How does Nucynta® (tapentadol) differ from other opioids when treating chronic, non-cancer pain?


In 2016, The Centers for Disease Control and Prevention (CDC) published a guideline for prescribing opioids for chronic pain in an effort to ensure prescribers and patients consider all safe and effective treatment options and minimize risks.1 Limited evidence is available to support the use of long-term opioid therapy for chronic pain and this topic is highly controversial, however, there is significant evidence regarding risks associated with long-term use including opioid use disorder and overdose.

Before prescribing tapentadol, the CDC recommends discussing and setting realistic goals for pain control with each patient.1 Additionally, non-opioid therapies should be tried and optimized. Pharmacotherapy options include nonsteroidal anti-inflammatory agents (NSAIDs), tricyclic antidepressants (TCAs), serotonin norepinephrine reuptake inhibitors (SNRIs) and anticonvulsants. Non-pharmacotherapy options include exercise therapy, weight loss, and cognitive behavioral therapy (CBT). Opioid therapy should be considered only if non-opioid alternatives provide inadequate pain relief and the expected benefits outweigh risks to the patient. Opioid naïve patients should be started at low doses of immediate release opioids and titrated as needed to appropriately manage pain while minimizing unwanted side effects.

Classification and Labeling

Tapentadol is a synthetic, centrally acting analgesic and is the only drug in the mu-opioid receptor agonist - norepinephrine reuptake inhibition (MOR–NRI) class of analgesics.2,3 Through the MOR mechanism, tapentadol interrupts pre- and postsynaptic ascending pain signals in the spinal cord and brain. The addition of the NRI mechanism causes an increase of norepinephrine within the synapse, thereby increasing pain inhibition in the descending pathways. Medications that affect norepinephrine reuptake are advantageous in treating chronic neuropathic pain.4 The synergy of these two mechanisms has additional benefit for treatment of both nociceptive and neuropathic components of chronic pain, while potentially offering the advantage of opioid sparing to mitigate side effects of opioid use.4,5

In the United States, tapentadol is currently available as brand name Nucynta (immediate release [IR]) and Nucynta ER (extended-release [ER]) tablets. The Food and Drug Administration (FDA) has approved tapentadol IR for the management of severe acute pain that is inadequately treated with alternatives. 2 Tapentadol ER is approved for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatments are inadequate.3 Tapentadol ER is also approved for treatment of severe neuropathic pain associated with diabetic peripheral neuropathy. Tapentadol ER is not indicated for an as-needed (prn) analgesic and should be avoided for treatment of acute, post-operative, or trauma-related pain. Tapentadol has a schedule II classification of controlled substance by the U.S. Drug Enforcement Administration (DEA).2,3 As with all DEA schedule II narcotics, the usual risks of opiate addiction, diversion, and misuse apply. Tapentadol is only approved for use in adults age 18 years or older, and safety and efficacy have not been studied in pediatric patients. Tapentadol should be used during pregnancy only if the potential benefits justify the risks; the drug should not be used during breastfeeding.


Similar to other opioids, tapentadol has a boxed warning for risk of addiction, abuse, and misuse, life-threatening respiratory depression, accidental ingestion, neonatal opioid withdrawal syndrome, and risks from concomitant use with benzodiazepines or other central nervous system (CNS) depressants.2,3

Respiratory depression is a primary safety concern for mu-opioid agonists, including tapentadol.6 Therefore, patients with severe respiratory illness should not be prescribed tapentadol. Older, cachectic, debilitated patients and those with an underlying respiratory illness should take the lowest effective dose to minimize the risk of life-threatening respiratory depression. Tapentadol is contraindicated for use with concurrent monoamine oxidase inhibitors (MAOIs) due to the risk of hemodynamic lability.

As a result of its dual mechanism, tapentadol may lower the seizure threshold in susceptible patients.2,3 Additionally, tapentadol is a weak serotonin reuptake inhibitor, so it is important to evaluate each patient for risk of serotonin syndrome. Although serotonin syndrome is a rare adverse event, review medication profiles and use with caution in patients taking SSRIs, SNRIs, TCAs, ondansetron, metoclopramide, trazodone, mirtazapine, and MAOIs.

Concomitant use of tapentadol ER and alcohol can increase serum tapentadol concentration and cause fatal overdose; patients should be instructed not to consume alcoholic beverages while on this medication.2,3 Additionally, the ER tablets must not be split, crushed, or broken because rapid absorption may be fatal.

Care should be taken when prescribing tapentadol for patients with hepatic disease. For patients with moderate impairment, Child-Pugh Score 7 to 9, the maximum dose of tapentadol IR is no more than 50 mg every 8 hours, and for the ER formulation, the dose should not exceed 100 mg every 24 hours.2,3 Neither formulation is recommended for patients with severe hepatic impairment, or Child-Pugh Score 10 to 15.

When compared to classic opioid analgesics, tapentadol may provide clinically meaningful benefits. Tapentadol has a lower affinity to MOR than morphine, but with comparable pain relief, likely due to the synergism of the NRI mechanism.4 Studies have shown that tapentadol ER in dosages of 100 to 250 mg twice daily is as effective as controlled-release (CR) oxycodone (20 to 50 mg) for the treatment of moderate to severe chronic knee or hip osteoarthritis or low back pain.7


The synergistic activity of MOR-NRI offers an opioid sparing effect which may provide benefit by reducing opioid adverse events.4 Tapentadol ER has shown significantly lower rates of gastrointestinal adverse events including constipation, nausea, and vomiting than oxycodone CR. 7 Additionally, the severity of constipation was lower with tapentadol than with classic opioids and 40 % less likely to occur than with oxycodone/naloxone.5,7 This may benefit geriatric patients who generally have higher rates of constipation due to age-related physiological changes.5

The NRI properties may benefit patients with a neuropathic pain component.4 The ER formulation is FDA labeled to treat diabetic peripheral neuropathy and a dose of 100 to 250 mg twice daily has shown statistically and clinically significant improvement in neuropathic pain over placebo.8

For patients who need to change opioid analgesics due to tolerance or unmanageable side effects, the unique dual mechanism and improved tolerability of tapentadol may be favorable. Studies in patients with osteoarthritis and low back pain have shown a decline in adverse events after switching to tapentadol from previous opioid therapies, as well as significant improvements in quality of life and pain control.4 To calculate the Morphine Milligram Equivalent, tapentadol has a conversion factor of 0.4. However, owing to is dual mechanism, it is unknown if this drug has the same dose-dependent associated risk with overdose as other opioids.1

Abuse, Misuse, and Diversion

In the United States, tapentadol has a DEA schedule II narcotic classification and requires a Risk Evaluation and Mitigation Strategy (REMS) to ensure the benefits outweigh the risks of addiction, abuse, and misuse.2,3 Tapentadol ER is available in a tamper-resistant formulation that hinders crushing and forms a gel when added to small amounts of liquid. During the first 2 years tapentadol was marketed in the US, the surveillance system Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS), showed low rates of abuse and diversion. Additionally, compared to patients on oxycodone, the risk of opioid doctor shopping was 3 times less likely for patients treated with tapentadol.9


In those patients who may benefit from opioid therapy, tapentadol may offer high analgesic potency with lower opioid load and better tolerability owing to its dual mechanisms of action. The norepinephrine reuptake inhibition may be useful for patients with a neuropathic pain component. Tapentadol may simplify treatment of chronic pain with one medication rather than prescribing a combination of different analgesics.


  1. Center for Disease Control and Prevention. Morbidity and Mortality Weekly Report. CDC Guideline for prescribing opioids for chronic pain – United States, 2016. MMWR Recomm Rep. 2016;65(1):1-52.
  2. Nucynta [package insert]. Stoughton, MA: Collegium Pharmaceutical, Inc.; 2019.
  3. Nucynta ER [package insert]. Stoughton, MA: Collegium Pharmaceutical, Inc.; 2019.
  4. Baron R, Eberhart L, Kern K, et al. Tapentadol prolonged release for chronic pain: a review of clinical trials and 5 years of routine clinical practice data. Pain Pract. 2017;17(5):678-700.
  5. Pergolizzi Jr J, Taylor Jr R, LeQuang JA, Raffa R, Bisney J. Tapentadol extended release in the treatment of seer chronic low back pain and osteroarthritis pain. Pain Ther. 2018;7(1):37-57.
  6. Erlich D, Bodine W. Tapentadol (Nucynta) for treatment of pain. Am Fam Physician. 2012;85(9):910-911.
  7. Wild JE, Grond S, Kuperwasser B, et al. Long-term safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain. Pain Pract. 2010;10(5):416-427.
  8. Schwartz S, Etropolski M, Shapiro D, et al. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo controlled trial. Curr Med Res Opin. 2011;27(1)151–162.
  9. Sanchez del Aguila M, Schenk M, Kern K, Drost T, Steigerwald I. Practical considerations for the use of tapentadol prolonged release for the management of severe chronic pain. Clin Ther. 2015;37(1):94–113.

Prepared by:
Corinne Puchalla, PharmD
Clinical Instructor
University of Illinois at Chicago College of Pharmacy

The information presented is current as of November 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.