Easing the Pain: Why Pharmacists and Clinicians Are Returning to Tricyclic Antidepressants

Easing the Pain: Why Pharmacists and Clinicians Are Returning to Tricyclic Antidepressants

tricyclic antidepressants

Depression as a medically treatable condition is a relatively new concept. It wasn’t until the second half of the twentieth century that patients began to feel less stigmatized about seeking help and that effective drugs were available to them.

If you were depressed in the ‘60s and ‘70s, you were often prescribed a tricyclic antidepressant. Tricyclic antidepressants have been around for the last 50 years or so, with amitriptyline being one of the more commonly used drugs in the class. They fell out of popularity when SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors) hit the market with cleaner side effect profiles and wider margins for error in dosing, meaning less potential for accidental or intentional overdose.

The actual indications for amitriptyline are relatively few: general depression, anxiety, and depression related to alcoholism, stroke, and Parkinson’s disease. It’s also been used off-label for a while to treat panic, bipolar disorder, PTSD (post-traumatic stress disorder), vascular headaches (especially migraines), IBS (irritable bowel syndrome), eating disorders, pediatric nocturnal enuresis, and ulcers, although the latter condition has been addressed better of late with histamine blockers and proton pump inhibitors.

While amitriptyline is still used used to treat depression in a small group of patients, it is back in a big way for other uses. Here’s a look at why.

Amitriptyline Resurgence

Where amitriptyline has received a big boost more recently is in the treatment of pain. Prescribed at much lower doses orally than for psychotropic use (around 5-25 mg versus up to 150 mg), it’s not addicting in the least, as it does not bind to opioid receptors. Nor does it mask unpleasant life conditions, making it a good alternative to benzodiazepines and narcotics, both of which are overprescribed and responsible for growing numbers of ER visits.

Typical off-label uses include the treatment of chronic back and neck pain, diabetic and chemotherapy induced neuropathy, postherpetic neuralgia, and complex regional pain syndrome (CRPS).

Science Behind Off-label Use

Amitriptyline is a tertiary amine, and as such inhibits the reuptake of the biogenic amines norepinephrine (NE) and serotonin (5HT) at axon terminals. The beauty of amitriptyline is that it works from brainstem to spinal cord, giving it effect on both central and peripheral nerves.

So, how do TCAs stack up against SSRIs to treat pain (SSRIs are also often prescribed for chronic pain)? They’re better, according to a 1992 study in the New England Journal of Medicine that’s still often cited today. In a double-blind, placebo controlled study of treatments for painful diabetic neuropathy, 74% of the patients who received amitriptyline experienced moderate or significant pain relief. While it might seem that patients who took the SSRI fluoxetine did well too, with 48% getting relief, the numbers don’t really speak until you look at the placebo group. There, 41% experienced pain relief, which was statistically not significantly different from the fluoxetine group, but it was for the amitriptyline group.

Other studies have continued to point out the efficacy of TCAs in managing neuropathic pain. However, one of the continuing issues with oral amitriptyline has been its potential side effects.

Side Effects

The side effect profile for amitriptyline includes the following:

  • dry mouth
  • constipation
  • drowsiness
  • sweating
  • minor tremor
  • increased appetite

Additionally, amitriptyline can worsen glaucoma, cardiac arrhythmias, and prostatic hypertrophy. It also amplifies the effects of alcohol and can cause increased nervousness or anxiety in users of SSRIs (although it is sometimes prescribed simultaneously to increase their effectiveness) and dextromethorphan, a common active ingredient in cough syrup. Demerol should not be given to patients taking amitriptyline.

Usually drowsiness with amitriptyline is transient, and by the time it passes, patients are starting to feel better. The dual challenges of this drug are getting patients to stick with it through the initial side effects long enough to see a response and urging them not to quit taking it once they feel better, thinking they are permanently cured.

Compounding Amitriptyline

One way around the side effects of oral amitriptyline is compounding it in a topical cream, and this accounts for a large number of its prescriptions today for neuropathic pain. A 2% solution is most common, and it is often combined with baclofen and/or ketamine. It is also frequently compounded with these agents:

  • carbamazepine
  • capsaicin
  • clonidine
  • guaifenesin
  • ibuprofen
  • ketoprofen
  • lidocaine

Newer studies involving amitriptyline have focused on peripheral analgesia. Significant serum concentrations are not detectable with topical applications, which means patients are subject to few or no side effects of the systemic drug. The complete mechanism of action for topical amitriptyline is still not completely clear, but it is thought that it alters cellular sodium channels, as well as adenosine receptors and decreases cyclic adenosine monophosphate (cAMP). A second messenger in neuron function and fight-or-flight response, cAMP is known to be a component in pain and hyperalgesia.

If you have patients who are struggling with neuropathic pain, a consultation with a compounding pharmaceutical provider, like PNA, can help you improve their quality of life. Patients with diabetic neuropathy, for example,  also frequently suffer from cardiac arrhythmias and are ideal candidates for topical amitriptyline.

Amitriptyline and the Future

TCAs, especially in topical form,  will continue to be a research subject for the foreseeable future and will likely gain further acceptance as their efficacy and mechanism of action are understood in greater detail. Topical amitriptyline’s relatively low cost, reduced side effect profile, minimal CYP interaction, and non-addictive qualities make it a viable choice in pain management.

Pharmaceutica North America is working at the forefront of pain therapy by providing top quality bulk pharmaceutical components for pharmacy and in-office compounding. When you purchase products from PNA, you know you are making a real difference in the lives of your patients.


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