Guidance provides clinically relevant details on counseling, drug classes

New, clinically relevant guidelines focusing on oral and topical medication treatment of painful diabetic neuropathy (PDN) were issued by the American Academy of Neurology (AAN), updating the group’s 2011 guidelines.

“An update was needed to review a large number of new randomized controlled trials of the treatment of pain in people with PDN and to highlight the alternatives to opioid use in this population,” reported Brian Callaghan, MD, MS, of the University of Michigan in Ann Arbor, and co-authors, in Neurology.

“Living with pain can greatly affect a person’s quality of life, so this guideline aims to help neurologists and other doctors provide the highest quality patient care based on the latest evidence,” Callaghan said in an AAN press release. “Painful diabetic neuropathy is very common, so people with diabetes who have nerve pain should discuss it with their doctor because treatment may help.”

Painful peripheral neuropathy occurs in about 16%-17% of people with diabetes and is more common in patients with longer duration of diabetes and poor glycemic control. It negatively affects physical and mental quality of life, and may often go untreated.

The guidelines provide recommendations as well as doses and criteria for success or failure of treatments for four classes of oral medications found to have efficacy in PDN: gabepentinoids such as gabapentin or pregabalin; sodium channel blockers such as carbamazepine, oxcarbazepine, lamotrigine, or lacosamide; tricyclic antidepressants (TCAs) such as amitriptyline, nortriptyline, or imipramine; and serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine, venlafaxine or desvenlafaxine. The use of opioids or combined opioid drugs to treat PDN is strongly discouraged.

Following a meta-analysis that included studies from January 2008 to April 2020 as well as Class I and II studies from the 2011 guidelines, the group published nine clinically actionable recommendations. All are level B (strong; should) unless otherwise noted.

  • Clinicians should assess patients with diabetes for peripheral neuropathic pain and its effect on these patients’ function and quality of life.
  • Patients should be counseled about realistic expectations, including the possibility of partial rather than complete pain resolution. “Patients expect a high degree of pain relief, and many expect complete pain resolution,” the authors wrote, noting that about 30% pain reduction is considered a success in clinical trials.
  • Since patients with diabetes may be more likely to have major depression and sleep disorders than the general population and both may influence pain perception, clinicians should assess and treat them as needed.
  • Medications from the four classes of oral medication with meta-analytic evidence for pain reduction in PDN—gabapentinoids, sodium channel blockers, TCAs, and SNRIs—should be offered to reduce pain.
  • Patients who prefer topical non-traditional or non-pharmacologic interventions may be offered agents supported by at least one randomized controlled trial including (Level C): topical (capsaicin, glyceryl trinitrate spray, Citrullus colocynthis), nontraditional (Ginkgo biloba), or nonpharmacologic treatment (cognitive behavioral therapy, exercise, tai chi, mindfulness).
  • “Individual pharmacologic agents from the TCA, SNRI, gabapentinoids, and sodium channel blocker classes have similar efficacy on neuropathic pain outcomes,” the AAN guideline authors wrote. “However, class and agent-specific differences exist in the potential for and nature of adverse effects.” In addition to efficacy, clinicians should consider adverse effects, co-morbidities, cost, and patient preference in offering treatments, while offering valproate only if multiple other agents have failed, and should not offer valproate to patients with reproductive potential.
  • The guidelines provide dose ranges and time intervals for determining success or failure for specific medications in each class, and patients should be counseled that a series of medication trials may be required to achieve a response. A treatment fails when either an effective dose over 12 weeks provides no clinically significant pain reduction or when side effects outweigh benefit. When a treatment fails, an agent from a different effective class of medication should be offered; partial improvement may lead to either replacement of the partially effective agent with one from a different class or the addition of another medication from a different class (combined therapy).
  • The use of opioids for chronic, noncancer pain was strongly discouraged in a 2014 AAN position paper and the 2016 CDC guideline that found poor evidence of long term efficacy and the likelihood of severe long-term adverse consequences. “The most important long-term adverse consequences include nearly universal dependence, high rates of more severe dependence and opioid use disorder, morbidity via overdose events, and excess mortality,” the AAN guideline authors wrote. “Whereas short-term pain reduction has been demonstrated in patients with PDN with opioids, no randomized trial of opioids over a long duration has demonstrated clinically meaningful improvement of pain and function, which would be needed to justify the severity of potential side effects.” Clinicians should not use opioids for the treatment of PDN (Level B) and that those taking opioids for the treatment of PDN may be offered a safe taper off opioids with replacement by non-opioid treatment (Level C).
  • Both tramadol and tapentadol are opioid/SNRI dual mechanism agents, and have the potential for severe adverse events, including respiratory depression, addiction, and overdose. Both have FDA black box warnings. “The efficacy of tramadol and tapentadol for painful neuropathy is only reported in studies of short duration,” the guideline authors wrote. Tramadol and tapentadol should not be used to treat PDN (Level C), and that patients taking either may be offered a safe taper off opioids with replacement by non-opioid treatment (Level C).

In addition to the PDN guidelines, a quality measurement set that aims to improve care and treatment for patients with any polyneuropathy was published simultaneously in Neurology.

Limitations of the meta-analysis and guidelines include their focus on oral and topical medications, and gaps in the evidence base.

“It is important to note that the recommended drugs and topical treatments in this guideline may not eliminate pain, but they have been shown to reduce pain,” Callaghan noted. “The good news is there are many treatment options for painful diabetic neuropathy, so a treatment plan can be tailored specifically to each person living with this condition.”

  1. New, clinically relevant guidelines focusing on oral and topical medication treatment of painful diabetic neuropathy were issued by the American Academy of Neurology, updating the group’s 2011 guidelines.

  2. The guidelines provide doses and criteria for success or failure of treatments for four classes of oral medications found to have efficacy: gabapentinoids, sodium channel blockers, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors. The use of opioids or combined opioid drugs is strongly discouraged.

Paul Smyth, MD, Contributing Writer, BreakingMED™

This guideline was developed with financial support from the American Academy of Neurology.

Callaghan reported relationships with University of Michigan, Ann Arbor Veterans Affairs, Dynamed, AAN, medical-legal work, Vaccine Injury Compensation Program, and NIH.

Cat ID: 394

Topic ID: 82,394,730,12,13,394,669,918,922,925