Information on Vivitrol is controlled by manufacturer Alkermes, and questions about craving — does the drug reduce craving or not? — have been difficult to get answered. First (in 2006) it was approved to treat alcoholism, but once it was approved to treat opioid use disorders in 2010, the company targeted that market, especially the criminal justice population. It blocks the effects of opioids, but whether it reduces craving is more a matter of who is talking than science.

There are few groups in the addiction field who have not accepted Alkermes’ support, either for conferences or other projects. Top researchers conduct studies for Alkermes, and they do discuss it. But repeated requests to interview experts at the company, which is based in Ireland for tax purposes but with offices in Boston, have been met with suggestions that we talk to third parties — until now.

The impetus came from Mary Jeanne Kreek, M.D., who was quoted in the Frontline documentary on heroin that aired last month on PBS. Kreek, who worked with Vincent Dole and Marie Nyswander on the discovery of methadone maintenance treatment for opioid addiction, is with Rockefeller University in New York City. She said, “But for opiate addicts, they have a relative endorphin deficiency. To block their opiate receptors with [naltrexone or Vivitrol] makes them feel rotten 24 hours a day” (from http://www.pbs.org/wgbh/frontline/article/the-options-and-obstacles-to-treating-heroin-addiction).

Kreek’s comments hit a nerve, because they align with much of the feeling in the patient community. This time, when we asked Alkermes for a response, we got one: from Bernard Silverman, M.D., vice president of medical affairs at Alkermes: “The comment of relative endorphin deficiency resulting in negative subjective experiences in people with opioid addiction is not consistent with either the Vivitrol clinical trial data or the Vivitrol postmarketing experience. In our pivotal phase 3 trial for opioid dependence, adverse events corresponding to possible endorphin deficiency among Vivitrol-treated patients, as compared to placebo, were low. The postmarketing pharmacovigilance data is consistent with the clinical trial experience, with more than 100,000 people who have received Vivitrol for opioid dependence since approval.”

Kreek sticks by her assertion. “Long-term heroin addicts who are taken off methadone treatment have a relative endorphin deficiency,” she told ADAW last week, noting that this is “relative to what they needed, not an absolute deficiency.” Methadone, a full agonist, and buprenorphine, a partial agonist, both are replacements for heroin or other opioids. “Naltrexone is the opposite of a replacement treatment,” she said. “It blocks the body’s own endorphins.” Endorphins are naturally occurring opioid neuropeptides that occur in the body; by blocking these endorphins, naltrexone makes people who have an excess number of receptors due to constant opioid use feel uncomfortable. Instead of blocking their craving, it does the opposite.

She added that it’s impossible to measure cravings in humans with the physiological markers used in mouse models. Subjective feelings of craving, however, include “feeling as if you can’t concentrate, having sleep problems, frequent waking and different types of insomnia,” she said.

There is little interest among opioid-addicted patients in Vivitrol, said Kreek. However, the criminal justice system is very interested. “The people who are arrested — they’re the most vulnerable population, and they do what we tell them to do,” said Kreek.

Patient advocates’ views

Walter Ginter, project director of the Medication Assisted Recovery Support Project and in long-term recovery from opioid addiction, was on Vivitrol. “I hated it. As a medication it sucks,” he said. For a criminal justice population who have no choice but to take Vivitrol or be in jail or arrested, it might work, he said. “But that isn’t treatment!” he added. Ginter said that being on naltrexone is like craving for a month “knowing that there’s nothing you can do about it.”

Sam Snodgrass, Ph.D., a behavioral pharmacologist who is also in long-term recovery from opioid addiction, said that any drug that blocks opioids from its receptors results in a “non-functional opioid system,” which places people in a state of dysphoria. But evidence to back that up is hard to come by, he said.

Naltrexone has the highest affinity for mu-opioid receptors, and it has been known for some time that administering naltrexone causes up-regulation of these receptors. The work by Kreek and others has shown that naltrexone could inhibit down-regulation of opioid receptors by preventing binding by endogenous opioids.

“If we do not have a functioning opioid system, we are not normal,” said Snodgrass, who works at the CATAR clinic in Arkansas, which dispenses buprenorphine and methadone. “The choice of Vivitrol over methadone or buprenorphine is not a medical one, but a moral one, based on ignorance, the belief that we get high off of these medications,” he said. “We don’t get high — we get normal.”

Creating a “mythology”?

David Gastfriend, M.D., has a lot of insight into the development of Vivitrol to treat opioid use disorders. He and Kreek had conversations about Vivitrol when he was still at Alkermes. She was opposed to the company trying to get approval for opioid dependence and told him so. Now scientific advisor at the Treatment Research Institute in Philadelphia, Gastfriend shed some light on the craving issue.

First, he said that there has been no replication of Kreek’s findings on any permanent deficit of endorphin output of patients with opioid addiction. However, he said that there could be receptor deficits in the immediate post-withdrawal phase, and this could account for the discomfort alluded to.

“I think we’ve created a mythology to try to understand why people stay on methadone and buprenorphine for extended time periods,” he told ADAW. “So until Vivitrol we have convinced ourselves that there must be some vitamin-like deficiency that can only be relieved through opioids.”

Researchers at Columbia University in New York City have identified a proportion of patients on Vivitrol who have anhedonia, irritability and insomnia, said Gastfriend. But the researchers say “it’s just a matter of managing the extended withdrawal properly,” said Gastfriend. “Then, patients stabilize and do well.”

Conditioned response

Charles O’Brien, M.D., Ph.D., vice chair of psychiatry at the University of Pennsylvania, completely disagrees with Kreek’s assertion. “The first thing we saw in our naltrexone study at the Philadelphia VA was that it does reduce craving,” he said. However, he admitted that physiological measures of craving require brain imaging. O’Brien is one of the country’s top addiction researchers and has worked on several Vivitrol studies.

“Craving is a conditioned response,” he told ADAW. “It goes completely against the opioid addicted physicians and other educated patients I have treated since 1973 with naltrexone who don’t want to be dependent on an opioid. Not only do they not feel rotten, but those who start off depressed get an excellent anti-depressant response to depression treatment so we have double-blind clinical trial evidence for the efficacy of naltrexone in depressed alcoholics.”

Cultural, not physiological

Gastfriend also noted that in the recruitment for patients for the New York University study under John Rotrosen, M.D. (see ADAW, July 27, 2015), some sites are recruiting people who stick with buprenorphine, and some with Vivitrol. It’s dependent on the location. In Boston, most participants want to be on an agonist — buprenorphine or methadone. But at Gosnold on Cape Cod, which has a tradition of providing drug-free treatment — and where patients likely self-select for it — most want Vivitrol.

“It’s not a physiological issue; it’s a cultural issue,” said Gastfriend.

Vivitrol cuts craving in half, said Gastfriend, who believes all medications should be available to patients. It decreases craving in two ways — physiologically, by blocking receptors, and psychologically, by the fact that the person knows he can’t get high, even if he wanted to. But how effective this psychological effect is may be more tied into the patient’s desires and expectations — or the culture of the treatment provider — than how the medication actually works.