Ultra-micronized palmitoylethanolamide (um-PEA) may be an innovative therapeutic intervention as an add-on therapy to Tapentadol (TP) for the management of chronic low back pain (CLBP), as well as to improve patient’s quality of life. Additionally, this combination treatment decreases the TP dose over time without any serious side effects.

Globally, low back pain (LBP) is one of the most common chronic pain conditions with a lifetime prevalence estimated to be >70% in industrialized countries. At present, various drugs like analgesics (paracetamol), non-steroidal anti-inflammatory drugs (NSAIDs), antidepressants, anticonvulsants, opioids, and topical treatments, with oral agents are recommended as first-line therapy. Although in relieving neuropathic pain, these classic drugs suffer from various side effects mainly at gastrointestinal level that limits their long-term uses. Tapentadol (TP) is a centrally acting analgesic used for the management of acute and chronic pain since 2009. Due to its dual analgesic principle (μ-opioid receptor agonism and noradrenaline reuptake inhibition) in a single molecule, this offers a better balance between efficacy and tolerability than other analgesic drugs. Palmitoylethanolamide (PEA), a member of the Nacylethanolamine family is produced by the mammalian cells and which is particularly abundant in brain tissues. It acts on the mast cells, cellular nucleus and inflammation genes involved in the generation and maintenance of pain. It down-regulates the mast cell activation and controlling microglial cell behaviors that plays important role in the pain modulation. Ultra-micronized-PEA (um-PEA) showed better pain control and tolerability when administered as an add-on therapy with low dose of any analgesics. Thus, Um-PEA may be considered as an effective add-on therapy to minimize the risks of chronic opioid treatment in diseases associated with chronic neuropathic pain.

Rationale behind the research:

• No significant results were shown by classicaly used drugs for treatment of LBP in earlier trials
• Therefore, this pilot study was conducted to assess the benificail use of um-PEA as an add-on therapy to tapentadol in the treatment of LBP

Objective:

To assess the effectiveness of um-PTA at 6 months as an add-on therapy to TP in the treatment of chronic low back pain.

Study outcomes measures:

• Pain intensity: Pain intensity was evaluated by visual analog scale (VAS). The VAS is a continuous scale comprised of a horizontal line, 10 cm (100 mm) in length, anchored by 2 verbal descriptors, one for each symptom (0 = no pain and 10 = the worst pain imaginable).
• Neuropathic pain: It was detected by DN4 quetionnaire, which includes four questions consisting of both sensory descriptors and signs related to bedside sensory examination
• Functional disability: Permanent functional disability was evaluated with Oswestry Disability Questionnaire (ODQ)
• Tolerability and monitoring of possible side effects

Time period: All the parameters were assessed at baseline (T0), 3 weeks (T1), 12 weeks (T2) and 24 weeks (T3–end of treatment).

Study Outcomes:

• VAS mean pain intensity score to decrease significantly over time in both groups when considered separately (p<0.0001). VAS values in the um-PEA–TP group decreased from 7.4 ± 0.08 (T0) to 4.5 ± 0.09 (T3), and in the control TP group from 7.7 ± 0.10 (T0) to 5.9 ± 0.09 (T3). The reduction in VAS mean score was statistically significant in the um-PEA–TP group compared to the TP group (p< 0.0001) (Figure 2)

Figure 2: Visual Analog Scale 

• DN4 questionnaire scores showed that the neuropathic component significantly decreased over time in both groups (p<0.0001), with a significantly higher reduction in favor of the prospective group (p<0.0001). Patients in the um-PEA-TP group with a DN4 mean score of 6.1±0.14 at baseline (T0), reached a mean score of 3.2 ± 0.13 (T3) at treatment end; patients in the TP group with a mean score of 6.1±0.09 (T0) achieved a mean score of 5.0±0.04 at T3 (Figure 3).

Figure 3: DN4 questionnaire scale

• ODQ questionnaire score evidenced a significant reduction between baseline and end of treatment in both groups (p<0.0001). The mean score for the um-PEA-TP group decreased from 56.9±1.55 (T0) to 37.7±2.38 (T3), while for the TP-only group it decreased from 54.6±2.20 to 44.6±3.02 showing a further significant difference in the um-PEA-TP group compared to the TP group (p<0.0012) (Figure 4).

Figure 4: ODQ questionnaire score

• TP dosage was significantly reduced in both groups between baseline and at the end of treatment (p<0.0001), with a greater reduction in favor of the um-PEA-TP group (p<0.0001). In fact, patients in the um-PEA-TP group received a mean dose of 203.3 ± 6.75 mg at study start (T0) which decreased to 121.7±6.20 mg after 6 months (T3). In contrast, patients in the TP group initially took a mean dose of 196.0±10.38 mg (T0), which decreased to 158.0±8.50 mg (T3) (Figure 5).

Figure 5: Tapentadol dosage

This study concluded that um-PEA may be an advanced therapeutic intervention as an add-on therapy to TP for the management of CLBP with a neuropathic component, also to improve patient quality of life. Additionally, this combination treatment allowed a reduction in TP dose over time and did not show any serious side effects.

The results of this study are more accurate than the previous studies which showed significant reduction on VAS and DN4 score in um-PEA-TP group than the TP group alone (p<0.0001). Few clinical studies showed the pain-relieving properties of m-PEA alone and as an add-on treatment for different chronic pain disorders without and with a neuropathic component. Domnguez et al in 2012 reported the results of double blind study in patients with lumbosciat¬ica. Similarly, in 2012 Gatti et al also reported the effectiveness of PEA as an add-on therapy with already using analgesic drug in the treatment of chronic pain. Cobellis et al in 2011 also reported the use of N-Palmitoylethanolamine in the treatment of pelvic pain. No study till now has evaluated this interaction between um-PEA and TP for the treatment of CLBP. This preliminary study provides promotive findings on the potential benefits of PEA addition to TP in patients affected by c CLBP and should stimulate confirmatory trials with larger patient cohorts. Thus, further prospective studies with a double-blind design and larger patient numbers are needed to confirm these findings.