Human Studies

Musculoskeletal (MSK) pain represents a considerable worldwide healthcare burden. This study aimed to gain consensus from practitioners who work with MSK pain patients, on the most appropriate primary care treatment options for subgroups of patients based on prognostic risk of persistent disabling pain. Agreement was sought on treatment options for the five most common MSK pain presentations: back, neck, knee, shoulder and multisite pain, across three risk subgroups: low, medium and high.

Charcot-Marie-Tooth disease (CMT) is most commonly caused by duplication of a chromosomal segment surrounding Peripheral Myelin Protein 22, or PMP22 gene, which is classified as CMT1A. Several candidate therapies reduce Pmp22 mRNA levels in CMT1A rodent models, but development of biomarkers for clinical trials in CMT1A is a challenge given its slow progression and the difficulty in obtaining nerve samples. Quantitative PCR measurements of PMP22 mRNA in dermal nerves were performed using skin biopsies in human clinical trials for CMT1A, but this approach did not show increased PMP22 mRNA in CMT1A patients compared to controls. One complicating factor is the variable amounts of Schwann cells (SC) in skin. The objective of the study was to develop a novel method for precise evaluation of PMP22 levels in skin biopsies that can discriminate CMT1A patients from controls.

Few investigations examine patterns of opioid and nonopioid analgesic prescribing and concurrent pain intensity ratings before and after institution of safer prescribing programs such as the October 2013 Veterans Health Administration system-wide Opioid Safety Initiative (OSI) implementation. We conducted a quasi-experimental pre-post observational study of all older U.S. veterans (≥50 years old) with osteoarthritis of the knee or hip. All associated outpatient analgesic prescriptions and outpatient pain intensity ratings from January 1, 2012 to December 31, 2016, were analyzed with segmented regression of interrupted time series. Standardized monthly rates for each analgesic class (total, opioid, nonsteroidal anti-inflammatory drug, acetaminophen, and other study analgesics) were analyzed with segmented negative binomial regression models with overall slope, step, and slope change. Similarly, segmented linear regression was used to analyze pain intensity ratings and percentage of those reporting pain. All models were additionally adjusted for age, sex, and race. Before OSI implementation, total analgesic prescriptions showed a steady rise, abruptly decreasing to a flat trajectory after OSI implementation. This trend was primarily due to a decrease in opioid prescribing after OSI. Total prescribing after OSI implementation was partially compensated by continuing increased prescribing of other study analgesics as well as a significant rise in acetaminophen prescriptions (post-OSI). No changes in nonsteroidal anti-inflammatory drug prescribing were seen. A small rise in the percentage of those reporting pain but not mean pain intensity ratings continued over the study period with no changes associated with OSI. Changes in analgesic prescribing trends were not paralleled by changes in reported pain intensity for older veterans with osteoarthritis.

Phantom limb pain (PLP) is a disabling and intractable sensation arising in about 80% of patients after amputation. The aim of this study was to evaluate the possibility to modulate nociceptive processing and pain perception with cerebellar transcranial direct current stimulation (ctDCS) in patients suffering from painful and non-painful phantom limb sensations. Fourteen upper limb amputees underwent ctDCS (anodal or sham, 2.0 mA, 20 min per day, 5 days a week). Clinical scores and electrophysiological parameters were assessed before tDCS, at the end of the 5-day treatment, 2 and 4 weeks later. Laser-evoked potentials (LEPs) were obtained from the stump using a Nd:YAP laser by pulses with short duration (5 ms) and small diameter spots (5 mm). Changes in visual analogue scores (VAS) were evaluated (chronic pain, paroxysmal pain, stump pain, phantom movements, phantom sensations). Anodal polarization significantly dampened LEP amplitudes (N1, p = 0.021 and N2/P2, p = 0.0034), whereas sham intervention left them unchanged. Anodal ctDCS significantly reduced paroxysmal pain (p < 0.0001), non-painful phantom limb sensations (p < 0.0001) and phantom limb movements (p = 0.0003), whereas phantom limb and stump pain did not change compared to the sham condition. Anodal ctDCS significantly improves both paroxysmal pain and non-painful phantom limb sensations, which are likely induced by maladaptive changes in the sensorimotor network and posterior parietal cortex respectively.

Complex Regional Pain Syndrome (CRPS) develops after fracture. The acute CRPS phenotype resembles exaggerated inflammation which is explained by local and systemic activation of a pro-inflammatory network including peptides and cytokines. Epidemiologic data suggest that inactivation of the peptidase angiotensin converting enzyme (ACE) in patients treated for hypertension increases the odds to develop CRPS. This hint lead us to investigate the serum protease network activity in CRPS patients vs. respective controls. For this purpose, we developed a dabsyl-bradykinin (DBK)-based assay and used it to investigate CRPS patients, as well as healthy (HC) and pain (painful diabetic neuropathy; dPNP) controls. The major result is that the degradation of DBK to fragments 1-8 and 1-5 in HC and dPNP is shifted to higher values for DBK1-8 and lower values for DBK 1-5 at one hour of incubation in CRPS patients. Using this novel reporter peptide assay, we have been able to show that the resolving protease network for mediators like BK might be different in CRPS patients; having a look at the the clinical signs, which resemble inflammation, this resolving protease network is probably less effective in CRPS.

To examine dorsal root ganglia and proximal nerve segments in patients carrying the Fabry-related GLA-gene variant p.D313Y in comparison to patients with classical Fabry mutations and healthy controls by morphometric and functional magnetic resonance neurography.