Tofisopam

“Mechanism and Pharmacokinetics

As mentioned, tapentadol (Fig. 1) is a centrally acting analgesic that binds to several receptors, and also inhibits norepinephrine (NE) reuptake. This combination effect of tapentadol has been proposed to improve the therapeutic potential of opioid analgesics [Miclescu, 2016]. Moreover, tapentadol has a half-life of around 4 hours and is excreted in the urine and stool.

The main differences between tapentadol and other traditional opioids is that these traditional types – namely, morphine and oxycodone – carry out their analgesic effects through the m-opioid receptor (MOR) agonism [Polati et al., 2019]. In contrast, tapentadol works differently as it produces an analgesic effect in individuals from two separate mechanisms [Polati et al., 2019] (Fig. 2). Once taken, tapentadol is excreted via the kidneys.

Some of the more well-described opioids include:

• Fentanyl
• Oxycodone
• Morphine
• Methadone
• Buprenorphine
• Remifentanil
• Tramadol

In terms of manufacturing, oxycodone and buprenorphine are considered semi-synthetic opioids. Whereas the others mentioned in the above list are classed as synthetic opioids [Franchi et al., 2019]. Tapentadol is also considered a synthetic opioid, with less opioid-related side effects [Franchi et al., 2019].”

Tapentadol can be taken orally and is available in tablet form in doses ranging from 25mg, 50mg, 75mg and 100mg. It can come in three types of administrations: (1) immediate release, (2) prolonged release, and (3) oral solution [Stollenwerk et al., 2018]. The immediate and prolonged release formulations are considered control release formualtions, and these types can provide analgesia for up to 12 hours [Meng et al., 2017]. Other work has found that immediate release (IR) Tapentadol is rapidly absorbed with oral bioavailability of ~30% after a single, 86mg dose.

Prior studies and phase trials investigating the use of tapentadol for back pain revealed an effective treatment and management of acute and chronic pain [Stollenwerk et al., 2018]. In addition, prolonged release (PR) form of Tapentadol administration and dose showed long-term pain relief in the context of back pain. Further, tapentadol was shown to be effective in randomised trials for the management and treatment of pain associated with, osteoarthritis, lower back, and cancer pain [Stollenwerk et al., 2018].

Side effects

There are some associated side effects with tapentadol use. In general, side effects brought on by opioids can cause severe problems with patients seeking pain relief [Pergolizzi Jr et al., 2018]. However, tapentadol may lower side effects in the context of chronic pain.

Some side effects, and a brief explanation of how tapentadol can overcome these, is given below:

• Gastrointestinal side effects: tapentadol has been shown (in randomised, double-blind studies) be associated with delayed gastric and small bowel transit time. This was found in comparison to placebo.
• Hormone levels: studies have shown tapentadol to have less effects sex hormone concentrations, in comparison to other pure opioid analgesics (oxytocin and morphine).
• Sleep disorders: tapentadol has been associated with better sleep quality, when administered in a prolonged-release formulation.

 Tapentadol and back pain

Several studies have demonstrated the use of tapentadol in lower back pain (LBP). Evidence has shown that tapentadol, based on its dual MOR-NRI action might be a better and effective treatment of chronic lower back pain [Coluzzi et al., 2019].

 Tapentadol and cancer pain

 Several lines of evidence suggest that tapentadol, in various populations of cancer patients, is well-tolerated and effective in cancer pain patients. Moreover, traditional opioids might not be as effective for cancer pain patients; and tapentadol can provide management of moderate-sever cancer pain in both opioid-naïve and opioid-mature (pre-treated) individuals [Kress et al., 2019].

 Tapentadol and abuse potential

 Tapentadol is considered an atypical opioid, unlike the main opioids most are familiar with. In this regard, tapentadol is associated with physical and psychologic dependency, in cases of long-term abuse [Pergolizzi Jr et al., 2018]. Statistical studies have shown that non-medical use of tapentadol (immediate release) occurred in less than 1% of patients. Another database study found that the risk of abuse was greater for oxytocin, compared to tapentadol (in those patients given a prescription opioid) [Pergolizzi Jr et al., 2018].

 Safety and tolerability

 Overall safety and tolerability of Tapentadol has been studied for some time.

In one important study assessing the tolerability and safety of Tapentadol in children and adolescents, researchers administered a single dose of Tapentadol oral solution (adult range dose – 50-100mg) to pediatric patients (2 to 18 years). Result showed good tolerability and safety, with an improvement in post-surgery pain intensity. Researchers noted that Tapentadol might be a new treatment option for pain management in younger cohorts [Muse et al., 2019].

Other research indicates that Tapentadol prolonged release (PR) use for up to two years is well tolerated. Further, patients who switched from traditional opioids to Tapentadol, showed a decrease in adverse events – mainly constipation and nausea [Deeks, 2018].

However, it should be known that prolonged release Tapentadol has been associated with respiratory depression at higher doses, or in patients who are sensitive to opioids that target the mu-opioid receptor (MOR agonists). Moreover, patients considering taking Tapentadol should stay away if they have impaired respiratory function; acute/severe bronchial asthma and/or hypercapnia and/or paralytic ileus [Deeks, 2018].

Approval

Tapentadol is currently approved for chronic pain across various countries. In the EU, tapentadol prolonged release (PR) is sold as the brand name Palexia® [Deeks et al., 2018]. Furthermore, in 2008 the FDA approved tapentadol extended release for the management of acute to moderate to severe pain in adults [Miclescu, 2016]. In 2012, the FDA approved tapentadol for use in the treatment of diabetic neuropathy-related pain [Miclescu, 2016].

“Freo, U., Romualdi, P., & Kress, H. G. (2019). Tapentadol for neuropathic pain: a review of clinical studies. Journal of pain research, 12, 1537–1551. https://doi.org/10.2147/JPR.S190162

Miclescu A. (2016). The switch from buprenorphine to tapentadol: is it worth?. Romanian journal of anaesthesia and intensive care, 23(2), 133–139. https://doi.org/10.21454/rjaic.7518/232.bup

Polati, E., Canonico, P. L., Schweiger, V., & Collino, M. (2019). Tapentadol: an overview of the safety profile. Journal of pain research, 12, 1569–1576. https://doi.org/10.2147/JPR.S190154

Franchi, S., Moschetti, G., Amodeo, G., & Sacerdote, P. (2019). Do All Opioid Drugs Share the Same Immunomodulatory Properties? A Review From Animal and Human Studies. Frontiers in immunology, 10, 2914. https://doi.org/10.3389/fimmu.2019.02914

Stollenwerk, A., Sohns, M., Heisig, F., Elling, C., & von Zabern, D. (2018). Review of Post-Marketing Safety Data on Tapentadol, a Centrally Acting Analgesic. Advances in therapy, 35(1), 12–30. https://doi.org/10.1007/s12325-017-0654-0

Meng, Z., Yu, J., Acuff, M., Luo, C., Wang, S., Yu, L., & Huang, R. (2017). Tolerability of Opioid Analgesia for Chronic Pain: A Network Meta-Analysis. Scientific reports, 7(1), 1995. https://doi.org/10.1038/s41598-017-02209-x

Pergolizzi, J. V., Jr, Taylor, R., Jr, LeQuang, J. A., Raffa, R. B., & Bisney, J. (2018). Tapentadol Extended Release in the Treatment of Severe Chronic Low Back Pain and Osteoarthritis Pain. Pain and therapy, 7(1), 37–57. https://doi.org/10.1007/s40122-018-0095-8

Coluzzi, F., Polati, E., Freo, U., & Grilli, M. (2019). Tapentadol: an effective option for the treatment of back pain. Journal of pain research, 12, 1521–1528. https://doi.org/10.2147/JPR.S190176

Kress, H. G., & Coluzzi, F. (2019). Tapentadol in the management of cancer pain: current evidence and future perspectives. Journal of pain research, 12, 1553–1560. https://doi.org/10.2147/JPR.S191543

Muse, D., Tarau, E., Lefeber, C., Sohns, M., Brett, M., Goldberg, J., & Rosenburg, R. (2019). Pharmacokinetics, safety, and efficacy of tapentadol oral solution for treating moderate to severe pain in pediatric patients. Journal of pain research, 12, 1777–1790. https://doi.org/10.2147/JPR.S197039

Deeks E. D. (2018). Tapentadol Prolonged Release: A Review in Pain Management. Drugs, 78(17), 1805–1816. https://doi.org/10.1007/s40265-018-1007-2

Chang, E. J., Choi, E. J., & Kim, K. H. (2016). Tapentadol: Can It Kill Two Birds with One Stone without Breaking Windows? The Korean journal of pain, 29(3), 153–157. https://doi.org/10.3344/kjp.2016.29.3.153

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