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Prolonged-release tapentadol: a review

Saowarat Snidvongs
Pain Fellow and Specialist Registrar
in Anaesthesia, 
Barts and The London NHS Trust,
London, UK
Chronic pain is a pain that outlasts its original stimulus  and persists for at least three months past the normal time for healing. A European survey concluded that chronic pain is a devastating and widespread condition with a significant socioeconomic impact affecting one in five adults.(1) More than a third of respondents suffered from chronic pain due to arthritis and osteoarthritis, with the back being the most common location for pain. Forty percent of those surveyed with chronic pain stated that their pain management was inadequate.
The poor response rate and perceived difficulties in chronic pain management have prompted research into new technologies that have a successful outcome and favourable side-effect profile. Tapentadol is the first new molecular entity in the class of oral centrally acting analgesics to enter the market in over two decades and was developed to overcome some of the existing issues associated with opioids and other analgesic agents, such as adverse gastrointestinal events. Prolonged‑release tapentadol is now available on prescription and has been approved by the Food and Drug Administration in the US for the management of moderate to severe chronic pain in adults who require continuous opioid analgesia for an extended period of time, and in the UK is indicated for the management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics. This review will discuss the currently available treatment options for chronic pain, the tolerability issues associated with opioid analgesics, the pharmacology of prolonged-release tapentadol and how it fits into its treatment area, its benefits and limitations.
Current treatment options for chronic pain
Chronic pain management options may be pharmacological or non-pharmacological. Oral pharmacological agents used to treat chronic pain include non-steroidal anti-inflammatory drugs, opioids, anticonvulsants and antidepressants. Non-pharmacological treatment can involve physical therapy, psychological input, acupuncture, neuromodulation and injection of therapeutic substances. The complex pathophysiology of chronic pain makes pharmacological treatment particularly challenging; for example, patients with a neuropathic component to their pain (owing to a lesion or dysfunction in the nervous system) tend to have a better response to multimodal therapy than to a single agent, possibly as a result of multiple pathological mechanisms at different sensory sites. The current mainstay of pharmacological management is opioid analgesia. Opioids are agonists at endogenous opioid receptors with inhibitory effects on pain transmission at the pre-synaptic and post-synaptic levels via neuronal hyperpolarisation. Their prescription rate has risen rapidly in recent years in the US and UK, with more women than men being prescribed opioids for chronic non-cancer pain and the highest prevalence of long-term opioid use in older women.(2)
Opioid side effects include constipation, nausea, somnolence, itching, dizziness and vomiting that might limit their use. Opioid-induced bowel dysfunction, for example, is caused by drug binding to opioid receptors in the gut causing constipation from a reduced gastric emptying time, inhibition of ion and fluid secretion, increased sphincter tone and slowed peristalsis. One systematic review has shown that patients will discontinue oral opioid analgesia because of side effects such as constipation, nausea and headache or inadequate pain relief.(3) An acceptable balance between efficacy and tolerability is required, and new drugs or drug combinations could address some of these concerns.
Tapentadol has a dual mode of action combining mu-opioid receptor agonism with noradrenaline reuptake inhibition in a single molecule. A synergistic interaction has been demonstrated between these two mechanisms,(4) which can, in part, explain its strong analgesic effect despite its low binding affinity to the mu-opioid receptor. Activation of mu-opioid receptors at afferent pain fibres reduces ascending pain signaling and enhances descending pain inhibition. As a result, the increased synaptic noradrenaline levels cause a reduction in pain signaling to the brain via descending inhibitory pain pathways.
Tapentadol is co-manufactured by Grünenthal, Aachen, Germany (as Palexia®) and Johnson & Johnson, New Brunswick, New Jersey, US (as Nucynta®). Figure 1 shows the chemical structure. It is a single chemical entity without pharmacologically active metabolites or racemates, limited protein binding, low potential for drug–drug interaction and inter-individual efficacy variation and no requirement for metabolic activation. In contrast, the less potent tramadol is a racemic mixture and requires further metabolism by the cytochrome P450 system for its weak mu-opioid agonism and monoamine reuptake inhibition.
The prolonged-release preparation allows for twice-daily dosing with a 12‑hour duration of activity. It is available as 50mg, 100mg, 150mg, 200mg and 250mg tablets. According to Grünenthal’s own data, it is approximately five-times less potent than controlled-release oxycodone and 2.5-times less potent than oral morphine. It was specifically developed for the management of moderate-to-severe chronic pain based on a safety and efficacy profile shown in early clinical trials pointing towards a favourable tolerability profile. The immediate release preparation was available first on the US market, and is licensed in the UK for the relief of moderate-to-severe acute pain in adults, which can be adequately managed only with opioid analgesics. Longer-acting analgesics provide a theoretical advantage over short-acting medications for chronic pain sufferers by limiting the peak and trough fluctuations in drug plasma concentration, potentially reducing the incidence of adverse events and resulting in increased patient compliance.
Clinical trials of prolonged-release tapentadol
Preclinical testing of tapentadol has demonstrated its efficacy in animal models of nociceptive, neuropathic visceral and inflammatory pain. Clinical trials have shown its safety and efficacy in patients with chronic nociceptive and neuropathic pain. Pooled data from three phase III studies of chronic osteoarthritis of the knee or low back pain concluded that prolonged‑release tapentadol was efficacious. Furthermore, these studies provided similar analgesic efficacy to controlled-release oxycodone, with a lower incidence of gastrointestinal side effects and fewer treatment discontinuations.(5) One trial including patients with chronic osteoarthritis pain in the knee, hip or low back area revealed that prolonged-release tapentadol was associated with better gastrointestinal tolerability than prolonged-release oxycodone and could provide sustainable pain relief for up to one year.(6) As a result, 8.6% of patients on tapentadol versus 21.5% of the patients on oxycodone discontinued the study drug due to gastrointestinal emergent adverse events (n=1117). Likewise, another trial in chronic osteoarthritis-related knee pain showed that, although both prolonged-release tapentadol and oxycodone were effective in managing pain, there were substantially fewer gastrointestinal treatment-emergent adverse events in the tapentadol group compared with the oxycodone group (43.0% versus 67.3%, respectively; 26.1% in placebo group; n=1023).(7) The third trial in moderate to severe chronic low back pain found that prolonged-release tapentadol was effective and had better gastrointestinal tolerability compared with oxycodone (43.7% versus 61.9%, respectively; 26.3% placebo; n=981).(8)
Patients with inadequately treated painful diabetic peripheral neuropathy were treated with an optimal dose of prolonged-release tapentadol during the open-label period of one randomised-withdrawal placebo-controlled trial (n=588).(9) This was followed by a double-blind phase where participants either continued the study medication or received a placebo (n=395).(9) Patients in the prolonged-release tapentadol arm had a statistically significant difference in the maintenance of clinically important improvement in pain compared with placebo, and the study drug was well tolerated throughout the study.
A systematic review of ten tapentadol trials in patients with severe pain concluded that the benefit–risk ratio of tapentadol was improved compared to other strong opioids such as oxycodone and morphine.(10) One analysis of prolonged-release tapentadol trials found that tapentadol was associated with increased work productivity compared to oxycodone, with less time missed from work and less impairment while working.(11)
Benefits and limitations of prolonged‑release tapentadol
The benefits of prolonged-release tapentadol in comparison to equianalgesic pure mu-opioid agonists include:
  • fewer gastrointestinal side effects that result in better tolerability
  • less need for dose escalation
  • good efficacy
  • better treatment adherence
  • less potential for drug–drug interaction
  • no known inter-individual efficacy variation.
Its limitations include:
  • adverse reactions in up to 10%. The most frequent of these are nausea, dizziness, constipation, headache and somnolence
  • in isolated cases there have been reports of serotonin syndrome in a temporal connection with the therapeutic use of tapentadol in combination with serotoninergic products such as selective serotonin reuptake inhibitors
  • risk of abuse, addiction, physical dependence and tolerance
  • should be administered with caution to patients with impaired respiratory functions
  • should not be used in patients who may be particularly susceptible to the intracranial effects of carbon dioxide retention, such as those with evidence of increased intracranial pressure, impaired conciousness or coma
  • should be prescribed with care in patients with a history of a seizure disorder or any condition that would put the patient at risk of seizures.
The heterogeneity of chronic pain sufferers necessitates a broad range of treatment options. Opioids are commonly used to treat chronic non-cancer pain although their efficacy is restricted by the potential to cause adverse events and by the development of tolerance from sustained exposure. Tapentadol has the advantage of an opioid-sparing effect by reducing the opioid side effects for a given level of analgesia while maintaining effective pain relief. Its unique pharmacological profile and broad spectrum of action makes it potentially suitable to treat more painful conditions such as neuropathic and mixed pain states than ‘classical’ opioids. At present, however, there are limited comparator data available with opioids other than oxycodone. Further trials are needed to reveal whether it has clinical usefulness in chronic pain management.
  1. Breivik H et al. Survey of chronic pain in Europe: Prevalence, impact on daily life and treatment. Eur J Pain 2006;10(4):287–333.
  2. Campbell CI et al. Age and gender trends in long-term opioid analgesic use for noncancer pain. Am J Public Health 2010;100(12):2541–47.
  3. Noble M et al. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev 2010;(1):CD006605.
  4. Schröder W et al. Synergistic interaction between the two mechanisms of action of tapentadol in analgesia. J Pharmacol Exp Ther 2011;337(1):312–20.
  5. Lange B et al. Efficacy and safety of tapentadol prolonged release for chronic osteoarthritis pain and low back pain. Adv Ther 2010;27(6):381–99.
  6. Wild JE et al. Long-term safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain. Pain Pract 2010;10(5):416–27.
  7. Afilalo M et al. Efficacy and safety of Tapentadol extended release compared with oxycodone controlled release for the management of moderate to severe chronic pain related to osteoarthritis of the knee: A randomised, double-blind, placebo- and active-controlled phase III study. Clin Drug Investig 2010;30(8):489–505.
  8. Buynak R et al. Efficacy and safety of tapentadol extended release for the management of chronic low back pain: Results of a prospective, randomised, double-blind, placebo- and active-controlled Phase III study. Expert Opin Pharmacother 2010;11(11):1787–1804.
  9. Schwartz S et al. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: Results of a randomised-withdrawal, placebo-controlled trial. Curr Med Res Opin 2011;27(1):151–62.
  10. Riemsma R et al. Systematic review of tapentadol in chronic severe pain. Curr Med Res Opin 201;27(10):1907–30.
  11. Cepeda MS et al. Effect of Tapentadol extended release on productivity: Results from an analysis combining evidence from multiple sources. Clin J Pain 2011; Jun 3 [Epub ahead of print].