Tricyclic Antidepressants: The Good, the Bad, and the Potentially Ugly

Tricyclic Antidepressants in Neuropathic Pain: The Good, the Bad, and the Potentially Ugly | Pharmacy Times | Kelsie Flynn, PharmD

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.

The drugs’ potential analgesic properties were noted long before in a study published in 1960.

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. 

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

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.

In addition, tricyclic antidepressants are not well tolerated by older patients.

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. 

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.

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.

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.

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.

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.

Anticholinergic medications are also strongly associated with significant sedation, as a result of the drugs’ affinity for the histamine 1 receptor. 

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.

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.


2 thoughts on “Tricyclic Antidepressants: The Good, the Bad, and the Potentially Ugly

  1. teeks55

    I’ve been on Triavil, an old tricyclic, for about 30+ years. It was prescribed to me shortly after being diagnosed with fibromyalgia. It really helped calm my intense muscle spasms.

    Triavil is part amitriptylene, part perphenazine. I believe it’s the perphenazine that quiets the spasms, just like many tranquilizers do….such as valium, etc. I know there is higher incidence of one particular side effect (tardive dyskenisia) which does scare me, but getting off this drug scares me more.

    The reduction of my muscle spasms was significant enough to have kept me taking it all these years, despite the higher chances of getting tardive dyskenisia the longer I take the drug. This side effect is described as developing uncontrolled movement, especially in the muscles of the face, but also other muscles, that may not go away if/when you quit taking the drug. Which means that it can actually change your brain to the point of causing these movements, sometimes permanently. That is very frightening.

    I’ve considered quitting the medication many times but always decided I would take my chances. I have tried various SSRI’s in hopes that maybe they might be something that I could switch over to….but they did not seem to help my pain at all, or else their own bad side effects made me quit taking them. The spasms were not a factor, since I did not quit taking the Triavil when I tried the SSRI’s.

    So I just continue on, hoping against hope that I do not end up with this awful tardive dyskenisia. I take things day by day. If I notice anything resembling “TD”, however slight, I will probably have no choice but to give up the one drug that has relieved the muscle spasms that made my life a living hell for 2 years before I was diagnosed. Keeping fingers crossed.

    Liked by 1 person

    1. Zyp Czyk Post author

      Thanks for this very interesting information. I’d never heard of a combination tri-cyclic like this.

      But it’s awful that you have to risk permanent TD. That you’re willing to take this risk should make it obvious how serious your symptoms are to anyone who doubts you.

      Liked by 1 person


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