Clinical Context

Multiple pharmacologic treatment options are available for diabetic peripheral neuropathy (DPN), and a previous systematic review of randomized controlled trials for such treatment attempted to compare different drug classes in terms of efficacy against neuropathy. The meta-analysis by Griebeler and colleagues included 65 controlled trials, with a total of more than 12,000 patients. The results of this study were published in the November 4, 2014 issue of the Annals of Internal Medicine.^[1]

Researchers found that half of the studies either had a high or unclear risk for bias. Antidepressants and anticonvulsants were both found to be more effective than placebo in the management of DPN. In 9 studies, serotonin-norepinephrine reuptake inhibitors (SNRIs) were more effective than anticonvulsants. Tricyclic antidepressants were more effective than capsaicin. All forms of pharmacotherapy were associated with adverse effects that might limit treatment.

Opioids were associated with a slight improvement in symptoms of DPN vs placebo in the meta-analysis, but SNRIs were more effective than opioids. Opioids are also associated with a high number of well-known adverse events, as well as a risk for misuse and abuse. Given this risk:benefit balance, are healthcare providers prescribing opioids for DPN? The current study by Fan and colleagues answered this question.

Study Synopsis and Perspective

Prescriptions for opioids as a first-line treatment for painful DPN outnumbered those for other medications between 2014 and 2018, despite the fact that the former is not recommended, new research indicates.

"We know that for any kind of chronic pain, opioids are not ideal. They're not very effective for chronic pain in general and they're definitely not safe," senior author Rozalina G. McCoy, MD, an endocrinologist and primary care clinician at the Mayo Clinic in Rochester, Minnesota, told Medscape Medical News.

That's true even for severe DPN pain or painful exacerbations, she added.

"There's a myth that opioids are the strongest pain meds possible...For painful neuropathic pain, duloxetine, pregabalin, and gabapentin are the most effective pain medications based on multiple studies and extensive experience using them," she explained, "[b]ut I think the public perception is that opioids are the strongest. When a patient comes with severe pain, I think there's that kind of gut feeling that if the pain is severe, I need to give opioids."

What's more, she noted, "Evidence is emerging for other harms, not only the potential for dependency and potential overdose, but also the potential for opioid-induced hyperalgesia. Opioids themselves can cause chronic pain. When we think about using opioids for chronic pain, we are really shooting ourselves in the foot. We're going to harm patients."

The American Diabetes Association DPN guidelines essentially say as much, advising opioids only as a tertiary option for refractory pain, she observed.

The new findings, from a retrospective review of Mayo Clinic electronic health data, were published online in JAMA Network Open^[2] by Jungwei Fan, PhD, also of Mayo Clinic, and colleagues.

The data also revealed that although opioid prescribing dropped over the study period, there was not a comparable rise in prescriptions of recommended pain medications, suggesting that the recent efforts by the Centers for Disease Control and Prevention to minimize opioid prescribing^[3] may have resulted in less overall treatment of significant pain. (The study had to be stopped in 2018 when the Mayo Clinic switched to a new electronic health record system, McCoy explained.)

"The proportion of opioids among new prescriptions has been decreasing. I'm hopeful that the rates are even lower now than they were 2 years ago. What was concerning to me was the proportion of people receiving treatment overall had gone down," McCoy noted.

"So, while it's great that opioids aren't being used, it's doubtful that people with DPN are any less symptomatic. So I worry that there's a proportion of patients who have pain who aren't getting the treatment they need just because we don't want to give them opioids. There are other options," McCoy said, including nonpharmacologic approaches.

The study involved 3495 adults with newly diagnosed DPN from all 3 Mayo Clinic locations in Rochester, Minnesota; Phoenix, Arizona; and Jacksonville, Florida during the period 2014-2018. Of those patients, 40.2% (1406) were prescribed a new pain medication after diagnosis; however, that proportion dropped from 45.6% in 2014 to 35.2% in 2018.

The odds of initiating any treatment were significantly greater among patients with depression (odds ratio [OR] = 1.61 [95% CI: 1.35, 1.93]), arthritis (OR = 1.21 [95% CI: 1.02, 1.43]), and back pain (OR = 1.34 [95% CI: 1.16, 1.55]; all, P < .05) but decreased over time among all patients.

Among those patients receiving drug treatment, opioids were prescribed to 43.8% whereas guideline-recommended medications (gabapentin; pregabalin; and SNRIs, including duloxetine) were prescribed to 42.9%.

Another 20.6% received medications deemed "acceptable" for treating neuropathic pain, including topical analgesics, tricyclic antidepressants, and other anticonvulsants.

Men were significantly more likely than women to receive opioids (OR = 1.26 [95% CI: 1.01. 1.59]; P < .05) whereas individuals diagnosed with comorbid fibromyalgia were less likely (OR = 0.67 [95% CI: 0.44, 0.99]; P < .05). Persons with comorbid arthritis were less likely to receive recommended DPN medications (OR = 0.76 [95% CI: 0.59, 0.99]; P < .05).

Use of opioids was 29% less likely in 2018 compared with 2014, although this difference did not achieve significance. Similarly, use of recommended medications was 25% more likely in 2018 compared with 2014, also not a significant difference.

Clinically, McCoy said that she individualizes treatment for painful DPN.

"I tend to use duloxetine if the patient also has a mood disorder including depression or anxiety, because it can also help with that," she explained. "Gabapentin can also be helpful for radiculopathy or for chronic low back pain. It can even help with degenerative joint disease like arthritis of the knees. So, you maximize benefit if you use one drug to treat multiple things."

All 3 recommended medications are generic now, although pregabalin still tends to be more expensive, she noted. Gabapentin can cause drowsiness, which makes it ideal for a patient with insomnia but much less so for a long-haul truck driver. Duloxetine does not cause sleepiness. Pregabalin can, but less so than gabapentin.

"I think that's why it's so important to talk to your patient and ask how the neuropathy is affecting them," she recommended. "What other comorbidities do they have? What is their life like? I think you have to figure out what drug works for each individual person."

Importantly, she advised, if one of the 3 does not work, stop it and try another.

"It doesn't mean that none of these meds work," she continued. "All three should be tried to see if they give relief."

Nonpharmacologic measures, such as cognitive behavioral therapy, acupuncture, or physical therapy, may help some patients as well.

Supplements such as vitamin B12 -- which can also help with metformin-induced B12 deficiency -- or α-lipoic acid may also be worth a try, as long as the patient is made aware of potential risks, she noted.

McCoy hopes to repeat this study using national data.

"I don't think this is isolated to Mayo...I think it affects all practices," she said.

Since the study, "[w]e [Mayo Clinic] have implemented practice changes to limit use of opioids for chronic pain... so I hope it's getting better. It's important to be aware of our patterns in prescribing."

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. McCoy reported receiving grants from the AARP Quality Measure Innovation program through a collaboration with OptumLabs and the Mayo Clinic's Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery.

Clinical Implications

• In a previous systematic review and meta-analysis by Griebeler and colleagues, antidepressants and anticonvulsants appeared to be the most effective pharmacotherapy options in the management of DPN.
• The current study by Fan and colleagues suggested that opioids may be prescribed at higher rates than guideline-based therapy in the management of DPN. Male sex was associated with a higher rate of opioid prescriptions whereas a history of fibromyalgia was associated with a lower rate of opioid prescriptions.
• Implications for the healthcare team: The healthcare team should use decision support technology to encourage the use of guideline-based treatment for DPN.

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