Learning Objectives: After participating in this continuing professional development activity, the provider should be better able to:
1. Examine the negative impact of long-term opioid therapy for chronic pain management.
2. Evaluate the support care needs of patients who are tapering long-term opioid therapy for chronic pain management.
3. Analyze the findings from a study that investigated adverse effects associated with opioid tapering.
Long-term opioid therapy for chronic pain carries a broadly unfavorable risk/benefit profile and can lead to complex dependence issues, addiction, overdose, suicide, and a host of other adverse events. High-dose opioid therapy magnifies these risks.
Given the increasingly negative publicity and inadequate pain relief associated with long-term opioid therapy, many patients have opted to taper their opioid dosage-gradually or rapidly.
However, a recent study appears to confirm the fears of prominent opioid researchers that tapering itself can be a life-threatening experience for a disturbing proportion of patients. And this raises a pivotal question: Is it safe for most patients with chronic pain to embark on long-term opioid therapy at all?
This is one of the critical issues in the treatment of back and other forms of chronic pain in the United States going forward.
Alicia Agnoli, MD, and colleagues took a retrospective look at more than 113,000 chronic pain patients on "higher doses" of medically prescribed opioids. All had stable daily dosages of at least 50 morphine milligram equivalents (MMEs) per day.1
They compared the results of patients who tapered their dosages by at least 15% over a several-month period with people who did not taper at all.
The results are alarming. "Among patients prescribed stable, long-term, higher-dose opioid therapy, tapering events were significantly associated with increased risk of overdose and mental health crisis," according to the authors. The risk of overdose among the patients who tapered was almost double that of those who didn't.
"Prescribers are really in a difficult position. There are conflicting desires of ameliorating pain among patients while reducing the risk of adverse outcomes related to prescriptions," said Agnoli, in a statement from the University of California, Davis. "Our study shows an increased risk of overdose and mental health crisis following dose reduction. It suggests that patients undergoing tapering need significant support to safely reduce or discontinue their opioids."
Unfortunately, that level of support and care does not exist in most medical systems across the United States.
"Our study results support the recent federal guidelines for clinicians considering opioid dose reduction for patients,"2 said Joshua Fenton, MD, of the University of California, Davis. "But I fear that most tapering patients aren't receiving close follow-up and monitoring to make sure they're coping well on lower doses."
And there does not appear to be an easy way to identify patients at high risk of adverse outcomes from tapering. There has not been much research to identify safe tapering practices or which patients require special precautions, said Fenton recently via email.
"Both the Department of Health and Human Services and the Centers for Disease Control and Prevention guidelines acknowledge the limited evidence base. Each guideline suggests that patients should be tapered if the risks of opioid therapy outweigh the benefits. This risk-benefit is a clinical determination and would ideally be discussed and agreed upon by the patient and the physician. The rapidity of tapering is another area of uncertainty; our study suggests faster tapers may be more risky, but risks were increased even in patients with slower dose reductions, so caution and close follow-up are needed in all tapering patients," he added.
Pain researcher Jane Ballantyne, MD, has warned about the dangers of tapering long-term opioid therapy for more than a decade. She and her colleagues have emphasized that many patients on long-term opioid therapy develop what has come to be known variably as opioid dependence, complex persistent opioid dependence, or refractory opioid dependence. (There is no widely agreed-upon terminology in this area.)
"When opioids were first promoted as safe and effective treatment for chronic pain, the argument for safety relied on the [idea] that dependence would reverse within days, and the treatment could be easily stopped after a taper, if necessary. But experience does not bear this out," Ballantyne and colleagues noted in a 2019 article.3
"As the number of patients grows who have difficulty tapering their opioids despite poor pain control, the pain and addiction fields have moved closer to accepting that withdrawal from opioid pain treatment is not simple or easily reversed," they added.
In a 2019 commentary, Roger Chou, MD, Anna Lembke, MD, and Ballantyne warned that tapering and complex opioid dependence could become staggering problems for both patients and the US health care system.4
There are millions of patients on long-term opioid therapy in the United States. Some of these-a common, current estimate is 1.5 million-suffer from opioid use disorder (OUD), including addiction. However, a much larger group falls short of satisfying the criteria for OUD. Instead, they display complex dependence with serious but unpredictable risks.
As addiction specialist Lembke noted in a 2020 article in the BackLetter,5 "It is essential that we build an infrastructure inside the house of medicine to help the millions of patients struggling with opioid dependence. Public policy to date has addressed opioid addiction and prevention, but the large cohort of patients who are opioid dependent but not addicted has been left behind."
"Many of these patients are struggling with the adverse effects of long-term opioid therapy, including the risks of addiction and overdose death. They will need an infusion of resources to support tapering and provide alternative treatments for pain. This is not just an addiction crisis, it is a pain crisis, and I would add it is an iatrogenic opioid-dependence crisis. This latter group has fallen between the cracks of our public policy measures."
Is the New Study Consistent With Prior Research?
A BackLetter editor asked Chou whether the new study by Agnoli et al1 documents the scale of risks that he and his colleagues have warned about.
"I think the results of the study are consistent with others we've seen on increased risk of adverse events in people undergoing opioid discontinuation/tapering. I do think it's consistent with what we have noted in terms of the difficulty in tapering patients," said Chou via email.
What Proportion of People Who Attempt Opioid Tapering Have a Successful Result?
Tapering opioids appears to result in a significant dose reduction for most long-term opioid users who attempt it.
In a recent study,2 Joshua Fenton, MD, and colleagues looked at the opioid dose trajectory among 113,618 insured or Medicare Advantage patients who engaged in tapering during the period from 2008 to 2018. These were all patients who were taking "higher doses" of opioids at baseline-at least 50 MMEs per day.
"Tapering was defined as >=15% relative reduction in average MME/day during any of six overlapping 60-day periods in the initial 7 months of follow-up after the period of stable baseline dosing. Average monthly dose was ascertained during consecutive 60-day periods up to 16 months of follow-up," according to Fenton et al.2
Over two-thirds of the group achieved long-term opioid dose reductions of at least 15% of their initial dose. And the proportion who achieved significant dosage reductions increased over the course of the study.
However, it was not clear from this study what proportion of patients who reduced their dosages also avoided worrisome adverse events.
A BackLetter editor asked lead author Fenton how many patients had broadly successful outcomes, in terms of both tapering success and a lack of adverse events such as overdoses or mental health crises.
"This is a good question, and I can't give a precise estimate," Fenton responded.
"Overall, it must be the case that most patients can achieve long-term dose reductions without serious adverse events such as emergency or hospital visits for overdose or mental health crisis. The latter events occurred in fewer than 10 persons per 100 person-years in the tapering group of our study," he explained.
"These serious events therefore affect a minority of patients, but this is a concerningly high event rate. Probably most patients who taper have less severe adverse effects, but incident depression that does not result in an emergency or hospital visits may be relatively common.
"Indeed, if one were to account for less serious adverse events with tapering, such as mild withdrawal or milder mood effects, I suspect that most tapering patients will experience some of these effects. Hence, tapering patients need close follow-up and monitoring, especially for withdrawal symptoms or worsening mental health."
Unfortunately, that type of careful follow-up and monitoring may not be routinely available in many US healthcare settings.
"As the study notes, it's consistent with the US Department of Health and Human Services guidance on tapering-as well as guidance from the Oregon Pain Guidance group and others," according to Chou.
"Like other research on this topic, the study does have limitations, in particular not being designed or able to know the indication for tapering- and residual confounding," he added.
Chou is referring to the fact that this study was not able to determine why the patients decided to taper their opioid use in the first place. This, of course, might have influenced outcomes.
Residual confounding refers to the possibility that unmonitored factors besides the opioid tapering might have contributed to the overdoses and mental health crises.
Chou also pointed to the fact that both rapid and slow tapering appeared to increase the risk of adverse events. "Though there was some dose-response relationship between the speed of tapering and risk of adverse events, I think the fact that there was increased risk even with 'slower' tapers suggests that people undergoing tapering as a whole are in general at higher risk-not necessarily [just] due to the taper," according to Chou.
"We of course need more data to understand how to safely taper and factors associated with adverse events. And as Anna, Jane, and I (and others) have suggested, many patients with prescription opioid dependence may in fact do better if they are transitioned to buprenorphine," he asserted.
Buprenorphine can play a key role in "medication-assisted treatment" of opioid dependence and addiction.
In the wake of the pandemic, changes in the licensing and regulation of buprenorphine have made it more widely available. However, access is still uneven in many parts of the United States, particularly for those on the fringes of society.
There are millions of patients in the United States and Canada on long-term opioid therapy-many on high doses. And, despite a recent downturn in opioid prescription rates, US physicians still commonly prescribe opioids for people with back pain-particularly the elderly. This will be an ongoing problem.
Large Retrospective Study of Tapering Risks
To briefly describe the recent study, Agnoli et al1 used data from the OptumLabs Data Warehouse covering the period from 2008 to 2019.
The researchers included patients with stable, long-term, elevated levels of daily opioid use (>=50 MMEs per day prescribed for at least 12 months). The patients in the tapering group had a mean age of 57.7 years (vs 58.3 years in the nontapering group). A little more than half were women and 38.8% were commercially insured.
They divided the group into 2 cohorts: (1) those engaged in opioid tapering (at least a 15% relative reduction in mean daily dose during 6 overlapping 60-day windows within a 7-month follow-up period); and (2) those who did not taper their doses.
The main study outcomes were: (1) emergency department visits and/or inpatient hospital admissions for drug overdose, alcohol intoxication, or drug withdrawal; and (2) evidence of a mental health crisis (depression, anxiety, and/or suicide attempt).
The results were worrisome. Study subjects in the tapering group had 9.3 opioid overdose events per 100 person-years versus 5.5 events in the nontapering group.
And there was a similar bulge in mental health crises among those tapering off opioids. Men and women in the tapering group had 7.6 mental health crisis events per 100 person-years versus 3.3 events in the nontapering group.
Overall, "undergoing opioid dose tapering was associated with statistically significant risk of subsequent overdose and mental health crisis," according to Agnoli et al.1
"These findings suggest that adverse events associated with tapering may be relatively common and support US Department of Health and Human Services (HHS) recommendations for more gradual dose reductions, when feasible, and careful monitoring for withdrawal, substance use, and psychologic distress," they explained.
As mentioned earlier, patients on higher baseline opioid dosage had an elevated risk of adverse outcomes than those on lower dosages. However, as an accompanying editorial by Marc Larochelle et al6 pointed out, a series of sensitivity analyses suggested that the adverse effects were not confined to men and women who engaged in rapid tapering.
Every researcher consulted for this article recommended caution in tapering going forward.
Steady Increase in the Proportion of Patients Who Attempted Opioid Tapering Over a 9-Year Period
Tapering opioids is clearly on the rise in the United States, according to recent studies. In a 2019 study,7 Joshua J. Fenton, MD, and colleagues from the University of California, Davis, looked at trends in dose tapering-and the rapidity of tapering-from 2008 to 2017-among more than 100,000 commercial insurance and Medicare Advantage enrollees.
The proportion tapering daily dosages increased from 10.5% in 2008 to 13.7% in 2015 to 16.2% in 2016 to 22.4% in 2017.
However, many of these subjects tapered more aggressively than is currently recommended. "Among patients tapering daily opioid doses, the mean (SD) maximum dose reduction was 27.6% (17.0%) per month, and 18.8% of patients had a maximum tapering rate exceeding 40% per month."
This type of rapid tapering seems to put people on long-term opioid therapy at risk for significant adverse events such as overdoses and mental health crisis. "The downstream effects of opioid tapering on pain, withdrawal, mental health, and overdose risk warrant careful evaluation," according to the researchers.
The 2016 Centers for Disease Control and Prevention prescribing guideline cautioned against higher-dose long-term opioid therapy and recommended tapering daily opioid doses by approximately 10% per week or less if the risks outweigh the benefits.8
As Larochelle et al6 noted in their editorial in JAMA, "It is increasingly clear that opioid tapering needs to be approached with caution. In almost all cases, rapid or abrupt discontinuation should be avoided. Achieving the goals of minimizing risk yet also improving pain and function will require individualizing care and evidence-based approaches with more nuanced strategies that embrace the clinical complexity of the population of patients with chronic pain."
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