Blood Pressure Drugs (ACE Inhibitors) May Cause Pain by Increasing Substance P | Research

The takeaway

ACE inhibitors captopril and enalapril increased substance P levels in spinal cord and nerve tissue, inducing mechanical pain sensitivity (allodynia) in mice through NK-1 receptor signaling.

ACE normally degrades substance P
Blocking ACE with blood pressure drugs allows pain-signaling substance P to accumulate in spinal cord tissue

What the researchers found

ACE inhibitors increase substance P levels in spinal cord and DRG, causing mechanical allodynia through NK-1R signaling. ACE normally degrades substance P, revealing a previously underappreciated pain-related side effect mechanism.

Why it matters

ACE inhibitors are among the most prescribed drugs worldwide. Understanding that they can cause pain sensitivity through substance P accumulation may explain unexplained pain complaints in patients taking these medications.

The numbers in context

10-day treatment; increased SP in DRG + spinal dorsal horn; allodynia reversed by L-733,060; intraplantar SP for 3 days caused allodynia; exogenous ACE blocked SP effect

How the study worked

Mouse model with 10-day captopril or enalapril treatment (IP or intrathecal). Paw withdrawal frequency to mechanical stimuli. Substance P immunohistochemistry in lumbar DRG and spinal dorsal horn. NK-1R antagonist (L-733,060) rescue. Exogenous ACE and SP injection experiments.

Who was studied

Mice receiving ACE inhibitors (captopril, enalapril) for 10 days

What this study cannot tell us

Mouse study — may not directly translate to human pain experiences. 10-day treatment may not reflect chronic clinical use. Only mechanical allodynia tested, not other pain types.

How to read the evidence

Well-designed preclinical study with multiple routes of administration and pharmacological confirmation. Pre-clinical evidence requiring human validation.

When this study was published

Published in 2021, revealing a novel pain-related side effect mechanism for one of the most commonly prescribed drug classes.

The bigger picture

This study reveals an unexpected connection between blood pressure regulation and pain processing through the shared substrate substance P. ACE degrades substance P along with angiotensin I, meaning that ACE inhibitor therapy may inadvertently affect pain pathways — a finding with broad clinical implications.

Questions still open

Do ACE inhibitor users experience more pain sensitivity than people on other blood pressure medications?
Could NK-1R antagonists help manage ACE inhibitor-related pain?
Is this mechanism relevant to the cough side effect of ACE inhibitors?

Common questions

Can blood pressure medication cause pain?

This mouse study suggests yes — ACE inhibitors like captopril and enalapril increased levels of substance P (a pain-signaling molecule) in the spinal cord, causing heightened sensitivity to touch. ACE normally breaks down substance P, so blocking ACE lets this pain molecule accumulate.

Should I stop taking my ACE inhibitor if I have pain?

Don't stop medications without consulting your doctor. This is a mouse study and may not directly apply to humans. However, if you've developed unexplained pain since starting an ACE inhibitor, discussing this research with your doctor could be worthwhile — alternative blood pressure medications exist.

Read the original research

Inhibition of angiotensin converting enzyme induces mechanical allodynia through increasing substance P expression in mice.

Neurochemistry international, 146, 105020

View on PubMed ↗Publisher’s paper ↗

Citation

Choi, Jae-Gyun; Choi, Sheu-Ran; Kang, Dong-Wook; Kim, Jaehyuk; Park, Jin Bong; Kim, Hyun-Woo. (2021). Inhibition of angiotensin converting enzyme induces mechanical allodynia through increasing substance P expression in mice.. Neurochemistry international, 146, 105020. https://doi.org/10.1016/j.neuint.2021.105020