Many patients suffer from chronic neck pain following a whiplash injury. A combination of cognitive, behavioural therapy with physiotherapy interventions has been indicated to be effective in the management of patients with chronic whiplash-associated disorders. The objective is to present the design of a randomised controlled trial (RCT) aimed at evaluating the effectiveness of a combined individual physical and cognitive behavioural-graded activity program on self-reported general physical function, in addition to neck function, pain, disability and quality of life in patients with chronic neck pain following whiplash injury compared with a matched control group measured at baseline and 4 and 12 months after baseline.The design is a two-centre, RCT-study with a parallel group design. Included are whiplash patients with chronic neck pain for more than 6 months, recruited from physiotherapy clinics and an out-patient hospital department in Denmark. Patients will be randomised to either a pain management (control) group or a combined pain management and training (intervention)group. The control group will receive four educational sessions on pain management, whereas the intervention group will receive the same educational sessions on pain management plus 8 individual training sessions for 4 months, including guidance in specific neck exercises and an aerobic training programme. Patients and physiotherapists are aware of the allocation and the treatment, while outcome assessors and data analysts are blinded. The primary outcome measures will be Medical Outcomes Study Short Form 36 (SF36), Physical Component Summary (PCS). Secondary outcomes will be Global Perceived Effect (-5 to +5), Neck Disability Index (0-50), Patient Specific Functioning Scale (0-10), numeric rating scale for pain bothersomeness (0-10), SF-36 Mental Component Summary (MCS), TAMPA scale of Kinesiophobia (17-68), Impact of Event Scale (0-45), EuroQol (0-1), craniocervical flexion test (22 mmHg - 30 mmHg), joint position error test and cervical range of movement. The SF36 scales are scored using norm-based methods with PCS and MCS having a mean score of 50 with a standard deviation of 10.The perspectives of this study are discussed, in addition to the strengths and weaknesses.http://www.ClinicalTrials.gov identifier NCT01431261.The study is registered in  The Danish National Board of Health estimates that 5-6,000 subjects per year in Denmark are involved in a traffic accident evoking whiplash-induced neck pain. About 43% of those will still have physical impairment and symptoms 6 months after the accident . For SweBesides chronic neck pain, patients with WAD may suffer from physical inactivity as a consequence of prolonged pain ,7. This because of conflicting evidence and few high-quality studies, no firm conclusions could be drawn about the most effective non-invasive interventions for patients with chronic WAD" [Studies have shown that physical training, including specific exercises targeting the deep postural muscles of the cervical spine, is effective in reducing neck pain -18 for pnic WAD" ,30. The nic WAD" . The resThis project is formulated on the expectation that rehabilitation of WAD patients with chronic neck pain must target cervical dysfunctions, training of physical function and the understanding and management of chronic pain in a combined therapy approach. Each single intervention is based upon former studies that have shown effectiveness ,18,20,32Using a randomised controlled trial (RCT) design, the aim of this study is to evaluate the effectiveness of: graded physical training, including specific neck exercises and general aerobic training, combined with education in pain management  versus education in pain management , measured on physical quality of life', physical function, neck pain and neck functions, fear of movement, post-traumatic symptoms and mental quality of life, in patients with chronic neck pain after whiplash injury.The study is conducted in Denmark as an RCT with a parallel group design. It will be a two-centre study, stratified by recruitment location. Patients will be randomised to either the Pain Management group (control) or the Pain Management and Training group (intervention). As illustrated in Figure The participants will be recruited from physiotherapy clinics in Denmark and from The Spine Centre of Southern Denmark, Hospital Lillebælt via an announcement at the clinics and the Hospital. Using physiotherapy clinics spread across Denmark, the patients will receive the intervention locally. The physiotherapy clinics in Denmark receive patients via referral from their general practitioners. The Spine Centre, a unit specialising in treating patients with musculoskeletal dysfunctions and only treating out-patients, receives patients referred from general practitioners and/or chiropractors.Two hundred adults with a minimum age of 18 years, receiving physiotherapy treatment or having been referred for physiotherapy treatment will be recruited. For patients to be eligible, they must have: chronic neck pain for at least 6 months following a whiplash injury, reduced physical neck function , pain primarily in the neck region, finished any medical /radiological examinations, the ability to read and understand Danish and the ability to participate in the exercise program. The exclusion criteria include: neuropathies/ radiculopathies  , neuroloThe Pain Management (control) group will receive education in pain management strategies. There will be 4 sessions of 11/2 hours, covering topics regarding pain mechanisms, acceptance of pain, coping strategies, and goal-setting, based upon pain management and cognitive therapy concepts [concepts ,26,36.The Pain Management plus Training (intervention) group will receive the same education in pain management as those in the control group plus 8 treatment sessions (instruction in neck exercises and aerobic training) with the same period of 4 months length. If the treating physiotherapist estimates additional treatments are needed, the treatment can be extended with 2 more sessions. Neck training: The treatment of neck-specific exercises will be progressed through different phases, which are defined by set levels of neck function. At the first treatment session, patients are tested for cervical neuromuscular function to identify the specific level at which to start neck training. A specific individually tailored exercise program will be used to target the neck flexor and extensor muscles. The ability to activate the deep cervical neck flexor muscles of the upper cervical region to increase their strength, endurance and stability function is trained progressively via the craniocervical training method using a biopressure feedback transducer [Aerobic training: The large trunk and leg muscles will be trained with a gradually increasing physical training program. Patients will be allowed to select activities such as walking, cycling, stick walking, swimming, and jogging. The baseline for training duration is set by exercising 3 times at a comfortable level, that does not exacerbate pain and aims at a rated perceived exertion (RPE) level of between 11 and 14 on a Borg scale [ansducer ,37. Exeransducer ,38. Aerorg scale . The inirg scale ,40. By uPatients' compliance will be administered by registration of their participation in the control and intervention group. The patients in the control group will be considered to have completed the pain management if they have attended 3 out of 4 sessions. The patiesnts in the intervention group will be considered to have completed if the patient has attended a minimum of 3 out of 4 pain management sessions and a minimum of 5 out of 8 trainings sessions. Each patient's home training with neck exercises and aerobic training will be registered by him/her in a logbook. Compliance with 75% of the planned home training will be considered as having completed the intervention.The participating physiotherapists will be recruited via an announcement in the Danish Physiotherapy Journal. The inclusion criteria consist of: being a qualified physiotherapist, working at a clinic and having at least two years of working experience as a physiotherapist, having attended a course in the described intervention and passed the related exam.At baseline the participants' information on age, gender, height and weight, type of accident, medication, development of symptoms over the last two months , expectation of treatment, employment and educational status will be registered. As a primary outcome measure, Medical Outcomes Study Short Form 36 (SF36) - Physical Component Summary (PCS) will be used ,42. The Patients will be tested at baseline, 4 and 12 months after baseline, except for GPE, which will only be measured 4 and 12 months after baseline.The power and sample size calculation is based on the primary outcome, being SF36-PCS 4 months after baseline. For a two-sample pooled t-test of a normal mean difference with a two-sided significance level of 0.05, assuming a common SD of 10, a sample size of 86 per group is required to obtain a power of at least 90% to detect a group mean difference of 5 PCS points ; the actAfter the baseline assessment, the participants are randomly assigned to either the control group or the intervention group. The randomisation sequence is created using SAS (SAS 9.2 TS level 1 M0) statistical software and is stratified by centre with a 1:1 allocation using random block sizes of 2, 4, and 6. The allocation sequence will be concealed from the researcher enrolling and assessing participants in sequentially numbered, opaque, sealed and stapled envelopes. Aluminium foil inside the envelope will be used to render the envelope impermeable to intense light. After revealing the content of the envelope, both patients and physiotherapists are aware of the allocation and the corresponding treatment. Outcome assessors and data analysts are however kept blinded. Prior to the outcome assessments, the patients will be asked by the research assistant not to mention the treatment to which they have been allocated.All the primary data analyses will be carried out according to a pre-established analysis plan; all analyses will be done applying SAS software . All descriptive statistics and tests are reported in accordance with the recommendations of the 'Enhancing the QUAlity and Transparency Of health Research' (EQUATOR) network; i.e., various forms of the CONSORT statement . Data wiThe baseline scores for the primary and secondary outcomes will be used to compare the control and intervention groups. The statistical analyses will be performed on the basis of the intention-to-treat principle, i.e. patients will be analysed in the treatment group to which they were randomly allocated. In the primary analyses, missing data will be replaced with the feasible and transparent 'Baseline Observation Carried Forward' (BOCF) technique, and for sensitivity also a multiple imputation technique will apply.Secondarily, to relate the results to compliance, a 'per protocol' analysis will be used as well. The 'per protocol' population he patients who have 'completed' the intervention to which they were allocated, according to the principles described in the intervention section above.The Regional Scientific Ethical Committee of Southern Denmark approved the study (S-20100069). The study conformed to The Declaration of Helsinki 2008  by fulfiAll subjects will receive information about the purpose and content of the project and give their oral and written consent to participate, with the possibility to drop out of the project at any time.This study will contribute to a better understanding of treating patients with chronic neck pain following a whiplash accident. The knowledge from this study can be implemented into clinical practice, as the study is based on a multimodal approach, mirroring the approach, which in spite of the current lack of evidence, is often used in a clinical physiotherapy setting. The study may also be included in systematic reviews thereby contributing to updating the knowledge about this population and to enhancing evidence-based treatment.Publishing the design of a study before the study is performed and the results obtained has several advantages. It allows the design to be finalised without its being influenced by the outcomes. This can assist in preventing bias as deviations from the original design can be identified. Other research projects will have the opportunity to follow a similar approach with respect to population, interventions, controls and outcome measurements. The challenges of this study are related to standardising the interventions, treating a non-homogeneous population, defining and standardising relevant outcome measures on a population with long-lasting symptoms and having a population from two different clinical settings. Standardisation of the interventions is obtained by teaching the involved physiotherapists in an instructional course. Population homogeneity will be handled by strict inclusion and exclusion criteria and by monitoring the baseline characteristics of the patients, and differences between groups based on other influences than the intervention/control will be possible to analyse statistically. This research design is composed as an 'add-on' design: both groups receive pain education; the intervention group receives additional physical training, including specific neck exercises and general training. Today there is insufficient evidence for the effect of treatment for patients with chronic neck pain following a whiplash accident. All participating patients will be referred for a treatment (control or intervention), as we consider it unethical not to offer some form of treatment, i.e. randomising the control group to a waiting list. The add-on design is chosen as a pragmatic workable solution in such a situation .For whiplash patients with chronic pain, the most responsive disability measures  are considered to be the Patient Specific Functional Scale and the numerical rating scale of pain bothersomeness . By usinThe authors declare that they have no competing interests.IRH drafted the manuscript. IRH, BJK and KS participated in the design of the study. All contributed to the design. RC, IRH; BJK and KS participated in the power and sample size calculation and in describing the statistical analysis as well as the allocation and randomization procedure. All authors read and approved the final manuscript. Suzanne Capell provided writing assistance and linguistic corrections.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/12/274/prepub


To test Antarth, a polyherbal phytomedicine, for its efficacy and safety in patients with osteoarthritis (OA) and compared with placebo.A total of 90 male or female adult patients who were diagnosed clinically and radiologically with OA were recruited in the study. Antarth or placebo was given 2 capsules b.i.d. for 3 months and the patients were assessed every month for its efficacy. Diclofenac sodium was allowed to be taken as rescue medication.P < 0.05). Reduction in consumption of rescue medication, diclofenac sodium, was more in Antarth than in placebo group.After 3 months of treatment, the reduction in severity of pain on Visual Analog Scale (VAS) was more in Antarth group compared to placebo but the difference between the two groups was not significant. However, pain during functioning of disabled joints while walking distance, squatting, sitting cross-legged and climbing steps were significantly reduced in Antarth group compared to placebo (In Patients’ Global Assessment, patients treated with Antarth were more satisfied than the ones treated with placebo. Observations were similar in Physicians’ Global Assessment too. There were no adverse events in both the groups. Due to changed lifestyle such as lack of exercise and changed food habits, lifestyle disorders such as arthritis, asthma, hypertension and diabetes are very common, particularly amongst urban population. Osteoarthritis (OA) is a progressive rheumatic disease characterized by the degeneration of articular cartilage. It is the most common of all rheumatic disorders. Drug the2Antarth is one such polyherbal Ayurvedic phytomedicine used for the treatment of arthritis. The present study was undertaken to evaluate its efficacy and safety in patients of OA.Male or female patients above the age of 18, diagnosed clinically and radiologically as osteoarthritis and suffering for more than 2 years, were recruited in the study. Predefined clinical features were pain in the knees, swelling, stiffness and joint tenderness in persons of age more than 45 years, complaining of difficulty in walking for more than 2 years.Radiological features were any one or more radiological signs like anterior spiking of patella, subchondral sclerosis, lipping or spurring of joint margin, osteophytes and reduction of medial joint space present. PatientsPatients selected as per the criteria mentioned above, were recruited in the study after obtaining written informed consent and allotted to treatment group as per randomization. Routine blood investigations such as complete blood count, liver function test, and renal function test were carried out before starting the treatment. X-ray of the affected knee – AP standing and lateral view – was also done to confirm the diagnosis of OA and to assess cartilage space changes. Antarth or placebo was given in a dose of two capsules b.i.d. for a period of 3 months. Diclofenac sodium 50 mg b.i.d. and Ranitidine 150 mg o.d. was allowed to be taken as rescue medication as and when required and the patients were asked to keep a record of number of tablets taken per month. Patients were asked to report to the study center every month and the compliance of medication was tested by counting the remaining tablets. Efficacy parameters assessed were i) severity of pain measured on Visual Analog Scale (VAS) of 0–10 and it was done in two ways; ii) Functional Disability of joint was assessed by measuring pain while a) walking distance, b) squatting, c) crossing legs and knees, and d) climbing steps and scored as 0 no pain, 1 mild pain, 2 moderate pain, 3 severe pain and 4 acute pain. After 3 months of treatment, again the blood investigations were carried out and Patients’ and Physicians’ Global Assessment was made. At all the three centers, opinion from radiologists was obtained regarding the pre and post treatment X-rays.Out of the 90 patients recruited in the study, 2 dropped out due to personal reasons. The results obtained from remaining 88 patients who completed 3 months of treatment were analyzed. The distribution of patients in both the groups was equal and the demographic data with respect to sex, age and body weight were matching . The vitP < 0.05) but was not significantly reduced in placebo group. There was a reduction of 35.8% in mean score for walking distance in Antarth group as compared to placebo group which showed a reduction of 32.6%. Pain while squatting was 1.9 ± 1.0 before treatment and 1.30 ± 0.8 after treatment, which was a reduction of 30.1% in Antarth group, whereas in placebo group the corresponding values were 2.0 ± 1.1 and 1.7 ± 1.1, respectively, which was a reduction of 15.6%. Similarly, pain scores while crossing legs before and after treatment were 1.8 ± 1.1 and 1.2 0.8, respectively, a reduction of 29.4% for Antarth, and for placebo group they were 1.8 ± 1.1 and 1.5 ± 1.1, respectively, a difference of 16.8%. Scores for pain while climbing steps before and after treatment were 1.5 ± 0.9 and 0.9 ± 0.8, respectively, a reduction of 43.4% for Antarth, and for placebo they were 1.8 ± 0.9 and 1.3 ± 1.1, respectively, a reduction of 27.8%. The difference in scores before and after treatment in Antarth group was significant in all the parameters (P < 0.05), whereas in placebo group it was not significant.The scores at the basal level for all the parameters of efficacy were similar in both the groups . SeveritConsumption of rescue medication, diclofenac sodium, in Antarth group, before treatment was 32.73 tablets per month, which reduced to 29.52 tablets per month after treatment with Antarth, which was a reduction of 34.37%, whereas in placebo group, it was 21.14 tablets per month before treatment and 4.73 tablets per month after treatment, which was a reduction of 22.38%. Though the difference within the group was significant, it was not significant between the groups.In Patients’ Global Assessment of efficacy of Antarth, almost all the patients (100%) were satisfied with the treatment with different grades, and none of them said it was not effective. But in placebo group, about 13% of the patients were not satisfied and said it was not effective. The satisfactory levels were as follows. About 6.82% of patients treated with Antarth were symptom free by the end of 3 months treatment, whereas none of the patients in placebo group were symptom free . About 5Similar response was reflected in physicians’ assessment. According to Physicians’ Global Assessment, efficacy of Antarth was as follows: Excellent (38.64%), Good (43.18%), Fair (18.18%) and Poor (0%). Corresponding values for placebo were 15.91, 40.91, 38.64 and 4.55%, respectively .None of the patients in both the groups reported any clinical adverse event or showed any change in laboratory investigations after treatment.14] However, COX-2-specific inhibitors can cause renal toxicity. Caution must be exercised, therefore, if they are used in patients with hypertension, congestive heart failure, or mild-to-moderate renal insufficiency; they should not be used in patients with severe renal insufficiency.Although there is no known cure for OA, treatment designed for the individual patient can reduce pain, maintain and/or improve joint mobility and limit functional impairment. The goals of contemporary management of the patient with OA include control of pain and improvement in function and health-related quality of life, with avoidance of toxic effects of therapy. Individuals with OA of the lower extremity may have limitations that impair their ability to perform activities of daily living (ADLs), such as walking, bathing, dressing, use of the toilet, and performing household chores. While physical therapy and occupational therapy play central roles in the management of patients with functional limitations, use of pharmacotherapy is essential to reduce pain during these activities. Most commonly used drug for this is paracetamol. But the drug is known to produce hepatotoxicity at higher doses and hence cannot be used for a longer time and in patients with impaired liver function and in chronic alcoholics.–9 AlternArthritis is a chronic disease with no cure but only symptomatic relief got through the use of suitable medications. But the medicines currently available are not safe for long-term use. Hence there is a need for an effective and safe remedy. The alternative systems of medicine claim to have such remedies. Antarth is one such phytomedicine developed on the principles of Ayurveda for the treatment of arthritis.P < 0.05). This indicates that Antarth has a better effect in reducing the pain in patients while performing these activities than placebo. Thus, it helps the patients in performing their day-to-day activities in a better way, thereby improving their quality of life.In OA, the chief complaint of the patients is the pain experienced during performing of some daily routine activities such as walking, sitting cross-legged, climbing steps, etc. These activities are hampered due to pain which affects the quality of life they lead. They are unable to perform their routine activities properly. Reduction of pain while performing these activities improves their lifestyle. The pain during activities like crossing legs, squatting and climbing steps was significantly reduced in Antarth group as compared with placebo group. Pain while crossing legs was reduced by 34.2% in Antarth group and by 16.8% in placebo group after treatment; during squatting it was reduced by 38.1% in Antarth group and 15.6% in placebo group; and while climbing steps it was reduced by 53.5% in Antarth group and 27.8% in placebo group. In all the three activities, the difference in reduction of pain after treatment between the two groups was significant (The fact that the quality of life is improved is evident from the Patient’s Global Assessment. About 7% of the patients treated with Antarth were totally symptom free by the end of 3 months treatment, whereas none were symptom free in placebo group. More than 55% of the patients treated with Antarth said it was very effective and about 40% said it was mild to moderately effective. Contrary to this, the patients treated with placebo were not fully satisfied with the treatment. About 28% of the patients treated said it was very effective and about 60% said it was mild to moderately effective. This indicates that the patients treated with Antarth were satisfied with the treatment. Similarly, Physician’s Global Assessment about the efficacy and safety of Antarth was better than that of placebo.Unlike the modern medicines which relieve only the symptoms of the disease, Ayurvedic medicines are claimed to be treating the cause of the disease, thereby relieving the symptoms. Although there is no evidence to this from modern perspectives, it is amply described in ancient Ayurvedic texts. This, however, needs to be confirmed using modern research methodologies.


The objectives of the study are: 1) to measure lumbar spine mobility and analyze the influence of the lower instrumented vertebra (LIV) in patients treated surgically for idiopathic scoliosis, and 2) to determine the correlation between the LIV, lumbar mobility, pain, and quality of life.40 patients  were included (mean age 27 years); average time since surgery was 135 months. The mean residual major curve Cobb angle was 35.4°. Lumbar mobility was measured during forward and lateral lumbar flexions using a dual digital inclinometer.Patients fulfilled the SRS22 Questionnaire and the Quality of Life in Spine Deformities Profile to estimate the perceived sensation of rigidity. Additionally, they rated the pain in the low back area.Lumbar mobility decreased in relation to the LIV. There was no correlation between lumbar range of motion and pain. The LIV do not correlated with the sensation of rigidity. The sensation of rigidity correlated both with SRS22 pain scale and the intensity of low back pain.Health-related quality of life was moderately correlated with the LIV and lumbar mobility.The LIV has an influence on lumbar mobility. The intensity of low back pain is mild in these patients and is not related to the LIV nor to lumbar mobility. The subjective perception of rigidity does not correspond to the loss of lumbar mobility, but rather, is determined by the coexistence of pain. The LIV has a moderate effect on the global quality of life.


Postoperative pain often is the limiting factor in the rehabilitation of patients after hip fracture surgery.We compared an approach using scheduled analgesic dosing with as-needed analgesic dosing in patients after hip fracture surgery, to compare these approaches in terms of (1) resting and dynamic pain intensity, (2) postoperative patient mobility, and (3) functional end points.We conducted a prospective cohort study of 400 patients who underwent surgical treatment of hip fractures at our hospital. The groups were formed sequentially, such that the first 200 patients formed the intervention group , and the next 200 patients were the control group . Resting and dynamic pain intensity, mobility, and functional performance were compared between the two analgesic protocols.As expected, analgesic consumption was lower in the control group . Despite the large difference in the amounts of analgesics consumed, resting and dynamic pain intensity showed improvement in each group and there was no difference between groups in terms of postoperative pain. However, there was a positive correlation between functional outcomes and analgesic consumption in the control group. The intervention group achieved higher functional performance on discharge . On discharge, fewer patients in the intervention group were wheelchair ambulators (3 versus 32), meaning more patients in the intervention group were able to walk.The study showed that a scheduled analgesic intake can improve the functional outcomes of patients with geriatric hip fractures after surgery.Level II, therapeutic study. See the guidelines for authors for a complete description of levels of evidence. In modern practice, postoperative care of patients with geriatric hip fractures is critically dependent on early mobilization , 35, 44.Pain management begins with assessment. However, the assessment of pain in elderly patients can be difficult. Elderly patients may be less inclined to report their pain for various reasons, including a fear-avoidance mentality, disinclination to trouble their caregivers, the stoic nature of their personalities, cultural influence, and others , 6, 7. MUnderreporting of pain by patients for any of the reasons described above can lead to the undertreatment of pain , 8, 24. We postulate that inadequate pain control can negatively affect the rate of functional recovery in the rehabilitation process after hip fracture surgery. Accordingly, we compared an approach using scheduled analgesic dosing with as-needed analgesic dosing in patients after hip fracture surgery, to compare these approaches in terms of (1) resting and dynamic pain intensity, (2) postoperative patient mobility, and (3) functional end points.We prospectively reviewed the efficacy of two analgesic regimens on rehabilitation outcomes of patients with hip fractures in an orthopaedic rehabilitation center during a 2-year period 2010–2012). We included 480 patients with (1) age of 65 years or older; (2) femoral neck, trochanteric, or subtrochanteric fractures; and (3) surgery with internal fixation or arthroplasty performed. Exclusion criteria included (1) patients with intolerance to the drug regimen; (2) patients taking other medications that contraindicated or interacted with the drug regimen; and (3) patients who refused to participate in the study. Eighty patients were excluded from the study according to our prespecified exclusion criteria. This left 400 patients who were included in the study. Two separate regimens were implemented in these two years. The intervention group, consisting of 200 consecutive patients admitted for hip fracture surgery between February and August 2010, received a scheduled analgesic protocol, consisting of tramadol 50 mg and paracetamol 500 mg three times a day for 3 weeks and then the same drugs three times a day as needed (pro re nata [PRN]) thereafter. The control group, consisting of the next 200 patients admitted to our center for hip fracture surgery, between September 2011 and March 2012, received analgesics on a PRN basis, including tramadol 50 mg and paracetamol 500 mg up to six times a day on request by the patient. The groups were comparable in terms of baseline characteristics . We used chi-square tests to compare categorical variables. We used paired t-tests to compare the changes of continuous variables within groups and independent t-tests to compare the changes of continuous variables between groups. We used the Pearson correlation test to perform simple correlation analyses. Statistical significance was conferred by a two-tailed p value of 0.05 or less. The interrater reliabilities for the Numerical Rating Scale were 0.874 at rest and 0.882 during activity. The interrater reliabilities for the Wong-Baker FACES® Pain Rating Scale were 0.860 at rest and 0.870 during activity. The interrater reliability for the Elderly Mobility Scale was 0.913. The interrater reliability for the Functional Independence Measure™ was 0.927, and the interrater reliability for the Modified Functional Ambulation Category was 0.901.We performed all statistical analyses using SPSSPatients experienced a greater level of dynamic pain than resting pain on admission. As expected, analgesic consumption was lower in the control group  Table . HoweverAlthough similar pain intensities were perceived by patients in both groups, the intervention group had a better ambulatory status at discharge (p < 0.001) Table . On discApart from enhanced ambulation outcomes, the intervention group achieved better mobility performance on discharge  Table . With scThe rate of complications occurring during the course of rehabilitation was similar. There were no fall incidents during hospitalization. Length of stay was longer in the intervention group. According to clinical experience, this discrepancy was attributable mainly to social factors, including time consumption in considering and arranging for placement and caregivers on discharge Table . There wThe importance of postoperative pain control in patients with geriatric hip fractures is well recognized , 9, 51, ® Pain Rating Scale [This study has numerous limitations. First, our major limitation was that the study was not a prospective randomized study. In addition, our large setting made it impossible for us to limit the number of assessors to a small number of staff to minimize interrater differences. However with on-the-job training, our interobserver reliability data suggested that this limitation was not severe. In elderly patients, one must monitor carefully for drug complications and drug interactions; this close monitoring resulted in a dropout rate of approximately 8% in the control group and 9% in the intervention group owing to nausea, and 6% in the control group and 7% in the intervention owing to contraindications or interactions with other medications. Forty-two percent of our control group and 37% of our intervention group had impaired cognition which could lead to an inadequate response to our Numerical Rating Scale assessments [ng Scale  to improFinally, we did not compare results according to several parameters including (1) types of fractures and surgeries, (2) comorbidity, and (3) postoperative complications, especially delirium which would have different responses on pain. In addition, 13% of our patients in the control group did not take any analgesic medication. The percentage of impaired cognition in this group and the impact on functional outcomes could be explored. A quantitative measurement of walking ability would strengthen the study.The answer to our question whether scheduled analgesic dosing after hip fracture surgery would decrease patients’ pain is somewhat counterintuitive and deserves further discussion. Similar to the study by Feldt and Oh, movement pain was substantially greater than resting pain in the groups . DespiteThe answer to our question regarding whether scheduled analgesic dosing after hip fracture surgery would enhance patient mobility was encouraging. Studies in postoperative samples have shown that early ambulation was important for recovery , 56. RehThe answer to our third question, whether scheduled analgesic dosing after hip fracture surgery would improve functional end points also was encouraging. The efficacy of our pain regimen was not reflected through a subjective pain score but was shown by the more objective Elderly Mobility Scale and Functional Independence Measure™ end points. In a study of functional outcomes, Arinzon et al.  found thWe found improved ambulatory status and functional outcomes in our patients after surgery for geriatric hip fractures by using a scheduled approach to analgesic delivery, which also effectively increased the analgesic dosage for patients during the first few weeks after fracture. However, not all pain in this patient population is from the surgery. Pain in these patients can come from several sources, including degenerative conditions of the hips or knees, pressure sores, concomitant injuries, or other medical conditions. In addition, analgesic medication is only one of the multiple methods for treatment for pain. In light of that, pain management should be individualized after clinical assessment of each patient.


Animal studies have shown that surgical trauma activates the descending noradrenergic pathway. However, perioperative patients have decreased concentrations of noradrenaline (NA) in the cerebrospinal fluid (CSF). We proposed that the descending monoaminergic pathway is altered in post-traumatic pain patients and that CSF monoamine neurotransmitters may be more closely related to affective symptoms. We investigated the levels of monoamine neurotransmitters and assessed pain in these patients.Patients were divided into a post-traumatic pain group, a pain-free group, a painful labor group, and a pain-free labor group. CSF was collected from all patients, and concentrations of NA, 3-methoxy-4-hydroxyphenylglycol (MHPG), dopamine, homovanillic acid, and 5-hydroxyindoleacetic acid (5-HIAA) were measured by high-performance liquid chromatography.P < 0.01) compared to the control group. The post-traumatic pain group displayed a significant negative correlation between NA and the respective total value of the short form of the McGill pain questionnaire (SF-MPQ), SF-MPQ (affective), and visual analog scale .In the post-traumatic pain group, lumbar CSF concentrations of NA and MHPG were significantly decreased (Post-traumatic pain patients demonstrated decreased concentrations of NAin CSF, indicating that descending noradrenergic pain control pathways may be inhibited. NA is more closely related to negative affects in post-traumatic pain patients. Classical neurotransmitters such as noradrenaline (NA), serotonin, dopamine (DA), and their metabolites are known as monoamines. Anatomical and physiological studies have shown that noradrenergic and serotonergic systems comprise one of the major components of descending monoaminergic pain control pathways . In addiBiogenic amines such as NA, serotonin, and DA modulate not only emotional and chronobiological processes but also the pathogenesis of affective disorders . It is nA few previous studies have shown that surgically induced trauma and pain can increase cerebrospinal fluid (CSF) concentrations of NA in rats and indicated that the descending noradrenergic pathway was activated . HoweverHowever, levels of NA, 3-methoxy-4-hydroxyphenylglycol (MHPG), DA, homovanillic acid (HVA), 5-HIAA, and 5-hydroxytryptamine (5-HT) in the CSF and affective symptoms have not been evaluated in patients with various types of acute pain. The primary aim of this study was to determine the concentrations of these neurochemical variables in order to assess the status of the descending monoaminergic pain control pathway in patients experiencing different kinds of acute pain. In addition, we evaluated the link between affective symptoms and descending pain control pathways with the short form of the McGill pain questionnaire (SF-MPQ).The patients were recruited at the Second Xiangya Hospital of Central South University. With the approval of the local Ethics Committee and written informed consent, 124 patients were enrolled. Study subjects were selected from a patient population that had received spinal anesthesia. Inclusion criteria included an age between 18 and 45 years, and an American Society of Anesthesiologists physical status of I–II, undergoing surgery with spinal anesthesia or combined spinal and epidural anesthesia. Patients with pain due to acute problems, such as trauma of the lower extremities, or an emergency cesarean section associated with labor pain, were recruited. All patients experienced pain for less than 24 h. The corresponding control groups were pain-free patients and elective cesarean section patients. Four groups of patients were studied. The first group consisted of 30 patients with sharps injuries in their lower extremities. The second group, which was the control group for the traumatic group, consisted of 33 pain-free patients undergoing elective surgery. To create a control group for the acute trauma pain group, we recruited patients with surgical diseases who were pain-free. The third group consisted of 30 at-term women undergoing painful, active labor. The fourth group consisted of 31 pain-free women having an elective cesarean section as the pain-free control group. Exclusion criteria included the use of an analgesic or any other medication preoperatively. Also excluded were patients with neuropathic pain, neurological disease, alcohol or drug abuse, or using any substances acting on the central nervous system. All patients in the four groups were premedicated with 100 mg of phenobarbital sodium intramuscularly, 30 min prior to transportation to the operating room. All patients received 500 mL of Ringer's lactate solution before anesthesia induction.Before surgery, patients completed a questionnaire using the visual analogue scale (VAS). Each patient used a 10-cm visual analog scale and the SF-MPQ in the shortest possible time. VAS scores and SF-MPQ were recorded preoperatively before lumbar puncture for spinal anesthesia.Samples were collected with subjects placed in the lateral position. The epidural space was identified at the L2–L3 or the L3–L4 interspace. Twenty minutes before lumbar puncture, a eutectic mixture of local anesthetic cream was applied to the lumbar area of the back to anesthetize the puncture site. After intradermal injection of 1% lidocaine, a 20-gauge introducer needle was used to penetrate the skin and superficial tissue. Epidural attempts were performed by anesthesiologists using an 18-gauge or 16-gauge Tuohy epidural needle. The loss-of-resistance-to-saline technique was used. The introducer was used because the Sprotte 90-mm 25-gauge pencil point spinal needle is very thin and has a relatively dull tip. The spinal needle was then inserted with the introducer through the L2–L3 or L3–L4 interspace and into the spinal canal. After obtaining free flow of the CSF, a total of 2 mL of CSF was collected. The fluid was immediately divided into 1-mL aliquots and frozen at –70°C until monoamines and their end-products were assayed.g) for 10 min. Acid supernatants were collected and measured by a high-performance liquid chromatography separation column and a 4-sensor coulometric electrochemical detector . Levels of NA, MHPG, DA, HVA, and 5-HIAA in the CSF were determined.The contents of the CSF were determined as previously described . After tpost-hoc test using the Bonferroni correction was calculated for paired comparison. To calculate correlations between different variables, Spearman's correlation coefficient was used. A P value of < 0.05 was considered statistically significant. Statistical analyses were performed using the statistical program PASW statistics 18©.Data are presented as a mean ± standard deviation (SD) or standard error of mean (mean ± SEM). Even after logarithmic transformation, CSF neurochemical variables were not normally distributed for the VAS and SF-MPQ, as well as for neurotransmitter concentrations. Therefore, these values are presented as median ± 25th and 75th percentiles. Non-parametric tests were used for the analyses. The influence of variables, such as height, weight, age, and sex, on the concentration of neurotransmitters was determined by a Mann–Whitney rank sum test. When comparing more than two group means, the non-parametric Kruskal–Wallis test was used. Because there was an α-error and a potential for inflation, a P < 0.05) in pregnant women compared to other groups. Although women in active, painful labor and women receiving an elective cesarean section were shorter than the control group, which consisted of an equal mixture of men and women, they were not shorter than the female trauma and pain-free patients , 1.05 ng/mL (MHPG), 0.59 ng/mL (DA), 0.70 ng/mL (5-HIAA), and 0.85 ng/mL (HVA). The average recovery ranged from 89.5% to 104.6%. All the investigated calibration curves were characterized by a high correlation coefficient; the correlation coefficient of the five substances was 0.9943 (NA), 0.9965 (MHPG), 0.9973 (DA), 0.9991 (5-HIAA), and 0.9932 (HVA). The intra-assay precision  of NA, MHPG, DA, HVA, and 5-HIAA was 0.9%–1.2%, 1.1%–1.3%, 0.7%–1.0%, 0.8%–1.1, and 1.0%–1.3%, respectively. The inter-assay precision was 1.6%–2.7%, 0.8%–1.7%, 0.9%–1.4%, 1.2%–2.4, and 1.8%–2.8%, respectively.As a primary outcome measure, median CSF levels of monoaminergic transmitters and metabolite concentrations in the four groups  are presented in P < 0.01). In the active, painful labor or the elective cesarean section group, 5-HIAA was significantly higher than in the pain-free group (P < 0.05), and NE and MHPG showed no significant change. Furthermore, there was a significant difference between the mean levels of 5-HIAA in the active, painful labor group and the elective cesarean group (P < 0.01).In patients with post-traumatic pain, compared to those in the pain-free control group, lumbar CSF concentrations of NA and MHPG were significantly decreased (The results of pain assessment are shown in P < 0.01). However, there was no significant difference in the sensory score of the SF-MPQ between the two groups  versus 14 ).There was no significant difference in the SF-MPQ scores between patients with post-traumatic pain ) and patients with on-going labor pain ). The affective score of the SF-MPQ in patients with post-traumatic pain was significantly higher than the score in the labor pain group  versus 3 ; r = –0.388, r = –0.433, and r = –0.367; P < 0.05). In the labor pain group, only 5-HIAA had a significant positive correlation with the SF-MPQ , SF-MPQ (sensory), SF-MPQ (affective), and VAS . Other neurochemical variables showed no significant correlations with the SF-MPQ , SF-MPQ (sensory), and VAS. Thus, our results indicate that depressive symptoms displayed a certain degree of correlation with NA and 5-HIAA in the trauma group.In patients with acute post-traumatic pain, a significant decrease in NA and MHPG was detected . In thisin vivo. Evaluating the various concentrations of neurotransmitters may provide additional information that will help put together the neurochemical processes occurring at the time the sample was taken. Many CSF transmitter studies have been performed in psychiatric disorders, such as depression  was not low. Strittmatter et al. (We found that there was a decreased CSF NA and MHPG concentration in post-traumatic pain patients. These patients usually experienced moderate affective symptoms. However, in the labor pain group, NA showed no significant changes. The reduction of NA is more closely linked to the affective dimension of post-traumatic pain than the sensory dimension. Our research showed a relationship between affective symptoms and pain, and the correlation coefficient (r et al.  showed tr et al.  found der et al. . In thesr et al. . We belir et al. . Howeverr et al.  found thWe observed that noradrenergic and serotonin systems showed a different, converse tendency, in post-traumatic pain, which is different from labor pain because it is usually accompanied by negative affective symptoms. These patients showed decreased NA concentrations in their CSF, indicating that descending noradrenergic pain control pathways may be inhibited. NA is more closely related to affective symptoms in post-traumatic pain patients. Negative emotions may suppress descending antinociceptive systems and promote transmission of noxious stimuli. Pregnant women may have more complex emotions, positive or negative, and their noradrenergic descending control systems are not suppressed, although serotonin antinociceptive systems are activated. The descending pain control system can inhibit nociceptive stimulus transmission.


Chronic neuropathic pain in thalamic pain syndrome remains intractable. Its poor response is ascribed to destruction of the integrated neuromatrix in experience of pain. Deep brain stimulation is a promising technique to modulate activity of implicated structures. However, traditional approaches targeting sensori-motor substrates have failed to affect disability. The offending lesion in thalamic pain syndrome that almost invariably destroys sensory pain pathways may render these classical approaches ineffective. Instead, we hypothesize that targeting structures representing emotion and affective behavior-ventral striatum/anterior limb of the internal capsule, may alleviate disability.We present the design of our phase I randomized, double-blinded, sham-controlled, crossover trial that examines safety, feasibility and efficacy of our proposed approach. In our ongoing trial, we intend to enroll ten patients with thalamic pain syndrome. Following implantation, patients are randomized to receive active deep brain stimulation to the ventral striatum/anterior limb of the internal capsule or sham for 3 months, after which they are crossed over. The primary endpoint is Pain Disability Index. Other outcomes include visual analog scale, depression and anxiety inventories, quality of life, and functional neuroimaging.Designing trials of deep brain stimulation for pain is challenging owing to the ethical-scientific dilemma of introducing a control arm, complicated blinding, heterogeneous etiologies, patient expectations, and inadequate assessment of disability. The quality of evidence in the field is classified as level III (poor) because it mainly includes a multitude of uncontrolled case series reporting variable outcomes, with little regard for the placebo effect related to implantation. Without valid data on efficacy, use of deep brain stimulation for pain remains “off label”. We present our trial design to discuss feasibility of conducting sham-controlled phase I studies that may represent significant refinement for the field. Double-blinding would reduce influence of patient expectations and therapeutic confusion amongst investigators. With a cross-over approach, the dilemma regarding including a control group can be mitigated. Use of homogeneous etiology, measurement of disability, depression and quality of life, besides pain perception, all represent strategies to evaluate efficacy rigorously. Functional imaging would serve to define mechanisms underlying observed effects and may help optimize future targeting.NCT01072656Clinicaltrials.gov  Chronic neuropathic pain, defined as ‘pain initiated or caused by a primary lesion or dysfunction in the nervous system’ , is one Poor responsiveness in TPS is attributed to disruption of the pain neuromatrix . The neuet al. initially demonstrated positive results across several central pain syndromes [Almost four decades ago  DBS was yndromes , but proyndromes -16. ThusWe suggest there may be several reasons for failure of traditional DBS that targets sensorimotor substrates in management of TPS. First, the offending lesion in TPS damages sensorimotor targets such as the ventral-posteromedial and ventral-posterolateral targets that are critical to conduct the effects of contemporary DBS ,17. SecoOur group has recently suggested departing from the traditional approach of targeting DBS to sensorimotor substrates and instead provided rationale for a novel DBS target involving VS/ALIC in the management of chronic neuropathic pain in TPS . ExaminiHere, we present the protocol design of our current pilot clinical trial where we examine: 1) safety and feasibility of delivering DBS to VS/ALIC in a double blinded, randomized, sham-controlled, crossover clinical trial in patients with TPS; 2) efficacy of the intervention with respect to pain-related disability, quality of life, neuropsychological and psychiatric outcomes and individual ratings of perception of pain; and 3) reorganization within affective networks of the pain neuromatrix with DBS delivered to VS/ALIC, which will be studied using functional magnetic resonance imaging (fMRI) and magneto-encephalography (MEG).We hypothesize that DBS targeting VS/ALIC will modulate the affective component of TPS and consequently, improve pain-related disability.http://clinicaltrials.gov/ct2/show/NCT01072656) as a clinical trial. The Institutional Review Board of the Cleveland Clinic has approved the study. Informed consent is obtained from all interested participants in accordance with policies of the Board.A pilot, randomized, sham-controlled, double-blinded, two-group crossover clinical trial design is being employed to evaluate the safety and effectiveness of DBS targeting VS/ALIC in TPS. Patients with TPS are being enrolled, and then randomized to active DBS or sham following implantation, after which they are crossed over. The study has been approved by the Food and Drug Administration with an Investigational Device Exemption as a phase I clinical trial, and is registered  but not DBS are also candidates, provided that the MCS hardware has been removed. Inclusion and exclusion criteria are discussed in detail below.•Age > 21 years•Diagnosis of TPS >6 months•MRI-confirmed lesion affecting the posterior thalamus or dorsal or ventral vicinity of thalamus or brain stem•Patients with lesions involving the semi-oval white matter in topography consistent with sensory thalamo-cortical connections and presenting with clinical syndrome consistent with TPS•Chief complaints of intractable hemibody pain that has remained at an average score >5 on the visual analog scale  for 30 days, pinprick hypoesthesia over the affected hemibody (anesthesia dolorosa), severe allodynia, significant pain-related disability (Pain Disability Index or PDI score >30), failure to respond to at least one medication within each class of drugs prescribed commonly for central pain syndrome, including antidepressants, anti-seizure medications and oral narcotics.•Issues with psychiatric health, including inability to cope with implantable hardware, severe uncontrolled depression, bipolar disorder, severe obsessive compulsive disorder, suicide ideation within 12 months prior to enrollment or communication of a plan should the investigational treatment fail or imminent suicide risk  and the Columbia-Suicide Severity Rating Scale (C-SSRS) and the Beck Depression Inventory (BDI)•Unstable physical health, other neurological lesions or MRI-based incidental findings unrelated to the offending lesion, women of childbearing age who are pregnant at the time of enrollment or are not using adequate contraception•Co-morbidities including ongoing anticoagulation/anti-aggregation therapy, uncontrolled hypertension or major organ system failure•Prior or concurrent therapies related to TPS, including previous ablative intracranial surgery for management of TPS, previous DBS therapy or simultaneous enrollment in another clinical trial for TPS•Issues with cognitive health or ability to communicate, such as inability to provide informed consent, severe aphasia or inability to comply with the logistical requirements of the research studyPatients are being recruited from the Cleveland Clinic Neurological Institute Centers and from the Cleveland Clinic Pain Management Center. Other institutions in Northeastern Ohio and neighboring states have also been contacted about the study. These centers have access to the objectives of the study, intended population and study criteria, but patients are only enrolled and treated at the Cleveland Clinic.Screening involves standard review of history, physical and neurological examination, review of MRI within the past year, pain questionnaires, psychiatric evaluation, pain psychological evaluation and laboratory tests. Patients meeting selection criteria are enrolled.Phase II, or pre-operative baseline evaluation Figure , involveAll enrolled patients receive DBS implantation bilaterally in the VS/ALIC target. DBS lead implantation is completed in the same fashion as previously described by our group, but for the VS/ALIC target ,24. The 2/phase, using the formula:DBS programming is initiated at least a month after DBS surgery to allow for resolution of microlesional effects. In acute programming, patients are asked to report changes in mood, anxiety, pain or suffering with activation of one or more electrode contacts. If the affective reporting of pain is not influenced, then settings affecting mood and anxiety can be chosen for chronic stimulation. All stimulation settings are planned below a charge density of 30 μC/cmOnce optimal settings are determined, stimulation is turned off for about a month in order to minimize the effects of experience and memory of stimulation. Patients are then randomized to either the DBS group that receives active stimulation programmed to the settings found to be optimal during titration in phase IV, or to the sham group that receives 0 V  stimulation. As a technical detail, for minimizing risk to blinding procedures, the pulse generator is always kept on during all phases so that if any patients have tests that could indicate the status of the generator, it will always appear to be turned on Patients are randomized in a 1:1 ratio to one of the two groups.Upon completion of the third month post-crossover, all patients are reprogrammed to the optimized stimulation settings, as deemed necessary by the investigators at that time to maximize clinical benefits. There is no sham stimulation after this point. The goal is to reduce pain-related disability. Follow-up assessment of outcomes is conducted at month 9, 12, 18 and 24.Risks can be related to the procedures for implantation of DBS hardware, or the stimulation of the target area. Additional risks could be related to conducting MRI with implanted DBS. Events or instances that can present as risks are noted in detail in Table Our current trial is a double-blinded study where neither patients nor investigators performing outcome assessments know whether DBS or sham is delivered. Maintaining a blinded study is important because of the subjective nature of reports of pain and disability. Loss of blinding may occur due to the magnitude of the therapeutic effect or any other subjective perception that indicates that active DBS or sham is delivered. Safeguards have been incorporated to prevent loss of experimental blinding; for instance, stimulation is turned to 0 V after the programming and titration in phase IV to minimize the chance of memory of stimulation affecting the patient’s perception of receiving active DBS or sham in blinded phase V. In addition, patients and blinded investigators are asked separately via questionnaire, what they believe is the status of the stimulation (active or sham). At the end of the study, we will evaluate how effective the blinding strategy was in order to guide us forward.Outcomes of pain, pain-related suffering and disability, depression and anxiety, functional status, motor abilities, and suicidal ideation are collected at several time points Figure .Instead of using the historically accepted criterion of 50% analgesia (using the VAS), we instead chose a 40% effect on the PDI as our primary endpoint. The PDI measures disability in physical and psychosocial categories spanning across domains such as family, sexual, social, recreational, self-care, occupational and life-support domains . Its strSecondary endpoints include: 1) 40% improvement in PDI in 50% of patients at 2-year follow up; 2) affirmative response to the prospect of receiving the treatment again if the same outcome were to be achieved; and 3) 50% reduction in VAS at 2-year follow up.Other outcomes include neuropsychological pain, and cognitive and psychiatric assessments Figure , Table 1•The McGill Pain Questionnaire consists of descriptors of pain, including sensory, affective, evaluative and miscellaneous categories •The Beck Depression and Anxiety Inventories are self-report measures to document the level of depression  and anxi•Tests of manual dexterity: the box and block test specifically measures the grasp and release function of the paretic hand.•EuroQOL (EQ-5D VAS) is a measure of health-related quality of life that has been employed in previous DBS studies in neuropathic pain •C-SSRS  provides•MADRS is a valid, acceptable, reliable and sensitive patient-reported outcome assessing severity of depression •Neuropsychological tests of cognitive function will include the California Verbal Learning Test, the Wechsler memory Scale, the Delis-Kaplan Executive Function System and the Wisconsin Card Sorting TestIn functional neuroimaging, fMRI and MEG are utilized to help define affective-cognitive networks associated with allodynia and anticipation of pain in chronic TPS, and their potential modulation with DBS of the VS/ALIC; fMRI has been performed safely in patients with DBS implants in our previous studies . Our groBoth MEG and fMRI are exploratory in this study. With fMRI, one of our goals is to evaluate resting state fMRI, comparing networks when DBS is turned on versus when it is turned off. Patients will undergo resting-state fMRI at pre-operative baseline, during the randomized blinded phase and during follow up. Thus, by comparing the DBS-on and DBS-off conditions, we will be able to assess the effects of active versus sham DBS without confounds related to placebo or study-related effects. The next goal is to correlate changes in the neural networks related to the placebo effect; we intend to do so by comparing effects of DBS-off stimulation between active, sham and pre-operative baseline phases. With MEG, we aim to harness its high temporal resolution to assess possible effects of DBS on pain anticipation. The primary hypothesis is that DBS will have a significant effect upon the affective sphere of chronic pain. Pain anticipation is one of the conditions leading to pain habituation and chronic pain. Thus, we theorize that improvements in the affective sphere will also be correlated to how cortical networks in patients with TPS modulate in pain anticipation. In order to test this concept, we have created a visual paradigm of pain anticipation that consists of a simple, three-second countdown. The type of visual paradigm encodes whether or not a painful stimulus would follow the countdown. One of the limitations related to this paradigm is that we do not have a full characterization of how healthy individuals respond to pain anticipation in this task. This can limit our understanding of how processing of pain anticipation is abnormal in individuals with TPS, and could as well limit the interpretation of effects of active DBS. In order to address these limitations, we are also evaluating a cohort of 10 healthy subjects to allow comparisons.The goal of this study is to evaluate the safety and feasibility of delivering DBS to the VS/ALIC in patients with TPS in a double-blinded, randomized, sham-controlled, crossover clinical trial. A Data Safety and Monitoring Board (DSMB) has been established as an advisory group to evaluate adverse events and judge overall integrity and conduct of the study. DSMB review at the outset, half-way through the enrollment process and at the end, will record numbers of participants enrolled, participants lost to follow up, deviations from protocol, threats to blinding and adverse events, following which, decisions about continuation or recommendations for changing or ending the study could be made.If DBS is acutely and significantly effective in patients who are randomized to receive DBS of the VS/ALIC first, then there is a chance that patients may notice substantial worsening of the pain (assuming that the intervention is effective) and the validity of the experimental blinding may be compromised. In this case, to investigate the effect on blinding, we will record the patient’s and the blinded investigator’s subjective perception (to the best of their ability to guess) of whether active DBS or sham was being delivered during the blinded phase. If the relapse in pain is considered to be threatening or if there is suicidal ideation, then stimulation will be re-initiated and/or patient will be allowed to escape randomization ,36. On tSince the study is designed as a randomized, sham-controlled, double-blinded study, we will also be able to evaluate whether any potential trend indicates efficacy, which would help compute effect sizes and variance in DBS versus sham phases to estimate sample sizes for adequate power in future. Our within-subject, crossover design would also yield the magnitude of placebo effect related to the surgical process itself that is an important practical issue to consider in effect-size estimates for the future.This study was initially planned to involve a total of 34 patients. The sample size was estimated based on changes in PDI in patients with central pain syndrome in an earlier study . It was t-test at α = 0.05. Despite the sample size limitation, we expect the study to be informative in estimating the magnitude of the placebo effect after DBS for pain, as well as variances in outcome that to date are unknown. These will be valuable in designing subsequent phase II and III studies.Due to the small sample size of the proposed pilot phase I trial, procedures for corrections for multiple comparisons cannot be instated; the scope of the subsequent phase II trial would be better suited to include such procedures. By examining only a priori hypotheses, we aim to mitigate the probability of making type I errors. Therefore, we will compare the differences in the primary and secondary outcomes in the third month of DBS with those in the third month of sham stimulation using the paired Our protocol aims to test the safety, feasibility and preliminary efficacy of a novel, neuromodulation therapy for intractable TPS. Our approach is based on the premise that failure of traditional cerebral neuromodulation in TPS with DBS ,5,13,16 The ethical-scientific dilemma of introducing a control arm is particularly intense in neurosurgery, given the risk of interventions to the brain. However, since DBS allows for all patients to be implanted at first and then be randomized to active stimulation or sham, studies have explored randomized controlled designs in the use of DBS, particularly in movement disorders -42. ThusDespite the inclusion of a placebo-controlled phase, altogether, patient expectations from undergoing a clinical-like investigational DBS procedure, therapeutic confusion within the investigative team, and unintentional cues during programming, can introduce several unwanted influences in clinical trial design. By introducing blinding for patients and employing a team where the investigator collecting outcome data is blinded and the surgeon and programming physicians are unaware of outcomes during the blinded phase, we aim to minimize unintentional cues and ensure investigator equipoise . We are Finally, to allow systematic study of efficacy, adequate controls in enrollment and analysis would be critical. We are maintaining diagnostic consistency by restricting inclusion only to TPS etiology. Although such a step limits the sample size, it addresses the criticism of previous DBS studies where heterogeneity of etiologies and targets affected concrete conclusions about therapeutic efficacy . With reThe benefits of DBS in chronic neuropathic pain, especially in TPS, are still less than adequate, to justify approval for widespread clinically labeled use. We propose that identifying better clinical alternatives in DBS may potentially improve efficacy of the approach. More importantly, however, it is incumbent on the field to incorporate well-controlled, blinded trial designs to explore the benefits of current as well as novel DBS targets. Based on recent recommendations, our trial involving DBS of the VS/ALIC may serve as an example of feasibly creating protocols that improve the quality of the evidence base.The trial is ongoing and is actively enrolling.ALIC: anterior limb of internal capsule; BDI: Beck Depression Inventory; C-SSRS: Columbia-Suicide Severity Rating Scale; DBS: deep brain stimulation; DSMB: Data Safety and Monitoring Board; EuroQOL(EQ-5D): Euro Quality of Life scale; fMRI: functional magnetic resonance imaging; IPG: implantable pulse generator; MADRS: Montgomery-Asburg Depression Rating Scale; MCS: motor cortex stimulation; MEG: Magneto-encephalography; MRI: magnetic resonance imaging; NEO_FFI: NEO Five Factor Inventory; PANAS: Positive and Negative Affect Schedule; PDI: Pain Disability Index; TPS: thalamic pain syndrome; VAS: visual analog scale; VS: ventral striatum.AM has the following conflicts of interest to disclose, none of which are directly pertinent to this research: Intellect Medical , ATI and Cardionomics (shareholder), and Monteris (consultant).All authors made significant intellectual contributions. AM is the principal investigator. AM and DM developed the approach discussed here as an intervention. EP created the first draft, which was reviewed and edited critically by all other authors, and was included in revisions by EP. All authors read and approved the final manuscript.EP is project staff in Departments of Biomedical Engineering, Physical Medicine and Rehabilitation and Center for Neurological Restoration at the Cleveland Clinic.DM is the chairman of Department of Psychiatry & Psychology and Center for Behavioral Health at the Cleveland Clinic.AM is the Director of the Center for Neurological Restoration, Department of Neurological Surgery at the Cleveland Clinic.


Supported self-management, acupuncture and information can help reduce the symptoms of low back pain. These approaches are currently recommended by NICE guidance as treatment options for patients with persistent low back pain. However, there has been no previous evaluation of a service providing them together for this common problem. The purpose of this service evaluation was to report patient outcomes and experiences of the Beating Back Pain Service (BBPS), a pilot service based in a primary and community care setting, delivering acupuncture, self-management and information to patients with chronic low back pain.Patients completed a questionnaire at three time points: pre-BBPS, immediately post-BBPS and three months post-BBPS. Outcome measures included the Bournemouth Questionnaire , EuroQoL-5D , Pain and Self-efficacy Questionnaire, and additional questions on medication use, physical activity, understanding of pain and positive well-being. Additionally, the STarT Back (measuring risk of developing chronic pain) was collected at BBPS information sessions. Non-parametric tests were used to evaluate pre- and post- variables. Questionnaires also collected qualitative data (open-text responses) regarding patient views and experiences of the BBPS, which were analysed using thematic analysis.80 (out of 108) patients who attended the initial BBPS information session agreed to participate in the service evaluation . 65 patients attended subsequent BBPS acupuncture and/or self-management sessions and were asked to complete post-treatment questionnaires; complete datasets were available for 61 patients.There were statistically significant improvements over time for pain (p <0.0001), quality of life (p = 0.006), understanding of pain (p <0.001), physical activity (p = 0.047) and relaxation (p = 0.012). Post-hoc analysis revealed that scores improved between baseline and post-treatment, these improvements were maintained at 3-month follow-up (except relaxation). Patients receiving a combination of acupuncture and self-management sessions produced the most positive results. Patient satisfaction with the BBPS was high.The BBPS provided a MSK pain management service that many patients found effective and valuable. Combining self-management with acupuncture was found to be particularly effective, although further consideration is required regarding how best to engage patients in self-management. One third of the UK population is affected by low back pain each year and around 20% of those affected  will consult their GP about their pain  and placNICE  guidelines recommend that self-management, acupuncture and information should be provided for patients with persistent low back pain , howeverAcupuncture and self-management may also have wider benefits than pain reduction. Patient outcomes and experience data suggest that acupuncture may also improve patients’ quality of life and well-being, reduce medication use, and improve coping/self-management -27. AddiIt is important to consider how the NHS can best translate such research findings to provide effective treatments that are also acceptable to patients with low back pain. Yet, no studies have assessed the effectiveness  of a service providing acupuncture, self-management and information for chronic low back pain on the NHS. Evaluation is crucial to determine how to properly deliver complex treatment pathways to achieve the best clinical outcomes and acceptability. The current movement within the NHS towards a more user-centred service where the Government is keen that any modernisation of the NHS involves putting patients “at the centre of everything the NHS does” . Thus, i1 and delivered within a primary and community care setting. It aimed to provide early intervention for low back pain patients in order to reduce the use of chronic pain management services and referrals to secondary care. The BBPS accepted referrals of patients from GPs, and NHS physiotherapists and osteopaths. Inclusion criteria included: diagnosis of non-specific low back pain of more than six week duration, aged over 18 years old, and patient initially willing to participate in the service and evaluation. Exclusion criteria included: presence of red flags2, inability to communicate in English (no money was available for translation), mental health problems, and substance abuse. On referral to the BBPS all patients initially attended a group session that provided information on pain and how to manage it. Based upon their risk of developing chronic pain (measured by STarT Back as described below) patients could then elect to receive an individualised combination of acupuncture, self-management groups and using the BBPS pack . Patients identified as most at risk for developing persistent symptoms were encouraged to attend acupuncture and self-management sessions, rather than just acupuncture and/or BBPS pack. This new service design was informed by current guidelines which recommend the provision of acupuncture, self-management and information for persistent low back pain .” P19Some participants said that treatment had not helped their pain and one reported a temporary worsening of their condition after treatment. One patient reported sometimes feeling tired and depressed after acupuncture treatment.“For my problem I didn’t notice a big benefit.” P79When asked how acupuncture and self-management sessions could be improved, the overwhelming number of suggestions related to expanding and extending the service. Patients wanted more acupuncture sessions of longer duration, others suggested maintenance sessions would be appropriate. Some patients wanted to see the whole service more widely available on the NHS and one person suggested the service could be extended to people with all types of pain. Three patients reported that they would have liked more flexible times / locations for the self-management course. One patient explained how some of the self-management group were hoping to continue meeting once sessions had finished so that they could continue to share experiences and support one another.“Happy with the quality, could have done with more sessions.” P31“Six sessions are not enough to treat someone who has severe back pain. I also think there is a need of maintenance as per acupuncture principles.” P13“[Make it] more readily available on the NHS.” P14Other changes to the Service suggested by patients included the provision of written information such as online self-management information or a typed sheet explaining why acupuncture should work. One patient suggested having more information on the self-management course related to posture and what is good and bad for the back, this information was subsequently added to the self-management sessions. One patient suggested an online booking facility; another would have liked to have seen the BBPS more linked with osteopathy and chiropractor courses.“Both courses should be linked with osteopathy and chiropractor courses.” P22“Maybe a printed out sheet of the treatment given with explanation of why it should work would be helpful.” P80Many participants praised the practitioners that delivered the BBPS; they had found practitioners professional, knowledgeable and efficient. In particular, what was prominent in the analysis was the praise practitioners received for their humanistic qualities, including kindness, understanding, empathy, encouraging and caring.“I felt that I was listened to when I was describing what was going on and they even took note and interest in my other medical problems. Seemed more understanding and compassionate than any consultation I have had under the NHS.” P61“The people who run the course are very professional, caring and very friendly. They give much support and help to us all. [Acupuncturist] is wonderful, very professional and efficient.” P35with acupuncture for patients most at risk of developing chronic pain worked best, particularly 3 months post intervention. A short course of acupuncture may relieve patients back pain, but if causal factors linked to pain  are not rectified relapse may occur. Thus, our findings show that self-management training may work synergistically with acupuncture.This service evaluation reported on patient outcomes and experiences of the BBPS, a pilot service delivering acupuncture, self-management and information to patients with chronic low back pain. This pilot service was delivered in a primary and community care setting and helped to implement NICE  guidance for persistent low back pain locally, by working with local GPs and health professionals . Findingand community care, by experienced healthcare professionals. In addition, the BBPS was delivered in a ‘real life’ setting that used the STarT Back to recommend  treatment options for patients. This resulted in discordance between recommended treatment options and actual treatment received for some BBPS patients (i.e. patient attendance at recommended self-management sessions was relatively poor). Nevertheless, this evaluation found no differences in pain change scores regardless of the risk of developing chronic pain. For example those at high risk of developing chronic pain improved just much as those at low risk, whereas usually poorer outcomes would be expected for those more at risk of developing chronic symptoms in non-triaged samples [BBPS patient treatment recommendations  were based on the patient’s risk of developing chronic pain, which was ascertained using the STarT Back questionnaire completed by patients at BBPS information sessions. The importance of tailoring back pain treatment with individuals’ prognostic indictors has been highlighted by researchers and clinical guidelines . A recen samples ,48. Our  samples . Taken tPatient improvements reported by this service evaluation occurred despite high levels of pain chronicity and mental health issues among patients, which can result in poorer responses to treatment -51. AnxiNevertheless, engaging BBPS patients in self-management was challenging. Other studies have also found that chronic pain patients may fail to follow self-management advice . DespiteParticipants in our service evaluation reported that they particularly valued the humanistic qualities  of practitioners delivering the BBPS. The importance of such qualities in healthcare professionals has been reported elsewhere ,60,61 anThis service evaluation is of potential interest to commissioners; firstly it demonstrates that it is possible to incorporate treatment modalities with differing underlying philosophies (i.e. Chinese acupuncture) into the NHS that are well received by patients. Secondly, although this evaluation does not compare and contrast the BBPS with other modes of CAM provision on the NHS, it does suggest that it is possible to provide CAM in a primary and community care setting, contributing to the growing body of literature that suggests that CAM can successfully be provided on the NHS in GP settings ,24,27, sThe current service evaluation does not report on the efficacy of the service, rather it focuses on patient outcomes and experiences of the service and some of the ‘real life’ issues involved in delivering such a service. Thus it may be useful for commissioners considering how to implement NICE low back pain guidance , but canIn addition, the evaluation only focuses on the patient experiences of the Service and not service providers or healthcare professionals involved in the Service (e.g. those able to refer to the Service). Such views and experiences would be useful in obtaining a complete picture of the usefulness of the BBPS and elucidate topics such as integrating an externally provided service into the NHS and challenges (and how they were met) with patient adherence to the self-management aspect of the programme. The Service Evaluation also did not investigate the cost implications of the Service, it is recommended that future evaluation collect such data, as this is a key interest of commissioners.The evaluation showed that the BBPS provided patients with a MSK pain management service that many found effective and valuable. The service was delivered in a primary and commuity care setting and assisted in implementing NICE Guidance for persistent low back pain locally, by working with local GPs and health professionals. Efficient BBPS triaging of patients allowed resources to be distributed appropriately according to patient need. Patients using the BBPS experienced improvements  in their pain, quality of life, understanding of their pain, physical activity levels and relaxation, which continued 3 months after they finished treatment (with the exception of relaxation). In addition, over one third of patients maintained a clinically significant improvement in their pain. These results are despite high levels of pain chronicity and mental health issues, which can result in poorer responses to treatment. Combining self-management with acupuncture was found to be particularly effective, although further consideration is required regarding how best to engage patients in self-management.1The BBPS was delivered prior to NHS reform, when PCTs were still in existence.2Red flags are warning signs that indicate MSK pain may be a symptom of a more serious underlying issue and further investigations are needed .The authors declare that they have no competing interests.DP designed and oversaw the delivery of the BBPS, DR designed the evaluation with input from MP and AC. AC, DR and MP contributed to service evaluation implementation, and data analysis and interpretation. AC, DR and MP wrote the manuscript, DP contributed to aspects of the writing of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6882/13/300/prepub


The effectiveness of intranasal (IN) fentanyl as an analgesic for painful pediatric limb injuries in the Emergency Department (ED) has been reported previously. However, efficacy of IN ketamine in sub-dissociative doses is not well studied in the ED setting. A non-blinded pilot study undertaken by this study group suggested that IN ketamine showed similar analgesic effectiveness to that reported with IN fentanyl in similar non-blinded studies. The aim of this randomized, controlled, equivalence trial is to compare the analgesic effect of sub-dissociative dose IN ketamine with IN fentanyl for children with isolated musculoskeletal limb injuries.U tests will be computed to compare median change in the primary outcome measure for IN ketamine and fentanyl. A sample size of 36 participants per group is needed to detect the expected 40 mm reduction in pain rating with a 95% confidence interval (CI) no greater than ± 10 mm at 30 minutes. Rescue analgesia will be given as IN fentanyl or intravenous morphine.This is a prospective, randomized, controlled, double-blind equivalence trial of children agedthree to thirteen years and less than 50 kg body weight, with isolated musculoskeletal limb injury, presenting to the ED with moderate to severe pain, defined as a verbal response of at least six to a standard 11-point scale . Pain score, sedation, satisfaction with analgesic intervention, and adverse effects will be assessed over a 60 minute interval for each participant. Intranasal ketamine (1 mg/kg) or fentanyl (1.5 microgram/kg) will be administered via blinded syringe and mucosal atomization device in a standardized volume at 0.03 ml/kg, with a maximum volume of 1.5 ml divided equally to both nares. Participants will also receive 10 mg/kg ibuprofen orally. The primary outcome measure will be median change in pain score from pre-administration to 30 minutes post-administration. Non-parametric Mann–Whitney This is the first randomized-controlled trial comparing the efficacy of these two analgesic agents via the intranasal route. If IN ketamine is found to be equally effective to IN fentanyl for this indication, it will provide another analgesic agent that may be considered for the relief of acute pain in children in the ED.ACTRN12612000795897.Australian New Zealand Clinical Trials Registry Children with painful limb injuries frequently present to hospital Emergency Departments (ED) . AccordiConsidered the current standard of care in Australian EDs , advantaKetamine is a N-methyl D-aspartate (NMDA) receptor antagonist, in use since the 1960s as an anesthetic, amnesic and analgesic agent. It remains a popular general anesthetic worldwide as it provides sedation without compromising airway reflexes . At sub-Use of the IN route for the delivery of sub-dissociative doses of ketamine for pain relief is a relatively novel concept in the pediatric population and the analgesic response is not well characterized. To our knowledge, there are no studies comparing the efficacy of IN fentanyl to IN ketamine in children or adults. The primary aim of this clinical trial is to compare the analgesic efficacy of a sub-dissociative dose of IN ketamine with IN fentanyl in pediatric patients presenting to the ED with moderate to severe pain due to isolated musculoskeletal limb injuries. It is hypothesized that IN ketamine and IN fentanyl will provide equally effective pain relief in this patient group.This is a prospective, randomized, controlled, double-blind equivalence trial. The trial will be conducted in the ED of two Monash Health hospitals: Monash Medical Center, a tertiary referral hospital at which the Pediatric ED has an annual census of 29,000 patients; and Dandenong Hospital, an urban district hospital at which the general ED has an annual census of 57,000 patients, of whom approximately 25% are children. Participant inclusion and exclusion criteria are shown in Table Forty numbered syringes will be block-randomized at each site to contain either ketamine or fentanyl using a four block-randomization table as described by Altman and Bland (1999) . Each sy® Hospira Pty Ltd, Melbourne, Australia). For both fentanyl and ketamine, 3 ml syringes will be prepared. Fentanyl syringes will be made by drawing up 1.5 mL of fentanyl citrate parenteral solution for injection (50 mcg/mL) into a 3 mL syringe. Ketamine syringes will be prepared by diluting 0.5 mL ketamine parenteral solution (100 mg/mL) with 1.0 mL of sodium chloride 0.9% to make a final concentration of 50 mg/1.5 mL (33.3 mg/mL). The trial syringes will be given an expiry of one week from manufacture. Four syringes of the block-randomized batch will be prepared weekly by the pharmacy at each hospital site. Each week, unused syringes will be deemed expired and destroyed by the pharmacy. Unused, expired syringes will be re-made with the same numbers and drug allocations until all syringe numbers are accounted for. Syringe production rate may vary through the study period depending on the recruitment rate.Fentanyl citrate 50 mcg/ml  and Ketamine 200 mg/ml : for children aged seven years and older, required marking of a standard 100 mm line labeled ‘no pain’ at the left hand end and ‘worst pain ever’ at the right hand end. The severity rating at a single time point is the measurement (mm) from the left hand end of the line. Change in severity is recorded as positive for movement to the left (less pain) and negative towards the right (more pain).The patient will be asked to describe change in pain severity as; ‘a lot less’, ‘a little less’, ‘the same’, ‘a little more’ or ‘a lot more’.The patient/parent/guardian will be asked to describe satisfactions of pain severity change as; ‘satisfied’, ‘not satisfied’ or ‘no opinion’.The description of sedation will incorporate assessment by the medical staff member and the patient/parent/guardian. The attending doctor will assess the degree of sedation using the University of Michigan Sedation Scale (UMSS). This has been validated previously in analgesic and sedation studies in children . The pat® Wolf Troy Medical, Salt Lake City, UT, USA). For analgesic dose-volumes equal to and less than 0.5 mL, the entire dose will be administered in one nare. Doses above 0.5 mL will be divided equally and administered to both nares. Oral ibuprofen (10 mg/kg)  will then be administered within the first 15 minutes of IN administration of the study medication unless this drug has already been given in the past four hours. The parent/guardian will then be given the full written participant information to procure written consent for ongoing participation and data collection. Review of need for additional analgesia will occur across the 60-minute data collection period. If rescue analgesia is needed, participation in the study will be terminated at that time. Data collected to time of termination will be retained and included in the statistical analyses. Rescue analgesia will be either further IN fentanyl or intravenous morphine depending upon the treating doctor’s preference.On identification of an eligible patient Table , the attThe primary outcome measure will be median reduction in pain severity scores 30 minutes (T30) after study medication administration. Secondary outcome measures will include; VAS change in pain severity 15 and 60 minutes , subjective description of change in pain severity, satisfaction of pain change, sedation, adverse events, need for rescue analgesia at T15, T30 and T60, and need for rescue analgesia at T15, T30 and T60.U or Fisher’s exact tests as appropriate. Pain severity at each time point and change in severity between time points will be reported as median millimeter (mm) with interquartile range and compared using the Mann–Whitney U test. Previous research supports combination of severity measures from the VAS and FPS-R [U test. Patient/parent satisfaction and need for rescue medication will be reported as number and percentage and compared using Fisher’s exact test. Adverse events will be described as type and incidence.Patient age, sex, and weight will be reported as median with interquartile range or number and percentage and compared using either Mann–Whitney nd FPS-R . The UMSThe required sample size of 36 per group has been calculated using the assumption that the desired primary clinical outcome is that pain should be at least ‘a little’ better by 30 minutes post-study medication administration. Based on previous reports of response to analgesia in children ,17 we deWhile a number of descriptive observational studies have reported the analgesic effects of IN ketamine in sub-dissociative doses in non-ED settings in adults, no trials have compared the efficacy of ketamine to other analgesic agents in a blinded fashion. There is a paucity of literature describing the use of IN ketamine in acute pain in the ED in either adults or children. As a result, this study aims to assess the effectiveness of IN ketamine and fentanyl in a systematic blinded fashion in the ED.Prior to our dose-finding study , the effThis trial may be limited by selection bias as some participants with eligible limb injuries may have already received opioid analgesia prior to ED presentation. As a result, this will be a non-consecutive, convenience data set. Furthermore, we will not exclude children who have received non-opioid oral analgesia in this study. Patients with a pain score greater than 6/10 on presentation can be assumed to have a failed response to non-opioid analgesia and as a result, would normally require opioid analgesia for pain relief. However, it is likely that some patients receiving non-opioid analgesia prior to presentation may have a reduction in pain scores below those that would allow recruitment in this study. This also has the potential to prolong the recruitment period for our target sample size.This clinical trial has the Human Research Ethics Committee (HREC) approval of Monash Health HREC Committee B. The trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000795897). The trial protocol has been reviewed by the Monash Health Drug and Therapeutics committee. A trial safety monitoring committee has been incorporated into the study design to review adverse event incidents and ongoing analgesic efficacy in the trial.Provision of IN analgesia is a common practice for pediatric patients in the ED. Currently, IN fentanyl is the medication of choice based upon data form observational studies. We aim to assess whether the efficacy of IN ketamine is comparable to that of IN fentanyl in children with moderate to severe pain and isolated limb injuries. A positive result in this study may result in considering the addition of ketamine as an alternative analgesic to IN opioids in children with moderate to severe pain in the ED setting.Recruitment commenced in November 2012 for the 84 participants needed for the trial. It is anticipated recruitment will be completed by the end of 2013.CI: Confidence interval; ED: Emergency department; FPS-R: Faces Pain Scale - Revised; IN: Intranasal; NMDA: N-methyl D-aspartate; UMSS: University of Michigan Sedation Scale; VAS: Visual Analogue Pain Score.The authors declare they have no competing interests.AG, the principle investigator, conceived, designed, and submitted the study for ethics committee assessment and approval. RM was responsible for statistical design and sample size computation. DE-W, BS, TF, and RC each made substantial contribution to one or more of: study design, preparation of the manuscript and critical revision. All authors read and approved the final manuscript.