Apomorphine, sold under the brand name Apokyn among others, is a type of aporphine having activity as a non- selective

dopamine agonist A dopamine agonist is a compound that activates dopamine receptors. There are two families of dopamine receptors, D1-like and D2-like. They are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the D2-like ...

which activates both D₂-like and, to a much lesser extent, D₁-like receptors. It also acts as an

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.5-HT₂ and α-adrenergic receptors with high

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

. The compound is an alkaloid belonging to nymphaea caerulea, or blue lotus, but is also historically known as a

morphine Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...

decomposition product made by boiling morphine with concentrated acid, hence the ''-morphine'' suffix. Contrary to its name, apomorphine does not actually contain morphine or its skeleton, nor does it bind to

opioid receptor Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostati ...

s. The ''apo-'' prefix relates to it being a

derivative (" omesfrom morphine"). Historically, apomorphine has been tried for a variety of uses, including as a way to relieve anxiety and craving in alcoholics, an emetic (to induce vomiting), for treating stereotypies (repeated behaviour) in farmyard animals, and more recently in treating

erectile dysfunction Erectile dysfunction (ED), also referred to as impotence, is a form of sexual dysfunction in males characterized by the persistent or recurring inability to achieve or maintain a Human penis, penile erection with sufficient rigidity and durat ...

. Currently, apomorphine is used in the treatment of

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

. It is a potent

emetic Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, preg ...

and should not be administered without an

antiemetic An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may ...

such as

domperidone Domperidone, sold under the brand name Motilium among others, is a dopamine antagonist medication which is used to treat nausea and vomiting and certain gastrointestinal problems like gastroparesis (delayed gastric emptying). It raises the ...

. The emetic properties of apomorphine are exploited in veterinary medicine to induce therapeutic

emesis Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pregna ...

in canines that have recently ingested toxic or foreign substances. Apomorphine was also used as a private treatment of heroin addiction, a purpose for which it was championed by the author

William S. Burroughs William Seward Burroughs II (; February 5, 1914 – August 2, 1997) was an American writer and visual artist. He is widely considered a primary figure of the Beat Generation and a major Postmodern literature, postmodern author who influen ...

. Burroughs and others claimed that it was a "metabolic regulator" with a restorative dimension to a damaged or dysfunctional dopaminergic system. Despite anecdotal evidence that this offers a plausible route to an abstinence-based mode, no clinical trials have ever tested this hypothesis. A recent study indicates that apomorphine might be a suitable marker for assessing central

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

system alterations associated with chronic heroin consumption. There is, however, no clinical evidence that apomorphine is an effective and safe treatment regimen for opiate addiction.

Medical uses

Parkinson's disease

The use of apomorphine to treat "the shakes" was first suggested by Weil in France in 1884, although seemingly not pursued until 1951. Its clinical use was first reported in 1970 by Cotzias et al., although its emetic properties and short half-life made oral use impractical. A later study found that combining the drug with the

improved results significantly. The commercialization of apomorphine for Parkinson's disease followed its successful use in patients with refractory motor fluctuations using intermittent rescue injections and continuous infusions. Apomorphine is used in advanced

intermittent hypomobility ("off" episodes), where a decreased response to an anti-Parkinson drug such as L-DOPA causes muscle stiffness and loss of muscle control. While apomorphine can be used in combination with L-DOPA, the intention is usually to reduce the L-DOPA dosing, as by this stage the patient often has many of

dyskinesia Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Dyskinesia can be anything from a slight tremor of t ...

s caused by L-DOPA and hypermobility periods. When an episode sets in, the apomorphine is injected subcutaneously or applied sublingually, and signs subside. It is used an average of three times a day. Some people use portable mini-pumps that continuously infuse them with apomorphine, allowing them to stay in the "on" state and using apomorphine as an effective monotherapy.

Alzheimer's disease

Apomorphine is reported to be an inhibitor of

amyloid beta Amyloid beta (Aβ, Abeta or beta-amyloid) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor prot ...

protein fiber formation, whose presence is a hallmark of

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

. Thus apomorphine is a potential therapeutic under the amyloid hypothesis. While it promotes

oligomerization In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relativ ...

of the Aβ40 group of molecules, it inhibits more advanced fibril formation; this is thought to be due to the autoxidation that occurs at the

hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...

groups. Once this functional group was altered, the inhibitory effect could be seen to decrease, reducing either the indirect or direct interference of the fibril formation. The protective effects of apomorphine were tested in mouse models with mutations in genes related to AD, such as the

amyloid precursor protein Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many biological tissue, tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of s ...

gene. Apomorphine was seen to significantly improve memory function through the increased successful completion of the Morris Water Maze. The levels of the aberrant proteins that lead to neuronal disruption were also tested in the brains of mice. Treatment was seen to decrease the intraneuronal levels of the more aggressive Aβ42 molecule when compared to the control mice. This result is consistent with the finding that another protein linked to AD,

tau protein The tau proteins (abbreviated from tubulin associated unit) form a group of six highly soluble protein isoforms produced by alternative splicing from the gene ''MAPT'' (microtubule-associated protein tau). They have roles primarily in maintainin ...

, was seen to decrease with apomorphine treatment.

Contraindications

The main and absolute contraindication to using apomorphine is the concurrent use of

adrenergic receptor The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like b ...

antagonists; combined, they cause a severe drop in blood pressure and

fainting Syncope , commonly known as fainting or passing out, is a loss of consciousness and muscle strength characterized by a fast onset, short duration, and spontaneous recovery. It is caused by a decrease in blood flow to the brain, typically from ...

Alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

causes an increased frequency of

orthostatic hypotension Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when they are standing up ( orthostasis) or sitting down. Primary orthostatic hypotension is also often referred to as ne ...

(a sudden drop in blood pressure when getting up), and can also increase the chances of

pneumonia Pneumonia is an Inflammation, inflammatory condition of the lung primarily affecting the small air sacs known as Pulmonary alveolus, alveoli. Symptoms typically include some combination of Cough#Classification, productive or dry cough, ches ...

and

heart attacks A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom is retr ...

Dopamine antagonists A dopamine antagonist, also known as an anti-dopaminergic and a dopamine receptor antagonist (DRA), is a type of Pharmaceutical drug, drug which blocks dopamine receptors by receptor antagonism. Most antipsychotics are dopamine antagonists, and ...

, by their nature of competing for sites at dopamine receptors, reduce the effectiveness of the agonistic apomorphine. IV administration of apomorphine is highly discouraged, as it can crystallize in the veins and create a blood clot (

thrombus A thrombus ( thrombi) is a solid or semisolid aggregate from constituents of the blood (platelets, fibrin, red blood cells, white blood cells) within the circulatory system during life. A blood clot is the final product of the blood coagulatio ...

) and block a pulmonary artery (

pulmonary embolism Pulmonary embolism (PE) is a blockage of an pulmonary artery, artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include dyspnea, shortness of breath, chest pain ...

Side effects

Nausea and vomiting are common side effects when first beginning therapy with apomorphine; antiemetics such as trimethobenzamide or domperidone, dopamine antagonists, are often used while first starting apomorphine. Around 50% of people grow tolerant enough to apomorphine's emetic effects that they can discontinue the antiemetic. Other side effects include orthostatic hypotension and resultant fainting,

sleepiness Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

, runny nose,

sweating Perspiration, also known as sweat, is the fluid secreted by sweat glands in the skin of mammals. Two types of sweat glands can be found in humans: eccrine glands and apocrine glands. The eccrine sweat glands are distributed over much of the ...

, paleness, and flushing. More serious side effects include dyskinesias (especially when taking L-DOPA), fluid accumulation in the limbs (

edema Edema (American English), also spelled oedema (British English), and also known as fluid retention, swelling, dropsy and hydropsy, is the build-up of fluid in the body's tissue (biology), tissue. Most commonly, the legs or arms are affected. S ...

), suddenly falling asleep,

confusion In psychology, confusion is the quality or emotional state of being bewildered or unclear. The term "acute mental confusion"

and

hallucinations A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...

, increased heart rate and heart palpitations, and persistent erections ( priapism). The priapism is caused by apomorphine increasing arterial blood supply to the

penis A penis (; : penises or penes) is a sex organ through which male and hermaphrodite animals expel semen during copulation (zoology), copulation, and through which male placental mammals and marsupials also Urination, urinate. The term ''pen ...

. This side effect has been exploited in studies attempting to treat

Pharmacology

Mechanism of action

Apomorphine's R-enantiomer is an

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of both D₁ and D₂ dopamine receptors, with higher activity at D₂. The members of the D₂ subfamily, consisting of D₂, D₃, and D₄ receptors, are inhibitory

G protein–coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...

s. The D₄ receptor in particular is an important target in the signaling pathway, and is connected to several neurological disorders. Shortage or excess of dopamine can prevent proper function and signaling of these receptors leading to disease states. Apomorphine improves motor function by activating dopamine receptors in the

nigrostriatal pathway The nigrostriatal pathway is a bilateral dopaminergic pathway in the brain that connects the substantia nigra pars compacta (SNc) in the midbrain with the dorsal striatum (i.e., the caudate nucleus and putamen) in the forebrain. It is one of th ...

, the

limbic system The limbic system, also known as the paleomammalian cortex, is a set of brain structures located on both sides of the thalamus, immediately beneath the medial temporal lobe of the cerebrum primarily in the forebrain.Schacter, Daniel L. 2012. ''P ...

, the

hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...

, and the

pituitary gland The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the human brain, brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus contr ...

. It also increases blood flow to the

supplementary motor area The supplementary motor area (SMA) is a part of the motor cortex of primates that contributes to the control of movement. It is located on the midline surface of the hemisphere just in front of (anterior to) the primary motor cortex leg representa ...

and to the

dorsolateral prefrontal cortex The dorsolateral prefrontal cortex (DLPFC or DL-PFC) is an area in the prefrontal cortex of the primate brain. It is one of the most recently derived parts of the human brain. It undergoes a prolonged period of maturation which lasts into adulthoo ...

(stimulation of which has been found to reduce the

tardive dyskinesia Tardive dyskinesia (TD) is an iatrogenic disorder that results in involuntary repetitive body movements, which may include grimacing, sticking out the tongue or smacking the lips, which occurs following treatment with medication. Additional mo ...

effects of L-DOPA). Parkinson's has also been found to have excess

iron Iron is a chemical element; it has symbol Fe () and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, forming much of Earth's o ...

at the sites of neurodegeneration; both the (''R'')- and (''S'')-enantiomers of apomorphine are potent iron chelators and radical scavengers. Apomorphine also decreases the breakdown of dopamine in the brain (though it inhibits its synthesis as well). It is an upregulator of certain neural growth factors, in particular NGF but not

BDNF Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the cano ...

epigenetic In biology, epigenetics is the study of changes in gene expression that happen without changes to the DNA sequence. The Greek prefix ''epi-'' (ἐπι- "over, outside of, around") in ''epigenetics'' implies features that are "on top of" or "in ...

downregulation of which has been associated with addictive behaviour in rats. Apomorphine causes vomiting by acting on dopamine receptors in the chemoreceptor trigger zone of the medulla; this activates the nearby vomiting center.

Pharmacokinetics

While apomorphine has lower

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

when taken orally, due to not being absorbed well in the GI tract and undergoing heavy

first-pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the ...

, it has a bioavailability of 100% when given subcutaneously. It reaches peak plasma concentration in 10–60 minutes. Ten to twenty minutes after that, it reaches its peak concentration in the

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...

. Its lipophilic structure allows it to cross the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

. Apomorphine possesses

for the following

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

s (note that a ''higher'' ''K''_i indicates a ''lower'' affinity): Note: Values for humans are used. If there is more than one value listed for humans, their average is used. It has a ''K''_i of over 10,000 nM (and thus negligible affinity) for β-adrenergic, H₁, and

mACh The Mach number (M or Ma), often only Mach, (; ) is a dimensionless quantity in fluid dynamics representing the ratio of flow velocity past a Boundary (thermodynamic), boundary to the local speed of sound. It is named after the Austrian physi ...

. Apomorphine has a high

clearance rate In criminal justice, clearance rate is calculated by dividing the number of crimes that are "cleared", a criminal charge being laid, or convicted by the total number of crimes recorded. Various groups use clearance rates as a measure of crimes s ...

(3–5 L/kg/hr) and is mainly metabolized and excreted by the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

. It is likely that while the cytochrome P450 system plays a minor role, most of apomorphine's metabolism happens via auto-

oxidation Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...

, ''O''-glucuronidation, ''O''-methylation, ''N''-demethylation, and

sulfation Sulfation (sometimes spelled sulphation in British English) is the chemical reaction that entails the addition of SO3 group. In principle, many sulfations would involve reactions of sulfur trioxide (SO3). In practice, most sulfations are effected ...

. Only 3–4% of the apomorphine is excreted unchanged and into the urine. The

half-life Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''Half Life: ...

is 30–60 minutes, and the effects of the injection last for up to 90 minutes. Toxicity depends on the route of administration; the LD₅₀s in mice were 300 mg/kg for the oral route, 160 mg/kg for

intraperitoneal The peritoneum is the serous membrane forming the lining of the abdominal cavity or coelom in amniotes and some invertebrates, such as annelids. It covers most of the intra-abdominal (or coelomic) organs, and is composed of a layer of mesothe ...

, and 56 mg/kg intravenous.

Chemistry

Properties

Apomorphine has a

catechol Catechol ( or ), also known as pyrocatechol or 1,2-dihydroxybenzene, is an organic compound with the molecular formula . It is the ''ortho'' isomer of the three isomeric benzenediols. This colorless compound occurs naturally in trace amounts. It ...

structure similar to that of dopamine.

Synthesis

Several techniques exist for the creation of apomorphine from morphine. In the past,

had been combined with

hydrochloric acid Hydrochloric acid, also known as muriatic acid or spirits of salt, is an aqueous solution of hydrogen chloride (HCl). It is a colorless solution with a distinctive pungency, pungent smell. It is classified as a acid strength, strong acid. It is ...

at high temperatures (around 150 °C) to achieve a low yield of apomorphine, ranging anywhere from 0.6% to 46%. More recent techniques create the apomorphine in a similar fashion, by heating it in the presence of any acid that will promote the essential dehydration rearrangement of morphine-type

alkaloids Alkaloids are a broad class of naturally occurring organic compounds that contain at least one nitrogen atom. Some synthetic compounds of similar structure may also be termed alkaloids. Alkaloids are produced by a large variety of organisms i ...

, such as

phosphoric acid Phosphoric acid (orthophosphoric acid, monophosphoric acid or phosphoric(V) acid) is a colorless, odorless phosphorus-containing solid, and inorganic compound with the chemical formula . It is commonly encountered as an 85% aqueous solution, ...

. The method then deviates by including a water scavenger, which is essential to remove the water produced by the reaction that can react with the product and lead to decreased yield. The scavenger can be any reagent that will irreversibly react with water such as

phthalic anhydride Phthalic anhydride is the organic compound with the formula C6H4(CO)2O. It is the anhydride of phthalic acid. Phthalic anhydride is a principal commercial form of phthalic acid. It was the first anhydride of a dicarboxylic acid to be used commer ...

or titanium chloride. The temperature required for the reaction varies based upon choice of acid and water scavenger. The yield of this reaction is much higher: at least 55%. Morphine to Apomorphine

Historical medical uses

The pharmacological effects of the naturally-occurring analog aporphine in the blue lotus (''Nymphaea caerulea'') were known to the ancient Egyptians and Mayans, with the plant featuring in tomb frescoes and associated with entheogenic rites. It is also observed in Egyptian erotic cartoons, suggesting that they were aware of its erectogenic properties. The modern medical history of apomorphine begins with its synthesis by Arppe in 1845 from morphine and

sulfuric acid Sulfuric acid (American spelling and the preferred IUPAC name) or sulphuric acid (English in the Commonwealth of Nations, Commonwealth spelling), known in antiquity as oil of vitriol, is a mineral acid composed of the elements sulfur, oxygen, ...

, although it was named ''sulphomorphide'' at first. Matthiesen and Wright (1869) used hydrochloric acid instead of sulfuric acid in the process, naming the resulting compound ''apomorphine''. Initial interest in the compound was as an emetic, tested and confirmed safe by London doctor Samuel Gee, and for the treatment of stereotypies in farmyard animals. Key to the use of apomorphine as a behavioural modifier was the research of Erich Harnack, whose experiments in rabbits (which do not vomit) demonstrated that apomorphine had powerful effects on the activity of rabbits, inducing licking, gnawing and in very high doses convulsions and death.

Treatment of alcoholism

Apomorphine was one of the earliest used pharmacotherapies for

alcoholism Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World He ...

. The Keeley Cure (1870s to 1900) contained apomorphine, among other ingredients, but the first medical reports of its use for more than pure emesis come from James Tompkins and Charles Douglas. Tompkins reported, after injection of 6.5 mg ("one tenth of a grain"):Douglas saw two purposes for apomorphine:This use of small, continuous doses (1/30th of a grain, or 2.16 mg by Douglas) of apomorphine to reduce alcoholic craving comes some time before

Pavlov Pavlov (or its variant Pavliv) may refer to: People *Pavlov (surname) (fem. ''Pavlova''), a common Bulgarian and Russian last name *Ivan Pavlov, Russian physiologist famous for his experiments in classical conditioning Places Czech Republic *Pavlo ...

's discovery and publication of the idea of the "conditioned reflex" in 1903. This method was not limited to Douglas; the Irish doctor Francis Hare, who worked in a sanatorium outside London from 1905 onward, also used low-dose apomorphine as a treatment, describing it as "the most useful single drug in the therapeutics of inebriety". He wrote:He also noted there appeared to be a significant prejudice against the use of apomorphine, both from the associations of its name and doctors being reluctant to give hypodermic injections to alcoholics. In the US, the

Harrison Narcotics Tax Act The Harrison Narcotics Tax Act (Ch. 1, ) was a United States federal law that regulated and taxed the production, importation, and distribution of opiates and coca products. The act was proposed by Representative Francis Burton Harrison of Ne ...

made working with any morphine derivatives extremely hard, despite apomorphine itself not being an opiate. In the 1950s the neurotransmitter

was discovered in the brain by Katharine Montagu, and characterised as a neurotransmitter a year later by Arvid Carlsson, for which he would be awarded the Nobel Prize. A. N. Ernst then discovered in 1965 that apomorphine was a powerful stimulant of dopamine receptors. This, along with the use of sublingual apomorphine tablets, led to a renewed interest in the use of apomorphine as a treatment for alcoholism. A series of studies of non-emetic apomorphine in the treatment of alcoholism were published, with mostly positive results. However, there was little clinical consequence.

Aversion therapy

Aversion therapy Aversion therapy is a form of psychological treatment in which the patient is exposed to a stimulus while simultaneously being subjected to some form of discomfort. This conditioning is intended to cause the patient to associate the stimulus wit ...

in alcoholism had its roots in Russia in the early 1930s, with early papers by Pavlov, Galant and Sluchevsky and Friken, and would remain a strain in the Soviet treatment of alcoholism well into the 1980s. In the US a particularly notable devotee was Dr Voegtlin, who attempted aversion therapy using apomorphine in the mid to late 1930s. However, he found apomorphine less able to induce negative feelings in his subjects than the stronger and more unpleasant emetic emetine. In the UK, however, the publication of J. Y. Dent's (who later went on to treat Burroughs) 1934 paper "Apomorphine in the treatment of Anxiety States" laid out the main method by which apomorphine would be used to treat alcoholism in Britain. His method in that paper is clearly influenced by the then-novel idea of aversion:However, even in 1934 he was suspicious of the idea that the treatment was pure conditioned reflex – "though vomiting is one of the ways that apomorphine relives the patient, I do not believe it to be its main therapeutic effect." – and by 1948 he wrote:This led to his development of lower-dose and non-aversive methods, which would inspire a positive trial of his method in Switzerland by Dr Harry Feldmann and later scientific testing in the 1970s, some time after his death. However, the use of apomorphine in aversion therapy had escaped alcoholism, with its use to treat homosexuality leading to the death of a British Army Captain Billy Clegg Hill in 1962, helping to cement its reputation as a dangerous drug used primarily in archaic behavioural therapies.

Opioid addiction

In his ''Deposition: Testimony Concerning a Sickness'' in the introduction to later editions of ''

Naked Lunch ''Naked Lunch'' (first published as ''The Naked Lunch'') is a 1959 novel by American author William S. Burroughs. The novel does not follow a clear linear plot, but is instead structured as a series of non-chronological "routines". Many of thes ...

'' (first published in 1959),

wrote that apomorphine treatment was the only effective cure to opioid addiction he has encountered: He goes on to lament the fact that as of his writing, little to no research has been done on apomorphine or variations of the drug to study its effects on curing addiction, and perhaps the possibility of retaining the positive effects while removing the side effect of vomiting. Despite his claims throughout his life, Burroughs never really cured his addiction and was back to using opiates within years of his apomorphine "cure". However, he insisted on apomorphine's effectiveness in several works and interviews. There is renewed interest in the use of apomorphine to treat addiction, in both

smoking cessation Smoking cessation, usually called quitting smoking or stopping smoking, is the process of discontinuing tobacco smoking. Tobacco smoke contains nicotine, which is Addiction, addictive and can cause Substance dependence, dependence. As a resu ...

and alcoholism. As the drug is known to be reasonably safe for use in humans, it is a viable target for repurposing. Apomorphine has been researched as a possible treatment for erectile dysfunction and female hypoactive sexual desire disorder, though its efficacy has been limited. Nonetheless, it was under

development Development or developing may refer to: Arts *Development (music), the process by which thematic material is reshaped * Photographic development *Filmmaking, development phase, including finance and budgeting * Development hell, when a proje ...

as a treatment for

by TAP Pharmaceuticals under the brand name Uprima. In 2000, TAP withdrew its

new drug application The Food and Drug Administration's (FDA) New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. Some 30% or less of initial ...

after an FDA review panel raised questions about the drug's safety, due to many clinical trial subjects fainting after taking the drug.

Alternative administration routes

Two routes of administration are currently clinically utilized: subcutaneous (either as intermittent injections or continuous infusion) and sublingual. Other non-invasive administration routes were investigated as a substitute for parenteral administration, reaching different preclinical and clinical stages. These include: peroral, nasal, pulmonary, transdermal, rectal, and buccal, as well as iontophoresis methods.

Veterinary use

Apomorphine is used to inducing vomiting in

dogs The dog (''Canis familiaris'' or ''Canis lupus familiaris'') is a domesticated descendant of the gray wolf. Also called the domestic dog, it was selectively bred from a population of wolves during the Late Pleistocene by hunter-gatherers ...

after ingestion of various toxins or foreign bodies. It can be given subcutaneously, intramuscularly, intravenously, or, when a tablet is crushed, in the

conjunctiva In the anatomy of the eye, the conjunctiva (: conjunctivae) is a thin mucous membrane that lines the inside of the eyelids and covers the sclera (the white of the eye). It is composed of non-keratinized, stratified squamous epithelium with gobl ...

of the eye. The oral route is ineffective, as apomorphine cannot cross the blood–brain barrier fast enough, and blood levels don't reach a high enough concentration to stimulate the chemoreceptor trigger zone. It can remove around 40–60% of the contents in the stomach. One of the reasons apomorphine is a preferred drug is its reversibility: in cases of prolonged vomiting, the apomorphine can be reversed with dopamine antagonists like the

phenothiazines Phenothiazine, abbreviated PTZ, is an organic compound that has the formula S(C6H4)2NH and is related to the thiazine-class of heterocyclic compounds. Derivatives of phenothiazine are highly bioactive and have widespread use and rich history. ...

(for example, acepromazine). Giving apomorphine after giving acepromazine, however, will no longer stimulate vomiting, because apomorphine's target receptors are already occupied. An animal who undergoes severe

respiratory depression Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide (hypercapni ...

due to apomorphine can be treated with

naloxone Naloxone, sold under the brand name Narcan among others, is an opioid antagonist, a medication used to reverse or reduce the effects of opioids. For example, it is used to restore breathing after an opioid overdose. Effects begin within two ...

. Apomorphine does not work in

cats The cat (''Felis catus''), also referred to as the domestic cat or house cat, is a small domesticated carnivorous mammal. It is the only domesticated species of the family Felidae. Advances in archaeology and genetics have shown that the ...

, who have too few dopamine receptors.

Society and culture

* Apomorphine has a vital part in

Agatha Christie Dame Agatha Mary Clarissa Christie, Lady Mallowan, (; 15 September 1890 – 12 January 1976) was an English people, English author known for her 66 detective novels and 14 short story collections, particularly those revolving ...

's detective story '' Sad Cypress''. * The 1965

Tuli Kupferberg Naphtali "Tuli" Kupferberg (September 28, 1923 – July 12, 2010) was an American counterculture poet, author, singer, editorial cartoonist, comic artist, columnist, publisher, and co-founder of the rock band The Fugs. Biography Naphtali Ku ...

song "Hallucination Horrors" recommends apomorphine at the end of each verse as a cure for hallucinations brought on by a humorous variety of intoxicants; the song was recorded by

The Fugs The Fugs are an American rock band formed in New York City in late 1964, by the poets Ed Sanders and Tuli Kupferberg, with Ken Weaver (musician), Ken Weaver on drums. Soon afterward, they were joined by Peter Stampfel and Steve Weber of the Holy ...

and appears on the album Virgin Fugs.

Related compounds

Mdo-npa, the methylenedioxy analog of apomorphine, has greater

and a longer duration of action.

References

{{Authority control 5-HT2A antagonists 5-HT2B antagonists 5-HT2C antagonists Alpha blockers Catechols Dibenzoquinolines D1 receptor agonists D2 receptor agonists D3 receptor agonists D4 receptor agonists D5 receptor agonists Erectile dysfunction drugs Sexual orientation and medicine Emetics