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Buprenorphine for Treatment-Resistant Depression

Posted by Rudiger on June 25, 2001, at 17:47:12

The following are excerpts from an editorial in the June 15th, 1996 issue of the journal Biological Psychiatry. The editorial outlines the (irrational) reasons buprenorphine is not used more often in cases of clinical depression that has not responded to every other available treatment.

Buprenorphine for Depression: The Un-adoptable Orphan

Buprenorphine [BPN] in low (circa 0.3 mg qid) transmucosally (under the tongue or by nose drops) can be dramatically effective in cases of treatment for refractory depression. Its safety and efficacy are not secrets, yet it has received little study and currently receives little clinical use.

Early in BPN's history, Emrich et al (1982) found it a potent antidepressant in drug-refractory depressives. Sporadic supporting reports have appeared in the literature from time to time since then. Most recently, Bodkin et al (1995) reviewed the literature and reported an open trial of 10 cases to further document BPN's value as an antidepressant. When the drug works, it works quickly. Bodkin et al say they see results within several days. We have found that most patients experience benefits of an adequate dose within three hours. The only intolerable side effects are nausea and dysphoria. The effects are seen in 10% to 20% of patients and are quickly obvious....

We have personally treated five patients with BPN in whom the results were impressive. Three were more or less typical cases of depression who had failed adequate trials with various treatments, including, in one case, a thorough course of ECT. Of the two less typical patients, one was a case of panic disorder with onset in childhood and what could better be called dysthymia rather than typical depression.... All five patients were followed for several years while good results were maintained.

Given BPN's availability and demonstrated efficacy, why is it so rarely used in treating depression? Therein hangs a tale. Reckitt and Colman Pharmaceuticals, Inc. [R&C] received their NDA to market BPN as a parenteral analgesic more than a decade ago. It appears that their grand strategy was to get BPN approved as an over-the-counter analgesic. It does indeed have a remarkable safety profile. At high doses, it produces less respiratory depression and cognitive obtunding than morphine, perhaps due to its antagonist action....

Addiction and tolerance are not serious problems. Patients who abruptly stop the drug complain of fatigue, dysphoria, upset stomach, and sometimes piloerection. This pallid imitation of narcotic withdrawal is generally not associated with craving, and indeed patients do not usually associate their symptoms with having stopped the drug until they experience the relief occasioned by restarting their treatment. There are reports of the drug being abused, but then some substace abusers will abuse almost anything. We were told that San Quentin stopped using white scouring powder because substance-abusing inmates were injecting it into themselves!

One handicap BPN has had as an antidepressant was the absence of any interest in that application on the part of the manufacturer. The idea of selling BPN as an OTC analgesic was not an unreasonable one, but it did not lead R&C to pursue work on the psychotropic properties of their drug.

It appears tha BPN can be used much as methadone is used in maintaining opiate addicts. While doses of up to 32mg have been used, doses in the order of 6 to 12mg seem best. Compare this to the 0.15mg to 0.3mg doses that are effective in depression. Several studies have reported that BPN is indeed effective in treating opiate dependence, although less so than methadone (Kosten et al 1993 and Strain et al 1994). However, BPN's use in treating addicts, plus the ominous "-norphine" suffix in its name, have been even more of a deterrent to BPN's exploitation as an antidepressant than has R&C's narrow focus on its analgesic applications.

Comparing BPN with classic mu agonist opiates is unfair. BPN is a derivative of thebaine, which has partial mu agonist and kappa antagonist activities. As a partial agonist, it seems to act as a mu antagonist at higher doses, and this provides some protection against it being used in escalating doses by substance abusers. In addition, in low doses it produces minimal or no euphoria. We have a little packet of reprints to send out to pharmacists who call accusingly and question why we are prescribing such a "dangerous narcotic."...

We have continually been frustrated by the resounding lack of interest our colleagues have shown in BPN as an antidepressant. In spite of some promising pilot work, Veterans Administration workers treating post-traumatic stress disorder have declined to study BPN because so many of their clients are substance abusers, and BPN is "narcotic-like."

We discovered that someone had contracted with Cygnus, Inc. to develop a BPN patch. That was accomplished, but the contracting company dropped the project. The developed BPN patch now sits on their shelf. However, after a few cordial lunches, Cygnus indicated they would need a million dollars up front to reactivate production of the patch for a clinical trial. Small business grants are limited to $100,000 to start, so that would not get Cygnus back into the BPN patch business. Also, treatment-refractory depression does not sound like an appealing market to business types. We are not sure the market is so small, and it has been suggested that as many as 20-30% of depressed patients may be treatment-refractory. But certainly, for a single physician, patient accrual is slow. While the patent on BPN has run out, orphan drug status might allow a company to be protected against competition while it recoups its investment and more. But so far there is little interest from industry.

Academia has been similarly uninterested, but with better reason. It's too bad that substance abuse takes a hight priority than depression in congress, but then what is one to expect. And our wildest fantasy does not have the National Institutes of Mental Health approving the trial of such an oddball drug for treatment-refractory depression. In our mind's eye we can see the pink sheet: Reviewer No. 1 says: "We already know that BPN works in depression, so why do it again?", while reviewer No. 2 says: "It's too much of a long shot in these times of short money."...

Research is the art of the possible, and none of us these days can afford to espouse lost causes. But your local pharmacist can dispense BPN without a triplicate, and even supply a syringe and needle so the patient can withdraw the drug form the vial and squirt it under the tongue. You will find it in the Physician's Desk Reference under the trade name "Buprenex" injectable, 0.3mg/ml. So even if the orphan remains un-adoptable, you might want to try BPN on an occasional drug-refractory depressive, and so keep it alive, at least in the lore of those who do tertiary psychopharmacology.

Enoch Callaway
University of California-San Francisco
Tiburon, CA


Bodkin JL, Zornberg GL, Lucas SE, Cole JO. (1995): Buprenorphine treatment of refractory depression. Journal of Clinical Psychopharmacology, 16:49-57.
Emrich HM, Vogt P, Herz. (1982): Possible antidepressive effects of opioids: action of buprenorphine. Annals of the New York Academy of Sciences, 398:108-112.
Kosten TR, Schottenfeld R, Ziedonis D, Falcioni J. (1993): Buprenorphine versus methadone maintenance in opioid dependence. J Nerv Mental Dis 181:358-364.
Strain EC, Stitzer ML, Liebson IA, Bigelow GE. (1994): Buprenorphine vs. methadone in the treatment of opioid-dependent cocaine users. Psychopharmacology 116:401-406.




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