Tapentadol; A Unique ; Rational Opioid Option for Neuropathic Pain
Tapentadol (in the form of Nucynta ER®) was FDA approved for diabetic neuropathy pain on August 29, 2012. This is especially timely considering the recent brouhaha initiated by PROP. It is in fact the first opioid to be approved for chronic pain with an additional specific indication for diabetic peripheral neuropathy (DPM).
Tapentadol is a unique opioid in that it has both µ agonist activity and is a norepinephrine (NE) reuptake inhibitor. Some have likened it [incorrectly] to tramadol. While there are some similarities, there are very important differences. For example, the µ receptor binding affinity of tramadol is 6000x less that of morphine, similar to dextromethorphan, but tapentadol binding affinity is just 50x less; tapentadol has ONLY NE reuptake inhibiting properties, but tramadol has both NE and serotonin (5-HT) reuptake inhibition activity, the latter of which may increase risk of serotonin-mediated side effects; and the pharmacokinetics are worlds apart.
Tapentadol is chemically most similar to tramadol when compared to other opioids. Its binding affinity to the µ-opioid receptor is significant, earning tapentadol schedule II status (see Online MPA Degrees for a summary of schedules) from the DEA. Tapentadol and tramadol are 3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol monohydrochlorides and 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl cyclohexanol hydrochlorides respectively. Practically this means if a patient has difficulty tolerating a chemical class from more traditional opioids, tapentadol or tramadol may be viable options.
The metabolism of tramadol is dependent on cytochrome P450 (CYP450) iso-enzymes 3A4, 2D6, and 2B6. Tramadol’s NE activity discussed above is relatively low compared to tapentadol and SNRIs such as duloxetine (Cymbalta®) and milnacipran (Savella®). Tramadol’s µ-opioid receptor (encoded by gene OPRM1) is affected by the parent drug and O-desmethyltramadol (metabolite M1). In actuality, the M1 metabolite contributes to more analgesia than the parent compound, the combination of which is likely enhanced by the scant NE reuptake inhibition, but first pass metabolism is required prior to any significant opioid analgesia. Further metabolism of the M1 metabolite occurs via N-demethylation to N-desmethyl-tramadol (M2), which is ultimately catalyzed by CYP2B6 and CYP3A4. There are at least 3 more metabolites (M3-5) that are ultimately glucuronidated to inactive forms in the liver. Obviously, this is quite complex and creates a large potential for drug interactions with CYP450 substrates.
Tapentadol conversely does not rely on the CYP450 system for metabolism and the metabolic pathway is pretty simple, lending itself to virtually no drug interactions specific to CYP450. But of course, the same precautions are necessary when combining tapentadol with sedatives and/or respiratory depressants (For other warnings and prescribing information, see package insert). Seventy percent is excreted in urine following conjugation, 55% as O-glucuronide and 15% as sulfate; a small percentage is eliminated as parent drug.
From a practical standpoint, the significant NE activity of tapentadol makes it particularly useful for neuropathic pain syndromes. From a clinical standpoint, we generally reserve chronic opioids for treatment failures on other medications or for patients in whom risks of other therapies are NOT outweighed by benefits (i.e. alpha-2-δ-subunit calcium ligand gated ion channel inhibitors; gabapentin, pregabalin in fall-risk patients). It’s certainly no secret that usefulness of serotonin norepinephrine reuptake inhibitors (SNRI’s) for neuropathic pain is well established. Examples include duloxetine (Cymbalta®) and milnacipran (Savella®), with few toxicities compared to traditional tricyclic antidepressants (TCA’s) options. Perhaps the landmark study outlining NE as the essential crème de la crème activity required for neuropathic pain analgesia by antidepressants is Mitchell Max, 1992. Max compared amitriptyline (NE & 5-HT) to desipramine (NE only) to fluoxetine (5-HT only) to placebo. Patients on amitriptyline or desipramine responded equally well for treating DPN, but fluoxetine and placebo patients responded equally poorly. This outcome suggests that for TCAs (and most likely all antidepressants), NE alone is responsible for DPN analgesia, but presumably 5-HT activity [alone or combined] contributes to annoying side effects and an increased toxicity profile.
Kudos to the FDA for recognizing an important niche’ for tapentadol in the treatment of diabetic peripheral neuropathy. For more information on unique opioids in the treatment of neuropathic pain, see “Treatment of Neuropathic Pain: the Role of Unique Opioid Agents. Practical Pain Management” on paindr.com
http://paindr.com/tapentadol-a-unique-rational-opioid-option-for-neuropathic-pain/
Tapentadol is chemically most similar to tramadol when compared to other opioids. Its binding affinity to the µ-opioid receptor is significant, earning tapentadol schedule II status (see Online MPA Degrees for a summary of schedules) from the DEA. Tapentadol and tramadol are 3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol monohydrochlorides and 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl cyclohexanol hydrochlorides respectively. Practically this means if a patient has difficulty tolerating a chemical class from more traditional opioids, tapentadol or tramadol may be viable options.
The metabolism of tramadol is dependent on cytochrome P450 (CYP450) iso-enzymes 3A4, 2D6, and 2B6. Tramadol’s NE activity discussed above is relatively low compared to tapentadol and SNRIs such as duloxetine (Cymbalta®) and milnacipran (Savella®). Tramadol’s µ-opioid receptor (encoded by gene OPRM1) is affected by the parent drug and O-desmethyltramadol (metabolite M1). In actuality, the M1 metabolite contributes to more analgesia than the parent compound, the combination of which is likely enhanced by the scant NE reuptake inhibition, but first pass metabolism is required prior to any significant opioid analgesia. Further metabolism of the M1 metabolite occurs via N-demethylation to N-desmethyl-tramadol (M2), which is ultimately catalyzed by CYP2B6 and CYP3A4. There are at least 3 more metabolites (M3-5) that are ultimately glucuronidated to inactive forms in the liver. Obviously, this is quite complex and creates a large potential for drug interactions with CYP450 substrates.
Tapentadol conversely does not rely on the CYP450 system for metabolism and the metabolic pathway is pretty simple, lending itself to virtually no drug interactions specific to CYP450. But of course, the same precautions are necessary when combining tapentadol with sedatives and/or respiratory depressants (For other warnings and prescribing information, see package insert). Seventy percent is excreted in urine following conjugation, 55% as O-glucuronide and 15% as sulfate; a small percentage is eliminated as parent drug.
From a practical standpoint, the significant NE activity of tapentadol makes it particularly useful for neuropathic pain syndromes. From a clinical standpoint, we generally reserve chronic opioids for treatment failures on other medications or for patients in whom risks of other therapies are NOT outweighed by benefits (i.e. alpha-2-δ-subunit calcium ligand gated ion channel inhibitors; gabapentin, pregabalin in fall-risk patients). It’s certainly no secret that usefulness of serotonin norepinephrine reuptake inhibitors (SNRI’s) for neuropathic pain is well established. Examples include duloxetine (Cymbalta®) and milnacipran (Savella®), with few toxicities compared to traditional tricyclic antidepressants (TCA’s) options. Perhaps the landmark study outlining NE as the essential crème de la crème activity required for neuropathic pain analgesia by antidepressants is Mitchell Max, 1992. Max compared amitriptyline (NE & 5-HT) to desipramine (NE only) to fluoxetine (5-HT only) to placebo. Patients on amitriptyline or desipramine responded equally well for treating DPN, but fluoxetine and placebo patients responded equally poorly. This outcome suggests that for TCAs (and most likely all antidepressants), NE alone is responsible for DPN analgesia, but presumably 5-HT activity [alone or combined] contributes to annoying side effects and an increased toxicity profile.
Kudos to the FDA for recognizing an important niche’ for tapentadol in the treatment of diabetic peripheral neuropathy. For more information on unique opioids in the treatment of neuropathic pain, see “Treatment of Neuropathic Pain: the Role of Unique Opioid Agents. Practical Pain Management” on paindr.com
http://paindr.com/tapentadol-a-unique-rational-opioid-option-for-neuropathic-pain/
