Article Text

Efficacy and safety of sufentanil sublingual tablet system in postoperative pain management: a systematic review and meta-analysis
  1. Pugazhenthan Thangaraju1,
  2. Shoban Babu Varthya2,
  3. Sajitha Venkatesan3,
  4. Thangaraju Tamilselvan4 and
  5. Surjit Singh2
  1. 1Pharmacology, AIIMS Raipur, Raipur, India
  2. 2Pharmacology, AIIMS Jodhpur, Jodhpur, India
  3. 3Microbiology, AIIMS Raipur, Raipur, India
  4. 4Pharmacology, SRM University, Gangtok, India
  1. Correspondence to Dr Surjit Singh, Pharmacology, AIIMS Jodphur, Jodhpur 342005, India; sehmby_ss{at}yahoo.com

Abstract

Background Sufentanil sublingual tablet system (SSTS) is a recently approved formulation for postoperative pain management that has become popular due to its pharmacokinetic properties such as good bioavailability, rapid attainment of equilibrium and elimination without any metabolites, along with its pharmacodynamic properties such as rapid onset and effective pain reduction. It is also relatively well tolerated by patients.

Objective This is a quantitative analysis of the efficacy and safety of SSTS in patients with moderate to severe postoperative pain.

Design This is a systematic review and meta-analysis. Databases such as Cochrane Library, MEDLINE and EMBASE were searched for eligible articles.

Settings Randomised controlled trials published after 2000 in English language and which assessed at least one of the outcome measures of interest with pain intensity difference between 12 hours and a maximum of 96 hours.

Participants Adults with moderate to severe postoperative pain and taking SSTS for pain management.

Methods Data were analysed using Review Manager (RevMan) V.5.3. Risk of bias (RoB) assessment was done using RoB-2 scale, and overall grading of evidence of each outcome was done using GRADEpro Guideline Development Tool.

Results Analysis of SSTS versus control indicates a statistically significant reduction in summed pain intensity difference at 12 hours (mean difference (MD)=−12.33 (95% CI −15.5 to −9.17), p<0.00001), summed pain intensity difference at 48 hours (MD=−43.57 (95% CI −58.65 to −28.48), p<0.00001), time-weighted total pain relief over 12 hours (MD=−4.77 (95% CI −6.28 to −3.27), p<0.00001) and pain intensity difference (MD=–0.73 (95% CI −1.00 to −0.46), p<0.00001) with SSTS, alongside high quality of evidence. Success of treatment as assessed by Patient Global Assessment (OR=4.01 (95% CI 2.74 to 5.89), p<0.00001) and Healthcare Professional Global Assessment (OR=4.46 (95% CI 3.03 to 6.56), p<0.00001) scoring at 72 hours was observed in a significantly high number of individuals using SSTS, with high quality of evidence. There was no difference in adverse events except for dizziness (RR=1.90, 95% CI 1.02 to 3.52). There was a significantly higher number of total adverse events in orthopaedic surgery in the SSTS group than in the comparator.

Conclusion SSTS is effective in postoperative pain management in patients with moderate to severe pain. It also has good tolerability and high patient satisfaction.

PROSPERO registration number CRD42018115458.

  • pain
  • pharmacology
  • supportive care

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Key messages

What was already known?

  • Sufentanil sublingual tablet system (SSTS) is a new formulation that has faster absorption compared with oral route and has better tolerability compared with intravenous route.

What are the new findings?

  • Pain intensity reduced as early as within 1 hour during post-operative period due to the high lipid solubility of SSTS. Pain reduction in the SSTS group was significantly higher than in the placebo group.

  • Patients and healthcare professionals achieved higher satisfaction with the new delivery modality compared with patient-controlled analgesic therapy. There were no significant differences in adverse events except for dizziness in the SSTS group.

What is their significance?

  • SSTS will help us achieve better pain control clinically along with higher patient and physician satisfaction scores with regard to standard treatment.

  • High quality evidence generated from current review helps us rely more on SSTS for better pain control and it is unlikely that further research can change the effect estimate.

Introduction

The burden of moderate to severe postoperative pain is approximately 70% in patients undergoing surgery.1 Annually about 312.9 million surgeries are performed across the world and nearly 60% of these surgeries are performed in high expenditure countries, where each surgery costs about >$1000. This signifies the need for high satisfactory management of acute postoperative pain.2 At the same time, postoperative pain management plays an important role in rapid recovery and mobility, which ultimately improves patients’ overall outcome.1

Current guidelines on postoperative pain management suggest that systemic therapy with opioids stands as first-line therapy in major surgeries with associated moderate to severe pain.3 The analgesic action of opioids mediates through the central nervous system (CNS) and the peripheral nervous system. In the CNS, the opioids’ analgesic actions are mediated through the periaqueductal grey, locus coeruleus, rostral ventral medulla and substantia gelatinosa of the dorsal horn. The adverse effects of opioids such as nausea and vomiting result from direct stimulation of the chemoreceptor trigger zone for emesis in the area postrema of the medulla, while headache and dizziness are due to anticholinergic actions, and respiratory depression due to depression of the respiratory centre, along with carotid and aortic body depression.4–8 Postoperatively, these adverse events worsen the recovery of patients. To achieve balance between effective analgesic actions and minimal adverse events, we need a specially designed method which can be effectively used by patients according to their needs.9

Patient-controlled analgesia (PCA) has become a very popular tool in pain management due to good patient satisfaction in pain control. One such method is the sufentanil sublingual tablet system (SSTS). Sufentanil is a selective µ-opioid agonist that has better pharmacokinetic and pharmacodynamic profiles compared with other opioids such as morphine.10 Sufentanil has high therapeutic index and has no secondary metabolites as seen with morphine (morphine-3-glucuronide and morphine-6-glucuronide). Hydromorphone produces excessive sedation. In the study of Bovill et al,11 it was observed that SSTS was superior to oral therapy due to the faster absorption of sufentanil. It also prevents first pass metabolism when given by SSTS. Similarly, in comparison with intravenous route, SSTS prevents high peak plasma concentration as well as associated adverse effects such as sedation, respiratory depression and postoperative nausea and vomiting. Willsie et al12 observed that SSTS was well tolerated by patients even after taking multiple doses at an interval of 20 min.

Postoperative pain management with SSTS appears to be a novel approach in patients undergoing orthopaedic, gynaecological, abdominal and other surgeries. We conducted a meta-analysis to study whether sublingual sufentanil tablets can be an option for pain management after various surgical procedures.

Methods

Protocol and registration

The systematic review was done as per the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The protocol was registered with PROSPERO (International Prospective Register of Systematic Reviews).

Types of studies, participants and interventions

In this study, we included randomised, placebo-controlled trials and observational studies that assessed the efficacy of SSTS in pain intensity reduction. We included studies where postoperative patients were enrolled to evaluate the efficacy of SSTS based on differences in pain intensity after 12–96 hours of operation, were published in English from 2000, reported full text, and with a sample size of at least 50 participants for observational studies or 10 participants per group for randomised controlled trials.

Type of outcome measures

Primary outcome

The primary outcome was time-weighted summed pain intensity difference (SPID) at 12 hours and 48 hours. SPID12 mean values are measured in quantum of change in pain intensity from baseline to 12 hours during the postoperative period. Similarly SPID48 is mean change in pain intensity from baseline to 48 hours during the postoperative period. Here the total amount of pain reduced after the intervention when compared with baseline and therefore the results are shown with negative values.

Secondary outcomes

The secondary outcomes were pooled mean difference (MD) for time-weighted total pain relief over 12 hours (TOTPAR12) and pain intensity difference (PID) at 1 hour during the postoperative period. Additional safety outcomes are ‘Patient Global Assessment (PGA) and Healthcare Professional Global Assessment (HPGA)’ at 24 hours, 48 hours and 72 hours during the postoperative period.

Safety outcomes

In this study, we analysed commonly encountered adverse events such as nausea, vomiting, pruritus and dizziness.

Information sources and search strategy

A literature search using the terms ‘Sufentanil’, ‘SSTS’, ‘patient controlled analgesia’, ‘post-operative patients’, ‘post-operative pain’ and ‘pain intensity’ was performed on EMBASE, MEDLINE/Index Medicus, PubMed Central, Scopus and Web of Science. Additional studies were identified through cross-references and meta-analyses conducted to evaluate SSTS for postoperative pain management. All human studies published in full text or abstract forms and are published in English language were initially screened for inclusion. After initial review of the abstracts, relevant studies were identified and a detailed evaluation of the full text was done.

Study collection and data extraction

All data on authorship, year of publication, study design, study population, baseline patient characteristics, SSTS dose, type of surgery, number of patients and relevant outcomes were extracted from the selected studies. The whole process was undertaken independently by two authors and all conflicts were resolved by discussion among all authors.

Quality assessment: risk of bias

Risk of bias (RoB) of included studies was evaluated by two independent authors using Cochrane Collaboration risk of bias assessment V.2.0 tool (RoB-2) for randomised clinical trials, with data imputation in RoB-2 Excel sheet.13 Any discrepancies were resolved with the opinion of a third author. The components assessed with RoB-2 were bias due to randomisation process, deviation from intended intervention, missing data, outcome measurement and reporting of outcomes. Robvis (Risk-of-Bias VISualization) was used for synthesis of RoB graph.14

Data synthesis

Data on study characteristics (study setting, inclusion and exclusion criteria, and randomisation), patient characteristics (age and gender), treatment characteristics (sufentanil and placebo arm), RoB analysis and different outcomes were collected from the included trials. Observed data were combined using Review Manager (RevMan) V.5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). SPID, TOTPAR and PID were summarised as Mean difference (MD) with 95% CI, and dichotomous data were summarised as Odds ratio (OR) with 95% CI or Risk ratio (RR) with 95% CI. Heterogeneity was assessed based on the calculated I2 (the proportion of total variability explained by heterogeneity), estimated using the restricted maximum likelihood-based method. We set predecided criteria for significant heterogeneity as I2 >40%. The analysis was done using fixed effect model even if heterogeneity was greater than 40% in most pooled analyses, as heterogeneity was not taken care of by random effect model. Reasons for heterogeneity were assessed and explained. For high heterogeneity, inconsistency was downgraded for quality evidence in the GRADEpro analysis. To assess publication bias, funnel plot assessment and Egger’s regression test were applied.

Assessment of quality of evidence: GRADEpro analysis

The overall quality of evidence for each of the outcomes was assessed using the GRADEpro Guideline Development Tool (GDT) software based on the principles of the Grading of Recommendations, Assessment, Development and Evaluations (GRADE).15 RoB, directness of evidence, consistency and precision of results, risk of publication bias, magnitude of effect, dose–response gradient, and influence of residual plausible confounding were assessed in order to grade the overall quality of evidence of the individual outcomes. The final overall GRADE may be high, moderate, low or very low. The online version of the GRADEpro GDT software was accessed from https://gradepro.org/.16

Results

Six studies were included in the final analysis, of which Singla et al17 and Mikowitz et al18 have multiple groups based on dose and surgery. Literature search and study selection are presented in figure 1. The characteristics of the included studies are shown in table 1. The selected studies have a total of 1495 patients, 921 in the SST group and 574 in the placebo group. Two studies were conducted in patients undergoing abdominal surgery,19 20 two studies were conducted in patients undergoing orthopaedic surgery,17 21 and two studies were conducted in both abdominal and orthopaedic surgeries.18 22 Non-comparator single-group studies were excluded.10 23 24 SSTS was administered after recovery from the postoperative care unit. The data primarily collected from the studies were study design, SST dose, pain indicators (SPID at 12 and 48 hours; TOTPAR at 12 hours; PGA at 24, 48 and 72 hours; and HPGA), number of patients discontinued due to ineffectiveness, and commonly reported adverse events such as nausea, vomiting, pruritus and dizziness.

Figure 1

PRISMA flow chart depicting the study selection process. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses. PK;Pharmacokinetics.

Table 1

Study characteristics of the included studies in the systematic review

Risk of bias: RoB-2

The overall RoB was recorded as low in all included studies, except for two studies done by Minkowitz et al18 and Melson et al.22 Information on concealment of randomisation was lacking in these two studies, which generated a ranking of some concerns for bias in randomisation . With regard to SPID12 and SPID48, assessment of outcomes was blinded and therefore rated to be of low RoB. Due to blinded nature of assessment, randomization concealment bias was unable to modulate the results in favor of intervention. In all studies, SPID was assessed as the primary outcome, and the overall RoB was assessed as low in all except two (figure 2). The weighted summary plot of RoB is shown in online supplemental figure S.

Figure 2

RoB-2: risk of bias in randomised clinical trials evaluating sufentanil in postoperative pain.

Synthesis and interpretation of meta-analysis results

Pooled MD for time-weighted SPID from baseline over the 12-hour study period (SPID12)

Three studies comprising a total of 540 patients (314 in the SSTS group and 226 in the placebo group) evaluated SPID12. There was a statistically significant decrease in SPID12 scores with SSTS compared with the control (pooled MD=−12.33 (95% CI −15.5 to −9.17), p<0.0001, I2=0%). This improvement seems to be clinically significant (figure 3).

Figure 3

Time-weighted summed pain intensity difference from baseline over the 12-hour study period in sufentanil versus control. IV;nverse Variance, TK; Total knee arthroplasty, ABD; abdominal surgery

Pooled MD for time-weighted SPID from baseline over the 48-hour study period (SPID48)

Three studies comprising a total of 945 patients (607 in the SSTS group and 338 in the placebo group) evaluated SPID48. There was a statistically significant decrease in SPID48 scores with SSTS compared with the control (pooled MD=−43.57 (95% CI −58.65 to −28.48), p<0.00001, I2=91%) (figure 4).

Figure 4

Time-weighted summed pain intensity difference from baseline over the 48-hour study period in sufentanil versus control. IV; Inverse Variance.

Pooled MD for time-weighted total pain relief over 12 hours (TOTPAR12)

Three studies comprising a total of 515 patients (301 in the SSTS group and 214 in the placebo group) were included in pooling the MD for TOTPAR12. The pooled MD was −4.77 (95% CI −6.28 to −3.27), with an I2 of 56%. The test for overall effect was significant (<0.00001) (online supplemental figure 1S).

PID at 1 hour from baseline

Four studies comprising a total of 1206 patients (714 in the SSTS group and 392 in the placebo group) were included in pooling the MD for PID at 1 hour. The pooled MD was –0.73 (95% CI −1.0 to −0.46), with an I2 of 0%. The test for overall effect was significant (<0.00001) (figure 5).

Figure 5

Pain intensity difference at 1 hour from baseline in sufentanil versus control. IV - Inverse Variance

PGA at 24 hours

Three studies comprising a total of 752 patients (537 in the SSTS group and 215 in the placebo group) were included in pooling the OR for PGA at 24 hours. The pooled OR was 3.72 (95% CI 2.65 to 5.21), with an I2 of 0%. The test for overall effect was significant (<0.00001) (online supplemental figure 2Sa).

PGA at 48 hours

Three studies comprising a total of 875 patients (607 in the SSTS group and 268 in the placebo group) were included in pooling the OR for PGA at 48 hours. The pooled OR was 3.21 (95% CI 2.37 to 4.35), with an I2 of 79%. The test for overall effect was significant (<0.00001) (online supplemental figure 2Sb).

PGA at 72 hours

Two studies comprising a total of 591 patients (430 in the SSTS group and 161 in the placebo group) were included in pooling the OR for PGA at 72 hours. The pooled OR was 4.01 (95% CI 2.74 to 5.89), with an I2 of 72%. The test for overall effect was significant (<0.00001) (online supplemental figure 2Sc).

HPGA of method of pain control at 24 hours

Three studies comprising a total of 752 patients (537 in the SSTS group and 215 in the placebo group) were included in pooling the OR for HPGA at 24 hours. The pooled OR was 3.91 (95% CI 2.79 to 5.48), with an I2 of 0%. The test for overall effect was significant (<0.00001) (online supplemental figure 3Sa).

HPGA of method of pain control at 48 hours

Three studies comprising a total of 678 patients (474 in the SSTS group and 204 in the placebo group) were included in pooling the OR for HPGA at 48 hours. The pooled OR was 4.68 (95% CI 3.27 to 6.69), with an I2 of 67%. The test for overall effect was significant (<0.00001) (online supplemental figure 3Sb).

HPGA of method of pain control at 72 hours

Two studies comprising a total of 591 patients (430 in the SSTS group and 161 in the placebo group) were included in pooling the OR for HPGA at 72 hours. The pooled OR was 4.46 (95% CI 3.03 to 6.56), with an I2 of 77%. The test for overall effect was significant (<0.00001) (online supplemental figure 3Sc).

Adverse events

In our systematic review, we analysed adverse events such as nausea, vomiting, pruritus and dizziness. In addition, subgroup analysis of adverse events except nausea and vomiting based on type of surgery was performed. The reason for exclusion of nausea and vomiting is that their incidence is usually high during abdominal surgeries.

Nausea

Six studies comprising a total of 1369 patients (922 in the SSTS group and 447 in the placebo group) were included in pooling the Risk ratio (RR) for nausea. The pooled RR was 1.05 (95% CI 0.89 to 1.24), with an I2 of 64%. The test for overall effect was not significant (p=0.55) (online supplemental figure 4Sa).

Vomiting

Six studies comprising a total of 1369 patients (922 in the SSTS group and 447 in the placebo group) were included in pooling the RR for vomiting. The pooled RR was 1.37 (95% CI 0.91 to 2.06), with an I2 of 0%. The test for overall effect was not significant (p=0.14) (online supplemental figure 4Sb).

Dizziness

Six studies comprising a total of 1369 patients (922 in the SSTS group and 447 in the placebo group) were included in pooling the RR for dizziness. The pooled RR was 1.90 (95% CI 1.02 to 3.52), with an I2 of 0%. The test for overall effect was significant (p=0.04) (online supplemental figure 4Sc).

Pruritus

Six studies comprising a total of 1378 patients (922 in the SSTS group and 456 in the placebo group) were included in pooling the RR for pruritus. The pooled RR was 1.37 (95% CI 0.73 to 2.55), with an I2 of 52%. The test for overall effect was not significant (p=0.33) (online supplemental figure 4Sd).

Subgroup analysis of adverse events

Six studies comprising a total of 1369 patients (922 in the SSTS group and 447 in the placebo group) were included in pooling the RR for adverse events. The pooled RR in abdominal surgeries was 0.93 (95% CI 0.62 to 1.39), with an I2 of 0%, and the test for overall effect was not significant (p=0.71). The pooled RR in orthopaedic surgeries was 2.20 (95% CI 1.46 to 3.31), with an I2 of 0%, and the test for overall effect was significant (p=0.002). The pooled RR in both surgeries was 0.94 (95% CI 0.79 to 1.13), with an I2 of 62%, and the test for overall effect was not significant (p=0.52). The pooled RR in overall adverse events was 1.16 (95% CI 0.99 to 1.36), with an I2 of 74%, and the test for overall effect was not significant (p=0.07) (online supplemental figure 5S).

Publication bias

As data from the subgroups of two studies were used for synthesis of forest plot for SPID12 and TOTPAR, the publication bias cannot be assessed from funnel plot asymmetry or Egger’s regression test for these outcomes. Publication bias was low, although the funnel plot for four studies appears to be asymmetrical around the intervention effect estimate for PID (online supplemental figure 6S). Funnel plot has limited utility in predicting publication bias if studies are fewer than 10. We applied regression test for funnel plot asymmetry, which showed a value of t=−1.7340 and a p value of 0.2251, indicating low publication bias.

Egger’s regression test for SPID48 showed low publication bias (p=0.7756) and high quality for PGA and HPGA (PGA p=0.5682; HPGA p=0.2989).

GRADE analysis of the primary and secondary outcomes

The GRADE recommendation for the primary outcome (SPID12 and SPID48) was ‘high’ evidence quality as there were no serious issues in the RoB analysis (table 2). The GRADE recommendation for TOTPAR and PID was ‘high’ evidence quality as there were no serious issues with indirectness, inconsistency or imprecision. In TOTPAR, dose–response gradient was observed, which further strengthens the quality of evidence. The GRADE recommendation for PGA and HPGA was also ‘high’ evidence quality as there were no serious issues with RoB. Due to the presence of large effect (OR of 3.72 and 3.91, respectively), high-quality evidence was generated. The overall GRADE was ‘high’ quality evidence.

Table 2

GRADE recommendations for primary and secondary outcomes of sublingual sufentanil versus placebo for pain management after surgery

Discussion

SSTS is one of the advanced innovative formulations which can be administered with preprogrammed handheld device using Radiofrequency Identification (RFID) technology to monitor dosing. It involves a non-invasive preparation, with a fixed-dosage strength and patient-controlled modality, allowing the patient to administer the drug when required.22 Sufentanil shows its analgesic action primarily by binding to the µ-receptors in the CNS. It decreases pain intensity and increases pain threshold and emotional response.1 The potency of sufentanil is 10 times greater than fentanyl and 100 times greater than morphine, with a high therapeutic index.25

Katz et al26 observed that there is a gap between invasive and non-invasive analgesic options for postoperative patients. SSTS is a high lipid soluble compound that allows sufentanil to absorb across the transbuccal mucosa into the systemic circulation and rapidly enters the CNS and achieves CNS equilibrium.22 This permits faster onset of action, effective relief of pain and greater patient satisfaction, along with improved tolerability.26

This preparation has a handheld dispenser system that enables easy administration by healthcare providers or the patients themselves. Usually the patient administers the drug as the pain becomes unbearable. This mechanism enables modification of prescribed medication and dosing parameters and at the same time prevents potential complications due to overdosing.26

In the present systematic review of studies, quantitative analysis of various efficacy indicators, such as SPID12, SPID48 and TOTPAR12, and subjective analysis of PGA and HPGA at 24, 48 and 72 hours, favoured the SSTS group over the control. Therefore, the findings of this systematic review indicate that SSTS is effective over placebo in controlling moderate to severe postoperative pain in patients undergoing abdominal and orthopaedic surgeries. The qualitative analysis evaluated by PGA and HPGA also favours the SSTS group over the control, and majority of the patients showed good to very good satisfaction. Dransart et al27 also observed that, among patients and healthcare professionals, overall satisfaction achieved was higher for SSTS compared with intravenous PCA. Similarly in a single-arm study conducted by Meijer et al28 observed that the proportion of patients who achieved high satisfaction scores were significantly higher than the patients with low satisfaction scores.

PID indicates the time to onset of analgesic action29 also favours the SSTS group at 1 hour, as observed in an earlier study conducted by Miner et al,30 where pain intensity and pain relief at 1 hour significantly reduced from baseline. Due to its high lipophilicity and with 20% non-ionised fraction at physiological pH, sufentanil takes less time to establish plasma/CNS equilibrium (kinetic equilibrium) than other drugs such as oxycodone, hydromorphone and morphine, resulting in a rapid onset of action. SSTS shows substantially longer plasma half times than intravenous sufentanil. The half-life of sublingual sufentanil increases with increase in dose frequency and strength. Patients were allowed to administer repeatedly as needed postoperatively, producing sustained analgesic action without exacerbating pain intervals. This phenomenon is due to the presence of a greater fraction of the drug at the terminal elimination phase.18 22

With regard to safety, we evaluated gastrointestinal system (ie, nausea, vomiting), nervous system (ie, dizziness) and dermal (pruritus) tolerability. There were no significant differences in gastrointestinal and dermal adverse events. However, there was a significant increase in dizziness, which may be due to the GABAergic activity of sufentanil, which contributes to its sedative properties.31 32 We also conducted a subgroup analysis of overall adverse events from included studies based on the type of surgery. We observed that in orthopaedic surgeries there was a significant increase in the total number of adverse events, and this may be due to the cumulative dose per day in orthopaedic surgery being higher than abdominal surgery.33

In postoperative pain management, patients usually demand multiple doses of analgesic, which results in dose stacking. In case of opioids, which takes slower time to achieve equilibrium, repeated administration after surgery due to incomplete analgesia can lead to adverse events due to accumulation of more drugs or their metabolites in the body.34 The median time of sufentanil to peak plasma concentration of 18 min (Tmax) after sublingual administration exactly matches that of the period of lockout. During this period, the drug cannot be readministered from the SSTS device. The rapid attainment of pharmacokinetic equilibrium with sufentanil and the lack of any active metabolites allow a very close correlation between dosing and maximal effects and help minimise the risk of dose stacking. A phase III study done by Melson et al22 observed sedation in fewer patients, again suggesting decrease in dose stacking.19

In Singla et al17 and Ringold et al,19 use of rescue medication was higher in the placebo group than in the treatment arm, which indicates SSTS provides sustained analgesia. Similarly, the proportion of patients who discontinued the study was lower in the SSTS group than in the control.18–22

Currently available PCA systems are intravenous morphine PCA, transdermal fentanyl PCA, SSTS and so on. PCA provides effective analgesia with less interanalgesic pain incidence, shorter duration of hospital stay and high patient satisfaction by controlling their treatment. The potential advantages of SSTS over parenteral PCA are primarily due to the non-invasive mode of administration. Other advantages of SSTS over intravenous PCA are the prevention of intravenous line blockage and catheter-related bloodstream infection, early patient mobility, and low risk of needle stick injury among healthcare professionals.26 SSTS, at the same time, has its own disadvantages. Patients’ eating, drinking or smoking behaviour can alter the absorption of sublingual dosages.26 Another limitation of the SSTS formulation is that it requires adequate oral hydration for dissolution and therefore adequate oral hydration must be maintained during the postoperative period.

Strength and limitations

As there are fewer elderly patients and patients with comorbidities, it is difficult to generalise the use of SSTS to elderly patients with comorbidities, although Hutchins et al,35 in a single-arm study, observed that it is well tolerated in patients with renal and liver failure, along with a significant decrease in pain intensity and pain relief. Due to variations in efficacy endpoint assessment time points used in the study, we were unable to perform subgroup analysis based on the type of surgery. Another potential limitation is the results of our systematic review being mainly applicable to postsurgery patients undergoing abdominal and orthopaedic surgeries with moderate to severe pain. Hence, the results cannot be extrapolated to other pain such as tumour-related pain.

However, this study met most of the methodological criteria of systematic reviews, and all included studies were randomised, double-blind, placebo-controlled trials. According to the quality assessment scale, the quality of each study in this meta-analysis has low RoB.

GRADE conclusion

The overall quality of this systematic review is high as critical outcomes such as SPID12, SPID48, TOTPAR and PID have high quality of evidence. Other important outcomes such as PGA and HPGA also have high quality of evidence. This evidence suggests that further research is very unlikely to have any important impact on our confidence on the estimates or to change the estimates.

Conclusion

Existing evidence from the present systematic review of randomised controlled trials on SSTS versus control indicates a statistically and clinically significant reduction in SPID12 (12 points of MD in pain intensity), SPID48 (43 points of MD in pain intensity), TOTPAR (approximately 5 points of MD in pain intensity) and PID (approximately 1 point of MD in pain intensity), alongside high quality of evidence. Success of treatment as assessed by PGA and HPGA scoring was observed in a significantly high number of individuals using SSTS, with high quality of evidence. Hence, it can be concluded that SSTS is effective in postoperative pain management in patients with moderate to severe pain. SSTS also has good tolerability and high patient satisfaction.

Ethics statements

Patient consent for publication

Acknowledgments

We are thankful to the GRADEpro GDT site for allowing us to generate the grading of evidence and summary of findings table using their online software (available at gradepro.org).

References

Footnotes

  • PT and SBV are joint first authors.

  • PT and SS contributed equally.

  • Correction notice This article has been updated since it was first published. The article type has been changed to Systematic review.

  • Contributors PT: conceptualisation, methodology. SBV: methodology, data curation, writing-original draft preparation. SV: visualisation, investigation. TT: supervision. SS: methodology, data curation, writing-reviewing and editing.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.