Bergamot rehabilitation AgaINst agitation in dementia (BRAINAID): Study protocol for a randomized, double‐blind, placebo‐controlled trial to assess the efficacy of furocoumarin‐free bergamot loaded in a nanotechnology‐based delivery system of the essential oil in the treatment of agitation in elderly affected by severe dementia

Abstract

Pain is underdiagnosed and often not adequately treated, contributing to behavioral and psychological symptoms of dementia (BPSD). BPSD are treated with atypical antipsychotics that are associated with severe cerebrocardiovascular effects. Interestingly, treatment of pain may reduce agitation. Research is focusing on nonpharmacological treatment, such as aromatherapy, for pain and BPSD in dementia. This clinical study will assess the effect on agitation in severely demented elderly of BEO loaded in a nanotechnological odorless cream indistinguishable from placebo. This is a protocol for a randomized, double-blind, placebo-controlled trial (NCT04321889). A total of 134 patients aged ≥65 years with severe dementia (mini-mental state examination <12) will be recruited and randomly allocated 1:1 to either BEO or placebo group. After baseline screening, BEO (80 mg) cream or placebo cream will be trans-dermally applied on both arms twice a day for 4 weeks with a 4-week followup period. The effect on agitation will be the primary endpoint. Any adverse events will be reported. A double-blind, clinical trial evaluating efficacy and safety of an essential oil endowed with strong analgesic properties has never been carried out before. This study could form the basis for a safer and more effective treatment of BPSD in severe dementia.

Preclinical Characterization of Antinociceptive Effect of Bergamot Essential Oil and of Its Fractions for Rational Translation in Complementary Therapy

“…This deepening of the characterization of the neuropharmacological profile of BEO is fundamental to elucidate all of its properties since BEO may provide an effective option for the management of agitation that is closely connected to under-treated pain [29] and, unfortunately, that is managed with antipsychotics, doubling the risk of death caused by cardiocerebrovascular accidents in the elderly [30], something that is even more relevant during the pandemic [31]. In fact, BEO has been engineered in the pharmaceutical form of a nanotechnological cream for its delivery [32], and the clinical trial for proof of concept in severe dementia (NCT04321889) [33] is ongoing. Future studies need to clarify the role of the single components since the whole phytocomplex is endowed with the highest amount of pharmacological activity.…”

Translational Value of the Transdermal Administration of Bergamot Essential Oil and of Its Fractions

“…Interestingly, all three main components exerted a significant analgesic effect in both the first and the second phase, accounting for the efficacy of the whole essential oil in this experimental pain model, selected precisely because it is characterized by a late phase of pain behavior induced by central sensitization and affected by aging [ 22 ]. In fact, the demonstration of the analgesic properties of the different fractions and of BEO components after transdermal administration is necessary for clinical use since BEO in the pharmaceutical form of a base cream incorporating a nanotechnological delivery system based on solid lipid nanoparticles [ 36 ] is under investigation in an active clinical trial for proof of concept of the management of severe dementia with agitation through analgesia (NCT04321889) [ 37 ]; this is fundamental since clinical studies for the treatment of several forms of pain often exclude cognitively impaired patients [ 38 , 39 ], not testing the most novel therapies [ 40 ] and not informing about the best analgesic practice in this fragile population subjected to physiological modifications and variability in drug response [ 41 ]. The DEC fraction was enriched with 44% limonene, confirming the previous observation supporting the role of d -limonene in analgesia.…”

ROBOCOP (ROBOtic Care of Poststroke Pain): Study Protocol for a Randomized Trial to Assess Robot-Assisted Functional and Motor Recovery and Impact on Poststroke Pain Development

“…In fact, fragile populations are often subjected to limited and inappropriate pain treatment (66)(67)(68). The next step will consist in investigating the effect of this neurorehabilitation procedure on the use of analgesics, both synthetic and of natural origin, as the essential oil of bergamot endowed with analgesic (69) and flumazenil insensitive anxiolytic-like (70) properties and which has been engineered allowing double-blind clinical trials (71,72).…”