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-2oxo-(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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Agonists selectively acting at NOP, MOP, DOP and KOP receptors as well as mixed opioid receptor agonists are known to exert anti-hypersensitive efficacy in the rat spinal nerve ligation (SNL) model of neuropathic pain. To investigate the relative contribution of individual opioid receptor activation to the overall efficacy of mixed opioid receptor agonists, selective doses of respective opioid receptor antagonists have to be employed. In order to identify such selective antagonist doses, doses of the selective NOP, MOP, DOP and KOP receptor agonists Ro65-6570, morphine, SNC-80 and U50488H, that produced maximum efficacy without apparent side effects, were challenged by each of the receptor antagonists J-113397 (NOP receptor), naloxone (MOP receptor), naltrindole (DOP receptor) and nor-binaltorphimine (KOP receptor). J-113397, naloxone, naltrindole and nor-binaltorphimine at intraperitoneal doses of 4.64, 1, 10, and 10 mg/kg, respectively, inhibited anti-hypersensitive effects mediated by the corresponding cognate NOP, MOP, DOP and KOP receptor selective agonists. Selectivity could be demonstrated for MOP, DOP and NOP receptor antagonists, as they did not attenuate effects mediated by agonists acting on non-cognate receptors, whereas the KOP receptor antagonist nor-BNI demonstrated partial cross-antagonism of the DOP receptor agonist SNC-80. Thus, specific doses of opioid receptor antagonists that completely but still selectively attenuate full anti-hypersensitive efficacy of corresponding opioid receptor agonists were identified in the rat SNL model.

Cebranopadol is a novel, first-in-class analgesic with agonist activity at the nociceptin/orphanin FQ opioid peptide (NOP) receptor as well as the classical opioid peptide receptors. This study investigated the anti-hypersensitive effect of cebranopadol in a rat model of arthritic pain. Selective antagonists were used to probe the involvement of the NOP receptor and the p-opioid peptide (MOP) receptors. Experimental mono-arthritis was induced by intra-articular injection of complete Freund's adjuvant into the left hind knee joint. Intravenous (i.v.) administration of cebranopadol 0.8-8.0 mu g/kg to rats 5 days after induction of arthritis elicited dose-dependent increases in weight bearing on the affected limb. The quarter-maximal effective dose (ED25) for this anti-hypersensitive effect of cebranopadol was 1.6 mu g/kg i.v. (95% confidence interval [CI: 0.8, 1.6). The ED25 increased to 3.2 mu g/kg i.v. (95% CI: 2.4, 4.0) following pretreatment with the selective NOP receptor antagonist J-113397 and to 18.3 mu g/kg i.v. (95% CI: 9.6, 146.0) following pretreatment with the MOP receptor antagonist naloxone (at intraperitoneal antagonist doses of 4.64 mg/kg and 1.0 mg/kg, respectively). The MOP receptor agonist morphine and the NOP receptor agonist Ro65-6570 also elicited increases in weight bearing on the affected limb. The anti-hypersensitive effect of morphine 2.15 mg/kg i.v. was inhibited by naloxone but not by J-113397. Conversely, the anti-hypersensitive effect of Ro65-6570 0.464 mg/kg i.v. was inhibited by J-113397 but not by naloxone. In conclusion, cebranopadol evoked potent anti-hypersensitive efficacy in a rat model of arthritic pain, and this involved agonist activity at both the NOP and MOP receptors.

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.

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.

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.

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.

Buprenorphine and the mixed agonists/antagonists nalbuphine and pentazocine, formerly classified as µ-opioid (MOP) receptor antagonists, have more recently been shown to be partial to full agonists of the human MOP receptor. These receptors do not necessarily have to be maximally activated for a full physiological response. Partial agonists can also sufficiently stimulate signaling processes leading to a full analgesic response, as shown by the effectiveness of buprenorphine, nalbuphine and pentazocine in animal pain models and in clinical settings where these drugs induce analgesia with full efficacy without a ceiling effect. Submaximal doses of MOP receptor analgesics combined with submaximal doses of buprenorphine, pentazocine, or nalbuphine result in additive to over-additive antinociceptive effects in animal experiments. Only when doses are given that exceed the therapeutic dose range may the antinociceptive effect be reduced to the effect of either opioid alone. The analgesic effects of pentazocine and nalbuphine combined with morphine are reported to be additive or over-additive in various clinical pain conditions. Buprenorphine, which clinically behaves as a full MOP receptor agonist for pain relief, can be combined with full opioid agonists without precipitating withdrawal. Thus, the overall evidence on the analgesic effects of buprenorphine, pentazocine or nalbuphine combined with opioid analgesics under various clinical pain conditions contradicts the consensus that these compounds diminish MOP receptor analgesia when co-administered with a full MOP receptor agonist.

Peripheral receptors may contribute to the effects of systemically administered centrally available analgesics. In the present study, we analysed the effect of local peripheral injection of the nociceptin/orphanin FQ peptide (NOP) receptor agonist Ro65-6570 and compared it to the µ-opioid peptide (MOP) receptor agonist morphine in streptozotocin-induced diabetic polyneuropathy in rats. Ro65-6570 and morphine were injected intraplantarly into the hind paw of diabetic rats, and mechanical withdrawal thresholds were determined in both paws (ipsi- and contralateral to the injection site). Ro65-6570 in the dose range of 7.1–71.4nmol/animal showed antihyperalgesic effects with maximal efficacy of 57.1±15.4% maximal possible effect (MPE) at the dose of 23.8nmol/animal. Intraplantar administration of morphine showed dose-dependent antihyperalgesic effects in the dose range of 25.8–257.8nmol/animal in a similar efficacy range with a maximal efficacy of 76.0±12.1% MPE at the dose of 257.8nmol/animal. Both compounds did not induce overt confounding side effects across the tested dose range. The NOP receptor antagonist J-113397 and the MOP receptor antagonist naloxone, intraplantarly co-administered with the respective agonists, selectively and completely prevented the antihyperalgesic action of the respective NOP and MOP receptor agonist. These results indicate that the activation of peripheral NOP and MOP receptors by Ro65-6570 and morphine, respectively, mediated antihyperalgesic effects in rats with diabetic polyneuropathy.