The effects of an analgesic treatment (lidocaine patches) on brain activity in chronic low back pain (CBP) and in knee osteoarthritis (OA) were investigated using serial fMRI (contrasting fMRI ...between before and after two weeks of treatment). Prior to treatment brain activity was distinct between the two groups: CBP spontaneous pain was associated mainly with activity in medial prefrontal cortex, while OA painful mechanical knee stimulation was associated with bilateral activity in the thalamus, secondary somatosensory, insular, and cingulate cortices, and unilateral activity in the putamen and amygdala. After 5% lidocaine patches were applied to the painful body part for two weeks, CBP patients exhibited a significant decrease in clinical pain measures, while in OA clinical questionnaire based outcomes showed no treatment effect but stimulus evoked pain showed a borderline decrease. The lidocaine treatment resulted in significantly decreased brain activity in both patient groups with distinct brain regions responding in each group, and sub-regions within these areas were correlated with pain ratings specifically for each group (medial prefrontal cortex in CBP and thalamus in OA). We conclude that the two chronic pain conditions involve distinct brain regions, with OA pain engaging many brain regions commonly observed in acute pain. Moreover, lidocaine patch treatment modulates distinct brain circuitry in each condition, yet in OA we observe divergent results with fMRI and with questionnaire based instruments.
Objective
This pooled analysis of 3 randomized, placebo‐controlled trials (16–24 week treatment and 8–24 week follow‐up) assessed safety of subcutaneous tanezumab (2.5–10 mg every 8 weeks) in 1,840 ...patients with hip or knee osteoarthritis.
Methods
Overall treatment‐emergent adverse events (TEAEs) and TEAEs of abnormal peripheral sensation (APS) were prospectively assessed in 3 trials. Joint safety events (primary osteonecrosis, rapidly progressive osteoarthritis RPOA, subchondral insufficiency fracture, and pathologic fracture; adjudicated by an independent expert committee) and TEAEs potentially associated with sympathetic neuropathy were prospectively assessed in 2 trials.
Results
During the treatment period, overall TEAE rates were 51.7% for placebo and 39.5–54.8% for tanezumab 2.5–10 mg; treatment discontinuation rates were 2.0% for placebo and 0–1.3% for tanezumab. Rates of composite joint safety events (predominantly RPOA type 1) over the treatment plus follow‐up period were 0% for placebo and 0.5–3.2% for tanezumab 2.5–5 mg (5 mg was statistically greater than placebo); total joint replacement rates with tanezumab (5.9–7.0%) were not significantly different from placebo (4.5%). Rates of TEAEs of APS (predominantly paresthesia and hypoesthesia) were 2.2% for placebo and 3.2–12.8% for tanezumab 2.5–10 mg. Rates of TEAEs potentially associated with sympathetic neuropathy (predominantly bradycardia and orthostatic hypotension) were 0.8% for placebo and 0.5–2.8% for tanezumab 2.5–5 mg (exposure‐adjusted rates were not significantly different from placebo).
Conclusion
Tanezumab was generally well tolerated. TEAEs of APS (mostly mild and transient) and joint safety events were infrequent but more common with tanezumab than placebo. A tanezumab dose of 2.5 mg demonstrated a more favorable safety profile than higher doses.
Experiences and memories are often mismatched. While multiple studies have investigated psychological underpinnings of recall error with respect to emotional events, the neurobiological mechanisms ...underlying the divergence between experiences and memories remain relatively unexplored in the domain of chronic pain. Here we examined the discrepancy between experienced chronic low back pain (CBP) intensity (twice daily ratings) and remembered pain intensity (n = 48 subjects) relative to psychometric properties, hippocampus morphology, memory capabilities, and personality traits related to reward. 77% of CBP patients exaggerated remembered pain, which depended on their strongest experienced pain and their most recent mood rating. This bias persisted over nearly 1 year and was related to reward memory bias and loss aversion. Shape displacement of a specific region in the left posterior hippocampus mediated personality effects on pain memory bias, predicted pain memory bias in a validation CBP group (n = 21), and accounted for 55% of the variance of pain memory bias. In two independent groups (n = 20/group), morphology of this region was stable over time and unperturbed by the development of chronic pain. These results imply that a localized hippocampal circuit, and personality traits associated with reward processing, largely determine exaggeration of daily pain experiences in chronic pain patients.
To evaluate whether subjects with knee or hip osteoarthritis (OA) pain on non-steroidal anti-inflammatory drugs (NSAIDs) received greater benefit when tanezumab monotherapy replaced or was ...coadministered with NSAIDs.
Subjects (N=2700) received intravenous tanezumab (5 or 10 mg) or placebo every 8 weeks with or without oral naproxen 500 mg twice daily or celecoxib 100 mg twice daily. Efficacy was assessed as change from baseline to week 16 in three co-primary endpoints: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function and Patient's Global Assessment (PGA) of OA. Safety assessments included adverse events, physical and neurological examinations, laboratory tests and vital signs.
Although all tanezumab treatments provided significant improvements in WOMAC Pain and Physical Function over either NSAID alone, only tanezumab+NSAIDs were significant versus NSAIDs with PGA and met the prespecified definition of superiority. Combination treatment did not substantially improve pain or function over tanezumab monotherapy. Adverse event frequency was higher with tanezumab than with NSAIDs and highest with combination therapy. Higher incidence of all-cause total joint replacements occurred with tanezumab+NSAID versus tanezumab monotherapy or NSAIDs. Rapidly progressive OA incidence was significantly greater versus NSAID in all tanezumab groups except tanezumab 5 mg monotherapy.
Subjects receiving partial symptomatic relief of OA pain with NSAIDs may receive greater benefit with tanezumab monotherapy. While only coadministration of tanezumab with NSAIDs met the definition of superiority, combination treatment did not provide important benefits over tanezumab monotherapy; small differences in efficacy were negated by treatment-limiting or irreversible safety outcomes.
NCT00809354.
The objective of this study is to validate a placebo pill response predictive model-a biosignature-that classifies chronic pain patients into placebo responders (predicted-PTxResp) and nonresponders ...(predicted-PTxNonR) and test whether it can dissociate placebo and active treatment responses. The model, based on psychological and brain functional connectivity, was derived in our previous study and blindly applied to current trial participants. Ninety-four chronic low back pain (CLBP) patients were classified into predicted-PTxResp or predicted-PTxNonR and randomized into no treatment, placebo treatment, or naproxen treatment. To monitor analgesia, back pain intensity was collected twice a day: 3 weeks baseline, 6 weeks of treatment, and 3 weeks of washout. Eighty-nine CLBP patients were included in the intent-to-treat analyses and 77 CLBP patients in the per-protocol analyses. Both analyses showed similar results. At the group level, the predictive model performed remarkably well, dissociating the separate effect sizes of pure placebo response and pure active treatment response and demonstrating that these effects interacted additively. Pain relief was about 15% stronger in the predicted-PTxResp compared with the predicted-PTxNonR receiving either placebo or naproxen, and the predicted-PTxNonR successfully isolated the active drug effect. At a single subject level, the biosignature better predicted placebo nonresponders, with poor accuracy. One component of the biosignature (dorsolateral prefrontal cortex-precentral gyrus functional connectivity) could be generalized across 3 placebo studies and in 2 different cohorts-CLBP and osteoarthritis pain patients. This study shows that a biosignature can predict placebo response at a group level in the setting of a randomized controlled trial.
Summary
Rapid bone loss can occur after spinal cord injury (SCI) and a standard of care to prevent or treat this phenomenon is an active area of research. Using advanced analysis techniques, this ...study demonstrates that zoledronic acid, a possible treatment, prevented loss of bone strength at the hip following SCI.
Introduction
Bone loss below the level of neurological lesion is a well-known complication of spinal cord injury (SCI), and effective preventive treatment for this phenomenon is an active area of research. Zoledronic acid has demonstrated efficacy to attenuate bone loss at the hip after SCI, but previous studies relied on measurements from dual-energy X-ray absorptiometry. The purpose of this investigation was to more thoroughly characterize changes to bone mineral and strength at the proximal femur in individuals receiving zoledronic acid in the acute SCI stage; we also examined the influence of ambulatory ability on bone outcomes.
Methods
Participants randomized to either zoledronic acid (
n
= 29) or placebo (
n
= 30) received computed tomography (CT) scans and ambulatory assessments at baseline and 6 and 12 months following drug infusion. CT-based finite element (FE) modeling was used to predict changes in proximal femoral strength associated with treatment.
Results
After 12 months, FE-predicted bone strength was reduced by a mean (SD) of 9.6 (17.9)% in the zoledronic acid group versus 24.6 (24.5)% in the placebo group (
p
= 0.007). These differences in strength were explained by reductions in CT measurements of both trabecular (
p
< 0.001) and cortical (
p
≤ 0.021) bone at the femoral neck and trochanteric region. Ambulation ability influenced select trabecular and cortical parameters, but we were unable to detect an impact on FE-predicted bone strength.
Conclusion
These findings demonstrate that treatment with zoledronic acid in acute SCI attenuates losses in proximal femoral strength, which may reduce the risk of hip fractures across patients with varying degrees of ambulatory abilities.
Introduction
We sought to predict analgesic response to daily oral nonsteroidal anti-inflammatory drugs (NSAIDs) or subcutaneous tanezumab 2.5 mg (every 8 weeks) at week 16 in patients with ...moderate-to-severe osteoarthritis, based on initial treatment response over 8 weeks.
Methods
Data were derived from three randomized controlled trials of osteoarthritis. A two-step, trajectory-focused, analytics approach was used to predict patients as responders or non-responders at week 16. Step 1 identified patients using a data-element combination method (based on pain score at baseline, pain score at week 8, pain score monotonicity at week 8, pain score path length at week 8, and body site knee or hip). Patients who could not be identified in step 1 were predicted in step 2 using a k-nearest neighbor method based on pain score and pain response level at week 8.
Results
Our approach predicted response with high accuracy in NSAID-treated (83.2–90.2%,
n
= 931) and tanezumab-treated (84.6–91.0%,
n
= 1430) patients regardless of the efficacy measure used to assess pain, or the threshold used to define response (20%, 30%, or 50% improvement from baseline). Accuracy remained high using 50% or 20% response thresholds, with 50% and 20% yielding generally slightly better negative and positive predictive value, respectively, relative to 30%. Accuracy was slightly better in patients aged ≥ 65 years relative to younger patients across most efficacy measure/response threshold combinations.
Conclusions
Analyzing initial 8-week analgesic responses using a two-step, trajectory-based approach can predict future response in patients with moderate-to-severe osteoarthritis treated with NSAIDs or 2.5 mg tanezumab. These findings demonstrate that prediction of treatment response based on a single dose of a novel therapeutic is possible and that predicting future outcomes based on initial response offers a way to potentially advance the approach to clinical management of patients with osteoarthritis.
ClinicalTrials.gov Identifiers
NCT02528188, NCT02709486, NCT02697773.
Spinal cord injury (SCI) is associated with bone fragility and fractures around the knee. The purpose of this investigation was to validate a computed tomography (CT) based finite element (FE) model ...of the proximal tibia and distal femur under biaxial loading, and to retrospectively quantify the relationship between model predictions and fracture incidence. Twenty-six cadaveric tibiae and femora (
n
= 13 each) were loaded to 300 N of compression, then internally rotated until failure. FE predictions of torsional stiffness (
K
) and strength (
T
ult
) explained 74% (
n
= 26) and 93% (
n
= 7) of the variation in experimental measurements, respectively. Univariate analysis and logistic regression were subsequently used to determine if FE predictions and radiographic measurements from CT and dual energy X-ray absorptiometry (DXA) were associated with prevalent lower-limb fracture in 50 individuals with SCI (
n
= 14 fractures). FE and CT measures, but not DXA, were lower in individuals with fracture. FE predictions of
T
ult
at the tibia demonstrated the highest odds ratio (4.98;
p
= 0.006) and receiver operating characteristic (0.84;
p
= 0.008) but did not significantly outperform other metrics. In conclusion, CT-based FE model predictions were associated with prevalent fracture risk after SCI; this technique could be a powerful tool in future clinical research.
PDF
