Introduction
Many people dealing with chronic pain or inflammation want options beyond acetaminophen (paracetamol), ibuprofen, aspirin, or even opioids. While these medications are effective, they can bring side effects especially if used long-term.
That’s why interest is growing in natural pain relief supplements. Some target inflammation, others influence chemical signalling in the nervous system, and some may even support joint repair.
This article reviews some of the most studied options: White Willow Bark, Palmitoylethanolamide (PEA), Cannabidiol (CBD), Curcumin (from turmeric), Omega-3 fatty acids, and Glucosamine/N-Acetyl-Glucosamine (NAG). Also featured is a promising repurposed medication called Low-Dose Naltrexone (LDN) which is gaining traction with off-label use and increasing research for a whole range of conditions as well as pain management.
Always check with a healthcare professional before starting new supplements or combining them with medications. This article is informational only and not medical advice.
White Willow Bark for Pain Relief
How White Willow Works
White Willow (Salix alba), native to Europe and Asia, has been used for centuries to reduce pain and inflammation. Its bark contains salicin, which the body converts into salicylic acid—the chemical inspiration for modern aspirin.
Benefits of White Willow Bark
Research suggests it may relieve:
- Arthritis but evidence in knee/hip osteoarthritis is mixed: one double-blind trial did not show superiority to placebo over 6 weeks, while others report modest improvements. Expect variability across extracts and doses.
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Low back pain in a standardized daily dose of 120 mg to 240 mg of salicin
Traditional use suggests it may reduce:
- Fever
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Muscle and joint pain
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Chronic pain
Safety & interactions
White willow is generally well tolerated short-term (no serious adverse events reported in trials delivering 120–240 mg salicin up to 8 weeks), but aspirin-like gastrointestinal effects can occur and drug interactions are possible—particularly with NSAIDs and anticoagulants/antiplatelets. Avoid combining with other NSAIDs unless advised by a clinician. Review important safety information from Memorial Sloan Kettering Cancer Center.
Palmitoylethanolamide (PEA) and Cannabidiol (CBD) for Pain Relief and Inflammation
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PEA: Fatty acid amide with anti-inflammatory and analgesic properties.
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CBD: Non-psychoactive cannabinoid with evidence for neuropathic and inflammatory pain relief.
Both show potential synergy for pain management.
Palmitoylethanolamide (PEA)
PEA is a naturally occurring fatty acid amide produced in the body. It has emerged in research as a modulator of nerve activity and inflammation—likely acting through neuroprotective and endocannabinoid-like pathways, including PPAR‑α activation, which influences gene expression related to inflammation and pain signaling.
Clinical evidence looks promising. A 2025 systematic review and meta-analysis involving nearly 800 patients found that PEA significantly reduced chronic pain—both neuropathic and nociceptive—within about four to six weeks, while also improving quality of life and showing strong tolerability. An earlier meta analysis echoed those findings, showing a clear advantage over placebo with few adverse effects reported.
Safety-wise, PEA has been well tolerated in clinical use, with no serious adverse events or drug interactions documented to date (Wikipedia).
Cannabidiol (CBD)
CBD, a non‑intoxicating compound from hemp or cannabis plants, operates on the body’s endocannabinoid system, which helps regulate pain, inflammation, and inflammation-related signaling (See Medically Reviewed Info on Cannabinoids).
In a small randomized controlled trial, a topical CBD oil significantly reduced neuropathic pain—including reductions in intense, sharp, cold, and itchy sensations—compared to a placebo after four weeks.
However, caution is advised if choosing any CBD product: Product quality varies widely, and studies have found some products contain inaccurate CBD levels or unwanted substances. One landmark study in JAMA found that just 30% of online-sold CBD products were accurately labeled, while the rest over‑ or under‑delivered on dosage—yet the authors didn’t dismiss CBD outright; rather, they stressed that consumers and practitioners must rely on verified, third‑party—tested products to ensure both safety and efficacy.
PEA + CBD Synergy
Early preclinical work suggests a synergistic effect: in a 2021 animal study, hemp oil with CBD didn’t relieve neuropathic pain on its own—but when combined with PEA, the duo produced a significantly greater pain‑relieving effect than either alone.
Curcumin (Turmeric Extract) for Joint Pain & Inflammation
Mechanism of Action
Curcumin, the active compound in turmeric, reduces pain and inflammation by inhibiting pro-inflammatory cytokines and enzymes.
Research on Curcumin
One study suggests curcumin can be as effective as ibuprofen for knee osteoarthritis, with fewer gastrointestinal side effects.
It may also help with:
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Rheumatoid arthritis
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Cardiovascular health
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Mood support (depression, anxiety)
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Neuroprotection
Absorption and Bioavailability
Curcumin has low natural absorption.
⚠️ Curcumin and Liver Safety
Not all curcumin supplements are equal when it comes to the liver.
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BCM-95 (Curcugreen): Uses turmeric’s own essential oils to improve absorption. Research suggests it may actually support liver health by lowering inflammation.
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With Black Pepper (Piperine): Boosts absorption by blocking liver enzymes. This can overwhelm the liver and has been linked to cases of liver injury and even hepatitis.
Takeaway: If you’re concerned about liver safety, BCM-95 curcumin is generally considered the safer option compared to curcumin combined with black pepper extract.
Use caution (and medical advice) with anticoagulants/antiplatelets, warfarin, some chemotherapy, statins, and diabetes medicines; avoid or monitor in gallbladder disease or bleeding disorders. Quality and contamination issues have been flagged in some markets—another reason to choose reputable brands and formulations.
Omega-3 Fatty Acids and Inflammation
How Omega-3s Reduce Pain
Omega-3 fatty acids, found in fish oil, krill oil, and flaxseed, lower inflammation by reducing pro-inflammatory cytokines and supporting anti-inflammatory molecules.
Benefits for Joint Health and Lupus
Omega-3 supplementation can:
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Reduce rheumatoid arthritis symptoms, decrease morning stiffness and swelling, and support mobility and flexibility
Meta-analyses such as this report small but real improvements in joint tenderness, morning stiffness, and/or reduced NSAID use in many trials (effect sizes vary across studies, doses, and durations).
- May anecdotally help with other inflammatory pain types
Effective Doses
A practical, commonly studied intake for anti-inflammatory aims is around 2–3 g/day combined EPA+DHA, typically for ≥12 weeks. (Discuss personalized dosing with your clinician).
Safety Notes
A large contemporary analysis published in the Journal of the American Heart Association suggests no meaningful increase in clinically significant bleeding at commonly used or even higher doses; still, coordinate with your clinician if you use anticoagulants/antiplatelets or require surgery.
Glucosamine and N-Acetyl-Glucosamine (NAG)
What They Are
Glucosamine and N-Acetyl-Glucosamine (NAG) are naturally occurring compounds that support joint and cartilage health.
Benefits of Glucosamine
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Provides building blocks for cartilage repair
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May reduce stiffness and improve joint function
NAG vs Glucosamine
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NAG is more readily absorbed and may support gut and skin health in addition to joints. However while promising, clinical data for joint pain are limited.
- NAG shows potential as a relatively cheap and nontoxic treatment for chronic inflammatory bowel disease (IBD).
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Glucosamine requires conversion in the body but is widely studied for joint support.
Safety Considerations
Both are considered safe when used correctly. However, some glucosamine supplements are shellfish-derived, which may be an issue for those with allergies.
Low-Dose Naltrexone (LDN) for Chronic Pain (Prescription Only)
How LDN Works
At low doses (commonly 1.5–4.5 mg), Naltrexone blocks opioid receptors briefly, triggering the body to increase endorphin release. These endorphins act as natural painkillers and modulate immune function. Naltrexone may also modulate microglia/TLR-4, which can shift neuroinflammation (common in mental health disorders) and pain processing.
Conditions That May Benefit
LDN shows promise in:
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Autoimmune conditions (a large study is underway for Crohn’s disease, and a successful pilot study was carried out for multiple sclerosis)
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Potentially long-COVID
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Mental health issues and many others – click here to search for all current LDN research
LDN vs Traditional Pain Medications
Unlike opioids, LDN is non-addictive, safe, and often effective in cases where traditional painkillers fail. However, it is still considered experimental, and more research is needed. To that end, the LDN Research Trust is a charity working to raise funds for research trials. They have helped over 100,000 people obtain LDN from a General Practitioner or Consultant in many western countries.
Conclusion: Natural Pain Relief Supplements vs Traditional Medications
Natural pain relief supplements such as White Willow Bark, Curcumin, Omega-3s, Glucosamine, Palmitoylethanolamide (PEA), Cannabidiol (CBD), and the medication Low-Dose Naltrexone (LDN) provide promising alternatives for managing chronic pain and inflammation.
Each compound works differently—some reduce inflammation, others support endorphins or joint repair. While individual responses vary, these options may reduce reliance on NSAIDs or opioids, under professional guidance.
Exploring these supplements with your doctor may help you build a safer, more holistic pain management plan tailored to your needs.
Note: This page is part of an actively evolving resource. We’re continually updating and refining it as new evidence and insights become available.
Have a suggestion, correction, or update you think would improve this page? Contact us— we’d love your input.
