Accepted

Chronic pain is a common health problem, for which the treatment is complex and challenging. Non-invasive brain stimulation techniques, specifically transcranial alternating current stimulation (tACS), show promise as a well-tolerated new therapeutic modality with few side effects. This is supported by growing evidence of an association between altered neuronal oscillations and chronic pain. However, to date, only a handful of studies with variable methodology have evaluated tACS for potential applicability to patients with chronic pain.

To summarize the recommendations on the interventional management of subacute and chronic non-radicular low back pain (LBP) from the 21 quality-appraised CPGs identified in the previously published paper: "Quality of Clinical Practice Guidelines on Interventional Management of Low Back Pain: A Systematic Review". By disseminating this information, we aim to facilitate the implementation of these recommendations into clinical practice.

This study aimed to identify and assess the evidence on the association between idiopathic chronic low back pain (LBP) and cognitive function in individuals with LBP. A secondary aim was to explore whether changes in cognitive function are associated with pain characteristics and psychological factors (e.g., catastrophizing and fear of movement). Eleven studies were included in this systematic review and four meta-analyses were conducted. Low to very low quality evidence suggests impaired cognitive function in individuals with LBP compared to asymptomatic controls for problem solving ((k=5; d= 0.33; CI=0.16-0.50; z=3.85 p=0.0001), speed of information processing (k=5; d= 0.44; CI=0.22-0.65; z=4.02 p<0.0001), working memory (k=6; d= 0.50; CI=0.34-0.66; z=6.09 p<0.0001) and delayed memory (k=3; d= 0.34; CI=0.07-0.6, z=2.49 p=0.02). The association between LBP intensity and psychological factors and cognitive function was inconclusive. More studies are needed to explore these associations and improve evidence in this field. The results of this study suggest that cognitive aspects should be considered during the rehabilitation process of patients with LBP, and raise further questions, including whether individuals with LBP are at a greater risk of developing dementia or whether targeting cognitive function will increase the probability of success of LBP treatment. These questions should, also, be considered in future studies.

There is still an unmet clinical need to develop new pharmaceuticals for effective and safe pain management. Current pharmacotherapy offers unsatisfactory solutions due to serious side effects related to the chronic use of opioid drugs. Prescription opioids produce analgesia through activation of the mu-opioid receptor (MOR) and are major contributors to the current opioid crisis. Multifunctional ligands possessing activity at more than one receptor represent a prominent therapeutic approach for the treatment of pain with fewer adverse effects. We recently reported on the design of a bifunctional MOR agonist/neuropeptide FF receptor (NPFFR) antagonist peptididomimetic, (H-Dmt-DArg-Aba-βAla-Bpa-Phe-NH), and its antinociceptive effects after subcutaneous (s.c.) administration in acute and persistent pain in mice with reduced propensity for unwanted side effects. In this study, we further investigated the antinociceptive properties of in a mouse model of visceral pain after s.c. administration and the potential for opioid-related liabilities of rewarding and sedation/locomotor dysfunction following chronic treatment. produced a significant dose-dependent inhibition of the writhing behavior in the acetic acid-induced writhing assay with increased potency when compared to morphine. We also demonstrated the absence of harmful effects caused by typical MOR agonists, i.e., rewarding effects (conditioned-place preference test) and sedation/locomotor impairment (open-field test), at a dose shown to be highly effective in inhibiting pain behavior. Consequently, displayed a favorable benefit/side effect ratio regarding these opioid-related side effects compared to conventional opioid analgesics, such as morphine, underlining the development of dual MOR agonists/NPFFR antagonists as improved treatments for various pain conditions.