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This paper presents and discusses recent evidence on the pathophysiological mechanisms of pain. The role of tapentadol-an analgesic molecule characterized by an innovative mechanism of action (i.e., µ-opioid receptor [MOR] agonism and inhibition of noradrenaline [NA] reuptake [NRI])-in the modulation of pain, and the most recent pharmacological evidence on this molecule (e.g., the µ-load concept) are also presented and commented upon. Narrative review. Solid evidence has highlighted the importance of central sensitization in the transition from acute to chronic pain. In particular, the noradrenergic system holds a major role in limiting central sensitization and the progression to chronic pain. Therefore, pharmacological modulation of the noradrenergic system appears to be a well-grounded strategy for the control of chronic pain. Tapentadol is characterized by a to-date-unique mechanism of action, since it acts both as a MOR agonist and as an inhibitor of NA reuptake. The synergistic interaction of these two mechanisms allows a strong analgesic effect by acting on both ascending and descending pathways. Of note, the reduced µ-load of tapentadol has two important consequences: first, it limits the risk of opioid-related adverse events, as well as the risk of dependence; second, the NA component becomes predominant at least in some types of pain with consequent specific clinical efficacy in the treatment of neuropathic and chronic pain. According to these characteristics, tapentadol appears suitable in the treatment of chronic pain conditions characterized by both a nociceptive and a neuropathic component, such as osteoarthritis or back pain.
Learn More >Constipation is the most common adverse event (AE) of opioid therapy. This multicenter, phase 2 study evaluated the efficacy and safety of linaclotide in treating opioid-induced constipation (OIC) in patients with chronic noncancer pain syndromes (NCT02270983). Adults with OIC (<3 spontaneous bowel movements [SBMs]/week) related to chronic noncancer pain were randomized 1:1:1 to receive linaclotide 145 µg, linaclotide 290 µg, or placebo once daily for 8 weeks. The primary endpoint was change from baseline in 8-week SBM frequency rate (SBMs/week). Secondary efficacy endpoints included 6/8-week SBM 3 + 1 responders, time to first SBM, and changes from baseline in 8-week stool consistency, abdominal bloating, and straining. Additional endpoints included treatment satisfaction and adequate relief responders. In total, 254 patients were randomized: 87, 88, and 79 received linaclotide 145 µg, linaclotide 290 µg, and placebo, respectively. The mean changes from baseline in SBMs/week during the treatment period were 2.9 and 3.5 in the linaclotide 145 and 290 µg groups (P < 0.01 for both doses), respectively, vs 1.6 in the placebo group. Diarrhea, the most common AE, was generally mild, resulting in 1.1%, 5.7%, and 1.3% of patients discontinuing in the linaclotide 145 μg, linaclotide 290 μg, and placebo groups, respectively. No serious AEs related to diarrhea were reported in any treatment group. Compared with placebo, linaclotide-treated patients had significant improvements in stool consistency, straining, abdominal bloating, and treatment satisfaction scores (P < 0.05). Linaclotide significantly improved OIC symptoms and was well tolerated in patients with chronic noncancer pain.
Learn More >Painful conditions affect a significant population in the United States. As the scientific understanding of the benefits and harms of opioid therapy has evolved, so too has the application of prescription opioid therapy for the treatment of pain. The rapid increase in the use of prescription and illicit opioids over the past decade has contributed to a public health crisis commonly referred to as the "opioid crisis." In this article, the ethical approaches to treating patients with opioid pharmaceuticals as well as the development of regulation of opioid therapy in Washington State are reviewed.
Learn More >Numerous guidelines targeting safe use of opioids for chronic pain have been published but substantial challenges persist in clinical application of best practice recommendations. This article describes a pragmatic approach to clinical care of adults with chronic pain receiving long-term opioid therapy. Three components of care are emphasized: (1) medical and mental health assessment before initiating opioid therapy, (2) clinical surveillance during the course of long-term opioid therapy, and (3) clinical considerations and strategies governing opioid tapering. A pressing need exists for ongoing research to further clarify the optimal role that long-term opioid therapy has in treatment of chronic pain.
Learn More >While triptans are used to treat migraine, there is evidence that they also reduce inflammation induced pain at the spinal level. The cellular mechanisms underlying this spinal enhancement are unknown. We examined whether inflammation alters sumatriptan modulation of synaptic transmission in the rat spinal dorsal horn.
Learn More >Increasing evidence suggests that activation of satellite glia cells (SGCs) in sensory ganglia play important roles in the development of neuropathic pain. The present study aimed to investigate the involvement of SGC activation in a novel model of motor nerve injury induced pain hypersensitivity. The neuropathic pain model was established by cervical 8 ventral root avulsion (C8VA). Glial fibrillary acidic protein (GFAP) was used as a marker of SGC activation. Unilateral C8VA resulted in mechanical allodynia, but not thermal hyperalgesia in bilateral paws. Expectedly, SGCs were robustly activated on as early as 1 day and persisted for at least 7 days in the ipsilateral and contralateral dorsal root ganglia (DRG) of C6, C7 and C8 after C8VA. Double immunofluorescence showed that almost all the activated SGCs enveloped neurofilament 200 (NF200) positive myelinated neurons in DRG. Local application of fluorocitrate (FC), a glial metabolism inhibitor, significantly decreased the number of activated SGCs and alleviated bilateral mechanical allodynia. These results suggest that SGC activation contributed to ipsilateral and mirror-image pain hypersensitivity after C8VA. Inhibition of SGC activation represented a promising therapeutic strategy for the management of neuropathic pain following brachial plexus root avulsion.
Learn More >Maladaptive plasticity involving increased expression of AMPA-type glutamate receptors is involved in several pathologies, including neuropathic pain, but direct inhibition of AMPARs is associated with side effects. As an alternative, we developed a cell-permeable, high-affinity (~2 nM) peptide inhibitor, Tat-P -(C5) , of the PDZ domain protein PICK1 to interfere with increased AMPAR expression. The affinity is obtained partly from the Tat peptide and partly from the bivalency of the PDZ motif, engaging PDZ domains from two separate PICK1 dimers to form a tetrameric complex. Bivalent Tat-P -(C5) disrupts PICK1 interaction with membrane proteins on supported cell membrane sheets and reduce the interaction of AMPARs with PICK1 and AMPA-receptor surface expression in vivo. Moreover, Tat-P -(C5) administration reduces spinal cord transmission and alleviates mechanical hyperalgesia in the spared nerve injury model of neuropathic pain. Taken together, our data reveal Tat-P -(C5) as a novel promising lead for neuropathic pain treatment and expand the therapeutic potential of bivalent inhibitors to non-tandem protein-protein interaction domains.
Learn More >Sleep disorders and circadian dysregulation appear to be associated with primary headache disorders.
Learn More >Morphine is frequently used for pain relief, but long-term morphine therapy in patients with chronic pain results in analgesic tolerance and hyperalgesia. There are no effective therapeutic treatments that limit these detrimental side effects. We found pretreatment with melatonin could decrease morphine-induced analgesic tolerance. There was a significant activation of the NLRP3 inflammasome in the prefrontal cortex and the peripheral blood of morphine-treated mice compared to control animals, which could be blocked by melatonin. The inflammasome activation induced by morphine was mediated by the microglia. SiRNA knockdown or pharmacological inhibition of the NLRP3 abolished the morphine-induced inflammasome activation. Co-administration of melatonin and low-dose morphine had better analgesia effects in the murine models of pain and led to a lower NLRP3 inflammasome activity in brain tissues. Mice deficient for Nlrp3 had a higher nociceptive threshold and were less sensitive to develop morphine-induced analgesic tolerance and acetic acid-induced pain relative to wild-type animals. Concordantly, we observed a significantly elevated level of serum IL-1β, which indicates an increase of NLRP3 inflammasome activity associated with the reduced level of serum melatonin, in heroin-addicted patients relative to healthy individuals. Our results provide a solid basis for conducting a clinical trial with the co-administration of melatonin and morphine for the relief of severe pain.
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