Venlafaxine

Venlafaxine is a serotonin and noradrenaline reuptake inhibitor (SNRI) structurally unrelated to the SSRIs or TCAs. Unlike SSRIs, which have relatively low toxicity in overdose when taken on their own venlafaxine appears to be proconvulsant in overdose with 5 - 14% of venlafaxine poisonings having a seizure. The most common morbidity is due to an excess of serotonin in the synapses. This gives rise to a constellation of the clinical signs of serotonin toxicity. Serotonin toxicity occurred in 29% of patients with overdoses of venlafaxine alone in one study. The symptoms of an agitated delirium, tremor, clonus & fever (plus other symptoms) can be distressing. The occurrence of serotonin toxicity identifies a subset of patients with significant toxicity who are at risk of acute respiratory failure & death. Severe toxicity is more likely when SSRI are taken with other serotonergic drugs .

The FTI (fatal toxicity index, deaths per million prescriptions) for venlafaxine is significantly higher than the FTI of SSRIs, other atypical antidepressants (data not available for bupropion or St John’s Wort) and in the range of some of the less toxic TCAs at 13.2 (CI 9.2 to 18.5).

Co-ingestions of venlafaxine & monoamine oxidase inhibitors in any amount are high risk. See drug interactions causing serotonin toxicity.

Venlafaxine is a bicyclic antidepressant structurally and pharmacologically related to the non-opioid analgesic tramadol, but not to any conventional anti-depressant medications. Both venlafaxine and its major metabolite, o-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and noradrenaline reuptake and weak inhibitors of dopamine reuptake (serotonin > noradrenaline » dopamine). Venlafaxine has no notable monoamine oxidase inhibitor activity and minimal affinity for muscarinic, cholinergic, histamine or a1- and a2-adrenergic receptors. It does however have a dose-dependent blocking effect on sodium channels.

The mechanism of seizure activity is unclear. Animal models suggest the cardiotoxicity and QRS widening are due to Na+ channel blockade which is dose dependent.

Most other adverse effects are due to excessive concentrations of serotonin, particularly in the central nervous system. The receptor that appears to be most important in toxicity symptoms is 5-HT2a. As other aspects of serotonin production and metabolism are unaltered, toxicity is minor unless there is increased production of serotonin or inhibition of serotonin metabolism. See serotonin toxidrome.

Venlafaxine is only available as an extended release preparation in Australia. Absorption from the gastrointestinal tract is good (more than 90% of an oral dose is absorbed rapidly) but bioavailability at therapeutic doses is relatively low at 42% due to high first pass liver metabolism. Bioavailability can potentially be reduced by a factor of 29% with the use of a single dose of activated charcoal (SDAC) and whole bowel irrigation (WBI). Whilst both reduce the peak plasma concentration seen in overdose the combination had a greater effect and is thus in practice likely to be more efficacious in preventing toxicity.

Plasma protein binding is low for venlafaxine (27%) and for ODV (30%). Volumes of distribution are large (7.5 L/kg (V) and 5.7 L/kg (ODV)).

Venlafaxine is metabolised to ODV by CYP2D6 with both parent and metabolites excreted in urine.

A study based on 76 ingestions to a regional toxicology service found the half life in overdose to be 12.9 hours and also showed a 35% increase in clearance with the use of SDAC.

The highest recommended dose for venlafaxine is 225 mg/day. Plasma concentrations during therapeutic use are approximately 30 to 70 microg/L. Adverse effects in therapeutic use are predominantly those attributable to serotonergic effects such as nausea, nervousness, dizziness, sweating, and insomnia. In addition dry mouth, hypertension and sedation are common.

A detailed prospective clinical study of 51 sequential venlafaxine poisonings from a single centre found the common findings were seizures, serotonergic toxicity, and minor ECG changes with little or no anticholinergic or sedative effect.

In overdose, venlafaxine has minimal CNS depression but can cause agitation as part of the spectrum of serotonin toxicity as well as significant seizure activity. Toxicity may be delayed for a significant period of time due to the extended release nature of the preparation.

The occurrence of serotonin toxicity is not necessarily an indication for specific treatment although it does identify a group of patients who require close observation as serotonin toxicity can be life threatening.

The occurrence of fever & respiratory failure (associated with muscle rigidity) are poor prognostic features. Fortunately they occur relatively rarely and usually with large ingestions.

Complications of serotonin toxicity include:

• Severe hyperthermia
• Dehydration
• Seizures from serotonin toxicity alone are rare (note: if the patient is conscious repeated muscle activity is more commonly spontaneous continued clonus)
• Injuries while delirious (self-inflicted or iatrogenic)
• Respiratory failure

Seizures are a feature of venlafaxine overdose. A study which looked at 319 patients who ingested venlafaxine on 436 occasions found an overall incidence of 5%. The probability of seizures increases with increasing dose ingested however decontamination with SDAC either with or without WBI was found to reduce this risk. Most seizures appear to occur within 16 hours of ingestion but may potentially occur for up to 24 hours. They are usually self limited in nature and respond to parenteral benzodiazepines.

The probability of seizures from venlafaxine (Kumar et al 2011):

Venlafaxine has been reported to cause cardiotoxicity with fatal ventricular fibrillation having been produced by an ingestion of 8.4g. Other cases involving ventricular arrhythmias have also ingested very large (> 7g) overdoses.

However a review of data from 369 ECGs in 273 ingestions with a median ingested dose of 1500 mg (range 75mg to 13 500mg), showed that only minor cardiovascular effects were observed. Abnormal QT heart rate pairs were only observed in 22 (6%) of patients when plotted on the QT Nomogram. This contrasted with a previous study which suggested Venlafaxine caused QT prolongation in overdose, based on calculation of QTc values on ECG. However such a finding is likely to be spurious as the calculation of the QTc is known to be erroneously high in patients with tachycardia which is also a key finding in Venlafaxine overdose.

The small number of patients who developed a QRS duration > 120 ms had ingested > 5g and hence consistent with previous cases showing that cardiotoxicity was related to significant dose ingestions.

Patients ingesting venlafaxine who develop an abnormal ECG (increased QRS duration) should be monitored until the ECG returns to normal. This is much more likely in ingestions > 5g and cardiac monitoring should be considered routinely in large ingestions however is not necessary for the more common smaller ingestions.

Patients with serotonin toxicity should have electrolytes, creatine phosphokinase & assessment of ventilation.

Includes poisoning with any other serotonergic drug, all causes of serotonin toxicity and tricyclic antidepressants.

Treatment is a combination of supportive care. Serotonin antagonists can be considered in more severe cases.

The use of serotonin antagonists appears to avoid the need for aggressive intervention in some cases and reduces symptoms of toxicity in most patients. Since chlorpromazine can theoretically lower the seizure threshold it should be used with considerable caution in venlafaxine poisoning.

• IV access & fluids
• Titrated benzodiazepines to manage agitation and muscle rigidity
• In more severe cases patients with serotonin toxicity may require aggressive treatment which may include ventilation, paralysis & active cooling in severe cases
• Our experience is that patients with extreme rigidity, carbon dioxide retention and hypotension respond well to muscle paralysis and ventilation

Oral activated charcoal should be given to all patients ingesting more than 1,000 mg of venlafaxine who present within 2 hours
Activated charcoal should be given to any patients who co-ingest venlafaxine with a monoamine oxidase Inhibitor.

Whole bowel irrigation should be given to patients who have ingested more than 60 mg/kg or 7 grams of the extended release preparation. As there is a risk of seizure patients should be intubated to protect the airway.

No specific antidote exists for venlafaxine induced cardiac arrhythmias, although intravenous sodium bicarbonate and calcium appeared effective in one case. Sodium bicarbonate would seem the preferred agent given it has much less toxicity, fewer contraindications and is accepted as effective in treating many other sodium channel blocking drugs. Thus, treatment of tachy & bradyarrhythmias should be similar to that used in TCA poisoning with alkalinisation as the first line therapy.

High dose benzodiazepines followed by barbiturates are the preferred agents for refractory seizures. The use of sodium channel blocking drugs (e.g. phenytoin, carbamazepine) to control seizures might contribute to cardiotoxicity and these drugs are generally ineffective in drug-induced seizures.

There is no evidence of enhanced elimination with forced diuresis, urinary pH manipulation, haemodialysis or haemoperfusion.

Discharge after clinical toxicity has resolved. There are no specific long term sequelae.

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