Pharmacology/Drug Development

Treatment with opioids not only inhibits nociceptive transmission but also elicits a rebound and persistent increase in primary afferent input to the spinal cord. Opioid-elicited long-term potentiation (LTP) from TRPV1-expressing primary afferents plays a major role in opioid-induced hyperalgesia and analgesic tolerance. Here, we determined whether opioid-elicited LTP involves vesicular glutamate transporter-2 (VGluT2) or vesicular GABA transporter (VGAT) neurons in the spinal dorsal horn of male and female mice and identified underlying signaling mechanisms. Spinal cord slice recordings revealed that µ-opioid receptor (MOR) stimulation with DAMGO initially inhibited dorsal root-evoked EPSCs in 87% VGluT2 neurons and subsequently induced LTP in 49% of these neurons. Repeated morphine treatment increased the prevalence of VGluT2 neurons displaying LTP with a short onset latency. In contrast, DAMGO inhibited EPSCs in 46% VGAT neurons but did not elicit LTP in any VGAT neurons even in morphine-treated mice. Spinal superficial laminae were densely innervated by MOR-containing nerve terminals and were occupied by mostly VGluT2 neurons and few VGAT neurons. Furthermore, conditional knockout in dorsal root ganglion neurons diminished DAMGO-elicited LTP in lamina II neurons and attenuated hyperalgesia and analgesic tolerance induced by repeated treatment with morphine. In addition, DAMGO-elicited LTP in VGluT2 neurons was abolished by protein kinase C inhibition, gabapentin, knockout, or disrupting the α2δ-1-NMDA receptor interaction with an α2δ-1 C terminus peptide. Thus, brief MOR stimulation distinctively potentiates nociceptive primary afferent input to excitatory dorsal horn neurons via α2δ-1-coupled presynaptic NMDA receptors, thereby causing hyperalgesia and reducing opioids' analgesic actions.Opioid drugs are potent analgesics for treating severe pain and are commonly used during general anesthesia. However, opioid use often induces pain hypersensitivity, rapid loss of analgesic efficacy, and dose escalation, which can cause dependence, addiction, and even overdose fatality. This study demonstrates for the first time that brief opioid exposure preferentially augments primary sensory input to genetically identified glutamatergic excitatory, but not GABAergic/glycinergic inhibitory, neurons in nociceptive dorsal horn circuits. This opioid-elicited synaptic plasticity is cell type-specific and mediated by protein kinase C- and α2δ-1-dependent activation of NMDA receptors at primary sensory nerve terminals. These findings elucidate how intraoperative use of opioids aggravates postoperative pain and increases opioid consumption and suggest new strategies to improve opioid analgesic efficacy.

The primary aim of this pilot study was to test the feasibility and acceptability of a prototype of a novel digital system enabling somatosensory training at home by means of a gamified mobile application in patients with chronic pain. The secondary aims were to test the effect size of the intervention on clinical outcomes to power a subsequent randomized controlled trial. We conducted a pilot randomized controlled trial in patients with fibromyalgia. This was an 8-week crossover study, which included a 4-week somatosensory training phase (daily use with the novel digital system) and a 4-week control phase (no use of this new system) in a random order. Feasibility was tested by objectively measuring the adherence and retention rates. Acceptability and changes in pain and disability were measured through data from subjective questionnaires. Thirty-five patients completed the study. The satisfaction questionnaire indicated high training enjoyment, ease of use for daily training and interest to continue to use the intervention after the study. The adherence (93%) and retention (94%) rates were high. The effect sizes were moderate for pain intensity (0.57). The novel gamified technology for remotely delivered somatosensory training is feasible in a group of patients with fibromyalgia, and results in high engagement, satisfaction, and adherence. A subsequent clinical trial with the final version of the technology platform, including a longer training with more sensory training tasks and a bigger sample size is necessary.

Neuroinflammation in the peripheral nervous system has been linked to cancer metastasis-induced bone pain. The stimulator of interferon genes (STING), an innate immune sensor for cytosolic DNA, plays an important role in inflammation and cancer metastasis and is reported to be a critical regulator of nociception. Here, we examined the role of STING in primary nociceptive neurons and chronic pain to determine if it could be a new target for treating bone cancer pain (BCP).

This guideline provides recommendations for clinicians providing pain care, including those prescribing opioids, for outpatients aged ≥18 years. It updates the CDC Guideline for Prescribing Opioids for Chronic Pain – United States, 2016 (MMWR Recomm Rep 2016;65[No. RR-1]:1-49) and includes recommendations for managing acute (duration of <1 month), subacute (duration of 1-3 months), and chronic (duration of >3 months) pain. The recommendations do not apply to pain related to sickle cell disease or cancer or to patients receiving palliative or end-of-life care. The guideline addresses the following four areas: 1) determining whether or not to initiate opioids for pain, 2) selecting opioids and determining opioid dosages, 3) deciding duration of initial opioid prescription and conducting follow-up, and 4) assessing risk and addressing potential harms of opioid use. CDC developed the guideline using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Recommendations are based on systematic reviews of the scientific evidence and reflect considerations of benefits and harms, patient and clinician values and preferences, and resource allocation. CDC obtained input from the Board of Scientific Counselors of the National Center for Injury Prevention and Control (a federally chartered advisory committee), the public, and peer reviewers. CDC recommends that persons with pain receive appropriate pain treatment, with careful consideration of the benefits and risks of all treatment options in the context of the patient's circumstances. Recommendations should not be applied as inflexible standards of care across patient populations. This clinical practice guideline is intended to improve communication between clinicians and patients about the benefits and risks of pain treatments, including opioid therapy; improve the effectiveness and safety of pain treatment; mitigate pain; improve function and quality of life for patients with pain; and reduce risks associated with opioid pain therapy, including opioid use disorder, overdose, and death.

Utilizing cannabis as a therapeutic option for chronic pain (CP) has increased significantly. However, data regarding the potential immunomodulatory effects of cannabis in CP patients remain scarce. We aimed at exploring the relationship between cannabis use and inflammatory cytokines and chemokines among a cohort of CP patients. Adult patients with a CP diagnosis and medical authorization of cannabis were enrolled. Patients completed validated clinical questionnaires and self-reported the effectiveness of cannabis for symptom management. Patients' blood and cannabis samples were analyzed for the presence of four major cannabinoids, two major cannabinoid metabolites, 29 different cytokines/chemokines, and cortisol. The multivariable linear regression model was used to identify cannabis and patient factors associated with immune markers. Fifty-six patients (48±15 years; 64% females) were included, with dried cannabis (53%) being the most common type of cannabis consumed. Seventy percent of products were considered delta-9-tetrahydrocannabinol (Δ-THC)-dominant. The majority of patients (96%) self-reported effective pain management, and 76% reported a significant decrease in analgesic medication usage (≤0.001). Compared with males, female patients had higher plasma levels of cannabidiol (CBD), cannabidiolic acid, Δ-THC, and 11-hydroxy-Δ-tetrahydrocannabinol but lower concentrations of delta-9-tetrahydrocannabinolic acid and 11-nor-9-carboxy-Δ-tetrahydrocannabinol (THC-COOH). Females had significantly lower eotaxin levels (=0.04) in comparison to male patients. The regression analysis indicated that high cannabis doses were related to increased levels of interleukin (IL)-12p40 (=0.02) and IL-6 (=0.01), whereas female sex was associated with decreased eotaxin (≤0.01) concentrations. Blood CBD levels were associated with lower vascular endothelial growth factor (=0.04) concentrations, and THC-COOH was a factor related to decreased tumor necrosis factor alpha (=0.02) and IL-12p70 (=0.03). This study provides further support for the patient-perceived effectiveness of cannabis in managing CP symptoms and reducing analgesic medication consumption. The results suggest a potential sex difference in metabolizing cannabinoids, and the varying immune marker concentrations may support a possible immunomodulatory effect associated with patient sex and cannabis product type. These preliminary findings provide grounds for further validation using larger, well-designed studies with longer follow-up periods.

Painmanagement after oral surgeries is essential to enhance recovery, reduce negative outcomes and improve the experience of the patient. Naltrexone (NTX) is a non-selective opioid receptor antagonist that has been shown to modulate neuro-inflammation when employed in low to ultra-low doses. In addition, ultra-low dose naltrexone (ULDN) has been shown to potentiate opioids' analgesia and to have opioid-sparing effects. Herein it was investigated the effect of ULDN in a model of postoperative orofacial pain in rats, and it was tested the hypothesis that blockade of TLR4-signalling pathway contributes to its antinociceptive effect. Systemic NTX reduced heat hyperalgesia in female rats and heat and mechanical hyperalgesia in male rats after incision surgery. Combined treatment with NTX and morphine, both at ineffective doses, resulted in a significant reduction of heat hyperalgesia in male rats. NTX injection at the incision site failed to change heat hyperalgesia, but injection at the trigeminal ganglion (TG) or subnucleus caudalis (Sp5C) caused a significant reduction in heat hyperalgesia. At these sites, blockade of TLR4 impeded NTX effect. Lipopolysaccharide (LPS) injection in the intraoral mucosa resulted in facial heat hyperalgesia and increase in IL-1β levels in the TG, which were reduced by systemic NTX. Stimulation of macrophages with LPS resulted in increase of nitric oxide, IL-1β and CXCL-2 levels which were reduced by NTX. Altogether, these results provide evidence for an antinociceptive effect of ULDN in postoperative orofacial pain and suggest that blockade of TLR4 and downstream signaling pathway contribute to its effect.

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that predominantly affects the axial skeleton and is characterized by inflammatory back pain. While much has been published regarding non-steroidal anti-inflammatory drugs and tumor necrosis factor inhibitors, other classes of medications which leverage alternate molecular mechanisms receive less attention. In this review, we summarize a few of the novel targets in axSpA, review the putative mechanism of action of therapies that focus on these targets, and reference the germane recently completed, ongoing, or proposed randomized controlled clinical trials. The agents addressed include inhibitors of interleukin-23, interleukin-17, janus kinases, granulocyte-macrophage colony-stimulating factor, macrophage migration inhibitory factor, antibodies recognizing T cell receptor beta variable 9 gene positive clones, as well as inhibitors of mitogen-activated protein kinase-activated protein kinase-2.

Glial cells, such as microglia and astrocytes, in the trigeminal spinal subnucleus caudalis (Vc) are activated after trigeminal nerve injury and interact with Vc neurons to contribute to orofacial neuropathic pain. Complement C1q released from microglia has been reported to activate astrocytes and causes orofacial mechanical allodynia. However, how C1q-induced phenotypic alterations in Vc astrocytes are involved in orofacial pain remains to be elucidated. Intracisternal administration of C1q caused mechanical allodynia in the whisker pad skin and concurrent significant upregulation of glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 in the Vc. Immunohistochemical analyses clarified that C1q induces a significant increase in the cytokine interleukin (IL)-1β, predominantly in Vc astrocytes and partially in Vc microglia. The number of c-Fos-positive neurons in the Vc increased significantly in response to C1q. IL-1 receptor antagonist (IL-1Ra) was used to analyze the involvement of IL-1β in C1q-induced mechanical allodynia. Intracisternal administration of IL-1Ra ameliorated C1q-induced orofacial mechanical allodynia. The present findings suggest that IL-1β released from activated astrocytes and microglia in the Vc mediates C1q-induced orofacial pain.