Long-Term Opioids for Neuropathy Linked to Adverse Events

Fran Lowry

May 24, 2017

People with polyneuropathy who take long-term opioids for 90 days or more have a higher risk for depression, opioid dependency, and overdose than do their counterparts receiving shorter durations of opioid therapy, a new retrospective study shows.

Moreover, long-term opioid therapy does not appear to improve functional status in such individuals.

The findings are published online May 22 in JAMA Neurology.

"In general, opioid chronic therapy did not tend to have benefits for patients with peripheral neuropathy in our study, and if anything, it was associated with negative outcomes," lead author, E. Matthew Hoffman, DO, PhD, Mayo Clinic, Rochester, Minnesota, told Medscape Medical News.

Dr E. Matthew Hoffman

"Another key finding was that there was a subset of patients who were on chronic opioid therapy who did not seem to have had an adequate trial of non-opioid medications that are commonly recommended for neuropathic pain. That was a small group, but that is a group of patients in whom we could have done better," Dr Hoffman said.

"Neuropathy is very common in the population, especially in older people," senior author, Christopher J. Klein, MD, Mayo Clinic, told Medscape Medical News.

Dr Christopher J. Klein

"Over the age of 65, the rate of persons with neuropathy of some type is over 6%, and it's about 2% in the entire population, so we are talking about a huge number of people with pain, and there has been debate about how to help those who have pain as a component of their neuropathy," Dr Klein said.

In this retrospective population-based cohort study, the researchers reviewed prescriptions given to patients with polyneuropathy between January 1, 2006, and December 31, 2010, in Olmsted County, Minnesota. They also looked at outcomes through 2016.

They compared the outcomes of 2892 patients with polyneuropathy who had been treated with long-term opioids (>90 days) with the outcomes of 14,435 age- and sex-matched patients who did not receive long-term opioid treatment (control group).

Of the patients with polyneuropathy, 18.8% (n = 545 patients) received long-term opioids compared with only 5.4% (n = 780) of controls.

Patients were more likely to have been prescribed long-term opioid therapy for musculoskeletal pain (52.5%) as opposed to neuropathic pain (24.0%).

Female sex was associated with a greater likelihood of being prescribed long-term opioid therapy (P < .001), as was having a Charlson Comorbidity Index medical comorbidity with the exception of paralysis, cancer, and AIDS.

The findings showed poorer outcomes for patients treated with long-term opioids.

After adjustment for age, sex, and medical comorbidities, the adjusted hazard ratio (AHR) was 1.53 (95% confidence interval [CI], 1.29 - 1.82) for depression, 2.85 (95% CI, 1.54 - 5.47)  for opioid dependence, and 5.12 (95% CI, 1.63 - 19.62) for opioid overdose.

Patients receiving long-term opioid therapy also had worse functional status, including an increased reliance on gait aids (AHR, 1.9; 95% CI, 1.4 - 2.6).

"Clearly, being on long-term opioids does not benefit patients," Dr Klein said. "There is more to learn about this, but what we've learned so far from this is that patients need to be informed that there really are no data to suggest that they are going to do better on this regimen. One thing I can tell you for sure, if you're not on opioids, you're not going to develop opioid addiction."

Dr Hoffman added: "I would like to see more conversation between patients and providers regarding this issue and perhaps more cautious prescribing practices until we have some very strong data that these medications do help. This study doesn't support that they do. In fact, they may be being used without level 1 or strong evidence in their favor."

In an accompanying editorial, Nora D. Volkow, MD, director of the National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland, and Walter Koroshetz, MD, director of the National Institute of Neurological Disorders and Stroke, also part of the National Institutes of Health, write that the study findings question the justification for using long-term opioid therapy for polyneuropathy.

"However, because opioids were prescribed more often for treatment of nonneuropathic indications, the study's findings do not alter the evidence underlying the most current guidelines, which advise against opioids as first-line treatment for neuropathic pain in most cases because of concerns regarding long-term safety," they point out.

Dr Volkow and Dr Koroshetz also note that the study highlights the limited options currently available for the management of chronic pain conditions. They call for more research on the neurobiology of "these complex pain conditions" as well as the need to develop new medications.

"In this respect, recent advances on the structural biology of the opioid μ receptor have led to the development of biased opioid agonists that favor binding to the G protein–coupled receptor protein and not to the β arrestin (biased agonists) that, in animal models, show equivalent analgesia to that of typical opioids but with reduced tolerance and adverse effects," they write.

"Similarly, successes with biologics that interfere with the source of the pain, such as etanercept, to inhibit tumor necrosis factor in patients with rheumatoid arthritis, and tanezumab, a monoclonal antibody against nerve growth factor in patients with osteoarthritis, may change the focus to prevention as they inhibit the generation of pain."

Until such newer medications become available, they suggest changes in the healthcare system to include training of physicians in the screening and management of pain, and insurance coverage of comprehensive pain management programs.

Such measures "are needed to ensure that patients receive the most effective treatments for their chronic pain conditions," the editorialists conclude.

The authors and editorialists have disclosed no relevant financial relationships.

JAMA Neurol. Published online May 22, 2017. Abstract, Editorial

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