PainX Technical Data

PainX Technical Data

Nutrients that May Assist

Magnesium amino acid chelate
Meta Mag® Magnesium bisglycinate
Palmitoylethanolamide (PEA)
Palmidrol (Palmitoylethanolamide) (Levagen+™)

Actions

  • Reduces muscle tension and spasm
  • Reduces nerve inflammation and sensitivity
  • Anti-nociceptive

Clinical Applications

  • Muscle cramps and spasms
  • Lower back pain
  • Fibromyalgia
  • Migraine headaches

Highly Bioavailable PEA and Magnesium for Neuromuscular Support and Pain

Chronic pain affects 17% to 25% of individuals, with musculoskeletal conditions being the most common cause. Chronic inflammation and nerve damage can increase pain sensitivity, worsening neuromuscular pain.

Magnesium and palmitoylethanolamide (PEA) have been shown to reduce muscle tension and nerve sensitivity. Magnesium induces muscle relaxation and reduces the activity of glutamate, a neurotransmitter that increases pain signaling. Similarly, PEA reduces nerve inflammation and pain perception by enhancing the endogenous cannabinoid system (ECS). Therefore, magnesium and PEA can address multiple pain drivers, improving patient quality of life (see Figure 1).

Figure 1: Magnesium and PEA address multiple drivers of pain.

Background Information

Drivers of Pain Sensitivity

Pain perception occurs when noxious stimuli, like tissue damage, are detected by nociceptors (pain receptors). These receptors transmit pain signals via primary afferent neurons to the spinal cord, and then to the brain through secondary neurons.[14] Pain transmission can be amplified by:

  • Peripheral nerves: Inflammation around nerve endings triggers nociceptor activation. Chronic tissue inflammation increases neuron sensitivity, elevating pain signaling. [14]
  • Spinal cord: Neurotransmitters like glutamate and GABA are involved in pain processing. Imbalances, such as increased glutamate activity, heighten pain transmission. [15]
  • Brain: Neuroinflammation and activation of glial cells (astrocytes and microglia) can promote pain signaling by increasing glutamate activity in the central nervous system (CNS). [14]

Types of Pain in Neuromuscular Disorders

  • Nociceptive-dominant pain: Linked to acute tissue inflammation, injury, or damage. [16]
  • Neuropathic-dominant pain: Due to nerve inflammation and compression (e.g., sciatica). [16]
  • Nociplastic pain (central sensitization): Arises from increased nociceptor sensitivity without clear tissue damage, associated with neuroplastic remodeling driven by nerve growth factor (NGF). [16]

Effective Pain Control

Effective pain control involves managing multiple factors. In muscular disorders, prolonged inflammation leads to muscle hyperexcitation, causing pain, restricted mobility, and limited tissue repair. [3]

In nerve damage conditions, neuropeptides like substance P and CGRP activate inflammatory mediators (e.g., IL-1, IL-6, TNF-α), increasing nociceptor sensitivity and glial activation in the CNS.[17,18] Practitioners can reduce neuromuscular pain by supporting muscle relaxation and minimizing inflammatory nerve damage. [19]

Managing Neuromuscular Pain with Natural Medicine

Magnesium and PEA (palmitoylethanolamide) regulate pain signaling. The combination of Meta Mag® magnesium bisglycinate and PEA Levagen+™ enhances pain management. [3,20-23] Magnesium reduces neural excitation and pain transmission, while PEA promotes ECS activity by enhancing cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) expression and activity, reducing inflammation and pain perception. [24,25]

PEA minimizes pain sensitivity by:

  • Enhancing endogenous cannabinoid (eCB) activity of anandamide (AEA) and 2-arachidonylglycerol (2-AG) on CB1 and CB2. [6-10];
  • Inhibiting eCB-degrading enzyme FAAH, potentiating AEA activation of CB1 and CB2. 8,26]

PEA also mitigates glial cell activation[8,11] and desensitizes pain receptors. [9,13]

Enhancing PEA and Magnesium Levels to Restore Homeostasis

PEA is an endogenous lipid produced by nerve cells and immune cells in response to tissue damage.[28] Following its release, PEA interacts with specific receptors to moderate inflammation and pain perception. [28,29] However, in chronic inflammatory states, microglial activation can enhance PEA degradation, [29,30] thereby decreasing its availability in CNS. As such, promoting PEA availability through supplementation can support its endogenous activity.

That said, due to its lipid-soluble structure, standard PEA has poor water solubility,[31] limiting its bioavailability in the gastrointestinal tract.[32] Whilst micronisation technology enhances the solubility of PEA, [32] its naturally lipophilic properties can impact absorption into the bloodstream.

To address these limitations, LipiSperse® technology helps boost PEA absorption. This has been shown to increase PEA uptake by 170%, resulting in a 600 mg/d dose of Levagen+™ PEA equating to approximately 1,020 mg/.[33] Further to this, Meta Mag® Magnesium bisglycinate features superior bioavailability when compared to other forms of supplemental magnesium, such as magnesium oxide and.[34-36] Therefore, the highly-bioavailable combination of PEA and Meta Mag® Magnesium bisglycinate offers unparalleled therapeutic value to enhance patient outcomes.

Actions

Reduces Muscle Tension and Spasm

Insufficient magnesium intake is linked to muscle tension.[37] This happens when low magnesium levels hinder muscle depolarization, prolonging intracellular calcium levels and muscle contractions.[38] Magnesium also blocks calcium ions from entering synaptic nerve terminals, reducing pain signal transmission to the CNS. [39] Additionally, magnesium inhibits presynaptic acetylcholine release, which affects muscle recruitment.[40]

Beyond the musculoskeletal system, low magnesium promotes vasoconstriction of endothelial smooth muscle, contributing to conditions like migraines.[40] Adequate magnesium supports healthy circulation by promoting vasodilatory mediators (e.g., nitric oxide),[41] enhancing oxygen and nutrient supply for muscle repair.[3]

Reduces Nerve Inflammation and Sensitivity

PEA reduces pain amplification by down-regulating the activation of mast cells, microglia, and astrocytes, thereby minimizing nerve inflammation and pain sensitivity.[11,12] It shifts mast cells from an activated to a resting state and deactivates glial cells.[42,43] These effects are linked to PEA’s stimulation of peroxisome proliferator-activated receptor alpha (PPAR-α),[24,27,45,46] which regulates proteins like nuclear factor kappa B (Nf-κB) that signal the release of inflammatory cytokines (e.g., Il-6, Il-1β, TNF-α).

Additionally, PEA enhances the expression of CB2 receptor proteins through PPAR-α, promoting pain regulation via the ECS.[11] PEA has also been shown to reduce pain hypersensitivity and improve pain tolerance, highlighting its ability to decrease nerve inflammation and sensitivity. [12,47,48]

Anti-nociceptive

Following peripheral pain transmission, high amounts of glutamate are released in the CNS, binding to N-methyl-D-aspartate (NMDA) receptors. This activation triggers intracellular calcium release, propagating pain signals to the brain and promoting pain perception.[14] Magnesium blocks neuronal calcium channels, inhibiting glutamate release and reducing pain signaling. [5] Low magnesium levels are linked to chronic pain, [5,49] highlighting the importance of adequate magnesium intake.

Pain perception can also be minimized by modulating nociceptor sensitivity. Activation of the transient receptor potential vanilloid type 1 (TRPV1) receptor stimulates the release of neuropeptides (e.g., substance P, CGRP) and neurotransmitters (e.g., glutamate), signaling pain to the CNS.[50]

In chronic inflammation, TRPV1 channels become sensitized, lowering their activation thresholds and heightening pain signaling.[51] PEA desensitizes TRPV1 by stabilizing intracellular calcium levels, preventing synaptic depolarization [13] PEA also desensitizes TRPV1 via CB1 and CB2 receptor activation by increasing 2-AG and AEA levels.[9],[52], Additionally, PEA down-regulates mast cell activation and the release of TNF-α and NGF, further reducing TRPV1 sensitivity and minimizing nociception. [11]

Clinical Applications

Muscle Cramps and Spasms

In a randomised double-blinded placebo-controlled trial conducted in 43 pregnant women, 300 mg/d of magnesium bisglycinate over four weeks reduced cramp intensity and frequency by 50% (p<0.05).[4] Magnesium citrate (300 mg/d) over six weeks (n=17) was also found to be effective in improving patient muscle cramp ratings in 78% of patients compared to 54% of the placebo group (p<0.03).[20] As such, these findings indicate the benefits of magnesium to moderate muscular cramps and spasms.

Lower Back Pain

In an open-labeled clinical trial in 35 patients taking pregabalin and opioid medication, 1,200 mg/d PEA was administered over four weeks, followed by 600 mg/d for another four weeks. PEA treatment resulted in a reduction of subjective pain intensity from 43% to 17% (p<0.0001).[53]

1,200 mg/d PEA has also been observed to reduce back pain over six months.[54] In this study, 63% of participants reported >30% reduction in pain scores (p<0.01) and reduced opioid usage (p<0.001).

In a randomised double-blind placebo-controlled trial (n=636), 300 mg/d and 600 mg/d of PEA for three weeks led to a clinically significant reduction in back pain. At the end of the trial, pain scores were greatly improved from 71% down to 21% in patients taking 600 mg/d of PEA (p<0.05).[42,55]

Further to this, PEA has been found to reduce back pain severity in 20 patients who were non-responders to pharmacotherapy. In this open-label clinical study, 1,200 mg/d of PEA combined with oxycodone was shown to decrease in pain scores from 72% to 25% after 30 days (p<0.001).[56] These results are comparable to several other studies evaluating the benefits of PEA to reduce back pain, outlined in Table 1.

Fibromyalgia

In an eight-week randomised, double-blinded, placebo-controlled crossover study (n=20), 300 mg/d of magnesium citrate significantly reduced the number of tender points in fibromyalgia patients across 18 pain sites (15.19 ± 2.54 down to 11.70 ± 6.78; p<0.032). Positive improvements were observed within fibromyalgia impact questionnaire (FIQ) scores measuring physical function (reduced from 35.41 ± 12.12 down to 23.64 ± 8.29; p<0.008).[21]

In an open-label clinical trial over three months (n=35), 1,200 mg/d PEA for 4 weeks followed by 600 mg/d for 8 weeks with pregabalin and duloxetine showed benefits. PEA significantly reduced tender points by 50% (p<0.0001), as well as median pain scores (40% down to 30%; p<0.001).[57]

Migraines and headaches

In a randomised, controlled trial 600 mg/d of magnesium in 40 migraine sufferers for three months led to 33% reduction in migraine frequency and a 47% reduction in migraine severity compared to the placebo group, who experienced a 16% and 0% reduction, respectively (p<0.001).[40]

In 81 patients, 600 mg/d of magnesium citrate prescribed for 12 weeks yielded similar symptom relief.[58] In this study, magnesium therapy led to a 41.6% reduction in migraine frequency compared to a 15.8% reduction in the placebo group (p<0.05). Furthermore, the treatment group reported fewer migraine days and reduced medication use (p<0.025).

In addition, PEA has also been shown to improve migraine pain. [59] In a prospective single-blind study conducted over 12 weeks, 1,200 mg/d of PEA combined with NSAIDs significantly reduced pain and frequency of migraine attacks. Specifically, PEA was shown to reduce pain scores from 7.5± 1.1 in men and 7.9 ± 0.8 in women down to 5.3 ± 2.5 in men and 6.3 ± 2.5 in women (p<0.02).

Research supports the use of PEA Levagen+™ to support acute headache and migraine symptom relief. [60,61] Across two randomised double-blind placebo-controlled studies, 525mg – 600mg of PEA Levagen+™ demonstrated positive effects. In patients experiencing tension headache, 525 mg of PEA Levagen+™ reduced headache pain scores by at least 85%, which was comparable to ibuprofen use after two and four hours.[61]

In migraine patients, 600mg of PEA Levagen+™ resolved migraine symptoms in 90% of the PEA group vs. 45% in the placebo group after two hours in patients who did not use rescue medication. Further, the PEA group reported significantly greater changes from the baseline in symptom scores at 90 minutes and four hours compared to the placebo group.[60] Collectively, these findings support magnesium and PEA to reduce the severity of chronic pain.

Summary of Ingredients

Condition

Study Details

Outcome

Chronic leg cramps[20]

300 mg/d Magnesium citrate

6 weeks; Randomised, double-blind, and cross-over placebo-controlled trial

Magnesium reduced leg cramps by 78% compared to a 54% reduction in the placebo group (p<0.03).

Chronic jaw pain[62]

Week 1: 900 mg/d PEA

Week 2: 600 mg/d PEA

2 weeks; Triple blind randomised-controlled clinical trial

PEA significantly decreased pain intensity scores (reduced from 69.9% down to 7.6%) compared to ibuprofen (reduced from 68.4% down to 37.4%; p<0.0001).

Lumbar pain with nerve compression[55]

300 mg/d or 600 mg/d PEA

3 weeks; Randomised, double-blind placebo-controlled trial

300 mg/d of PEA reduced pain scores from 65% to 36%, while 600 mg/d of PEA reduced pain scores from 71% to 21%. Comparatively, placebo decreased scores from 66% to 46% (p<0.05).

Chronic back pain (following failed surgery)[53]

1,200 mg/d PEA for 4 weeks, followed by 600mg/d for 4 weeks alongside pregabalin and opioid medication.

2 months; Open label clinical trial

Two months of PEA treatment resulted in reduction of subjective pain intensity from 43% to 17% (p<0.0001).

Lower back pain[54]

1,200 mg/d PEA + opioid pain relief

6 months; Observational clinical trial

63% of participants reporting >30% reduction in pain scores (p<0.01). PEA significantly reduced burning pain, numbness, hyperalgesia and doses of opioid pain relief required (p<0.001). Changes in pain-related disability indicated a shift from severe to moderate pain (p<0.01).

Fibromyalgia[57]

1,200 mg/d PEA for 4 weeks, followed by 600 mg/d for 8 weeks alongside pregabalin and duloxetine.

3 months; Open-label clinical trial

PEA significantly reduced fibromyalgia pain combined with pharmaceutical treatment. The number of tender points reduced from 8/18 to 4/18 sites (p<0.0001) and subjective pain scores out of 10 were reduced from 4.0 ± 0.11 down to 3.0 ± 0.12 (p<0.001).

Fibromyalgia[21]

300 mg/d Magnesium citrate

8 weeks; Randomised double-blinded, placebo-controlled crossover study

Magnesium reduced the number tender points (from 15.19 ± 2.54 down to 11.70 ± 6.78; p<0.032), and fibromyalgia impact questionnaire scores (reduced from 35.41 ± 12.12 down to 23.64 ± 8.29; p<0.008).

Headache[61]

525 mg of PEA Levagen+™ vs. 400 mg ibuprofen

Acute use over 4 months; Double-blind, randomized comparator-controlled clinical study.

Pain scores were reduced by at least 85% of the starting pain score over four hours with both PEA and ibuprofen. PEA reduced headache pain at 2 and 4 hours to equivalent levels to ibuprofen.

Migraine[40]

600 mg/d Magnesium citrate

12 weeks; Randomised double-blind placebo-controlled study

Magnesium treatment led to a 33% reduction in migraine frequency compared to 16% in the placebo group (p<0.005), and a 47% reduction in intensity compared to 0% in the placebo group (p<0.001).

Migraine[58]

600 mg/d Magnesium citrate

12 weeks; Randomised double-blind placebo-controlled trial

Between weeks 9 to 12, magnesium therapy led to a 41.6% reduction in migraine frequency compared to a 15.8% reduction in the placebo group (p<0.05). The magnesium group also reported significantly fewer days with migraines and reduced use of pharmaceutical relief (p<0.025).

Migraine[62]

600 mg of PEA Levagen+™ upon onset of migraine symptoms (average severity score 5.5/10), with an additional 600mg dose at 2 hours if required.

Acute use over 4 months; Randomised double-blind placebo-controlled study.

After two hours, 600mg of PEA led to resolution of migraine symptoms in 90% of the PEA group vs. 45% with placebo in patients who did not use rescue medication. The PEA group reported significantly greater changes from the baseline at 90 minutes and four hours compared to the placebo group.

Safety Information

Disclaimer: In the interest of supporting Healthcare Practitioners, all safety information provided at the time of publishing is in accordance with Natural Medicine Database (NATMED PRO), renowned for its professional monographs which include a thorough assessment of safety, warnings, and adverse effects.

For further information on specific interactions with medications, please contact Clinical Support on 1800 777 648, or via email, anz_clinicalsupport@metagenics.com

Pregnancy and Lactation

  • Possibly unsafe/insufficient reliable information available; avoid using.[63]

Contraindications

  • Levodopa/Carbidopa; magnesium can reduce bioavailibility of this medication.[63]

References

  1. Husak AJ, Bair MJ. Chronic pain and sleep disturbances: a pragmatic review of their relationships, comorbidities, and treatments. Pain Med. 2020;21(6):1142-1152. doi:10.1093/pm/pnz343
  2. Briggs AM, Woolf AD, Dreinhöfer K, Homb N, Hoy DG, Kopansky-Giles D, et al. Reducing the global burden of musculoskeletal conditions. Bull World Health Organ. 2018;96(5):366-368. doi:10.2471/BLT.17.204891
  3. McSwan J, Gudin J, Song XJ, et al. Self-healing: a concept for musculoskeletal body pain management - scientific evidence and mode of action. J Pain Res. 2021;14:2943-58. doi:10.2147/JPR.S321037
  4. Supakatisant C, Phupong V. Oral magnesium for relief in pregnancy-induced leg cramps: a randomised controlled trial. Matern Child Nutr. 2015;11(2):139-45. doi:10.1111/j.1740-8709.2012.00440.x
  5. Decollogne S, Tomas A, Lecerf C, Adamowicz E, Seman M. NMDA receptor complex blockade by oral administration of magnesium: comparison with MK-80. Pharm Biochem and Behavior. 1997;58(1):261-8
  6. Grotenhermen F. Cannabinoids and the endocannabinoid system. Cannabinoids. 2006;1(1):10-4
  7. Wang J. Glial endocannabinoid system in pain modulation. Int J Neurosci. 2019;129(1):94-100
  8. Peritore AF, Siracusa R, Crupi R, Cuzzocrea S. Therapeutic efficacy of palmitoylethanolamide and its new formulations in synergy with different antioxidant molecules present in diets. Nutrients. 2019;11(9). e2175. doi:10.3390/nu11092175
  9. Petrosino S, Schiano Moriello A, et al. The anti-inflammatory mediator palmitoylethanolamide enhances the levels of 2-arachidonoyl-glycerol and potentiates its actions at TRPV1 cation channels. Br J Pharmacol. 2016;173(7):1154-62. doi:10.1111/bph.13084
  10. Ho WS, Barrett DA, Randall MD. ‘Entourage’ effects of N-palmitoylethanolamide and N-oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors. Br J Pharmacol. 2008;155(6):837-46. doi:10.1038/bjp.2008.324
  11. Grabacka M, Pierzchalska M, Płonka PM, Pierzchalski P. The role of PPAR alpha in the modulation of innate immunity. Int J Mol Sci. 2021;22(19):10545. doi:10.3390/ijms221910545
  12. Skaper SD, Facci L, Giusti P. Mast cells, glia and neuroinflammation: partners in crime? Immunology. 2014;141(3):314-27. doi:10.1111/imm.12170
  13. Ambrosino P, Soldovieri MV, Russo C, Taglialatela M. Activation and desensitization of TRPV1 channels in sensory neurons by the PPARα agonist palmitoylethanolamide. Br J Pharmacol. 2013;168(6):1430-44
  14. Ralston SH, Penman ID, Strachan M, Hobson R. Davidson’s principles and practice of medicine. 23rd ed. Edinburgh (UK): Elsevier/Churchill Livingstone; 2018
  15. Christensen J, Noel M, Mychasiuk R. Neurobiological mechanisms underlying the sleep-pain relationship in adolescence: A review. Neurosci Biobehav Rev. 2019;96:401-13. doi:10.1016/j.neubiorev.2018.11.006
  16. Skirven TM, Osterman AL, Fedorczyk JM, Amadio PC, Feldscher SB, Shin EK. Rehabilitation of the hand and upper extremity. 7th ed. Philadelphia (USA): Elsevier; 2021
  17. Héron A, Dubayle D. A focus on mast cells and pain. J Neuroimmunol. 2013;264(1-2):1-7. doi:10.1016/j.jneuroim.2013.09.018
  18. Colloca L, Ludman T, Bouhassira D, et al. Neuropathic pain. Nat Rev Dis Primers. 2017;3:17002
  19. Ji RR, Berta T, Nedergaard M. Glia and pain: is chronic pain a gliopathy? Pain. 2013;154 Suppl 1(1):S10-S28. doi:10.1016/j.pain.2013.06.022
  20. Roffe C, Sills S, Crome P, Jones P. Randomised, cross-over, placebo controlled trial of magnesium citrate in the treatment of chronic persistent leg cramps. Med Sci Monit. 2002;8(5):CR326-330
  21. Bagis S, Karabiber M, As I, Tamer L, Erdogan C, Atalay A. Is magnesium citrate treatment effective on pain, clinical parameters and functional status in patients with fibromyalgia? Rheumatol Int. 2013;33(1):167-72
  22. Jerkovic D, Tadin A, Gavic L, Vladislavic NZ, Grgic N, Macan D. Effect of orally administered magnesium on postoperative pain level and trismus after surgical removal of the lower third molars: a randomized, double-blind, placebo-controlled trial. Clin Oral Investig. 2020;24(12):4649-59. doi:10.1007/s00784-020-03335-z
  23. Re G, Barbero R, Miolo A, Di Marzo V. Palmitoylethanolamide, endocannabinoids and related cannabimimetic compounds in protection against tissue inflammation and pain: potential use in companion animals. Vet J. 2007;173(1):21-30. doi:10.1016/j.tvjl.2005.10.003
  24. Donvito G, Nass SR, Wilkerson JL, et al. The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain. Neuropsychopharmaco. 2018;43(1):52-79. doi:10.1038/npp.2017.204
  25. Lu HC, Mackie K. An introduction to the endogenous cannabinoid system. Biol Psychiatry. 2016;79(7):516-25. doi:10.1016/j.biopsych.2015.07.028
  26. Alhouayek M, Muccioli GG. Harnessing the anti-inflammatory potential of palmitoylethanolamide. Drug Discov Today. 2014;19(10):1632-9
  27. Davis MP, Behm B, Mehta Z, Fernandez C. The potential benefits of palmitoylethanolamide in palliation: a qualitative systematic review. Am J Hosp Palliat Care. 2019;36(12):1134-154.
  28. D’Aloia A, Molteni L, Gullo F, et al. Palmitoylethanolamide modulation of microglia activation: characterization of mechanisms of action and implication for its neuroprotective effects. Int J Mol Sci. 2021;22(6):3054. doi:10.3390/ijms22063054
  29. Muccioli GG, Stella N. Microglia produce and hydrolyze palmitoylethanolamide. Neuropharmacology. 2008;54(1):16–22. doi:10.1016/j.neuropharm.2007.05.015
  30. Guasti L, Richardson D, Jhaveri M, et al. Minocycline treatment inhibits microglial activation and alters spinal levels of endocannabinoids in a rat model of neuropathic pain. Mol Pain. 2009;5(1):35–35. doi:10.1186/1744-8069-5-35
  31. Beggiato S, Tomasini MC, Ferraro L. Palmitoylethanolamide (PEA) as a potential therapeutic agent in Alzheimer’s disease. Front Pharmacol. 2019;10:821
  32. Gabrielsson L, Mattsson S, Fowler CJ. Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy. Br J Clin Pharmacol. 2016;82(4):932-42
  33. Briskey D, Mallard AR, Rao A. Increased absorption of palmitoylethanolamide using a novel dispersion technology system (LipiSperse®). J Nut Food Sci. 2020;5(2):1-6
  34. Graff D. Bioavailability of magnesium chelazome® Albion® Research Notes. 2000;9(1)
  35. Hartle JW, Morgan S, Poulsen T. Development of a model for in-vitro comparative absorption of magnesium from five magnesium sources commonly used as dietary supplements. FASEB Journal. 2016;128(6)
  36. Schuette SA, Lashner BA, Janghorbani M. Bioavailability of magnesium diglycinate vs magnesium oxide in patients with ileal resection. JPEN J Parenter Enteral Nutr. 1994;18(5):430-5. doi:10.1177/0148607194018005430
  37. Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney (AU): Elsevier/Churchill Livingstone; 2015
  38. Potter JD, Robertson SP, Johnson JD. Magnesium and the regulation of muscle contraction. Fed Proc.1981;40(12):2653-6. PMID: 7286246
  39. Jerkovic D, Tadin A, Gavic L, Vladislavic NZ, Grgic N, Macan D. Effect of orally administered magnesium on postoperative pain level and trismus after surgical removal of the lower third molars: a randomized, double-blind, placebo-controlled trial. Clin Oral Investig.2020;24(12):4649-59. doi:10.1007/s00784-020-03335-z
  40. Köseoglu E, Talaslıoglu A, Gönül AS, Kula M. The effects of magnesium prophylaxis in migraine without aura. Magnes Res.2008;21(2):101-8
  41. Euser AG, Cipolla MJ. Magnesium sulfate for the treatment of eclampsia: a brief review. 2009;40(4):1169-75
  42. Keppel Hesselink JM, Kopsky DJ. Palmitoylethanolamide, a neutraceutical, in nerve compression syndromes: efficacy and safety in sciatic pain and carpal tunnel syndrome. J Pain Res.2015;8:729-34
  43. Steels E, Venkatesh R, Steels E, Vitetta G, Vitetta L. A double-blind randomized placebo-controlled study assessing safety, tolerability and efficacy of palmitoylethanolamide for symptoms of knee osteoarthritis. 2019;27(3):475-485
  44. Artukoglu BB, Beyer C, Zuloff-Shani A, Brener E, Bloch MH. Efficacy of palmitoylethanolamide for pain: a meta-analysis. Pain Physician.2017;20(5):353-62
  45. Schifilliti C, Cucinotta L, Fedele V, Ingegnosi C, Luca S, Leotta C. Micronized palmitoylethanolamide reduces the symptoms of neuropathic pain in diabetic patients. Pain Res Treat.2014;2014:849623
  46. Orefice NS, Alhouayek M, Carotenuto A, et al. Oral palmitoylethanolamide treatment is associated with reduced cutaneous adverse effects of interferon-β1a and circulating proinflammatory cytokines in relapsing-remitting multiple sclerosis. 2016;13(2):428-38
  47. Esposito E, Cuzzocrea S. Palmitoylethanolamide is a new possible pharmacological treatment for the inflammation associated with trauma. Mini Rev Med Chem.2013;13(2):237-55. PMID: 22697514
  48. Bartolucci ML, Marini I, Bortolotti F,et al. Micronized palmitoylethanolamide reduces joint pain and glial cell activation. Inflamm Res.2018;67(10):891-901. doi:10.1007/s00011-018-1179-y
  49. Kirkland A, Sarlo G, Holton K. The role of magnesium in neurological disorders. 2018;10(6):730. doi:10.3390/nu10060730
  50. Jara-Oseguera A, Simon SA, Rosenbaum T. TRPV1: on the road to pain relief. Curr Mol Pharmacol.2008;1(3):255-69. doi:10.2174/1874467210801030255
  51. Malek N, Pajak A, Kolosowska N, Kucharczyk M, Starowicz K. The importance of TRPV1-sensitisation factors for the development of neuropathic pain. Mol Cell Neurosci.2015;65:1-10. doi:10.1016/j.mcn.2015.02.001
  52. De Petrocellis L, Davis JB, Di Marzo V. Palmitoylethanolamide enhances anandamide stimulation of human vanilloid VR1 receptors. FEBS Lett.2001;506(3):253-6. doi:10.1016/s0014-5793(01)02934-9
  53. Paladini A, Varrassi G, Bentivegna G, Carletti S, Piroli A, Coaccioli S. Palmitoylethanolamide in the treatment of failed back surgery syndrome. Pain Res Treat. 2017;2017:1486010. doi:10.1155/2017/1486010
  54. Passavanti MB, Fiore M, Sansone P, et al. The beneficial use of ultramicronized palmitoylethanolamide as add-on therapy to tapentadol in the treatment of low back pain: a pilot study comparing prospective and retrospective observational arms. BMC Anesthesiol. 2017;17(1):171. doi:10.1186/s12871-017-0461-9
  55. Guida G, de Martino M, de Fabiani A, Cantieri L, Alexandre A, Vassallo GM, et al. La palmitoiletanolamida (Normast) en el dolor neuropatico cronico por lumbociatalgia de tipo compresivo: estudio clinico multicentrico [A multicenter clinical study of palmitoylethanolamide in chronic neuropathic pain: compression lumboischialgia]. Dolor. 2010;25(1):35–42. Spanish.
  56. Desio P. Combination of oxycodone and palmitoylethanolamide for low back pain treatment. AMC. 2011;1(2):62–71.
  57. Del Giorno R, Skaper S, Paladini A, Varrassi G, Coaccioli S. Palmitoylethanolamide in fibromyalgia: results from prospective and retrospective observational studies. Pain Ther. 2015;4(2):169-78. doi:10.1007/s40122-015-0038-6
  58. Peikert A, Wilimzig C, Köhne‐Volland R. Prophylaxis of migraine with oral magnesium: results from a prospective, multi‐center, placebo‐controlled and double‐blind randomized study. Cephalalgia. 1996;16(4):257-63.
  59. Chirchiglia D, Cione E, Caroleo MC, et al. Effects of add-on ultramicronized N-palmitolethanolamide in patients suffering of migraine with aura: a pilot study. Front Neurol. 2018;9:674. doi:10.3389/fneur.2018.00674
  60. Briskey D, Skinner R, Smith C, Rao A. Effectiveness of Palmitoylethanolamide (Levagen+) compared to a placebo for reducing pain, duration, and medication use during migraines in otherwise healthy participants-a double-blind randomised controlled study. Pharmaceuticals (Basel). 2024;17(2):145. Published 2024. doi:10.3390/ph17020145
  61. Briskey D, et al. Efficacy of Palmitoylethanolamide (Levagen+ TM) compared to ibuprofen for reducing headache pain severity and duration in healthy adults: a double-blind, parallel, randomized clinical trial. Food and Nutrition Sciences. 2022;13(7):690-701. doi:10.4236/fns.2022.137050
  62. Marini I, Lavinia Bartolucci M, Bortolotti F, Rosaria Gatto M, Alessandri Bonetti G. Palmitoylethanolamide versus a nonsteroidal anti-inflammatory drug in the treatment of temporomandibular joint inflammatory pain. J Orofac Pain. 2012;26(2):99.
  63. Natural Medicines Database. AusDi; 2024. Accessed September 20, 2024. https://ausdi.hcn.com.au/

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