Little Evidence That Antidepressants Work for Chronic Pain

By Drs. Hollie Birkinshaw and Tamar Pincus

About one in five people globally live with chronic pain, and it is a common reason for seeing a doctor, accounting for one in five GP appointments in the UK.

With growing caution around prescribing opioids – given their potential for addiction – many doctors are looking to prescribe other drugs, “off-label”, to treat long-term pain. A popular option is antidepressants.

In the UK, doctors can prescribe the following antidepressants for “chronic primary pain” (pain without a known underlying cause): amitriptyline, citalopram, duloxetine, fluoxetine, paroxetine and sertraline. Amitriptyline and duloxetine are also recommended for nerve pain, such as sciatica.

However, our review of studies investigating the effectiveness of antidepressants at treating chronic pain found that there is only evidence for one of these drugs: duloxetine.

We found 178 relevant studies with a total of 28,664 participants. It is the largest-ever review of antidepressants for chronic pain and the first to include all antidepressants for all types of chronic pain.

Forty-three of the studies (11,608 people) investigated duloxetine (Cymbalta). We found that it moderately reduces pain and improves mobility. It is the only antidepressant that we are certain has an effect. We also found that a 60mg dose of duloxetine was equally effective in providing pain relief as a 120mg dose.

In comparison, while 43 studies also investigated amitriptyline (Elavil), the total number of participants was only 3,372, indicating that most of these studies are very small and susceptible to biased results.

The number of studies and participants for the other antidepressants are:

• Citalopram (Celexa): five studies with 209 participants

• Fluoxetine (Prozac): 11 studies with 622 participants

• Paroxetine (Paxil): nine studies with 960 participants

• Sertraline (Zoloft): three studies with 210 participants.

The evidence for amitriptyline, citalopram, fluoxetine, paroxetine and sertraline was very poor, and no conclusions could be drawn about their ability to relieve pain.

This is particularly important as UK prescribing data shows 15,784,225 prescriptions of amitriptyline in the last year. It is reasonable to assume that a large proportion of these may be for pain relief because amitriptyline is no longer recommended for treating depression.

This suggests that millions of people may be taking an antidepressant to treat pain even though there is no evidence for its usefulness. In comparison, 3,973,129 duloxetine prescriptions were issued during the same period, for a mixture of depression and pain.

In light of our findings, which were published in May 2023, the UK’s National Institute for Health and Care Excellence (Nice) recently updated its advice to doctors on how to treat chronic pain.

The updated Nice guidance now suggests 60mg of duloxetine to treat [chronic primary pain] and the same drug and dose to treat nerve pain.

Limited Treatments Options

GPs often report frustration at the limited options available to them to treat patients experiencing chronic pain. Amitriptyline is cheap to prescribe – only 66p per pack (US 82.5 cents) – which may explain the high number of prescriptions for this drug.

This is an example of how the gap between evidence and clinical practice could harm patients. Although our review was unable to establish the long-term safety of antidepressant use, previous research has highlighted the high rates of side-effects for amitriptyline, including dizziness, nausea, headaches and constipation.

It’s important to bear in mind, though, that pain is a very individual experience, and the evidence in our review is based on groups of people. We acknowledge that certain drugs may work for people even when the research evidence is inconclusive or unavailable. If you have any concerns about your pain medication, you should discuss this with your doctor.

Hollie Birkinshaw, PhD, is a Research Fellow at University of Southampton. She specializes in research involving chronic musculoskeletal pain, and the integration of psychology in pain and health services. Birkinshaw receives funding from the UK’s National Institute for Health and Care Research (NIHR).

Tamar Pincus, PhD, is a Professor of Health Psychology at University of Southampton. Her research focuses on the psychological aspects of chronic pain. Pincus receives funding from NIHR, Medical Research Council and Versus Arthritis.  

This article originally appeared in The Conversation and is republished with permission.

Cheap Drugs May Prevent Migraine Just as Effectively as Expensive Ones

By Pat Anson, PNN Editor

Two drugs commonly used to treat depression and high cholesterol are just as effective at preventing migraine as CGRP inhibitors, according to a large new study.

They are also a heck of a lot cheaper.  

Researchers at the Norwegian Center for Headache Research analyzed the prescription drug history of over 100,000 migraine patients in Norway from 2010 to 2020. Their goal was to see if patients reduced their use of medications used to treat acute migraine pain – such as triptan – once they started taking drugs used to prevent migraine.

“When the withdrawal of acute migraine medicines changed little after starting preventive medicines, or people stopped quickly on the preventive medicines, the preventive medicine was interpreted as having little effect,” explained lead investigator Marte-Helen Bjørk, MD, a Professor in the Department of Clinical Medicine, University of Bergen.

“If the preventive medicine was used on long, uninterrupted periods, and we saw a decrease in the consumption of acute medicines, we interpreted the preventive medicine as having good effect.”

Beta blockers are often the first drugs used to prevent migraine attacks, but Bjørk and her colleagues found that three other medications were associated with lesser use of triptans: amitriptyline, simvastatin and CGRP inhibitors.

Amitriptyline is a tricyclic antidepressant that is mostly taken for depression, while simvastatin is a statin used to treat high cholesterol. Both drugs are also used off-label for migraine prevention.

CGRP inhibitors are a relatively new class of medication that block calcitonin gene-related peptides, a protein that binds to nerve receptors in the brain and triggers migraine pain. Since 2018, the FDA has approved over half a dozen CGRP medications, which are considered the biggest innovation in migraine treatment in decades.

However, CGRP drugs are not cheap. Eight doses of Nurtec, a tablet taken daily to prevent and treat migraine, can cost over $1,000, while the listed price for Emgality is $679 for a self-injectable syringe used once a month for migraine prevention. Prices will vary for patients, depending on insurance and whether they qualify for a patient assistance program.

By comparison, amitriptyline and simvastatin are screaming bargains. A bottle of 30 simvastatin tablets will cost about $14, while amitriptyline costs about $13 for a supply of 28 tablets.

When it comes to reducing triptan use, amitriptyline, simvastatin and the CGRP inhibitors performed about the same. During the first 90 days of treatment, nearly 57% of patients taking simvastatin reduced their triptan use, compared to 53% of patients taking amitriptyline and 55% of those taking CGRP medicines.

The study findings, recently published in the European Journal of Neurology, show that patients taking beta blockers, topiramate or clonidine were more likely to keep taking triptans.

“Our analysis shows that some established and cheaper medicines can have a similar treatment effect as the more expensive ones. This may be of great significance both for the patient group and Norwegian health care” says Bjørk, who has already started work on a clinical trial to see if other cholesterol-lowering drugs can prevent migraine.

Migraine affects about 1 billion people worldwide and 39 million in the United States, according to the American Migraine Foundation. In addition to headache pain, migraine can cause nausea, blurriness or visual disturbances, and sensitivity to light and sound. Women are three times more likely to suffer from migraines than men.