Tapentadol is 'Third-Tier' Drug for Diabetic Neuropathic Pain

Lara C. Pullen, PhD

June 04, 2014

The opioid analgesic tapentadol (Nucynta, Janssen Pharmaceuticals) is approved for use in patients with painful diabetic peripheral neuropathy in the United States, but it is expensive, and most insurance companies require physicians to first attempt multiple other drugs before prescribing it, says the lead author of a new paper describing the efficacy and tolerability of this agent.

The agent is also a scheduled narcotic, which further deters doctors; thus, tapentadol is currently a "third-tier" drug for the treatment of diabetic peripheral neuropathy, Aaron I. Vinik, MD, PhD, from East Virginia Medical School in Norfolk, told Medscape Medical News.

Dr. Vinik and colleagues' findings were published online May 21 in Diabetes Care. While the results show tapentadol is an effective treatment for diabetic peripheral neuropathy, "it is not being prescribed as much as I thought it would be," he said.

John D. England, MD, from the department of neurology at Louisiana State University Health Sciences Center School of Medicine in New Orleans, who was not involved with this research, agrees that doctors are uncomfortable prescribing this agent.

"[Tapentadol] is a [Drug Enforcement Administration] schedule II narcotic and has significant potential for abuse and addiction. It is only indicated for moderate to severe pain. For the treatment of neuropathic pain, there are many other drugs that are safer and have fewer adverse effects. This drug, like all opioids, would be a last-tier option for neuropathic pain," he explained in an email.

Dr. Vinik says he also has another reason to hesitate when considering tapentadol for this indication, "I prescribe it in very specific circumstances. I am keen on managing diabetic peripheral neuropathy based on comorbidity," he elaborated.

Tapentadol ER Effective and Well Tolerated

An extended-release (ER) formulation of tapentadol was approved for use in painful diabetic peripheral neuropathy by the Food and Drug Administration in August 2012, and the United States is currently the only country in which this agent is approved for this indication.

In the newly published study by Dr. Vinik and colleagues, adults with moderate to severe diabetic peripheral neuropathy pain were titrated to tapentadol ER 100 to 250 mg twice daily during a 3-week open-label period. Patients with 1-point or more reduction in pain intensity (11-point numerical rating scale) at the end of titration were then randomized to receive placebo or tapentadol ER, at the optimal dose determined from titration, for a 12-week, double-blind, fixed-dose maintenance phase.

The primary end point was mean change in average pain intensity from the start to week 12 of the double-blind maintenance phase.

A total of 358 patients completed the titration period; 318 patients (placebo, n=152; tapentadol ER, n=166) were randomized and received 1 or more doses of double-blind study medication. Mean pain intensity was 7.33 at the start and 4.16 at week 3 of the open-label titration period (mean change, –3.22).

The mean change in pain intensity (a positive value indicates worsening of pain) from start of double-blind treatment to week 12 was 1.30 for placebo vs 0.28 for tapentadol ER (P < .001 in favor of tapentadol).

Dr. Vinik said while there was quite a high rate (35%) of gastrointestinal disturbances, such as nausea and vomiting, observed with tapentadol ER, as well as a high rate of dizziness (12%) and headache (4%), the side effects did not stop patients from taking the medication.

"Tapentadol ER (100–250 mg [twice daily]) was effective and well tolerated for the management of moderate to severe chronic pain associated with diabetic peripheral neuropathy," he and his colleagues conclude.

Treating Pain Based on Comorbidity

However, in practice, Dr. Vinik noted that many patients with painful diabetic neuropathy also experience sleep disorders, anxiety, and/or depression. So physicians should ideally prescribe drugs that will treat as many of these comorbidities as possible, looking for the best fit with the total clinical picture of a patient.

If a pharmaceutical treatment can ameliorate sleep disturbance, it may also have a significant effect on pain, he noted. Unfortunately, in the case of tapentadol and many other drugs prescribed for diabetic neuropathy, their effect on sleep has not been well studied, he observed.

While many physicians and patients believe a number of commonly prescribed medications to have a beneficial effect on sleep, research shows that while an agent may make a patient tired, for example, it doesn't necessarily help the patient to sleep. For instance, a commonly prescribed drug for diabetic neuropathy, duloxetine (Cymbalta, Eli Lilly), actually fragments sleep, he explained.

Dr. Vinik suggests that, when treating a patient with diabetic peripheral neuropathy and sleep disturbance, a gabapentinoid may be the best option.

Anxiety is a common comorbidity with diabetic neuropathy, too, but unfortunately, tapentadol is also not particularly effective for anxiety, he added, noting that tricyclic antidepressants may be the best option for these 2 coexisting conditions.

He warns, however, that tricyclics may have cardiac effects, and thus physicians should take care to evaluate the cardiac status of patients before and after prescribing these older antidepressants.

Depression and Diabetic Neuropathy: A Good Fit for Tapentadol?

The other common comorbidity, occurring in approximately half of all patients with diabetic neuropathy is depression. While tricyclics may be an effective treatment for depression alone, they do not appear to ease the pain of patients with both conditions.

While he cautioned that patients who are bipolar do not respond well to either tapentadol or duloxetine, he said that the unique properties of tapentadol — it is a combination of a µ-opioid-receptor agonist and a norepinephrine-reuptake inhibitor in a single molecule — means it is possible for the physician to prescribe 1 drug instead of 2 for patients with diabetic peripheral neuropathy and classic depression.

For this reason, tapentadol is a good addition to the physician arsenal and can be extremely beneficial for the right patient because it not only relieves pain but also has the potential to elevate mood, he concluded.

Editorial support was funded by Janssen Research & Development and Grünenthal. Dr. Vinik received funding for this study from Janssen; disclosures for the authors are listed in the article. Dr. English has reported no relevant financial relationships.

Diabetes Care. Published online May 21, 2014. Abstract

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