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ISSN:1435-1463, ISSN:0300-9564, Journal of Neural Transmission, 129 (5), 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") use has been linked to persistent alterations of the brain serotonergic (5-HT) system in animal and human studies, but the molecular underpinnings are still unclear. Cytoskeletal structures such as neurofilament light chain (NfL) are promising markers of drug-induced brain toxicity and may be involved in MDMA neurotoxicity. The brain-derived neurotrophic factor (BDNF) promotes the growth and sprouting of 5-HT neurons and its differential response to MDMA administration was suggested to mediate dose- and region-dependent 5-HT damage by MDMA. However, the role of BDNF pre-treatment in preventing MDMA neurotoxicity and the potential effects of MDMA on NfL are still elusive. Therefore, a differentiated 5-HT neuronal cell line obtained from rat raphe nucleus (RN46A) was treated in vitro with either MDMA, BDNF, MDMA + BDNF, or vehicle. Cell viability (measured by MTT) and intracellular NfL levels (immunocytochemistry assay) were reduced by MDMA, but partially rescued by BDNF co-treatment. Our findings confirmed that BDNF levels can influence MDMA-induced 5-HT damage, and support BDNF to be a crucial target for neuroprotective interventions of the 5-HT system. We also provide evidence on the sensitivity of NfL to MDMA neurotoxicity, with potential implications for in-vivo monitoring of drug-induced neurotoxicity.

Flaminia Coluzzi,1,2 Francesca Felicia Caputi,3 Domenico Billeci,4 Antonio Luigi Pastore,1,5 Sanzio Candeletti,3 Monica Rocco,2,6 Patrizia Romualdi3 1Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Polo Pontino, Latina, Italy; 2Unit of Anesthesia, Intensive Care and Pain Medicine, Sant’Andrea University Hospital, Rome, Italy; 3Department of Pharmacy and Biotechnology, Alma Mater Studiorum University, Bologna, Italy; 4Division of Neurosurgery, Ca’Foncello Hospital, ASL Marca Trevigiana, University of Padova, Treviso, Italy; 5Unit of Urology, Sapienza c/o I.C.O.T, Polo Pontino, Latina, Italy; 6Department of Clinical and Surgical Translational Medicine, Sapienza University of Rome, Rome, ItalyCorrespondence: Flaminia ColuzziDepartment of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, Polo Pontino 04100, Latina, ItalyTel +39 06 33775673Email flaminia.coluzzi@uniroma1.itAbstract: In patients suffering from moderate-to-severe chronic kidney disease (CKD) or end-stage renal disease (ESRD), subjected to hemodialysis (HD), pain is very common, but often underestimated. Opioids are still the mainstay of severe chronic pain management; however, their prescription in CKD and HD patients is still significantly low and pain is often under-treated. Altered pharmacokinetics and the lack of clinical trials on the use of opioids in patients with renal impairment increase physicians’ concerns in this specific population. This narrative review focused on the correct and safe use of opioids in patients with CKD and HD. Morphine and codeine are not recommended, because the accumulation of their metabolites may cause neurotoxic symptoms. Oxycodone and hydromorphone can be safely used, but adequate dosage adjustments are required in CKD. In dialyzed patients, these opioids should be considered as second-line agents and patients should be carefully monitored. According to different studies, buprenorphine and fentanyl could be considered first-line opioids in the management of pain in CKD; however, fentanyl is not appropriate in patients undergoing HD. Tapentadol does not need dosage adjustment in mild-to-moderate renal impairment conditions; however, no data are available on its use in ESRD. Opioid-related side effects may be exacerbated by common comorbidities in CKD patients. Opioid-induced constipation can be managed with peripherally-acting-μ-opioid-receptor-antagonists (PAMORA). Unlike the other PAMORA, naldemedine does not require any dose adjustment in CKD and HD patients. Accurate pain diagnosis, opioid titration and tailoring are mandatory to minimize the risks and to improve the outcome of the analgesic therapy.Keywords: opioids, chronic kidney disease, pain, hemodialysis, neuropathic pain, PAMORA

Flaminia Coluzzi,1,2 Francesca Felicia Caputi,3 Domenico Billeci,4 Antonio Luigi Pastore,1,5 Sanzio Candeletti,3 Monica Rocco,2,6 Patrizia Romualdi3 1Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Polo Pontino, Latina, Italy; 2Unit of Anesthesia, Intensive Care and Pain Medicine, Sant’Andrea University Hospital, Rome, Italy; 3Department of Pharmacy and Biotechnology, Alma Mater Studiorum University, Bologna, Italy; 4Division of Neurosurgery, Ca’Foncello Hospital, ASL Marca Trevigiana, University of Padova, Treviso, Italy; 5Unit of Urology, Sapienza c/o I.C.O.T, Polo Pontino, Latina, Italy; 6Department of Clinical and Surgical Translational Medicine, Sapienza University of Rome, Rome, ItalyCorrespondence: Flaminia ColuzziDepartment of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, Polo Pontino 04100, Latina, ItalyTel +39 06 33775673Email flaminia.coluzzi@uniroma1.itAbstract: In patients suffering from moderate-to-severe chronic kidney disease (CKD) or end-stage renal disease (ESRD), subjected to hemodialysis (HD), pain is very common, but often underestimated. Opioids are still the mainstay of severe chronic pain management; however, their prescription in CKD and HD patients is still significantly low and pain is often under-treated. Altered pharmacokinetics and the lack of clinical trials on the use of opioids in patients with renal impairment increase physicians’ concerns in this specific population. This narrative review focused on the correct and safe use of opioids in patients with CKD and HD. Morphine and codeine are not recommended, because the accumulation of their metabolites may cause neurotoxic symptoms. Oxycodone and hydromorphone can be safely used, but adequate dosage adjustments are required in CKD. In dialyzed patients, these opioids should be considered as second-line agents and patients should be carefully monitored. According to different studies, buprenorphine and fentanyl could be considered first-line opioids in the management of pain in CKD; however, fentanyl is not appropriate in patients undergoing HD. Tapentadol does not need dosage adjustment in mild-to-moderate renal impairment conditions; however, no data are available on its use in ESRD. Opioid-related side effects may be exacerbated by common comorbidities in CKD patients. Opioid-induced constipation can be managed with peripherally-acting-μ-opioid-receptor-antagonists (PAMORA). Unlike the other PAMORA, naldemedine does not require any dose adjustment in CKD and HD patients. Accurate pain diagnosis, opioid titration and tailoring are mandatory to minimize the risks and to improve the outcome of the analgesic therapy.Keywords: opioids, chronic kidney disease, pain, hemodialysis, neuropathic pain, PAMORA