This is the third of a three-part series on opioid analgesic management for the aftermath of the prescription opioid epidemic. Today we'll be discussing tapentadol (Nucynta), a unique/next-generation broad-spectrum analgesic agent that happens to be a weak, atypical opioid. At the outset, I would like to disclose that I've never received financial nor material benefits of any sort from any drug manufacturer including Ortho-McNeil-Janssen, Johnson & Johnson, Depomed, or Collegium.
Tapentadol is a tramadol analog but has significant advantages over that parent compound, including no active metabolite (in contrast to O-desmethyltramadol, which is notably more potent than tramadol), and nearly insignificant serotonergic component (in contrast to tramadol, which markedly impacts the safety profile of the latter drug in terms of drug-drug interactions).
It is a weak opioid agonist ( of morphine in terms of mu-opioid receptor binding/activation), but in concert with norepinephrine reuptake inhibition (NRI) it yields significantly synergistically increased analgesic efficacy, as well as reduced tolerance and reduced adverse effect profile discussed in much greater detail below. Unfortunately, in the post-OxyContin era, with prevalent misinformation regarding opioids, tapentadol has gotten a bad rap. One major issue is that CMS and most morphine milligram equivalent (MME) conversions -- which of course are all based upon subjective pain relief report -- are very inaccurate/misleading: the MME for tapentadol is generally thought to be 0.4, but in reality is actually closer to 0.06 based on actual pharmacologic data.
As such, falsely elevated potency claims (in concert with aggressive and expected denials from payers owing to patented/brand-name drug status without generics available) have led to reticence among providers, pharmacists, and healthcare plans to offer this novel and highly effective agent to many of the tens of millions of people who would doubtless benefit.
Let's take a closer look at the data...
Efficacy
Any prescription should follow an informed benefit-risk ratio analysis. Along those lines, let's start with potential benefit.
One clue should be the fact that the federal government (which, in case you've slept through the past two decades, has been increasingly and understandably advocating against chronic opioid therapy in chronic non-cancer pain) has approved tapentadol for the treatment of not only severe acute and severe chronic pain, but also specifically for diabetic peripheral neuropathy pain, a distinction awarded otherwise only to duloxetine and pregabalin.
Neuropathic pain is notoriously difficult to control, and from a pharmacologic standpoint options are limited by a fairly broad adverse effect profile from anticonvulsants, tricyclics, etc. The data on opioid efficacy in neuropathic pain is mixed at best (with the atypical opioids tramadol, tapentadol, buprenorphine, and methadone showing the most success) and I don't need to remind anybody of the even broader adverse effect profile from opioids.
Having said that, tapentadol shows unusual benefit in neuropathic pain -- likely owing to the conjoint NRI activity, which among other things, increases dorsal horn modulation of afferent nociceptive transmission. And this isn't limited to DPN; several recent meta-analyses and have demonstrated clear benefit in . To the extent that chronic pain represents central sensitization, with maladaptive CNS neural plasticity at the core of the pathologic state, tapentadol may well be among the most logical candidates to prevent such -- again bearing in mind the FDA approval for severe acute pain.
From a more mundane antinociceptive perspective -- acute and especially chronic pain -- tapentadol also shows tremendous benefit in widely prevalent difficult-to-manage including chronic low back pain and osteoarthritis/degenerative joint disease.
Safety and Abuse Liability
From the risk side of the equation, tapentadol has shown in comparison to traditional opioids to date, which is of course to be expected given its weak MOR agonism. Respiratory, gastrointestinal, and neurologic adverse effects are notably less prevalent than with other opioids.
Not surprisingly, there is strong real-world of minimal abuse liability despite DEA Schedule II status. In all fairness, limited availability of the agent may be partially responsible for decreased abuse and diversion statistics. Having said that, in our practice tapentadol is the most commonly prescribed opioid (followed by tramadol and buprenorphine), and we have seen zero cases over the past decade of dependence and addictive behaviors such as requests for continuous escalation or early refill requests. This is in line with data showing that when adjusted for utilization, tapentadol still shows abuse and diversion. Furthermore -- and again in sharp contrast to any other opioid molecule including tramadol and buprenorphine -- we have never seen a single case of withdrawal upon discontinuation, whether abrupt or tapered. Given that opioid withdrawal comprises a huge contributor to chronic seeking and use, this phenomenon is not trivial.
One final fun fact to consider: naloxone administration doesn't reduce the analgesic efficacy of tapentadol. Besides giving support and pharmacologic context to virtually everything discussed above, it begs the question: might tapentadol also have a unique niche in treating folks on naltrexone (Vivitrol)? This is something we will be exploring more in the near future...
Tapentadol in the Therapeutic Armamentarium
In short, accumulating evidence demonstrates that tapentadol is a highly effective broad-spectrum analgesic with minimal adverse effects and abuse liability -- safer in many cases than NSAIDs and certainly in comparison to traditional opioids. Its widely publicized MME is erroneously high, and multiple lines of convergent evidence show that its main analgesic effect is most likely owing to CNS NRI activity rather than opioid activity, as evidenced by failure of naloxone to reverse therapeutic benefit. It deserves greater attention and consideration in the therapeutic armamentarium for an increasingly prevalent and difficult-to-treat spectrum of both acute and especially chronic pain conditions.
is a board-certified anesthesiologist, pain physician, and addictionologist practicing in Alaska (the military sent him there and he decided to stay). If he wasn't trying to guide people in improving their own lives, teaching medical students to do the same, or writing about it, he'd probably be outdoors right now slogging up a mountain with a good friend or two.