Table 3.

Pre-clinical and clinical effects of PEA in micronized and co-micronized formulations in pain syndromes sustained by neuroinflammation. Abbreviations: bid, twice a day; CCI, chronic constriction injury; FSMP, food for special medical purpose; i.p., intra-peritoneal; i.pl., intra-plantar; NP, neurophatic pain; p.o., oral. PEA-m, micronized PEA; PEA-um, ultra-micronized PEA; PEA, palmitoylethanolamide; s.c., subcutaneous; SNI, spared nerve injury.

Disease/Model/Condition			Subject	Formulation	RoA	Main Effect	Ref.
Acute and chronic pain	Pre-clinical	CCI	Mice	PEA (30 mg/kg, 14 days)	s.c. or i.p.	Anti-neuroinflammatory and anti-nociceptive	[103,104,105]
		Formalin	Mice	PEA (5–10 mg/kg, 7 days)	i.p.	Anti-neuroinflammatory and anti-nociceptive	[106]
		SNI	Mice	PEA (10 mg/kg, 15–30 days)	i.p.	Anti-nociceptive	[107]
		Oxaliplatin	Rats	PEA (30 mg/kg, 21 days)	i.p.	Anti-nociceptive	[108]
		Formalin and carrageenan-	Mice	PEA (50 μg/10 μL)	i.pl.	Anti-nociceptive	[109]
		Morphine	Rats	PEA-m (30 mg/kg, 11 days) + morphine	s.c.	Attenuation of development in tolerance to morphine	[110]
		SNI	Mice	PEA-um (10 mg/kg, 15 days)	i.p.	Anti-nociceptive and improvement of cognitive-decline	[111]
		Tibia fracture	Mice	PEA-m and PEA-um (300 mg/kg and 600 mg/kg, 28 days)	p.o.	Anti-nociceptive and improvement of fracture regeneration	[112]
		Sciatic nerve injury	Rats	PEA-um (5 mg/kg, 14 days) + paracetamol	p.o. by gavage	Anti-neuroinflammatory and anti-nociceptive	[113]
		Post-operative pain	Rats	PEA-m (10 mg/kg at different time points before/after incision)	p.o. by gavage	Anti-neuroinflammatory and anti-nociceptive	[114]
	Clinical	Chronic pain associated to different pathological conditions	610 patients	FSMP based on PEA-um (600 mg/bid, 3 weeks and 600 mg/die, 4 weeks) + analgesic drugs	p.o.	Reduction of pain severity	[115]
		Diabetic or traumatic chronic NP	30 patients	FSMP based on PEA-um (1200 mg/die, 40 days)	p.o. (sachet or tablet)	Reduction of pain and paraesthesia/dysesthesia scores. Quality of life amelioration	[116]
		Low back pain related to nonsurgical lumbar radiculopathy	155 patients	First cycle: Acetaminophen/codeine for 7 days + FSMP based on PEA-um (1200 mg/die, 30 days). Second cycle: FSMP based on PEA-um (600 mg/die, 30 days) + acetaminophen/codeine for 30 days	p.o.	First cycle: pain relief in all patients with mild pain and in 75% with moderate pain. Second cycle: Pain relief and improvement of disability in all patients with moderate pain. Improvement of disability in 74% of patients with severe pain	[117]
		Chronic low back pain	55 patients	FSMP based on PEA-um (600 mg/bid, 6 months) + tapentadol	p.o.	Pain relief. Reduction of disability and analgesic dose requirement.	[118]
		Failed back surgery syndrome	35 patients	FSMP based on PEA-um (1200 mg/die for the first month + 600 mg/die for the second month) + tapentadol and pregabalin	p.o.	Pain relief	[119]
		Lumbosciatica (95) and lumbocruralgia (25) pain	120 patients	FSMP based on PEA-um (600 mg/bid, 20 days followed by 600 mg of PEA-um/die, 40 days) + analgesic drugs + rehabilitation and decontracting massage	p.o.	Reduction of pain severity and disability for low back pain. Quality of life amelioration	[120]
		Waiting for carpal tunnel syndrome surgery and affected by sleep disorders and painful symptoms	42 patients	FSMP based on PEA-um (600 mg/bid during the pre- and post-surgery periods)	p.o.	Amelioration of sleep quality and mitigation of painful stimuli	[121]
Chronic pelvic pain	Pre-clinical	Endometriosis plus ureteral calculosis	Rats	PEA-um (10 mg/kg, 25 days)	p.o.	Anti-neuroinflammatory and reduction of the number and duration in pain crises and cyst diameter	[122]
	Clinical	Endometriosis-related pain	4 patients	FSMP based on PEA-m and polydatin (400 mg + 40 mg/bid, 90 days)	p.o.	Pain relief and reduction in the use of analgesic drugs	[123]
		Symptoms of severe pelvic pain and suspected endometriosis	24 women	FSMP based on PEA-m and polydatin (400 mg + 40 mg/bid, 90 days)	p.o.	Pain relief and quality of life amelioration. Reduction in the use of NSAIDs	[124]
		Chronic pelvic pain related to endometriosis after laparoscopic conservative surgery	61 patients	FSMP based on PEA-m and polydatin (400 mg + 40 mg/bid, 90 days)	p.o.	Reduction of dysmenorrhea, dyspareunia and pelvic pain.	[125]
		Chronic pelvic pain due to endometriosis	47 women	FSMP based on PEA-m and polydatin (400 mg + 40 mg/bid, 90 days)	p.o.	Reduction of dysmenorrhea, dyspareunia and pelvic pain.	[126]
		Primary dysmenorrhea	110 young patients	FSMP based on PEA-m and polydatin (400 mg + 40 mg/die taken from the 24th day of cycle for 10 days)	p.o.	Pain relief	[127]
		Diagnosis of endometriosis and pregnancy desire	30 women	FSMP based on PEA-um (600 mg/bid, 10 days) and PEA-m and polydatin (400 mg + 40 mg/bid, 80 days)	p.o.	Amelioration in painful symptoms, quality of life and psychological well-being	[128]
Migraine pain	Clinical	Superficial cranial pain	1 patient	FSMP based on PEA-um (600 mg/day, 4 months) + topiramate	p.o.	Pain relief	[129]
		Migraine with aura	20 patients	FSMP based on PEA-um (1200 mg/die, 3 months) + NSAIDs	p.o.	Pain relief and reduction in the use of NSAIDs	[130]
		Diagnosis of migraine without aura	70 pediatric patients	FSMP based on PEA-um (600 mg/day, 3 months)	p.o.	Reduction of the headache attack frequency by >50% per month in 63.9% of patients.	[131]
Fibromyalgia	Clinical	Fibromyalgia	80 patients	FSMP based on PEA-um (600 mg/bid, 30 days) and PEA-m (300 mg/bid, 2 months) + duloxetine and pregabalin	p.o.	Amelioration in pain intensity	[132]
		Diagnosis of fibromyalgia	407 patients	FSMP based on PEA-um (600 mg/day, add-on treatment)	p.o.	359 patients recorded an amelioration in the pain score and quality of life	[133]