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Diurnal variations in pain hypersensitivity are common in chronic pain disorders. Temporal exacerbation of neuropathic pain hypersensitivity is dependent on diurnal variations in glucocorticoid secretion from the adrenal glands. We previously demonstrated that spinal expression of serum- and glucocorticoid-inducible kinase-1 (SGK-1) is associated with glucocorticoid- induced exacerbation of pain hypersensitivity, but there are no available strategies to inhibit SGK-1 in the spinal cord. By screening a clinically approved drug library (more than 1,200 drugs), we found that sulfasalazine (SSZ) has inhibitory effects on SGK-1. SSZ is a prodrug composed of 5-aminosalicylic acid and sulfapyridine linked by N=N bond, which is therapeutically effective for inflammatory bowel diseases. However, the N=N bond in SSZ was necessary for its inhibitory action against SGK-1. Although intrathecal injection of SSZ to nerve-injured mice significantly alleviated mechanical pain hypersensitivity, no significant anti- neuropathic pain effects of SSZ were detected after oral administration due to its low bioavailability and limited spinal distribution, which were associated with efflux by the xenobiotic transporter breast cancer resistance protein (BCRP). Concomitant oral administration of SSZ with febuxostat (FBX), which is an approved drug to inhibit BCRP, improved the distribution of SSZ to the spinal cord. The concomitant oral administration with FBX also increased the anti-neuropathic pain effects of SSZ. Our study revealed a previously unrecognized pharmacological effect of SSZ to alleviate SGK-1-induced painful peripheral neuropathy, and concomitant oral administration of SSZ with FBX may also be a preventative option for diurnal exacerbation of neuropathic pain hypersensitivity.
Learn More >Many national guidelines recommend the use of patient provider agreements (PPAs) when prescribing opioids for chronic pain. There are no standards for PPA content, readability, or administration processes.
Learn More >TRPV1, a member of the transient receptor potential (TRP) family, is a nonselective calcium permeable ion channel gated by physical and chemical stimuli. In the skin, TRPV1 plays an important role in neurogenic inflammation, pain and pruritus associated to many dermatological diseases. Consequently, TRPV1 modulators could represent pharmacological tools to respond to important patient needs that still represent an unmet medical demand. Previously, we reported the design of capsaicinoid-based molecules that undergo dermal deactivation (soft drugs), thus preventing their long-term dermal accumulation. Here, we investigated the pharmacological properties of the lead antagonist, 2-((4-hydroxy-2-iodo-5-methoxybenzyl) amino)-2-oxoethyl dodecanoate (AG1529), on heterologously expressed human TRPV1 (hTRPV1), on nociceptor excitability and on an in vivo model of acute pruritus. We report that AG1529 competitively blocked capsaicin-evoked activation of hTRPV1 with micromolar potency, moderately affected pH-induced gating, and did not alter voltage- and heat-mediated responses. AG1529 displays modest receptor selectivity as it mildly blocked recombinant hTRPA1 and hTRPM8 channels. In primary cultures of rat dorsal root ganglion (DRG) neurons, AG1529 potently reduced capsaicin-evoked neuronal firing. AG1529 exhibited lower potency on pH-evoked TRPV1 firing, and TRPA1-elicited nociceptor excitability. Furthermore, AG1529 abolished histaminergic and inflammation mediated TRPV1 sensitization in primary cultures of DRG neurons. Noteworthy, dermal wiping of AG1529, either in an acetone-based formulation or in an anhydrous ointment, dose-dependently attenuated acute histaminergic itch in a rodent model. This cutaneous anti-pruritic effect was devoid of the normal nocifensive action evoked by the burning sensation of capsaicin. Taken together, these preclinical results unveil the mode of action of AG1529 on TRPV1 channels and substantiate the tenet that this capsaicinoid-based soft drug is a promising candidate for drug development as a topical anti-pruritic and anti-inflammatory medication.
Learn More >A few modes of perioperative local analgesia have been studied in order to reduce postoperative pain after laparoscopy, including preemptive local anesthetics in the trocar sites and intraperitoneal anesthetics administration at the end of the surgery. However, the evidence regarding their efficacy are conflicting. In addition, the combination of both aforementioned methods has been rarely studied. Our aim was to evaluate whether subcutaneous trocar site and/or intraperitoneal analgesia reduce pain after gynecologic operative laparoscopy. This was a single-centered, randomized, controlled, double-blinded trial. The patients were randomly assigned to one of four equally sized groups: group 1-subcutaneous and intraperitoneal analgesia; group 2-subcutaneous analgesia and intraperitoneal placebo; group 3-subcutaneous placebo and intraperitoneal analgesia; Group 4-subcutaneous and intraperitoneal placebo. The patients, the surgeons, and the pain evaluators were all blinded to the patient's allocation. Included were patients who underwent elective operative laparoscopy. Exclusion criteria were: active infection, pregnancy, known sensitivity to Bupivacaine-Hydrochloride, chronic pelvic pain, surgeries with additional vaginal procedures, conversion to laparotomy, and malignancy. A total of 9 ml of Bupivacaine-Hydrochloride (Marcaine) 0.5%, or Sodium-Chloride 0.9%, as a placebo, were injected subcutaneously to the trocar sites (3 ml to each trocar site), prior to skin incision. In addition, 10 ml of Bupivacaine-Hydrochloride 0.5%, diluted with 40 ml of Sodium-Chloride 0.9% (a total of 50 ml solution), or 50 ml of Sodium-Chloride 0.9%, as a placebo, were injected intraperitoneally at the end of the surgery. By utilizing the 10 cm Visual-analogue-scale (VAS) we assessed post-operative pain at rest at 3, 8, and 24 h, and during ambulation at 8 and 24 h. The study was approved by the local Institutional Review Board and has been registered at clinicaltrials.gov. We conformed to the CONSORT recommendations. Between December 2016 and July 2019, a total of 119 patients were included in the study. Demographic and interventional characteristics were similar among the groups. The level of postoperative pain, either at rest or with change of position, was not significantly different between the groups, at all-time points. Application of subcutaneous and/or intraperitoneal analgesia is not effective in reducing pain after gynecologic operative laparoscopy.Clinical trial identification number: NCT02976571. Date of trial registration 11/29/2016. URL of the registration site: https://clinicaltrials.gov .
Learn More >We aimed to investigate the prevalence of dysautonomia in complex regional pain syndrome (CRPS) via the combined autonomic nervous system (ANS) function tests, including the deep breathing test (DBT), orthostatic test (OST) and sympathetic skin response (SSR).
Learn More >Headache is an important manifestation during SARS-CoV-2 infection. In this study, we aim to identify factors associated with headache in COVID-19 and headache characteristics.
Learn More >Approximately 20% of knee osteoarthritis patients undergoing total knee arthroplasty (TKA) report chronic postoperative pain. Studies suggest that preoperative variables such as impaired descending pain control, catastrophizing, function, and neuropathic pain-like symptoms may predict postoperative pain 12 months after TKA, but the combined prediction value of these factors has not been tested. The current prospective cohort study aimed to combine preoperative risk factors to investigate the predictive value for postoperative pain 12 months after TKA.
Learn More >Limited evidence exists exploring perceptions of which aspects of a pain management program are perceived as valuable and impactful. The aim of this study was to explore patient beliefs about which aspects of a pain management program were valued and/or had perceived impact. One-on-one structured interviews were conducted with 11 adults three months after their completion of the Spark Pain Program at Westmead Hospital, Sydney, Australia. Concepts in the transcripts were inductively identified and explored, utilizing thematic analysis to better understand their relevance to the study aim. : Four themes emerged: (1) "The program overall was positive, but…"; (2) "I valued my improved knowledge and understanding of pain, but…"; (3) "I valued the stretching/relaxation/pacing/activity monitoring"; and (4) "I valued being part of a supportive and understanding group". Participants reported that they liked being treated as an individual within the group. A lack of perceived personal relevance of key messages was identified in some participants; it appears that patients in pain programs must determine that changes in knowledge, beliefs, and attitudes are personally relevant in order for the changes to have a significant impact on them. This study provides new insights into aspects of a pain management program that were perceived as valuable and impactful, areas that "missed the mark", and hypotheses to guide the implementation of service delivery and program redesign.
Learn More >Functional gastrointestinal disorders (FGIDs), characterized by chronic abdominal complaints without a structural or biochemical cause, are common diseases that are frequently encountered by specialists in internal medicine. Collectively, irritable bowel syndrome (IBS) and functional dyspepsia are estimated to affect up to 22% of the population, and are often associated with additional somatic and pain complaints, all without an obvious structural source [1,2]. An appreciation of the current understanding of the mechanistic basis for these disorders is key to developing treatment goals and optimization of patient management strategies. In recent years, the brain-gut axis increasingly has been recognized as a central factor in the experience of functional abdominal pain disorders, including the most recent Rome IV guidelines which identify FGIDs as disorders of gut-brain interaction [3]. The brain-gut axis (BGA), simply defined, is a complex network of bidirectional communication between the central and enteric nervous systems. This axis broadly includes all the systems involved with communication between the GI tract and central nervous system (CNS), with principle inputs into this network occurring between the CNS, enteric nervous system (ENS), and autonomic nervous systems (ANS), but also includes interfaces with numerous other factors, including endocrine hormones and immune effector cells as well as interactions with the gut microbiota. Perturbances to this system have been found to play a critical role in the development of visceral hypersensitivity, bowel dysregulation, and mood. This review will summarize the principle processes involved in the neurologic and biologic function of the brain-gut axis, our current understanding of its role in functional GI disorders, and potential targets for therapeutic intervention.
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