Local pain and spreading hyperalgesia induced by intramuscular injection of nerve growth factor are not reduced by local anesthesia of the muscle

Injections with local anesthesia for therapeutic and diagnostic purposes are common clinical practice. This double-blind placebo controlled study explores the rational of local anesthetic blocks for the detection of muscle pain as the primary generator in spreading hyperalgesic conditions.

Statin therapy induces ultrastructural damage in skeletal muscle in patients without myalgia

Muscle pain and weakness are frequent complaints in patients receiving 3-hydroxymethylglutaryl coenzymeA (HMG CoA) reductase inhibitors (statins). Many patients with myalgia have creatine kinase levels that are either normal or only marginally elevated, and no obvious structural defects have been reported in patients with myalgia only. To investigate further the mechanism that mediates statin-induced skeletal muscle damage, skeletal muscle biopsies from statin-treated and non-statin-treated patients were examined using both electron microscopy and biochemical approaches. The present paper reports clear evidence of skeletal muscle damage in statin-treated patients, despite their being asymptomatic. Though the degree of overall damage is slight, it has a characteristic pattern that includes breakdown of the T-tubular system and subsarcolemmal rupture. These characteristic structural abnormalities observed in the statin-treated patients were reproduced by extraction of cholesterol from skeletal muscle fibres in vitro. These findings support the hypothesis that statin-induced cholesterol lowering per se contributes to myocyte damage and suggest further that it is the specific lipid/protein organization of the skeletal muscle cell itself that renders it particularly vulnerable.

Association between statin-associated myopathy and skeletal muscle damage

BACKGROUND: Many patients taking statins often complain of muscle pain and weakness. The extent to which muscle pain reflects muscle injury is unknown. METHODS: We obtained biopsy samples from the vastus lateralis muscle of 83 patients. Of the 44 patients with clinically diagnosed statin-associated myopathy, 29 were currently taking a statin, and 15 had discontinued statin therapy before the biopsy (minimal duration of discontinuation 3 weeks). We also included 19 patients who were taking statins and had no myopathy, and 20 patients who had never taken statins and had no myopathy. We classified the muscles as injured if 2% or more of the muscle fibres in a biopsy sample showed damage. Using reverse transcriptase polymerase chain reaction, we evaluated the expression levels of candidate genes potentially related to myocyte injury. RESULTS: Muscle injury was observed in 25 (of 44) patients with myopathy and in 1 patient without myopathy. Only 1 patient with structural injury had a circulating level of creatine phosphokinase that was elevated more than 1950 U/L (10x the upper limit of normal). Expression of ryanodine receptor 3 was significantly upregulated in patients with biopsy evidence of structural damage (1.7, standard error of the mean 0.3). INTERPRETATION: Persistent myopathy in patients taking statins reflects structural muscle damage. A lack of elevated levels of circulating creatine phosphokinase does not rule out structural muscle injury. Upregulation of the expression of ryanodine receptor 3 is suggestive of an intracellular calcium leak.

No Effect of Acupuncture in the Relief of Delayed-Onset Muscle Soreness: Results of a Randomized Controlled Trial

BACKGROUND Delayed-onset muscle soreness (DOMS) is a common symptom in people participating in exercise, sport, or recreational physical activities. Several remedies have been proposed to prevent and alleviate DOMS. DESIGN AND METHODS A five-arm randomized controlled study was conducted to examine the effects of acupuncture on eccentric exercise-induced DOMS of the biceps brachii muscle. Participants were recruited through convenience sampling of students and general public. Participants were randomly allocated to needle, laser, sham needle, sham laser acupuncture, and no intervention. Outcome measures included pressure pain threshold (PPT), pain intensity (visual analog scale), and maximum isometric voluntary force. RESULTS Delayed-onset muscle soreness was induced in 60 participants (22 females, age 23.6 ± 2.8 years, weight 66.1 ± 9.6 kg, and height 171.6 ± 7.9 cm). Neither verum nor sham interventions significantly improved outcomes within 72 hours when compared with no treatment control (P > 0.05). CONCLUSIONS Acupuncture was not effective in the treatment of DOMS. From a mechanistic point of view, these results have implications for further studies: (1) considering the high-threshold mechanosensitive nociceptors of the muscle, the cutoff for PPT (5 kg/cm) chosen to avoid bruising might have led to ceiling effects; (2) the traditional acupuncture regimen, targeting muscle pain, might have been inappropriate as the DOMS mechanisms seem limited to the muscular unit and its innervation. Therefore, a regionally based regimen including an intensified intramuscular needling (dry needling) should be tested in future studies, using a higher cutoff for PPT to avoid ceiling effects.

[Glomerulonephritis and vasculitis as causes of arterial hypertension]

The various types of glomerulonephritis, including many forms of vasculitis, are responsible for about 15% of cases of end-stage renal disease (ESRD). Arterial hypertension represents a frequent finding in patients suffering from glomerulonephritis or vasculitis and hypertension also serves as an indicator for these severe types of diseases. In addition, there are symptoms and signs like hematuria, proteinuria and renal failure. Especially, rapidly progressive glomerulonephritis (RPGN) constitutes a medical emergency and must not be missed by treating physicians. This disease can either occur limited to the kidneys or in the context of a systemic inflammatory disorder, like a vasculitis. If left untreated, RPGN can lead to a necrotizing destruction of glomeruli causing irreversible kidney damage within several months or even weeks. With respect to the immunologically caused vasculitis, there are - depending upon the severity and type of organ involved - many clinical warning signs to be recognized, such as arterial hypertension, hemoptysis, arthalgias, muscle pain, palpable purpura, hematuria, proteinuria and renal failure. In addition, constitutional signs, such as fever and loss of body weight may occur concurrently. Investigations of glomerulonephritis or vasculitis must contain a careful and complete examination of family history and medications used by the respective patient. Thereafter, a thorough clinical examination must follow, including skin, joints and measurement of arterial blood pressure. In addition, a spectrum of laboratory analyses is required in blood, such as full blood screen, erythrocyte sedimentation rate, CRP, creatinine, urea and glucose, and in urine, including urinalysis looking for hematuria, red cell casts and proteinuria. Importantly, proteinuria needs to be quantified by the utilization of a random urine sample. Proteinuria > 3g/d is diagnostic for a glomerular damage. These basic tests are usually followed by more specialized analyses, such as a screening for infections, including search for HIV, hepatitis B or C and various bacteria, and for systemic inflammatory diseases, including tests for antibodies, such as ANA, anti-dsDNA, ANCA, anti-GBM and anti-CCP. In cases of membranous nephropathy, antibodies against phospholipase-A2-receptor need to be looked for. Depending upon the given clinical circumstances and the type of disease, a reasonable tumor screening must be performed, especially in cases of membranous and minimal-change nephropathy. Finally, radiological examinations will complete the initial work-up. In most cases, at least an ultrasound of the kidney is mandatory. Thereafter, in most cases a renal biopsy is required to establish a firm diagnosis to define all treatment options and their chance of success. The elimination of a specific cause for a given glomerulonephritis or vasculitis, such as an infection, a malignancy or a drug-related side-effect, remains the key principle in the management of these diseases. ACE-inhibitors, angiotensin receptor-blockers, aldosteron antagonists and renin-inhibitors remain the mainstay in the therapy of arterial hypertension with proteinuria. Only in cases of persistently high proteinuria, ACE-inhibitors and angiotensin receptor blockers can be prescribed in combination. Certain types of glomerulonephritis and essentially all forms of vasculitis require some form of more specific anti-inflammatory therapy. Respective immunosuppressive drug regimens contain traditionally medications, such as glucocorticoids (e. g. prednisone), cyclosporine A, mycophenolate mofetil, cyclophosphamide, and azathioprine. With respect to more severe forms of glomerulonephritis and vasculitis, the antibody rituximab represents a new and less toxic alternative to cyclophosphamide. Finally, in certain special cases, like Goodpasture's syndrome or severe ANCA-positive vasculitis, a plasma exchange will be useful and even required.

[Efficacy of specific physiotherapy for temporomandibular joint dysfunction of muscular origin]

INTRODUCTION: Little explanation is given to patients with temporomandibular disorders and muscles dysfunction on the mechanism and the expected results of conservative treatment. The purpose of this prospective study was to evaluate the efficacy of specific physical therapy prescribed after this explanation was given and also after using a flat occlusal splint adapted only if muscle pain remained after physical therapy. MATERIAL AND METHOD: Twenty-seven patients with temporomandibular joint dysfunction of muscular origin were evaluated after a mean of six sessions of specialized physical therapy with professionals. Patients were treated by oral and facial massages and were trained for self-reeducation. They were also trained for a specific exercise named the "propulsive/opening maneuver". Every patient was questioned on the subjective evolution of pain and the current maximal pain was evaluated with the Visual Analogical Scale (VAS). Clinical evaluation focused on tenderness of masticator muscles and also assessed the changes in the amplitude of mouth opening. RESULTS: Ninety-three percent of the patients treated by specific physical therapy had a significant reduction of their maximal pain feeling (p<0.05). The recovery of an optimal mouth opening without deviation was also improved as was the protrusion. For 33% of the patients a flat nighttime occlusal splint was necessary as a complementary treatment. Twenty-two percent of the patients decided to change their treatment for alternative therapies (osteopathy, acupuncture, etc.). Fifty percent of the patients were convinced of the efficacy of the prescribed treatment. DISCUSSION: Patients who undertake the specific physical therapy and who regularly practice self-physical therapy succeed in relaxing their masticator muscles and in decreasing the level of pain. Explanations given by the doctor concerning the etiology of pain, during temporomandibular joint dysfunction of muscular origin, and the purpose of specific physical therapy increase the capacity of self-relaxation. A flat occlusal splint is indicated for patients who grind their teeth and for those whose pain resists to physical therapy.

Rhabdomyolysis in association with simvastatin and amiodarone

OBJECTIVE To report a case of severe myopathy associated with concomitant simvastatin and amiodarone therapy. CASE SUMMARY A 63-year-old white man with underlying insulin-dependent diabetes, recent coronary artery bypass surgery, and postoperative hemiplegia was treated with aspirin, metoprolol, furosemide, nitroglycerin, and simvastatin. Due to recurrent atrial fibrillation, oral anticoagulation with phenprocoumon and antiarrhythmic treatment with amiodarone were initiated. Four weeks after starting simvastatin 40 mg/day and 2 weeks after initiating amiodarone 1 g/day for 10 days, then 200 mg/day, he developed diffuse muscle pain with generalized muscular weakness. Laboratory investigations revealed a significant increase of creatine kinase (CK) peaking at 40 392 U/L. Due to a suspected drug interaction of simvastatin with amiodarone, both drugs were stopped. CK normalized over the following 8 days, and the patient made an uneventful recovery. An objective causality assessment revealed that the myopathy was probably related to simvastatin. DISCUSSION Myopathy is a rare but potentially severe adverse reaction associated with statins. Besides high statin doses, concomitant use of fibrates, defined comorbidities, and concurrent use of inhibitors of cytochrome P450 are important additional risk factors. This is especially relevant if statins predominantly metabolized by CYP3A4 are combined with inhibitors of this isoenzyme. Amiodarone is a potent inhibitor of several different CYP isoenzymes, including CYP3A4. CONCLUSIONS Avoiding the concomitant use of drugs with the potential to inhibit CYP-dependent metabolism (eg, amiodarone) or elimination of statins may decrease the risk of statin-associated myopathy. Alternatively, if drug therapy with a potent CYP inhibitor is inevitable, choosing a statin without relevant CYP metabolism (eg, pravastatin) should be considered.

Neuromechanical gait adaptations in women with joint hypermobility - an exploratory study

BACKGROUND Joint hypermobility is known to be associated with joint and muscle pain, joint instability and osteoarthritis. Previous work suggested that those individuals present an altered neuromuscular behavior during activities such as level walking. Therefore, the aim of this study was to explore the differences in ground reaction forces, temporal parameters and muscle activation patterns during gait between normomobile and hypermobile women, including symptomatic and asymptomatic hypermobile individuals. METHODS A total of 195 women were included in this cross-sectional study, including 67 normomobile (mean 24.8 [SD 5.4] years) and 128 hypermobile (mean 25.8 [SD 5.4] years), of which 56 were further classified as symptomatic and 47 as asymptomatic. The remaining 25 subjects could not be further classified. Ground reaction forces and muscle activation from six leg muscles were measured while the subjects walked at a self-selected speed on an instrumented walkway. Temporal parameters were derived from ground reaction forces and a foot accelerometer. The normomobile and hypermobile groups were compared using independent samples t-tests, whereas the normomobile, symptomatic and asymptomatic hypermobile groups were compared using one-way ANOVAs with Tukey post-hoc tests (significance level=0.05). FINDINGS Swing phase duration was higher among hypermobile (P=0.005) and symptomatic hypermobile (P=0.018) compared to normomobile women. The vastus medialis (P=0.049) and lateralis (P=0.030) and medial gastrocnemius (P=0.011) muscles showed higher mean activation levels during stance in the hypermobile compared to the normomobile group. INTERPRETATION Hypermobile women might alter their gait pattern in order to stabilize their knee joint.

Generalized expansion of nociceptive reflex receptive fields in chronic pain patients

Widespread central hypersensitivity is present in chronic pain and contributes to pain and disability. According to animal studies, expansion of receptive fields of spinal cord neurons is involved in central hypersensitivity. We recently developed a method to quantify nociceptive receptive fields in humans using spinal withdrawal reflexes. Here we hypothesized that patients with chronic pelvic pain display enlarged reflex receptive fields. Secondary endpoints were subjective pain thresholds and nociceptive withdrawal reflex thresholds after single and repeated (temporal summation) electrical stimulation. 20 patients and 25 pain-free subjects were tested. Electrical stimuli were applied to 10 sites on the foot sole for evoking reflexes in the tibialis anterior muscle. The reflex receptive field was defined as the area of the foot (fraction of the foot sole) from which a muscle contraction was evoked. For the secondary endpoints, the stimuli were applied to the cutaneous innervation area of the sural nerve. Medians (25-75 percentiles) of fraction of the foot sole in patients and controls were 0.48 (0.38-0.54) and 0.33 (0.27-0.39), respectively (P=0.008). Pain and reflex thresholds after sural nerve stimulation were significantly lower in patients than in controls (P<0.001 for all measurements). This study provides for the first time evidence for widespread expansion of reflex receptive fields in chronic pain patients. It thereby identifies a mechanism involved in central hypersensitivity in human chronic pain. Reverting the expansion of nociceptive receptive fields and exploring the prognostic meaning of this phenomenon may become future targets of clinical research.

Muscle ischaemia in patients with orthostatic hypotension assessed by velocity recovery cycles

Patients with orthostatic hypotension may experience neck pain radiating to the occipital region of the skull and the shoulders while standing (so-called coat-hanger ache). This study assessed muscle membrane potential in the trapezius muscle of patients with orthostatic hypotension and healthy subjects during head-up tilt (HUT), by measuring velocity recovery cycles (VRCs) of muscle action potentials as an indicator of muscle membrane potential.

Cervical muscle area measurements in whiplash patients: Acute, 3, and 6 months of follow-up

To investigate the role of the cervical spine muscles in whiplash injury. We hypothesized that (i) cervical muscle hypotrophy would be evident after a 6-month follow-up and, (ii) cervical muscle hypotrophy would correlate with symptom persistence probably related to pain or inactivity.

Hip abductor defect repair by means of a vastus lateralis muscle shift

Scarring or detachment of the hip abductors, particularly of the gluteus medius, from their insertion may lead to severe abductor weakness, recurrent dislocations, pain, and diminished quality of life. We performed a retrospective study to evaluate whether vastus lateralis shift is associated with satisfactory results and low rate of complications. Eleven adults underwent vastus lateralis shift to bridge a well-documented abductor muscles' insertion defect. Preoperative and postoperative hip functions were assessed applying the Merle d'Aubigne score, British Medical Council scale, and Visual Analog Scale. Significant postoperative improvement was noted in mean Merle d'Aubigne score, gluteus medius muscle force, and quality of life. Vastus lateralis shift represents a viable treatment option for hip abductor deficiency, significantly improving abductor strength and overall quality of life.

miR-199a-5p regulates urothelial permeability and may play a role in bladder pain syndrome

Defects in urothelial integrity resulting in leakage and activation of underlying sensory nerves are potential causative factors of bladder pain syndrome, a clinical syndrome of pelvic pain and urinary urgency/frequency in the absence of a specific cause. Herein, we identified the microRNA miR-199a-5p as an important regulator of intercellular junctions. On overexpression in urothelial cells, it impairs correct tight junction formation and leads to increased permeability. miR-199a-5p directly targets mRNAs encoding LIN7C, ARHGAP12, PALS1, RND1, and PVRL1 and attenuates their expression levels to a similar extent. Using laser microdissection, we showed that miR-199a-5p is predominantly expressed in bladder smooth muscle but that it is also detected in mature bladder urothelium and primary urothelial cultures. In the urothelium, its expression can be up-regulated after activation of cAMP signaling pathways. While validating miR-199a-5p targets, we delineated novel functions of LIN7C and ARHGAP12 in urothelial integrity and confirmed the essential role of PALS1 in establishing and maintaining urothelial polarity and junction assembly. The present results point to a possible link between miR-199a-5p expression and the control of urothelial permeability in bladder pain syndrome. Up-regulation of miR-199a-5p and concomitant down-regulation of its multiple targets might be detrimental to the establishment of a tight urothelial barrier, leading to chronic pain.

Managing chronic whiplash associated pain with a combination of low-dose opioid (remifentanil) and NMDA-antagonist (ketamine)

The aim was to investigate the efficacy of a combination of low-dose remifentanil (REMI) and ketamine (KET) compared to the single drugs and placebo (P) on whiplash associated pain (WAD) in a double-blind, randomized, placebo-controlled, cross-over study. Twenty patients with chronic (>1 year) WAD were included. Four different drug combinations were tested in four sessions: placebo/placebo (P/P), placebo/remifentanil (P/REMI), ketamine/placebo (KET/P) and ketamine/remifentanil (KET/REMI). Target concentrations were 1 and 2ng/ml (stepwise) for remifentanil and 100ng/ml for ketamine. Habitual pain intensity was assessed on a visual analogue scale (VAS). Experimental pain was assessed with electrical stimulation (single and repeated) of tibialis anterior (TA) muscle, pressure pain algometry applied over infraspinatus (IS) and TA muscles and VAS scores after intramuscular hypertonic saline infusion in TA. KET/REMI significantly reduced habitual pain. KET/REMI infused at low REMI target concentration (1ng/ml) significantly elevated electrical intramuscular pain thresholds (single and repeated). Pain thresholds to electrical stimulation were similarly increased by both P/REMI and KET/REMI at 2ng/ml target concentration. Pressure pain thresholds were increased by both KET/REMI and P/REMI. VAS-scores after intramuscular saline were also similarly decreased by both REMI combinations. Seven out of 20 subjects were non-responders (<50% pain relief). No correlation was found between effects on spontaneous pain and experimental pain. KET/REMI showed an analgesic effect on habitual pain. Experimental pain was attenuated by both combinations containing the opioid, however, KET seemed to enhance the effect of REMI on electrical pain thresholds when a low REMI target concentration was used.

Effect of therapeutic exercise for hip osteoarthritis pain: results of a meta-analysis

OBJECTIVE: Recommendations for lower extremity osteoarthritis (OA) and exercise have been primarily based on knee studies. To provide more targeted recommendations for the hip, we gathered evidence for the efficacy of exercise for hip OA from randomized controlled trials. METHODS: A bibliographic search identified trials that were randomized, controlled, completed by >or=60% of subjects, and involved an exercise group (strengthening and/or aerobic) versus a non exercise control group for pain relief in hip OA. Two reviewers independently performed the data extraction and contacted the authors when necessary. Effect sizes (ES) of treatment versus control and the I(2) statistic to assess heterogeneity across trials were calculated. Trial data were combined using a random-effects meta-analysis. RESULTS: Nine trials met the inclusion criteria (1,234 subjects), 7 of which combined hip and knee OA; therefore, we contacted the authors who provided the data on hip OA patients. In comparing exercise treatment versus control, we found a beneficial effect of exercise with an ES of -0.38 (95% confidence interval [95% CI] -0.68, -0.08; P = 0.01), but with high heterogeneity (I(2) = 75%) among trials. Heterogeneity was caused by 1 trial consisting of an exercise intervention that was not administered in person. Removing this study left 8 trials (n = 493) with similar exercise strategy (specialized hands-on exercise training, all of which included at least some element of muscle strengthening), and demonstrated exercise benefit with an ES of -0.46 (95% CI -0.64, -0.28; P < 0.0001). CONCLUSION: Therapeutic exercise, especially with an element of strengthening, is an efficacious treatment for hip OA.