From the Guidelines
Using nortriptyline and duloxetine together is not recommended due to the increased risk of serotonin syndrome and other adverse effects, and alternative treatment options should be considered first, as suggested by the Mayo Clinic Proceedings guidelines 1. When considering the treatment of neuropathic pain, the guidelines recommend initiating therapy with one or more of the following: a secondary-amine TCA (nortriptyline, desipramine) or an SSNRI (duloxetine, venlafaxine) 1. However, combining these medications can lead to excessive serotonin accumulation and increase the risk of serotonin syndrome, a potentially serious condition. Some key points to consider when treating neuropathic pain include:
- Assessing pain and establishing the diagnosis of neuropathic pain
- Identifying relevant comorbidities that might be relieved or exacerbated by treatment
- Explaining the diagnosis and treatment plan to the patient and establishing realistic expectations
- Initiating therapy with one or more of the recommended first-line medications, such as nortriptyline or duloxetine, but not necessarily together 1. The guidelines also recommend reassessing pain and health-related quality of life frequently and adjusting treatment as needed, which may include adding or switching medications 1. In terms of specific medications, nortriptyline is a secondary-amine TCA that has been shown to be effective in treating neuropathic pain, but it can have cardiac toxicity and requires caution in patients with ischemic cardiac disease or ventricular conduction abnormalities 1. Duloxetine, on the other hand, is an SSNRI that has been shown to be effective in treating painful diabetic neuropathy and has a simpler dosing regimen, but it can cause nausea and other adverse effects 1. Overall, while nortriptyline and duloxetine can be effective treatments for neuropathic pain, combining them is not recommended due to the increased risk of adverse effects, and alternative treatment options should be considered first, as suggested by the Mayo Clinic Proceedings guidelines 1.
From the FDA Drug Label
Drugs Metabolized by CYP2D6 — Co-administration of duloxetine delayed-release capsules with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), phenothiazines and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with duloxetine delayed-release capsules
Co-administration of duloxetine and nortriptyline should be approached with caution. Plasma nortriptyline concentrations may need to be monitored and the dose of nortriptyline may need to be reduced if co-administered with duloxetine 2.
From the Research
Combination of Nortriptyline and Duloxetine
- There is no direct evidence in the provided studies regarding the combination of nortriptyline and duloxetine.
- However, the studies provide information on the pharmacology and safety of duloxetine, which can be used to infer potential interactions with other medications.
- Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor, and its use with other medications that affect serotonin and norepinephrine levels should be done with caution 3, 4.
- Nortriptyline is a tricyclic antidepressant that also affects serotonin and norepinephrine levels, and its combination with duloxetine may increase the risk of serotonin syndrome or other adverse effects.
- A study on serotonin syndrome associated with the combination of tramadol and antidepressants suggests that the risk of serotonin syndrome is higher with certain combinations of medications, but it does not provide specific information on the combination of nortriptyline and duloxetine 5.
- Another study on the efficacy of antidepressants for chronic pain management found that duloxetine was consistently the highest-ranked antidepressant for pain relief, but it does not provide information on the combination of duloxetine with other medications 6.
- A meta-analysis comparing mirtazapine with selective serotonin reuptake inhibitors for the treatment of major depressive disorder found that mirtazapine and SSRIs differ with respect to their side-effect profile but not their overall efficacy in the treatment of MDD 7.