Albert Cilia-Vincenti


C hronic pain is a substantial medical concern because it is common, can be debilitating, and pain medications may be more dangerous than originally thought.

Analgesic drugs taken for even a few days are now claimed to increase myocardial infarction risk by 48%, using ibuprofen, and by 53% when using naproxen.1 Chronic use of NSAIDs like ibuprofen is claimed to increase kidney function impairment by 32%.2 Furthermore, the current opioid epidemic in the US is said to claim over 100 overdose deaths daily.

The challenge in pain control is both addressing the cause of the pain and switching off the pain signal. Is there a safe alternative? Two natural compounds are claimed to work together to reduce the underlying causes of pain. The first compound, palmitoylethanolamide (PEA), is an antiinflammatory fatty acid derivative produced by the body in response to inflammation-inducing damage;3 it acts at the site of tenderness, turning off the pain signal.4,5 The second, honokiol, a Magnolia tree extract, modulates pain perception in the brain. These two compounds are claimed not to cause dependence because they do not act via opioid receptors.

The nature of PEA was first identified by Nobel Laureate Rita Levi-Montalcini, the co-discoverer of the nerve growth factor and the pain signal development and transmission mechanisms.6-8 PEA is said to be an endocannabinoid, a natural neurochemical signalling molecule which does not bind to specific cannabinoid receptors, and which has no documented risk of dependency or adverse effects. This distinguishes it from most other chronic pain treatments.9

Several studies have established PEA as a powerful, peripherally-acting pain reliever.4,5 One study was conducted on 636 sciatic pain sufferers randomly assigned to placebo or one of two doses of PEA (300mg or 600mg daily). After 3 weeks, both pain reduction and quality–of-life scores were significantly better than placebo, and the larger dose had better outcomes.10,11

In pain studies, determination of how many patients would need to be treated to achieve a 50% pain reduction is called the “number needed to treat”. The standard number to treat for a useful pain intervention is less than 5, with 1 being statistically perfect (every treated patient achieves at least 50% pain reduction).

In this PEA study, the number needed to treat in the 600mg daily group was just under 3 at week 2 and only 1.5 at week 3.10,12 A number needed to treat as low as 1.5 is virtually unknown in pain reduction, indicating such a high level of effectiveness which surpasses most pharmaceutical standards.

In another PEA study with carpal tunnel syndrome, subjects were randomly assigned to three groups, placebo, 600mg and 1,200mg daily for 30 days.13 Nerve conduction measurements at the start and end of the study showed that PEA had slowed median nerve conduction. A faster nerve conduction indicates pain signals are being generated at the sore site. Therefore, this study indicated that PEA recipients’ nerve conduction improvements matched their reduced symptoms compared to controls.

In a study on patients with temporomandibular joint pain, subjects were randomly assigned to 600mg ibuprofen 3 times daily for 2 weeks or 300mg PEA twice daily for 2 weeks. The PEA group experienced significantly greater decrease in pain.14 Another study showed that mice treated with morphine plus PEA were less prone to develop morphine tolerance compared with animals on morphine alone.15 This suggests that PEA combined with an opioid could decrease the risk of tolerance and addiction.

Honokiol has been identified as the second compound that could approach pain reduction from a different aspect to provide deeper, complementary, more consistent relief. It operates in the central nervous system to affect how pain is perceived. It binds to GABA receptors, GABA being a neurotransmitter inducing calming, pain-dampening signals.16,17

Loss of GABA receptors and reduced GABA signalling is involved in the transition from acute to chronic pain, leaving the CNS exposed to continued stimulus from an old injury.18-20 Honokiol mimicks GABA actions, interfering with the chronic pain cycle by restoring a central natural pain-dampening effect. This is being followed up by pharmaceutical companies.21 Oral honokiol is quickly absorbed and distributed throughout the brain.22-24

An animal study has shown how capable honokiol is in its CNS pain-relieving action. Mice were injected with a variety of substances known to activate hyperalgesia receptors.25 Then they were treated with either honokiol or a control injection.

For each pain-inducing substance the mice were timed on how long they spent licking the painful site, longer licking meaning more severe pain perception. They were then timed on how long they took to withdraw their paw from a hot water bath. In each case, the honokiol-treated animals showed significant reductions in licking time, and significant increases in paw withdrawal time from the hot bath. These actions indicated a reduction in pain and demonstrated how honokiol can help break the chronic pain cycle.

By inference, a honokiol-PEA combination could provide a complementary dual action approach to chronic pain, without the risks seen with conventional analgesic drugs.

Chronic inflammation in the CNS may be involved in the pathogenesis of neurodegenerative conditions such as Parkinson’s and Alzheimer’s diseases. In a study of 30 advanced Parkinson’s patients being treated with levodopa, a cognitive test battery before and after receiving 1,200mg PEA daily for three months and 600mg daily for the rest of the year, found a significant and progressive reduction in both motor and nonmotor symptoms.26 PEA appears to have potential for some reversal of symptoms of chronic neurodegenerative diseases.

PEA is available in Europe under the trade name Normast® .  A PEA-Honokiol combination product is marketed as ComfortMAXTM by Life Extension Europe, the European division of Life Extension, an American food supplement company.



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