Opioid antagonists vs. agonists: A battle to fight addiction
Maybe it's that cigarette when you're having a drink with friends or that piece of chocolate you must have after lunch. Cravings come in all forms.
While a far cry from the addictive nature of opioids, many can get a sense of what seems like an uncontrollable need for a fix.
Alleviation of cravings is a key element setting one opioid abuse treatment apart from the others.
While the need for treatments becomes more urgent as the opioid epidemic grows, stigma about addiction has made it a hard space to crack, with few pharmaceutical companies interested. Alkermes plc's addiction treatment Vivitrol (naltrexone) is one of the few exceptions, standing out as an alternative to traditional means of treating addiction like methodone, which is habit-forming itself.
Elsewhere, the mounting numbers of overdoses encountered by first responders have boosted use of the reversal agent naloxone.
More than 23 million Americans are addicted to drugs and alcohol, and the economic impact on the healthcare system totals $700 billion annually, according to a recent report from trade group BIO. In 2016, over 42,000 Americans died from an opioid overdose, data from the Centers for Disease Control and Prevention show. Forty percent of those deaths involved a prescription opioid.
Despite the enormous societal cost, the report notes only 29 compounds in the pipeline for addiction treatment — 18 for substance abuse, five for alcohol addiction and three for smoking cessation. In oncology, by comparison, more than 2,600 programs are underway.
There are just four Food and Drug Administration-approved treatments on the market for addiction treatment, with another OK'd for use as an emergency reversal agent.
Vivitrol, an opioid antagonist, is one of the most well known. The drug works by blocking the uptake of endorphins to opioid receptors in the brain, thus limiting the ability to get high. First approved in 2006 for alcohol dependence, Vivitrol's label was expanded in October 2010 to include prevention of relapse from opioid abuse after detoxification. Six clinical studies have tested Vivitrol's ability to help control cravings more than other addiction treatments, and have shown patients have fewer cravings when on the opioid antagonist.
Naltrexone, Vivitrol's active pharmaceutical ingredient, was first approved in 1984 as a daily oral formulation for opioid addiction; it eventually lost patent protection and is available as a generic today. But uptake of the oral drug was minimal as patients weren't motivated to stay on it. Enter Alkermes plc, which used its long-acting technology to turn naltrexone into a once-monthly injectable, thereby addressing the adherence problem.
Growth of the product didn't happen overnight, though. In fact, it wasn't until opioid overdoses began to mount in the U.S. that the drug really found a niche.
Alkermes CEO Richard Pops will be the first to admit Vivitrol isn't a blockbuster. It brought in $2.6 million in 2007, its first full year on the market for alcohol dependence. Sales had increased slightly to $29 million by 2011 following the drug's approval to treat opioid addiction. But use of the drug didn't really tick up until 2017, when sales jumped to $269 million as the opioid epidemic reached national crisis levels.
"This drug was left for dead by our pharmaceutical company partner. We took it back. Wall Street said, 'Abandon it. You're gonna lose money on it,' " Pops said in an interview with BioPharma Dive.
The replacement therapies
The other drugs on the market for substance abuse treatment are opioid agonists, which work instead by essentially taking the place of an opioid and providing a less euphoric feeling.
Available since 1947, methadone was once the treatment of choice for drug addicts.
Subutex, better known by its generic name buprenorphine, was introduced to market in 2002 as an alternative treatment to methadone. But it was later found to be highly abusable.
In fact, the Drug Enforcement Administration and the Substance Abuse and Mental Health Services Administration have put a cap on the number of buprenorphine prescriptions.
Physicians are restricted to prescribing the drug to a maximum of 30 patients, but can apply to SAMHSA and have that cap increased to as many as 275. The limits were put in place because of the drug's abuse potential, although were eased slightly in 2016 amid the ongoing opioid crisis and the need for treatment.
Buprenorphine was later combined with the opioid antagonist naloxone, creating Suboxone and curbing its abuse potential. The naloxone component has no effect if the combo is taken orally as intended, but is meant to block the opioid receptors if injected, crushed or dissolved. Studies have shown, however, that for the medication to be effective it must be given in higher doses. Patients also need to stay on treatment indefinitely or risk relapse.
"Methadone and Suboxone are indicated for maintenance treatment of opioid dependency; so you're substituting the illicit opioid for a replacement opioid," said Pops in an interview.
Still, a 2017 study in The Lancet found Vivitrol and Suboxone were equally safe and effective in treating addiction.
"So [Vivitrol is] actually for a completely different patient than somebody that wants to be on a replacement medicine the rest of their lives," noted Pops, who pointed to examples of younger people who get addicted in college and don't necessarily want to stay on a replacement for the remainder of their lives.
Department of Health and Human Services Secretary Alex Azar recently called naltrexone the "best option" for treating opioid addiction for use in prisons post detox. But he added that HHS supports all forms of treatment.
Vivitrol is now used in approximately 630 criminal justice programs across 40 states.
No longer a street drug
Treating addiction and dependence isn't as straightforward as it may seem. Addiction of all kinds has always had a stigma attached to it. Some are quick to blame the user and suggest it's a problem of their own making instead of treating the addiction like a disease that needs treatment.
As opioid addiction in the U.S. continues to rise, the epidemic itself has evolved as well. Opioid abuse was once mostly abuse of illegal drugs like heroin and seen as a problem of "junkies" living on the street or criminals.
But more and more, legally prescribed painkillers like oxycodone have become the opioid of choice, with illicit fentanyl now increasingly being linked to overdose and death. The face of the opioid crisis has changed as well, with most of the deaths being young, white adults in rural parts of the country. A drug like fentanyl, which is used medically as an anesthesia, is now cheaper than heroin and easier to acquire illicitly.
Still, stigma persists and getting treatment to patients can be an arduous task. Most companies in the space are not marketing to patients or physicians, but instead are marketing to first responders, policy makers and caregivers.
In an emergency
Naloxone, another opioid antagonist, has increasingly become a tool in the response to the epidemic. The drug is mainly used in emergency situations to reverse the effects of an opioid overdose. While it was once only given as an injection, a nasal spray form was approved in early 2016. The drug, dubbed Narcan, is made by Opiant Pharmaceuticals Inc. and marketed by Adapt Pharma Inc. It is now approved in both 2 mg and 4 mg doses.
Opiant CEO Roger Crystal acknowledged in an interview with BioPharma Dive that Narcan can't save everyone. The drug needs to be administered immediately after an overdose once a patient stops breathing. This is typically the responsibility of the first responder, whether that be a police officer or EMT or even a family member.
The drug can be purchased at most pharmacies without a prescription and many states have programs that distribute it to law enforcement. From 1996 to 2014, more than 26,500 opioid overdoses in the U.S. were reversed by laypersons using naloxone, according to statistics from the National Institutes of Health.
Crystal noted the nasal spray option is much easier to use than the injection.
President Trump threw his support behind the drug's use on March 19 during a speech in New Hampshire, saying Narcan will be provided to schools to combat the opioid crisis.
And Vivitrol won't be the lone antagonist for addiction treatment on the market for long. Narcan developer Opiant currently has its own nasal spray version of naltrexone entering Phase 2 testing for alcohol dependence.
Elsewhere, the NIH is working to develop a vaccine against opioid addiction, according to recent research published in the Journal of Medicinal Chemistry. The compound, which is still in animal studies, showed it could stop the illicit substances from crossing the blood-brain barrier.
Editor's note: This story has been updated to clarify a quote from Richard Pops.
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