The clinical utility of tender point (TP) examination in patients reporting chronic widespread pain (CWP) is the subject of contemporary debate. The objective of this study was to assess the relationship between mechanical hyperalgesia assessed by manual TP examination and clinical disease severity. 271 women with CWP were recruited from a clinical setting. Data collection included patient-reported symptoms, health-related quality of life variables, and observation-based measures of functional ability, muscle strength, 6-minute walk, and pressure pain thresholds measured by cuff algometry. TP examination was conducted according to ACR-guidelines. Relationships between disease variables and TP count (TPC) were analyzed with logistic regression in a continuum model, allowing the TPC to depend on the included disease variables and two regression models carried out for a TPC threshold level, varying between 1 and 17. The threshold analyses indicated a TPC threshold at 8, above which a large number of disease variables became consistently significant explanatory factors, whereas none of the disease variables reached a significance level in the continuum model. These results support the premise that the presence of mechanical hyperalgesia influences symptomatology in CWP and that the severity of clinical expression is related to a threshold of TPs, rather than being part of a continuum. Fibromyalgia is a characterized subgroup of patients presenting with chronic widespread pain (CWP) and widespread mechanical hyperalgesia. These characteristics are enshrined in the 1990-ACR criteria . The undA positive relationship between TP count (TPC) and psychological distress seems well established, although a quite variable association between the TPC and clinical disease severity has been reported –15. In tThe WHO international classification of functioning, disability, and health (ICF) can serve as a framework when defining clinical disease severity . The ICFThe objective of this study was to evaluate the relationship between TPC threshold and clinical disease severity in patients with CWP using the multidimensional ICF measurement framework. It was hypothesized that the clinical disease burden in patients with CWP would be influenced by the presence and spread of mechanical hyperalgesia, as evaluated by the manual TP examination.The study was cross-sectional with systematic data collection on consecutive female patients diagnosed with CWP at rheumatologic examination and accepted for enrolment in an interdisciplinary rehabilitation program tailored for this patient population at the department of rheumatology, Frederiksberg Hospital. A comprehensive baseline assessment based on the brief ICF core set for CWP  was implThe referral diagnosis of CWP was based on the 1990-ACR definition of wide spread pain  . Measures of psychological distress  were low to moderate in the overall study population and no significant group differences were present.Within the body domain, patients with a TPC above 8 reported significantly higher levels of pain intensity, tiredness, fatigability, and muscle stiffness and had lower levels of knee muscle strength and walking ability (6-MW) and lower pressure pain thresholds as measured with CPA. However, CPA pain thresholds overall showed only a weak correlation with the number of TPs [pain threshold: P = 0.004], indicating a higher degree of observable effort and/or fatigability during ADL-task performance. No significant differences between groups were noted for measures relating to the level of participation  or personal factors  at this TPC level.Within the domain of activity and participation, the TPC threshold of 8 or more was associated with significantly higher self-reported ratings of functional disability and also ADL motor ability measures of the AMPS were significantly lower in patients with a TPC above 8 [1.04 versus 1.29 logits,  threshold on the number of TPs rather than being part of a continuum. Logistic regression analyses indicated that a TPC of 8 defined a threshold above which a large number of variables linked to pain and pain-related interference with everyday life became consistently significant explanatory factors  and self-reported well-being measured with the SF-36. None of these variables appeared as significant explanatory factors at lower TPC thresholds and pain catastrophizing and pain self-efficacy variables never entered the model. This finding was in accordance with the results of the multivariate/full model and supports the notion that the relationship between psychological distress and CWP is not solely due to TPs, but most likely pertains to the affective component of pain.It is noteworthy that in the univariate/marginal model onlythe ADL motor ability measure of the AMPS was consistently significant throughout the entire range of TPC thresholds. Functional ability is considered a core outcome in clinical pain research , 29–31. TPC threshold analyses in the multivariate/full model with the TPC pain response cutoff set at 2 indicated a shift in explanatory variables similar to the shifts in the univariate/marginal model and at the same thresholds. However, whereas the results in the marginal model were more consistently significant, the behavior of the full model suggested a change in explanatory variables. The results of the multivariate/full model indicated that at lower TPC thresholds covariates related to function  seemed to show the strongest and most consistent relationship with number of TPs. Contrary to the findings in the univariate/marginal model, self-reported level of pain and fatigue never entered the full model as significant explanatory factors. Pain reduction following treatment has been shown to parallel improvements in other outcomes in patients with CWP, including self-reported physical and social functioning, sleep, and interference with work . The intSeveral studies have reported a positive relationship between number of TPs and self-reported somatosensory symptoms of neuropathic pain in patients with CWP and fibromyalgia –39, as wEvaluated in an ICF-measurement framework covering core set categories identified for the multidimensional assessment of CWP, the negative impact on measures obtained at the body level and level of activity and participation was substantial. In accordance with the existing literature , 42 the Limitations and Generalizability. The study was conducted in a specialized tertiary-care setting and patients encountered are not necessarily representative of patients from the overall referral population. It has been reported that patients with CWP in referral clinics demonstrate higher pain severity and negative consequences related to pain than similar patient groups found in the community [ommunity . Howeverommunity  the stud threshold rather than a TPC continuum. Provided the requirement of a moderate or greater pain response at palpation, the major shift of disease severity occurred at a TPC of ≥8. This relationship was not observed if the TPC in individual patients was based on a TP cutoff set at mild tenderness, suggesting that a hyperalgesic pain response at palpation should be required in order for TPs to be considered a primary identifier of pain hypersensitivity. These findings are at odds with the affective spectrum disorder hypothesis [Patients with CWP encountered in the clinical setting exhibit a positive relationship between the number of TPs and severity of the clinical pain condition through a TPCpothesis  and suppAnnex A contains a detailed description of the applied questionnaires and observation-based assessment methods, and two figures showing the distribution of patients according number of tender points with the cutoff for the pain response at tender point examination set at 1 and 2, respectively.Click here for additional data file.


Chronic musculoskeletal pain (CMSKP) is attentionally demanding, complex and multi-factorial; neuroimaging research in the population seen in pain clinics is sparse. A better understanding of the neural activity underlying attentional processes to pain related information compared to healthy controls may help inform diagnosis and management in the future.n = 15) and healthy controls (n = 14) while completing a modified Stroop task using pain-related, positive-emotional, and neutral control words.Blood oxygenation level dependent functional magnetic resonance imaging (BOLD fMRI) compared brain responses in patients with CMSKP (Response times in the Stroop task were no different for CMSKP patients compared with controls, but patients were less accurate in their responses to all word types. BOLD fMRI responses during presentation of pain-related words suggested increases in neural activation in patients compared to controls in regions previously reported as being involved in pain perception and emotion: the anterior cingulate cortex, insula and primary and secondary somatosensory cortex. No fMRI differences were seen between groups in response to positive or control words.Using this modified Stroop tasks, specific differences were identified in brain activity between CMSKP patients and controls in response to pain-related information using fMRI. This provided evidence of differences in the way that pain-related information is processed in those with chronic complex musculoskeletal pain that were not detectable using the behavioural measures of speed and accuracy. The study may be helpful in gaining new insights into the impact of attention in those living with chronic pain. Chronic musculoskeletal pain (CMSKP) poses a major clinical, social and economic problem , 2 and cNeuroimaging has improved our understanding of the neural processes underlying cognition, emotion and context that influence pain perception –11. The The Stroop paradigm focuses on the fact that cognitive interference occurs when the processing of one stimulus feature impedes the simultaneous processing of a second stimulus and is a well established paradigm for assessing attentional bias , 15. It To our knowledge, the only neuroimaging study to use a Stroop paradigm in a clinical pain population to date  examinedThe present study aims to examine the attentional, behavioural and activation differences between patients with complex CMSKP  and healthy controls using a Stroop paradigm. Using this paradigm, we will investigate whether (a) there is a general deficit in attentional control (as assessed by the modified Stroop) between patients and controls, (b) there is a specific attentional bias for pain-related stimuli , (c) there are BOLD signal differences in patients compared to controls in pain and emotion related brain regions in response to the Stroop task including primary (SI) and secondary (SII) somatosensory cortices, prefrontal cortex, insula and anterior cingulate cortex (ACC) , 24.With Dyfed Powys Research Ethics Committee approval, thirty participants were recruited and provided informed written consent for the study. Fifteen patients were recruited from a pain management program and a multidisciplinary pain clinic in South Wales and 15 matched healthy (pain-free) controls were recruited from a volunteer panel. Criteria used to match the patient with the healthy control were age, gender, educational level attainment, marital and work status. All participants received small honorarium for their participation to cover travel costs and refreshments.Patients had been assessed by a pain specialist after primary care management and this had proven ineffective due to the complex nature of the patient’s condition. Patients had been deemed suitable for specialist pain treatment and were awaiting this treatment. Criteria for patient inclusion in the study were: a physician-diagnosis of chronic non-malignant pain  from 0 (no pain) to 100 (worst possible pain). Using the same scale, they also rated their worst pain, least pain, pain intensity over the last week and last 3 month period, and the degree to which the pain interfered with activities of daily living over the previous week. The 101-point (i.e. 0–100) NRS of pain intensity is recommended as a core outcome measure in clinical trials of chronic pain . Prior tThe Hospital Depression and Anxiety Scale (HADS)  was usedThe Stroop task  is a welPain-related words (affective and sensory) from the McGill Pain Questionnaire (MPQ)   which demonstrated no statistically significant differences between the control and interference words.Positive emotional, sensory pain-related, and affective pain-related (collectively ‘interference’) words were then matched with neutral words (household objects) based on how often they were used in the English language, word length, and the number of orthographic neighbours  using the English Lexical Project  databaseThe implemented protocol was based on the research by Whalen and colleagues ; who oriwork as quickly as possible, but do not sacrifice accuracy for speed, and do not blur your vision in an attempt to make the task easier – keep the words in sharp focus’. Subjects made their response using two response boxes, one held in each hand. Subjects used their middle and index finger of their left hand when their response was 1 and 2 respectively, and the index and middle finger of their right hand when their response was 3 and 4, respectively. Each trial lasted 1.5 s and there were 16 trials in a 24 s block. Each run included 16 blocks, of which there were 2 blocks for each word-type, 2 blocks for each corresponding control word set and four fixation-cross (rest) blocks (24 s duration) presented on the screen at the beginning and end of both runs and twice within a run  for each participant.Imaging was performed on a 3 T MRI system  using an 8-channel receive-only head coil. Functional MRI data were acquired with a gradient-echo, echo-planar imaging sequence, scanning parameters were: repetition time (TR)/echo time (TE) = 3000 ms/35 ms, 20.5 cm field of view, acquired on a 64 x 64 matrix with 53 contiguous 3.2 mm slices. Each run consisted of 138 repetitions. For anatomic localization, a T1-weighted, three-dimensional fast-spoiled gradient echo acquisition was performed, with a voxel resolution 1x1x1 mmP-value of less than 0.05. Statistical analysis was performed using SPSS software version 16.0 for Windows .To test for differences in Stroop reaction times (RTs), a repeated-measures analysis of variance (RM-ANOVA) was used. The dependent variable was the RT and the fixed factor was the study group . Run 1 and run 2 were analyzed separately to test for habituation; a comparison was undertaken between the two runs looking for statistically different response latencies. The number of accurate responses was compared between groups  using independent t-tests. Participants were judged to be responding accurately if the number pressed on the button box corresponded to the number of words presented on the screen. Significance was set at www.fmrib.ox.ac.uk/fsl). The functional data for each subject was motion corrected , part of FSL  and fie.A second-level, fixed effects analysis was performed to combine the two runs for each subject.A third level, mixed effects analysis was performed to indicate differences between patients and control groups. Two third level analyses were performed, one including HADS as a covariate as suggested in a previous Stroop study  and one Data were analysed at three levels:Z > 2.3 and cluster corrected (Family Wise Error) at a significance threshold of p = 0.05 [Each interference word group  was compared with the corresponding control word group. The affective and sensory interference words were also examined when combined together to reflect the way the McGill Questionnaire is used clinically, as the word groups are not separated to provide a final score . Combinip = 0.05 . FLAME [p = 0.05  was usedU test. As expected, patients and controls differed in pain scores and patients median current numerical rating score was 60 (range 40 – 70) . The HADS illustrated that patients had more psychological distress compared to controls , age range 25 to 83 years old, including 15 patients with pain and 14 age, gender and educational level attainment-matched controls. One control subject was unable to tolerate being in the scanner and withdrew from the study. No patient complained of increased pain during the scanning period. Pain scores and HADS were compared between groups with a Mann–Whitney Patients’ clinical characteristics are described in Table There were no statistically significant RT differences for any word group  between patients and controls in an individual run or combined runs Table . No habiGeneralised linear mixed model (SPSS Version 20) was used to analyse the data. A separate analysis was carried out for each word type  and level (Control and Interference) for both runs 1 and 2 . To allow for multiple testing, the significance level was set at 0.05/12 = 0.004. ‘Patient or Control’ and ‘repeat’ (each run comprised two repeats) were added as fixed effects and patient ID was added as a random effect, to allow for multiple responses. None of the analyses indicated a significant difference between patients and controls.There were no behavioural differences between the two runs of the Stroop task and therefore imaging analysis results were pooled across runs . Whole bWhen affective and sensory MPQ words (PRStroop) were combined in the second level analysis and in the third level analysis, differences in BOLD responses were observed in centres involved in pain, emotion and attention between pain words and control words in patients contrasted with controls when HADS was used as a covariate see Fig.  and whenThe sensory pain interference words compared to control words showed differences in BOLD signal changes in patients relative to controls in the right insular cortex, right frontal operculum and right central opercular cortex Fig.  in the tTo our knowledge, this is the first study that uses a Stroop paradigm in a complex CMSKP group of patients needing specialist pain management. The findings demonstrate that pain-related words used in a PRStroop task resulted in BOLD signal differences between CMSKP patients and healthy controls in pain processing centers in the brain. Larger BOLD signal increases were seen in the patient group compared to the control group in pain-related regions including the ACC, insula, parietal operculum and SI, SII see Fig. . SimilarPrevious studies using pain-related versions of Stroop have been equivocal; some have not demonstrated differences in RTs , 41, 45 The lack of a Stroop effect may imply that RTs may be an imperfect or at least less sensitive measure of cognition . PatientPain has multiple dimensions; the sensory-discriminative , affective-motivational  and cognitive-evaluative components . While tWe also propose that pain-related words, in the absence of induced noxious stimulation, can activate the areas of the brain associated with affective-motivational aspects of pain in CMSKP patients. Regions involved in the affective-motivational dimension of pain include the insula cortex and rostral ventral ACC , inferioThe parietal operculum and inferior parietal lobe see Fig.  also shoThe cognitive-evaluative component of pain involves evaluation and interpretation of the meaning of pain and emotional distress. BOLD signal differences were seen in patients compared to controls in the central opercular cortex, paracingulate and in the left frontal pole. The central opercular cortex and frontal pole  are invoWhen HADS was not used as a covariate in the analysis, there appeared to be more ACC, frontal pole, central opercular cortex, Heschl’s gyrus and planum temporale weighted differences between patients and controls when compared to the third level analysis which included HADS. ACC involvement in anxiety and depression is well recognised –80 and aNonetheless, there are a number of limitations. There are problems in studying pain-cognition interactions in patients with severe and complex chronic pain, such as seen in those referred to specialist pain centres; extricating pain-related cognitive effects from those resulting in pain treatments, especially opioids, and separating pain-related effects on cognition from the effects of the emotional distress that is a key feature of chronic pain . TherefoThe use of a pain word task is non-invasive, does not require pain induction, and causes activation in brain regions associated with pain. Our study has shown that patients with complex CMSKP attend to pain-related information differently from healthy controls, which is reflected by BOLD signal changes in regions known to process pain and emotion. Patients with CMSKP did not demonstrate a specific behavioural Stroop effect, but performed worse across all Stroop tasks when compared to controls. This study adds to the literature regarding how people living with pain attend to pain-related information and offers insight to those living with complex needs where evidence is sparse. Research such as this, can support further studies looking at adapting or developing new ways of assessing cognitive biases that are more sensitive based on further imaging research to help improve diagnosis.


Objective: One of the critical components in the postoperative care is pain. Given that little research has been done regarding the analgesic effects of intra-articular injection of ketamine, this study was aimed to compare the analgesic effect of intra-articular and extra-articular injection of morphine and ketamine compound in arthrotomy surgery under spinal anesthesia.Methods: A total of 50 patients were candidate for arthrotomy surgery, aged 18-60 years were divided randomly into two groups. At the end of surgery, the first group was treated with combination of intra-articular morphine and ketamine compound and the second group was treated with combination of extra-articular morphine and ketamine compound. The amount of postoperative pain was recorded in the hours of 2,4,6,12,24 respectively. Also 24 hours consumption of rescue analgesic was recorded.Results: The pain severity (VAS) in the hours of 2, 4, 6, 12 and 24 after surgery in the intra-articular injection group was significantly lower than the extra-articular injection group (P<0.05). Postoperative morphine consumption in intra-articular injection group (3.2±3.78) was significantly less than the extra-articular injection group (6.36±5.22) (p = 0.018).Conclusion: Postoperative pain severity of intra-articular injection of ketamine and morphine in knee surgery is less than extra-articular injection. After discovering the path of pain in the 19th century, significant improvements have been achieved in the field of pain management.2-14 In a study about intra articular injection of morphine performed in 2013 by Ozdemir et al. The authors concluded that intra articular morphine combined with levobupivacaine or bupivacaine decreases analgesic requirements and shortens the postoperative duration of analgesic use after knee arthroscopic surgery.15 In another study Arti et al. in 2013 showed the effectiveness of intra articular morphine in comparison to meperidine or methadone in pain relief after arthroscopic menisectomy.16 On of the other techniques for reducing pain was to reduce postoperative pain in knee surgery performed by Andersen et al. In their study ultrasound-guided saphenous nerve catheter was placed postoperatively in the adductor canal at midthigh level. They concluded that the combination of a continuous saphenous nerve block with single-dose local infiltration analgesia offered better pain relief on the day of surgery than local infiltration analgesia alone.17Morphine and other opioids are used to control pain after surgery that have numerous side effects such as nausea, vomiting, respiratory depression, constipation, and loss of consciousness as well as the possibility of physical dependence and abuse, finding an alternative method has always been considered.12Detection of N-Methyl-D-aspartate (NMDA) receptor and its role in reducing the pain has caused a new development in the use of ketamine medicine. A lot of reports have been published about the use of low dose ketamine as a NMDA receptor antagonist in relieving the pain and reducing the need for systemic opioids. This drug blocks NMDA receptors in the posterior horn postsynaptic membrane of the spinal cord and inhibits the pain transmission through the pain fibers to the central nervous system, resulting in reduced pain or no pain sensation. Recent research has shown that ketamine has a topical analgesic effect, as well.- Ketamine can be used in many routs such as intravenous, oral, intramuscular, intranasal, subcutaneous, or intra-anal or epidural and has rarely been used intra-articularly.21,Given that little research has been done regarding the analgesic effect of intra-articular injection of ketamine and different answers are reported in this respect;After obtaining approval from the Ethics Committee of Ahvaz Jundishapur University of Medical sciences (ETH-622), 50 patients candidate for arthrotomy lower limb surgery (knee) at ages 18-60 years, in ASA class 1 and 2 as inclusion criteria were randomly divided into two groups of 25 patients. The method of randomization was: Table of random numbers, computer-generated. Written informed consent was obtained from all patients. The first group was treated with a combination of morphine and ketamine compound by intra-articular injection and the second group was treated with the same compound extra-articularly. At the beginning of taking patients to the operating room, patients’ profile and the necessary information were collected using medical history records and as the exclusion criteria, all patients with a chronic history of narcotic or analgesic and patients who did not give consent to spinal anesthesia, were excluded from the study.The amount of pain felt by the patient was measured separately using the visual analogue scale (VAS) index .At this scale, the number 10 represents the most severe levels of pain perception and zero indicates that the patient does not feel any pain.Before spinal anesthesia appropriate monitoring  were attached and 10 Kg / cc Ringer’s serum was infused. All patients underwent the spinal anesthesia by an anesthesiologist. Then the spinal anesthesia was performed by spinal needle No.25 "EXEL” brand in the L4-L5 orL3- L4 space. After insurance of detection of true space of subarachnoid and fluid output of cerebro-spinal fluid (CSF) 12.5mg hyperbaric bupivacaine was injected. Blood pressure in the first ten minutes, every three minutes, and then every five minutes was recorded and measured. If the systolic blood pressure was below 90 mm Hg or a decrease of 25% compared to the initial pressure, a 5-mg dose of ephedrine was injected. Patient’s sensory level was assessed through pin prick method, and surgery was permitted at the level of T10. Before surgery, the tourniquet pressure of 150 mm Hg above systolic pressure was closed, and at the end of the surgery and 10 minutes before opening the tourniquet of first group, morphine 5mg and ketamine 0.5mg/kg, dissolved in 20 ml of serum normal saline was injected intra-articularly, and in the second group morphine 5 mg and ketamine 0.5mg/kg, which dissolved in 20 ml of normal saline serum was injected extra-articularly. In intra-articular injection of knee, intra-synovial injection was administered and in the extra-articular injection, extra-synovial injection and inside the joint capsule (intra-capsular) was performed. Injections were administered by an orthopedic specialist. Sex, age, weight and the time of closed tourniquet of all patients were registered .The amount of postoperative pain were recorded at the hours of 2, 4, 6, 12, 24, by a person who did not know how to classify groups. If there was an analgesic request by the patient, 0.07mg/kg intravenous morphine was injected and the time of first analgesic request, and amount of post-operative opioid consumption was recorded as well.The data were reported as mean ± SD. After checking the homogeneity of variances and normality of distribution of data, the independent T-test was used to compare postoperative pain and opioid consumption between the two groups in different hours (The power of study was 80%).Demographic characteristics of participants are shown in et al. in 2006 in Norway conducted a study, in which 60 patients were divided into two groups. Patients in the case group, received 5mg in 20ml of intra-articular morphine and control group received 20ml normal saline. In this study, no significant difference in the severity or pain relief between the two groups was observed within 48 hours after surgery. They concluded that intra-articular prescription of morphine 5mg has no significant clinical effect on the pain relief after knee arthroscopy surgery.25Pain as stress, induce psychological and physiological responses and the patient's response to pain is different, the consequences of pain have a direct effect on mortality and postoperative complications, recovery time and patient satisfaction from the health system.et al. in a prospective randomized study in 2006 examined the effects of intra-articular injection of different doses of ketamine on pain severity after arthroscopic knee surgery. In terms of the amount of pain and time of asking for postoperative analgesia, no significant statistical difference existed between five groups. The results of this study showed that intra-articular injections of ketamine was not effective in reliving postoperative pain, opioid consumption and the time of ask for analgesic after diagnostic arthroscopy.26Dal et al. in Turkey in 2004 examined the effects of intra-articular prescription of ketamine on analgesia after arthroscopic surgery. In this study, 60 patients were divided into four groups. The first group received ketamine 0.5mg/kg, the second group received neostigmine 0.5mg in 20ml, the third group received bupivacaine 20ml of 0.5%, and the fourth group received a placebo. They concluded that in the first three groups of postoperative pain, opioid consumption after surgery was significantly reduced. The study also showed that intra-articular prescription of ketamine provides extended and effective analgesia as neostigmine, but the impact is less than bupivacaine.The results of this study indicate the necessity for further studies on the use of intra-articular morphine and ketamine. The study examined the combined effect of both drugs in the intra-articular and extra- articular form, and similar to other studies of intra-articular ketamine, no side effects such as euphoria were found.Postoperative pain severity of intra-articular injection of ketamine and morphine in knee surgery is less than extra-articular injection.


Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by motor and nonmotor signs and symptoms. To date, many studies of PD have focused on its cardinal motor symptoms. To study the nonmotor signs of early PD, we investigated the reactions solicited by heat pain stimuli in early untreated PD patients without pain using fMRI. The activation patterns of contact heat stimuli (51°C) were assessed in 14 patients and 17 age- and sex-matched healthy controls. Patients with PD showed significant decreases in activation of the superior temporal gyrus (STG) and insula compared with controls. In addition, a significant relationship between activation of the insula and STG and the pain scores was observed in healthy controls but not in PD. This study provided further support that the insula and STG are important parts of the somatosensory circuitry recruited during the period of pain. The hypoactivity of the STG and insula in PD implied that functions including affective, cognitive, and sensory-discriminative processes, which are associated with the insula and STG, were disturbed. This finding supports the view that leaving early PD untreated could be tied directly to central nervous system dysfunction. Parkinson's disease (PD), the second most common neurodegenerative disease, belongs to a group of conditions called motor system disorders. Although difficulties with movement are prominent in PD patients, the nonmotor signs and symptoms are likewise frequent in these patients. Nonmotor symptoms include cognitive impairment, sleep disorders, dysautonomia, and pain. Pain is one of the most frequent nonmotor symptoms that affect PD patients. Several recent epidemiological studies have found that 70–80% of patients with PD suffer from pain sensations .Pain in PD patients is thought to result from deficient sensory information. Previous studies have indicated that patients with PD exhibit numerous abnormalities in somatosensory perception –5. HowevThe aforementioned studies demonstrate that some problems remain unclear. For example, the same treatment sometimes produced different results, which we inferred might be due to differences in treatment duration or measurement method. Although drugs such as levodopa and STN-DBS have been demonstrated to be valid treatments for patients with PD, their mechanisms remain unclear. Thus, this work focused on drug-naive early PD patients and explored a neural mechanism that could be used for clinical diagnosis.Little is known about the sensory symptoms of drug-naive early PD patients and their mechanisms. Luo et al. , using rThe current study aimed to explore the functional reorganization of pain-related pathways in early drug-naive PD patients without pain through whole-brain blood oxygenation of level-dependent (BOLD) fMRI during pain stimulus using a contact heat-evoked potential stimulator (CHEPS). Moreover, to understand how functional activation causes changes in the pain matrix, we investigated the relationship between pain and brain activation.A total of 14 right-handed patients with a diagnosis of idiopathic PD were enrolled in the MRI study at the Neurology Department of the Institute of Neurological Disease, North Sichuan Medical College, China. The diagnosis of early PD was made according to the UK PD Society Brain Bank diagnostic criteria [A total of 17 right-handed, age- and sex-matched healthy participants were selected for the control group with no history or presentation of any Diagnostic and Statistical Manual of Mental Diseases Axis-V diagnosis, with no neurologic illness, and, as assessed by clinical evaluations and medical records, with no brain lesion on traditional MRI. All subjects underwent an MRI examination prior to entering the present study to exclude subjects with any relevant structural abnormalities. None of the patients had T2-weighted hyperintensities in the deep white matter. The study was performed according to the standards set by the Declaration of Helsinki and was approved by the Ethics Committee of the Affiliated Hospital of North Sichuan Medical College; written informed consent was obtained for all subjects.2 and a heating thermofoil  covered with a 25-μm layer of thermoconductive plastic. The experiments included the 51°C thermal stimulus. All stimuli were initiated from a baseline temperature of 32°C increased to a target temperature 51°C applied by computer-controlled brief radiant pulses. Twenty stimuli were included in each session. The interval of stimuli was manipulated within 16, 20, or 24 seconds at random to avoid habituation. The subjective perception of the experimental pain was recalled and assessed by the subjects, who were asked to verbally rate the intensity of the experimental pain by means of a visual analog scale (VAS) ranging from zero (“no pain”) to ten (“worst pain imaginable”) once outside the scanner. Finally, warm sense thresholds (WST) and heat-induced pain thresholds (HPT) were measured by quantitative sensory testing (QST) for each subject.Contact heat stimulation (CHS) was delivered to the skin of the right dorsal forearm using CHEPS , a heat-foil with rapid rising time at high temperatures (up to 70°C/S) developed to study pain activation related to thermal and nociceptive pathways. CHEPS has a probe with (at one end) a thermode area of 572.5 mmAll fMRI data were acquired using gradient echo-planar imaging (EPI) sequences in a 3 T MRI scanner  with a 32-channel phased array head coil. The imaging parameters were as follows: thickness, 4 mm (no gap); TR = 2,000 ms; TE = 30 ms; FOV = 240 mm × 240 mm; flip angle = 90°; and matrix = 64 × 64. Two hundred and five volumes (35 slices per volume) were obtained during 410 seconds of an fMRI session. To ensure steady-state longitudinal magnetization, the first five volumes were excluded. During data acquisition, participants were instructed to relax with their eyes closed without falling asleep . Anatomihttp://www.fil.ion.ucl.ac.uk/spm/). Each dataset was realigned. The time was corrected to reflect differences in image acquisition time between slices, followed by normalization to transform the image to match the template supplied with SPM (MNI 152) [3. Finally, images were smoothed using an isotropic Gaussian kernel .Preprocessing of the fMRI data was performed using the SPM8 software package  . Then, tt-test was used to determine brain activity within each group ), whereas a two-sample t-test model  was used for between-group comparisons to control for age and gender effects.For each subject, data were analyzed on a pixel level using the general linear model (first level). In this model, the time course produced by a time pulse function of stimuli convolved with a canonical hemodynamic response function was used as an interesting regressor to analyze task-dependent activation. Meanwhile, the six parameters of head motion were designated as noninteresting regressions. Then, a one-sample β value). We obtained the correlation between the mean β value and the subjective scores of pain (VAS and QST) using partial correlation analysis with covariates of age and gender.To investigate the relationship between the altered functional variables and the clinical variables, we chose the significantly altered boxes as the region of interest (ROI) and calculated the mean value of the regression coefficients  and the mini-mental state examination (MMSE). The pain threshold of each subject was assessed by means of VAS and QST once outside the scanner. The demographics and clinical characteristics of subjects are shown in Within the control group, the bilateral STG, insula, supramarginal gyrus, putamen, contralateral superior parietal lobule, supplementary motor area, cingulate cortex, rolandic operculum, primary somatosensory cortex (S1), calcarine fissure, and ipsilateral frontal gyrus of the cerebellum were strongly activated in response to 51°C heat stimuli . In the During heat stimulation, patients with PD showed decreased activation of the bilateral STG, insula and ipsilateral temporal pole, and middle temporal gyrus  under thβ values in ROIs  and indices , when controlling for the effect of age and gender, were observed  were observed in the control group, whereas only the stimuli-ipsilateral insula cortex (right) had a positive relationship with the VAS score in the PD group. No correlation was discovered in the stimuli-contralateral insula cortex (left) in either group. In the relationship analysis of QST (including HPT and WST) and mean β value, a negative correlation was noteworthy in the bilateral STG and INS.R in the control group, whereas no correlation was found in the PD group. No correlation was found between WST score and the fMRI signal in either group.Linear partial correlation coefficients between the mean values of observed . In the In this fMRI study, patients with PD demonstrated significantly attenuated activation of the STG and insula during noxious heat stimulation (51°C). Furthermore, pain was evaluated using the VAS scale, and thermal thresholds were evaluated using QST. After the heat pain (51°C) stimulus, significant alteration between two groups was investigated.Activity in the STG has been reported in many pain-induced studies –20, althIn our study, contralateral (relative to the stimuli) STG was more highly activated in HC during the thermal pain task, whereas it was hypoactive in the PD patients. There were three reasons associated with this finding. First, the STG was incorporated into the somatosensory circuitry. Our study suggests that the STG would be associated with pain perception and negative emotion. The STG perceives the increased sense of negative emotion, which includes the unpleasant feelings produced by pain. The STG also likely plays a role in the efference copy function mediated by the putamen, which is involved in pain processing , 22. In The insula plays a key role in processing noxious and innocuous thermal stimuli . The insPD, beyond its hallmark motor symptoms, causes variable degrees of cognitive impairment in a high percentage of patients . The preDespite the fact that the diagnosis of Parkinson's disease is predominantly based on clinical signs, neuroimaging offers great promise for the study of disease pathogenesis and evolution, particularly for studying brain functional changes during the early stage of disease. We provided evidence of abnormal activation in early drug-naive PD patients during a heat pain stimulus. In particular, we report observably decreased activation upon nociceptive pain (51°C) in PD subjects without pain symptoms. This result should contribute to the future clinical treatment of pain in PD patients. Furthermore, this finding supports the crucial role of the insula and STG in pain processing, as the insula is the most impaired region during perception of the heat stimulus in the PD group. In summary, our findings add to the growing evidence that early PD could be related directly to central nervous system dysfunction involving pain.


This cross-sectional study sought to identify dimensions underlying measures of impairment, disability, personal factors, and health status in patients with cervical radiculopathy.One hundred twenty-four patients with magnetic resonance imaging-verified cervical radiculopathy, attending a neurosurgery clinic in Sweden, participated. Data from clinical tests and questionnaires on disability, personal factors, and health status were used in a principal-component analysis (PCA) with oblique rotation.pain and disability, explained 56%. The second component, health, fear-avoidance beliefs, kinesiophobia, and self-efficacy, explained 9.2%. The third component including anxiety, depression, and catastrophizing explained 7.6%. The strongest-loading variables of each dimension were “present neck pain intensity,” “fear avoidance,” and “anxiety.”The PCA supported a 3-component model including 14 variables from clinical tests and questionnaires, accounting for 73% of the cumulative percentage. The first component, Pain and functioning, Health, beliefs, and kinesiophobia, and Mood state and catastrophizing captured aspects of importance for cervical radiculopathy. Since the variables “present neck pain intensity,” “fear avoidance,” and “anxiety” had the strongest loading in each of the three dimensions; it may be important to include them in a reduced multidimensional measurement set in cervical radiculopathy.The three underlying dimensions identified and labeled  Spondylosis, disc protrusion, or both are reportedly responsible for CR in 68% of patients, and disc protrusion alone in 22%.4 CR affects both sexes, with a peak incidence in the age group 40 to 60 years.1Cervical radiculopathy (CR) forms an important subgroup of neck disorders. The annual incidence is approximately 85 cases per 100,000 in the population.6 which is also suggested as first-line treatment.8 Patients whose pain does not naturally resolve may require surgical intervention, especially if they have significant extremity or myotomal weakness or severe pain; or if the conservative treatment is unsuccessful.9Patients with CR are often initially treated conservatively10 In patients with neck- and shoulder pain psychosocial factors are important predictors for development of chronic pain with low levels of pain catastrophizing being favorable for outcome.12 However, it is unclear which factors contribute to the development of chronic pain and disability in CR patients.The development of chronic pain may involve an interaction between the injury, the experience of pain and psychological factors such as anxiety, depression, fear-avoidance beliefs, kinesiophobia, and catastrophizing.13 Less is known about this disability in the form of activity limitations and participation restrictions; or about personal factors such as anxiety, depression, fear avoidance behavior, kinesiophobia, self-efficacy, and coping strategies. To form a complete picture and capture important aspects of patients with CR, a broad measurement battery including clinical tests and questionnaires is needed.14 Such a battery could involve a risk that measures might overlap. Additionally, a battery could be a burden for the patient in pain due to the time and effort needed. Hence the importance of exploring whether there are common underlying dimensions that explain the CR patient's characteristics. It is also important to identify variables as key measures for inclusion in a measurement battery for CR. The present aim was therefore to identify dimensions underlying measures of disability, personal factors, and health status in CR patients.In the few descriptions of nonsurgically treated patients with CR, they are presented in terms of magnetic-resonance imaging findings and body functions such as radiating pain, sensory and motor impairments, neck motion range, and muscle endurance.15 and/or a cervical extension test. Exclusion criteria were former cervical fracture, luxation, and surgery; spinal infection and malignity; known drug abuse; diagnosed psychiatric disorders; other diseases or disorders that could interfere with participation in treatment or measurements, and unfamiliarity with the Swedish language. A total of 124 patients , 59 men and 65 women, fulfilled the criteria and were included. All patients had the diagnosis cervical disc disorder with radiculopathy (M50.1) classified in the International Classification of Diseases, 10th version (ICD-10). Sixteen of the 124 patients had 1 additional diagnosis and 4 had 2 additional diagnoses; systemic lupus erythematosus with organ or system involvement (M32.1), deforming dorsopathy, unspecified (M43.9), other spondylosis cervical spondylosis without myelopathy or radiculopathy (M47.8), spondylosis, unspecified (M47.9), spinal stenosis (M48.0), other specified spondylopathies ossification of posterior longitudinal ligament (M48.8), lumbar and other intervertebral disc disorders (M51.0), cervicalgia (M54.2), nerve root and plexus compressions in other dorsopathies (G55.3). None of the patients were in a structured rehabilitation program but were screened for enrolment in a randomized clinical trial to evaluate exercise treatment. Oral and written information was given and all patients provided signed informed consent before enrolment. The study was approved by the Regional Ethical Review board in Stockholm and procedures were conducted in accordance with the Helsinki Declaration. The study follows the STROBE guidelines for reporting observational studies.This cross-sectional study comprised analyses of clinical examinations, test results, and questionnaire answers in patients with CR recruited from a university-hospital neurosurgery clinic in Sweden. Inclusion criteria were CR and pathology of relevance for CR verified with magnetic-resonance imaging, and positive results on the Spurling sign testA standardized neurological assessment protocol was performed by the same test leader (author and physiotherapist M.H.). It included bilateral examination of sensory function (light touch and pin prick) in dermatomes C4–C8; motor function  of key muscles in myotomes C4–T1; and reflexes for C5–C7 . An abnormal sensory and/or motor function in at least one of the tested dermatomes and myotomes, respectively, or an abnormal response in at least one of the tested reflexes, was classified as impairment.16 using a goniometer  measuring the angle between the two goniometer arms in degrees. The centre of the goniometer was placed at the orifice of the external ear from where one arm hung vertically and the other pointed to the C7–T1 spinal motion segment.Neutral head posture in sitting was measured as described by Engh et alActive range of motion of neck flexion, extension, lateral flexion, and rotation in the sitting position was measured using a cervical-range-of-motion instrument .18Neck-muscle endurance time was measured in seconds during submaximal, static, dorsal, and ventral neck muscle contractions performed in prone and supine positions, respectively, as previously described.21 and the sharpened Romberg test performed with eyes closed (tandem standing with right or left foot behind).22 Participants were allowed 3 trials. If no steps in the figure-of-eight test were incorrect in the first or second trial, no further trials were performed. The Romberg test was measured in seconds and terminated if the participants opened his or her eyes, or reached the maximum value of 30 seconds. If this was reached in the first or the second trial no third trial was performed. The mean value of the trials was calculated for each test.Balance function was evaluated in the walking-in-figure-of-eight test2) was calculated for descriptive purposes.Weight (kilograms) and height (meters) were measured and body mass index  and chronic (≥3 months) neck pain. Present neck pain intensity was assessed on a visual analogue scale (VAS) ranging from 0 (no) to 100 mm (worst imaginable). Average neck pain, arm pain, and headache intensity were calculated as the mean of VAS ratings (mm) of current, best, and worst during the previous week. Average dizziness intensity was calculated as the mean VAS ratings (mm) of dizziness at rest, during motion, and perceived unsteadiness problems.24 was used to assess the effect of neck pain on functioning and disability. The NDI consists of 10 items rated on a 6-point scale, ranging from 0 to 5. Results are summed to a total score that can be expressed as a percentage. A higher percentage score indicates greater disability.The Neck Disability Index (NDI)25 was used to assess self-perceived disability imposed by dizziness. Its 25 items are rated on a 3-point scale , and summed to a total score. A higher score indicates more disability. The DHI includes 3 response levels: functional, emotional, and physical, but in this study only the total sum score was used.The Dizziness Handicap Inventory (DHI)26 was used to assess catastrophic thoughts or feelings in relation to painful experiences. The PCS consists of 13 items which are rated on a 5-point scale from 0 to 4, and summed to a total score. Higher scores indicate higher levels of pain catastrophizing.The Pain Catastrophizing Scale (PCS)27 was used for evaluating anxiety and depression. Its 14 items (7 anxiety and 7 depression) are rated on a 4-point scale (range 0–3). A higher score indicates a higher level of anxiety or depression.The Hospital Anxiety and Depression Scale (HADS)28 for assessing patients’ perceived confidence in performing different activities in spite of pain consists of 20 items rated on an 11-point scale, ranging from 0 to 10, and summed to a total score. Higher scores reflect greater self-efficacy.The Self-Efficacy Scale (SES)30 is a self-reported inventory that focuses specifically on patients’ beliefs about how physical activity and work affect their pain. Its 16 items are rated on a 7-point scale, ranging from 0 to 6, and summed to a total score. Higher scores indicate higher levels of fear-avoidance beliefs.The Fear Avoidance Beliefs Questionnaire (FABQ)32 was used to assess the patients’ current pain-related fear of movement/(re)injury. The TSK has 17 items rated on a 4-point scale from 1 to 4. After inverting the score for items 4, 8, 12, and 16, a total sum-score for all items is calculated. Higher scores indicate higher levels of kinesiophobia.The Tampa Scale of Kinesiophobia (TSK)33 was used to assess patients’ use of cognitive and behavioral strategies to cope with pain. The CSQ consists of 50 items which are rated on a 7-point scale, ranging from 0 to 6, and 48 items are summed to a total score. The 2 additional items are reported separately and evaluate the patient's self-perceived control over pain (CSQ-COP) and ability to decrease pain (CSQ-ADP).The Coping Strategies Questionnaire (CSQ)35 was used to assess patients’ confidence in performing an exercise program despite potential barriers. The 6 ESES items are rated on a 10-point scale, ranging from 1 to 10, and summed to a total score. Higher scores indicate greater confidence.The Exercise Self-Efficacy Scale (ESES)36 The IPAQ-short consists of questions about time spent in sitting, walking, moderate-intensity physical activity and in vigorous intensity physical activity to estimate total weekly physical activity expressed as MET-hours per week .The short version of the International Physical Activity Questionnaire (IPAQ-short) was used to measure patients’ self-reported physical activity during the previous 7 days.37 This six-graded scale ranges from hardly any physical activity to heavy or very heavy exercise regularly and several times a week.Physical activity levels during the previous summer and winter half-years were assessed with the Saltin-Grimby Physical Activity Level Scale.38 The EQ-5D consists of 5 dimensions . These are rated on 3 levels . The answers are converted to an index score using the time-trade-off value set. Negative index scores were set to zero and possible scores ranged from 0 to 1 .39 The EQ-5D VAS consists of a 200 mm vertical line, scored 0 (worst imaginable) to 100 (best imaginable), on which the respondent marks his/her own perceived health state today.The EuroQol 5D (EQ-5D) consisting of the EQ-5D Index and EQ-5D VAS was used as a measure of health status.Descriptive statistics were used to present mean and standard deviation (SD), minimum and maximum values, frequency, and percentage.Missing data in the questionnaires were handled as follows: for missing items less than 30%, an imputation value was calculated, that is, the mean value of the nonmissing item. Questionnaires with more than 30% missing data were excluded from the analyses.40 Variables were chosen from clinical examinations and tests, and questionnaires  with oblique rotation was carried out to identify underlying dimensions. Oblique rotation was chosen as it was assumed that components would be correlated.es Table . The EQ-es Table  and 1 wa41 These indicated that 3 components should be extracted. The variables excluded from iteration and those included in the final model are presented in Table P < 0.05.40Iterations of the PCA were conducted until variables fulfilled the criteria to be included, that is, until the individual Kaiser-Meyer-Olkin (KMO) value and/or communalities were over 0.50. The number of components to be extracted was based on the Kaiser criterion of eigenvalues equal to or exceeding one and on inspection of the Scree plot.41 that is, loadings over 0.71 = excellent, loadings between 0.63 and 0.70 = very good, between 0.55 and 0.62 = good, between 0.45 and 0.54 = fair, and loadings below 0.32 = poor. The component correlation matrix showing correlation coefficients between components was used to evaluate independence of the underlying dimensions.The pattern matrix containing information about the unique contribution of a variable to the component and the structure matrix taking account of the relationship between components were used to present the results of the PCA with oblique rotation. Component loadings were interpreted as suggested by Tabachnick and Fidell,All the analyses were performed using the soft ware Statistical packages for the social sciences for Windows (release 22).2 indicating that some half were overweight. Sensory impairments were more common than motor impairments. Ventral neck-muscle endurance time was on average much shorter than that of dorsal neck muscles. The mean VAS values for present and average pain intensities ranged from 27 to 43 mm, which can be considered mild.42Patients’ characteristics and descriptive data from clinical examinations, tests, and questionnaires are presented in Tables P < 0.001.The final model was a 3-component solution, indicated by both eigenvalues and the Scree plot, accounting for 73% of the total variance. Included were 14 of the originally 20 variables  explained 56% of the variance and had 4 variables with component loadings over 0.63, that is, in the range very good to excellent. These variables concerned pain and functioning in relation to pain. Thus, the component was labeled Health, beliefs, and kinesiophobia (Table The second component (C2), explaining 9.2% of the variance, had 3 of 4 variables with component loadings in the range very good to excellent, those with the highest loadings being the FABQ and the EQ-5D Index. This component was labeled Mood state and catastrophizing (Table The third component (C3) explained 7.6% of the variance and had 2 variables with component loadings interpreted as excellent and one with a loading considered good. The strongest-loaded variable was HADS anxiety, closely followed by HADS depression. The component was labeled ng Table .Pain and functioning and Health, beliefs, and kinesiophobia −0.40, for Pain and functioning and Mood state and catastrophizing 0.47, and for Health, beliefs, and kinesiophobia and Mood state and catastrophizing −0.49.The component correlation matrix showed that correlation coefficients between components were close-to-moderate, indicating that an oblique-rotated solution was to be preferred and that the underlying dimensions could be interrelated. Correlation coefficients were for Pain and functioning, Health, beliefs, and kinesiophobia, and Mood state and catastrophizing.This study gives a thorough description of nonsurgical patients with CR from the perspective of impairments, disability, personal factors, and health status. Our main finding was the 3-component solution with 14 variables that clustered into the underlying dimensions Pain and functioning appeared to be the most important component of the model as it accounted for most of the variance. Our findings are supported by 2 earlier studies reporting strong relations between neck-specific disability and pain intensity.43 Other studies have reported a positive relation between instruments measuring pain and physical functioning (r = 0.53–0.70).45Health, beliefs, and kinesiophobia, is supported by previously reported findings of relations between measures of such variables.47That fear-avoidance beliefs and self-efficacy loaded on the same component, Mood state and catastrophizing, the structure matrix indicated that it was also related to the component Health, beliefs, and kinesiophobia. Earlier studies show that pain-catastrophizing thoughts could predict pain-related fear which could lead to avoidance of movement.50 Fear-avoidance beliefs in patients with neck pain are important since they may predict disability and return to work.51Although the variable PSC had its highest loading in the component Pain and functioning as they had their highest component loadings there. However, these variables seemed to be related to the other 2 components as shown by the moderate correlations presented in the structure matrix. Dizziness and unsteadiness in patients with CR is sparsely evaluated,53 but has shown a larger impact on perceived health-related-quality-of-life than pain intensity levels in individuals with mechanical neck pain, including those with degenerative changes in the cervical spine.54 An explanation of balance disturbances in patients with cervical pain might be a change in cervical structure55 with altered proprioception56 leading to motor control deficits,57 which might affect neck-muscle endurance. Experimental studies on healthy people have shown neck muscle fatigue to have an impact on balance and posture.59 Limited neck-muscle endurance was previously shown to be a significant impairment and strongly related to pain in patients with CR.61 Interestingly, dorsal muscle endurance time was moderately correlated both to the component Pain and functioning and to Mood state and catastrophizing. Patients with high levels of neck pain are more depressed than people without.62 However, the relation between endurance time, depression, and pain catastrophizing ought to be studied further since it might contribute to worse health status in patients with CR.We decided to group the variables related to dizziness (average dizziness intensity and DHI) in the component 41 We chose to use only total scores for each questionnaire in order to reduce the number of variables. As there were missing data, imputations were made when possible to maximize the sample size. There were 93 valid cases for the current set of variables, which should thus be acceptable for performing the PCA as the communalities in our model were consistently above the 0.6 level.Although the criteria for performing a PCA were fulfilled, there are issues to be discussed. A common rule for sample size is that there should be 10–15 participants per variable. On the other hand, the literature suggests that 5–10 participants for each variable included may be adequate for robust results if all communalities are above 0.6.Most variables had high component loadings on 1 component and low on the others. Some variables, however, seemed to be related to more than 1 component. An explanation might be that we used total scores from questionnaires and not scores from possible subscales.63 There are various ways to choose how many components to retain from a PCA, for example, the choice may be based on eigenvalues, Scree plots, percentage of variance explained, sufficient variables with high loadings in each component and the communalities. Our 3-component model was supported by eigenvalues over 1, high explained variance, high component loadings, and communalities. The variables that provided most information (highest loadings) in each component, respectively, in our PCA model were neck pain, fear-avoidance beliefs, and anxiety. It might be important to always include these when assessing patients with CR. However, with regard to variable loadings and pattern matrix, there are reasons to consider also the variables measuring the impact of pain on functioning and disability, health status, kinesiophobia, and depression, so as to capture a broad picture of patients with CR. Further research is needed for evaluating the importance of these variables as outcome measures in intervention studies.Although our primary focus was to identify underlying dimensions, a PCA is also applicable for data reduction without losing the original information. This is achieved by summarizing many variables into fewer components while trying to explain as much data variance as possible.Pain and functioning; Health, beliefs, and kinesiophobia; and Mood state and catastrophizing in measures of disability, personal factors, and health status in patients with CR. Pain, fear avoidance beliefs, and anxiety provided most information in the components and it is therefore suggested that these variables are important to include in assessments of patients with CR.We identified three underlying dimensions, that is,


The family practitioner plays an important role in the prevention, diagnosis, and early management of chronic pain. He/she is generally the first to be consulted, the one most familiar with the patients and their medical history, and is likely the first to be alerted in case of inadequate pain control or safety and tolerability issues. The family practitioner should therefore be at the center of the multidisciplinary team involved in a patient's pain management. The most frequent indications associated with chronic pain in family practice are of musculoskeletal origin, and the pain is often multimechanistic. Fixed-dose combination analgesics combine compounds with different mechanisms of action; their broader analgesic spectrum and potentially synergistic analgesic efficacy and improved benefit/risk ratio might thus be useful. A pain specialist meeting held in November 2010 agreed that the fixed-dose combination tramadol/paracetamol might be a useful pharmacological option for chronic pain management in family practice. The combination is effective in a variety of pain conditions with generally good tolerability. Particularly in elderly patients, it might be considered as an alternative to conventional analgesics such as NSAIDs, which should be used rarely with caution in this population. One of the major reasons for patients presenting at a primary care practice is pain; according to surveys, around 40% of patients consult their family doctor mainly owing to pain, and 20–40% of those have been suffering from pain for more than 6 months , 2. HighChronic pain affects quality of life and personal relationships and is often accompanied by depression, sleep disorders, and also low self-esteem . In addiFor many indications, a combination of nonpharmacological and pharmacological treatments will likely lead to the best outcome. Chronic pain management is basically a balancing act between the obvious goal of pain reduction and the goals of safety and quality of life of the affected patients. Whereas a number of medications are suitable for the short-term treatment of acute pain, patients with chronic pain require long-term, sometimes life-long treatment, and finding effective, safe, and tolerable pain treatments may become a challenge. In addition, many affected patients are elderly , 13, 14,A consensus meeting of pain specialists from different fields was held in November 2010 in Paris, France, in order to review and discuss the management of moderate-to-severe chronic pain with special emphasis on the use of paracetamol, NSAIDs, and tramadol/paracetamol as an example for fixed-dose combination analgesics. Discussions about available treatment options for chronic pain management and current guidelines and treatment recommendations for various conditions and patient populations were continued after the meeting; the final consensus on pain management options for pain indications frequently seen by a family practitioner is presented in this paper.the location and cause of pain;the frequency with which the pain occurs and potential exacerbating and relieving factors;previous treatment received by patient, and its efficacy; the severity of pain, and its quality ;the chronification stage of pain;the impact of pain on the patient , his/her family or caregivers.Chronic pain can be categorized as nociceptive pain (caused by tissue damage or disease), neuropathic pain , or mixed pain with both nociceptive and neuropathic components . In addiInitial pain assessment should also include documentation of pain frequency , of presence or absence of triggers, and of presence or absence of somatosensory abnormalities such as increased or decreased perception of stimuli . Simple scores should be used to assess pain intensity in order to monitor the progression/improvement of pain with a time-saving method during the family practitioner visit. Pain intensity is usually assessed using 11-point rating scales with 0 indicating “no pain” and 10 indicating “worst imaginable pain” or along a 100 mm horizontal line, with ratings measured from the left edge . Visual For a comprehensive diagnosis of chronic pain, a determination of pain type is also necessary and should include the use of neuropathic pain assessment tools such as pain DETECT , DN4 Do, or LANSOne way of defining pain as chronic has been on the basis of its duration, that is, if it lasts for more than 3 or 6 months , 23; howInitial and follow-up pain intensity assessments are essential but not sole indicators for successful or unsuccessful treatment. Other factors such as improved mobility or independence of the patient, working ability, improved coping and psychological status, and overall quality of life might be equally important to the patient (see the following).Chronic pain has an enormous impact on quality of life and daily activities of the patient. It affects sleep in the majority of patients, impairs physical activities, the ability to attend to household chores, and employed work, and restricts many patients in terms of relationships and social activities . AdditioGiven primary practice reality with a short-time frame available for each individual patient, many physicians may shy away from the extra time spent in completing and evaluating additional questionnaires. However, these tools may enable a more efficient and thus in the long-term time-saving approach. In particular, focusing on the patient's individual needs may reduce a substantial burden for the patient and avoid long periods of unnecessary suffering owing to unsuitable treatment approaches. The family practitioner plays an important role in the prevention, diagnosis, and early management of chronic pain. He/she is usually the physician who is most familiar with the patient and his/her medical history, keeps an overview on the various therapies prescribed by him-/herself and other specialists, and is likely to be the first to be alerted in the case of inadequate pain control or if safety issues owing to comorbidities or comedications arise. Since the family practitioner usually also builds a trusting relationship with the patient, the patient is most likely to disclose concerns, potential side effects of medications, effects of the treatments/pain on his/her daily life and social network, and so forth. The family practitioner might be able to identify unmet needs of the patient, requirements for patient information, and education and potential requirements to involve the family/partners in the overall treatment plan and care. For many indications, in particular musculoskeletal diseases, a multimodal treatment approach combining both nonpharmacological and pharmacological treatments will likely lead to the best outcome in terms of pain relief and improvement of quality of life. The family practitioner should be at the core of a multidisciplinary team for pain management including, for example, pain specialists, physiotherapists, and others. Nonpharmacological treatments may include changes in diet, weight loss, changes in lifestyle, exercise, or massage that can be easily accessible to primary care physicians. Other options like acupuncture, thermotherapy, transcutaneous electrical nerve stimulation (TENS), surgery, and many others are beyond the scope of this paper. This section will focus on general considerations concerning available pharmacological treatment options.Paracetamol  is a very popular medication, which is available over-the-counter as well as in prescription medications. It has analgesic and antipyretic but, unlike nonsteroidal anti-inflammatory drugs, no confirmed anti-inflammatory properties, although there have been studies pointing to some anti-inflammatory effects , 39. ItsNSAIDs are very effective drugs with antipyretic, anti-inflammatory, and analgesic efficacy rendering them useful for many acute pain conditions. They are widely used over-the-counter and prescription products and are contained in many combination formulations. NSAIDs are associated with gastrointestinal, cardiovascular, and renal side effects and mortality with an estimated 3500 to 16,500 deaths per year due to NSAID-related gastrointestinal bleeding in USA . In addiOwing to these safety issues, all NSAIDs should be used for the shortest possible duration at the lowest effective dose. In the elderly in particular, NSAIDs should be used “rarely and with extreme caution in highly selected individuals” . In geneOpium has been used since antiquity for treating pain. In modern times, synthetic opioids have been added to the naturally derived compounds. Some of the side effects and special issues related to opioids might restrict their long-term use, at least in some patients . ConstipOpioids are associated with different levels of tolerance, dependence, and addiction potential. These are three distinct phenomena. Tolerance describes the state in which a patient requires increasingly higher doses of the opioid to achieve the same level of pain relief. In some cases, tolerance is a normal response to opioid therapy; it can sometimes be managed by opioid rotation, that is, switching to other opioids . ManifesHowever, these dangers are frequently overestimated, and opioids are often the only choice for severe pain and can be a good choice for special patient groups such as the elderly. They also present an alternative when long-term NSAID treatment is not recommended. The transdermal formulations of fentanyl and buprenorphine in particular appear to be effective with low toxicity and good tolerability profiles, especially at low doses . μ-opioid receptors and inhibition of neuronal reuptake of norepinephrine and serotonin) [Tramadol has been on the market since 1977 and is considered a type of opioid. However, it is different from most other opioids because of its multiple mechanism of analgesic action (binding to rotonin) , 61. Trarotonin) , 63; itsrotonin) . TramadoSide effects include nausea, vomiting, dizziness, drowsiness, sweating, and dry mouth; reports of drug dependence and abuse are rare . IsolateTopical analgesics are an important pain management option which provides localized pain relief. Overall, this group is efficacious with a good safety profile . Due to The clearest evidence for the efficacy of anticonvulsants in pain relief was found in patients suffering from neuropathic pain . SeveralDose-related side effects occur with all anticonvulsants; the majority are CNS related  . There aThere is evidence of antidepressant analgesia independent of their effect on depression or other psychiatric disorders . TricyclThe selective serotonin norepinephrine reuptake inhibitors (SNRIs), duloxetine and venlafaxine, are first-line treatments for neuropathic pain, and duloxetine and milnacipran are recommended for fibromyalgia treatment. Overall, they are better tolerated than TCAs with nausea as the main side-effect. Caution is advised for venlafaxine in patients with cardiac disease . Glucocorticoids have clinically important anti-inflammatory and immunosuppressive effects which are, among others, used in the treatment of rheumatic diseases . Safety Since most pain conditions involve more than one underlying pain generating process and pain is transmitted via a large number of different pathways, a practical treatment approach is using drugs or drug combinations with different mechanisms of action and thus different targets. However, not all combinations are ideal because a combination of two or more individual compounds may lead to additive or even synergistic analgesic effects but might also lead to a higher than anticipated side-effect rate. Thorough testing of combinations and determining the right dose ratio of the individual components are therefore required. A recent review covers these issues in detail . Fixed-dose combination analgesic products reduce the pill burden and may require lower dosages than the individual compounds. They are, however, inflexible, and doses may not be ideal for particular patients. Many fixed-dose combination analgesics contain paracetamol, and patients may exceed the recommended daily paracetamol intake of 4 g for healthy adults . Family Fixed-dose combinations with an opioid include codeine/paracetamol, oxycodone/paracetamol, tramadol/paracetamol, and others. These products may be opioid sparing, because they provide effective analgesia at lower opioid doses than opioids taken in monotherapy. This was shown in two studies comparing tramadol/paracetamol with tramadol monotherapy in the management of subacute low back pain  and painAnalgesic synergy of fixed-dose combination products for pain relief in humans has, to our knowledge, so far only been demonstrated for tramadol/paracetamol . DetailsThis section lists the most common chronic pain indications encountered by the family practitioner and available treatment guidelines/recommendations for the individual indications. A summary of the studies investigating treatment with tramadol/paracetamol for a given indication is included. The majority of chronic pain patients in primary care suffer from musculoskeletal pain . IndicatP = 0.05) and constipation , which was more common for codeine/paracetamol treatment. Patients completing this study could participate in an 23-month open-label extension study [The efficacy and tolerability of tramadol/paracetamol were compared to codeine/paracetamol in adult patients with chronic nonmalignant low back pain, osteoarthritis pain, or both . At baseon study . They reP < 0.001). Quality of sleep improved in 54.9% of all patients. A total of 4.2% of the patients reported adverse events, most commonly gastrointestinal disorders.The ELZA study assessed efficacy and safety of tramadol/paracetamol in 5495 patients aged over 12 years who presented with moderate-to-severe pain (for more than 3 months in 15.6% of the patients) to general practitioners in France . The mosThe SALZA study assessed the clinical benefits of tramadol/paracetamol in 2663 patients aged ≥65 years with moderate-to-severe pain in French general practices . The mosThese studies show the efficacy of fixed-dose tramadol/paracetamol with a good safety profile in the treatment of chronic musculoskeletal pain both under randomized study conditions and, more importantly, in clinical practice. The clinical benefits in the elderly in particular are noteworthy and suggest tramadol/paracetamol as an alternative to conventional analgesics such as NSAIDs, which should be considered rarely with extreme caution in this population . Prevalence of osteoarthritis (OA) increases with advancing age; the greatest disease burden is attributable to the involvement of the hip or knee joints . Pain isOA management is focused on symptom control, prevention of disease progression, minimization of disability, and improvement of quality of life  and requP < 0.001) on a 4-point scale (from 0 = none to 3 = severe) [P = 0.019) in the subgroup of 113 elderly patients [OA pain management using tramadol/paracetamol fixed-dose combination as an add-on treatment to NSAIDs or COX-2 inhibitors or as monotherapy was investigated in four studies –99. Addi severe) . Treatmepatients . P = 0.025). Improvement in WOMAC physical function was also significantly better than that in the placebo group (P = 0.049). Withdrawal due to adverse events occurred in 13.1% tramadol/paracetamol and 3.9% placebo patients. No serious adverse events occurred that were related to the study medication.Patients with knee or hip OA and with at least moderate pain  despite treatment with stable doses of celecoxib or rofecoxib received tramadol/paracetamol or placebo as add-on therapy for 3 months . Pain inP < 0.0005) following the 4-week add-on therapy maintained their pain-improved state with either agent for the next 8 weeks. One tramadol/paracetamol patient withdrew due to adverse events. Korean patients with knee OA and moderate pain despite stable doses of meloxicam or aceclofenac received add-on treatment with tramadol/paracetamol for 4 weeks . All patP < 0.001). A second Korean study investigated the effect of tramadol/paracetamol titration on the development of adverse events in patients with knee OA on stable NSAID therapy . PatientIn all studies, the most common treatment-related adverse events were nausea, vomiting, constipation, dizziness, and somnolence. These adverse effects can be avoided in the majority of patients with a thorough titration of tramadol/paracetamol.These studies suggest the effectiveness of tramadol/paracetamol as an add-on option to NSAIDs in the management of OA pain. However, in light of today's knowledge about NSAIDs, long-term treatment with NSAIDs cannot be considered safe any longer and maintenance treatment with tramadol/paracetamol with NSAIDs for flares is likely the safer option.Low back pain is very common and is nonspecific for the majority of patients . It can The efficacy of tramadol/paracetamol for the treatment of chronic low back pain was assessed in two studies , 107. BoP = 0.015) compared to placebo and provided better pain relief (P < 0.001) and improved scores on measures of functioning and quality of life. Cumulative incidence of discontinuation due to insufficient pain relief was significantly lower for the combination product . Treatment-related adverse events were reported for 23.6% of tramadol/paracetamol and 3.8% placebo patients with discontinuation rates due to adverse events more frequently observed for the active agent (18.6% versus 5.7%). In the first study, patients had a mean baseline pain score  of 71.1 mm (tramadol/paracetamol group) and 68.8 mm (placebo group) . CombinaP < 0.001) and improved quality of life and emotional and mental health. The withdrawal rate due to adverse events was 28.1% for tramadol/paracetamol and 7.6% for placebo. Main treatment-related adverse events in the combination group were nausea (12%), dizziness (10.8%), and constipation (10.2%). The mean baseline pain score of the patients included in the second study was 68 mm . TramadoIn summary, the two studies show moderate benefits of tramadol/paracetamol treatment compared to placebo for patients with chronic low back pain over a 3-month period. However, a multimodal approach is often required to achieve adequate pain relief. Rheumatoid arthritis (RA) is a common inflammatory disease characterized by persistent synovitis, systemic inflammation, and autoantibodies . The etiP = 0.018). Mean daily pain relief scores were also significantly greater (P = 0.037) but physical function did not differ between the groups. Adverse events (57.6% versus 22.4% for placebo) and discontinuations due to adverse events (19% versus 3%) were significantly more common in the active group (P < 0.001). This study indicates some short-term efficacy of tramadol/paracetamol in RA pain management. In light of the long-term safety problems with NSAIDs, alternative long-term maintenance treatment with tramadol/paracetamol accompanied by add-on NSAIDs treatment for flares should be investigated in further studies. The administration of tramadol/paracetamol in RA pain was investigated in one study. Patients with RA pain inadequately controlled by NSAIDs and disease-modifying antirheumatic drugs received one tramadol/paracetamol tablet tid or matching placebo for one week as add-on to their treatment regimen . Mean paDiabetic polyneuropathy is a frequent long-term complication of diabetes. In approx. 6% of type 1 and 18% of type 2 diabetic patients, this condition is associated with neuropathic pain which has a profound impact on quality of life . TraditiP = 0.001) with a greater number of treatment responders . Significantly greater improvements than placebo were also observed for further pain measures, sleep interference, global impression, and several quality of life measures and mood. The adverse event rate was similar for both groups with nausea (11.9% versus 3.3%), dizziness, and somnolence (both 6.3% versus 1.3%) more common under combination treatment. Two studies have assessed the efficacy of tramadol/paracetamol for painful DPN , 110. InP = 0.744). Improvements in further pain measures, sleep interference, and quality of life were comparable between groups. The incidence of adverse events was not significantly different between treatments except for nausea/vomiting , and similar withdrawal rates due to adverse events were reported (13.9% versus 13.1%).The second study compared the efficacy of tramadol/paracetamol and gabapentin in type 2 diabetes with painful symmetric neuropathy in the lower limbs . Mean paOverall, the two studies suggest that fixed-dose tramadol/paracetamol is well tolerated and leads to pronounced pain relief in the treatment of painful DPN. Pain is a common occurrence in elderly patients living in the community. Most elderly patients (85%) experience moderate or severe pain; for a third of them this pain is continuous . MusculoThe efficacy and safety of tramadol/paracetamol fixed-dose combination were assessed in a subset of patients ≥65 years of age with OA flare pain in a placebo-controlled, randomized study  and in ePain is one of the major reasons for patients to consult their family practitioner. The family practitioner plays an important role in the prevention, diagnosis, and early management of chronic pain and should be at the core of the multidisciplinary team for pain management. The diagnostic work-up of pain should include quality of life parameters and an evaluation of the specific situation of the patient.The goal of pain management is not only pain relief, but also should include improvements in restrictions of daily activities and social life and in quality of life to increase the overall well-being of the patient.Long-term treatment of chronic pain is often associated with safety and tolerability issues and must be individualized for each patient. NSAIDs are useful short-term analgesics but are associated with gastrointestinal, cardiovascular, and renal side effects and mortality. Their long-term use in the management of chronic pain needs to be carefully weighted against potential side effects.Pain is often multimechanistic. Fixed-dose combination analgesics combine compounds with different mechanisms of action and might thereby be useful in the treatment of multimechanistic pain. They might provide a broader analgesic spectrum, potentially synergistic analgesic efficacy, and an improved benefit/risk ratio. Analgesic synergy was demonstrated for the fixed-dose combination tramadol/paracetamol. The combination was effective in a variety of different pain conditions frequently encountered by the family practitioner and showed good tolerability.Tramadol/paracetamol might be considered in particular in elderly patients as an alternative to conventional analgesics such as NSAIDs, which should be used rarely with extreme caution in this population.However, studies are required to investigate the long-term use of fixed-dose combinations.


Radiotherapy has a good effect in palliation of painful bone metastases, with a pain response rate of more than 60%. However, shortly after treatment, in approximately 40% of patients a temporary pain flare occurs, which is defined as a two-point increase of the worst pain score on an 11-point rating scale compared to baseline, without a decrease in analgesic intake, or a 25% increase in analgesic intake without a decrease in worst pain score, compared to baseline. A pain flare has a negative impact on daily functioning and mood of patients. It is thought to be caused by periostial edema after radiotherapy. Dexamethasone might diminish this edema and thereby reduce the incidence of pain flare. Two non-randomized studies suggest that dexamethasone reduces the incidence of a pain flare by 50%. The aim of this trial is to study the effectiveness of dexamethasone to prevent a pain flare after palliative radiotherapy for painful bone metastases and to determine the optimal dose schedule.This study is a three-armed, double-blind, placebo-controlled multicenter trial. We aim to include 411 patients with uncomplicated painful bone metastases from any type of primary solid tumor who receive short schedule radiotherapy . Arm 1 consists of daily placebo for four days, arm 2 starts with 8 mg dexamethasone before the (first) radiotherapy and three days placebo thereafter. Arm 3 consists of four days 8 mg dexamethasone. The primary endpoint is the occurrence of a pain flare. Secondary endpoints are pain, quality of life and side-effects of dexamethasone versus placebo. Patients complete a questionnaire  at baseline, daily for two weeks and lastly at four weeks.This study will show whether dexamethasone is effective in preventing a pain flare after palliative radiotherapy for painful bone metastases and, if so, to determine the optimal dose.NCT01669499This study is registered at ClinicalTrials.gov:  Radiotherapy, with a single fraction of 8 Gray as the gold standard, has a good effect in palliation of painful bone metastases, with a pain response rate of more than 60%.  However,Two prospective observational studies show that approximately 40% of patients experience a pain flare ,4. Hird A survey among patients who experienced a pain flare showed that having a pain flare had a negative effect on daily functioning of patients and on their mood . Most paThe pain flare is thought to arise through edema of the periostium of the irradiated bone. Dexamethasone, an anti-inflammatory drug decreasing edema, may be an effective drug. Two small studies were performed to study the effect of dexamethasone on the incidence of pain flare ,7. In thBoth studies concluded that randomized trials are necessary to study the effectiveness of dexamethasone for prevention of a pain flare. No randomized trials have been published so far. Therefore, the aim of this trial is to study the effectiveness of dexamethasone to prevent a pain flare after palliative radiotherapy for painful bone metastases and to determine the optimal dose schedule.This three-armed, prospective, randomized, placebo-controlled multicenter study is being led by the University Medical Center Utrecht. The study is supported by grants from the Dutch Cancer Society and ZonMw. It is registered at ClinicalTrials.gov: NCT01669499. The study compares two different dose schedules of dexamethasone with a placebo  or suspected unexpected serious adverse reactions (SUSAR), as defined in the study protocol, are reported to the central medical ethics committee and to the central committee of medical research involving human subjects.Participating patients fill out a questionnaire at baseline , then daily until day 15 and a final questionnaire at day 29. The questionnaire contains the Brief Pain Inventory , which nAnalysis will be by intention-to-treat. Patients who have received at least one fraction of radiotherapy, irrespective of study medication intake, and have returned questionnaires are evaluable. Descriptive analyses of baseline characteristics will be performed. Comparison of occurrence of pain flare between the three arms will be assessed using the Chi-Square test. Comparison of pain intensity, quality of life items and side effects at baseline and over time between the three arms will be done using multilevel analysis. Since the risks of the study using well-known medication are considered minimal, an interim analysis will not be performed.Assuming a reduction of 50% (from 40 to 20%) of the occurrence of a pain flare by administering a single dose of 8 mg dexamethasone, a total of 411 patients are necessary (137 per arm) to reach a power of 90% given a significance level of 5% (2-sided), and assuming a drop-out of 20% during follow-up. In the Netherlands, around 3000 patients are eligible for this study yearly. With 12 out of 21 institutions participating and an estimated participation rate of 20%, the total study time needed is about 2 years.Up to 40% of patients experience a pain flare after palliative radiotherapy for painful bone metastases ,4. A paiA recent publication from Chiang et al. (published after the initiation of our study) in patients treated with stereotactic radiotherapy for painful bone metastases showed an incidence of pain flare of 68%. However, this might be an overestimation. Firstly, they did not mention to require pain score and analgesic intake to return to baseline, to distinguish it from progression. Secondly, initiation of corticosteroids during or after treatment was considered to be indicative of a pain flare . NeverthUsing consensus definitions of endpoints in literature is important, to be able to compare studies . Most puIn conclusion, if this study proves the effectiveness of dexamethasone in the prevention of a pain flare after palliative radiotherapy for painful bone metastases, this should lead to a change in supportive care. Since we use a commonly accepted definition of pain flare, comparison between our results and future results from other trials may be possible. It may also lead to studies of the benefit of dexamethasone in preventing a pain flare after stereotactic radiotherapy.BPI: Brief Pain Inventory; EORTC QLQ-C15-PAL: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 15 for use in Palliative care; EORTC QLQ-BM22: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for patients with Bone Metastases; SAE: Serious adverse event; SUSAR: Suspected unexpected serious adverse reaction.The authors declare that they have no competing interests.The study protocol was drafted by AdG, YMvdL and AKLR. PGW and JIG participated in critical review of the study protocol. PGW is responsible for coordinating the data acquisition. This article was conceived and drafted by PGW, AdG and YMvdL. AKLR and JIG critically reviewed the manuscript. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/14/347/prepub