Update on Opioid Dependence and Its Treatment

While regulatory controls on methadone clinics for opioid dependence resulted in treatment being physically and functionally isolated from conventional medical care, the delivery of an office-based treatment of buprenorphine (Subutex) and the buprenorphine/naloxone combination product (Suboxone) over the past decade has facilitated the return of treatment to “mainstream medicine both for psychiatry and primary care,” said John A. Renner Jr, MD, Associate Professor of Psychiatry at Boston University School of Medicine.

During his presentation at the APA meeting, Renner discussed medications approved to treat opioid dependence, current efforts to enhance medication adherence through the use of novel formulations, and the influence of regulatory controls on clinical practice.

The US is in the midst of a very significant epidemic of opiate pharmaceutical abuse, warned Renner, who is also Director of the Addiction Psychiatry Residency Training Program at Boston University Medical Center and the VA Boston Healthcare System. 

According to the latest National Survey on Drug Use and Health (NSDUH), an estimated 7 million people used prescription drugs nonmedically in 2009 and 2010, second only to rates of marijuana use. Of those 7 million, 5.1 million engaged in nonmedical use of pain relievers, including the opiates oxycodone (OxyContin) and hydrocodone/ acetaminophen (Vicodin).

Also of concern, he said, is that “there is liberal prescribing of more potent opioids,” and that as many as 35% of individuals who receive legitimate long-term medical treatment for pain meet criteria for opioid addiction.

Approved treatment drugs
According to Renner, methadone, a synthetic opioid, was developed during World War II for analgesia.  The FDA approved it in 1947 for detoxification treatment of opioid addiction (heroin or other morphine-like drugs) and for maintenance treatment of opioid addiction.
 

In 2002, the FDA announced the approval of buprenorphine and a combination drug of buprenorphine and naloxone. According to the FDA, buprenorphine is intended for use at the beginning of treatment for drug abuse, while the combination drug is to be used in maintenance treatment of opiate addiction. Naloxone-an opioid antagonist-has been added to buprenorphine to guard against intravenous abuse of buprenorphine by individuals physically dependent on opiates. Both drugs are supplied in 2- and 8-mg tablets that are used sublingually.
 

In 2010, buprenorphine/naloxone combination became available in the form of a sublingual film (Suboxone Film), which is faster dissolving than the tablet combination. Each film strip is individually wrapped in a compact unit-dose pouch, with a 10-digit code printed on each pouch to facilitate medication counts and to deter diversion into the illegal drug market.

In 2010, the FDA also approved an extended release form of naltrexone, an opioid antagonist, administered by intramuscular injection (Vivitrol) to treat and prevent relapse after patients with opioid dependence have undergone detoxification treatment.¹ The injection is given once a month. 

Regulatory issues
“The biggest struggle with methadone revolves around the regulatory system,” according to Renner. “There are constraints on prescribing and limits on how to use the drug that really inhibit treatment in many significant ways,” he said. 
 

For example, most opioid-dependent individuals delay entering treatment for 4 or 5 years, primarily because regulations require that they come to the clinic every day to get their methadone. This inhibits higher functioning individuals from getting into treatment early, Renner explained. Methadone clinic regulations also require documentation of a one-year history of addiction, making it impossible to treat people in the early stages of addiction. Clinicians are placed in the “unfortunate situation of telling someone with a 3-month history of addiction to go away and come back in a year.

In contrast, physicians with proper training and certification have been allowed since 2002 to prescribe buprenorphine in their offices for patients to take home. Renner, along with Petros Levounis, MD, MA, wrote The Handbook of Office-Based Buprenorphine Treatment of Opioid Dependence to help psychiatrists and other physicians integrate buprenorphine treatment into their clinical practices. 
 

Another difference is that patients who receive buprenorphine must meet criteria for opioid dependence, but the dependence can be less than a year.  
 

The shift to physician offices has increased patient acceptance and facilitated earlier treatment, according to Renner. “Three times as many people are on buprenorphine long-term treatment as on methadone treatment,” he said. “More than 1 million people have been treated with buprenorphine.”
From a clinical perspective, Renner added, people are coming into treatment earlier, so many are easier to treat, less deteriorated, and responding better to treatment.

Benefits and cautions
Benefits for long-term treatment of opioid dependency with either methadone or the buprenorphine/naloxone combination include reduced use of heroin and other drugs, reduced criminal behavior, and improved social functioning.  
 

Renner cautioned that there is a very high relapse rate after termination of long-term treatment with either drug.  “We really need to adhere very strongly to chronic disease model,” he said.  “People do well in long-term treatment.”
 

Because methadone has a long half-life, physicians should be very careful about how they dose patients, and should go slowly.  It usually takes two to three weeks to get to the target dose of 80 to 120 mg per day, he said.
 

There is a need to identify patients who are either slow or fast metabolizers of methadone, according to Renner.  Slow metabolizers are at risk for overdose, since the drug will accumulate. In fast metabolizers, the dose doesn’t last 24 hours; they may go into withdrawal early in the morning and arrive sick at the methadone clinic or having used heroin. Federal regulations prohibit the administration of 2 methadone doses in the same day.
 

Cases of QT interval prolongation and torsades de pointes have been observed during treatment with methadone, particularly when given in higher doses. Patients with significant risk factors for QT prolongation should be closely monitored. These risk factors include having a history of cardiac arrhythmia or prolonged QT interval; having a family history of premature death; being older, and taking other medications that possess QT interval-prolonging properties
 

There is no known prolonged QT interval with buprenorphine. Thus the solution for patients experiencing or at risk for QT interval prolongation while taking methadone is to switch them to buprenorphine.
 

Renner explained that because buprenorphine is an opioid partial agonist, its maximal effects are less than those of full agonists, such as methadone. Respiratory depression from buprenorphine or the combination formulation is less likely than from other opioids. Also, he said, there is no evidence of significant disruption of cognitive or psychomotor performance with buprenorphine maintenance dosing. 
 

Both methadone and buprenorphine are safe and effective for use in pregnant women, Renner said.  But there are advantages with buprenorphine for the neonate. Jones and colleagues² found evidence from studies using a wide range of designs that prenatal exposure to buprenorphine resulted in less severe neonatal abstinence syndrome relative to methadone.

Counseling issues
With methadone treatment, clinicians learned over the years that counseling was very important, Renner said, and patients did much better if the counseling was provided by skilled psychotherapists. Yet in two studies involving buprenorphine, frequent physician medication monitoring was found to be equal to and more effective than intensive drug counseling. 

These findings reinforce the notion that seeing one’s private doctor regularly and getting 20 minutes of his or her time is a really powerful way of managing medications and may be more effective than manualized group therapy. Renner added that more research is needed on this issue.

References1. Krupitsky E, Nunes EV, Ling W, et al. Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial. Lancet. 2011;377:1506-1513.

2. Jones HE, Finnegan LP, Kaltenbach K. Methadone and buprenorphine for the management of opioid dependence in pregnancy. Drugs. 2012;72:747-757.