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Tapentadol-ER for the Treatment of Diabetes Associated Peripheral Neuropathy (DPN)

The FDA recently approved tapentadol-ER (Nucynta ER) for the treatment of peripheral neuropathy in diabetics…. 

With an increasing number of patients being diagnosed with diabetes, complications associated with the disease are becoming more common. Diabetic peripheral neuropathy (DPN) is the most common neuropathic pain seen in patients with diabetes, affecting up to 50% of patients. It is characterized as a burning or tingling sensation that affects the lower limbs. Painful DPN is associated with increased morbidity, mortality and substantial costs to the healthcare system.

Tapentadol-ER is a schedule II opioid analgesic that is commonly used for the treatment of moderate to severe chronic pain. It is unique in its dual acting mechanism in which it works as both a weak mu-opioid receptor agonist and a norepinephrine-reuptake inhibitor.

This distinct mechanism is said to represent a new pharmacological class of medications: MOR-NRI. Tapentadol ER is a weak mu-opioid receptor agonist, having an 18 fold decrease in receptor affinity when compared to morphine. Despite this decrease in affinity, tapentadol ER only produces a two to three fold decrease in analgesic effects when studied in animals. It also acts on the alpha-2 receptor located on the noxious nerve fibers in the spinal cord and throughout the central nervous system, inhibiting transmission of pain impulses. The dual acting mechanism of tapentadol-ER works to control the complex pathology that is neuropathic pain.

Until this approval the only options for FDA approved medications to treat diabetic peripheral neuropathy (DPN) were pregabalin and duloxetine.

Tapentadol ER provides sufficient pain relief with convenient twice daily dosing. The starting dose for opioid-naïve patients is 50mg twice daily and can be titrated to an effective dose of 100mg to 250mg twice daily. The maximum daily dose is 250mg twice daily. The maximum serum concentration is increased by 17% when taken in combination with a high fat breakfast but according to package labeling may be administered without regards to food.

Tapentadol-ER undergoes extensive hepatic metabolism and therefore must be adjusted in patients with hepatic impairment. The usual adjustment is extension of administration duration to once every 24 hours in patients with mild to moderate hepatic impairment (Child-Pugh Score of 7 to 9). It is contraindicated in patients with severe hepatic impairment. Tapentadol ER and its metabolites are excreted by the kidneys; however, no dose adjustments are required for patients with renal impairment.

The efficacy and safety of tapentadol ER has been studied in two DPN studies. Both studies were placebo controlled randomized studies in which patients had either type 1 or type 2 diabetes and painful DPN for a period of at least six months. Pain intensity was at least a 5 on an 11 point scale. In both studies approximately two-thirds of participants were opioid-naïve. Both studies came to the conclusion that tapentadol ER provided statistically significant improvement of pain intensity as compared to that of placebo.

Treatment related adverse effects were reported at 70.9% for those taking tapentadol ER and 51.8% for those taking placebo. The most common side effects were nausea, diarrhea, anxiety and dizziness. Most were mild to moderate and did not lead to discontinuation of the medication.

Practice Pearls:
  • The incidence of diabetes is on the rise as is the complication of neuropathy
  • The FDA approval of tapentadol ER for treatment of diabetic peripheral neuropathy provides practitioners an additional therapeutic option with a convenient twice daily dosing regimen.
  • Tapentadol ER has a unique dual mechanism suggesting that it may be particularly useful for complex pain associated with DPN.

Consult Pharm. 2013 Oct;28(10):672-5. doi: 10.4140/TCP.n.2013.672

Comment from Dr. Aaron Vinik, Diabetes In Control Advisory Board member, and study author:

Pain associated with DPN is a common complication of diabetes affecting 10-26% of patients for which the only approved drugs are Pregabalin and Duloxetine which at best reduce pain by 30% in about half the patients treated leaving a significant portion of the affected population without resort to significant pain relief. A paradox here is that third party payors insist that less expensive drugs such as the tricyclics should be used as first line despite the fact that they have cardiovascular cautions as well as not paying heed to the need for attention to the comorbidities of sleep loss, depression and anxiety as determinants of choice of initial therapies. However, the problem occurs when first line therapies have failed and the need for greater reduction of pain arises wherein a combination of drugs acting through different parts of the pain pathway have proved useful. The problem with this approach is that this increases the burden of drugs patients with diabetes must take with untoward effects, particularly cognitive impairment, which can have a disastrous impact on decision-making and is the cause of induced hypoglycemia and its consequences. Tapendalol represents a proposed new class of centrally acting analgesics combining two mechanisms of action: u-opiod receptor agonism and norepinephrine reuptake inhibition. Tapentadol extended release has been shown to be effective and well-tolerated for the management of severe, chronic pain in randomized, double blind, placebo-controlled and/or active comparator controlled phase 3 studies. Two studies (of which I am first author and coauthor of the second) were designed using a randomized withdrawal multicenter placebo control design and reached their primary endpoint and in August 2012 tapentadol ER received FDA approval for the mangement of pain associated with DPN in adults when a continuous around the clock opiod analgesic was needed for an extended period of time. To determine if subgroups would benefit, the data from the two studies were pooled. The results of this pooled analysis indicated that tapentadol ER is effective and well-tolerated for the management of neuropathic pain associated with DPN, improved measures of health related quality of life and had constent efficacy across different patient subgroups divided by age, gender, race, opiod experience and pain intensity. Sensitivity analyses showed that in the tepentadol arm ( n=360) compared with placebo ( n=342) the drug 54% achieved >30% pain reduction and 38.9% >50% pain reduction and the significant side effects were nausea, vomiting, dizziness, and somnolence. These figures argue in favor of using the drug as a second or third tier drug with the recognition that its effects are modest and there is the potential for habituation. Ultimately, what is needed is a drug that will reverse the pathogenic process and that the need for pain-relieving drugs will be the bandaid to be used in the interval before the damge to the nervous system has been resolved.