Weighing the Benefits of Long-term Opioid Use for Pain Management

Review

No evidence for use of long-term opioid pain medications: Ann Intern Med. 2015 Feb 17;162(4):276-86.

This systematic review was performed and funded by the Agency for Healthcare Research and Quality to evaluate the evidence for the use of opioid pain medications of greater than three months duration in patients with chronic pain.

Study Methods

Inclusion criteria were studies of adults (³18 years old) with pain of >3 months duration who had been prescribed opioids for long-term use, which was defined as use on “most days >3 months.” Studies included also consisted of those of opioid therapy versus placebo, no therapy, another drug, or nondrug therapies in addition to studies of risk-mitigation strategies and varying dosing strategies, looking for answers to the key questions for the review. These included: effectiveness for pain, function, and quality of life; risks, including abuse, addiction, overdose, falls, fractures, motor vehicle accidents, endocrinological harms, and cardiovascular events; accuracy and effectiveness of risk mitigation strategies.

A total of 40 publications met inclusion and exclusion criteria. Unfortunately, no articles evaluated effectiveness of long-term therapy for >1 year or effect of risk-mitigation strategies. 19 studies evaluated harm, 17 evaluated different dosing strategies, and 4 evaluated the accuracy of risk assessment instruments.

Results

While no studies were available to evaluate the benefits of long-term opioids, many studies were available that evaluated harm. Multiple adverse outcomes were determined to be present at different morphine equivalent doses (MED), which is defined as: “the dose and route of an opioid the patient has received over the last 24 hours to a parenteral morphine equivalent.”

Rates of opioid abuse or dependence ranged from 0.004% in those without an opioid prescription to 0.7% with MED of 1 to 36mg/day, (OR 14.9 [95%CI 10.4-21.5]), and a rate of 6.1% with MED of >120mg/day (OR 122.5 [95%CI 72.8-206]). Prevalence of misuse/abuse also varied between settings, having greater likelihood in pain clinics compared to primary care clinics (8-16% and 0.6-8.0%, respectively).

The risk of any overdose was increased in a dose-dependent fashion such that with a MED 20 to 49mg/d, the adjusted HR for overdose was 1.44 (CI, 0.57-3.62), and a MED ³200mg/d, the adjusted HR was 8.87 (CI, 3.99-19.72) when compared to a MED <20mg/d.

Fracture risk was increased in patients taking opioids versus those not using opioids (n=21,739, adjusted OR 1.27 [CI, 1.21-1.33]). Opioid use was associated with increased use of testosterone replacement or erectile dysfunction medication (n=11,327, adjusted OR 1.45 [CI, 1.12-1.87]), and an increased risk of motor vehicle accidents with MED ³ 20mg/d (n=5300, OR 1.21-1.42). Risk of myocardial infarction was also elevated with opioid use versus no opioid use (n=297,314, adjusted incidence rate ratio 2.66 [CI 2.3-3.13]).

Results of different dosing strategies between short-acting and long-acting opioids were inconsistent. In a head-to-head study, methadone (n=28,554) appeared to have lower risk of all-cause mortality compared to morphine (n=79,938, adjusted HR 0.56 [CI 0.51-0.62]), but this result was inconsistent with results from another retrospective cohort study (n=5684), which showed no significant difference for the same outcome.

Risk assessment instrument studies identified were of fair to poor quality and reported inconsistent results of the 10-item Opioid Risk Tool, resulting in a wide range of both sensitivities and specificities. The 14-item Screener and Opioid Assessment showed similar inaccuracy.

Conclusion

No evidence is currently available to show benefit in pain, function, or quality of life with the use of long-term opioid pain medications. Furthermore, increased risks of using chronic opioids were identified including abuse, addiction, overdose, fractures, hypogonadism (males), motor vehicle accidents, and myocardial infarction.

Discussion

The headline associated with this article may imply a more dramatic result than the data shows. When suggesting there is no evidence for use of long-term narcotics, many may interpret the message as “evidence suggests there is no role for long-term narcotics.“ In reality, this study finds there are no studies published that demonstrate effectiveness in adult users of long-term narcotics.

But, the authors did find and report on the increasing body of evidence showing the harms of long-term opioids. Specifically, they reported the profound increased risk of addiction in patients taking a morphine equivalent dose (MED) of greater than 120mg per day. This dose is relatively low and is an MED equivalent to:

Oxycodone/acetaminophen (Percocet, others): 10/325: two pills every 6 hours

Hydrocodone/acetaminophen (Vicodin, others) 5/300: two pills every 4 hours

Fentanyl Patch (Duragesic, others) 50 mcg every 72 hours.

The concept of chronic narcotics-inducing adverse events is unlikely to surprise most primary care providers who care for patients with chronic pain. It is the magnitude of the harmful effects that is most concerning.

This review did not cover all-cause mortality in association with opioid use. In 2013, the CDC reports that approximately 44,000 accidental opioid overdose deaths occurred (or, on average, 120 overdose deaths per day) (http://www.cdc.gov/homeandrecreationalsafety/overdose/facts.html.)

This review looked at all causes of pain, to include cancer pain in those patients not at the end of life. It aimed to be a more inclusive evaluation of pain when compared to a 2013 Cochrane review that included 15 studies examining long-term pain medications, including tramadol, for the treatment of chronic low back pain.² That review specifically looked at RCTs evaluating therapy of at least four weeks’ duration, which is in contrast to the definition of “chronic pain” which is typically described as greater than three months’ duration. In the Cochrane review, five studies examined the beneficial effects of tramadol (n=1378), which was found to have benefit when compared to placebo (SMD -0.55, 95% CI -0.66 to -0.44; low-quality evidence). However, when compared to celecoxib, the difference was not significant. The Cochrane review recognized that most of the studies included were of very low-quality evidence, which probably limit the overall utility. Only six trials of moderate quality showed a difference in pain with opioid medications compared to placebo (n=1887, SMD 0.43 [95%CI -0.52 to -0.33]) and function (SMD -0.26 [95%CI -0.37 to -0.15]). However, only a few trials compared opioids to non-opioid medications (NSAIDs or antidepressants) and those that did failed to show a statistically significant difference in effectiveness.

The concepts and findings of these two papers beg for investigation for the potential benefits of opioids for over a few months of regular use. In the meantime, the evidence is growing that opioids are associated with more harms and no long term benefits. While it is very important that we attempt to answer the long-term benefit question, it will take profound results of benefit to surmount the evidence of severe harm.

References

1. Chaparro LE, Furlan AD, Deshpande A, Mailis-Gagnon A, Atlas S, Turk DC. Opioids compared to placebo or other treatments for chronic low-back pain. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD004959. DOI: 10.1002/14651858.CD004959.pub4.

About the Author

Scott P. Grogan, DO, MBA, FAAFP is a faculty family physician at the Dwight David Eisenhower Army Medical Center Family Medicine Residency at Fort Gordon, GA and an Assistant Professor of Family Medicine at the Uniformed Services University of Health Sciences.