Viscosupplementation for the treatment of osteoarthritis of the knee (Review)

Background Osteoarthritis (OA) is the most prevalent chronic joint disorder worldwide and is associated with significant pain and disability. Objectives To assess the effects of viscosupplementation in the treatment of OA of the knee. The products were hyaluronan and hylan derivatives (Adant, Arthrum H, Artz (Artzal, Supartz), BioHy (Arthrease, Euflexxa, Nuflexxa), Durolane, Fermathron, Go-On, Hyalgan, Hylan G-F 20 (Synvisc Hylan G-F 20), Hyruan, NRD-101 (Suvenyl), Orthovisc, Ostenil, Replasyn, SLM-10, Suplasyn, Synject and Zeel compositum). Search strategy MEDLINE (up to January (week 1) 2006 for update), EMBASE, PREMEDLINE, Current Contents up to July 2003, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched. Specialised journals and reference lists of identified randomised controlled trials (RCTs) and pertinent review articles up to December 2005 were handsearched. Selection criteria RCTs of viscosupplementation for the treatment of people with a diagnosis of OA of the knee were eligible. Single and double-blinded studies, placebo-based and comparative studies were eligible. At least one of the four OMERACT III core set outcome measures had to be reported (Bellamy 1997). Data collection and analysis Each trial was assessed independently by two reviewers for its methodological quality using a validated tool. All data were extracted by one reviewer and verified by a second reviewer. Continuous outcome measures were analysed as weighted mean differences (WMD) with 95% confidence intervals (CI). However, where different scales were used to measure the same outcome, standardized mean differences (SMD) were used. Dichotomous outcomes were analyzed by relative risk (RR). Main results Seventy-six trials with a median quality score of 3 (range 1 to 5) were identified. Follow-up periods varied between day of last injection and eighteen months. Forty trials included comparisons of hyaluronan/hylan and placebo (saline or arthrocentesis), ten trials included comparisons of intra-articular (IA) corticosteroids, six trials included comparisons of nonsteroidal anti-inflammatory drugs (NSAIDs), three trials included comparisons of physical therapy, two trials included comparisons of exercise, two trials included comparisons of arthroscopy, two trials included comparisons of conventional treatment, and fifteen trials included comparisons of other hyaluronans/hylan. The pooled analyses of the effects of viscosupplements against 'placebo' controls generally supported the efficacy of this class of intervention. In these same analyses, differential efficacy effects were observed for different products on different variables and at different timepoints. Of note is the 5 to 13 week post injection period which showed a percent improvement from baseline of 28 to 54% for pain and 9 to 32% for function. In general, comparable efficacy was noted against NSAIDs and longer-term benefits were noted in comparisons against IA corticosteroids. In general, few adverse events were reported in the hyaluronan/hylan trials included in these analyses. Authors' conclusions Based on the aforementioned analyses, viscosupplementation is an effective treatment for OA of the knee with beneficial effects: on pain, function and patient global assessment; and at different post injection periods but especially at the 5 to 13 week post injection period. It is of note that the magnitude of the clinical effect, as expressed by the WMD and standardised mean difference (SMD) from the RevMan 4.2 output, is different for different products, comparisons, timepoints, variables and trial designs. However, there are few randomised head-to-head comparisons of different viscosupplements and readers should be cautious, therefore, in drawing conclusions regarding the relative value of different products. The clinical effect for some products, against placebo, on some variables at some timepoints is in the moderate to large effect-size range. Readers should refer to relevant tables to review specific detail given the heterogeneity in effects across the product class and some discrepancies observed between the RevMan 4.2 analyses and the original publications. Overall, the analyses performed are positive for the HA class and particularly positive for some products with respect to certain variables and timepoints, such as pain on weight bearing at 5 to 13 weeks postinjection. In general, sample-size restrictions preclude any definitive comment on the safety of the HA class of products; however, within the constraints of the trial designs employed no major safety issues were detected. In some analyses viscosupplements were comparable in efficacy to systemic forms of active intervention, with more local reactions but fewer systemic adverse events. In other analyses HA products had more prolonged effects than IA corticosteroids. Overall, the aforementioned analyses support the use of the HA class of products in the treatment of knee OA.

The relationship of adult attachment to emotion, catastrophizing, control, threshold and tolerance, in experimentally-induced pain

Although insecure attachment has been associated with a range of variables linked with problematic adjustment to chronic pain, the causal direction of these relationships remains unclear. Adult attachment style is, theoretically, developmentally antecedent to cognitions, emotions and behaviours (and might therefore be expected to contribute to maladjustment). It can also be argued, however, that the experience of chronic pain increases attachment insecurity. This project examined this issue by determining associations between adult attachment characteristics, collected prior to an acute (coldpressor) pain experience, and a range of emotional, cognitive, pain tolerance, intensity and threshold variables collected during and after the coldpressor task. A convenience sample of 58 participants with no history of chronic pain was recruited. Results demonstrated that attachment anxiety was associated with lower pain thresholds; more stress, depression, and catastrophizing; diminished perceptions of control over pain; and diminished ability to decrease pain. Conversely, secure attachment was linked with lower levels of depression and catastrophizing, and more control over pain. Of particular interest were findings that attachment style moderated the effects of pain intensity on the tendency to catastrophize, such that insecurely attached individuals were more likely to catastrophize when reporting high pain intensity. This is the first study to link attachment with perceptions of pain in a pain-free sample. These findings cast anxious attachment as a vulnerability factor for chronic pain following acute episodes of pain, while secure attachment may provide more resilience. (c) 2006 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Effect of experimentally induced low back pain on postural sway with breathing

Although breathing perturbs balance, in healthy individuals little sway is detected in ground reaction forces because small movements of the spine and lower limbs compensate for the postural disturbance. When people have chronic low back pain (LBP), sway at the ground is increased, possibly as a result of reduced compensatory motion of the trunk. The aim of this study was to determine whether postural compensation for breathing is reduced during experimentally induced pain. Subjects stood on a force plate with eyes open, eyes closed, and while breathing with hypercapnoea before and after injection of hypertonic saline into the right lumbar longissimus muscle to induce LBP. Motion of the lumbar spine, pelvis, and lower limbs was measured with four inclinometers fixed over bony landmarks. During experimental pain, motion of the trunk in association with breathing was reduced. However, despite this reduction in motion, there was no increase in postural sway with breathing. These data suggest that increased body sway with breathing in people with chronic LBP is not simply because of reduced trunk movement, but instead, indicates changes in coordination by the central nervous system that are not replicated by experimental nociceptor stimulation.

Adult attachment, anxiety, and pain self-efficacy as predictors of pain intensity and disability

Pain self-efficacy and anxiety have each been shown to contribute substantially to pain intensity and pain-related disability. Although adult attachment theory has been related separately to chronic pain, anxiety, and self-efficacy, it has not before been investigated with either pain self-efficacy or anxiety in the context of chronic pain. This study investigated the interrelations between these aspects of the chronic pain experience and their relative contributions towards pain intensity and disability. A clinical sample of 152 chronic pain patients participated in this study, completing self-report measures of attachment, self-efficacy, pain intensity, and disability, prior to attending a multidisciplinary pain clinic. Results revealed that fearful and preoccupied (anxious) attachment categories were associated with low pain self-efficacy, while high scores on the attachment dimension of comfort with closeness were linked with high pain self-efficacy, particularly for males. Insecure attachment (whether defined in terms of categories or dimensions) was related to higher levels of anxiety. Pain self-efficacy proved a stronger predictor of pain intensity than did anxiety and was a stronger predictor of disability than pain intensity or anxiety. In addition, comfort with closeness moderated the associations between pain self-efficacy and disability, pain self-efficacy and pain intensity, and anxiety and disability. Together, these findings support the value of adopting an attachment theoretical approach in the context of chronic pain. Treatment considerations and future research directions are considered. (c) 2006 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Labor force activity among Australians with musculoskeletal disorders comorbid with depression and anxiety disorders

Aim: Musculoskeletal disorders (MSD) are a leading cause of work-related disability. This investigation explored the impact of MSD comorbid with depression and anxiety disorders, on labor force activity. Methods: The Australian Bureau of Statistics provided confidentialized data files collected from a household sample of 37,580 people. MSD, affective, and anxiety disorders were identified and employment restrictions were assessed at four levels of severity. Results: Anxiety and depression of six months duration was present in 12.1% of people with MSD. Comorbidity magnified the negative impacts of single conditions on labor force activity. Most at risk were people with back problems and comorbid depression, people with arthritis or other MSD and comorbid anxiety, males with MSD and comorbid depression, and females with MSD and comorbid anxiety. Conclusions: The results suggest that the occupational rehabilitation needs of people with MSD comorbid with depression or anxiety may currently be underestimated.

The burden of musculoskeletal disease - a global perspective

Musculoskeletal diseases are one of the major causes of disability around the world and have been a significant reason for the development of the Bone and Joint Decade. Rheumatoid arthritis, osteoarthritis and back pain are important causes of disability-adjusted-life years in both the developed and developing world. COPCORD studies in over 17 countries around the world have identified back and knee pain as common in the community and are likely to increase with the ageing population. Musculoskeletal conditions are an enormous cost to the community in economic terms, and these figures emphasise how governments need to invest in the future and look at ways of reducing the burden of musculoskeletal diseases by encouraging exercise and obesity prevention campaigns.

Re-treatment of chronic hepatitis C patients after relapse: efficacy of peginterferon-alpha-2a (40 kDa) and ribavirin

SUMMARY. We conducted a randomized multinational study to determine whether 48 weeks of re-treatment with peginterferon- alpha-2a (40 kDa) plus ribavirin would induce a sustained virological response (SVR) in relapsed chronic hepatitis C patients. Patients who had previously relapsed during 24 weeks of untreated follow-up, after having achieved an end-of-treatment virological response with 24 weeks of peginterferon-alpha-2a (40 kDa)/ribavirin combination therapy, within a phase III trial, were studied. Although the recommended dosage was the same as that used at the end of the initial trial, adjustments were permitted. Data on serious adverse events, or adverse events that resulted in dose reductions or discontinuations, were collected. Following re-treatment, the overall SVR rate in the 64 patients was 55%. The SVR rates in patients infected with hepatitis C virus (HCV) genotype 1 and non-1 genotypes were 51% and 63%, respectively. Early (week 12) virological responses were seen in 39 patients (61%) and were predictive of an SVR. Re-treatment was well tolerated. The most frequent adverse events recorded were fatigue (5%) and abdominal pain (3%). Dosages of peginterferon-alpha-2a (40 kDa) and/or ribavirin were modified because of adverse events in 3% and 13% of patients, and because of laboratory abnormalities in 23% and 5% of patients, respectively. Thus, a 48-week course of peginterferon-alpha-2a (40 kDa) plus ribavirin induces an SVR in 55% of patients who relapsed during follow-up after 24 weeks of combination therapy. Physicians should not hesitate to offer re-treatment to patients who relapse after an initial, 24-week course of combination therapy, or who have prematurely stopped treatment because, for example, of laboratory abnormalities.

N-type calcium channel blockers: Novel therapeutics for the treatment of pain

Highly selective Cav2.2 voltage-gated calcium channel (VGCC) inhibitors have emerged as a new class of therapeutics for the treatment of chronic and neuropathic pain. Cone snail venoms provided the first drug in class with FDA approval granted in 2005 to Prialt (ω-conotoxin MVIIA, Elan) for the treatment of neuropathic pain. Since this pioneering work, major efforts underway to develop alternative small molecule inhibitors of Cav2.2 calcium channel have met with varied success. This review focuses on the properties of the Cav2.2 calcium channel in different pain states, the action of ω-conotoxins GVIA, MVIIA and CVID, describing their structure-activity relationships and potential as leads for the design of improved Cav2.2 calcium channel therapeutics, and finally the development of small molecules for the treatment of chronic pain.

Low back pain patients demonstrate increased hip extensor muscle activity during standardized submaximal rotation efforts

Study Design. A comparative study of trunk and hip extensor muscle recruitment patterns in 2 subject groups. Objective. To examine for changes in recruitment of the hip and back extensor muscles during low level isometric trunk rotation efforts in chronic low back pain (CLBP) subjects by comparison with matched asymptomatic control subjects. Summary of Background Data. Anatomic and biomechanical models have provided evidence that muscles attaching to the thoracolumbar fascia (TLF) are important for providing stabilization to the lumbopelvic region during trunk rotation. This has guided rehabilitation programs. The muscles that link diagonally to the posterior layer of the TLF have not previously been examined individually and compared during low-level trunk rotation efforts in CLBP patients and matched controls. Methods. Thirty CLBP patients and 30 matched controls were assessed using surface electromyography (EMG) as they performed low-level isometric rotation efforts while standing upright. Muscles studied included latissimus dorsi, erector spinae, upper and lower gluteus maximus, and biceps femoris. Subjects performed the rotation exertion with various levels of external trunk support, related to different functional tasks. Results. EMG results demonstrated that subjects with CLBP had significantly higher levels of recruitment for the lower and upper gluteus maximus (P < 0.05), hamstrings (P < 0.05), and erector spinae muscles (P < 0.05) during rotation to the left compared with the control subjects. Conclusion. This study provided evidence of increased muscle recruitment in CLBP patients when performing a standardized trunk rotation task. These results may have implications for the design of therapeutic exercise programs for CLBP patients.

Symptom prevalence and clustering of symptoms in people living with chronic hepatitis C infection

Quality of life has been shown to be poor among people living with chronic hepatitis C However, it is not clear how this relates to the presence of symptoms and their severity. The aim of this study was to describe the typology of a broad array of symptoms that were attributed to hepatitis C virus (HCV) infection. Phase I used qualitative methods to identify symptoms. In Phase 2, 188 treatment-naive people living with HCV participated in a quantitative survey. The most prevalent symptom was physical tiredness (86%) followed by irritability (75%), depression (70%), mental tiredness (70%), and abdominal pain (68%). Temporal clustering of symptoms was reported in 62% of participants. Principal components analysis identified four symptom clusters: neuropsychiatric (mental tiredness, poor concentration, forgetfulness, depression, irritability, physical tiredness, and sleep problems); gastrointestinal (day sweats, nausea, food intolerance, night sweats, abdominal pain, poor appetite, and diarrhea); algesic (joint pain, muscle pain, and general body pain); and dysesthetic (noise sensitivity, light sensitivity, skin. problems, and headaches). These data demonstrate that symptoms are prevalent in treatment-naive people with HCV and support the hypothesis that symptom clustering occurs.

Opioids and NMDA receptors: Neuro-excitation and abnormal pain behaviours

In the clinical setting, chronic administration of high doses of systemic morphine may result in neuro-excitatory behaviours such as myoclonus and allodynia in some patients. Additionally, high doses of m-opioid agonists such as morphine administered chronically by the intrathecal route in both rats and humans, as well as DAMGO in rats, have been reported to produce neuro-excitatory behaviours. However, more recently, it has begun to be appreciated that even at normal analgesic doses, opioids such as morphine are capable not only of activating pain inhibitory systems (analgesia/antinociception), but they also activate pain facilitatory systems such that post-opioid allodynia/hyperalgesia may be evident after cessation of opioid treatment. Whilst it is well documented that opioid receptors mediate the inhibitory effects of opioid analgesics, the excitatory and pro-nociceptive effects of opioids appear to involve indirect activation of N-methyl-D-aspartate (NMDA) receptors, such that the extent of pain relief produced may be the net effect of these two opposing actions. Apart from the NMDA-nitric oxide (NO) pro-nociceptive signaling cascade, considerable evidence also implicates dynorphin A as well as the endogenous anti-opioid peptides cholecystokinin (CCK), neuropeptide FF (NPFF) and orphanin FQ/nociceptin, in mediating opioid-induced neuro-excitation and abnormal pain behaviours. Apart from the neuro-excitatory effects that may be produced by the parent opioid, systemic administration of some opioid analgesics such as morphine and hydromorphone in rats and humans results in their rapid conversion to 3-glucuronide metabolites that also contribute significantly to the neuro-excitatory and abnormal pain behaviours produced

Psychophysiological responses to pain identify reproducible human clusters

Pain is a ubiquitous yet highly variable experience. The psychophysiological and genetic factors responsible for this variability remain unresolved. We hypothesised the existence of distinct human pain clusters (PCs) composed of distinct psychophysiological and genetic profiles coupled with differences in the perception and the brain processing of pain. We studied 120 healthy subjects in whom the baseline personality and anxiety traits and the serotonin transporter-linked polymorphic region (5-HTTLPR) genotype were measured. Real-time autonomic nervous system parameters and serum cortisol were measured at baseline and after standardised visceral and somatic pain stimuli. Brain processing reactions to visceral pain were studied in 29 subjects using functional magnetic resonance imaging (fMRI). The reproducibility of the psychophysiological responses to pain was assessed at 1 year. In group analysis, visceral and somatic pain caused an expected increase in sympathetic and cortisol responses and activated the pain matrix according to fMRI studies. However, using cluster analysis, we found 2 reproducible PCs: at baseline, PC1 had higher neuroticism/anxiety scores (P ≤ 0.01); greater sympathetic tone (P < 0.05); and higher cortisol levels (P ≤ 0.001). During pain, less stimulus was tolerated (P ≤ 0.01), and there was an increase in parasympathetic tone (P ≤ 0.05). The 5-HTTLPR short allele was over-represented (P ≤ 0.005). PC2 had the converse profile at baseline and during pain. Brain activity differed (P ≤ 0.001); greater activity occurred in the left frontal cortex in PC1, whereas PC2 showed greater activity in the right medial/frontal cortex and right anterior insula. In health, 2 distinct reproducible PCs exist in humans. In the future, PC characterization may help to identify subjects at risk for developing chronic pain and may reduce variability in brain imaging studies. © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.