Sufentanil sublingual tablet system for the management of postoperative pain

Introduction: Intravenous patient-controlled opioid analgesia has been an important improvement in addressing insufficient management of acute postoperative pain for over 40 years. However, there are number of weaknesses for intravenous patient-controlled analgesia, including operator and device error, intravenous line patency issues, and risk of catheter-related infection, all of which contribute to the complications and increase in cost of care. The sublingual sufentanil tablet system is a major evolution in both drug and technological management of postoperative pain.

Areas covered: We reviewed the use of the sublingual sufentanil tablet system in management of moderate to severe postoperative pain in hospitalized patients, with a particular focus on the pharmacological properties of sufentanil and clinical use in different surgical patients.

Expert opinion: The sublingual sufentanil tablet system can decrease intravenous opioid based patient-controlled analgesia related complications and safety issues. Current clinical studies have demonstrated this noninvasive-novel system to be safe and effective in management of acute pain in the postsurgical setting. Researchers should focus on comparing it with other available patient controlled analgesia modalities and evaluating the efficiency and cost effectiveness of the sublingual sufentanil tablet system.     

Non-invasive patient-controlled analgesia in the management of acute postoperative pain in the hospital setting

Objective: Acute postoperative pain is experienced by the majority of hospitalized patients undergoing surgical procedures, with many reporting inadequate pain relief and/or high levels of dissatisfaction with their pain management. Patient-controlled analgesia (PCA) ensures patient involvement in acute pain control, a key component for implementing a quality management system. This narrative article overviews the clinical evidence for conventional PCA and briefly discusses new, non-invasive PCA systems, namely the sufentanil sublingual tablet system (SSTS) and the fentanyl iontophoretic transdermal system (FITS).

Methods: A Medline literature search (“patient-controlled analgesia” and “acute postoperative pain”) was conducted to 1 April 2017; results from the main clinical trials are discussed. Additional literature was identified from the reference lists of cited publications.

Results: Moderate to low quality evidence supports opioid-based intravenous PCA as an efficacious alternative to non-patient-controlled systemic analgesia for postoperative pain. However, despite the benefits of PCA, conventional intravenous PCA is limited by system-, drug- and human-related issues. The non-invasive SSTS and FITS have demonstrated good efficacy and safety in placebo- and intravenous morphine PCA-controlled trials, and are associated with high patient/healthcare practitioner satisfaction/ease of care ratings and offer early patient mobilization.

Conclusions: Evidence-based guidelines for acute postoperative pain management support the use of multimodal regimens in many situations. As effective and safe alternatives to conventional PCA, and with the added benefits of being non-invasive, easy to use and allowing early patient mobilization, the newer PCA systems may complement multimodal approaches, or potentially replace certain regimens, in hospitalized patients with acute postoperative pain.     

Indirect treatment comparison of two non-invasive patient-controlled analgesia treatments for acute post-operative pain management

Objectives: To evaluate the relative clinical efficacy, safety, and tolerability associated with two non-invasive patient-controlled analgesia (PCA) treatments, sufentanil sublingual tablet system (SSTS) and fentanyl iontophoretic patient-controlled transdermal system (PCTS). These two treatments have recently been approved in the EU for the management of acute moderate-to-severe post-operative pain in adult patients.

Methods: As no head-to-head trials comparing SSTS and PCTS currently exist, indirect treatment comparison (ITC) analyses were conducted to evaluate SSTS or PCTS versus intravenous (IV) morphine PCA.

Results: Five studies, four assessing PCTS and one assessing SSTS, were included in this analysis. SSTS had statistical or numerical advantages over PCTS for both patient global assessment (PGA) and healthcare professional global assessment (HPGA) outcomes at all time points investigated. SSTS was also associated with greater patient ease of use (weighted mean difference [WMD]: 0.13; 95% confidence interval [CI]: ?0.02–0.28) and a higher patient satisfaction score (WMD: 0.31; 95% CI: 0.05–0.57; p?=?.019) compared with PCTS. In terms of tolerability, all-cause withdrawals from treatment were reported to be less likely with SSTS (risk ratio: 0.65; 95% CI: 0.42–1.02). No significant differences were observed between SSTS and PCTS in terms of safety and adverse events.

Conclusions: In the absence of direct head-to-head data, the combination of promising phase III trial results compared to IV morphine PCA, a SLR comparison against other opioid treatments, and the results of this exploratory analysis present a strong rationale in support of SSTS as a key option for management of post-operative pain.     

An up-to-date overview of sublingual sufentanil for the treatment of moderate to severe pain

ABSTRACT

Introduction

Sufentanil is a selective µ-opioid agonist, used intravenously and intrathecally for moderate to severe acute pain. Sublingual sufentanil nanotablets have been developed; 15 mcg tablet for a patient-controlled analgesia device and 30-mcg tablet for a single-dose device administered by a healthcare professional. Dosing interval is a minimum of 20 min for a 15 mcg tablet and a treatment duration of up to 72 hours. The single 30-mcg nanotablet dosing interval is 1 hour. Mean plasma elimination half-life is 13 hours and bioavailability 47–57% after the first sublingual sufentanil tablet.     

The role of sublingual sufentanil nanotabs for pain relief

Introduction: The authors discuss a novel patient controlled analgesia system utilizing a preprogrammed device that delivers a small submucosal tablet of sufentanil.

Areas covered: This submucosal sufentanil system is not yet commercially available. A literature review of the current patient controlled analgesia systems and current information of this device are discussed.

Expert opinion: This novel device has the potential to enhance patient safety as it is preprogrammed and delivers a standard dose of sufentanil, a rapidly acting opioid devoid of active metabolites.     

Iontophoretic transdermal fentanyl for the management of acute perioperative pain in hospitalized patients

Introduction: Intravenous (I.V.) morphine administered through a patient-controlled system currently represents the gold standard treatment for moderate to severe acute postoperative pain. To fix the limitations showed by the available I.V. patient-controlled analgesia (PCA) systems that may restrict its use in the clinical practice a needle-free, iontophoretic, fentanyl patient-controlled transdermal system has been developed and recently approved by the United States Food and Drug Administration (FDA) and by the European Medicines Agency (EMA).

Areas covered: This review aims at describing the technology, pharmacology and clinical efficacy of fentanyl iontophoretic transdermal system (ITS) in the treatment of acute pain. A literature search was conducted in the PUBMED database using the term ‘fentanyl iontophoretic transdermal system’ through September 2015 and results from the main clinical trials are discussed.

Expert opinion: In 2015, the appropriate treatment of acute pain after surgery is still a challenge and it represents a primary goal in the care of the surgical patient. When regional analgesia techniques are not applicable and systemic analgesia is required, patient controlled systems represent the standard of care for opioid administration. The fentanyl ITS presents several potential advantages compared to the currently used PCA devices. In particular, it does not require intravenous lines and eliminates the potential for drug administration errors, observed with manually programmed standard PCA devices. Nevertheless, further studies are needed to address eventual inter-individual variability especially for opioid tolerant patients.     

Sublingual,transdermal and intravenous patient-controlled analgesia for acute post-operative pain: systematic literature review and mixed treatment comparison

Objective: To conduct a systematic literature review (SLR) and quantitative analysis to assess the comparative efficacy and safety of the sufentanil sublingual tablet system (SSTS) against other available patient controlled analgesia (PCA) options for post-operative analgesia.

Methods: An SLR was conducted for studies published between 2004 and 2016. Due to study heterogeneity, subgroup analyses were conducted controlling for differences in imputation methods for missing values, baseline pain severity, and type of surgery. Where sufficient data was available, a mixed treatment comparison (MTC) was performed.

Results: The MTC and subgroup analyses used 13 studies. In direct meta-analysis, there was a statistically significant difference in favor of SSTS compared with intravenous (IV) PCA (morphine) at 24?hours for the patient global assessment (PGA) scores of “good” or “excellent”. For the Pain Intensity Score, there were numerical but not statistically significant differences in favor of the SSTS versus IV PCA (morphine) and the patient controlled transdermal system (PCTS) (fentanyl) in the MTC at 6?hours (standardized mean difference ?0.27 [credible interval ?2.78, 2.09] and ?0.36 [?3.89, 3.03], respectively). The onset of pain relief was earlier with the SSTS versus IV PCA (morphine) as shown by the Pain Intensity Difference. Likewise, the onset was earlier compared with PCTS (fentanyl) where data was available. There was a significant difference in favor of SSTS compared with IV PCA (morphine) and with PCTS (fentanyl) for any adverse event, and numerical improvements for withdrawals due to adverse events.

Conclusions: This meta-analysis shows that SSTS is an option for non-invasive management of moderate-to-severe post-operative pain which can be more effective, faster in onset and better tolerated than IV PCA (morphine) and PCTS (fentanyl).     

舒芬太尼与芬太尼应用于术后患者自控静脉镇痛的比较

目的比较等效剂量舒芬太尼与芬太尼用于术后患者自控镇痛的临床效应。方法 40例ASAⅠ～Ⅱ级择期腹部手术患者随机分为2组,每组20例。2组麻醉诱导和用药方式相同,手术结束时均给予芬太尼0.02 mg和氟哌利多1.5 mg静脉注射。然后行患者自控静脉镇痛(PCIA),舒芬太尼与芬太尼组分别给予舒芬太尼0.1 mg和芬太尼1.0 mg,以氯化钠注射液稀释至100 mL,静脉泵入。观察术后48 h内2组VAS评分、镇静评分,患者满意度以及不良反应。结果舒芬太尼组术后4、8 h的VAS评分为(2.7±1.5)、(2.3±1.0),低于芬太尼组(3.4±1.6、3.1±1.1,P<0.05);镇静评分为(2.4±0.5)、(2.3±0.6),高于芬太尼组(1.2±0.6、1.1±0.5,P<0.05)。2组患者PCIA按压次数、总体满意度、不良反应发生率无显著差异(P>0.05)。结论舒芬太尼与等效剂量芬太尼相比,镇痛作用更加完善、镇静作用强于芬太尼,用于术后静脉镇痛安全、有效。     

舒芬太尼、芬太尼用于开胸术后镇痛的对比观察

目的分析探讨舒芬太尼和芬太尼用于患者自控静脉镇痛（PCIA）的镇痛效果和不良反应。方法选择ASAⅡ～Ⅲ级择期开胸手术患者74例,随机分成舒芬太尼（观察组）和芬太尼（对照组）,每组各37例。分别记录术后4h、8h、l2h、24h、48h各时间段内的疼痛、镇静、恶心、呕吐评分。结果术后4h、8h、l2h、24h、48h各时间段内观察组的疼痛、镇静评分均低于对照组（P〈0.05）;两组患者不良反应发生率比较差异无统计学意义（P〉0.05）。结论舒芬太尼用于开胸手术后静脉镇痛效果确切,不良反应少,镇静效果好,优于芬太尼,值得临床上推广使用。     

50例舒芬太尼联合氟比洛芬酯对腹部手术后PCIA的镇痛效果及安全性分析

目的：观察和评估舒芬太尼联合氟比洛芬酯对腹部手术后患者静脉自控镇痛（PCIA）的镇痛效果、对CRP、IL-6水平的影响和安全性。方法：选取择期行腹部手术的患者100例,均采用静吸复合全麻,术后行静脉自控镇痛。随机分为观察组和对照组各50例,观察组采用舒芬太尼75μg+氟比洛芬酯100 mg+0.9%氯化钠溶液+昂丹司琼8 mg;对照组采用舒芬太尼150μg+0.9%氯化钠溶液+昂丹司琼8 mg。对比分析两组患者术后24 h内VAS评分、Ramesay镇静评分、舒芬太尼的使用总量、中位PCIA的按压次数、不良反应的发生率、CRP和IL-6水平,以及满意度评分。结果：观察组患者的VAS评分,Ramesay镇静评分,舒芬太尼的使用总量和不良反应的发生率低于对照组患者（P＞0.05）。两组患者术后CRP和IL-6水平明显高于术前,且观察组患者术后CRP和IL-6水平明显低于对照组患者（P＜0.01）;观察组患者的满意度明显高于对照组患者（P＜0.05）。结论：舒芬太尼联合氟比洛芬酯对腹部手术后PCIA效果较好,能减少患者舒芬太尼的使用量,保证安全有效的镇痛效果,有效降低手术对患者机体的应激反应的影响,减轻炎症反应,减少不良反应的发生率,提高患者的满意度,安全性较高。     

Alpha-2 agonists in acute pain management

Importance of the field: This review explores the significance of alpha-2 agonists used clinically in acute pain management.

Areas covered in this review: Although alpha-2 agonists have been reported to have an analgesic effect, they are not commonly used clinically for acute pain management. Clinical studies on use of alpha-2 agonists for acute pain management are reviewed and discussed. A literature search was done using Medline with the keywords ‘alpha-2 agonist’, ‘clonidine’, ‘dexmedetomidine’, ‘fadolmidine’, ‘pharmacokinetics’, ‘pharmacodynamics’, ‘postoperative analgesia’, ‘epidural’, ‘intrathecal’, ‘peripheral nerve block’ and various combinations with these keywords. The years 1977 – 2009 have been included, with particular focus on clinical studies from between 1990 and 2009.

What the reader will gain: This article helps to clarify the clinical use of alpha-2 agonists in acute pain management according to current, up-to-date evidence. Clinically, available alpha-2 agonists, including clonidine and dexmedetomidine, are discussed in detail.

Take home message: Alpha-2 agonists, especially clonidine, seem to be promising with regard to acute postoperative pain management. However, more clinical evidence on dexmedetomidine is necessary to confirm its definite role in acute postoperative pain control.     

An expert opinion on postoperative pain management,with special reference to new developments

Importance of the field: Recently, much attention has been directed towards the effect of opioid-sparing strategies on postoperative morbidity and hospitalization, and on different nociceptive mechanisms involved in various postoperative pain states and surgical procedures. This has resulted in an increased interest in secondary, or adjunct, analgesics and procedure-specific analgesic methods.

Areas covered in this review: The present paper aims to review and discuss recent developments within the field of various adjunct, systemic analgesics and local/regional anesthetic methods for management of postoperative pain, based on evidence from randomized, clinical trials published within the last 5 years.

What the reader will gain: The reader will gain insight into the current role of pregabalin, glucocorticoids and systemic lidocaine for the management of postoperative pain. In addition, the current status of local infiltration analgesia for hip and knee arthroplasty, transversus abdominis plane block for abdominal operations, and the analgesic effect of wound instillation of capsaicin are reviewed.

Take home message: The evidence of a substantial analgesic effect of pregabalin on acute postoperative pain is questionable, and more convincing evidence of the role of glucocorticoids and systemic lidocaine is needed before they should be recommended as analgesics in daily clinical practice. Local infiltration analgesia after hip and knee arthroplasty, transversus abdominis plane block after abdominal operations and local application of capsaicin lend some promise, but there is still a lack of well-performed RCTs to draw any firm conclusions. Procedure-specific analgesic combinations within well-defined rehabilitation paradigms should be explored further to reduce adverse effects associated with the use of conventional analgesic treatment protocols, and to improve postoperative outcome.     

氟比洛芬酯在妇科术后镇痛中的应用

目的本研究拟将氟比洛芬酯应用于术后病人自控静脉镇痛,以观察其镇痛效果。方法将60例全身麻醉下接受妇科开腹手术的女性患者随机分为两组,在术后开始应用不同配方的镇痛泵,分别为舒芬太尼组（S组）和舒芬太尼＋氟比洛芬酯组（SF组）。于术后1h、4h、8h、24h和48h随访患者,记录两组镇痛效果,累计镇痛药消耗量及不良反应。结果两组病人的人口统计学无显著差异。术后各个时间点的静息和活动VAS评分均没有显著差异。SF组的舒芬太尼消耗量从术后4h开始明显少于S组。恶心呕吐发生率没有统计学差异。结论镇痛泵中加入氟比洛芬酯可以使术后舒芬太尼的用量减少,而疼痛评分和副作用发生率没有变化。     

Influence of intraoperative remifentanil and sufentanil on sensory perception: a randomized trial

Objective: The clinical relevance of pro- and hyperalgesic effects of opioids is still a matter of debate. Particularly for remifentanil, an increased postoperative need for analgesics has been demonstrated suggesting opioid-induced hyperalgesia as a possible cause. The aim of the study was therefore to investigate the effect of intraoperatively applied remifentanil compared to sufentanil on somatosensory thresholds investigated with the quantitative sensory testing (QST) battery of the German Research Network on Neuropathic Pain (DFNS).

Research design and methods: Twenty-three patients undergoing surgery of the female breast were randomly assigned to intraoperative remifentanil (0.4?μg?×?kg^?1?×?min^?1) or sufentanil (0.25?μg?×?kg^?1 bolus, 0.15?μg?×?kg^?1, repetition after 60?min) application. Anesthesia was maintained BIS-guided (Bispectral index^TM) with propofol and postoperative analgesia was ensured with paracetamol (max. 3?g/24?h). Quantitative sensory testing was performed in the region of dermatome Th 5 in the mid-axillary line preoperatively and 20?h postoperatively.

Clinical Trial registration: The study was registered at the German registry for clinical studies (DRKS00009002).

Main outcome measures: Comparison of somatosensory thresholds before versus after surgery and application of intraoperative remifentanil or sufentanil.

Results: Sixteen patients could be finally included in the analysis. No differences of mechanical or thermal detection or pain thresholds were observed between pre- and postoperative testing or between remifentanil and sufentanil.

Conclusion: A change of somatosensory thresholds or a clinically relevant opioid-induced hyperalgesia in the selected small patient sample (segmental resections or mastectomy with or without sentinel lymph node biopsy, surgery length <90?minutes, sufficient postoperative pain medication with paracetamol due to rather low postoperative pain intensities) with remifentanil or sufentanil was not detected 20?h after surgery.     

舒芬太尼与丁丙诺啡对老年骨科患者术后镇痛效果比较

目的：比较等效剂量舒芬太尼与丁丙诺啡对骨科老年病人患者术后镇痛的效果。方法选择60例ASAⅠ～Ⅱ级65～78岁的下肢骨折需行切开复位内固定术的患者,随机分为舒芬太尼组（S）和丁丙诺啡组（D）,每组30例。2组均采用静脉自控镇痛（PCIA）给药,S组：舒芬太尼100μg,D组：丁丙诺啡1．2 mg,总量100 ml,术后5、10、20及40 h行VAS疼痛与Ramsay评分,记录PCA有效按压次数及不良反应发生率。结果2组VAS疼痛评分、Ramsay评分及PCA有效按压次数差异均无统计学意义,而不良反应发生率D组显著高于S组（P＜0．01）。结论等效剂量舒芬太尼与丁丙诺啡用于骨科老年病人术后镇痛效果相当,但舒芬太尼不良反应发生率较低,更适合于骨科老年病人的术后镇痛。     

Comparison of intrathecal bupivacaine and levobupivacaine combined with opioids for Caesarean section

ABSTRACT

Objective: To date, racemic bupivacaine is the most popular local anaesthetic for spinal anaesthesia in parturients undergoing elective Caesarean delivery. However, data suggests that S-enantiomers like levobupivacaine may produce differential sensory and motor blockade. The aim of the present study was to compare fixed doses of intrathecal hypertonic levobupivacaine 0.5% (10?mg) and bupivacaine 0.5% (10?mg) combined with either intrathecal fentanyl (10 and 20?µg), or sufentanil (5?µg) in terms of sensory and motor block characteristics.

Research design and methods: 60 parturients with singleton pregnancy and > 34 weeks of gestation who underwent elective Caesarean delivery participated in this randomized, double-blinded clinical trial. They received spinal anaesthesia with either levobupivacaine or bupivacaine and the above mentioned opioids added (n = 10 parturients/group). Sensory block was assessed bilaterally by loss of cold sensation, and the degree of motor block was determined according to the Bromage scale every minute until delivery, subsequently at 5-min intervals until the end of surgery, and at 15-min intervals thereafter until complete resolution of spinal anaesthesia. A visual analogue scale was used postoperatively to measure duration of analgesia at 15-min intervals.

Main outcome measures: Levobupivacaine produced a significantly shorter and less pronounced motor blockade than racemic bupivacaine regardless of the kind and dose of opioid added. Duration of motor block Bromage 3 was 53 ± 14?min, 23 ± 18?min and 41 ± 8?min compared to 65 ± 25?min, 70 ± 19?min and 65 ± 22?min in the bupivacaine groups. Also, only n = 5/30 parturients reached Bromage3 in the levobupivacaine groups versus n = 21/30 parturients in the bupivacaine groups. No parturient experienced intraoperative pain. Adding sufentanil 5?µg to either local anaesthetic significantly prolonged duration of effective analgesia compared to supplemental fentanyl 10 or 20?µg.

Conclusions: Based on our data, 10?mg of hypertonic levobupivacaine 0.5% combined with sufentanil 5?µg was the most appropriate anaesthetic regimen in parturients undergoing elective Caesarean delivery in spinal anaesthesia.     

临床药师建议姑息性镇静 治疗1例难治性癌痛

临床药师参与了1例晚期前列腺癌伴难治性癌痛患者的治疗过程。通过开展疼痛评估、药学监护,利用药学专业知识提供合理用药建议,协助医师制定舒芬太尼自控镇痛联合小剂量咪达唑仑持续泵入的终末期姑息性镇静治疗方案,有效促进临床精准使用镇痛镇静药物,改善了患者的生存质量。     

Decreased pain tolerance before surgery and increased postoperative narcotic requirements in abstinent tobacco smokers

IntroductionThe clinical influence of smoking cessation on pain tolerance before surgery and postoperative pain perception is not fully understood. This clinical study investigated the effect of smoking cessation on pain threshold during the perioperative period in patients undergoing hepatic resection.MethodsWe enrolled 148 male patients (68 non-smokers and 80 abstinent smokers) who underwent hepatic resection and received postoperative patient-controlled intravenous analgesia. Patients were tested for preoperative pain thresholds in response to electrical stimuli. We recorded the cumulative amount of extra morphine equivalent required during the first 48 h after surgery. Pain intensity was evaluated at 1 h, 6 h, 24 h and 48 h after surgery using the visual analogue scale (VAS). Additionally, button-pressing consumption was recorded by a patient-controlled analgesia (PCA) pump.ResultsThe groups did not differ with respect to baseline clinical characteristics. Compared with non-smokers, abstinent smokers exhibited lower pain thresholds before surgery and demanded a larger quantity of extra morphine equivalent during the first 48 h after surgery. Abstinent smokers also exhibited more severe postoperative pain than non-smokers. Postoperative complications, such as nausea, vomiting, dizziness, sedation, and respiratory depression, did not significantly differ between the two groups.ConclusionsIn this study, smokers deprived of cigarettes exhibited decreased pain tolerance before surgery and required a larger quantity of postoperative extra morphine equivalent than non-smokers. Health care providers must be aware of the potential for increased narcotic requirements in smokers.