Archives of Academic Emergency Medicine. 2022; 10(1): e14

LE T T E R TO ED I TO R

Intravenous Lipid Emulsion for treating Tramadol-
Induced Seizures: Surprising but Worth Considering for
Future Studies; a Letter to Editor
Bruno Mégarbane1∗, Ahmed S. Gouda2

1. Department of Medical and Toxicological Critical Care, Lariboisière Hospital; Paris, University; INSERM UMRS-1144, Paris, France.

2. National Egyptian Center for Toxicological Researches, Faculty of Medicine, University of Cairo, Cairo, Egypt.

Received: January 2022; Accepted: January 2022; Published online: 9 February 2022

Cite this article as: Mégarbane B, S. Gouda A. Intravenous Lipid Emulsion for treating Tramadol-Induced Seizures: Surprising but Worth

Considering for Future Studies; a Letter to Editor. Arch Acad Emerg Med. 2022; 10(1): e14. https://doi.org/10.22037/aaem.v10i1.1541.

Dear Editor;

We read with interest the article reporting benefits of intra-

venous lipid emulsion (ILE) in preventing tramadol-induced

in-hospital seizures in poisoned patients (1). We would first

like to congratulate the authors for this impressive random-

ized investigation. However, we wish to comment on their

findings.

The main presumed mechanism of action for ILE in acutely

poisoned patients, named “lipid sink”, is limiting tissue

distribution of lipophilic drugs potentially causing toxicity.

Based on an in vitro model, ILE’s ability to sequester a drug

was shown to parallel its octanol-water partition coefficient

(2), defined as the ratio of its concentration in a water-

saturated octanolic phase to its concentration in an octanol-

saturated aqueous phase and usually expressed as “LogP”.

Prediction of drug binding with ILE was additionally im-

proved by combining its LogP with volume of distribution

(VD), together accounting for 88% of ILE-attributed varia-

tion in its serum concentration decrease (2). With a LogP of

1.34 (3), only 1% decrease in serum tramadol level should be

expected with ILE. By combining its LogP and VD of 2.7L/kg

(3), predicted lipid extraction efficiency would also remain

extremely low (<10%), precluding any important clinical ben-

efit. Noteworthy, this issue would have been different in case

of much more lipophilic opioids such as fentanyl (LogP of

4.05 and VD of 4L/kg), with a predicted ILE-related decrease

in serum concentration of >40% (2, 3).

Another issue when considering ILE to reverse toxicity af-

∗Corresponding Author: Bruno Mégarbane; Hôpital Lariboisière, Réanima-
tion Médicale et Toxicologique, 2 Rue Ambroise Paré, 75010 Paris, France.
E-mail: Bruno.megarbane@lrb.aphp.fr, ORCID: https ://orcid.org/0000-0002-
2522-2764 .

ter oral exposure is the delay between ingestion and hospi-

tal admission, which is important since patients are usually

referred after the onset of the first toxic symptoms. Man-

agement commonly starts at a time in the poisoning course

when the drug distribution phase is almost complete. How-

ever, ILE’s ability to redistribute the toxicant from its target

organs is much more controversial.

Although tramadol causes a high risk of seizure, seizure event

rate in tramadol-overdosed patients was determined at 38%

(95%CI: 27- 49) versus 37% (95%CI: 12 - 62) in tramadol

abusers and 3% (95%CI: 2 - 3) in users with therapeutic

dosage (4). Seizure risk is dose-dependent, more marked in

patients with existing seizure disorders or previous seizure

history. Various co-ingestions such as serotonergic medi-

cations may increase the risk, while benzodiazepines, fre-

quently used in addicts, may decrease it. These observations

suggest that one in three tramadol-exposed patients admit-

ted to the emergency department is actually at risk of seiz-

ing. In Kazemifar’s trial, 56% of the included patients seized

before receiving one of the two arm treatments and 37% of

the controls presented in-hospital seizures (1). In this view,

patients included in the study appeared at an unusually ele-

vated risk of seizing, especially given the relatively low mean

ingested tramadol dose reported with a huge standard devi-

ation (229 ± 135 mg in the intervention and 195 ± 156 mg in

the control group, whereas the pharmacological single dose

is 100 mg and the daily dose 400 mg).

Tramadol typically results in early, single, brief, self-limiting

generalized tonic-clonic seizures, often occurring within 4-

6h post-ingestion (5). Multiple seizure risk is also low

(6). Clinical toxicologists even stated the lack of need to

administer anticonvulsants for seizure prophylaxis beyond

that required for treating ongoing convulsions or other co-

morbidities in tramadol-poisoned patients who presented an

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B. Mégarbane et al. 2

initial seizure (6). Interestingly, a decision tree based on read-

ily available parameters on admission was published in the

journal to help clinicians identifying tramadol-poisoned pa-

tients at high risk for seizure (area under the ROC curve =

0.77; 95%CI: 0.67–0.87) to possibly treat them with prophy-

lactic anticonvulsants (7).

Current recommendations on ILE use were published by

an international collaborative workgroup supported by the

American and European societies of clinical toxicology (8).

When managing life-threatening toxicity, guidelines recom-

mended not using ILE as first-line therapy. As part of treat-

ment modalities and if other therapies fail, guidelines rec-

ommended using ILE only in bupivacaine toxicity, but sug-

gested using ILE for toxicity due to other local anesthet-

ics, amitriptyline, and bupropion. Recommendations were

neutral for all other toxins and variable for the manage-

ment of non-life-threatening toxicity, relying on the expected

risk/benefit balance for each involved toxicant.

Despite possible biases and surprising results, Kazemi-

far’s findings (1) clearly question whether tramadol-induced

seizure prophylaxis should be added to the list of ILE indica-

tions. Alternatively, in tramadol-poisoned patients at risk of

seizures or respiratory depression, more specific antidotes,

i.e., naloxone, diazepam, or their combination, might also

be considered, as suggested in a rat model (9). Therefore, to

improve tramadol-poisoned patients’ management, further

randomized studies with better design and larger cohorts,

comparing ILE with alternative therapeutic strategies should

be considered.

1. Declarations

1.1. Acknowledgment

None.

1.2. Authors’ contributions

Bruno Mégarbane wrote the first draft. Ahmed S. Gouda

commented on the draft. Both authors agreed with the final

version of the manuscript.

1.3. Financial disclosure

The authors declare no financial interests in relation to the

manuscript.

1.4. Funding support

None declared.

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	Declarations
	References