An Opioid for Depression

In a recent report on the ongoing painkiller addiction epidemic (1), CBS News looked at West Virginia, “a state that is attempting a drastic solution: allowing addicts to sue the doctorswhogot themhooked.”According to the article, “West Virginia has the highest rate of overdose deaths in the nation,” and “each year doctors write the equivalent of one painkiller prescription for every man, woman, and child” in the state. Addiction to prescription opioids is a national epidemic, which is inspiring crisis solutions, as the CBS News reports, but opioids obviously have substantial therapeutic uses. Potential therapeutic uses beyond analgesia are described in this issue in two articles reporting studies of buprenorphine—one by Fava et al. (2), using buprenorphine adjunctively as an antidepressant, and the other by Yovell et al. (3), using it in ultra-low doses (0.1–0.2 mg/day) as a rapid treatment for severe suicidal ideation in patientswithout substance abuse. Buprenorphine is a partial mu-opioid agonist that unfortunately has been abused worldwide (4–6). The antidepressant potential of opioids has been known for centuries, but their dependence-producing properties led to the rapid adoption of new antidepressants once they became available in the 1950s, starting with monoamine oxidase inhibitors (7, 8). However, buprenorphine is a somewhat unusual opioid, and its unusual properties led to its becoming a very important treatment agent for over 3 million opioid-dependent patients in the United States since it received approval from the Food and Drug Administration (FDA) for this indication in 2002 (9). Its intranasal or intravenous abuse occurs at doses typically below 2 mg, at which it acts primarily as a mu-opioid agonist and kappa-opioid antagonist. However, as the dose is increased to 8 mg or higher, buprenorphine becomes a muopioid antagonist, such that in contrast to other opioids, it can precipitate withdrawal in individuals who are already opioid dependent, and it rarely produces overdoses. At these higher antagonist doses, in the range of 8–24mg sublingually daily, it has been a very effective treatment for opioid dependence by relieving withdrawal and craving while blocking other opioids and blocking even itself from producing overdoses (10). Interestingly, the Fava et al. depression study (2) implements the higher antagonist buprenorphine dose of 8 mg daily and combines it with a mu-opioid antagonist (samidorphan) to further focus on buprenorphine’s kappa-opioid antagonism rather thanmuagonism(11).However, theYovell et al. suicidal ideation study used a maximum buprenorphine dosage of 0.8mg/dayandstartedat0.1 or0.2mg/day,whicharedosages well into the range where analgesia and abuse can occur, particularly without including a concomitant mu-opioid antagonist. An important point is thatmu-opioid antagonists such asnaltrexonearenotabusedandhavenot shownantidepressant or suicide prevention effects (12). Thus, “clamping” basal endogenous mu-opioid tone into a more normal neutral range or simply kappa antagonism appear to be possiblemechanisms of action for buprenorphine’s efficacy in depression, as had been suggested by earlier work (13–16). Several pharmaceutical companies have new kappa antagonists in clinical trials. None of these kappa antagonists seem in danger of being classified by the Drug Enforcement Administration (DEA) as having abuse potential, while buprenorphine is a DEA schedule III agent. Thus, regulatory hurdles might be encountered with this new formulation of buprenorphine, as has been the case for ketamine’s use in depression. Thus, we are offered two new studies showing that buprenorphine can help treat a very common disorder—depression, which affects many patients whose illnesses are resistant to our current treatments. However, this opioid agonist has abuse liability and the potential to produce opioid dependence in opioid-naive patients, particularlywhen used at low intranasal doses. This intranasal abuse can be a gateway to opioid dependence among adolescents and chronic pain patients even with formulations that also contain an opioidantagonist suchasnaloxone.To reduce thepotential for intranasal abuse, two formulations other than pills have been developed: a mucosal film and a depot implant that is inserted under the skin (17, 18). The implant can deliver themedication formonths.Using either one of these technologies for delivery might vastly reduce the abuse liability during long-term outpatient dispensingwith take-home doses of the film for even a month. Using the depot implant would be impractical for initial dose adjustments over the first few days or weeks, but the mucosal film would certainly offer this adjustment potential. We therefore might have a new medication for addressing treatment-resistant depression. Its potential for producing opioid dependence remains to be determined in longer-term studies, but the diversion of buprenorphine from patients without substance abuse to the “doctor shoppers” who have prescription opioid use disorders seems less likely with these newly developed formulations. In contrast to the wildfire adoption of ketamine for acute depression, buprenorphinehasexcellent long-term safety data and has almost no possibility for overdose.