Opioid-Like Drug Limited Major Depression

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The use of opioids for treating depression is limited by abuse potential, but an investigational drug is showing promise in early clinical trials by providing the benefits of opioids while counteracting the mu opioid agonism thought to contribute to abuse potential.

ALKS 5461 combines buprenorphine, which is a partial mu agonist, and ALKS 33, a novel counteracting mu antagonist, Dr. Elliot W. Ehrich of Alkermes PLC, Waltham, Mass., reported at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

ALKS 33 was designed to provide minimally metabolized, highly potent, and sublingually bioavailable mu antagonism to allow for effective coformulation of the two agents. In an initial clinical trial, ALKS 33 at 10-mg and 20-mg oral doses completely blocked mu agonist effects of serial pulses of remifentanil in opioid-experienced volunteers. The effects were assessed by both physiologic measures such as pupilometry and subjective measures such as visual analogue scale assessment of drug liking and drug high.

The duration of blockade was greater than 24 hours following a single dose, Dr. Ehrich said. Subsequently, a drug-drug interaction study was performed to identify the ALKS 33 and buprenorphine ratio that would provide complete blockade. The findings showed that when administered together with 8 mg of buprenorphine, ALKS 33 caused partial attenuation of mu effects at a 1-mg dose, and complete blockade of mu effects at doses of 4 mg or greater.

In addition, a double-blind, placebo-controlled pilot study showed rapid efficacy of ALKS 5461 in 32 patients with major depressive disorder who failed to respond adequately to treatment with selective serotonin reuptake inhibitors (SSRIs) or selective serotonin-norepinephrine reuptake inhibitors (SNRIs), he said.

Patients were randomized to receive daily sublingual treatment with ALKS 5461 at an 8:1 ratio of buprenorphine and ALKS 33, which provided partial blockade of buprenorphine mu agonist effects, or a 1:1 ratio, which provided complete blockade of the effects. Patients continued on their SSRI or SNRI treatments.

Based on outcomes using the Hamilton Depression Rating Scale (HAMD-17) and the Montgomery-Asberg Depression Rating Scale (MADRS), efficacy was seen with both dose ratios at 7 days.
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read more @ http://www.familypracticenews.com/n...ression/42c91154e32e86af2484c21f3269b91c.html
 
I found a picture of ALKS 33 online...

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It's the one in the middle.
 
I thought the mu agonism was the key to the antidepressant effect.

Here's the extent of my knowledge base on this though: these three sentences from the Wikipedia article on buprenorphine:

Endogenous opiates, such as endorphins and enkephalins, mediate pain perception in the body. In the brain, they are significantly involved in regulating mood and behavior, and decreasing the perception of pain and depression. Even a partial agonist at the µ-opioid receptor (like buprenophine) releases serotonin and dopamine in the CNS, but to a lesser degree than full agonists do. This slight release of serotonin and dopamine may contribute to the anti-depressant properties of buprenorphine, especially those with a pre-existing mental disorder.
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And so then what is the mechanism of antidepression if mu receptors are entirely shuttered?
 
23536 said:
I thought the mu agonism was the key to the antidepressant effect.

Here's the extent of my knowledge base on this though: these three sentences from the Wikipedia article on buprenorphine:



And so then what is the mechanism of antidepression if mu receptors are entirely shuttered?
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Buprenorphine has a very complex action in the brain.

Buprenorphine has an extremely high binding affinity at the µ- and κ-opioid receptor. It has partial agonist activity at the µ-opioid receptor, partial or full agonist activity at the ORL1/nociceptin and δ-opioid receptor, and competitive antagonist activity at the κ-opioid receptor.
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http://en.wikipedia.org/wiki/Buprenorphine#Pharmacology_and_pharmacokinetics
 
I was in a research study a long time ago to test the abuse potential of suboxone and they gave massive doses of dilaudid, for this study they used remifentanyl, wonder how strong that stuff is and why not one of the other fent analogs or even fent itself.
 
So not sure i understand this completely but the point of the antagonist is sothat it lowers abuse potential of the agonist that helps with depression? If you can trust pain patients why can't you trust depression patients?
 
Sounds like it's some action of bupe other than mu agonism that helps with depression, so they block the mu opioid receptor (at least, I dunno how selective that antagonist is) to reduce addiction and side-effects.
 
My understanding of it, is that they are adding in the antagonist, so that buprenorphine can be an antidepressant, without causing mu-agonist induced euphoria.

You know, because giving a depressed person a reason to live would be a really, really bad thing or something like that. 8( :|
 
Do recall that mu agonism may cause side effects not "needed" in a depresant like chemical dependance, constipation, iiritability, memory loss etc.

If the pharmies can develop a drug that has the rapid antidepressant properties of opioids but without the dependence liability, all the more power to them.
 
I know with ultra low dose naltrexone (ULDN) the microgram usage of naltrexone can prevent tolerance and physical dependency from developing rapidly. Partial agonists already develop dependency more slowly, so possibly tossing in an antagonist can nearly negate it and also potentiating the effects of the agonist. If I remember correctly, bupe is a kappa antagonist, and kappa receptors are known for dysphoria (aside from oxycodone use), so maybe antagonism of kappa receptors has mood elevating effects. Also it's an epsilon opioid antagonist. I have no idea what the epsilon receptors do though.
 
thank you, very informative.
I still think you might as well give em a full agonist the euphoria might help depressed people although I can see why they thought the addiction potential outweighed it.
 
Maybe I'm odd but i don't find opiates to be of much use in treating depression or in my case bipolar depression. Sure if i take a shot of hydromorphone I'm going to feel real good for 5 minutes but that's about it and even that usually only works when I'm getting sick. I do find that they help stabilize my moods abit and stop the impulsive thoughts.

I would like to give bupe a try but since I'm on morphine for chronic pain i don't think that's really a option sadly.
 
Bupe is used for chronoc pain in some patients as the analgesia from bupe is quite high. There is temgesic (sp?) pills and patches along with buprenex which is injectable solution.
 
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