Antidepressants as a tool for pain relief : how an accidental discovery changed chronic pain treatment.
Introduction
Imagine walking into your doctor’s office with chronic back pain, nerve pain from diabetes, or the all-over ache of fibromyalgia, and leaving with a prescription for an antidepressant. Your first thought might be: “Does my doctor think this pain is all in my head, that I’m imagining it?”
It’s a common reaction, and it comes from a misunderstanding about what these medications actually do. The truth is more interesting, and it started with doctors noticing something they couldn’t quite explain.
This is the story of how medications designed for depression accidentally became pain treatments, what we’ve learned about how they work, and what you should actually expect if you take them. It’s a story about scientific discovery, honest limitations, and understanding that chronic pain isn’t just about a hurt body part, it’s about a whole system that needs help getting back in balance.
Whether you’re living with chronic pain, caring for someone who is, or treating patients in your practice, this story matters. Because understanding what these medications can and can’t do changes how we approach one of medicine’s most challenging problems.
The beginning: a happy accident
Picture this: It’s the 1960s.
A psychiatrist prescribes amitriptyline to help someone with depression. A few weeks later, the patient returns for a follow-up visit. “Doc,” they say, “I’m not sure the medication is helping my mood much, but you know that terrible nerve pain I mentioned? It’s actually better.”
The doctor pauses. That’s… odd.
Over the next few years, similar stories kept popping up. Cancer patients on antidepressants mentioned their pain improved. People with diabetes and painful feet found relief. And here’s the really strange part: the pain often got better before their mood improved, sometimes within days instead of the usual four to six weeks it takes for these medications to help depression.
This wasn’t supposed to happen. These were anti-depressants. They were designed to fix sad brains, not painful bodies.
But the patients kept telling the same story. So doctors started paying attention.
What antidepressants actually are
Let’s back up and explain what these medications do. Your brain runs on chemicals called neurotransmitters, think of them like text messages between brain cells. Two important ones are serotonin and norepinephrine. They help control your mood, but they also do something else: they help control pain.
Normally, when these chemical messages get sent, they’re quickly cleaned up and recycled. Antidepressants block that cleanup process. It’s like letting the messages stick around longer so they can do more work.
There are different types:
• Tricyclics (TCAs) like amitriptyline or nortriptyline, the old-school ones from the 1960s
• SNRIs like duloxetine, newer ones that target serotonin and norepinephrine
• SSRIs like fluoxetine, sertraline, etc. These only work on serotonin, and they don’t help much with pain
Following the clues: how scientists figured out the pain connection
Once doctors noticed patients’ pain improving, scientists started asking: Why would a depression medication help with pain?
They began studying pain pathways in the brain and spinal cord. And they discovered something fascinating.
Your brain doesn’t just receive pain signals, it actively decides how loud those signals should be. Imagine a volume knob that can turn pain up or down. This system lives deep in your brainstem, in areas with names like the “locus coeruleus” and “periaqueductal gray.” (Scientists aren’t great at naming things so you can spell them easily.)
These brain regions send messages down your spinal cord using, you guessed it, serotonin and norepinephrine. When these chemicals reach your spinal cord, they tell pain signals to quiet down before they even reach your conscious brain.
This is why soldiers sometimes don’t feel wounds in battle, or why you might not notice a cut until you see blood. Your brain has a natural pain dimmer switch to help us survive (during wars or time facing a lion).
But, here’s the problem in chronic pain: that dimmer switch breaks. Studies in animals showed that when pain becomes chronic, the locus coeruleus gets exhausted. It runs out of norepinephrine. Instead of turning pain down, the system starts turning it up. You develop what scientists call “descending facilitation”, your brain actually amplifies pain signals instead of quieting them (this is the “highway” I talked about in my recent article about central sensitization, you should read it too!).
And that’s where antidepressants come in. By keeping serotonin and norepinephrine around longer, they help restore your brain’s broken pain control system.
What the research actually shows
Let’s review now what works and what doesn’t. In 2024, researchers did the biggest analysis ever—176 studies with over 28,000 people with chronic pain (Birkinshaw et al., 2024). Here’s what they found:
Duloxetine (brand name Cymbalta) is the only antidepressant with solid evidence. At 60mg daily, it provides:
• About 15 more people out of 100 get meaningful pain relief compared to a sugar pill
• Small to moderate improvements in pain, physical function, and sleep
• The effect is real but modest, we’re talking about making pain more manageable, not making it disappear.
Milnacipran (approved in the US) might work for fibromyalgia, but we need better studies to be sure.
Tricyclics like amitriptyline? Here’s where it gets uncomfortable. They’re recommended as first-line treatment in many guidelines, especially for nerve pain. But when researchers looked hard at the evidence, they couldn’t find good proof they actually work (Ferreira et al., 2023). They’ve been prescribed for decades based on older, smaller studies that wouldn’t meet today’s standards. It’s a case where practice got ahead of science.
SSRIs don’t work for pain. They’re great for depression and anxiety, but they don’t help chronic pain.
The sleep-pain-mood triangle: why it’s all connected
Here’s where the story gets more interesting. Chronic pain doesn’t travel alone, it usually brings companions named Poor Sleep and Low Mood. And these three feed off each other in a vicious cycle.
When you’re in pain, you can’t sleep well. When you don’t sleep, your body becomes more sensitive to pain, your pain volume knob gets stuck on high. When pain persists and sleep suffers, mood tanks. When mood is low, pain feels worse and harder to cope with. Round and round it goes.
Studies following fibromyalgia patients over time found something surprising: poor sleep predicts worse pain the next day more strongly than pain predicts worse sleep (Bigatti et al., 2008). This suggests that fixing sleep might actually be more important than we thought.
Different antidepressants affect this triangle differently:
Amitriptyline (or Nortriptyline) taken at bedtime makes you sleepy and improves deep sleep. For someone with fibromyalgia who can’t sleep because of pain, this double effect can be helpful, assuming they can tolerate the side effects (careful with high doses!).
Duloxetine works mainly on the pain pathways directly. It might improve mood / anxiety, and sleep might get better because you’re hurting less, but it’s not a sleep medication.
Mirtazapine (another antidepressant) seems to help both sleep and pain, but the evidence is weaker. (Careful with weight gain with this one!)
The key insight: when treating chronic pain, we’re not just turning down a pain signal. We’re trying to help someone function and live their life. If a medication helps them sleep better so they have energy during the day, or lifts their mood enough that they can return to activities they love, that matters, even if the pain reduction itself is modest.
What to realistically expect
Let’s talk straight (I like that better). If you’re prescribed duloxetine or a low-dose tricyclic for chronic pain, here’s what science tells us:
What might happen:
• Pain becomes somewhat more manageable—think “I can do more” rather than “pain is gone”
• Physical function improves a bit—maybe you can walk further or do more household tasks
• Sleep might improve, especially with nighttime tricyclics
• Mood might lift slightly
• These small improvements across multiple areas can add up to better quality of life
What won’t happen:
• Complete pain relief
• Immediate results (needs 1-2 weeks, sometimes longer)
• A cure for the underlying problem
Side effects to watch for:
• Nausea, especially when starting (usually temporary)
• Dry mouth, constipation (more with tricyclics)
• Dizziness
• Sexual side effects
• Weight gain (especially mirtazapine and tricyclics)
• Drowsiness (can be good or bad depending on timing)
The older tricyclics have more side effects, which is why many people can’t reach doses high enough to help pain. The newer SNRIs like duloxetine are generally easier to tolerate.
‼️ Important: Never stop these medications suddenly. They need to be tapered slowly to avoid withdrawal symptoms like dizziness, nausea, and feeling like you have the flu.
My final words : a tool, not a miracle
Antidepressants for chronic pain are like reading glasses for an aging eye, they help compensate for a system that’s not working right anymore. They won’t fix the underlying problem (just like glasses don’t cure presbyopia), but they can make daily life more manageable.
— The best evidence supports duloxetine 60mg for conditions like (can take morning or supper, depending on if affects sleep or not):
• Fibromyalgia
• Diabetic nerve pain
• Chronic musculoskeletal pain
Tricyclics (always take in the evening for bedtime) might help some people, but side effects often get in the way. They’re worth trying if duloxetine doesn’t work or isn’t an option, but keep expectations realistic.
—> These medications work best as part of a bigger plan that includes:
• Physical therapy or gentle exercise
• Sleep hygiene
• Pain psychology or cognitive behavioral therapy
• Pacing activities to avoid boom-bust cycles
• Sometimes other medications
Think of chronic pain management like managing diabetes, you’re aiming for control and function, likely not cure. Antidepressants can be one useful tool in the toolbox, especially when sleep and mood are part of the picture.
To conclude with this
What we know now is this: chronic pain changes how the nervous system works. It’s not weakness or imagination—it’s your brain’s volume control getting stuck on high, your sleep architecture falling apart, and your mood taking hit after hit from relentless discomfort. Antidepressants, particularly duloxetine, can help reset some of these systems. Not dramatically. Not for everyone. But enough to matter for many people trying to reclaim their lives.
We now know the brain has its own pain control system that can break down, and that some medications can help restore it. We understand that treating chronic pain means addressing the whole person, not just the painful body part.
But here’s what the numbers and studies can’t fully capture: the person who can finally sleep through the night, walk their dog again, or return to work part-time. The parent who can play with their kids without spending the next day in bed. The individual who went from barely surviving to actually living.
That’s what chronic pain management is really about, not erasing pain, but reducing it enough that life can happen around it. And for that goal, antidepressants can be genuinely helpful, especially when combined with movement, psychological support, sleep strategies, and realistic expectations.
If you’re considering these medications, ask questions. Understand that meaningful doesn’t mean miraculous. Know the side effects. Give them time to work (2-4 weeks after initiation of the treatment to see benefits). And remember that managing chronic pain is more marathon than sprint, it requires patience, adjustment, and usually more than one approach.
And for the millions living with chronic pain, that accidental discovery opened a door to relief that, while imperfect, is real. For some of my patients, they described those treatments “game changer” in their life. Sometimes in medicine, that’s exactly what progress looks like.
Thanks for reading, don’t forget to share to spread awareness and to leave a comment to tell me if this read was helpful, and if there is any other topic you would like me to discuss next. I wish you’ll continue to read more to empower yourself and take the control of your chronic pain journey. Reclaim your life ❤️
Check my Insta page for more @letstalkchronicpain.
References
1. Birkinshaw H, et al. (2024). Antidepressants for pain management in adults with chronic pain: a network meta-analysis. Health Technol Assess 28(62):1-155.
2. Ferreira GE, et al. (2023). Efficacy, safety, and tolerability of antidepressants for pain in adults: overview of systematic reviews. BMJ 380:e073415.
3. Narayan SW, et al. (2024). Efficacy and safety of antidepressants for pain in older adults: A systematic review and meta-analysis. Br J Clin Pharmacol 90(12):2854-2871.
4. Obata H (2017). Analgesic mechanisms of antidepressants for neuropathic pain. Int J Mol Sci 18(11):2483.
5. Bigatti SM, et al. (2008). Sleep disturbances in fibromyalgia syndrome: relationship to pain and depression. Arthritis Rheum 59:961-967.
6. Choy EH (2015). The role of sleep in pain and fibromyalgia. Nat Rev Rheumatol 11:513-520.
