REVIEW ARTICLE
Pharmacokinetics and pharmacodynamics of sublingual sufentanil for postoperative pain management
T. van de Donk,1 S. Ward,2 R. Langford3 and A. Dahan,4
1 PhD Student, 4 Professor, Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands;
2 Lead Nurse, 3 Honorary Consultant, Pain and Anaesthesia Research Centre, St Bartholomew’s Hospital, London, UK.
Correspondence to: R. Langford Email: richard.langford@me.com
Keywords: Acute pain, Opioid, Postoperative pain, Sufentanil Short title: Sublingual sufentanil for postoperative pain
TvdD and SW are joint first authors and contributed equally.
E-mail addresses:
T. van de Donk t.van_de_donk@lumc.nl
S. Ward sward10626@me.com
R. Langford richard.langford@me.com
Albert Dahan a.dahan@lumc.nl
Summary
Achieving successful treatment remains a challenge. Recently, a sufentanil sublingual tablet system has been developed for treatment of moderate to severe pain in the postoperative setting. The phenylpiperidine sufentanil is a potent analgesic that rapidly crosses the blood-brain barrier and selectively activates the mu-opioid receptor at central sites. The sublingual tablet system makes use of a hand-held dispenser system, which contains forty sublingual 15 μg sufentanil micro-tablets. The patient can release one tablet at 20-min intervals using a unique radiofrequency adhesive tag, which is wrapped around the patient’s thumb. In this review, the authors discuss (1) sublingual sufentanil’s pharmacology as basis for its suitability in the treatment of postoperative pain; (2) the current evidence of the efficacy of the sublingual sufentanil system in postoperative pain treatment; and (3) advantages and limitations of the sublingual system. Our critical appraisal lead us to conclude that, albeit a potent opioid, sufentanil is suited for the transmucosal route due to its pharmacokinetic profile, including rapid onset, absence of active metabolites and low tissue accumulation. The efficacy and safety of the sufentanil sublingual tablet system was proven in a limited set of studies in over 600 patients and further independent studies are required to determine the position of the system amongst all other forms of postoperative pain treatment. We conclude that the sublingual sufentanil tablet system allows effective pain relief and allows patients to control their own pain relief and allows early postoperative mobility.
Introduction
Despite multiple options to manage acute postoperative pain, achieving successful treatment remains a challenge [1-5]. The development of modern acute pain management has featured the implementation of opioid-sparing, multimodal therapies together with local anaesthetic techniques. Evidence-based procedure- specific analgesic approaches are encouraged, especially if a targeted regional anaesthetic block is appropriate for a particular operative procedure. Nevertheless, parenteral and oral opioids remain the mainstay of pain management. A recent trend has been towards regularly administered oral opioids, with on-request
supplementation for breakthrough pain; however there is a risk of prolonged
‘analgesic gaps’ if supplements are dependent on nursing administration.
Sufentanil is a potent opioid analgesic, a thienyl derivate of fentanyl, that was first synthesised in the early 1970s [6]. It has an established role as an intravenous component of balanced general anaesthesia, or administered epidurally in combination with a local anaesthetic. Sufentanil is suitable for transmucosal
application [7-10]. A sublingual sufentanil tablet has been developed recently for the treatment of moderate to severe post-operative pain in the hospital setting; this is delivered via a patient-controlled hand-held delivery system [7-10]. In this review, we will critically discuss the pharmacokinetics and pharmacodynamics of sufentanil, and examine its use in postoperative pain treatment.
Pharmacokinetics and pharmacodynamics
Sufentanil acts selectively at the μ-opioid receptor to produce analgesia and opioid- related adverse events. It has various properties that make it suitable for the treatment of postoperative pain.
Pharmacokinetics. Fig. 1, left panel, shows the mean sufentanil plasma concentration (Cp) in 22 healthy volunteers following administration of a 15 μg dose by various routes [6]. Following intravenous administration the maximum plasma concentration (CMAX) is 335 pg.ml-1 at 3 min, followed by a steep decline in Cp. This fits with a three
compartment pharmacokinetic model with an early distribution half-life of 1.4 min, redistribution half-life of 17.7 min and terminal elimination half-life of 164 min [11].
The short early distribution half-life makes intravenous sufentanil unsuitable for postoperative pain treatment, as the analgesic effect will be short-lived. Sublingual sufentanil has a 10-fold lower CMAX of 34.5 pg.ml-1 at 70 min, but a 25-fold longer early distribution half-life causing a more prolonged action. The bioavailability of oral sufentanil is poor at 9%, which results in a CMAX of 3.6 pg.ml-1 at 60 min; in
comparison, the bioavailability of sublingual sufentanil is 60% [10].
Fig. 1, right panel, shows the mean plasma concentration of repeated sublingual sufentanil administration in 38 healthy volunteers; 40 15 μg tablets were
administered at 20 min intervals [10]. A semi-steady-state Cp was reached after 13 doses at 4 h. The CMAX of 245 pg.ml-1, reached at 12 h, was 8-fold higher than after a single sublingual dose.
Context-sensitive half-time. The context-sensitive half-time (CSt½) is the time needed for the Cp of a drug to decrease by 50% from a steady-state [12]. The ideal CSt½ is not too short, allowing return of pain, or too long with protracted recovery from therapy. The CSt½ of sufentanil is about 1 h after a 6 h intravenous infusion [13].In contrast, the CSt½ of fentanyl is > 6 h following a similar infusion [13]. The use of repeated sublingual sufentanil tablets mimics the continuous infusion of intravenous sufentanil. Context-sensitive half-times are therefore comparable, although the data presented in Fig. 1, right panel, indicate that the time to a 50% reduction in plasma concentration approaches 2 h. We argue that this is advantageous as this may coincide with prolonged pain relief.
Potency. Sufentanil is one of the most potent opioids used in clinical practice. It is 12- times more potent than fentanyl, based on effect-site concentration, and about 400- times more potent than morphine based on dose [11,14]. The therapeutic
index/therapeutic window is the lethal dose in 50% of animals divided by the effective dose in 50% (LD50/ED50) [15]. The therapeutic index of sufentanil is ≈ 26,700, compared with 280 for fentanyl, 70 for morphine) and 5 for pethidine.
However, it remains to be established whether such a difference translates into any tangible clinical benefit.
Onset of action. Sufentanil is highly lipophilic and therefore readily crosses the blood- brain barrier [16]. Scott et al. estimated the blood-effect-site equilibration half-life (t½ke0) by measuring the lag time between changes in plasma sufentanil
concentration and changes in spectral edge frequency of the electroencephalogram.
They calculated the t½ke0 for sufentanil at 6.2 min, similar to that of fentanyl at 6.6 min [14].14 In comparison, the t½ke0 of morphine and its active metabolite morphine- 6-glucuronide are approximately 3 h and 6 h, respectively [17,18]. The difference is shown in Fig. 2, where plasma and effect-site concentrations of sufentanil and morphine following repeated administrations are simulated. The concentration of morphine in the central nervous system, the presumed effect-site, lags significantly behind its plasma concentration. In contrast, the effect-site concentration of sufentanil follows the plasma concentration with minimal lag during repeated sublingual administrations. The differences in pharmacokinetic and
pharmacodynamic behaviour are responsible for sufentanil being more titrateable than morphine, as changes in plasma concentration are rapidly translated into changes in effect.
Metabolism. Sufentanil is metabolized by the liver and enterocytes of the small intestines, catalysed by the cytochrome P450 enzyme system [19]. The CYP3A4 subsystem is responsible for the N-dealkylation of sufentanil to mostly inactive metabolites. An active metabolite, desmethylsufentanil, has 10% of the activity of sufentanil but is produced in minute quantities and therefore is not clinically
relevant. The metabolism of sufentanil in the gastrointestinal tract is responsible for the low bioavailability following oral administration, so if a patient accidentally swallows a sublingual tablet there will be under-dosing. While the absence of clinically relevant metabolites makes sufentanil an option in mild-to-moderate renal impairment, there is insufficient data in patients with severe renal impairment, and hence careful patient monitoring is advised [20-22].
The sufentanil sublingual tablet system in clinical studies
The sufentanil sublingual tablet system makes use of a hand-held dispenser system.
The hand-held system contains a cartridge that contains 40 sublingual 15 μg
sufentanil micro-tablets. The patient can release one tablet; to prevent unauthorised use by someone other than the intended patient, the system is initialised with a unique radiofrequency adhesive tag, which is wrapped around the patient’s thumb.
The thumb tag has to be in close proximity of the blue responder on the front of the device to activate the system and release a single tablet (Fig. 3). After each successful demand, the sufentanil sublingual tablet system has a 20-min lockout time, before the system will permit another dose to be self-administered. For safety reasons (e.g., to prevent theft) the system can be tethered to the bed or other fixed objects. A specific access card allows nurses and doctors to interact with the system. Such interactions include opening of the system, filling of the system with a first cartridge, removal of a cartridge, replacement of an empty cartridge and linking the thumb tag to one specific device. It is important to realize that the system is active for 72 hours.
When opioid pain control is required for longer periods a second system (with a new cartridge) needs to be activated. The initial development programme included seven regulatory Phase I trials conducted in healthy subjects, and three Phase II dose finding trials, investigating 5, 10 and 15 μg doses, in patients after abdominal or orthopaedic surgery. There have been a further three Phase III (regulatory) clinical studies that investigated the efficacy and safety of the sufentanil sublingual tablet system versus placebo or an active comparator in postoperative patients [6-8]. All these studies have been sponsored by the company that developed the sufentanil sublingual tablet system (AcelRx Pharmaceuticals Inc., Redwood City, CA, USA).
Two double-blind randomised placebo-controlled trials were performed in major orthopaedic (primary hip or knee arthroplasty) and general surgery patients,
respectively. In the study by Ringold et al. [8], patients after open abdominal surgery had a significantly greater decrease in (summed) pain intensity scores during
treatment with sublingual sufentanil compared to placebo (mean scores ± SEM placebo 55.6 ± 13.1 vs. sublingual sufentanil 106.6 ± 10.1, p = 0.001; measurement period 72 h). Safety parameters, including adverse events and vital signs, were
similar between treatment groups. Similar observations were made in orthopedic surgery (placebo -11 ± 11 vs. sublingual sufentanil 76 ± 7, p < 0.001; measurement period 48 h), although a higher incidence of nausea and vomiting was observed in patients treated with sublingual sufentanil [7].
There is currently one more clinically relevant randomised study that compared SL sufentanil with an active comparator, intravenous patient-controlled analgesia (PCA) morphine [9], albeit non-blinded. The study was performed in 357 patients after major abdominal or joint replacement surgery. The primary endpoint was based on achieving ‘good’ or ‘excellent’ scores of ‘Patient Global Assessment at 48 h’ as rated on a 4-point scale. The sufentanil sublingual tablet system demonstrated significance for both non-inferiority (p < 0.001) and superiority (p = 0.007) as compared to PCA morphine. A possible explanation is that the sufentanil sublingual tablet system had a faster onset of action compared to intravenous PCA morphine, as observed by significantly better pain scores at 1, 2 and 4 h (p < 0.01), and also longer mean dosing intervals for the sufentanil sublingual tablet system compared to intravenous PCA morphine. The nature and rate of adverse events were similar between the two groups, with most being mild or moderate, and typical for postoperative patients receiving opioid analgesics. Arterial oxygen saturation showed a statistically
significant lower percentage of patients experiencing oxygen desaturation episodes <
95% in the sufentanil sublingual tablet system group versus intravenous PCA morphine (p = 0.03), but this finding requires corroboration in further and larger studies [9]. Three patients and five patients in the sufentanil sublingual tablet system group and to intravenous PCA morphine group, respectively, experienced serious adverse events, all of which were transient in nature [9].
Analysis of the 600 individuals in the full phase I-III data set, who have received sublingual sufentanil, revealed the following adverse events, probably or possibly related to sufentanil treatment: nausea (in approx. 30% of patients), reported oxygen desaturations (7%), constipation (6%) and dizziness (5%) [15]. Other side effects included headache, pruritus, hypotension, confusion, orthostatic hypotension and sedation. These did occur at frequencies below 5%. These frequencies are
comparable to other forms of postoperative opioid treatment such as intravenous morphine patient-controlled analgesia (PCA) [9,15].
The sufentanil sublingual tablet system in clinical practice: current advantages and limitations
The sufentanil sublingual tablet system was developed, and subsequently authorised, for acute moderate to severe post-operative pain management for in-patients. One important advantage of the sufentanil sublingual tablet system is that patients can receive their pain medication without dependency on a patent intravenous
connection, and hence avoids some risks with to intravenous PCA systems, such as obstruction or displacement of the intravenous cannula, infection, syphoning and restricting mobility.
Since sublingual sufentanil is a potent opioid, safety is an important issue, as it is with all opioid analgesics. It should therefore be emphasised that requirements for patient observation and monitoring are the same for the sufentanil sublingual tablet system, as for any post-operative patients on strong opioid medication. Moreover, the system will be applied with a new drug-delivery system, which may be a source for error.
Hence, the implementation of the system will obviously require training of all staff involved in the set-up, maintenance, discontinuation and disposal, as well as specific sufentanil teaching for clinicians currently unfamiliar with this analgesic.
As with all centrally acting drugs, sufentanil interacts with other central nervous system depressants such as benzodiazepines, barbiturates, other opioids and general anaesthetics. Another issue that deserves attention is the question how to transition from intra-operative to post-operative analgesic management. Even if intravenous sufentanil has been used intra-operatively (it is currently available and commonly used in various European countries), intravenous sufentanil boluses may not be regarded as suitable for rescue analgesia in the recovery room following emergence from anaesthesia. One possible approach, already an established routine in most institutions, would be to administer other opioids such as morphine or piritramide as
a bridging technique from intra- to post-operative management, but again local protocols will need to be devised and disseminated.
As a strong opioid, sufentanil is a schedule II controlled drug, and hence its security and disposal need to be managed and documented appropriately. Several options for destruction and reconciliation may be considered such as retaining the cartridge for reconciliation back to the pharmacy department, ejecting the tablets from the cartridge dispenser, crushing, and dissolving in water for disposal as per local
practice, and disposing of the cartridge within a sharps disposal box for incineration.
However, institutions should follow their local guidelines and develop a specific policy prior to implementing the sufentanil sublingual tablet system.
The sufentanil dose of the sufentanil sublingual tablet system is fixed and only one lockout interval is available. Conventional, programmable intravenous PCA systems allow flexibility in drug choice and dose settings. Although flexibility is linked to a risk of drug and programming errors, the fixed dose of the sufentanil sublingual tablet system may result in use limitations. The dose may be considered too much for a few underweight, elderly or frail patients, or too little for patients requiring higher opioid doses. Patients on long-term high-dose opioids (prescribed or recreational use) require baseline provision of their usual daily opioid equivalent dosage, and often, higher additional opioid doses to manage the acute pain [23]. To date there is no experience of using the sufentanil sublingual tablet system in such patients, as they were excluded from the clinical trials. The sufentanil sublingual tablet system may not be deemed suitable, although it remains to be seen whether the
pharmacokinetic and pharmacodynamic characteristics of sufentanil render it suitable for patients on pre-existing low to medium opioid dose therapy.
Some of us already have clinical experience with the sufentanil sublingual tablet system (AD). There were some start-up issues but after having treated some 100 patients it is obvious that pain relief is good and patient satisfaction high. The tablet consumption varies considerably with some patients using just one or two tablets during their complete recovery phase following surgery while others use one or two
tablets per hour. This suggests that we still need to find the appropriate indication for the sufentanil sublingual tablet system both in terms of patient selection as well as in terms of surgical intervention. With respect to patient selection, some patients may have difficulty in operating the system. It is evident that a confused or (mildly) cognitive impaired patient is better off with another form of pain relief. Still, the majority of patients indicated that they were satisfied with the sufentanil sublingual tablet system, mostly because of efficacy, the ability to control their own pain relief and mobility. Note that all patients on the sufentanil sublingual tablet system additionally received paracetamol and when possible a non-steroidal anti- inflammatory drug.
In conclusion, the sufentanil sublingual tablet system is an innovative technique for postoperative pain relief. Sufentanil, albeit a potent opioid, is especially suited for the transmucosal route due to its pharmacokinetic profile, including rapid onset, absence of active metabolites, and low tissue accumulation. The drug is administered via a hand-held drug delivery system without reliance on an intravenous access line. The efficacy of the sufentanil sublingual tablet system has been studied in a limited number of regulatory studies, which are all sponsored by the manufacturer of the system. Future studies from independent sources are required to assess the position of the system amongst all other forms of postoperative pain treatment. As discussed by the National Institute for Health and Care Excellence (NICE) “the sublingual sufentanil tablet system may provide an alternative option to intravenous PCA morphine for some people with moderate to severe pain” [24]. We agree and like to add that suitable patients need to have good cognition, vision and use of their hand to safely operate the system. The major advantage of the sublingual sufentanil tablet system is improved mobility, which may be an advantage for many but certainly not all patients.
Conflicts of interest
Two meetings of the authors were facilitated by Grünenthal Ltd, who also provided honoraria for authorship. The manuscript was written without any editorial input or influence from Grünenthal Ltd. AD, RL and SW have received speaker and/or consultancy fees from Grünenthal Ltd. TvdD - no competing interests declared.
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Captions to figures
Figure 1. Left panel. Plasma concentration (Cp) of sufentanil following the intravenous (orange symbol), sublingual (blue symbol) or oral (green symbol) administration of a 15 μg dose. Right panel. Cp following 40 consecutive doses of sublingual sufentanil 15 μg at 20 min intervals (horizontal red bars). Data redrawn from [10].
Figure 2. Plasma concentration (Cp, blue line) and effect site concentration (Ce, orange line) with repeated drug administration. Left panel. Sublingual sufentanil (assuming 6.2 min blood-effect-site equilibration half-life [17]) A sublingual tablet was administered at 51 ± 3-min intervals. Right panel. Intravenous morphine (Cp, green line, and Ce, red line, are for morphine and its active metabolite morphine-6- glucuronide); intravenous morphine administration at 30 min intervals initially, and at 1 h intervals after 4 h (assuming 2.8 h blood-effect-site equilibration half-life for morphine and 7 h for morphine-6-glucuronide [25]). Simulation by Dennis Fisher MD.
Figure 3. Dispenser tip positioned for a patient activated dose of sublingual sufentanil
