02 September 2011
After a re-submission by the manufacturer, the Scottish Medicines Consortium (SMC) has accepted tapentadol▼ prolonged-release (Palexia® SR) tablets for restricted use within NHS Scotland, for the treatment of severe chronic pain which can be adequately managed only with opioid analgesics. It is restricted for use in patients in whom morphine sulphate modified release has failed to provide adequate pain control or is not tolerated. In a meta-analysis, tapentadol prolonged-release demonstrated non-inferior efficacy, but superior gastro-intestinal (GI) tolerability compared to oxycodone modified-release (MR) tablets. No direct comparative data with other opioids are available.
Readers should note that SMC recommendations only apply in Scotland and that the advice only applies to tapentadol prolonged-release tablets, and not tapentadol immediate release. The manufacturer has not made a submission for the latter tablets at the time of this recommendation.
Local decision-making bodies elsewhere may wish to consider their approach to the management of severe chronic pain in adults and the place in therapy of tapentadol prolonged-release tablets based on the available evidence. NICE clinical guidelines are available for the management of painful conditions such as neuropathic pain, osteoarthritis and low back pain. These guidelines were produced prior to the launch of the tapentadol products, hence neither product is included. A review of the osteoarthritis guideline is currently under consideration. Other possible NICE outputs for pain related guidance have been discussed; the current consultation on Quality Standard topics includes a suggested topic remit for pain management in young people and adults.
What is the background to this?
Tapentadol is a Schedule 2 Controlled Drug. It acts as a mu-opioid receptor agonist with noradrenaline reuptake inhibition properties. The prolonged-release tablets are licensed for the management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics. The most common adverse effects include nausea, dizziness, constipation, headache and somnolence.
Oral morphine is usually considered to be the first-line opioid analgesic in patients with severe pain. Other agents are used in patients who fail to respond to or cannot tolerate morphine.
Tapentadol prolonged-release tablets are taken every twelve hours, with doses titrated under close medical supervision to provide adequate analgesia whilst minimising adverse effects. They are available in 50, 100, 150, 200 and 250mg strengths at a cost of between £24.91 and £124.55 for 56 tablets (Mims August 2011).
Oxycodone MR tablets cost between £24.94 for 56 x 10mg tablets and £299.31 for 56 x 120mg tablets.
Additional information on relevant comparator costs is included in the SMC report.
What does the SMC assessment say?
Efficacy data were analysed from three randomised, double-blind, phase III studies involving a total of 2975 patients in the intention to treat population. Two studies included patients with osteoarthritis of the knee and the third low back pain. All three compared tapentadol prolonged-release with oxycodone MR and placebo. Patients had required analgesia for at least three months (non-opioids or opioids at doses equivalent to 160mg or less of oral morphine per day) but were dissatisfied with their current medication. During a three-week period patients received tapentadol prolonged-release tablets titrated up from 50mg twice daily to an optimal dose of 100 to 250mg twice daily, oxycodone MR titrated from 10mg twice daily up to 20 to 50mg twice daily or placebo. After which, patients received maintenance treatment for 12 weeks. The primary efficacy outcome was change from baseline in average pain intensity over the maintenance period, using last observation carried forward for missing data due to early discontinuation.
The design of the studies did not allow for the use of breakthrough doses of the relevant drug during either dose titration or maintenance therapy. For treatment of lower back pain or osteoarthritis pain, limited use of paracetamol 1g daily was allowed during the titration phase.
A pre-planned meta-analysis (MA) of these studies was undertaken; only 34% of the MA population (n=2959, intention to treat) had received opioids within the previous three months. The aim of the MA was to assess whether tapentadol prolonged-release had superior gastro-intestinal (GI) tolerability to oxycodone MR and, if that was so, then to demonstrate that tapentadol prolonged-release was non-inferior in terms of efficacy. Only 56% of patients who received tapentadol prolonged-release, 38% who received oxycodone MR and 59% on placebo completed the maintenance phase. The higher drop-out rate in the oxycodone MR group, mainly due to adverse effects, may have resulted in an imbalance between the groups. The SMC state that the lower discontinuation rate in patients treated with tapentadol prolonged-release appears to reflect the improved tolerability of this medicine compared to oxycodone MR, which may be an advantage in some patients.
The MA found that tapentadol prolonged-release demonstrated significantly better GI tolerability than oxycodone MR (constipation 17% versus 33%, nausea and vomiting 23% versus 43%, respectively). Tapentadol prolonged-release was non-inferior to oxycodone MR with respect to pain intensity.
The manufacturer’s economic case was based on an in-house subgroup analysis in patients (n=889) with severe pain and prior opioid experience. The SMC considered that the economic case for tapentadol prolonged-release was demonstrated, despite weaknesses in the quality of data from this sub-group analysis.
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