Efficacy and safety of a T-type calcium channel blocker in patients with neuropathic pain: A proof-of-concept, randomized, double-blind and controlled trial.

BACKGROUND: T-type calcium channels have been shown to play an important role in the initiation and maintenance of neuropathic pain and represent a promising therapeutic target for new analgesic treatments. Ethosuximide (ETX), an anticonvulsant and a T-type channel blocker has shown analgesic effect in several chronic pain models but has not yet been evaluated in patients with neuropathic pain. METHODS: This proof-of-concept, multicentre, double-blind, controlled and randomized trial compared the efficacy and safety of ETX (given as add-on therapy) to an inactive control (IC) in 114 patients with non-diabetic peripheral neuropathic pain. After a 7-day run-in period, eligible patients aged over 18 years were randomly assigned (1:1) to ETX or IC for 6 weeks. The primary outcome was the difference between groups in the pain intensity (% of change from the baseline to end of treatment) assessed in the intention-to-treat population. This study is registered with EudraCT (2013-004801-26) and ClinicalTrials.gov (NCT02100046). RESULTS: The study was stopped during the interim analysis due to the high number of adverse events in the active treatment group. ETX failed to reduce total pain and showed a poor tolerance in comparison to IC. In the per-protocol analysis, ETX significantly reduced pain intensity by 15.6% (95% CI -25.8; -5.4) from baseline compared to IC (-7.8%, 95% CI -14.3; -1.3; p = 0.033), but this result must be interpreted with caution because of a small subgroup of patients. CONCLUSION: Ethosuximide did not reduce the severity of neuropathic pain and induces, at the doses used, many adverse events. SIGNIFICANCE: This article shows that ETX is not effective to treat neuropathic pain. Nevertheless, per-protocol analysis suggests a possible analgesic effect of ETX. Thus, our work adds significant knowledge to preclinical and clinical data on the benefits of T-type calcium channel inhibition for the treatment of neuropathic pain.

[Serotoninergic antidepressants and opiate analgesics: a sometimes-painful association. A case report]. / Antidépresseurs sérotoninergiques et antalgiques opiacés : une association parfois "douloureuse"! A propos d'un cas clinique.

CASE-REPORT: We report a case of serotonin syndrome caused by interaction between nasal fentanyl, oxycodone and escitalopram. Due to chronic painful episodes with paroxistic level of pain, a 66-year-old patient, treated for prostate adenocarcinoma and bone metastases received an association of major opiate analgesics (oxycodone 120 mg/day for 6 months, and fentanyl nasal spray four puff of 200 microg/puff). After the addition, for mood disorders, of a small dose of escitalopram (5 mg/day), he developed severe serotoninergic features including diaphoresis, night sweating, tremor, diarrhea, visual disorders with mydriasis and weight loss of 8.8 lbs (4 kg). Discontinuation of escitalopram resulted in complete resolution of his symptoms within 48 h except for persistent blurred vision. DISCUSSION: The clinical manifestations of this case meet Sternbach's criteria of serotonin syndrome. Its possible etiologic factors include adverse drug reaction and pharmacodynamic interaction between selective serotonin reuptake inhibitor (SSRI) antidepressant and opioid analgesics. The Naranjo probability scale suggested a probable causality of escitalopram, oxycodone and fentanyl treatment on the serotonin syndrome. Serotonin syndrome occurrence is estimated around 0.04% in the literature with incidence rates between 14 to 16% in voluntary overdose with serotoninergic agents. It is an infrequent syndrome with, most of the time, a mild to moderate clinical expression. Nevertheless, lethal evolution might occur resulting from either monotherapy with serotoninergic agents (eg: SSRI antidepressants) or the combination of several medications that will increase serotoninergic transmission and therefore intra cerebral serotonin levels. Its physiopathology is related to a hyperstimulation of 5-HT(1A) receptors. Its clinical manifestations involve mental status impairment and cognitive disorders, neuromuscular disorders and neurovegetative impairment. The prescription of SSRI antidepressants among patients depressed, and in pain, exhibiting somatic diseases, and who require regimens of major opiate or related analgesics, is not without risk. CONCLUSION: Clinicians and especially psychiatrists should be aware of possible interaction and the risk of serotonin syndrome when a patient receives a combination of different opioid analgesics and serotonin reuptake inhibitor antidepressants. Improved information and collaboration with somatic and pain specialists and the general practitioners could help reduce the occurrence of this syndrome which can have dreadful consequences. Patients must be informed of such complications, which means that patients should be asked for a history of such events and monitored for serotoninergic adverse events, in order to avoid delays in this diagnosis.