Nutraceuticals:

Palmitoylethanolamide (PEA) – Central Sensitization

PEA has been shown to be effective for chronic pain of multiple types, especially with neuropathic (nerve) pain. Nerve pain can be associated with Central Sensitization (CS) in which the experience of pain becomes abnormally magnified. Treatment of CS is challenging and requires multi-modal management with the use of medications and behavioral approaches. PEA is a nutraceutical with good evidence for benefit in treating CS.

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Definitions and Terms Related to Pain

 

Key Terms:

Central Sensitization (CS):

  • Central sensitization (CS) of pain occurs when a patient’s nervous system is persistently in a high pain activity state. When this happens, even if the peripheral nervous system sends limited signals of painful stimulation, the central nervous system responds as if there has been a high level of input, which results in amplification of pain signals to the brain and consciousness. So patients become hypersensitive to pain.
  • Ordinary touch may be perceived as painful (allodynia), or a painful stimulus is perceived as magnified (hyperalgesia).
  • Because of central sensitization, pain can be made even worse by cold temperatures and changes in an emotional state.
  • Central sensitization can be an important contributing process to the chronic pain experience. It is a process associated with many chronic pain syndromes, especially fibromyalgia, chronic headaches, interstitial cystitis, irritable bowel syndrome and also chronic neck and back pain.

Allodynia:

  • A painful response to a normally innocuous, or non-painful stimulus
  • Allodynia is a term that describes the experience of pain from a stimulus which does not normally provoke pain. Like hyperalgesia, allodynia can be a consequence of central sensitization. It is also commonly accompanies fibromyalgia, diabetic neuropathy and chronic headaches. An example is a patient with diabetic neuropathy whose feet are sensitive to putting on socks.

Hyperalgesia:

  • Hyperalgesia is an exaggerated, increased painful response to a stimulus which is normally painful.
  • Hyperalgesia can be a consequence of central sensitization and is also thought to occur with chronic exposure to opioids, although the clinical significance of this is uncertain.

 

Palmitoylethanolamide (PEA) – Central Sensitization

The evidence for PEA’s efficacy in treating allodynia and hyperalgesia is among the strongest in the PEA literature, supported by both a well-designed human random controlled trial (RCT) demonstrating effects on quantitative sensory testing parameters and robust preclinical mechanistic studies. While more research is needed to explore these potential benefits of PEA, its excellent safety profile and affordability argues strongly for patient trials.

Key Human Clinical Evidence

The pivotal study is a high quality randomized, double-blind, placebo-controlled crossover trial in 14 healthy volunteers who received PEA 400 mg three times daily (1,200 mg/day) or placebo for 4 weeks.[1] Using the validated “Repetitive Phasic Heat Application” pain model, investigators measured specific parameters of peripheral sensitization, central sensitization, and descending pain modulation.

This study is particularly important because it demonstrates that PEA acts on both peripheral and central mechanisms as well as enhancing the body’s endogenous pain control systems.

The results demonstrated:

Central Sensitization Parameters:

  • Wind-up ratio significantly decreased after PEA treatment  — wind-up is a hallmark of spinal cord hyperexcitability where repeated stimulation produces progressively increasing pain responses
  • Average distance of mechanical allodynia significantly reduced  — the area of skin surrounding an injury site that becomes painful to normally non-painful touch

Peripheral Sensitization Parameters:

  • Heat pain tolerance significantly increased
  • Cold pain tolerance significantly prolonged
  • Pressure pain tolerance increased

Descending Pain Modulation:

  • Conditioned pain modulation (CPM) significantly enhanced — CPM reflects the brain’s ability to inhibit pain through descending nerve pathways from the brain to the spinal cord., Impaired CPM is associated with chronic pain.

 

Mechanistic Understanding from Preclinical Studies

The anti-allodynica and anti-hyperalgesia effects of PEA are mediated through multiple receptor systems and cellular targets:

Receptor-Mediated Mechanisms:

In a chronic constriction injury (CCI) model of neuropathic pain, PEA relieves both thermal hyperalgesia and mechanical allodynia through CB1, PPARγ, and TRPV1 receptors.[2] The proposed mechanism involves the “entourage effect” — PEA inhibits fatty acid amide hydrolase (FAAH), the enzyme that degrades the endocannabinoid anandamide, thereby increasing anandamide tissue levels and enhancing its analgesic action.[2]

Anandamide is the bodies naturally occurring cannabinoid, a compound that works in the body with many clinical effects, including pain relief. Anandamide is different from, but analogous to, endorphins which are the bodies naturally occurring opioids.

Additionally, PEA directly activates PPARα, which modulates TRPV1 activity. In dorsal root ganglia neurons, PEA preincubation significantly reduced capsaicin-evoked calcium responses (from 63.9% to 42.9% of KCl response, p<0.001), demonstrating direct desensitization of TRPV1 channels involved in pain transmission.[3]

Mast Cell and Glial Cell Modulation:

PEA’s anti-allodynic effects are strongly linked to its ability to downmodulate mast cell activation and glial cell reactivity.[4][5] In the CCI model, PEA significantly reduced production of TNF-α and nerve growth factor (NGF) — mediators released by activated mast cells that contribute to peripheral sensitization.[2] In the spinal cord, PEA normalizes the activation of microglia and astrocytes that occurs with neuropathic pain, and increases expression of the anti-inflammatory cytokine IL-10.[6]

A particularly elegant study demonstrated that PEA-conditioned microglial cells, when transplanted into mice with formalin-induced neuropathic-like pain, normalized the activity of sensitized spinal nociceptive neurons — while vehicle-conditioned microglia did not.[6] This provides direct evidence that PEA’s effects on glial phenotype contribute to its anti-allodynic properties.

Spinal Cord Effects:

Ultramicronized PEA crosses the blood-spinal cord barrier and reaches the spinal cord, where it downregulates distinct inflammatory and oxidative pathways.[7] In vivo electrophysiological recordings show that formalin injection increases the duration and frequency of evoked activity in spinal nociceptive neurons — changes that are normalized by PEA treatment in a dose-dependent manner.[6] In diabetic peripheral neuropathy models, PEA reduced spinal microglia activation (IBA-1), phospho-P38 MAPK, and NF-κB inflammatory pathways.[8]

Clinical Implications

The convergence of human and preclinical evidence suggests PEA is particularly well-suited for pain conditions characterized by:

  • Central sensitization (fibromyalgia, chronic widespread pain, nociplastic pain)
  • Mechanical allodynia (neuropathic pain conditions)
  • Cold hyperalgesia
  • Thermal hyperalgesia
  • Impaired conditioned pain modulation (CPM) – ability of the brain to suppress pain signals coming up from the spinal cord

The 2025 meta-analysis confirmed PEA’s efficacy across all pain types, including nociplastic pain , which is defined by central sensitization in the absence of clear tissue or nerve damage. Nociplastic pain is the hallmark of fibromyalgia, but it also accompanies other conditions as well[9]

References

  1. Meta-Analysis of Palmitoylethanolamide in Pain Management: Addressing Literature Gaps and Enhancing Understanding. Viña I, López-Moreno M. Nutrition Reviews. 2025;83(7):e1604-e1618. doi:10.1093/nutrit/nuae203.
  2. Palmitoylethanolamide in the Treatment of Chronic Pain: A Systematic Review and Meta-Analysis of Double-Blind Randomized Controlled Trials. Lang-Illievich K, Klivinyi C, Lasser C, et al. Nutrients. 2023;15(6):1350. doi:10.3390/nu15061350.
  3. The Nuclear Receptor Peroxisome Proliferator-Activated Receptor-Alpha Mediates the Anti-Inflammatory Actions of Palmitoylethanolamide. Lo Verme J, Fu J, Astarita G, et al. Molecular Pharmacology. 2005;67(1):15-9. doi:10.1124/mol.104.006353.
  4. Palmitoylethanolamide: A Natural Compound for Health Management. Clayton P, Hill M, Bogoda N, Subah S, Venkatesh R. International Journal of Molecular Sciences. 2021;22(10):5305. doi:10.3390/ijms22105305.
  5. Pharmacokinetic-Pharmacodynamic Influence of N-Palmitoylethanolamine, Arachidonyl-2′-Chloroethylamide and WIN 55,212-2 on the Anticonvulsant Activity of Antiepileptic Drugs Against Audiogenic Seizures in DBA/2 Mice. Citraro R, Russo E, Leo A, et al. European Journal of Pharmacology. 2016;791:523-534. doi:10.1016/j.ejphar.2016.09.029.
  6. Palmitoylethanolamide (PEA) as a Potential Therapeutic Agent in Alzheimer’s Disease. Beggiato S, Tomasini MC, Ferraro L. Frontiers in Pharmacology. 2019;10:821. doi:10.3389/fphar.2019.00821.
  7. A Novel Composite Formulation of Palmitoylethanolamide and Quercetin Decreases Inflammation and Relieves Pain in Inflammatory and Osteoarthritic Pain Models. Britti D, Crupi R, Impellizzeri D, et al. BMC Veterinary Research. 2017;13(1):229. doi:10.1186/s12917-017-1151-z.
  8. Effects of Palmitoylethanolamide (PEA) on Nociceptive, Musculoskeletal and Neuropathic Pain: Systematic Review and Meta-Analysis of Clinical Evidence. Scuteri D, Guida F, Boccella S, et al. Pharmaceutics. 2022;14(8):1672. doi:10.3390/pharmaceutics14081672.
  9. Palmitoylethanolamide for the Treatment of Pain: Pharmacokinetics, Safety and Efficacy. Gabrielsson L, Mattsson S, Fowler CJ. British Journal of Clinical Pharmacology. 2016;82(4):932-42. doi:10.1111/bcp.13020.

Is there evidence that PEA may be effective against Cold hyperalgesia?

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