced cancer patients. Our results suggest that poor pain management may be associated with intractable depression. The inclusion of interventions that effectively improve psychospiritual distress may contribute to pain management strategies for advanced cancer patients. Moderate to severe pain affects 70–80 % of advanced cancer patients . AlthougAdvanced cancer patients often exhibit symptoms of weakness, pain, anorexia, and cachexia . There iAlthough advanced cancer patients experience both psychological and physical pain, treatment is mostly targeted at alleviating the physical symptoms . HoweverAdvanced cancer patients often experience suffering of the whole person. Thus, in order to better manage cancer pain, it is important to consider not only biomedical factors but also the level of psychosocial and spiritual distress of the patient . There hThis is a prospective observational study. Participants were selected from patients with advanced cancer, not responsive to any caner therapy administrated by oncologists and consecutively admitted to the Palliative Care Unit of the National Taiwan University Hospital between October 2006 and December 2007. All patients provided informed consent. The conscious levels of patients were divided into six categories by primary care physicians: alertness , lethargy , obtundation (slow response to orders), delirium (confusion), stupor (near-unconsciousness) and coma (unconsciousness). The inclusion criteria is that the individual’s level of consciousness had to be clear enough  to report symptoms both on admission and one week after admission. The participants were under active, total care, provided by a multidisciplinary team of physicians, nurses, psychologists, social workers, clinical Buddhist chaplains, and volunteers. The physicians managed the patients’ symptoms by pharmacologic and non-pharmacologic strategies and coordinated the care team. The nurses provided routine nursing care. The psychologists provided psychotherapy, such as cognitive behavioral therapy, positive thinking, problem solving, relaxation strategies and so on. The social workers provided psychosocial and financial support. The clinical Buddhist chaplains provided spiritual support including life review, fulfillment of spiritual needs, and prayer for the patients and their family. Team meetings were held on a weekly basis. This study was approved by the ethical committee at the National Taiwan University Hospital.Patient demographics  were obtained from routine records. The symptom assessment tool was a “Symptom Reporting Form” which was used to assess physical, psychosocial and spiritual distress using different scale systems , 8. InfoThe “Symptoms Reporting Form” was designed by experienced specialists and has been used in our previous studies –9, 19–21improved versus not improved groups). The patients whose pain scores reported one week after admission were lower than those on admission were assigned to the improved group; the other patients were assigned to the not improved group. Descriptive measures of data were summarized as frequencies and percentages for categorical and interval variables, and mean ± standard deviation (SD) for non-categorical variables. The t test and mixed designed analysis of variance (ANOVA) with one between-subject factor “pain group” and one within-subject factor “time” were used to explore the relationships between cancer pain and psychospiritual factors. Statistical significance was defined as a p value less than 0.05. All data were analyzed by using SAS 9.2 statistical software.Participants were assigned to one of two groups based on whether their pain scores were lower one week after admission or not (improved group) and 74 (31.2 %) patients reported no improvement in cancer pain (not improved group). The demographic and diagnostic data were not significantly different between the two groups  men and 126 (53.2 %) women. The mean age of all patients was 64.05 ± 13.87 years. The most common primary cancer sites included lung (19.4 %), liver (17.7 %), and colon/rectum (8.9 %). The mean survival was 39.54 ± 47.72 days. The median survival was 22.5 days (ranging from 7 to 418 days). One week after admission, 163 (68.8 %) patients reported an improvement in cancer pain (p < 0.001). However, measures of the psychospiritual variables were not significantly different between the two groups. One week after admission, pain scores were no longer significantly different between the two groups. It is important to note, however, that depression scores were significantly higher in the not improved group one week after admission (p = 0.016). Table improved group . However, in the not improved group, the improvement of depression and family/social support was not significant.Table p’s < 0.05), indicating that, being in palliative care for one week, patients reported an improvement in psychospiritual distress   Table .Table 4Iimproved group, all parameters of psychospiritual distress were simultaneously significantly ameliorated. However, the improvement of certain psychosocial variables was not significant in the not improved group. This effect was particularly dramatic for depression; while other measures of psychological distress, such as anxiety and anger, improved significantly in the not improved group, depression scores did not. In the improved group, however, depression improved significantly within one week following admission. To our knowledge, this is the first study to report that improvement in cancer pain is associated with an improvement in depression.For overall patients, we demonstrated that psychospiritual distress improved under our active total care. In the improved group pain was significantly ameliorated one week after admission even though pain scores were significantly higher upon admission in these individuals. Since the severities of psychospiritual distress of the two groups at admission were similar, physical distress may contribute to the significant difference of pain severities in two groups at admission. Consequently, the outcome that pain in the improved group significantly improved may result from that most physical distress were relieved by pharmacological therapy such as opioid analgesics. This is consistent with our previous observations that better pain management could be achieved following the implementation of educational programs on opioid analgesia in 1990 in Taiwan [It is very interesting that in the n Taiwan .not improved group. Mori et al. recently reported on three advanced cancer patients with intractable pain, the cause of which was attributed to severe psychosocial distress [However, pain in some patients did not improve but worsened, even under holistic care provided by a multidisciplinary team. Although the level of psychospiritual distress was not significantly different between the two groups upon admission, depression did not improve significantly one week after admission in the distress . Althougdistress . In addiPain is a complex multidimensional subjective experience and psychosocial components play an important role in cancer pain management . Zaza annot improved group at admission, whereas this does not mean that pain was easy to treat with analgesics in these patients particularly when psychospiritual factors were difficult to manage. In the not improved group, depression and family/social support did not significantly improve. Demoralization, one of the troublesome psychological distress, is very common in cancer patients in Taiwan with the reported prevalence of 49.1 % [Although pain and depression are highly prevalent in cancer patients  and litef 49.1 % . Joblessf 49.1 % . Althougf 49.1 % , family f 49.1 % ; indeed,f 49.1 % . These ptotal pain, pain consisting of physical, psychological, social and spiritual components, is very important in the care of advanced cancer patients [The concept of total care provided by a palliative care team will result in an increased likelihood of improving depression, especially when pain is successfully controlled . Furtherpatients . Palliatpatients . Unquestpatients .not improved group). As such, while our results suggest that poor pain management may be associated with intractable depression, the inverse may equally be true, namely that addressing psychospiritual distress maybe impeded by intractable pain and symptom issues. Fourth, all participants in the study were Taiwanese, so the results should be confirmed in other ethic background. Fifth, our pain assessment tool was a single-dimensional numerical rating scale. A multidimensional tool such as the Melzack Pain Questionnaire will give more information related to the components of pain.Our study has some limitations. First, only individuals whose level of consciousness was clear enough  to report symptoms were recruited. Second, this study was conducted in a palliative care unit where active total care was provided. We did not assess other advanced cancer patients in other types of wards, or at home. Third, this is an observational study, and the findings therefore cannot confirm causality. Specifically, while many patients’ psychospiritual distress improved post admission, a number of patients saw no significant difference (There is a time-dependent relationship between pain relief and improvement of psychospiritual distress in advanced cancer patients. Routine assessment of psychospiritual distress factors should be considered in cancer pain management. More aggressive psychospiritual support may improve pharmacological pain management strategies in advanced cancer patients.


Pain in advanced cancer is complex and multifaceted. In older patients comorbidities and age-related functional decline add to the difficulties in managing cancer pain. The current emphasis on care in the community, and preference by patients with life-limiting disease to receive care in the home, has meant that patients and their family caregivers have become increasingly responsible for the day-to-day management of cancer pain. An appreciation of patients’ and caregivers’ roles and perspectives managing pain is, therefore, fundamental to addressing cancer pain in this setting. Consequently, we sought to explore and describe their perspectives and roles.A qualitative descriptive approach was used. Semi-structured interviews were conducted with a purposeful sample of patient- family caregiver dyads. Participants included 18 patients aged 65 years and over, with advanced cancer, receiving palliative care at home, and 15 family caregivers. The interview data were analysed using thematic analyses. Strategies were used to establish rigour.Two main themes were identified. The first theme, "Communicating the pain", represented pain assessment and incorporated four subthemes in which participants described: their roles in pain assessment, the identification and expression of pain, and the communication of pain between patients and caregivers. The second theme, "Finding a solution", comprised of four subthemes that reflected participants’ roles and approaches in controlling pain; as well as their beliefs about cancer pain control, experience with side effects, and perspectives on the goals of treatment.The findings support other studies in identifying knowledge and attitudinal barriers to pain control; while adding to the literature by highlighting practical and relational barriers faced by older patients and their family caregivers. Health care professionals can do much to address the barriers identified by: correcting misconceptions regarding cancer pain, facilitating the communication of pain within dyads, and ensuring that patients and family caregivers have the knowledge, skills, and ability to assess and implement pain treatment strategies. This support needs to be individually tailored to meet the ongoing needs of both members of the dyad so that the shared goals of pain management are accomplished. Pain continues to be a significant issue for people with advanced cancer. Estimates across studies suggest a pooled prevalence of 64% and 70%Cancer pain management in advanced disease is complex. Nociceptive and neuropathic pain typically occurs as a result of damage to underlying tissue and nerves; therefore, the sensory characteristics vary depending on the etiology and extent of damage. As a reAdding to the complexity is the subjective and multidimensional nature of pain. EvidencBarriers to optimal pain control at the patient and caregiver level largely reflect these intricacies. The subjective nature of pain, for instance, means there is a reliance on patients’ communication of pain for accurate and comprehensive assessment. Barriers to perception and communication of pain include: sensory and cognitive impairment, misconcEffective pain management depends not only on an accurate assessment of pain, but the selection and implementation of the most effective approach taking into consideration access to pain treatment options and patients’ preferences. Research examining how cancer pain is managed in the home has highlighted the extensive roles and demands placed on patients and their caregivers,30-33. AEven when the most effective pain treatment option is identified and available, it may not be implemented. A major barrier contributing to inadequate pain control is patients’ reluctance to take opioids,29,36; aTaken together, the findings emphasise the need to fully understand the perspectives of those responsible for the day-to-day management of cancer pain. Though studies have identified barriers and raised awareness of issues faced by patients with advanced cancer and their caregivers, there is relatively little understanding of how pain is managed from the dyadic perspectives of older patients and their caregivers within the home setting. The higher prevalence of cancer in old age, increasA qualitative descriptive approach with an inductive thematic analysis was used to describe and interpret data obtained through semi-structured interviews with participants. A naturFollowing ethics approval from the University of Ottawa research ethics committee, a purposeful sample of patients and family caregivers was recruited through an organization that coordinates home care services across a large urban area. To be eligible, patient participants had to be: diagnosed with advanced cancer (stage III or IV); aged 65 years or older; experiencing cancer pain for at least one month; determined as cognitively able and well enough to provide consent and reliable information by the case manager identifying the patient; English or French speaking; receiving palliative care services at home. Eligible caregivers were identified by a participating patient as the person providing the majority of care at home, and were English or French speaking. Sample size was based on informational redundancy; where no new information is forthcoming.To fully describe the sample we collected information on patients’ level of physical functioning with the Palliative Performance Scale (PPS), and curCharacteristics of patients and caregivers are shown in Table Written informed consent was obtained from patients and caregivers prior to interviewing. Individual interviews were conducted with patients and caregivers separately in all but one case. A semi-structured interview format was used for flexibility, but with some focus to examine the phenomenon of interest. The present article reports on pain management as part of a larger investigation, where questions regarding pain perceptions and experiences were also included. For exa○ How do you typically respond when you are in pain?○ What do you do to show your caregiver that you have pain?Prompts/follow up questions:    Do you spontaneously report your pain or wait to be asked by your caregiver?○ Are you able to communicate your pain to your family caregiver?○ How does your family caregiver assess your cancer pain?Prompts/follow up questions:    In what ways?○ How do you deal with cancer pain?Prompts/follow up questions:    What helps to control the cancer pain?○ What are some of the challenges you face with managing cancer pain at home?○ How do you see your role in managing your pain?Prompts/follow up questions:    What is your family caregiver’s role in managing your cancer pain?○ Do you discuss these roles?○ Do you have any concerns about how your cancer pain is/will be managed ?○ How does _________ typically respond when he/she has pain?○ Do you feel that your _______ is able to communicate his/her cancer pain to you?○ How do you assess your _________ cancer pain?Prompts/follow up questions:    What types of information do you take into consideration when you assess his/her pain?  What helps in assessing his/her pain?  What hinders pain assessment?○ What do you do when _________ he/she is in pain?○ How do you see your role in managing your _______cancer pain?Prompts/follow up questions:    Is managing your ______ pain a role you want to play?  Do you feel adequately prepared to help in the management of his/her cancer pain?○ What are some of the challenges you face with managing cancer pain at home?○ Do you have any concerns about how your _______ cancer pain is/will be managed ?All interviews were audiotaped and transcribed. The transcripts were compared against the audio-recordings for accuracy by the first author (CM). The interviewers’ field notes were also added to each transcription to provide greater contextual information and enhance interpretation. NVivo 10, a qualitative analysis software program was used to organize the data for analysis. Data analysis was conducted by the first (CM) and third (AD) authors. All individual interviews were read in their entirety several times to become familiar with the data. Questions and responses specific to pain management were separated from those exploring pain perceptions since this was the focus of the inquiry. The manifest or surface level content was initially coded to identify and describe the types of assessment, cues to pain, and expressions of pain explicit in participants’ responses. A thematic analysis was conducted to gain a deeper understanding of the underlying latent content of the responses within their context and to capture the richness of the phenomenon,. Each tr"Communicating the pain" represented pain assessment, while "Finding a solution" reflected pain treatment. Figure The focus of the inquiry was on patients’ and caregivers’ management of pain. From an analysis of the data two overriding themes were identified; "Communicating the pain" encompassed four subthemes. "Adopting roles in pain assessment" reflected patients’ and caregivers’ roles in pain assessment, while "Identifying and describing the pain" incorporated participants’ descriptions of pain and the challenges they experienced. Patients’ verbal and non-verbal expression of pain were identified in the subtheme "Revealing and concealing pain", whereas "Monitoring the pain" captured caregivers’ perspectives on pain assessment.Patients adopted the lead role in pain assessment; reflecting the subjective nature of the cancer pain experience. In contrast, caregivers had more limited roles and awareness of patients’ pain, particularly when patients were self-managing pain, or did not live with the caregiver. Talking about his wife one patient commented,Well, I mean basically most of the time, she won’t even know I’m in pain. That I am taking the medication that I am on. I take it myself. I am self-medicating" (P 15)."Further restricting their role was the finding that patients were not always forthcoming with information regarding their pain, and caregivers were sometimes not included in discussions with health care professionals visiting the home. Even with this limited role, however, caregivers spoke of being watchful and observing patients for signs of pain, and checking patients’ notes and medication records to see how many analgesics had been taken. They also supported patients by attending health care appointments outside of the home. The following comment best describes these roles for the most part,"I guess …as part of the team. He’s, the number one player, always. Then there are the doctors who help him. I support him. Like with speaking up when he is really in pain and he doesn’t discuss it with the doctors" (FCG 15).Declining patient health and functioning meant a corresponding increase in caregivers’ roles in controlling pain; knowledge of patients’ pain became necessary with this active role. As a consequence, caregivers became more involved in discussions with health care professionals, alongside the patient. Even so, clinicians’ reliance on patients’ self-report of pain meant that patients retained a central role. The presence of cognitive impairment was the only factor that impacted patients’ ability to comprehensively report their pain. In these instances, caregivers’ assessments supplemented the information provided by patients to health care professionals. Regardless of patients’ and caregivers’ typical roles and responsibilities, escalating uncontrollable pain diminished patients’ levels of functioning, and caregivers became key in initiating contact with health care professionals."stabbing", "burning", "sharp"), frequency, location, and temporal characteristics . They were also able to identify when pain was most likely to occur  and factors likely to exacerbate it . Patients with cognitive impairment and their caregivers were more limited in their descriptions . As the pain scale from the ESAS was used clinically, most patients provided a number indicating the intensity of their pain, which was useful for describing the intensity of the pain and monitoring the effectiveness of strategies to control it, as the following quote from a daughter caregiver illustrates,Most patients were able to provide information on the characteristics of their pain in terms of the physical sensation ."…you know it’s hard sometimes to differentiate what’s holding her back. Is it the pain or is it the effects of the chemo…" (FCG 5). Albeit, pain that was localized to the primary cancer site, areas of metastases , and distinctive pains such as "pin and needles" from diabetic neuropathy, were easier to identify. Interestingly, some patients did not identify pain as such; instead it was referred to as "discomfort", "cramp" or an "ache". Expectations regarding suffering with advanced cancer and death became a marker for current pain, as one patient remarked, "I can’t say that I have suffered terribly. I don’t know what is down the road but I understand bone cancer can become very painful" (P 5). At the same time, increasing pain or new pains brought concerns given the association with advancing disease and death.Reference was frequently made by patients to pain in various locations around the body, which made it difficult for patients and caregivers to identify the origin of the pain. Painful comorbidities  and symptoms , added another level of complexity to the assessment, as the following comment illustrates, Most patients stated that they were open and verbally communicated their pain to caregivers. However, concerns about bothering caregivers meant that often patients would avoid telling caregivers until pain became intense and difficult to manage, as the following response illustrates,"Yes I tell her but I don’t want to stress her out any more about it …. I wait until she asks you know. She is busy with her own life and her own things. I don’t want her to have to worry about me you know" (P 7)."its [pain] just an accepted part of our relationship" (P 15). He went on to add that dealing with pain continually meant, "We got to the point where we communicate only about our pain, only when it is was so overwhelming" (P 15).There was also reluctance to communicate pain in couples who were both dealing with longstanding health issues , to protect one another from bearing additional pain. Describing the communication of pain in his relationship, a patient stated "ouch". Non-verbally, facial expressions such as grimacing or wincing and behaviours aimed at alleviating the pain, such as holding, rubbing or massaging the painful area, and taking analgesics were described by patients. A daughter caregiver described her mother’s reaction to pain in the following way,Pain was expressed non-verbally and verbally. Vocalisations of different sounds indicative of pain were sometimes referred to and comprised of moaning, whimpering, and interjections such as "The traits of her face.. they are not the same traits. The way she speaks too. The voice will also weaken when she has pain. If she suffers, the tone of her voice drops. She will not speak clearly. Then when she has really bad pain the tone of her voice drops much more" (FCG 3).Well it started out at Christmas where it [the pain] was crippling me. I couldn’t even walk and every step was an eternity with the pain. I can’t describe how terrible it was" (P 2).Living with pain affected all aspects of patients’ lives to some degree and these effects on functioning were often used to illustrate the intensity of the pain, as one patient described, ""I just. I just … I JUST DO" (FCG 15). Verbal interaction with patients was the main approach to assess pain. Often non-verbal indicators were used to initiate these interactions, or to corroborate the pain communicated verbally. Caregivers’ knowledge of the patient was integral in making their assessment. Caregivers’ familiarity with the patient and constant contact meant that they had baseline knowledge from which to observe for changes, "I feel that I have an advantage because I know him. I know his background. You know. I know how he looks, how he compares to today, compared to yesterday, or a year ago" (FCG 15).Although caregivers’ mentioned discussing the patients’ pain, illness, and its management with health care professionals, learning how to assess pain was, for the most part, a case of figuring it out. As one caregiver remarked, This knowledge and experience meant that caregivers became accustomed to how patients responded to pain. For example, caregivers were often aware of patients’ reticence to communicate their pain,"She says it when it is worse. That’s how we know. When she says: "I have pain", it is when it is worse. I know that she has pain and that she will not say it each time that she has pain" (FCG 13).. This meant that some types of pain were easier to identify than others,The communication of pain in these cases became an indicator that the pain was overwhelming. Given patients’ reluctance, caregivers relied on non-verbal indicators of pain that corresponded with patients’ pain expressions and behaviours. Visual pain indicators such as restricted functioning were more apparent when pain was intense, and not only provided information on the presence and intensity of pain, but also the location"His arthritis pain, I can’t tell because unless he tells me about it, I don’t see it on him. You know? For the mouth pain, I can tell whether he was eating or not. You know, or whether he is drinking or not" (FCG 15).At the same time, reduced functioning was not always a reliable indicator of pain because fatigue and weakness also affected patients’ functional level,"Well, I don’t know much about pain, his pain because he has always had it. You know … the only indication is when he sleeps more but now he is sleeping more because he is tired and from the cancer treatment" (FCG 15).. However, not all caregivers had this knowledge, experience, or contact with patients, which made pain assessment difficult without the verbal communication of pain. Speaking about her mother, a daughter caregiver acknowledged, ""I know visually when she needs a pain pill. I might see her go get one but to watch her moving or listen to her talking I don’t know unless she says I need one" (FCG 5).For some, especially older partner caregivers, their own experiences with illness  and associated pain, helped in understanding some types of pain"Finding a solution" consisted of four subthemes. In the subtheme "Navigating roles in pain control", patients’ and caregivers’ roles in managing patients’ pain were identified. "Implementing pain control strategies" included various pharmacological and non-pharmacological approaches to pain relief, while unwanted side effects from pharmacological approaches were identified in "Dealing with side effects". "Believing in pain control" captured participants’ beliefs and expectations regarding cancer pain and its treatment.Participants assumed various roles in pain treatment. There was a strong desire from patients to maintain independence in managing their pain,"He is good with his medication…He tends to be very independent that way. He likes to take it himself. He does not consult me or want me to administer it for him" (FCG 15)."forgetfulness", which would necessitate caregiver intervention in terms of reminding the patient to take medications and monitoring analgesic use. This raised concerns when patients were self-medicating. A partner caregiver expressed his apprehension,In cases where patients were self-managing with pain medications caregivers’ played a more supportive role with responsibility for attending appointments and obtaining medications. Still, functional and sensory losses associated with aging, co-morbidities, symptoms, and side effects from treatments contributed in making self-management difficult. Even in instances where patients were largely responsible for deciding on the pain treatment approach, caregivers living with patients were involved in pain treatment decisions and assisted with the administration of non-pharmacological approaches  and pharmacological approaches to pain relief . Of particular note were impairments in patients’ cognitive functioning, often referred to as "Her memory is not as good as it was in the short term. She knows it because sometimes she says "I don’t know if I took it [analgesic]". That is dangerous, so I see if she took it first, I ask her if she took it, then … I talk with her "would you like to take this or that pill, this painkiller or another?"(FCG 17).This created frustration and distress for caregivers who witnessed unnecessary suffering as a result of patients forgetting to take medications for pain. Changes in cognitive functioning also blurred patients’ and caregivers’ roles, which were not easily negotiated and became a source of conflict for some,"Well, I cannot take him in hand anyway. Sometimes when he forgets to take his drugs, when I remind him, he does not like that.. it’s perhaps all that belongs to him now. For that reason, I cannot tell him" (FCG 9).Increasing functional impairment brought with it greater caregiver responsibility. For some the responsibility was extensive including deciding on the most appropriate pain treatment options, administering non-pharmacological interventions, and complex prescribed pharmacological regimes, and controlling side effects. As one caregiver described,"I tried to take him down to 1515 but it [analgesia] was much too low. He started having withdrawal; he’s having a withdrawal breakthrough now. His pain is starting to breakthrough a bit now even with the 1815. I have to go back up. I manage the going up and down. I manage the constipation as much as I can. I gave him three enemas the other day because sometimes he needs enemas to relieve himself. He gets so constipated" (FCG 2).wait and see" approach where they would wait to see if the pain could be tolerated, or would resolve without pharmacological intervention. Describing her mother’s response to pain, a caregiver responded,Pain control strategies could be divided into pharmacological and non-pharmacological approaches. Pharmacological approaches were most often mentioned and consisted of long acting medications for cancer pain, medications for breakthrough pain, and adjuvant medications . Several patients were prescribed an opioid pain medicine that was administered by mouth, a transdermal patch, or morphine pump. Participants also mentioned other analgesics used for non-cancer pain (e.g. arthritis) and comorbidities. Although pharmacological approaches were the predominant response, patients were often reluctant to use them, especially for acute breakthrough pain. Instead, patients would prefer to use a ""Mom has a very high pain tolerance and she is of the mind that I don’t take anything until I really need it. So it took a while to learn that in this instance you don’t wait until you really need it because then you need too much or it takes too long" (FCG 5).. Particular strategies were chosen to alleviate different types of pain. If the pain was attributed to arthritis, or soreness due to remaining in one position for too long, then massage and repositioning were used. Elevating the patient’s legs helped with pain due to swollen legs and circulatory conditions, while heat eased muscular type pains.Caregivers on the other hand were more apt to use pharmacological approaches and would encourage patients to do the same. Non-pharmacological interventions, as illustrated in Table "dopey", "getting mixed up", and "forgetful", although they were unsure whether it was a consequence of aging, the disease process, or the medications. Some side effects paralleled the cancer- related symptoms of fatigue and weakness making it difficult to differentiate between the two symptoms. Medication side-effects added to functional limitations, for example, patients with pre-existing mobility problems became more unsteady, which reduced usual activities and became a safety concern. Certain medications also prevented patients from engaging in activities such as driving and using equipment. Morphine pumps were also seen as an inconvenience. Indeed, some patients showed a preference for pain over the side effects, "Cause he (caregiver) keeps saying "take your medication. Take your pain killer. Stop the pain" But, I would rather have the pain than be constipated" (P 13).A common concern associated with pharmacological approaches was unwanted side effects. Participants spoke of patients being The majority of patients believed that pain was inevitable and could not be entirely controlled so there was "acceptance" of some level of pain. Difficulties gaining control over the pain further contributed towards this. As a result, the goal of pain treatment for many patients was to reduce the pain to a tolerable level, while minimizing unwanted medication side effects. There was some reticence toward pharmacological approaches. Patients’ expressed concerns regarding opioids because of fears about tolerance and addiction; which sometimes led them to delay, or omit taking medications."I don’t want to take the extra morphine but sometimes I may have to. [Interviewer] What would be some of the reasons you would not want to take your medication if you’re having pain? [Patient] Not to get too addicted to it" (P 2).Still a few patients who were initially hesitant to take medications became more confident in taking analgesics on a regular basis, when they gained a better understanding of the medications and their effectiveness,"I realized from trying to not take pills a few months ago that in a sense .. I was more or less doing myself more harm than good by trying to be this little brave old lady that could do without the pill. And after that I realized you know, like if you speak to me and put the pros and cons out. I will try to get the picture" (P 8).Caregivers often shared the belief that pain was inevitable with advanced cancer and old age, but were more varied in their beliefs regarding pain control and the goals of pain management; though a few expressed unease about the number of medications patients were taking given their age. Revealing her belief that pain was inevitable, a daughter caregiver remarked,My concern is how long can someone like her be on this many painkillers… she was on them for almost a year. It’s just that it’s such a strong medication, and it’s not good for you, like you take painkillers because you are in pain, then the pain goes away, but in her case it will never go away" (FCG 4).""battle" that took time, since changes in patients’ pain over the illness trajectory meant ongoing modifications to medications. Once pain control was achieved, caregivers were more confident and less concerned about the use of pharmacological approaches. Comparing the goals of pain treatment at the dyadic level revealed the shared overall goal of avoiding patient suffering, and the preference for home care, however, differences in patients’ and caregivers’ expectations and beliefs regarding pain, and its treatment indicated that the specific pain treatment goals were not always congruent. Comparing dyadic responses revealed that patients were more apt to tolerate pain by reducing or coming off medications, specifically opioids, if it meant a reduction in unwanted side effects and they could remain at home. Caregivers, on the other hand, favoured the continued use of analgesics including opioids to eliminate the pain and avoid in-patient care.Other caregivers believed that medications should control the pain. However, achieving control was characterised as a The purpose of this study was to explore and describe the roles and perspectives of older patients with advanced cancer and their family caregivers in pain management in the home. The findings, similar to those from other studies-33, illuParticipants described their roles and responsibilities as evolving over time in concert with changes in patients’ functioning and needs. In some instances, patients were managing their pain with minimal assistance from caregivers. Though there has been an emphasis in the literature on caregivers’ experiences in managing patients’ pain, the findings, similar to others, indicate that even at the end of life patients are able to maintain an active role in managing their health care needs. PatientAt the same time, it is important to be mindful that progressive disease and declining functioning may compromise the ability of patients to self-manage. Although we did not include a formal assessment of cognitive functioning, it became evident during the interviews and through discussion with caregivers that some patients were manifesting indicators of a mild level of cognitive impairment. This type of impairment was a serious concern for the caregivers of patients who were self-medicating with pain relievers; overmedication was a safety issue, whereas, under medication compromised pain control. Cognitive impairment is a significant problem facing older patients with cancer as it not uncommon in advanced cancer due to the disease, treatments, and psychological sequelae. Cancer Although patients’ and caregivers’ roles were generally described as cooperative and supportive, this was not always an easy alliance. There was reluctance by some patients to relinquish roles, preferring instead to maintain independence despite requiring assistance. These findings may represent patients’ attempts to maintain a level of control over the situation as they deal with losses associated with role changes, cancer, pain, and dying. Certainly, patients’ reluctance to disclose information regarding their pain constrained caregivers’ awareness of pain and its treatment and, to some extent, caregivers’ involvement in managing pain. Patient’s rationale for concealing pain from others was to avoid burdening others; a finding observed in other studies,27. The All patients, including those who showed signs of mild cognitive impairment, were able to provide an assessment of their pain. This observation corroborates the well-established finding that patients with mild and moderate cognitive impairment are able to provide a valid self-report of pain. These fIn our study, verbal communication between the patient and caregiver was the most significant pain cue; however, similar to findings from other studies,27, patiFor these older patients and their caregivers, previous experiences with pain and symptoms from comorbidities meant that they were knowledgeable about various treatment options and what had worked for them in the past. There was some evidence that pain strategies were linked to different types of pain, particularly for pre-existing non-cancer chronic pain. Patients’ expressed a definite preference for non-pharmacological approaches Table ; a findiImportantly, the goals of pain management should not be based on misconceptions regarding the inevitability of pain, but informed by the effectiveness of interventions and patients’ preferences. Patients and caregivers in our study did not share the same goals when it came to pain management; even though the ultimate objective was to maintain care within the home. Thus the goal to be pain free cannot be assumed in older patients since many factors play into their decisions. Maintaining independence, for example, may be more important with a tolerable level of pain, than to be pain free and unable to function due to side effects. Understanding cancer pain within the broader context of patients’ and caregivers’ knowledge, beliefs, and experiences, is essential for appreciating their choices and pain management goals.Consistent with others, our findings highlight that pain management for patients and caregivers is more than merely monitoring for pain and adhering to prescribed regimens,31-35. IThe focus of our study was on older patients and caregivers. However, it is critical to acknowledge that barriers to optimal pain management occur at the system- and health care professional-levels, and that these barriers likely intersect to affect pain management at the individual patient- and caregiver-level. AttentiOur findings support other studies in identifying knowledge and attitudinal barriers to pain control, while adding to the literature by highlighting practical and relational barriers faced by older patients and their caregivers. Health care professionals can do much to address the barriers identified by: correcting misconceptions regarding cancer pain and its management, facilitating the communication of pain within dyads, and ensuring that patients and family caregivers have the necessary knowledge, skills and ability to assess and implement the most appropriate pain treatment strategy based on patients’ preferences. This support needs to be individually tailored to meet the ongoing needs of both members of the dyad so that shared goals of pain management are accomplished.PPS: Palliative performance scale; ESAS: Edmonton symptom assessment scale; SD: Standard deviation.The authors declare that they have no competing interests.CM, TH and ML designed the study and developed the methodology; CM collected the data; CM and AD performed the analyses and TH and ML verified the analyses; CM and AD wrote the manuscript and TH and ML critically reviewed it. All authors read and approved the final manuscript. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-684X/13/39/prepub


Materials and Methods. Fifty consecutive chronic sciatica patients were enrolled in the study. DN under IRT control was performed for all patients regardless of gluteus minimus (GM) active TrPs examination. Then, the vasomotor response and its agreement with TrPs examination were evaluated. Results. The prevalence of GM active TrPs was 32%. DN provokes intensive vasodilatation for TrPs-positive patients only, with the localization dependent on referred pain during the procedure  not the daily complaint. The increase of vasodilatation was, for example, for thigh, TrPs-positive +30.29% (P < 0.05) versus TrPs-negative +4.08%. Additionally, a significant skin temperature increase was observed for TrPs-positive only, for example, thigh +1.5 ± 1.3°C (maximum) and +1.2 ± 1.0°C (average) (both P < 0.05). Conclusion. GM active TrPs prevalence among chronic sciatica patients was around one in three. Every TrPs-positive subject presented with vasodilatation under IRT in the area of DN related referred pain. Although TrPs involvement in chronic sciatica patients is possible, further studies on a bigger group of patients are still required.Vasomotor responses to dry needling (DN) of trigger points (TrPs) under infrared thermovision (IRT) camera control and TrPs coexistence in chronic sciatica patients have never been studied.  Tsk) changes in biological systems are defined as the difference of thermal energies received and lost by conduction transfer and advection, as well as metabolic reactions, for example, chemically released ones, and can be observed by IRT [Dry needling (DN), called western acupuncture, is a common treatment technique for myofascial pain syndrome (MPS). MPS is caused by the presence of trigger points (TrPs) which are defined as hyperirritable nodules within taut bands of skeletal muscles and are divided into active and latent –3. An acd by IRT , 16. If However, the presence of autonomic phenomena, for example, vasoconstriction and vasodilation, coincident with TrP referred pain area was thought to be limited to severe active TrPs exclusively . It is nThe aim of this study was to 1) evaluate the prevalence of active gluteus minimus trigger points among chronic sciatica patients; (2) assess vasomotor responses to dry needling under IRT control of TrPs-positive and TrPs-negative sciatica patients and their agreement with the results of palpatory TrPs diagnostic criteria by Travell and Simons [ evaluateThe study was conducted in accordance with the Declaration of Helsinki approved by the Ethics Committee of Poznan University of Medical Sciences (number 630/13). All subjects gave written informed consent to participate in the study before data collection. A detailed description of all examination and treatment procedures, including dry needling and risks involved in the study, was provided to the participants. The participants had the right to refuse DN treatment and withdraw from the study at any time without penalty.Fifty consecutive patients with chronic sciatica from the University Pain Clinic  6.13 ± 2.47; symptoms duration 5 ± 1.2 months) were enrolled in the experimental study. All participants were diagnosed by an experienced neurologist based on magnetic resonance imaging evaluation and clinical bedside examination accompanied by a positive straight leg test. Participants were to manifest negligible pain symptoms in the contralateral leg. Key inclusion criteria were as follows: age between 30 and 60 (inclusive), both lower limbs present, and history of unilateral low back pain radiating down to lower extremities (a minimum of 3 months) with leg pain ≥ 3 on 1–10-point scale VAS, with this being the dominant pain problem. Patients were excluded from a study for a number of reasons, that is, Cauda Equina Syndrome, previous back surgery, spinal tumors, pregnancy, coagulant treatment, disseminated intravascular coagulation, diabetes, epilepsy, infection, inflammatory rheumatologic diseases, stroke, and oncological history.All subjects were evaluated towards myofascial pain syndrome coexistence based on Travell and Simons diagnostic criteria, namely, 1) taut band palpable (if muscle accessible), (2) exquisite spot tenderness of a nodule in the taut band, (3) patient's recognition of current pain complaint by pressure on the tender nodule (identifies an active trigger point), and (4) painful limit to full stretch range of motion [ taut ban(A) The IRT Statement. A thermovision touchless camera (NEC-AVIO TVS-200EX) using a 8–14 μm wave band, temperature resolution better than 0.08°C, and sensitivity 80 mK and working in real time was applied. The camera was equipped with a high-speed (60 Hz) uncooled FPA 320 × 240 (H × V) pixels VOx (vanadium oxide) microbolometer. The equipment allows taking images with spatial resolution of 1.68 mrad and field of view (FOV) 30.6° × 23.1° (H × V). For data analysis , a specialist program “Thermography Studio 2007 Professional” was used.Thermographic images were recorded by an expert following a standard protocol recommended by the Academy of Neuro-Muscular Thermography. The expert also evaluated the images . PatientTo obtain the stability of patient body temperature and to ensure the adjustment of the recording camera's temperature to the interior conditions, the evaluation began 30 minutes after the patient had entered the examination room. Thermal isolation of the evaluated area from other thermal factors that might have influenced the evaluation, including other parts of the patient's and doctor's bodies, was ensured. Moreover, when performing thermovision imaging, the general rules of camera usage were followed.(B) Dry Needling. The patient's position for needling of the gluteus minimus muscle was side-lying position. The muscle was needled with flat palpation perpendicular to the muscle along the counter of the iliac crest. Strong depression of the subcutaneous tissue was applied in order to reduce the distance of the skin from the muscle. Depth of penetration depended on the amount of adipose tissue [e tissue . Therape(C) The Protocol of Dry Needling under Infrared Thermography ControlPhase I (Patient's Preparation). The patients were asked to draw their current pain pattern on the diagram. Once the drawing was complete, based on the diagnostic criteria set by Travell and Simons, trigger points coexistence was confirmed [onfirmed . In the Phase II (Dry Needling under IRT Control)Part A: IRT side-to-side comparison of the painful subarea to the same subarea in the opposite extremity of the patient at rest (standing position).Part B: dry needling session under IRT control.For part B, the area to be observed by IRT was chosen according to the gluteus minimus referred pain pattern. The examined patients were positioned on the side, on the uninvolved extremity with the hip and knee flexed. In this position, thermovision images of the patient were recorded.For adequate representation of dimensions, a calibration standard has been applied. The next step involved recording the “base” image. The image was recorded to establish the initial level of the patient's temperature parameters. When all of the above-mentioned conditions were met, needling of two previously marked points was performed.The needle pierced the skin and reached the painful point with referred pain. The recognizable pain started to withdraw partially and repeatedly and eventually both the pain and muscle fiber contraction subsided. The time of needling was 5 minutes for any given point.During the whole procedure, the subarea of referred pain reported by the patient  was recorded. At the end of the procedure, the patients were asked to answer the question “Was the pain evoked by needling similar to your daily pain?”Phase III (Post-DN Observation under IRT Control). After the needling of both marked points was ended, further thermovision imaging was performed. The IRT observation lasted for six consecutive minutes after DN.Phase IV . The thermovision material was gathered during the evaluation stage of the study. The study consisted of the following:side-to-side comparison  part of the body): before using the technique of dry needling, each patient was subject to infrared observation of the initial state. In each case, four infrared images on each side of the patient  and one additional image of the foot (top view) were taken. To avoid the effect of the shortcut of the image, the thermovision camera was placed at the knee height. The particular regions of interest—thigh, calf, and foot—were compared, respectively, with each other (region of the left and right leg);comparative assessment of thermovision material representing the following stages of dry needling under ITR control:state before procedure,state directly after DN (phase II),observation of the subject for six consecutive minutes after DN (phase III).temperature value of the highest temperature point in a given subarea,maximum, minimum, and average temperature value of a given subarea,2) of constant temperature.values of the surface areas  or one part of the lower limb, for example, buttock and thigh only. Because of that the evaluated leg was divided into three measurement subareas . Within every subarea, the measurement of the following parameters was recorded:(D) Thermogram Analysis towards Vasomotor Reactions Presence. After the infrared image calibration procedure, the measurements of area size were performed automatically in Thermography Studio 2007 Professional. As a result of scaling, each of the image pixels obtained size in mm2 corresponding to the actual size of the area. To scale the size of objects recorded on thermographic images, the pattern (standard) length was used. After placing the patient in the position for the examination, a special “reference” image using the standard length was performed. Then, before the analysis was conducted, each series of thermal images performed for the patient was calibrated using the calibration element registered in the image. The calibration pattern was placed in the immediate vicinity of the patient's feet. In the software (Thermography Studio), the calibration element was defined by corresponding length and in this manner thermographic images were scaled to the real size.2 were calculated to percentage.On each recorded thermogram, in the whole measurement area , 0.7°C isothermal-areas were identified (range of temperature from 23.7 to 40.0°C). According to the three-sigma rule, data were grouped for three temperature ranges . The calculations were performed for particular subareas . The data obtained for three range temperature areas in cmTmax before procedure were isolated (gray picture).If the high range temperature increase was observed, the isothermal-areas higher than U tests were performed in order to observe that data are representative of the full population of possible data values. Tests were applied to compare the differences in the three temperature ranges  for average temperature (Tavr), maximum temperature (Tmax), and percentage size of isothermal-areas .Exact one- and two-way Mann-Whitney P < 0.05. Statistical analysis was performed using IBM SPSS Statistics, version 20.Pearson correlation with two-tailed significance test was applied to define the dependency of vasomotor phenomenon occurrence. All comparisons were completed, with trigger points coexistence being the differentiating criterion. Values in text, figures, and are expressed as ± standard error of the mean (SEs). Significance level was set at Tavr) comparison before dry needling session revealed ΔTavr of 0.01°C. DN related referred pain was reported during the procedure by every TrPs-positive subject in the thigh and by every second TrPs-positive subject in the calf. Among non-TrPs subjects some patients (n = 5) were needle reactive and reported needle sensation on the thigh.In the group of subjects, the prevalence of gluteus minimus active trigger points (TrPs) was 32%. All TrPs-positive subjects recognized referred pain evoked during dry needling (DN) as their daily pain. Side-to-side (painful to nonpainful leg) average skin temperature . Detailed analysis of measured subareas confirmed the same .Infrared thermovisual camera revealed DN-related short-term vasodilation in the area of expected vasomotor reactions  . The prelusively . Pearson U test confirmed that dry needling provoked a significant percentage high temperature (HT%) isothermal-area increase only when TrPs coexisted (phases II and III both P < 0.05). That HT% increase was significant in the area of the expected vasomotor reactions . For the foot, an insignificant decrease of HT% was confirmed. Among TrPs-negative patients, an insignificant HT% decrease  and an insignificant HT% increase (thigh) were observed.The exact two-way Mann-WhitneyDetailed values of HT% changes dependent on TrPs presence were shown in  U test confirmed that dry needling provokes a significant skin temperature (Tsk) increase (maximum and average) for TrPs-positive patients only for both phases . Additionally, the significant Tsk increase was confirmed only in the area of the expected vasomotor reactions   . On the ermogram .Among TrPs-positive subjects, the value of a significant maximum temperature increase in phases II and III, respectively, was for the thigh +1.29 ± 1.22°C and +1.5 ± 1.30°C; for the calf +0.46 ± 0.71°C and +0.7 ± 1.0°C. The value of a significant average temperature increase in phases II and III, respectively, was for the thigh 1.31 ± 0.88°C and 1.2 ± 1.0°C; for the calf 0.54 ± 0.72°C and 0.4 ± 0.8°C.r = 0.896, P < 0.005; calf r = 0.606, P < 0.005) not the daily pain reported by the patients  for the thigh and calf  after glutamate injection to latent TrPs and no reactions after injection to non-TrPs [Tsk reactions. All of these doubts should be looked at in the future. Another hypothetical explanation can be given by Sandberg et al. [This study demonstrated that at least one in three chronic sciatica patients presented with gluteus minimus TrPs coexistence. Dry needling under IRT control of sciatica subjects revealed vasodilation coincident with the patient's pain area only when TrPs coexisted Figures  and 2. Tpatients . Additioand calf . Althougent TrPs . Interesnon-TrPs . It is dg et al. . They prg et al. . The higg et al. , 26. SurOn the other hand, it may not be the kind of noxious stimuli per se but rather the time of stimulation which explains such intensive vasomotor reactions. Additionally, evoking the twitch response, which is a spinal cord reflex characteristic of TrPs only, might have some meaning for revealing vasodilatation. Further studies are required to resolve these doubts.Tsk of around ±1.0°C [Tsk of more than 0.3°C, with vessel reactions occurring mainly distally (the feet) [Tsk in the present study is much higher than the one achieved by cold exposure but it is similar or just a little higher when compared with outcomes of acupuncture needle stimulation. However, acupuncture stimulation provoked vasodilation only locally.However, acupuncture studies show that needle stimulation of acupoints provokes both decrease and increase in d ±1.0°C , 27. Thehe feet) . The outP < 0.05) was confirmed only for the thigh. According to the theory of myofascial pain syndrome, TrPs referred pain may follow its pattern either in full or in part; thus the same is observed in the present study. Only half of the TrPs-positive patients reported DN sensation in the calf. Moreover, significant widening of thigh HT% isothermal-area in TrPs-positive patients is contrary to an insignificant slight widening or shrink in non-TrPs subjects , coincident with the area of the expected TrPs referred pain. However, a significant HT% increase , reflex changes in skin blood flow (SkBF) are mediated by two branches of the sympathetic nervous system . Despite the fact that the cutaneous active vasodilator system is the most studied one, especially SkBF, the precise mechanisms thanks to which the cutaneous active vasodilator system functions remain somewhat enigmatic . In thise fibers . It is ke fibers , 32–34. e fibers . In thisAdditionally, it seems that the biphasic nature of vasodilatation  is similThis study is limited by the absence of a control group. DN provoked significant vasodilation above the initial maximal temperature before procedure for TrPs-positive subjects. This was not observed for TrPs-negative subjects. Thus, it is required that the influence of DN on healthy subjects is examined. Another limitation of the study is the lack of the analysis of the TrPs-negative subjects who reported needle sensation as likely TrPs. According to the literature, it is more probable to evoke the referred pain from TrPs by needle than by snapping palpation . Due to The prevalence of active trigger points among chronic sciatica patients was around one in three. Every TrPs-positive subject presented with dry needling related short-term vasodilatation in the area of referred pain. Although the involvement of TrPs in chronic sciatica patients is possible, further studies on a bigger group of patients are still required.


This paper presents functional MRI work on emotional processing in depersonalization disorder (DPD). This relatively neglected disorder is hallmarked by a disturbing change in the quality of first-person experience, almost invariably encompassing a diminished sense of self and an alteration in emotional experience such that the sufferer feels less emotionally reactive, with emotions experienced as decreased or “damped down,” so that emotional life seems to lack spontaneity and subjective validity. Here we explored responses to emotive visual stimuli to examine the functional neuroanatomy of emotional processing in DPD before and after pharmacological treatment. We also employed concurrent skin conductance measurement as an index of autonomic arousal. In common with previous studies we demonstrated that in DPD, there is attenuated psychophysiological response to emotional material, reflected in altered patterns of (i) regional brain response, (ii) autonomic responses. By scanning participants before and after treatment we were able to build on previous findings by examining the changes in functional MRI response in patients whose symptoms had improved at time 2. The attenuation of emotional experience was associated with reduced activity of the insula, whereas clinical improvement in DPD symptoms was associated with increased insula activity. The insula is known to be implicated in interoceptive awareness and the generation of feeling states. In addition an area of right ventrolateral prefrontal cortex emerged as particularly implicated in what may be “top-down” inhibition of emotional responses. The relevance of these findings to the wider study of emotion, self-related processes, and interoception is discussed. Depersonalization disorder (DPD) is characterized by a persistent and distressing alteration in the quality of subjective experience, such that the individual experiences both themselves  and their surroundings  as oddly estranged and unreal. Although depersonalization and derealization are separable phenomena, in practice they usually co-occur , we hypothesized that DPD patients who had improved clinically would at time 2 show significantly increased activation, compared to time 1, of anterior insula in response to emotional material.That DPD patients would show generally reduced skin conductance responses (SCRs) to IAPS stimuli compared to healthy controls, and that at time 2 this effect would be influenced by response to treatment in a similar manner to the fMRI findings i.e., that DPD patients who improved clinically would, at time 2, have an SCR profile resembling that seen in controls, with significantly more autonomic response to emotional stimuli than in the same patients at time 1 or non-improved patients at time 2.The key hypothesis, in its simplest form, was that patients who show a significant response to treatment [defined as a 30% or greater reduction in Cambridge Depersonalization State Scale (CDSS) scores at time 2 relative to time 1 . Patients were recruited according to the following inclusion and exclusion criteria: (1) Meeting diagnostic criteria for primary DPD. Where other psychopathology  was present, it was a requirement that this was secondary to chronic depersonalization, such that the latter was the predominant presenting symptom, and had been the dominant symptom for the duration of the condition . Each statement is rated on a simple visual analog scale between 0 and 100, such that the maximum possible score is (22 × 100) = 2200. The BDI is a widely used instrument for probing mood state and other mental and behavioral aspects of relevance to depression, and SAI is another widely used anxiety scale that has two sections, one probing anxiety-related experiences over the preceding 6 months (Trait), and one asking respondents to rate feelings or experiences in the moment (State) . Estimated verbal IQ, assessed using the NART  in the fourth, see Table Of the original clinical sample of 14, four patients did not return for scans at time 2  were also recruited . Mean symptom scale scores for the control group were: CDSS 38.7 (SD 48.0), BDI 2.56 (2.73), SSAI 31.6 (SD 8.61).p = 0.16). Unpaired t-tests were performed to check for other differences between the groups. There were no significant differences between groups for age  or estimated verbal IQ . There were highly significant differences between groups on the three clinical rating scales: the BDI , the SSAI , and the CDSS .Although the patient group contained relatively more males , the difference in the gender composition of the two groups was not statistically significant  SC5SA preamplifier, a SC5AL amplifier, and real-time PSYLAB online signal processing software. These devices employ a 24-bit A/D converter, filter the response signal at 10 Hz to prevent aliasing, and have an output range of 0–100 MicroSiemens. SCR was then sampled at 100 Hz without further compression and stored offline serially, including stimulus presentation points. Security measures were included to prevent electric shocks, radiofrequency (RF) burning, and to protect SCL signals from scanner-induced magnetic distortion using screened cables. Shielding of the wires received a 5.6-kOhm correction by resistors that produced a stable 1% shift of the signal. The cable was led from the magnetically shielded scanner environment through a Faraday cage, and the signal filtered at 1000 pF by capacitors to a copper cap before signal processing. Water soluble jelly  was used as an electrolyte contact medium between electrodes and skin. Before the application of electrodes, all subjects washed their hands using a plain nonabrasive soap  contrast  at the Maudsley Hospital, London. One hundred T2fMRI data were analyzed with the software XBAM, developed at the Institute of Psychiatry, using a non-parametric approach . The best fit between the weighted sum of these convolutions and the time series at each voxel was computed using a constrained BOLD effect model  where Y is the vector of BOLD effect sizes for each individual, X is the contrast matrix for the particular inter condition/group contrasts required, a is the mean effect across all individuals in the various conditions/groups, b is the computed group/condition difference and e is a vector of residual errors. The model is fitted by minimizing the sum of absolute deviations rather than the sums of squares to reduce outlier effects. The null distribution of b is computed by permuting data between conditions/groups  and refitting the above model. Group difference maps are computed as described above at voxel or cluster level by appropriate thresholding of the null distribution of b. BOLD effect maps were used to compute significant group/condition differences rather than standardized measures such as SSQratio, F or t as these contain explicit noise components (error SSQ or error variance), raising the possibility that group differences resulting from F, SSQratio or t comparisons could reflect differences in noise rather than signal.All subjects scored >95% correct responses when judging whether scenes depicted in IAPS images were taking place outdoors or indoors, with no difference between the groups.The following variables were examined: number of fluctuations (amplitude of over 0.02 microsiemens), amplitude of the largest fluctuation, and mean SCL (skin conductance level) across the epoch. These variables were computed for (i) the whole epoch (WE) , (ii) the first 30-s emotional block within each session (E1), and (iii) the first 30-s neutral block within each session (N1). As the experiment progresses, the likelihood of SCR responses in subsequent blocks being contaminated by responses to stimuli from earlier blocks increases. Therefore, SCR variables were not computed for individual blocks occurring after the first emotional and neutral blocks of each session. This resulted in a total of 9 SCR variables designated as WEflucs, WEamp, WEmean , E1flucs, E1amp, E1mean , and N1flucs, N1amp, N1mean .Initial exploratory statistics performed on these nine variables, subdivided by group, showed that these data exhibited considerable variance that violated the assumptions of normality, even after log transformation. This was largely due to the data being positively skewed . For this reason, non-parametric tests were used to compare within and across groups.n = 25), two-tailed Wilcoxon signed-rank tests were used to compare SCR responses in the first emotional and neutral blocks of each scanning epoch . Fluctuations in the initial emotional blocks (E1flucs) were significantly greater than those in initial neutral blocks . There were no significant differences in amplitude of highest fluctuation or mean SCL. Similar results were obtained in the DPD patient group at time 1, n = 14, where E1flucs was significantly greater than N1flucs , with no significant differences in mean SCL.Within the normal control group , right supramarginal gyrus. Areas significantly more activated by viewing neutral images were cerebellum, left middle temporal gyrus, right supramarginal gyrus, and left insula. These results are summarized in Table Areas significantly more activated by viewing aversive images were areas of right lateral prefrontal cortex, bilateral primary visual cortex, bilateral anterior cingulate cortex (ACC), and left medial prefrontal cortex. Middle temporal gyrus was significantly activated by viewing neutral images in contrast to aversive images , and cerebellum. For the reverse comparison, one large cluster in cerebellum was observed (Table Findings from the controls vs. patients (at time 1) comparison are summarized in Table n = 5) was compared with time 2 data for those patients who did not show any such reduction. See Table For this comparison, time 2 data for DPD patients who showed a clinically significant reduction in CDSS score  in view of the established relationship between depersonalization and anxiety  for the whole scanning session and, in addition, for the first 30-s aversive and neutral stimulus blocks, giving a total of nine dependent variables. Tests of the hypothesis that DPD patients (at time 1) would be generally less autonomically reactive than healthy controls produced significant results for five of the nine variables, and non-significant trends in the same direction for the other four variables. Taken as a whole, these findings provide strong evidence to support the above hypothesis. It should be noted that this effect was not specific to responses to emotional stimuli: the findings from neutral blocks are similar to those from emotional blocks. As discussed above, the study by Sierra et al. , found dThere is also older work supporting the idea that depersonalization is associated with diminished emotional arousal and autonomic reactivity. There are reports of individuals with episodic depersonalization in whom periods of depersonalization were associated with SCR response patterns that were strikingly different  from SCR responses recorded from the same individuals at times when they were not experiencing depersonalization symptoms . Keeping this caveat in mind, it appears that while measures of SCR reactivity appear to reliably discriminate patients from controls, they do not appear to have predictive value in terms of response to pharmacotherapy or progress over time, and nor are improvements in clinical state necessarily mirrored by corresponding changes in autonomic responses. This may reflect the fact that at time 2, even those patients who exhibited a significant fall in CDSS score compared to time 1 nevertheless still had CDSS scores well above the clinical cut-off for this scale, with only one exception. In other words, four of these five patients still had definite symptoms of DPD, despite having improved clinically to a significant degree. The improvement appears to be reflected in changes in neural activation pattern in response to the IAPS images (discussed in detail below), but this is not mirrored by changes in autonomic response. This suggests that the inhibition of autonomic emotional response is a core feature of the DPD syndrome which is one of the last aspects to “normalize” when patients improve clinically, whether this improvement is spontaneous or in response to specific treatment interventions. Although patients who improved were designated as “improvers” for the purposes of this study, it cannot be definitively stated that their improvement was in fact due to the prescribed pharmacotherapy. The study was not designed as a formal treatment trial- rather it is an observational study of changes over time in a group of patients, and the cause of these changes cannot be definitely inferred. However, the response rate of 50% (among the 10 patients who were re-scanned at time 2) is consistent with a previous study of lamotrigine (either as monotherapy or in combination with antidepressant medication) . In contrast, no visual cortical areas were more active in DPD patients than in controls. However, in DPD patients at time 2, the pattern of results in visual cortex is more complex. Both improvers and non-improvers show bilateral visual cortical activations at time 2, with different areas being significantly more active in each of these two subgroups. However, it is of note that in the responder subgroup, visual cortex was significantly more active at time 2 than at time 1, suggesting that a reduction in CDSS score is associated with increased modulation of sensory cortex by emotional processing. It may be that as this modulatory effect increases, different areas of secondary sensory cortex are recruited, perhaps accounting for the different patterns of visual cortical activity seen in the two subgroups.In contrast to the SCR data, the functional MRI results suggest a clear pattern of association between changes in mental state over time and corresponding changes in regional brain activity. At time 1, DPD patients showed significant activation in response to aversive images in right lateral prefrontal cortex , bilateral primary visual cortex, bilateral ACC, and left medial prefrontal cortex. Visual cortical activations are frequently seen in functional neuroimaging studies when emotionally salient material is presented in the visual modality, as in the current study. This is thought to reflect the “modulation” of sensory cortex by back projections from areas involved in emotional processing  of right ventrolateral prefrontal cortex. In a previous fMRI study of DPD  material , a state in which experience of both the self and the surrounding world feel oddly attenuated. Thus work in DPD may provide a clinical sounding-board for the notion that, while insular cortex may not be essential for interoceptive experience, its activity is important in some way that adds important higher-order experiential features  anterior insula activity is a plausible biological substrate for both desomatization symptoms and the phenomenon of de-affectualization which is the explicit target of this study. It may be, then, that the subjective alteration of experience that is the core of the depersonalized state is rooted in a lack of anterior insula activity. The fact that this lack of activity appears to be amenable to treatment- or, at least, that it is not fixed over time- is encouraging, as it suggests a potential neurobiological target for future treatment strategies in DPD.NM recruited most of the participants, designed and ran the fMRI experiments, carried out the bulk of the data analysis and interpretation, prepared the figures, and wrote most of the manuscript. MS recruited the remaining participants and contributed to theoretical discussion of the findings. AS contributed to data analysis and theoretical discussion. VG and MB contributed to the analysis both theoretically (writing software routines) and practically (helping to write the Methods section). AD supervised the work and contributed to the conceptual background and theoretical discussion.NM was supported by a Wellcome Trust Research Training Fellowship, ref 065799/Z/01/Z.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.