Opioid-Like Drug Limited Recalcitrant Major Depression

PHOENIX – 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.

"Hopefully (the findings) will ultimately enable broad utilization of opioid modulation in psychiatric disorders."

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.

"What was a little surprising to us was that we actually saw a greater reduction [in symptoms] with full vs. partial blockade," Dr. Ehrich said, adding that the patterns on MADRS scores were similar with both ratios, but "every patient on the full blockade ratio demonstrated a response."

Furthermore, treatment was well tolerated, he said. The most common adverse events were those typically seen with opioid treatment, including dizziness, nausea, vomiting, and sedation, which occurred more frequently with partial blockade.

These early findings suggest that the therapeutic effects of opioids in mood disorders can be decoupled from the mu agonist effects of drug high and euphoria, thereby "bringing the ‘opium cure’ into the 21st century in the context of the most pharmacologically rational and responsible way, and in the context of data from controlled clinical trials," Dr. Ehrich said.

Indeed, ALKS 5461 may represent a new rapid-onset treatment approach for depression and other psychiatric disorders, such as addictive disorder, he said.

A phase II study of the agent is underway in patients with major depressive disorder, and a cocaine-interaction study is also underway.

"Hopefully (the findings) will ultimately enable broad utilization of opioid modulation in psychiatric disorders," he said.

The ALKS 5461 studies were funded in part by the National Institute on Drug Abuse. Dr. Ehrich is employed by Alkermes, which is developing ALKS 5461.

PHOENIX – 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.

"Hopefully (the findings) will ultimately enable broad utilization of opioid modulation in psychiatric disorders."

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.

"What was a little surprising to us was that we actually saw a greater reduction [in symptoms] with full vs. partial blockade," Dr. Ehrich said, adding that the patterns on MADRS scores were similar with both ratios, but "every patient on the full blockade ratio demonstrated a response."

Furthermore, treatment was well tolerated, he said. The most common adverse events were those typically seen with opioid treatment, including dizziness, nausea, vomiting, and sedation, which occurred more frequently with partial blockade.

These early findings suggest that the therapeutic effects of opioids in mood disorders can be decoupled from the mu agonist effects of drug high and euphoria, thereby "bringing the ‘opium cure’ into the 21st century in the context of the most pharmacologically rational and responsible way, and in the context of data from controlled clinical trials," Dr. Ehrich said.

Indeed, ALKS 5461 may represent a new rapid-onset treatment approach for depression and other psychiatric disorders, such as addictive disorder, he said.

A phase II study of the agent is underway in patients with major depressive disorder, and a cocaine-interaction study is also underway.

"Hopefully (the findings) will ultimately enable broad utilization of opioid modulation in psychiatric disorders," he said.

The ALKS 5461 studies were funded in part by the National Institute on Drug Abuse. Dr. Ehrich is employed by Alkermes, which is developing ALKS 5461.

PHOENIX – 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.

"Hopefully (the findings) will ultimately enable broad utilization of opioid modulation in psychiatric disorders."

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.

"What was a little surprising to us was that we actually saw a greater reduction [in symptoms] with full vs. partial blockade," Dr. Ehrich said, adding that the patterns on MADRS scores were similar with both ratios, but "every patient on the full blockade ratio demonstrated a response."

Furthermore, treatment was well tolerated, he said. The most common adverse events were those typically seen with opioid treatment, including dizziness, nausea, vomiting, and sedation, which occurred more frequently with partial blockade.

These early findings suggest that the therapeutic effects of opioids in mood disorders can be decoupled from the mu agonist effects of drug high and euphoria, thereby "bringing the ‘opium cure’ into the 21st century in the context of the most pharmacologically rational and responsible way, and in the context of data from controlled clinical trials," Dr. Ehrich said.

Indeed, ALKS 5461 may represent a new rapid-onset treatment approach for depression and other psychiatric disorders, such as addictive disorder, he said.

A phase II study of the agent is underway in patients with major depressive disorder, and a cocaine-interaction study is also underway.

"Hopefully (the findings) will ultimately enable broad utilization of opioid modulation in psychiatric disorders," he said.

The ALKS 5461 studies were funded in part by the National Institute on Drug Abuse. Dr. Ehrich is employed by Alkermes, which is developing ALKS 5461.