October 4, 2023

Palmitoylethanolamide and Acetyl-L-carnitine in Fibromyalgia

Supplements appear to be synergistic with duloxetine and pregabalin in trial
Over time, supplementing fibromyalgia treatment with palmitoylethanolamide and acetyl-L-carnitine improves symptoms.


Salaffi F, Farah S, Sarzi-Puttini P, Di Carlo M. Palmitoylethanolamide and acetyl-L-carnitine act synergistically with duloxetine and pregabalin in fibromyalgia: results of a randomised controlled study. Clin Exp Rheumatol. 2023;41(6):1323-1331.

Study Objective

To evaluate the efficacy of supplementing ongoing pregabalin (PGB) and duloxetine (DLX) treatment in fibromyalgia patients with palmitoylethanolamide (PEA) and acetyl-L-carnitine (ALC) over 24 weeks

Key Takeaway

The combination of PGB and DLX with PEA and ALC was effective, but sufficient time is required for significant clinical effect. 


Randomized clinical trial


For the trial, 142 patients met the 2011 American College of Rheumatology diagnostic criteria for fibromyalgia; all were female, with 68 in the control group and 62 in the treatment group at the end of the trial. Mean age was 53.4 years in the control group and 52.9 years in the treatment group. Disease duration was 6.1 years in control and 5.09 years in treatment; body mass index (BMI) was 26.2 and 25.9, respectively. 


For the first week, DLX at 30 mg per day plus PGB at 75 mg per day. Then beginning in week 2, DLX at 60 mg per day and PGB at 150 mg per day for 24 weeks. After 12 weeks, the patients were randomly divided 1:1 into 2 groups. The control group continued this treatment for the duration of the trial. The treatment group added PEA at 600 mg twice daily and ALC at 500 mg twice daily. No other treatment was allowed.

Primary Outcomes

Primary outcome was the Widespread Pain Index (WPI), while secondary outcomes were the Fibromyalgia Impact Questionnaire (FIQ) and modified Fibromyalgia Assessment Status (FASmod). Patients completed each electronically and anonymously every 2 weeks. WPI assesses pain in 19 body regions; FIQ uses 21 items to determine the health domains of function, overall impact, and symptoms as well as memory, tenderness, balance, and environmental awareness; and FASmod assesses fatigue and sleep disturbance based on a regional pain scale. A decrease from baseline of at least 30% was considered clinically relevant.

Investigators used the Shapiro-Wilk test to determine if variables were normally distributed and the Mann-Whitney U test to compare the 2 groups; they calculated Spearman correlation coefficients between variables. Investigators processed data on MedCalc Statistical Software v20.07, and P<0.05 was considered statistically significant.

Key Findings

Although 142 patients began the trial, 12 were lost to follow-up after randomization (week 12), leaving 68 in the control and 62 in the treatment group (130 total). After 12 weeks, all 130 showed a significant reduction in FIQ (P=0.041), while changes in FASmod (P=0.066) and WPI (P=0.065) did not reach significance. In the treatment group, WPI area under the curve (AUC) and percentage change were P=0.487 and P=0.477, respectively. For FASmod, the changes were P=0.0173 and P=0.0001, respectively, and for FIQ, they were P=0.0333 and P=0.0033, respectively.

Patients tolerated PEA and ALC well. The most frequently reported adverse events were dizziness, headache, nausea, blurred vision, sleepiness, and dry mouth. After randomization, no one discontinued treatment during the trial.


The authors did not identify funding sources or provide disclosures.

Practice Implications and Limitations

Fibromyalgia, which affects about 2% of the population, is a challenging condition with no simple tests or distinct etiology. The CDC (Centers for Disease Control and Prevention) has identified 7 possible risk factors: being female (women are twice as likely as males to experience fibromyalgia), stressful or traumatic events or posttraumatic stress disorder (PTSD), repetitive injuries, illness including viruses, family history, rheumatoid arthritis or lupus, and obesity.1 Treatments recommended by the CDC include medications, aerobic exercise and muscle strengthening, patient education, stress management (meditation, yoga, massage), sleep hygiene, and cognitive behavioral therapy (CBT).1 The authors of this trial favored fibromyalgia as the prototype of central sensitization syndrome and its classification as a nociplastic pain with amplification via glial cell activation and the presence of neuroinflammation both in the peripheral and central nervous system. Inflammation may be due to mitochondrial dysfunction, but they did not speculate on this mechanism.

The logic behind this trial was based on the following information. PGB blocks calcium channels, slowing presynaptic neurotransmitters and postsynaptic excitability.2 DLX is a serotonin and norepinephrine reuptake inhibitor (SNRI) that can reduce pain intensity over a 12- to 26-week timeframe. PEA can affect chronic widespread pain, as can ALC.3 ALC increases the effects of nerve growth factor, is an acetyl-group donor, acetylates p65 (also known as RelA) in the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) NFkB family, and contributes to mitochondria energy homeostasis and detoxification.4 PEA is endogenous but may be lacking or insufficient in cases of fibromyalgia. Exogenous sources include egg yolk, peanuts, and soybeans. Exercise and some microbiome organisms can increase its levels. The half-life of PEA is 5 to 10 minutes, thus the need for frequent dosing.5

My clinical experience with PEA has been disappointing. This may be at least partially due to its extremely short half-life. Figures 2, 3, and 4, all of which show changes along a 24-week timeline, offer a probable explanation for obscured observation of any benefit in the clinic. In this trial, the treatment group did not see improvement in WPI, FASmod, or FIQ until at least week 16, with greatest improvement in week 24. The modest improvements seen at 2 to 6 weeks, which then regressed, are likely placebo effects and attention effects from patients being in a clinical trial. Fibromyalgia is notable for being slow to respond to treatment, and this trial was no exception. Treatment of fibromyalgia requires patience and persistence ranging from 4 to 6 months. Patients can effectively use ALC in diabetic neuropathy and chemotherapy-induced neuropathy (or their  prevention) with responses seen sooner than with PEA.4

The paper was succinct, well-written, and easy to follow. This team has published several papers on fibromyalgia in Italian women. Study limitations include lack of male subjects, lack of blinding, absence of funding information, and absence of author disclosures.

In summary, duloxetine at 60 mg/d with pregabalin 150 mg/d combined with palmitoylethanolamide 600 mg twice daily and acetyl-L-carnitine 500 mg twice daily after 24 weeks led to a clinically significant 30% or more reduction in FASmod and FIQ scores, but not in WPI scores, in female fibromyalgia patients in the treatment group.

Categorized Under


  1. Centers for Disease Control and Prevention. Fibromyalgia. Centers for Disease Control and Prevention website. Accessed Sept 12, 2023.
  2. Raso GM, Russo R, Calignano A, Meli R. Palmitoylethanolamide in CNS health and disease. Pharmacol Res. 2014;86:32-41.
  3. Parisi S, Ditto MC, Borrelli F, Fusaro E. Efficacy of a fixed combination of palmitoylethanolamide and acetyl-l-carnitine in the treatment of neuropathies secondary to rheumatic disease. Minerva Med. 2021;112(4):492-499.
  4. Chiechio S, Copani A, Gereau RW 4th, Nicoletti F. Acetyl-l-carnitine in neuropathic pain: experimental data. CNS Drugs. 2007;21 Suppl 1:31-38.
  5. Berry MD. Mammalian central nervous system trace amines. J Neurochem. 2004.90(2):257-271.