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Background and aims In the Western world, it has become clear that we are facing a crisis of overuse, abuse and improperly prescribed use of opioids. As part of the ongoing discussion on opioid use, the use and prescription of tramadol have been addressed in recent years. A significant portion of this discussion should adequately address the risk factors for the use of weak opioid products such as tramadol. The risk factors which characterise the long-term tramadol use are still incompletely understood. Thus, we aimed to describe the characteristics of Danish patients using tramadol in more detail, under different scenarios and determinants of subsequent usage patterns. Methods We conducted a nationwide cohort study to identify individuals purchasing tramadol from 01/01/2004 to 31/12/2015 who are age 16 + years old by using data from The Danish National Databases; these databases consist of unique information for all citizens in Denmark. Logistic regression analyses were used to assess the potential risk factors for repeated tramadol use. Results The final cancer-free cohort consisted of N = 941,839 tramadol users: 54.4% women, with a mean age of 53.2 years. The number of chronic noncancer pain (CNCP) was 430,641 individuals, and 56% of the total third who repeated the use of tramadol with two + purchased prescriptions were CNCP patients. The increased risk of repeated use for CNCP was, among others, associated with: male sex (HR 1.21), age 69-110 (HR 1.72), back/spine pain men (HR 1.47), women (HR 1.46), spondylopathies (HR 1.24), male osteoporosis (HR 1.22), multimorbid ulcer/skin (HR 1.28), region of municipality Northern Jutland (HR 1.74), Central Jutland (HR 1.75), number of co-medication 4-9 (HR 1.33), dementia (HR 1.27). Factors associated with decreased risk: co-medication ischemic heart disease (HR 0.85), diagnosis headache (HR 0.70), household income highest tertile (HR 0.81), unknown (HR 0.70), single women (HR 0.96). Conclusions This study proved a widespread prescribed use of tramadol in Denmark, and, as know from the literature, weak opioid use may lead to long-term use of high potent opioids, this usage is inappropriate, in general, but especially for the treatment of CNCP. Implications When striving to reduce the overuse of opioids, focus on the extensive use of tramadol may be essential. The current study indicates an excessive and not appropriately prescribed use of tramadol among Danish CNCP patients. In addition to being inappropriate, such use may also have an impact on the growing problem of an illicit Internet market for this drug. Thus, the situation must be taken seriously. The current study confirms the recent clinical guideline and the National Recommendations in Denmark, which emphasises the risks of problematic use of tramadol. The research may also be relevant in other comparable countries. Caution must especially be taken with CNCP patients with comorbidities like diabetes, lung disease, dementia, and osteoporosis.
Learn More >Naringenin (2S)-5,7-dihydroxy-2-(4-hydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-one is a natural flavonoid found in fruits from the citrus family. Since (2S)-Naringenin is known to racemize, its bioactivity might be related to one or both enantiomers. Computational studies predicted that (2R)-Naringenin may act on voltage-gated ion channels, particularly the N-type calcium channel (CaV2.2) and the NaV1.7 sodium channel – both key for pain signaling. Here we set out to identify the possible mechanism of action of Naringenin. Naringenin inhibited depolarization-evoked Ca2+ influx in acetylcholine-, ATP- and capsaicin-responding rat dorsal root ganglion (DRG) neurons. This was corroborated in electrophysiological recordings from DRG neurons. Pharmacological dissection of each of the voltage-gated Ca2+ channels subtypes could not pinpoint any selectivity of Naringenin. Instead, Naringenin inhibited NaV1.8-dependent, tetrodotoxin (TTX)-resistant while sparing tetrodotoxin sensitive (TTX-S) voltage-gated Na+ channels as evidenced by the lack of further inhibition by the NaV1.8 blocker A-803467. The effects of the natural flavonoid were validated ex vivo in spinal cord slices where Naringenin decreased both the frequency and amplitude of sEPSC recorded in neurons within the substantia gelatinosa. The antinociceptive potential of Naringenin was evaluated in male and female mice. Naringenin had no effect on the nociceptive thresholds evoked by heat. Naringenin's reversed allodynia was in mouse models of post-surgical and neuropathic pain. Here, driven by a call by the NCCIH's strategic plan to advance fundamental research into basic biological mechanisms of action of natural products, we advance the antinociceptive potential of the flavonoid Naringenin.
Learn More >The non-selective activation of central and peripheral opioid receptors is a major shortcoming of currently available opioids. Targeting peripheral opioid receptors is a promising strategy to preclude side effects. Recently, we showed that fentanyl-derived μ-opioid receptor (MOR) agonists with reduced acid dissociation constants (pK) due to introducing single fluorine atoms produced injury-restricted antinociception in rat models of inflammatory, postoperative and neuropathic pain. Here, we report that a new double-fluorinated compound (FF6) and fentanyl show similar pK, MOR affinity and [S]-GTPγS binding at low and physiological pH values. In vivo, FF6 produced antinociception in injured and non-injured tissue, and induced sedation and constipation. The comparison of several fentanyl derivatives revealed a correlation between pK values and pH-dependent MOR activation, antinociception and side effects. An opioid ligand's pK value may be used as discriminating factor to design safer analgesics.
Learn More >The transient receptor potential ankyrin 1 (TRPA1) channel functions as an irritant sensor and is a therapeutic target for treating pain, itch, and respiratory diseases. As a ligand-gated channel, TRPA1 can be activated by electrophilic compounds such as allyl isothiocyanate (AITC) through covalent modification or activated by noncovalent agonists through ligand binding. However, how covalent modification leads to channel opening and, importantly, how noncovalent binding activates TRPA1 are not well-understood. Here we report a class of piperidine carboxamides (PIPCs) as potent, noncovalent agonists of human TRPA1. Based on their species-specific effects on human and rat channels, we identified residues critical for channel activation; we then generated binding modes for TRPA1-PIPC interactions using structural modeling, molecular docking, and mutational analysis. We show that PIPCs bind to a hydrophobic site located at the interface of the pore helix 1 (PH1) and S5 and S6 transmembrane segments. Interestingly, this binding site overlaps with that of known allosteric modulators, such as A-967079 and propofol. Similar binding sites, involving π-helix rearrangements on S6, have been recently reported for other TRP channels, suggesting an evolutionarily conserved mechanism. Finally, we show that for PIPC analogs, predictions from computational modeling are consistent with experimental structure-activity studies, thereby suggesting strategies for rational drug design.
Learn More >The gamma-aminobutyric acid type B (GABA) receptor agonist, the sodium salt of gamma-hydroxybutyrate (GHB), significantly improved pain, sleep disturbance and fatigue in fibromyalgia (FM) patients. However, the use of GABA receptor agonists is limited by their undesirable side-effects. To clarify whether GABA receptor positive allosteric modulator (PAM) approach would achieve analgesia with less side-effects than GABA receptor agonist in FM, we investigated the potential of a novel GABA receptor PAM, ASP8062, for FM treatment. We examined the in vitro profiles of ASP8062, the effects of a GABA receptor PAM and an agonist on pain in a rat model of FM, and the sleep/wake cycle, EEG during sleep stages and motor coordination in rats. ASP8062 showed PAM activity on human and rat GABA receptors. Oral administration of ASP8062 significantly reversed the decrease in muscle pressure threshold in reserpine-induced myalgia rats. The analgesic effects of ASP8062 were significantly blocked by a GABA receptor antagonist. ASP8062 had a significant effect on motor coordination at a 1000-fold higher dose than the analgesic dose in rats. ASP8062 significantly decreased total REM sleep time and frequency of sleep interruptions, and increased the power in delta waves frequency during non-REM sleep in rats. ASP8062, a novel GABA receptor PAM, has therapeutic potential to exert analgesic effects with less side-effects compared to GABA receptor agonists in patients with FM.
Learn More >Ketamine is a drug largely used in clinical practice as an anesthetic and it can also be used as an analgesic to manage chronic pain symptoms. Despite its interactions with several other signaling systems such as cholinergic, serotoninergic and adrenergic, it is accepted that NMDA receptor antagonism is the main mechanism of action of this drug. In this study we investigated the actions of endogenous opioids in the mechanism of peripheral analgesia induced by ketamine. The nociceptive threshold for mechanical stimuli was measured in Swiss mice using the Randall and Selitto test. The drugs used in this study were administered via intraplantar injection. Our results demonstrated that non selective opioid receptor antagonism (naloxone), selective μ- and δ-opioid receptors antagonism (clocinamox and naltrindole, respectively) but not κ-opioid receptor antagonism (nor-binaltorphimine NORBNI) antagonized ketamine-induced peripheral antinociception in a dose-dependent manner. In addition, administration of aminopeptidase inhibitor bestatin significantly potentiated ketamine-induced peripheral antinociception. Ketamine injection in the right hind paw induced β-endorphine synthesis in the epithelial tissue of the hindpaw. Together these results indicate a role for μ- and δ-opioid receptors and for the endogenous opioid β-endorphine increased synthesis in ketamine-induced peripheral analgesia mechanism of action.
Learn More >It is widely known that visceral pain is more prevalent in women than in men, and this phenomenon is interpreted as a consequence of the gonadal hormone modulation of pain perception and transduction. Uterine cervical distension might cause obstetric and gynecologic pain with clinical relevance to visceral pain. In this study, we focused on the roles of 17β-estradiol and progesterone in visceral nociception with the use of a rat model of uterine cervical distension. Female ovariectomized rats were injected with 17β-estradiol (E) or progesterone (P) for 21 days, after which visceral pain-induced spinal c-fos expression and visceromotor reflex changes were compared between ovariectomized and hormone-substituted groups. We found that uterine cervical distension induced a drastic increase in spinal c-fos expression and visceromotor reflex activity, and ovariectomy inhibited the increase in c-fos expression induced by visceral pain; this inhibition was reversed by estrogen but not progesterone replacement. This study demonstrates that estrogen is involved in uterine cervical nociception, while progesterone plays less of a significant role.
Learn More >Neural uptake of glutamate is executed by the structurally related members of the SLC1A family of solute transporters: GLAST /EAAT1, GLT-1 /EAAT2, EAAC1 /EAAT3, EAAT4, ASCT2. These plasma membrane proteins ensure supply of glutamate, aspartate and some neutral amino acids, including glutamine and cysteine, for synthetic, energetic and signaling purposes, whereas effective removal of glutamate from the synaptic cleft shapes excitatory neurotransmission and prevents glutamate toxicity. Glutamate transporters (GluTs) possess also receptor-like properties and can directly initiate signal transduction. GluTs are physically linked to other glutamate signaling-, transporting- and metabolizing molecules (e.g., glutamine transporters SNAT3 and ASCT2, glutamine synthetase, NMDA receptor, synaptic vesicles), as well as cellular machineries fueling the transmembrane transport of glutamate (e.g., ion gradient-generating Na/K-ATPase, glycolytic enzymes, mitochondrial membrane- and matrix proteins, glucose transporters). We designate this supramolecular functional assembly as 'glutamosome'. GluTs play important roles in the molecular pathology of chronic pain, due to the predominantly glutamatergic nature of nociceptive signalling in the spinal cord. Down-regulation of GluTs often precedes or occurs simultaneously with development of pain hypersensitivity. Pharmacological inhibition or gene knock-down of spinal GluTs can induce/aggravate pain, whereas enhancing expression of GluTs by viral gene transfer can mitigate chronic pain. Thus, functional up-regulation of GluTs is turning into a prospective pharmacotherapeutic approach for the management of chronic pain. A number of novel positive pharmacological regulators of GluTs, incl. pyridazine derivatives and β-lactams, have recently been introduced. However, design and development of new analgesics based on this principle will require more precise knowledge of molecular mechanisms underlying physiological or aberrant functioning of the glutamate transport system in nociceptive circuits.
Learn More >In 2018, the United States Food and Drug Administration (FDA) approved Aimovig (erenumab) for the prevention of migraine. Erenumab is the first FDA approved antibody therapeutic against a G-protein-coupled receptor, the canonical receptor of calcitonin gene related peptide (CGRP-R). A novel, epitope-focused antigen was created to reconstruct the extracellular domains of the CGRP-R in a stable conformation. Successful inoculation of XenoMouse animals and careful screening yielded multiple candidate molecules for high potency and exquisite selectivity toward the CGRP-R over related receptors. These efforts led to the discovery of erenumab which has demonstrated the desired efficacy and safety profiles in multiple clinical studies for the prevention of migraine. The innovation developed in the discovery of erenumab furthers the ability to target G-coupled protein receptors using antibody approaches.
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