Tapentadol

Tapentadol (Palexia^®) sustained release (SR) tablets were registered with the Therapeutic Goods Administration in January 2011 and achieved listing on the Pharmaceutical Benefits Scheme (PBS) in November 2013. The Pharmaceutical Benefits Advisory Committee (PBAC) approved the listing as a restricted benefit for chronic severe disabling pain that is unresponsive to non-opioid analgesics. This listing is on a basis of similar efficacy and cost compared with oxycodone controlled release (CR) and tramadol SR. Tapentadol is classified as a Schedule 8 medicine in Australia and is available in 50mg, 100mg, 150mg, 200mg and 250mg formulations with a maximum quantity of 28 tablets.

Tapentadol is a centrally acting synthetic analgesic combining µ-agonist activity with noradrenaline reuptake inhibition. This dual mechanism of action interacts in a synergistic way to provide strong analgesia. Compared to morphine, tapentadol has approximately 18 times less binding affinity to µ-opioid receptors, however animal studies show the analgesic potency is only two to three times less. This suggests that inhibition of noradrenaline reuptake compensates for the decrease in µ-opioid receptor agonism, contributing to its analgesic efficacy, particularly in the treatment of neuropathic pain.

How does it compare?

In comparison to oxycodone CR; three trials (two published, and one unpublished) were submitted for regulatory approval. These studies investigated the relative efficacy and safety of tapentadol with other analgesics for lower back pain and osteoarthritis of the knee. Tapentadol demonstrated non-inferiority to oxycodone and a significant reduction in average pain intensity compared with placebo.

In both published trials, oxycodone CR had a higher rate of discontinuation due to adverse events than tapentadol (32.3% versus 16.7%, and 43.0% versus 19.2%). Gastrointestinal tolerability was superior for tapentadol, with a lower reported incidence of constipation, nausea and vomiting.

In comparison to tramadol; tramadol and tapentadol both display μ-agonist activity in addition to their effects on the reuptake of noradrenaline. This dual action suggests that tapentadol may be an alternative to tramadol. Furthermore, tramadol has comparatively weak opioid activity compared with tapentadol and an additional serotonin reuptake inhibition.

Tapentadol does not require metabolic activation to exert its analgesic effect, however tramadol must be metabolised to an active µ-opioid receptor agonist. The efficacy of tramadol therefore can vary across different patient groups.

The majority of clinical trials conducted with tapentadol have used oxycodone as the comparator. Therefore, further research is required to determine the relative safety and efficacy of tapentadol SR and tramadol.

Prescribing considerations

Tapentadol SR tablets release the active ingredient slowly over twelve hours and are therefore not intended for break-through pain. It is suggested in the trials that paracetamol is used for this purpose.

The very common side effects tapentadol SR can cause are nausea, constipation, dizziness, drowsiness and headaches. Tapentadol also has the potential to induce physical dependence of the opioid type. Preliminary data from use of the immediate release formulation in the United States has shown there may be lower potential for abuse and dependence than with other opioid analgesics.

Tapentadol is contraindicated in patients with respiratory depression or those who have taken a monoamine oxidase inhibitor (MAOI) in the last 14 days. Caution must be exercised when used with other central nervous system (CNS) depressants as the additive side effects may result in respiratory depression, hypotension, profound sedation or coma. Tapentadol only has a weak effect on serotonin reuptake, however there is a possible risk of serotonin syndrome when used with other serotonergic medicines, for example selective serotonin reuptake inhibitors (SSRIs), serotonin noradrenaline reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), MAOIs, St John’s Wort and triptans.

Tapentadol is extensively metabolised in the liver to inactive metabolites which are primarily excreted by the kidneys. No dose adjustment is required in mild renal or hepatic impairment. Moderate hepatic impairment leads to reduced metabolism and therefore greater exposure to tapentadol. These patients should be carefully monitored and dose reductions may be required. Tapentadol has not been studied in patients with severe renal or hepatic impairment, therefore it should be avoided in these patient groups.

Dosing

• For people not currently taking opioid analgesics, the commencing dose is 50mg tapentadol SR, twice daily
• The estimated equi-effective dose ratio is oxycodone SR 1mg to tapentadol SR 5.3mg
• For titration, increase twice daily doses by 50mg every three until analgesia is achieved
• Total daily doses of greater than 500mg have not been studied
• To avoid withdrawal symptoms, a gradual taper is recommended

Opioid analgesics do not provide clinically worthwhile pain relief for all users, however may be considered for patients who continue to experience severe disabling pain despite trialling other non-opioid options. This includes non-pharmacological treatments such as physiotherapy and cognitive behavioural therapy. The role of long-term opioid analgesics for people with chronic pain remains controversial and the evidence for efficacy overall is weak.

Tapentadol is an alternative to other opioid analgesics such as oxycodone and tramadol. Similar to other strong opioids, it may cause gastrointestinal adverse effects, CNS and respiratory depression, and potential abuse. Advantages may be a lower potential for adverse effects, abuse and tolerance compared to other opioid analgesics.