Tricylic Antidepressant Therapy for Depression and Neuropathic Pain

Tricyclic Antidepressant Therapy for Depression and Neuropathic Pain
by Wise Young, PhD MD
W. M. Keck Center for Collaborative Neuroscience
Rutgers University, 604 Allison Rd, Piscataway, NJ 08854-8082
16 December 2008, last revised 20 December 2008

Many people take tricyclic antidepressant drugs for neuropathic pain and for depression. They are called tricyclic antidepressant (TCA) because they are small molecules with three rings.  The original tricyclic antidepressant was imipramine.  Members of the drug family include amitriptyline (also called Elavil, Endep, Tryptanol, Tripiline, Amyzol) , desipramine (norpramin, pertograne), doxepin (Adapin, Sinequan), nortriptyline (Aventyl, Pamelor, Noritren), and many others.  In this article, I will review their use, mechanism, toxicity, and withdrawal.

Mechanisms of Action

The mechanisms of tricyclic antidepressants were not well understood until recently. They are believed to block the re-uptake of neurotransmitters norepinephrine and serotonin by neurons but not dopamine.  They may also bind to muscarinic and histamine H1 receptors.  While the pharmacological effects of the drugs can often be seen immediately, anti-depressive effects are typically not seen for several weeks.

When neurons release catecholaminergic neurotransmitters (e.g. serotonin, norepinephrine), the length of time that they act depends on the speed with which they are broken down (by monoamine oxidase) and are taken up the neurons (re-uptake).  A family of proteins called biogenic amine transporters take up catecholaminergic neurotransmitters.

Tricyclic antidepressants bind to biogenic amine transporters and interfere with re-uptake of neurotransmitters.  Thus, these drugs are like the serotonin uptake blockers except that they are less selective.   It is possible that they may have other mechanisms of action at lower doses.

Treatment for Depression

In 2004, Moncrieff, et al. [1] did a Cochrane Review of 9 clinical trials from 1990-2000, involving 751 participants and comparing TCA drugs.  Combining the studies showed consistent and significant effects of antidepressant drugs.  One the trials was strongly positive, skewing the other results.  If this trial were removed, this reduced the effect. Conservative analyses suggest small drug effects and a large placebo effect on depression.

In 2007, Bramness, et al. [2] assessed the relationship between antidepressant sales and suicide rates in Norway.  Sales of non-tricyclic antidepressants (non-TCA) and suicides were clearly negatively related, i.e. increased sales of the non-TCA was associated with decreases of suicide.  Mottram, et al. [3] examined elderly patients and found that TCA compared less favorably due to high withdrawal rate from side-effects.

In 2008, Nieuwenhuijsen, et al. [4] did a Cochrane Review of 2556 participants in randomized clinical trials examining interventions in depressed workers.  They found no evidence of an effect of medication alone, enhanced primary care, psychological interventions, or combinations of these.

Treatment for Neuropathic Pain

In 2007, Saarto & Wiffen [5] updated a 2005 Cochrane Review on the effects of antidepressant drugs on neuropathic pain.  The review included  61 trials of 20 antidepressants (3293 participants) and concluded that  TCA drugs provided significant but moderate pain relief.  There was limited evidence for efficacy of selective serotonin uptake blockers for treatment of neuropathic pain.  One of three patients given a TCA drug or venlafaxine achieved moderate pain relief.

In 2006, the European Federation of Neurological Societies [6] reviewed clinical trial evidence and concluded that there was level A evidence for efficacy of TCA, gabapentin, pregabalin, and opioids for neuropathic pain.  In addition, some evidence supported the use of topical lidocaine for post-herpetic syndrome and venlafaxine and duloxetine for diabetic neuropathy.

In 2005, Namaka, et al. [7] proposed a treatment algorithm whereby the first-line therapies included tricyclic antidepressants, anti-epileptic drugs, topical anti-neuralgics, and analgesics.  If the patient does not respond to treatment with at least 3 different agents within a drug class, agents from a second drug class may be tried.  Patients that do not respond to monotherapy may respond to combinations.  This is now widely accepted.

Toxicity of TCA

Because TCA is the lowest cost first-line therapy, they are tried in almost all patients with depression and neuropathic pain.  From this perspective, it is paramount that the toxicity and interaction of TCA drugs with other drugs be considered in planning treatment programs.

  1. Monoamine oxidase (MAO) inhibitors.  Nortriptyline should not be used in concurrently with a MAO inhibitor because the combination can cause high body temperatures (hyperpyretic crisis), severe convulsions, and fatalities.  All MAO inhibitors should be discontinued at least two weeks for Nortriptyline is started.  Some MAO drugs include isoarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate).
  2. Hypersensitivity.  Patients that are hypersensitive to dibenzazepine may also be allergic to nortriptyline.
  3. Myocardial infarction. Nortriptyline should not be given during the acute recovery period after MI.
  4. Alcohol consumption.  Alcohol potentiates the effects of nortriptyline and may lead to increased suicide attempts or overdoses.
  5. Schizophrenia.  Patients with schizophrenia may have an exacerbation of their psychosis.
  6. Manic depression.  Nortriptyline may cause symptoms of the manic phase to emerge, as well as patient hostility and epilepiform seizures.
  7. Anti-cholinergic and sympathomimetic drugs.  Close supervision is required when nortriptyline is used with anti-cholinegic and sympathomimetic drugs since TCA drugs influence the effects of these drugs on multiple systems.
  8. Suicide.  If a depressed patient has a history of suicide, it is important that the least possible quantity of drug be dispensed at any given time because depressed patients often take high doses of tricyclic antidepressants for suicide.
  9. Diabetes.  Both elevation and lowering of blood sugar levels have been reported with nortriptyline.

The major difference between TCA use for depression and neuropathic pain is dose.  For example, the typical doses of amitriptyline used for depression and neuropathic pain are 125 mg/day and 25 mg/day respectively.  Rintala, et al. [8] found that amitriptyline (25-50 mg/day) was significantly better than placebo or gabapentin for relieving chronic neuropathic pain in persons with spinal cord. At the doses, side effects should be less.

Drug Interactions and Adverse Reactions

Tricyclic antidepressants enhances the effects of many drugs because it interferes with neurotransmitter uptake.  However, some drugs interfere with metabolism of tricyclic antidepressants.

  • Cimetidine increases plasma concentrations of tricyclic antidepressants.
  • Chlorporamide (250 mg/day) and nortriptyline (125 mg/day) may be associated with significant hypoglycemia in a patient with type II diabetes.
  • Amitriptyline enhances the effects of alcohol and other CNS depressants.
  • Amitriptyline and disulfiram may cause delirium.

Common side-effects include drowsiness, dizziness, insomnia, blurred vision, rash, and dry moth.  High doses of tricyclic antidepressants have the following adverse reactions:

  • Cardiovascular:  hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, and stroke.
  • Psychiatric:  confusion states with hallucination, disorientation, delusions, anxiety, restlessness, agitation, insomnia, panic, nightmares, hypomania, exacerbation of psychosis.
  • Neurologic:  numbness and tingling (paresthesias) of the limbs, discoodination, ataxia, tremors, peripheral neuropathy, extrapyramidal symptoms, seizures, EEG alterations, and tinnitus
  • Anticholinergic:  Dry mouth, sublingual adenitis, blurred vision, changes in accomodation, mydriasis, constipation, paralytic ileus, urinary retention, delayed micturition (urination).
  • Allergy.  skin rash, petechiae, urticaria, photosensitization, edema (face and tongue), drug fever, cross-sensitivity to related drugs.
  • Hematologic.  Bone marrow depression, agranulocytosis, eosinophilia, purpura, thrombocytopenic purpura.
  • Gastrointestinal.  Nausea, vomiting, anorexia, epigastric distress, diarrhea, strange taste,
  • Endocrine
  • Others

Abrupt withdrawal of tricyclic antidepressants can cause withdrawal symptoms and the drug should be slowly discontinued over a period of time.  However, this is usually for relatively high doses of the drug, i.e. 125 mg/day.  At the low doses (10-20 mg/day) that are used for neuropathic pain, ramping down may not be necessary.

Summary and Conclusions

Tricyclic antidepressant (TCA) drugs are commonly used for depression and neuropathic pain.  In depression, they do have significant but modest effects on depression, in part because of strong placebo effects.  In neuropathic pain, however, tricyclic antidepressants have been found to be as good or better than other therapies, including anti-epileptic drugs like gabapentin and pregabalin.  However, only about a third of patients responded to TCA drugs and it provides only moderate pain relief.  On the other hand, TCA drugs are often used in combination with other drugs.  In general, TCA has more side-effects than selective serotonin re-uptake inhibitors (SSRI) and the drugs are deadly when taken in overdose.  The TCA dose of neuropathic pain is much lower than for depression and therefore should cause less side-effects and may not require systematic staged withdrawal.  On the other hand, TCA drugs interact with many drugs even at low doses and therefore treatment programs with TCA must be carefully designed and regularly reviewed.    


  1. Moncrieff J, Wessely S and Hardy R (2004).  Active placebos versus antidepressants for depression.  Cochrane Database Syst Rev CD003012.
  2. Bramness JG, Walby FA and Tverdal A (2007).  The sales of antidepressants and suicide rates in Norway and its counties 1980-2004.  J Affect Disord 102: 1-9.
  3. Mottram P, Wilson K and Strobl J (2006).  Antidepressants for depressed elderly.  Cochrane Database Syst Rev CD003491.
  4. Nieuwenhuijsen K, Bultmann U, Neumeyer-Gromen A, Verhoeven AC, Verbeek JH and van der Feltz-Cornelis CM (2008).  Interventions to improve occupational health in depressed people.  Cochrane Database Syst Rev CD006237.
  5. Saarto T and Wiffen PJ (2007).  Antidepressants for neuropathic pain.  Cochrane Database Syst Rev CD005454.
  6. Attal N, Cruccu G, Haanpaa M, Hansson P, Jensen TS, Nurmikko T, Sampaio C, Sindrup S and Wiffen P (2006).  EFNS guidelines on pharmacological treatment of neuropathic pain.  Eur J Neurol 13: 1153-69.
  7. Namaka M, Gramlich CR, Ruhlen D, Melanson M, Sutton I and Major J (2004).  A treatment algorithm for neuropathic pain.  Clin Ther 26: 951-79.
  8. Rintala DH, Holmes SA, Courtade D, Fiess RN, Tastard LV and Loubser PG (2007).  Comparison of the effectiveness of amitriptyline and gabapentin on chronic neuropathic pain in persons with spinal cord injury.  Arch Phys Med Rehabil 88: 1547-60.


2 Responses to “Tricylic Antidepressant Therapy for Depression and Neuropathic Pain”

  1. Dan Brown Says:

    Dear Dr. Young,

    I have seen posts on other forums quoting you as saying the prognosis for alcohol neuropathy is good, assuming the patient abstains for at least five years. Would you mind sending me your original quote and research upon which you base your statement that alcohol neuropathy is reversible?


    Dan Brown

  2. SATISH Says:


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