ˇ)$ˇ˙& ˙! 2016; 20: 1411-1422 Sublingual sufentanil, a new ... · ing interest in Italy on the topic of “pain”, in par - ticular after the introduction of Law 38/2010, that

Abstract. – Despite the availability of na-tional and international guidelines, adequatepostoperative pain (POP) management is still achallenge in Italy. One of the potential reasonsfor the high incidence of surgical patients com-plaining moderate to severe pain is the difficultapplication of the currently recommended anal-gesic techniques in clinical practice. In particu-lar, morphine, the most commonly used sys-temic opioid in the POP treatment, has someunfavorable pharmacodynamic and pharmaco-kinetic characteristics for POP management,suggesting a potential relevant improvementby using different opioids.

Many of sufentanil properties make it partic-ularly suitable for POP control: a high affinityfor the µ opioid receptor, the highest therapeu-tic index compared to any other opioid used inclinical practice and the absence of clinicallyrelevant active metabolites.

The elevated potency, together with the highlipophilicity of sufentanil, allow the preparation ofa nanotablet, 3 mm of diameter and 0.75 mm ofthickness, containing 15 µg of active drug. Thesublingual route allows a longer time of drugplasmatic permanence in comparison to IV route,overcoming the need for continuous dosing.

The patient-controlled system, considered inthe present review, is preprogrammed to deliv-er one sublingual tablet of sufentanil with a 20-minute lockout period with a radiofrequencyidentification thumb tag allowing only the pa-tient to activate the on demand button.

Phase II and III studies have assessed the ef-ficacy of this system in POP management,showing that it was considered more satisfac-tory than the IV PCA morphine system by bothpatients and nurses.

The introduction of this simple and innovativesystem of patient-controlled analgesic adminis-tration could represent an opportunity for Italy toupdate the current practice in POP management.

European Review for Medical and Pharmacological Sciences

Sublingual sufentanil, a new opportunity for the improvement of postoperative pain management in Italy

P. SACERDOTE1, F. COLUZZI2, A. FANELLI3

Corresponding Author: Andrea Fanelli, MD; e-mail: [email protected] 1411

Key Words:PCA, Postoperative pain, Sublingual, Sufentanil.

Introduction

Inadequate post-operative pain (POP) manage-ment is still a major burden for most healthcaresystems. About 70% of the 240 million post-sur-gical patients every year suffer from moderate tosevere pain1.

Uncontrolled POP may result in significant clini-cal and psychological changes that may lead to anumber of medical complications, including pneu-monia, infections, deep vein thrombosis, cardiovas-cular events, and depression. Pain relief has a keyrole in multimodal strategies to improve surgicaloutcome, together with preoperative assessment, in-formation and optimization, reduction of surgicalstress, rapid mobilization, and early oral nutrition2.

In the current practice, the effectiveness ofPOP management is mainly evaluated throughthe cost of treatment, the length of stay, and thenumber of unanticipated readmission; however,these “here and now” outcomes could not be theright questions to ask. A good-quality periopera-tive care should be measured through patient-centred outcome studies in terms of patients’ sat-isfaction, quality of recovery, quality of life, andincidence of long-term morbidities, such aschronic post-surgical pain (CPSP)3.

International and national guidelines4,5 recom-mend three analgesic techniques, including intra-venous (IV) patient-controlled analgesia (PCA),epidural analgesia (EA), and continuous periph-eral nerve blocks (CPNB).

2016; 20: 1411-1422

1Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy2Department of Medical and Surgical Sciences and Biotechnologies, Unit of Anaesthesia, IntensiveCare and Pain Medicine, Sapienza University of Rome, Rome, Italy3Department of Medical and Surgical Sciences, Anesthesia and Pain Therapy, Policlinico S. Orsola-Malpighi, Bologna, Italy

P. Sacerdote, F. Coluzzi, A. Fanelli

site-specific local anaesthetic (LA) delivery, bet-ter analgesia, and prevention of premature anal-gesic block regression12. However, even with theintroduction of ultrasound, PNBs are associatedwith an increased risk of infection and likelihoodof hematoma compared with systemic analge-sia13. Moreover, CPNBs require additional timeto discuss with the patient, to perform the block,and to obtain the onset of analgesia14.

The most interesting question is why thesetechniques and drugs introduced over the past 20years for acute pain management have not im-proved postoperative outcomes. One possible ex-planation is the gap between a clinically mean-ingful advantage and the availability of resourcesnecessary to use these techniques, including thegreater risk of possible complications that requireadditional clinical surveillance15.

Recognizing the barriers to effective POPmanagement is the first step to achieving optimalpost-operative analgesia16.

In Italy, two surveys have been conducted in2006 (Post Operative Pain Survey in Italy - POP-SI)17 and 2012 (POPSI-2)18 on POP management,including data on commonly used analgesic tech-niques and protocols, healthcare professionals(HCPs) education, availability of Acute Pain Ser-vices (APS), and perceived barriers to clinical im-provement. Both surveys included about 600 Ital-ian anaesthesiologists with homogeneous regionaldistribution across the Country. Despite the grow-ing interest in Italy on the topic of “pain”, in par-ticular after the introduction of Law 38/2010, thatassures the right of citizens to have access to paintherapy, the most recent survey showed noprogress in the treatment of acute pain, confirm-ing the suboptimal management, probably relatedto organizational, cultural, and economic obsta-cles18. A recent survey involving about 300 Ital-ian nurses, who daily play a key role in pain man-agement and spend more time with patients thanany other HCP, showed a low level of knowledgein the assessment and management of POP19. Im-plementation of specific training for all the actorsinvolved in the perioperative period (anaesthesi-ologists, nurses, surgeons, physiotherapists, pa-tients, and relatives) is mandatory. However, ac-cording to the results of POPSI-2, in the last yearsin Italy there was a significant reduction of con-tinuing medical education in postoperative paincontrol, probably related to the lack of interest bypharmaceutical and medical device companies,which may support the financial expenses of sci-entific sessions18.

IV-PCA is nowadays the gold standard ofacute pain control. The patient is directly in-volved in POP management and the dose of anal-gesics is tailored on real patient’s need. These el-ements play a key role in providing better anal-gesia and superior patient satisfaction than PRN(pro re nata - as needed) parenteral opioids.There is no evidence that one opioid via IV-PCAis better than another, however, on an individualpatient basis, one opioid may be more indicatedthan another (i.e. morphine for obese patientsand fentanyl for patients with renal impairment)6.However, IV-PCA requires systematic informa-tion of patients and adequate caregivers training,which may need additional time in the periopera-tive period. Moreover, IV-PCA pumps are proneto technical problems, including operator errors(i.e. programming and drug mistakes, inappropri-ate prescription and concentration, accidental bo-lus administration during syringe change, mis-connections) and patient’s errors (i.e. failure tounderstand the device or activation of the pumpby others, such as caregivers or relatives)7.

Regional techniques are used alternatively todirect drug delivery in proximity to the receptoror near the target tissue.

EA provides better postoperative analgesiacompared with parenteral opioids, regardless ofanalgesic drug, location of catheter placement,and type and time of pain assessment8. More-over, EA has been shown to significantly reducethe incidence of postoperative pulmonary com-plications (PPCs) and to hasten return to postop-erative gastrointestinal (GI) function9. However,EA is limited by the high rate of failure (aboutone-third of patients receiving either lumbar orthoracic epidural analgesia)10, the potential forneurological damage subsequent to spinalhematoma (permanent injury 1:24,000 to1:54,000 treated patients) and the risk of infec-tions. The increasing use of chronic anticoagu-lant therapy for cardiovascular diseases, includ-ing new oral anticoagulants for atrial fibrillation,significantly limited the use of EA, in favor of al-ternative regional analgesic techniques, such asparavertebral blocks for thoracic surgery andTransversus Abdominus Plane (TAP) block forabdominal and gynecological surgery.

Finally, in orthopaedic surgery, regardless ofcatheter location, CPNBs have been shown toprovide superior analgesia and fewer opioid-in-duced side effects11. When compared with sin-gle-shot peripheral nerve blocks, CPNBs presenta number of advantages, including prolonged

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The most upsetting result of these surveys isthat in Italy the most commonly used analgesictechnique is the continuous IV infusion of anal-gesics through elastomeric pump systems (Figure1). There is no scientific support for the IV useof these devices, as neither randomized con-trolled trials have ever tested their efficacyagainst proved analgesic techniques, nor recom-mendations and guidelines include them amongthe suggested analgesic approaches. Further-more, few papers are available on elastomericpumps use for LA continuous infusion (perineur-al or near the surgical wound). However, 50% ofItalian patients continue to be treated with con-tinuous infusion of opioids or other analgesics.Use of elastomeric pumps presents a number oflimitations. They do not guarantee tailored post-operative analgesia and often their use is accom-panied by under-dosing of opioids to avoid therisks of a continuous infusion without any safetyfeedback. The main reasons for not using PCApumps in Italy resulted the costs that limit theavailability, and the length of training for care-givers. Lack of economic resources is also themain reason for the limited number of APS in theCountry. Consequently, most of the used proto-cols are not universally accepted, but have beenwritten in the hospital local setting and often arenot completely shared even among anaesthesiol-ogists of the same unit18.

The introduction of simple and innovative sys-tems of PCA delivery could represent an oppor-

tunity for Italy to update the current practice inPOP management.

The ideal opioid for patient-controlledanalgesia

Moderate to severe POP is usually controlledusing a multimodal approach, including opioids.Although it is clear that all opioids share the samemechanism of actions, the single molecules havespecific pharmacodynamic and pharmacokineticcharacteristics that should drive the choice of theopioid according to the type of pain that need tobe treated, the most convenient route of adminis-tration, and the characteristic of each patient20-22.

The theoretical characteristics for and idealopioid for post-operative pain control are:• a rapid and consistent onset of action support-

ed by a fast equilibration between plasma andthe central nervous system (CNS) with a limit-ed efflux transporter effect;

• be devoid of active metabolites that may accu-mulate post-operatively increasing the risk forprolonged sedation or other adverse effects;

• a limited effect of hepatic or renal dysfunctionon clearance;

• an acceptable tolerability profile.Morphine has some unfavorable pharmacody-

namics and pharmacokinetic characteristics forPOP treatment, suggesting a relevant improve-ment by using different opioids; However, it rep-resents the most commonly used opioid for POPcontrol in Italy18,22-24.

Figure 1. Analgesic techniques in 2006 vs.2012 in Italy.

Clinical Pharmacology of SufentanilSufentanil is a highly lipophilic synthetic

piperidine derivative opioid, synthesized in themid-1970s and since then used in anesthesiologyfor intravenous, epidural and subarachnoid ad-ministration25,26.

This molecule has many pharmacodynamicproperties that make it particularly suitable forpost-operative pain control. Sufentanil has a highaffinity for the µ opioid receptor27; it is 300-400fold more potent than morphine and 5-10 foldmore potent than fentanyl28-30.

The preclinical pharmacology indicates thatsufentanil has the highest therapeutic index (ratiobetween the toxic drug dose and the dose thatgives a therapeutic effect in animal studies) com-pared to any opioids used in the clinic (Table I)28.In support to clinical relevance of the high thera-peutic index a few clinical studies have suggest-ed a lower incidence of respiratory depressionthan fentanyl and morphine (Figure 2)24,30.

Sufentanil, as well as fentanyl, is metabolizedin the liver by CYP3A4 and have no clinicallyrelevant active metabolites (Table I)31. In con-

trast, morphine glucuronide metabolites (Mor-phine 3-Glucuronide and Morphine 6-Glu-curonide) are active, and their accumulation rep-resents a risk for a prolonged duration of actionand untoward effects. A phase III study, compar-ing sufentanil sublingual tablet versus IV mor-phine PCA over a 48-hour dosing period, showeda significant accumulation of plasma morphine3-Glucoronide in the morphine group30.

Rate of Equilibration Between the plasma and Effector Sites (opioid Receptor) in central Nervous System

An important parameter to be considered in thechoice of the optimal opioid for PCA is the equili-bration half-life between the plasma and the µ-opioid receptor site in the CNS, known as t½Ke0

22,23.Obviously, opioids function at CNS receptors,

and the plasma/CNS equilibration half time is a re-liable parameter for predicting onset of action. Thet½Ke0 is experimentally calculated by evaluating anobjective CNS opioid effect (such as miosis orEEG) and comparing the kinetic of this effect withplasma drug concentration, therefore, determining


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Figure 2. Oxygen desaturation events in aphase III study SSTS vs. IV PCA MS30.

Plasma/CNS equilibration

Opioid Therapeutic index*28 Active metabolites31 half-life (t1/2ke0) min

Fentanyl 277 No (CYP3A4) 6.622,32

Morphine 71 M3G-M6G 168.022-23,

Sufentanil 26716 No (CYP3A4) 6.232

Table I. Main pharmacodinamic and pharmacokinetic properties of opioids commonly used for POP treatment.

*Therapeutic index is the ratio of LD50/ED50 in preclinical studies; M3G: Morphine-3-glucuronide; M6G: Morphine-6-glu-curonide

Sufentanil 15 mcg

Sublingual Sublingual Sublingual after repeated 40 repeated

Parameter IV single dose doses doses

AUC0-inf (h.pg/ml) Mean (SD) 273.8 (61.1) 125.5 (47.7) 4216.6 (1225) 75.1 (22.4)

Cmax (pg/ml) Mean (SD) 445.1 (312.0) 35.0 (12.2) 276 (77) 249.6 (72.1)

Tmax (h) Mean (SD) 0.1 (0.0) 0.9 (0.3) 10.9(0.5) 0.4 (0.2)

PT1/2 (h) Mean (SD) 0.2 (0.1) 2.2 (0.9) ND 2.5 (0.6)

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the time needed for equilibration between site ofeffect and plasma concentration. For opioids thatare lipophilic such as fentanyl and sufentanil thisequilibration is rapid (Table I)28,31. The presence ofefflux transporters such as Glycoprotein P repre-sents a limiting factor for a fast equilibration.Sufentanil is not a substrate for Glycoprotein P,thus guaranteeing a fast and repetitive onset of ac-tion33. In contrast morphine and its metabolites aremore hydrophilic, have a limited ability to diffusein a lipidic environment (CNS) and are substratefor efflux transporters33; as a consequence the plas-ma/CNS equilibration of morphine and its metabo-lites can take hours at difference with the few min-utes needed for sufentanil and fentanyl (Table I).In the IV PCA setting, the delayed equilibrationmay be overcome by a possible initial overshoot ofdrug administration by patients or by rescue drugbolus, adding a risk for side effects.

Therefore, based on its therapeutic index, lackof active metabolites and short t1/2Ke0, sufentanilhas optimal characteristics for postoperativePCA. The obvious question is why this moleculeis not routinely used for IV PCA. The answer isthat sufentanil when injected IV has a rapid highCmax, followed by a short alpha-redistributionhalf-life, thus resulting in a rapid onset, as de-scribed above, but also in a very short durationof action requiring a high redosing frequency.This pharmacokinetic problem has been over-come by administering sufentanil via the sublin-gual route rather than IV.

pharmacokinetic of Sufentanil SublingualTablet

The elevated potency together with the highlipophilicity of sufentanil allows the preparation

of nanotablet, 3 mm diameter and 0.75 mm thick,containing 15 µg of active principle (sufentanilsublingual tablet 15 µg, SST). The small dimen-sions of the nanotablet are intended to minimizetaste and salivation, when placed under thetongue, reducing swallowing of saliva containingdrug and maximizing transmucosal uptake.

Sublingual absorption of SST was evaluated inseveral studies, and results demonstrated the fa-vorable pharmacokinetics that is obtained cou-pling sufentanil with the sublingual route of ad-ministration34,35.

SST, delivered sublingually as single dose,demonstrated a media plasma half time (Pt1/2, i.e.the time from Tmax to time at which plasmaconcentration reached half of Cmax after drugdiscontinuation) of 2.2 hours, significantlylonger than that measured after IV administrationof 0.2 hours (Table II)34. The sublingual route al-lows a longer time of drug permanence in plas-ma, and one of the main concern of using sufen-tanil for IV PCA, that was the need for too fre-quent dosing, was therefore overcome.

Sufentanil undergoes a significant first passeffect by the liver, that causes bioavailability byos to be low, <10%34. As already reported above,the high potency of sufentanil can be exploited inthe nanotablet adhesive formulation that reducesthe amount of sufentanil solubilized in the salivaand inadvertently swallowed; together with sub-lingual route of administration there is guaranteefor a rather high bioavailability, that in relationto IV administration is 59%.

The pharmacokinetic properties of a single-dose administration of sufentanil 15 µg by IVroute of administration reached a mean Cmax of445 pg/ml, while the measured Cmax after sub-

Table II. Pharmacokinetic properties of 15 µg of sufentanil administered as IV bolus or as SST in single and repeated-dose34-35.

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lingual route of the same dose was 35.0 pg/ml(Table II)34,35. These data clearly indicate thatsublingual administration avoids the peak plasmaconcentrations that can be of concern for safety.

In the treatment of POP, the patients can selfadminister repeated doses of SST with a lockoutperiod of 20 minutes. The pharmacokinetic para-meters of repeated dosing of SST, one tabletevery 20 minutes for 40 doses was assessed inhealthy volunteers. As expected both Cmax andAUC were greater after repeated administrationcompared with those after single dose of SST(Table II)34,35. However, it is important to under-line that the mean Cmax measured with repeatedsublingual administration of sufentanil tablets atmaximal frequency of dosing (every 20 minutes)was 249.6 pg/ml, that remained lower than thatachieved after a single IV dose of sufentanil(445.1 pg/ml). These results suggest a great mar-gin of tolerability for SST also after repeateddosing, avoiding rapid high plasma concentra-tions that may produce undesirable adverse ef-fects (Figure 3).

Another important parameter that needs to betaken into consideration in the patient– con-trolled self administration paradigm with repeat-ed sufentanil dosing administration, is the Pt1/2

following the last dose of SST after 40 sequentialdoses every 20 minutes compared to a singledose. It is important that this parameter would re-main fairly stable allowing a predictable andconsistent offset of the analgesic effect of sufen-tanil after the last administration, avoiding therisk of delayed adverse effects. The mean Pt1/2 af-ter a single dose administration of SST was cal-culated to be 2.2 hours, that become 2.5 hours af-ter the last repeated (of 40 sequential doses)

dose, indicating no risk of drug accumulation(Table II). It has also to be underlined that in thisstudy34, SST was administered at the maximumallowed frequency (every 20 minutes), while inthe phase 3 studies, the median interval betweendosing in patients was 80-100 minutes30,35,37.

In contrast, for fentanyl it has been reportedthat a prolonged infusion over 4 hours results ina relevant increase of its Pt1/2, due to high volumeof distribution and its long elimination half-life(Pt1/2 = 180 minutes after 4 hours and 290 min-utes after 8 hour infusion)38.

Risk of Drug interactionsSufentanil is metabolized in the liver by the

CYP3A4 enzyme, and as a consequence co-ad-ministration of drugs that affect CYP3A4 mayalter sufentanil metabolism. Indeed in a phase 1study, ketoconazole a well known CYP3A4 in-hibitor was co-administered, and a slightly high-er but not significantly different sufentanil peakplasma levels were measured (mean Cmax of 40pg/ml with sufentanil alone and 46 pg/ml togeth-er with ketoconazole)35. The clinical relevance ofinteractions in the post-operative context is how-ever questionable, considering the short time ofopioid administration in a well-controlled hospi-tal environment. Moreover, the patient-controllednature of this type of analgesia allows the pa-tients to adjust for any altered metabolism ofsufentanil.

Use of SST in Renal or Hepatic ImpairmentIn a phase 3 study30 there were no significant

differences in plasma sufentanil concentrationsmeasured at 24 or 48 hours between patients withrenal impairment (glomerular filtration rate esti-


Figure 3. Sufentanil plasma concentra-tion after single and repeated SST doses34.

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mate based upon creatinine) and those with nor-mal renal function. Moreover, no significant dif-ferences for plasma sufentanil were measuredwhen comparing those patients with mild tomoderate hepatic impairment (as assessed by as-partate and alanine aminotransferases and totalbilirubin) and those with normal hepatic func-tion. Indeed, as reported above, sufentanil doesnot possess active metabolites that could eventu-ally accumulate in renal impairment.

The efficacy of SST in the Treatment ofacute postoperative pain

SST, the new sublingual formulation ofsufentanil, was object of two phase 2 studiesevaluating different dosages in the managementof POP following elective total knee replace-ment (TKR) and open abdominal surgery(OAS)36. In the post-anesthesia care unit pa-tients were randomized to receive placebo, oran active treatment with sublingual sufentanil(5, 10, or 15 μg in the TKR study and 10 or 15μg in the OAS trial). The study drug was ad-ministered by an investigator as needed at therequest of the patient with a minimum intervalof 20 minutes. One-Hundred-One and 94 pa-

tients were respectively enrolled and random-ized in the TKR and the OAS study. Thesummed pain intensity difference (SPID) scoresfor the 15 μg dose were higher than placebo atall time points in the TKR study and at all timepoints starting from the first 3 hours for theOAS study. The percentages of patient discon-tinuation in the studies due to inadequate anal-gesia were dose related. The average interdos-ing interval for the patients treated with the 15μg dosage was 73 to 101 minutes and con-firmed the hypothesis that the sublingual ad-ministration of sufentanil can effectively treatPOP without the need of frequent on demanddoses. The prevalence of adverse events (AEs)was similar among groups, except for a higherincidence of pruritus in the groups treated withsufentanil.

The phase 2 dose-finding studies showed thatthe dose of 15 μg of sublingual sufentanil (SST)was the optimal dosage in terms of efficacy andsafety (Table III and Table IV) and it was the onetested in the phase 3 program.

In the phase 3 studies, SST was administeredwith a preprogrammed, noninvasive patient-con-trolled system (sufentanil sublingual tablet sys-

Total knee arthroplasty Open abdominal surgery

Sublingual sufentanil Placebo (n = 24) Sublingual sufentanil Placebo

(n = 30)

Efficacy 5 µg 10 µg 15 µg 10 µg 15 µg

parameter (n=24) (n=25) (n=20) (n=29) (n=29)

SPID-12, LS mean (SEM) 3 (6) 1 (6) 13 (6)* -7 (6) 22 (4)** 28 (4)** 3 (3)

TOTPAR-12 17 (2) 13 (2) 19 (3) 12 (2) 23 (2)** 26 (2)** 14 (2)

Discontinuation due to 13 (54) 11 (44) 5 (25)** 16 (67) 7 (24)** 3 (10)** 21 (71)

inadequate analgesia, n (%)

Table III. Main efficacy results of the phase II studies, sublingual sufentanil tablets versus placebo35.

*p<0.05 compared with placebo; **p<0.001 compared with placebo.

Possibly or probably related AEs Open abdominal surgery or total knee arthoplasty (%)

occurring in ≥5% in any group5 µg (n=24) 10 µg (n=55) 15 µg (n=49) Placebo (n=54)

Nausea 29 40 37 32

Vomiting 8 11 6 6

Dizziness 13 4 2 2

Pruritus 4 7 12* 0

Table IV. Adverse Events of the phase II studies, sublingual sufentanil tablets versus placebo35.

AE: Adverse event, *p=0.042 vs. placebo.

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tem – SSTS; Zalviso®). The device was prepro-grammed to deliver one sublingual tablet ofsufentanil with a 20-minute lockout period. A ra-diofrequency identification thumb tag allows on-ly the patient to activate the on demand button.To better understand the results of these studies,it is important to underline that patients involvedwere not treated with a multimodal approach andthe enrollment was not limited by age and bodymass index (BMI).

Two placebo-controlled trials and one activecomparator study were conducted in patients un-dergoing major abdominal and orthopedic surg-eries30,37,39.

The two placebo-controlled studies evaluatedthe efficacy and safety of SSTS for the manage-ment of moderate to severe acute postoperativepain in patients undergoing major open abdominalor orthopedic surgery37,39. Patients were random-ized to receive SSTS 15 μg or an identical systemcontaining placebo tablets. Patients treated withthe SSTS showed a significantly higher SPID andtotal pain relief (TOTPAR) scores compared withpatients in the placebo group. The effectiveness ofsufentanil was confirmed by a greater drop in painintensity compared with baseline (PID score) thanin the placebo group. In both the studies patientsin the SSTS group showed an average interdosingtime significantly higher compared with the 20minutes preprogrammed lockout period. In themajority of the patients, a single cartridge of 40nanotablets was enough to provide analgesia for atleast 48 hours39.

Compared with the patients treated with place-bo, a higher percentage in the SSTS group re-ported “success” on the patient global assessment(PGA) as well as, at the same time points, more

health care professionals reported “success” onthe health care professional global assessment(HPGA).

Patients in the SSTS group showed a similarsafety profile in terms of AEs considered poten-tially related to study drug compared with pa-tients in the placebo system group. This data isrelevant due to the fact that the population in thetwo placebo-controlled studies can be consideredat high risk of AEs. In fact, a significant percent-age of patients enrolled were older than 65 yearsof age or with a BMI ≥30 kg/m2, reflecting thereal-life.

The active comparator study was conductedand published by Melson et al30, to evaluate theefficacy and safety of SSTS compared to thegold standard IV PCA morphine sulfate (IV PCAMS). To test the analgesic efficacy of the drugsinvolved in the study, as well as the deliverymethod, the two groups (SSTS vs IV PCA MS)were compared in terms of 48 hours patient glob-al assessment (PGA 48) of method of pain con-trol. The parameters selected for the IV PCA MS(bolus of 1 mg with a lockout period of 6 min-utes) were based on the daily practice of manyhospitals. Moreover, they allowed an equivalentdose of morphine compared to sufentanil in thesame 20 minute time period (15 μg SST = 3 mgIV MS based on 300 to 400 potency factor and60% bioavailability of SST).

Three hundred fifty-seven patients undergoingopen abdominal or orthopedic major jointsurgery (SSTS [n = 177] and IV PCA MS [n =180]) were treated and the 79% completed the 48hours study period. There were no significantdifferences between the two groups related to theproportion of patients who discontinued from thestudy due to an AE or inadequate analgesia. The78.5% of the patients in the SSTS groupachieved “success” on the PGA 48 compared tothe 65.6% in the IV PCA MS group, demonstrat-ing a statistical superiority. Also, the HPGA wasstatistically in favor of SSTS at all time points.The two groups did not present significant differ-ences in terms of SPID and TOTPAR scores,even if patients treated with sublingual sufentanilshowed a faster onset of pain reduction with asignificantly greater PID at 1, 2, and 4 hours(Figure 4). The faster onset of the analgesic ef-fect of SSTS compared with IV PCA MS wasconfirmed by the time required to achieve amean PID of 1.3 (1.3 hours vs. 7 hours) whichhas been demonstrated clinically significant inthe treatment of acute pain40.


Adverse Event occurring SSTS % IV PCA MS (%)in ≥5% in any group (n = 177) (n = 180)

Nausea 42.9 40.0

Vomiting 13.0 11.1

Constipation 11.3 8.3

Oxygen saturation decreased 9.6 9.4

Headache 7.9 6.7

Hypotension 6.2 11.1

Dizziness 5.6 3.3

Pruritus 4.0 7.8

Table V. Adverse events in the phase III study comparingSSTS vs. IV PCA MS (AE > 5% in either treatment group)30.

IV PCA MS, Intravenous patient-controlled analgesia mor-phine sulfate, SSTS, sufentanil sublingual tablet system.

The mean interdosing interval during the studyperiod was 81 minutes and 47 minutes, in theSSTS and IV PCA MS groups respectively.

There were no significant differences for anyadverse event between treatment groups (TableV). Nevertheless, in a high-risk population (forage (52.4% ≥ 65 years) and BMI (42.9% ≥ 30) alower percentage of patients in the SSTS groupcompared with IV PCA MS experienced oxygendesaturation episodes (< 95% recorded on pulseoximetry) (Figure 2). This difference betweenthe two groups can be explained by the fact thatmorphine has a lower therapeutic index and a de-

layed effector site penetration compared withsufentanil. Moreover, the morphine activemetabolite morphine-6-glucuronide (M6G) couldincrease the risk of oxygen desaturation in partic-ular in patients with renal impairment.

Based on the easy-of-care (EOC) question-naire completed by patients and nurses the SSTSwas considered easier to use compared with theIV PCA system and more satisfactory by both,patients and nurses (Table VI).

Conclusions

Even nowadays, the treatment of acute postop-erative pain remains a challenge. Despite theavailability of national and international guide-lines, a significant percentage of patients still ex-periences moderate to severe pain after surgery16.These guidelines recommend continuous regionalanalgesic techniques (epidural or peripheral nerveblocks) or the systemic administration of opioidstrough a patient-controlled device as therapies ofchoice after scheduled surgeries characterized bymoderate to severe pain4,5. One of the possiblereasons that can justify the high incidence of un-controlled pain in the postoperative period is thepoor adherence to these guidelines17,18. In fact, inItaly the most commonly used pain treatment inthe postoperative context is a continuous infusionof morphine through an elastomeric pump. Even

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EOC parameter, mean (SD) Orthopedic and open abdominal surgeries

SSTS IV PCA MS p-value

Patient EOC

n 177 180EOC total, mean (SD) 4.5 (0.5) 4.1 (0.7) <0.001Confidence with device 4.7 (0.6) 4.5 (0.8) 0.015Comfort with device 4.5 (0.7) 4.3 (0.7) 0.041Ease of movement 4.7 (0.7) 3.9 (1.4) <0.001Dosing confidence 4.7 (0.7) 4.5 (0.9) 0.003Pain control 3.6 (1.3) 3.2 (1.4) 0.004Knowledge/understanding 4.5 (0.9) 4.1 (1.1) <0.001Overall satisfaction 4.2 (1.0) 3.8 (1.0) 0.004Nurse EOC

n 44 43EOC total, mean (SD) 4.3 (0.6) 3.8 (0.8) 0.017Time-consuming 0.9 (0.7) 1.2 (0.9) 0.076Bothersome 0.5 (0.6) 1.1 (0.9) 0.006Overall satisfaction 3.9 (0.7) 3.4 (0.6) <0.001

Table VI. EOC questionnaire in the phase III study comparing SSTS vs. IV PCA MS35.

AE: Adverse event, *p=0.042 vs. placebo.

Figure 4. PID over the first hours of treatment in the phaseIII study comparing SSTS vs. IV PCA MS30.

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where the electronic PCA devices are available,they are not used systematically probably due tosome limitations of the currently available IVPCA devices. These limits include for instancethe requirement of an IV line with a potential in-creased risk of infection and analgesic gaps dueto IV catheter infiltration or IV tubing obstruc-tion. Moreover, the possibility of program modi-fications of the electronic pump can lead to med-ical and nurse errors with an increased risk of un-der and over-treatment41 and significant costs foreach error event42.

The sufentanil sublingual tablet system is in-stead preprogrammed and it does not require anIV line. The non programmable nature of SSTSin the fragile patient may be perceived as a limi-tation but if it is important to underline that datafrom the phase 3 program of SSTS showed an ef-fective treatment of pain with a significantlyhigher mean interdosing interval compared withthe preprogrammed lockout, giving the possibili-ty to achieve the therapeutic dose through a widerange of on-demand administrations until the at-tainment of the 20 minutes interdosing interval.In this view, the choice not to limit the enroll-ment of patients in the phase 3 program by ageand BMI, avoiding the selection of a populationfar from real practice, makes the safety profileshowed by SSTS clinically significant. More da-ta related to the effectiveness of the SSTS in thehighly opioid-tolerant patients has to be collect-ed, due to the fact that this small group of pa-tients should probably benefit of a tailored ap-proach to postoperative pain.

The selection of an opioid with a close associ-ation between patient dosing and peak of CNSeffect is fundamental to avoid dose accumulationand to reduce the occurrence of side effects34.Morphine presents a slow-equilibrating time andsometimes requires multiple doses to optimizethe analgesia in the initial period of treatment,potentially followed by a delayed opioid balancewith CNS μ receptors, therefore producing AEs.The dose-stacking phenomenon is exacerbatedby the fact that the active metabolite of mor-phine, M6G, has an even longer equilibrationtime with the CNS compared to morphine43. Onthe contrary, sufentanil presents a faster uptakefrom the plasma to the μ-opioid effector site inthe CNS with a t1/2Ke0 of 6.2 minutes.

In conclusion, a peak of plasma concentration of18 min after repeated sublingual administrationshowed by Willsie et al, matching with the lockoutperiod of 20 minutes preprogrammed for the SSTS

device, a rapid equilibration time with CNS andthe lack of active metabolites make sufentanil theideal opioid for PCA administration. Moreover, toguarantee adherence to the guidelines, the nano-tablets of sublingual sufentanil can be deliveredonly through a specific preprogrammed patient-controlled device, that potentially decreases therisk of and-over-treatment related to drug and/ormedical errors. The SSTS was also favorably ratedby HCP, including nurses.

A non-invasive and easy to use patient-con-trolled device with an effective and safe opioidlike the SSTS system may hopefully represent analternative to the too frequently used elastomericpumps, improving the adherence of the Italianpostoperative pain management to the currentlyavailable guidelines.

Further studies are needed to better understandthe clinical role of SSTS within a multimodal ap-proach to postoperative pain management.

authors’ Declaration of personal interests

Andrea Fanelli has served as speaker for Ibsa, asconsultant for Abbvie, Angelini and Molteni and asadvisory board member for Grunenthal.

Paola Sacerdote has served as Advisory BoardMember for Grunenthal, and as speaker for HelsinnHealthcare.

Flaminia Coluzzi has served as Advisory BoardMember for Grunenthal and as speaker for Angeli-ni and Mundifarma.

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ˇ)$ˇ˙& ˙! 2016; 20: 1411-1422 Sublingual sufentanil, a new ... · ing interest in Italy on the topic of “pain”, in par - ticular after the introduction of Law 38/2010, that