Toward Composite Pain Biomarkers of Neuropathic Pain-Focus on Peripheral Neuropathic Pain.

Chronic pain affects ~10-20% of the U.S. population with an estimated annual cost of $600 billion, the most significant economic cost of any disease to-date. Neuropathic pain is a type of chronic pain that is particularly difficult to manage and leads to significant disability and poor quality of life. Pain biomarkers offer the possibility to develop objective pain-related indicators that may help diagnose, treat, and improve the understanding of neuropathic pain pathophysiology. We review neuropathic pain mechanisms related to opiates, inflammation, and endocannabinoids with the objective of identifying composite biomarkers of neuropathic pain. In the literature, pain biomarkers typically are divided into physiological non-imaging pain biomarkers and brain imaging pain biomarkers. We review both types of biomarker types with the goal of identifying composite pain biomarkers that may improve recognition and treatment of neuropathic pain.

Sex-specific differences in the efficacy of traditional low frequency versus high frequency spinal cord stimulation for chronic pain.

INTRODUCTION: Spinal cord stimulation (SCS), an FDA-approved therapy for chronic pain, uses paresthesia (low frequency SCS (LF-SCS)) or paresthesia-free (such as high-frequency SCS (HF-SCS)) systems, providing analgesia through partially-elucidated mechanisms, with recent studies indicating a sexual dimorphism in pain pathogenesis (Bretherton et al., Neuromodulation, 2021; Paller et al., Pain Med 10:289-299, 2009; Slyer et al., Neuromodulation, 2019; Van Buyten et al., Neuromodulation 20:642-649, 2017; Mekhail et al., Pain Pract, 2021). We aim to evaluate SCS therapy sex effects based on paradigm, utilizing visual analog scores (VAS), perceived pain reduction (PPR), and opioid use. METHODS: A retrospective cohort study of SCS patients implanted between 2004 and 2020 (n = 237) was conducted. Descriptive statistics and linear mixed methods analyses were used. RESULTS: HF-SCS (10 kHz) was implanted in 94 patients (40 females, 54 males), and LF-SCS in 143 (70 females, 73 males). At 3 months and 6 months, HF-SCS (p < 0.001) and LF-SCS (p < 0.005) had lower VAS scores compared to baseline (p < 0.005), with no differences across groups. PPR improved in both post-implantation (p < 0.006) and at 3 months (p < 0.004 respectively), compared to baseline persisting to 6 (p < 0.003) and 12 months (p < 0.01) for HF-SCS, with significantly better PPR for HF-SCS at 3 (p < 0.008) and 6 (p < 0.001) months compared to LF-SCS. There were no differences in opioid use from baseline for either modality; however LF-SCS patients used more opioids at every time point (p < 0.05) compared to HF-SCS. VAS was improved for all modalities in both sexes at 3 months (p = 0.001), which persisted to 6 months (p < 0.05) for HF-SCS males and females, and LF-SCS females. Female HF-SCS had improved PPR at 3 (p = 0.016) and 6 (p = 0.022) months compared to baseline, and at 6 (p = 0.004) months compared to LF-SCS. Male HF-SCS and LF-SCS had improved PPR post-implantation (p < 0.05) and at 3 months (p < 0.05), with HF-SCS having greater benefit at 3 (p < 0.05) and 6 (p < 0.05) months. LF-SCS males but not females used less opioids at 6 months (p = 0.017) compared to baseline; however this effect did not persist. On linear mixed model analyses, including age, sex and stimulator type, VAS decreased with age, at each timepoint, and had a trend towards increasing with female sex, while PPR increased at 3 and 6 months and lastly HF-SCS was associated with decreased opioid use. DISCUSSION: PPR at 3 and 6 months improved to a greater extent in HF-SCS. HF-SCS females had improved PPR at 3 and 6 months, and only LF-SCS males used less opioids at 6 months, potentially indicating sex-based pathway. Future studies should further elucidate differences in sex-based pathways and identify optimal SCS opioid-sparing paradigms for chronic pain patients.

Spinal cord stimulation in chronic pain: evidence and theory for mechanisms of action.

Well-established in the field of bioelectronic medicine, Spinal Cord Stimulation (SCS) offers an implantable, non-pharmacologic treatment for patients with intractable chronic pain conditions. Chronic pain is a widely heterogenous syndrome with regard to both pathophysiology and the resultant phenotype. Despite advances in our understanding of SCS-mediated antinociception, there still exists limited evidence clarifying the pathways recruited when patterned electric pulses are applied to the epidural space. The rapid clinical implementation of novel SCS methods including burst, high frequency and dorsal root ganglion SCS has provided the clinician with multiple options to treat refractory chronic pain. While compelling evidence for safety and efficacy exists in support of these novel paradigms, our understanding of their mechanisms of action (MOA) dramatically lags behind clinical data. In this review, we reconstruct the available basic science and clinical literature that offers support for mechanisms of both paresthesia spinal cord stimulation (P-SCS) and paresthesia-free spinal cord stimulation (PF-SCS). While P-SCS has been heavily examined since its inception, PF-SCS paradigms have recently been clinically approved with the support of limited preclinical research. Thus, wide knowledge gaps exist between their clinical efficacy and MOA. To close this gap, many rich investigative avenues for both P-SCS and PF-SCS are underway, which will further open the door for paradigm optimization, adjunctive therapies and new indications for SCS. As our understanding of these mechanisms evolves, clinicians will be empowered with the possibility of improving patient care using SCS to selectively target specific pathophysiological processes in chronic pain.

Sphingosine-1-phosphate receptor 3 promotes neointimal hyperplasia in mouse iliac-femoral arteries.

OBJECTIVE: The objective of this study was to define a role for sphingosine-1-phosphate receptor 3 (S1PR3) in intimal hyperplasia. METHODS AND RESULTS: A denudation model of the iliac-femoral artery in wild-type and S1PR3-null mice was used to define a role for S1PR3 in the arterial injury response because we found in humans and mice that expression of S1PR3 was higher in these arteries compared with carotid arteries. At 28 days after surgery, wild-type arteries formed significantly larger lesions than S1PR3-null arteries. Bromodeoxyuridine labeling experiments demonstrated that on injury, wild-type arteries exhibited higher medial as well as intimal proliferation than S1PR3-null arteries. Because S1PR3 expression in vitro was low, we expressed S1PR3 in S1PR3-null smooth muscle cells (SMCs) using retroviral-mediated gene transfer to study the effects of S1PR3 on cell functions and signaling. SMCs expressing S1PR3, but not vector-transfected controls, responded to sphingosine-1-phosphate stimulation with activation of Rac, Erk, and Akt. SMCs expressing S1PR3 also migrated more. CONCLUSIONS: In humans and mice, S1PR3 expression was higher in iliac-femoral arteries compared with carotid arteries. S1PR3 promoted neointimal hyperplasia on denudation of iliac-femoral arteries in mice, likely by stimulating cell migration and proliferation through activation of signaling pathways involving Erk, Akt, and Rac.