Chronic Osteoarthritis Pain Research Articles

The Relationship Between Reminiscence Functions, Optimism, Depressive Symptoms, Physical Activity, and Pain in Older Adults.

The study purpose was to examine the association between reminiscence functions, optimism, depressive symptoms, physical activity, and pain in older adults with chronic lower extremity osteoarthritis pain. One hundred ninety-five community-dwelling adults were interviewed using the Modified Reminiscence Functions Scale, Brief Pain Inventory, Life Orientation Test-Revised, Center for Epidemiologic Studies Short Depression Scale, and Physical Activity Scale for the Elderly in random counterbalanced order. Structural equation modeling supported chronic pain as positively associated with depressive symptoms and comorbidities and unrelated to physical activity. Depressive symptoms were positively associated with self-negative reminiscence and negatively associated with optimism. Spontaneous reminiscence was not associated with increased physical activity or reduced pain. Individuals may require facilitated integrative reminiscence to assist them in reinterpreting negative memories in a more positive way. Facilitated integrative reminiscence about enjoyed past physical activity is a potential way to increase physical activity, but must be tested in future research. [Res Gerontol Nurs. 2016; 9(5):223-231.].

Efficacy and safety of fulranumab as monotherapy in patients with moderate to severe, chronic knee pain of primary osteoarthritis: a randomised, placebo- and active-controlled trial.

The efficacy and safety of monotherapy with fulranumab, a monoclonal antibody that neutralises human nerve growth factor (NGF), was evaluated compared with placebo and an active comparator, controlled-release (CR) oxycodone, in patients with moderate to severe chronic knee pain of primary osteoarthritis (OA). In this phase-2, double-blind (DB), double-dummy, placebo- and active-controlled study, patients (40-80years) were randomised (1:1:1:1) to placebo, fulranumab 3 or 9mg every 4weeks (Q4 wk), or oxycodone CR twice-daily. Primary efficacy end-point: responder rates based on percent improvement in average osteoarthritis-related pain intensity (OAPI) scores from baseline to week-12 or when Food and Drug Administration (FDA) put a clinical hold on all anti-NGF trials, whichever was earlier. Secondary efficacy end-points: average OAPI score (week-16), Western Ontario and McMaster Osteoarthritis Index Global Score and subscales (pain, physical function, stiffness), and Patient Global Assessment. As of an FDA clinical hold on all anti-NGF trials, only 196/300 patients were randomised and 33% (65/196) had completed 12weeks of the 16-week DB phase. Responders were patients who did not withdraw and whose pain improved. Responder rates were not significantly different between fulranumab treatment groups (3mgQ4wk: 71%, p=0.739; 9mgQ4wk: 80%, p=0.843) and placebo (77%), whereas, oxycodone CR (56%) had significantly lower responder rates in comparison to both fulranumab (3mgQ4wk: p=0.008; 9mgQ4wk: p=0.012) and placebo (p=0.0021). Secondary efficacy results were consistent with primary. None of the joint replacements (four in three patients) were adjudicated as rapidly progressing OA/osteonecrosis. Low sample size because of early termination make interpretation of this study difficult, but fulranumab monotherapy resulted in significantly better pain relief and function compared with oxycodoneCR (but not against placebo) and was generally well-tolerated. ClinicalTrials.gov: NCT01094262.

Methodological Issues in Conducting Pilot Trials in Chronic Pain as Randomized, Double-blind, Placebo-controlled Studies

The efficacy of tapentadol extended release (ER) for managing chronic pain has been demonstrated in large-scale, randomized, controlled, phase 3 studies (N=318-1,030) in patients with chronic osteoarthritis (OA) pain, low back pain (LBP), and pain related to diabetic peripheral neuropathy (DPN), which led to registration in many regions, including the United States and Europe. 2 pilot 12-week, randomized, double-blind, placebo-controlled phase 2 studies of tapentadol ER for chronic pain (OA knee pain or LBP, n=91; DPN or peripheral herpetic neuralgia [PHN] pain; n=91) were conducted in Japan. These small exploratory studies were substantially underpowered compared with the registration trials. Patients in both studies were randomized (2:1) to tapentadol ER (25-250 mg) or placebo for 12 weeks (≤6-week titration plus maintenance periods). For the primary efficacy endpoint (change in pain intensity from baseline to last week of treatment; last observation carried forward), both studies failed to differentiate between tapentadol ER and placebo; least-squares mean differences (95% confidence intervals) for tapentadol ER vs. placebo were -0.1 (-1.04, 0.80) in the OA/LBP study and -0.1 (-1.10, 0.99) in the DPN/PHN study. More than 80% of patients took concomitant analgesics during these studies. Tapentadol was well tolerated. Both studies were associated with methodological issues, including populations with different disease entities, small sample sizes, use of concomitant analgesics, and possible placebo effect that may have led to the failure to differentiate between tapentadol ER and placebo.

P.2.004 Nonsedative doses of a GABA-B positive allosteric modulator normalise VTA neuroadaptations and self-administration induced by drugs of abuse in mice

We tested novel positive allosteric modulators (PAMs) of the γ-aminobutyric acid receptor B (GABAB), ADX71943 and ADX71441in the monosodium iodoacetate model of chronic osteoarthritis pain in rats with the objective to delineate the role of peripheral versus central GABAB receptor populations in modulation of chronic pain. Anesthetized Sprague-Dawley rats received an injection of monosodium iodoacetate into the knee and were tested for hyperalgesia starting post-MIA day 14. Effects of compounds on ipsilateral joint compression threshold were evaluated on post-MIA day 14 (after acute treatment), as well as after repeated, daily treatment on days 21 and 28 (ADX71943 only) and were compared to those of celecoxib (30 mg/kg, p.o.). The PAMs were also tested in the rat rotarod test for potential muscle-relaxant effects. Acutely, ADX71943 (1–30 mg/kg, p.o.), the peripherally restricted PAM, resulted in similar increases in pain threshold across the doses on day 14, while showing reduced efficacy on day 21 and no efficacy on day 28. A clear reduction in the efficacy of celecoxib across testing was also noted in this experiment. Acutely ADX71441 (0.3–15 mg/kg, p.o.), the central-peripheral PAM, resulted in over 2-fold increases in pain threshold at 15 mg/kg (but not at lower doses) on day 14, while causing more modest effects on day 21. Celecoxib increased pain threshold after both acute and daily treatment, showing overall similar efficacy. Thus, early, presumably more inflammatory phase of osteoarthritis pain in more sensitive to GABAB PAMs with peripherally restricted profile, while later, presumably more neuropathic phase is more sensitive to PAMs with central-peripheral profile.

When Is Osteonecrosis Not Osteonecrosis?: Adjudication of Reported Serious Adverse Joint Events in the Tanezumab Clinical Development Program.

Tanezumab, a monoclonal antibody against nerve growth factor, has demonstrated efficacy in clinical trials of chronic pain in osteoarthritis (OA) and chronic low back pain. Unexpected adverse events (AEs) described as osteonecrosis (ON) occurred during tanezumab development, leading the US Food and Drug Administration to impose a partial clinical hold for all indications except cancer pain. A blinded Adjudication Committee (AC) including orthopedic surgeons, rheumatologists, and an orthopedic pathologist reviewed and adjudicated joint-related AEs in the tanezumab clinical program. The AC adjudicated all reported cases of ON as well as cases of total joint replacements (TJRs) not reported as ON for which radiographs obtained within 9 months of the surgery were available. The AC prespecified categories for joint safety events including primary ON, worsening OA (rapid progression of OA [RPOA], normal progression of OA, insufficient information to distinguish between rapid and normal progression of OA), other, or insufficient information to distinguish between primary ON and worsening OA or another diagnosis. The AC reviewed events in 249 of 386 patients with an investigator-reported AE of ON and/or a TJR. Two events were adjudicated as primary ON, 200 events were adjudicated as worsening OA (68 of which were classified as RPOA), 29 events had another diagnosis, 11 had insufficient information to distinguish primary ON from worsening OA, and 7 did not have committee member consensus. Despite initial reports, tanezumab treatment was not associated with an increase in ON but was associated with an increase in RPOA. Higher doses of tanezumab, tanezumab administered with nonsteroidal antiinflammatory drugs, and preexisting subchondral insufficiency fractures were risk factors for RPOA in this cohort.

Cingulate GABA levels inversely correlate with the intensity of ongoing chronic knee osteoarthritis pain.

BackgroundThis study aims to investigate the role of the mid-anterior cingulate cortex γ-aminobutyric acid levels in chronic nociceptive pain. The molecular mechanisms of pain chronification are not well understood. In fibromyalgia, low mid-anterior cingulate cortex γ-aminobutyric acid was associated with high pain suggesting a role of prefrontal disinhibition. We hypothesize that mid-anterior cingulate cortex GABAergic disinhibition may underpin chronic pain independent of the pain etiology and comorbid negative affect. Proton magnetic resonance spectra were acquired at 3T from the mid-anterior cingulate cortex in 20 patients with chronic painful knee osteoarthritis, and 19 healthy pain-free individuals using a point resolved spectroscopy sequence optimized for detection of γ-aminobutyric acid. Participants underwent questionnaires for negative affect (depression and anxiety) and psychophysical pain phenotyping.ResultsNo differences in mid-anterior cingulate cortex γ-aminobutyric acid or other metabolite levels were detected between groups. Ratings of perceived intensity of ongoing osteoarthritis pain were inversely correlated with γ-aminobutyric acid (r = −0.758, p < 0.001), but no correlations were seen for negative affect or pain thresholds. The pain γ-aminobutyric acid interrelation remained strong when controlling for depression (r = −0.820, p < 0.001). Combined levels of glutamine and glutamate were unrelated to psychometric or to pain thresholds.ConclusionOur study supports mid-anterior cingulate cortex γ-aminobutyric acid as a potential marker of pain severity in chronic nociceptive pain states independent of negative affect. The findings suggest that GABAergic disinhibition of the salience network may underlie sensitization to averse stimuli as a mechanism contributing to pain chronification.

Neural correlates of hyperalgesia in the monosodium iodoacetate model of osteoarthritis pain.

BackgroundThe mechanisms driving osteoarthritic pain remain poorly understood, but there is increasing evidence for a role of the central nervous system in the chronification of pain. We used functional magnetic resonance imaging to investigate the influence of a model of unilateral knee osteoarthritis on nociceptive processing.ResultsFour to five weeks post intra-articular injection of monosodium iodoacetate (MIA, 1 mg) into the left knee, Sprague Dawley rats were anesthetized for functional magnetic resonance imaging studies to characterize the neural response to a noxious stimulus (intra-articular capsaicin injection). In a two-arm cross-over design, 5 µM/50 µl capsaicin was injected into either the left knee (n = 8, CAPS-MIA) or right control knee (n = 8, CAPS-CON), preceded by contralateral vehicle (SAL) injection. To assess neural correlates of mechanical hyperalgesia, hindpaws were stimulated with von Frey hairs (8 g: MIA; 15 g: control knee, based on behavioral withdrawal responses). The CAPS-MIA group exhibited significant activation of the periaqueductal gray, unilateral thalamus and bilateral mensencephalon, superior-colliculus, and hippocampus, with no significant activation in the other groups/conditions. Capsaicin injection increased functional connectivity in the mid-brain network and mediodorsal thalamic nucleus, hippocampus, and globus pallidus, which was significantly stronger in CAPS-MIA compared to CAPS-CON groups. Mechanical stimulation of the hyperalgesic (ipsilateral to MIA knee) and normalgesic (contralateral) hindpaws evoked qualitatively different brain activation with more widespread brainstem and anterior cingulate (ACC) activation when stimulating the hyperalgesic paw, and clearer frontal sensory activation from the normalgesic paw.ConclusionsWe provide evidence for modulation of nociceptive processing in a chronic knee osteoarthritis pain model with stronger brain activation and alteration of brain networks induced by the pro-nociceptive stimulus. We also report a shift to a medial pain activation pattern following stimulation of the hyperalgesic hindpaw. Taken together, our data support altered neural pain processing as a result of peripheral and central pain sensitization in this model.

Determinants of patient preferences for total knee replacement: African-Americans and whites.

IntroductionPatient preferences contribute to marked racial disparities in the utilization of total knee replacement (TKR). The objectives of this study were to identify the determinants of knee osteoarthritis (OA) patients’ preferences regarding TKR by race and to identify the variables that may mediate racial differences in willingness to undergo TKR.MethodsFive hundred fourteen White (WH) and 285 African-American (AA) patients with chronic knee pain and radiographic evidence of OA participated in the study. Participants were recruited from the community, an academic medical center, and a Veterans Affairs hospital. Structured interviews were conducted to collect socio-demographics, disease severity, socio-cultural determinants, and treatment preferences. Logistic regression was performed, stratified by race, to identify determinants of preferences. Clinical and socio-cultural factors were entered simultaneously into the models. Stepwise selection identified factors for inclusion in the final models (p < 0.20).ResultsCompared to WHs, AAs were less willing to undergo TKR (80 % vs. 62 %, respectively). Better expectations regarding TKR surgery outcomes determined willingness to undergo surgery in both AAs (odds ratio (OR) 2.08, 95 % confidence interval (CI) 0.91-4.79 for 4th vs. 1st quartile) and WHs (OR 5.11, 95 % CI 2.31-11.30 for 4th vs. 1st quartile). Among AAs, better understanding of the procedure (OR 1.80, 95 % CI 0.97-3.35), perceiving a short hospital course (OR 0.81, 95 % CI 0.58-1.13), and believing in less post-surgical pain (OR 0.73, 95 % CI 0.39-1.35) and walking difficulties (OR 0.66, 95 % CI 0.37-1.16) also determined willingness. Among WHs, having surgical discussion with a physician (OR 1.96, 95 % CI 1.05-3.68), not ever receiving surgical referral (OR 0.56, 95 % CI 0.32-0.99), and higher trust in the healthcare system (OR 1.58, 95 % CI 0.75-3.31 for 4th vs. 1st quartile) additionally determined willingness. Among the variables considered, only knowledge-related matters pertaining to TKR attenuated the racial difference in knee OA patients’ treatment preference.ConclusionsExpectations of surgical outcomes influence preference for TKR in all patients, but clinical and socio-cultural factors exist that shape marked racial differences in preferences for TKR. Interventions to reduce or eliminate racial disparities in the utilization of TKR should consider and target these factors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0864-2) contains supplementary material, which is available to authorized users.

Predictive factors and clinical biomarkers for treatment in patients with chronic pain caused by osteoarthritis with a central sensitisation component.

SummaryAimsThe aim of this non‐systematic review was to provide a practical guide for clinicians on the evidence for central sensitisation in chronic osteoarthritis (OA) pain and how this pain mechanism can be addressed in terms of clinical diagnosis, investigation and treatment.MethodsThe authors undertook a non‐systematic review of the literature including a MEDLINE search (search terms included central sensitisation, osteoarthritis, osteoarthrosis) for relevant and current clinical studies, systematic reviews and narrative reviews. Case reports, letters to the editor and similar literature sources were excluded. Information was organised to allow a pragmatic approach to the discussion of the evidence and generation of practical recommendations.ResultsThere is good evidence for a role of central sensitisation in chronic OA pain in a subgroup of patients. Clinically, a central sensitisation component in chronic OA pain can be suspected based on characteristic pain features and non‐pain features seen in other conditions involving central sensitisation. However, there are currently no diagnostic inventories for central sensitisation specific to OA. Biomarkers may be helpful for confirming the presence of central sensitisation, especially when there is diagnostic uncertainty. Several non‐pharmacological and pharmacological treatments may be effective in OA patients with central sensitisation features. Multimodal therapy may be required to achieve control of symptoms.DiscussionClinicians should be aware of central sensitisation in patients with chronic OA pain, especially in patients presenting with severe pain with unusual features.

Long-term Safety and Efficacy of Tapentadol Extended Release Following up to 2 Years of Treatment in Patients With Moderate to Severe, Chronic Pain: Results of an Open-label Extension Trial

PurposeTapentadol extended release (ER) has demonstrated efficacy and safety for the management of moderate to severe, chronic pain in adults. This study evaluated the long-term safety and tolerability of tapentadol ER in patients with chronic osteoarthritis or low back pain. MethodsPatients were enrolled in this 1-year, open-label extension study after completing one of two 15-week, placebo-controlled studies of tapentadol ER and oxycodone controlled release (CR) for osteoarthritis knee pain (NCT00421928) or low back pain (NCT00449176), a 7-week crossover study between tapentadol immediate release and tapentadol ER for low back pain (NCT00594516), or a 1-year safety study of tapentadol ER and oxycodone CR for osteoarthritis or low back pain (NCT00361504). After titrating the drug to an optimal dose, patients received tapentadol ER (100–250 mg BID) for up to 1 year (after finishing treatment in the preceding studies); patients who were previously treated with tapentadol ER in the 1-year safety study received tapentadol ER continuously for up to 2 years in total. FindingsOf the 1,154 patients in the safety population, 82.7% were aged >65 years and 57.9% were female; 50.1% had mild baseline pain intensity. Mean (SD) pain intensity scores (11-point numerical rating scale) were 3.9 (2.38) at baseline (end of preceding study) and 3.7 (2.42) at end point, indicating that pain relief was maintained during the extension study. Improvements in measures of quality of life (eg, EuroQol-5 Dimension and the 36-item Short Form Health Survey [SF-36]) health status questionnaires) achieved during the preceding studies were maintained during the open-label extension study. Tapentadol ER was associated with a safety and tolerability profile comparable to that observed in the preceding studies. The most common treatment-emergent adverse events (incidence ≥10%; n = 1154) were headache (13.1%), nausea (11.8%), and constipation (11.1%). Similar efficacy and tolerability results were shown for patients who received up to 2 years of tapentadol ER treatment. ImplicationsPain relief and improvements in quality of life achieved during the preceding studies were maintained throughout this extension study, during which tapentadol ER was well tolerated for the long-term treatment of chronic osteoarthritis or low back pain over up to 2 years of treatment. (ClinicalTrials.gov identifier: NCT00487435.)

Predictors of the placebo analgesia response in randomized controlled trials of chronic pain

A large number of analgesics have failed to prove superiority over placebo in randomized controlled trials (RCTs), and as this has been related to increasing placebo responses, there is currently an interest in specifying predictors of the placebo response. The literature on placebo mechanisms suggests that factors related to patients' expectations of treatment efficacy are pivotal for the placebo response. Also, general characteristics of RCTs have been suggested to influence the placebo response. Yet, only few meta-analyses have directly tested these hypotheses. Placebo data from 9 industrially sponsored, randomized, double-blind, placebo-controlled, multicenter phase III trials in 2017 adult patients suffering from chronic painful osteoarthritis (hip or knee) or low back pain were included. The primary outcome was pain intensity. Based on previous studies, we chose 3 expectancy-related primary predictors: type of active medication, randomization ratio, and number of planned face-to-face visits. In addition, explorative analyses tested whether RCT and patients' characteristics predicted the placebo response. Opioid trials, a high number of planned face-to-face visits, and randomization ratio predicted the magnitude of the placebo response, thereby supporting the expectancy hypothesis. Exploratory models with baseline pain intensity, age, washout length, and discontinuation because of adverse events accounted for approximately 10% of the variability in the placebo response. Based on these results and previous mechanisms studies, we think that patients' perception of treatment allocation and expectations toward treatment efficacy could potently predict outcomes of RCTs.

Efficacy and tolerability of a hydrocodone extended-release tablet formulated with abuse-deterrence technology for the treatment of moderate-to-severe chronic pain in patients with osteoarthritis or low back pain.

This double-blind, placebo-controlled study evaluated the efficacy and safety of hydrocodone extended release (ER) developed with abuse-deterrence technology to provide sustained pain relief and limit effects of alcohol and tablet manipulation on drug release. Eligible patients with chronic moderate-to-severe low back or osteoarthritis pain were titrated to an analgesic dose of hydrocodone ER (15–90 mg) and randomized to placebo or hydrocodone ER every 12 hours. The primary efficacy measure was change from baseline to week 12 in weekly average pain intensity (API; 0=no pain, 10=worst pain imaginable). Secondary measures included percentage of patients with >33% and >50% increases from baseline in weekly API, change from baseline in weekly worst pain intensity, supplemental opioid usage, aberrant drug-use behaviors, and adverse events. Overall, 294 patients were randomized and received ≥1 dose of placebo (n=148) or hydrocodone ER (n=146). Weekly API did not differ significantly between hydrocodone ER and placebo at week 12 (P=0.134); although, in post hoc analyses, the change in weekly API was significantly lower with hydrocodone ER when excluding the lowest dose (15 mg; least squares mean, −0.20 vs 0.40; P=0.032). Significantly more patients had >33% and >50% increase in weekly API with placebo (P<0.05), and mean weekly worst pain intensity was significantly lower with hydrocodone ER at week 12 (P=0.026). Supplemental medication usage was higher with placebo (86%) than hydrocodone ER (79%). Incidence of aberrant drug-use behaviors was low, and adverse events were similar between groups. This study did not meet the primary endpoint, although results support the effectiveness of this hydrocodone ER formulation in managing chronic low back or osteoarthritis pain. Use of the hydrocodone ER 15-mg dose, a robust placebo response, and use of supplemental analgesics, particularly in the placebo group, may have limited detection of a statistically significant treatment effect, and additional research is needed to clarify these findings.

Magnetic Resonance Arthrography and the Prevalence of Acetabular Labral Tears in Patients 50 Years of Age and Older: Is It Really Indicated?

Objectives:Arthroscopy for acetabular labral tears has minimal impact on pain and function in patients older than 50 years of age in the setting of concomitant osteoarthritis. Despite this, many physicians continue to seek diagnoses of labral tears in older arthritic patients with magnetic resonance arthrography. The inefficacy of surgical management and the suggested high prevalence of this condition in both symptomatic and asymptomatic patients call into question the utility of diagnosis through an invasive and expensive imaging modality. The purpose of this study is to assess the frequency of acetabular labral tears in patients aged 50 years and older with hip pain and to correlate the likelihood of a labral tear with the severity of osteoarthritis as visualized on conventional radiograph.Methods:From 2004-2013, 208 patients aged 50 years and older who underwent hip MR arthrogram and hip radiographs within a 12-month period were identified. Age, gender, grade and location of labral tear, hip alpha angle, hip Tönnis grade, and hip joint space width were documented for each patient. Labral tears and alpha angle were identified and measured on MR arthrogram. Tönnis grade and joint space width were measured on hip radiographs by a musculoskeletal radiologist.Results:On MR arthrography, labral pathology was identified in 93% of patients (73.1% labral tearing, 20.2% labral fraying or degeneration). In patients with moderate to severe osteoarthritis (Tönnis grade 2-3), 100% had labral pathology (73.1% labral tearing, 26.9% labral fraying or degeneration). Similarly, in patients with joint space width ≤ 2mm, 100% had labral pathology (81.2% labral tearing, 18.8% labral fraying or degeneration). There were no statistically significant correlations between labral tear grade and Tönnis grade or joint space width.Conclusion:Given the high frequency of tears, as well as the questionable efficacy of arthroscopic surgical intervention in these patients, only good surgical candidates with chronic hip pain and minimal evidence of osteoarthritis (joint space width > 2mm, Tönnis grade 0-1) on initial radiographic evaluation should be considered for magnetic resonance arthrography.

Cooled radiofrequency system relieves chronic knee osteoarthritis pain: the first case-series.

Knee osteoarthritis is a frequent cause of chronic knee pain. Therapeutic solutions include intra-articular injections with short-term pain relief and surgical therapy. Radiofrequency (RF) of genicular nerves has been previously reported with varying success. Cooling tissue adjacent to the electrode (cooled RF) increases the radius of lesion. We present here the first retrospective data on pain relief and changes in function after such cooled RF denervation. We reviewed the records of nine patients with chronic knee pain who underwent cooled RF of genicular nerves. Visual analogue scale (VAS) and Western Ontario McMaster Universities OA index (WOMAC) were analysed. We observed an improvement in VAS pain scores 2 ± 0.5 at one month, 2.3 ± 0.7 at three months, 2.1 ± 0.5 at six months, and 2.2 ± 0.2 at 12 months after the procedure, and WOMAC score 20 ± 2, at one month, 22 ± 0.5 at three months, 21 ± 1.7 at six months, and 20 ± 1.0 at 12 months. The majority of patients with chronic knee pain experienced a clinically relevant degree of pain relief and improved function following cooled RF of genicular nerves at one, three, six and 12 months follow-up.

Letter to the Editor: Infrapatellar Saphenous Neuralgia After TKA Can Be Improved With Ultrasound-guided Local Treatments

To the Editor, We read the retrospective case series conducted by Clendenen and colleagues and appreciate their efforts in exploring a patient population with infrapatellar saphenous neuralgia after TKA [1]. Their research indicates ultrasound-guided injection to the infrapatellar branch of the saphenous nerve is a potential approach for recalcitrant pain following TKA. In their results, the response rate to the injection combining corticosteroid and local anesthesia was 56.3% (9 out of 16). Since there was no comparative group, we are unaware that this advanced approach is superior to conservative treatments like manual exercise or physical therapy. However, a more-than-50% success rate with nerve block draws attention to the neuropathic component in patients with persistent knee pain after TKA. Peripheral and central sensitization could potentially be associated with chronic intractable pain in knee osteoarthritis [2]. Although the present research supports the role of peripheral neuralgia in relentless postarthroplasty knee pain [1], central sensitization might partly account for the patients failing to respond to nerve block. Therefore, oral medication modifying central pain perception can be considered in combination with medication targeting nociceptive pain [3]. Additionally, evaluation tools designed for measuring neuropathic pain, such as the PainDETECT score and the DN4 questionnaire [2], should be implemented to monitor treatment effectiveness. Another concern is the diagnosis for entrapment of the infrapatellar branch of the saphenous nerve, which was made by the response to injection in the present study. The potential segment of nerve entrapment is from the vastoadductor membrane to the medial femoral epicondyle [4]. Whether the entrapped nerves presented with swelling, hypoechogenicity, or hypervascularity is of interest, but this information is lacking in this case series. Besides recording the sonographic images of the affected side, we suggest the authors also compare the nerve echotexture with the asymptomatic side, which is the easiest way to identify nerve damage by ultrasound.

Exercise, Not to Exercise, or How to Exercise in Patients With Chronic Pain? Applying Science to Practice

Exercise is an effective treatment strategy in various chronic musculoskeletal pain disorders, including chronic neck pain, osteoarthritis, headache, fibromyalgia and chronic low back pain. Although exercise can benefit those with chronic pain (CP), some patients (eg, those with fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome and chronic whiplash associated disorders) encounter exercise as a pain inducing stimulus and report symptom flares due to exercise. This paper focuses on the clinical benefits and detrimental effects of exercise in patients with CP. It summarizes the positive and negative effects of exercise therapy in migraine and tension-type headache and provides an overview of the scientific evidence of dysfunctional endogenous analgesia during exercise in patients with certain types of CP. Further, the paper explains the relationship between exercise and recovery highlighting the need to address recovery strategies as well as exercise regimes in the rehabilitation of these patients. The characteristics, demands and strategies of adequate recovery to compensate stress from exercise and return to homeostatic balance will be described. narrative review. Exercise is shown to be effective in the treatment of chronic tension-type headache and migraine. Aerobic exercise is the best option in migraine prophylaxis, whereas specific neck and shoulder exercises is a better choice in treating chronic tension-type headache. Besides the consensus that exercise therapy is beneficial in the treatment of CP, the lack of endogenous analgesia in some CP disorders should not be ignored. Clinicians should account for this when treating CP patients. Furthermore, optimizing the balance between exercise and recovery is of crucial merit in order to avoid stress-related detrimental effects and achieve optimal functioning in patients with CP. Exercise therapy has found to be beneficial in CP, but it should be appropriately and individually tailored with emphasis on prevention of symptom flares and applying adequate recovery strategies.

The SAR development of substituted purine derivatives as selective CB2 agonists for the treatment of chronic pain

Osteoarthritis (OA) and the associated joint pain are highly prevalent and a leading cause of disability. We have previously reported the identification of a series of purines as selective CB2 agonists and the identification of compound 1 as a clinical candidate for the treatment of joint pain. In this article we describe the further SAR development of the purine scaffold leading to the discovery of compound 6 as a potent, CNS penetrating CB2 agonist with high selectivity for CB2 over CB1 and oral efficacy in animal models of chronic OA pain.

MECHANISMS OF CHRONIC PAIN AT OSTEOARTHROSIS OF THE KNEE

The main symptom of osteoarthritis (OA) is pain. Mechanisms of chronic pain in OA have not been fully investigated yet. Objective: to study key mechanisms of chronic pain in patients with knee OA. Subjects and methods. Authors examined 80 women aged 45–65 years, with chronic pain due to OA of the knee. Clinical rheumatologic and neurologic examinations, screening for neuropathic pain (PainDETECT and DN4 questionnaires), estimation of duration and intensity of pain, WOMAC assessment and evaluation of affective disorders (HADS questionnaire) were performed. X-ray and ultrasonography were used to assess destructive changes of the knee. Results. According to DN4 questionnaire, 25 (30%) patients scored 4 and more, i. e. had signs of neuropathic pain, whereas 55 (70%) did not (scored less than 4). Although neurologic examination did not reveal lesions of somatosensory system in neither of groups, assessment of the pain sensitivity showed hyperalgesia in 60% of cases. Patients with signs of neuropathic pain typically have secondary hyperalgesia propagating far from the damaged joint. Conclusion. 30% of patients with osteoarthritis have pain of different intensity determined by nociceptive and neuropathic mechanisms. At the same time the absence of lesions of somatosensory system does not let us to consider the pain neuropathic and indicates that it has dysfunctional nature. Signs of neuropathic pain associated with secondary hyperalgesia may be a clinical symptom of central sensitization. Due to this fact, reasonable therapy of osteoarthritis-associated chronic pain should include, besides NSAIDs, central acting drugs for neuropathic pain treatment.

Pain and decreased cognitive function negatively impact physical functioning in older adults with knee osteoarthritis.

We hypothesized that among community-dwelling older adults without dementia with advanced chronic knee osteoarthritis (OA) pain: 1) higher levels of self-reported pain would be associated with decreased executive cognitive function and decreased physical function; and 2) decreased cognitive function would be associated with decreased physical function. Substudy on 79 older adults who were participants in a Veterans Affairs clinical trial of periosteal stimulation therapy for advanced painful knee OA. Participants were ≥ 60 years, had radiographic evidence of Kellgren-Lawrence 3 or 4 knee OA on a standing anterior-posterior X-ray, had pain of at least moderate intensity and of at least 3 months' duration, and knee pain severity greater than pain severity in other parts of the body. Measures included computerized cognitive tests of executive function, pain, and physical function (gait speed and stair climbing). As pain scores worsened, gait speed and stair climbing worsened (P = 0.007 and P = 0.035, respectively). Lower performance on the executive function tests was also significantly associated with decreased gait speed and stair climbing (P = 0.002 and P = 0.014, respectively). We did not find a significant relationship between pain and cognitive function. We explored the relationship between pain and physical function adjusted for executive functioning and found that pain was no longer associated with gait speed (P = 0.06). Worse pain scores and executive function scores were associated with worse physical function in older adults with painful knee OA. This suggests that slower gait speed in patients could be an indication to clinicians to monitor their patient's cognitive function. Executive function in particular affected the relationship between gait speed and pain, suggesting a possible mediating relationship.

Tapentadol Prolonged Release for Managing Moderate to Severe, Chronic Malignant TumorRelated Pain

Background: Tapentadol prolonged release (PR) is effective and well tolerated for chronic osteoarthritis, low back, and diabetic peripheral neuropathic pain. Objectives: To evaluate the efficacy and tolerability of tapentadol PR compared with placebo and morphine controlled release (CR) for managing moderate to severe chronic malignant tumor-related pain. Study Design: Randomized-withdrawal, parallel group, active- and placebo-controlled, double-blind phase 3 study (NCT00472303). Setting: Primary, secondary, and tertiary care settings in 16 countries. Methods: Eligible patients (pain intensity ≥ 5 [11-point numerical rating scale] on prior analgesics) were randomized (2:1) and titrated to their optimal dose of tapentadol PR (100 – 250 mg bid) or morphine sulfate CR (40 – 100 mg bid) over 2 weeks. Morphine sulfate immediate release 10 mg was permitted as needed for rescue medication (no maximum dose). Patients who completed titration and, during the last 3 days of titration, had mean pain intensity &lt; 5 (based on twice-daily ratings) and mean rescue medication use ≤ 20 mg/day continued into a 4-week maintenance period; patients who received morphine CR during titration continued taking morphine CR, and those who received tapentadol PR were re-randomized (1:1) to tapentadol PR or placebo bid. Response during maintenance (primary efficacy endpoint) was defined as having: 1) completed the maintenance period, 2) a mean pain intensity &lt; 5 during maintenance, and 3) used an average of ≤ 20 mg/day of rescue medication during maintenance. Response at the end of titration was defined similarly, with pain intensity and rescue medication averages based on the last 3 days of titration. Results: Of 622 patients screened, 496 were randomized, treated during titration, and evaluable for safety; 327 were re-randomized, treated during maintenance, and evaluable for safety; and 325 were evaluable for efficacy. The adjusted responder rate estimate during maintenance (logistic regression adjusting for treatment group, pooled center, and pain intensity at start of maintenance) was significantly higher with tapentadol PR (64.3%) than with placebo (47.1%; odds ratio (OR), 2.02 [95% confidence interval (CI), 1.12 – 3.65]; P = 0.02). Based on responder rates at the end of titration, tapentadol PR (76.0% [174/229]) was non-inferior to morphine CR (83.0% [83/100]). The lower limit of the 95% CI for the between-groups difference (−15.5%) was within the pre-specified 20% non-inferiority margin. During titration, incidences of treatment-emergent adverse events (TEAEs) were 50.0% (169/338) with tapentadol PR and 63.9% (101/158) with morphine CR; incidences of nausea, vomiting, and dry mouth were lower with tapentadol PR than with morphine CR. During maintenance, incidences of TEAEs were 56.3% (63/112), 62.3% (66/106), and 62.4% (68/109) with placebo, tapentadol PR, and morphine CR, respectively. Limitations: Statistical comparisons between tapentadol PR and morphine CR were limited to descriptive statistics during the maintenance period because of the pre-selection of responders to tapentadol PR or morphine CR during titration. Conclusions: Results obtained during maintenance indicate that tapentadol PR (100 – 250 mg bid) is effective compared with placebo for managing moderate to severe chronic malignant tumor-related pain. Based on results obtained during titration, tapentadol PR provides comparable efficacy to that of morphine sulfate CR (40 – 100 mg bid), but is associated with better gastrointestinal tolerability. Key words: Tapentadol PR, cancer pain, tumor-related pain, malignant pain, chronic pain, morphine CR, non-inferiority, efficacy, tolerability