How Long Does Nortriptyline Take to Work For Pain?

Nortriptyline is a tricyclic antidepressant (TCA) approved by the US FDA for the treatment of depression, but your doctor may also prescribe it for persistent pain, such as peripheral neuropathy, fibromyalgia, and postherpetic neuralgia. It may take days or weeks for tricyclic drugs to take effect, so it is not recommended for acute pain.
Antidepressants are mainly used for treating major depressive disorder, anxiety, and other mood disorders. They are often categorized based on their mechanism of action; each group/class of antidepressant work in different ways:

  • Monoamine Oxidase Inhibitors (MAOI) – iproniazid, harmaline, moclobemide, selegiline;
  • Dopamine Reuptake Inhibitors (DRI)– bupropion, amineptine;
  • Serotonin-Norepinephrine Reuptake Inhibitors (SNRI) – duloxetine, nefazodone, venlafaxine;
  • Selective Serotonin Reuptake Inhibitors (SSRI) – alaproclate, citalopram, fluoxetine, paroxetine, sertraline;
  • Selective Serotonin Reuptake Enhancer (SSRE) – tianeptine;
  • Tricyclic Antidepressant (TCA)– amitriptyline, desipramine, doxepin, imipramine, nortriptyline, opipramol;
  • Tetracyclic Antidepressants – amoxapine, maprotiline.

Some antidepressants are also categorized as “atypical.” These are drugs that do not act in a typical manner relative to most antidepressants in their class. Examples of atypical antidepressants include bupropion, mirtazapine, trazodone, agomelatine, and tianeptine. Antidepressive agents that work for chronic pain are referred to as “pain-active” antidepressants. Chronic pain is typically defined as pain lasting for at least three to six months. It can be neuropathic, non-neuropathic, or due to an abnormality of pain processing, or a combination of all these.

What is neuropathic pain?

In 2008, the definition for neuropathic pain was revised from “pain initiated or caused by a primary lesion or dysfunction in the nervous system” to “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.” The term “dysfunction of the nervous system” was removed from the International Association for the Study of Pain (IASP) definition to make the diagnosis more specific. The revision was led by NeupSIG, the special interest group on neuropathic pain of IASP. Nerve pain is not a single disease entity but a syndrome of pain and other sensory symptoms with multiple potential causes.
The characteristic of neuropathic pain may be different from patient to patient. Some individuals describe it as a “stabbing” pain in the middle of the night. Other people may experience chronic prickling, burning, or tingling sensation that lasts all day. Without adequate treatment, nerve pain can be unbearably painful. Simple analgesics are not effective for this type of pain. Examples of neuropathic pain syndromes include:

  • Tumor growth around nerve structures;
  • Post-surgical pain syndromes (post-mastectomy, post-radical neck dissection, post-hepatectomy);
  • Pain caused by chemotherapy drugs.

TCAs are the most studied antidepressant for the treatment of chronic pain. It is also recommended as one of the first-line agents for peripheral neuropathic pain. Other first-line treatment options include SNRIs (venlafaxine, duloxetine), and topical lidocaine.

Efficacy of safety of TCAs for chronic pain

The efficacy of TCAs for neuropathic pain was first established in the 1980s. But researchers reported a case series in 1962 in which imipramine provided 60% to 70% pain relief among patients with non-articular rheumatism. In another study, amitriptyline (the parent drug of nortriptyline) was able to relieve diabetic nerve pain in patients with normal or depressed mood. It was found that the analgesic effects (pain relief) of TCAs occur more rapidly, about a week or less, at lower doses than those used for antidepressive effects. Aside from pain relief, TCAs have the ability to elevate mood, normalize sleep patterns, and cause muscle relaxation—making it a beneficial adjunct for pain management in patients with concomitant mood disorder.

Mechanism of action

The analgesic effect of TCAs can be due to their various pharmacological actions:

  • Serotonergic – inhibits reabsorption of serotonin;
  • Noradrenergic – interacts with α receptors;
  • Adenosine receptor action – inhibits reuptake of adenosine;
  • Opioidergic properties;
  • Anti-inflammatory properties.

Each drug in the group differs in their effectiveness and propensity to cause side effects. For post-herpetic neuralgia and painful diabetic neuropathy, amitriptyline and nortriptyline are equally effective, but the latter have fewer side effects. The increased adverse effects associated with TCAs reduces patient compliance. While SSRI have lesser side effects, they are somewhat ineffective for chronic pain. SNRIs have a relatively low risk for side effects and a higher chance of relieving symptoms.


The rule of thumb in taking TCAs for chronic pain is to “start low and go slow.” The initial dose for nortriptyline is 10–25mg in a single dose at bedtime. The dose can be titrated upwards with 10–25mg steps every three to seven days until notable pain relief is achieved, or intolerable side effects appear. Your doctor may prescribe a different starting dose than the one listed here. Strictly follow the prescription instructions given to you and do not stop taking your nortriptyline medication without your doctor’s advice.