2-PENTADECYL-2-OXAZOLINE AS AN OPIOID ADJUVANT TO PREVENT OR TREAT HYPERALGESIA

Description

Applicant: EPITECH GROUP SpA Title: “2-PENTADECYL-2-OXAZOLINE AS AN ADJUVANT OPIOIDS TO PREVENT OR TREAT HYPERALGESIA” Description 5 Field of invention technique The subject of this invention is a formulation containing PEA-OXA to counteract, in humans and animals, hyperalgesia induced by opioid hyperactivation (OIH) by controlling hyperactivation of microglia and other immune cells. State of the art Opioid analgesics are widely used in the management of acute and chronic pain, although the their use has long been associated with the potential for abuse 10 and other serious problems that still limit it today the use. Among the most relevant complications, the continuous use opioids can, paradoxically, worsen instead that reduce pain. 15 The condition in which the administration of a opioid causes an increase in pain sensitivity It is called opioid-induced hyperalgesia (OIH). Identifying and combating OIH is crucial importance as, at a clinical level, it can be 20 confused with opioid tolerance, or with a worsening of the ongoing pathology, and induce to the improper increase in dosages resulting in poor pain management. In fact, OIH not only cannot be resolved by increasing the dosage (as instead occurs in case of tolerance), but the increase of the 5 dosage may accelerate the onset of tolerance. Unfortunately, OIH is a phenomenon that does not occur only after chronic treatment with opioids. It can, in fact, arise in case of acute treatments, for example after surgery. 10 From a chemical point of view, opioids are alkaloids and can be of natural origin (morphine, codeine and thebaine, also called opiates because derivatives of opium), semi-synthetic (heroin, oxycodone and hydrocodone) or totally synthetic (fentanyl, 15 pethidine, levorphanol, methadone, tramadol and dextropropoxyphene). Among synthetic opioids, fentanyl, a analgesic with potency and toxicity at least one hundred times greater higher than that of morphine, it is used, together with 20 of its analogues, as an anesthetic and analgesic both in both human and veterinary medicine. In Italy, fentanyl is prescribed as general anesthetic in major surgery and in palliative therapy for terminal pain 25 oncological. To date, the World Health Organization (WHO) has included this drug in the drug list essential for pain in patients with cancer in advanced stages, while its use for treatment 5 of chronic non-oncological pain is still the subject of of controversies. The reservations that still remain on the use of the opioids such as fentanyl are certainly linked at the onset of numerous side effects. In 10 In particular, like other opioids, fentanyl induces OIH in humans and companion animals. The pathophysiological mechanisms underlying OIH are not have not yet been fully clarified; however, Recent evidence highlights the role played by 15 central and peripheral immune cells in the onset of OIH and other adverse effects of opioids. In In particular, fentanyl can activate cells immune using receptors and pathways pro-inflammatory agents, including the complex 20 Toll-like receptor 4 / differentiation factor myeloid 2 (TLR4 / MD-2). Hyperactivation of this pathway, contributes to exacerbate the pro- inflammatory and pro-nociceptive and favor the onset of OIH. Among the inflammatory stimuli that activate TLR4 / MD- 25 2 there is lipopolysaccharide (LPS), an endotoxin bacterial. Opioids, by interacting with TLR4 / MD-2, intensify the LPS-induced inflammatory response both in vitro and in vivo. These results were confirmed by molecular docking studies that have demonstrated how natural and synthetic opioids bind 5 the TLR4 / MD-2 complex through interaction with LPS on MD-2. In clinical practice, to combat OIH, use opioid antagonist molecules, among others these nalorphine and naltrexone or more commonly the 10 naloxone. It is interesting to note that naloxone is a non-competitive antagonist of TLR4 and acts by blocking the dimerization of the TLR4 / MD-2 complex. It is It is in this way that naloxone reduces the appearance of the main side effects of opioids, 15 including OIH. Naloxone is a narcotic that acts on the central nervous system and is not free from side effects important side effects such as anxiety, disorientation, confusion and hallucinations, aggression, nausea, vomiting, diarrhea, abdominal pain, rhinorrhea and, in the most severe cases 20 severe, pulmonary depression. For these reasons, the need remains urgent develop new therapies to effectively manage and safer, the side effects of opioids. In in this context, the ideal would be to use molecules 25 that interfere with the TLR4 / MD-2 pathway, such as naloxone, but that they have no further effects collateral. The inventors of this patent application they surprisingly found that the oxazoline of the 5 palmitoylethanolamide or PEA-OXA (hereinafter referred to as PEA-OXA), is active in counteracting the onset of OIH without presenting the side effects of naloxone. PEA-OXA recapitulates many of the protective effects of its main metabolite, palmitoylethanolamide (PEA): 10, in fact, has the same safety profile but is characterized by interesting intrinsic properties, not common to PEA. In particular, it has been demonstrated that PEA-OXA, like naloxone, antagonizes dimerization of the TLR4 / MD-2 complex thus inhibiting the activation of the 15 microglia. Recently, using a cell line engineered HEK-Blue, characterized by the presence of all elements of the TLR4 pathway, it was demonstrated that PEA, unlike PEA-OXA, does not interacts with the TLR4 / MD-2 pathway and that its effects 20 protective agents are not mediated by interaction with the TLR4 receptor but by other mechanisms. Taken together, these findings suggest that PEA-OXA, may represent the ideal candidate for use as an adjuvant to opioids, for 25 to safely and effectively combat induced OIH from the opioid fentanyl and any other effects side effects of opioids that may depend on the TLR4 / MD2 complex. Summary of the invention This invention arises from the surprising 5 discovery that PEA-OXA interferes with the action of fentanyl on the TLR-4 / MD-2 complex, responsible action of immune hyperactivation and onset of OIH. The invention therefore involves an increase in profile patient safety, both in terms of reduced 10 incidence and severity of side effects, in in particular the OIH, typical of this opioid. An object of the invention is therefore PEA-OXA for use as an adjuvant to opioids to prevent or treat the onset of OIH, in which PEA-OXA is administered in 15 association or in combination with opioids, in in particular fentanyl, in which said administration is separate, joint or simultaneous. A further object of the invention is PEA-OXA for use in the treatment of OIH. 20 A further object of the invention is a composition containing PEA-OXA and an opioid, preferably fentanyl, particularly for use in prevention of the onset of OIH. These and further items, as outlined in the 25 annexed claims, will be described below of the description. The text of the claims must be considered included in the description for the purposes of the assessment of sufficiency of description. Further features and advantages of the invention will result from the description given below of 5 favorite examples of implementation, given for the sake of clarity indicative and not limiting. Brief description of the figures Figure 1 represents the experimental scheme of the in vivo study. Fig. 1A: preventive scheme, Fig. 1B scheme 10 treatment; Figure 2 shows the effects of PEA treatment- OXA 30 µM on the reduction of cytokine release pro-inflammatory IL-1β induced by exposure to LPS + fentanyl-treated microglial cells and fruit 15 of microglial hyperactivation 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 shows the effects of PEA treatment- OXA 30 µM on the reduction of the expression levels of 20 IL-1β and IL-6 genes quantified in microglia hyperactivated following exposure of cells to LPS + fentanyl: A) IL -1 β: ***p ˂ 0.001 LPS vs CTR; °°p ˂ 0.01 LPS + ### F vs. LPS; p < 0.001 LPS + F + PEA-OXA vs LPS + F. 25 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. Detailed description of the invention The present invention relates in a first PEA-OXA appearance for use as an adjuvant to opioids to prevent or treat the onset of OIH, in which PEA- 5 OXA is administered in association or in combination to opioids, in which such administration is separate, joint or simultaneous. With the terms “in association” or “in combination” It refers to both combination therapy and therapy 10 where PEA-OXA and the opioid are contained in a single dosage form. By “separate” administration we mean a administration of PEA-OXA and the opioid, administered at different times which can range from 15 1 minute at various hours, for example at 8, 12 or 14 hours of distance from each other. In particular, with “use as an adjuvant of opioids to prevent the onset of OIH” means an administration of PEA-OXA at ​​a previous time 20 the administration of the opioid. By “joint” administration we mean a administration of PEA-OXA and the opioid contained in a single dosage form, i.e. a composition or a pharmaceutical or veterinary formulation. 25 “Simultaneous” administration means a administration of PEA-OXA and the opioid in forms of separate dosages, but administered simultaneously, or within a time of separation between the administration of PEA-OXA and that of the opioid, or vice versa, no longer than 1 minute. 5 A further object of the invention is PEA-OXA for use in the treatment of opioid-induced OIH. In the present invention, opioids are selected between natural opioids or opiates, such as morphine, codeine and thebaine, semi-synthetic opioids, such as heroin, 10 oxycodone and hydrocodone, or synthetic opioids, such as fentanyl, pethidine, levorphanol, methadone, tramadol and dextropropoxyphene. Preferably, the opioid is fentanyl. A further object of the present invention is a 15 composition comprising PEA-OXA and an opioid. Preferably, the composition of the invention is consisting of a dry PEA-OXA / opioid mixture. Whether they are administered separately or together in a single formulation, PEA-OXA and 20 opioids are administered in a PEA-weighted ratio OXA / opioid ratio between 100:1 and 600:1, preferably between 150:1 and 500:1. On the basis of these weight ratios, for which it was showed a significant inhibitory effect on OIH, the 25 minimum daily dose of PEA-OXA, both in a therapy of combination that in a PEA-OXA / opioid composition, will be at least between 1 mg / day and 500 mg / day. These doses may vary depending on the subject and especially if the subject is a child or adult 5 or older. It will still be possible to use doses of PEA-OXA higher than those described above, which were found to be sufficient to achieve an OIH inhibition effect. Therefore, the overall daily dose of PEA-OXA 10 administered to a subject, either in the form of therapy of combination that in the above composition with a opioid or for treatment after onset of OIH, may be between 200 and 2000 mg / day, preferably between 300 and 1500 mg / day or between 400 and 15 1200 mg / day. These daily doses can be divided into dose unit for one administration, for example, from 1 to 4 times a day. The dose will also depend on the route. chosen for administration. It will be necessary to consider 20 that it may be necessary to arrange for changes to the dosage depending on the age and weight of the patient and also of the extent of OIH to be treated. The exact dose and the route of administration will ultimately be at the discretion of the user of the attending physician. For the purposes of the invention, PEA-OXA alone, the opioid alone or the composition containing PEA-OXA and opioid may be included in formulations pharmaceutical or veterinary and can be formulated in 5 dosage forms for oral administration, buccal, parenteral, rectal, topical or transdermal. For oral administration, the compounds of the invention can be found, for example, under form of tablets or capsules, hard or soft, prepared in 10 conventional way with pharmaceutically excipients acceptable as binding agents (e.g. starch pregelatinized corn, polyvinylpyrrolidone or hydroxypropyl methylcellulose); filling agents (e.g. example lactose, microcrystalline cellulose or hydrogen 15 calcium phosphate); lubricants (e.g. calcium stearate magnesium, talc or silica); disintegrants (e.g. potato starch or sodium starch glycolate); or agents inhibitors (e.g. sodium lauryl sulfate). tablets can be coated with well-known methods 20 in art. Liquid preparations for the oral administration may occur, for example, in the form of solutions, syrups or suspensions or they can be presented as freeze-dried products or granules to be reconstituted, before use, with water or 25 other suitable vehicles. Such liquid preparations can be prepared through the methods conventional with pharmaceutical additives acceptable as suspending agents (e.g. sorbitol syrup, cellulose derivatives or fats 5 edible hydrogenated); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. oil of almonds, oily esters, ethyl alcohol or vegetable oils fractionated); and preservatives (e.g. methyl- or propyl- p-hydroxybenzoates, sorbic acid, benzoic acid or their 10 salts). The preparation may also appropriately contain flavourings, colourings and sweetening agents. Preparations for oral administration can be formulated in an appropriate way to allow the controlled release of the active ingredient. 15 For buccal administration, the compounds of the invention can be found in the form of tablets or granules formulated in the conventional way, suitable for a absorption at the level of the buccal mucosa. Formulations Typical buccal administration tablets are 20 sublingual. The compounds of the invention can be formulated for parenteral administration by injection. Injection formulations can be presented in the form of a single dose, for example in vials, 25 with an added preservative. The compositions can to present themselves in this form as suspensions, solutions or emulsions in oily or aqueous vehicles and can contain form agents such as agents of suspension, stabilizers and / or dispersants. In alternative, the active ingredient or the mixture of ingredients 5 active ingredients can be found in powder form to be reconstituted, before use, with a suitable vehicle, for example with sterile water. The compounds of the invention may also be formulated according to rectal formulations such as suppositories or 10 retention enemas, for example containing the basic components of common suppositories such as cocoa butter or other glycerides. In addition to the formulations described previously, the compounds of the invention may also 15 be formulated as a deposit preparation for the administration over the course of a day up to a week. Such long-acting formulations can be administered by implantation (for example in a subcutaneous, transcutaneous or intramuscular) or for 20 intramuscular injection. So, for example, the composition can be formulated with appropriate polymeric or hydrophobic materials (for example under form of an emulsion in a suitable oil) or resins ion exchange or as minimally soluble derivatives. The compounds or composition of the invention may also be administered in the form of oral sprays or nasal sprays. A further object of the invention is also 5 dietary compositions, food supplements, feeds complementary foods and foods for special medical purposes (AFMS) including PEA-OXA. The term "food for special medical purposes" refers to they mean the products authorized according to the regulation 10 (EU) 2016 / 128. This term refers to a product to be administered under medical supervision, assimilating so this AFMS to a drug. The formulations according to the invention can be prepared according to conventional methods, such as those 15 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. 20 EXPERIMENTAL PART BIOLOGICAL EXPERIMENTATION To evaluate the effect of PEA-OXA on induced microglial hyperactivation from the opioid fentanyl, primary microglial cells were obtained from cerebral cortices of newborn rats (Sprague-Dawley) of 1-2 days of age (Facci L. et al, Astrocyte / microglia cocultures as a model to study neuroinflammation, Methods Mol. Biol. 2018; 1727:127– 5 137). Microglia were exposed to fentanyl (F, 10 µM) and to LPS (10 ng / ml), in the absence or presence of PEA-OXA (30 µM) for 24h. At the end of the treatments, the medium culture was collected and used to quantify 10 the pro-inflammatory interleukin (IL)-1β with technique ELISA using a commercially available kit (Antigenix America, Huntington Station, NY, USA). The absorbance of each sample was detected at 450 nm and IL-1β concentration was determined 15 referring 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). 20 Gene transcript analyses were conducted using the Real Time-PCR (RT-PCR) technique to quantify the expression of the IL-1β and IL-6 genes. In In short, total RNA was extracted from the cells microglia using the TRIzol reagent (Invitrogen). 25 The quality and quantity of the extracted RNA were determined using the Agilent RNA 6000 Nano instrument Kit (Agilent Technologies). RNA Reverse Transcription complementary DNA (cDNA) was performed thanks to the Superscript III reverse transcriptase (Invitrogen). The RT- 5 PCR was performed as described in Barbierato, M. et al, Astrocyte-microglia cooperation in the expression of a pro-inflammatory phenotype, CNS Neurol. Disorder. Drugs Targets 2013§; 12:608–618. For the in vivo study, approximately three-month-old C57BL / 6 mice 10 were used to evaluate the efficacy of PEA-OXA to reduce OIH induced by the opioid fentanyl. Before the study began, the animals were were subjected to an acclimatization period of 1 week at the stables of the University of Padua, 15 following all experimental procedures and protocols in accordance with the principles of care and well-being of laboratory animals approved by the Ministry of Italian Health (Legislative Decree 2014 / 26), from European directives (EU Directive 2010 / 63) and the ARRIVE guidelines. 20 To induce OIH, the protocol was used 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. 25 Before the start of the experiment, the von Frey test was performed at baseline to measure the threshold of animal pain. Four days before the administration of fentanyl, 20 µl containing 1 mg / ml of Freund's complete adjuvant (CFA) (Sigma-Aldrich) were injected into the hind leg of the animals 5 to simulate a nociceptive insult. The Von Frey test is was repeated the day after the injection with CFA (D-3). Four days later (D0), the animals were subjected to the Von Frey behavioral test, before the pre-treatment with PEA-OXA (10 or 30 mg / kg). Fentanyl, 10 four subcutaneous injections (sc, 4 x 60 µg / kg) performed at 15 minute intervals each on the other hand, it was administered 1 hour after PEA-OXA. For To assess the development of OIH, the von Frey test is was repeated 1h, 1, 2 and 4 days after the 15 administration of fentanyl (Fig. 1A, scheme preventive). Similarly, a second group of animals, four days after LPS administration (D0), is was subjected to the Von Frey behavioral test 1 hour before 20 of the administration of the four sc injections of fentanyl. Treatment with PEA-OXA (10 or 30 mg / kg) is was administered 1 hour after the opioid. To evaluate the development of OIH, the von Frey test was repeated 2h, 1, 2 and 4 days after administration of 25 fentanyl (Fig. 1B, treatment schedule). Control animals were subjected to the same procedures, injecting the same volumes of vehicles of the substances used. As described above, all animals were 5 were subjected to the Von Frey test, a behavioral test that assesses the pain threshold of animals. The mice were placed inside a box equipped with a metal grid on the bottom and sensitivity mechanics was evaluated in the mid-plantar area of 10 each hind leg thanks to a mechanical stimulus consisting in the application of a filament (Ugo Basile) connected to a force between 0 and 5 g. The gradual and increasing stimuli coming from below the network were applied with an interval of 5 s 15 thanks to a metal probe. Latency was defined as the maximum force that causes paw withdrawal (Chen D et al., 2024, above). STATISTICAL ANALYSIS Statistical analyses were performed using 20 GraphPad Software, version 3.03 (GraphPad Software Inc., La Jolla, CA, United States). The results of the Studies were expressed as mean ± standard error of the mean (SEM). Statistical differences from the in vitro study are 25 were analyzed with one-way ANOVA followed by test Holm-Sidak's post-hoc study while the results of the study in vivo were subjected to two-way ANOVA analysis followed by appropriate post-hoc tests for comparisons multiples. A p-value < 0.05 is considered significant. 5 RESULTS OF THE EXPERIMENTS As reported in Fig. 2, the exposure of cells microglia to LPS induces a marked increase in IL-1β release (***p ˂ 0.001 LPS vs CTR). Exposure of microglia to LPS + fentanyl increases 10 further release of IL-1β (°°°p ˂ 0.001 LPS + F vs LPS), index of hyper-activation of cells microglia. Treatment with PEA-OXA 30 µM reduces significantly hyperactivation of cells microglia induced by stimulation with LPS + F. Nello 15 specifically, IL-1β levels released after PEA-OXA 30 µM are about 180 ng / ml vs 600 ng / ml released in ### absence of treatment (Fig. 1, p < 0.001 LPS + F + PEA-OXA vs LPS + F). As reported in Fig. 3, the exposure of cells 20 microglia to LPS induces a marked increase of the expression of the IL-1β (Fig. 3A) and IL-6 (Fig. 3B) (***p ˂ 0.001 LPS vs CTR). The exposure of the LPS + fentanyl-treated microglia further increases IL-1β gene expression (°°p ˂ 0.01 LPS + F vs LPS) 25 and IL-6 (°p ˂ 0.05 LPS + F vs LPS) hyper-activating the microglial cells. Treatment with 30 µM PEA-OXA significantly reduces gene transcripts in the microglia hyper-activated by LPS + F treatment. Nello specifically, the expression of the IL-1β and IL-6 genes is significantly reduced by pre-treatment with PEA- ### 5 OXA 30 µM compared to untreated microglia (p < 0.001 LPS + F + PEA-OXA vs LPS + F). *** *** The invention will now be further described for by means of the following example formulations. 10 Examples of formulation PEA-OXA = 2-pentadecyl-2-oxazoline Example 1 - Hard capsule for human use Acid-resistant vegetable gelatin capsule format “0” 15 PEA-OXA 300 mg Corn Dextrin 100 mg Silicon Dioxide 10 mg Magnesium Stearate 10 mg Example 2 - Gastro-resistant tablet 20 PEA-OXA 400 mg Dextrose 52 mg Rice starch 120 mg Microcrystalline cellulose 120 mg Polysorbate 80 plant origin 8 mg 25 Silicon Dioxide 10 mg Gastro-resistant coating 40 mg Example 3 - Orodispersible granules PEA-OXA 400 mg Glyceryl Palmitostearate 100 mg Sorbitol 180 mg 5 Fructose 180 mg Aroma 50 mg Polysorbate 80 10 mg PVP K30 10 mg Sucrose Palmitate 20 mg 10 Example 4 - 2.0 g suppositories Suppository base (C10-18 Triglycerides- Polysorbate 65) 1695 mg PEA-OXA 200 mg Example 5 - Soft capsule for human use 15 Bovine gelatin 237 mg PEA-OXA 200 mg Glycerol 129 mg Sunflower oil 366 mg Medium chain triglycerides 51.5 mg 20 Vegetable fat 50.8 mg Soy lecithin 30.0 mg Water 18.8 mg Glyceryl monostearate 8.8 mg Example 6 - Single-dose injectable solution 25 PEA-OXA 10 mg Soy lipids 200 mg Egg lecithin 24 mg Glycerol 100 mg Water for injections q.s. up to 2 ml Example 7 - Nasal Spray Multidose bottle of 10 5 ml / spray dose 0.15 ml Methyl-beta-cyclodextrin 1000 mg Glycerol 85 mg Sodium dibasic phosphate dodecahydrate 28 mg Potassium Citrate Tribasic Monohydrate 25 mg 10 Hyaluronic acid sodium salt 7.5 mg Sodium phosphate monobasic dihydrate 6.3 mg PEA-OXA 5 mg Sodium Chloride 3 mg Citric Acid Monohydrate 0.19 mg 15 Water for injections qb to 10 ml Example 8 - Lyophilized powder for inhalation nasal PEA-OXA 0.3 mg Methyl-beta-cyclodextrin 68 mg 20 Potassium Citrate tribasic 2 mg Lactose 29.7 mg Hard gelatin capsule size 4.

Claims

l. 2-Pentadecyl-2-oxazoline (PEA-OXA) for use as an adjuvant to opioids to prevent the onset or in the treatment of opioid-induced hyperalgesia (OIH), where PEA-OXA is administered in association with or in combination with opioids, where such administration is separate, joint, or simultaneous.

2. 2-Pentadecyl-2-oxazoline for use according to claim 1, wherein the opioids are 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. 2-Pentadecyl-2-oxazoline for use according to any of claims 1 to 3, wherein the 2-Pentadecyl-2-oxazoline and the opioid are administered in a PEA-OXA / opioid weight ratio of between 100:1 and 600:1, preferably between 150:1 and 500:

1.

5. 2-Pentadecyl-2-oxazoline for use according to any of claims 1 to 4, wherein the minimum daily dose of 2-Pentadecyl-2-oxazoline, whether in a combination therapy or in a PEAOXA / opioid composition, is at least 1 mg / day and up to 500 mg / day. I0207872-GL 6. 2-Pentadecyl-2-oxazoline for use according to any of claims 1 to 5, wherein the overall daily dose of PEA-OXA administered to a subject, either in the form of combination therapy or in said composition with an opioid or for treatment after onset of OIH, is between 200 and 2000 mg / day, preferably between 300 and 1500 mg / day or between 400 and 1200 mg / day.

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

8. 2-Pentadecyl-2-oxazoline for use as an adjuvant to opioids to prevent the onset or in the treatment of OIH, where 2-pentadecyl-2-oxazoline is contained in a dietary composition, a food supplement, a complementary feed or a food for special medical purposes (FSMP).