Why Aren’t There More Medications for Substance Use Disorders?

According to the Centers for Disease Control and Prevention, more than 33,000 people died from opioid overdose in the United States in 2015—one of many signs of the rising trend in opioid abuse.

iStock/smartstock

“Whether it is the rapid rise of prescription opioid addiction or the longstanding challenge of alcohol dependence, substance misuse and substance use disorders can—and do—prevent people from living healthy and productive lives,” U.S. Surgeon General Vivek Murthy, M.D., M.B.A., wrote in the preface of the report “Facing Addiction in America” released in November 2016. This report was the first by a Surgeon General calling attention to the growing numbers of Americans with substance use disorders and the public health consequences associated with alcohol and drug use.

Despite the increasing demand for addiction treatment and wide recognition that addiction is a neurological disease, pharmaceutical companies do not seem to be rushing into the realm of addiction research. Several factors may be largely to blame, said Phil Skolnick, Ph.D., director of the Division of Therapeutics and Medical Consequences at the National Institute on Drug Abuse (NIDA).

“Drug development is inherently risky, and there are few successes and many failures,” he told Psychiatric News. For a long time, the industry has had the perception that pharmacotherapies for addictive disorders are unlikely to provide a large and profitable market, he explained. “It’s not true,” Skolnick pointed out, “but that’s the perception.”

No new molecules were approved for any type of substance use disorders in 2016. There are currently five FDA-approved medications for treating substance use disorder—methadone and buprenorphine for opioid use disorders, acamprosate and disulfiram for alcohol use disorders, and naltrexone for both opioid use and alcohol use disorders.

Methadone, naltrexone, and buprenorphine—all of which interact with opioid receptors—have been the mainstay of medication-assisted treatment for opioid dependence for decades. As buprenorphine has become more popular in recent years, more companies have started to explore alternative formulations of the medication that require less frequent follow-up.

In May 2016, the FDA approved the long-acting buprenorphine implant (Probuphine), which has a duration of action for six months. A monthly subcutaneous depot injection of buprenorphine is being developed by Indivisor PLC, a spinoff from Reckitt Benckeiser and the maker of Subutex and Suboxone tablets. The company announced positive results from a phase 3 clinical trial in August 2016 and is planning to file a new drug application with the FDA in 2017. In addition, Insys Therapeutics is developing a sublingual spray formulation for buprenorphine, naloxone, and a combination of both drugs.

For newer medications to treat opioid withdrawal, the company US Worldmeds LLC, in collaboration with NIDA, is currently testing lofexidine—an antihypertensive medication that has been available in United Kingdom for treating opioid withdrawal for years—in a phase 3 trial. Like clonidine, which is often used in detoxification of opioid addiction, lofexidine inhibits the heightened noradrenergic activity associated with opioid withdrawal and relieves associated symptoms.

Similarly, a class of molecules, known as peroxisome proliferator-activated receptor (PPAR)-gamma agonists, is being explored for the treatment of substance use disorders. Two small clinical studies showed that a PPAR-gamma agonist reduced cocaine and heroin cravings in patients with cocaine use disorder and heroin use disorder, respectively, according to announcements by Omeros Corporation. In collaboration with NIDA, Omeros is testing PPAR-gamma agonists for multiple substance use disorders, including opioid addiction.

According to Skolnick, NIDA is also working with AstraZeneca to study a type 2 metabotropic glutamate receptor (mGluR2) modulator, known as AZD8529, in a phase 2 trial for smoking cessation, with potential implications for other substance use disorders. The drug was originally developed to treat schizophrenia but failed to show efficacy in clinical trials.

Other researchers are examining the possibility that vaccines may offer protection from drugs of abuse. An article published in Angewandte Chemie in February 2016 described the development of a vaccine that binds to and blocks the effects of fentanyl, a synthetic opioid. This vaccine was developed by researchers at the Scripps Research Institute, led by Kim Janda, Ph.D., a professor of chemistry. Janda also developed a vaccine against heroin that has been tested in animals. According to the report, mice administered the fentanyl vaccine “gained significant protection from lethal fentanyl doses.”

Efforts are also underway to identify new options for patients with alcohol use disorder. Researchers at the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and AbbVie Inc. in October 2016 published encouraging results from a phase 2 study of ABT-436, a vasopressin 1b receptor antagonist. They found that patients with alcohol use disorder who took ABT-436 for 12 weeks had a significantly greater number of days abstinent compared with placebo. NIAAA is also conducting clinical trials on nalmefene tablet, an opioid antagonist that was approved in Europe in 2013 to reduce drinking in alcohol-dependent patients. Nalmefene is currently available in the United States only as an injectable drug used to reverse opioid overdose.

To date, no medications have been approved for the treatment of cocaine, methamphetamine, or marijuana use disorders—a factor Skolnick attributes in part to the challenges associated with conducting such trials with patients who often have low rates of adherence.

He cited a recent study of TV-1380—a recombinant enzyme that causes cocaine to be rapidly metabolized in the body before entering the brain—which was co-funded by Teva Pharmaceuticals and NIDA. While the treatment led to a small reduction in cocaine use, the effect was not considered large enough for the company to recommend the drug for further development.

Despite the limited number of new candidates, the development of medications for substance use disorder may soon get a boost. The 21st Century Cures Act, signed into law on December 21, 2016, allocates $1 billion for the prevention and treatment of opioid addiction over the next two years. The law also contains provisions aimed at stimulating more and faster new drug approvals by the FDA. “If the act is implemented as intended, it might send the industry back into the field,” said Skolnick. ■