Archive for the ‘new pill formulation’ Category

Buprenorphine for Depression: ALKS 5461


Many of my patients have asked me if their medication also treats depression, since they noticed a lifting of their mood after starting buprenorphine (Suboxone, Zubsolv) for the treatment of their opioid addiction. I told them I thought they felt less depression because their brains no longer are in the cycle of intoxication and withdrawal, and also because their life circumstances improved.

Maybe I’m wrong about this.

A new product containing buprenorphine may soon be marketed for depression, and by that I mean just depression, not addiction and depression. Alkermes, the same company that had a disappointment with their depot buprenorphine product last year, started Phase 3 studies last summer on their new product, ALKS5461, after their Phase 1 and 2 studies had positive results.

This product under study contains buprenorphine and a new opioid blocker owned by Alkermes, called samidorphan. In theory, the samidorphan blocks the opioid receptors, leaving only kappa receptors open to buprenorphine. Buprenorphine then attaches to kappa receptors, where it acts as an antagonist. Kappa receptors are usually acted on by dynorphins, opioid peptides that stimulate kappa receptors and cause depression. Dynorphins may also be involved in the stress response, so if buprenorphine can block these kappa receptors, theoretically mood would improve.

The phase 1 and Phase 2 trials of ALKS 5461 showed rapid improvement in the mood of patients already taking antidepressants. These were small studies but of relatively high quality, with double-blinding and placebo control, so Phase 3 studies were started quickly. We won’t know results of the phase 3 study for some time, since the study won’t be over until summer of 2016, so I wouldn’t expect data until 2017.

This new medication is being studied as an adjuvant to the treatment of depression, which means it’s not meant to be used alone, but with established medications in the SSRI (selective serotonin reuptake inhibitors like paroxetine, sertraline, etc.) and SNRI (selective norepinephrine-serotonin reuptake inhibitors like venlafaxine, etc.) groups. Alkermes hopes to get it approved for treatment-resistant depression.

Alkermes is also studying ALKS 5461 as a possible treatment for cocaine addiction, though no data are available on that yet.

Theoretically, this preparation wouldn’t cause opioid addiction because the buprenorphine will be blocked from attaching to the opioid receptor. That makes sense to me, but I also know people are very different. My biggest concern when reading about this new preparation is that real life isn’t as precise as we would like for it to be.

My big questions are: What if some of the patients get an opioid effect from the buprenorphine in the ALKES 5461 product? Do we know for sure that the blocker, samidorphan, will bind to every human mu opioid receptor? Are there genetic differences that will influence response and addiction potential? We already know that people who have major depressive disorder are at increased risk for addiction, and it would be bad if these people developed an opioid addiction while being treated for depression.

On the other hand, depression can be a devastating illness. This new medication will be intended for people who don’t get responses to currently available antidepressants. These patients probably feel desperate for any improvement in their mood, and are willing to accept the risk of unintended complications.

If the Phase 3 studies show good results and this medication gets approved to manufacture and market, it would be a novel way to treat depression. I’m fascinated to see what will happen.

New Opioids

I’ve blogged about states that have passed new laws addressing the prescribing of opioids, but the manufacturers of prescription opioids medications also have made changes to help reduce the potential for medication misuse. Of course, opioids will never be misuse-proof, but at least it’s a little harder to misuse some of the newer ones.

Oxecta is a new immediate-release brand of the drug oxycodone. It’s formulated so that it breaks into chunks when crushed, instead of a powder. When it’s mixed with water, it forms a gel so that it can’t be injected. This pill contains sodium laurel sulfate, a substance that irritates the nose if snorted.

Lazanda is a new delivery form of a very potent opioid, fentanyl. This brand is designed to be used as a nasal spray, which I would expect to be very addictive. The preparation itself has no anti-abuse features, but in order to distribute, dispense, prescribe, or be prescribed this medication, parties have to sign an agreement and be enrolled with the drug company. This extra scrutiny is hoped to deter diversion by distributor, pharmacy, doctor, or patient. Physicians must take a training program specific for this brand, and be enrolled with the drug company as a prescriber, or pharmacies can’t dispense to the patient.

Patients also need to complete a patient-prescriber agreement. Many people (like me) think doctors aren’t likely to jump through these extra hoops to prescribe this particular brand, when other brands of the same medication are already on the market, though not in the form of nasal spray.

Remoxy, another brand of oxycodone, hasn’t yet been FDA approved. Supposedly, it’s resistant to injection or snorting, and also has been formulated to be resistant to alcohol extraction.

Drug companies are now required by the FDA to have plans to evaluate and mitigate the risks associated with the opioid drugs they manufacture, particularly if they make sustained release or long-acting opioid preparations. This cooperation by drug manufacturers is a necessary part of turning the tide of opioid addiction in this country.

Last year, Purdue Pharma re-formulated OxyContin, making it more difficult to crush to snort or inject.  I noticed a sudden drop-off in patients entering treatment for pain pill addiction who said OxyContin was their drug of choice. During the years 2002 through 2007, nearly all of the opioid addicts I admitted to treatment said OxyContin was their preferred drug. It became obvious that the re-formulation made a big difference.

Addicts can and will still abuse these medications orally to get high, but the new formulations really do reduce abuse by making pills less likely to be snorted or injected.

The New OxyContin Formulation

Over the last three weeks, at least five of the opioid addicts I’ve admitted to treatment said they wanted help because they couldn’t abuse the new form of OxyContin.

 And I say: Hallelujah! It’s about time!!

 This new tablet, approved by the FDA in April of this year, appeared recently on the black markets of this area, replacing the older, more easily abused OxyContin. The new tablet is bioequivalent to the older tablet, meaning the same amount of oxycodone, the active ingredient, is available to the body when swallowed whole, as it’s meant to be. In other words, the same amount of pain reliever is given to the body. However, it’s more difficult to crush for the purpose of snorting or injecting, because it turns into a gummy ball.

Purdue Pharma, the drug company that makes OxyContin, admits this new formulation isn’t abuse-proof, but hopes it will be more resistant to abuse.

The patients I’ve talked to say the new tablet is a big disappointment. One patient, who usually chews her pill to get a faster high, said it was like trying to chew a jelly bean. Other patients said they could crush the tablet, but got a kind of gelatinous mess that was impossible to snort or inject.

 For pain relief, the opioid in OxyContin lasts much longer when it’s taken as directed and swallowed whole. Addicts prefer to crush and snort or inject because of the quick high they feel with this route of administration. But when used in this way, it leaves the body faster, and the addict usually needs to find more opioid within six to eight hours to avoid withdrawal.

Before I applaud Purdue Pharma for this change, my cynical mind asks a few questions: Why didn’t the company make this change earlier?

In 2002, a Purdue Pharma representative testified before congress, saying that the company was working on a re-formulation of OxyContin, to make it harder to use intravenously. This representative said they expected to have the re-formulated pill on the market within a few years. (1)  But it took eight more years.

Sterling, the drug company that makes Talwin, another opioid pain medication, was able to re-formulate their drug within a few years when they discovered it was being abused frequently. This was in the 1980s, when, presumably, medication technology wasn’t as advanced as today. Sterling added naloxone, an opioid blocker that’s inactive when taken by mouth, but puts an addict into withdrawal when it’s crushed and injected. It worked great. Talwin isn’t a commonly abused drug.

 I’m assuming that Purdue Pharma holds the patent for this new formulation that makes their tablet gummy when crushed. Purdue probably teaches its sales staff to market the new OxyContin as a safer option than older versions, perhaps available in cheaper generics. So did they wait to re-formulate until their patent was ready to expire? I don’t know, but time will tell.

At any rate, this drug is now just a little bit safer, for now. People with addictions are often clever and creative. I won’t be surprised if soon there’s a way to defeat this new technology.

Just think what addicted people could do, if they directed their talent and intelligence in ways that would help and not hurt them. There would be no stopping them.

1. United States Senate. Congressional hearing of the Committee on Health, Education, Labor, and Pensions, on Examining the Effects of the Painkiller OxyContin, 107th Congress, Second Session, February, 2002.