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Apomorphine

Apomorphine is a synthetic, non-ergoline derivative of morphine that functions as a potent dopamine agonist, primarily acting on D1 and D2 receptors in the central nervous system to mimic the effects of dopamine.^[1]^[2] It is administered subcutaneously for rapid relief of "off" episodes in patients with advanced Parkinson's disease, where it provides quick symptom control with an onset within 5-10 minutes and a duration of about 30-60 minutes. A sublingual film formulation (Kynmobi) is also approved for this indication since 2020. In February 2025, the FDA approved a continuous subcutaneous infusion device (Onapgo) for advanced Parkinson's disease.^[3]^[4]^[5] First synthesized in 1845 from morphine, apomorphine has a long history of medical use, initially as an emetic to induce vomiting and later explored for its antiparkinsonian properties starting in the late 19th century.^[1]^[2] By the mid-20th century, its role in Parkinson's treatment was established through subcutaneous delivery, bypassing gastrointestinal absorption issues that limited oral forms due to emetic side effects.^[2] Pharmacologically, it exhibits high lipophilicity for swift brain penetration, alongside antioxidant properties that may offer neuroprotective benefits, though its primary mechanism involves stimulating postsynaptic dopamine receptors to alleviate motor symptoms like bradykinesia and rigidity.^[2] Beyond Parkinson's, apomorphine was formerly approved in some countries for sublingual use in treating erectile dysfunction by activating hypothalamic dopamine pathways, though it has since been withdrawn from the market.^[6] and it remains a veterinary emetic for inducing vomiting in cases of poisoning.^[2] Common side effects include nausea, hypotension, and dyskinesia, necessitating antiemetic premedication and careful monitoring, particularly given its potential for impulse control disorders and cardiovascular risks.^[3] As an orphan drug for advanced Parkinson's since its U.S. approval in 2004, apomorphine continues to be a valuable option for patients unresponsive to levodopa, with ongoing research exploring its broader neuroprotective potential in neurodegenerative diseases.^[1]^[2]

Medical uses

Parkinson's disease

Apomorphine serves as a rescue therapy for "off" episodes in advanced Parkinson's disease, providing rapid relief from hypomobility by stimulating dopamine receptors to improve motor function.^[7] Administered subcutaneously, it reduces the time spent in the off state, with clinical trials demonstrating an average daily off time reduction of approximately 2 to 4 hours through intermittent use, equivalent to 1-2 hours of benefit per effective dose depending on dosing frequency.^[7] This on-demand approach is particularly valuable for patients experiencing unpredictable motor fluctuations despite optimized oral levodopa therapy.^[8] The primary forms of apomorphine for Parkinson's disease include intermittent subcutaneous injection, such as Apokyn, and continuous subcutaneous infusion via devices like ONAPGO, which received FDA approval on February 4, 2025, for managing motor fluctuations in advanced disease.^[5] For intermittent use, dosing typically starts at 2 mg subcutaneously during an off episode, titrated based on response and tolerance to a maintenance range of 2-6 mg per dose (maximum 6 mg), with no more than 5 doses per day.^[8] Continuous infusion begins at 1 mg/hour, adjustable up to a maximum of 6 mg/hour for up to 16 hours daily, with supplemental bolus doses of 0.5-2 mg as needed for breakthrough off episodes.^[3] Efficacy is supported by randomized controlled trials showing significant improvements in motor function, with subcutaneous apomorphine improving Unified Parkinson's Disease Rating Scale (UPDRS) part III motor scores by 20-30 points from baseline off-state levels, onset of action within 10-20 minutes, and duration of effect lasting 40-60 minutes per intermittent dose.^[7] In the pivotal TOLEDO trial for continuous infusion, patients experienced an LS mean reduction in daily off time of 2.55 hours compared to 0.90 hours with placebo over 12 weeks, alongside increased good-quality on time without troublesome dyskinesia.^[3] These benefits are achieved without oral levodopa-like delays, making apomorphine a key adjunctive therapy.^[7] To mitigate nausea, a common initial side effect, apomorphine is typically initiated with concomitant antiemetics such as trimethobenzamide in the United States or domperidone internationally, with studies indicating reduced vomiting incidence during the first 8 weeks of therapy.^[9] For long-term continuous use, infusion site management is essential, as skin reactions including nodules and erythema occur in up to 63% of patients; regular rotation of sites (e.g., abdomen, thighs, back) every 24 hours, avoiding irritated areas, helps prevent complications like localized discomfort or infection.^[3] Mild site reactions are generally manageable, with low discontinuation rates in multicenter studies.^[10]

Erectile dysfunction and other indications

Apomorphine has been investigated for the treatment of erectile dysfunction (ED), particularly in its sublingual formulation known as Uprima, which was developed for mild-to-moderate psychogenic ED.^[6] This form acts centrally as a dopamine agonist to enhance sexual arousal and facilitate erection without directly affecting vascular smooth muscle.^[11] Clinical trials demonstrated success rates of approximately 50-60% for achieving erections sufficient for intercourse, compared to 30-35% with placebo, with a median onset of action around 18-19 minutes.^[12]^[11] Uprima received marketing authorization in the European Union in 2001 for men with ED but was discontinued in many markets by 2004-2006, with EU marketing authorization non-renewal effective in May 2006 due to reported side effects, such as nausea and hypotension, as well as competition from more effective phosphodiesterase-5 (PDE5) inhibitors like sildenafil.^[13]^[14] Although its use has largely been phased out, apomorphine remains a potential option in select cases, such as patients incompatible with nitrates, owing to its non-vasodilatory mechanism.^[11] Beyond ED, apomorphine is under preclinical investigation for Alzheimer's disease (AD), where it has shown promise in reducing intraneuronal amyloid-β accumulation and improving memory function in mouse models.^[15] In the 3xTg-AD mouse model of AD, apomorphine treatment decreased amyloid-β and phosphorylated tau levels while enhancing cognitive performance, effects attributed to promotion of amyloid-β degradation via insulin-degrading enzyme activation.^[15]^[16] It also ameliorated neuronal insulin resistance in these models by restoring insulin signaling pathways, potentially mitigating AD pathology at early and late stages.^[16] Emerging research highlights apomorphine's potential in addressing neuronal insulin resistance, a shared feature in neurodegenerative conditions, though its role in inhibiting necroptosis remains exploratory without clinical validation as of 2025.^[16] No approvals from regulatory bodies like the FDA exist for apomorphine in AD or other neurodegenerative indications.^[16] Off-label applications, such as for reducing anxiety or substance cravings, are rare and not recommended due to insufficient evidence and potential risks.^[17]

Clinical safety

Contraindications

Apomorphine is contraindicated in individuals with a known hypersensitivity to the drug or any of its components, including sulfites such as sodium metabisulfite present in certain formulations, due to the risk of severe allergic reactions, anaphylaxis, or angioedema.^[3] Concomitant use with 5HT3 receptor antagonists, such as ondansetron, granisetron, or dolasetron, is also absolutely contraindicated, as it has been associated with profound hypotension, loss of consciousness, and potentially life-threatening outcomes.^[3] Apomorphine should be used with caution in Parkinson's patients with dementia or significant confusion, as it may aggravate hallucinations, psychotic-like behaviors, or cognitive decline. It is contraindicated in patients with major psychotic disorders per some guidelines (e.g., UK SmPC), while US FDA labels recommend avoiding in those with pre-existing psychosis.^[18]^[3]^[19] The drug's emetic properties further heighten risks in such cases by potentially inducing severe nausea and vomiting that could worsen disorientation. Animal reproduction studies indicate potential fetal harm (e.g., increased neonatal mortality in rats and malformations in rabbits at doses similar to human exposure). There are no adequate human data; apomorphine may cause fetal harm when administered to pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk.^[3] It is unknown if apomorphine is excreted in human breast milk. There are no data on effects on breastfed infants or milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need and any potential adverse effects on the breastfed infant from apomorphine or the underlying maternal condition.^[3] Safety and effectiveness of apomorphine have not been established in pediatric patients (under 18 years of age) and it is not approved for use in this population.^[3]

Side effects

Apomorphine is associated with a range of adverse effects, primarily due to its dopaminergic action, with gastrointestinal symptoms being the most prevalent. Nausea and vomiting occur in up to 30% of patients, particularly during initial treatment, and are often mitigated through co-administration of antiemetics such as trimethobenzamide for the first few weeks.^[20]^[3] Other common side effects, affecting more than 10% of users, include yawning, drowsiness or somnolence (reported in 13-22% of cases), and exacerbation of dyskinesia (around 15%).^[21]^[3]^[20] Patients may experience sudden onset of sleep or somnolence during daily activities, including driving or operating machinery, reported in 11-35% of patients across formulations. Discontinuation or dose reduction may be necessary if significant daytime sleepiness occurs.^[3]^[8] Serious adverse effects, occurring in 1-10% of patients, encompass orthostatic hypotension (up to 44% post-dose, potentially leading to syncope), hallucinations (4-6%), and injection-site reactions such as nodules or erythema (affecting 17-44% of subcutaneous infusion users).^[3]^[20] These reactions necessitate careful management, including dose adjustments and site rotation to prevent complications like cellulitis.^[3] Apomorphine may cause impulse control disorders, including pathological gambling, hypersexuality, compulsive shopping, or binge eating, similar to other dopamine agonists; monitor patients and consider dose reduction or discontinuation if urges develop.^[3]^[22] Rare side effects, seen in less than 1% of cases, include allergic or hypersensitivity reactions (such as urticaria or swelling in about 6%), prolongation of the QT interval (4%, with risk of torsades de pointes in susceptible individuals).^[20]^[3] Use caution in patients with risk factors for QT prolongation, such as congenital long QT syndrome or concomitant use of QT-prolonging drugs; baseline ECG is recommended.^[3] In long-term use, particularly with continuous subcutaneous infusion, tolerance to apomorphine's antiparkinsonian effects may develop after several hours to days of administration, sometimes requiring dose escalation to maintain efficacy.^[23] Subcutaneous nodules, occurring in 24-63% of chronic users, are managed through regular site rotation and monitoring to avoid progression to panniculitis.^[24]^[25] Patients receiving apomorphine require ongoing monitoring, including regular blood pressure assessments to detect hypotension, electrocardiograms (ECG) in those with cardiac risk factors for QT prolongation, and annual skin examinations for infusion users to evaluate nodule formation and prevent infections.^[3]^[20]

Administration

Subcutaneous routes

Subcutaneous administration of apomorphine is a primary method for managing motor fluctuations in Parkinson's disease (PD), offering rapid systemic delivery via intermittent injections or continuous infusion.^[26] For intermittent subcutaneous injection, a test dose of 1-2 mg (0.1-0.2 mL of the 10 mg/mL solution) is administered under medical supervision to assess tolerability and efficacy, followed by titration to an effective dose typically ranging from 2-6 mg (0.2-0.6 mL) per injection as needed during OFF episodes.^[8] This is delivered using a prefilled pen injector, with injections limited to a maximum of 5 per day and at least 2 hours between doses to minimize side effects.^[8] Onset of action occurs within 10-20 minutes, with peak clinical effect generally reached at 30-60 minutes post-injection, providing quick relief comparable to levodopa but without oral absorption delays.^[27]^[28] Continuous subcutaneous infusion delivers apomorphine steadily via a portable pump, typically over 12-16 waking hours at an initial rate of 1 mg per hour, titrated up to 3-4 mg per hour (maximum 6 mg per hour) based on response, resulting in a total daily dose of 30-100 mg including any supplemental boluses.^[3]^[29] The U.S. Food and Drug Administration approved ONAPGO in 2025 specifically for this infusion method in advanced PD patients experiencing OFF episodes despite optimized oral therapy.^[3] To prevent tolerance, infusions are paused overnight for at least 4 hours, though continuous 24-hour use is generally avoided.^[30]^[31] Preparation for both methods requires aseptic technique; intermittent injections use the undiluted solution directly from the pen, while infusions necessitate dilution of the 5 mg/mL concentrate with preservative-free normal saline (typically to 1 mg/mL) in a sterile reservoir to prevent precipitation and ensure stability.^[30]^[3] The solution is stored at room temperature (15-30°C or 59-86°F), protected from light, and discarded if discolored or containing particles; prepared infusions should be used within 24 hours.^[8]^[3] Patient training is essential for safe self-administration, including instruction on priming the pen or pump, selecting and rotating injection sites (abdomen at least 2 inches from the navel, upper arms, thighs, or upper back for infusions), and monitoring for local reactions like nodules.^[8]^[3] Caregivers may assist with infusions, and rotation every 1-2 hours or daily site changes reduces skin irritation.^[26] A key advantage of subcutaneous routes is the rapid onset due to direct absorption into the bloodstream, bypassing first-pass hepatic metabolism and enabling faster reversal of OFF episodes than oral dopaminergic agents.^[28]

Sublingual and other routes

Apomorphine has been administered sublingually in the form of films or tablets, primarily at doses of 2-3 mg for the treatment of erectile dysfunction (ED).^[32] This route allows for rapid absorption through the oral mucosa, with an onset of action typically occurring in 18-19 minutes.^[33] However, bioavailability is relatively low at approximately 10-20%, largely attributable to partial swallowing of the drug, which subjects a portion to gastrointestinal metabolism.^[34] Sublingual apomorphine for ED, marketed as Uprima, has been discontinued in many regions due to limited efficacy and market challenges.^[35] Sublingual apomorphine film is FDA-approved as Kynmobi since 2020 for the acute, on-demand treatment of OFF episodes in patients with advanced Parkinson's disease, at doses of 10, 15, 20, 25, or 30 mg placed under the tongue, with a maximum of 5 doses per day and at least 2 hours between doses.^[20] Onset of action is approximately 30 minutes, with effects lasting up to 90 minutes. Bioavailability is improved compared to earlier formulations due to the film design minimizing swallowing. Post-hoc analyses as of 2025 have confirmed long-term tolerability and efficacy, with significant improvements in Unified Parkinson's Disease Rating Scale scores for motor symptoms during OFF periods.^[36]^[37] Common limitations include the drug's intensely bitter taste, which can induce nausea, and variable absorption influenced by patient technique and saliva production, often requiring antiemetic premedication.^[38] Other non-subcutaneous routes include intranasal and rectal administration, both of which remain investigational or historical. Intranasal delivery of apomorphine, often explored as a powder or spray, demonstrates bioavailability of approximately 45% relative to subcutaneous injection in humans, due to direct absorption into the bloodstream bypassing significant first-pass effects.^[39] Nonetheless, it is limited by nasal irritation, which has hindered widespread adoption despite its rapid onset in treating parkinsonian off-states.^[40] Rectal administration, typically via suppositories at doses around 200 mg, provides sustained plasma levels but achieves lower peak concentrations compared to mucosal routes and has seen limited use due to poor patient acceptance and discomfort.^[41]^[42] Key limitations of sublingual and similar mucosal routes include variable absorption influenced by patient technique and saliva production, as well as the drug's intensely bitter taste, which frequently induces nausea and reduces compliance.^[38] These factors can affect suitability for acute rescue therapy in Parkinson's disease (PD), where onset times often exceed 20 minutes.^[43]

Pharmacology

Mechanism of action

Apomorphine functions as a dopamine receptor agonist, exhibiting high affinity at the D4 receptor and moderate affinities at the D2, D3, and D5 receptors, with low affinity at the D1 receptor. It exhibits particularly high affinity at the D4 receptor (Ki = 4.4 nM), alongside moderate affinities at D2 (Ki = 35–83 nM), D3 (Ki ≈ 26 nM), and D5 (Ki = 15 nM) receptors, and low affinity at D1 (Ki = 370 nM).^[44] This binding profile allows apomorphine to mimic endogenous dopamine signaling across multiple receptor subtypes, contributing to its therapeutic effects in dopaminergic deficiency states.^[45] In the central nervous system, apomorphine primarily stimulates D2-like receptors in striatal pathways, enhancing motor control and alleviating parkinsonian symptoms such as bradykinesia and rigidity by restoring dopaminergic transmission in the basal ganglia.^[46] It also activates receptors in the chemoreceptor trigger zone of the area postrema, inducing emesis through direct D2 agonism; this central mechanism operates independently of peripheral serotonin 5-HT3 receptor pathways typically involved in other emetic stimuli.^[47] Additionally, apomorphine displays weak agonism at alpha-2 adrenergic receptors, which can lead to vasodilation and orthostatic hypotension as a side effect.^[45] Downstream signaling varies by receptor subtype: D1-like receptor activation couples to Gs proteins, stimulating adenylyl cyclase to increase cyclic AMP (cAMP) levels and promote excitatory effects in striatal medium spiny neurons, while D2-like receptor stimulation couples to Gi/o proteins, inhibiting adenylyl cyclase and reducing cAMP to modulate inhibitory pathways.^[48] Despite its derivation from morphine, apomorphine lacks affinity for opioid receptors and exerts no opioid-like effects.^[7] In preclinical models of Alzheimer's disease, apomorphine has demonstrated neuroprotective potential by promoting intraneuronal degradation of amyloid-β peptides, thereby reducing plaque formation and improving cognitive function.^[15]

Pharmacokinetics

Apomorphine exhibits route-dependent absorption characteristics, with subcutaneous administration providing nearly complete bioavailability of approximately 100%, leading to a rapid onset of action within 10 to 20 minutes.^[49] Sublingual administration results in lower bioavailability of about 18% relative to subcutaneous dosing, with an onset typically occurring between 15 and 30 minutes.^[50] Oral administration is limited by extensive first-pass hepatic metabolism, yielding bioavailability below 5%.^[51] Following absorption, apomorphine is rapidly distributed throughout the body, achieving a volume of distribution of approximately 3 L/kg, which reflects its extensive tissue penetration.^[1] It is approximately 90% bound to plasma proteins, primarily albumin, independent of concentration in the therapeutic range.^[34] Due to its high lipophilicity, apomorphine readily crosses the blood-brain barrier, enabling quick central nervous system effects.^[46] Apomorphine undergoes primarily hepatic metabolism through phase II conjugation pathways, including glucuronidation and sulfation, with minimal involvement of cytochrome P450 enzymes.^[52] The major metabolites, such as apomorphine sulfate and apomorphine glucuronide, are pharmacologically inactive.^[53] Elimination of apomorphine is rapid, with a subcutaneous half-life of 30 to 60 minutes, and over 90% of the dose is excreted renally as conjugated metabolites.^[1] In patients with mild to moderate renal impairment, there is no significant accumulation, as the elimination half-life remains unaffected.^[8] Pharmacokinetic drug interactions with apomorphine are limited, as it does not significantly inhibit or induce cytochrome P450 enzymes; however, co-administration with potent CYP3A4 inhibitors may increase exposure due to minor N-demethylation via this pathway.^[45] Antiemetics such as domperidone, commonly used to mitigate nausea, do not alter apomorphine's pharmacokinetic profile.^[54]

Chemistry

Properties

Apomorphine, in its free base form, has the chemical formula C₁₇H₁₇NO₂ and a molecular weight of 267.32 g/mol.^[55] The hydrochloride salt, commonly used in pharmaceutical formulations, exists as the hemihydrate with the formula C₁₇H₁₇NO₂·HCl·½H₂O and a molecular weight of 312.8 g/mol. The free base appears as a white to off-white crystalline powder, often forming hexagonal plates when crystallized from chloroform and petroleum ether or rods from ether.^[55] The hydrochloride hemihydrate salt is a white to grayish-white, glistening crystalline powder.^[56] Solubility of apomorphine is pH-dependent, with the free base being insoluble or sparingly soluble in water (approximately 10–20 mg/L at neutral pH) but freely soluble in acidic conditions due to protonation of the tertiary amine group.^[55]^[57] The hydrochloride salt exhibits greater water solubility, dissolving at about 10–20 mg/mL in aqueous solutions at acidic pH (around 4–5), and is sparingly soluble in alcohol while very slightly soluble in chloroform and ether.^[58] Apomorphine has a pKa of 8.92 for its phenolic hydroxyl group and an additional pKa around 7.2 for the tertiary amine, contributing to its ionization behavior in physiological environments.^[55] It possesses moderate lipophilicity, with a logP value of approximately 2.6.^[59] The compound is sensitive to oxidation and light exposure, with solutions rapidly turning green upon contact with air due to autoxidative degradation; the free base decomposes at around 195°C.^[55] To maintain stability, apomorphine and its salts should be stored protected from light and oxygen, preferably at 2–8°C for aqueous formulations, though the solid salt is stable at room temperature under inert conditions.^[60]

Synthesis

Apomorphine was first synthesized in 1869 by August Matthiessen and Charles R. A. Wright through the treatment of morphine with concentrated hydrochloric acid, yielding apomorphine hydrochloride, which they named "apomorphia."^[14] Earlier attempts included heating morphine with sulfuric acid in 1845 by Adolf Edvard Arppe, who termed the product "sulfomorphide," and further refinements by Laurent and Gerhardt in 1848.^[14] The classical synthesis of apomorphine involves direct acid-catalyzed rearrangement of morphine, typically by heating with concentrated sulfuric acid (1845), hydrochloric acid (1869), or other strong acids like hydroiodic acid (HI) or phosphoric acid, yielding apomorphine in moderate efficiency (around 50%).^[14]^[61] Modern synthetic routes include total synthesis starting from phenethylamine derivatives, as demonstrated in seminal work by Neumeyer et al. in 1973, which provided racemic apomorphine through a sequence of cyclizations and functional group manipulations. However, commercial production predominantly relies on semi-synthesis from thebaine, an opium alkaloid, involving oxidation to introduce necessary functionalities followed by cyclization to the aporphine core, offering improved efficiency over natural extraction methods due to cost considerations.^[62] The product is typically purified as the hydrochloride salt to enhance water solubility and stability.^[61]

Historical uses

Treatment of addictions

Apomorphine has been employed historically in the treatment of alcoholism from the late 19th century to the mid-20th century, primarily via subcutaneous injections administered to induce nausea and vomiting in conjunction with alcohol consumption, thereby aiming to diminish cravings through conditioned aversion.^[14] This approach was incorporated into early regimens like the Keeley Cure, which combined apomorphine with other agents to address alcohol dependence.^[14] Proponents, including physician John Yerbury Dent, advocated for its use not only for aversion but also for its sedative properties that reportedly alleviated anxiety and reduced the urge to drink during withdrawal.^[14] Early clinical observations suggested variable success, with historical reports indicating positive outcomes in a majority of cases based on reduced alcohol intake and sustained abstinence over follow-up periods.^[63] In the context of opioid addiction, apomorphine was explored in the late 19th and early 20th centuries as a potential aid during morphine withdrawal, leveraging its pharmacological profile to ease symptoms while avoiding full opioid dependence.^[14] Dent extended its use to heroin addiction in the 1940s, treating notable cases such as author William S. Burroughs, who underwent the "apomorphine cure" to manage withdrawal symptoms through sedation and aversion.^[64]^[14] Trials from this era involved subcutaneous administration to manage acute withdrawal, providing temporary symptomatic relief such as sedation, but outcomes were constrained by the drug's pronounced emetic effects and frequent relapses post-treatment.^[14] Limited data underscored its role as a short-term adjunct rather than a curative agent.^[14] The therapeutic rationale for apomorphine's role in addiction centered on its dopaminergic modulation of brain reward pathways, where it acts as a non-selective agonist at D1- and D2-like receptors to influence mesolimbic dopamine transmission and potentially attenuate reward-seeking behaviors.^[45] However, at doses used for addiction management, its primary mechanism relied on emetic induction via chemoreceptor trigger zone stimulation, overshadowing subtler dopaminergic effects on craving reduction.^[45] This dual action—emetic for aversion and dopaminergic for reward pathway interference—differentiated it from purely behavioral interventions, though side effects like persistent nausea limited broader adoption. Apomorphine's application in addiction treatment declined in the mid-20th century due to inconsistent results, pronounced side effects, and lack of rigorous randomized evidence, with more targeted pharmacotherapies such as naltrexone emerging in the 1980s and 1990s.^[14]

Aversion therapy

Apomorphine played a significant role in 20th-century aversion therapy for treating alcoholism, particularly from the 1930s to the 1960s, by inducing emesis to condition patients against alcohol consumption.^[14] This approach, popularized in clinics such as those employing variants of the Keeley Cure, involved subcutaneous injections of apomorphine timed to coincide with alcohol ingestion or exposure to alcohol-related cues, aiming to associate the substance with intense nausea and vomiting.^[14] Pioneered by figures like John Yerbury Dent in 1934, the method sought to establish a conditioned reflex aversion, often extending to other addictions like smoking or opioids.^[14] The standard protocol entailed multiple sessions over days to weeks, with apomorphine administered subcutaneously in doses typically ranging from 3 to 6 mg, immediately before or during alcohol consumption to synchronize the emetic response.^[65] Treatment was frequently combined with supportive psychotherapy to reinforce behavioral changes, and sessions were tailored to the severity of addiction, sometimes incorporating additional agents like emetine for enhanced conditioning.^[14] However, side effects such as severe nausea, sedation, hypotension, and rare cardiovascular collapse contributed to high patient dropout rates, limiting adherence.^[14] Efficacy studies from the 1950s reported variable short-term abstinence rates, including more modest outcomes around 50% short-term sobriety, though long-term maintenance was poor due to relapse and side effect intolerance.^[14] By the 1970s, the practice had largely been abandoned owing to ethical concerns over coercive conditioning and the emergence of evidence-based alternatives like cognitive behavioral therapy (CBT).^[14] Today, apomorphine aversion therapy is viewed as historically significant but ethically problematic, with modern treatments prioritizing patient autonomy and non-aversive interventions.^[14]

Veterinary uses

As an emetic in dogs

Apomorphine serves as a first-line emetic agent in dogs for the decontamination of ingested toxins, such as chocolate or rodenticides, particularly when administration occurs within approximately 2 hours of exposure and no contraindications are present.^[66] It induces vomiting by acting as a dopamine D2 receptor agonist on the chemoreceptor trigger zone in the central nervous system.^[67] Clinical studies have demonstrated high efficacy, with emesis successfully induced in 94% of treated dogs following toxin ingestion.^[66] The standard dosing regimen is 0.02–0.04 mg/kg administered intravenously (IV), or approximately 0.25 mg/kg via subconjunctival administration by placing a crushed tablet or instilling a diluted solution into the conjunctival sac.^[68]^[69] Onset of emesis is rapid with IV administration, typically occurring within 1–5 minutes, while subconjunctival routes produce effects in 4–15 minutes.^[70]^[71] If needed, effects can be reversed with naloxone at 0.01–0.04 mg/kg IV or intramuscularly to mitigate any post-emetic sedation without interfering with the initial vomiting response.^[71] Compared to alternatives like 3% hydrogen peroxide, apomorphine offers greater reliability in inducing emesis (94% success rate versus 90%) and avoids gastrointestinal irritation, such as esophagitis or retching without productive vomiting, which can occur with oral hydrogen peroxide.^[66]^[68] Since 2021, ropinirole ophthalmic solution (Clevor) is an FDA-approved alternative for dogs, providing similar efficacy without the need for reversal agents.^[72] It is particularly advantageous in clinical settings due to its parenteral administration options and reversibility. Contraindications include use in cats, where apomorphine is ineffective for emesis induction and may instead cause central nervous system depression, as well as in dogs with compromised neurological status, such as those exhibiting ataxia, coma, seizures, or hyperactivity beyond mild lethargy.^[68]^[66]

Administration and reversal

In veterinary practice, apomorphine is delivered to dogs primarily through parenteral routes to induce emesis reliably. The intravenous (IV) route provides the fastest onset of action, typically within 1–5 minutes, and requires dilution to a concentration of approximately 0.325 mg/mL to reduce the risk of vein irritation during administration.^[70]^[73] Intramuscular (IM) or subcutaneous (SC) routes offer slower onset, generally 5–13 minutes, but are useful when IV access is challenging, with comparable efficacy to IV when dosed appropriately.^[74] Subconjunctival administration, using a diluted ophthalmic solution placed in the conjunctival sac, is a convenient clinic-based option that avoids needlestick risks and achieves emesis in most cases.^[67] Preparation of apomorphine for injection involves reconstituting tablets (e.g., 6.5 mg) by dissolving them in 20 mL sterile water for injection or sterile saline to achieve approximately 0.325 mg/mL, ensuring complete dissolution before use.^[73] Reconstituted solutions are unstable and should be prepared fresh for each administration, with any unused portion discarded to maintain efficacy and sterility.^[71] Reversal of apomorphine effects is indicated if vomiting or sedation persists, using naloxone at a dose of 0.01–0.04 mg/kg administered intravenously to antagonize central nervous system depression without halting the emetic response prematurely.^[71] In cases of hypotension, a known potential side effect, supportive care including intravenous fluid therapy and monitoring of vital signs is essential to stabilize the patient.^[70] Safety protocols emphasize close monitoring of the dog for at least 1 hour following administration to detect and manage adverse effects such as lethargy, hypersalivation, or respiratory changes. Repeat dosing should be avoided if the initial dose fails, due to the risk of central nervous system toxicity; alternative emetics may be considered if necessary.^[68]

Society and culture

Brand names and formulations

Apomorphine is commercially available under several brand names for the treatment of Parkinson's disease (PD) and, historically, erectile dysfunction (ED), with formulations tailored to specific routes of administration. In the United States, Apokyn (apomorphine hydrochloride injection, 10 mg/mL) is provided as prefilled syringes for subcutaneous use in acute, intermittent "off" episodes associated with advanced PD, distributed by MDD US Operations, LLC, a subsidiary of Supernus Pharmaceuticals, Inc.^[8] Kynmobi (apomorphine hydrochloride sublingual film, available in 15 mg, 25 mg, 30 mg, and 45 mg strengths) was a non-invasive alternative for the same indication but was discontinued in the US in 2023; it remains available in Europe, produced by Sunovion Pharmaceuticals Inc. (now part of Sumitomo Pharma).^[75]^[76] As of February 2025, ONAPGO (apomorphine hydrochloride injection for subcutaneous infusion via a dedicated pump) represents the first continuous delivery system approved for motor fluctuations in advanced PD, developed by Supernus Pharmaceuticals Inc. and supplied in infusion kits that may include antiemetic components to manage nausea.^[5] In Europe, generic and branded versions such as APO-Go (apomorphine hydrochloride solution for injection or infusion, 5 mg/mL or 10 mg/mL) are available in prefilled pens or cartridges for subcutaneous administration, primarily manufactured by Britannia Pharmaceuticals Ltd., a subsidiary of STADA Arzneimittel AG.^[19] Kynmobi has been launched in Germany (2024), France (2024), Portugal and Spain (2025), with further expansions planned in the EU.^[77] For ED treatment, Uprima (apomorphine hydrochloride sublingual tablets, 2 mg or 3 mg) was previously marketed but discontinued in the US and EU; limited availability persists in select Asian markets and Canada through legacy stocks or compounding, though it is no longer actively promoted.^[6] Veterinary formulations of apomorphine are primarily used as an emetic in dogs. In the US, apomorphine hydrochloride tablets (typically 3 mg) are compounded by pharmacies such as Wedgewood Pharmacy for oral or injectable use, while human formulations like Apokyn are sometimes adapted off-label.^[78] Internationally, branded products include Zoetis' Apomorphine Emetic Tablets (6.5 mg apomorphine hydrochloride) in Australia and New Zealand for inducing vomiting in cases of toxin ingestion, and Dechra's Apovomin (injectable solution) or Dômes Pharma's Emedog (subcutaneous injection, 1 mg/mL) in the UK and Europe.^[79]^[80]

Legal status and availability

Apomorphine is classified as a prescription-only medication in the United States, requiring a valid prescription from a licensed healthcare provider, but it is not designated as a controlled substance under the federal Drug Enforcement Administration schedules.^[8] Globally, apomorphine holds prescription-only status in major jurisdictions, including Australia (Schedule 4), Canada, the United Kingdom (Prescription Only Medicine), and the European Union, where it is authorized through national agencies under the decentralized procedure.^[45]^[81] In the United States, the Food and Drug Administration first approved apomorphine hydrochloride injection (Apokyn) on April 20, 2004, for the acute, intermittent treatment of hypomobility, or "off" episodes, in advanced Parkinson's disease.^[82] Subsequent approvals include the sublingual film formulation (Kynmobi) on May 21, 2020, for the same indication (discontinued in the US in 2023), and the subcutaneous infusion device (Onapgo) on February 4, 2025, for continuous motor fluctuation management in advanced Parkinson's disease.^[83]^[5] In the European Union, the European Medicines Agency has overseen approvals since 1995 for subcutaneous injections and continuous infusions via pump for Parkinson's disease, with the sublingual film (Kynmobi) receiving decentralized marketing authorization starting in 2023, including launches in Germany and France by 2024.^[84]^[85] For veterinary applications, apomorphine is not approved by the FDA for use in animals and is employed extra-label by veterinarians primarily as an emetic in dogs, available through compounding pharmacies or human formulations under veterinary prescription; it is not over-the-counter in the US or most countries.^[86] In some European countries, veterinary formulations exist but remain prescription-based.^[87] Apomorphine is widely accessible for Parkinson's disease treatment in the European Union through pharmacies and specialty distributors, with subcutaneous injections and sublingual films readily available since their approvals; in the United States, subcutaneous injections remain accessible, though Onapgo availability is currently limited due to supply constraints as of November 2025, and Kynmobi is discontinued.^[88]^[89] Veterinary use is common in clinical settings for toxin-induced emesis in dogs. Its former sublingual formulation for erectile dysfunction (Uprima), approved in Europe in 2001, was withdrawn in 2006 due to commercial reasons, limiting current non-Parkinsonian access.^[6] The annual wholesale acquisition cost for the apomorphine subcutaneous infusion device (Onapgo) in the US is approximately $119,000 as of 2025, reflecting its specialized delivery for advanced Parkinson's management.^[90] In Europe, generic versions such as Dacepton have lowered costs, with analyses showing apomorphine infusion at around €20,782 per quality-adjusted life year gained, making it a more affordable option compared to branded alternatives.^[91] Historical ethical concerns surrounding apomorphine aversion therapy, particularly its use in behavioral conditioning during the mid-20th century, have led to legal restrictions on non-medical applications, including court rulings deeming such practices as cruel and unusual punishment in certain contexts, thereby confining modern use to approved therapeutic indications.^[92]

Morphine-derived compounds

Apomorphine belongs to the class of semi-synthetic compounds derived from morphine, a primary alkaloid extracted from the opium poppy Papaver somniferum. Among morphine-derived opioids, codeine serves as a key precursor obtained through the methylation of morphine's phenolic hydroxyl group, yielding a milder analgesic with antitussive properties.^[93] Similarly, thebaine, another natural opium alkaloid, acts as a versatile precursor for synthesizing potent semi-synthetic opioids such as oxycodone via oxidation and reduction steps that modify its diene structure in the C-ring of the morphinan skeleton.^[94] In the synthesis of apomorphine, codeine can be converted to apocodeine as an intermediate through acid-catalyzed rearrangement, which then isomerizes to the active apomorphine form, often in a one-pot process using agents like methanesulfonic acid. This pathway highlights apomorphine's position within the morphine lineage, where apocodeine represents a critical structural pivot involving dehydration and ring modification.^[95] Other notable morphine-derived compounds include naloxone, an opioid antagonist synthesized from thebaine through a series of oxidations, allylation, and demethylation steps to introduce an allyl group at the nitrogen, enabling competitive blockade of mu-opioid receptors.^[94] Unlike these derivatives, which retain mu-opioid receptor activity—either agonistic like codeine and oxycodone or antagonistic like naloxone—apomorphine is distinctive in its lack of mu-opioid agonism due to structural modifications that eliminate analgesic effects while preserving the core morphinan skeleton.^[95] This rearrangement, typically involving heating morphine with concentrated hydrochloric or sulfuric acid, alters the ether bridge and phenolic positioning, redirecting its pharmacological profile away from opioid pathways.^[14]

Dopamine agonists

Apomorphine is classified as a non-ergoline dopamine agonist primarily used in Parkinson's disease (PD) for its rapid onset of action in managing motor fluctuations. Unlike many other dopamine agonists, it directly stimulates both D1 and D2 receptor families, providing effects qualitatively similar to levodopa, though with a shorter duration.^[96] Non-ergoline agonists such as pramipexole and ropinirole exhibit higher selectivity for D2/D3 receptors compared to apomorphine's broader D1/D2 affinity. These agents are typically administered orally and have longer elimination half-lives of 8-12 hours for pramipexole and approximately 6 hours for ropinirole, allowing for sustained symptom control in early to advanced PD.^[96]^[97] In contrast, apomorphine's subcutaneous administration results in a rapid peak plasma concentration within 10-20 minutes and a short half-life of about 30-60 minutes, making it unsuitable for chronic maintenance but effective for intermittent use.^[98] Ergoline-derived agonists like bromocriptine have a broader receptor profile, activating D1 and D2 receptors but with potential off-target effects leading to risks such as retroperitoneal fibrosis and cardiac valvulopathy. Bromocriptine, with an elimination half-life of 2-8 hours, is given orally and has largely been supplanted by non-ergolines due to these fibrotic concerns; apomorphine is often preferred for acute "off" episode rescue in advanced PD because it avoids such long-term risks while providing quick relief.^[99]^[100]^[7] Other non-ergoline options include rotigotine, delivered via transdermal patch for continuous subcutaneous absorption, which maintains steady plasma levels over 24 hours and supports both motor and non-motor symptom management in PD without the pulsatile dosing of oral agents. Apomorphine stands out for its pharmacokinetic profile, with onset in under 20 minutes ideal for unpredictable "off" episodes, though it carries a higher risk of nausea and vomiting due to its potent emetic effects mediated by chemoreceptor trigger zone stimulation.^[7]

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Bromocriptine: Uses, Interactions, Mechanism of Action - DrugBank
Parent drug and metabolites are almost completely excreted via the liver, and only 6% eliminated via the kidney. Half-life. 2-8 hours. Clearance. Not Available.