What is the Best Antidepressant for Nerve Pain?

Key Takeaways

Historically, tricyclic antidepressants (TCAs) are the most commonly used antidepressants for treating neuropathic pain. However, data supporting the use of TCAs for pain relief are outdated.
Duloxetine (Cymbalta) is the only antidepressant FDA-approved for the treatment of neuropathic pain. However, venlafaxine and bupropion are also prescribed for off-label treatment of neuropathic pain.
Anticonvulsants and antidepressants can be used in combination with conventional pain relievers and prescription medications such as gabapentin (Neurontin) and pregabalin (Lyrica) to maximize nerve pain relief.

Several medications are used for the treatment of neuropathic pain (nerve pain), including antidepressants. Please continue reading to find out which antidepressants work best for treating pain that is neuropathic in origin.

Which antidepressants are best for nerve pain?

Some antidepressants that are most effective for neuropathic pain syndromes include:

Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) are the most commonly used antidepressants for the treatment of neuropathic pain. They prevent the reuptake of both serotonin and norepinephrine.

The tertiary amines (amitriptyline, imipramine, doxepin) may be somewhat more effective than the secondary amines (nortriptyline, desipramine). Many people get moderate pain relief at lower doses of TCAs than those used for treating depression.

However, the use of tricyclic antidepressants in clinical practice for pain conditions is limited by their side effects, which include weight gain, orthostatic hypotension (low blood pressure with changes in position), anticholinergic effects (dry mouth, constipation, urinary retention, blurred vision, decreased sweating), and cardiovascular effects, including increased heart rate. Because of these adverse effects, other options should be considered in elderly patients.

Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (SSRIs) mainly prevent the reuptake of serotonin. They are less effective treatment options for neuropathic pain compared to tricyclic antidepressants.

Among SSRIs, paroxetine (Paxil) and citalopram (Celexa) have shown modest effectiveness in people with a neuropathic pain condition. Another SSRI, fluoxetine (Prozac), was found to be ineffective for nerve pain.

Like many antidepressants, SSRIs can cause side effects such as weight gain, sexual dysfunction, and withdrawal symptoms if the drug is discontinued abruptly.

Serotonin Norepinephrine Reuptake Inhibitors

Serotonin norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine (Effexor) can be beneficial for neuropathic pain at doses that are typically used to treat depression.

Venlafaxine may be particularly effective when used with an anticonvulsant drug called gabapentin, which is a first-line treatment for neuropathic pain. Want to learn more about anticonvulsants? Read our blog comparing top seizure medications.

The pain-relieving effects of venlafaxine are comparable to imipramine and other tricyclic antidepressants with milder side effects. Side effects of venlafaxine may include increased blood pressure and withdrawal symptoms if the drug is stopped suddenly.

Another SNRI, duloxetine (Cymbalta), is the only antidepressant approved by the U.S. Food and Drug Administration (FDA) for the treatment of neuropathic pain. It is typically prescribed at doses ranging between 60 mg and 120 mg daily.

There are no head-to-head comparative studies between duloxetine and tricyclic antidepressants evaluating pain relief in people with chronic pain. Common side effects of duloxetine include drowsiness, dizziness, fatigue, and nausea.

Atypical Antidepressants

Atypical antidepressants such as bupropion (Wellbutrin) prevent the reuptake of norepinephrine and dopamine. Studies in patients with neuropathic pain have found that this antidepressant medication has similar effectiveness as tricyclic antidepressants (TCAs). However, bupropion is not safe for people with seizure disorders or eating disorders. Learn what medications can help treat an eating disorder.

Is there any research on the efficacy of antidepressants for nerve pain?

There are studies on the effects of antidepressants such as duloxetine and amitriptyline for chronic pain and nerve pain. However, the trials were small and only lasted a few months.

A meta-analysis was conducted in 2021, analyzing the data of past research to evaluate the safety and efficacy of antidepressants for the treatment of chronic pain. Here’s the finding of this meta-analysis:

TCAs and other antidepressants did not reduce pain and disability from back pain. While TCAs and SNRIs may help with sciatica, the certainty of evidence ranges from low to very low.
The effects of SNRIs on pain and disability are small. On a scale of 0 to 100, antidepressants result in a 4-point improvement in pain.
Participants with chronic pain and depression did not experience more optimal results compared to those with chronic pain alone.
The benefit of antidepressants for osteoarthritis or chronic low back pain and neck pain is very modest and temporary.

Is there a medication that treats both depression and pain?

Yes, some antidepressant medications that are commonly used to treat depression can also treat chronic pain.

Most antidepressants exert their effects by increasing the levels of certain natural chemicals in the central nervous system. Experts believe that these same effects also reduce pain signals and make antidepressant medicines effective for pain management.

Antidepressants are also believed to treat pain through their influence on histamine receptors and sodium channels.

It is worth noting that depression and sleep disturbance are 2-5 times more common in people with chronic pain compared to the general population. Doctors may, therefore, consider prescribing antidepressants for treating neuropathic pain and depression with a single medication.

Which antidepressant is prescribed most often for nerve pain?

The most commonly prescribed antidepressants for the treatment of neuropathic pain are tertiary amines (tricyclic antidepressants) such as amitriptyline (Elavil), imipramine (Tofranil), and doxepin (Sinequan).

Other antidepressant medications, including venlafaxine (Effexor), duloxetine (Cymbalta), bupropion (Wellbutrin), and secondary amines (TCAs) such as desipramine (Norpramin) and nortriptyline (Pamelor) also have nerve pain-relieving effects.

Antidepressant drugs that are only modestly effective for neuropathic pain include SSRIs such as paroxetine (Paxil) and citalopram (Celexa). The SSRI fluoxetine (Prozac) is not effective for nerve pain.

What causes chronic pain that is neuropathic in origin?

Neuropathic pain occurs from changes in pain signals in the central nervous system (brain and spinal cord) or nerve damage in the peripheral nervous system (in the rest of the body). It tends to be a chronic pain (long-lasting) and burning, stabbing, tingling, or electric shock-like in nature.

In contrast, nociceptive pain originates outside the nervous system, for example, from conditions that affect musculoskeletal health, such as knee osteoarthritis. It tends to be aching and throbbing in nature.

Very often, neuropathic pain is diabetic peripheral neuropathic pain. It is caused by damage to the peripheral nerves by high blood sugar levels in people with diabetes.

In addition to diabetic neuropathy, many other chronic pain conditions can cause neuropathic pain. Common causes include peripheral neuropathy, postherpetic neuralgia from shingles, alcohol use disorder, conditions affecting the facial nerve, nerve compression, nerve inflammation, tumors pressing on a nerve, trauma or injury to nerves, postoperative pain, HIV/AIDS, conditions of the central nervous system, such as stroke, multiple sclerosis, or Parkinson’s disease, chemotherapy and radiation therapy, and phantom limb pain in people with amputations.

What is the drug of choice for neuropathic pain?

Your doctor may use a combination of medications to manage your neuropathic pain. They may start you on a low dose and increase to higher doses, if needed, based on your response. It takes a nuanced approach to find the medications and doses that work best.

Some of the drugs that have positive effects on neuropathic pain include:

Over-the-counter pain medications such as acetaminophen and nonsteroidal anti-inflammatory drugs such as ibuprofen.
Anticonvulsant medications such as gabapentin (Neurontin) and pregabalin (Lyrica). Trying to decide on Pregabalin vs. gabapentin? What’s the difference?
Antidepressant prescriptions (as listed above).
Topical medications such as capsaicin and lidocaine applied to the affected area in the form of creams, ointments, or patches.

Other measures such as physical therapy, massage, exercise, and psychological counseling are also useful in treating pain.

If medications do not control neuropathic pain, healthcare providers may offer nerve blocks, nerve stimulation, or surgery to remove painful nerves.

What is the strongest drug for nerve pain relief?

There are no head-to-head clinical trials to explore the efficacy of medications for nerve pain.

However, doctors may choose to add an anticonvulsant or an antidepressant to the use of conventional pain medications.

Keep in mind that the only antidepressant that is FDA-approved for neuropathic pain is duloxetine (Cymbalta). Other antidepressant drugs are used off-label for nerve pain.

Talk to your doctor if you are prescribed an antidepressant for chronic pain but experience minimal relief or are not sure they are working.

Never stop taking them on your own since many of these antidepressants and anticonvulsants need to be slowly tapered over time (gradually reduce the dosing) to avoid unpleasant withdrawal effects.

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