piperidines and Acute-Pain

To evaluate analgesic efficacy and safety/tolerability of the nonbenzodiazepine antispasmodic pridinol (PRI) in patients with muscle-related pain.. Systematic review and meta-analysis of randomized placebo-controlled trials (RCTs) according to PRISMA guidelines and Cochrane recommendations. Data sources included Google Scholar, Embase, PubMed, ClinicalTrials.gov, EU Clinical Trials Registry, Chinese Clinical Trial Registry, UMIN Clinical Trials Registry, and product manufacturer archives from inception to 31 January 2022. Eligibility criteria for study selection were randomized, placebo-controlled trials with PRI in adults (≥18 years) with muscle-related pain. Data extraction, synthesis, and analysis carried out by two reviewers independently identified studies, extracted data, and assessed the risk of bias using the Cochrane risk of bias tool. Categorial global response rates (number of patients) based on clinical judgement of study physicians (as primary efficacy endpoint), and response on pain at rest, pain at movement, stiffness, tenderness, and movement restriction (as secondary efficacy endpoints), as well as the number of patients with drug-related adverse events (DRAEs) were meta-analytically evaluated using the Review Manager Software version 5.4.1.. The results from this meta-analysis as based on two placebo-controlled studies in adult patients with mild to moderate acute muscle pain demonstrate that a 3-week monotherapy with PRI showed a comparable safety profile, but significantly better analgesic effects and improvements of related impairments such as stiffness, tenderness, and movement restrictions compared with placebo - irrespective of its mode of administration.. Muscle pain is one of the most common pain problems worldwide.In the majority of cases, muscle pain is temporary, transient, and benign in nature. However, people affected may still experience severe pain and significant pain-related disabilities in daily life activities that may require temporary drug treatment – also in order to be able to undertake the non-drug treatment measures necessary to prevent recurrence.Current treatment recommendations for muscle pain are largely ´non-specific´ and limited to symptomatic pain-relieving measures (e.g. non-steroidal anti-inflammatories), while muscle relaxants – such as pridinol (PRI), which has been reapproved in Germany in 2017 and first time approved in the United Kingdom, Spain, and Poland in 2020 – are currently not recommended (primarily due to insufficient efficacy data from controlled clinical trials) but nevertheless frequently prescribed.Due to our systematic literature research of double-blind randomized and placebo-controlled trials, a 3-week monotherapy with PRI

Topics: Acute Pain; Adult; Aged; Double-Blind Method; Female; Humans; Male; Middle Aged; Myalgia; Piperidines; Randomized Controlled Trials as Topic

Opioids in general and remifentanil in particular can induce hyperalgesia. Preclinical data suggest that cannabidiol might have the capacity to reduce opioid-induced hyperalgesia (OIH). Thus, we investigated the effect of oral cannabidiol on OIH in healthy volunteers using an established pain model. Twenty-four healthy participants were included in this randomized, double-blinded, crossover study and received either a 1600-mg single-dose oral cannabidiol or placebo. Hyperalgesia, allodynia, and pain were induced by intracutaneous electrical stimulation. To provoke OIH, participants recieved an infusion of 0.1 µg/kg/min remifentanil over a time frame of 30 minutes, starting 100 minutes after oral cannabidiol ingestion. The primary outcome was the area of hyperalgesia (in square centimetres) up to 60 minutes after remifentanil administration. The area of allodynia (in square centimetres) and pain (numeric rating scale) were also assessed.Cannabidiol had no significant effect on hyperalgesia, allodynia, or pain at any time point of measurement compared with placebo. The area of hyperalgesia after remifentanil administration significantly increased compared with baseline (17.0 cm 2 [8.1-28.7] vs 25.3 cm 2 [15.1-39.6]; P = 0.013). Mean cannabidiol blood levels were 4.1 ± 3.0 µg/L (mean ± SD) at 130 minutes after ingestion and were 8.2 μg/L ± 6.9 µg/L (mean ± SD) at 200 minutes. Cannabidiol was well tolerated. We conclude that a high single-oral dose of 1600-mg cannabidiol is not effective in reducing OIH. Before excluding an effect of cannabidiol on OIH, research should focus on drug formulations enabling higher cannabidiol concentrations.

Topics: Acute Pain; Adult; Analgesics, Opioid; Cannabidiol; Cross-Over Studies; Double-Blind Method; Humans; Hyperalgesia; Nociceptive Pain; Piperidines; Remifentanil

Thoracotomy is one of the most painful surgical incisions. Little is known, however, about the effect of type of anaesthesia on chronic post-thoracotomy pain syndrome (CPTS). We therefore compared the incidence of CPTS after total intravenous anaesthesia (TIVA) and inhalation anaesthesia.. Patients (n = 366) were prospectively randomized into two groups: Group I (n = 173) received TIVA (propofol + remifentanil) and Group II (n = 170) received inhalation anaesthesia with sevoflurane. We assessed acute pain on postoperative days 1, 3 and 5, and the prevalence of CPTS at 3 and 6 months using a numerical rating scale (NRS).. The prevalence of CPTS was significantly lower in patients receiving TIVA than in those receiving inhalation anaesthesia at 3 months (38.2% versus 56.5%, P = 0.001) and at 6 months (33.5% versus 50.6%, P = 0.002), respectively. Moreover, allodynia-like pain was significantly less common in the TIVA group at 3 (P = 0.021) and 6 months (P = 0.032). NRS score of acute pain, however, did not differ significantly between the two groups.. TIVA with propofol and remifentanil may reduce the incidence of CPTS at 3 and 6 months.

Topics: Acute Pain; Adolescent; Adult; Aged; Analgesics; Anesthesia, Inhalation; Anesthesia, Intravenous; Anesthetics, Combined; Anesthetics, Inhalation; Anesthetics, Intravenous; Chronic Disease; Drug Administration Schedule; Esophageal Neoplasms; Female; Humans; Lung Neoplasms; Male; Methyl Ethers; Middle Aged; Pain Measurement; Pain, Postoperative; Piperidines; Propofol; Prospective Studies; Remifentanil; Sevoflurane; Thoracotomy; Young Adult

To evaluate efficacy and tolerability of the nonbenzodiazepine antispasmodic pridinol (PRI), as an add-on treatment in patients with muscle-related pain (MRP).. Exploratory retrospective analysis of depersonalized routine data provided by the German Pain e-Registry (GPeR) focusing on pain intensity, pain-related disabilities in daily life, wellbeing, and drug-related adverse events (DRAEs).Primary endpoint based on a global response composite of (a) a clinically relevant analgesic response (relative improvement ≥50% and/or absolute improvement ≥ the minimal clinical important difference) for pain intensity and disability in combination with (b) an improvement in wellbeing (all at end of treatment vs. baseline), and (c) lack of any DRAEs.. Between 1 January 2018 and 31 December 2020, the GPeR collected information on 121,803 pain patients of whom 1133 (0.9%; 54.5% female, mean ± SD age: 53.9 ± 11.8 years) received add-on PRI for the treatment of (mostly acute) MRP originating predominantly in the (lower) back (43.2%), lower limb (26.4%), or should/neck (21.1%). Average daily dose was 7.8 ± 1.8 (median 9, range 1.5-13.5) mg, duration of treatment 12.0 ± 10.2 (median 7, range 3-63) days. In total, 666 patients (58.8%) reported a complete, 395 (34.9%) a partial, and 72 (6.4%) patients no response - either because of lack of efficacy (. Based on this real-world data of the German Pain e-Registry, add-on treatment with PRI in patients with acute MRP under real-world conditions in daily life was well tolerated and associated with an improvement of pain intensity, pain-related disabilities, and overall wellbeing.. Muscle pain is one of the most common pain problems worldwide.In the majority of cases, muscle pain is temporary, transient, and benign in nature. However, people affected may still experience severe pain and significant pain-related disabilities in daily life activities that may require temporary drug treatment – also to be able to undertake the non-drug treatment measures necessary to prevent recurrence.Current treatment recommendations for muscle pain are largely “non-specific” and limited to symptomatic pain-relieving measures (e.g. NSAIDs), whereas muscle relaxants are currently not recommended (primarily due to insufficient efficacy data from controlled clinical trials) but are nevertheless frequently prescribed.In our analysis of depersonalized data from the German Pain e-Registry, the add-on treatment with pridinol proved to be effective and well tolerated in patients with muscle pain who have so far responded only insufficiently to recommended analgesic and adjuvant therapiesThe available real-world evidence data on efficacy and tolerability of PRI show a beneficial and clinically relevant activity, but confirmation by active or placebo-controlled clinical studies is still lacking.

Topics: Acute Pain; Adult; Aged; Female; Humans; Male; Middle Aged; Muscles; Parasympatholytics; Piperidines; Registries; Retrospective Studies

Topics: Acute Pain; Analgesics; Animals; Behavior, Animal; CHO Cells; Cricetinae; Cricetulus; Cycloheptanes; Humans; Hyperalgesia; In Vitro Techniques; Inflammation; Male; Mice; Models, Molecular; Molecular Docking Simulation; Morphine; Movement; Naloxone; Naltrexone; Nociceptin; Oligopeptides; Opioid Peptides; Pain Management; Piperidines; Receptors, Opioid, mu

Indiscriminate activation of opioid receptors provides pain relief but also severe central and intestinal side effects. We hypothesized that exploiting pathological (rather than physiological) conformation dynamics of opioid receptor-ligand interactions might yield ligands without adverse actions. By computer simulations at low pH, a hallmark of injured tissue, we designed an agonist that, because of its low acid dissociation constant, selectively activates peripheral μ-opioid receptors at the source of pain generation. Unlike the conventional opioid fentanyl, this agonist showed pH-sensitive binding, heterotrimeric guanine nucleotide-binding protein (G protein) subunit dissociation by fluorescence resonance energy transfer, and adenosine 3',5'-monophosphate inhibition in vitro

Topics: Acute Pain; Adenosine Monophosphate; Analgesia; Analgesics, Opioid; Animals; Computer Simulation; Constipation; Drug Design; Fentanyl; Fluorescence Resonance Energy Transfer; GTP-Binding Protein alpha Subunits; HEK293 Cells; Humans; Hydrogen-Ion Concentration; Ligands; Models, Molecular; Pain Management; Piperidines; Protein Binding; Protein Conformation; Rats; Receptors, Opioid, mu; Respiratory Insufficiency; Transfection

1-(1-Cyclooctylpiperidin-4-yl)-indolin-2-one (SR14150) and 1-(1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)piperidinl-4-yl)-indolin-2-one (SR16835) are moderately selective nociceptin/orphanin FQ (NOP) receptor agonists. In the [(35)S]guanosine 5'-O-(3-thiotriphosphate) assay in vitro, SR14150 is a partial agonist at both the NOP and μ-opioid receptors, whereas SR16835 is a full agonist at the NOP receptor and has low efficacy at μ receptors. These compounds were tested for antinociceptive and antiallodynic activity, using mice in chronic pain, subsequent to spinal nerve ligation (SNL) surgery. When administered subcutaneously to mice after SNL surgery, SR14150 but not SR16835 increased tail-flick latency, which was blocked by the opioid antagonist naloxone, but not by the NOP receptor antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111). In contrast, both SR14150 and SR16835 had antiallodynic activity when mechanical allodynia was measured with von Frey monofilaments. This effect was completely blocked by SB-612111 but not by naloxone. On the other hand, morphine antinociception and antiallodynia were both blocked by naloxone and potentiated by SB-612111. These results indicate that, in mice, circuitry mediating antinociceptive activity in acute and chronic pain states is different. It is possible that during a chronic pain state, an up-regulated NOP system in the spinal cord leads to NOP receptor-mediated antiallodynia, which is blocked by NOP antagonists. However, supraspinal up-regulation could lead to an attenuation of morphine antinociception and antiallodynia, which can be alleviated by an NOP receptor antagonist. Thus, although neither NOP agonists nor antagonists are effective as analgesics in acute pain, they may have efficacy as analgesics, either alone or in combination with morphine, for treatment of chronic pain.

Topics: Acute Pain; Animals; Chronic Pain; Cycloheptanes; Hot Temperature; Hyperalgesia; Indoles; Ligation; Male; Mice; Mice, Inbred ICR; Morphine; Naloxone; Narcotic Antagonists; Nociceptin Receptor; Piperidines; Receptors, Opioid; Sciatic Nerve