What are the major interactions between valproate and amitriptyline (Elavil)?

From the Guidelines

Valproate and amitriptyline can have significant interactions that require careful monitoring when used together, with valproate potentially increasing amitriptyline blood levels and leading to toxicity. When considering the combination of valproate and amitriptyline, it is crucial to understand the potential interactions between these two medications. The primary concern is that valproate can inhibit the metabolism of amitriptyline through the cytochrome P450 enzyme system, potentially leading to increased amitriptyline blood levels and toxicity 1. This interaction may result in an increased risk of side effects such as sedation, confusion, anticholinergic effects (dry mouth, constipation, blurred vision), and cardiac conduction abnormalities.

Some key points to consider when using valproate and amitriptyline together include:

• The potential for increased risk of serotonin syndrome, characterized by agitation, confusion, rapid heart rate, high blood pressure, dilated pupils, and muscle rigidity
• The additive effect of central nervous system depression, which may be more pronounced when these medications are used in combination
• The need for careful dose adjustment, potentially starting with lower initial doses of amitriptyline (25-50% reduction may be appropriate)
• The importance of monitoring blood levels if available and watching closely for signs of toxicity
• Patient education on potential side effects and the need to report symptoms like excessive drowsiness, confusion, irregular heartbeat, or severe constipation immediately

While the combination of valproate and amitriptyline may be beneficial in certain cases, such as for patients with bipolar depression or certain pain syndromes, it is essential to approach this combination with caution and careful management, as supported by recent studies on combination therapies for neuropathic pain 1.

From the FDA Drug Label

Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate.

The major interactions between valproate and amitriptyline are:

• Decreased plasma clearance of amitriptyline by 21%
• Decreased net clearance of nortriptyline by 34%
• Increased amitriptyline levels
• Rare association with toxicity Key considerations for co-administration include:
• Monitoring amitriptyline levels
• Potential dose reduction of amitriptyline/nortriptyline 2

From the Research

Major Interactions between Valproate and Amitriptyline

• The combination of valproate and amitriptyline can lead to a significant increase in amitriptyline and nortriptyline serum levels 3, 4.
• This increase in serum levels can be attributed to the decreased first-pass metabolism and inhibition of systemic metabolism of amitriptyline by valproate 4.
• The elevated nortriptyline plasma levels can also be due to the modest inhibition of nortriptyline elimination by valproate 4.
• As a result, a lower dose of amitriptyline may be considered when valproate is administered concomitantly to avoid adverse effects such as anticholinergic delirium 3, 4.
• Therapeutic drug monitoring is advisable when combining valproate and amitriptyline to ensure safe and effective treatment 3.

Clinical Implications

• The interaction between valproate and amitriptyline can have significant clinical implications, particularly in patients with psychiatric or neurologic conditions who are commonly prescribed both medications 3, 4.
• Healthcare providers should be cautious when prescribing valproate and amitriptyline together and monitor patients closely for signs of adverse effects or toxicity 3, 4.
• Further studies are needed to fully understand the mechanisms and clinical significance of the interaction between valproate and amitriptyline 3, 4.