Clinical Notes : Pharmacology

178. Atypical Opioids : Tapentadol

 

The atypical opioids Tramadol, Tapentadol and Buprenorphine (1)

  • Atypical opioids differ from conventional opioids as they do not rely exclusively on mu-receptor agonism for their analgesic effect.

  • The atypical opioids, buprenorphine, tramadol and tapentadol, have different effects and different adverse effects including toxicity and abuse potential compared with conventional opioids.

 

  • These differences result in improved outcomes and reduced risks with the use of atypical opioids for individual patients and society as a whole.

 

  • Atypical opioids are the preferred strong analgesics for chronic pain that requires pharmacological treatment.

 

 

  • Tramadol is currently the preferred atypical opioid for the treatment of neuropathic pain, osteoarthritis and cancer pain.

    • 50 mg orally (immediate-release) every 4-6 hours when required, maximum 400 mg/day

    • orally (extended-release) 100-300 mg once daily, maximum 300 mg/day

  • Tapentadol is currently the preferred atypical opioid for the treatment of chronic pain.

    • Palexia 50, 75, or 100 mg every 4 to 6 hours depending on the intensity of pain

    • On the first day, a second dose may be given 1 hour after the initial dose if pain relief is inadequate

    • subsequent doses should be given every 4 to 6 hours, adjusted according to response

    • maximum total dose of 700 mg on the first day and of 600 mg daily on subsequent days

 

  • Transdermal Buprenorphine is particularly suitable for use in the elderly.

    • Butrans Patch delivers buprenorphine in a range of 5 to 20 micrograms/hour

    • initial dosages should not exceed 5 micrograms/hour in all patients

    • patches should be replaced every 7 days with the new patch being applied to a different site; use of the same area of the skin should be avoided for the next 3 to 4 weeks.

 
 
 

Pharmacology

 

The analgesic effect of tapentadol is based on its combined effect as a mu-opioid receptor agonist and a noradrenaline reuptake inhibitor.(2)

 

The affinity of tapentadol for the human mu-receptor is about 18 times lower than that of morphine (but tapentadol is only three times less potent than morphine), whereas the reuptake inhibition of noradrenaline is similar to that of an SNRI such as venlafaxine.

 

The high analgesic efficacy is explained by the extensive synergy between the two mechanisms of action.(3)

 

Although often regarded as being similar to tramadol, tapentadol differs with regard to its almost complete lack of a serotonergic effect and the fact that metabolites do not contribute to its analgesic effect.(4) (18)

This explains why no causal relationship between tapentadol and serotonin syndrome has been established and there are no clinically relevant drug interactions between tapentadol and antidepressants.(5)

 

 

Efficacy

 

In settings of osteoarthritis, chronic low back pain, neuropathic pain due to diabetic polyneuropathy and cancer pain, tapentadol provides equianalgesic efficacy to conventional opioids such as oxycodone and morphine.(6) (19)

 

In contrast to conventional opioids such as oxycodone, tapentadol significantly improves the quality of life of patients with chronic pain due to osteoarthritis and low back pain.(7)

 

The rotation from tramadol to tapentadol can be performed in one step and leads to better outcomes in most patients.(8)

 

Advantages of tramadol are :

  • the lowest rate of major medical adverse effects, hospitalisations and serious adverse effects of all opioids on the US market, including tramadol.

 

  • In contrast to conventional opioids, tapentadol causes significantly less opioid-induced ventilatory impairment. (9)

 

  • Very low mortality rate :

    • no fatalities from tapentadol use in the USA since 2009.(10)

    • four, possibly five, deaths from single-drug tapentadol overdose world-wide over nine years, which is in stark contrast to, and orders of magnitude lower than, the mortality caused by conventional opioids.(11)

 

  • Slow-release tapentadol shows significant less gastrointestinal adverse effects, namely nausea, vomiting and constipation, than the slow-release preparation of the conventional opioid oxycodone.(7)

 

  • Extremely well tolerated in the elderly, with similar advantages seen in patients aged older than 75 years.(12) (19)

 

  • Less testosterone suppression than oxycodone, with only 11% of patients taking tapentadol compared with 46% of patients taking oxycodone presenting with testosterone levels below the normal range.(13)

 

 

Dependence, abuse potential and diversion

 

  • Physical dependence on tapentadol is limited and therefore withdrawal symptoms occur rarely and are mild to moderate, even with abrupt cessation.(14)

 

  • Tapentadol abuse has been described, but rates are lower than with conventional opioids such as oxycodone, suggesting a significantly lower potential for abuse.(15) (20) (21) (22)

This results in significantly lower rates of doctor shopping (obtaining medication from multiple prescribers) than oxycodone.(16)

 
 
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1. Schug SA

The atypical opioids: buprenorphine, tramadol and tapentadol

MedicineToday : Conventional and Atypical Opioids Supplement September 2018

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2. Tzschentke TM, Christoph T, Kogel BY.

The mu-opioid receptor agonist/noradrenaline reuptake inhibition (MOR-NRI) concept in analgesia: the case of tapentadol.

CNS Drugs 2014; 28: 319-329.

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3. Christoph T, Schroder W, Tallarida RJ, De Vry J, Tzschentke TM.

Spinal-supraspinal and intrinsic mu-opioid receptor agonist-norepinephrine reuptake inhibitor (MOR-NRI) synergy of tapentadol in diabetic heat hyperalgesia in mice.

J Pharmacol Exp Ther 2013; 347: 794-801.

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4. Raffa RB, Buschmann H, Christoph T, et al.

Mechanistic and functional differentiation of tapentadol and tramadol.

Expert Opin Pharmacother 2012; 13: 1437-1449.

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5. Gressler LE, Hammond DA, Painter JT.

Serotonin syndrome in tapentadol literature: systematic review of original research.

J Pain Palliat Care Pharmacother 2017; 31: 228-236.

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6. Vinik AI, Shapiro DY, Rauschkolb C, et al.

A randomized withdrawal, placebo-controlled study evaluating the efficacy and tolerability of tapentadol extended release in patients with chronic painful diabetic peripheral neuropathy.

Diabetes Care 2014; 37: 2302-2309.

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7. Lange B, Kuperwasser B, Okamoto A, et al.

Efficacy and safety of tapentadol prolonged release for chronic osteoarthritis pain and low back pain.

Adv Ther 2010; 27: 381-399.

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8. Kress HG, Koch ED, Kosturski H, et al.

Direct conversion from tramadol to tapentadol prolonged release for moderate to severe, chronic malignant tumour-related pain.

Eur J Pain 2016; 20: 1513-1518.

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9. van der Schrier R, Jonkman K, van Velzen M, et al.

An experimental study comparing the respiratory effects of tapentadol and oxycodone in healthy volunteers.

Br J Anaesth 2017; 119: 1169-1177.

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10. Murphy DL, Lebin JA, Severtson SG, Olsen HA, Dasgupta N, Dart RC.

Comparative rates of mortality and serious adverse effects among commonly prescribed opioid analgesics.

Drug Saf 2018 ; 41: 787-795.

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11. Channell JS, Schug S.

Toxicity of tapentadol: a systematic review.

Pain Manag 2018; Aug 6. doi: 10.2217/pmt-2018-0027 [epub ahead of print].

12. Vorsanger G, Xiang J, Biondi D, et al.

Post hoc analyses of data from a 90-day clinical trial evaluating the tolerability and efficacy of tapentadol immediate release and oxycodone immediate release for the relief of moderate to severe pain in elderly and nonelderly patients.

Pain Res Manag 2011; 16: 245-251.

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13. Baron R, Jansen JP, Binder A, et al.

Tolerability, safety, and quality of life with tapentadol prolonged release (PR) compared with oxycodone/naloxone PR in patients with severe chronic low back pain with a neuropathic component: a randomized, controlled, open-label, phase 3b/4 trial.

Pain Pract 2016; 16: 600-619.

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14. Sanchez Del Aguila MJ, Schenk M, Kern KU, Drost T, Steigerwald I.

Practical considerations for the use of tapentadol prolonged release for the management of severe chronic pain.

Clin Ther 2015; 37: 94-113.

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15. Vosburg SK, Severtson SG, Dart RC, et al.

Assessment of tapentadol API abuse liability with the researched abuse, diversion and addiction-related surveillance system.

J Pain 2018; 19: 439-453.

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16. Cepeda MS, Fife D, Vo L, Mastrogiovanni G, Yuan Y.

Comparison of opioid doctor shopping for tapentadol and oxycodone: a cohort study.

J Pain 2013; 14: 158-164.

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17. Faria J, Barbosa J, Moreira R, Queiros O, Carvalho F, Dinis-Oliveira RJ.

Comparative pharmacology and toxicology of tramadol and tapentadol.

Eur J Pain 2018; 22: 827-844.

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18. Wiffen PJ, Derry S, Naessens K, Bell RF.

Oral tapentadol for cancer pain.

Cochrane Database Syst Rev 2015; (9): CD011460.

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19. Biondi DM, Xiang J, Etropolski M, Moskovitz B.

Tolerability and efficacy of tapentadol extended release in elderly patients ≥ 75 years of age with chronic osteoarthritis knee or low back pain.

J Opioid Manag 2015; 11: 393-403.

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20. Cepeda MS, Fife D, Ma Q, Ryan PB.

Comparison of the risks of opioid abuse or dependence between tapentadol and oxycodone: results from a cohort study.

J Pain 2013; 14: 1227-1241

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21. Butler SF, McNaughton EC, Black RA.

Tapentadol abuse potential: a postmarketing evaluation using a sample of individuals evaluated for substance abuse treatment.

Pain Med 2015; 16: 119 -13 0.

22. McNaughton EC, Black RA, Weber SE, Butler SF.

Assessing abuse potential of new analgesic medications following market release: an evaluation of Internet discussion of tapentadol abuse.

Pain Med 2015; 16: 131-140.

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The following meds are available in Ireland :

Tramadol (Tradol, Tramadol HCL, Tramake, Tramapine, Xymel, Zydol)

Tapentadol (Palexia)

Transdermal Buprenorphine (Butrans, Transtec)

 

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