Human Studies

Damage to thinly-myelinated and unmyelinated nerve fibers causes small fiber pathology, which is increasingly found in pain syndromes such as small fiber neuropathy (SFN) and fibromyalgia syndrome (FMS). The peripheral nerve endings of the small nerve fibers terminate within the epidermis, where they are surrounded by keratinocytes that may act as primary nociceptive transducers.We performed RNA sequencing of keratinocytes obtained from patients with SFN, FMS, and healthy controls. We found 141 deregulated protein coding genes between SFN patients and healthy controls and no differentially expressed genes between FMS patients and healthy controls. When comparing SFN with FMS patients, we detected 167 differentially expressed protein coding genes (129 upregulated, 38 downregulated). Further analysis revealed enriched inflammatory pathways. Validation of selected candidates in an independent cohort confirmed higher expression of the pro-inflammatory mediators interleukin-8, C-X-C motif chemokine 3, endothelin receptor type A, and the voltage-gated sodium channel 1.7 in SFN compared to FMS patients.We provide a diverse keratinocyte transcriptome signature between SFN and FMS patients, which may hint towards distinct pathomechanisms of small fiber sensitization in both entities and lay the basis for advanced diagnostics.

Limited research of how to best taper opioids brings about an ethical and clinical dilemma. Experiments using overt and concealed administration of opioids have demonstrated the benefits of a concealed reduction to eliminate negative expectations and prolong analgesic benefits. This may allow for opioid tapering without significant increases in pain. Based on this, we investigated patient and provider acceptance of a concealed opioid reduction for chronic pain.

Aberrant synaptic plasticity is hypothesised to underpin chronic pain. Yet, synaptic plasticity regulated by homeostatic mechanisms have received limited attention in pain. We investigated homeostatic plasticity in the human primary motor cortex (M1) of 21 healthy individuals in response to experimentally induced muscle pain for several days. Experimental pain was induced by injecting nerve growth factor into the muscle belly of the right extensor carpi radialis brevis muscle. Pain and disability were monitored until day 21. Homeostatic plasticity was induced on day 0, 2, 4, 6, and 14 in the left M1 using anodal transcranial direct stimulation (tDCS) applied for 7 and 5 min, separated by a 3-min rest period. Motor-evoked potentials (MEP) to transcranial magnetic stimulation assessed the homeostatic response. On days 0 and 14, MEPs increased following the first block of tDCS (p < 0.004), and decreased following the second block of tDCS (p < 0.001), consistent with a normal homeostatic response. However, on days 2 (p = 0.07) and 4 (p = 0.7), the decrease in MEPs after the second block of tDCS was attenuated, representing an impaired homeostatic response. Findings demonstrate altered homeostatic plasticity in the M1 with the greatest alteration observed after 4 days of sustained pain. This study provides longitudinal insight into homeostatic plasticity in response to the development, maintenance, and resolution of pain over the course of 14 days.

To explore associations of intracortical excitability with clinical characteristics in a large sample of subjects with phantom limb pain (PLP).

: The aim of the study was to assess the development of widespread non-joint pain (WNP) in a cohort of patients with early rheumatoid arthritis (RA), the associated health-related quality of life (HRQoL), and clinical and demographic risk factors for WNP.: Incident cases with RA, from the Swedish population-based study Epidemiological Investigation of Rheumatoid Arthritis (EIRA), with a follow-up of at least 3 years, constituted the study population. WNP was defined as pain outside the joints in all four body quadrants and was assessed at the 3 year follow-up. Patients who reported WNP were compared to patients without WNP regarding HRQoL, measured by the Short Form-36, at 3 years, and clinical and demographic characteristics at the time of RA diagnosis.: A total of 749 patients constituted the study sample, of whom 25 were excluded after reporting already having severe pain before RA diagnosis. At the 3 year follow-up, 8% of the patients reported having WNP as well as statistically significant worse HRQoL. At the time of RA diagnosis, the patients with WNP had worse pain and pain-related features, while no difference was seen in the inflammatory parameters.: WNP occurs in a substantial subset of patients with RA, also early in the course of the disease, and the HRQoL for these patients is significantly reduced. Patients who develop WNP at 3 years are already distinguishable at the time of diagnosis by displaying more pronounced pain ratings together with an average level of inflammatory disease activity.