WO2024194263A1

WO2024194263A1 - Serotonin 5ht2a receptor antagonist for use in treating side effects resulting form mu opioid receptor agonist overdose

Info

Publication number: WO2024194263A1
Application number: PCT/EP2024/057173
Authority: WO
Inventors: Nora DIGRANES; Henning Andreas HAGA; Janicke NORDGREEN; Andreas LERVIK
Original assignee: Norwegian University of Life Sciences UMB
Current assignee: Norwegian University of Life Sciences UMB
Priority date: 2023-03-17
Filing date: 2024-03-18
Publication date: 2024-09-26
Anticipated expiration: 2025-09-17

Abstract

The invention provides a method of treating one or more side effects resulting from µ-opioid receptor agonist overdose (e.g. a fentanyl overdose) in a subject such as a human by administering a serotonin 5HT_2A receptor antagonist, such as ketanserin, after administration or ingestion of the p-opioid receptor agonist. Optionally, the ketanserin may be co-administered with other active agents such as naloxone. Related uses and pharmaceutical compositions, products or kits for this purpose are also provided.

Description

42.192.163792/01 Method and composition The present invention provides methods of treating one or more side effects resulting from µ-opioid receptor agonist overdose in a subject by administering a serotonin 5HT_2A receptor antagonist of formula II or IIa, as described hereinafter. The serotonin 5HT_2A receptor antagonist may be co-administered with naloxone and pharmaceutical compositions, kits and products for this purpose are also provided. Preferably, the µ-opioid receptor agonist is fentanyl and the 5HT_2A receptor antagonist is ketanserin. Background The µ-opioid receptor (MOR) is a G protein-coupled receptor that neuromodulates several physiological functions, in particular nociception. These receptors are the primary target of opioid drugs used in the clinic (e.g. morphine, codeine, oxycodone, fentanyl and tramadol), and are responsible for their analgesic properties but also for side effects associated with their acute and chronic use. The receptors mediate opioid rewarding and euphoric properties that underly their abuse potential. Acute effects include depressed respiration, slowing of the gastrointestinal motility, nausea, vomiting, constipation, dizziness, itch, cough suppression, miosis, hallucinations, dysphoria and sedation. Chronic use of opioids induces continued activation of the MORs-related signalling pathways (G protein signalling) and can lead to homeostatic changes, e.g. tolerance, hyperalgesia, and physical dependence. The misuse and/or abuse of prescribed opioid drugs after an initial therapeutic use or in patients that self-medicate led to the opioid crisis that broke out in North America in the early years of the 2000s. Opioid overdosage leads to roughly 70,000 deaths in the United States annually (National Center for Health Statistics, 2023, Provisional drug overdose death counts. National Vital Statistics System, US Department of Health & Human Services) and is reported as the most prevalent cause of death in young adults aged 18-50 in the United States (Torralva and Janowsky, 2019, supra). Fentanyl and fentanyl analogues (including alfentanil, sufentanil, remifentanil, carfentanil, acetylfentanyl and furanylfentanyl), are µ-opioid receptor agonists that act as potent narcotic analgesics and are used therapeutically but are also a major cause of opioid overdoses. They are used via various routes of administration for analgesia, sedation and anaesthesia (Torralva and Janowsky, 42.192.163792/01 2019, J. Pharmacol. Exp. Ther., 371(2), 453-475). For the management and treatment of breakthrough (sudden) pain, fentanyl and its analogues/derivatives are administered by transmucosal methods (e.g. orally via lozenge or spray). Fentanyl and fentanyl analogues are also administered via a transdermal patch to treat chronic pain (United Nations Office on Drugs and Crime, 2017, Recommended Methods for the Identification and Analysis of Fentanyl and its Analogues in Biological Specimens. Laboratory and Scientific Section, Vienna). During surgery and for the purposes of anaesthesia, fentanyl and fentanyl analogues are administered via intramuscular and intrathecal routes, or intravenously (Stanley, 2014, The Journal of Pain, 15, 1215-1226). In light of their potent narcotic analgesic effects, fentanyl and its analogues are also used recreationally. Powdered forms are usually used directly or mixed with other substances, such as heroin, and administered by intranasal or intravenous routes, or smoked (United Nations Office on Drugs and Crime, 2017, supra). However, due to their potency and toxicity, fentanyl and fentanyl analogues are responsible for a high proportion of the opioid-related overdoses and deaths each year, particularly in the United States. Around 41 per cent of an estimated 7,100 heroin-related deaths in the United States between 2012 and 2014 involved the recreational use of fentanyl (Frank and Pollack, 2017, New England Journal of Medicine, 376, 605–607). In 2015, the United States Drug Enforcement Administration (DEA) issued a warning of fentanyl-laced heroin (United States Department of Justice Drug Enforcement Administration (2016) National Drug Threat Assessment Summary). Opioid, and particularly fentanyl abuse, is also present in other countries worldwide. Between 2005 and 2014, Canada, Sweden, Estonia, Germany, the United Kingdom, Finland and Greece reported almost 1,500 deaths related to fentanyl use (Mounteney et al., 2015, International Journal of Drug Policy, 26, 626– 631; Kronstrand et al., 1997, Forensic Science International, 88, 185–195; Canadian Centre on Substance Canadian Community Epidemiology Network on Drug Use, 2016, CCENDU Bulletin: Novel Synthetic Opioids in Counterfeit Pharmaceuticals and Other Illicit Street Drugs). Opioid overdose induces dose-dependent respiratory depression, hypoxia and death. In fentanyl/fentanyl analogue overdose, in addition to respiratory depression, muscle rigidity (including so-called ‘wooden chest’) and vocal cord 42.192.163792/01 closure (VCC, also known as laryngospasm) is also observed at relatively low doses. These effects subsequently lead to blockage of the airways due to the accumulation of froth as well as cerebral and pulmonary oedema (United Nations Office on Drugs and Crime, 2017, supra). Unless prompt treatment and respiratory support is provided, intoxication from high doses will likely result in death (Helander et al., 2017, Clinical Toxicology, 55, 589–599). Naloxone, a non-selective opioid-receptor antagonist, is most commonly used to treat overdose caused by high doses of opioids, such as fentanyl and its analogues/derivatives, by reversing opioid-induced muscle rigidity, respiratory depression and rapid cyanosis (Torralva and Janowsky, 2019, supra). However, even if administered promptly, naloxone lacks effectiveness, particularly for treating rigidity and cyanosis. Mixed results have been obtained using naloxone to treat overdose involving fentanyl or its analogues (Farkas et al., 2020, Ann. Emerg. Med., 75(1), p39-48). Further, naloxone is typically not administered to those who require immediate intubation and ventilator support due to pulmonary aspiration (Helander et al., 2017, supra). Naloxone is therefore limited in its ability to reverse the effects of overdose due to the use of potent levels of opioids such as fentanyl or fentanyl analogues. Other treatments of overdose resulting from fentanyl have focussed on targeting the α1 adrenergic receptor (see for example WO2021/1174116). WO2023/069880 teaches the use of substituted heterocycle fused ɣ-carbolines which have D1 receptor and biased µ-opioid receptor activity. Thus, there is a need to develop more effective therapeutics for treating µ- opioid receptor mediated overdose, i.e. which results from a µ-opioid receptor agonist, e.g. a fentanyl/fentanyl analogue-induced overdose and associated symptoms including wooden chest syndrome, laryngospasm, seizures, myoclonus, tremors, shivering, cyanosis and muscle rigidity. It has now been found that the serotonin 5HT2A receptor is implicated in the development of the overdose symptoms and targeting that receptor with an antagonist with a compound of formula II/IIa reverses the effects of µ-opioid receptor agonist overdose (such as by fentanyl and fentanyl analogues) in individuals. As described in the examples, it has been shown that in pig models the effect of fentanyl can be entirely reversed using the serotonin 5HT2A receptor antagonist ketanserin. This was found to be more effective than naloxone 42.192.163792/01 treatment. This therefore provides a new therapeutic strategy and life-saving tool for treating overdose victims. Thus, in a first aspect, the present invention provides a method of treating one or more side effects resulting from µ-opioid receptor agonist overdose in a subject by administering a serotonin 5HT2A receptor antagonist after administration or ingestion of said µ-opioid receptor agonist, wherein serotonin 5HT2A receptor antagonist is a compound with the formula II or IIa:

wherein, R1 is an oxygen atom (oxo group), sulphur atom (thione group) or a C1-C3 alkyl group; R2 is a halogen atom, preferably F or Cl; and X and/or Y is a carbon or nitrogen atom, or a pharmaceutically acceptable salt thereof. As used herein “and/or” refers to one or both (or more) of the recited options being present, e.g. A and/or B includes the options i) A, ii) B or iii) A and B. 42.192.163792/01 Treatment As referred to herein "treatment" (or treating) refers to reducing, alleviating or eliminating one or more side effects of the overdose which is being treated, relative to the side effects prior to treatment. Treatment may be (or may be intended to be) curative, but may alternatively be palliative (i.e. designed merely to limit, relieve or improve the side effects of the overdose, or to extend survival). Preferably, the one or more side effects are reversed in their entirety. Side effects Various effects result from µ-opioid receptor agonist overdose and those effects may differ between individuals. Common side effects (or symptoms of overdose) include muscle rigidity, wooden chest syndrome, laryngospasm, seizures, myoclonus, tremors, shivering and cyanosis. As referred to herein “muscle rigidity” denotes muscular tension, rigor or stiffness in which the muscles are unable to relax normally. “Wooden chest syndrome” is an example of muscle rigidity in which in particular the thoracic and abdominal muscles become rigid making ventilation difficult. This syndrome is commonly associated with high doses of opioids. “Laryngospasm” is also referred to as vocal cord closure in which the vocal cords spasm such that there is difficulty in speaking or breathing. “Seizures” result in uncontrolled behaviours, movements or levels of consciousness and are caused by uncontrolled bursts of electrical activity in the brain. “Mycoclonus” refers to sudden, brief, involuntary twitching or jerking of a muscle or group of muscles. “Tremors” refers to involuntary rhythmic shaking movement in one or more parts of the body. “Shivering” refers to involuntary tightening and relaxing of muscle in rapid succession. “Cyanosis” is characterized by tissue which has a bluish-purple hue as a result of inadequate oxygenation of the blood. These side effects may be modest or severe in nature. However, they are indicative of overdose or potential overdose and warrant treatment as described herein. Reference herein to “one or more” side effects reflects the fact that subjects that have overdosed may present in different ways and may not exhibit all side effects and/or the timing of the appearance of those side effects may differ. Therefore, a subject, at the time of treatment, may display only one side effect, or may display more than one side effect. For example, 2, 3 or more side effects may be observed. In particular, the subject may exhibit muscle rigidity and optionally additionally laryngospasm, cyanosis and/or seizures at the time of treatment. 42.192.163792/01 µ-opioid receptor agonist The µ-opioid receptor agonist refers to any molecule that activates the µ-opioid receptor. As discussed above, the µ-opioid receptor is a G protein-coupled receptor that neuromodulates several physiological functions, in particular nociception. “Agonists” to the µ-opioid receptor bind to the receptor and activate its signalling pathway. These include natural agonists such as β-endorphin. Exogenous agonists include weak opioids such as codeine and tramadol and strong opioids such as oxycodone, morphine, hydromorphone, meperidine, tapentadol, methadone, fentanyl, sufentanil and remifentanil. In particular, the method of the invention is used to treat overdose resulting from fentanyl and fentanyl analogues or derivatives. Analogues and derivatives of fentanyl are those which similarly act as agonists to the µ-opioid receptor and have similar (relative to fentanyl) effects on the subject when administered, i.e. have analgesic effects at low, therapeutic doses, but result in one or more of the side effects as described herein when used at higher doses that may be considered an overdose. Thus, in a preferred aspect, the fentanyl analogue or derivative is a µ-opioid receptor agonist that results in one or more of muscle rigidity, wooden chest syndrome, laryngospasm, seizures, myoclonus, tremors, shivering and cyanosis, when administered/ingested at overdose levels, and optionally respiratory depression (particularly muscle rigidity, wooden chest syndrome, laryngospasm, seizures and/or cyanosis). Fentanyl has the structure as shown below:

42.192.163792/01 In a preferred aspect, the µ-opioid receptor agonist (or the fentanyl analogue or derivative) is a phenylpiperidine derivative. In a further preferred aspect fentanyl, analogues or derivatives are structurally related to fentanyl, and include halogen-, C₁-C₆ alkyl-, or hydroxy- substituted fentanyl. For example, preferred fentanyl analogues or derivatives include those in which the phenyl group attached to the nitrogen atom is substituted with a halogen atom, in which a C₁-C₆ alkyl group (e.g. CH₃ group) is attached to the α and/or β carbon or the piperidine ring is substituted with a C₁-C₆ alkyl group (e.g. CH₃ group). The propionyl group may also be varied, particularly by replacement of the ethyl group with other C₁-C₆ alkyl groups. In other derivatives and analogues, the phenyl group attached to the β carbon atom may be replaced by other 5-6 membered cyclic groups. In a preferred aspect, the µ-opioid receptor agonist is a compound with the formula I:

wherein, R1 is a cyclic group, preferably a 5- or 6-membered ring, preferably an aryl group (e.g. a phenyl group) or a heterocyclic group (e.g. a thienyl, pyrrolyl, tetrazolyl or furanyl group), wherein said cyclic group may be substituted e.g. by an alkyl (e.g. a C1-C3 alkyl group) and/or an oxo group, or R1 is -COOCH3; R2 and R3 are each a hydrogen atom, a hydroxy group or a C1-C3 alkyl group, e.g. a methyl group; 42.192.163792/01 or R₁ and R₂ together with the carbon atom to which they are bound form an aryl group, preferably a phenyl group; R₄, where present, is a C₁-C₃ alkyl group, e.g. a methyl group; R₅ is a hydrogen atom, -CH₂OCH₃, or -COOCH₃; R₆ is a -COR₇ group or a hydrogen atom, wherein R₇ is a C₁-C₄ alkyl, C₃-C₄ cycloalkyl or C₁-C₄ alkenyl group, optionally interrupted by an oxygen atom (e.g. -CH₃, -CH₂CH₃, -CH₂CH₂CH₃, -CH=CH₂, -CH(CH₃) ₂, -CH(CH₂) ₂, -CH₂CH₂CH₂CH₃ or -CH₂OCH₃) or a phenyl, furanyl, tetrahydrofuranyl or thienyl group; and R₈, where present, is a halogen atom, e.g. F or Cl, or an -OCH₃ group, or a pharmaceutically acceptable salt thereof. As referred to herein said 5- or 6-membered ring may be an aromatic or non-aromatic ring. Such rings include cycloalkyl hydrocarbon rings such as a cyclopentyl or cyclohexyl ring. Such rings also include heterocyclic groups which contain one or more heteroatom ring members (ring-forming atoms), e.g. O, S or N. Further included are aryl groups which are all-carbon aromatic rings with 6 carbons. Substitution refers to the group replacing an existing bond, atom or group, e.g. replacing a hydrogen atom. Groups which are optionally interrupted by an oxygen atom, refer to the inclusion of an oxygen atom between bound atoms, e.g. in an alkyl group to form an alkyl ether. An alkyl group is a saturated aliphatic hydrocarbon including straight chains and branched chains. The term "C_1-C4 alkyl," for example refers to linear or branched radicals of 1 to 4 carbon atoms (i.e. methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl). C3-C4 cycloalkyl groups refers to cyclopropyl or cyclobutyl groups. An alkenyl group is an aliphatic hydrocarbon having at least one carbon- carbon double bond, including straight chains and branched chains having at least one carbon-carbon double bond. The term "C2-C4 alkenyl" means straight or branched chain unsaturated radicals (having at least one carbon-carbon double bond) of 2 to 4 carbon atoms, including, but not limited to, ethenyl, 1-propenyl, 2- propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl. An oxo group refers to =O. When an oxo is substituted on a carbon atom, they together form a carbonyl moiety [-C(=O)-]. 42.192.163792/01 R₁ and R₂ together with the carbon atom to which they are bound may form an aryl group. For example, when the aryl group is a phenyl group R₁ and R₂ together provide C₅H₄ in the phenyl group. Halogens as referred to herein include fluorine, chlorine, bromine and iodine. Pharmaceutically acceptable salts of these compounds are also encompassed in the invention. Appropriate salts include for example acetate, bromide, chloride, citrate, hydrochloride, maleate, mesylate, nitrate, phosphate, sulphate, tartrate, oleate, stearate, tosylate, calcium, meglumine, potassium and sodium salts. Compounds described herein include isomers of such compounds, e.g. enantiomers thereof. Compounds may be used as an individual enantiomer or racemic mixtures thereof. In a preferred aspect, R₆ is a -COR_7. In this case the compound may be described by formula Ia, below.

wherein, R₁ is a cyclic group, preferably a 5- or 6- membered ring, preferably an aryl group (e.g. a phenyl group) or a heterocyclic group (e.g. a thienyl, pyrrolyl, tetrazolyl or 42.192.163792/01 furanyl group), wherein said cyclic group may be substituted e.g. by an alkyl (e.g. a C₁-C₃ alkyl group) and/or an oxo group, or R₁ is -COOCH₃; R₂ and R₃ are each a hydrogen atom, a hydroxy group or a C₁-C₃ alkyl group, e.g. a methyl group; or R₁ and R₂ together with the carbon atom to which they are bound form an aryl group, preferably a phenyl group; R₄, where present, is a C₁-C₃ alkyl group, e.g. a methyl group; R₅ is a hydrogen atom, -CH₂OCH₃, or -COOCH₃; R₇ is a C₁-C₄ alkyl, C₃-C₄ cycloalkyl or C₁-C₄ alkenyl group, optionally interrupted by an oxygen atom (e.g. -CH₃, -CH₂CH₃, -CH₂CH₂CH₃, -CH=CH₂, -CH(CH₃)₂, -CH(CH₂)₂, -CH₂CH₂CH₂CH₃ or -CH₂OCH₃) or a phenyl, furanyl, tetrahydrofuranyl or thienyl group; and R₈, where present, is a halogen atom, e.g. F or Cl, or an -OCH₃ group, or a pharmaceutically acceptable salt thereof. In preferred aspects, in the above described formulae, R1 is a phenyl group, thienyl group, -COOCH3, or an oxo- and C2 alkyl-substituted tetrazolyl group; R2 and R3 are hydrogen atoms or R1 and R2 together with the carbon atom to which they are bound form a phenyl group; R4 is absent or a methyl group; R5 is a hydrogen atom, -CH2OCH3, or -COOCH3; R6 = -COR7 or a hydrogen atom; R7 = -CH3, -CH2CH3, -CH2CH2CH3, -CH=CH2, -CH(CH3) 2, -CH(CH2) 2, -CH2CH2CH2CH3 or -CH2OCH3, or a phenyl, furanyl, tetrahydrofuranyl or thienyl group; and R8 is absent. Preferred µ-opioid receptor agonists are selected from: i) fentanyl (R1 = phenyl group; R2 = H; R3 = H; R4 = absent; R5 = H; R6 = -COR7; R7 = -CH2CH3; R8 = absent); ii) alfentanil (R1 = oxo- and C2 alkyl- substituted tetrazolyl group; R2 = H; R3 = H; R4 = absent; R5 = -CH2OCH3; R6 = -COR7; R7 = -CH2CH3; R8 = absent); iii) sufentanil (R1 = thienyl group; R2 = H; R3 = H; R4 = absent; R5 = -CH2OCH3; R6 = -COR7; R7 = -CH2CH3; R8 = absent); iv) remifentanil (R1 = is -COOCH3; R2 = H; R3 = H; R4 = absent; R5 = -COOCH3; R6 = -COR7; R7 = -CH2CH3; R8 = absent); 42.192.163792/01 v) carfentanil (R₁ = phenyl; R₂ = H; R₃ = H; R₄ = absent; R₅ = -COOCH₃; R₆ = -COR₇; R₇ = -CH₂CH₃; R₈ = absent); vi) acetylfentanyl (R₁ = phenyl group; R₂ = H; R₃ = H; R₄ = absent; R₅ = H; R₆ = -COR₇; R₇ = -CH₃; R₈ = absent); vii) furanylfentanyl (R₁ = phenyl group; R₂ = H; R₃ = H; R₄ = absent; R₅ = H; R₆ = -COR₇; R₇ = furanyl; R₈ = absent); viii) 4-ANPP (R₁ = phenyl group; R₂ = H; R₃ = H; R₄ = absent; R₅ = H; R₆ = H; R₈ = absent); ix) 4-fluoroisobutyryl fentanyl (R₁ = phenyl group; R₂ = H; R₃ = H; R₄ = absent; R₅ = H; R₆ = -COR₇; R₇ = -CH(CH₃) ₂; R₈ = F); x) cyclopropyl fentanyl (R₁ = phenyl group; R₂ = H; R₃ = H; R₄ = absent; R₅ = H; R₆ = -COR₇; R₇ = -CH(CH₂) ₂; R₈ = absent); xi) methoxyacetyl fentanyl (R₁ = phenyl group; R₂ = H; R₃ = H; R₄ = absent; R₅ = H; R₆ = -COR₇; R₇ = -CH₂OCH₃; R₈ = absent); xii) acryl fentanyl (R₁ = phenyl group; R₂ = H; R₃ = H; R₄ = absent; R₅ = H; R₆ = -COR7; R7 = -CH=CH2; R8 = absent); xiii) butyryl fentanyl (R1 = phenyl group; R2 = H; R3 = H; R4 = absent; R5 = H; R6 = -COR7; R7 = -CH2CH2CH3; R8 = absent); xiv) 3-methyl fentanyl (R1 = phenyl group; R2 = H; R3 = H; R4 = -CH3; R5 = H; R6 = -COR7; R7 = -CH2CH3; R8 = absent); xv) THF fentanyl (R1 = phenyl group; R2 = H; R3 = H; R4 = absent; R5 = H; R6 = - COR7; R7 = tetrahydrofuranyl group; R8 = absent); xvi) benzyl fentanyl (R1 and R2 together with the carbon atom to which they are bound form a phenyl group; R3 = H; R4 = absent; R5 = H; R6 = -COR7; R7 = - CH2CH3; R8 = absent); xvii) 2-thiofuranyl fentanyl (R1 = phenyl group; R2 = H; R3 = H; R4 = absent; R5 = H; R6 = -COR7; R7 = thienyl group; R8 = absent); and xviii) benzoylbenzyl fentanyl (R1 and R2 together with the carbon atom to which they are bound form a phenyl group; R3 = H; R4 = absent; R5 = H; R6 = -COR7; R7 = phenyl group; R8 = absent). Other preferred fentanyl analogues/derivatives include U-47700 (3,4- dichloro-N-[(1R,2R)-2-(dimethylamino)cyclohexyl]-N-methylbenzamide) and U- 48800 (2-(2,4-dichlorophenyl)-N-((2S)-2-(dimethylamino)cyclohexyl)-N- methylacetamide). 42.192.163792/01 Overdose An “overdose” as described herein refers to an amount that leads to one or more of the above-described side effects. In particular, an overdose is typified by side effects which may potentially be fatal to the subject. An overdose may be achieved by a specific dose of the µ-opioid receptor agonist or may result from rapid administration of the agonist to the subject thus resulting in a rapid increase of the agonist in the blood of the subject. The overdose may result from recreational or therapeutic uses and may be intended or unintended. The overdose may result from the use of one or more µ-opioid receptor agonist. The first evidence of the overdose may be the appearance of one or more side effects as described hereinbefore. The amount or timing of administration/ingestion to achieve overdose may be different for different subjects and may be dependent on age, weight, health, tolerance etc. of the subject and the route and mode of administration of the agonist. The µ-opioid receptor agonist may be administered/ingested via a variety of routes, but is conveniently (and commonly) ingested by insufflation (e.g. nasally), ophthalmically, orally, transdermally or by injection or smoking. In some cases, the likelihood of an overdose may be assessed by examining blood serum levels of the agonist. However, since different agonists have different potency and act differently in different subject depending on tolerance, the level in blood serum likely to lead to an overdose will vary for the different agonists. By way of example, fentanyl may be used at a serum concentration of 1-2 ng/ml for analgesia and may be used at 10-20 ng/ml for anaesthesia (where ventilation is assisted). However, as little as 1 ng/ml in serum may be fatal. Some derivatives are even more potent, e.g. methyl fentanyl, sufentanil and carfentanil which are more than 10 times as potent as fentanyl and even lower levels in the serum are likely to cause an overdose. Thus, in a preferred aspect, the overdose results in a blood serum concentration of said µ-opioid receptor agonist of at least 0.1 ng/ml or 1, 2, 3, 5 or 10 ng/ml (e.g. up to 100 ng/ml), wherein preferably said µ-opioid receptor agonist is fentanyl. The dose may be lower for more potent analogues, e.g. at least 0.3 ng/ml or 0.5, 1, 2 or 5 ng/ml (e.g. up to 10 ng/ml). Whilst different amounts of the agonist may lead to an overdose, in one example, an overdose results from administration/ingestion of at least 5, 10 or 20 µg/kg of the agonist (e.g. fentanyl). 42.192.163792/01 Serotonin 5HT_2A receptor antagonist The serotonin 5HT_2A receptor is a G_q-coupled protein receptor which is widely expressed, including in the brain, gut and cardiovascular system. The serotonin 5HT_2A receptor antagonist refers to a molecule that blocks the serotonin 5HT_2A receptor. “Antagonists” to the receptor prevent activation of its signalling pathway. Such antagonists include methylergonovine, clozapine, pirenperone, altanserin, ritanserin and ketanserin. The antagonists are effective in treating overdose as described herein. The serotonin 5HT_2A receptor antagonist for use in the invention may be a quinazoline derivative. The serotonin 5HT_2A receptor antagonist for use in the invention is a compound with the formula II:

wherein, R1 is an oxygen atom (oxo group), sulphur atom (thione group) or a C1-C3 alkyl group; R2 is a halogen atom, preferably F or Cl; and X and/or Y is a carbon or nitrogen atom, or a pharmaceutically acceptable salt thereof. For the avoidance of doubt, when X is a (neutral) nitrogen atom its valency dictates that the ring in which it appears is represented by two double bonds, i.e. as shown in formula IIa, below. When X and/or Y is a carbon atom, hydrogen atoms are provided as necessary to satisfy valency, i.e. X and/or Y is CH or C, as appropriate. Preferably, X is a carbon atom (C) and/or preferably Y is a nitrogen atom (N). The antagonist may also be in the form of formula IIa, 42.192.163792/01

wherein, R₁, R₂, X and Y is as defined above, or a pharmaceutically acceptable salt thereof. Preferably, X is a nitrogen atom (N) and/or Y is a carbon atom (C). The alkyl group and halogen atom are as described hereinbefore. In preferred aspects, the serotonin 5HT_2A receptor antagonist is ketanserin (R₁ = oxygen (oxo group), R₂ = F, X = carbon, Y = nitrogen, formula II), altanserin (R₁ = sulphur (thione group) , R₂ = F, X = carbon, Y = nitrogen, formula II) or pirenperone (R₁ = -CH₃, R₂ = F, X = nitrogen, Y = carbon, formula IIa). Subject The “subject” as used herein refers to a mammal, particularly a primate (preferably a human), domestic or companion animal, livestock or laboratory animal. Thus, preferred animals include humans, cats, dogs, horses, donkeys, sheep, pigs, goats, cows, monkeys, mice, rats, rabbits or guinea pigs. The subject may be any animal (preferably human) that has overdosed, or is suspected to have overdosed, on a µ-opioid receptor agonist. Administration Conveniently, the serotonin 5HT2A receptor antagonist (which is a compound of formula II or IIa) is administered in the form of a pharmaceutical composition. Such compositions are described in more detail hereinafter. The serotonin 5HT2A receptor antagonist or pharmaceutical compositions containing it may be administered in any appropriate manner. The quantity and mode of administration will be determined by such factors as the condition of the patient/subject, the route of administration, the serotonin 5HT2A receptor antagonist to be administered, the µ-opioid receptor agonist that has been ingested, the observed side effects and circumstances under which administration is to be performed (e.g. hospital, first aider etc.). Any convenient route may be used for administration of the serotonin 5HT2A receptor antagonist. In general, in light of the urgency of the treatment, 42.192.163792/01 administration that is simple and allows rapid uptake is preferred, particularly administration that may be easily performed without specialist training, e.g. by a first aider, first responder or companion. Thus, in preferred aspects, nasal administration, e.g. with a spray is preferred. In the alternative, other forms of administration may be used. For example, administration may alternatively be e.g. oral, rectal, topical, vaginal or parenteral. Oral administration as used herein includes buccal and sublingual administration. Topical administration as used herein includes transdermal administration. Parenteral administration as defined herein includes subcutaneous, intramuscular, intravenous, intraperitoneal and intradermal administration. In a preferred aspect, administration is nasal, intramuscular, intradermal, subcutaneous or intravenous. The total dose of serotonin 5HT_2A receptor antagonist (i.e. a compound of formula II or IIa as described hereinbefore, such as ketanserin) is the total amount of the antagonist to be administered to said subject to achieve treatment of the overdose, i.e. to treat one or more side effects and is selected accordingly. Conveniently, the total dose may be 0.01 to 10 mg/kg. For example, for an adult of 70 kg a dose of 0.7-700 mg in total may be administered. In a preferred aspect, the total dose is 0.1 to 10 mg/kg, e.g.0.1-2.5 mg/kg or 0.5-5 mg/kg, e.g.0.1-1 mg/kg, 0.1-2 mg/kg, 0.5-2 mg/kg or 1-2 mg/kg. The dose administered over the treatment window is considered to be the total dose and may be made up of one or more doses. A dose is considered the application of a serotonin 5HT2A receptor antagonist (or a second or further active(s) as described hereinafter) at a single time or over a continuous time period, e.g. added as a single bolus/spray/capsule or administered continuously over a discrete time period. When administered over a period of time, preferably administration of a dose is performed over 1-60 minutes, e.g. over 1-30 minutes, e.g.1-2 minutes. The antagonist may be administered in a single dose or in more than one dose to provide the total dose over the treatment period. Thus, for example, a first dose may be provided and depending on whether the side effects are improved a second and optionally further doses may be administered, e.g. within minutes of each other. Thus, for example, a first dose may be administered and followed up with a second dose 1-5 minutes later and, for example, a third dose 5-60 minutes later. The dose administered over that treatment window is the total dose. The treatment window over which the total dose is administered may be from 1-120 minutes, e.g. from 1-30 or 1-10 minutes. 42.192.163792/01 The antagonist is (or is to be) administered after administration or ingestion of the µ-opioid receptor agonist. In light of the urgency of treatment, administration of the serotonin 5HT_2A receptor antagonist is commenced as soon as possible. In some cases, this may be immediately after ingestion of the µ-opioid receptor agonist, e.g. hospital situations where an overdose is immediately apparent. In other instances, administration may occur as soon as overdose side effects are observed. These may occur very quickly (e.g. within minutes) after ingestion of the µ-opioid receptor agonist or several minutes later, e.g. up to 30 or 60 minutes later. Conveniently, the serotonin 5HT_2A receptor antagonist is administered (commenced) immediately or up to 10 minutes after administration/ingestion of said µ-opioid receptor agonist. In some cases, some delay may be possible dependent on the consumed dose of the agonist, e.g. up to 240 minutes after administration/ingestion of the agonist, but ideally the antagonist is administered as soon as practicable to achieve a positive outcome, e.g. from 0-120 or 1-120 minutes after ingestion of the agonist, preferably within 1, 5, 10 or 30 minutes of ingestion/administration. Co-administration with naloxone Whilst the serotonin 5HT2A receptor antagonist may be used as the sole active in the treatment of the overdose, in other cases at least one additional active agent may also be used. This may include other actives considered suitable for treating one or more of the side effects. In a preferred aspect, the second active is naloxone (n-allylnoroxymorphone) and the serotonin 5HT2A receptor antagonist is co-administered with naloxone. The co-use of these agents is particularly advantageous as naloxone alone is not effective in treating the overdose, but is useful in reversing respiratory depression. The co-use of ketanserin and naloxone has been shown to improve both survival and opening of closed vocal cords after fentanyl treatment, see Example 3. Alternative or additional active agents may be used which provide a beneficial, if not curative, effect, e.g. to preserve blood pressure in normal ranges following ketanserin treatment. Naloxone is usually administered at a dose of 0.4 to 2 (or 4) mg to treat opioid overdose in an adult human and may be repeated at 2-3 minute intervals. A lower dose may be used intravenously (e.g.0.4 mg) compared to, for example, a nasal dose (e.g.2-4 mg). A similar dose and timing may be used in the methods of the invention. Alternatively, the timing protocol as described above for the serotonin 5HT2A receptor antagonist may be used. However, the co-use of 42.192.163792/01 naloxone and the serotonin 5HT_2A receptor antagonist may allow lower doses of one or both agents to be used. In a preferred aspect, naloxone, when used, is administered at a total dose of 0.005 to 0.5 mg/kg in said subject (i.e.0.35 to 35 mg/kg in a 70kg adult). In a preferred aspect, a total dose of 0.005 to 0.1 mg/kg is used. This dose may be used for intravenous administration. For nasal administration, for example, a dose of 0.03 to 0.06 mg/kg may be used. As with the serotonin 5HT_2A receptor antagonist, this may be administered over one or more doses, e.g. using the timing as proposed for the antagonist. Conveniently, the route of administration used for the naloxone is the same as for the serotonin 5HT_2A receptor antagonist, though alternative administration routes may be used, if preferred. Co-administration refers to administration of the active agents as part of the same treatment of the overdose, e.g. commencing administration within at least 5, 10 or 30 minutes of each other. Thus, the serotonin 5HT_2A receptor antagonist and naloxone (and optionally additional active agents) may be administered to the subject separately, simultaneously or sequentially. “Separate” administration, as used herein, means that the antagonist and naloxone (and optionally additional agent) are administered to the subject at the same time, or at least substantially the same time, but by different administrative routes. “Simultaneous” administration, as used herein, means that the antagonist and naloxone (and optionally additional active agent) are administered to the subject at the same time, or at least substantially the same time, by the same administrative route. By “sequential” administration, as used herein, is meant that the antagonist and naloxone (and optionally additional active agent) are administered to the subject at different times. Sequential administration may be performed in which the two drugs are administered from 5 seconds to 10 minutes or 30 seconds to 10 minutes apart. The administration of one drug may be followed immediately by the other drug, without a time interval. In a preferred aspect, the antagonist (e.g. ketanserin) is administered at the same time as, or before administration of, the second drug (e.g. naloxone). When administered to a subject sequentially, the two drugs may be administered by the same administrative route or by different administrative routes. Preferably, the antagonist (and any additional active agents) for use according to the invention are administered to the subject in need thereof in a therapeutically effective amount. By “therapeutically effective amount” is meant an amount sufficient to show benefit to the condition of the subject. Whether an 42.192.163792/01 amount is sufficient to show benefit to the condition of the subject may be determined by the physician/veterinarian. Pharmaceutical composition The serotonin 5HT_2A receptor antagonist which is a compound of formula II or IIa, and optionally naloxone and any further active agent(s), when present, may each be administered to the subject to be treated in the form of a pharmaceutical composition. Such a composition may contain one or more pharmaceutically acceptable diluents, carriers or excipients. "Pharmaceutically acceptable" as used herein refers to ingredients that are compatible with other ingredients of the compositions as well as physiologically acceptable to the recipient. The nature of the composition and carriers or excipient materials, dosages etc. may be selected in routine manner according to choice and the desired route of administration, etc. Dosages may likewise be determined in routine manner and may depend upon the nature of the molecule, age of patient/subject, mode of administration etc., as discussed hereinbefore. As further discussed herein, when the antagonist is used with a second active agent (such as naloxone, and optionally a third active agent) they may be administered to the subject in the same pharmaceutical composition or in separate pharmaceutical compositions. A pharmaceutical composition may be prepared for administration to a subject by any suitable means, particularly to achieve the modes of administration discussed above. Pharmaceutical compositions as disclosed herein include liquid solutions or syrups, solid compositions such as powders, granules, tablets or capsules, or sprays and any other style of composition commonly used in the art. Suitable pharmaceutically acceptable diluents, carriers and excipients for use in such compositions are well known in the art. For instance, suitable excipients include lactose, maize starch or derivatives thereof, stearic acid or salts thereof, vegetable oils, waxes, fats and polyols. Suitable carriers or diluents include carboxymethylcellulose (CMC), methylcellulose, hydroxypropylmethylcellulose (HPMC), dextrose, trehalose, liposomes, polyvinyl alcohol, pharmaceutical grade starch, mannitol, lactose, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose (and other sugars), magnesium carbonate, gelatin, oil, alcohol, detergents and emulsifiers such as the polysorbates. Stabilising agents, wetting agents, emulsifiers, sweeteners etc. may also be used. 42.192.163792/01 Liquid pharmaceutical compositions, whether they be solutions, suspensions or other like form, may include one or more of the following: sterile diluents such as water for injection, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono- or diglycerides which may serve as a solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as dextrose. A parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. An injectable pharmaceutical composition is preferably sterile. For nasal sprays, aqueous or oil formulations may be used with co-solvents and/or surfactants to improve solubility. A further aspect of the invention provides a pharmaceutical composition comprising a serotonin 5HT_2A receptor antagonist and naloxone and one or more pharmaceutically acceptable diluents, carriers or excipients, wherein the serotonin 5HT2A receptor antagonist is a compound with the formula II or IIa as defined hereinbefore. The pharmaceutical composition is suitable for administration as described hereinbefore, and particularly is suitable for nasal or intramuscular administration. In a further aspect of the invention, the pharmaceutical composition is for use in therapy. In particular, the present invention provides the pharmaceutical composition comprising the antagonist and naloxone as defined herein for use in treating one or more side effects resulting from µ-opioid receptor agonist overdose in a subject, wherein said serotonin 5HT2A receptor antagonist is to be administered after administration or ingestion of said µ-opioid receptor agonist and wherein the µ-opioid receptor agonist, side effects, administration, subject and overdose are as described hereinbefore. Medical treatments In an alternative embodiment, the invention provides a serotonin 5HT2A receptor antagonist for use in treating one or more side effects resulting from µ- opioid receptor agonist overdose in a subject, wherein said serotonin 5HT2A receptor antagonist is to be administered after administration or ingestion of said µ- opioid receptor agonist, and wherein the µ-opioid receptor agonist, serotonin 5HT2A receptor antagonist, side effects, administration, subject and overdose are as described hereinbefore. In a preferred aspect of this embodiment, the invention 42.192.163792/01 provides the serotonin 5HT_2A receptor antagonist for the above use, wherein the serotonin 5HT_2A receptor antagonist is co-administered with naloxone, wherein preferably the naloxone is administered as defined hereinbefore. In a further alternative embodiment, the present invention provides use of a serotonin 5HT_2A receptor antagonist in the preparation of a medicament for treating one or more side effects resulting from µ-opioid receptor agonist overdose in a subject, wherein said serotonin 5HT_2A receptor antagonist is to be administered after administration or ingestion of said µ-opioid receptor agonist, and wherein the µ-opioid receptor agonist, serotonin 5HT_2A receptor antagonist, side effects, administration, subject and overdose are as described hereinbefore. In a preferred aspect of this embodiment, the invention provides that the medicament is co- administered with naloxone, wherein preferably said naloxone is to be administered as defined hereinbefore. The naloxone may be used to prepare the medicament, i.e. to provide a medicament containing both the antagonist and the naloxone. Product The invention also provides a product comprising a serotonin 5HT2A receptor antagonist and naloxone as a combined preparation for simultaneous, separate or sequential use in treating one or more side effects resulting from µ- opioid receptor agonist overdose in a subject, wherein said serotonin 5HT2A receptor antagonist is to be administered after administration or ingestion of said µ- opioid receptor agonist, and wherein the µ-opioid receptor agonist, serotonin 5HT2A receptor antagonist, side effects, administration, subject and overdose are as described hereinbefore. The simultaneous, separate or sequential administration is as described hereinbefore. In the products for use according to the invention, the antagonist and naloxone (and any additional active agent that may be present) may be provided as separate components, e.g. in separate compositions, which may be provided together in a single container or in separate containers. Alternatively, the antagonist and naloxone (and any additional active agent that may be present) may be provided in a single composition in a single container. Kits The invention also provides a kit for use in treating one or more side effects resulting from µ-opioid receptor agonist overdose in a subject, wherein said serotonin 5HT_2A receptor antagonist is to be administered after administration or ingestion of said µ-opioid receptor agonist, said kit comprising: 42.192.163792/01 a) a first container containing a serotonin 5HT_2A receptor antagonist; and b) a second container containing naloxone, wherein the µ-opioid receptor agonist, serotonin 5HT_2A receptor antagonist, side effects, administration, subject and overdose are as described hereinbefore. The products and kits as described hereinbefore may additionally contain other actives as described hereinbefore for the pharmaceutical compositions of the invention. Each therapeutic agent in the products or kits may be provided in any appropriate form, e.g. in an aqueous solution or as a lyophilisate. Such kits and products may be used for putting the methods or uses of the invention into practice. Conveniently, they may contain other components useful for putting the methods or uses of invention into practice, e.g. they may further comprise a suitable buffer or instructions for putting the methods or uses of the invention into effect. In light of the intended use of the kits and products of the invention, they are provided in an easy-to-use presentation allowing use by non-specialists without medical training. Conveniently, when the product contains a single composition, it is in a form immediately suitable for administration (e.g. preloaded in a nasal spray or preloaded in an injection device). When two separate components are provided, e.g. in the product or the kit, these are similarly immediately suitable for administration to avoid any administration delay. The methods described in the Examples form further preferred aspects of the invention. All combinations of the preferred features described above are contemplated, particularly as described in the Examples. The invention will now be described in more detail in the following non-limiting Examples with reference to the following drawings in which: Figure 1 shows stiff gait/posture patterns displayed by pigs in response to treatment and time illustrated with a box-and-whisker plot (with interquartile range, and median illustrated within the box. Upper and lower range by whiskers as vertical lines extending from the box). With duration (seconds (s)) of the pattern. Data for each timeslot (baseline, injection, 1, 2 and 3) are summarized as cumulative duration for 10 minutes. Pigs in the saline-saline group (solid, black) received saline for all injections. Pigs in the fentanyl-ketanserin (vertical lines) and fentanyl-saline 42.192.163792/01 (solid, dark grey) group received 5 µg/kg fentanyl for injection 1 and 10 µg/kg fentanyl for injection 2, and then ketanserin or saline respectively for injection 3. Figure 2 shows acceleration quantified as average rectified mean value, m/s² in response to treatment and time. Pigs were under isoflurane anaesthesia at baseline (0-20 minutes) and throughout the study period. Fentanyl infusion (7.5 µg kg^-1 hour^-1) was initiated at minute 21 and throughout the study period. Pigs in the ketanserin group (solid black line and error bars) were administered 1 mg/kg ketanserin IV at minute 66. Pigs in the naloxone group (stippled grey line and grey error bars) were administered naloxone 0.1 mg/kg IV at minute 66. Data is reported as median and interquartile range. Figure 3 shows spontaneous electromyography (EMG) quantified as RMS µV in response to treatment and time. Data is reported as median and interquartile range. The average RMS is calculated from the acquired signal for the three channels used in each pig (Ch1:11/12 pigs, Ch2:10/12 pigs, Ch3:9/12 pigs). Pigs were under isoflurane anaesthesia at baseline (0-20 minutes) and throughout the study period. Fentanyl infusion (7.5 µg kg^-1 hour^-1) was initiated at minute 21 and kept throughout the study period. Pigs in the ketanserin group (solid black line and error bars) were administered 1 mg/kg ketanserin IV at minute 66. Pigs in the naloxone group (stippled grey line and grey error bars) were administered naloxone 0.1 mg/kg IV at minute 66. Figure 4 shows the experimental timeline of the rat overdose study. The experimental outcome was either 1) no resolution of vocal cord closure (VCC) and immediate euthanasia, 2) partial or complete resolution of VCC and regained spontaneous ventilation, in which case the experiment was continued for another five minutes, or 3) partial or complete resolution of VCC, but apnoeic, such that the animal was euthanized immediately. Figure 5 shows survival percentage (%) in response to antagonist injection after fentanyl-induced overdose (25 µg/kg). Survival was set at outcome 2 (see Figure 4 legend), in which case rats regained an open vocal cord and ventilation. Statistical analyses were performed with a Chi-Square test (p (Prob> χ², likelihood ratio)). *** denotes significant differences p<0.0001. n.s = not significant. 42.192.163792/01 Figure 6 shows the duration of vocal cord closure (VCC) in seconds for the different treatment groups in a box-plot with median value indicated by a horizontal line within each box and the range displayed as whiskers extending from the box. Statistically significant differences are denoted with *** tested by a Kruskal-Wallis test with Dunn’s multiple comparisons (p<0.001). n.s = not significant. Figure 7 shows the difference in glottic opening from baseline after fentanyl induced vocal cord closure (VCC) in 21 rats (Ketanserin n=11, naloxone n=10). The difference is illustrated as a box-plot, where the median value is illustrated with a horizontal line within the box, and whiskers the 5-95^th percentile. Dots illustrates the value obtained from each rat. * denotes statistical differences between the groups tested with a t-test (p<0.05). Examples Example 1 Fentanyl increases locomotion, stiff gait, and repetitive behaviours in pigs that can be reversed with ketanserin The behavioural effects of fentanyl and the antagonistic effect of ketanserin was investigated in pigs. Pigs are used extensively as laboratory animals, both for pig- focused research, but also as models for human medicine (Walters et al., 2017, Lab. Anim. (NY), Vol.46(4), p167-172). Materials & Methods Ketanserin tartrate (Tocris Bioscience, batch no.: 4B/264887) was prepared according to the manufacturer’s instructions with sterile water (sterile water, Fresenius Kabi) and diluted with hypertonic saline (7.2%, Covetrus) to obtain an isotonic solution of 3 mg/ml with ketanserin. A dose of 1mg/ml was used. Fentanyl (fentanyl 50 µg/ml, Hameln) was prepared at a dosage of 5 µg/kg for the first injection, and 10 µg/kg for the second injection. Two dosages were used. The 5 µg/kg dose reflects a clinical dosage, with a target plasma level between 0.5-2 ng/ml which is a range expected to provide analgesia when extrapolated from 42.192.163792/01 humans (Calis et al., 1992, Clin. Pharm., Vol.11(1), p22-36; Harvey-Clark et al., 2000, Lab. Anim., Vol.34(4), p386-398). The second dose of 10 µg/kg was used to exaggerate behavioural changes in pigs based on observations from a pilot study. The cumulative dose of 15 µg/kg was considered to equate to an overdose. Saline (NaCl 9 mg/ml, Fresenius Kabi) was prepared in an equivalent volume to fentanyl (5 µg/kg or 10 µg/kg) for injection 1 and 2, and ketanserin (1 mg/kg) for injection 3 or 4. Four injections for each pig were prepared on the experimental day. Injections 1 and 2 were stored in room temperature, while injections 3 and 4 were kept in a warm water bath (40-60°C) until used. Fourteen mixed breed pigs (25% Norwegian land race, 25% Yorkshire and 50% Duroc), weighing 17-25 kg and 59 ± 1.2 days old were included in a randomised, blinded, prospective, balanced three-group study. Pigs were acclimatised and provided with environmental enrichments. Ten pigs received first 5 and then 10 µg/kg of fentanyl intravenously via a central venous placed catheter. Ten minutes after the second dose of fentanyl (as shown in Table 1 below), ketanserin 1 mg/kg and saline was given intravenously as third and fourth injections in a cross-over manner. The fourth injection was provided to ensure that all pigs under fentanyl influence were treated with ketanserin to mitigate the effects of fentanyl. Four control pigs received four injections of saline. Details of the experimental groups and their treatment are set out in the table below (n=number of experimental animals): Table 1 Experimental Baseline Injection 1 Injection 2 Injection 3 Injection 4 phase (time = 0) (time = 20 (time = 30 (time = 40 (time = 50 mins) mins) mins) mins) Experimental group Fentanyl- - Fentanyl 5 Fentanyl 10 Ketanserin Saline ketanserin (n=5) µg/kg µg/kg 1 mg/kg Fentanyl-saline - Fentanyl 5 Fentanyl 10 Saline Ketanserin 1 (n=5) µg/kg µg/kg mg/kg 42.192.163792/01 Saline-saline - Saline Saline Saline Saline (n=4) Behaviour was video recorded. Baseline video was recorded for 10 minutes and after each injection behaviour was recorded for 10 minutes. Distance moved was automatically measured by commercially available software, and behaviours manually scored in retrospect. Distance moved after fentanyl or saline injections was compared in a linear-mixed model. Median and range for frequency and duration of distinct behavioural patterns were calculated. Alpha was set at 0.05. Results Fentanyl inhibited resting and playing and induced different repetitive behaviours. The mean (SD) distance moved in the control group and fentanyl group was 21.3 (13.0) and 57.8 (20.8) metres respectively (p<0.05 for pairwise comparison). Pigs adopted a freeze behaviour on administration of fentanyl which was reversed by injection with ketanserin (data not shown). A stiff gait/posture pattern was seen after fentanyl injection for median (range) 187 (56-393) seconds per 10 minutes after 5 µg/kg, and 300 (165-362) seconds after 10 µg/kg. This was reduced to 0 (0-4) seconds after ketanserin administration, and 125 (96-338) seconds after saline administration. Pigs in the control group had a median (range) duration of the stiff gait/posture pattern of 0 (0) seconds. The results are shown in Figure 1. Conclusion Direct motor and behavioural effects are induced by fentanyl, but can be reversed using ketanserin. In particular, a stiff gait/posture was adopted by pigs in response to both low and higher doses of fentanyl. The induced rigidity was completely reversed by injection of ketanserin. These effects are indicative of a role of the 5HT2A receptor in fentanyl induced side effects in pigs. 42.192.163792/01 Example 2 Serotonin antagonist ketanserin reverses fentanyl-induced shivering/tremors/motor activity in pigs Shivering in anaesthetised pigs is an acknowledged phenomenon and has been coupled to fentanyl (Ringer et al., 2016, Lab. Anim.50, 312-314; Haga et al., 2021, Vet. Anaesth. Analg., 48, 230-238). The effects of ketanserin (targeting the serotonin 5HT_2A receptor) or naloxone (targeting the µ-opioid receptor) on fentanyl- induced shivering/tremors/motor activity were assessed. Materials & Methods Ketanserin tartrate was sourced and prepared as described in Example 1 to provide a 3mg/ml solution. A dose of 1 mg/kg was used. Fentanyl (fentanyl 50 µg/ml, Hameln) was diluted with saline (NaCl 9 mg/ml, Fresenius Kabi) to provide a 10 µg/ml solution. Naloxone (Naloxone 0.4 mg/ml, Hamel) was prepared in a syringe to a dosage of 0.1 mg/kg, and then diluted with sterile saline (NaCl 9 mg/ml, Fresenius Kabi) to obtain the same volume as with 1 mg/kg ketanserin from a 3 mg/ml solution. The antagonist injection with either ketanserin or naloxone was placed in a sealed bag in warm water bath (40-60°C) until used. Twelve mixed breed pigs (25% Norwegian land race, 25% Yorkshire and 50% Duroc), weighing 22-31 kg and aged 66 ± 2.3 days old were included in a randomised, balanced, blinded prospective, two group study of 6 pigs each (ketanserin group and naloxone group). Pigs were acclimatised and provided with environmental enrichments. Anaesthesia was induced with isoflurane (IsoFlo vet 100%, Zoetis) vaporized in 100% oxygen administered by a facemask (Midmark), endotracheally intubated and mechanically ventilated. To achieve an equal anaesthetic depth of all pigs, end- tidal isoflurane (ET-iso) was individually titrated to the lowest possible concentration 42.192.163792/01 which resulted in absence of spontaneous movement but maintained the cornea reflex. A peripheral venous catheter was placed in the lateral auricular vein. After maintenance of a baseline (post-instrumentation) anaesthetised pigs were administered fentanyl at 7.5 µg kg^-1 hour^-1 for 46 minutes intravenously, followed by injection of naloxone 0.1 mg/kg or ketanserin 1 mg/kg intravenously for one minute. The experiment was video recorded. To record motor activity an accelerometer (Hioki 8430-20 Memory Hilogger) attached to the neck recorded movement continuously and electromyography (EMG) was used to record motor activity from motor units around a concentric needle electrode. Acceleration was quantified as an average rectified mean value (ARV) for every 10 seconds. EMG data was quantified as RMS (µV) from the recorded channels. Data was extracted from baseline, at the end of the fentanyl infusion, and three minutes after antagonist injection from each pig. The difference in acceleration (ARV) and EMG activity (RMS) were calculated. Using an alpha of 5% the change in acceleration and motor unit activity within groups between these time points were tested by Wilcoxon Signed-Rank tests. Data are reported as median (interquartile range). Results At baseline, acceleration was 0.128 m/s² and increased significantly (p = 0.0034) to 0.254 m/s² after fentanyl infusion accompanied by visually evident shivering and/or tremors. Ketanserin significantly (p = 0.0313) reduced acceleration to 0.129 m/s², and abolished shivering/tremors. Naloxone gave a non-significant (p = 0.437) reduction of acceleration to 0.165 m/s², and reduced shivering/tremors in four, while increased shivering/tremors in two, pigs. The results are summarised in Table 2 below and shown in Figure 2. 42.192.163792/01 Table 2 Movement (acceleration, m/s2), Shivering/tremors median Baseline 0.128 (0.097-0.224) None After fentanyl 0.252 (0.113-0.564) Observed administration Following 0.129 (0.097-0.230) None ketanserin Following 0.165 (0.156-0.383) Some reduced, naloxone some increased Pigs had a baseline RMS (µV) EMG activity of median (interquartile range) 6.8 (3.3- 55.1) µV which was significantly (p = 0.001) increased to 25.7 (3.8-153) µV under fentanyl influence. Injection of ketanserin significantly (p = 0.0313) decreased RMS (µV) EMG activity to median (interquartile range) 4.3 (3.5 - 6.2) µV. RMS (µV) EMG activity after naloxone injection was 7.2 (3.7-18.6), the reduction was not statistically significant (p = 0.156). Spontaneous EMG RMS (µV) are shown in Figure 3 for the two groups. Although not quantified, muscle rigidity was also observed following fentanyl administration. Naloxone did not reverse this rigidity whereas pigs treated with ketanserin did not display muscle rigidity and had a calm and quiet recovery. Conclusion Fentanyl induced motor activity with visually evident shivering/tremors in pigs under isoflurane anaesthesia. Ketanserin abolished motor activity (including shivering/tremors) in pigs. However, naloxone did not significantly reverse the induced motor activity. Example 3: Ketanserin and naloxone reverses vocal cord closure (VCC) in a rat fentanyl- overdose study In this experiment, the synergistic potential of ketanserin and naloxone on VCC in rats was investigated. The hypothesis was that ketanserin would relax laryngeal musculature, resulting in the opening of the glottis to improve fentanyl-induced VCC compared to saline-controls. In addition, it was hypothesised that this could enable the effect of naloxone on respiration to increase survival. 42.192.163792/01 Material and methods: A blinded, prospective, randomized four-group study was designed and 62 male Sprague-Dawley rats (Janvier Labs, France) were allocated into independent groups by a person not involved in the experiment. They were between 8-10 weeks when included in the study and allowed 1 week of acclimatization from arrival until the experiment started. α-chloralose (25 g, C0128, Sigma-Aldrich) was prepared twice a week as an anaesthetic agent. Before use, it was filtered through a sterile filter (Millex GS filter unit 22 µm, Merck Millipore, Germany). Ketanserin tartrate (Tocris Bioscience) was dissolved in sterile water (Sterile Water, Fresenius Kabi) by gentle heating to 60°C and rapid stirring. To obtain an isotonic solution, it was further diluted with hypertonic saline (Hypertonic saline 7.2%, Covetrus) to a solution of 1.0 mg/ml ketanserin. Aliquots of 2 ml were prepared and placed at -20°C until used. When used on the experimental day it was thawed by gentle warming and gentle shaking. Test drugs were prepared on the morning of the experimental day by a person not involved in the experimental procedure. Based on group allocation, injections were prepared by personnel not involved in the experiment according to Table 3 in pre- marked syringes with injection number and rat number. Injections 1 and 3 were placed in a sealed plastic bag labelled with the correct rat number, while injection 2 was placed in a separate plastic bag with the rat number, and then in a water bath that was kept at 60^oC. Treatment groups consisted of a saline control group (Sal-Sal-Sal), a fentanyl- saline control group (Fen-Sal-Sal), a fentanyl-ketanserin monotherapy group (Fen- Ket-Sal), and a dual therapy group with Fentanyl-Ketanserin-Naloxone (Fen-Ket- Nal). 42.192.163792/01 Table 3: Illustrates the experimental groups and their respective injections. n= number of animals. Group n Injection 1 Injection 2 Injection 3 Sal-Sal-Sal 8 Saline in Saline in equivalent Saline in equivalent volume volume as for equivalent volume as for fentanyl 25 ketanserin 2 mg/kg as for naloxone 2 µg/kg mg/kg Fen-Sal- 18 Fentanyl 25 µg/kg Saline in equivalent Saline in Sal volume as for equivalent volume ketanserin 2 mg/kg as for naloxone 2 mg/kg Fen-Ket- 18 Fentanyl 25 µg/kg Ketanserin 2 mg/kg Saline in Sal equivalent volume as for naloxone 2 mg/kg Fen-Ket- 18 Fentanyl 25 µg/kg Ketanserin 2 mg/kg Naloxone 2 mg/kg Nal Each rat was transported into the experimental room in a rodent cage where anaesthesia was induced with isoflurane (Fuxien vet., 1000 mg/g, Vetpharma Animal Health, Barcelona, Spain) vaporized in oxygen at 5% until the animal reached a recumbent position with a SomnoSuite Small Animal Anaesthesia machine (Kent Scientific, Torrington, Connecticut). The rat was positioned on its back on a rodent surgical table (SurgiSuite, Kent Scientific), and anaesthesia was maintained with isoflurane in 100% oxygen through a nose cone (Low profile Anaesthesia Mask, large, Kent Scientific) and a non-rebreathing system. Then the rat was attached to monitoring equipment that belonged to the SomnoSuite system, with a pulsoxymeter, a rectal temperature probe and a CODA Non-invasive Blood Pressure Monitor (Kent Scientific) on the tail. Vascular access was established in one of the femoral veins with a 26 G over-the- needle catheter (IV Catheter small wings 0.6x19 mm, Vetnordic, Denmark). A prefilled infusion set (Alaris product, 209 cm 4.3 ml, BD) was attached and an infusion with α-chloralose (5 mg/ml) was initiated with a 10 ml syringe (Omnifix Luer solo, Braun, Germany) and a syringe driver (Alaris Guardrails plus, CareFusion). To transition from maintaining anaesthesia with isoflurane to total intravenous anaesthesia (TIVA), α-chloralose was infused at a rate of 120 mg kg^-1 hour^-1 over 20 to 30 minutes to a maximum dosage of 60 mg/kg. Isoflurane was titrated down while keeping track of respiratory rate and heart rate, muscle tone, palpebral and cornea reflexes, and the withdrawal reflex to pinching the toes with anatomic 42.192.163792/01 forceps, until the rat had no spontaneous movement and a weak response to toe pinch. α-chloralose was continued until the rat had a relaxed muscle tone, absent palpebral reflex, but intact cornea reflex, and a present, but sluggish response to toe pinch. There was a minimum 10-minute equilibration period from turning of isoflurane until the start of baseline. Oxygen was withdrawn at least five minutes before injection of fentanyl. Experimental timeline: An oropharyngeal intubation wedge, made from the barrel of a 0.5 ml insulin syringe (U100, 0.33x12 mm, Vetnordic) cut into 7.0 cm with a 45° angle, was positioned in the mouth of the rat to allow displacement of the tongue and epiglottis and full visualization of the laryngeal opening. An endoscope (1.9 mm, NanoScope, Arthrex) was placed within the wedge, and video images of the larynx transferred to the monitor (Nanoscope consol, Arthrex). In the case of saliva obscuring the image, a syringe with a MILA 16 G intravenous catheter (Equivet HiFlow, 16 Gx7.6 cm) was used as suction to clear saliva from the pharyngeal cavity. When a clear image was retrieved of the larynx, a 30-second baseline recording was initiated followed by injection 1 and flushed by 0.3 ml saline (Natriumklorid 9 mg/ml, B.Braun) over 6 seconds. This was immediately followed by injection 2 over 10 seconds, and injection 3 over 20 seconds, finished with a 0.3 ml saline flush. Respiration was set as present or apnoeic, and patency of the glottic opening was scored as open or closed, at 30 seconds (0:30), 50 seconds (0:50), 1 minute and 30 seconds (1:30), 2 minutes (2:00), and 2 minutes and 30 seconds (2:30) after injection 1. Three minutes after injection one, the experimental outcome could be either 1) no resolution of VCC and immediate euthanasia, 2) partial or complete resolution of VCC and regained spontaneous ventilation, in which case the experiment was continued for another five minutes, or 3) partial or complete resolution of VCC, but the animal remained apnoeic, rendering it to immediate euthanasia. Euthanasia was performed by decapitation with a guillotine (Nemi Scientific, Braintree Scientific Inc.). The experimental timeline is illustrated in Figure 4. Retrospective analysis of the videos of the larynx was performed by a blinded investigator who was not involved in the experiment. The total duration of VCC (seconds) was measured. VCC was defined as a sustained closure of the glottic opening for 10 seconds. 42.192.163792/01 To evaluate the effect of ketanserin or saline on laryngeal musculature a second blinded analysis of the videos was performed in which the relative glottic diameter was calculated from baseline (25-30 seconds) and after antagonist injection (55-65 seconds) for the two groups; Fen-Sal-Sal and Fen-Ket-Sal for the rats that had VCC within the time frame 30-50 seconds, and an opening within the time frame 55-65 seconds (n =11 ketanserin, n=10 saline group). A relative glottic diameter was obtained by measuring the diameter of the glottic opening divided by the diameter of epiglottis. Then the differences in the diameter from baseline to after injection of either saline or ketanserin were calculated. Data followed normal distribution, and the differences in means were compared with a t- test. Results: Survival Survival (outcome 2) was 94% in the ketanserin-naloxone (Fen-Ket-Nal) treatment group, which was statistically significantly (p<0.0001) higher than the control groups receiving either saline (Fen-Sal-Sal) or ketanserin monotherapy (Fen-Ket-Sal) after fentanyl. There was no statistical difference in survival between the ketanserin monotherapy and saline group (p=0.1025). No rats in the saline control group (Sal- Sal-Sal) developed VCC. Survival (outcome 2) in the groups that received fentanyl overdose is illustrated in Figure 5. Statistical analyses were performed with a Chi- Square test (p (Prob> χ², likelihood ratio)). Glottis opening Rats that received ketanserin-naloxone had a significantly (p<0.0001) increased chance of an opened glottis post-antagonist injection at the time points 0:50, 1:30, 2:00, and 2:30 post fentanyl injection compared to saline or ketanserin alone (Tables 4 and 5). Glottic diameter The difference in relative glottic opening from baseline after fentanyl and antagonist injection was significantly lower in the rats that received ketanserin relative to those that received saline (p = 0.0344). With a mean difference in glottic opening of 42.192.163792/01 -0.134 for the ketanserin group (Fen-Ket-Sal) and -0.233 for the saline group (Fen- Sal-Sal). This is illustrated in Figure 7. Table 4: Vocal cord opening at pre-set time points after fentanyl injections in the treatment groups that received ketanserin only (Fen-Ket-Sal) or ketanserin and naloxone (Fen-Ket-Nal) post fentanyl. χ² analysis was performed to test for differences in response between groups. n = number of animals that display the response. Time 0:10 0:50 1:30 2:00 2:30 post fentanyl (min) Vocal Closed Open Closed Open Closed Open Closed Open Closed Open cord n n n n n n n n n n opening Fen-Ket- 18 0 11 7 5 13 0 18 1 17 Sal Fen-Ket- 16 2 0 18 0 18 0 18 0 18 Nal p (Prob> p =0.1871 *** *** *** *** χ², p<0.0001 p<0.0001 p<0.0001 p<0.0001 likelihood ratio) Table 5: Vocal cord opening at pre-set time points after fentanyl injections in the treatment groups that received saline only (Fen-Sal-Sal) or ketanserin and naloxone (Fen-Ket-Nal) post-fentanyl. χ² analysis was performed to test for differences in response between groups. n = number of animals that display the response. Time 0:10 0:50 1:30 2:00 2:30 post fentanyl (min) Vocal Closed Open Closed Open Closed Open Closed Open Closed Open cord n n n n n n n n n n opening Fen-Ket- 16 2 0 18 0 18 0 18 0 18 Nal Fen-Sal- 16 2 10 8 12 6 2 16 0 18 Sal p (Prob> p =1.0000 *** *** *** *** χ², p=0.0001 p<0.0001 p<0.0001 p<0.0001 likelihood ratio) 42.192.163792/01 Rats that received ketanserin monotherapy after fentanyl injection had an increased chance of earlier glottis reopening than control rats that received saline (as observed at 1:30 in Table 6, p = 0.0102). Table 6: Vocal cord opening at pre-set time points after fentanyl injections in the treatment groups that received ketanserin only (Fen-Ket-Sal) or saline only (Fen- Sal-Sal) post-fentanyl. χ² analysis was performed to test for differences in response between groups. n = number of animals that display the response. Time 0:10 0:50 1:30 2:00 2:30 post fentanyl (min Vocal Closed Open Closed Open Closed Open Closed Open Closed Open cord n n n n n n n n n opening n Fen-Ket- 18 0 11 7 5 13 0 18 1 17 Sal Fen-Sal- 16 2 10 8 12 6 2 16 0 18 Sal p (Prob> p =0.1871 p = 0.9396 * p = 0.2328 p = 0.2396 χ², p = 0.0102 likelihood ratio) The duration (seconds) of VCC was statistically significantly (p<0.0001) shorter for the dual therapy group receiving ketanserin and naloxone as compared to the saline and ketanserin monotherapy groups, respectively. Statistical analysis was performed with Kruskal-Wallis test with Dunns’ multiple comparisons test, alpha was set at 0.05. There was no statistical difference between the saline and ketanserin monotherapy groups in duration of VCC (Figure 6). Conclusion: Combination therapy with ketanserin and naloxone increased the survival rate for fentanyl-induced overdose in rats from 0% with naloxone monotherapy as reported in a previous study (Miner et al., 2021, Drug Alc. Depend., 227, 108974, using fentanyl at 25 and 50 µg/kg and naloxone at 1 and 2 mg/kg) to 94% as reported here. The combination therapy resolved VCC and restored respiration. Ketanserin alone gave an earlier reopening of glottis than observed for a control group receiving saline, however, did not increase survival in this study. The trend towards lower survival with ketanserin monotherapy was not statistically significant. It is hypothesized that this may reflect the use of rats as the subject as they are likely to 42.192.163792/01 be more vulnerable during temporary hypotension caused by ketanserin combined with fentanyl induced apnoea. The earlier resolution of ketanserin on vocal cord opening relative to use of saline and the significant effect of ketanserin relative to saline on the glottic diameter after fentanyl induced VCC in the rats suggests an effect of ketanserin on laryngeal muscle rigidity. The combined effect on survival by using ketanserin and naloxone in this study suggest that ketanserin significantly potentiates survival after fentanyl- overdose, possibly due to muscle rigidity resolutions in line with Examples 1 and 2.

Claims

42.192.163792/01 Claims 1. A method of treating one or more side effects resulting from µ-opioid receptor agonist overdose in a subject by administering a serotonin 5HT_2A receptor antagonist after administration or ingestion of said µ-opioid receptor agonist, wherein serotonin 5HT_2A receptor antagonist is a compound with the formula II or IIa:

wherein, R1 is an oxygen atom (oxo group), sulphur atom (thione group) or a C1-C3 alkyl group; R₂ is a halogen atom, preferably F or Cl; and X and/or Y is a carbon or nitrogen atom, or a pharmaceutically acceptable salt thereof. 2. The method as claimed in claim 1, wherein said µ-opioid receptor agonist is a compound with the formula I:

42.192.163792/01

wherein, R₁ is a cyclic group, preferably a 5- or 6-membered ring, preferably an aryl group (e.g. a phenyl group) or a heterocyclic group (e.g. a thienyl, pyrrolyl, tetrazolyl or furanyl group), wherein said cyclic group may be substituted e.g. by an alkyl (e.g. a C₁-C₃ alkyl group) and/or an oxo group, or R₁ is -COOCH₃; R₂ and R₃ are each a hydrogen atom, a hydroxy group or a C₁-C₃ alkyl group, e.g. a methyl group; or R₁ and R₂ together with the carbon atom to which they are bound form an aryl group, preferably a phenyl group; R4, where present, is a C1-C3 alkyl group, e.g. a methyl group; R5 is a hydrogen atom, -CH2OCH3, or -COOCH3; R₆ is a -COR₇ group or a hydrogen atom, wherein R₇ is a C₁-C₄ alkyl, C₃-C₄ cycloalkyl or C₁-C₄ alkenyl group, optionally interrupted by an oxygen atom (e.g. -CH₃, -CH₂CH₃, -CH₂CH₂CH₃, -CH=CH₂, -CH(CH₃) ₂, -CH(CH₂) ₂, -CH₂CH₂CH₂CH₃ or -CH2OCH3 ) or a phenyl, furanyl, tetrahydrofuranyl or thienyl group; and R8, where present, is a halogen atom, e.g. F or Cl, or an -OCH3 group, or a pharmaceutically acceptable salt thereof. 3. The method as claimed in claim 2, wherein said µ-opioid receptor agonist is selected from i) fentanyl (R1 = phenyl group; R2 = H; R3 = H; R4 = absent; R5 = H; R6 =

42.192.163792/01 -COR₇; R₇ = -CH₂CH₃; R₈ = absent), ii) alfentanil (R₁ = oxo- and C₂ alkyl- substituted tetrazolyl group; R₂ = H; R₃ = H; R₄ = absent; R₅ = -CH₂OCH₃; R₆ = -COR₇; R₇ = -CH₂CH₃; R₈ = absent), iii) sufentanil (R₁ = thienyl group; R₂ = H; R₃ = H; R₄ = absent; R₅ = -CH₂OCH₃; R₆ = -COR₇; R₇ = -CH₂CH₃; R₈ = absent), iv) remifentanil (R₁ = is -COOCH₃; R₂ = H; R₃ = H; R₄ = absent; R₅ = -COOCH₃; R₆ = -COR₇; R₇ = -CH₂CH₃; R₈ = absent), v) carfentanil (R₁ = phenyl; R₂ = H; R₃ = H; R₄ = absent; R₅ = -COOCH₃; R₆ = - COR₇; R₇ = -CH₂CH₃; R₈ = absent), vi) acetylfentanyl (R₁ = phenyl group; R₂ = H; R₃ = H; R₄ = absent; R₅ = H; R₆ = -COR₇; R₇ = -CH₃; R₈ = absent), and vii) furanylfentanyl (R₁ = phenyl group; R₂ = H; R₃ = H; R₄ = absent; R₅ = H; R₆ = -COR₇; R₇ = furanyl; R₈ = absent). 4. The method as claimed in any one of claims 1 to 3, wherein said serotonin 5HT2A receptor antagonist is ketanserin (R1 = oxygen (oxo group), R2 = F, X = carbon, Y = nitrogen), altanserin (R1 = sulphur (thione group), R2 = F, X = carbon, Y = nitrogen) or pirenperone (R1 = -CH3, R2 = F, X = nitrogen, Y = carbon). 5. The method as claimed in any one of claims 1 to 4, wherein said side effect is selected from muscle rigidity, wooden chest syndrome, laryngospasm, seizures, myoclonus, tremors, shivering and cyanosis, preferably laryngospasm. 6. The method as claimed in any one of claims 1 to 5, wherein said serotonin 5HT2A receptor antagonist is co-administered with naloxone. 7. The method as claimed in any one of claims 1 to 6, wherein said serotonin 5HT2A receptor antagonist, and optionally said naloxone, is administered nasally, intramuscularly, intradermally, subcutaneously or intravenously. 8. The method as claimed in any one of claims 1 to 7, wherein said serotonin 5HT2A receptor antagonist is administered at total dose of 0.01 to 10 mg/kg in said subject, preferably 0.1 – 1 mg/kg.

42.192.163792/01 9. The method as claimed in any one of claims 6 to 8, wherein said naloxone is administered at a total dose of 0.005 to 0.5 mg/kg in said subject. 10. The method as claimed in any one of claims 1 to 9, wherein the subject is a human. 11. The method as claimed in any one of claims 1 to 10, wherein said overdose results in a blood serum concentration of said µ-opioid receptor agonist of at least 1 ng/ml, wherein preferably said µ-opioid receptor agonist is fentanyl. 12. The method as claimed in any one of claims 1 to 11, wherein said µ-opioid receptor agonist is administered by sufflation (e.g. nasally), ophthalmically, transdermally, orally or by injection or smoking. 13. The method as claimed in any one of claims 1 to 12, wherein said serotonin 5HT2A receptor antagonist is administered within 30 minutes of administration or ingestion of said µ-opioid receptor agonist. 14. A serotonin 5HT2A receptor antagonist for use in treating one or more side effects resulting from µ-opioid receptor agonist overdose in a subject, wherein said serotonin 5HT2A receptor antagonist is to be administered after administration or ingestion of said µ-opioid receptor agonist, and said serotonin 5HT2A receptor antagonist is a compound with the formula II or IIa as defined in claim 1, wherein preferably i) said µ-opioid receptor agonist is as defined in claim 2 or 3; ii) said serotonin 5HT2A receptor antagonist is as defined in claim 4; iii) said side effects are as defined in claim 5; iv) said serotonin 5HT2A receptor antagonist is to be administered as defined in claim 7, 8 or 13; v) said subject is as defined in claim 10; vi) said µ-opioid receptor agonist achieves a blood serum concentration as defined in claim 11; and/or vii) said µ-opioid receptor agonist is to be administered as defined in claim 12.

42.192.163792/01 15. The serotonin 5HT_2A receptor antagonist for use as claimed in claim 14, wherein said serotonin 5HT_2A receptor antagonist is co-administered with naloxone, wherein preferably said naloxone is administered as defined in claim 7 or 9. 16. Use of a serotonin 5HT_2A receptor antagonist in the preparation of a medicament for treating one or more side effects resulting from µ-opioid receptor agonist overdose in a subject, wherein said serotonin 5HT_2A receptor antagonist is to be administered after administration or ingestion of said µ-opioid receptor agonist, and said serotonin 5HT_2A receptor antagonist is a compound with the formula II or IIa as defined in claim 1, wherein preferably i) said µ-opioid receptor agonist is as defined in claim 2 or 3; ii) said serotonin 5HT_2A receptor antagonist is as defined in claim 4; iii) said side effects are as defined in claim 5; iv) said serotonin 5HT_2A receptor antagonist is to be administered as defined in claim 7, 8 or 13; v) said subject is as defined in claim 10; vi) said µ-opioid receptor agonist achieves a blood serum concentration as defined in claim 11; and/or vii) said µ-opioid receptor agonist is to be administered as defined in claim 12. 17. The use as claimed in claim 16, wherein said medicament is co- administered with naloxone, wherein preferably said naloxone is to be administered as defined in claim 7 or 9. 18. A pharmaceutical composition comprising a serotonin 5HT2A receptor antagonist and naloxone and one or more pharmaceutically acceptable diluents, carriers or excipients, wherein said serotonin 5HT2A receptor antagonist is a compound with the formula II or IIa as defined in claim 1, wherein preferably said serotonin 5HT2A receptor antagonist is as defined in claim 4. 19. The pharmaceutical composition as claimed in claim 18, wherein said composition is suitable for nasal or intramuscular administration. 20. The pharmaceutical composition as defined in claim 18 or 19 for use in therapy.

42.192.163792/01 21. The pharmaceutical composition as defined in claim 18 or 19 for use in treating one or more side effects resulting from µ-opioid receptor agonist overdose in a subject, wherein said serotonin 5HT_2A receptor antagonist is to be administered after administration or ingestion of said µ-opioid receptor agonist, wherein preferably i) said µ-opioid receptor agonist is as defined in claim 2 or 3; ii) said side effects are as defined in claim 5; iii) said serotonin 5HT_2A receptor antagonist is to be administered as defined in claim 7, 8 or 13; iv) said subject is as defined in claim 10; v) said µ-opioid receptor agonist achieves a blood serum concentration as defined in claim 11; vi) said µ-opioid receptor agonist is to be administered as defined in claim 12; and/or vii) said naloxone is to be administered as defined in claim 7 or 9. 22. A product comprising a serotonin 5HT2A receptor antagonist and naloxone as a combined preparation for simultaneous, separate or sequential use in treating one or more side effects resulting from µ-opioid receptor agonist overdose in a subject, wherein said serotonin 5HT2A receptor antagonist is to be administered after administration or ingestion of said µ-opioid receptor agonist, and said serotonin 5HT2A receptor antagonist is a compound with the formula II or IIa as defined in claim 1, wherein preferably i) said µ-opioid receptor agonist is as defined in claim 2 or 3; ii) said serotonin 5HT2A receptor antagonist is as defined in claim 4; iii) said side effects are as defined in claim 5; iv) said serotonin 5HT2A receptor antagonist is to be administered as defined in claim 7, 8 or 13; v) said subject is as defined in claim 10; vi) said µ-opioid receptor agonist achieves a blood serum concentration as defined in claim 11; viii) said µ-opioid receptor agonist is to be administered as defined in claim 12; and/or ix) said naloxone is to be administered as defined in claim 7 or 9.

42.192.163792/01 23. A kit for use in treating one or more side effects resulting from µ-opioid receptor agonist overdose in a subject, wherein said serotonin 5HT_2A receptor antagonist is to be administered after administration or ingestion of said µ-opioid receptor agonist, said kit comprising: a) a first container containing a serotonin 5HT_2A receptor antagonist which is a compound with the formula II or IIa as defined in claim 1; and b) a second container containing naloxone, wherein preferably i) said µ-opioid receptor agonist is as defined in claim 2 or 3; ii) said serotonin 5HT_2A receptor antagonist is as defined in claim 4; iii) said side effects are as defined in claim 5; iv) said serotonin 5HT_2A receptor antagonist is to be administered as defined in claim 7, 8 or 13; v) said subject is as defined in claim 10; vi) said µ-opioid receptor agonist achieves a blood serum concentration as defined in claim 11; x) said µ-opioid receptor agonist is to be administered as defined in claim 12; and/or xi) said naloxone is to be administered as defined in claim 7 or 9.