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1.  Development and Validation of a Precise, Single HPLC Method for the Determination of Tolperisone Impurities in API and Pharmaceutical Dosage Forms 
Scientia Pharmaceutica  2012;81(1):123-138.
A novel, sensitive, stability-indicating HPLC method has been developed for the quantitative estimation of Tolperisone-related impurities in both bulk drugs and pharmaceutical dosage forms. Effective chromatographic separation was achieved on a C18 stationary phase with a simple mobile phase combination delivered in a simple gradient programme, and quantitation was by ultraviolet detection at 254 nm. The mobile phase consisted of a buffer and acetonitrile delivered at a flow rate 1.0 ml/min. The buffer consisted of 0.01 M potassium dihydrogen phosphate with the pH adjusted to 8.0 by using diethylamine. In the developed HPLC method, the resolution between Tolperisone and its four potential impurities was found to be greater than 2.0. Regression analysis showed an R value (correlation coefficient) of greater than 0.999 for the Tolperisone impurities. This method was capable of detecting all four impurities of Tolperisone at a level of 0.19 μg/mL with respect to the test concentration of 1000 μg/mL for a 10 µl injection volume. The tablets were subjected to the stress conditions of hydrolysis, oxidation, photolysis, and thermal degradation. Considerable degradation was found to occur in base hydrolysis, water hydrolysis, and oxidation. The stress samples were assayed against a qualified reference standard and the mass balance was found to be close to 100%. The established method was validated and found to be linear, accurate, precise, specific, robust, and rugged.
doi:10.3797/scipharm.1209-17
PMCID: PMC3617673  PMID: 23641333
Tolperisone; Validation; Impurities; Degradation; HPLC
2.  Aceclofenac–tizanidine in the treatment of acute low back pain: a double-blind, double-dummy, randomized, multicentric, comparative study against aceclofenac alone 
European Spine Journal  2009;18(12):1836-1842.
Tizanidine and aceclofenac individually have shown efficacy in the treatment of low back pain. The efficacy and tolerability of the combination have not yet been established. The objective of the study was to evaluate the efficacy and safety of aceclofenac-tizanidine fixed dose combination against aceclofenac alone in patients with acute low back pain. This double-blind, double-dummy, randomized, comparative, multicentric, parallel group study enrolled 197 patients of either sex in the age range of 18–70 years with acute low back pain. The patients were randomized to receive either aceclofenac (100 mg)–tizanidine (2 mg) b.i.d or aceclofenac (100 mg) alone b.i.d for 7 days. The primary efficacy outcomes were pain intensity (on movement, at rest and at night; on VAS scale) and pain relief (on a 5-point verbal rating scale). The secondary efficacy outcomes measures included functional impairment (modified Schober’s test and lateral body bending test) and patient’s and investigator’s global efficacy assessment. aceclofenac–tizanidine was significantly superior to aceclofenac for pain intensity (on movement, at rest and at night; P < 0.05) and pain relief (P = 0.00) on days 3 and 7. There was significant increase in spinal flexion in both the groups from baseline on days 3 and 7 with significant difference in favour of the combination group (P < 0.05). There were significantly more number of patients with excellent to good response for the aceclofenac–tizanidine treatment as compared to aceclofenac alone (P = 0.00). Both the treatments were well tolerated. In this study, aceclofenac–tizanidine combination was more effective than aceclofenac alone and had a favourable safety profile in the treatment of acute low back pain.
doi:10.1007/s00586-009-1019-4
PMCID: PMC2899439  PMID: 19421791
Aceclofenac-tizanidine; Acute LBP; Aceclofenac
3.  Epileptic seizure after treatment with thiocolchicoside 
Background:
Adverse drug reactions are important determinants of inpatient and outpatient morbidity. Thiocolchicoside is a semisynthetic derivate of naturally occurring colchicoside, which is largely used in humans as a centrally acting muscle relaxant. Epileptic seizures after thiocolchicoside intake have been reported in individuals with a history of epilepsy, acute brain injury or possible blood–brain barrier disruption.
Case report:
We report the case of a 66-year-old male patient presenting a sudden epileptic seizure temporally related to the intake of thiocolchicoside for muscle contracture and pain. The probably causes of the seizures were thiocolchicoside intake and cerebral microhemorrhages attributed to cerebral amyloid angiopathy.
Discussion:
Drugs only rarely cause focal seizures. Our case indicates that thiocolchicoside can precipitate seizures in predisposed patients, and that its use should be avoided in patients with brain diseases (and therefore lower seizure thresholds) or blood–brain barrier disruption. This information should be provided in the drug package insert.
PMCID: PMC2731019  PMID: 19707540
adverse drug reaction; thiocolchicoside; coltrax; epileptic seizure; muscle relaxant; cerebral amyloid angiopathy
4.  Reversed phase-high performance liquid chromatographic method for simultaneous estimation of tolperisone hydrochloride and etodolac in a combined fixed dose oral formulations 
Pharmaceutical Methods  2011;2(2):124-129.
A reversed-phase liquid chromatographic (RP-HPLC) method was developed for the simultaneous determination of tolperisone hydrochloride (TOLP) and etodolac (ETD) in a combined fixed dose oral formulation. The analysis was carried out using a phenomenax C-18, pre-packed column. A mobile phase containing a phosphate buffer (pH 5.5) : Methanol : Acetonitrile : Tri-ethylamine (40 : 40 : 20 : 1.5), with the pH adjusted to orthophosphoric acid, was pumped at a flow rate of 1.0 ml min1 with a UV-detector and PDA detection at 257 nm. Retention time was 3.91 minutes and 6.89 minutes for TOLP and ETD, respectively. The method was validated for linearity, accuracy, precision, sensitivity, and specificity. The method showed good linearity in the range of 3 – 21 μg ml for TOLP μg / ml and 8 – 56 μg / ml for ETD. The detection limit of the proposed method was 0.16 μg / ml and 0.58 μg / ml for TOLP and ETD, respectively. The quantification limit of the proposed method was 0.51 μg / ml and 1.7 μg / ml for TOLP and ETD, respectively. The % recovery was within the range of 99.42 – 101.15 for TOLP and 98.63 – 100.94 for ETD. The percentage RSD for precision of the method was found to be less than 2%. The method was validated as per the International Conference on Harmonization (ICH) guidelines. The developed method could be applied for routine analysis of TOLP and ETD in tablet dosage form.
doi:10.4103/2229-4708.84458
PMCID: PMC3658046  PMID: 23781442
Etodolac; high performance liquid chromatography; tolperisone; validation
5.  Chemometrics-Assisted UV Spectrophotometric and RP-HPLC Methods for the Simultaneous Determination of Tolperisone Hydrochloride and Diclofenac Sodium in their Combined Pharmaceutical Formulation 
Scientia Pharmaceutica  2013;81(4):983-1001.
Chemometrics-assisted UV spectrophotometric and RP-HPLC methods are presented for the simultaneous determination of tolperisone hydrochloride (TOL) and diclofenac sodium (DIC) from their combined pharmaceutical dosage form. Chemometric methods are based on principal component regression and partial least-square regression models. Two sets of standard mixtures, calibration sets, and validation sets were prepared. Both models were optimized to quantify each drug in the mixture using the information included in the UV absorption spectra of the appropriate solution in the range 241–290 nm with the intervals λ = 1 nm at 50 wavelengths. The optimized models were successfully applied to the simultaneous determination of these drugs in synthetic mixture and pharmaceutical formulation. In addition, an HPLC method was developed using a reversed-phase C18 column at ambient temperature with a mobile phase consisting of methanol:acetonitrile:water (60:30:10 v/v/v), pH-adjusted to 3.0, with UV detection at 275 nm. The methods were validated in terms of linearity, accuracy, precision, sensitivity, specificity, and robustness in the range of 3–30 μg/mL for TOL and 1–10 μg/mL for DIC. The robustness of the HPLC method was tested using an experimental design approach. The developed HPLC method, and the PCR and PLS models were used to determine the amount of TOL and DIC in tablets. The data obtained from the PCR and PLS models were not significantly different from those obtained from the HPLC method at 95% confidence limit.
doi:10.3797/scipharm.1306-01
PMCID: PMC3867252  PMID: 24482768
Tolperisone; Diclofenac; Chemometrics; PCR; PLS; HPLC
6.  Benefit of Using Muscle Relaxants in the Routine Treatment Protocol of Oral Submucosal Fibrosis: A Pilot Study 
The aim of this present work is to describe the nature and extent of fibrosis within muscle and to correlate this with the mouth opening (MO) in OSE patients and to prove our results in improvement of mouth opening in patients with OSMF with use of “muscle relaxants” along with other modalities of treatment . The study was conducted on 40 patients who visited our outpatient department with grade 3 (<19 mm) mouth opening. 20 of these patients underwent the routine treatment protocol of weekly injection of hyaluronidase with hydrocortisone and antioxidant capsules with added lycopene for 1 month. The remaining test subjects in addition to the routine injections and antioxidants were given skeletal muscle relaxants like thiocolchicoside or chlorzoxazone. The mouth opening (interincisal distance of maxillary and mandibular incisors at maximum possible mouth opening) was measured and graded as follows: grade 1 (>40 mm), grade 2 (20–39 mm) and grade 3 (<19 mm) with the help of vernier callipers after the study period of 1 month. 17 out of the 20 test patients who received muscle relaxants in addition to the routine protocol showed marked improvement with shift from grade 3 (<19 mm) to grade 1 (>40 mm) i.e. a greater than 20 mm improvement in mouth opening. Using muscle relaxants as a adjuvant therapy in the routine protocol of treatment of oral submucosal fibrosis will not only cater and halt the problem of fibrosis but also will take care of the muscle spasm and inflammation which also inadvertently contribute to the restricted mouth opening. We found excellent improvement on adding muscle relaxants to the routine protocol which was not just an objective but also a subjective success.
doi:10.1007/s12070-011-0234-6
PMCID: PMC3227817  PMID: 23024934
Oral submucosal fibrosis (OSM); Mouth opening (MO)
7.  Thiocolchicoside Exhibits Anticancer Effects through Downregulation of NF-κB Pathway and Its Regulated Gene Products Linked to Inflammation and Cancer 
The discovery of new uses for older, clinically approved drugs is one way to expedite drug development for cancer. Thiocolchicoside, a semisynthetic colchicoside from the plant Gloriosa superba, is a muscle relaxant and used to treat rheumatologic and orthopedic disorders because of its analgesic and anti-inflammatory mechanisms. Given that activation of the transcription factor NF-κB plays a major role in inflammation and tumorigenesis, we postulated that thiocolchicoside would inhibit NF-κB and exhibit anticancer effects through the modulation of NF-κB–regulated proteins. We show that thiocolchicoside inhibited proliferation of leukemia, myeloma, squamous cell carcinoma, breast, colon, and kidney cancer cells. Formation of tumor colonies was also suppressed by thiocolchicoside. The colchicoside induced apoptosis, as indicated by caspase-3 and poly(ADP-ribose) polymerase cleavage, and suppressed the expression of cell survival [e.g., Bcl-2, X-linked inhibitor of apoptosis (XIAP), MCL-1, bcl-xL, cIAP-1, cIAP-2, and cFLIP] proteins. Cell proliferation biomarkers such as c-MYC and phosphorylation of phosphoinositide 3-kinase and glycogen synthase kinase 3β were also blocked by thiocolchicoside. Because most cell survival and proliferation gene products are regulated by NF-κB, we studied the effect of thiocolchicoside on this transcription factor and found that thiocolchicoside inhibited NF-κB activation, degradation of inhibitory κBα (IκBα), IκBα ubiquitination, and phosphorylation, abolished the activation of IκBα kinase, and suppressed p65 nuclear translocation. This effect of thiocolchicoside on the NF-κB pathway led to inhibition of NF-κB reporter activity and cyclooxygenase-2 promoter activity. Our results indicate that thiocolchicoside exhibits anticancer activity through inhibition of NF-κB and NF-κB–regulated gene products, which provides novel insight into a half-century old drug.
doi:10.1158/1940-6207.CAPR-10-0037
PMCID: PMC3142676  PMID: 20978115
8.  The Role of the Orthopaedic Surgeon 
Treatment for patients with vertebral compression fractures (VCFs) should address pain and mobility, and aim to prevent further fractures. Restoration of vertebral height to improve the spinal deformity is also of primary importance. Traditionally, osteoporosis-induced VCFs have been treated with bed rest, narcotic analgesics, braces, and physical therapy. However, immobility is known to have a negative impact on muscle strength and bone mass and may cause serious general health complications, narcotics can worsen mood and mentation problems, and brace wear is not well tolerated by the elderly. These fractures have a considerable impact on quality of life, and although most of them heal, the height loss and deformity remain uncorrected. Vertebroplasty and balloon kyphoplasty are minimally invasive treatment options for VCFs. Kyphoplasty is designed to reduce and stabilise the fracture in a controlled way, to correct the spinal deformity and to provide immediate pain relief, mobility, and an improved quality of life. The main differences between balloon kyphoplasty and vertebroplasty are the greater potential of the kyphoplasty procedure to restore the vertebral height and kyphosis angle of the fractured vertebra and (although the clinical significance of this has not yet been demonstrated) its lower percentage of cement extravasation; the latter is related to lower injection pressures, and facilitated by a higher cement viscosity and by the cavity created in the fractured vertebrae.
Worldwide, over 95,000 VCFs in 75,000 patients have been treated with balloon kyphoplasty. Accordingly, the orthopaedic surgeon today plays a leading role in the “Fracture Unit”, not only on the therapeutic side, but also on the diagnostic side. The kyphoplasty kit can allow percutaneous bone biopsy, often very important in order to obtain a correct diagnosis. In order to justify resource allocation and patient selection for new osteoporotic fracture treatment technologies, it is also becoming increasingly important to determine the cost-effectiveness of treatments. In a recent study we highlighted why spine surgery is important in VCFs, comparing the efficacy and safety of kyphoplasty and of non-surgical management for the treatment of acute osteoporotic VCFs. Our aim was to test the hypothesis that kyphoplasty would result in greater improvement in quality of life with a better cost-effectiveness ratio at 24 months’ follow up. Between January 2005 and September 2008, we randomly assigned 60 patients with one fresh (< 6 weeks) painful osteoporotic VCF to undergo either percutaneous surgical treatment with Medtronic Kyphoplasty (Group A, n=32) or conservative treatment (Group B, n=28), preceded by 40 days of bed rest and followed by 40 days of hyperextension back brace wear (type C35). The baseline characteristics were similar in the two groups: the average age was 67 years and 7 months, min. 62 - max. 89 years, in Group A, and 66 years and 5 months, min. 64 - max. 78 years, in Group B. The fractured levels were T12=10, L1=11, L2=5, L3=6 in Group A and T12=7, L1=13, L2=5, L3=3 in Group B. According to the Magerl classification the VCFs in both groups were prevalently A1.2 (13 cases in A and 16 in B) and A1.3 (14 cases in A and 8 in B). In all cases standing lateral spinal radiographs were taken at baseline, 3 months, 6 months, 12 months and 24 months to evaluate vertebral kyphosis (VK) and regional kyphosis (RK). Vertebral kyphosis was measured from the superior endplate to the inferior endplate of the fractured vertebra. Regional kyphosis was measured from the inferior endplate of the intact adjacent distal vertebra to the superior endplate of the intact adjacent proximal vertebra. Pain was evaluated at baseline, 3 months, 6 months, 12 months and 24 months with the VAS pain scale. Each patient had a card to be used for recording medical and non-medical costs sustained in the course of the 24 months.
The primary endpoint was the difference, between the groups, in VK and VAS pain scale score changes from baseline to 3, 6, 12 and 24 months: the surgical treatment group always showed better results. Mean VK was 11.50 degrees at baseline, 6.50 degrees at 3 months, 6.37 degrees at 6 months, and 6.38 degrees at 12 and 24 months in Group A and 12.6 degrees at baseline, 10.50 degrees at 3 months, 10.70 degrees at 6 months, and 11.80 degrees at 12 and 24 months in Group B. The VAS pain score was 9 (baseline), 2 (3 mths), 1 (6 mths), 2 (12 and 24 mths) in Group A and 9 (baseline), 7 (3 mths), 4 (6 mths), 5 (12 and 24 mths) in Group B.
The secondary endpoint was the difference, between surgical and conservative treatments, in medical (hospitalisation, surgical procedure, convalescence and 24-months follow up) and non-medical costs sustained. Group A recorded higher hospitalisation costs (average 9 days, € 4551) than Group B (average 5 days, € 2681). For the surgically treated group there was also an additional surgical procedure cost (average € 4,483.09).
The convalescence was longer in Group B (average 95 days, medical costs: € 2018,59) than in Group A (average 15 days, medical costs: € 192,92). Obviously, non-medical costs were also higher in Group B (€ 3390,00) than in Group A (€ 210,00). Between 3 and 24 months we recorded three cases of back pain Group A and 17 in Group B, with an additional cost of € 47,53 in the first group and € 1319,56 in the second. Therefore, on the whole, the surgical treatment had an average cost of € 9484,54 while the conservative treatment had an average cost of € 9409,15. However it is important to underline that in the second group there was also another non-medical cost that is difficult to quantify: that of family caregiving, which corresponds to 1 person’s days of absence from work (average 14 days, min. 5, max. 22).
The cost-effectiveness relationship becomes even better for the surgically treated group if we analyse the complications. In the first group we recorded seven asymptomatic minor complications (3 cases of vein leakage and 4 of intradiscal leakage) that did not generate supplementary medical or non-medical costs; instead, in the second group we recorded 13 complications (6 cases of decubitus ulcers and 7 cases of bronchitis) generating an additional cost of ⇔ 4325. Therefore, this study confirmed that kyphoplasty may today be the gold standard in the treatment of fresh osteoporotic VCFs. Accordingly, orthopaedic surgeon is destined to play an ever more important role within a superspecialist team.
PMCID: PMC3213845
9.  Balloon Kyphoplasty 
Executive Summary
Objective
To review the evidence on the effectiveness and cost-effectiveness of balloon kyphoplasty for the treatment of vertebral compression fractures (VCFs).
Clinical Need
Vertebral compression fractures are one of the most common types of osteoporotic fractures. They can lead to chronic pain and spinal deformity. They are caused when the vertebral body (the thick block of bone at the front of each vertebra) is too weak to support the loads of activities of daily living. Spinal deformity due to a collapsed vertebral body can substantially affect the quality of life of elderly people, who are especially at risk for osteoporotic fractures due to decreasing bone mass with age. A population-based study across 12 European centres recently found that VCFs have a negative impact on health-related quality of life. Complications associated with VCFs are pulmonary dysfunction, eating disorders, loss of independence, and mental status change due to pain and the use of medications. Osteoporotic VCFs also are associated with a higher rate of death.
VCFs affect an estimated 25% of women over age 50 years and 40% of women over age 80 years. Only about 30% of these fractures are diagnosed in clinical practice. A Canadian multicentre osteoporosis study reported on the prevalence of vertebral deformity in Canada in people over 50 years of age. To define the limit of normality, they plotted a normal distribution, including mean and standard deviations (SDs) derived from a reference population without any deformity. They reported a prevalence rate of 23.5% in women and a rate of 21.5% in men, using 3 SDs from the mean as the limit of normality. When they used 4 SDs, the prevalence was 9.3% and 7.3%, respectively. They also found the prevalence of vertebral deformity increased with age. For people older than 80 years of age, the prevalence for women and men was 45% and 36%, respectively, using 3 SDs as the limit of normality.
About 85% of VCFs are due to primary osteoporosis. Secondary osteoporosis and neoplasms account for the remaining 15%. A VCF is operationally defined as a reduction in vertebral body height of at least 20% from the initial measurement. It is considered mild if the reduction in height is between 20% and 25%; moderate, if it is between 25% and 40%; and severs, if it is more than 40%. The most frequently fractured locations are the third-lower part of the thorax and the superior lumbar levels. The cervical vertebrae and the upper third of the thorax are rarely involved.
Traditionally, bed rest, medication, and bracing are used to treat painful VCFs. However, anti-inflammatory and narcotic medications are often poorly tolerated by the elderly and may harm the gastrointestinal tract. Bed rest and inactivity may accelerate bone loss, and bracing may restrict diaphragmatic movement. Furthermore, medical treatment does not treat the fracture in a way that ameliorates the pain and spinal deformity.
Over the past decade, the injection of bone cement through the skin into a fractured vertebral body has been used to treat VCFs. The goal of cement injection is to reduce pain by stabilizing the fracture. The secondary indication of these procedures is management of painful vertebral fractures caused by benign or malignant neoplasms (e.g., hemangioma, multiple myeloma, and metastatic cancer).
The Technology
Balloon kyphoplasty is a modified vertebroplasty technique. It is a minimally invasive procedure that aims to relieve pain, restore vertebral height, and correct kyphosis. During this procedure, an inflatable bone tamp is inserted into the collapsed vertebral body. Once inflated, the balloon elevates the end plates and thereby restores the height of the vertebral body. The balloon is deflated and removed, and the space is filled with bone cement. Creating a space in the vertebral body enables the application of more viscous cement and at a much lower pressure than is needed for vertebroplasty. This may result in less cement leakage and fewer complications. Balloons typically are inserted bilaterally, into each fractured vertebral body. Kyphoplasty usually is done under general anesthesia in about 1.5 hours. Patients typically are observed for only a few hours after the surgery, but some may require an overnight hospital stay.
Health Canada has licensed KyphX Xpander Inflatable Bone Tamp (Kyphon Inc., Sunnyvale, CA), for kyphoplasty in patients with VCFs. KyphX is the only commercially available device for percutaneous kyphoplasty. The KyphX kit uses a series of bone filler device tubes. Each bone filler device must be loaded manually with cement. The cement is injected into the cavity by pressing an inner stylet.
In the United States, the Food and Drug Administration cleared the KyphX Inflatable Bone Tamp for marketing in July 1998. CE (Conformité European) marketing was obtained in February 2000 for the reduction of fracture and/or creation of a void in cancellous bone.
Review Strategy
The aim of this literature review was to evaluate the safety and effectiveness of balloon kyphoplasty in the treatment of painful VCFs.
INAHTA, Cochrane CCTR (formerly Cochrane Controlled Trials Register), and DSR were searched for health technology assessment reports. In addition, MEDLINE, EMBASE, and MEDLINE In-Process & Other Non-Indexed Citations were searched from January 1, 2000 to September 21, 2004. The search was limited to English-language articles and human studies.
The positive end points selected for this assessment were as follows:
Reduction in pain scores
Reduction in vertebral height loss
Reduction in kyphotic (Cobb) angle
Improvement in quality of life scores
The search did not yield any health technology assessments on balloon kyphoplasty. The search yielded 152 citations, including those for review articles. No randomized controlled trials (RCTs) on balloon kyphoplasty were identified. All of the published studies were either prospective cohort studies or retrospective studies with no controls. Eleven studies (all case series) met the inclusion criteria. There was also a comparative study published in German that had been translated into English.
Summary of Findings
The results of the 1 comparative study (level 3a evidence) that was included in this review showed that, compared with conservative medical care, balloon kyphoplasty significantly improved patient outcomes.
Patients who had balloon kyphoplasty reported a significant reduction in pain that was maintained throughout follow-up (6 months), whereas pain scores did not change in the control group. Patients in the balloon kyphoplasty group did not need pain medication after 3 days. In the control group, about one-half of the patients needed more pain medication in the first 4 weeks after the procedure. After 6 weeks, 82% of the patients in the control group were still taking pain medication regularly.
Adjacent fractures were more frequent in the control group than in the balloon kyphoplasty group.
The case series reported on several important clinical outcomes.
Pain: Four studies on osteoporosis patients and 1 study on patients with multiple myeloma/primary cancers used the Visual Analogue Scale (VAS) to measure pain before and after balloon kyphoplasty. All of these studies reported that patients had significantly less pain after the procedure. This was maintained during follow-up. Two other studies on patients with osteoporosis also used the VAS to measure pain and found a significant improvement in pain scores; however, they did not provide follow-up data.
Vertebral body height: All 5 studies that assessed vertebral body height in patients with osteoporosis reported a significant improvement in vertebral body height after balloon kyphoplasty. One study had 1-year follow-up data for 26 patients. Vertebral body height was significantly better at 6 months and 1 year for both the anterior and midline measurements.
Two studies reported that vertebral body height was restored significantly after balloon kyphoplasty for patients with multiple myeloma or metastatic disease. In another study, the researchers reported complete height restoration in 9% of patients, a mean 56% height restoration in 60% of patients, and no appreciable height restoration in 31% of the patients who received balloon kyphoplasty.
Kyphosis correction: Four studies that assessed Cobb angle before and after balloon kyphoplasty in patients with osteoporosis found a significant reduction in degree of kyphosis after the procedure. In these studies, the differences between preoperative and postoperative Cobb angles were 3.4°, 7°, 8.8°, and 9.9°.
Only 1 study investigated kyphosis correction in patients with multiple myeloma or metastatic disease. The authors reported a significant improvement (5.2°) in local kyphosis.
Quality of life: Four studies used the Short Form 36 (SF-36) Health Survey Questionnaire to measure the quality of life in patients with osteoporosis after they had balloon kyphoplasty. A significant improvement in most of the domains of the SF-36 (bodily pain, social functioning, vitality, physical functioning, mental health, and role functioning) was observed in 2 studies. One study found that general health declined, although not significantly, and another found that role emotional declined.
Both studies that used the Oswestry Disability Index found that patients had a better quality of life after balloon kyphoplasty. In one study, this improvement was statistically significant. In another study, researchers found that quality of life after kyphoplasty improved significantly, as measured with the Roland-Morris Disability Questionnaire. Yet another study used a quality of life questionnaire and found that 62% of the patients that had balloon kyphoplasty had returned to normal activities, whereas 2 patients had reduced mobility.
To measure quality of life in patients with multiple myeloma or metastatic disease, one group of researchers used the SF-36 and found significantly better scores on bodily pain, physical functioning, vitality, and social functioning after kyphoplasty. However, the scores for general health, mental health, role physical, and role emotional had not improved. A study that used the Oswestry Disability Index reported that patients’ scores were better postoperatively and at 3 months follow-up.
These were the main findings on complications in patients with osteoporosis:
The bone cement leaked in 37 (6%) of 620 treated fractures.
There were no reports of neurological deficits.
There were no reports of pulmonary embolism due to cement leakage.
There were 6 cases of cardiovascular events in 362 patients:
3 (0.8%) patients had myocardial infarction.
3 (0.8%) patients had cardiac arrhythmias.
There was 1 (0.27%) case of pulmonary embolism due to deep venous thrombosis.
There were 20 (8.4%) cases of new fractures in 238 patients.
For patients with multiple myeloma or metastatic disease, these were the main findings:
The bone cement leaked in 12 (9.6%) of 125 procedures.
There were no reports of neurological deficits.
Economic Analysis
Balloon kyphoplasty requires anesthesia. Standard vertebroplasty requires sedation and an analgesic. Based on these considerations, the professional fees (Cdn) for each procedure is shown in Table 1.
Professional Fees for Standard Vertebroplasty and Balloon Kyphoplasty
Balloon kyphoplasty has a sizable device cost add-on of $3,578 (the device cost per case) that standard vertebroplasty does not have. Therefore, the up-front cost (i.e., physician’s fees and device costs) is $187 for standard vertebroplasty and $3,812 for balloon kyphoplasty. (All costs are in Canadian currency.)
There are also “downstream costs” of the procedures, based on the different adverse outcomes associated with each. This includes the risk of developing new fractures (21% for vertebroplasty vs. 8.4% for balloon kyphoplasty), neurological complications (3.9% for vertebroplasty vs. 0% for balloon kyphoplasty), pulmonary embolism (0.1% for vertebroplasty vs. 0% for balloon kyphoplasty), and cement leakage (26.5% for vertebroplasty vs. 6.0% for balloon kyphoplasty). Accounting for these risks, and the base costs to treat each of these complications, the expected downstream costs are estimated at less than $500 per case. Therefore, the expected total direct medical cost per patient is about $700 for standard vertebroplasty and $4,300 for balloon kyphoplasty.
Kyphon, the manufacturer of the inflatable bone tamps has stated that the predicted Canadian incidence of osteoporosis in 2005 is about 29,000. The predicted incidence of cancer-related vertebral fractures in 2005 is 6,731. Based on Ontario having about 38% of the Canadian population, the incidence in the province is likely to be about 11,000 for osteoporosis and 2,500 for cancer-related vertebral fractures. This means there could be as many as 13,500 procedures per year in Ontario; however, this is highly unlikely because most of the cancer-related fractures likely would be treated with medication. Given a $3,600 incremental direct medical cost associated with balloon kyphoplasty, the budget impact of adopting this technology could be as high as $48.6 million per year; however, based on data from the Provider Services Branch, about 120 standard vertebroplasties are done in Ontario annually. Given these current utilization patterns, the budget impact is likely to be in the range of $430,000 per year. This is because of the sizable device cost add-on of $3,578 (per case) for balloon kyphoplasty that standard vertebroplasty does not have.
Policy Considerations
Other treatments for osteoporotic VCFs are medical management and open surgery. In cases without neurological involvement, the medical treatment of osteoporotic VCFs comprises bed rest, orthotic management, and pain medication. However, these treatments are not free of side effects. Bed rest over time can result in more bone and muscle loss, and can speed the deterioration of the underlying condition. Medication can lead to altered mood or mental status. Surgery in these patients has been limited because of its inherent risks and invasiveness, and the poor quality of osteoporotic bones. However, it may be indicated in patients with neurological deficits.
Neither of these vertebral augmentation procedures eliminates the need for aggressive treatment of osteoporosis. Osteoporotic VCFs are often under-diagnosed and under-treated. A survey of physicians in Ontario (1) who treated elderly patients living in long-term care homes found that although these physicians were aware of the rates of osteoporosis in these patients, 45% did not routinely assess them for osteoporosis, and 26% did not routinely treat them for osteoporosis.
Management of the underlying condition that weakens the vertebral bodies should be part of the treatment plan. All patients with osteoporosis should be in a medical therapy program to treat the underlying condition, and the referring health care provider should monitor the clinical progress of the patient.
The main complication associated with vertebroplasty and balloon kyphoplasty is cement leakage (extravertebral or vascular). This may result in more patient morbidity, longer hospitalizations, the need for open surgery, and the use of pain medications, all of which have related costs. Extravertebral cement leakage can cause neurological complications, like spinal cord compression, nerve root compression, and radiculopathy. In some cases, surgery is required to remove the cement and release the nerve. The rate of cement leakage is much lower after balloon kyphoplasty than after vertebroplasty. Furthermore, the neurological complications seen with vertebroplasty have not seen in the studies of balloon kyphoplasty. Rarely, cement leakage into the venous system will cause a pulmonary embolism. Finally, compared with vertebroplasty, the rate of new fractures is lower after balloon kyphoplasty.
Diffusion – International, National, Provincial
In Canada, balloon kyphoplasty has not yet been funded in any of the provinces. The first balloon kyphoplasty performed in Canada was in July 2004 in Ontario.
In the United States, the technology is considered by some states as medically reasonable and necessary for the treatment of painful vertebral body compression fractures.
Conclusion
There is level 4 evidence that balloon kyphoplasty to treat pain associated with VCFs due to osteoporosis is as effective as vertebroplasty at relieving pain. Furthermore, the evidence suggests that it restores the height of the affected vertebra. It also results in lower fracture rates in other vertebrae compared with vertebroplasty, and in fewer neurological complications due to cement leakage compared with vertebroplasty. Balloon kyphoplasty is a reasonable alternative to vertebroplasty, although it must be reiterated that this conclusion is based on evidence from level 4 studies.
Balloon kyphoplasty should be restricted to facilities that have sufficient volumes to develop and maintain the expertise required to maximize good quality outcomes. Therefore, consideration should be given to limiting the number of facilities in the province that can do balloon kyphoplasty.
PMCID: PMC3387743  PMID: 23074451
10.  A Novel Tool for the Assessment of Pain: Validation in Low Back Pain 
PLoS Medicine  2009;6(4):e1000047.
Joachim Scholz and colleagues develop and validate an assessment tool that distinguishes between radicular and axial low back pain.
Background
Adequate pain assessment is critical for evaluating the efficacy of analgesic treatment in clinical practice and during the development of new therapies. Yet the currently used scores of global pain intensity fail to reflect the diversity of pain manifestations and the complexity of underlying biological mechanisms. We have developed a tool for a standardized assessment of pain-related symptoms and signs that differentiates pain phenotypes independent of etiology.
Methods and Findings
Using a structured interview (16 questions) and a standardized bedside examination (23 tests), we prospectively assessed symptoms and signs in 130 patients with peripheral neuropathic pain caused by diabetic polyneuropathy, postherpetic neuralgia, or radicular low back pain (LBP), and in 57 patients with non-neuropathic (axial) LBP. A hierarchical cluster analysis revealed distinct association patterns of symptoms and signs (pain subtypes) that characterized six subgroups of patients with neuropathic pain and two subgroups of patients with non-neuropathic pain. Using a classification tree analysis, we identified the most discriminatory assessment items for the identification of pain subtypes. We combined these six interview questions and ten physical tests in a pain assessment tool that we named Standardized Evaluation of Pain (StEP). We validated StEP for the distinction between radicular and axial LBP in an independent group of 137 patients. StEP identified patients with radicular pain with high sensitivity (92%; 95% confidence interval [CI] 83%–97%) and specificity (97%; 95% CI 89%–100%). The diagnostic accuracy of StEP exceeded that of a dedicated screening tool for neuropathic pain and spinal magnetic resonance imaging. In addition, we were able to reproduce subtypes of radicular and axial LBP, underscoring the utility of StEP for discerning distinct constellations of symptoms and signs.
Conclusions
We present a novel method of identifying pain subtypes that we believe reflect underlying pain mechanisms. We demonstrate that this new approach to pain assessment helps separate radicular from axial back pain. Beyond diagnostic utility, a standardized differentiation of pain subtypes that is independent of disease etiology may offer a unique opportunity to improve targeted analgesic treatment.
Editors' Summary
Background
Pain, although unpleasant, is essential for survival. Whenever the body is damaged, nerve cells detecting the injury send an electrical message via the spinal cord to the brain and, as a result, action is taken to prevent further damage. Usually pain is short-lived, but sometimes it continues for weeks, months, or years. Long-lasting (chronic) pain can be caused by an ongoing, often inflammatory condition (for example, arthritis) or by damage to the nervous system itself—experts call this “neuropathic” pain. Damage to the brain or spinal cord causes central neuropathic pain; damage to the nerves that convey information from distant parts of the body to the spinal cord causes peripheral neuropathic pain. One example of peripheral neuropathic pain is “radicular” low back pain (also called sciatica). This is pain that radiates from the back into the legs. By contrast, axial back pain (the most common type of low back pain) is confined to the lower back and is non-neuropathic.
Why Was This Study Done?
Chronic pain is very common—nearly 10% of American adults have frequent back pain, for example—and there are many treatments for it, including rest, regulated exercise (physical therapy), pain-killing drugs (analgesics), and surgery. However, the best treatment for any individual depends on the exact nature of their pain, so it is important to assess their pain carefully before starting treatment. This is usually done by scoring overall pain intensity, but this assessment does not reflect the characteristics of the pain (for example, whether it occurs spontaneously or in response to external stimuli) or the complex biological processes involved in pain generation. An assessment designed to take such factors into account might improve treatment outcomes and could be useful in the development of new therapies. In this study, the researchers develop and test a new, standardized tool for the assessment of chronic pain that, by examining many symptoms and signs, aims to distinguish between pain subtypes.
What Did the Researchers Do and Find?
One hundred thirty patients with several types of peripheral neuropathic pain and 57 patients with non-neuropathic (axial) low back pain completed a structured interview of 16 questions and a standardized bedside examination of 23 tests. Patients were asked, for example, to choose words that described their pain from a list provided by the researchers and to grade the intensity of particular aspects of their pain from zero (no pain) to ten (the maximum imaginable pain). Bedside tests included measurements of responses to light touch, pinprick, and vibration—chronic pain often alters responses to harmless stimuli. Using “hierarchical cluster analysis,” the researchers identified six subgroups of patients with neuropathic pain and two subgroups of patients with non-neuropathic pain based on the patterns of symptoms and signs revealed by the interviews and physical tests. They then used “classification tree analysis” to identify the six questions and ten physical tests that discriminated best between pain subtypes and combined these items into a tool for a Standardized Evaluation of Pain (StEP). Finally, the researchers asked whether StEP, which took 10–15 minutes, could identify patients with radicular back pain and discriminate them from those with axial back pain in an independent group of 137 patients with chronic low back pain. StEP, they report, accurately diagnosed these two conditions and was well accepted by the patients.
What Do These Findings Mean?
These findings indicate that a standardized assessment of pain-related signs and symptoms can provide a simple, quick diagnostic procedure that distinguishes between radicular (neuropathic) and axial (non-neuropathic) low back pain. This distinction is crucial because these types of back pain are best treated in different ways. In addition, the findings suggest that it might be possible to identify additional pain subtypes using StEP. Because these subtypes may represent conditions in which different pain mechanisms are acting, classifying patients in this way might eventually enable physicians to tailor treatments for chronic pain to the specific needs of individual patients rather than, as at present, largely guessing which of the available treatments is likely to work best.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000047.
This study is further discussed in a PLoS Medicine Perspective by Giorgio Cruccu and and Andrea Truini
The US National Institute of Neurological Disorders and Stroke provides a primer on pain in English and Spanish
In its 2006 report on the health status of the US, the National Center for Health Statistics provides a special feature on the epidemiology of pain, including back pain
The Pain Treatment Topics Web site is a resource, sponsored partly by associations and manufacturers, that provides information on all aspects of pain and its treatment for health care professionals and their patients
Medline Plus provides a brief description of pain and of back pain and links to further information on both topics (in English and Spanish)
The MedlinePlus Medical Encyclopedia also has a page on low back pain (in English and Spanish)
doi:10.1371/journal.pmed.1000047
PMCID: PMC2661253  PMID: 19360087
11.  Validation of the Tunisian version of the Roland-Morris questionnaire 
European Spine Journal  2004;14(2):171-174.
Our aim was to validate a culturally adapted, Tunisian-language version of the Roland-Morris Disability Questionnaire (RMDQ), which is a reliable evaluation instrument for low-back-pain disability. A total of 62 patients with low back pain were assessed by the questionnaire. Reliability for the 1-week test/re-test was assessed by a construction of a Bland Altman plot. Internal construct validity was assessed by Cronbach’s αtest. External construct validity was assessed by association with pain, the Schober test and the General Function Score. Sensitivity to change was determined using a t-test for paired data to compare RMDQ scores at inclusion and at completion of the therapeutic sequence of local corticosteroid injections. We also compared the questionnaire score with the General Function Score, both taken after completion of the therapeutic sequence. The constructed Bland Altman plot showed good reliability. Internal consistency of the RMDQ was found to be very good and the Cronbach’s α test was 0.94, indicating a good internal construct validity. The questionnaire is correlated with the pain visual analogue scale (r=33; p=0.0001), with the Schober test (r=0.27; p=0.0001) and the General Function Score (r=56; p=0.0001) indicating an adequate external construct validity. The RMDQ administered after the therapeutic sequence is sensitive to change (r=0.83; p=0.000). Comparison of the questionnaire score to the General Function Score, after completion of the therapeutic sequence, was satisfactory (r=0.75; p=0.000). We conclude that the Tunisian version of the Roland-Morris questionnaire has good reliability and internal consistency. Furthermore, it has a good internal- and external construct validity and high sensitivity to change. It is an adequate and useful tool for assessing low-back-pain disability.
doi:10.1007/s00586-004-0730-4
PMCID: PMC3476696  PMID: 15150702
Low back pain; Roland-Morris Disability Questionnaire
12.  Intrathecal Baclofen Pump for Spasticity 
Executive Summary
Objective
To conduct an evidence-based analysis of the effectiveness and cost-effectiveness of intrathecal baclofen for spasticity.
The Technology
Spasticity is a motor disorder characterized by tight or stiff muscles that may interfere with voluntary muscle movements and is a problem for many patients with multiple sclerosis (MS), spinal cord injury (SCI), cerebral palsy (CP), and acquired brain injury (ABI).(1). Increased tone and spasm reduces mobility and independence, and interferes with activities of daily living, continence and sleep patterns. Spasticity may also be associated with significant pain or discomfort (e.g., due to poor fit in braces, footwear, or wheelchairs), skin breakdown, contractures, sleep disorders and difficulty in transfer.
Goals of treatment are to decrease spasticity in order to improve range of motion, facilitate movement, reduce energy expenditure and reduce risk of contractures. Existing treatments include physical therapy, oral medications, injections of phenol or botulinum toxin, or surgical intervention.
Baclofen is the oral drug most frequently prescribed for spasticity in cases of SCI and MS.(1) Baclofen is a muscle relaxant and antispasticity drug. In the brain, baclofen delivered orally has some supraspinal activity that may contribute to clinical side effects. The main adverse effects of oral baclofen include sedation, excessive weakness, dizziness, mental confusion, and somnolence.(2) The incidence of adverse effects is reported to range from 10% to 75%.(2) Ochs et al. estimated that approximately 25-30% of SCI and MS patients fail to respond to oral baclofen.(3;4)
Adverse effects appear to be dose-related and may be minimized by initiating treatment at a low dose and gradually titrating upwards.(2) Adverse effects usually appear at doses >60 mg/day.(2) The rate of treatment discontinuation due to intolerable adverse effects has generally been reported to range from 4% to 27%.(2)
When baclofen is administered orally, only a small portion of the original dose crosses the blood brain barrier and enters the central nervous system (CNS) fluid, which is the site of drug action. In order to bypass the oral route, baclofen may be administered intrathecally by infusion directly to the CNS.
Candidates for intrathecal baclofen infusion are patients with spasticity who have intractable spasticity uncontrolled by drug therapy, or who experience intolerable side effects from oral baclofen.
Advantages of intrathecal baclofen infusion are:
Direct drug administration to the cerebrospinal fluid (CSF)
The central side effects of oral baclofen, such as drowsiness or confusion, appear to be minimized with intrathecal administration.
The intrathecal delivery of baclofen concentrates the drug in the CSF at higher levels than those attainable via the oral route.
Intrathecal administration can use concentrations of baclofen of less than one hundredth of those used orally.(5)
Adjustable/programmable continuous infusion makes it possible to finely titrate patients’ doses and to vary the doses over the hours of the day. For example, the dose can be relatively low to give the patients the extensor tone needed for ambulation during the day and increased at night, thereby improving quality of sleep.
Reversible (in contrast to surgery).
A patient who is a candidate for intrathecal baclofen infusion must have no contraindications to the insertion of an intrathecal catheter (e.g., anticoagulant therapy, coagulopathy, local or systemic infection, anatomical abnormality of the spine).
Review Strategy
The Medical Advisory Secretariat reviewed the literature to assess the effectiveness, safety, and cost-effectiveness of intrathecal baclofen to treat patients who have intractable spasticity uncontrolled by drug therapy, or who experience intolerable side effects to oral baclofen.
The Medical Advisory Secretariat used its standard search strategy to retrieve international health technology assessments and English-language journal articles from selected databases.
Summary of Findings
Level 2 evidence supports the effectiveness of intrathecal baclofen infusion for the short-term reduction of severe spasticity in patients who are unresponsive or cannot tolerate oral baclofen
Level 3 evidence supports the effectiveness of intrathecal baclofen for the long-term reduction of severe spasticity in patients who are unresponsive or cannot tolerate oral baclofen
Level 4 qualitative evidence demonstrates functional improvement for patients who are unresponsive or cannot tolerate oral baclofen
Intrathecal baclofen is cost-effective with costs which may or may not be avoided in the Ontario health system
True functional use remains to be determined
PMCID: PMC3382401  PMID: 23074476
13.  Open-label, randomized, controlled pilot study of the effects of a glucosamine complex on Low back pain 
Background:
A series of studies has suggested some efficacy of glucosamine in arthrosis of the knee, but virtually no documentation exists regarding its effects on low back pain.
Objectives:
The primary objective of this study was to examine whether a 12-week course of a glucosamine complex (GC) could benefit patients having low back pain despite a course of noninvasive physical therapy. In addition, we sought to delineate the subgroup of responders.
Methods:
This open-label, randomized, controlled study was conducted at the Division of Rheumatology and Physical Medicine, Erasme University Hospital, Brussels, Belgium. Male and female outpatients aged 40 to 80 years with low back pain (duration, ≥ 12 weeks; pain score on 10-cm visual analog scale [VAS] [0 = none to 10 = worst imaginable], ≥3 cm) despite noninvasive physical therapy (massage, stretching, heat application, and analgesics for ≥4 weeks) were included. Patients were randomly assigned to receive, in addition to conventional treatment (CT) (physical therapy plus analgesics/antiinflammatories), a GC (enriched with sulfonyl methane, silicon, and a botanical extract of Ribes nigrum) or CT alone (control) for 12 weeks. Pain at rest and on movement (effort) and early morning lumbar stiffness were measured every 4 weeks using the VAS. The primary end point was improvement in VAS score for pain at rest at 12 weeks. Two validated questionnaires were used to assess improvements in quality of life (QOL) (Oswestry Disability Questionnaire [ODQ] [10 items; scale: 0 = no disability to 60 = maximal disability] and Roland-Morris Disability Questionnaire [RMDQ] [24 items; scale: 0 = no disability to 24 = severe disability]). Responders were defined as patients who positively assessed the efficacy of the GC. At each visit, patients were also asked about possible adverse events.
Results:
Of 36 enrolled patients, 32 completed the study (18 men, 14 women; mean [SE] age, 64 [2] years; 17 in the GC group and 15 in the control group). Four patients were lost to follow-up. At week 4, changes from baseline VAS scores for pain at rest and lumbar stiffness were significantly greater in the GC group compared with the control group (P < 0.001 and P = 0.011, respectively). At week 4, QOL was found to be improved, as measured using the ODQ, in the GC group compared with the control group (P = 0.028), but the between-group difference as measured using the RMDQ was not significant. The improvements from baseline on the questionnaires were sustained over the 12-week period in the GC group (all, P < 0.001). Gastrointestinal adverse effects were reported by 1 GC-treated patient and 1 patient in the control group, but neither patient withdrew from the study. Of the 17 GC-treated patients, 9 considered themselves responders, but the profile of a responder could not be delineated.
Conclusions:
In this study in patients with low back pain, analgesic effect and improvement in QOL were found with the use of GC. GC was well tolerated.
doi:10.1016/j.curtheres.2005.12.009
PMCID: PMC3965983  PMID: 24678073
arthrosis; back pain; glucosamine; methylsulfonylmethane; silicon; Ribes nigrurn
14.  Day and night pain measurement in rheumatoid arthritis 
Annals of the Rheumatic Diseases  1998;57(7):434-436.
OBJECTIVE—An attempt was made to see if rheumatoid arthritis (RA) patients can use visual analogue scales (VAS) to distinguish and grade the severity of pain at night, during rest, and on joint movement and to determine if discriminate measurement of these three pain components enhances the value of VAS estimation.
METHODS—Two hundred and fifty two consecutive RA patients were evaluated by a single observer using 10 cm VAS for pain at night, at rest during the day, and on movement. Values were correlated against age, disease duration, joint tenderness, swollen joint count, erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and Larsen x ray scores.
RESULTS—Night pain was recorded by 71 (28%) and this component of pain was lower than VAS scores for daytime rest and movement. However, those with nocturnal pain had significantly more joint tenderness (p<0.0001), swollen joints (p<0.0001), and higher ESR and CRP. Age, disease duration, and radiographic scores were similar in those with and without night pain. Correlations of joint tenderness were apparent for all three pain scores but only nocturnal pain correlated with swollen joints (p<0.001) and CRP (p<0.005). Age, disease duration, and radiographic severity correlated with daytime rest or movement scores but not nocturnal pain.
CONCLUSION—Patients were able to distinguish and estimate the severity of pain at rest, on movement, and at night. The occurrence of night pain characterised those with more active disease and night pain VAS measurement correlated best with measures of joint inflammation whereas daytime pain scores, both at rest and on movement, seemed influenced by the degree of permanent joint damage. Thus, discrete measurement of rest, movement, and nocturnal pain may provide useful information about RA disease status.

 Keywords: nocturnal pain; joint inflammation
PMCID: PMC1752669  PMID: 9797572
15.  Efficacy and safety of diclofenac diethylamine 1.16% gel in acute neck pain: a randomized, double-blind, placebo-controlled study 
Background
Neck pain (NP) is a common musculoskeletal disorder in primary care that frequently causes discomfort. Non-steroidal anti-inflammatory drugs (NSAIDs) may be used to reduce neck pain and associated inflammation and facilitate earlier recovery. Topical diclofenac diethylamine (DDEA) 1.16% gel is clinically proven to be effective and well tolerated in acute and chronic musculoskeletal conditions, but until now no clinical data existed for its use in acute NP. The aim of this study was to assess the efficacy and safety of DDEA 1.16% gel compared with placebo gel in acute NP.
Methods
In a randomized, double-blind, placebo-controlled study, patients with acute NP (n = 72) were treated with DDEA 1.16% gel (2 g, 4x/day, for 5 days) or placebo. Efficacy assessments included pain-on-movement (POM), pain-at-rest (PAR), functional neck disability index (NDI) and response to treatment (decrease in POM by 50% after 48 h). Adverse events (AEs) were recorded throughout the study.
Results
The primary outcome, POM at 48 h, was statistically significantly lower with DDEA gel (19.5 mm) vs. placebo (56.9 mm) (p < 0.0001), representing a clinically relevant decrease from baseline (75% vs. 23%, respectively). All POM scores were significantly lower with DDEA gel vs. placebo from 1 h, as were PAR and NDI scores from first assessment (24 h) onwards (all p < 0.0001). Response to treatment was significantly higher with DDEA gel (94.4%) vs. placebo (8.3%) (p < 0.0001). There were no AEs with DDEA gel.
Conclusions
DDEA 1.16% gel, which is available over-the-counter, was effective and well tolerated in the treatment of acute neck pain. The tools used to assess efficacy suggest that it quickly reduced neck pain and improved neck function. However, questions remain regarding the comparability and validity of such tools. Further studies will help ascertain whether DDEA 1.16% gel offers an alternative treatment option in this common, often debilitating condition.
Trial registration
ClinicalTrials.gov identifier: NCT01335724
doi:10.1186/1471-2474-14-250
PMCID: PMC3847223  PMID: 23964752
Acute neck pain; Diclofenac diethylamine gel; Neck function; Pain relief; Safety
16.  The Effects of Stabilization and Mckenzie Exercises on Transverse Abdominis and Multifidus Muscle Thickness, Pain, and Disability: A Randomized Controlled Trial in NonSpecific Chronic Low Back Pain 
Journal of Physical Therapy Science  2014;25(12):1541-1545.
[Purpose] This study compared the effectiveness of stabilization and McKenzie exercises on pain, disability, and thickness of the transverse abdominis and multifidus muscles in patients with nonspecific chronic low back pain. [Subjects] Thirty patients were randomly assigned into two groups: the McKenzie and stabilization exercise groups. [Methods] Before and after intervention, pain, disability, and thickness of the transverse abdominis and multifidus muscles were evaluated by visual analogue scale, functional rating index, and sonography, respectively. The training program was 18 scheduled sessions of individual training for both groups. [Results] After interventions, the pain score decreased in both groups. The disability score decreased only in the stabilization group. The thickness of the left multifidus was significantly increased during resting and contracting states in the stabilization group. The thickness of the right transverse abdominis during the abdominal draw-in maneuver, and thickness of the left transverse abdominis during the active straight leg raising maneuver were significantly increased in the stabilization group. The intensity of pain, disability score, thickness of the right transverse abdominis during the abdominal draw-in manouver, and thickness of the left transverse abdominis during active straight leg raising in the stabilization group were greater than those on the Mackenzie. [Conclusion] Stabilization exercises are more effective than McKenzie exercises in improving the intensity of pain and function score and in increasing the thickness of the transverse abdominis muscle.
doi:10.1589/jpts.25.1541
PMCID: PMC3885835  PMID: 24409016
Chronic low back pain; Stabilizaton exercises; Muscle thickness
17.  Low back pain (acute) 
Clinical Evidence  2008;2008:1102.
Introduction
Low back pain (LBP) affects about 70% of people in resource-rich countries at some point. Acute low back pain is usually perceived as self-limiting; however, one year later, as many as 33% of people still have moderate-intensity pain and 15% have severe pain. It has a high recurrence rate; 75% of those with a first episode have a recurrence. Although acute episodes may resolve completely, they may also increase in severity and duration over time.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of oral drug treatments for low back pain? What are the effects of local injections for low back pain? What are the effects of non-drug treatments for low back pain? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 34 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, advice to stay active, analgesics (paracetamol, opioids), back exercises, back schools, bed rest, behavioural therapy, electromyographic biofeedback, epidural corticosteroid injections, lumbar supports, massage, multidisciplinary treatment programmes, muscle relaxants, non-steroidal anti-inflammatory drugs (NSAIDs), spinal manipulation (in the short term), temperature treatments (short wave diathermy, ultrasound, ice, heat), traction, and transcutaneous electrical nerve stimulation (TENS).
Key Points
Low back pain is pain, muscle tension, or stiffness, localised below the costal margin and above the inferior gluteal folds, with or without referred or radicular leg pain (sciatica), and is defined as acute when pain persists for less than 12 weeks. Low back pain affects about 70% of people in resource-rich countries at some point.Acute low back pain is usually self-limiting, although 2-7% develop chronic pain. Acute low back pain has a high recurrence rate with less-painful symptoms recurring in 50-80% of people within a year; one year later, as high as 33% still experience moderate-intensity pain and 15% experience severe pain.
NSAIDs have been shown to effectively improve symptoms compared with placebo. However, their use is associated with gastrointestinal adverse effects. Muscle relaxants may also reduce pain and improve overall clinical assessment, but are associated with some severe adverse effects including drowsiness, dizziness, and nausea.The studies examining the effects of analgesics such as paracetamol or opioids were generally too small to detect any clinically important differences.
We found no studies examining the effectiveness of epidural injections of corticosteroids in treating people with acute low back pain.
With regard to non-drug treatments, advice to stay active (be it as a single treatment or in combination with other interventions such as back schools, a graded activity programme, or behavioural counselling) seems the most effective. Spinal manipulation (in the short term) also seems to reduce pain, but not functional outcomes, compared with sham treatments.We found insufficient evidence to judge the effectiveness of acupuncture, back schools, behavioural therapy, massage, multidisciplinary treatment programmes (for either acute or subacute low back pain), ortemperature treatments in treating people with acute low back pain.We found no evidence examining the effectiveness of electromyographic biofeedback, lumbar supports, traction, or TENS in the treatment of acute low back pain. Back exercises do not seem to increase recovery time compared with no treatment, although there is considerable heterogeneity among studies with regard to the definition of back exercise. There is also disparity among studies in the definition of generic and specific back exercise. Bed rest does not improve symptoms any more effectively than other treatments, but does produce a number of adverse effects including joint stiffness, muscle wasting, loss of bone mineral density, pressure sores, and venous thromboembolism.
PMCID: PMC2907975  PMID: 19445792
18.  Low back pain (acute) 
Clinical Evidence  2011;2011:1102.
Introduction
Low back pain affects about 70% of people in resource-rich countries at some point in their lives. Acute low back pain can be self-limiting; however, 1 year after an initial episode, as many as 33% of people still have moderate-intensity pain and 15% have severe pain. Acute low back pain has a high recurrence rate; 75% of those with a first episode have a recurrence. Although acute episodes may resolve completely, they may increase in severity and duration over time.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of oral drug treatments for acute low back pain? What are the effects of local injections for acute low back pain? What are the effects of non-drug treatments for acute low back pain? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 49 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, advice to stay active, analgesics (paracetamol, opioids), back exercises, back schools, bed rest, behavioural therapy, electromyographic biofeedback, epidural corticosteroid injections, lumbar supports, massage, multidisciplinary treatment programmes, muscle relaxants, non-steroidal anti-inflammatory drugs (NSAIDs), spinal manipulation, temperature treatments (short-wave diathermy, ultrasound, ice, heat), traction, and transcutaneous electrical nerve stimulation (TENS).
Key Points
Low back pain is pain, muscle tension, or stiffness, localised below the costal margin and above the inferior gluteal folds, with or without referred or radicular leg pain (sciatica), and is defined as acute when pain persists for <12 weeks. Low back pain affects about 70% of people in resource-rich countries at some point in their lives.Acute low back pain may be self-limiting, although there is a high recurrence rate with less-painful symptoms recurring in 50% to 80% of people within 1 year of the initial episode; 1 year later, as many as 33% of people still experience moderate-intensity pain and 15% experience severe pain.
NSAIDs have been shown to effectively improve symptoms compared with placebo. However, their use is associated with gastrointestinal adverse effects. Muscle relaxants may also reduce pain and improve overall clinical assessment, but are associated with some severe adverse effects including drowsiness, dizziness, and nausea.The studies examining the effects of analgesics such as paracetamol or opioids were generally too small to detect any clinically important differences.
We found no studies examining the effectiveness of epidural injections of corticosteroids in treating people with acute low back pain.
With regard to non-drug treatments, advice to stay active (be it as a single treatment or in combination with other interventions such as back schools, a graded activity programme, or behavioural counselling) may be effective. We don't know whether spinal manipulation improves pain or function compared with sham treatments.We found insufficient evidence to judge the effectiveness of acupuncture, back schools, behavioural therapy, massage, multidisciplinary treatment programmes (for either acute or subacute low back pain), lumbar supports, TENS, or temperature treatments in treating people with acute low back pain.We found no evidence examining the effectiveness of electromyographic biofeedback or traction in the treatment of acute low back pain. Back exercises may decrease recovery time compared with no treatment, but there is considerable heterogeneity among studies with regard to the definition of back exercise. There is a large disparity among studies in the definition of generic versus specific back exercise. Bed rest does not improve symptoms any more effectively than other treatments, but does produce a number of adverse effects including joint stiffness, muscle wasting, loss of bone mineral density, pressure sores, and venous thromboembolism.
PMCID: PMC3217769  PMID: 21549023
19.  Acute low back pain is marked by variability: An internet-based pilot study 
Background
Pain variability in acute LBP has received limited study. The objectives of this pilot study were to characterize fluctuations in pain during acute LBP, to determine whether self-reported 'flares' of pain represent discrete periods of increased pain intensity, and to examine whether the frequency of flares was associated with back-related disability outcomes.
Methods
We conducted a cohort study of acute LBP patients utilizing frequent serial assessments and Internet-based data collection. Adults with acute LBP (lasting ≤3 months) completed questionnaires at the time of seeking care, and at both 3-day and 1-week intervals, for 6 weeks. Back pain was measured using a numerical pain rating scale (NPRS), and disability was measured using the Oswestry Disability Index (ODI). A pain flare was defined as 'a period of increased pain lasting at least 2 hours, when your pain intensity is distinctly worse than it has been recently'. We used mixed-effects linear regression to model longitudinal changes in pain intensity, and multivariate linear regression to model associations between flare frequency and disability outcomes.
Results
42 of 47 participants (89%) reported pain flares, and the average number of discrete flare periods per patient was 3.5 over 6 weeks of follow-up. More than half of flares were less than 4 hours in duration, and about 75% of flares were less than one day in duration. A model with a quadratic trend for time best characterized improvements in pain. Pain decreased rapidly during the first 14 days after seeking care, and leveled off after about 28 days. Patients who reported a pain flare experienced an almost 3-point greater current NPRS than those not reporting a flare (mean difference [SD] 2.70 [0.11]; p < 0.0001). Higher flare frequency was independently associated with a higher final ODI score (ß [SE} 0.28 (0.08); p = 0.002).
Conclusions
Acute LBP is characterized by variability. Patients with acute LBP report multiple distinct flares of pain, which correspond to discrete increases in pain intensity. A higher flare frequency is associated with worse disability outcomes.
doi:10.1186/1471-2474-12-220
PMCID: PMC3198993  PMID: 21974962
20.  Effectiveness of massage therapy for subacute low-back pain: a randomized controlled trial 
BACKGROUND: The effectiveness of massage therapy for low-back pain has not been documented. This randomized controlled trial compared comprehensive massage therapy (soft-tissue manipulation, remedial exercise and posture education), 2 components of massage therapy and placebo in the treatment of subacute (between 1 week and 8 months) low-back pain. METHODS: Subjects with subacute low-back pain were randomly assigned to 1 of 4 groups: comprehensive massage therapy (n = 25), soft-tissue manipulation only (n = 25), remedial exercise with posture education only (n = 22) or a placebo of sham laser therapy (n = 26). Each subject received 6 treatments within approximately 1 month. Outcome measures obtained at baseline, after treatment and at 1-month follow-up consisted of the Roland Disability Questionnaire (RDQ), the McGill Pain Questionnaire (PPI and PRI), the State Anxiety Index and the Modified Schober test (lumbar range of motion). RESULTS: Of the 107 subjects who passed screening, 98 (92%) completed post-treatment tests and 91 (85%) completed follow-up tests. Statistically significant differences were noted after treatment and at follow-up. The comprehensive massage therapy group had improved function (mean RDQ score 1.54 v. 2.86-6.5, p < 0.001), less intense pain (mean PPI score 0.42 v. 1.18-1.75, p < 0.001) and a decrease in the quality of pain (mean PRI score 2.29 v. 4.55-7.71, p = 0.006) compared with the other 3 groups. Clinical significance was evident for the comprehensive massage therapy group and the soft-tissue manipulation group on the measure of function. At 1-month follow-up 63% of subjects in the comprehensive massage therapy group reported no pain as compared with 27% of the soft-tissue manipulation group, 14% of the remedial exercise group and 0% of the sham laser therapy group. INTERPRETATION: Patients with subacute low-back pain were shown to benefit from massage therapy, as regulated by the College of Massage Therapists of Ontario and delivered by experienced massage therapists.
PMCID: PMC1231369  PMID: 10906914
21.  How Well Do Clinical Pain Assessment Tools Reflect Pain in Infants? 
PLoS Medicine  2008;5(6):e129.
Background
Pain in infancy is poorly understood, and medical staff often have difficulty assessing whether an infant is in pain. Current pain assessment tools rely on behavioural and physiological measures, such as change in facial expression, which may not accurately reflect pain experience. Our ability to measure cortical pain responses in young infants gives us the first opportunity to evaluate pain assessment tools with respect to the sensory input and establish whether the resultant pain scores reflect cortical pain processing.
Methods and Findings
Cortical haemodynamic activity was measured in infants, aged 25–43 wk postmenstrual, using near-infrared spectroscopy following a clinically required heel lance and compared to the magnitude of the premature infant pain profile (PIPP) score in the same infant to the same stimulus (n = 12, 33 test occasions). Overall, there was good correlation between the PIPP score and the level of cortical activity (regression coefficient = 0.72, 95% confidence interval [CI] limits 0.32–1.11, p = 0.001; correlation coefficient = 0.57). Of the different PIPP components, facial expression correlated best with cortical activity (regression coefficient = 1.26, 95% CI limits 0.84–1.67, p < 0.0001; correlation coefficient = 0.74) (n = 12, 33 test occasions). Cortical pain responses were still recorded in some infants who did not display a change in facial expression.
Conclusions
While painful stimulation generally evokes parallel cortical and behavioural responses in infants, pain may be processed at the cortical level without producing detectable behavioural changes. As a result, an infant with a low pain score based on behavioural assessment tools alone may not be pain free.
Rebeccah Slater and colleagues show that although painful stimulation generally evokes parallel cortical and behavioral responses in infants, pain may produce cortical responses without detectable behavioral changes.
Editors' Summary
Background.
Pain is a sensory and emotional experience. It is normally triggered by messages transmitted from specialized receptors (nociceptors) in the body to integrative centers in the spinal cord and brainstem and on to the brain, where it undergoes higher sensory and cognitive analysis, allowing the body to respond appropriately to the stimuli. While the experience of pain may be considered to be unpleasant, it is a useful tool in communicating to us and to others that there is something wrong with our bodies. Ultimately, these responses help restrict further damage to the body and start the process of healing.
In a clinical setting, the ability to communicate about pain allows an individual to seek strategies to ease the pain, such as taking analgesics. Being unable to effectively communicate one's experience of pain leaves the individual vulnerable to prolonged suffering. One such vulnerable group is infants.
Ignored and untreated pain in infants has been shown to have immediate and long-term effects as a result of structural and physiological changes within the nervous system. For example, the body responds to untreated pain by increased release of stress hormones, which may be associated with increased morbidity and mortality in the short term. Long-term effects of pain may include altered pain perception, chronic pain syndromes, and somatic complaints such as sleep disturbances, feeding problems, and inability to self-regulate in response to internal and external stressors. It has been proposed that attention deficit disorders, learning disorders, and behavioral problems in later childhood may be linked to repetitive pain in the preterm infant.
Why Was This Study Done?
Until as recently as the 1990s, newborns in some clinical centres underwent surgery with minimal anesthesia. Also, newborns received little or no pain management postoperatively or for painful procedures such as lumbar punctures or circumcisions. Since then, there has been growing awareness amongst clinicians that pain may be experienced from the earliest stages of postnatal life and that inadequate analgesia may lead to the type of long-term consequences mentioned above. However, gauging how much pain infants and young children are experiencing remains a substantial challenge. The researchers in this study wanted to assess the association between cortical pain responses in young infants and currently used tools for the assessment of pain in these infants. These current tools are based on behavioral and physiological measures, such as change in facial expression, and it is possible that these tools do not give an adequate measure of pain especially in infants born preterm.
What Did the Researchers Do and Find?
Twelve clinically stable infants were studied on 33 occasions when they required a heel lance to obtain a blood sample for a clinical reason. The researchers examined the relationship between brain activity and a clinical pain score, calculated using the premature infant pain profile (PIPP) in response to a painful event. Activity in the somatosensory cortex was measured noninvasively by near-infrared spectroscopy, which measures brain regional changes in oxygenated and deoxygenated hemoglobin concentration. The PIPP is a well-established pain score that ascribes a value to infant behavior such as change in facial expression.
They found that changes in brain activity in response to a painful stimulus were related to the PIPP scores. These changes were more strongly linked to the behavioral components of the PIPP, e.g., facial expression, than physiological components, e.g., heart rate. They also found that a positive brain response could occur in the absence of any facial expression.
What Do These Findings Mean?
Behaviors to communicate pain require motor responses to sensory and emotional stimuli. The maturity of this complex system in infants is not clearly understood. The results of this study raise further awareness of the ability of infants to experience pain and highlight the possibility that pain assessment based on behavioral tools alone may underestimate the pain response in infants.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050129.
Important papers on pain in human neonates are discussed in the open access Paediatric Pain Letter with links to original articles
The Institute of Child Health in London has a Web site describing a three-year international project on improving the assessment of pain in hospitalized children, with many useful links
The International Association for the Study of Pain (IASP) provides accurate and up-to-date information and links about pain mechanisms and treatment
doi:10.1371/journal.pmed.0050129
PMCID: PMC2504041  PMID: 18578562
22.  MIS Fusion of the SI Joint: Does Prior Lumbar Spinal Fusion Affect Patient Outcomes? 
Background:
Sacroiliac (SI) joint pain is a challenging condition to manage as it can mimic discogenic or radicular low back pain, and present as low back, hip, groin and/or buttock pain. Patients may present with a combination of lumbar spine and SI joint symptoms, further complicating the diagnosis and treatment algorithm [1-3]. SI joint pain after lumbar spinal fusion has been reported in the literature. Both clinical and biomechanical studies show the SI joint to be susceptible to increased motion and stress at the articular surface with up to 40-75% of patients developing significant SI joint degeneration after 5 years.
In a recent case series study of 50 patients who underwent minimally invasive SI joint arthrodesis, 50% had undergone previous lumbar spinal fusion and 18% had symptomatic lumbar spine pathology treated conservatively [4].
The purpose of this study is to determine if history of previous lumbar fusion or lumbar pathology affects patient outcomes after MIS SI joint fusion surgery.
Methods:
We report on 40 patients with 24 month follow up treated with MIS SI joint fusion using a series of triangular porous plasma coated titanium implants (iFuse, SI-Bone, Inc. San Jose, CA). Outcomes using a numerical rating scale (NRS) for pain were obtained at 3-, 6-, 12- and 24 month follow up intervals. Additionally, patient satisfaction was collected at the latest follow up interval. Patients were separated into 3 cohorts: 1) underwent prior lumbar spine fusion (PF), 2) no history of previous lumbar spine fusion (NF), 3) no history of previous lumbar spine fusion with symptomatic lumbar spine pathology treated conservatively (LP). A repeated measures analysis of variance (rANOVA) was used to determine if the change in NRS pain scores differed across timepoints and subgroups. A decrease in NRS by 2 points was deemed clinically significant [5].
Results:
Mean age was 54 (±13) years and varied slightly but not statistically between groups. All subgroups experienced a clinically and statistically significant reduction in pain at all time points (mean change >2 points, p<0.001). There was a statistically significant effect of cohort (p=0.045), with the NF cohort (no prior lumbar spinal fusion) having a somewhat greater decrease in pain (by approximately 1 point) compared to the other 2 groups (PF and LP).Patient reported satisfaction by cohort was: 89% (NF), 92% (PF) and 63% (LP).Overall satisfaction rate was 87%.
Discussion and Conclusion:
Patients with SI joint pain, regardless of prior lumbar spine fusion history, show significant improvement in pain after minimally invasive SI joint fusion. The presence of symptomatic lumbar spine pathology potentially confounds the treatment affect, as patients may not be able to discriminate between symptoms arising from the SI joint and the lumbar spine. These patients expressed a lower satisfaction with surgery. Patients without other confounding lumbar spine pathology and who have not undergone previous spine surgery tend to be younger and experience a greater reduction in pain.
doi:10.2174/1874325001307010163
PMCID: PMC3664440  PMID: 23730380
Sacroiliac (SI) joint; lumbar fusion; minimally invasive surgery; MIS arthrodesis.
23.  Effectiveness and Tolerability of Tapentadol Prolonged Release Compared With Prior Opioid Therapy for the Management of Severe, Chronic Osteoarthritis Pain 
Clinical Drug Investigation  2013;33:607-619.
Background
Tapentadol prolonged release (PR; 100–250 mg twice daily) has been efficacious and well tolerated for managing moderate-to-severe, chronic osteoarthritis hip or knee pain in phase 3 studies with washout of previous analgesic treatment.
Objective
The objective of this study was to evaluate the effectiveness and tolerability of tapentadol PR (50–250 mg twice daily) after direct rotation from World Health Organization (WHO) step III opioids in patients with severe osteoarthritis knee pain who previously responded to WHO step III therapy but showed poor tolerability.
Methods
This open-label, phase 3b study (NCT00982280) was conducted from October 2009 through June 2010 (prematurely terminated due to slow recruitment and study drug shortages) in clinical care settings in Europe and Australia. The study population included patients with severe, chronic osteoarthritis knee pain who had taken WHO step III opioids daily for ≥2 weeks before screening, responded to therapy (average pain intensity [11-point numerical rating scale-3 (NRS-3)] ≤5 at screening), and reported opioid-related adverse effects as their reason for changing analgesics. Patients switched directly from WHO step III therapy to tapentadol. Patients received oral tapentadol PR (50–250 mg twice daily) during 5-week titration and 7-week maintenance periods. Oral tapentadol immediate release (IR) was permitted (≤twice/day, ≥4 h apart) for acute pain episodes due to index pain or withdrawal symptoms following discontinuation of previous opioids (combined dose of tapentadol [PR and IR] ≤500 mg/day). This study was planned to evaluate conversion to tapentadol PR, based on responder rate 1 (percentage of patients with same/less pain [NRS-3] versus Week −1) at Week 6 (primary endpoint), adverse events (AEs), and discontinuation rates. Equianalgesic ratios were calculated for tapentadol prior to WHO step III opioids (PR and PR plus IR formulations).
Results
Of 82 patients enrolled, 63 received study medication. In the per-protocol population, responder rate 1 at Week 6 (last observation carried forward) was 94.3 % (50/53; P < 0.0001 vs. the null hypothesis rate [<60 %]). Mean (standard deviation) pain intensity scores were 4.7 (0.66) at baseline, 2.5 (1.46) at Week 6, and 1.8 (1.41) at Week 12 in the main analysis population (change from baseline at Weeks 6 and 12, P < 0.0001). Tapentadol to transdermal buprenorphine equianalgesic ratios (PR [n = 48], 262.9:1; PR plus IR [n = 48], 281.1:1) and tapentadol to oral oxycodone equianalgesic ratios (PR [n = 4], 4.3:1; PR plus IR [n = 6], 4.6:1) were calculated for the main analysis population. In the safety population, prevalence of AEs reported as associated with prior opioids at Week −1 (reasons for rotation) and related to tapentadol treatment at Week 12 decreased over time; the most common were nausea (46.0 vs. 24.1 %) and constipation (31.7 vs. 7.4 %). Overall, 14.3 % of patients discontinued the study early; reasons included AEs (9.5 %), lack of efficacy (3.2 %), and withdrawal of consent (1.6 %).
Conclusions
Significant improvements in effectiveness were observed for tapentadol PR (50–250 mg twice daily) versus WHO step III opioids in patients with severe, chronic osteoarthritis knee pain who previously responded to WHO step III therapy. Equianalgesic ratios were calculated for tapentadol to transdermal buprenorphine and oral oxycodone and were in line with observations from previous phase 3 studies.
Electronic supplementary material
The online version of this article (doi:10.1007/s40261-013-0102-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s40261-013-0102-0
PMCID: PMC3751342  PMID: 23912473
24.  Treatment of chronic low back pain incorporating active patient participation and chiropractic: a retrospective case report 
Journal of Chiropractic Medicine  2005;4(4):200-205.
Abstract
Objective
To present a retrospective case report about a patient who suffered from chronic lower back pain for sixteen years, finding little relief from numerous medical and traditional chiropractic interventions, until active patient participation was incorporated in the chiropractic treatment process.
Clinical Features
A 43-year-old female experienced severe right lumbar, right sacrum, and right acetabular pain and muscle spasms occurring after playing a vigorous tennis match 16 years earlier. Pain intensity was rated as 8 out of 10 on a variable analog scale. Prior treatments included prolonged bed rest, cortisone injection, chiropractic manipulation, stretching, acupuncture, physical therapy, and other rehabilitation interventions. By the time of presentation she also experienced right arm and right upper back pain. A lumbar MRI scan showed an L4/5 disc bulge. Patrick's, Yeoman's and Kemp's tests were positive on her right side. She had an asymmetrical gait pattern with a right hip hike, lateral shift and rotation of the pelvis. Weakness of the left gluteus maxi-mus, gluteus medius, and right erector spinae muscles was present. Motion palpation revealed several fixations. There was tenderness to palpation of the right psoas muscle and a trigger point in the right illiacus muscle.
Intervention and Outcome
Home-based rehabilitation including low-tech muscle-specific patient controlled dynamic spinal stabilization exercises, cardiovascular training and various stretching techniques was incorporated with chiropractic manipulation. Significant improvement was noted within a 40 week treatment course.
Conclusion
Incorporation of active patient participation seemed to be a significant factor in the resolution of the patient's low back pain. Active patient participation improved the quality of life for this patient.
doi:10.1016/S0899-3467(07)60152-9
PMCID: PMC2647049  PMID: 19674663
Low Back Pain; Chiropractic; Rehabilitation; Exercise Therapy
25.  Naturopathic Care for Chronic Low Back Pain: A Randomized Trial 
PLoS ONE  2007;2(9):e919.
Objective
Chronic low back pain represents a substantial cost to employers through benefits coverage and days missed due to incapacity. We sought to explore the effectiveness of Naturopathic care on chronic low back pain.
Methods
This study was a randomized clinical trial. We randomized 75 postal employees with low back pain of longer than six weeks duration to receive Naturopathic care (n = 39) or standardized physiotherapy (n = 36) over a period of 12 weeks. The study was conducted in clinics on-site in postal outlets. Participants in the Naturopathic care group received dietary counseling, deep breathing relaxation techniques and acupuncture. The control intervention received education and instruction on physiotherapy exercises using an approved education booklet. We measured low back pain using the Oswestry disability questionnaire as the primary outcome measure, and quality of life using the SF-36 in addition to low back range of motion, weight loss, and Body Mass Index as secondary outcomes.
Results
Sixty-nine participants (92%) completed eight weeks or greater of the trial. Participants in the Naturopathic care group reported significantly lower back pain (−6.89, 95% CI. −9.23 to −3.54, p = <0.0001) as measured by the Oswestry questionnaire. Quality of life was also significantly improved in the group receiving Naturopathic care in all domains except for vitality. Differences for the aggregate physical component of the SF-36 was 8.47 (95% CI, 5.05 to 11.87, p = <0.0001) and for the aggregate mental component was 7.0 (95% CI, 2.25 to 11.75, p = 0.0045). All secondary outcomes were also significantly improved in the group receiving Naturopathic care: spinal flexion (p<0.0001), weight-loss (p = 0.0052) and Body Mass Index (−0.52, 95% CI, −0.96 to −0.08, p = 0.01).
Conclusions
Naturopathic care provided significantly greater improvement than physiotherapy advice for patients with chronic low back pain.
Trial Registration
Controlled-Trials.com ISRCTN41920953
doi:10.1371/journal.pone.0000919
PMCID: PMC1976391  PMID: 17878954

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