Use and misuse of opioid agonists in opioid addiction

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Although methadone (an opioid agonist) and buprenorphine (a partial opioid agonist) have evidence to support their use in treating opioid use disorder, they remain misunderstood and underutilized. In this article, we outline the risks and benefits of using these drugs as maintenance therapy in opioid-dependent patients.


  • Opioid use disorder is potentially lethal and has become more prevalent in the United States over the past few decades.
  • The opioid agonist methadone and the partial agonist buprenorphine are the currently recommended treatments for patients who need opioid maintenance therapy. However, they carry the risk of adverse effects (eg, respiratory depression, QTc interval prolongation, hepatotoxicity), diversion, and overdose.
  • Patients being considered for opioid agonist therapy need a comprehensive assessment including a thorough medical history and physical examination, psychiatric evaluation, psychosocial appraisal, and determination of readiness to change.
  • When methadone and buprenorphine are properly prescribed they confer significant benefits, including reduction or elimination of opioid use, reductions in overdose risk, and positive changes in behavior and lifestyle.



For a patient struggling with opioid addiction, opioid agonist therapy with methadone or buprenorphine can reduce craving and opioid use and may even save his or her life. But many clinicians are unfamiliar with this evidence-based treatment,1,2 which is best started early in the course of addiction.3

See related editorial

This article outlines the pharmacology of these drugs, their clinical uses, and the challenges of using them to treat opioid addiction.


Opioid addiction, formally known as opioid use disorder, is a pattern of opioid misuse leading to clinically significant impairment in multiple areas of life. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, lists 11 diagnostic criteria, but only 2 need to be present within the past year to make the diagnosis4:

  • Taking opioids longer or in higher doses than was intended
  • A persistent desire or unsuccessful efforts to cut down or control opioid use
  • Spending a great deal of time obtaining, using, or recovering from using opioids
  • Craving opioids
  • Repeatedly failing to fulfill obligations at work, school, or home due to opioid use
  • Continuing to use opioids even though it causes or exacerbates social or interpersonal problems
  • Giving up or curtailing important social, occupational, or recreational activities because of opioid use
  • Repeatedly using opioids in situations in which it is physically hazardous
  • Continuing to use opioids despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance
  • Tolerance
  • Withdrawal.

Recent estimates indicate that 2.23 million people in the United States have opioid use disorder (426,000 with heroin and 1.8 million with prescription opioids).5

Progression from prescription opioids to heroin

We have observed that many patients with opioid use disorder start by misusing prescription opioids. Over time, tolerance can develop, which drives patients to use higher and higher doses.6

As the addiction progresses, a subset of prescription opioid users advances to using heroin, which is typically less expensive and easier to obtain.7 Most patients start with the intranasal route but eventually inject it intravenously.6,7

For many addicts, heroin use has medical consequences such as hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infection, psychiatric problems such as depression and anxiety, and illegal activities such as theft and sex work.8 People who use heroin appear to have more severe addiction and a lower socioeconomic status than prescription opioid users.9–11 But recently, a growing number of middle class individuals are becoming addicted to heroin.12


Methadone is a long-acting synthetic opioid that functions as a full agonist on the mu-opioid receptor. The drug binds, occupies, and stimulates the receptor, preventing withdrawal symptoms and reducing opioid cravings for at least 24 hours.13

Adverse effects of methadone

The most common adverse effects include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating.14 Other adverse effects:

Unintentional overdose. The risk is serious, as a single 30-mg dose can be fatal in people who are opioid-naïve.13

QTc prolongation, which can lead to torsade de pointes. This risk, which is dose-related, must be taken into consideration in patients who have any cardiac symptoms (eg, syncope, arrhythmia), pathology (familial QT prolongation), or other risk factors for QTc prolongation (eg, hypokalemia, QTc-prolonging medications).15

Respiratory depression, which can be fatal. This dose-related risk is heightened during the first 4 weeks of treatment if titration is too rapid or if methadone is used in combination with other drugs that cause central nervous system or respiratory depression.13,14

Starting methadone

To prevent respiratory depression and death related to rapid induction, the general rule is to start methadone at a low daily dose (20–30 mg) depending on the patient’s withdrawal symptoms.14 During this period, patients need to be closely monitored and educated on the perils of concomitant use of central nervous system depressants.14

In most patients, the dose is titrated up until their withdrawal symptoms and cravings are eliminated, which generally requires 60 to 120 mg daily.14 Hepatic and renal impairment, pregnancy, and advanced age can alter methadone pharmacokinetics and may therefore necessitate dose adjustment.


Buprenorphine is an alkaloid thebaine opioid derivative that acts as a partial mu-opioid agonist and a kappa antagonist.16 Like methadone, buprenorphine is used to manage cravings and withdrawal symptoms.16 Dosages of 4 to 16 mg (up to 32 mg) per day of buprenorphine are usually required to adequately control opioid cravings.16

Sublingual and subdermal products

Buprenorphine is currently available in the United States in sublingual and subdermal formulations.16,17

Sublingual buprenorphine is usually combined with naloxone in a 4:1 ratio to deter intravenous use. Intravenous injection of the combination product can precipitate withdrawal due to the antagonist action of naloxone. (Taken orally or sublingually, naloxone is poorly absorbed and has little or no clinical effect.) Buprenorphine-naloxone is available in tablets, a sublingual film strip, and a buccal film strip. Buprenorphine is also available by itself in a sublingual formulation.

The US Food and Drug Administration has approved a buprenorphine subdermal implant, Probuphine. Four rods, about 1 inch long, are placed under the skin in the inner aspect of the upper arm and provide the equivalent of 8 mg of buprenorphine daily for 6 months.17 However, this method is formulated only for maintenance treatment and cannot be used for induction. Additionally, it is recommended that the implants be surgically removed at the end of 6 months, after which another set of implants can be inserted in the other arm or the patient can switch to sublingual therapy, depending on the clinical situation and patient preference.17

Generally safer than methadone

Buprenorphine works on the same receptor as methadone and therefore has a similar side effect profile. However, buprenorphine has a ceiling effect, which greatly reduces the risk of fatal respiratory depression.18 It also does not cause clinically significant QTc prolongation and is preferable in patients who have cardiac risk factors.18

Another advantage is that buprenorphine has fewer identified medication interactions than methadone.18 Further, induction of buprenorphine in patients with opioid use disorder has been shown to be safer than methadone.19

Although buprenorphine has been found to be 6 times safer than methadone with regard to overdose among the general population,20 it can still cause fatal intoxication if used in combination with central nervous system depressants.21

Buprenorphine has been also associated with hepatotoxicity, though the risk of new-onset liver disease appears to be low.22

Next Article:

A rational approach to opioid use disorder in primary care

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