2-pentadecyl-2-oxazolines as opioid adjuvants to prevent or treat hyperalgesia

Abstract

To provide compounds and compositions for reducing most common opioid-induced hyperalgesia associated with microglial hyperactivation.SOLUTION: 2-pentadecyl-2-oxazoline (PEA-OXA) for use as an opioid adjuvant for preventing the development of or in the treatment of opioid-induced hyperalgesia (OIH), wherein the PEA-OXA is administered with or in combination with an opioid. Wherein the administration is separate, together or simultaneous.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The subject of the present invention is a formulation comprising PEA-OXA for alleviating opioid-induced hyperalgesia (OIH) in humans and animals by controlling the hyperactivation of microglia and other immune cells. [Background technology]

[0002] Opioid analgesics are widely used in the management of acute and chronic pain, but their use has long been associated with potential abuse and other serious problems that still limit their use today.

[0003] Among the most serious complications, continued use of opioids can paradoxically exacerbate rather than relieve pain.

[0004] The condition in which administration of opioids causes increased pain sensitivity is defined as opioid-induced hyperalgesia (OIH).

[0005] Identifying and alleviating OIH is of fundamental importance because, at the clinical level, it can be confused with opioid tolerance or the worsening of an ongoing disease, leading to an inappropriate increase in dosage and, consequently, inadequate pain control. In fact, OIH cannot be resolved by increasing the dosage (as occurs in the case of tolerance), which may accelerate the development of tolerance.

[0006] Unfortunately, OIH is a phenomenon that does not occur exclusively after chronic opioid treatment, and in fact can occur in acute cases, for example after surgical procedures.

[0007] From a chemical point of view, opioids are alkaloids and can be of natural origin (morphine, codeine and thebaine, also called opiates because they are derived from opium), semi-synthetic (heroin, oxycodone and hydrocodone), or fully synthetic (fentanyl, pethidine, levorphanol, methadone, tramadol and dextropropoxyphene).

[0008] Among synthetic opioids, fentanyl, an analgesic with at least 100 times higher potency and toxicity than morphine, is used, along with its analogues, as an anesthetic and analgesic in both human and veterinary medicine.

[0009] In Italy, fentanyl is prescribed as a general anesthetic for major surgical procedures and for the palliative treatment of terminal cancer pain.

[0010] To date, the World Health Organization (WHO) has included this drug on its list of essential medicines for pain in advanced cancer patients, but its use for the treatment of chronic non-cancer pain remains a subject of controversy.

[0011] Remaining concerns regarding the use of opioids such as fentanyl certainly relate to the occurrence of numerous side effects. In particular, like other opioids, fentanyl induces OIH in humans and companion animals.

[0012] The pathophysiological mechanisms underlying OIH have not yet been fully elucidated; however, recent evidence highlights the role played by central and peripheral immune cells in the development of OIH and other adverse effects of opioids. In particular, fentanyl can activate immune cells using proinflammatory receptors and pathways, including the toll-like receptor 4 / myeloid differentiation factor 2 complex (TLR4 / MD-2). Overactivation of this pathway contributes to exacerbating proinflammatory and pronociceptive processes and promoting the development of OIH. Among the inflammatory stimuli that activate TLR4 / MD-2 are lipopolysaccharide (LPS) and bacterial endotoxin. By interacting with TLR4 / MD-2, opioids enhance LPS-induced inflammatory responses both in vitro and in vivo. These results were confirmed by molecular docking studies showing that natural and synthetic opioids bind to the TLR4 / MD-2 complex through their interaction with LPS on MD-2.

[0013] In clinical practice, opioid antagonist molecules, particularly nalorphine and naltrexone, or more commonly naloxone, are used to alleviate OIH. It is interesting to note that naloxone is a noncompetitive TLR4 antagonist, acting by blocking the dimerization of the TLR4 / MD-2 complex. It is precisely in this manner that naloxone reduces the occurrence of major opioid side effects, including OIH. Naloxone is a narcotic that acts on the central nervous system and is not without serious side effects, such as anxiety, disorientation, confusion and hallucinations, aggression, nausea, vomiting, diarrhea, abdominal pain, rhinorrhea, and, in the most severe cases, pulmonary depression.

[0014] For these reasons, there remains a pressing need to develop new treatments to manage opioid side effects in more effective and safe ways. Ideally, herein would be the use of molecules that interfere with the TLR4 / MD-2 pathway, such as naloxone, but without additional side effects.

[0015] The inventors of the present patent application have surprisingly found that palmitoylethanolamide oxazoline or PEA-OXA (hereinafter referred to as PEA-OXA) is effective in preventing the onset of OIH without exhibiting the side effects of naloxone.

[0016] PEA-OXA reproduces many of the protective effects of its major metabolite, palmitoylethanolamide (PEA): it exhibits, in fact, the same safety profile, but features intriguing unique properties not typical of PEA. In particular, PEA-OXA has been shown to antagonize the dimerization of the TLR4 / MD-2 complex, similar to naloxone, and thus inhibit microglial activation. Recently, using a modified HEK-Blue cell line characterized by the presence of all components of the TLR4 pathway, it was shown that PEA, unlike PEA-OXA, does not interact with the TLR4 / MD-2 pathway and that its protective effect is not mediated by interaction with the TLR4 receptor but by other mechanisms.

[0017] Taken together, these results suggest that PEA-OXA may represent an ideal candidate to be used as an opioid adjuvant to alleviate, in a safe and effective manner, OIH induced by the opioid fentanyl and any other side effects of opioids that may depend on the TLR4 / MD-2 complex. Summary of the Invention

[0018] The present invention stems from the surprising discovery that PEA-OXA blocks the action of fentanyl on the TLR4 / MD-2 complex, an action that contributes to immune hyperactivation and the development of OIH.

[0019] The present invention therefore includes an improved safety profile for patients with regard to both a reduction in the incidence and severity of side effects typical of this opioid, particularly OIH.

[0020] An object of the present invention is therefore PEA-OXA for use as an opioid adjuvant for preventing or treating the onset of OIH, wherein PEA-OXA is administered together or in combination with an opioid, in particular fentanyl, said administration being separate, together or simultaneous.

[0021] A further object of the present invention is PEA-OXA for use in the treatment of OIH.

[0022] A further object of the present invention is a composition comprising PEA-OXA and an opioid, preferably fentanyl, especially for use in the prevention of the onset of OIH.

[0023] These and further objects are set forth in the following description, as outlined in the appended claims, the text of which should be considered included in this specification for purposes of assessing the sufficiency of the disclosure.

[0024] Further features and advantages of the present invention will become apparent from the following description of preferred embodiments, given by way of example and not of limitation. [Brief explanation of the drawings]

[0025] [Figure 1] Figure 1 shows the experimental scheme of the in vivo study: Figure 1A: prevention scheme, Figure 1B: treatment scheme. [Figure 2] Figure 2 shows the effect of treatment with 30 μM PEA-OXA on reducing the release of the pro-inflammatory cytokine IL-1β induced by exposure of microglial cells to LPS + fentanyl, resulting from overactivation of microglia by fentanyl. ***p<0.001, LPS vs. CTR; °°°p<0.001, LPS+F vs. LPS; ###p<0.001, LPS+F + PEA-OXA vs. LPS+F. [Figure 3]Figure 3 shows the effect of treatment with 30 μM PEA-OXA on the reduction of IL-1β and IL-6 gene expression levels quantified in hyperactivated microglia after exposure of cells to LPS + fentanyl. A) IL-1β: ***p<0.001, LPS vs. CTR; °°p<0.01, LPS + F vs. LPS; ###p<0.001, LPS + F + PEA-OXA vs. LPS + F. B) IL-6: ***p<0.001, LPS vs. CTR; °p<0.05, LPS + F vs. LPS; ###p<0.001, LPS + F + PEA-OXA vs. LPS + F. [Figure 4] Figure 4 shows the effect of PEA-OXA on acute fentanyl-induced secondary hyperalgesia. Time course of the hyperalgesic effect of fentanyl (red curve) and the effect of PEAOXA (EPT4102) at 50 mg / kg (green curve). Nociceptive thresholds were measured once daily from baseline (BL) to D4. Data are presented as mean ± SEM (n = 6–9 mice per group). Results were analyzed by two-way ANOVA followed by Turkey's multiple comparison test. *p<0.05, **p<0.01, ***p<0.001 vs. the control group at the corresponding time points. DETAILED DESCRIPTION OF THE INVENTION

[0026] In a first aspect, the present invention relates to PEA-OXA for use as an opioid adjuvant for preventing or treating the onset of OIH, wherein the PEA-OXA is administered together or in combination with an opioid, said administration being separate, together or simultaneous.

[0027] The terms "in association" or "in combination" refer to both combination therapy and therapy in which PEA-OXA and an opioid are contained in a single dosage form.

[0028] "Separate" administration means administration of the PEA-OXA and the opioid at different times, which may range from one minute to several hours, for example, 8, 12 or 14 hours apart from each other.

[0029] In particular, "use as an opioid adjuvant to prevent the onset of OIH" refers to administration of PEA-OXA at ​​a time prior to administration of an opioid.

[0030] Administration "together" means administration of PEA-OXA and opioid in a single dosage form, ie, pharmaceutical or veterinary composition or formulation.

[0031] "Concurrent" administration means administration of PEA-OXA and opioid in separate dosage forms, administration of PEA-OXA and opioid in separate dosage forms but at the same time, i.e., within a time interval of not more than one minute between administration of PEA-OXA and administration of the opioid, or vice versa.

[0032] A further object of the present invention is PEA-OXA for use in the treatment of opioid-induced OIH.

[0033] In the present invention, the opioid is selected from natural opioids or opiates such as morphine, codeine and thebaine, semi-synthetic opioids such as heroin, oxycodone and hydrocodone, or synthetic opioids such as fentanyl, pethidine, levorphanol, methadone, tramadol and dextropropoxyphene. Preferably, the opioid is fentanyl.

[0034] A further object of the present invention is a composition comprising PEA-OXA and an opioid. Preferably, the composition of the present invention consists of a PEA-OXA / opioid dry blend.

[0035] Whether they are administered separately or together in a single formulation, the PEA-OXA and opioid are administered in a PEA-OXA / opioid weight ratio of 100:1 to 600:1, preferably 150:1 to 500:1.

[0036] Based on these weight ratios at which significant effects in inhibiting OIH were observed, the minimum daily dose of PEA-OXA in both the combination treatment and the PEA-OXA / opioid composition is at least 1 mg / day to 500 mg / day.

[0037] Such doses may vary depending on the subject, particularly if the subject is a child, adult, or elderly.

[0038] However, it is possible to use higher doses of PEA-OXA than those mentioned above, which have proven sufficient to achieve an inhibitory effect on OIH.

[0039] Thus, the total daily dose of PEA-OXA administered to a subject, both in the form of a combination therapy and in the composition with an opioid, or for treatment after the onset of OIH, may range from 200 to 2000 mg / day, preferably from 300 to 1500 mg / day or from 400 to 1200 mg / day.

[0040] Such a daily dose may be divided into unit doses for administration, for example, 1 to 4 times per day. The dose also depends on the selected route of administration. It should be noted that dosage variations may be necessary depending on the age and weight of the patient and the severity of the OIH being treated. The exact dose and route of administration are ultimately at the discretion of the attending physician.

[0041] For purposes of the present invention, PEA-OXA alone, opioid alone, or a composition containing PEA-OXA and an opioid may be included in a pharmaceutical or veterinary preparation and may be formulated into a dosage form for oral, buccal, parenteral, rectal, topical, or transdermal administration.

[0042] For oral administration, the compounds of the present invention can be in the form of hard or soft tablets or capsules, which can be prepared in a conventional manner using, for example, pharmaceutically acceptable additives such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); excipients (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or inhibitors (e.g., sodium uryl sulfate). Tablets can also be coated using methods well known in the art. Liquid preparations for oral administration can be in the form of solutions, syrups, or suspensions, or can be provided as lyophilized products or granules that are reconstituted with water or other suitable vehicles before use. Such liquid preparations can be prepared by conventional methods using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or edible hydrogenated fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethanol, or fractionated vegetable oils); and preservatives (e.g., methyl- or propyl-p-hydroxybenzoate, sorbic acid, benzoic acid, or salts thereof). The preparations can also contain flavoring agents, coloring agents, and sweetening agents.

[0043] Preparations for oral administration may be suitably formulated to give controlled release of the active ingredient.

[0044] For buccal administration, the compounds of the present invention may be in the form of tablets or granules formulated in a conventional manner suitable for absorption at the level of the buccal mucosa. A typical buccal formulation is a sublingual tablet.

[0045] The compound of the present invention can be formulated for parenteral administration by injection.Injection preparations can be provided in single-dose form, for example, in ampoules, with added preservatives.Compositions can be in the form of suspension, solution or emulsion in oily or aqueous vehicles, and can contain formulation agents, such as suspending agents, stabilizing agents and / or dispersing agents.Alternatively, active ingredient or mixture of active ingredients can be in the form of powder, which is reconstituted with suitable vehicle, for example, sterile water, before use.

[0046] The compounds of the present invention may also be formulated in rectal preparations such as suppositories or retention enemas, eg, containing common suppository bases such as cocoa butter or other glycerides.

[0047] In addition to the above-mentioned formulation, the compound of the present invention can be formulated as depot preparation for administration for a period ranging from 1 day to 1 week.This long-acting preparation can be administered by implantation (for example, subcutaneous, transdermal or intramuscular) or by intramuscular injection.Therefore, for example, composition can be formulated with suitable polymeric material or hydrophobic material (for example, in the form of emulsion in suitable oil) or ion exchange resin, or as minimally soluble derivative.

[0048] The compounds or compositions of the present invention may be administered in the form of an oral or nasal spray.

[0049] Further objects of the present invention also include dietary compositions, nutritional supplements, complementary feeds and foods for special medical purposes (FSMP) comprising PEA-OXA.

[0050] The term "food for special medical purposes" refers to products that are authorized in accordance with Regulation (EU) 2016 / 128. This term refers to products that are administered under medical supervision, thus making the FSMP comparable to a medicinal product.

[0051] The formulations according to the invention may be prepared by conventional methods such as those described in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., NY, USA, 17th edition, 1985 or in Remington, The Science and Practice of Pharmacy, Edited by Allen, Loyd V., Jr, 22nd edition, 2012 or later editions. [Example]

[0052] (Experimental part) (Biological Testing) To evaluate the effect of PEA-OXA on microglial hyperactivation induced by the opioid fentanyl, primary microglial cells were obtained from the cerebral cortex of 1- to 2-day-old neonatal Sprague-Dawley rats (Facci L. et al., Astrocyte / microglia cocultures as a model to study neuroinflammation, Methods Mol. Biol. 2018;1727:127-137).

[0053] Microglia were exposed to fentanyl (F, 10 μM) and LPS (10 ng / ml) in the absence or presence of PEA-OXA (30 μM) for 24 hours. At the end of treatment, the medium was collected and used to quantify the pro-inflammatory interleukin (IL)-1β using ELISA technology with a commercially available kit (Antigenix America, Huntington Station, NY, USA). The absorbance of each sample was measured at 450 nm, and the IL-1β concentration was determined by reference to a standard curve obtained with known amounts of IL-1β (Bisceglia F. et al., Prenylated curcumin analogues as multipotent tools to tackle Alzheimer's disease, ACS Chem. Neurosci. 2019;10:1420-1433).

[0054] Gene transcript analysis was performed using real-time PCR (RT-PCR) to quantify the expression of IL-1β and IL-6 genes. Briefly, total RNA was extracted from microglial cells using TRIzol Reagent (Invitrogen). The quality and quantity of the extracted RNA were determined using an Agilent RNA 6000 Nano Kit (Agilent Technologies). Reverse transcription of RNA into complementary DNA (cDNA) was performed using Superscript III reverse transcriptase (Invitrogen). RT-PCR was performed as described in Barbierato, M. et al., Astrocyte-microglia cooperation in the expression of a pro-inflammatory phenotype, CNS Neurol. Disord. Drug Targets 2013;12:608-618.

[0055] In an in vivo study, approximately 3-month-old C57BL / 6 mice were used to evaluate the efficacy of PEA-OXA in alleviating OIH induced by the opioid fentanyl.

[0056] Before the start of the study, animals underwent a one-week acclimatization period in the animal facilities of the University of Padua, with all procedures and experimental protocols following the principles of care and welfare of laboratory animals approved by the Italian Ministry of Health (Legislative Decree 2014 / 26), European Directives (EU Directive 2010 / 63), and the ARRIVE guidelines.

[0057] To induce OIH, we used the procedure described in Chen D. et al., The blockade of neuropeptide FF receptor 1 and 2 differentially contributed to the modulating effects on fentanyl-induced analgesia and hyperalgesia in mice, Eur J Pharmacol. 2024; 969: 176457.

[0058] Before the start of the experiment, a von Frey test was performed at baseline to measure the animal's pain threshold. Four days before fentanyl administration, 20 μl of 1 mg / ml complete Freund's adjuvant (CFA) (Sigma-Aldrich) was injected into the animal's hind paw to mimic nociceptive injury. The von Frey test was repeated the day after CFA injection (D-3). Four days later (D0), animals were subjected to the von Frey behavioral test and then pretreated with PEA-OXA (10 or 30 mg / kg). Fentanyl, administered as four subcutaneous injections (sc, 4 × 60 μg / kg) at 15-minute intervals, was given 1 hour after PEA-OXA. To assess the development of OIH, the von Frey test was repeated 1 hour, 1 day, 2 days, and 4 days after fentanyl administration (Figure 1A, prophylaxis scheme).

[0059] Similarly, Group 2 animals were subjected to the von Frey behavioral test 4 days after LPS administration (D0), 1 hour before administration of four sc injections of fentanyl. Treatment with PEA-OXA (10 or 30 mg / kg) was administered 1 hour after the opioid. To assess the development of OIH, the von Frey test was repeated 2 hours, 1 day, 2 days, and 4 days after administration of fentanyl (Figure 1B, treatment scheme).

[0060] Control animals were injected with the same volume of the vehicle of the substance used and underwent the same procedure.

[0061] As described above, all animals were subjected to the von Frey test, a behavioral test that assesses pain threshold in animals.

[0062] Mice were placed in a box with a metal mesh floor, and mechanical sensitivity was assessed in the mid-plantar region of each hind paw by mechanical stimulation consisting of the application of a filament (Ugo Basile) delivering a force ranging from 0 to 5 g.

[0063] Increasing stimuli were delivered from beneath the mesh using a metal stylus at 5 second intervals.

[0064] Latency was defined as the maximum force eliciting paw withdrawal (Chen D et al., 2024, supra).

[0065] (statistical analysis) Statistical analysis was performed using GraphPad software, version 3.03 (GraphPad Software Inc., La Jolla, CA, United States). Test results were expressed as mean ± standard error of the mean (SEM).

[0066] Statistical differences in in vitro studies were analyzed using one-way ANOVA followed by Holm-Sidak post-hoc tests, whereas in vivo results were analyzed using two-way ANOVA followed by appropriate post-hoc tests for multiple comparisons. A p-value <0.05 was considered significant.

[0067] (Experimental results) As shown in Figure 2, exposure of microglial cells to LPS induces a significant increase in IL-1β release (***p < 0.001, LPS vs. CTR). Exposure of microglial cells to LPS + fentanyl further increases IL-1β release (p < 0.001, LPS + F vs. LPS), indicating hyperactivation of microglial cells. Treatment with 30 μM PEA-OXA significantly reduces the hyperactivation of microglial cells induced by stimulation with LPS + F (Figure 1, ###p < 0.001, LPS + F + PEA-OXA vs. LPS + F).

[0068] As shown in Figure 3, exposure of microglial cells to LPS induces a significant increase in the expression of IL-1β (Figure 3A) and IL-6 (Figure 3B) genes (***p < 0.001, LPS vs. CTR). Exposure of microglia to LPS + fentanyl further increases the expression of IL-1β (p < 0.01, LPS + F vs. LPS) and IL-6 (p < 0.05, LPS + F vs. LPS) genes, overactivating microglial cells. Treatment with 30 µM PEA-OXA significantly reduces gene transcripts in microglia overactivated by LPS + F treatment. Specifically, IL-1β and IL-6 gene expression is significantly reduced by pretreatment with 30 µM PEA-OXA compared to untreated microglia (###p < 0.001, LPS + F + PEA-OXA vs. LPS + F).

[0069] Effect of PEAOXA on fentanyl-induced hyperalgesia in an acute inflammatory model (Experimental Procedure) All procedures were performed in accordance with the EU guidelines for the care and use of laboratory animals and the Italian Ministry of Health guidelines (DL 26 / 2014) and were approved by the Institutional Review Board for Animal Research (Organismo Preposto al Benessere Animale, OPBA) of the University of Padua and the Italian Ministry of Health. Male wild-type (C57BL / 6J) mice, 2.5 to 3 months old, were used in all experiments. Mice were housed in groups of 4 to 5 per cage under a 12-h light / dark cycle in a temperature- and humidity-controlled environment and provided with free access to food and water. Experimental groups consisted of 6 to 9 mice and were randomly assigned to either the control or treatment group.

[0070] The effects of PEAOXA (EPT4102) on hyperalgesia were evaluated using a model of fentanyl-induced analgesia and secondary hyperalgesia. Experiments were performed according to a previously published protocol (Chen D., Zhang M., Zhang Q., et al. (2024). The blockade of neuropeptide FF receptor 1 and 2 differentially contributed to the modulating effects on fentanyl-induced analgesia and hyperalgesia in mice. Eur. J. Pharmacol. 969, 176457). During the week prior to the start of the experimental procedure, animals were weighed daily, gently handled for 5 minutes to acclimate them to the experimenter, and allowed to acclimate to the experimental room. To induce inflammatory pain, mice were injected with 20 μl of complete Freund's adjuvant (CFA; Merck, Milan, Italy) (1 mg / ml) into the right hind paw. Four days after CFA injection, fentanyl (Merck, Milan, Italy) was administered subcutaneously (sc) at 0.06 mg / kg, four times at 15-minute intervals. This protocol initially produced a short-term analgesic effect, followed by the development of hyperalgesia. PEAOXA (EPT4102) was suspended in saline containing 0.5% carboxymethylcellulose (CMC) and administered intraperitoneally (ip) in a final volume of 100 μl 1 hour before fentanyl administration. The vehicle control group received an equal volume of 0.5% CMC solution.

[0071] The study included the following experimental groups (see Figure 4): Control group: CFA was administered to the right hind paw of mice; Fentanyl group: mice were administered CFA followed by fentanyl; EPT4102 50+F group: Mice were administered CFA, PEAOXA (EPT4102) 50 mg / kg, and fentanyl.

[0072] To evaluate the effect of PEAOXA on fentanyl-induced hyperalgesia, a tail-immersion test was performed. The latency to withdraw the tail was measured (seconds). A decrease in latency indicated an increase in hyperalgesia. To reduce stress and improve consistency, animals were acclimatized by immersing their tails in room-temperature water for two consecutive days before testing. On the test day, mice were gently restrained, and the distal end of their tails was immersed in a water bath maintained at 49°C. Tail-withdrawal latency was measured with a stopwatch to assess nociceptive responsiveness. A maximum cutoff time of 20 seconds was set to prevent tissue damage. Each mouse underwent three trials, spaced 10 minutes apart, and the mean latency was calculated as the nociceptive response. This test was performed on day 0 (BL, basal level before any treatment) to establish a baseline value, and then repeated once daily for five consecutive days to monitor the effects of treatment.

[0073] (statistical analysis) All data are expressed as the mean ± standard error of the mean (SEM) from a minimum of six mice per group. Statistical analysis was performed using GraphPad Prism software, version 8.4 (San Diego, CA, USA). Data were analyzed by two-way ANOVA followed by Turkey's post hoc analysis when applicable. *Differences were considered statistically significant when p<0.05.

[0074] (result) We investigated the effects of PEAOXA (EPT4102) on models of acute fentanyl-induced analgesia and secondary hyperalgesia. This finding is consistent with previous findings (Elhabazi K., Humbert JP, Bertin I., et al. (2017). Rf313, an orally bioavailable neuropeptide Ff receptor antagonist, opposes effects of Rf-Amide-Related Peptide-3 and opioid-induced hyperalgesia in rodents. Neuropharmacology 118, 188-198; Hammoud H., Elhabazi K., Quillet R., et al. (2018). Aminoguanidine hydrazone derivatives as nonpeptide Npff1 receptor antagonists reverse opioid-induced hyperalgesia. ACS Chem. Neurosci. 9, 2599-2609; Chen et al., 2024). Subcutaneous injection of fentanyl in mice resulted in an early analgesic response (data not shown), followed by delayed hyperalgesia that persisted for several days. Tail withdrawal latency in the fentanyl-treated group was significantly reduced and statistically different from that in the control group from days 1 to 3 (Figure 4, lower curve) (p<0.001 on day 1, p<0.05 on day 2, p<0.01 on day 3, vs. control group). The analgesic effect induced by fentanyl was not altered by intraperitoneal administration of 50 mg / kg of PEAOXA (EPT4102) (data not shown). In contrast, after prophylactic treatment with PEAOXA (EPT4102), no significant difference in tail withdrawal latency was observed between the control and PEAOXA-treated groups (Figure 4, middle curve), suggesting that PEAOXA treatment prevented the development of fentanyl-induced hyperalgesia.

[0075] The present invention is further described by the following formulation examples.

[0076] (Formulation example) PEA-OXA = 2-pentadecyl-2-oxazoline

[0077] [Table 1]

[0078] [Table 2]

[0079] [Table 3]

[0080] [Table 4]

[0081] [Table 5]

[0082] [Table 6]

[0083] [Table 7]

[0084] [Table 8]

Claims

1. 2-pentadecyl-2-oxazoline (PEA-OXA) for use as an opioid adjuvant for preventing the development of or in the treatment of opioid-induced hyperalgesia (OIH), wherein the PEA-OXA is administered together or in combination with an opioid, said administration being separate, simultaneous or simultaneous.

2. 2-Pentadecyl-2-oxazoline for use according to claim 1, wherein the opioid is selected from natural opioids or opiates such as morphine, codeine and thebaine, semi-synthetic opioids such as heroin, oxycodone and hydrocodone, or synthetic opioids such as fentanyl, pethidine, levorphanol, methadone, tramadol and dextropropoxyphene.

3. 2-Pentadecyl-2-oxazoline for use according to claim 2, wherein the opioid is fentanyl.

4. 4. The method of claim 1, wherein the 2-pentadecyl-2-oxazoline and the opioid are administered in a PEA-OXA / opioid weight ratio of 100:1 to 600:1, preferably 150:1 to 500:

1.

5. 5. 2-pentadecyl-2-oxazoline for use according to any one of claims 1 to 4, wherein the minimum daily dose of 2-pentadecyl-2-oxazoline in both the combination treatment and the PEA-OXA / opioid composition is at least 1 mg / day to 500 mg / day.

6. 2-pentadecyl-2-oxazoline for use according to any one of claims 1 to 5, wherein the total daily dose of PEA-OXA administered to a subject is 200 to 2000 mg / day, preferably 300 to 1500 mg / day or 400 to 1200 mg / day, both in the form of a combination therapy and in said composition with an opioid, or for treatment after the onset of OIH.

7. A pharmaceutical or veterinary composition comprising 2-pentadecyl-2-oxazoline, optionally an opioid, for use in the treatment or prevention of opioid-induced hyperalgesia, wherein said opioid is preferably fentanyl.

8. 2-pentadecyl-2-oxazoline for use as an opioid adjuvant for preventing the development of or in the treatment of OIH, wherein the 2-pentadecyl-2-oxazoline is included in a dietary composition, a dietary supplement, a complementary feed or a food for special medical purposes (FSMP).

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