Clinical outcomes associated with orphenadrine deliberate self-poisoning: a retrospective poisons centre study.

INTRODUCTION: Orphenadrine overdoses can cause antimuscarinic toxicity, respiratory failure, refractory seizures and cardiotoxicity. The dose-toxicity relationship is poorly defined. Orphenadrine is marketed as immediate and sustained release formulations, and it is not known how the formulation impacts on toxicity. We determined the clinical toxicity of orphenadrine in patients referred to a regional poisons centre. METHODS: Retrospective case series of patients in New South Wales with orphenadrine deliberate self-poisoning from January 2016 to April 2022 referred to the New South Wales Poisons Information Centre. Demographics, history of exposure, treatment and outcomes were extracted from clinical databases. Receiver-operating characteristic curves were constructed to determine thresholds predicting toxicity. RESULTS: Forty-eight patients were identified, with information on clinical outcomes in 46 patients and doses in 41 patients. All patients were older than 12 years. The median orphenadrine dose was 770 mg (range 210-10,000 mg), 59 per cent as the immediate release formulation, and 67 per cent reported coingestants. Doses of sustained release formulations were significantly greater than immediate release formulations, median 2,750 mg versus 595 mg. Common clinical features were drowsiness (59 per cent), sinus tachycardia (37 per cent) and confusion (33 per cent). Three patients had mild hypotension, three were intubated for coma, and two had seizures; no patients suffered ventricular dysrhythmias. All patients survived, with 75 per cent being medically cleared within 24 hours of presentation. A dose-toxicity relationship was observed, but conclusions are limited by the small number of cases with moderate or severe toxicity. DISCUSSION: All patients survived, and severe cardiac and neurological toxicity were not observed. This contrasts to published case reports noting severe poisoning at similar or lower doses. Formulation may have an impact on outcomes, with lesser toxicity from sustained release products. CONCLUSIONS: Orphenadrine doses up to 10 g were associated with antimuscarinic toxicity and sedation, but not severe cardiotoxicity. More research exploring the effect of dose and formulation on outcomes is required.

Full recovery from a potentially lethal dose of orphenadrine ingestion using conservative treatment: a case report.

Intoxication by orphenadrine is uncommon. The clinical features consist of both central and peripheral anticholinergic effects. Ingestion of 2 to 3 g orphenadrine in an adult has been associated with fatality. A 46-year-old female was brought to our emergency department 1.5 hours after ingesting 40 tablets of 100 mg orphenadrine. She became stuporous 3 hours post-ingestion and developed generalized convulsions 1 hour later. Fifty-five hours post-ingestion, she had recovered and was found to have anterior shoulder dislocation. In addition, severe rhabdomyolysis and persistent nausea were observed. All of the above-noted toxic effects resolved with conservative treatment. Although orphenadrine intoxication can cause convulsions and hemodynamic instability, there is no available antidote and treatment remains supportive.

Determination of orphenadrine plasma levels using HPLC with diode array detection and a novel solid-phase extraction procedure in psychiatric patients.

Orphenadrine is an antimuscarinic agent mainly used for the treatment of parkinsonism and to alleviate the neuroleptic syndrome induced by antipsychotic drugs. A new, rapid analytical method, based on liquid chromatography with diode array detection (DAD), has been developed and applied to the determination of orphenadrine in plasma of schizophrenic patients for therapeutic drug monitoring and toxicological purposes. The chromatographic separation was performed on a pentafluorophenyl reversed phase column with a mobile phase composed of acetonitrile-phosphate buffer mixture. DAD detection was carried out at 220 nm. A careful and rapid solid-phase extraction procedure on cyanopropyl cartridges was chosen for plasma sample purification and pre-concentration obtaining good extraction yield values for the analyte (>96.0%). The assays showed a linear response for orphenadrine (30-1000 ng mL(-1)). The method is also precise and selective. Thus, the method developed seems to be suitable for routine analysis of orphenadrine in psychiatric patients. Moreover, it was applied to plasma samples from a psychotic patient who had tried to poison himself with 1000 mg of orphenadrine and was undergoing polypharmacy.

Acute intoxication with orphenadrine and clozapine.

This report describes a fatal intoxication with two different drugs: clozapine and orphenadrine. A 38-year-old man was found dead in the bedroom of his residence. Near the body were found various empty pharmaceutical boxes, employed in schizophrenic therapy, two of them containing clozapine and orphenadrine. High concentrations of clozapine and orphenadrine detected in blood, urine and gastric content were related to death. These compounds were identified and quantitated by liquid-liquid extraction followed by gas chromatographic/mass spectrometry (GC/MS) analysis.

Central anticholinergic syndrome from orphenadrine in a 3 year old.

Orphenadrine (N,N-dimethyl-2(o-methyl-alpha-phenylbenzyloxy)ethylamine) is an analog of diphenhydramine with central and peripheral anticholinergic properties. It is commonly prescribed both as a muscle relaxant and as an adjunct to antipsychotic medications to prevent parkinsonism. We report a case of orphenadrine poisoning in a 3-year-old boy following ingestion of no more than two 100-mg tablets. Central anticholinergic toxicity was prominent, manifested by hallucinations and severe agitation. Orphenadrine can cause profound toxicity in children after ingestion of small doses, and should be considered as a potential cause for acute delirium in childhood.

Orphenadrine poisoning in a child: clinical and analytical data.

Orphenadrine is an anticholinergic drug used mainly in the treatment of Parkinson's disease. It has a peripheral and central effect and a known cardiotoxic effect when taken in large doses. We report the successful outcome of the treatment of a 2 1/2-year-old girl who accidentally ingested 400 mg of orphenadrine hydrochloride (Disipal). One hour after ingestion she presented neurological symptoms: confusion, ataxic walking, and periods of severe agitation. Generalized tonic-clonic seizures appeared resistant to the administration of multiple antiepileptics. They ceased after a supplementary dose of intravenous diazepam, endotracheal intubation, and mechanical ventilation. An episode of ventricular tachycardia responded well to i. v. lidocaine. Physostigmine was administered in three successive doses. The initial orphenadrine plasma level (3,55 microg/ml) was in the toxic range, associated with high mortality. The calculated elimination half-life was 10.2 h and the molecule and/or its metabolites were found up to 90 h after ingestion.

[Fatalities caused by anticholinergic antiparkinsonian drugs. Analysis of findings in a 11-year national material]. / Dødsfall forårsaket av antikolinerge antiparkinsonmedikamenter. Analysefunn i et nasjonalt 11-årsmateriale.

All autopsy samples received at the National Institute of Forensic Toxicology during the years 1986-1996 which contained anticholinergic antiparkinsonian drugs were reviewed. Of a total of 69 cases, orphenadrine was present in 57 (83%), biperiden in 8 (12%), procyclidine in 3 (4%), and trihexyphenidyl/benzhexol in 1 (1%) of the subjects. The measured concentrations were assessed in light of previously published data. Of 21 cases where causality between drug ingestion and death was classified as either highly probable (18/21) or possible (3/21), all subjects tested positive for orphenadrine. In the autopsy samples from these patients, orphenadrine concentrations in the 4.5-600 mumol/l range (mean 62.5 mumol/l, SD 126.5 mumol/l) were determined. Because of a low national autopsy rate, there is reason to believe that the actual numbers of drug-related deaths in this period may have been significantly higher. It is concluded that orphenadrine is responsible for a disproportionally high number of overdose deaths.

[Clinical pharmacology of anticholinergic antiparkinson agents. A review with emphasis on acute toxicity]. / Antikolinerge antiparkinsonmedikamenters kliniske farmakologi. En oversikt med vekt på akutt toksisitet.

Today, anticholinergic antiparkinsonian drugs are primarily used to ameliorate extrapyramidal side-effects induced by neuroleptic agents. Orphenadrine dominates quantitatively among these drugs in Norway, presumably because it is assumed to carry a lower risk of abuse. There are numerous reports of deaths following orphenadrine overdoses. Orphenadrine has complex pharmacokinetic properties and a narrow therapeutic index. After an overdose, it confers toxic effects of rapid onset to several organ systems. No specific and effective therapy for orphenadrine intoxication has been established. For the two other drugs in this class which are marketed in Norway, biperiden and benztropine, toxicity is mainly connected to their anticholinergic properties. Notably, no reports of lethalities after overdoses of biperiden seem to be available. A small number of accounts of deaths following benztropine intoxication have been published. Neither of these two agents, and benztropine in particular, has been subjected to comprehensive pharmacokinetic evaluations. The relatively extensive use of orphenadrine should be discouraged.

Reversal of orphenadrine-induced ventricular tachycardia with physostigmine.

A 3-year-old boy developed confusion, generalized tonic-clonic seizures, and sustained ventricular tachycardia following ingestion of an unknown quantity of orphenadrine (Norflex). Although refractory to precordial thump, synchronous cardioversion, and lidocaine, the ventricular tachycardia was reversed by intravenous administration of the tertiary acetylcholinesterase inhibitor physostigmine. We discuss the underlying physiology and manifestations of anticholinergic overdose, the specific manifestations of orphenadrine overdose, and the current recommendations regarding the utilization and toxicity of physostigmine in the treatment of anticholinergic syndromes and orphenadrine intoxication.

Life-threatening ventricular arrhythmia (torsades de pointes) after haloperidol overdose.

A 48-year-old woman developed QT prolongation and episodes of life-threatening ventricular tachycardia (torsades de pointes) after intentional overdose of haloperidol and orphenadrine. The arrhythmia did not respond to conventional anti-arrhythmic therapy but was suppressed by atrial overdrive pacing. A literature review identified haloperidol as the most likely cause of the torsades de pointes.

Death caused by orphenadine poisoning.

The number of deaths as a consequence of orphenadine poisoning seems to increase, mostly among severely psychotic males. The lethal dose corresponds to the weekly average dose used in the treatment of neuroleptic extrapyramidal side effects. Based on the literature, the serious, rapidly incipient, cardiac, and neurologic symptoms of poisoning are emphasized. The handing out of orphenadine to suicidal persons must be restricted, and even small overdoses (1-2 g) ought to result in the immediate initiation of observation at an intensive care unit.

Orphenadrine serum levels in a poisoned patient.

A patient ingested about 5 g of orphenadrine hydrochloride. He had gastric lavage and oral administration of activated charcoal. The main symptoms were neuropsychiatric in nature. Possible relation between serum levels of the drug and time course of the toxic effects are described.

[Acute poisoning by orphenadrine]. / Intoxication aiguë par l'orphénadrine.

From January 1974 to June 1983, the Paris Poison Control Centre collected 84 cases of overdosage with orphenadrine alone or in combination. Prior papers emphasized fatalities related to orphenadrine poisoning. This retrospective study suggests an underestimated incidence of anticholinergic drugs abuse in our country. The clinical picture of orphenadrine poisoning associates drowsiness, agitation, confusion, delirium and seizures. Anticholinergic symptoms are often noted: mydriasis, sinus tachycardia, dryness of the mouth and urinary retention. No severe cardiac disturbance was found in these patients.

A report on the analysis of orphenadrine in post mortem specimens.

A discussion of the methods reported for the analysis of orphenadrine is given. The drug levels in biological specimens and the methods reported vary widely. The stability and extractability of orphenadrine is investigated and a method suggested, which uses subtilisin digestion of tissue followed by extraction with 1-chlorobutane. Body fluids are extracted directly by 1-chlorobutane after pH adjustment. Analysis is performed by gas chromatography with a nitrogen selective detector and no interferences are observed from bland specimens. The following levels are results from a case of a 19-year-old male who was found dead 2.5 hours after last being seen alive. This laboratory analysed the case using diphenhydramine as an internal standard: blood 18.1 micrograms/mL, liver 242 micrograms/g, urine 7.0 micrograms/mL, stomach contents 1452 mg.