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Efficacy of fentanyl iontophoretic transdermal system in postoperative pain—A meta-analysis
Acute Pain (2009) 11, 65—74
Efficacy of fentanyl iontophoretic transdermal system in postoperative pain—–A meta-analysis Keah-How Poon a,∗, Kian-Hian Tan b, Kok-Yuen Ho b a
Department of Anaesthesia, National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074, Singapore b Department of Anaesthesia and Surgical Intensive Care, Singapore General Hospital, Singapore Received 17 February 2009 ; received in revised form 13 April 2009; accepted 6 May 2009
KEYWORDS Analgesia; Fentanyl; Iontophoresis; Postoperative; Transdermal
Summary Background: Postoperative analgesic modalities include patient-controlled techniques via various routes such as intravenous and epidural. A transdermal delivery route using iontophoretic technology appears promising. Recent randomised controlled trials have suggested that fentanyl iontophoretic transdermal system (ITS) was of equivalent efficacy to intravenous morphine patient-controlled analgesia (PCA). The objective of this meta-analysis was to assess the efficacy and safety of this system in the management of acute postoperative pain. Methods: A meta-analysis of two placebo-controlled and four active-controlled randomised trials which satisfied the inclusion criteria was performed according to the QUOROM guidelines. Results: Fentanyl ITS was superior to placebo for postoperative analgesia using withdrawal secondary to inadequate analgesia and pain scores as outcome measures. Fentanyl ITS was equivalent to morphine PCA when Patient Global Assessment was used as primary outcome measure. However, there were significantly more patients in the fentanyl ITS group who withdrew due to inadequate analgesia. This may be related to the pharmacokinetic profile of fentanyl ITS. Adverse effect and safety profile seemed favourable. Conclusions: Fentanyl ITS is a promising novel modality for postoperative analgesia that is superior to placebo but may not be equivalent to morphine PCA as claimed by individual trials and recent reviews. Its use appears to be safe. © 2009 Elsevier B.V. All rights reserved.
1. Introduction ∗
Corresponding author. Tel.: +65 67724208; fax: +65 67775702. E-mail addresses: [email protected], [email protected] (K.-H. Poon).
Patient-controlled analgesia (PCA) with intravenous (IV) opioid is a widely used technique for the treatment of acute postoperative pain [1,2]. However, limitations include the need for IV access,
1366-0071/$ — see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.acpain.2009.05.001
66 restrictions on mobility if bigger pumps are used, and the potential for system-related events such as pump failures, programming errors and syringe errors, which may interrupt pain control [3]. IV PCA pumps also require considerable staff time and resources [4]. Studies have also shown that despite efforts in improving postoperative pain control such as the development and implementation of pain management guidelines [5,6] and acute pain services, postoperative pain remains inadequately managed [7,8]. The high lipid solubility and potency allows fentanyl to be delivered transdermally. The recent development in technology has led to the usage of iontophoresis (electro-transport) to deliver ionisable drugs, such as fentanyl hydrochloride (HCl), into or through the skin by application of an external electrical field [9,10]. Using this technology, a fentanyl HCl patient-controlled iontophoretic transdermal system (ITS) was developed that is a needle-free, pre-programmed, self-contained, self-adhesive, on-demand drug-delivery system (IONSYSTM , Janssen-Cilag NV, Beerse, Belgium). This development allows transdermal fentanyl to be used in the setting of moderate to severe acute postoperative pain. Since 2004, studies have been published to show the efficacy and adverse effects of this system compared with both placebo and IV PCA for postoperative pain. All the studies concluded that fentanyl ITS was superior to placebo and comparable to IV PCA morphine. All of these studies were industry sponsored. The objective of this meta-analysis was to assess the efficacy and safety of fentanyl ITS in the management of acute postoperative pain by pooling and analysing data from these studies.
2. Methods We followed the QUOROM guidelines for reporting meta-analyses [11].
2.1. Search Published reports of randomised controlled trials that investigated the use of fentanyl ITS for postoperative pain management were searched in Medline (1966—2008), Cochrane Central Register of Controlled Trials (2008), Embase and CINAHL. Free text and MeSH terms ‘fentanyl’, ‘iontophoretic’, ‘transdermal’, ‘pain’, ‘analgesia’, ‘analgesic’, ‘postoperative’ and ‘surgery’ were used for searching. Search was performed without language restriction but limited to randomised trials in humans. The last electronic search was in
K.-H. Poon et al. June 2008. Additional studies from the bibliographies of reviews or reports were also identified.
2.2. Selection criteria Only randomised, placebo-controlled trials and trials that compared fentanyl ITS with morphine PCA were selected. Reviews and abstracts were not considered.
2.3. Validity assessment One author (K.H.P.) screened the abstracts of all retrieved reports and excluded those that did not meet the inclusion criteria. Two reviewers (K.H.P. and K.H.T.) then read all included reports independently. Quality and validity of the studies were assessed using the Jadad score and Oxford Pain Validity Score respectively [12,13]. Discrepancies were resolved by discussion or by consulting the third reviewer (K.Y.H.).
2.4. Data abstraction A data abstraction form was created and the following data were collected: (i) type of surgery; (ii) number of patients; (iii) placebo or active comparator (i.e. morphine PCA); (iv) outcome measures of efficacy; and (v) adverse effects. The primary outcome reported in placebo-controlled trials was the percentage of patients who withdrew from the study due to inadequate analgesia. Outcome measures in the fentanyl ITS vs. morphine PCA trials included Patient Global Assessment (PGA) of method of pain control (primary outcome), pain intensity and dropout due to inadequate analgesia. Pain intensity measured on a visual analog score (VAS, 0—100 mm, 0 = no pain and 100 = maximum pain) was analysed quantitatively. Pain Numeric Rating Scale (NRS) reported on a 0—10 scale was converted to 0—100. The following adverse effects were noted for analysis: nausea, vomiting, pruritus, headache, constipation, urinary retention, dizziness, somnolence and hypoxia.
2.5. Meta-analyses Both dichotomous and continuous data were extracted. Continuous data were analysed as weighted mean differences (WMD) with 95% confidence intervals (CI). When mean values and standard deviations were not reported, data were extracted from the graphs. Data presented with standard error were converted to standard deviation to allow pooling of results for meta-analysis. Dichotomous data were summarised using odds
67
p < 0.05 p < 0.05 244/240 12 3 Viscusi et al. [21]
OPVS, Oxford Pain Validity Score; ITS, iontophoretic transdermal system.
p < 0.05 p < 0.05
Major abdominal, orthopaedic, thoracic Major abdominal, orthopaedic, thoracic 142/47 2 Chelly et al. [16]
12
Pain intensity scores (last recorded) Withdrawal due to inadequate analgesic Type of surgery Number of patients ITS/placebo OPVS Quality score Clinical trial
Fig. 1 Flow chart of screened, excluded and analysed papers.
Table 1
Nine publications that described the use of fentanyl ITS in postoperative pain management were identified between 1998 and 2008 (Fig. 1) [14—22]. All reports were published in English. One was published in abstract form and was excluded [15]. Two other studies were excluded because one was a subgroup analysis of a larger trial by Viscusi et al. in 2004 and the other was an analysis of pooled data from three randomised trials that were included in our meta-analysis [14,22]. Six valid randomised trials were therefore included in the analysis [16—21]. Two placebo-controlled trials with a total of 673 patients (382 in fentanyl ITS group and 291 in placebo group) were included in the analysis (Table 1) [16,21]. Four fentanyl ITS vs. morphine PCA trials were included in the analysis. A total of 2597 patients were studied, of whom 1285 patients received fentanyl ITS and 1312 patients received morphine PCA (Table 2) [17—20].
Randomised, double-blinded, placebo-controlled trials of fentanyl ITS for postoperative pain management.
3. Results
Adverse effects
ratio (OR) with 95% CI. A fixed effects model was used by default. If the statistical test for heterogeneity was positive, a random effects model was utilised. If the 95% CI included 1, it was assumed that there was no statistically significant difference between fentanyl ITS and the comparator. Analyses were performed using Review Manager (RevMan) Version 5.0 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008). Data were graphically plotted using forest plots.
More freq opioid related side effects in ITS group
Efficacy of fentanyl ITS
3.1. Fentanyl ITS vs. placebo trials
OPVS, Oxford Pain Validity Score; ITS, iontophoretic transdermal system; PCA, patient-controlled analgesia. a The following reported adverse effects: nausea, vomiting, pruritus, headache, GI disorders, urinary retention, dizziness, somnolence, hypoxia.
NS NS NS Major abdominal, orthopaedic, thoracic 10 3 Viscusi et al. [20]
316/320
p < 0.05 NS Abdominal, pelvic 252/254 10 Minkowitz et al. [19] 3
395/404 9 3 Hartrick et al. [18]
NS
Less nausea and pruritus in ITS (p < 0.05) Less pruritus in ITS (p < 0.05) NS p < 0.05 NS
p < 0.05
NS NS 3 Grond et al. [17]
9
322/334
Major abdominal, orthopaedic Unilateral THR
NS
NS
Adverse effectsa Withdrawal due to inadequate analgesic Patient Global Assessment Type of surgery OPVS Number of patients ITS/PCA morphine Quality score Clinical trial
Table 2
Pain intensity scores (last recorded)
K.-H. Poon et al.
Randomised, active-controlled trials of fentanyl ITS for postoperative pain management.
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A significantly smaller percentage of patients withdrew from the study due to inadequate analgesia when they received fentanyl ITS for postoperative pain control (OR: 0.32; 95% CI: 0.23—0.45) (Fig. 2). Patients receiving fentanyl ITS also demonstrated lower pain scores when compared to those in the placebo group (WMD: −17.47 mm; 95% CI: −21.64 to −13.30 mm) (Fig. 3). Other secondary outcome measures were not pooled for analysis because the data were too disparate.
3.2. Fentanyl ITS vs. morphine PCA trials The primary outcome measure of PGA (i.e., patients rating their method of pain control as ‘‘good’’ and ‘‘excellent’’) did not show any statistically significant difference between fentanyl ITS and morphine PCA groups (OR: 0.95; 95% CI: 0.78—1.16) (Fig. 4). The number of patients in either group who withdrew from the study did not differ (OR: 1.13; 95% CI: 0.91—1.39). However, when the number of patients who dropped out of the trial due to inadequate analgesia was compared, a statistically significant greater number of patients withdrew from the fentanyl ITS group (OR: 2.01; 95% CI: 1.47—2.74) (Fig. 5). Comparing pain scores at 24 h from the end of surgery, patients in the fentanyl ITS group have marginally lower pain scores compared with patients in the morphine PCA group (WMD: −1.74 mm; 95% CI: −3.37 to −0.12 mm) (Fig. 6). The number of patients who withdrew from the study due to adverse events was lower in the fentanyl ITS group when compared to the morphine PCA group (OR: 0.66; 95% CI: 0.46—0.94) (Fig. 7). Quantitative analysis showed that patients who received fentanyl ITS experienced less nausea (OR: 0.84; 95% CI: 0.72—0.99) and less pruritus (OR: 0.55; 95% CI: 0.41—0.75) when compared to patients who received morphine PCA. On the other hand, the incidence of headache was higher in the fentanyl ITS group (OR: 1.61; 95% CI: 1.18—2.19). There was no statistically significant difference between the groups in the incidence of vomiting, constipation, urinary retention, dizziness, somnolence and hypoxia (Fig. 8). There were 5 patients who developed clinically relevant respiratory depression, out of 1312 patients from the four trials (incidence of 0.38%). None were found in the fentanyl ITS groups. However, this did not reach statistical significance (OR: 0.29; 95% CI: 0.06—1.40).
Efficacy of fentanyl ITS
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Fig. 2 Meta-analysis: fentanyl ITS vs. placebo. Number of patients withdrawn due to inadequate analgesia; OR, odds ratio; CI, confidence interval.
Fig. 3 Meta-analysis: fentanyl ITS vs. placebo. Last measured pain intensity scores post-surgery. WMD, weighted mean difference; CI, confidence interval.
Fig. 4 Meta-analysis: fentanyl ITS vs. morphine PCA. Patient Global Assessment (PGA) of method of pain control. OR, odds ratio; CI, confidence interval.
Fig. 5 Meta-analysis: fentanyl ITS vs. morphine PCA. Number of patients who dropped out of study due to inadequate analgesia. OR, odds ratio; CI, confidence interval.
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K.-H. Poon et al.
Fig. 6 Meta-analysis: fentanyl ITS vs. morphine PCA. Pain intensity scores at 24 h post-surgery. WMD, weighted mean difference; CI, confidence interval.
Fig. 7 Meta-analysis: fentanyl ITS vs. morphine PCA. Number of patients who dropped out of study due to adverse effects. OR, odds ratio; CI, confidence interval.
4. Discussion 4.1. Efficacy This meta-analysis of six trials with reasonable quality and good validity scores confirmed some findings of the individual trials as well as a recent review [22]. First, fentanyl ITS was superior in efficacy to placebo using ‘‘withdrawal due to inadequate analgesia’’ and ‘‘last recorded pain intensity scores’’ as outcome measures. Second, fentanyl ITS was not inferior in efficacy to morphine PCA if PGA of method of pain control was measured. An unexpected and key finding of this metaanalysis was the higher withdrawal due to inadequate analgesia in the fentanyl ITS group. The OR of 2.01, in favour of morphine PCA meant that for every patient in the morphine PCA group who dropped out, there would be two patient dropouts in the fentanyl ITS group. This was statistically significant and clinically important. This finding was also noted in the review by Viscusi [22] as well as two of the four individual trials. The review paper did not explain for this difference. Hartrick and Minkowitz’s groups attributed the statistically significant higher withdrawal rates from the fentanyl ITS groups to patients being biased towards morphine PCA as this was a widely accepted standard practice of postoperative pain
management [18,19]. However, we postulate that this result could also be related to the pharmacokinetic characteristics of fentanyl ITS based on the following observations. The pharmacokinetic studies in healthy male volunteers showed that the initial fentanyl dose received iontophoretically was only 16 mcg. The presumed 40 mcg dose was achieved only after 10 h of continuous therapy [23,24]. If 40 mcg of fentanyl is necessary for analgesic effect as verified clinically [25], then it will be expected that for the first 10 h, patients using the fentanyl ITS system are more likely to experience either more pain or a greater need for supplemental analgesia or both. It can also be argued that a surrogate measure of this inadequate analgesia is the withdrawal rates due to inadequate analgesia. Based on the findings of our meta-analysis, there was no difference between the fentanyl ITS and morphine PCA groups in supplemental analgesic use in the first 3 h. There was inadequate data available for meta-analysis to look at the pain intensity scores in the first few postoperative hours. However, a higher withdrawal rate due to inadequate analgesia was observed in the fentanyl ITS group compared to morphine PCA group; our key finding in this meta-analysis. Therefore, it is possible that fentanyl ITS is inferior to morphine PCA in terms of efficacy, especially in the immediate postoperative period.
Efficacy of fentanyl ITS
Fig. 8 Meta-analysis: fentanyl ITS vs. morphine PCA. Adverse effects. OR, odds ratio; CI, confidence interval.
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72 The use of IV PCA minimises analgesic gaps compared to conventional intermittent parenteral (IM/SC) opioid administration by reducing factors related to nursing and pharmacokinetic variables. However, other issues peculiar to IV PCA can contribute to new analgesic gaps. A blocked IV catheter with delay in resiting and an empty pump which is not timely refilled are examples. Fentanyl ITS seems to offer advantages of bypassing such nursing and equipment variables. However, it would seem that if our hypothesis is right, the pharmacokinetic profile of fentanyl ITS can result in analgesic gaps in the first 10 h and hence, account for the higher withdrawal rates due to inadequate analgesia. This initial analgesic gap may have to be covered with either oral or parenteral analgesics, which may not be feasible nor desirable in some cases. A foreseeable application may be its use in combination with a single shot neuraxial or peripheral nerve block; an increasingly popular perioperative analgesic modality. This can typically last between 6 and 10 h and may represent a bridge to the analgesic gap of fentanyl ITS.
4.2. Advantages and adverse effects of fentanyl ITS Fentanyl ITS has received FDA approval since May 2006. It uses low electrical current proprietary electrotransport technology to deliver 40 mcg of fentanyl over a 10-min period transdermally with up to 6 doses available per hour. This dose was chosen based on results of a fentanyl IV PCA dosefinding study, which demonstrated this dose to be the best combination for analgesic efficacy and an acceptable side effect profile [25]. This system operates for 24 h, or until a maximum of 80 doses is delivered, whichever occurs first. There are several purported advantages of this novel fentanyl ITS. Its compact and self-contained preparation allows greater patient mobility and ease of use. The pre-programmed drug-delivery system obviates the need for drug preparation and programming which can save time and resources as well as minimise errors. In this meta-analysis, two of the studies reported ease of use by patient and ease of care by nurses [17,18]. These showed a statistically significant difference favouring fentanyl ITS. Another obvious appeal is the transdermal, needleless delivery system. A needleless system will minimise risks associated with the use of needles. These include needlestick injuries by healthcare staff, thrombophlebitis and difficult IV access issues in patients. However, it must be mentioned that the trade-off is the development of skin application
K.-H. Poon et al. site reactions, which were common but mild. Our quantitative analysis reported a lower withdrawal rate secondary to adverse effects in the fentanyl ITS group. When individual adverse effects were examined, fentanyl ITS resulted in less nausea and pruritus but more headache compared to morphine PCA. The reason for this higher incidence of headache remained unclear and a search in current literature did not reveal a direct correlation. The other adverse effects including vomiting, constipation, urinary retention, dizziness, somnolence and hypoxia were similar between the two groups. More importantly, clinically relevant respiratory depression (bradypnoea <8 breaths per minute and excessive sedation) did not occur in any of the 1683 patients who used fentanyl ITS. In contrast, five cases of clinically relevant respiratory depression occurred in the 1312 patients who used morphine PCA. It appeared that fentanyl ITS might have an edge in terms of side effect profile over morphine PCA, both mild and severe.
4.3. Limitations There are some limitations in this meta-analysis. All the studies were industry sponsored. This can introduce publication bias as positive studies are more likely to be published. There were limited randomised controlled trials (two placebo-controlled and four active-controlled) available for analyses. However, the total number of patients was respectable (637 and 2597) and should provide a reasonable level of confidence with regards to reducing errors due to chance. Moreover, reported outcomes varied between trials, both in the outcome measures as well as the ways of reporting. These differences prevented pooling of some results for analyses.
4.4. Conclusion Fentanyl ITS is a promising, novel patientcontrolled analgesic delivery system. All six trials (two placebo-controlled and four morphine PCA-controlled) concluded that fentanyl ITS was superior to placebo, non-inferior to morphine PCA and safe. All six trials were industry sponsored. Based on the results of this meta-analysis, fentanyl ITS was superior to placebo in acute pain management. However, a similar conclusion cannot be drawn when fentanyl ITS was compared to morphine PCA. Using PGA — the primary outcome for all the trials — fentanyl ITS was equivalent to morphine PCA. However, when withdrawal rates due to inadequate analgesia were analysed, fentanyl ITS was less efficacious, especially in the initial
Efficacy of fentanyl ITS postoperative period. We postulate that the efficacy issue could be related to the pharmacokinetic profile of fentanyl ITS. This may be the Achilles heel of such a drug-delivery system. Future studies must be designed to test our hypothesis that the higher dropout rates due to inadequate analgesia with fentanyl ITS is indeed time-dependent and related to the failure of the delivery system to match the analgesic requirements of patients in the early postoperative period. Until we can determine the precise reason for the high dropouts, we recommend that physicians using this system be cognisant of the fact that the patients may have increased requirements for breakthrough medications. The fentanyl ITS system (IONSYSTM , JanssenCilag NV, Beerse, Belgium) has been withdrawn from the market since September 2008, during preparation of this manuscript. Janssen-Cilag had detected corrosion of a component of the system in one batch of Ionsys. As this defect could result in the self-activation of the system, the potential risks resulting from fentanyl overdose (including respiratory depression) were deemed to outweigh the benefits. The European Medicines Agency thus recommended the suspension of the marketing authorisation of Ionsys even though there have been no reports of serious adverse events associated with malfunction of the device [26]. There were, however, no suggestions from the report that the withdrawal was related to efficacy issues such as those discussed in this paper.
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[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
Conflict of interest statement This work is not industry funded and none of the authors have any financial interest in the subject matter discussed in this manuscript.
[16]
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[1] Rawal N, Allvin R. Acute pain services in Europe: a 17 nation survey of 105 hospitals. The EuroPain Acute Pain Working Party. Euro J Anaesthesiol 1998;15:354—63. [2] Walder B, Schafer M, Henzi I, Tramer MR. Efficacy and safety of patient controlled analgesia for acute postoperative pain. A quantitative systematic review. Acta Anaesthesiol Scand 2001;45:795—804. [3] Vicente KJ, Kada-Bekhaled K, Hillel G, Cassano A, Orser BA. Programming errors contribute to death from patient-controlled analgesia: case report and estimate of probability. Can J Anaesth 2003;50:328—32. [4] Choiniere M, Rittenhouse BE, Perreault S, Chartrand D, Rosseau P, Smith B, et al. Efficacy and costs of patientcontrolled analgesia versus regularly administered intramuscular opioid therapy. Anesthesiology 1998;89:1377—88. [5] American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain
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pump for postoperative pain: a randomized controlled trial. JAMA 2004;291:1333—41. [21] Viscusi ER, Reynolds L, Tait S, Melson T, Atkinson LE. An iontophoretic fentanyl patient-activated analgesic delivery system for postoperative pain: a double-blind, placebocontrolled trial. Anesth Analg 2006;102:188—94. [22] Viscusi ER, Siccardi M, Damaraju CV, Hewitt DJ, Kershaw P. The safety and efficacy of fentanyl iontophoretic transdermal system compared with morphine intravenous patient-controlled analgesia for postoperative pain management: an analysis of pooled data. Anesth Analg 2007;105:1428—36. [23] Ortho-McNeil Inc. Ionsys (fentanyl iontophoretic transdermal system) prescribing information. Raritan, NJ;2006.
[24] Sathyan G, Jaskowiak J, Evashenk M, Gupta S. Characterisation of the pharmacokinetics of the fentanyl HCl patient-controlled transdermal system (PCTS): effect of current magnitude and multiple-day dosing and comparison with IV fentanyl administration. Clin Pharmacokinet 2005;44(Suppl 1):7—15. [25] Camu F, Van Aken H, Bovill JG. Postoperative analgesic effects of three demand dose sizes of fentanyl administered by patient controlled analgesia. Anesth Analg 1998;87:890—5. [26] http://www.emea.europa.eu/humandocs/PDFs/EPAR/ ionsys/Ionsys Q&A 60985608en.pdf. Last accessed on April 5, 2009.
Available online at www.sciencedirect.com
Efficacy of fentanyl iontophoretic transdermal system in postoperative pain—–A meta-analysis Keah-How Poon a,∗, Kian-Hian Tan b, Kok-Yuen Ho b a
Department of Anaesthesia, National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074, Singapore b Department of Anaesthesia and Surgical Intensive Care, Singapore General Hospital, Singapore Received 17 February 2009 ; received in revised form 13 April 2009; accepted 6 May 2009
KEYWORDS Analgesia; Fentanyl; Iontophoresis; Postoperative; Transdermal
Summary Background: Postoperative analgesic modalities include patient-controlled techniques via various routes such as intravenous and epidural. A transdermal delivery route using iontophoretic technology appears promising. Recent randomised controlled trials have suggested that fentanyl iontophoretic transdermal system (ITS) was of equivalent efficacy to intravenous morphine patient-controlled analgesia (PCA). The objective of this meta-analysis was to assess the efficacy and safety of this system in the management of acute postoperative pain. Methods: A meta-analysis of two placebo-controlled and four active-controlled randomised trials which satisfied the inclusion criteria was performed according to the QUOROM guidelines. Results: Fentanyl ITS was superior to placebo for postoperative analgesia using withdrawal secondary to inadequate analgesia and pain scores as outcome measures. Fentanyl ITS was equivalent to morphine PCA when Patient Global Assessment was used as primary outcome measure. However, there were significantly more patients in the fentanyl ITS group who withdrew due to inadequate analgesia. This may be related to the pharmacokinetic profile of fentanyl ITS. Adverse effect and safety profile seemed favourable. Conclusions: Fentanyl ITS is a promising novel modality for postoperative analgesia that is superior to placebo but may not be equivalent to morphine PCA as claimed by individual trials and recent reviews. Its use appears to be safe. © 2009 Elsevier B.V. All rights reserved.
1. Introduction ∗
Corresponding author. Tel.: +65 67724208; fax: +65 67775702. E-mail addresses: [email protected], [email protected] (K.-H. Poon).
Patient-controlled analgesia (PCA) with intravenous (IV) opioid is a widely used technique for the treatment of acute postoperative pain [1,2]. However, limitations include the need for IV access,
1366-0071/$ — see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.acpain.2009.05.001
66 restrictions on mobility if bigger pumps are used, and the potential for system-related events such as pump failures, programming errors and syringe errors, which may interrupt pain control [3]. IV PCA pumps also require considerable staff time and resources [4]. Studies have also shown that despite efforts in improving postoperative pain control such as the development and implementation of pain management guidelines [5,6] and acute pain services, postoperative pain remains inadequately managed [7,8]. The high lipid solubility and potency allows fentanyl to be delivered transdermally. The recent development in technology has led to the usage of iontophoresis (electro-transport) to deliver ionisable drugs, such as fentanyl hydrochloride (HCl), into or through the skin by application of an external electrical field [9,10]. Using this technology, a fentanyl HCl patient-controlled iontophoretic transdermal system (ITS) was developed that is a needle-free, pre-programmed, self-contained, self-adhesive, on-demand drug-delivery system (IONSYSTM , Janssen-Cilag NV, Beerse, Belgium). This development allows transdermal fentanyl to be used in the setting of moderate to severe acute postoperative pain. Since 2004, studies have been published to show the efficacy and adverse effects of this system compared with both placebo and IV PCA for postoperative pain. All the studies concluded that fentanyl ITS was superior to placebo and comparable to IV PCA morphine. All of these studies were industry sponsored. The objective of this meta-analysis was to assess the efficacy and safety of fentanyl ITS in the management of acute postoperative pain by pooling and analysing data from these studies.
2. Methods We followed the QUOROM guidelines for reporting meta-analyses [11].
2.1. Search Published reports of randomised controlled trials that investigated the use of fentanyl ITS for postoperative pain management were searched in Medline (1966—2008), Cochrane Central Register of Controlled Trials (2008), Embase and CINAHL. Free text and MeSH terms ‘fentanyl’, ‘iontophoretic’, ‘transdermal’, ‘pain’, ‘analgesia’, ‘analgesic’, ‘postoperative’ and ‘surgery’ were used for searching. Search was performed without language restriction but limited to randomised trials in humans. The last electronic search was in
K.-H. Poon et al. June 2008. Additional studies from the bibliographies of reviews or reports were also identified.
2.2. Selection criteria Only randomised, placebo-controlled trials and trials that compared fentanyl ITS with morphine PCA were selected. Reviews and abstracts were not considered.
2.3. Validity assessment One author (K.H.P.) screened the abstracts of all retrieved reports and excluded those that did not meet the inclusion criteria. Two reviewers (K.H.P. and K.H.T.) then read all included reports independently. Quality and validity of the studies were assessed using the Jadad score and Oxford Pain Validity Score respectively [12,13]. Discrepancies were resolved by discussion or by consulting the third reviewer (K.Y.H.).
2.4. Data abstraction A data abstraction form was created and the following data were collected: (i) type of surgery; (ii) number of patients; (iii) placebo or active comparator (i.e. morphine PCA); (iv) outcome measures of efficacy; and (v) adverse effects. The primary outcome reported in placebo-controlled trials was the percentage of patients who withdrew from the study due to inadequate analgesia. Outcome measures in the fentanyl ITS vs. morphine PCA trials included Patient Global Assessment (PGA) of method of pain control (primary outcome), pain intensity and dropout due to inadequate analgesia. Pain intensity measured on a visual analog score (VAS, 0—100 mm, 0 = no pain and 100 = maximum pain) was analysed quantitatively. Pain Numeric Rating Scale (NRS) reported on a 0—10 scale was converted to 0—100. The following adverse effects were noted for analysis: nausea, vomiting, pruritus, headache, constipation, urinary retention, dizziness, somnolence and hypoxia.
2.5. Meta-analyses Both dichotomous and continuous data were extracted. Continuous data were analysed as weighted mean differences (WMD) with 95% confidence intervals (CI). When mean values and standard deviations were not reported, data were extracted from the graphs. Data presented with standard error were converted to standard deviation to allow pooling of results for meta-analysis. Dichotomous data were summarised using odds
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p < 0.05 p < 0.05 244/240 12 3 Viscusi et al. [21]
OPVS, Oxford Pain Validity Score; ITS, iontophoretic transdermal system.
p < 0.05 p < 0.05
Major abdominal, orthopaedic, thoracic Major abdominal, orthopaedic, thoracic 142/47 2 Chelly et al. [16]
12
Pain intensity scores (last recorded) Withdrawal due to inadequate analgesic Type of surgery Number of patients ITS/placebo OPVS Quality score Clinical trial
Fig. 1 Flow chart of screened, excluded and analysed papers.
Table 1
Nine publications that described the use of fentanyl ITS in postoperative pain management were identified between 1998 and 2008 (Fig. 1) [14—22]. All reports were published in English. One was published in abstract form and was excluded [15]. Two other studies were excluded because one was a subgroup analysis of a larger trial by Viscusi et al. in 2004 and the other was an analysis of pooled data from three randomised trials that were included in our meta-analysis [14,22]. Six valid randomised trials were therefore included in the analysis [16—21]. Two placebo-controlled trials with a total of 673 patients (382 in fentanyl ITS group and 291 in placebo group) were included in the analysis (Table 1) [16,21]. Four fentanyl ITS vs. morphine PCA trials were included in the analysis. A total of 2597 patients were studied, of whom 1285 patients received fentanyl ITS and 1312 patients received morphine PCA (Table 2) [17—20].
Randomised, double-blinded, placebo-controlled trials of fentanyl ITS for postoperative pain management.
3. Results
Adverse effects
ratio (OR) with 95% CI. A fixed effects model was used by default. If the statistical test for heterogeneity was positive, a random effects model was utilised. If the 95% CI included 1, it was assumed that there was no statistically significant difference between fentanyl ITS and the comparator. Analyses were performed using Review Manager (RevMan) Version 5.0 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008). Data were graphically plotted using forest plots.
More freq opioid related side effects in ITS group
Efficacy of fentanyl ITS
3.1. Fentanyl ITS vs. placebo trials
OPVS, Oxford Pain Validity Score; ITS, iontophoretic transdermal system; PCA, patient-controlled analgesia. a The following reported adverse effects: nausea, vomiting, pruritus, headache, GI disorders, urinary retention, dizziness, somnolence, hypoxia.
NS NS NS Major abdominal, orthopaedic, thoracic 10 3 Viscusi et al. [20]
316/320
p < 0.05 NS Abdominal, pelvic 252/254 10 Minkowitz et al. [19] 3
395/404 9 3 Hartrick et al. [18]
NS
Less nausea and pruritus in ITS (p < 0.05) Less pruritus in ITS (p < 0.05) NS p < 0.05 NS
p < 0.05
NS NS 3 Grond et al. [17]
9
322/334
Major abdominal, orthopaedic Unilateral THR
NS
NS
Adverse effectsa Withdrawal due to inadequate analgesic Patient Global Assessment Type of surgery OPVS Number of patients ITS/PCA morphine Quality score Clinical trial
Table 2
Pain intensity scores (last recorded)
K.-H. Poon et al.
Randomised, active-controlled trials of fentanyl ITS for postoperative pain management.
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A significantly smaller percentage of patients withdrew from the study due to inadequate analgesia when they received fentanyl ITS for postoperative pain control (OR: 0.32; 95% CI: 0.23—0.45) (Fig. 2). Patients receiving fentanyl ITS also demonstrated lower pain scores when compared to those in the placebo group (WMD: −17.47 mm; 95% CI: −21.64 to −13.30 mm) (Fig. 3). Other secondary outcome measures were not pooled for analysis because the data were too disparate.
3.2. Fentanyl ITS vs. morphine PCA trials The primary outcome measure of PGA (i.e., patients rating their method of pain control as ‘‘good’’ and ‘‘excellent’’) did not show any statistically significant difference between fentanyl ITS and morphine PCA groups (OR: 0.95; 95% CI: 0.78—1.16) (Fig. 4). The number of patients in either group who withdrew from the study did not differ (OR: 1.13; 95% CI: 0.91—1.39). However, when the number of patients who dropped out of the trial due to inadequate analgesia was compared, a statistically significant greater number of patients withdrew from the fentanyl ITS group (OR: 2.01; 95% CI: 1.47—2.74) (Fig. 5). Comparing pain scores at 24 h from the end of surgery, patients in the fentanyl ITS group have marginally lower pain scores compared with patients in the morphine PCA group (WMD: −1.74 mm; 95% CI: −3.37 to −0.12 mm) (Fig. 6). The number of patients who withdrew from the study due to adverse events was lower in the fentanyl ITS group when compared to the morphine PCA group (OR: 0.66; 95% CI: 0.46—0.94) (Fig. 7). Quantitative analysis showed that patients who received fentanyl ITS experienced less nausea (OR: 0.84; 95% CI: 0.72—0.99) and less pruritus (OR: 0.55; 95% CI: 0.41—0.75) when compared to patients who received morphine PCA. On the other hand, the incidence of headache was higher in the fentanyl ITS group (OR: 1.61; 95% CI: 1.18—2.19). There was no statistically significant difference between the groups in the incidence of vomiting, constipation, urinary retention, dizziness, somnolence and hypoxia (Fig. 8). There were 5 patients who developed clinically relevant respiratory depression, out of 1312 patients from the four trials (incidence of 0.38%). None were found in the fentanyl ITS groups. However, this did not reach statistical significance (OR: 0.29; 95% CI: 0.06—1.40).
Efficacy of fentanyl ITS
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Fig. 2 Meta-analysis: fentanyl ITS vs. placebo. Number of patients withdrawn due to inadequate analgesia; OR, odds ratio; CI, confidence interval.
Fig. 3 Meta-analysis: fentanyl ITS vs. placebo. Last measured pain intensity scores post-surgery. WMD, weighted mean difference; CI, confidence interval.
Fig. 4 Meta-analysis: fentanyl ITS vs. morphine PCA. Patient Global Assessment (PGA) of method of pain control. OR, odds ratio; CI, confidence interval.
Fig. 5 Meta-analysis: fentanyl ITS vs. morphine PCA. Number of patients who dropped out of study due to inadequate analgesia. OR, odds ratio; CI, confidence interval.
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Fig. 6 Meta-analysis: fentanyl ITS vs. morphine PCA. Pain intensity scores at 24 h post-surgery. WMD, weighted mean difference; CI, confidence interval.
Fig. 7 Meta-analysis: fentanyl ITS vs. morphine PCA. Number of patients who dropped out of study due to adverse effects. OR, odds ratio; CI, confidence interval.
4. Discussion 4.1. Efficacy This meta-analysis of six trials with reasonable quality and good validity scores confirmed some findings of the individual trials as well as a recent review [22]. First, fentanyl ITS was superior in efficacy to placebo using ‘‘withdrawal due to inadequate analgesia’’ and ‘‘last recorded pain intensity scores’’ as outcome measures. Second, fentanyl ITS was not inferior in efficacy to morphine PCA if PGA of method of pain control was measured. An unexpected and key finding of this metaanalysis was the higher withdrawal due to inadequate analgesia in the fentanyl ITS group. The OR of 2.01, in favour of morphine PCA meant that for every patient in the morphine PCA group who dropped out, there would be two patient dropouts in the fentanyl ITS group. This was statistically significant and clinically important. This finding was also noted in the review by Viscusi [22] as well as two of the four individual trials. The review paper did not explain for this difference. Hartrick and Minkowitz’s groups attributed the statistically significant higher withdrawal rates from the fentanyl ITS groups to patients being biased towards morphine PCA as this was a widely accepted standard practice of postoperative pain
management [18,19]. However, we postulate that this result could also be related to the pharmacokinetic characteristics of fentanyl ITS based on the following observations. The pharmacokinetic studies in healthy male volunteers showed that the initial fentanyl dose received iontophoretically was only 16 mcg. The presumed 40 mcg dose was achieved only after 10 h of continuous therapy [23,24]. If 40 mcg of fentanyl is necessary for analgesic effect as verified clinically [25], then it will be expected that for the first 10 h, patients using the fentanyl ITS system are more likely to experience either more pain or a greater need for supplemental analgesia or both. It can also be argued that a surrogate measure of this inadequate analgesia is the withdrawal rates due to inadequate analgesia. Based on the findings of our meta-analysis, there was no difference between the fentanyl ITS and morphine PCA groups in supplemental analgesic use in the first 3 h. There was inadequate data available for meta-analysis to look at the pain intensity scores in the first few postoperative hours. However, a higher withdrawal rate due to inadequate analgesia was observed in the fentanyl ITS group compared to morphine PCA group; our key finding in this meta-analysis. Therefore, it is possible that fentanyl ITS is inferior to morphine PCA in terms of efficacy, especially in the immediate postoperative period.
Efficacy of fentanyl ITS
Fig. 8 Meta-analysis: fentanyl ITS vs. morphine PCA. Adverse effects. OR, odds ratio; CI, confidence interval.
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72 The use of IV PCA minimises analgesic gaps compared to conventional intermittent parenteral (IM/SC) opioid administration by reducing factors related to nursing and pharmacokinetic variables. However, other issues peculiar to IV PCA can contribute to new analgesic gaps. A blocked IV catheter with delay in resiting and an empty pump which is not timely refilled are examples. Fentanyl ITS seems to offer advantages of bypassing such nursing and equipment variables. However, it would seem that if our hypothesis is right, the pharmacokinetic profile of fentanyl ITS can result in analgesic gaps in the first 10 h and hence, account for the higher withdrawal rates due to inadequate analgesia. This initial analgesic gap may have to be covered with either oral or parenteral analgesics, which may not be feasible nor desirable in some cases. A foreseeable application may be its use in combination with a single shot neuraxial or peripheral nerve block; an increasingly popular perioperative analgesic modality. This can typically last between 6 and 10 h and may represent a bridge to the analgesic gap of fentanyl ITS.
4.2. Advantages and adverse effects of fentanyl ITS Fentanyl ITS has received FDA approval since May 2006. It uses low electrical current proprietary electrotransport technology to deliver 40 mcg of fentanyl over a 10-min period transdermally with up to 6 doses available per hour. This dose was chosen based on results of a fentanyl IV PCA dosefinding study, which demonstrated this dose to be the best combination for analgesic efficacy and an acceptable side effect profile [25]. This system operates for 24 h, or until a maximum of 80 doses is delivered, whichever occurs first. There are several purported advantages of this novel fentanyl ITS. Its compact and self-contained preparation allows greater patient mobility and ease of use. The pre-programmed drug-delivery system obviates the need for drug preparation and programming which can save time and resources as well as minimise errors. In this meta-analysis, two of the studies reported ease of use by patient and ease of care by nurses [17,18]. These showed a statistically significant difference favouring fentanyl ITS. Another obvious appeal is the transdermal, needleless delivery system. A needleless system will minimise risks associated with the use of needles. These include needlestick injuries by healthcare staff, thrombophlebitis and difficult IV access issues in patients. However, it must be mentioned that the trade-off is the development of skin application
K.-H. Poon et al. site reactions, which were common but mild. Our quantitative analysis reported a lower withdrawal rate secondary to adverse effects in the fentanyl ITS group. When individual adverse effects were examined, fentanyl ITS resulted in less nausea and pruritus but more headache compared to morphine PCA. The reason for this higher incidence of headache remained unclear and a search in current literature did not reveal a direct correlation. The other adverse effects including vomiting, constipation, urinary retention, dizziness, somnolence and hypoxia were similar between the two groups. More importantly, clinically relevant respiratory depression (bradypnoea <8 breaths per minute and excessive sedation) did not occur in any of the 1683 patients who used fentanyl ITS. In contrast, five cases of clinically relevant respiratory depression occurred in the 1312 patients who used morphine PCA. It appeared that fentanyl ITS might have an edge in terms of side effect profile over morphine PCA, both mild and severe.
4.3. Limitations There are some limitations in this meta-analysis. All the studies were industry sponsored. This can introduce publication bias as positive studies are more likely to be published. There were limited randomised controlled trials (two placebo-controlled and four active-controlled) available for analyses. However, the total number of patients was respectable (637 and 2597) and should provide a reasonable level of confidence with regards to reducing errors due to chance. Moreover, reported outcomes varied between trials, both in the outcome measures as well as the ways of reporting. These differences prevented pooling of some results for analyses.
4.4. Conclusion Fentanyl ITS is a promising, novel patientcontrolled analgesic delivery system. All six trials (two placebo-controlled and four morphine PCA-controlled) concluded that fentanyl ITS was superior to placebo, non-inferior to morphine PCA and safe. All six trials were industry sponsored. Based on the results of this meta-analysis, fentanyl ITS was superior to placebo in acute pain management. However, a similar conclusion cannot be drawn when fentanyl ITS was compared to morphine PCA. Using PGA — the primary outcome for all the trials — fentanyl ITS was equivalent to morphine PCA. However, when withdrawal rates due to inadequate analgesia were analysed, fentanyl ITS was less efficacious, especially in the initial
Efficacy of fentanyl ITS postoperative period. We postulate that the efficacy issue could be related to the pharmacokinetic profile of fentanyl ITS. This may be the Achilles heel of such a drug-delivery system. Future studies must be designed to test our hypothesis that the higher dropout rates due to inadequate analgesia with fentanyl ITS is indeed time-dependent and related to the failure of the delivery system to match the analgesic requirements of patients in the early postoperative period. Until we can determine the precise reason for the high dropouts, we recommend that physicians using this system be cognisant of the fact that the patients may have increased requirements for breakthrough medications. The fentanyl ITS system (IONSYSTM , JanssenCilag NV, Beerse, Belgium) has been withdrawn from the market since September 2008, during preparation of this manuscript. Janssen-Cilag had detected corrosion of a component of the system in one batch of Ionsys. As this defect could result in the self-activation of the system, the potential risks resulting from fentanyl overdose (including respiratory depression) were deemed to outweigh the benefits. The European Medicines Agency thus recommended the suspension of the marketing authorisation of Ionsys even though there have been no reports of serious adverse events associated with malfunction of the device [26]. There were, however, no suggestions from the report that the withdrawal was related to efficacy issues such as those discussed in this paper.
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[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
Conflict of interest statement This work is not industry funded and none of the authors have any financial interest in the subject matter discussed in this manuscript.
[16]
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