Last month, when Al­ler­gan’s $AGN once-tout­ed pipeline star ra­pastinel crashed and burned a slate of piv­otal de­pres­sion stud­ies, it looked like the ex­per­i­men­tal mod­u­la­tor of the NM­DA re­cep­tor would be shroud­ed in a cloak of in­vis­i­bil­i­ty — but re­searchers may have found a way to res­cue the ex­per­i­men­tal drug by re­pur­pos­ing it as a treat­ment for opi­oid de­pen­dence.

Ju­lia Fer­rante

In the Unit­ed States, the cri­sis of opi­oid abuse, mis­use and over­dose — from pre­scrip­tion painkillers, hero­in, and syn­thet­ic opi­oids such as fen­tanyl — has reached epi­dem­ic pro­por­tions, caus­ing 130 deaths every day, ac­cord­ing to NIH es­ti­mates. Once in with­draw­al, ad­dicts are left to cope with a myr­i­ad of symp­toms in­clud­ing anx­i­ety, ag­i­ta­tion, sleep prob­lems, mus­cle aches, run­ny nose, sweat­ing, nau­sea, vom­it­ing, di­ar­rhea and opi­oid crav­ings.

In or­der to man­age these of­ten de­bil­i­tat­ing symp­toms, with­draw­al is man­aged by sub­sti­tu­tion with a less pow­er­ful opi­oid, fol­lowed by grad­ual re­duc­tion or tran­si­tion to main­te­nance ther­a­py with FDA-ap­proved med­ica­tion-as­sist­ed treat­ment (MAT) drugs such as methadone, buprenor­phine or nal­trex­one, which can have un­pleas­ant and some­times dan­ger­ous side ef­fects and of­ten must be used for months to avoid re­lapse. Al­though the process of ta­per­ing opi­oid con­sump­tion and us­ing MAT to treat opi­oid ad­dic­tion is stan­dard-of-care, it sus­tains the brain changes that re­sult in ad­dic­tion in the first place, which can lead to re­lapse be­fore treat­ment is com­plet­ed, ac­cord­ing to re­searchers who eval­u­at­ed the use of ra­pastinel in opi­oid de­pen­dence.

The tri­al in rats test­ed the use of ra­pastinel ver­sus ke­t­a­mine — a com­mon­ly-used cat tran­quil­iz­er and par­ty drug known as Spe­cial K or Kit Kat — which has been pro­posed as an al­ter­na­tive, non-opi­oid treat­ment for opi­oid with­draw­al, but it has the po­ten­tial for abuse, in­duces a trance-like state and can cause hal­lu­ci­na­tions. In fact, J&J’s $JNJ ke­t­a­mine-based de­pres­sion drug Spra­va­to has al­ready won FDA ap­proval. Ra­pastinel binds to the same re­cep­tor as ke­t­a­mine but at a dif­fer­ent site, where it con­fers a milder ef­fect.

Cyn­thia Kuhn

The sci­en­tists first in­duced opi­oid de­pen­dence in male and fe­male ado­les­cent (be­tween 28 and 30 days old) Sprague-Daw­ley rats by in­ject­ing them with mor­phine in in­creas­ing dos­es twice a day for five days. On day six, rats were in­ject­ed with nalox­one and with­draw­al signs were quan­ti­fied. The rats were then giv­en ei­ther ke­t­a­mine in­jec­tions twice dai­ly (n=12), ra­pastinel in­jec­tions every oth­er day (n=14), or saline in­jec­tions (n=24). On day nine, when the rats were giv­en nalox­one to mea­sure with­draw­al signs, ra­pastinel-treat­ed rats ex­hib­it­ed sig­nif­i­cant­ly few­er with­draw­al signs than those treat­ed with ke­t­a­mine.

The find­ings sug­gest that treat­ment with ra­pastinel in­duced safer with­draw­al, sans any se­ri­ous side ef­fects, dur­ing the crit­i­cal first days in the ef­fort to ab­stain from opi­oid use — and the sci­en­tists hy­poth­e­sized this would lead to a de­creased risk of opi­oid re­lapse.

“Ra­pastinel re­search for opi­oid de­pen­den­cy is cur­rent­ly on­ly be­ing done in ro­dents, but if the drug con­tin­ues to have suc­cess­ful tri­als, it may en­ter clin­i­cal tri­als for use in hu­mans,” said Ju­lia Fer­rante, an un­der­grad­u­ate at Vil­lano­va Uni­ver­si­ty who con­duct­ed the re­search with Cyn­thia Kuhn, pro­fes­sor of phar­ma­col­o­gy and can­cer bi­ol­o­gy at Duke Uni­ver­si­ty.

The re­searchers are look­ing to keep test­ing ra­pastinel to in­ves­ti­gate its ef­fect on the mol­e­c­u­lar lev­el and to check whether it can re­duce the risk of re­lapse. The drug has a long way to go be­fore it cross­es the fin­ish line, but if ap­proved it would like­ly be ad­min­is­tered in­tra­venous­ly, pos­si­bly in an out­pa­tient set­ting, Fer­rante added.