Inflammopharmacology

https://doi.org/10.1007/s10787-022-01033-8 Inflammopharmacology
ORIGINAL ARTICLE

A randomized controlled trial assessing the safety and efficacy

of palmitoylethanolamide for treating diabetic‑related peripheral
neuropathic pain
Emily Pickering1,2 · Elizabeth L. Steels1,2 · Kathryn J. Steadman1 · Amanda Rao3 · Luis Vitetta4

Received: 28 June 2022 / Accepted: 30 June 2022

© The Author(s) 2022

Abstract
Background Peripheral neuropathy is a common complication of diabetes. The management of the associated neuropathic
pain remains difficult to treat.
Objective This study explored the safety, tolerability and efficacy of a palmitoylethanolamide (PEA) formulation in treating
diabetic-related peripheral neuropathic pain (PNP). Secondary outcomes included systemic inflammation, sleep and mood
changes in patients diagnosed with type 1 and type 2 diabetes and PNP.
Design This study was a single-centre, quadruple-blinded, placebo-controlled trial with 70 participants receiving 600 mg of
PEA or placebo daily, for 8 weeks, with a 94% rate of study participation completion. Primary outcomes were neuropathic
pain and specific pain types (the BPI-DPN and NPSI). The secondary outcomes were sleep quality (MOS sleep scale), mood
(DASS-21), glucose metabolism and inflammation.
Results There was a significant reduction (P ≤ 0.001) in BPI-DPN total pain and pain interference, NPSI total score and
sub-scores, except for evoked pain (P = 0.09) in the PEA group compared with the placebo group. The MOS sleep problem
index and sub-scores significantly improved (P ≤ 0.001). DASS-21 depression scores significantly reduced (P = 0.03), but
not anxiety or stress scores. Interleukin-6 and elevated C-reactive protein levels significantly reduced in the PEA group
(P = 0.05), with no differences in fibrinogen between groups (P = 0.78) at treatment completion. There were no changes in
safety pathology parameters, and the treatment was well tolerated.
Conclusions The study demonstrated that the PEA formulation reduced diabetic peripheral neuropathic pain and inflamma-
tion along with improving mood and sleep. Further studies on the mechanistic effectiveness of PEA as an adjunct medicine
and as a monotherapy pain analgesic are warranted.
Clinical Trial Registration Registry name: Australian New Zealand Clinical Trials Registry (ANZCTR), Registration number:
ACTRN12620001302943, Registration link: https://​anzctr.​org.​au/​Trial/​Regis​trati​on/​Trial​Review.​aspx?​id=​380826, Actual
study start date: 20 November 2020.

Keywords Diabetic neuropathy · Pain · Neuropathic pain · Diabetes · Palmitoylethanolamide · PEA · Inflammation

1
* Elizabeth L. Steels School of Pharmacy, University of Queensland, PACE
[email protected] Precinct, 20 Cornwall Street, Wooloongabba, Brisbane,
QLD 4102, Australia
Emily Pickering
2
[email protected] Evidence Sciences Pty. Ltd., Brisbane, QLD, Australia
3
Kathryn J. Steadman School of Human Movement and Nutrition Sciences,
[email protected] University of Queensland, Brisbane, QLD 4102, Australia
4
Amanda Rao Faculty of Medicine and Health, The University of Sydney,
[email protected] Sydney, NSW, Australia
Luis Vitetta
[email protected]

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 E. Pickering et al.

Abbreviations These symptoms develop and worsen in the distal nerve

AEs Adverse events endings of the feet and in severe instances spread towards
ANOVA Analysis of variance the central parts of the body (Calcutt 2020). Small nerve
ANZCTR​ Australian New Zealand Clinical Trials fibres make up 79–91% of peripheral nerve fibres (Said et al.
Registry 1992; Malik et al. 2005) and are more sensitive and prone
BMI Body mass index to damage than large nerve fibres. This results in the skin
BPI-DPN Brief pain inventory short form for diabetic of the toes and fingers to be the first areas affected by DPN
peripheral neuropathy (Zochodne 2014). In DPN, continuously high serum glu-
CRP C-reactive protein cose levels damage small blood vessels, causing reduced
DASS-21 21-Item depression anxiety stress score supply of oxygen and nutrients to the nerves (Bodman and
DPN Diabetic peripheral neuropathy Varacallo 2021). This compromises the myelin sheath insu-
DN4 Neuropathic pain diagnostic questionnaire lating layer of the nerve fibres, particularly that of small
ENCB Endocannabinoid nerve fibres, progressing to loss of integrity (Malik 2014).
FBG Fasting blood glucose The ongoing damage to small nerve fibres contributes to
HbA1c Glycosylated haemoglobin the development of foot ulcerations (Gibbons et al. 2010),
HDPE High-density polyethylene reduced vasodilation due to pressure ulcers (Koïtka et al.
IL-6 Interleukin-6 2004) and impaired heat and pain perception (Malik 2014).
ITT Intent to treat A recent murine model of diabetes (Yang et al. 2019) sug-
MOS Medical outcomes study—sleep scale gested that variation to blood glucose levels weakens the
NAEs  N-Acylethanolamines myelin sheath and nerve fibres and induces inflammation,
NF-KB Nuclear factor kappa-light-chain-enhancer of particularly increased pro-inflammatory cytokines such as
activated B cells tumour necrosis factor alpha (TNF-α), interleukin-6 (IL-6)
NHMRC National Health and Medical Research and nuclear factor kappa-light-chain-enhancer of activated
Council B cells (NF-KB). Consequently, the progressive reduction in
NPSI Neuropathic pain symptom inventory the integrity of the myelin sheath has been demonstrated to
PEA Palmitoylethanolamide lead to increasing severity of DPN (Malik 2014).
PNP Peripheral neuropathic pain Maintaining control of blood glucose levels is a pri-
QOL Quality of life mary treatment strategy for DPN along with medications
SD Standard deviation for the management of neuropathic pain which includes
S-LANSS Self-reported Leeds Assessment of Neuro- antiepileptics or anticonvulsants, tricyclic antidepressants,
pathic Symptoms and Signs serotonin–norepinephrine reuptake inhibitors and opioids
SPSS Statistical package for the social sciences (Australian Medicines Handbook 2019). Reports demon-
TNF-α Tumour necrosis factor alpha strate that PEA has potential as an analgesic treatment for
VAS Visual analogue scale DPN (D'amico et al. 2020). PEA belongs to the family of
N-acylethanolamines (NAEs) that are endogenous biologi-
cally active lipid mediators synthesized on demand by the
Introduction phospholipid membrane of cells (Alhouayek and Muccioli
2014; Mattace Raso et al. 2014). NAEs may assist in regu-
Diabetic peripheral neuropathy (DPN) is a neurodegenera- lating pain and inflammation with a neuroprotective effect
tive disorder of the peripheral nervous system. It is the most (Alhouayek and Muccioli 2014). PEA is also an endogenous
common complication of diabetes, estimated to affect up to ligand of the endocannabinoid system (ENCB) with neuro-
30% of this population, and is the leading cause of nerve modulator activity in the central nervous system (Clayton
pain, disability due to foot ulceration and amputation, dis- et al. 2021). PEA has been reported to have an entourage
turbances to gait and fall-related injuries (Juster-Switlyk and effect which can enhance the physiological effects of the
Smith 2016). DPN affects the motor, sensory and autonomic endogenous endocannabinoids such as N-arachidonoylethan-
nerves; however, it particularly targets the sensory nerves, olamine (i.e. anandamide). The overall effect is that through
which are responsible for the transmission of information N-arachidonoylethanolamine and the ENCB system, anti-
including touch, temperature and injury pain (Bodman and inflammatory and proapoptotic activities can inhibit pro-
Varacallo 2021). The characteristics of the nerve pain range inflammatory markers such as TNF-α and NF-KB (Sancho
from bouts of electric shocks and stabbing, abnormal sensa- et al. 2003). PEA is also considered to comprise a paral-
tions of tingling/pins and needles, spontaneous burning and lel endocannabinoid signalling system without the adverse
increased sensitivity to pressure and evoked pain by brush- effects such as those with exogenous endocannabinoids (e.g.
ing, pressure or cold temperatures (Bouhassira et al. 2004). THC).

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A randomized controlled trial assessing the safety and efficacy of palmitoylethanolamide…

Reduction in cellular PEA levels occurs due to prolonged Levagen+. The investigational product was formulated and
inflammation (Solorzano et al. 2009) and as a result from manufactured by Pharmako Biotechnologies Pty Ltd. under
nerve injury due to neuropathy (Franklin et al. 2003). An Good Manufacturing Practice guidelines. The investigational
early meta-analysis with a diverse variety of chronic neuro- product was provided as clear capsules (size 00) contain-
pathic pain conditions (three studies were specific for DPN) ing 350 mg of Levagen+ providing no less than 300 mg
demonstrated that PEA was progressively effective in reduc- Palmidrol per capsule, which contains excipients polyglyc-
ing chronic neuropathic pain with the report concluding that erol polyricinoleate (E476), coconut oil fractionated, lime
it has potential as a therapeutic strategy to manage chronic oil, olive oil, lecithin (sunflower and/or oat) (E322), silica
neuropathic pain (Paladini et al. 2016). (E551), vitamin E), which were administered at a twice-daily
PEA, though, has been reported to be poorly bioavailable dose, equating to a total of dosing of 600 mg/day of PEA
with oral-gut administration, hindering pharmacological over the 8-week study period. This dose has been shown to
efficacy (Gabrielsson et al. 2016). An increased absorbable be gut absorbed to an equivalent dose of 1.1025 g of micro-
form has been developed (Briskey et al. 2020) that has been nized PEA (Briskey et al. 2020). The matching placebo cap-
reported to provide enhanced bioavailability and as such effi- sule contained 350 mg of maltodextrin. The capsules were
cacy and dosing. The aim of the current clinical study was packaged in high-density polyethylene (HDPE) bottles with
to determine whether an enhanced bioavailable formulation a HDPE lid. The packaging, labelling and dosage adminis-
of PEA was safe, tolerable and effective for managing DPN- tration of the placebo were the same as the investigational
related pain and, moreover, and secondarily, this formulation product.
was effective in reducing inflammation and improving qual-
ity of life (QOL) associated with DPN, over an 8-week study Participant inclusion and exclusion criteria
period in patients diagnosed with diabetes.
Participants meeting all inclusion and exclusion criteria
were invited to participate in the clinical study. Males or
Methods females aged at least 18 years of age and diagnosed by a
treating physician with type 1 diabetes or type 2 diabetes and
Trial design with diabetic-related peripheral neuropathy were identified.
Participants confirmed experiencing neuropathic pain by
The clinical study was an interventional, single-centre, scoring more than four on the Neuropathic Pain Diagnostic
prospective, randomized, quadruple-blinded, placebo-con- Questionnaire (DN4) or scoring more than 12 on the Self-
trolled, parallel study investigating the safety, tolerability reported Leeds Assessment of Neuropathic Symptoms and
and efficacy of a PEA formulation on neuropathic pain. Signs (S-LANSS). All participants were administering pre-
The secondary outcomes of improvement in inflammation scribed anti-diabetic medications metformin and/or insulin.
markers and sleep quality and improved quality of life when Some participants (31/66, 47%) were also co-administering
administered as an adjunct analgesic to diabetic medications prescribed anti-diabetic medications with analgesic medica-
were also measured over 8 weeks. The study included men tions for pain. Participants were asked to continue taking
and women aged at least 18 years of age with a diagnosis of their prescribed medications for the duration of the study
type 1 or type 2 diabetes and who were prescribed glucose- and were permitted to take up to the maximum daily dose
lowering medications including either or both metformin (4 g/day) of paracetamol as pain rescue medication.
and insulin. The study was conducted in Brisbane, Australia, Potential participants were excluded if the peripheral neu-
in accordance with the principles of The Declaration of Hel- ropathy was due to hereditary sensory neuropathy, vitamin
sinki and Australian Good Clinical Practice Guidelines. The ­B12 or folate deficiency, paraneoplastic diseases, advanced
trial was registered with the Australian New Zealand Clinical liver disease, kidney disease, hypothyroidism, prolonged
Trials Registry (ANZCTR) no.: ACTRN12620001302943. phenytoin, warfarin or immunosuppressive drug use. Par-
ticipants were also excluded if they were administering
Investigational products herbal medicines for pain relief including, but not limited to,
turmeric/curcumin (Curcuma longa), boswellia (Boswellia
The investigational product was a proprietary formulation serrata), willow bark (Salix alba) or medicinal cannabis.
of palmitoylethanolamide (Palmidrol) which has previous Women who were pregnant, planning to become pregnant
approval by the Therapeutic Goods Association as an active or breastfeeding were excluded. Alcohol or substance abuse
ingredient in the listed medicines. The Palmidrol was pro- health issues, allergy or sensitivity to any of the ingredi-
vided by Gencor Pacific Ltd. and was combined with the ents in the investigational product or any clinically relevant
bioavailability enhancement technology system LipiSperse® abnormal findings, in the opinion of the investigators/clini-
as defined by Briskey et al. (2022), under the brand name cians, would make them not suitable for inclusion in the

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 E. Pickering et al.

study. All participants that met all criteria provided written (MOS). The MOS has been validated in patient populations
informed consent. experiencing neuropathic pain (Hays et al. 2005; Rejas et al.
2007). The MOS sleep score includes a Sleep Problem Index
Randomization, blinding and compliance and the following dimensions of sleep disturbance: experi-
ence disturbance to sleep, achieving adequate sleep, sleep
Eligible participants were randomly allocated to one of two quantity, daytime somnolence during the day, occurrence
study treatment groups with a ratio of 1:1. The study treat- of snoring and experiencing shortness of breath or headache
ments with PEA or placebo twice daily were provided to upon awakening. The 21-item Depression Anxiety Stress
participants in identical bottles labelled 001-070 sequen- Score (DASS-21) was also assessed at baseline and 8 weeks.
tially upon enrolment. Participants were independently This was a measure of mood distress along the three axes of
randomized prior to treatment medications being provided depression, anxiety and stress (Ng et al. 2007).
to the clinic. The clinical trial was quadruple masked (i.e. Blood markers were assessed at baseline and at 8 weeks,
participant, care provider, investigators, outcomes assessor) and these included HbA1c and fasting blood glucose (FBG),
to the allocation group of medications. Participant compli- as determined by the International Expert Committee guide-
ance was assessed by the number of capsules taken, with lines (The Expert Committee on the Diagnosis and Classifi-
greater than 80% of the capsules consumed being accepted cation of Diabetes Mellitus, 2003, The International Expert
as compliant with doses administered. Committee 2009), and inflammation markers c-reactive
protein (CRP), IL-6 and fibrinogen with normal reference
Clinical study outcomes ranges of 0–6 ml/L, 1.5–4.0 g/L and ≤ 1.8 pg/mL, respec-
tively. Blood safety markers were assessed at baseline and
The primary outcome investigated the safety, tolerability and 8 weeks and included a full blood count, liver function tests,
effectiveness of PEA administered concurrently with pre- platelets, electrolytes and kidney function. Product tolerabil-
scribed diabetic and pain medications to alleviate diabetic- ity was assessed regularly at each clinic interview and during
related neuropathic pain. The secondary outcomes included compliance checks by interviewers specifically documenting
a reduction in inflammatory markers and improvement in changes to treatment medications, new symptom concerns,
mood and sleep quality. new stressors or any mild, moderate or serious adverse
The primary outcome was considered as the overall events that ensued. An adverse event form in the case file
severity of neuropathic pain, assessed with the Brief Pain forms was used to document adverse events. Adverse events
Inventory Short Form for Diabetic Peripheral Neuropathy (AEs) were defined as any unfavourable changes in health,
(BPI-DPN). The BPI-DPN comprised a four-item Pain including abnormal laboratory findings that occur in any
Severity Score that rated worst pain, least pain, average pain clinical trial participant, primarily during the clinical trial
and present pain with a numerical rating score of 0 (i.e. no period or within a specified period, following completion
pain) to 10 (i.e. worst imaginable pain). Pain was assessed of the clinical trial. The safety testing procedures followed
at baseline, 2, 4, 6 and 8 weeks. Additionally, the BPI-DPN the NHMRC Safety Monitoring and Reporting in Clinical
also contains a 10-item Pain Interference Score, which was Trials guidelines (National Health and Medical Research
also measured at baseline, 4 and 8 weeks as a concomitant Council 2016).
primary outcome (Zelman et al. 2005). Additional pain asso-
ciated outcomes included the severity of the specific charac- Sample size
teristics of pain. The severity of the specific characteristics
of pain was assessed using the Neuropathic Pain Symptom G*Power was used to calculate the sample size, based on
Inventory (NPSI) at baseline, 4 weeks and 8 weeks. The a statistical difference (P < 0.05) between two independent
NPSI includes 12 items that allow discrimination and quan- means (active treatment and placebo groups, ratio 1:1) for
tification of five distinct clinically relevant dimensions of the primary outcome (BPI-DPN Pain Severity Index). With a
neuropathic pain syndromes, namely superficial spontaneous two-tailed, alpha error probability of 0.05 and a size effect of
burning, spontaneous pressing pain, paroxysmal pain (stab- 0.8, the required total sample size was 29 participants per arm.
bing, pins and needles), evoked pain (mechanical brushing), Allowing for 15% rate of attrition, the required sample size for
thermal allodynia (pressure)/hyperalgesia (contact with recruitment was inflated to a total of 70 eligible participants
cold) and dysesthesia/paraesthesia (pins and needles, tin- (in 1:1 ratio for active treatment group and placebo group (i.e.
gling). Each question provides a numerical rating score of 0 35 per treatment group)). A previous effect size analysis of
(i.e. no pain) to 10 (i.e. worst imaginable pain) (Bouhassira PEA for treatment of pain using the differences between days
et al. 2004). 0 and 21 of PEA treatment for visual analogue scale (VAS)
Impact on sleep patterns was measured at baseline, 4 and scores from a meta-analysis (Clayton et al. 2021), with the
8 weeks using the Medical Outcomes Study—Sleep Scale assumption that the VAS scores were normally distributed,

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A randomized controlled trial assessing the safety and efficacy of palmitoylethanolamide…

produced an estimated effect size (i.e. Cohen's d) value of 1.35 diabetes (Table 1). The groups had a different ratio of men
(95% CI 1.14–1.56) for the daily administration of 700 mg of to women, but there was no significant difference in base-
micronized PEA (Gabrielsson et al. 2016). line health parameters of body weight, BMI, blood pres-
sure and lifestyle factors (Table 1). All participants were
Statistical analysis taking prescribed diabetic medications, and the majority
were also taking prescribed pain medications as well as
An intent-to-treat (ITT) approach was used for data analy- other medications for co-morbidities (Table 1).
sis of the primary outcome, where all patients who were
randomized to receive treatment and completed baseline Correlations between glucose metabolism, pain,
and at least one subsequent assessment (including labora- sleep and mood
tory clinical markers) were included in the analysis. The
ITT single missing data points in those completing the study There was a wide range in fasting blood glucose (FBG)
were managed using the simple imputation method, with the and glycosylated haemoglobin (HbA1c) levels, despite
data from the last observation carried forward. Normality the participants taking prescribed anti-diabetic medica-
between groups was tested using the Kolmogorov–Smirnov tions (Table 3). The baseline FBG levels correlated with
and Shapiro–Wilk tests of normality. Demographics includ- HbA1c levels (r = 0.662, P < 0.001). There were correla-
ing age, gender, weight, height and BMI were assessed for tions between glucose metabolism and pain indices; par-
statistical differences between treatment groups at baseline ticularly, a negative correlation between HbA1c and NPSI
and week 8 by Chi-square and presented with mean/SD. evoked pain (r = − 0.251, P = 0.045) and FBG and BPI-
The pain scores were analysed for time and treatment effect PN Pain Severity Index (r = − 0.322, P = 0.01), BPI-PN
using repeated measures ANOVA. The QOL questionnaires total pain (r = − 0.370, P = 0.003), the NPSI paroxysmal
BPI-DPN, NPSI and MOS were analysed using t-tests (for pain (r = − 0.266, P = 0.03), evoked pain (r = − 0.347,
normally distributed data) and with Mann–Whitney U test P = 0.005) and paraesthesia/dysesthesia (r = − 0.257,
(for nonparametric data) between treatment groups. The P = 0.04). Furthermore, CRP positively correlated with
DASS-21 and the laboratory markers were assessed by both NPSI deep pain (r = 0.261, P = 0.04) and fibrinogen
t-tests. Change scores were also used for data with wide levels (r = 0.387, P = 0.002). There was also a positive cor-
variations in values and/or significant differences at base- relation between BPI-PN pain interference and depression
line. Effect of confounders, including pain medications, was scores (r = 0.431, P < 0.001), anxiety scores (r = 0.275,
assessed using linear regression analysis. The SPSS version P = 0.03), stress scores (r = 0.270, P = 0.03) and sleep
27 software was used for statistical analyses and for generat- quality (r = 0.276, P = 0.03). Furthermore, CRP positively
ing the graphical figures. Statistical significance was set at a correlated with both NPSI deep pain (r = 0.261, P = 0.04)
P < 0.05 (two-tailed). and fibrinogen levels (r = 0.387, P = 0.002) (Figs. 2 and 3).

Effect of treatment on neuropathic pain severity

Results and interference (BPI‑DPN)

Participant demographics Pain severity

A total of 235 prospective participants were recruited Pain severity as measured by the Brief Pain Inventory
through public social media activities. Prospective par- Short Form for Diabetic Peripheral Neuropathy (BPI-
ticipants registered their interest initially through an online DPN) was not statistically different between groups
screening form, followed by an e-consult of a comprehen- at baseline, (P = 0.46) with most participants in both
sive assessment including medical history and medica- groups exhibiting mild to moderate pain (score of 2–7),
tions to establish eligibility. A total of 70 participants aged (Table 2). Repeated measures ANOVA revealed a both
between 32 and 75 years met the inclusion and exclusion time [F (4,64) = 21.03, P < 0.001] and treatment [F
criteria and, following the provision of written informed (1,64) = 23.52, P < 0.001] effect for the investigational
consent, were enrolled in the study. product over 8 weeks of the study. Further analysis indi-
The final analysis group included 66 participants cated that there was a significant difference in pain severity
(Fig. 1, Table 1), 33 in each arm. Four participants were between groups at week 2 (P = 0.002), which continued
excluded from analysis: three due to incomplete baseline at weeks 4, 6 and 8 (P < 0.001) (Table 2). Interestingly,
assessments and one due to pre-existing (unknown) dis- a progressive and significant improvement in treatment
ease that was an exclusion criterion (Fig. 1). The cohort group over placebo group in pain scores was observed as
included three participants with type 1 and 62 with type 2 the study progressed.

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 E. Pickering et al.

Fig. 1  Participant progress CONSORT flow chart

Pain interference Table 3). By week 4, there was a significant difference between
the active treatment and placebo groups for total pain score
Pain interference as measured by the BPI-DPN was not signifi- (P ≤ 0.001), superficial spontaneous pain (P ≤ 0.001), deep
cantly different between treatment groups at baseline (P = 0.15), pain (P = 0.03), paroxysmal pain (P ≤ 0.001) and paraesthesia
(Table 2). When evaluating the effect of treatment on pain (P = 0.01). All these sub-scores were also found to be signifi-
interference at week 4 and week 8, significant differences were cantly different at week 8 for total pain (P ≤ 0.001), superfi-
observed between the two treatment groups [F (1,64) = 12.60, cial pain (P ≤ 0.001), deep pain (P = 0.002), paroxysmal pain
P ≤ 0.001] and the two time points [F (2,64) = 12.60, P ≤ 0.001]. (P ≤ 0.001) and paraesthesia (P ≤ 0.001). The sub-score for
At week 4, there was a significant difference between the means evoked pain, however, was not significantly different between
of the active treatment and placebo group (P = 0.001). Week groups at week 4 (P = 0.25) yet was trending towards a signifi-
8 means also were significantly different between groups cant difference by week 8 (P = 0.09).
(P ≤ 0.001) with a greater change from baseline in the active
group (−1.90) than the placebo group (−0.39). Influence of prescribed pain medications
on treatment effect
Effect of treatment on neuropathic pain symptoms
(NPSI) The use of pain medication was not associated with any
difference in BPI-PN pain severity, NPSI total and sub-
All measurements of neuropathic pain symptoms as measured scores at completion of treatment in either group. The
by the NPSI were similar between groups at baseline (P ≥ 0.05, mean pain medication index expressed as the number of

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A randomized controlled trial assessing the safety and efficacy of palmitoylethanolamide…

Table 1  Baseline Active group Placebo group P ­value1

Characteristics n = 35 n = 35

Total (n) % 33 (50%) 33 (50%) 1.000

Men (n) % 20 (60%) 15 (40%) 0.221
Women (n) % 13 (42%) 18 (58%)
Total Age (Av, range) 65.5 [53–79] 61.5 [32–75] 0.056
Men Age (Av, range) 67.8 [53–79] 61.2 [32–75] 0.046
Women Age (Av, range) 62.1 [53–74] 61.8 [50–71] 0.92
Total BMI (Av, range) 31.2 [23.5–42.3] 31.5 [22.9–39.5] 0.80
Men BMI (Av, range) 29.9 [23.5–37.4] 31.4 [25.1–37.8] 0.27
Women BMI (Av, range) 33.3 [24.4–42.3] 31.7 [22.9–39.5] 0.39
Medications taken at baseline n = 33 n = 33
Metformin only 23 21 0.669
Insulin only 6 8 0.562
Metformin and Insulin 4 4 1.000
Additional diabetic ­medications2 19 22 0.626
Analgesic medications
Ibuprofen 2 4 0.392
Paracetamol 7 7 1.000
Aspirin 1 3 0.302
Pregabalin 7 5 0.523
Other pain m­ edications3 2 2 1.000
Tricyclic ­antidepressants4 4 4 1.000
Blood pressure medications 17 19 0.655
Cholesterol medication 16 14 0.621
Anti-depressant/anti-anxiety5 7 13 0.370
1
Pearson Chi-Square test; all other P values assessed by two-tailed t test; statistical significance P < 0.05
2
Additional diabetic medications: semaglutide, empagliflozin, linagliptin, dulaglutide, dapagliflozin, acar-
bose, gliclazide MR, vildagliptin, sitagliptin, exenatide
3
Other pain medications: meloxicam (1) and tramadol (1), oxycodone (2)
4
May have been prescribed for pain relief and/or mood support
5
Includes tricyclic antidepressants (TCAs) which are also prescribed as a pain treatment for peripheral neu-
ropathy

non-treatment medication found no difference between analysis of participants with CRP levels of ≥ 5.0 mg/L at
treatment groups for total medications (prescribed and baseline was similar at baseline (P = 0.18); however, at
rescue) or rescue medications used. 8 weeks the active treatment and placebo group demon-
strated a significant difference between means (P = 0.05).
For IL-6, the groups were also similar at baseline
Effect of treatment on glucose metabolism (P = 0.44); however, a significant difference was recorded
and inflammatory markers at 8 weeks between the active treatment group and the
placebo group (P = 0.04).
The treatment groups varied widely in glucose metabo-
lism parameters (FBG and HbA1c) and the inflammatory Effect of treatment on sleep
markers (IL-6, fibrinogen and CRP) (Table 4). All mark-
ers were not significantly different at baseline (P > 0.05). The groups were similar at baseline for all the Medical
At 8 weeks, there was no significant difference between Outcomes Study—Sleep Scale (MOS) subscale scores
the active treatment and placebo group for fasting blood (P ≥ 0.05), (Table 5). At 8 weeks, there was a signifi-
glucose, HbA1c, fibrinogen and CRP when analysed as cant difference between the active treatment group com-
a whole group across all levels (P > 0.05). A sub-group pared with the placebo group in the sub-scores of sleep

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 E. Pickering et al.

Fig. 2  BPI-PN (A) Pain Severity scores at baseline, 2, 4, 6 and 8 weeks and (B) Pain interference score at baseline, 4 and 8 weeks scores for the
active treatment group and the placebo group

disturbance (P = 0.001), sleep adequacy (P = 0.001), Effect of treatment on the mood parameters
daytime somnolence (P ≤ 0.001), shortness of breath or depression, anxiety and stress
headache (P = 0.04) and the total sleep problem index
(P ≤ 0.001). There was no significant change after 8 weeks Groups were statistically different at baseline for depres-
for sleep quantity (P = 0.52) or snoring (P = 0.22). sion (active: 2.06 ± 2.95, placebo: 3.97 ± 3.75, P = 0.02) and

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A randomized controlled trial assessing the safety and efficacy of palmitoylethanolamide…

Fig. 3  Neuropathic Pain Symptom Inventory (NPSI) total and sub-scores for the active treatment group and the placebo group at 8 weeks

anxiety scores (active: 0.64 ± 1.34, placebo: 2.03 ± 2.89, in anxiety levels for either group by the end of 8 weeks
P = 0.02), but not stress scores (active: 2.94 ± 3.46, pla- (active: −0.333 ± 0.85 vs placebo: −0.545 ± 1.23, P = 0.42).
cebo: 4.15 ± 3.41, P = 0.16), so analysis was performed on
change scores. At 8 weeks, change scores were significantly Safety and tolerability of treatment
different between the active treatment and placebo groups
for depression (active: −1.27 ± 4.41 vs placebo: 0.09 ± 1.74, There were no changes observed for the independently
P = 0.02, d = −0.562, CI = −1.052 to −0.067) and were reported laboratory markers for participant electrolytes, kid-
trending towards significance for stress (active: −1.36 ± 2.46 ney and liver function. It is noteworthy, though, that blood
vs −0.39 ± 2.05, P = 0.09). There was no significant change glucose levels in both groups rose significantly over 8 weeks

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Table 2  BPI-PN pain outcome scores for active treatment group and placebo group at baseline, 2, 4, 6 and 8 weeks
Intention to treat
Outcome Time Point Group Mean ± ­SD1 Range P value Change from Effect size [95% CI]
baseline

BPI Severity ­score2 Baseline Active 4.77 ± 1.45 2.8–8.8 0.46 −0.135 [−0.617 to 0.349]
Placebo 4.96 ± 1.37 2.3–8.0
Week 2 Active 3.03 ± 1.39 1.0–7.9 0.002 −1.75 −0.790 [−1.289 to −0.286]
Placebo 4.14 ± 1.48 1.3–8.3 −0.80
Week 4 Active 2.49 ± 1.50 0.8–6.8 <0.001 −2.28 −1.131 [−1.648 to −0.607]
Placebo 4.27 ± 1.64 1.8–8.0 −0.70
Week 6 Active 2.30 ± 1.84 0.0–7.8 <0.001 −2.47 −1.324 [−1.853 to −0.785]
Placebo 4.54 ± 1.53 2.0–8.0 −0.42
Week 8 Active 1.72 ± 1.51 0.3–7.3 <0.001 −3.06 −1.811 [−2.381 to −1.231]
Placebo 4.19 ± 1.20 1.8–7.0 −0.77
BPI Baseline Active 3.49 ± 1.90 0.6–7.9 0.15 −0.398 [−0.884 to 0.091]
Interference ­score2 Placebo 4.26 ± 1.97 0.9–7.9
Week 4 Active 2.45 ± 1.85 0.1–6.4 0.001 −1.04 −0.882 [−1.385 to −0.373]
Placebo 4.11 ± 1.90 0.7–8.0 −0.15
Week 8 Active 1.60 ± 1.66 0.0–5.9 <0.001 −1.90 −1.303 [−1.831 to −0.766]
Placebo 3.87 ± 1.83 0.9–6.7 −0.39
1
Score given as average ± standard deviation
2
Shapiro–Wilk distribution test found these data (in one or both arms) to be not normally distributed; tests of significance were performed non-
parametrically with Mann–Whitney U. Active n = 33, Placebo n = 33. Statistical significance set at P ≤ 0.05

of the clinical trial period (change in fasting glucose from reduction in spontaneous burning pain, spontaneous pres-
baseline: active + 0.88 mmol/L (+11.12%) P = 0.129, pla- sure pain, paroxysmal pain and paraesthesia with no relief
cebo + 0.95 mmol/L (+10.85%) P = 0.041, Table 4). Haema- observed from evoked pain, which is the response to touch,
tology parameters remained constant throughout the 8-week pressure and cold. Furthermore, the reductions in neurologi-
clinical trial except for a significant difference in the eosino- cal pain were associated with lower levels of the inflamma-
phil count (0.04 vs −0.02, P = 0.01). There were several mild tion markers IL-6 and CRP as well as a lower pain interfer-
and short-duration adverse events reported by participants ence with life activities (i.e. walking, gardening, cooking,
during the 8-week study period, which resolved over a few household duties), reduction in depression symptoms and
days without withdrawing from the study. These included improvement in quality of sleep.
intermittent mild headaches (n = 1, active treatment; n = 1, The results of this study build on data from two previ-
placebo), episodes of constipation (n = 1, active treatment), ous clinical trials in patients diagnosed with DPN, albeit,
urticaria for 5 days (n = 1, active treatment), a severe fatigue with different doses of micronized PEA. It is notable that
episode (n = 1, placebo group) and respiratory infections not the analgesic effect of the PEA was significant from as
requiring additional medications (n = 3, placebo group) dur- early as 2 weeks. In a study that administered 600 mg of a
ing the study. All adverse events resolved during the 8-week micronized (non-emulsified) PEA, a significant reduction in
study period, and no participant was withdrawn from the neuropathic pain associated with DPN was observed after
study because of an adverse event. 30 days and 60 days (Schifilliti et al. 2014). Furthermore,
the use of a higher dose of 1200 mg/day of the micronized
(non-emulsified) PEA resulted in significantly reduced dia-
Discussion betic and traumatic chronic neuropathic pain after 40 days
of treatment (Cocito et al. 2014). The results of the present
The results of this study demonstrated that the formula- study highlight the variability that can be encountered with
tion of PEA was safe, tolerable and demonstrated analgesic different pain manifestations such as occurs with spontane-
efficacy for mild to moderate neuropathic pain in patients ous, evoked, paroxysmal pain between individuals diagnosed
diagnosed with diabetic-related peripheral neuropathy when with diabetes, which may reflect different mechanisms of
tested over an 8-week period over placebo. The treatment the disease (Attal et al. 2008). In the current and previous
reduced pain in different sensory nerves as shown by the studies, PEA was observed to have a significant effect in

13
 Table 3  NPSI Pain outcome scores for active treatment group and placebo group at baseline, 4 and 8 weeks
Outcome Group Baseline P value 4 weeks P value Change at Effect size [95% CI] 8 weeks P value Change at Effect size [95% CI]
4 weeks 8 weeks

Total pain score Active 0.48 ± 0.17 0.86 0.29 ± 0.12 <0.001 −0.18 −1.061 [−1.574 to −0.541] 0.22 ± 0.13 <0.001 −0.25 −1.587 [−2.137 to −1.027]
Placebo 0.47 ± 0.17 0.43 ± 0.13 −0.04 0.43 ± 0.13 −0.04
Superficial pain Active 5.94 ± 2.37 0.11 4.24 ± 2.15 <0.001 −1.70 −1.059 [−1.571 to −0.539] 3.21 ± 2.07 <0.001 −2.72 −1.651 [−2.207 to −1.086]
Placebo 6.85 ± 2.18 6.21 ± 1.52 −0.63 6.24 ± 1.56 −0.60
Deep pain Active 5.79 ± 4.44 0.881 3.68 ± 3.33 0.03 −2.10 −0.562 [−1.052 to −0.067] 2.79 ± 2.86 0.0021 −3.00 −0.841 [−1.342 to −0.334]
Placebo 6.06 ± 4.45 5.79 ± 4.13 −0.27 5.55 ± 3.66 −0.51
Paroxysmal pain Active 8.65 ± 4.30 0.911 4.29 ± 3.05 <0.001 −4.36 −0.991 [−1.500 to −0.476] 2.79 ± 2.35 <0.001 −5.86 −1.528 [−2.073 to −0.973]
Placebo 8.56 ± 4.34 7.55 ± 3.51 −1.02 7.22 ± 3.37 −1.33
Evoked pain Active 8.99 ± 6.11 0.551 7.02 ± 5.28 0.25 −1.97 −0.283 [−0.768 to 0.203] 6.27 ± 4.82 0.09 −2.72 −0.423 [−0.909 to 0.067]
Placebo 8.25 ± 5.79 8.51 ± 5.19 0.25 8.39 ± 5.20 0.14
A randomized controlled trial assessing the safety and efficacy of palmitoylethanolamide…

Paraesthesia Active 8.96 ± 3.02 0.201 4.77 ± 3.00 0.01 −4.18 −0.642 [−1.135 to −0.145] 3.12 ± 2.57 <0.001 −5.83 −1.473 [−2.014 to −0.922]
Placebo 7.91 ± 3.47 6.77 ± 3.22 −1.14 7.08 ± 2.79 −0.83

Active n = 33, Placebo n = 33. Statistical significance set at P = < 0.05

1
Shapiro–Wilk distribution test found these data (in one or both arms) to be not normally distributed
Tests of significance are performed nonparametrically with Mann–Whitney U scores given as average ± standard deviation

13
 E. Pickering et al.

Table 4  Effect of treatment on glucose metabolism and inflammatory markers at for the active treatment group and placebo group at baseline
and week 8
Test (Reference Range) Group Baseline Range P value 8 Weeks Range P value
Mean ± SD Mean ± SD

Fasting Blood Glucose Active 7.91 ± 2.28 3.8–12.8 0.23 8.89 ± 3.17 5.1–20.2 0.791
(3.0–7.7 mmol/L) Placebo 8.75 ± 3.26 3.3–19.0 9.13 ± 4.23 4.4–25.0
HbA1c mmol/L Active 58.35 ± 15.23 39.0–95.0 0.42 58.32 ± 16.47 37.0–96.0 0.531
(48–53 mmol/mol) Placebo 62.06 ± 20.73 36.0–121.0 62.97 ± 23.62 35–151
HbA1c % Active 7.49 ± 1.39 5.7–10.8 0.42 7.48 ± 1.51 5.5–11.0 0.531
(6.5–7%) Placebo 7.83 ± 1.90 5.4–13.3 7.91 ± 2.15 5.4–15.9
C-reactive Protein Active 5.32 ± 3.25 2.5–12.0 0.911 4.63 ± 3.19 2.5–12.0 0.261
(0–6 mg/L) Placebo 5.97 ± 4.91 2.5–21.0 6.13 ± 4.74 2.5–18.0
C-reactive protein Active 8.38 ± 1.89 5.0–12.0 0.18 6.17 ± 3.35 2.5–12.0 0.05
> 5.0 mg/L Placebo 10.13 ± 4.60 5.0–21.0 9.43 ± 5.07 2.5–18.0
Interleukin-6 Active 4.93 ± 1.79 1.0–9.0 0.44 4.13 ± 2.32 1.0–12.0 0.041
(< 6 pg/mL) Placebo 4.52 ± 2.27 1.0–12.0 5.44 ± 3.02 1.0–18.0
Fibrinogen Active 3.73 ± 0.83 2.31–6.46 0.531 3.55 ± 0.75 1.85–5.08 0.78
(1.50–4.00 g/L) 1 Placebo 3.56 ± 0.85 2.15–4.93 3.61 ± 0.96 1.17–5.98

Active treatment group n = 33, Placebo group n = 33. Statistical significance set at P ≤ 0.05
1
Shapiro–Wilk distribution test found these data (in one or both arms) to be not normally distributed; tests of significance were performed non-
parametrically with Mann–Whitney U

reducing the specific pain characteristic of paraesthesia/dys- levels of blood glucose levels also weaken the myelin
esthesia. PEA has also previously been shown to be effec- sheath and nerve fibres (Magrinelli et al. 2015). This pro-
tive in ameliorating pain associated with nerve compression cess, alongside the production of inflammatory markers, is
syndromes such as sciatic pain (Keppel Hesselink and Kop- thought to progress the development of peripheral neurop-
sky 2015; Domínguez et al. 2012), carpal tunnel syndrome athy (Jin and Park 2018). The inflammatory markers IL-6
(Conigliaro et al. 2011) and Charcot–Marie–Tooth neu- and CRP were significantly reduced after treatment with
ropathy (Putzu 2016) as well as knee osteoarthritis (Steels PEA in this study, and it is suggested that reducing inflam-
et al. 2019). The existing in-vitro, animal and human clinical mation was part of the mechanism underlying the observed
studies demonstrate and support the efficacy of PEA in the reduction in neuropathic pain. This is supported by recent
treatment of algesia in neuropathies resulting from various cellular macrophage studies that have reported that PEA
causes (Paladini et al. 2016). inhibits both TNF-α and IL-6 release (Del Re et al. 2021).
There is a strong correlation between pain and depression It is noteworthy that there was a correlation in this study
(Alghafri et al. 2020; Vas and Papanas 2020). The current between elevated baseline fasting blood glucose and pain,
study further confirms that PEA reduced depression symp- also HbA1c and pain as well as CRP and pain. These data
toms when administered as an adjunct to citalopram (Ghaz- draw a link between effective management of blood glu-
izadeh-Hashemi et al. 2018). Furthermore, we also report cose levels in pre-diabetics and diabetics with possible
that the administration of PEA was associated with improve- prevention and reduction in peripheral neuropathic pain.
ments in sleep adequacy, reduction in night-time sleep dis- A proportion of participants in this study were taking
turbances and daytime somnolence, confirming reports of a range of prescribed anti-diabetic medications and medi-
improved overall sleep quality in surgical patients (Evange- cations to manage the neuropathic pain, which showed
lista et al. 2018) and those patients with poor sleep quality, that PEA being effective as standalone treatment and
albeit without pain (Putzu 2016). an adjunct medication for pain relief. It was noteworthy
Prolonged hyperglycaemia observed in early or poorly that there was a significant placebo response observed,
controlled diabetes presents a metabolic disease with although PEA was significantly different to placebo, a phe-
inflammatory sequelae and with upregulation of nuclear nomenon often seen in pain studies. Further research into
factor-KB (NF-KB), which subsequently increases TNF-α effectiveness of PEA as an adjunct to long-term pain medi-
and drives a follow-on production of IL-6 and CRP (Yang cation should be further investigated. There are limitations
et al. 2019; Mu et al. 2017, Patel and Santani 2009). in this study that must be considered. The cohort was pri-
Recent animal studies suggest that varying and elevated marily type 2 diabetic and further research is needed with

13
 Table 5  MOS sleep sub-scores for active treatment group and placebo group at baseline, 4 weeks and 8 weeks
MOS Group Baseline P value 4 Weeks P value Change at Effect size 8 Weeks P value Change at Effect size
sub-scale Mean ± SD Mean ± SD 4 weeks [95% CI] Mean ± SD 8 weeks [95% CI]
(range) (range) (range)

Sleep distur- Active 3.54 ± 0.79 0.64 3.92 ± 0.75 0.071 0.37 0.458 4.20 ± 0.56 0.0011 0.65 0.843
bance* (1.75–4.75) (2.00–5.00) [−0.033 to 0.945] (2.25–5.00) [0.336 to 1.344]
Placebo 3.64 ± 0.91 3.55 ± 0.84 −0.09 3.62 ± 0.79 −0.02
(1.75–5.00) (2.00–5.00) (2.00–4.75)
Sleep adequacy* Active 3.50 ± 1.47 0.391 2.59 ± 1.27 0.04 −0.91 −0.507 2.12 ± 0.91 0.0011 −1.38 −0.831
(1.50–6.00) (1.00–5.50) [−0.995 to −0.014](1.00–4.00) [−1.331 to 0.324]
Placebo 3.15 ± 1.29 3.24 ± 1.31 0.09 3.05 ± 1.28 −0.11
(1.00–6.00) (1.00–5.50) (1.50–6.00)
Sleep quantity* Active 6.02 ± 1.58 0.09 6.74 ± 1.43 0.69 0.72 6.83 ± 1.28 0.52 0.82
(2.00–1.00) (3.00–1.00) (4.00–9.00)
Placebo 6.67 ± 1.53 6.88 ± 1.38 0.21 7.04 ± 1.39 0.38
(4.00–1.00) (4.00–1.00) (4.00–1.00)
Daytime somno- Active 4.44 ± 1.14 0.111 5.05 ± 0.89 0.001 0.61 0.923 5.30 ± 0.81 <0.0011 0.86 1.178
lence* (2.33–6.00) (3.00–6.00) [0.411 to 1.428] (3.33–6.00) [0.651 to 1.698]
Placebo 3.90 ± 1.34 3.99 ± 1.36 0.09 4.08 ± 1.23 0.18
(1.00–6.00) (1.00–6.00) (1.00–6.00)
Snoring** Active 3.67 ± 1.90 0.071 3.94 ± 1.85 0.43 0.27 3.91 ± 1.76 0.221 0.24
A randomized controlled trial assessing the safety and efficacy of palmitoylethanolamide…

(1.00–6.00) (1.00–6.00) (1.00–6.00)

Placebo 4.48 ± 1.66 4.39 ± 1.48 −0.09 4.45 ± 1.42 −0.03
(1.00–6.00) (1.00–6.00) (2.00–6.00)
Shortness of Active 5.76 ± 0.50 0.421 5.82 ± 0.46 0.11 0.06 5.93 ± 0.24 0.041 0.18 0.540
breath or head- (4.00–6.00) (4.00–6.00) (5.00–6.00) [0.047 to 1.029
ache** Placebo 5.36 ± 1.32 5.36 ± 1.17 0.00 5.54 ± 1.00) 0.18
(1.00–6.00) (2.00–6.00) (2.00–6.00)
Sleep Problem Active 4.01 ± 0.35 0.25 4.12 ± 0.37 0.01 0.11 4.20 ± 0.29 <0.001 0.18 0.859
Index** (3.22–4.78) (3.11–5.00) (3.11–4.78) [0.351 to 1.361]
Placebo 3.82 ± 0.58 3.82 ± 0.53 0.0003 3.86 ± 0.46 0.04
(2.11–4.67) (2.56–4.56) (2.78–4.44)

MOS score ratings depict the level of impact of each subcategory. Questions are a mix of positively (*) and negatively phrased (**) questions
1
Shapiro–Wilk distribution test found these data (in one or both arms) to be not normally distributed; tests of significance are performed nonparametrically with Mann–Whitney U. Active treat-
ment group n = 33, Placebo group n = 33. Statistical significance set at P ≤ 0.05

13
 E. Pickering et al.

larger cohorts of both type 1 and type 2 diabetics. The permitted by statutory regulation or exceeds the permitted use, you will
cohort had varying levels diabetic control (as measured by need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/.
HbA1c); therefor, larger studies may determine whether
glycaemic levels impacted on the effectiveness of PEA.
In addition, specific assessment of individual motor, sen-
sory and autonomic nerve fibres is required to understand
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