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Evidence: MediumPeptideResearch ChemicalEndogenous opioidNot a drugMeasured, not given

Enkephalin

The body's own opioid pentapeptides, studied in people almost entirely as a blood measurement

Met-enkephalin and leu-enkephalin are five-amino-acid opioid peptides identified in 1975. They act at delta and mu opioid receptors and are broken down within minutes. Human research measures them in blood rather than giving them, and a fragment of their precursor is being tested as a kidney marker.

View Dosing Data Read Research →
Overview

What is it?

The enkephalins were identified in 1975 as two related pentapeptides from brain with potent opioid activity, the first endogenous opioids found. They act mainly at delta-opioid receptors and are destroyed within minutes by peptidases, which is why they have never become medicines.

Human work takes two forms. One infused enkephalin in a controlled pain study, where it did nothing. The rest measures enkephalins or their precursor in blood, in liver failure, kidney failure and kidney injury, as markers of what the opioid system is doing rather than as treatment.

The precursor fragment proenkephalin is the part now being developed. In sepsis it flagged kidney decline even when creatinine was normal, and in chronic kidney disease it predicted major kidney events. Because it survives longer than the enkephalins themselves, it can be measured reliably, and it has been tested as an early signal of kidney injury.

The kidney work is now broad. A 2026 meta-analysis of sepsis studies found higher proenkephalin in those who developed kidney injury or died; in 1,436 ICU patients it predicted who would fail to come off dialysis; and after kidney transplantation it flagged delayed graft function up to eight days earlier than creatinine. It also predicted kidney injury and death in acute coronary syndromes and acute heart failure. Reference values now exist for children, in whom levels start high and fall until about age 20.

The therapeutic idea that remains is indirect: protect the body's own enkephalins rather than give them. Enkephalinase inhibitors such as racecadotril do this; they are not enkephalins, and their trials are listed under References. In Huntington's disease, low CSF proenkephalin is being studied as an early marker of striatal loss.

1975
Enkephalins discovered
the first endogenous opioids
0.87 vs 0.56
Delayed graft function, penKid vs creatinine
AUROC after kidney transplant
Minutes
Survival in blood
broken down by peptidases
Science

Mechanism of Action

Enkephalins are pentapeptide opioids made from proenkephalin; they act mainly at delta-opioid receptors and are broken down within minutes by peptidases.

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Opioid signalling

They activate delta-opioid receptors and are broken down quickly.

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Kidney filtration

The stable proenkephalin fragment is freely filtered by the kidney, so its blood level tracks filtration and kidney injury.

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Striatum

Low proenkephalin in cerebrospinal fluid predicted later striatal atrophy in Huntington's disease.

Evidence

Published Research

These are the studies in people, read from their PubMed abstracts: one infusion study and four measurement studies.

Human1996

Infused, it did not relieve pain

In seven healthy volunteers given adenosine to provoke chest pain in a double-blind study, intravenous met-enkephalin did not shift the dose-response curve for pain. Beta-endorphin, tested the same way, did counteract it.

PMID: 8905708
Human2018

Its precursor as a kidney-injury marker

In 111 hospitalised patients with chronic kidney disease having contrast procedures, proenkephalin measured the day after was higher in those who developed acute kidney injury (198 against 121 pmol/L). Its ability to identify injury, 0.79 by area under the curve, was similar to serum creatinine's 0.78.

PMID: 30009473
Human2007

Raised in liver failure

Plasma met-enkephalin was higher in patients with cirrhosis and at every grade of hepatic encephalopathy than in controls, and leu-enkephalin was higher in the more severe grades. Beta-endorphin did not differ between the groups.

PMID: 17684846
Human1987

Opposite directions in kidney failure

In 28 patients with chronic kidney failure against 13 healthy subjects, met-enkephalin was markedly higher and tracked plasma creatinine, while leu-enkephalin was suppressed.

PMID: 3110677
Human2018

Measuring them reliably is hard

A mass-spectrometry method for met- and leu-enkephalin in human plasma reached a limit of quantitation of 10 pg/mL and was linear to 2,000 pg/mL, in a study of how sample handling before analysis affects the result.

PMID: 29981318
Human2026

Sepsis: precursor and kidney decline

In pooled individual data from 2,203 ICU patients with sepsis, proenkephalin was independently associated with worsening kidney function within 48 hours (OR 3.4) and 28-day mortality (OR 1.6); among those with normal creatinine, a raised level meant 27.1% against 11.1% worsening kidney function.

PMID: 41877211
Human2026

Chronic kidney disease outcomes

Across 4,722 people in three cohorts, proenkephalin tracked kidney function inversely; in 581 patients with chronic kidney disease followed a median 8.7 years, each doubling more than doubled the risk of major adverse kidney events after adjustment.

PMID: 41105147
Human2026

Mortality in a general population

Among 1,021 REGARDS participants followed 11.6 years, each doubling of proenkephalin was linked to higher mortality (HR 1.22) until eGFR was added, when the association disappeared, suggesting it largely reflects kidney function.

PMID: 41838818
Human2026

Stopping dialysis in the ICU

In 1,436 critically ill patients, proenkephalin rose with AKI stage, separated patients needing kidney replacement therapy, and was the strongest independent predictor of failing to come off it.

PMID: 42571343
Human2025

Kidney transplant function

After kidney transplantation, penKid identified delayed graft function far better than creatinine (AUROC 0.87 against 0.56) and up to eight days earlier.

PMID: 40475974
Human2025

Acute coronary syndromes

In acute coronary syndromes, proenkephalin was independently associated with in-hospital AKI and 30-day mortality (hazard ratio 2.73), and a score built on it validated in external cohorts.

PMID: 39215600
Human2025

Acute heart failure

In emergency patients with acute heart failure, point-of-care proenkephalin of 90.5 pmol/L or more predicted worsening renal function and also predicted mortality at 30 days to 1 year.

PMID: 40869560
Human2026

Measuring kidney reserve

Proenkephalin-based measures of kidney functional reserve were higher in healthy people than cardiac surgery patients and gave a wider, more consistent range than creatinine clearance.

PMID: 42655869
Human2025

How the kidney clears it

Single-pass renal elimination of proenkephalin was about 24%, slightly above creatinine, consistent with free filtration; a combined proenkephalin-creatinine equation overestimated GFR by 26%.

PMID: 40493517
Human2026

Reference values in children

Serum proenkephalin falls through the first 20 years of life, with the 97.5th percentile dropping from 618 pmol/L in the first month to about 103 at age 20, then stable; there was no sex difference.

PMID: 42702244
Human2026

Huntington's disease

Lower CSF proenkephalin predicted later striatal atrophy in Huntington's disease and distinguished the earliest disease stages better than neurofilament light.

PMID: 41000014
Review2026

Sepsis meta-analysis

Across 9 studies of sepsis or septic shock, proenkephalin was higher in patients who developed acute kidney injury and in those who died; AKI was associated with penKid levels (odds ratio 2.50).

PMID: 42377086
Animal2024

Jaw pain in rats

In rats, enkephalin reduced temporomandibular joint pain-related behaviour.

PMID: 38874721
Human1999

Injected into skin

In 6 healthy volunteers, met-enkephalin injected into forearm skin (16 to 45 nmol) caused a dose-dependent flare, reduced by the antihistamine cetirizine, but no weal; repeated injections drew lymphocytes and monocytes into normal skin while damping a tuberculin hypersensitivity reaction.

PMID: 10086853
Dosing

Dosing Data

Enkephalins are not approved medicines; the amounts below are research injections of met-enkephalin into the skin of healthy volunteers.

Research doses given under supervision, not treatment doses. See a doctor before using any peptide.
ProtocolDoseFrequencyDurationRoute
Study: skin flare in healthy volunteers (single injections) Human studyPMID 1008685316, 30 or 45 nmol in 50 µLSingle injectionSingle sessionIntradermal
Study: skin inflammation and hypersensitivity (repeated injections) Human studyPMID 1008685345 nmol in 50 µLAt 0, 24 and 48 hours48 hoursIntradermal

Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.

No enkephalin dose
Met-enkephalin was injected into the skin, in nanomoles, in a research study; nothing here is prepared at home.
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Safety

Side Effects & Contraindications

Reported Side Effects

Only one of the studies read gave enkephalin to people.

● In the 1996 infusion study, met-enkephalin had no effect on provoked chest pain and no adverse effects were reported in the abstract
● No repeated-dosing study in people was found

Contraindications & Cautions

Not a medicine.

● Any use outside a supervised research study
● Enkephalins are opioid agonists; nothing is known about tolerance or dependence from giving them
Questions

Frequently Asked Questions

?What are enkephalins?

Two five-amino-acid opioid peptides, met-enkephalin and leu-enkephalin, identified in 1975. They act mainly at delta-opioid receptors and are broken down within minutes.

?Have they been given to people as painkillers?

The one controlled study we found infused met-enkephalin against provoked chest pain, and it had no effect. Beta-endorphin, tested the same way, did.

?What is proenkephalin?

The precursor they are cut from. A fragment of it survives long enough to be measured reliably and has been tested as an early marker of acute kidney injury.

?Why are they measured in liver and kidney disease?

Levels shift with those illnesses: met-enkephalin is raised in cirrhosis and in kidney failure, where leu-enkephalin is suppressed. These are measurements, not treatments.

?What is penKid?

It is a test for a stable fragment of proenkephalin (PENK A 119-159). Because the kidney filters it freely, blood levels track kidney function, and studies use it to predict kidney injury in sepsis, heart disease and after transplantation.

?Are there drugs that boost enkephalins?

Enkephalinase inhibitors such as racecadotril slow their breakdown; they are not enkephalins, and their trials are listed under References.

Bibliography

References

  1. [pubmed] Sylvén C, et al. "Beta-endorphin but not metenkephalin counteracts adenosine-provoked angina pectoris-like pain." Neuroreport, 1996;7(12):1982-4. PMID: 8905708.
  2. [pubmed] Breidthardt T, et al. "Proenkephalin for the early detection of acute kidney injury in hospitalized patients with chronic kidney disease." Eur J Clin Invest, 2018;48(10):e12999. PMID: 30009473.
  3. [pubmed] Kamel L, et al. "Plasma met-enkephalin, beta-endorphin and leu-enkephalin levels in human hepatic encephalopathy." East Mediterr Health J, 2007;13(2):257-65. PMID: 17684846.
  4. [pubmed] Zoccali C, et al. "Plasma met-enkephalin and leu-enkephalin in chronic renal failure." Nephrol Dial Transplant, 1987;1(4):219-22. PMID: 3110677.
  5. [pubmed] Ozalp A, et al. "Determination of methionine-enkephalin and leucine-enkephalin by LC-MS in human plasma: Study of pre-analytical stability." Anal Biochem, 2018;559:24-29. PMID: 29981318.
  6. [pubmed] Hughes J, et al. "Identification of two related pentapeptides from the brain with potent opiate agonist activity." Nature, 1975;258(5536):577-80. PMID: 1207728.
  7. [pubmed] Arlt B, et al. "Clinical utility of proenkephalin A 119-159 for prediction of worsening renal function and prognosis in patients with sepsis -results of a patient-level meta-analysis." Crit Care, 2026;30(1). PMID: 41877211.
  8. [pubmed] Würfel M, et al. "Proenkephalin predicts kidney function and major adverse kidney events in CKD." Nephrol Dial Transplant, 2026;41(5):876-887. PMID: 41105147.
  9. [pubmed] Pavlovich RN, et al. "Proenkephalin for Cardiovascular and All-Cause Mortality: The REasons for Geographic and Racial Differences in Stroke Study (REGARDS) Study." Am J Nephrol, 2026:1-15. PMID: 41838818.
  10. [pubmed] Yang S, et al. "A study on the prognosis of patients with sepsis or septic shock based on plasma proenkephalin levels: a meta-analysis." Biomarkers, 2026;31(5):406-414. PMID: 42377086.
  11. [pubmed] Gabriel DC, et al. "Proenkephalin A for assessing kidney integrity and guiding KRT liberation decisions in critically ill patients." Ann Intensive Care, 2026;16:100113. PMID: 42571343.
  12. [pubmed] Benning L, et al. "Proenkephalin A 119-159 in Kidney Transplantation: A Novel Biomarker for Superior Tracking of Graft Function Trajectories." Transpl Int, 2025;38:14366. PMID: 40475974.
  13. [pubmed] Wenzl FA, et al. "Proenkephalin improves cardio-renal risk prediction in acute coronary syndromes: the KID-ACS score." Eur Heart J, 2025;46(1):38-54. PMID: 39215600.
  14. [pubmed] Matsiras D, et al. "Predictive Value of Point-of-Care Proenkephalin for Worsening Renal Function and Mortality in Patients Presenting to Emergency Department with Acute Heart Failure." J Clin Med, 2025;14(16). PMID: 40869560.
  15. [pubmed] Rodrigues CE, et al. "Plasma proenkephalin-a facilitates measurement of human kidney functional reserve: From healthy kidney donors to polymorbid patients." Physiol Rep, 2026;14(16):e71083. PMID: 42655869.
  16. [pubmed] Sigurjonsson J, et al. "Renal elimination and eGFR prediction of proenkephalin." Scand J Clin Lab Invest, 2025;85(4):281-286. PMID: 40493517.
  17. [pubmed] Morath M, et al. "Reference values for serum proenkephalin A in a pediatric and young adult cohort." Clin Biochem, 2026;146:111189. PMID: 42702244.
  18. [pubmed] Farag M, et al. "Cerebrospinal Fluid Proenkephalin Predicts Striatal Atrophy Decades before Clinical Motor Diagnosis in Huntington's Disease." Mov Disord, 2026;41(1):95-106. PMID: 41000014.
  19. [pubmed] Moss LM, et al. "First-in-human trial to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of STR-324, a dual enkephalinase inhibitor for pain management." Br J Clin Pharmacol, 2022;88(1):103-114. PMID: 34046921.
  20. [pubmed] Southerland WA, et al. "Dual Enkephalinase Inhibitors and Their Role in Chronic Pain Management." Curr Pain Headache Rep, 2021;25(5):29. PMID: 33761014.
  21. [pubmed] Westlund KN, et al. "Enkephalin Rescues Temporomandibular Joint Pain-Related Behavior in Rats." Adv Neurobiol, 2024;35:125-136. PMID: 38874721.
  22. [pubmed] Nissen JB, et al. "Effect of intradermal injection of methionine-enkephalin on human skin." Acta Derm Venereol, 1999;79(1):23-6. PMID: 10086853.

Sources & Citations

Studies were read from their PubMed abstracts; enkephalins have no label. Read October 7, 2026.

Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.

Last reviewed: 2026-10-19