Tennis elbow is a common and often extremely painful musculoskeletal condition, which has considerable impact on individuals as well as economic implications for healthcare utilization and absence from work. Many management strategies have been studied in clinical trials. Whilst corticosteroid injections offer short term pain relief, this treatment is unpleasant and is used with caution due to an associated high risk of pain recurrence in the long term. Systematic reviews conclude that there is no clear and effective treatment for symptoms of pain in the first 6 weeks of the condition. There is a clear need for an intervention that is acceptable to patients and provides them with effective short-term pain relief without increasing the risk of recurrence. Transcutaneous electrical nerve stimulation (TENS) is an inexpensive, non-invasive, non-pharmacological form of analgesia that is commonly used in the treatment of pain. TENS has very few contraindications and is simple to apply. It also benefits from being patient controlled, thereby promoting self-management. This study aims to assess the effectiveness, in terms of pain relief, and cost-effectiveness of a self-management package of treatment that includes TENS.The design of the study will be a two-group pragmatic randomized clinical trial. 240 participants aged 18 years and over with tennis elbow will be recruited from 20-30 GP practices in Staffordshire, UK. Participants are to be randomized on a 1:1 basis to receive either primary care management  or primary care management with the addition of TENS, over 6 weeks. Our primary outcome measure is average intensity of elbow pain in the past 24 hours  at 6 weeks. Secondary outcomes include pain and limitation of function, global assessment of change, days of sick leave, illness perceptions, and overall health status. A cost-effectiveness analysis will also be performed. Patient adherence and satisfaction data will be collected at 6 weeks, 6 months and 12 months by postal questionnaire. A diary will also be completed for the first 2 weeks of treatment. Clinical effectiveness and cost-effectiveness analyses will be carried out using an intention-to-treat approach as the primary analysis.This paper presents detail on the rationale, design, methods and operational aspects of the trial.Current Controlled Trials. ISRCTN87141084 Tennis elbow is a painful, disabling musculoskeletal condition predominant in the 35-50 age group, and often causes considerable pain in normal daily activities such as gripping, carrying and lifting. Tennis elbow is traditionally considered to be self-limiting, but may last for 6-18 months . HoweverMore than 40 treatments have been proposed for tennis elbow, some of which have been investigated in clinical trials and systematic reviews . The oveTranscutaneous electrical nerve stimulation (TENS) is an inexpensive, safe, non-pharmacological form of analgesia. TENS units can be used in various clinical settings, are economically priced, and can be readily purchased by patients. TENS is simple to apply and is patient controlled, promoting self-management. The neurophysiological basis for pain relief from electrical stimulation such as TENS derives directly from the 'gate control' theory of pain . TENS han = 3) or inconclusive results (n = 4) [It has been argued that non-specific (placebo-related) factors of TENS comprise much of the total response. However experimental laboratory studies have clearly demonstrated the efficacy of TENS ,19, and  (n = 4)  included (n = 4) .n = 12 per group) restrict robust inferences. Weng et al [n = 20 per group) was again small.Only two previous studies have investigated TENS in tennis elbow. Halle et al  showed ang et al  showed aThe overall aim of this trial is to investigate if TENS, as a patient-controlled adjunct to routine primary care for tennis elbow, can provide superior short term pain relief and functional improvement compared with routine primary care alone, without increasing the risk of long-term recurrence.The primary objective of the trial is to investigate, at six weeks, pain relief from a self-management package of treatment that includes TENS in addition to primary care management , compared with primary care management alone, in patients presenting to their general practitioner (GP) with a first or new clinical diagnosis of tennis elbow.The secondary objectives of the trial are to investigate:• pain relief from TENS self-management at 6 and 12 months compared with primary care management alone.• differences in secondary outcomes  between TENS self-management and primary care management alone, at each time point.• differences in symptom recurrence between TENS self-management and primary care management alone, at 12 months.• the cost-effectiveness of TENS self-management as an addition to primary care management.• the influence of process measures, in particular patient adherence, expectations, and satisfaction with treatment.The design of the study will be a two-group pragmatic randomized clinical trial; this is illustrated in Figure Participants will be recruited from 20-30 GP practices in Staffordshire, England. The area covered by these practices is primarily urban with some rural and inner city areas, and is therefore broadly representative of the population in the UK.Male and female subjects aged 18 years and above who consult their GP with a first or new clinical diagnosis of tennis elbow  are eligible to take part.Participants must speak and understand English and be willing and able to give informed written consent. Exclusion criteria for the trial are: history of inflammatory arthritis or gross structural abnormality of the elbow; contraindications to TENS ; neuropathic pain; inability to apply TENS independently, complete written questionnaires, or read instruction leaflets written in English.GPs who are networked on the EMIS data system (a computerized system that maintains electronic patient records) will enter an appropriate diagnostic code (Read Code) for tennis elbow, and a 'pop-up' computer prompt will remind the GP that the patient is eligible for inclusion in the trial. At this point the GP will have the facility to enter a 'flag' onto the computer system if patients are unsuitable for the trial. A similar system to recruit patients to previous musculoskeletal trials in primary care has been used in this Centre . GPs whoAll patients who consent to further contact by a study nurse will then receive treatment by the GP, including analgesic prescription (where appropriate) and/or advice (e.g. paracetamol or co-codamol up to 8 tablets per day). Patients receiving prescribed anti-inflammatory or pain-relieving medication will be permitted to continue a stable dose. GPs will be asked to avoid corticosteroid injections or referral to physiotherapy for the first 6 weeks of the patient's participation in the trial.The study nurse will telephone patients within two working days to provide further information about the trial, establish that the patient has not received steroid injection or referral to physiotherapy from the GP and is eligible for the trial, and make an appointment for the Tennis Elbow Clinic. Patients will be notified that the consultation may take up to an hour. They will then be sent a letter to confirm their appointment, information about the clinic, and a duplicate trial information leaflet. If the appointment is within 24 hours, oral instructions about the clinic will be given by the study nurse.At the Tennis Elbow Clinic the study nurse will welcome patients and check their details. The study nurse will then explain the purpose of the clinic and the research being hosted within the clinic, check eligibility, and ask patients whether they wish to take part in the trial. Patients who are not eligible or do not wish to take part in the trial will be seen by a second treatment clinician (physiotherapist or nurse) and given information and advice on managing their tennis elbow according to usual practice. For patients giving preliminary consent, the study nurse will explain the trial in detail, gain written informed consent including permission for medical record review. The patient will then be provided with a baseline questionnaire to complete. The study nurse will check the baseline questionnaire for completeness, prior to randomization. The study nurse will remain blinded to treatment allocation throughout the trial. A post-study audit of the success of blinding procedures will be completed and a procedure for reporting incidents where blinding has been compromised will be in place.In addition to baseline outcome measurements, as appropriate, the baseline questionnaire will include:• Sociodemographic variables• Work-related variables: hours of paid work, job type, physical work load , psycho• Clinical characteristics: history of elbow pain, previous treatments, intensity and duration of symptoms, other co-existing pain problems.• Beliefs and expectations regarding treatment: items of the revised Illness Perceptions Questionnaire (IPQ-R)  suppleme• Illness perceptions .After completing baseline assessment consenting patients will be randomly allocated in a 1:1 ratio to six weeks of either primary care management alone or primary care management with TENS. Prior to the start of the trial, the trial coordinator, who is not involved in the selection and inclusion of patients, will supervise preparation of numbered, opaque and sealed tamper-proof envelopes containing the treatment allocation. The random sequence (based on simple randomization) will be generated using a computerized random-number generator. At the research clinic, after final enrolment and baseline assessment, the participant is allocated an individual study number, and receives the appropriate envelope from the research nurse. The participant then meets with the treating clinician, and the envelope is opened. The use of separate study and treating clinicians and sealed envelope randomization will ensure independent selection of patients and concealed allocation of treatment.Following randomization, the treating clinician will deliver whichever intervention the patient has been randomized to receive. The clinician will also give each patient a two-week daily diary to measure pain intensity and record usage of TENS and analgesics. Patients from both treatment arms will be advised that they can access their GP for ongoing care in the usual way if their elbow pain becomes worse.Patients will be sent postal questionnaires at 6 weeks, 6 months and 12 months, with reminder letters 2 and 4 weeks following first mail-out for those who do not respond. The study nurse will telephone patients who do not respond to the first reminder letter at six week follow up or the second reminder letter at six- or twelve-month follow up, to collect minimum data on the primary outcome.At the research clinic the treatment clinician will provide patients with the tennis elbow information leaflet and will reinforce the messages on advice and education contained within it. Patients will be informed of the usually self-limiting nature of tennis elbow and advised that while the elbow pain persists, they should avoid, whenever possible, repetitive elbow extension, forceful elbow activities, or activities that provoke pain. Potential ergonomic impact factors derived from sporting or working activities will be discussed and self-management in the form of rest/avoidance suggested, although absolute rest of the arm will not be advocated. In addition, the patient will be advised to gradually increase activity once acute pain has settled down and some basic progressive exercises will be explained.In addition to the control intervention described above, patients randomized to this group will be given a TENS machine and instructed on how to use it. They will be shown how to apply TENS locally, to the lateral aspect of the elbow and forearm, and will be encouraged to use the TENS machine at least once per day for one 45-minute treatment session, for each day that symptoms persist. Patients may use the TENS machine more often if they wish. The TENS parameter settings will be high frequency (110 Hz) at a pulse duration of 200 μs (frequency and pulse duration will be pre- programmed), with a self-selected intensity described as of 'strong but tolerable sensation' (measured as amplitude mA). Patients will be informed that they should feel an uncomfortable (but not painful) 'tingling' sensation and that they may experience muscle contractions and a local cooling of the area. Patients will be encouraged to use the TENS machine for a minimum of six weeks unless their symptoms have fully resolved before then.The selected TENS settings are those that, on the basis of the literature and our pilot laboratory work, are most likely to achieve analgesia. Patients will be required to rest during, and for approximately one hour after, the stimulation period, which will last 45 minutes. Application just before usual bedtime will be recommended so that the rest period can be incorporated into normal rest/sleep periods. An exact timing of stimulation is not essential provided that participants adhere to these conditions. The application of TENS will be the responsibility of the patient but the treating clinician will make an appointment for a telephone consultation approximately two days after the clinic to review the technical application of TENS and will be available via telephone (during the six-week treatment period) to assist patients with technical queries.Prior to recruitment of participants into the trial, the study treating clinicians will be trained to deliver the interventions in a standardized way. Training will include information regarding the clinical syndrome of tennis elbow, presenting symptoms, and treatment options. Guidance in the delivery of specific advice, in respect of work and ergonomic factors and exercises outlined in the leaflet, will also be given. Specific training in TENS will include: how it works, how it should be applied, how to check for contraindications and precautions, and how to train patients in its use. Technical difficulties with the TENS units are unlikely to occur but training will also be provided in fault finding in order to support patients in their use of TENS at their follow-up phone call. The core training will be covered in one day with a further day's training two weeks later, just prior to the start of the clinics, to practise delivering the interventions. A written manual of instructions on how to deliver the interventions will be given to each clinician.At the clinic, the study clinician will complete a case report form for each patient participating in the trial; this will record assessment findings relating to elbow pain and document advice and treatment given in clinic. Ten percent of these forms will be audited, and members of the study team will also visit the clinic periodically to ensure the appropriate delivery of advice and treatment.The TENS units to be used (TensCare itouch Easy™) will be pre-set with the stimulation parameters. Patients will be given basic coaching in use of the equipment - e.g. switching on and off and changing the battery. However, patients will not be instructed on how to change programmes within the machine and will be asked to ensure they do not attempt to do this.Clinical outcomes will be measured at baseline in clinic and by postal questionnaire at six weeks, six months and 12 months. There will also be a daily diary issued at clinic to be completed by participants over the first two weeks of treatment and returned by post on completion. The diary for the participants receiving TENS will have additional questions to record daily use of the TENS machine. Specific content is as follows:• Intensity of elbow pain in the past 24 hours ;• Sick leave or inability to carry out usual activities due to elbow pain;• Number and type of analgesics taken per day;• The use of TENS in minutes per day (for the TENS group).All participants will receive a postal questionnaire containing primary and secondary outcome measures. As the main focus of the trial is reduction of pain in patients with tennis elbow the primary outcome will be the average intensity of elbow pain over the past 24 hours scored on a 0-10 NRS scale. Secondary outcomes will be:• Days sick leave and ability to carry out usual activities• Self reported global change in elbow pain • Pain and limitation in function  )• Illness perception (items in the IPQ-R )• General Health: the EuroQoL EQ-5D  and SF-1• Health care resource use • Process measures:◦ Changes in beliefs and expectations of treatment (IPQ-R and specific items)◦ Satisfaction with treatment, feasibility, and applicability of TENS (0-10 NRS)◦ Compliance with treatment .In two previous trials of tennis elbow in primary care in the UK and the Netherlands, there was a 25% reduction in pain (1.5-point mean change (standard deviation 2.6) on a 0-10 NRS) in the usual care group at 4-6 weeks follow-up ,9. The oAn independent trial steering group will monitor adherence to interventions and recruitment rates and general progress against the plan.t test for independent samples. Mean estimates and 95% confidence intervals will be presented for differences between groups. The robustness of the findings will be tested through sensitivity analyses (see below). In addition, multilevel analysis will be carried out to estimate the overall effect of TENS treatment over time, taking account of clustering due to repeated measurements on the same individuals. Treatment main effects and the interaction of treatment and time will be modelled for short to long-term outcome data  and separately for the 2-week post-treatment time period covered by the pain diaries. Differences in secondary outcome measures will be estimated using similar statistical methods. In all cases, a significance level of 5% (two-tailed) is pre-stipulated. Hypothesis testing will be performed blind to treatment group.Descriptive statistics of baseline characteristics will be compared between study groups. An unadjusted analysis will focus on analysing the primary outcome measure (average pain intensity) at 6 weeks (the primary endpoint), using the The primary analysis will be carried out using an intention to treat (ITT) approach; a sensitivity analysis will use a per protocol approach , excludiA second sensitivity analysis will adjust for the following baseline covariates: age, gender, pain intensity (primary outcome measure) and corresponding baseline value for secondary outcome measures, if applicable; e.g. baseline function scores for the analysis involving limitation in function during follow-up.Descriptive statistics will be used to describe beliefs and expectations regarding treatment, compliance to advice regarding use of analgesics and use of the TENS units, and satisfaction with treatment. Compliance with TENS will be ascertained from questions about the duration, frequency, and dosage of use as recorded by the patient (in the two-week diary and follow-up questionnaire at 6 weeks). In exploratory subgroup analyses we will analyse whether better outcomes in key outcome measures are associated with:• older/younger patients• female/male sex• manual/non-manual workers• higher baseline expectations of or beliefs in TENS• higher scores on satisfaction• better compliance with advice or use of TENS.The economic analysis will adopt a societal perspective, where all relevant costs are measured, including direct health care costs incurred within both public and private sectors, and the indirect costs outside the health care sector associated with productivity loss. A cost-effectiveness analysis will be carried out with change in pain intensity as the clinical outcome of interest. Additionally, a cost-utility analysis will be performed to enable comparisons to be drawn with other areas of health care; utility will be measured using QALY values, which will be derived separately from (i) the EuroQoL EQ5D, and (ii) the SF-12 SF-6D. The ceiling QALY will be 1, which is equivalent to the year's follow up spent in full health.Data on health care resource use and time off work will be obtained from the patient questionnaires; a medical record review will be used to verify the self-complete data. NHS care will be costed as national averages , with inCost data alongside trials are invariably skewed. We will calculate 95% confidence intervals around differences in mean costs, EQ-5D scores, QALYs, and pain change scores using conventional parametric methods and bias-corrected and accelerated (BCa) bootstrapping (1000 replications) . The aimAn independent data monitoring committee will monitor the trial every 6 months. There will be no interim analyses.Ethical approval was obtained from the South Staffordshire Local Research Ethics Committee in May 2009 (ref number 09/H1203/31).The TATE trial will investigate the clinical and cost effectiveness of TENS in addition to usual primary care management for patients with tennis elbow. TENS may prove to be a suitable intervention for tennis elbow as it may help to reduce pain in the early stages of the condition, without the risk of side effects and/or recurrence in the long-term, and is an attractive treatment option as it facilitates self-management of the condition.We estimate that we will recruit 240 patients to the trial in 15 months if we involve 20-30 GP practices from north Staffordshire PCT. Trial recruitment is scheduled to begin in August 2009. Follow up is targeted for completion by November 2011 and results should be finalized for publication in spring 2012.The authors declare that they have no competing interests.All authors participated in the design of the trial and the drafting of the manuscript. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/10/156/prepub


Use of acupuncture has widely increased in patients with chronic low back pain. However, the evidence supporting its efficacy remains unclear. In this article, we report the design and the protocol of a multi-center randomized sham-controlled trial to treat chronic low back pain. Our goal is to verify the effect of acupuncture on chronic low back pain.This study is a multi-center randomized sham-controlled trial with 2 parallel arms. Participants included in the study met the following criteria: 1) low back pain lasting for at least the last 3 months, 2) a documented ≥ 5 points on a 10 cm visual analog scale for bothersomeness of low back pain at the time of screening and 3) between 18 and 65 years of age. Participants were blinded to the real and sham acupuncture treatments. The real acupuncture treatment group received real acupuncture 2 times a week, during a total of 12 sessions over 6 weeks. The control group received sham acupuncture during the same period. In order to assess the primary and secondary outcome measures, the participants were asked to fill out a questionnaire at the baseline and 6, 8, 12 and 24 weeks after starting the treatments. The primary outcome was measured using the visual analog scale for bothersomeness of low back pain at 8 weeks after the initiation of treatments.The result of this trial (which will be available in 2010) will demonstrate the efficacy of using acupuncture to treat chronic low back pain.This study is registered with the U.S. National Institutes of Health Clinical Trials registry: NCT00815529 Chronic low back pain (LBP) is one of the most important public health problems, as well as one of the main causes of disability among adults of working age . More thAlthough a wide range of standard treatments are available , back paIn this paper, we propose a randomized, sham-controlled study of patients with chronic low back pain, with a predetermined sample size and appropriate follow-up, which will enable us to investigate the efficacy of acupuncture on chronic low back pain.This study is a multicenter, randomized, non-penetrating sham-controlled study. The trial was conducted in the following three hospitals after obtaining permission from the Institutional Review Boards of three institutions: East-West Neo Medical Center of Kyung Hee University, Oriental Medicine Hospital of Sang Ji University, and Kyung Won Incheon Oriental Medicine Hospital. The patients were blinded to group allocation. The outcome assessment and the statistical analysis were performed by professionals who were blinded to the assignment of patients to either real or sham acupuncture Figure .October 2008-June 2010Patients aged between 18 and 65 years with non-radicular chronic low back pain of mechanical origin were recruited.Inclusion criteria were developed mainly to exclude patients with specific or complicated low back pain.• Between 18 and 65 years of age• Low back pain lasting for at least the previous 3 months• ≥ 5 points on a 10-cm visual analog scale for bothersomeness of low back pain at the time of screening• Intact on neurological examination • Non-specific, uncomplicated low back pain, i.e., ICD-10  codes:M51.3   Other specified intervertebral disc degenerationM54.5   Low back painM54.8   Other dorsalgiaM54.9   Dorsalgia, unspecifiedS33.5   Sprain and strain of lumbar spineS33.6   Sprain and strain of sacroiliac jointS33.7   Sprain and strain of other and unspecified parts of lumbar spine and pelvis• Participation agreement and signed informed consent• Radicular pain• Pain mainly below the knee, as clinical outcome is likely to vary• Serious spinal disorders, including malignancy, vertebral fracture, spinal infection, inflammatory spondylitis, and cauda equina compression• Patients who previously had spinal surgery or are scheduled to have one during the study• Other chronic diseases that could interfere with acupuncture treatment effects, including cardiovascular disease, diabetic neuropathy, fibromyalgia, rheumatoid arthritis, dementia and epilepsy• Chief musculoskeletal pain other than back pain• Acupuncture treatment for low back pain during the previous month• Conditions where acupuncture might not be safe, including clotting disorders, administration of an anticoagulant agent, pregnancy, and seizure disorders• Severe psychiatric or psychological disorder• Inability to read and write Korean• Pending lawsuits/receiving compensation due to low back pain• Patient taking corticosteroids, narcotics, muscle relaxant or herbal medicine to treat low back pain or any medication considered to be inappropriate by the investigator• Refusal to participate in the trial or informed consentParticipants were recruited through advertisements in local newspapers, the hospital monthly magazine, on a website and on bulletin boards. If patients were interested in participating, they were asked to answer questions to determine eligibility. If eligible, they were guided through the informed consent process. After written consent was obtained, a study researcher administered the baseline questionnaire followed by random allocation to either the real or sham acupuncture group. After randomization, the interviewer scheduled the treatment procedure.The patients were randomized per center in order to give each investigator the same chance to use individual, standard, and sham acupuncture to control the selection bias of the trial. The random code for randomization was generated by the medical statistician and was kept by a clinician who did not contact patients.Randomization was performed only after a subject was confirmed to be eligible and written informed consent was obtained. Subject details were recorded and a treatment arm and randomization number were allocated to the subject, and both of these were recorded in the subject's hospital file. The randomization form will be completed and returned to the principal investigator.In order to ensure balance within the two groups, blocked randomization was employed. This was made possible by using computer-generated random numbers from SAS software or other computer software. Different block sizes can be used. For a block of four, the possible assignment orders are AABB, ABAB, ABBA, etc. If there is an important predictor of outcome, stratified block randomization is available. For example, gender may be a strong predictor, and then block randomization within each of the two strata, male and female can be performed. The blinding credibility of the real and sham acupuncture treatments were evaluated at the baseline and at the end of the 6-week treatment.Licensed Korean Medicine Doctors (KMDs) who specialize in Korean Rehabilitation Medicine from the three participating hospitals should take the educational course to strictly adhere to the study protocol and to be familiar with administering study treatments; all participating KMDs underwent intensive and customized training for a full understanding of the "sham acupuncture" procedure, including details such as acupuncture points, depth, and manipulation. They were also trained to administer real acupuncture using a sham needle device.Both real and sham acupuncture groups received a total of 10-12 acupuncture sessions . In the real acupuncture group, disposable sterile needles (40 mm × 0.25 mm) were used , while non-penetrating sham needles with identical gauge were used in the sham control group . At the time of the first acupuncture session, all participants received an "exercise manual for low back pain patients" from the spine center of East-West Neo Medical Center of Kyung Hee University and were encouraged to do exercises according to the manual during the whole treatment period. This manual includes information on physical activity, exercise and appropriate life-style modification.A pre-defined, individualized acupuncture prescription in accordance with the characteristics of pain was employed. For this study, we developed a flexible treatment protocol by selecting a group of points that were predefined in every case, allowing the participating KMD some flexibility in the choice according to the diagnosis. The predefined points were carefully selected by a process of consensus with participating KMDs who were all experienced in low back pain. When we treated the patients in this research, we chose acupuncture points after the process of the meridian pattern identification. To treat low back pain, we assumed 3 types of meridian pattern identification according to the pain location .The acupuncture points included: Shenshu (BL23), Qihaishu (BL24), Dachangshu (BL25), Yimmen (BL37), Weizhong (BL40), Wangu (GB12), Daimai (GB26), Huantiao (GB30), Yanglingquan (GB34), Zulinqi (GB41), Dicang (ST4), Zusanli (ST36), Fushe (SP13), Fujie (SP14), Yaoyangguan (GV3), Mingmen (GV4), Xuanshu (GV5), Shenting (GV24) and Shuigou (GV26).Deqi sensation. The needles were left in place for 15-20 minutes.Acupuncture treatment was given using a sterile, disposable stainless steel needle (40 mm × 0.25 mm) with the aid of the tube of a sham acupuncture needle device. After the skin sterilization, the needles were inserted perpendicular to a depth of 5-20 mm with the patient lying down and blindfolded, followed by bidirectional rotation to induce As the real acupuncture group received treatment that reflects everyday practice, the acupuncture points were varied from visit to visit when the symptoms or pain changed.Non-penetrating sham needles by Park et al.  were usePatient completed a series of measurements to assess back pain-related dysfunction, pain, quality of life, and back pain-related costs.At the screening visit, patients were asked to fill out a questionnaire regarding age, gender, marital status, residence, occupation, and education. Medical history was also taken before physical check-ups and it was determined whether the patient would be included or not. The baseline (T0), 4 T1), 6 (T2), 8 (T3), 12 (T4), and 24 (T5) week follow-up measurements are summarized in Table , 6 (T2),The primary outcome was measured using the visual analogue scale (VAS) for bothersomeness of low back pain. Since our intension was not to simply evaluate the severity of pain, but also to understand the impact of chronic low back pain on the patients' life, we used the VAS not for pain intensity, but for bothersomeness of low back pain, as a primary outcome measurement. The patient was asked to mark, on a 10-cm VAS , the degree of bothersomeness due to low back pain experienced within the most recent one week from the day the assessment was performed. This measurement has substantial validity; it is highly correlated with measures of function and other outcome measures. BothersThere is ample evidence supporting the validity of the visual analogue scale (VAS) for pain intensity. Many studies have demonstrated the validity of its construct and its reliability ,15. ThisThe Oswestry Disability Index (ODI)  was usedHealth-related quality of life was measured at baseline, and at 6, 8, 12, and 24-week follow-ups, using the well-validated SF-36 , which hPatients completed the EuroQol 5-Dimension (EQ-5D)  at baselThe Korean version of Beck's Depression Inventory (BDI)  is a 21-Any adverse experiences at any clinic visit during the 12 sessions were monitored. The research team monitored serious adverse experiences, which were defined as treatment-related experiences.The trial would have been stopped if the principle investigator believed there was an unacceptable risk of serious adverse events in one of more of the treatment arms.Generally, a level of significance of α = 0.05 and a power of 1-ß = 0.80 were used. For two arms , we considered the two sample t-test model.Experimental group: real acupunctureControl group: sham acupuncturePrimary parameter: VAS for bothersomeness at 2 months after beginning of treatmentExpected mean difference and common standard deviation between two groups: 1.5 on a 0-10 VAS for bothersomeness, SD = 2.73Drop-out rate: 20%Sample size determination:where,N : total sample sizent : sample size for experimental groupnc : sample size for control groupr: number of experimental groups: number of control groupnt/nc)λ: ratio of experimental and control sample size ß: probability of type 2 errorα/2: α/2th quantile of standard normal distributionZß : ßth quantile of standard normal distributionZc-μt = 1.5, σ = 2.73[μin et al)Using formulas (1) above:For the equal allocation for the two groups, total sample size considering drop-out rate of 20% was calculated as 130 subjects.All statistical analysis was performed in the principle of ITT analysis  and PP analysis . In the case of ITT analysis, we applied the LOCF  rule. For all statistical analysis, SPSS Win. Ver.14.0 and a significance level of 0.05 were used.For the description of baseline characteristics, both demographical and clinical, for all subjects in the clinical trial, the mean with standard deviation, range with minimum and maximum for quantitative data and frequency with percentage for qualitative data are described.For the homogeneity test of the baseline characteristics, both demographical and clinical, between the two groups, two-sample t-test for quantitative data and Chi-square test for qualitative data were performed. If there were baseline characteristics showing statistical significance and possibility of covariance, ANCOVA  was used for analysis and adjustment of baseline characteristics.The two-sample T-test was used for VAS for bothersomeness of low back pain at baseline and at 8 weeks for the comparison of the two groups and to determine differences from baseline. ANCOVA and two-sample T-test was used between the differences at baseline VAS and 8 week VAS for each groups. Also, a 95% confidence interval was added for all analyses.Repeated measure two factor analysis will be used to analyze the difference and mean change among baseline, and 4, 6, 8, 12 and 24-week VAS, difference and mean change between groups, and interaction between groups and observed time. If necessary, a mixed model approach was also used.For the variable, VAS for pain intensity, Oswestry Disability Index (ODI), SF-36, EQ-5D, repeated measure two factor analysis was used to analyze the difference and mean change among baseline, 4, 6, 8, 12 and 24-week VAS, difference and mean change between groups, and interaction between groups and observed time. If necessary, a mixed model approach was also used.For medication use, the Chi-square test was used to analyze the different types of drugs between the groups, dose of drug and frequency of dose in a day among baseline, 4, 6, 8, 12 and 24-week VAS. Repeated measure two factor analysis was used to analyze the difference and mean change between groups, interaction between groups and observed time. If necessary, a mixed model approach was also used.All adverse effects were recorded and described as frequency and percentage. For the comparison of adverse effects between groups, the Chi-square test or Fisher's exact test were performed.Investigators entered the information required by the protocol into the Case Report Forms (CRFs). Non-obvious errors or omissions were entered into data query forms, which were returned to the investigational site for resolution. The data from all centers were gathered and summarized with respect to demographic baseline characteristics, effectiveness and safety observations.We adopted the visual analogue scale for bothersomeness (not pain) as the primary outcome measurement. This is because the target disease of this study is chronic low back pain. According to the clinical experience, we observed that some patients with chronic pain tend to be very bothered by even a small amount of pain and others are not bothered by even moderate pain. In clinical practice, we frequently find it is more essential and effective to try to improve bothersomeness due to chronic pain than to try to reduce that pain itself.Various randomized clinical trials that have investigated the efficacy of acupuncture tend to use different types of control groups, such as sham acupuncture, placebo acupuncture and a waiting list ,9,26,27.The results of this trial will be available in July 2010The authors declare that they have no competing interests.JHL were responsible for developing treatment protocol and preparation of the manuscript. HJP, HL, and IHS were responsible for the study design, provided the treatment protocols, and supervising of the protocol. MYS was contributed to the design of the study, provided the treatment protocols, and responsible for the acquisition of funding for the study. All authors have read, revised and approved the final manuscriptThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/11/118/prepub


To determine whether pre- and post-operative administration of intravenous ibuprofen (IV-ibuprofen) can significantly decrease pain and morphine use when compared with placebo in adult orthopedic surgical patients.This was a multi-center, randomized, double-blind placebo-controlled trial.This study was completed at eight hospitals; six in the United States and two in South Africa.A total of 185 adult patients undergoing elective orthopedic surgery.Patients were randomized to receive either 800 mg IV-ibuprofen or placebo every 6 hours, with the first dose administered pre-operatively. Additionally, all patients had access to intravenous morphine for rescue.Efficacy of IV-ibuprofen was demonstrated by measuring the patient's self assessment of pain using a visual analog scale  and a verbal response scale (VRS). Morphine consumption during the post-operative period was also assessed.P < 0.001); a 31.8% reduction in mean AUC-VAS assessed at rest  and a 20.2% reduction in mean VRS (P < 0.001) compared to those receiving placebo. Patients receiving IV-ibuprofen used 30.9% less morphine (P < 0.001) compared to those receiving placebo. Similar treatment emergent adverse events occurred in both study groups and there were no significant differences in the incidence of serious adverse events.In the immediate post-operative period, there was a 25.8% reduction in mean area under the curve-VAS assessed with movement (AUC-VASM) in patients receiving IV-ibuprofen (Pre- and post-operative administration of IV-ibuprofen significantly reduced both pain and morphine use in orthopedic surgery patients in this prospective randomized placebo-controlled trial. Opioids are considered the treatment cornerstone for severe post-operative pain . In the A previous randomized, placebo controlled trial in surgical patients, including those undergoing orthopedic procedures, evaluated pain reduction and the opioid sparing effect of intravenous ibuprofen (IV-ibuprofen) during multimodal post-operative pain management . This trThis was a multi-center, randomized, double-blind, placebo-controlled study of the safety and efficacy of IV-ibuprofen for post-operative pain following elective knee or hip replacement, reconstruction or arthroplasty with an anticipated need for post-operative hospitalization and IV morphine analgesia for at least 28 hours. This study was approved by institutional review boards or independent ethics committees at all participating sites. Efficacy was measured by comparing the patients' self-assessment of pain and morphine use in the post-surgical period.Patients who met all of the inclusion criteria and did not meet any exclusion criteria  were conIn previous clinical studies of IV-ibuprofen, the initial dose was administered intra-operatively. However, the current trial sought to determine if IV-ibuprofen would also have a significant effect on the onset of pain. Therefore, the first dose of study drug was administered prior to the surgical procedure. The study drug was infused over 30 minutes through either a peripheral or a central venous catheter. After surgery, all patients had access to PCA morphine.Previous clinical studies demonstrated that despite having access to morphine, patients receiving IV-ibuprofen not only used less morphine, but also reported lower pain scores . The plaThe trial was conducted in an in-patient setting at a total of eight surgical hospital sites. Six of the eight sites were in the United States: Dekalb Medical Center , Arkansas Surgical Hospital , Foundation Surgical Hospital , Memorial Hermann-Memorial City Hospital , Methodist Hospital , and Springhill Memorial Hospital . Two of the eight sites were in South Africa: Johannesburg General Hospital  and Eugene Marias Hospital . Enrollment was open to adults between ages 18 and 80 years who were scheduled for elective hip or knee replacement, reconstruction or arthroplasty, with an anticipated hospital stay and anticipated concomitant need for IV morphine analgesia for at least 28 hours post-procedure. Patients were required to weigh more than 30 kg, have adequate venous access as well as the ability to perform a pain intensity report, and not have a narcotic dependence or a known tolerance to opioids .Patients were randomized to receive either 800 mg of IV ibuprofen or placebo and the clinical trial duration was 7 days . The firUpon discharge from the operating room, all patients had access to intravenous morphine via a PCA pump. Initial settings were a 1 mg demand dose with a 5-minute lockout. If adequate pain control was not achieved the demand dose of morphine could be increased to 2 mg every 5 minutes, and additional morphine could be administered at the treating physician's discretion. However, basal infusions of morphine were not allowed. A data safety monitoring committee reviewed all serious adverse events reported during the study.All patients received general anesthesia using various anesthetics such as propofol or a member of the flurane drug family along with fentanyl for intraoperative narcotic maintenance (fentanyl dose was per the discretion of the anesthesiologist). Intraoperative use of any other analgesics including nonsteroidal agents was prohibited. Neuraxial anesthesia  were prohibited. Single shot and catheter-based regional techniques were also prohibited.The primary objective of this study was to determine the efficacy of IV-ibuprofen compared with placebo for the treatment of surgical pain during hours 6–28 post-operatively, demonstrated by patient self-assessment of pain with movement (VASM), using a visual analog scale (VAS). Secondary objectives included several efficacy measurements to help elucidate the analgesic effect of perioperative IV ibuprofen in the 6–28 hour time period including 1) the patients' self-assessment of pain at rest measured by the VAS assessed at rest (VASR), 2) pain measured by the verbal rating scale (VRS), and 3) differences in post-operative morphine consumption between groups.Prior to the scheduled 6-hour post-operative pain assessment, a VASM and VASR were performed as soon as the patient was awake and alert enough to properly perform the procedure. On average, patients were able to perform this assessment at 2.81 hours post-operatively. An additional secondary endpoint (deemed early post-op pain) examined the differences between treatment groups at this time.Pain assessments were performed at the following time points: immediately following surgery as soon as the patient was awake enough to comply with study procedures, at hours 6, 8, 12, 16, 20, 24, 28, and then 2 hours after any subsequent doses of study medication that was administered in the 28–72 hours post-operative period. Additionally, after the 28-hour mark, scheduled VAS scores were obtained each day until the study drug was discontinued.The VAS used was a standard 100-mm scale. VRS pain assessment measured a patient's self-report of pain on a numerical scale from 0 (no pain) to 4 (severe pain at rest and with movement). Additional measurements of efficacy included in the study were incidence of treatment failure, time to GI motility, time to resumption of ambulation, time to resumption of liquid intake and solid diet, incidence of opioid related side effects, and length of hospital stay.The safety profile of 800 mg IV-ibuprofen infused every 6 hours vs placebo was evaluated through comparison of treatment-emergent adverse events, as well as vital signs, clinical chemistry values, hematology and coagulation values, and transfusion requirements. Investigators were asked to report any adverse medical events (new events or worsening conditions) that occurred during the seven day study and to grade the event by intensity , record action taken with the study drug, causality to the study drug, required treatment, outcome, and time of resolution. Vital signs and laboratory results were monitored closely to investigate the effects of treatment, including renal-related effects and any possible impact on bleeding, during screening, at baseline, at hours 1, 3, 6, 9, 12, 24 hours after study drug administration, and daily through day 5 or discharge. Requirements for transfusions of blood products  were also collected. Clinical laboratory assessments included clinical chemistry . Hematology and coagulation assessments included white blood cell count and differential, hematocrit, hemoglobin, platelet count, activated partial thromboplastin time, and prothrombin time or INR. Lab results were assessed during screening, baseline, and on study days 1, 2, 3, and 5 or at discharge. Adverse event monitoring continued through day 14. In the event that a patient was discharged before the end of the study, safety assessments were conducted by follow-up visit or telephone.Patients were also evaluated with a combined safety assessment: 1) occurrence of diffuse pruritus; 2) occurrence of overt respiratory depression; 3) need for post-operative urinary indwelling catheter ; 4) incidence of post-operative vomiting or need for anti-emetic medication; and 5) the Richmond Agitation Sedation Scale. The initial Combined Safety Assessment was performed following surgery upon reversal of anesthesia, and then at post-operative hours 6, 8, 12, 16, 20, 24, and 28.The study population consisted of patients who were randomized and received at least one dose of study medication.t-test. Sample size estimates were done using NCSS/PASS software  ) was the primary efficacy endpoint, and the analysis of variance  were male and 120 (65%) were female. There was no difference in gender between treatment groups. In the study population, 136 participants (74%) were Caucasian, 43 (23%) were Black, 4 (2%) were Hispanic, 1 (<1%) was Asian, and 1 (<1%) indicated “Other” for race.P = 0.025).The mean height for all patients was 167.7 cm (±10.7 SD), and there was no difference in height between treatment groups. The mean weight for all patients was 92.6 kg (±22.5 SD). Weight ranged from a minimum of 55.0 kg to a maximum of 183.0 kg. There was a significant difference in weight between treatment groups: 800 mg IV-ibuprofen 89.2 (±20.8 SD); placebo 96.6 (±23.8 SD)  underwent a knee replacement, 40 (22%) underwent a hip replacement, 36 (19%) underwent a knee reconstruction, and 16 (9%) underwent a hip reconstruction and one (<1%) had the surgery cancelled.Clinical centers were asked to perform a baseline physical examination and to indicate whether body systems were normal or abnormal. Overall, the participants in this study had few abnormalities at baseline, except for the indication for surgery.There was no difference in the number of doses administered between the IV-ibuprofen and the placebo treatment groups, with a median of five doses (range = 1 to 13 doses). The mean number of doses for the IV-ibuprofen treatment group was 6 doses (±SD 2.0), and 5 doses (±SD 1.4) for the placebo treatment group.The primary objective of this study was to determine the efficacy of IV-ibuprofen compared with placebo for the treatment of post-operative surgical pain during hours 6–28 demonstrated by patient self-assessment of pain with movement, using a VAS. During the 6–28-hour post-operative period, when compared to patients receiving placebo, patients receiving IV-ibuprofen experienced:P < 0.001) (25.8% decrease in the mean AUC-VASM (< 0.001) .P < 0.001) (31.8% decrease in the mean AUC-VASR (< 0.001) .P < 0.001) (20.2% decrease in the mean AUC-VRS (< 0.001) .P < 0.001) (30.9% decrease in mean morphine consumption (< 0.001) .P = 0.003) and a 15.8% decrease in the mean VASR (P = 0.012) following surgery (mean 2.81 hours after surgery) when compared with placebo .Treatment-emergent adverse events (AEs) and serious adverse events (SAES) were reported in 164 (89%) of the 185 patients . In the P = 0.507).Nine subjects (5%) experienced a total of 11 SAEs. The relationship of SAEs to study drug was coded by the investigators as related, not related, and unknown or uncertain. In the IV-ibuprofen group, 6 of 99 (6%) participants experienced eight SAEs. In the placebo group, 3 of 86 (3%) participants experienced three serious adverse events. Of these 11 serious events, none were coded as related; four were coded as not related; and seven as unknown or uncertain. There was not a statistically significant difference in the number of patients experiencing SAEs when comparing the IV-ibuprofen treated patients with the placebo treated patients  requiring transfusions, and the placebo group, with 9 of 86 (10%) patients receiving packed red blood cells. There were no patient deaths during the 14 day study. While patients were excluded if they were receiving full dose anticoagulation therapy, approximately 19% of the patients enrolled in the study were receiving partial anticoagulation therapy in the 12 hours preceding surgery and 60% received anticoagulation therapy following surgery.P = 0.031), and significantly more patients in the placebo group who experienced dyspepsia (P = 0.045) , and abnormal laboratory measurements. In AEs experienced by at least three subjects, there were no clinically significant differences in the incidence of known AEs associated with oral ibuprofen in the IV-ibuprofen group when compared to placebo. In the treatment-emergent AEs experienced by at least three patients, there were significantly more patients in the IV-ibuprofen group who experienced vomiting (= 0.045) .Pain is the greatest concern of patients before surgery . AdminisNSAIDs carry warnings for cardiovascular and gastrointestinal risk and should be used with caution in patients with congestive heart failure, renal impairment, a risk for blood clots, and/or a history of ulcers or gastrointestinal bleeding. The only other available injectable NSAID, ketorolac, includes additional warnings for use in geriatric patients and is contraindicated for use in children . AdditioIV-ibuprofen, 800 mg administered every 6 hours starting with the onset of anesthesia in orthopedic surgery patients, reduced both pain and morphine consumption post-operatively. When compared with patients receiving placebo, patients receiving 800 mg IV-ibuprofen experienced less pain beginning in the early post-operative period and continuing at least through hour 28. There was a significant reduction in pain with movement and at rest with IV-ibuprofen as measured by the AUC-VAS during the 6–28-hour post-operative period. There was also a significant reduction in mean morphine consumption in the 6–28-hour post-operative period in patients receiving IV-ibuprofen.The safety analysis encompassed all 185 patients that participated in the study, 164 of which experienced treatment emergent-AEs (serious and nonserious). There was no difference in the general incidence of AEs between the IV-ibuprofen and placebo treatment groups. Events related to bleeding and coagulation times, and transfusion requirements, did not differ between the two groups. There were no deaths reported in this study. There were a total of 11 SAEs occurring in nine patients, with no statistically significant difference in the incidence of SAEs between the patients receiving placebo and the patients receiving IV-ibuprofen. The SAEs were consistent with those typically observed in patients undergoing surgery and treated with anesthesia and morphine.Pre- and post-operative administration of IV-ibuprofen significantly reduced both pain and morphine use in orthopedic surgery patients in this prospective randomized controlled trial. The 800 mg dose provided patients with analgesic benefit and narcotic reduction. Post-operative pain control protocols can now consider inclusion of IV-ibuprofen as an option to offer patients a significant analgesic benefit while reducing the risks associated with morphine administration.


Acute chest pain is a major health problem all over the western world. Active approaches are directed towards diagnosis and treatment of potentially life threatening conditions, especially acute coronary syndrome/ischemic heart disease. However, according to the literature, chest pain may also be due to a variety of extra-cardiac disorders including dysfunction of muscles and joints of the chest wall or the cervical and thoracic part of the spine. The diagnostic approaches and treatment options for this group of patients are scarce and formal clinical studies addressing the effect of various treatments are lacking.We present an ongoing trial on the potential usefulness of chiropractic diagnosis and treatment in patients dismissed from an acute chest pain clinic without a diagnosis of acute coronary syndrome. The aims are to determine the proportion of patients in whom chest pain may be of musculoskeletal rather than cardiac origin and to investigate the decision process of a chiropractor in diagnosing these patients; further, to examine whether chiropractic treatment can reduce pain and improve physical function when compared to advice directed towards promoting self-management, and, finally, to estimate the cost-effectiveness of these procedures. This study will include 300 patients discharged from a university hospital acute chest pain clinic without a diagnosis of acute coronary syndrome or any other obvious cardiac or non-cardiac disease. After completion of the clinic's standard cardiovascular diagnostic procedures, trial patients will be examined according to a standardized protocol including a) a self-report questionnaire; b) a semi-structured interview; c) a general health examination; and d) a specific manual examination of the muscles and joints of the neck, thoracic spine, and thorax in order to determine whether the pain is likely to be of musculoskeletal origin. To describe the patients status with regards to ischemic heart disease, and to compare and indirectly validate the musculoskeletal diagnosis, myocardial perfusion scintigraphy is performed in all patients 2–4 weeks following discharge. Descriptive statistics including parametric and non-parametric methods will be applied in order to compare patients with and without musculoskeletal chest pain in relation to their scintigraphic findings. The decision making process of the chiropractor will be elucidated and reconstructed using the CART method. Out of the 300 patients 120 intended patients with suspected musculoskeletal chest pain will be randomized into one of two groups: a) a course of chiropractic treatment (therapy group) of up to ten treatment sessions focusing on high velocity, low amplitude manipulation of the cervical and thoracic spine, mobilisation, and soft tissue techniques. b) Advice promoting self-management and individual instructions focusing on posture and muscle stretch (advice group). Outcome measures are pain, physical function, overall health, self-perceived treatment effect, and cost-effectiveness.This study may potentially demonstrate that a chiropractor is able to identify a subset of patients suffering from chest pain predominantly of musculoskeletal origin among patients discharged from an acute chest pain clinic with no apparent cardiac condition. Furthermore knowledge about the benefits of manual treatment of patients with musculoskeletal chest pain will inform clinical decision and policy development in relation to clinical practice.NCT00462241 and NCT00373828 Acute chest pain is believed to be one of the most common reasons for hospital admission in Denmark ,2. FigurChest pain patients with normal coronary perfusion have an excellent prognosis for survival, and a future risk of cardiac morbidity similar to that reported in the background population -9. Howevby proxy measure of validity with some success: Eighty percent of the CTA-positive patients had normal perfusion compared to 50% in the CTA-negative group. Moreover, results indicated that patients with CTA may benefit from chiropractic treatment.An extensive body of literature addresses patient assessment and management protocols for patients presenting with chest pain, but these focus primarily on cardiopulmonary -22, gastWe therefore decided to perform a multi-purpose clinical trial consisting of 1) a prospective, population-based, diagnostic evaluation study, 2) a single-blinded, randomized clinical trial (RCT), and 3) a cost-effectiveness analysis alongside the RCT.The aims are:• To determine the proportion of patients discharged from a university hospital chest pain clinic in whom their chest pain may be of musculoskeletal rather than cardiac origin. Specifically, we wish to determine the prevalence and character of musculoskeletal chest pain, and to describe cardiac status with respect to ischemic heart disease.• To investigate the diagnostic decision making process of a chiropractor in these patients, using MPS as an indirect measure of validity.• To determine the relative clinical effectiveness of chiropractic manual treatment versus advice directed towards promoting self-management using pain and patient-rated outcomes as primary outcome measures. Finally, we will estimate the cost-effectiveness of these procedures.This clinical trial is being conducted at Odense University Hospital in Odense, Denmark. The study began in 2006, and is ongoing. Approval has been granted by the regional ethics committee for Funen and Vejle Counties, Denmark, approval number #VF 20060002, and informed consent is obtained from all participants.Three hundred consecutive patients with an episode of suspected non-cardiac acute chest pain are being recruited among patients discharged from an acute chest pain clinic situated at a large specialized cardiology department. All patients have undergone a standardized evaluation program at the chest pain clinic ruling out any obvious and significant cardiac or non-cardiac disease, including acute coronary syndrome. Following discharge from the chest pain clinic, all patient records are screened for the inclusion and exclusion criteria into the present study, and potential participants are contacted personally or by telephone and invited to participate.The inclusion and exclusion criteria are presented in Table A record will be kept of the number of subjects excluded from the study, as well as those who are eligible for inclusion and choose not to participate.Interested individuals are assessed at baseline within seven days of admission. First, they complete a questionnaire including information on pain, general health, occupation, education, physical and lifestyle factors, expectation to treatment outcome, and baseline values for the outcome measures.Next, participants are examined using a standardized and previously validated study protocol . The exa1) A semi-structured interview including pain characteristics , symptoms from the lungs and gastrointestinal system, past medical history, height and weight, and risk factors for ischemic heart disease. Further, patients are classified into three types of chest pain: typical angina, atypical angina, or non-cardiac chest pain in accordance with Danish and international guidelines [idelines ,21. The idelines . Cardio-idelines .2) A general health examination including blood pressure and pulse, heart and lung stethoscopy, abdominal palpation, neck auscultation, clinical signs of left ventricular failure, neurological examination of the upper and lower extremities in terms of reflexes, sensibility to touch, muscle strength, and an orthopaedic examination of the neck and shoulder joints in order to rule out nerve root compression syndromes.3) A specific manual examination of the muscles and joints of the neck, thoracic spine and thorax, including active range of motion, manual palpation for muscular tenderness on 14 points of the anterior chest wall, palpation for segmental paraspinal muscular tenderness, motion palpation for joint-play restriction of the thoracic spine (Th1–8), and end play restriction of the cervical and thoracic spine [ic spine .The examination program together with the detailed case history will be applied by a chiropractor to make a diagnosis of pain from the musculoskeletal system, CTA, according to the previously established criteria .The timeline and overview of data collection is shown in Figure In order to evaluate the population in terms of ischemic heart disease all patients undergo MPS within two to four weeks following baseline evaluation. Using radionuclides the myocardial perfusion is evaluated to determine the presence of regional areas with decreased blood flow because of coronary artery disease. Detailed procedures for MPS are described in Appendix 1. MPS will also be used to compare and indirectly validate the musculoskeletal diagnosis.All CTA positive patients  will be included in the RCT. The aim of this part of the study is to establish the effectiveness of chiropractic treatment including spinal manipulation versus advice to promote self-management. Participants are only eligible for inclusion in the RCT if they are CTA positive and the examining clinician decides that manipulation might be the appropriate treatment. Patients for whom manipulation is thought not to be indicated will not be included in the RCT.The randomization sequence with a 1:1 allocation ratio has been computer generated by a researcher not involved in the project. Consecutively numbered sealed opaque envelopes containing the treatment allocation for each patient has been produced and eligible participants draw an envelope. The envelopes are arranged in blocks with varying block sizes. The examining clinician manages the hand over of the envelope to the participant, but is masked to the treatment allocation when determining eligibility to randomization.Participants will be randomized to receive one of two treatments: A course of chiropractic treatment including spinal manipulation (therapy group) or advice promoting self-management (advice group).Participants in the therapy group will be assigned to a chiropractor in their local community. Participating chiropractors will have a university chiropractic degree and at least five years of clinical experience. Each chiropractor chooses an individual treatment strategy based on a combination of their findings, the patient history, and pragmatic, routine practice. The treatment will be modified to accommodate the age and physical condition of each patient. The treatment must, however, include high velocity, low amplitude manipulation directed towards the thoracic and/or cervical spine in combination with any of the following: Joint mobilisation, soft tissue techniques, stretching, stabilising or strengthening exercises, heat or cold treatment, and advice. The protocol specifies up to ten treatment sessions of approximately 20 minutes, 1–3 times per week for four weeks, or until the patient is pain free if this occurs within less than four weeks. The type of manipulation technique will not be standardized, and the treating chiropractor can manipulate the lumbar spine if he/she determines to do so. The chiropractors record the types of treatment rendered at all sessions.Advice is given in an approximately 15-minute session following the baseline assessment, and is directed towards promoting self-management. The participants are told that their chest pain generally has a benign, self-limiting course. The participants receive individual instructions regarding posture and two or three exercises aiming to increase spinal or muscle stretch based on clinical evaluation. They are advised to seek medical attention for re-evaluation  in case of severe or unfamiliar chest pain. Further, the advice group is asked to refrain from seeking any manual treatment for the following four weeks.The outcomes are measures by self-report questionnaires that are collected at baseline, after four weeks (CTA positive patients only), and after three and 12 months  . Improvement in chest pain is rated by participants on a 7-point ordinal scale with responses ranging from "much worse" to "much better".• Ordinal 11-point box scales  will be used to rate chest pain "now" (i.e. on the day of examination/completion of questionnaire) together with the following types of pain over the last week: "worst" and "average" chest pain, "average" thoracic spine pain, "average" cervical spine pain, "average" shoulder and arm pain.• Improvement in chest pain and general health is rated by the participants using an ordinal 7-point scale using the categories: "Much worse", "worse", "a little worse", "no change", "a little better", "better", and "much better".• The general health status is measures by the Medical Outcomes Study Short Form 36-item Health Survey (SF-36) ,32. The • The Patient Specific Functional Scale is developed to assess functional limitations in a variety of clinical presentations . Partici• As a surrogate for the assessment of pain and quality of life, we will use the indicators "number of visits to family doctor", "number of hospitalizations", and "amount of prescribed drugs". The data will be obtained from the comprehensive national Danish central registers. Non-prescription medication use for chest pain is measured using self-report questionnaires at 12 and 52 weeks.• Information about adverse events and side effects will be collected for the therapy group by the treating chiropractor before and after each treatment session.• Prior to commencing treatment, patients are asked to rate their expectation towards treatment benefits on a 5-point scale, with responses ranging from "getting much worse" to "getting much better".• The Brief Illness Perception Questionnaire (B-IPQ) assesses perception of illness by asking patients for their own belief about their condition . The B-IDirect health care cost, direct non-health care cost and indirect cost are used in the economic evaluation as an indicator of cost-effectiveness. Cost data are collected through patient self-report questionnaires at 12 and 52 weeks. Direct costs for each patient will represent the one-year aggregated chest pain related health care costs based on utilization and estimated costs. Health care utilization (within and outside the study) is measured using standardized clinician treatment forms , and patient rated self-report questionnaires (baseline and weeks 12 and 52). Direct health care costs include costs related to study treatment, non-study health care health provider use, medication utilization, and hospitalizations for chest pain. Indirect costs of productivity loss is measured by patient self-report (weeks 12 and 52) using questions that measure lost or impacted work or activity days due to chest pain. The EuroQol 5D (modified version) ,36, a muAll items of the examination protocol will be compared between CTA positive and CTA negative patients. In order to show the importance of any single variable in the decision making process the variables will be compared both within all included patients and in subgroups. Using the Classification and Regression Trees (CART) method  the deciThe size of the study sample was estimated using data from the study by Christensen et al. . In thisThe baseline scores of the patient demographics , primary and secondary outcomes will be used to compare the two intervention groups. Differences between baseline and follow up measurements will be calculated and compared. If necessary, adjustment for baseline variable will be made, using analysis of covariance (ANCOVA). A confirmatory, secondary analysis using the repeated measures, multivariate analysis of covariance (MANCOVA) will be used as an overall test for differences between groups. This will include both the primary and secondary patient-rated outcomes. The statistical analysis 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. Finally, based on a prior definition of success, numbers needed to treat will be calculated. Outcomes of patient rated improvement will be dichotomized and success will be defined as patients rating "better" or "much better".A cost comparison of the therapy and advice group will be performed using data on direct and indirect costs. Cost differences between groups will be estimated using regression analysis where all chest pain-related costs in a year are regressed on treatment. A cost effectiveness analysis, using a mixed model linear regression analysis, will be conducted to compare the interventions, using patient-rated pain as the effective measure. Finally, a cost-utility analysis comparing the interventions will be performed using the EuroQol 5-D.This study is the result of a unique research collaboration between researchers with backgrounds in chiropractic, cardiology, nuclear medicine and biostatistics, and to our knowledge this is the first randomized clinical trial investigating the effect of manual treatment on chest pain of musculoskeletal origin.The design of this study has been a challenging process since no standardized and validated outcome measures for chest pain of musculoskeletal origin exists. The study by Christensen et al.  formed tby proxy measure to indirectly validate the CTA diagnosis. This is based on the hypothesis that in this population, patients who are CTA positive most likely will have fewer abnormal MPS than CTA negative patients. Data from the pilot study suggest that approximately 40% are CTA-positive, 15% have abnormal MPS, and 7% have both abnormal MPS and are CTA positive.An important part of the diagnostic procedure in this study is founded on manual examination of the muscles and joints. Palpation used as a diagnostic tool for spinal dysfunction has been subjected to criticism because of poor reproducibility and validity . One of We have chosen global perceived effect as one out of two primary outcome measures even though critique has been posted on the reliability and validity of global rating scales . Global Chiropractic therapy may be an effective treatment for patients with acute chest pain, but this has only been investigated in one non-randomized trial . A pragmIn this study we have focused on two conditions that may cause episodes of chest pain, i.e. ischemic heart disease and CTA. Many other conditions may be present in these patients that could cause chest pain. Optimally, a thorough follow up, including evaluation of esophageal-gastro-intestinal conditions, would have been preferable to potentially diagnose some of the CTA-negative patients, but due to limitations in funding and time restraints such evaluation has not been possible.In summary, this article presents the rationale and design of a multi-purpose study consisting of a prospective diagnostic study, and an RCT, with a cost-effectiveness study alongside the central trial. It is anticipated to be completed in 2008, at which time the results will be made available. The first part of this study may potentially demonstrate that a chiropractor is able to identify a subset of patients suffering from chest pain predominantly of musculoskeletal origin among patients dismissed from an acute chest pain clinic with no apparent cardiac condition. The long term goal is to establish whether manual palpation may be used as a part of the clinical examination to screen patients allowing for improvement in referral patterns. Furthermore knowledge about the benefits of manual treatment in patients with musculoskeletal chest pain will inform clinical decision and policy development in relation to clinical practice.The author(s) declare that they have no competing interests.MJS is the study manager and was involved in the design of the study, secured funding for the study, wrote the firsts draft of the manuscript and participated in subsequent revisions. HWC participated in the design of the study, in particular with respect to the design of the physical examination protocol, and commented on the manuscript. JH participated in the design of the study, in particular with respect to the design of questionnaires and outcome measures, and commented on the manuscript drafts. WV participated in the design, especially regarding data analysis, and commented on the manuscript. PFHC and TH both participated in the design of the study, in particular with respect to the cardiologic and nuclear medicine aspects of this study, and commented on the manuscript. All authors read and approved the final manuscript.99mTc-sestamibi  is given 20 min. after sublingual administration of 0.5 mg nitro-glycerine followed 30–60 min. later by imaging using a dual-head gamma camera. A semi-automatic quantitative interpretation of perfusion and functional data is carried out using standard processing software (Auto QUANT® 5.0.0) [-1. min-1 for six minutes and injection of 10 MBq. kg-1 (maximum 1100 MBq) of sestamibi between the third and the fourth minute of infusion. Similarly, from the images, the summed rest score (SRS) is calculated [All patients undergo an electrocardiographically gated rest MPS according to the rest part of a two-day protocol without attenuation correction . 99mTc-s® 5.0.0) . Abnorma® 5.0.0) . A studylculated . All stulculated .The pre-publication history for this paper can be accessed here:


Some patients with long-standing low back pain will benefit from treatment with strong opioids. However, it would be helpful to predict which patients will have a good response. A fixed-term opioid trial has been recommended, but there is little evidence to suggest how long this trial should be. We assessed data from a large-scale randomized comparison of transdermal fentanyl (TDF) and sustained-release oral morphine  to determine characteristics of treatment responders.This was a secondary analysis of a previously published 13-month randomized trial involving 680 patients with long-standing low back pain . Pain relief was recorded using visual analogue scales (VAS). Treatment response was defined as pain relief of at least 30% from baseline to any point during the trial. We used a step-wise logistic regression to identify variables that might predict response to treatment. Covariates included treatment group, sex, age, duration of pain, presence of neuropathic pain, baseline pain scores, educational/employment status, use of high doses of opioids, and social functioning (SF)-36 scores.2 = 11.06, p = 0.0259) and use of high doses of opioids .Over half the patients in both groups  were treatment responders. There were no differences between the TDF and SRM responders in terms of age, sex, type or duration of pain between responders and non-responders. The difference in response to treatment between responders and non-responders could be detected at 3 weeks. Lack of response after 1 month had a stronger negative predictive value  than the presence of response after 1 month. The most influential factors for predicting a response were employment status (χNo clear pattern of baseline pain (type or severity) or patient characteristics emerged that could be used to predict responders before the start of opioid treatment. However, a 1-month trial period appears sufficient to determine response and tolerability in most cases. Strong opioids are accepted as an option for patients with long-standing low back pain, but not all patients respond satisfactorily to this treatment. It would be helpful to be able to predict which patients are most likely to have a good, long-term response to strong opioid therapy to avoid exposing patients to ineffective treatments or side-effects. Even if it does not prove possible to identify good responders before starting treatment, it would be useful to know how long an opioid trial is required to determine response. We have analyzed findings from a randomized, controlled trial of transdermal fentanyl and sustained-release oral morphine in strong-opioid naive patients with chronic low back pain to gather information about predicting response and about the inter-relationships between analgesia and other effects of treatment.The primary study (FEN-INT-26) has been published separately . It inclPatients were excluded if they had conditions that were likely to predispose them to ventilatory depression, intolerance to morphine or fentanyl , skin problems that might affect transdermal delivery), a history of alcohol or substance abuse, or a life-limiting condition.Pain relief was assessed weekly using visual analogue scales for pain relief (VAS) from patient diaries. There were monthly assessments of pain . Adverse events were recorded throughout the study. For the purpose of this secondary analysis, treatment response was defined as pain relief of at least 30% from baseline to any point during the trial .We performed a step-wise logistic regression to identify variables that might predict response to treatment with strong opioids during the trial. Covariates included in the initial model were: randomization group (fentanyl or morphine), sex, age, duration of pain, presence of neuropathic pain, educational/employment status, use of high doses of opioids (>100 μg/h TDF or >390 mg/day SRM) during the trial, baseline scores for pain at rest, pain on movement, and SF-36 scores . The selection of covariates focused on those, which might have a possible effect on treatment outcome based on published literature and clinical experience . We examThe median age was 52 years (range 20–89), 61% of the 680 participants were women. The median duration of back pain was 87 months ; 51% of patients completed the study. Reasons for withdrawal included adverse events  and insufficient response .Treatment response was defined as a pain relief of at least 30% (VAS scores) at any time point during the trial. Over half the patients in both groups  were classified as treatment responders. There were no differences between the TDF and SRM responders in age, sex, type of pain (nociceptive or neuropathic) or duration of pain between responders and non-responders. The physical functioning score of the SF-36 differed only slightly between responders  and non-responders .Of the participants who experienced at least a 30% pain relief at any time during the trial, most (74% for TDF and 70% for SRM) also experienced at least a 50% reduction in pain severity in one of the back pain categories. There was no difference between the 50% responders and non-responders in baseline characteristics.The difference in response to treatment between responders and non-responders could be detected at 3 weeks. Both groups had similar pain severity after 1 week, but by 3 weeks the non-responders had, on average, more pain than at baseline, while the responders had less pain. This suggests that an assessment period of 1 month may be sufficient to determine responsiveness to a strong opioid.The amount of patients suffering from moderate to severe pain in any of the low back pain categories was lower in the responder group at endpoint compared to the non-responder group Figure . There wThe odds ratios for the likelihood of being classified as a responder at 6 and 12 months (depending on whether patients were responders at 1 month) are shown in Table Treatment responders were more likely to complete the study than non-responders (69% for 30% responders vs 28% for non-responders). The most common reason for non-completion was an adverse event. On average, the non-responders dropped out of the study significantly earlier than the treatment responders  was identical for responders and non-responders (24% in both groups).About half the participants were classified as treatment responders (i.e. had at least a 30% pain relief VAS AUC [Area under the curve]); over three-quarters of participants (530/680 = 78%) experienced some improvement in mental health, physical or social functioning (assessed by the SF-36) or an improvement in one of the specific back pain categories . Patients who had no response in any aspect tended to withdraw from the study after a short period . Only 10 (7%) of these non-responders completed the study. The commonest reason for withdrawal was an adverse event that occurred in 111/136 (82%) of the dropouts.The small group of non-responders who remained in the study for more than 4 weeks (n = 37) tended to be on higher opioid doses than other patients. The mean dose  at 5 weeks was 116  mg for non-responders compared with 94  mg for other participants. At 12 weeks, the mean doses were 156  mg and 114  mg, respectively.Some aspects of pain improved more than others with strong-opioid treatment, e.g. the responders reporting severe pain on movement fell from 66% at baseline to 21% at endpoint.Older patients  tended to use lower opioid doses than younger patients . The median daily doses at study endpoint were 58 mg for SRM and 43 μg/h (102 mg) for TDF for older patients compared with 116 mg SRM and 54 μg/h (130 mg) TDF for younger patients. The average morphine dose in older patients remained stable throughout the study; the mean morphine dose was 57 mg at baseline and 59 mg at endpoint, however the mean dose in patients who completed the study was 66 mg at month 13. The average fentanyl dose was 25 μg/h at baseline, 44 μg/h at endpoint , and 50 μg/h at month 13 (i.e. for patients who completed the study).The proportion of responders tended to be higher in the younger than the older age groups . However, no statistical significance could be detected, probably due to the small sample size. The proportion of patients who withdrew because of adverse events was higher in the elderly sub-group than in the younger patients: rates of withdrawal were 56% (n = 15) for SRM and 42% (n = 10) for TDF in the older group compared with 29% (n = 89) and 37% (n = 115), respectively in the younger patients.Most adverse events (AEs) were reported in the first few weeks of the study, except for sweating in the fentanyl group, which increased over time Figure . To examThe median daily opioid dose was lower for patients <75 years old who reported nausea than for those who did not (76 mg morphine (n = 159) or 38 μg fentanyl (n = 170) for patients with nausea vs 85 mg morphine (n = 151) or 48 μg fentanyl (n = 141) for those without). This pattern was not seen for those who reported constipation (median morphine dose of SRM patients <75 years was 84 mg for those with (n = 204) vs 72 mg for those without (n = 106) constipation, (doses for fentanyl 48 μg (n = 163) vs 38 μg (n = 148), respectively).Evidence that vomiting may limit treatment comes from the observation that patients who experienced at least a 30% pain relief were less likely to report this AE than non-responders (23% of responders and 33% of non-responders reported vomiting). However responders were more likely to report constipation than non-responders (67% vs 47%), perhaps reflecting the greater length of time they remained in the study since constipation tends to occur after several weeks of opioid treatment.Dose increases between 4 weeks and endpoint tended to be larger in patients who completed the study than those who dropped out. For example, the proportion of patients whose opioid dose more than doubled during this time was 24% for completers and 7% for non-completers.Demographic and baseline characteristics of the best and worst responders (top and bottom 15%) were compared. The mean (±standard error of the mean (SEM)) duration of chronic pain was no different in the poor responders than in the best responders (106 ± 10 vs 94 ± 8 months).No clear patterns emerged that might predict response, except that there were significantly more women in the SRM worst response group .Patients who left the study in the first month  were compared with those who withdrew from the study at a later stage (n = 199). Drop-outs within the first month were more likely to be due to adverse events (82% vs 59%) and less likely to be due to insufficient response (3% vs 15%) than with later withdrawals. The proportion of patients withdrawing consent was 9% among early dropouts and 6% among later withdrawals.Adverse events during the first month were compared between early dropouts and all patients who remained in the study for longer (n = 540). Nausea and vomiting were more common in early dropouts . Constipation and increased sweating were less frequent among early dropouts . Pruritus was similar in early dropouts and other patients .The effect of opioid dose was assessed by considering the sub-group of patients who received higher doses . The incidence of adverse events was similar in both dosage groups, except for sweating, which occurred more often in the higher dose group . The proportion of patients achieving at least 30% pain relief was higher in the higher dose group . A similar pattern was observed for the proportions achieving at least 50% pain relief, but the difference between dose groups (44% vs 39%) did not reach statistical significance when both treatments were considered together. There was a marked difference in the proportion of patients achieving at least 50% pain relief in the higher dose sub-group between those receiving TDF (52% responders) and those receiving SRM (29%). This difference was not observed in the lower dose group (39% responders in each treatment group).2 = 11.06, p = 0.0259) and use of high doses of opioids . The category 'non-professional' employment status, which included housewives but not unemployed, retired people or students, was associated with a lower likelihood of achieving a 30% response than the 'disabled' category (odds ratio compared with disabled category 0.412 (95% CI 0.24 to 0.70) p = 0.0010). The use of higher opioid doses during the trial gave an increased likelihood of achieving a 30% response. This effect was statistically significant (p = 0.049) in the first model, which included all covariates, but fell below statistical significance in the final model ).We performed a step-wise logistic regression using 13 key variables Table . No stroVariables predicting at least a 50% reduction in pain were similar, and employment status  was one of the most influential factors, however its contribution was not statistically significant (p = 0.127). The strongest predictor for 50% response was the presence of neuropathic pain, which was weakly predictive of poorer response (p = 0.0276). The odds ratio for the presence of neuropathic pain on the likelihood of 50% response was 0.695 (95% CI 0.50 to 0.96).By 1 month, 20% of patients had stopped treatment, and four out of five stopped treatment because of adverse events. However, 54% of patients had at least 30% pain relief during one time point of the trial and 69% of these patients were still on opioid treatment after 12 months, the dosages used by responders did not differ from those used by non-responders.This study provided an opportunity to investigate predictive factors for response and gives important information regarding the efficacy and natural course of adverse effects over 13 months. However, this study was not originally designed to test predictors and therefore many potentially important factors were not examined . As the study included only carefully selected patients with a long history of chronic low back pain, the findings need to be verified in a broader population.No clear pattern of baseline pain (type or severity) or patient characteristics  emerged that could be used to predict responders before the start of opioid treatment. However, this analysis did suggest that a 1-month trial period is sufficient to determine response and tolerability in most cases. The significant relationship between response at 1 month and response after 6 and 12 months suggests that if patients have not responded to a suitable dose of strong opioid after 1 month, then treatment should be stopped and alternative pain relief introduced. However, if patients experience at least a 30% reduction in pain at 1 month, then opioid treatment should be continued, as long-term benefit is more likely. Previous studies have also found an association between response to intravenous opioids and long-term treatment . As in tOur findings can be expressed in terms of the sensitivity and specificity of response at 1 month to predict response at 6 months. Specificity is the probability of a response at 1 month and 6 months (i.e. the true positive rate) and is calculated to be 0.505. Sensitivity is the probability of no response at 1 month for those with no response at 6 months (i.e. the true negative rate) and is calculated to be 0.810. Thus lack of response at 1 month has stronger negative predictive power than the positive predictive power of the presence of response at 1 month.We noted that there were significantly more women in the SRM worst response group than in the equivalent group for TDF (73% vs 49%). Whether this is an indicator of sex specific differences in response to opioid treatment needs further investigation.This large dataset allowed us to examine correlations between the main outcome of the original study (pain relief expressed by a decrease in VAS pain scores) and other measurements of pain. We found a statistically significant correlation between the pain relief score and the change in back pain category  from baseline to study endpoint.Gastrointestinal side effects are relatively common in patients receiving strong opioids for the first time. Nausea and vomiting appear to limit treatment in some cases, and may prevent titration to effective doses. Constipation tends to emerge after a few weeks of treatment, and occurred more frequently in patients receiving morphine than in those receiving transdermal fentanyl. The median daily opioid dose was lower in patients who reported nausea than in those who did not but this pattern was not seen for constipation. This suggests that the occurrence of nausea during the early weeks of treatment may limit dose titration, whereas constipation generally emerges later. The higher median dose of TDF in patients who reported constipation compared with those that did not might also reflect a dose-response effect, with constipation occurring only with higher doses of TDF.The rate of adverse effect reporting is affected by the reporting method. In our study, only adverse events volunteered by patients (or observed by clinicians) were reported, whereas, in other studies, patients have been questioned specifically about the occurrence of expected side effects. This may explain why the rates of adverse events in our study are lower than those in some previous studies of strong opioids . HoweverPatients aged over 75 years in the SRM group showed stable doses throughout the study, in contrast to older patients receiving TDF and to the younger patients in both groups. Older patients in the SRM group reported less pain relief than younger patients; this might also suggest that effective morphine doses were not reached. One possible explanation for this is that older patients are more susceptible to dose-related morphine side effects and this limited dose escalation. This assumption is supported by the higher dropout rate in the older patient group (56% in the TDF and 42% in the SRM group). Other studies have also noted that morphine side effects may be more pronounced in elderly patients .Only a small proportion of patients needed high opioid doses, but these patients tended to achieve additional pain relief.Patients who experienced effective pain relief (e.g. a decrease of at least 30% from baseline) tended to remain in the trial longer than those who did not get adequate analgesia. Some patients may have remained in the trial because of other benefits apart from the primary outcome, such as sleeping better. A few patients, who according to trial assessments had experienced no benefits, still completed the 13-month trial.Strong opioid treatment can be beneficial for some patients with severe low back pain. However, there appears to be no simple method of predicting who will benefit from a strong opioid before treatment is initiated. This analysis suggests that response to a trial period of 1 month gives a good indication of who will obtain sustained benefit. Neuropathic pain does not appear to rule out response to strong opioids, but it may be associated with a poorer response. Gastrointestinal side effects are common during the first weeks of treatment, and these may limit dose titration in some patients. The best way to determine who will tolerate a strong opioid appears to be a trial period of 1 month.The original study (FEN-INT-26) and the secondary analysis were funded by Janssen Pharmaceutica, the manufacturer of transdermal fentanyl. EK, KHS and RS were investigators in the original study and received funding from Janssen Pharmaceutica for this. They have also worked with Janssen on other clinical trials and received research funding and honoraria at various times. UR is an employee of Janssen Cilag.EK and UR had the original idea for this secondary analysis. JD performed the statistical analyses. EK, KS, RS, DJ and UR all reviewed and revised several drafts of the manuscript and provided critical comments. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Fractionation of palliative rt for bone metastases has not been addressed in Iran, where the most common clinical practice is the use of 30 Gy in 10 fractions. Thus, we decided to perform a randomized clinical trial to compare responses in our patients with those reported in the international literature.Despite high-level evidence in the literature, the use of single-fraction radiotherapy , “partial” , and “no response” (pain reduction of less than 1 grade).Adult patients with multiple painful uncomplicated bone metastases were randomized to 8 Gy in a single fraction or 30 Gy in 10 fractions. Pain was graded by the patients on a scale of 1 to 4 just before and again 1 month after the end of n = 27), sacrum or pelvis (n = 25), extremities (n = 14), ribs (n = 3), and sternum (n = 1). Patients graded their pain before rt in a range from 1.8 to 4.0 (mean: 3.2). All patients finished their scheduled course of rt without incident.We randomized 70 patients in this trial . Sites of treatment included spine  were available for evaluation of pain 1 month after treatment. At that time, pain was graded in a range from 1.0 to 4.0 (mean: 2.0). The reduction in pain grade ranged from –0.8 to 2.6 (mean: 1.1). We observed 8 (14%) complete responses, 33 (57%) partial responses, and 17 (29%) no responses, for an overall response rate of 71%.Unfortunately, 5 patients died less than 1 month after the end of p > 0.1). The mean reduction in pain was 1.1 in both groups. The 10-fraction group contained a higher number of complete responders (11 of 31 as compared with 6 of 27 in the 1-fraction group)—a result that was not statistically significant. The mean reduction in pain was 1.4 in patients 50 years of age or younger and 0.9 in patients more than 50 years of age (p = 0.01). Of the 8 complete responses, 7 (87.5%) were seen in the patients 50 years of age or younger, and the mean age of patients with a complete response (38.7 years) was significantly lower than that of patients with a partial response or no response .The number of responders was 21 (78%) among those who received a single fraction and 20 (65%) among those who received multiple fractions  did not have any significant effect on pain reduction. The only factor with a significant effect was age (p = 0.002).By logistic regression, patient sex, primary tumour, Our trial showed no significant difference in pain relief after palliative radiotherapy with 1 or 10 fractions in Iranian patients. The overall response rate was 71%, similar to results in the international literature. Younger patients responded better.