Ultramicronized palmitoylethanolamide treatment in central neuropathic pain following longstanding spinal cord injury: try to extinguish the fire after everything was burned
In a recent issue of PAIN, Andresen et al.3 reported the results of a randomized, double-blind, placebo-controlled clinical trial examining the effect of ultramicronized palmitoylethanolamide (PEA-um) as add-on therapy on neuropathic pain following spinal cord injury (SCI), as well as the effects on spasticity and psychological functioning. The ineffectiveness of PEA-um contrasts with current literature describing the beneficial effects of PEA-um in neuropathic pain.12,13 As the authors discuss, reasons for this negative outcome could relate to several factors (patient heterogeneity regarding causes and levels of SCI, concomitant medications and unresponsiveness to pain treatment). Unfortunately, the study does not provide details on medication dosing or on the length of pharmacological treatment before administration of PEA-um. Given a baseline pain score of 6.4, although most patients were already receiving a large amount of medications for pain and spasticity, it is difficult to expect a beneficial effect of PEA-um. In the trial by Andresen et al, in the PEA-um group, 77.7% of patients were already taking gabapentinoids (in contrast to 54% in the placebo group) along with many other drugs in combination (weak and strong opioids, antidepressants, other drugs) so, probably, they represent a group of patients particularly unresponsive to pain treatments. Furthermore, the timing of treatment effects on glia could be crucial in these patients. There is evidence that glial activation plays a major role in the development and maintenance of neuropathic pain after SCI in an animal model.9 For this reason, specific treatments aimed to reduce glial activation have been already tested in the early stages of spinal injury.15 In both treatment groups in the Andresen et al. trial, the duration of time from the trauma is relevant (9.4 years in the PEA-um group, 11.1 years in the placebo group) and makes a therapeutic response to a glial inhibitor unlikely when the glial activation may have already produced permanent structural modifications. Moreover, no explanation is given as to why there was a significant reduction of acetaminophen consumption in the PEA-um group compared with the placebo group. Some experimental data in the animal model of neuropathic pain have shown synergistic activity of PEA combined with acetaminophen and such synergistic effects might explain the observed reduction of acetaminophen consumption in the treatment group.6 In the trial by Andresen et al, the PEA-um group and the placebo group were not homogeneous with respect to gender. Specifically, in the placebo group, there were only 5 female patients compared with 14 in the PEA-um group. Although the possibility that gender is a predictor of the severity of neuropathic pain is controversial,4,5 research using an animal model of neuropathic pain showed a different response in regulating pain hypersensitivity mediated by microglia depending on gender.10 Andresen et al. reported that female gender is a risk factor for the development of neuropathic pain after SCI.2 In our opinion, therefore, it is necessary that in the clinical pain studies, different groups must be homogeneous with respect to gender. Despite the lack of significant results emerging from the trial of Andresen et al, an ever-growing body of evidence documenting the pain-relieving, anti-inflammatory and neuroprotective actions of PEA should encourage further studies on PEA-um effects in SCI particularly at shorter times postinsult.