Tricyclic Antidepressants in Neuropathic Pain: The Good, the Bad, and the Potentially Ugly

January 25, 2016

Although clinicians are able to identify the causes of neuropathic pain, the mechanism behind its treatment is more difficult to distinguish.

About 2 of every 100 individuals are estimated to have peripheral neuropathy, although among those aged 55 years or older, this incidence is thought to increase to 8 of every 100.1

The most common cause of peripheral neuropathy is seen as the progression of uncontrolled diabetes, which is estimated to affect between 16% and 26% of diabetics. However, diabetes isn’t the only disease associated with peripheral neuropathy.

Additional common causes include herpes zoster infection, which leads to postherpetic neuralgia in 8% to 19% of patients, as well as nerve damage resulting from surgery in an estimated 10% to 50% of cases.2 Other notable causes of peripheral neuropathy include exposure to toxins (Agent Orange), trauma, infection, chemotherapy, tumor infiltration, and immunologic disorders.3,4,5

Neuropathic pain is defined by the International Association for the Study of Pain (IASP) as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.6 It is generally described as a burning, sharp, stabbing, or shooting pain sensation, though it may also be associated with allodynia, hyperpathia, and hyperalgesia.7

Antidepressant Efficacy in Neuropathic Pain

Although clinicians are able to identify the causes of neuropathic pain, the mechanism behind its treatment is more difficult to distinguish.

Tricyclic antidepressants were introduced in painful diabetic neuropathy in the 1970s, based on findings from empiric observations. However, the drugs’ potential analgesic properties were noted long before in a study published in 1960.8

Although tricyclic antidepressants remained the mainstay of pharmacological treatment for neuropathic pain for years, the drugs’ true mechanism wasn’t revealed until 1992.

Two concomitant crossover studies conducted that year revealed the important role norepinephrine plays in neuropathic pain. The first study compared the tricyclic antidepressants desipramine and amitriptyline, with both drugs yielding a similar positive response to neuropathic pain. The second study compared the selective serotonin reuptake inhibitor (SSRI) fluoxetine with placebo, which yielded inferior results. 9

Overall, the researchers concluded that antidepressants mediate their analgesic effect in neuropathic pain via inhibition of norepinephrine reuptake.9

Effective Tricyclic Antidepressant Dosing for Neuropathic Pain

When prescribing any tricyclic antidepressant for the treatment of neuropathic pain, it is important to realize that these drugs are effective at much lower doses in this setting than in depression.

For example, amitriptyline and desipramine have been proven effective in neuropathic pain at doses of 25 mg to 75 mg daily and 50 mg to 150 mg daily, while the recommended dose for each drug in depression is 150 mg to 300 mg daily. Clinical trials have shown that higher doses of these drugs are not more clinically effective for neuropathic pain and even associated with increased risk for side effects.

Place for Tricyclic Antidepressants in Neuropathic Pain Treatment

Despite their established efficacy, tricyclic antidepressants have moved out of favor because of their limiting side effect profile, which includes dry mouth, sedation, and blurred vision.10,11,12 In addition, tricyclic antidepressants are not well tolerated by older patients and should be used with great caution or avoided in those with cardiac arrhythmias, congestive heart failure, orthostatic hypotension, urinary retention, or angle-closure glaucoma.13

Serotonin norepinephrine reuptake inhibitors have largely replaced tricyclic antidepressants because they work through the same pathway by inhibiting reuptake of norepinephrine and are better tolerated.

Though newer medication classes have more appealing side effect profiles, there is still a place for tricyclic antidepressants in neuropathic pain treatment. These drugs are not only effective, but also inexpensive, making them attractive to patients without insurance coverage or with limited budgets. For instance, amitriptyline and nortriptyline are commonly found on pharmacy $4 lists.

Tricyclic Antidepressant Receptor Selectivity and Affinity

It should be noted that the utility of tricyclic antidepressants and their associated negative side effects are not equally shared across this drug class.

Understanding the difference in receptor affinities of each specific tricyclic antidepressant is key in medication selection for analgesia. Unmasking each medication’s side effect profile can also better assess appropriateness on an individual patient level. As Table 1 shows, smaller Ki values represent greater affinity and antagonism for corresponding receptors.

Table 1

Tertiary Amines

Secondary Amines

Amitriptyline (Elavil)

Imipramine (Tofranil)

Doxepin (Silenor)

Clomipramine (Anafranil)

Nortriptyline (Pamelor)

Desipramine (Norpramin)

Protriptyline (Vivactil)

Amoxapine (Asendin)

Maprotiline (Ludiomil)

Available Form and Strength (mg)

Tablet: 10, 25, 50, 75, 100, 150

Tablet: 10, 25, 50

Capsule: 75, 100, 125, 150

Tablet: 3, 6

Capsule: 10, 25, 50, 75, 100, 150

Capsule: 25, 50, 75

Capsule: 10, 25, 50, 75

Tablet: 10, 25, 50, 75, 100, 150

Tablet: 5, 10

Tablet: 25, 50, 100, 150

Tablet: 25, 50, 75

FDA Indication(s)


MDD, nocturnal enuresis

Alcoholism, MDD, GAD, insomnia, pruritus






Bipolar, MDD, dysthymia, mixed GAD/MDD

Starting dose

10 mg, increase by 10 mg q3-7d

10 mg, increase by 10 mg q3-7d

10 mg, increase by 10 mg q3-7d

25 mg, increase by 25 mg q3-7 days

10 mg, increase by 10 mg q3-7d

25 mg, increase by 25 mg q3-7d

10 mg, increase by 10 mg q3-7d

25 mg, increase by 25 mg q3-7d

25 mg, increase by 25 mg q3-7d

Therapeutic dose for pain (mg)










Antidepressant target dose (mg)










Receptor Antagonism (Ki)

NA: 50

5-HT: 20

H1: 1

Alpha1: 27

Musc: 18

5-HT2a: 29

NA: 60


H1: 40

Alpha1: 32

Musc: 46

5-HT2a: 80

NA: 29.5

5-HT: 68

H1: 0.24

Alpha1: 24

Musc: 83

5-HT2a: 25

NA: 54

5-HT: 0.14

H1: 15

Alpha1: 32

Musc: 25

5-HT2a: 35

NA: 10


H1: 6.3

Alpha1: 55

Musc: 37

5-HT2a: 44

NA: 0.18

5-HT: 18

H1: 110

Alpha1: 100

Musc: 100

5-HT2a: 280

NA: 1.41

5-HT: 19.6

H1: 60*

Alpha1: N/A

Musc: N/A

5-HT2a: 26*

NA: 16

5-HT: 290

H1: N/A

Alpha1: N/A

Musc: N/A

5-HT2a: 0.5

NA: 11.1

5-HT: 5,800

H1: 1.67

Alpha1: N/A

Musc: N/A

5-HT2a: 51*

Adverse drug reactions

High risk: Anticholinergic, drowsiness, weight gain and sexual dysfunction

Moderate risk: Orthostatic hypotension, QTc prolongation

High risk: Orthostatic hypotension

Moderate risk: Weight gain, anticholinergic, drowsiness, QTc prolongation and sexual dysfunction

High risk:

Weight gain and drowsiness

Moderate risk: Anticholinergic,QTc prolongation, orthostatic hypotension and sexual dysfunction

Moderate risk: Anticholinergic, drowsiness, weight gain and sexual dysfunction

Low risk: Orthostatic hypotension and QTc prolongation

Moderate risk: QTc prolongation

Low risk: Anticholinergic and drowsiness

Moderate risk:

QTc prolongation

Low risk: Orthostatic hypotension and drowsiness

High risk: Sexual dysfunction

Moderate risk: QTc prolongation

Low risk: Orthostatic hypotension and anticholinergic

Moderate risk: Insomnia and agitation

Low risk: Anticholinergic, drowsiness, orthostatic hypotension, QTc prolongation and weight gain

Moderate risk: Drowsiness and QTc prolongation

Low risk: Anticholinergic, orthostatic hypotension and weight gain

Smaller Ki values represent greater potency. *Ki from clinical trials in rats. No human data available.

MDD=Major depressive disorder

GAD=Generalized anxiety disorder

OCD= Obsessive compulsive disorder

NA=Noradrenergic reuptake

5-HT=Serotonin reuptake

H1=Histamine 1

Alpha1=Alpha 1 adrenergic

Musc=Muscarinic acetylcholine

5-HT2a=Serotonin alpha 2

All data was extracted from the PDSP Ki database at

Therapeutic doses for pain were pulled from literature that showed efficacy in pain with limited side effect profile

Tricyclic antidepressants elicit their antidepressant and analgesic effects by inhibiting the reuptake of serotonin and norepinephrine. Since no 2 tricyclic antidepressants are identical, knowing each medication’s receptor potencies will help determine its benefit as an antidepressant and/or neuropathic pain treatment.

For example, clomipramine, a tricyclic antidepressant developed in the 1960s, is used much like an SSRI in the treatment of major depressive disorder, but it generally isn’t used in treatment of neuropathic pain. This is expected when comparing clomipramine’s affinity for the serotonin reuptake receptor (Ki= 0.14) to the affinity of the SSRI sertraline (Ki= 0.26).

The tricyclic antidepressants most commonly used in the treatment of neuropathic pain are amitriptyline, imipramine, nortriptyline, and desipramine, as they all are potent norepinephrine reuptake inhibitors.

Amitriptyline and imipramine are often attempted first, but it is common to switch to nortriptyline or desipramine if the patient is unable to tolerate the drug, or it lacks efficacy. This can be predicted by assessing Ki values.

Amitriptyline’s active metabolite, nortriptyline, is 5 times more potent than its parent drug with Ki values of 10 and 50, respectively. The same can be said of imipramine (Ki= 60) and its active metabolite, desipramine (Ki= 0.18).

The utility of tricyclic antidepressants in disease management and the prevalence of treatment-limiting side effects can both be predicted by receptor potency.

Anticholinergic side effects are strongly associated with tricyclic antidepressants and elicited by strong antagonism at the muscarinic receptor. Higher potency results in blurred vision, urinary retention, constipation, dry mouth, drowsiness, and memory impairment, which limit the drugs’ use in the elderly.

Amitriptyline (Ki=18) and clomipramine (Ki=25) have the strongest affinity at this receptor, so they are not as well tolerated. Nortriptyline (Ki=37), the active metabolite of amitriptyline, retains some potency as a muscarinic receptor antagonist, but it is better tolerated than its parent drug.

Patients may tolerate tricyclic antidepressants well when they are used alone, but the drugs’ side effects are additive when combined with other anticholinergic medications (benzodiazepines) and/or opioids.

With an estimated 259 million opioid prescriptions written in 2012, the risk of concomitant prescribing is high, but this doesn’t mean that all tricyclic antidepressants should be excluded.14 In patients currently on anticholinergic medications and/or opioids, addition of desipramine (Ki=100)—which has lower potency for the muscarinic receptor—may improve tolerability.

Anticholinergic medications are also strongly associated with significant sedation, as a result of the drugs’ affinity for the histamine 1 receptor. When comparing antagonism at this particular receptor, doxepin (Ki=0.24), amitriptyline (Ki=1), and maprotiline (Ki=1.67) are the biggest offenders.

As these medications are dosed once daily, this side effect may prove beneficial in patients with sleeping disorders. However, a hangover effect has been reported and should be evaluated on a case-to-case basis.

It is also important to note the potential for orthostatic hypotension, which is induced by antagonism at the alpha 1 adrenergic receptor. Just like potency at all other receptors, it varies between members of the tricyclic antidepressant class.

Doxepin (Ki=24) has the greatest potency at this particular receptor and should be used with caution in patients with low blood pressure, those who have pre-existing orthostasis, and those at a high fall risk or in the elderly population.

As a class, tricyclic antidepressants are unique and often challenging to use, and their side effect profile will continue to limit their clinical utility in many patients. However, intolerance to first-line medications is common in the treatment of neuropathic pain, and so an intimate knowledge of each tricyclic antidepressant’s strengths and weaknesses will likely serve health care professionals well as they endeavor to customize solutions to provide better patient care.

Using tricyclic antidepressant receptor affinity to select an optimal medication that accounts for an individual patient’s comorbidities allows for anticipation and avoidance of unnecessary side effects and improved patient efficacy and safety. Application of these concepts is generally unique to pharmacy practice and serves to improve pharmacists’ clinical utility and generate trust among their fellow health care professionals.

This article was reviewed and edited by Timothy J. Atkinson, PharmD, a clinical pharmacy specialist in pain management at the VA Tennessee Valley Healthcare System.


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