Inhibition of experimental visceral pain in rodents by cebranopadol.

The aim of this study was to investigate the efficacy of cebranopadol in two rodent models of visceral pain. Cebranopadol is a first-in-class analgesic with agonist activity at the nociceptin/orphanin FQ opioid peptide receptor and classical µ-, δ- and κ-opioid peptide receptors. Colitis was induced in Naval Medical Research Institute mice by intra-rectal infusion of mustard oil. The effects of intravenous cebranopadol pretreatment on spontaneous pain behaviours and referred allodynia and hyperalgesia were assessed. Pancreatitis was induced in Sprague-Dawley rats by intravenous administration of dibutyltin dichloride. After 6 days, the effects of intravenous cebranopadol on withdrawal reactions to mechanical abdominal stimulation with von Frey filaments were assessed. In mice with experimental colitis, cebranopadol dose-dependently inhibited spontaneous pain behaviours and allodynic and hyperalgesic withdrawal reactions, with half-maximal effective dose values of 4.6 µg/kg [95% confidence interval (CI): 2.9-7.9] for inhibition of spontaneous pain behaviours, 2.2 µg/kg (95% CI: 1.3-3.4) for inhibition of referred allodynia and 2.4 µg/kg (95% CI: 1.4-3.6) for inhibition of referred hyperalgesia in mice with colitis. In rats with experimental pancreatitis, cebranopadol dose-dependently inhibited abdominal tactile allodynia (half-maximal effective dose, 0.13 µg/kg; 95% CI: 0.03-0.49). Behavioural manifestations of visceral pain were almost completely abolished at the highest doses tested in mice (17.2 µg/kg, intravenous) and rats (2.4 µg/kg, intravenous). We conclude that cebranopadol is a potent and effective antiallodynic and antihyperalgesic agent in rodent models of visceral pain.

Cebranopadol: A Novel First-in-Class Potent Analgesic Acting via NOP and Opioid Receptors.

Cebranopadol is a novel first-in-class analgesic with highly potent agonistic activity at nociceptin/orphanin FQ peptide (NOP) and opioid receptors. It is highly potent and efficacious across a broad range of preclinical pain models. Its side effect profile is better compared to typical opioids. Mechanistic studies have shown that cebranopadol's activity at NOP receptors contributes to its anti-hyperalgesic effects while ameliorating some of its opioid-type side effects, including respiratory depression and abuse potential. Phase II of clinical development has been completed, demonstrating efficacy and good tolerability in acute and chronic pain conditions.This article focusses on reviewing data on the preclinical in vitro and in vivo pharmacology, safety, and tolerability, as well as clinical trials with cebranopadol.

RNA interference-based functional knockdown of the voltage-gated potassium channel Kv7.2 in dorsal root ganglion neurons after in vitro and in vivo gene transfer by adeno-associated virus vectors.

Activation of the neuronal potassium channel Kv7.2 encoded by the KCNQ2 gene has recently been shown to be an attractive mechanism to inhibit nociceptive transmission. However, potent, selective, and clinically proven activators of Kv7.2/Kv7.3 currents with analgesic properties are still lacking. An important prerequisite for the development of new drugs is a model to test the selectivity of novel agonists by abrogating Kv7.2/Kv7.3 function. Since constitutive knockout mice are not viable, we developed a model based on RNA interference-mediated silencing of KCNQ2. By delivery of a KCNQ2-specific short hairpin RNA with adeno-associated virus vectors, we completely abolished the activity of the specific Kv7.2/Kv7.3-opener ICA-27243 in rat sensory neurons. Results obtained in the silencing experiments were consistent between freshly prepared and cryopreserved dorsal root ganglion neurons, as well as in dorsal root ganglion neurons dissociated and cultured after in vivo administration of the silencing vector by intrathecal injections into rats. Interestingly, the tested associated virus serotypes substantially differed with respect to their transduction capability in cultured neuronal cell lines and primary dorsal root ganglion neurons and the in vivo transfer of transgenes by intrathecal injection of associated virus vectors. However, our study provides the proof-of-concept that RNA interference-mediated silencing of KCNQ2 is a suitable approach to create an ex vivo model for testing the specificity of novel Kv7.2/Kv7.3 agonists.

Limited potential of cebranopadol to produce opioid-type physical dependence in rodents.

Cebranopadol is a novel potent analgesic agonist at the nociceptin/orphanin FQ peptide (NOP) and classical opioid receptors. As NOP receptor activation has been shown to reduce side effects related to the activation of µ-opioid peptide (MOP) receptors, the present study evaluated opioid-type physical dependence produced by cebranopadol in mice and rats. In a naloxone-precipitated withdrawal assay in mice, a regimen of seven escalating doses of cebranopadol over 2 days produced only very limited physical dependence as evidenced by very little withdrawal symptoms (jumping) even at cebranopadol doses clearly exceeding the analgesic dose range. In contrast, mice showed clear withdrawal symptoms when treated with morphine within the analgesic dose range. In the rat, spontaneous withdrawal (by cessation of drug treatment; in terms of weight loss and behavioral score) was studied after 4-week subacute administration. Naloxone-precipitated withdrawal (in terms of weight loss and behavioral score) was studied in the same groups of rats after 1-week re-administration following the spontaneous withdrawal period. In both tests, cebranopadol-treated rats showed only few signs of withdrawal, while withdrawal effects in rats treated with morphine were clearly evident. These findings demonstrate a low potential of cebranopadol to produce opioid-type physical dependence in rodents. The prospect of this promising finding into the clinical setting remains to be established.

Antihyperalgesic, Antiallodynic, and Antinociceptive Effects of Cebranopadol, a Novel Potent Nociceptin/Orphanin FQ and Opioid Receptor Agonist, after Peripheral and Central Administration in Rodent Models of Neuropathic Pain.

Cebranopadol is a novel and highly potent analgesic acting via nociceptin/orphanin FQ peptide (NOP) and opioid receptors. Since NOP and opioid receptors are expressed in the central nervous system as well as in the periphery, this study addressed the question of where cebranopadol exerts its effects in animal models of chronic neuropathic pain. Mechanical hypersensitivity in streptozotocin (STZ)-treated diabetic rats, cold allodynia in the chronic constriction injury (CCI) model in rats, and heat hyperalgesia and nociception in STZ-treated diabetic and control mice was determined after intraplantar (i.pl.), intracerebroventricular (i.c.v.), or intrathecal (i.th.) administration. In STZ-treated rats, cebranopadol (i.pl.) reduced mechanical hypersensitivity in the ipsilateral paw, but had no effect at the contralateral paw. In CCI rats, cebranopadol (i.pl.) showed antiallodynic activity at the ipsilateral paw. After administration to the contralateral paw, cebranopadol also showed ipsilateral antiallodynic activity, but with reduced potency and delayed onset. In diabetic mice, cebranopadol i.th. and i.c.v. decreased heat hyperalgesia with full efficacy and similar potency for both routes. Cebranopadol also produced significant antinociception in nondiabetic controls. Thus, cebranopadol exerts potent and efficacious antihyperalgesic, antiallodynic, and antinociceptive effects after local/peripheral, spinal, and supraspinal administration. The contralateral effects after i.pl. administration were likely due to systemic redistribution. After central administration of cebranopadol, antihyperalgesic efficacy is reached at doses that are not yet antinociceptive. This study shows that cebranopadol is effective after peripheral as well as central administration in nociceptive and chronic neuropathic pain. Thus, it may be well-suited for the treatment of chronic pain conditions with a neuropathic component.

The noradrenergic component in tapentadol action counteracts µ-opioid receptor-mediated adverse effects on adult neurogenesis.

Opiates were the first drugs shown to negatively impact neurogenesis in the adult mammalian hippocampus. Literature data also suggest that norepinephrine is a positive modulator of hippocampal neurogenesis in vitro and in vivo. On the basis of these observations, we investigated whether tapentadol, a novel central analgesic combining µ-opioid receptor (MOR) agonism with norepinephrine reuptake inhibition (NRI), may produce less inhibition of hippocampal neurogenesis compared with morphine. When tested in vitro, morphine inhibited neuronal differentiation, neurite outgrowth, and survival of adult mouse hippocampal neural progenitors and their progeny, via MOR interaction. By contrast, tapentadol was devoid of these adverse effects on cell survival and reduced neurite outgrowth and the number of newly generated neurons only at nanomolar concentrations where the MOR component is predominant. On the contrary, at higher (micromolar) concentrations, tapentadol elicited proneurogenic and antiapoptotic effects via activation of ß2 and α2 adrenergic receptors, respectively. Altogether, these data suggest that the noradrenergic component in tapentadol has the potential to counteract the adverse MOR-mediated effects on hippocampal neurogenesis. As a proof of concept, we showed that reboxetine, an NRI antidepressant, counteracted both antineurogenic and apoptotic effects of morphine in vitro. In line with these observations, chronic tapentadol treatment did not negatively affect hippocampal neurogenesis in vivo. In light of the increasing long-term use of opiates in chronic pain, in principle, the tapentadol combined mechanism of action may result in less or no reduction in adult neurogenesis compared with classic opiates.

Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist.

Cebranopadol (trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine) is a novel analgesic nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonist [Ki (nM)/EC50 (nM)/relative efficacy (%): human NOP receptor 0.9/13.0/89; human mu-opioid peptide (MOP) receptor 0.7/1.2/104; human kappa-opioid peptide receptor 2.6/17/67; human delta-opioid peptide receptor 18/110/105]. Cebranopadol exhibits highly potent and efficacious antinociceptive and antihypersensitive effects in several rat models of acute and chronic pain (tail-flick, rheumatoid arthritis, bone cancer, spinal nerve ligation, diabetic neuropathy) with ED50 values of 0.5-5.6 µg/kg after intravenous and 25.1 µg/kg after oral administration. In comparison with selective MOP receptor agonists, cebranopadol was more potent in models of chronic neuropathic than acute nociceptive pain. Cebranopadol's duration of action is long (up to 7 hours after intravenous 12 µg/kg; >9 hours after oral 55 µg/kg in the rat tail-flick test). The antihypersensitive activity of cebranopadol in the spinal nerve ligation model was partially reversed by pretreatment with the selective NOP receptor antagonist J-113397[1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one] or the opioid receptor antagonist naloxone, indicating that both NOP and opioid receptor agonism are involved in this activity. Development of analgesic tolerance in the chronic constriction injury model was clearly delayed compared with that from an equianalgesic dose of morphine (complete tolerance on day 26 versus day 11, respectively). Unlike morphine, cebranopadol did not disrupt motor coordination and respiration at doses within and exceeding the analgesic dose range. Cebranopadol, by its combination of agonism at NOP and opioid receptors, affords highly potent and efficacious analgesia in various pain models with a favorable side effect profile.

Spinal-supraspinal and intrinsic µ-opioid receptor agonist-norepinephrine reuptake inhibitor (MOR-NRI) synergy of tapentadol in diabetic heat hyperalgesia in mice.

Tapentadol is a µ-opioid receptor (MOR) agonist and norepinephrine reuptake inhibitor (NRI) with established efficacy in neuropathic pain in patients and intrinsic synergistic interaction of both mechanisms as demonstrated in rodents. In diabetic mice, we analyzed the central antihyperalgesic activity, the occurrence of site-site interaction, as well as the spinal contribution of opioid and noradrenergic mechanisms in a hotplate test. Tapentadol (0.1-3.16 µg/animal) showed full efficacy after intrathecal as well as after intracerebroventricular administration (ED50 0.42 µg/animal i.t., 0.18 µg/animal i.c.v.). Combined administration of equianalgesic doses revealed spinal-supraspinal synergy (ED50 0.053 µg/animal i.t. + i.c.v.). Morphine (0.001-10 µg/animal) also showed central efficacy and synergy (ED50 0.547 µg/animal i.t., 0.004 µg/animal i.c.v., 0.014 µg/animal i.t. + i.c.v.). Supraspinal potencies of tapentadol and morphine correlated with the 50-fold difference in their MOR affinities. In contrast, spinal potencies of both drugs were similar and correlated with their relative systemic potencies (ED50 0.27 mg/kg i.p. tapentadol, 1.1 mg/kg i.p. morphine). Spinal administration of the opioid antagonist naloxone or the α2-adrenoceptor antagonist yohimbine before systemic administration of equianalgesic doses of tapentadol (1 mg/kg i.p.) or morphine (3.16 mg/kg i.p.) revealed pronounced influence on opioidergic and noradrenergic pathways for both compounds. Tapentadol was more sensitive toward both antagonists than was morphine, with median effective dose values of 0.75 and 1.72 ng/animal i.t. naloxone and 1.56 and 2.04 ng/animal i.t. yohimbine, respectively. It is suggested that the antihyperalgesic action of systemically administered tapentadol is based on opioid spinal-supraspinal synergy, as well as intrinsic spinally mediated MOR-NRI synergy.

A novel dual mode-of-action anti-hyperalgesic compound in rats which is neuroprotective and promotes neuroregeneration.

Chronic neuropathic pain (CNP) can result from surgery or traumatic injury, but also from peripheral neuropathies caused by diseases, viral infections, or toxic treatments. Opioids, although very effective for acute pain, do not prevent the development of CNP, and are considered as insufficient treatment. Therefore, there is high need for effective and safe non-opioid options to treat, prevent and eventually reverse CNP. A more effective approach to alleviating CNP would constitute a treatment that acts concurrently on various mechanisms involved in relieving pain symptoms and preventing or reversing chronification by enhancing both neuroprotection and neuroregeneration. We have identified and characterized GRT-X (N-[(3-fluorophenyl)-methyl]-1-(2-methoxyethyl)-4-methyl-2-oxo-(7-trifluoromethyl)-1H-quinoline-3-caboxylic acid amide), a novel drug which is able to activate both voltage-gated potassium channels of the Kv7 family and the mitochondrial translocator protein 18 kDa (TSPO). The dual mode-of-action (MoA) of GRT-X was indicated in in vitro studies and in vivo in a rat model of diabetic neuropathy. In this model, mechanical hyperalgesia was dose-dependently inhibited. After severe crush lesion of cervical spinal nerves in rats, GRT-X promoted survival, speeded up regrowth of sensory and motor neurons, and accelerated recovery of behavioral and neuronal responses to heat, cold, mechanical and electrical stimuli. These properties may reduce the likelihood of chronification of acute pain, and even potentially relieve established CNP. The absence of a conditioned place preference in rats suggests lack of abuse potential. In conclusion, GRT-X offers a promising preclinical profile with a novel dual MoA.

Antinociceptive and antihyperalgesic effects of tapentadol in animal models of inflammatory pain.

The novel analgesic tapentadol HCl [(-)-(1R,2R)-3-(3-dimethylamino)-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines µ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI) in a single molecule and shows a broad efficacy profile in various preclinical pain models. This study analyzed the analgesic activity of tapentadol in experimental inflammatory pain. Analgesia was evaluated in the formalin test (pain behavior, rat and mouse), carrageenan-induced mechanical hyperalgesia (paw-pressure test, rat), complete Freund's adjuvant (CFA)-induced paw inflammation (tactile hyperalgesia, rat), and CFA knee-joint arthritis (weight bearing, rat). Tapentadol showed antinociceptive activity in the rat and mouse formalin test with an efficacy of 88 and 86% and ED(50) values of 9.7 and 11.3 mg/kg i.p., respectively. Tapentadol reduced mechanical hyperalgesia in carrageenan-induced acute inflammatory pain by 84% with an ED(50) of 1.9 mg/kg i.v. In CFA-induced tactile hyperalgesia, tapentadol showed 71% efficacy with an ED(50) of 9.8 mg/kg i.p. The decrease in weight bearing after CFA injection in one knee joint was reversed by tapentadol by 51% with an ED(25) of 0.9 mg/kg i.v. Antagonism studies were performed with the MOR antagonist naloxone and the α(2)-noradrenergic receptor antagonist yohimbine in the carrageenan- and CFA-induced hyperalgesia model. In the CFA model, the serotonergic receptor antagonist ritanserin was also tested. The effect of tapentadol was partially blocked by naloxone and yohimbine and completely blocked by the combination of both, but it was not affected by ritanserin. In summary, tapentadol showed antinococeptive/antihyperalgesic analgesic activity in each model of acute and chronic inflammatory pain, and the antagonism experiments suggest that both MOR activation and NRI contribute to its analgesic effects.

The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates conditioned place preference induced by various addictive and non-addictive drugs in rats.

We have recently reported that the metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates acquisition of conditioned place preference (CPP) induced by heroin and ketamine. The present study investigated to what extent this effect of MPEP can be generalized to other classes of drugs, such as the stimulants nicotine and cocaine, and to drugs that produce CPP in the rat despite a lack of abuse potential in humans, such as buspirone and clonidine. Adult male Sprague Dawley rats were subjected to a standard unbiased CPP protocol (six conditioning sessions lasting 20 minutes for nicotine and 40 minutes for the other compounds). Rats were conditioned with either nicotine (0.05-0.2 mg/kg, subcutaneously), cocaine [1-10 mg/kg, intraperitoneally (i.p.)], buspirone (0.3-3 mg/kg, i.p.) or clonidine (0.2-0.6 mg/kg, i.p.) in combination with MPEP (0 or 10 mg/kg, i.p.). For nicotine and cocaine, the minimal effective dose to induce CPP was lowered by pre-treatment with MPEP. While buspirone and clonidine did not induce CPP when given alone (i.e. combined with MPEP vehicle), both compounds induced CPP after pre-treatment with MPEP. It is concluded that MPEP consistently potentiates acquisition of drug-induced reward, independent of the mechanism of action of the co-administered drug. We suggest that the proposed anti-abuse effect of MPEP may be due to a substitution-like effect.

Critical evaluation of the use of extinction paradigms for the assessment of opioid-induced conditioned place preference in rats.

The rewarding effects of drugs of abuse are often studied by means of the conditioned place preference (CPP) paradigm. CPP is one of the most widely used models in behavioral pharmacology, yet its theoretical underpinnings are not well understood, and there are very few studies on the methodological and theoretical aspects of this model. An important drawback of the classical CPP paradigm is that it often does not show dose-dependent results. The persistence of the conditioned response, i.e. the time required until the CPP effect is extinct, may be related to the strength of conditioning, which in turn may be related to the rewarding efficacy of a drug. Resistance to extinction may therefore be a useful additional measure to quantify the rewarding effect of drugs. In the present study we examined the persistence of drug-environment associations after conditioning with morphine (1, 3 and 10 mg/kg i.p.), oxycodone (0.3, 1 and 3 mg/kg i.p.) and heroin (0.05, 0.25 and 0.5 mg/kg i.p.) by repeated retesting in the CPP apparatus (15-min sessions, 5 days/week) until the rats reached extinction (i.e. less than 55% preference over 3 consecutive sessions). Following an unbiased CPP protocol, morphine, oxycodone and heroin induced CPP with minimal effective doses of 3, 1 and 0.25 mg/kg, respectively, and with similar effect sizes for each CPP-inducing dose. The number of sessions required for extinction was positively correlated with the dose of the drug (experiment 1: 18 and 45 sessions for 3 and 10 mg/kg morphine, and 19 and 27 sessions for 1 and 3 mg/kg oxycodone; experiment 2: 12 and 24 sessions for 3 and 10 mg/kg morphine, and 10 and 14 sessions for 0.25 and 0.5 mg/kg heroin). These findings suggest that the use of an extinction paradigm can extend the quantitative assessment of the rewarding effect of drugs - however, within certain limits only. The present paradigm appears to be less suited for comparing the rewarding efficacy of different drugs due to great test-retest variability. Finally, the additional potential gain of information using this paradigm has to be weighed against the considerably large amount of additional time and effort.

Pharmacology of bisphosphonates in pain.

The treatment of pain, in particular, chronic pain, remains a clinical challenge. This is particularly true for pain associated with severe or rare conditions, such as bone cancer pain, vulvodynia, or complex regional pain syndrome. Over the recent years, there is an increasing interest in the potential of bisphosphonates in the treatment of pain, although there are few papers describing antinociceptive and anti-hypersensitizing effects of bisphosphonates in various animal models of pain. There is also increasing evidence for clinical efficacy of bisphosphonates in chronic pain states, although the number of well-controlled studies is still limited. However, the mechanisms underlying the analgesic effects of bisphosphonates are still largely elusive. This review provides an overview of preclinical and clinical studies of bisphosphonates in pain and discusses various pharmacological mechanisms that have been postulated to explain their analgesic effects. LINKED ARTICLES: This article is part of a themed issue on The molecular pharmacology of bone and cancer-related bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc.

The nociceptin/orphanin FQ receptor system as a target to alleviate cancer-induced bone pain in rats: Model validation and pharmacological evaluation.

BACKGROUND AND PURPOSE: Cancer-induced bone pain remains inadequately controlled, and current standard of care analgesics is accompanied by several side effects. Nociceptin/orphanin FQ peptide (NOP) receptor agonists have demonstrated broad analgesic properties in rodent neuropathic and inflammatory pain models. Here, we investigate the analgesic potential of NOP receptor activation in a rodent cancer-induced bone pain model. EXPERIMENTAL APPROACH: Model validation by intratibial inoculation in male Sprague Dawley rats was performed with varying MRMT-1/Luc2 cell quantities (0.5-1.5 × 106 ·ml-1 ) and a behavioural battery (>14 days post-surgery) including evoked and non-evoked readouts: paw pressure test, cold plate, von Frey, open field, and weight distribution. Anti-allodynic potential of the endogenous NOP receptor ligand nociceptin (i.t.) and NOP receptor agonist Ro65-6570 ( i.p.) was tested using von Frey filaments, followed by a combination experiment with Ro65-6570 and the NOP receptor antagonist J-113397 (i.p.). Plasma cytokine levels and NOP receptor gene expression in dorsal root ganglion (DRG, L4-L6) and bone marrow were examined. KEY RESULTS: Inoculation with 1.5 × 106 ·ml-1 of MRMT-1/Luc2 cells resulted in a robust and progressive pain-related phenotype. Nociceptin and Ro65-6570 treatment inhibited cancer-induced mechanical allodynia. J-113397 selectively antagonized the effect of Ro65-6570. MRMT-1/Luc2-bearing animals demonstrated elevated plasma cytokine levels of IL-4, IL-5, IL-6 and IL-10 plus unaltered NOP-r gene expression in DRG and reduced expression in bone marrow. CONCLUSION AND IMPLICATIONS: Nociceptin and Ro65-6570 selectively and dose-dependently reversed cancer-induced bone pain-like behaviour. The NOP receptor system may be a potential target for cancer-induced bone pain treatment. LINKED ARTICLES: This article is part of a themed issue on The molecular pharmacology of bone and cancer-elated bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc.

Population Pharmacokinetics of Tapentadol in Children from Birth to <18 Years Old.

OBJECTIVE: The main aim of this analysis was to characterize the pharmacokinetics (PK) of tapentadol in pediatric patients from birth to <18 years old who experience acute pain, requiring treatment with an opioid analgesic. PATIENTS AND METHODS: Data from four clinical trials and 148 pediatric patients who received a single dose of tapentadol oral or intravenous solution were included. Population PK analysis was performed to determine the contribution of size-related (bodyweight) and function-related (maturation) factors to the changes in oral bioavailability (F), volume of distribution (V), and clearance (CL) with age. Simulations were carried out to compare pediatric exposures to reference adult values. RESULTS: A one-compartment model with allometric scaling on disposition parameters (using theoretical or estimated exponents) and maturation functions on CL and F best described tapentadol PK. The estimated allometric exponents for CL (0.603) and V (0.820) differed slightly from the theoretical values of 0.75 for CL and 1 for V. A maximum in CL/F was observed at about 2-3 years when expressed on a bodyweight basis. Results for younger children as well as the F estimate were sensitive to the scaling approach, but CL/F and V/F as a function of age for the two scaling approaches led to similar curves within the bioequivalence range except below 5 weeks of age. Model-based simulations indicated that the doses used in the included clinical trials lead to exposures within the lower half of the targeted adult exposure. CONCLUSION: The development of tapentadol is one of the first examples following a systematic approach for analgesic drug development for children. Our analysis enabled a full characterization and robust understanding of tapentadol PK in children from birth to <18 years, including preterm infants, and showed the importance of evaluating the sensitivity of the inferences of the PK parameters to the selected scaling approach.

RNA interference-mediated silencing of Kv7.2 in rat dorsal root ganglion neurons abolishes the anti-nociceptive effect of a selective channel opener.

INTRODUCTION: Development of agonistic analgesic drugs requires proof of selectivity in vivo attainable by selective antagonists or several knockdown strategies. The Kv7.2 potassium channel encoded by the KCNQ2 gene regulates neuronal excitability and its activation inhibits nociceptive transmission. Although it is a potentially attractive target for analgesics, no clinically approved Kv7.2 agonists are currently available and selectivity of drug candidates is hard to demonstrate in vivo due to the expenditure to generate KCNQ2 knockout animals and the lack of Kv7.2 selective antagonists. The present study describes the set-up of an RNA interference-based model that allows studying the selectivity of Kv7.2 openers. METHODS: Adeno-associated virus (AAV) vectors were used to deliver the expression cassette for a short hairpin RNA targeting KCNQ2. Heat nociception was tested in rats after intrathecal AAV treatment. RESULTS: Surprisingly, screening of AAV serotypes revealed serotype 7, which has rarely been explored, to be best suited for transduction of dorsal root ganglia neurons following intrathecal injection. Knockdown of the target gene was confirmed by qRT-PCR and the anti-nociceptive effect of a Kv7.2 agonist was found to be completely abolished by the treatment. DISCUSSION: We consider this approach not only to be suitable to study the selectivity of novel analgesic drugs targeting Kv7.2, but rather to serve as a general fast and simple method to generate functional and phenotypic knockdown animals during drug discovery for central and peripheral pain targets.

Sila-Ibuprofen.

The synthesis, characterization, biological activity, and toxicology of sila-ibuprofen, a silicon derivative of the most common nonsteroidal anti-inflammatory drug, is reported. The key improvements compared with ibuprofen are a four times higher solubility in physiological media and a lower melting enthalpy, which are attributed to the carbon-silicon switch. The improved solubility is of interest for postsurgical intravenous administration. A potential for pain relief is rationalized via inhibition experiments of cyclooxygenases I and II (COX-I and COX-II) as well as via a set of newly developed methods that combine molecular dynamics, quantum chemistry, and quantum crystallography. The binding affinity of sila-ibuprofen to COX-I and COX-II is quantified in terms of London dispersion and electrostatic interactions in the active receptor site. This study not only shows the potential of sila-ibuprofen for medicinal application but also improves our understanding of the mechanism of action of the inhibition process.

Novel insights on the management of pain: highlights from the 'Science of Relief' meeting.

The 'Science of Relief' event, held in Milan on 10-11 May 2019, was aimed at promoting dialog between different stakeholders among scientific associations, pharma industry, healthcare services and related institutions. The goal was to renew interest and attention on the management of pain, sharing new solutions in order to bring the patients and their quality of life to the center of attention. An international group of scientists and clinicians presented and discussed new and known evidence in the field of chronic pain, from physiopathology and diagnosis to the choice of appropriate and timely pharmacological treatments. This paper reports the highlights of those presentations.

Mu-opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) receptor activation both contribute to the discriminative stimulus properties of cebranopadol in the rat.

The novel potent analgesic cebranopadol is an agonist at nociceptin/orphanin FQ peptide (NOP) and classical opioid receptors, with the highest in-vitro activity at NOP and mu-opioid peptide (MOP) receptors, and somewhat lower activity at kappa-opioid peptide (KOP) and delta-opioid peptide (DOP) receptors. We addressed the question of which of these pharmacological activities contribute to the stimulus properties of cebranopadol using a rat drug discrimination procedure. First, cebranopadol was tested in generalization tests against a morphine cue, including receptor-specific antagonism. Second, cebranopadol was established as a cue, and MOP, NOP, KOP and DOP receptor-selective agonists were tested in generalization tests. Third, cebranopadol in combination with receptor-selective antagonists was tested against the cebranopadol cue. Cebranopadol generalized to the morphine cue. Full generalization was only seen at clearly supra-analgesic doses. The effect of cebranopadol was reduced by naloxone, but was enhanced by the NOP receptor antagonist J-113397. In cebranopadol-trained rats, cebranopadol as well as morphine produced generalization. A NOP receptor agonist did not, while a DOP receptor agonist and a KOP receptor agonist weakly generalized to the cebranopadol cue. Conversely, generalization of cebranopadol was reduced by naloxone and J-113397, but not by a DOP or a KOP receptor antagonist. These results suggest a contribution of MOP receptor activity and a relative lack of contribution of DOP and KOP receptor activity to cebranopadol's stimulus properties. The findings regarding the contribution of NOP receptor activity were equivocal, but interestingly, the morphine-like stimulus property of cebranopadol appears to be reduced by its intrinsic NOP receptor activity.

Does 'Strong Analgesic' Equal 'Strong Opioid'? Tapentadol and the Concept of 'µ-Load'.

INTRODUCTION: The distinct properties of the centrally-acting analgesic tapentadol derive from the combined contributions of an opioid component and a nonopioid component. However, the opioid component's relative contribution to analgesic and adverse effects has not previously been elucidated. Tapentadol's analgesic effect derives from the combined contribution of an opioid mechanism and a nonopioid mechanism, the extent of which can vary for different pains. Likewise, the interaction can vary for various adverse effects. Hence, the contribution of each mechanism to adverse effects can be different from the contribution to analgesia. We here estimate the percent contribution of each component of the mechanism of action to analgesia and to adverse effects. AREAS COVERED: Several approaches to in vitro and in vivo data to estimate the contribution of tapentadol's opioid component to analgesia and to the two important opioid adverse effects, respiratory depression and constipation. The results are then compared with clinical data. EXPERT OPINION: Traditional opioids, such as morphine, oxycodone, and others, produce their analgesic effects primarily through a single mechanism-the activation of µ-opioid receptors (MOR). Therefore, the contribution of the opioid component to adverse effects is 100%. In contrast, the newer strong analgesic tapentadol produces its analgesic effect via two separate and complementary analgesic mechanisms, only one of which is µ-opioid. We applied standard drug-receptor theory and novel techniques to in vitro and in vivo data to estimate by several different ways the µ-load of tapentadol (the % contribution of the opioid component to the adverse effect magnitude relative to a pure/classical µ-opioid at equianalgesia) in respiratory depression and constipation, and we compared the results to clinical evidence. The estimate is remarkably consistent over the various approaches and indicates that the µ-load of tapentadol is ≤ 40% (relative to pure MOR agonists, which have, by definition, a µ-load of 100%). FUNDING: Grünenthal GmbH.