Interest in the possibility that depression (from today's point of view especially anhedonia and so-called anhedonic depression) might reflect opioid deficiency, began in the early 1980s, when two studies reported a temporary remission of depressive symptoms following injections of beta-endorphin, a non-selective endogenous opioid receptor agonist. However, number of contradictory findings were later published. Despite unique role of opioid signalling in mediating hedonic responses, research on the pharmacological role of opioid system has frozen. To date no studies have specifically evaluated opioid system in reward liking or other aspects of reward processing in major depressive disorder.
In your opinion, is it still possible that research on effective anti-anhedonic antidepressants will be in the future again targeted to the opioid system?
I think there should be research, especially with regard to endorphins. Obviously, exogenous opioids (kappa and mu-binding) are excellent anxiolytics and antidepressants, but have two big problems: (1) patients develop tolerance to them quickly and (2) the dose response curve goes flat at relatively low doses, not to mention the biggest problem of all, such treatment has historically resulted in tragic opioid addiction. So in terms of reality, that is, pharmaceutical companies sponsoring studies -- it would be very hard to get by an IRB in the US or HRA in the UK, or any ethics board anywhere. If I recall correctly the last such study was in the early 80s, at a prominent psychiatric hospital, with treatment refractive depressive (TRD) patients, and the results were a disaster. Oxycodone provided temporarily relief, but most of the patients became addicted to opioids. Which fate is worse? Both TRD and OUD can be lethal, but right now the "freeze" you mentioned is a result of the near-impossibility of conducting such studies because of (arguably quite valid!) ethics considerations. That said, these neurobiological pathways need to be better understood, as any clinician knows that you can (temporarily, and at the pt's peril) "cure" depression and anxiety with an exogenous opioid.
Well thank you! Opioid dependence is probably the biggest potential obstacle to such studies. But what about intravenous beta-endorphin? Do you think that the risk of addiction is comparable high also in its case?
Yes
Tramadol is immediately available off label.
I have had success with tramadol in certain patients with PTSD and also in a patient with severe, treatment-resistant, chronic (many year) depression. (The multi-year, severe depressive patient was not placebo responsive in that a multiplicity of other psychopharmacological agents failed to budge his mood). The PTSD patients I typically dose at about 100 mg daily, but the latter individual has been taking tramadol 250 mg daily for years with no decline is efficacy. However, he prophylactically goes off tramadol for a week once per year to retain sensitivity of the opioid component. Tramadol also has monoamine reuptake inhibitions effects, like classical antidepressants (if weaker in this respect).
Good comments by the way -- your original and the reply
β-Endorphin is a direct mu agonist, so I would guess there is substantial addiction risk with IV b-endorphin in pts, although I am not aware of any studies that have shown this.
Tramadol is probably the safest opioid option for treatment refractory pts, and I think merits further study. I would have the following questions:
(1) How much of the efficacy is from the serotonin reuptake inhibition (only slightly weaker than SSRIs, I think) and how much is from the opioid agonist binding? I would guess it is the latter.
(2) The long-term 250mg pt with "no decrease in efficacy" after years is particularly interesting. Is this supplemented with any prescribed or non-prescribed substances? (for example, OTC diphenhydramine can substantially "boost" the impact -- and morbidity/mortality risk -- of any opioid) Also, it would be interesting to how the prophylactic once-a-year week-long cessation is reducing tolerance sufficiently, and whether the pt experiences significant discomfort and/or resurgence of TRD during this week.
I'm sure both of you are aware of the OUD risks here, and are balancing them against the TRD/PTSD treatment benefits. I hope some statistically significant studies can be done on weak opioid-binding substances (like Tramadol) to see if *most* pts respond in the same way. As I said a few months ago, the studies with strong mu-agonists (e.g. oxycodone) that were done in the 80s "cured" the TRD but engendered OUD in many pts. I have not searched the literature, but I think off-label (weak) opioids for TRD is now relatively uncharted territory with the associated risks.
My personal opinion is that mu-binding opioid antidepressants will not be developed/marketed any time soon, but I'm glad to see that some pts are benefitting from cautious prescribing of weak mu-agonists.
Low dose buprenorphine has been used to treat depression off label with some success including in my patients.
That sounds interesting. Do you have any publications or paper about it?
I appreciated the debate about this question. In my view opioid action could be useful to alleviate psychological pain of the dépressive sindrome but not other clusters of symptoms ( anergia-apatia, lack of interest, lack of concentration and so on ). Indeed the opioid action could be very useful in some case but for me off label prescription would be too risky. What about if some patient get two problems ( opioid dependence and resistant depression ? ) . By the way, I listened to a BBC podcast ( " Inquiry" ) telling a huge problem of dependency with oxicodone.
I think it is worth mentioning here that the rapid antidepressant effect of ketamine is apparently also due to interaction with the opioid system, because it is blocked by naltrexone.
A small study showed that pretreatment with naltrexone (multiple brands), an opioid blocker, dramatically blocked the antidepressant effect of ketamine, suggesting that ketamine's acute antidepressant effects require activation of the opioid system.:
https://www.medscape.com/viewarticle/901338?nlid=124804_2052&src=WNL_mdplsnews_180831_mscpedit_psyc&uac=243637EZ&spon=12&impID=1727337&faf=1
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