A Perspective on Tapentadol Therapy
We wish to address 3 underappreciated, but salient points regarding tapentadol therapy using a case-based approach: First, the rarity of a true opioid allergy; second, the chemical similarity of phenylpropylamine opioids (tramadol, tapentadol); and, third, the unique pharmacodynamic attributes of tapentadol in the treatment of complex regional pain syndrome (CRPS).
Patient TA presented with a 2013 diagnosis of CRPS, which commenced following a tibial plateau fracture in 2012, subsequent to a re-fracture of the same bone 7 to 8 months later. TA reported feeling “pins and needles” in his right foot, radiating to his ankle, and sharp, shooting pain bilaterally to his legs and upper arms. He also complained of lower back spasms that remained throughout the course of treatment. Due to continuous neurological pain throughout his body without visible neurological lesion, the patient was eventually diagnosed with CRPS.
According to the 2013 American Academy of Pain Medicine CRPS Guidelines, there is little guidance for the treatment of CRPS due to the absence of true diagnostic criteria.1 Therefore, pharmacotherapy options are often guided by clinician-specific trials and experience. TA had previously undergone several treatments, including: sympathetic nerve blocks that offered temporary relief; failed trials of adjuvant nonsteroidal anti-
inflammatory drug therapy (celecoxib [Celebrex], meloxicam [Mobic], ibuprofen, indomethacin, naproxen) and various opioids (methadone, morphine, hydromorphone, tramadol, and oxycodone); the anticonvulsants gabapentin and pregabalin (Lyrica), along with serotonin and norepinephrine reuptake inhibitor therapy, including duloxetine (Cymbalta); and, finally diazepam and cyclobenzaprine.
Upon his next visit, TA had been inadequately maintained on hydrocodone/acetaminophen (10 mg/325 mg) twice daily, as needed. He reported having an allergic reaction to tramadol, including “passing out,” following an intravenous dose that was administered while in Europe. He also reported extreme nausea and vomiting due to both duloxetine and pregabalin.
A past trial of methadone proved efficacious in the management of his pain, but caused extreme somnolence. Should an opioid be initiated, an extended-release option with unique properties (ie, multiple mechanisms of action, nonopioid receptor targets) is preferable due to the failure of previous therapies and the extent and “around-the-clock” nature of the pain experienced by the patient. A short-acting opioid may be considered for breakthrough pain, if necessary.1
It is important to note that true opioid allergies are rare, although urticaria, pruritus, and hypotension may impact the differential diagnosis.2 Otherwise, symptoms are generally pseudoallergies provoked by endogenous histamine release from mast cells, which are often mislabeled as a true allergy.2 True opioid allergy symptoms include anaphylaxis, maculopapular rash, severe hypotension, or angioedema.2 If the patient is indeed allergic to one class of opioids, the risk of cross-reactivity is variable, depending upon chemical classification.
Phenylpiperidines, diphenylheptanes, and phenylpropyl amines all possess low cross-sensitivity risk to phenanthrene opioids.3 The phenanthrenes, which include oxycodone, morphine, and buprenorphine, pose a probable risk within the same chemical class, much like beta lactam antibiotics. This further implicates the importance of properly documenting a true versus pseudoallergy when considering opioid options.4
Tapentadol vs Tramadol
TA experienced extreme nausea and vomiting with duloxetine, pregabalin, and tramadol. We, therefore, suspected an intolerance to serotonin reuptake inhibition that likely was not attributable to tramadol, as a chemical entity. Consideration was then made for the use of tapentadol (Nucynta); however, there was concern due to the patient’s previous medication reactions, and failure of tramadol, as both are phenylpropylamines. Despite this fact, their mechanisms of action vary in that, unlike the partial agonist tramadol, the full agonist tapentadol has relatively no activity to inhibit serotonin reuptake, and has a far greater opioid receptor binding affinity (6000 versus 18 times less than morphine).5 Although they are structurally similar, unlike tramadol, tapentadol only affects norepinephrine reuptake, and is a more powerful pure opioid agonist that does not undergo cytochrome P450 metabolism. The norepinephrine activity from both tramadol and tapentadol can be especially useful in treating neuropathic pain.6
Since CRPS is a chronic pain condition of the peripheral and central nervous system, it is by definition a neuropathic pain syndrome. Norepinephrine reuptake inhibition in the central nervous system may inhibit pain transmission originating from the descending nerve stem, thus supporting the use of norepinephrine reuptake inhibiting medications. FDA-approved package labeling of tapentadol indicates use for moderate to severe pain, “severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate,” but also specifies “neuropathic pain associated with diabetic peripheral neuropathy.”7
For reasons previously stated, it was determined that TA likely had serotonin reuptake inhibition pharmacological sensitivity, not an allergy to tramadol. There was no evidence that our patient had, in fact, experienced a true allergy as all accounts were historical. Regardless of presumed tramadol sensitivity, tapentadol seemed like an excellent option for around-the-clock neuropathic pain management for this patient.
After full consent, TA was challenged with a supervised tapentadol 50 mg trial, which yielded no reported side effects, and significant pain improvement within 30 minutes. He reported baseline pain of 6 or 7 out of 10 on a visual analog scale. Upon initiation of regularly dosed tapentadol, pain decreased to 3 out of 10. TA has since been maintained on tapentadol (50 mg) every 4 to 6 hours, as needed, with excellent and consistent efficacy. Our goal is to transition TA to tapentadol ER once a stable IR dose is found.