Your Own Painkillers

Your body makes its own opioids. They ease pain, calm stress and help you bounce back after a bad day. This guide explains how that system works, and what two medicines, low-dose naltrexone and buprenorphine, do to it.

Locks and keys inside you

Nerve cells carry tiny locks on their surface, called receptors. Your body makes keys that fit them. When a key turns a lock, the cell changes what it does. Pain signals get quieter, stress settles, or you feel a lift.

Scientists found the locks in 1973 [Ref: Pert & Snyder, Science 1973], and the first natural keys, the enkephalins, two years later [Ref: Hughes et al., Nature 1975]. Drugs like morphine work only because they happen to fit locks your body already had.

Three families of natural keys

Endorphins

The "big" painkiller. Released during injury, stress and hard exercise. Mainly fit the mu lock.

Enkephalins

Small, fast-acting keys in the brain, spinal cord and gut. Fit delta and mu locks.

Dynorphins

The "stress brake" keys. Fit the kappa lock. Too much makes you feel low and uneasy.

Four locks: tap each card

Mutap to flip

Mu: relief and reward

Eases pain, gives warmth and pleasure. Also slows breathing, which is why too much morphine or heroin kills.

Deltatap to flip

Delta: mood and calm

Linked to lower anxiety and steadier mood in animal studies. Less well understood in people.

Kappatap to flip

Kappa: the misery switch

Turned on by long-term stress. Makes the world feel flat, grim and unrewarding. Blocking it is a target for depression treatment.

NOPtap to flip

NOP: the odd cousin

Same family, different key (nociceptin). Its effects on pain are mixed and still being worked out.

One-line summary: mu = relief, kappa = misery, and your brain keeps them in balance.

What switches your painkillers on?

These are three well-known experiments. Each shows the system working in real people. The grey and red tags tell you how much weight each one can carry: small studies are interesting, not proof.

🏃 Running

Brain-scan study

10 people

No comparison group

Ten athletes had brain scans before and after a two-hour run. After the run, their own opioids were sitting on the locks in mood and emotion areas. The more euphoric they felt, the stronger the signal. The "runner's high" is real.

[Ref: Boecker et al., Cerebral Cortex 2008;18(11):2523–31]

💊 Belief (the placebo effect)

Randomised, double-blind

Dental surgery patients

After wisdom-tooth surgery, patients given a dummy pill felt less pain. Then they were given naloxone, a drug that blocks opioid locks. Their pain came back. Only the patients the dummy pill had helped got worse. So believing a treatment will work can make your brain release its own painkillers.

Important: this does not mean pain is imaginary or "all in your head". The pain was real, and the relief was real chemistry. Expectation is one more switch on a real biological system.

[Ref: Levine, Gordon & Fields, Lancet 1978;2(8091):654–7]

Fair warning: a later study showed placebo can also work through non-opioid routes. Belief uses more than one pathway. [Ref: Grevert, Albert & Goldstein, Pain 1983]

💔 Being rejected

Brain-scan study

18 people

In a scanner, volunteers were told people they liked did not like them back. Their brains released opioids, as if treating a physical injury. People who scored high on resilience released more.

[Ref: Hsu et al., Molecular Psychiatry 2013;18(11):1211–17]

People with depression released less after rejection, so the hurt lasted longer.

[Ref: Hsu et al., Molecular Psychiatry 2015;20:193–200]

So emotional pain and physical pain share the same repair kit. Exercise, hope and good relationships all top it up.

Try it: put a key in the mu lock

Not every key does the same thing. Pick one and watch what happens to the lock.

How hard the lock is switched on

How tightly the key grips

Illustration only. The bar lengths show the idea, not measured values.

Pick a key above.

Full agonist

Turns the lock all the way. Strong relief, strong risks. Example: morphine.

Partial agonist

Turns it only part-way, however much you take. Example: buprenorphine.

Antagonist

Fits the lock and turns nothing. It just blocks other keys. Examples: naloxone, naltrexone.

Low-dose naltrexone (LDN)

⚠ Safety first. LDN can stop opioid painkillers (codeine, tramadol, morphine) from working. Never start it while taking any opioid, including buprenorphine or methadone, because it can cause sudden withdrawal. Tell any surgeon, dentist or A&E team that you take it.

Naltrexone is a blocker. At the normal dose of 50 mg it is used to help people with alcohol or opioid problems. "Low-dose" means about 1.5 to 4.5 mg, roughly a tenth of that. In the UK, using it this way is off-label: doctors can prescribe it, but it is not licensed for these conditions.

Theory 1: the short blackout

Drag the slider through one day after a bedtime dose.

10 pm, dose taken

Illustration only. The curve shapes are drawn to explain the theory. They are not measured blood levels or receptor data.

The dose briefly blocks the opioid locks.

The idea, from Ian Zagon and Patricia McLaughlin at Penn State, is that a short block makes the body react by making more of its own opioids and more locks. After the drug wears off, you are left with a stronger natural system [Ref: Zagon & McLaughlin, Life Sciences 1984;35:2057–64].

Honest point: this rebound has been shown in animals. Nobody has properly measured it in patients.

Theory 2: calming the brain's immune cells

The brain has its own immune cells, called microglia. When they are irritated they release chemicals that make pain louder. Naltrexone can block an alarm switch on these cells called TLR4, and that reversed pain in rats [Ref: Hutchinson et al., European Journal of Neuroscience 2008] [Ref: Wang et al., British Journal of Pharmacology 2016;173(5):856–69].

Honest point: the rats received much more drug than a 1.5–4.5 mg tablet puts into a human. That dose gap is the biggest hole in the LDN story.

Theory 3: a growth brake

One of your natural keys, met-enkephalin, also slows how fast some cells divide, including immune cells. LDN may adjust this brake [Ref: Zagon & McLaughlin, Life Sciences 1984;35:2057–64]. This theory is mainly used to explain effects in gut and immune diseases.

Does it actually work? The scoreboard

These verdicts are a plain-English judgement of the published trials. They are not a score from any official body.

Fibromyalgia

Mixed: best trial negative

What the trials found

Randomised crossover

31 people

In a small 2013 trial of 31 women, pain dropped about 29% on LDN against 18% on placebo [Ref: Younger et al., Arthritis & Rheumatism 2013;65(2):529–38].

Randomised, double-blind

99 people

Best quality so far

A bigger, better 2024 trial of 99 women on 6 mg found no real difference from placebo for pain [Ref: Due Bruun et al., Lancet Rheumatology 2024;6(1):e31–9]. When two trials disagree, the better one counts more.

Crohn's disease

Weak: two small trials

What the trials found

Systematic review

Two small trials

A Cochrane review found only very small trials. They hint at benefit and are too weak to be sure [Ref: Parker et al., Cochrane Database of Systematic Reviews 2018, CD010410].

Multiple sclerosis

Weak: small trials, no effect on disease

What the trials found

Small pilot trials

Small trials showed slight improvements in how people felt, and no proof that it slows the disease [Ref: Cree et al., Annals of Neurology 2010].

Long COVID, ME/CFS

Very weak: no placebo-controlled proof yet

What the trials found

Clinic reports

No placebo group

Mostly reports from clinics, without placebo comparisons. Larger trials are under way. Treat claims online with caution.

Bottom line: LDN is cheap and usually well tolerated. The best evidence so far is mixed to negative. Some people say it helps them, but nobody can yet promise it will help you. The most common side effect is vivid dreams or broken sleep in the first weeks.

The best-known clinical researcher in this area is Jarred Younger (now at the University of Alabama at Birmingham).

Buprenorphine: the half-turn key

⚠ Safety first. Buprenorphine is an opioid, and your body can become dependent on it. With alcohol, sleeping tablets or benzodiazepines it can stop your breathing. Never stop it suddenly without your prescriber.

Buprenorphine does two jobs at once:

At the mu lock

It grips very tightly but turns the lock only part-way. You get some relief, and the effect hits a ceiling. That ceiling makes it much less likely than morphine or heroin to stop your breathing when taken on its own.

At the kappa lock

It blocks the misery switch. Many scientists think this is why people describe it as calming and why it may lift mood.

Why sources disagree: some papers call buprenorphine a "kappa partial agonist". Technically it turns the kappa lock a tiny amount, so little that in practice it acts as a blocker. Both descriptions are about the same drug, seen at different levels of detail.

Because it grips so tightly, it pushes other opioids off the lock. That is why it is used to treat opioid addiction. It does not change nerve cells in some hidden way. It works directly on the locks.

Could it treat depression?

Randomised, double-blind

142 people

Funded by the drug maker

A 2016 trial added a tiny dose of buprenorphine, plus a second drug to stop the "high", to antidepressants in people who had not got better. Their mood improved at the lower dose [Ref: Fava et al., American Journal of Psychiatry 2016;173(5):499–508]. In 2019 the US regulator (FDA) still refused to approve the combination, because the overall evidence was not strong enough.

Not a casual drug. Buprenorphine is still an opioid. Your body can become dependent on it. Mixed with alcohol, sleeping tablets or benzodiazepines such as diazepam, it can stop your breathing. Only take it as prescribed.

Stay safe: tick each point once you have read it

LDN blocks opioid painkillers. Codeine, tramadol, morphine and similar drugs may not work while you take it. Never start LDN while taking opioids, including buprenorphine or methadone. It can throw you into sudden withdrawal. Tell your surgeon, dentist or A&E that you take LDN. They may need to stop it before an operation. Don't stop or change any medicine without talking to your prescriber. Buprenorphine plus alcohol or sedatives is a dangerous mix. A medicine is one tool. Movement, sleep, people who care about you and talking therapy all feed the same natural system.

✅ All six points read.

Quick quiz

References

[Ref: Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science 1973;179:1011–14]
[Ref: Hughes J, Smith TW, Kosterlitz HW, et al. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 1975;258:577–80]
[Ref: Levine JD, Gordon NC, Fields HL. The mechanism of placebo analgesia. Lancet 1978;2(8091):654–7]
[Ref: Grevert P, Albert LH, Goldstein A. Partial antagonism of placebo analgesia by naloxone. Pain 1983;16:129–43]
[Ref: Boecker H, et al. The runner's high: opioidergic mechanisms in the human brain. Cerebral Cortex 2008;18(11):2523–31]
[Ref: Hsu DT, et al. Response of the μ-opioid system to social rejection and acceptance. Molecular Psychiatry 2013;18(11):1211–17]
[Ref: Hsu DT, et al. It still hurts: altered endogenous opioid activity in the brain during social rejection and acceptance in major depressive disorder. Molecular Psychiatry 2015;20:193–200]
[Ref: Zagon IS, McLaughlin PJ. Naltrexone modulates body and brain development in rats: a role for endogenous opioid systems in growth. Life Sciences 1984;35:2057–64]
[Ref: Hutchinson MR, et al. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4). European Journal of Neuroscience 2008;28:20–29]
[Ref: Wang X, et al. Pharmacological characterization of the opioid inactive isomers (+)-naltrexone and (+)-naloxone as antagonists of toll-like receptor 4. British Journal of Pharmacology 2016;173(5):856–69]
[Ref: Younger J, Noor N, McCue R, Mackey S. Low-dose naltrexone for the treatment of fibromyalgia. Arthritis & Rheumatism 2013;65(2):529–38]
[Ref: Due Bruun K, et al. Naltrexone 6 mg once daily versus placebo in women with fibromyalgia: a randomised, double-blind, placebo-controlled trial. Lancet Rheumatology 2024;6(1):e31–9]
[Ref: Parker CE, Nguyen TM, Segal D, MacDonald JK, Chande N. Low dose naltrexone for induction of remission in Crohn's disease. Cochrane Database of Systematic Reviews 2018;CD010410]
[Ref: Cree BAC, Kornyeyeva E, Goodin DS. Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Annals of Neurology 2010;68:145–50]
[Ref: Fava M, et al. Opioid modulation with buprenorphine/samidorphan as adjunctive treatment for inadequate response to antidepressants. American Journal of Psychiatry 2016;173(5):499–508]

This page is for education. It is not personal medical advice. Talk to your own doctor or pharmacist about any medicine.