Key points from the evidence

The content of this evidence summary was up-to-date in March 2016. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

The sufentanil sublingual tablet system is pre‑programmed to dispense a single tablet, on a patient‑controlled, as needed basis to manage post‑operative pain.

In 2 randomised controlled trials (RCTs), the sufentanil sublingual tablet system was statistically significantly better than placebo at reducing pain intensity over 48 hours following elective major orthopaedic or open abdominal surgery. In a third, open‑label RCT with methodological limitations, the sufentanil sublingual tablet system was found to be non‑inferior to intravenous (IV) morphine patient‑controlled analgesia (PCA) for participant‑ and nurse‑assessed pain control. The European public assessment report (EPAR) states that the risks associated with sufentanil are consistent with other opioids, including the adverse event profile and the abuse potential.

The sufentanil sublingual tablet system may provide an alternative option to IV morphine PCA for some people with moderate to severe acute post‑operative pain. Suitable groups may include those who are in relatively good health and for whom improved mobility is an advantage, who can safely use the device and are unlikely to need PCA for more than 72 hours.

Regulatory status: The sufentanil sublingual tablet system (Zalviso) received a European marketing authorisation in September 2015. It is anticipated that this product will be launched in September 2016. Sufentanil is classified as a schedule 2 controlled drug subject to the requirements of the Misuse of Drugs Regulations 2001.

Effectiveness

At 48 hours, the sufentanil sublingual tablet system:

  • was statistically significantly better than placebo at reducing post‑operative pain intensity (2 double-blind RCTs, n=426 and n=178).

  • was non‑inferior to IV morphine PCA for the primary outcome of participant and nurse reported successful post‑operative pain control assessment (1 open‑label RCT, n=359).

  • produced a clinically important 50% pain reduction in over a third of participants in the sufentanil groups, compared with less than a fifth of participants in the placebo groups and was comparable to morphine (EPAR).

Safety

  • The sufentanil summary of product characteristics reports that the most common adverse events include nausea and vomiting, and fever. The most serious adverse reaction of sufentanil is respiratory depression. Adverse events were comparable to morphine in the open‑label study.

  • The summary of product characteristics provides further information on contraindications, adverse effects and interactions. These are consistent with other opioids.

  • According to the EPAR, there is a potential for misdosing with the sufentanil device due to tablet misplacement, and for diversion of dispensed tablets.

Patient factors

  • In studies, 6.9% of subjects in the sufentanil group, 11.1% in the IV morphine PCA group and 6.0% in the placebo group experienced adverse events leading to discontinuation (EPAR).

  • The sufentanil sublingual tablet system offers another choice for post‑operative pain relief with studies finding it to be 'user friendly'.

  • Patients should not eat or drink and should minimise talking for 10 minutes after each dose of sufentanil.

  • Healthcare professionals should consider the potential for abuse when prescribing or administering sufentanil, and ensure the individual understands how to operate the administration device correctly.

  • The sufentanil sublingual tablet system is restricted to use for acute moderate to severe post‑operative pain, in the hospital setting and for a maximum duration of 72 hours.

Resource implications

  • The cost of sufentanil sublingual tablet system is confidential until launch. It is likely that the cost of sufentanil tablets and the administration device will be significantly more than the current standard of care, for example IV morphine PCA.

  • IV morphine PCA costs £5.25 for a 50 ml vial of morphine sulfate 1 mg/1ml for intravenous infusion (British National Formulary [BNF], February 2016). This is the cost of morphine sulfate only (excluding VAT) and does not include any procurement discounts or the cost of administration.

Introduction and current guidance

Acute pain is the body's normal response to tissue damage, following injury or trauma, such as surgery. Of people who have surgery, almost 60% will experience severe pain in the post‑operative period and effective control of this pain can contribute to their recovery and rehabilitation, and prevent progression from acute to chronic pain.

NICE has not published guidance on managing acute post‑operative pain. In its core standards, the Faculty of Pain Medicine recommends that, if no national guidance is available, specialist pain management services should consider the development, approval and implementation of local pain management protocols and prescribing guidance. All patients with acute pain should have an individualised analgesic plan appropriate to their clinical condition that is effective, safe and flexible.

Acute pain following injury or trauma, responds well to analgesic medicines such as paracetamol, nonsteroidal anti‑inflammatory drugs and opioids, with the desired outcome being mild or no pain with minimal adverse effects. In its advice on opioids for managing acute pain, the Faculty of Pain Medicine advises that opioids may be less effective for acute pain than medicines with other mechanisms of action, and that they are best used in combination with other analgesics and local anaesthetics as appropriate. See the Core standards for pain management services in the UK for more information.

People who undergo surgery may control post‑operative pain by self‑administering small doses of IV opioid (such as morphine) using programmable pumps (patient‑controlled analgesia or PCA). There is moderate to low quality evidence that PCA is an effective alternative for post‑operative analgesia, with slightly better pain control and increased patient satisfaction when compared with non‑patient controlled methods (McNichol et al. 2015).

Full text of introduction and current guidance.

Product overview

Sufentanil (Zalviso) is indicated for the management of moderate to severe acute post‑operative pain in adults, in a hospital setting only. It should be prescribed only by physicians who are experienced in the management of opioid therapy, particularly opioid adverse events such as respiratory depression. Sufentanil is self‑administered sublingually leading to rapid analgesia. Sufentanil is classified as a schedule 2 controlled drug subject to the requirements of the Misuse of Drugs Regulations 2001. Prescribing guidance for controlled drugs can be found in the BNF and the NICE guidance on the safe use and management of controlled drugs.

The administration device, which contains a cartridge of 40 sufentanil 15 micrograms sublingual tablets, is pre‑programmed to dispense a single tablet on a patient‑controlled, as needed basis, with a minimum of 20 minutes (lockout interval) between doses, over a period of up to 72 hours (the maximum recommended treatment duration, summary of product characteristics).

According to the marketing authorisation holder, the sufentanil sublingual tablet system has a number of built‑in security features to minimise unauthorised access to, and dispensing of the tablets. These include a locked in tamper‑resistant tablet cartridge, visible and audible alarms indicating if the dispenser has been pried from the controller, a tethering cable to secure the device to the bedrail, an adhesive patient thumb tag paired with the device to reduce the risk of 'proxy' dosing, and an authorised access card for each healthcare professional interacting with the system. The device programming cannot be overridden to increase the frequency of dispensing (personal communication, Grünenthal Ltd).

Full text of product overview.

Evidence review

  • In 2 RCTs, conducted in US hospitals, the sufentanil sublingual tablet system was statistically significantly better at reducing pain intensity over 48 hours following elective major surgery compared with placebo. Treatment differences for time‑weighted summed pain intensity difference (SPID) were 87.6 (95% CI 66.2 to 109.0, p<0.001) following knee and hip replacement (Jove et al. 2015) and 50.0 (95% CI 19.9 to 80.1, p=0.001) after open abdominal surgery (Ringold et al. 2015). However, these outcomes are difficult to interpret and the clinical importance of these findings is unclear.

  • In the 2 RCTs (Jove et al. 2015 and Ringold et al. 2015), participant withdrawals due to inadequate analgesia were statistically significantly less frequent in the sufentanil group compared with placebo (14.3% compared with 48.1% of people following hip or knee replacement, p<0.001 and 17.4% compared with 31.6% after open abdominal surgery, p=0.035, for sufentanil and placebo respectively).

  • Participants and nurses each rated the overall ease‑of‑care of the system as greater than 4 on the 0 to 5‑point scale (where 0 is not at all and 5 is a very great deal) in both RCTs, suggesting that the device was easy to use.

  • In Melson et al. 2014, a phase III randomised, open‑label, non‑inferiority trial, sufentanil was compared with the current standard of care, IV morphine PCA, for the management of acute post‑operative pain following major open abdominal or hip or knee replacement surgery. The treatment difference for the proportion of participants reporting successful pain control achieved the predefined criteria for non‑inferiority of sufentanil compared with morphine, and superiority over morphine was also demonstrated (treatment difference 12.9%, p=0.007). However, the clinical importance of the difference between the 2 treatments for these outcomes is difficult to interpret and according to the EPAR the strength of the primary end‑point is uncertain. As this trial was performed in addition to the 2 RCTs the Committee for Medicinal Products for Human Use (CHMP) agreed that it could be accepted as supportive evidence for efficacy of the sufentanil sublingual tablet system.

  • For secondary endpoints, there was no significant difference between sufentanil and morphine for pain intensity (p=0.569) or pain relief (p=0.055) over 48 hours. Participant withdrawals due to inadequate analgesia were less frequent in the sufentanil group compared with the morphine group (7.3% compared with 8.9%, no analysis reported).

  • Participants and nurses were statistically significantly satisfied with the sufentanil sublingual tablet system (p=0.004 and p<0.001 respectively) and rated it as easy to use (p<0.001 and p=0.017 respectively), compared with IV PCA morphine. However these results may be subject to bias because participants and nurses were aware of which treatment had been allocated due to the open‑label study design.

  • The EPAR reports that, because the primary endpoint was difficult to interpret, the CHMP requested further responder analyses to be performed to determine the clinical relevance of the achieved effect in pain reduction with sufentanil sublingual tablet system from the results of the 3 studies. These post‑hoc analyses for Ringold et al. 2015 and Jove et al. 2015 showed that a clinically important 50% pain reduction was achieved in 37% and 31% of sufentanil participants in these trials compared with 17.5% and 9.6% of placebo participants. The responder analysis for Melson et al. 2014, comparing sufentanil and morphine, determined there was a similar clinically important pain reduction in both treatment groups (30% and 32% of participants, respectively). The CHMP concluded that the 3 phase III studies provide sufficient evidence of the efficacy of sufentanil sublingual tablets in acute post‑operative pain.

  • The EPAR states that during phase II and phase III trials, 685 people were exposed to the proposed marketed dose of sublingual sufentanil. However, there is wider experience with IV and epidural sufentanil in other countries outside of the UK. According to the EPAR, the risks associated with sublingual sufentanil are in line with the well‑known class effects of opioids, including the adverse event profile and abuse potential.

  • In the phase III, placebo‑controlled trials (Jove et al. 2015 and Ringold et al. 2015) the most common adverse events included nausea (46.9% in the sufentanil group and 36.4% in the placebo group), pyrexia (17.7% compared with 11.1%) and vomiting (11.7% compared with 6.2%). In the open‑label phase III trial (Melson et al. 2014), which compared sufentanil with morphine, the rates of common opioid adverse events were similar. The summary of product characteristics provides further information on contraindications, adverse effects and interactions of sufentanil.

  • The CHMP concluded that safety and efficacy data from the 3 key studies of sufentanil sublingual could not be extrapolated to other acute pain indications, longer duration of treatment or other clinical settings; therefore, the marketing authorisation for the sufentanil sublingual tablet system is restricted to moderate to severe acute post‑operative pain in a hospital setting for up to 72 hours (European public assessment report).

  • The studies only included people in relative good health who were undergoing elective major open abdominal and hip and knee replacement, limiting generalisability to other populations or types of surgery. People on chronic opioid therapy were excluded from all 3 phase III RCTs, and people with a history of alcohol or opioid abuse were excluded from the 2 placebo controlled studies (Jove et al. 2015 and Ringold et al. 2015). Data on using sufentanil sublingually for post‑operative pain in these populations are limited. The summary of product characteristics reports that people on chronic opioid therapy or opioid addicts may require higher analgesic doses than the sufentanil sublingual tablet administration device can deliver.

  • In 2014, the US Federal Drug Administration (FDA) did not approve a new drug application for the sufentanil sublingual tablet system and to ensure proper use of the device, has requested additional information from the manufacturer before it can reconsider a marketing application. A trial evaluating the usability and functionality of the sufentanil sublingual tablet system is due to start in 2016 (Clinical trials identifier NCT02662764).

Full text of evidence review.

Context

Acute pain responds well to analgesic medicines such as paracetamol, nonsteroidal anti‑inflammatory drugs and opioids. According to the British National Formulary (BNF) a combination of opioid and non‑opioid analgesics is used to treat post‑operative pain and that consulting hospital protocols for details of PCA is advisable.

The cost of the sufentanil sublingual tablet system is confidential until launch. The current opioid of choice for PCA is IV morphine (European public assessment report), which costs £5.25 for a 50 ml vial of morphine sulfate 1 mg/1ml for intravenous infusion (BNF, February 2016). This is the cost of morphine sulfate only (excluding VAT) and does not include any procurement discounts or other costs incurred, such as administration. Other examples of opioids that are used for post‑operative analgesia include fentanyl (PCA), oxycodone (PCA or orally) and diamorphine (PCA). The cost of other opioid analgesics will depend on the preparation chosen and the dosage used, in addition to any procurement discount and other associated costs.

Full text of context.

Estimated impact for the NHS

A potential benefit of the sufentanil sublingual tablet system is as an alternative to IV PCA, therefore avoiding some associated problems and with improved mobility of the patient. However, specialists consulted during the development of this evidence summary advised that any individual having major surgery sufficient to need strong opioid analgesia will likely have an IV infusion in situ. Specialists advised that moving away from IV infusions encourages mobility and compliance with physiotherapy goals and subsequently the use of oral opioids in these situations is considered to be increasing. The disadvantage of oral opioids is the nursing time required to administer controlled drugs to the patient and using a PCA system mitigates for this. The risks of moving around whilst taking strong opioids are the same, irrespective of the mode of analgesia.

In studies with identified methodological weaknesses, the sufentanil sublingual tablet system has been shown to be a user friendly device, which is better than placebo and comparable to IV morphine PCA at reducing post‑operative pain, with an adverse event and abuse risk consistent with other opioids. There is a potential for misdosing with the device due to tablet misplacement and a potential risk of diversion once the tablet has been dispensed. The summary of product characteristics warns that the potential for abuse should be considered when prescribing or administering sufentanil where there is concern about an increased risk of misuse, abuse or diversion.

Educational materials are available for healthcare professionals, which provide guidance on appropriate use of the system and minimising risk.

The summary of product characteristics states that before the sufentanil sublingual tablet system is used, healthcare professionals should ensure that patients understand how to operate the administration device correctly. Only patients who are able to understand and follow the instructions to operate the administration device should use sufentanil sublingual tablets and the ability of the patient to use the device appropriately should be taken into consideration by prescribers. For example, the person's visual or cognitive function and manual dexterity will need to be taken into account. Prescribers should also note that the marketing authorisation for sufentanil sublingual tablet system is restricted to 72 hours duration for the management of post‑operative pain. Consequently it may be necessary to alter analgesia for patients requiring treatment for longer than this.

As well as efficacy, safety and individual user factors, local decision makers will need to take cost into account when considering the likely place in therapy of the sufentanil. The cost of the sufentanil sublingual tablet system is not yet known. It is likely that the cost of sufentanil tablets and the administration device will be significantly more than the current standard of care, for example the cost of IV morphine PCA. Maintenance costs for the administration device will be covered during the 2 year warranty period (personal communication Grünenthal Ltd).

Full text of estimated impact for the NHS.

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.