Introduction 

Maintaining control of blood glucose levels is a primary treatment strategy for diabetic peripheral neuropathy (DPN) along with neuropathic pain management which includes antiepileptics or anticonvulsants, tricyclic antidepressants, serotonin–norepinephrine reuptake inhibitors and opioids. However, neuropathic pain management remained difficult. A meta-analysis demonstrated that palmitoylethanolamide was progressively effective in reducing chronic neuropathic pain. An increased absorbable form of palmitoylethanolamide has been developed to improve the bioavailability, efficacy and dosing. This formulation was effective in reducing inflammation and improving quality of life associated with DPN, over an 8-week study in diabetics.

Aims

Primary: To assess the safety, tolerability and efficacy of an enhanced bioavailable formulation of palmitoylethanolamide in treating diabetic-related peripheral neuropathic pain

Secondary: To evaluate the improvement in inflammation markers, sleep quality and quality of life with palmitoylethanolamide, when administered as an adjunct analgesic to diabetic medications over 8 weeks

Patient Profile 

Method

Study Design

• Interventional, single-centre, prospective, randomized, quadruple-blinded, placebo-controlled, parallel study
• Patients received 600 mg of palmitoylethanolamide or placebo daily for 8 weeks

Endpoints

• Primary endpoints: neuropathic pain and specific pain types (the Brief Pain Inventory Short Form for Diabetic Peripheral Neuropathy, BPI-DPN; and Neuropathic Pain Symptom Inventory, NPSI)
• Secondary outcomes: sleep quality (Medical Outcomes Study—Sleep Scale, MOS sleep scale), mood (21-item Depression Anxiety Stress Score, DASS-21), glucose metabolism (HbA1c and fasting blood glucose) and inflammation (C-reactive protein, IL-6 and fibrinogen)
• Blood safety markers: full blood count, liver function tests, platelets, electrolytes and kidney function
• Tolerability

Results 

Efficacy 

• Palmitoylethanolamide progressively and significantly lowered pain severity (assessed by BPI-DPN) as compared to placebo, which was evident at week 2 (P = 0.002), and continued at weeks 4, 6 and 8 (P < 0.001, Figure 1)
• Significant differences in pain interference scores were achieved with palmitoylethanolamide versus placebo (P ≤ 0.001, Figure 1) and at both the time points (week 4 and week 8, P ≤ 0.001); a greater change from baseline was noted with palmitoylethanolamide at week 8 (−1.90 vs. −0.39; P ≤ 0.001) 
• Neuropathic pain symptoms were significantly lower in palmitoylethanolamide group versus placebo, measured as NPSI total pain score (change -0.18; P ≤ 0.001, Figure 1) and sub-scores:  superficial spontaneous pain (P ≤ 0.001), deep pain (P = 0.03 & P = 0.002), paroxysmal pain (P ≤ 0.001) and paraesthesia (P = 0.01 & P ≤ 0.001)
• Palmitoylethanolamide group was associated with significant improvement of the MOS sleep problem index and sub-scores of sleep disturbance (P = 0.001), sleep adequacy (P = 0.001), daytime somnolence (P ≤ 0.001), shortness of breath or headache (P = 0.04) and the total sleep problem index (P ≤ 0.001) at 8 weeks
• No significant difference noted between both the groups for fasting blood glucose, HbA1c, fibrinogen and C-reactive protein (P > 0.05); however, interleukin-6 levels were significantly lower versus placebo at 8 weeks (P = 0.04)
• In a sub-group of patients with CRP levels >5.0 mg/L at baseline, elevated C-reactive protein levels significantly reduced in the palmitoylethanolamide group (P = 0.05)
• At 8 weeks, change scores were significantly lower in palmitoylethanolamide group versus placebo for depression (active -1.27 vs placebo 0.09, P = 0.02) and were trending towards significance for stress (active -1.36 vs -0.39, P = 0.09); no change in anxiety levels was noted (P = 0.42)
• DASS-21 depression scores significantly reduced (P = 0.03)

Figure 1: Effect of palmitoylethanolamide on the primary endpoints

Safety   

• The palmitoylethanolamide treatment was well tolerated and no patient withdrawals occurred due to any adverse event
• Several mild and short-duration adverse events reported by participants resolved over a few days (intermittent mild headaches, episodes of constipation, urticaria for 5 days, a severe fatigue episode and respiratory infections not requiring additional medications)
• No changes occurred in the laboratory markers for electrolytes, kidney and liver function
• Blood glucose levels rose significantly over 8 weeks (change in fasting glucose from baseline: palmitoylethanolamide +11.12%, P = 0.129 and placebo +10.85%, P = 0.041)
• Haematology parameters remained constant throughout the 8 weeks except for a change in the eosinophil count in palmitoylethanolamide group (0.04 vs -0.02, P = 0.01)

Conclusion 

Palmitoylethanolamide formulation, with enhanced bioavailability, was safe, tolerable and reduced diabetic peripheral neuropathic pain and inflammation along with improving mood and sleep when tested over an 8-week period over placebo in patients with diabetic-related peripheral neuropathy.

Inflammopharmacol 2022; 30: 2063-2077