Access to the PPM Journal and newsletters is FREE for clinicians.
17 Articles in Volume 20, Issue #3
20/20 with Dr. Suzanne Amato Nesbit: Clinical Pharmacy Roles and Disparities
A Clinician’s Guide to Treating Chronic Overuse Injuries
Adhesive Arachnoiditis: No Longer a Rare Disease
Analgesics of the Future: Cebranopadol as an Opioid Alternative
Ask the PharmD: What role do vitamin D supplements play in treating dysmenorrhea?
Behavioral Pain Medicine: Managing the Affective Components of Pain
Chronic Fatigue Syndrome: Naltrexone as an Alternative Treatment
Chronic Pain and Coronavirus
Connecting the Dots: How Adverse Childhood Experiences Predispose to Chronic Pain
Editorial: Why Are ER Opioids Out of Favor?
Fibromyalgia as a Neuropathic Pain Disorder: The Link to Small Fiber Neuropathy
How the COVID-19 Pandemic Is Transforming Pain Care
Hydroxychloroquine Use and Risk in the Management of Systemic Lupus Erythematosus
Management of Trigeminal Neuralgia in Multiple Sclerosis
Optimizing Care Using a Trauma-Informed Approach
Pediatric Pain Management: A Review of Clinical Diagnosis and Management
The Use of Low Dose Naltrexone in the Management of Chronic Pain

Editorial: Why Are ER Opioids Out of Favor?

Pain management and addiction medicine expert Jennifer P. Schneider, MD, PhD, makes the case for the return of extended-release opioids.
Pages 6-8

Extended-release (ER) opioids are increasingly viewed as an inappropriate treatment for chronic pain. At a community health clinic visit earlier this year, I was told that their physicians are currently discouraged from prescribing ER opioids. If physicians insist on ER formulations from time to time, then the only one easily available to their patients is generic ER morphine; otherwise providers need to spend time on substantial paperwork, with an uncertain outcome.

How can this be? For decades, clinicians have had extensive experience with prescribing ER opioids for chronic pain and, in most cases, have found them to be effective and not dangerous. I would argue that the reasons given for avoiding ER opioids are often invalid and based in misunderstanding. Herein, I also review some of the benefits of ER opioids as compared to immediate-release (IR) products.


Pain specialists who prescribe opioids have a great deal of evidence for the long-term efficacy of opioids. (Image: iStock)

Possible Explanations for Preferring IR Formulations


The Acute vs Chronic Argument

Clinicians have been told that IR opioids are preferred for acute pain, but that for ongoing pain we should switch to an ER formulation. However, there is no evidence that opioids, in general, are effective for chronic pain; thus, there’s no reason to switch.

The reality: There has been very little interest in initiating long-term studies of opioids. Most studies follow patients for perhaps 3 months, with extension trials up to a year. In contrast, pain specialists who prescribe opioids have a great deal of evidence for the long-term efficacy of opioids. One of the very few long-term studies, published 10 years ago and based on my clinical experience,1 described a cohort of 197 patients who had been maintained on high-dose opioids (less problematic a decade ago) for a range of 1 to 12 years (mean: 4.5 years). The patients were stable; most were functional; and only 6.6% had been discharged or weaned during this period.

According to a 2016 editorial in NEJM, “Groups lobbying against prescribing opioids for chronic pain remind us that the effectiveness of long-term therapy has been inadequately studied. I believe that this is a case of absence of evidence rather than evidence of absence."2 The authors made an important distinction: The reason that “there is no evidence” is simply because no one has actually looked into this practice.

In the Krebs SPACE Trial,3 published in JAMA in 2018, 240 patients with persistent chronic hip or knee OA-
related pain who had not been treated with opioids were randomized either to receive opioids for a 12-month trial or not. The outcome showed no benefit in either function or pain. The widely publicized conclusion was: “Results do not support initiation of opioid therapy for moderate to severe chronic back pain or hip or knee osteoarthritis pain.” The authors also emphasized that the opioid-treated group had more side effects such as nausea and constipation. Instead, they favored non-opioid medications such as NSAIDs.

However, a recent closer look at the methodology of this study has revealed several deficiencies.4 For one, the printed article surprisingly did not provide the actual opioid dosage; the data available only online showed a mean dose of only 21 MME (equivalent to three 5-mg oxycodone/day). These low doses skewed the outcome against getting a significant benefit from opioid treatment. Additionally, the study did not track NSAID-associated toxicities such as elevated blood pressure, GERD, GI bleed, or kidney dysfunction. A mean dose of perhaps 50 to 60 MME would have given more meaningful results. Fudin further outlines this study’s flaws.5

The Opioid Argument

Extended-release opioids generally contain higher quantities of opioid, and, therefore, must be more dangerous. To prove this, a widely cited study concluded that patients taking ER opioids have a higher risk of opioid-related deaths than do patients taking only IR opioids.

The reality: A widely cited 2015 study in JAMA compared overdose deaths in a group of patients on ER opioids with another group on IR opioids, and concluded that ER opioids result in more overdose deaths.6

However, a group of experts who evaluated the methodology reported that “patients receiving ER opioids tend to be on higher doses and are sicker, with many comorbidities. Often, they are also on other drugs, including benzodiazepines, compared with acute pain patients on IR opioids, who might otherwise be young and healthy."7 In other words, the two compared groups were different in several ways, demonstrating that the JAMA study did not in fact prove that ER opioids per se are less safe or that the same dose in IR formulation is safer. Of consideration, on the other hand, is that illicitly obtained, non-abuse deterrent ER products, when crushed, do provide a higher immediate dose (see more below).

The Addiction Argument

Taking opioids for more than a few days results in a very high risk of addiction: Another widely cited study found that 90 days after a group of chronic pain patients were begun on opioids, the risk of addiction was approximately 15 times the risk of a control group of chronic pain patients who were not begun on opioids.8 The authors concluded that this study shows a “substantially higher odds of developing opioid use disorder (OUD, that is, addiction).”

The reality: The 15-fold risk represents an “odds ratio”– the ratio of the odds of the opioid-treated group compared to the odds of the control group – which was not treated with opioids. The relevant question should be: “What percent of the treated group developed de novo addiction after 90 days?” The answer was 0.72%. The reason the odds ratio was so high was the risk of de novo addiction in the untreated group was extremely low. Thus, what this paper actually showed was that, after 90 days of opioid treatment, the risk of new addiction was less than 1%.

The most likely reason that so many people believe the risk of addiction after opioid initiation is extremely high is that they confuse two different concepts, addiction (now termed OUD) with physical dependence. A person is considered physically dependent on a drug or substance if he experiences a specific set of withdrawal symptoms when the drug is stopped. This is true of almost all patients who have been on more than 60 mg MME for more than a month or so.

In contrast, addiction is present when a person has lost control over use of a drug (or behavior), continues despite significant adverse consequences, and his relationship with that substance has become his highest priority.9 (See my prior editorial on the terminology of opioid addiction and dependence.)

National Institute on Drug Abuse Director Nora Volkow, MD, has written, “Addiction occurs in only a small percentage of people who are exposed to prescription opioids, even among those with preexisting vulnerabilities.” She estimates a less than 5% risk.10

The Cost Argument

Generic IR opioids are less expensive, milligram for milligram, than the ER versions of the same drug.

The reality: This argument holds up, and it is a big reason that insurance companies resist paying for ER opioids, supporting such a decision by citing the above explanations.

The Real Benefitsof Extended-Release Opioids

Since an ER opioid does not provide better analgesia than the same dose of the same IR opioid, why and when are the ERs preferred?

Less Clock-Watching, More Sleep

As summarized by Argoff,11 “ERs have better adherence, less clock-watching, better sleep, and are less likely to produce euphoria.”

Because each dose lasts longer, patients on an ER formulation will less frequently experience “end-of-dose failure,” meaning that the analgesia wears off, leading to desperate waiting for it to be time to take the next dose. On the flip side, with an ER formulation, they are less likely to miss a dose, as there is less need to always have the pill bottle with them.

Finally, because immediate-release morphine- and codeine-related opioids have a duration of action of about 4 to 6 hours, patients on an ER opioid (which typically last 8 to 12 hours, 24 hours, or 2 to 3 days) are less likely to awaken in the middle of the night with pain; a bed-time dose will last until morning. It is worth stating that, while ER opioids generally help patients to obtain a full night’s sleep, it is difficult to compare the effect of either product on actual REM sleep.

Less Euphoria, Lower Street Value

The reason that opioid addicts prefer to inject opioids rather than take pills and that marijuana users prefer to smoke rather than eat pot is that the former method gets the drug into the brain faster. The consequence of this was explained in the Diagnostic and Statistical Manual of Mental Disorders: “Routes of administration that produce more rapid and efficient absorption into the bloodstream (eg, IV, smoking, ‘snorting’) tend to result in a more intense intoxication and an increased likelihood of an escalating pattern of substance use…. Similarly, rapidly acting substances are more likely than slower-acting substances to produce immediate intoxication."12

The faster a drug reaches brain, the more likely it is to produce mood changes such as euphoria. This speed is why drug addicts prefer to crush pills and inject or inhale them rather than swallow many pills. When in 2010 the first ER oxycodone (OxyContin) was changed to a crush-resistant formulation, its street value plummeted. Many addicts then transitioned to heroin (now laced with fentanyl), which is much less safe, and, coupled with other factors, the opioid overdose crisis took off. Currently, most ER opioids have abuse-deterrent properties and are crush-resistant, whereas IR opioids are more likely to be diverted. IR oxycodone tends to be worth about $1 per mg on the street.

Because ER opioids are less likely than IR opioids to produce mood changes, I contend it is in the best interest of chronic pain patients who have a history of opioid addiction but can benefit from opioids, to be prescribed only an abuse-deterrent ER formulation or a patch. (If the addiction history is recent, it is wise to refer the patient to a pain and addiction specialist).

Prescribers who attempt to transition chronic pain patients after months or years on an IR opioid (eg, 10 or 20 mg IR oxycodone qid) to the same dose in an ER formulation sometimes report that the patient resists the change. This response can be true for compliant patients for whom diversion or addiction is not an issue. A possible explanation is that they may have a previously undiagnosed depression, and that these patients, in addition to getting pain relief for whatever pain they were experiencing, were also inadvertently getting chemical help for their depression.

Psychiatrist Anna Fels’ 2016 opinion piece in the New York Times, titled “Are Opioids the Next Antidepressant?” provides evidence for why she supports this possibility.13 What this implies is that there may be a cohort of patients who were initially treated for acute pain, who may no longer need chronic opioids for pain relief, but resist getting off their IR opioids because they feel better on it. Users do not experience euphoria, but rather, less depression, unaware that the opioid is now serving to treat their depression. Such patients might be better served by psychological counseling and, if needed, non-opioid antidepressants. Early transition to ER opioids may avoid this resistance.


The Federation of State Medical Boards has advised, “When initiating opioid therapy, the lowest dose possible should be given and titrated to effect. It is generally suggested to begin opioid therapy with a short-acting opioid and rotate to a long-acting/extended-release if indicated."14

In addition, clinicians need to remember that pain is not uniform. Most patients with chronic conditions experience “break-through pain,” which may be caused by temporarily increased activity, by emotional experiences, weather, disease progression or flare-up, and sometimes for no obvious reason. For patients with round-the-clock pain, ER opioids are sometimes preferable to IR. In many cases, patients benefit from a combination of timed ER doses supplemented as needed with IR opioid doses.

In my view, IR opioids generally should be used when initiating pain treatment, but ongoing opioid treatment should usually involve transition to ER formulations. Notwithstanding, the package insert for some ER opioids (eg, ER morphine, Butrans, Nucynta) reflects FDA indications such that low doses may be prescribed for chronic pain as an initial prescription without regular use of an IR opioid prior to initiation of the ER product.

Last updated on: June 18, 2020
Continue Reading:
What’s In A Name? In This Case, That Which We Call Addiction Is Not Dependence
close X