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Paraldehyde

Paraldehyde is an organic compound with the chemical formula C₆H₁₂O₃, existing as a cyclic trimer of acetaldehyde and known systematically as 2,4,6-trimethyl-1,3,5-trioxane.^[1] It appears as a clear, colorless liquid with a pleasant odor, possessing a melting point of 12.6°C, boiling point of 124.5°C, and density of 0.99 g/cm³, and it is moderately soluble in water at 125 g/L.^[1] Historically introduced in the 19th century, paraldehyde served as one of the earliest synthetic sedative-hypnotic agents, acting as a central nervous system depressant to induce sedation, hypnosis, and anticonvulsant effects.^[1] It was widely employed for treating convulsive disorders such as status epilepticus, managing symptoms of alcohol withdrawal including delirium tremens, and addressing nervous and mental conditions like insomnia and agitation in psychiatric settings.^[2] Administered orally, rectally, or via injection, its pharmacological action involves central nervous system depression, believed to occur via reduction of acetylcholine release in response to neuronal depolarization, though the exact mechanism remains unclear.^[1] Despite its efficacy, paraldehyde's use has significantly declined since the mid-20th century due to the development of safer alternatives like benzodiazepines and the availability of more tolerable anticonvulsants.^[2] Common side effects include drowsiness, nausea, gastric irritation, and a characteristic unpleasant breath odor, while serious risks encompass respiratory depression, dependence with prolonged use, and toxicity in overdose manifesting as confusion or coma.^[2] It is contraindicated in patients with liver disease, gastrointestinal ulcers, or those using disulfiram, and it interacts additively with other CNS depressants.^[2] Regulatorily classified as a DEA Schedule IV controlled substance in the United States due to its low potential for abuse relative to higher schedules, paraldehyde is now rarely prescribed and primarily retained for niche applications in resource-limited settings or veterinary medicine.^[1] Additionally, it is recognized as a hazardous substance under EPA regulations for its flammability and irritant properties.^[1]

Introduction

Overview

Paraldehyde is an organic compound with the chemical formula C₆H₁₂O₃, recognized as the cyclic trimer of acetaldehyde.^[1]^[3] It forms a six-membered ring structure consisting of three acetaldehyde units linked via oxygen atoms, distinguishing it from its linear polymer forms. This compound appears as a colorless, volatile liquid at room temperature, characterized by a strong, pungent odor and a disagreeable, burning taste.^[4]^[5] Paraldehyde exhibits limited solubility in water, approximately 12.5 g per 100 mL at 25°C, but is fully miscible with ethanol, ether, and fixed oils, which facilitates its handling in various formulations.^[1]^[6] Paraldehyde was first observed in 1835 by the German chemist Justus von Liebig during studies on acetaldehyde polymerization, with its empirical formula determined shortly thereafter; it was synthesized in pure form in 1848 by Valentin Hermann Weidenbusch using acid-catalyzed treatment of acetaldehyde.^[7] As an older central nervous system depressant, paraldehyde retains niche applications today as a sedative and anticonvulsant in refractory seizures, alongside industrial roles in resin synthesis.^[8]^[9]

History

Paraldehyde was first observed in 1835 by the German chemist Justus von Liebig as a polymerization product of acetaldehyde during distillation experiments.^[7] This accidental discovery marked the initial recognition of the compound, though its structure and potential applications remained unexplored for over a decade. In 1848, Valentin Hermann Weidenbusch, another of Liebig's students, achieved the intentional synthesis of paraldehyde through acid-catalyzed trimerization of acetaldehyde, establishing a reproducible method for its production.^[7] The compound's medical adoption began in 1882 when Italian physician Vincenzo Cervello introduced it into clinical practice in the United Kingdom as a safer alternative to chloral hydrate for sedation.^[8] It quickly gained popularity in the early 20th century for managing psychiatric conditions and epileptic seizures, valued for its rapid onset and relatively low toxicity compared to earlier sedatives.^[1] By the mid-20th century, paraldehyde had become a staple treatment for severe cases of delirium tremens and status epilepticus, often administered rectally or intramuscularly in emergency settings due to its effectiveness in controlling agitation and convulsions.^[8] Its prominence waned in the 1970s as benzodiazepines, such as diazepam and chlordiazepoxide, emerged as preferred alternatives owing to their easier administration, broader safety profile, and reduced risk of adverse effects.^[10] Production in the United States ceased by the 1990s amid manufacturing challenges and the availability of superior options, leading to its withdrawal from mainstream Western markets.^[11] Nevertheless, as of 2025, paraldehyde persists in niche roles in some developing regions, particularly sub-Saharan Africa, where it remains a first-line intramuscular agent for emergency seizure control in resource-limited settings when benzodiazepines are unavailable.^[12]

Chemistry

Structure and stereochemistry

Paraldehyde features a six-membered 1,3,5-trioxane ring formed by the cyclization of three acetaldehyde molecules, with methyl substituents at the 2, 4, and 6 positions. This structure adopts a chair-like conformation analogous to that of cyclohexane, providing stability through minimized torsional strain.^[1] The molecule exists as two diastereomers: the cis diastereomer, in which all three methyl groups occupy equatorial positions, and the trans diastereomer, featuring two axial methyl groups and one equatorial. The cis form is thermodynamically more stable, as the trans configuration incurs significant steric repulsion from 1,3-diaxial interactions between the axial methyl groups. In typical syntheses and equilibrium mixtures, the cis diastereomer predominates.^[13] Each diastereomer possesses two interconvertible chair conformers via ring inversion.^[14] Structural analyses reveal an average C-O bond length of approximately 1.42 Å within the ring, accompanied by C-C bond lengths around 1.51 Å and O-C-O bond angles near 110°. The ring exhibits puckering, with torsion angles reflecting the chair distortion typical of heterocyclic six-membered rings.^[15] Nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography provide confirmation of these structural features.^[13]

Physical and chemical properties

Paraldehyde is a clear, colorless liquid at room temperature, with a density of approximately 0.994 g/cm³ at 20 °C.^[1]^[16] Its melting point is 12.6 °C, and it boils at 124 °C under standard pressure.^[1]^[16] The compound exhibits a characteristic aromatic odor, often described as pleasant or sweet, accompanied by a disagreeable, burning taste.^[1]^[16]^[5] Paraldehyde shows moderate solubility in water, approximately 125 g/L at 25 °C, and is miscible with most organic solvents such as ethanol, chloroform, ether, and oils.^[1]^[5] It is volatile, with a vapor pressure ranging from 11 to 25 mmHg at 20–25 °C, facilitating easy evaporation.^[1]^[16] In terms of stability, paraldehyde oxidizes slowly upon exposure to air and light, decomposing to acetaldehyde and acetic acid, which can cause the liquid to turn yellow-brown over time.^[1] It remains chemically stable under standard ambient conditions but is incompatible with strong acids and oxidizers.^[1]^[16] Thermodynamically, the standard enthalpy of formation for liquid paraldehyde is -681.8 kJ/mol, while its heat of vaporization is approximately 41–46 kJ/mol.^[17]

Synthesis

Paraldehyde is synthesized through the acid-catalyzed cyclotrimerization of acetaldehyde, a process first achieved in 1848 by German chemist Valentin Hermann Weidenbusch, who treated acetaldehyde with hydrochloric or sulfuric acid.^[7] This reaction involves the condensation of three molecules of acetaldehyde ($3 \ce{CH3CHO} \rightarrow \ce{C6H12O3}), forming a cyclic trimer known as 2,4,6-trimethyl-1,3,5-trioxane, and is exothermic with a standard enthalpy change of \Delta H = -113 \, \mathrm{kJ/mol}.^[18] The mechanism proceeds via protonation of the carbonyl oxygen of acetaldehyde, facilitating nucleophilic attack by another acetaldehyde molecule to form hemiacetal intermediates, followed by cyclization and dehydration under acidic conditions.^[19] In laboratory settings, paraldehyde is typically prepared by adding concentrated sulfuric acid (0.5–1% by weight) to anhydrous acetaldehyde at room temperature (approximately 20 °C), with the reaction completing within 1–2 hours and yielding over 90% of the trimer, predominantly the cis isomer due to thermodynamic stability.^[4] The mixture is then neutralized with a base such as calcium carbonate to quench the catalyst.^[20] Temperature plays a critical role in product distribution: at around 20 °C, the trimer (paraldehyde) predominates, while cooling to -10 °C favors formation of the tetramer (metaldehyde) as a solid precipitate; the polymerization exists in reversible equilibrium, shifting toward depolymerization upon heating above 80 °C.^[21] Purification involves distillation under reduced pressure (typically 20–50 mmHg at 50–60 °C) to separate unreacted acetaldehyde monomer (boiling point 21 °C) and minor paracetaldehyde impurities (higher oligomers), yielding a clear, colorless liquid product.^[20] Alternatively, fractional freezing can isolate the paraldehyde by solidifying impurities.^[19] Modern industrial variants employ heterogeneous catalysts such as cation-exchange resins (e.g., sulfonic acid-functionalized polystyrene like Amberlyst-15) in fixed-bed reactors, allowing for continuous operation at 15–30 °C with reaction times of 1–5 hours and improved catalyst recyclability over traditional homogeneous acids like H₂SO₄ or HCl.^[22] These resin-based methods reduce corrosion and simplify downstream processing while maintaining high selectivity for the trimer.^[23]

Reactivity

Paraldehyde, a cyclic trimer of acetaldehyde, exhibits reactivity primarily through its acetal-like structure, which allows for ring opening and transformation under specific conditions. The most prominent reaction is depolymerization, which reverses the formation of the trimer and yields acetaldehyde. This occurs upon heating with dilute acids, such as hydrochloric acid at 100 °C, according to the equation:

\ce{C6H12O3 ->[HCl, 100^\circ C] 3 CH3CHO}

This acid-catalyzed process involves protonation of the oxygen atoms in the ring, facilitating cleavage and reversion to the monomer.^[1] Depolymerization is also observed with other mineral acids like sulfuric acid and proceeds readily at elevated temperatures, highlighting paraldehyde's sensitivity to acidic environments.^[1] Hydrolysis of paraldehyde in water under acidic conditions proceeds slowly via ring opening, producing acetaldehyde and water. This reaction is analogous to the depolymerization but occurs in aqueous media, where the protonated acetal undergoes nucleophilic attack by water, leading to stepwise dissociation of the cyclic structure. At 25 °C in various aqueous acid solutions, the rate depends on the acidity, with stronger acids accelerating the process.^[24] Unlike neutral or basic aqueous conditions, where paraldehyde remains stable, acidic hydrolysis underscores its vulnerability to protonation.^[1] Oxidation represents another key reactivity pathway for paraldehyde. Exposure to air or light during prolonged storage leads to slow oxidation, forming peroxy compounds and ultimately acetic acid, which imparts a characteristic odor and discoloration.^[1] Paraldehyde also reacts vigorously with bromine water, first depolymerizing to acetaldehyde and then undergoing α-bromination to yield bromal (tribromoacetaldehyde). The overall stoichiometry is:

\ce{C6H12O3 + 9 Br2 -> 3 CBr3CHO + 9 HBr}

This transformation is typically conducted in solvents like ethyl acetate and exemplifies paraldehyde's susceptibility to strong oxidants.^[25] Under basic conditions, paraldehyde is generally inert and does not undergo significant decomposition, distinguishing it from its acid-sensitive behavior. However, in the presence of formaldehyde and base, it can participate in reactions forming higher oligomers or resinous materials, leveraging its acetal functionality for cross-linking.^[24] Overall, paraldehyde's stability to bases contrasts with its reactivity toward strong acids and oxidants, limiting its handling to inert conditions for storage and use.^[6]

Pharmacology

Mechanism of action

Paraldehyde functions as a central nervous system (CNS) depressant, exerting its pharmacological effects through enhancement of inhibitory neurotransmission. Although its precise mechanism remains incompletely elucidated, evidence indicates that it inhibits the synaptosomal disposal of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain, thereby prolonging GABA availability and amplifying its suppressive effects on neuronal activity.^[26] This action parallels the GABA_A receptor modulation seen with barbiturates, which facilitate chloride conductance to hyperpolarize neurons and dampen excitability, but paraldehyde achieves CNS depression without equivalent direct receptor binding or pronounced respiratory suppression at therapeutic doses.^[26]^[27] In its anticonvulsant role, paraldehyde stabilizes neuronal membrane potentials by curtailing the spread of hyperexcitable impulses, as evidenced by its ability to stop motor seizures in lithium-pilocarpine-induced status epilepticus models in immature rats.^[28] Animal studies further demonstrate dose-dependent reductions in acetylcholine release following neuronal depolarization, contributing to seizure suppression without the specificity of modern antiepileptics.^[1]^[8] The hypnotic properties of paraldehyde arise from its depression of the ascending reticular activating system, promoting sedation and sleep induction while exerting negligible analgesic effects.^[29] As a non-selective CNS depressant, it produces broad inhibitory effects with comparatively limited influence on cardiovascular or respiratory centers relative to ethanol, allowing therapeutic use in settings requiring sedation without rapid ventilatory compromise.^[27] Historical research constraints have precluded detailed binding affinity studies, but rodent EEG investigations consistently reveal paraldehyde-induced slowing and synchronization of brain waves, underscoring its dose-proportional sedative impact.^[30]^[31]

Pharmacokinetics

Paraldehyde is rapidly absorbed from the gastrointestinal tract following oral administration, with approximately 93% bioavailability and peak plasma concentrations reached within 20-60 minutes. It is also quickly absorbed via rectal or intramuscular routes, though specific bioavailability data for these are limited.^[8]^[32] The drug distributes widely to body tissues, including the brain and cerebrospinal fluid, owing to its lipophilic nature that enables easy passage across the blood-brain barrier. In adults, the volume of distribution is approximately 0.89 L/kg, reflecting extensive tissue penetration.^[33]^[32] Metabolism primarily occurs in the liver through depolymerization to acetaldehyde, followed by oxidation via aldehyde dehydrogenase to acetic acid, and further breakdown to carbon dioxide and water; cytochrome P450 enzymes are involved in the initial depolymerization step. About 70-90% of an administered dose undergoes hepatic metabolism, with no active metabolites produced.^[8]^[32]^[34] Elimination occurs mainly through pulmonary excretion, with 11-30% of the dose exhaled unchanged, accounting for the characteristic breath odor; renal clearance is minimal, involving only 0.1-2.5% as unchanged drug. The plasma half-life in adults ranges from 3.4 to 9.8 hours (mean approximately 7 hours), though it may be prolonged in neonates or with concurrent use of drugs like phenobarbital.^[8]^[34]^[33]

Medical applications

Sedative and hypnotic uses

Paraldehyde has been employed primarily as a sedative and hypnotic agent for managing acute agitation, insomnia among psychiatric patients, and delirium tremens during alcohol withdrawal.^[35]^[36]^[1] In clinical practice during the 19th and early 20th centuries, particularly in asylums and mental hospitals, paraldehyde was administered orally or rectally at doses of 5-10 g for adults, typically inducing sleep within 15-30 minutes.^[3]^[7]^[32] This agent provided reliable hypnosis with minimal residual effects such as hangover, making it a preferred alternative to barbiturates for short-term use before the 1950s, when concerns over barbiturate dependency arose.^[37]^[27] Historical evidence from clinical observations in psychiatric settings demonstrated its effectiveness in sedating manic or agitated patients, with reports indicating successful calming in a substantial proportion of cases, though no large-scale modern randomized controlled trials exist due to its declining use.^[38]^[39] By 2025, paraldehyde has become largely obsolete in developed countries, supplanted by safer benzodiazepines for sedation, but it retains occasional application in resource-limited settings for refractory agitation where alternatives are unavailable.^[40]^[41] A common side effect includes a persistent garlic-like odor on the breath.^[8]

Anticonvulsant uses

Paraldehyde serves as an anticonvulsant primarily for the management of status epilepticus, particularly in pediatric cases refractory to first-line benzodiazepines, as well as for controlling seizures in eclampsia and muscle spasms in tetanus.^[8]^[42]^[43]^[44] Its efficacy in these emergency settings stems from its rapid central nervous system depressant action, which interrupts prolonged convulsive activity without requiring immediate intravenous access in all cases.^[45] The standard dosage for anticonvulsant use is 0.1-0.15 mL/kg administered intramuscularly for children, or 0.3 mL/kg paraldehyde diluted 1:1 with oil administered rectally (total 0.6 mL/kg), often for rectal delivery to minimize irritation. Adults typically receive 5-10 mL IM or up to 10-12 mL rectally.^[32]^[46]^[33] Onset of action occurs within 5-15 minutes following intramuscular or rectal administration, with anticonvulsant effects lasting 4-8 hours, allowing for repeat dosing as needed while monitoring for recurrence.^[32]^[3] A key advantage of paraldehyde in anticonvulsant therapy is its lack of significant respiratory depression at therapeutic doses, distinguishing it from benzodiazepines and making it valuable for neonates and in resource-limited environments where ventilatory support may be unavailable.^[45]^[47] This profile supports its application in high-risk populations, including infants with immature respiratory systems. As of 2025, paraldehyde is rarely used in developed countries due to commercial unavailability and preference for benzodiazepines, but remains an option in guidelines for refractory cases where IV access is difficult.^[48] In contrast, its use in Western countries remains limited under 2025 guidelines, which prioritize benzodiazepines such as lorazepam or midazolam due to superior efficacy profiles and ease of administration.^[49]^[50] Clinical evidence from studies in the 1960s through 1980s, including retrospective analyses and case series, reported seizure control rates of 60-90% with paraldehyde in status epilepticus, often achieving cessation within the first hour of administration.^[51]^[52] More recent case reports highlight its utility in refractory scenarios, such as benzodiazepine-resistant convulsions, where it provided rapid termination without additional immediate interventions.^[42]

Administration

Paraldehyde is administered via several routes to achieve therapeutic effects, primarily for sedation and seizure control, with route selection influenced by the need for rapid onset and patient condition. The primary routes include oral, rectal, intramuscular (IM), and, less commonly, intravenous (IV).^[53]^[2] Oral administration involves dilution in milk or water to minimize gastric irritation, while rectal use employs a 1:1 dilution with olive oil or vegetable oil for enema delivery to facilitate absorption.^[53]^[54] IM injections are given deeply into the gluteal muscle, avoiding nerve trunks, and IV administration requires dilution to prevent complications.^[46]^[55] Paraldehyde is supplied in 5 mL glass ampoules or vials to prevent adsorption or reaction with plastic or rubber materials, which can degrade the drug.^[46]^[55] For IV use, it is diluted 1:10 with normal saline or 5% dextrose to form a 5% solution, and administration occurs slowly via glass tubing to avoid pulmonary issues.^[2]^[54] No more than 5 mL should be injected per IM site to reduce pain and tissue damage.^[46]^[55] Dosing guidelines vary by route, age, and indication, with repeats typically every 4-6 hours as needed. For oral sedation in adults, 5-10 mL is used, diluted appropriately; children receive 0.15-0.3 mL/kg.^[2]^[56] Rectal dosing for seizures in children is 0.3 mL/kg paraldehyde diluted 1:1 with olive or vegetable oil (total volume 0.6 mL/kg of 50% solution), up to 10-12 mL in adults, providing rapid absorption.^[54]^[57] IM doses for adult sedation are 5-10 mL, and for children with seizures, 0.1-0.15 mL/kg; anticonvulsant doses in adults range from 5-10 mL.^[46]^[55] Maximum daily limits include 30 mL on the first day for alcohol withdrawal, reducing thereafter.^[46] Precautions emphasize safe handling and monitoring to mitigate risks. Store paraldehyde below 25°C in a cool, dark place, as it decomposes when exposed to light or air, potentially turning brownish or developing a vinegar-like odor, rendering it unusable.^[53]^[46] Use only freshly opened ampoules, and discard after single use; if crystallized, warm gently to liquefy.^[55] Avoid aspiration during oral or rectal administration to prevent chemical pneumonia, and monitor for local reactions such as pain or sterile abscess at IM sites.^[2]^[53] Historically, IV administration of paraldehyde declined after the 1970s due to risks of vein irritation, pulmonary edema, and circulatory collapse, leading to a preference for rectal routes in emergencies for faster, safer delivery.^[27]^[58]^[42]

Safety and adverse effects

Side effects

Paraldehyde administration commonly results in a strong, fruity odor on the breath due to its pulmonary excretion. This odor is a frequent and characteristic effect observed in most users.^[8] With oral use, gastrointestinal disturbances such as nausea, vomiting, and stomach pain are typical adverse reactions. These effects arise from local irritation in the digestive tract. Local reactions vary by administration route. Intramuscular injection often causes pain, redness, swelling, and sterile abscess formation at the site, potentially leading to skin sloughing or fat necrosis.^[46] Rectal administration may produce irritation, tenesmus, pain, or bleeding.^[60] Intravenous use carries a risk of vein phlebitis and thrombophlebitis.^[46] Respiratory issues can occur, particularly if paraldehyde is aspirated, leading to coughing, choking, or pulmonary edema.^[3] Bronchospasm is a rare complication.^[8] Other effects include central nervous system symptoms such as dizziness, ataxia (manifesting as clumsiness or unsteadiness), drowsiness, and hangover-like sensations. Allergic reactions, including skin rash, occur infrequently.^[46]

Toxicity and contraindications

Paraldehyde overdose can lead to severe central nervous system depression, manifesting as respiratory depression, hypotension, coma, pulmonary edema, and potentially fatal cardiac failure.^[8] Doses exceeding typical therapeutic limits, such as more than 30 mL in adults, heighten the risk of these outcomes, with symptoms including nausea, vomiting, drowsiness, and unconsciousness progressing to life-threatening complications.^[61] The oral LD50 in rats is 1.53 g/kg, indicating moderate acute toxicity compared to other sedatives.^[62] Management of acute overdose focuses on supportive care, including airway protection, mechanical ventilation for respiratory failure, vasopressors for hypotension, and monitoring for metabolic acidosis; hemodialysis may be considered in severe cases to enhance elimination, though its efficacy for paraldehyde specifically remains unestablished.^[33] Chronic exposure to paraldehyde carries risks of dependence, tolerance, and organ damage, including toxic hepatitis and nephritis with prolonged use.^[8] As paraldehyde undergoes hepatic metabolism to acetaldehyde via cytochrome P450 enzymes, extended administration may induce liver enzyme activity, potentially altering the metabolism of co-administered drugs.^[63] The metabolite acetaldehyde is classified by the International Agency for Research on Cancer (IARC) as possibly carcinogenic to humans (Group 2B), raising concerns for long-term oncogenic potential through DNA adduct formation, though direct evidence for paraldehyde itself is limited. Despite this, paraldehyde exhibits relatively low acute environmental toxicity, with rapid volatilization and biodegradation mitigating persistence in soil and water.^[64] Paraldehyde is contraindicated in patients with severe respiratory diseases, such as bronchopulmonary disorders, due to the risk of exacerbated depression and aspiration.^[29] It is also contraindicated in severe hepatic impairment, where reduced metabolism can prolong exposure and worsen toxicity.^[33] Use during pregnancy is contraindicated because paraldehyde readily crosses the placenta, potentially causing respiratory depression in the neonate.^[46] Paraldehyde potentiates the effects of other central nervous system depressants, including alcohol and opioids, leading to additive respiratory and sedative risks that can precipitate overdose.^[8] Caution is advised with disulfiram, which inhibits acetaldehyde dehydrogenase and can elevate paraldehyde and metabolite levels, intensifying toxicity.^[65]

Non-medical applications

Industrial uses

Paraldehyde serves as a key intermediate and solvent in the production of various resins, where it facilitates processing and formulation by dissolving gums, waxes, and other components.^[66] It is incorporated into adhesives and coatings, acting as an indirect food additive in adhesive compositions for packaging materials.^[1] In these applications, paraldehyde's cyclic trimer structure provides lower volatility compared to monomeric aldehydes, enabling more controlled handling during resin synthesis and application.^[67] As a solvent, paraldehyde is employed in rubber accelerators and organic synthesis, where it substitutes for acetaldehyde to minimize secondary reactions and improve safety due to its reduced toxicity and stability.^[1] It functions as a rubber additive, promoting vulcanization and acting as an antioxidant in tire and elastomer production.^[66] Additionally, paraldehyde is used as a dyestuff intermediate and solvent for fats, oils, and leather processing, supporting the textile and chemical industries.^[67] Paraldehyde acts as a preservative in industrial formulations, leveraging the antimicrobial properties and chemical stability of its trimer form to inhibit microbial growth in products such as cosmetics and pharmaceuticals.^[27] Global production of paraldehyde reached approximately 18,400 metric tons in 2024, with major applications in chemical intermediates for resins and dyes accounting for over 9,000 tons.^[68] Usage in the rubber sector involves low thousands of tons annually, reflecting steady demand despite the rise of greener alternatives in solvent-based processes.^[68] Key advantages include its lower toxicity relative to acetaldehyde, allowing safer industrial handling, and its ability to depolymerize under controlled conditions for in-situ acetaldehyde generation in reactions.

Other applications

In veterinary medicine, paraldehyde has been employed as a sedative and anticonvulsant agent, particularly in laboratory animals for procedures involving anesthesia or seizure control. For instance, it is administered intramuscularly in combination with ketamine (50 mg/kg) to induce anesthesia in rabbits at doses of 0.5 mL/kg.^[70] Similar applications include intraperitoneal administration in rats to terminate status epilepticus, typically at 0.3 mL/kg after prolonged seizure activity.^[71] In experimental pigs, intraperitoneal paraldehyde facilitates anesthesia during surgical interventions.^[72] Rectal administration has been explored in some contexts for rapid anticonvulsant effects, though its use remains limited to research settings due to the availability of more modern alternatives. As a laboratory reagent, paraldehyde serves as a solvent in microscopy mounting media, such as Euparal, where it aids in preserving and embedding specimens for long-term observation by dissolving resins like sandarac and facilitating slide preparation. In analytical chemistry, it functions as a solvent for processing waxes, oils, and resins, and has been utilized in methods for detecting or quantifying related compounds like acetaldehyde in aqueous solutions. Historically, paraldehyde was recognized as a generally recognized as safe (GRAS) flavoring agent in food products, including baked goods, beverages, and candies, at low concentrations (e.g., up to 200 ppm in baked goods), contributing subtle notes derived from its acetaldehyde structure.^[73] This application extended to masking unpleasant odors or tastes in early pharmaceutical formulations, though such uses have largely diminished. Emerging research as of 2025 explores paraldehyde's role in synthesizing biodegradable polymers, where it acts as a source of acetaldehyde to form cyclic acetal linkages in polyols for degradable polyurethanes, enabling acid-triggered breakdown for applications in sustainable materials and drug delivery.^[74] Due to its pungent odor and the development of safer, less volatile alternatives, paraldehyde has been phased out from many non-medical applications, with its use now confined to niche laboratory and research contexts.

Regulatory status

Availability

Production of paraldehyde is limited to a few manufacturers, primarily in Europe and Asia, including Lonza Group in Switzerland, BASF SE and Merck KGaA in Germany, and Godavari Biorefineries in India, with additional production from Chinese firms such as Nuote Chemical and Bojing Chemical.^[75]^[76] In the United States, production has been discontinued and the drug is no longer commercially available.^[77] Paraldehyde is supplied in forms such as 5 mL sealed glass ampoules for intramuscular or intravenous injection, oral solutions, and rectal preparations diluted in oil.^[53]^[33] Veterinary formulations exist in some countries for anticonvulsant use in animals, particularly dogs.^[78]^[1] Globally, paraldehyde remains accessible in many developing nations for treating seizures, including status epilepticus, where it serves as an alternative anticonvulsant in resource-limited settings.^[34] As of 2025, bulk industrial quantities are available at around $5 per kg.^[79] Due to its incompatibility with plastics and rubbers, paraldehyde must be packaged in glass containers to prevent degradation.^[1] When stored in tight, light-resistant glass at temperatures not exceeding 25°C, it maintains stability with a shelf life of 2–3 years if unopened, though it decomposes rapidly after exposure to air.^[1]^[33]

Legal classification

In the United States, paraldehyde is classified as a Schedule IV controlled substance under the Controlled Substances Act administered by the Drug Enforcement Administration (DEA), reflecting its low potential for abuse relative to substances in Schedule III.^[1] Although commercial production was discontinued due to the availability of safer alternatives, it remains accessible through state-licensed compounding pharmacies for human and veterinary applications or via importation under appropriate regulatory oversight.^[53]^[80] Internationally, paraldehyde is designated with the World Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) classification code N05CC05, categorizing it as an anxiolytic within the group of aldehydes and their derivatives.^[81] In the European Union and the United Kingdom, it is regulated as a prescription-only medicine, requiring authorization from a qualified healthcare professional for dispensing, and is often prepared as a "special" formulation or imported due to limited commercial availability.^[82]^[60] In Australia, paraldehyde is scheduled as a Schedule 4 substance under the Poisons Standard, classifying it as a prescription-only poison with restrictions on supply and possession to mitigate risks associated with its use.^[83] Paraldehyde's low abuse potential has generally precluded its inclusion in higher tiers of international drug scheduling under United Nations conventions, such as the 1971 Convention on Psychotropic Substances, though it is occasionally monitored in contexts involving industrial chemical precursors due to its non-medical applications.^[1] As of 2025, however, paraldehyde has seen renewed inclusion in pediatric emergency protocols for low-resource settings, particularly in parts of Africa and Asia where it remains unrestricted in emergency medical kits for managing convulsions when benzodiazepines are unavailable.^[84]^[47] Export controls on paraldehyde are minimal under UN frameworks, with no specific dual-use restrictions listed in the 1988 Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances, though general chemical export notifications may apply in cases of large-scale industrial shipments to prevent diversion.^[85] This regulatory landscape underscores its transition from a widely used sedative to a niche agent in resource-limited emergency care.

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One method of operation is to convert the acetaldehyde to paraldehyde in the presence of a condensing agent or acid catalyst such as sulfuric acid, and to ...Missing: mechanism | Show results with:mechanism
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US3403168A - Preparation of metaldehyde - Google Patents
The metaldehyde is separated by filtration, washed with acetaldehyde, and dried at 35 C. The remaining mixture of paraldehyde and n-pentane is distilled whereby ...
[21]
[PDF] Russian Chemical Reviews, 37 (1), 1968 17
It has been stated in recent communications that, apart from sulphuric acid, cation-exchange resins can be used as catalysts in this reaction V7-20. The ...<|separator|>
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CN102250054A - Preparation method for paraldehyde
The preparation method is characterized by comprising the following steps: taking acetaldehyde liquid and strong acid cation resin according to a mass ratio of ...Missing: Weidenbusch 1848
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Paraldehyde - an overview | ScienceDirect Topics
Paraldehyde is defined as an organic compound that serves as a reactant in the high-temperature liquid-phase pressure synthesis of 2-methyl-5-ethylpyridine (MEP) ...
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bromine - Organic Syntheses Procedure
2. The use of sulfur as a catalyst increases the yield 5–10 per cent and causes no trouble in the purification.
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Effects of Anesthetic Agents on Synaptosomal GABA Disposal
The ability of many neurotropic agents to inhibit GABA breakdown was studied by assessing synaptosomal "GABA disposal". ... Pentobarbital, ethanol, paraldehyde, ...
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Paraldehyde - an overview | ScienceDirect Topics
Paraldehyde was introduced into medical practice more than 100 years ago and it was used clinically as a sedative, hypnotic, and antiepileptic agent.Missing: peak 20th
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Outcome of status epilepticus in immature rats varies according to ...
Purpose: To test effects of paraldehyde on behavioral outcome of status epilepticus (SE) in developing rats. Methods: Motor SE was induced by LiCl-pilocarpine ...Missing: EEG study
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Paraldehyde: Uses, Dosage, Side Effects and More | MIMS Singapore
It is believed to cause CNS depression, including the ascending reticular activating system leading to hypnosis or sedation and anticonvulsant activity (in sub- ...Missing: minimal | Show results with:minimal
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EEG in anaesthetized rats - PubMed
The constancy of rat EEG during surgical anaesthesia induced by phenobarbital, cholorose, paraldehyde, and inactin was investigated.
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Abstract: The constancy of rat EEG during surgical anaesthesia induced by phenobarbital, cholorose, paraldehyde, and inactin was investigated.
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Paraldehyde: Uses, Dosage, Side Effects and More | MIMS Philippines
Mechanism of Action: Paraldehyde is a cyclic trimer of acetaldehyde with unknown mechanism of action. It is believed to cause CNS depression, including the ...
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Paraldehyde - The Epilepsy Prescriber's Guide to Antiepileptic Drugs
It is now used primarily as an alternative to diazepam or subsequent to diazepam administration for premonitory or early and established status epilepticus.
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Trimethadione, Paraldehyde, Phenacemide, Bromides, Sulthiame ...
Aug 1, 2016 · Seventy to eighty percent of paraldehyde is metabolized by the liver, 20% to 30% is exhaled by the lungs, and a very small amount is excreted ...<|control11|><|separator|>
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Management of Alcohol Withdrawal Delirium: An Evidence-Based ...
Jul 12, 2004 · In the study comparing rectal paraldehyde use and IV diazepam administration, satisfactory control of agitation was achieved in all 17 patients ...
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Psychopharmacology: From serendipitous discoveries to rationale ...
In the late 19th century and into the early 20th century, drugs such as paraldehyde, chloral hydrate and bromides were being used as treatments for anxiety ...
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The Pharmacology of Nonalcohol Sedative Hypnotics
Dec 12, 2016 · Barbiturates have largely been replaced by benzodiazepines because the latter drugs have greater safety and less potential for abuse; however, ...
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Jul 23, 2018 · In this paper, the authors review the history of the pharmacological treatment of bipolar disorder, from the first nonspecific sedative agents introduced in ...
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[PDF] On the 50th anniversary of John Cade's discovery of the anti-manic ...
with sedation by bromides or paraldehyde. Electroconvulsive therapy (usually unmodified) could be lifesaving, but was feared by patients, and offered no ...
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Normal-dose physical de- pendence was first suspected in the early 1970s but it was not until the early 1980s that scientific evidence was adduced to establish ...
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Management and monitoring strategies for severe cerebral malaria
Oct 8, 2025 · Paraldehyde is rarely used in high-resource settings but remains a pragmatic option for acute seizure control in low-resource environments, ...
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Paraldehyde Toxicity During Treatment of Status Epilepticus
... paraldehyde followed by a drip of 20 mg/kg/hr should result in safe, rapid control of status epilepticus when first-line anticonvulsant drugs have failed.
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paraldehyde in the treatment of eclampsia
The results of treating ecIampsia with rectal or intramuscular paraldehyde are reported, and it is recommended as a safe and valuable drug for this purpose. In ...
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[PDF] Intramuscular Paraldehyde - Semantic Scholar
spasms of tetanus, hydrophobia, strychnine poisoning and eclampsia. In dyspnoea of cardiac origin it was safely used. Both dyspnoea and restlessness were.
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The role of paraldehyde and lidocaine in the management of status ...
Jun 28, 2008 · Paraldehyde is one of the oldest sedative and hypnotic agents with anticonvulsant properties. Though it is not now used as a sedative or ...
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[PDF] Paraldehyde Injection BP - Phebra
Paraldehyde is soluble 1 in 10 of water, but is only soluble 1 in 17 in boiling water. It is miscible with alcohol, chloroform, ether and volatile oils.Missing: ethanol | Show results with:ethanol
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Full article: Optimal Management of Status Epilepticus in Children in ...
Paraldehyde was the first rescue medication to be used in 19 (35.9%) episodes (seven of the 30 children) and in the remaining 34 episodes, it was used after ...
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[PDF] National List of Essential Medicines, 2011
Paraldehyde injection, 500 mg/ml in. 2-ml ampoule. 6. Anti-infective Medicines. 6.1. Anthelmintics. 6.1.1. Intestinal Anthelmintics. Albendazole tablet ( ...
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Pharmacotherapy for Status Epilepticus | Drugs
Aug 27, 2015 · Paraldehyde is a drug ... An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action.<|control11|><|separator|>
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Evidence-Based Guideline: Treatment of Convulsive Status ...
Another class III study compared intranasal lorazepam (0.1 mg/kg) to IM paraldehyde (0.2 mL/kg) in 160 pediatric patients presenting to an emergency department ...<|separator|>
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Paraldehyde Therapy in Childhood Status Epilepticus - JAMA Network
received 4% solutions, half had good and half had poor seizure control. There were three in the10% group with good, fair, and poor responses. The single 6% ...Missing: countries | Show results with:countries
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Paraldehyde / administration & dosage*; Paraldehyde / therapeutic use; Prospective Studies; Safety; Treatment Outcome. Substances. Anticonvulsants; Paraldehyde.
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Paraldehyde (oral route, injection route, rectal route) - Mayo Clinic
Feb 1, 2025 · Paraldehyde will cause your breath to have a strong unpleasant odor. This effect will last until about one day after you have stopped using ...Missing: appearance | Show results with:appearance
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Paraldehyde - The Epilepsy Prescriber's Guide to Antiepileptic Drugs
Jun 1, 2018 · Usual Dosage Range · Rectal: 1:1 paraldehyde: vegetable oil solution, 0.3 mL/kg per dose (300 mg/kg of paraldehyde); may repeat every 2–4 hours.
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Paraldehyde Injection BP (Solution for injection) - NPS MedicineWise
May 1, 2018 · It is a colourless or pale yellow transparent liquid, with a strong odour and disagreeable burning taste. Paraldehyde is soluble 1 in 10 of ...
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Paraldehyde U.S.P
IM 5ml every 4-6 hours for 24 hours, then every 6 hours on following days, not to exceed 30ml. Sedation: PO/PR 4-10ml. IM 5ml; IV ...
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None
### Summary of Paraldehyde Enema Guidelines
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Toxicity of Intravenous Paraldehyde - Sage Journals
The intravenous administration of paraldehyde as recommended for clinical anesthesia is not without danger. In experimental animals there is a narrow margin ...
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Paraldehyde and olive oil enema | Great Ormond Street Hospital
Paraldehyde is a medicine given to treat seizures or status epilepticus. It works by damping down (suppressing) the nervous system so that a seizure will stop.Missing: current industry
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Paraldehyde - an overview | ScienceDirect Topics
Its onset of action is slower than for medications described earlier. The effective half-life of paraldehyde is 6 hours. It may be more effective for SE ...
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Metabolism of paraldehyde to acetaldehyde in liver microsomes ...
A concentration-dependent acetaldehyde (AcH) generation was observed when paraldehyde was incubated with the mouse liver microsomal fraction.
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Use of paraldehyde in neonates - Indian Pediatrics - Editorial
Although paraldehyde has been advocated as an effective anticonvulsant drug in the newborn(1), it is sparingly used in neonates because of its various toxic ...Missing: resource- | Show results with:resource-
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Metabolism of paraldehyde to acetaldehyde by rat liver microsomes
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[PDF] Paraldehyde - NJ.gov
delayed. PHYSICAL DATA. Vapor Pressure: 25.3 mm Hg at 68oF (20oC). Flash Point: 96oF (35.5oC). Water Solubility: Slightly soluble. OTHER COMMONLY USED NAMES.Missing: ethanol | Show results with:ethanol
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Paraldehyde - an overview | ScienceDirect Topics
It is a colorless liquid with a pleasantly sweet odor. It has a burning taste. Paraldehyde is a flammable liquid with a flashpoint of 35.5 °C. The melting point ...
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Paraldehyde Market | Industry Analysis Report, 2034
Sep 9, 2025 · The Paraldehyde Market Market recorded global production volumes of approximately 18,400 metric tonnes in 2024, with Asia-Pacific ...
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Paraldehyde Market Report | Global Forecast From 2025 To 2033
The global paraldehyde market size was valued at approximately USD 150 million in 2023, and it is projected to reach around USD 220 million by 2032.
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Paraldehyde Market Shifts: Strategic Analysis 2025-2032 - LinkedIn
Oct 28, 2025 · The market size was valued in the hundreds of millions USD in 2022, with projected growth of around 4% annually through 2030. Key segments ...
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Neonatal Seizures and Neonatal Syndromes - The Epilepsies - NCBI
Primidone, valproate, lignocaine, carbamazepine and paraldehyde (now not available in the USA) are also used mainly as adjunctive AEDs if others fail. Of the ...
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paraldehyde - Drug Central
paraldehyde Veterinary Use | Indications/Contra | FAERs-F | FAERs-M | Orange Bk | BioActivity | · Description: · Drug dosage: · ADMET properties: · Approvals:.
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CAS No.123-63-7,Paracetaldehyde Suppliers,MSDS download
123-63-7. Paraldehyde CAS NO.: 123-63-7. Min.Order: 1 Kilogram. FOB Price: USD $ 5.0-5.0 ... In 1829, paraldehyde was first synthesized by Wildenbusch. In 1882 ...
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Veterinary Pharmacy for Compounded Pet Medications
We provide custom pet-friendly compounded medications for over 80% of the veterinarians in the United States.Veterinary Practices · Pet Owners · Veterinary Compounding · Contact Us
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N05CC05 - ATCDDD - ATC/DDD Index - FHI
The DDDs are based on use of the drugs as hypnotics. The DDD for melatonin is based on dose recommendations in EU for the 2 mg depot tablet.
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The Prescription Only Medicines (Human Use) Order 1997
This Order may be cited as the Prescription Only Medicines (Human Use) Order 1997 and shall come into force on 18th August 1997.
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Paraldehyde (Phebra) - Healthdirect
It is Schedule 4 : Prescription Only Medicine. open tool tip to find out more. 5x5mL pack. Pregnant or planning a pregnancy ? (AHT). For the active ingredient ...
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[PDF] Hospital care for children
paraldehyde (see page 342). Avoid giving rectal paraldehyde or ... If a transfusion reaction occurs, first check the blood pack labels and patient's.<|separator|>
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[PDF] United Nations Conference for the adoption of a Protocol on ...
Feb 19, 1971 · The Official Records of the United Nations Conference for the adoption of a Protocol on Psychotropic Substances are published in two volumes.