Patient-Controlled Transdermal Fentanyl Versus Intravenous Morphine Pump After Spine Surgery

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1 Ptient-Controlled Trnsderml Fentnyl Versus Intrvenous Morphine Pump After Spine Surgery Emily M. Lindley, PhD; Kenneth Millign, BS; Ryn Frmer, MD; Evlin L. Burger, MD; Viks V. Ptel, MD bstrct Ptient-controlled nlgesi (PCA) is regulrly used to mnge pin following mjor surgery. The fentnyl hydrochloride iontophoretic trnsderml system (ITS) ws developed to overcome some of the limittions of intrvenous (IV) PCA. The smll, self-dhesive, needle-free disposble system is pplied to the skin on the upper rm or chest nd is controlled by ptients clicking button on the device. The uthors identified ptients who were underwent spinl surgery from 2 prior multicenter, rndomized studies nd nlyzed their dt. Of the 1296 ptients in the originl trils, 170 underwent spine surgery procedures: 90 were rndomized to the fentnyl ITS (40 mcg/ctivtion) nd 80 to IV PCA morphine (1 mg/dose). More ptients treted with the fentnyl ITS rted their method of pin control s excellent cross ll time points, but differences did not rech sttisticl significnce. However, investigtors rtings of excellent stisfction with study tretment were significntly higher for the fentnyl ITS. Discontinution rtes nd overll dverse event rtes were similr between groups. The only significnt difference ws tht ptients treted with the fentnyl ITS hd higher rte of ppliction site rections thn infusion site rections in the IV PCA morphine group; the rections were typiclly mild-to-moderte erythem tht resolved shortly fter removl of the fentnyl ITS device nd did not require further tretment. Rtings of stisfction with pin control method were consistently higher for the fentnyl ITS thn the IV PCA morphine. The 2 groups hd similr sfety profile. These results suggest tht the fentnyl ITS ppers to be sfe, efficcious lterntive to IV PCA in spine surgery ptients. [Orthopedics. 2015; 38(9):e819-e824.] The uthors re from the Deprtment of Orthopedics, University of Colordo, Anschutz Medicl Cmpus, Denver, Colordo. The uthors hve no relevnt finncil reltionships to disclose. Dr Ptel ws not involved in the peer review of this mnuscript. Correspondence should be ddressed to: Emily M. Lindley, PhD, Deprtment of Orthopedics, University of Colordo, Anschutz Medicl Cmpus, E 17th Pl, Mil Stop F432, Auror, CO (Emily.lindley@ucdenver.edu). Received: September 30, 2014; Accepted: Jnury 6, doi: / SEPTEMBER 2015 Volume 38 Number 9 e819

2 The effective mngement of postopertive pin is n essentil component of periopertive ptient cre. Indequte control of postopertive pin is not only source of gret nxiety for ptients, but cn lso led to delys in mobiliztion nd dischrge nd cn increse the risk for deep venous thrombosis, pneumoni, pulmonry embolism, poor wound heling, tchycrdi, hypertension, nd the development of chronic pin. 1-6 Postopertive pin following spine surgery is primrily due to dissection of soft tissues nd muscles t the surgery site. Surgicl exposures typiclly disrupt highly innervted nd dense muscle lyers tht then ultimtely involve the periosteum, which contins nerves tht possess lower threshold for pin thn other nerve fibers in this deep lyer of tissue. 7,8 Current stndrd of cre for postopertive pin mngement of spine surgery ptients typiclly includes systemic dministrtion of opioids vi intrvenous (IV) ptient-controlled nlgesi (PCA) for 24 to 48 hours postopertively, with subsequent conversion to orl opioids nd nonsteroidl nti-inflmmtory drugs (NSAIDs). Ptient-controlled nlgesi ws developed in the lte 1960s nd hs become widely used method of postopertive pin control with equivlent efficcy nd greter ptient stisfction when compred with intrmusculr, epidurl, or orl pin control. 9,10 Intrvenous PCA llows ptients to self-dminister fixed doses of opioid nlgesics s needed for pin control. Although IV PCA is well-estblished periopertive pin mngement tool, it is not without disdvntges. Although some limittions primrily involve inconvenience to ptients nd stff, such s mobility restrictions nd preprtion time, others include the potentil for compromises in ptient sfety. For exmple, IV ctheters cn become clotted off or infiltrte into the subcutneous tissue, both of which would typiclly require n dditionl venipuncture to reestblish ptent IV ccess. 11 In ddition to ctheter problems, pump filures nd progrmming errors hve lso been reported. 12 A recent ntionl survey of PCA prctices found strtling lck of consistency in dherence to sfety procedures in hospitls cross the country. 14 Although 70% of PCA dverse events re ttributble to errors ssocited with PCA pump use, such s progrmming incorrect drug doses nd concentrtions, or ttchment problems, 13 only 1 of 10 hospitls surveyed followed recommended double checks to verify correct PCA pump progrmming nd dosges for ptients. 14 Such errors ssocited with PCA pump use hve led to oversedtion, nd even deth. 15 To overcome some of the limittions nd potentil sfety concerns ssocited with IV PCA nlgesic dministrtion, new phrmceuticl technologies hve been developed in recent yers. One such lterntive nlgesic delivery system is the fentnyl iontophoretic trnsderml system (ITS). Fentnyl ITS is needle-free nd dministers preprogrmmed dose of 40-µg fentnyl vi iontophoresis, noninvsive process by which 170-µA current propels ionized molecules cross the skin brrier nd into systemic circultion. 16 Previous studies hve showed comprble serum fentnyl concentrtions between IV nd ITS dministrtion nd found tht demogrphic vribles, such s ge, sex, rce, nd body mss index, hd no significnt effect on serum concentrtions. 17 It is lso worth noting tht multiple-dy dministrtion of fentnyl ITS does not ffect the phrmcokinetics of drug dministrtion. 18 The efficcy nd sfety of fentnyl ITS for postopertive pin mngement hs been studied in severl lrge ctivecontrolled clinicl trils in more thn 1000 ptients However, these trils included ptients from vriety of surgicl specilties, such s those undergoing mjor bdominl, orthopedic, nd thorcic surgery. Thus, the purpose of the current nlysis is to specificlly evlute whether fentnyl ITS is s efficcious s IV PCA morphine in mnging postopertive pin control in ptients who hve undergone spine surgery procedures. Mterils nd Methods Study Design This ws retrospective review of dt collected prospectively in 2 multicenter, rndomized, open-lbel, ctive-controlled, phse lll studies. 19,21 Ptients who underwent ny spine surgicl procedure in these 2 studies were identified nd their efficcy nd sfety dt were used for nlysis. The full methodologicl detils of the studies hve been previously reported. 19,21 Briefly, surgicl ptients were enrolled in the study if they were scheduled to undergo generl nesthesi nd were nticipted to require t lest 24 hours of postopertive prenterl opioids for nlgesi. Ptients were excluded if they received long-lsting regionl or spinl nesthetic intropertively or if they were expected to require long-term continuous regionl nesthetics, convlescence in n intensive cre unit, or dditionl surgery within 36 hours following the initil surgery. Ptients were lso excluded if they received opites other thn morphine, fentnyl, sufentnil, or lfentnil (50 mg of meperidine ws llowed for shivering). Ptients who were intubted or who hd skin disese tht would prohibit plcement of the fentnyl ITS ptch were lso excluded. Ptients were rndomized in 1:1 fshion, strtified by loction, to receive either fentnyl ITS or IV PCA morphine. Becuse the studies were open-lbel, neither ptients nor investigtors were blinded to the study drug tretment. Mediction Dosing Regimens Per common prctice, postopertively ptients were first titrted to comfort, if needed, with bolus doses of opioids (morphine, fentnyl, sufentnil, lfentnil). Hour 0 of the study ws considered the time of IV PCA or fentnyl ITS device ttchment. e820 Copyright SLACK Incorported

3 Fentnyl ITS is pre-progrmmed to relese 40-µg dose over 10-minute period on ctivtion. The system is ctivted by depressing dosing button on the device twice within 3 seconds, t which time n udible beep indictes ctivtion. The system is pre-progrmmed to deliver up to 6 doses per hour or 80 doses in totl over 24 hours, whichever occurs first. This results in mximum of 3.2 mg of fentnyl per 24 hours. The system turns off when 80 doses or 24 hours is reched nd must be replced with new ITS device if dditionl opioid nlgesi is needed. Intrvenous morphine PCA pumps were progrmmed to deliver n ondemnd 1-mg bolus of morphine with 5-minute lockout period. Ptients were llowed mximum of 10 on-demnd doses in ny 1-hour period, or totl of 240 doses in 24-hour period, equting to mximum of 240 mg of morphine per 24 hours. Efficcy Anlyses Ptient dt were included in the efficcy nlyses if the PCA device ws enbled for t lest 3 hours. The primry efficcy endpoint in both ctive-controlled studies ws the proportion of ptients who chieved successful pin mngement t 24 hours postopertively, s ssessed using the Ptient Globl Assessment (PGA) of pin control. Prticipnts were red the following question loud: Overll, would you rte this method of pin control during the lst 24 hours s being poor, fir, good, or excellent? Success ws defined s response of good or excellent. Assessments were lso performed t the 48- nd 72-hour timepoints for ptients who remined in the study. Other efficcy endpoints included the proportion of ptients who reported excellent pin mngement on the PGA t ech ssessment, nd ptient self-reported pin intensity scores using either the visul nlog scle (VAS) or numericl rting scle (NRS). Investigtor globl ssessments of pin control were lso performed t 24, 48, nd 72 hours using the sme PGA scle (poor, fir, good, or excellent). For the VAS, prticipnts mrked the intensity of their pin by drwing line perpendiculr to 100-mm scle, with 0 mm equting to no pin nd 100 mm equting to the worst possible pin. For the NRS, prticipnts rted their pin on scle of 0 to 10, with 0 being no pin nd 10 being the worst possible pin. To llow for comprison of pin intensity cross the 2 clinicl trils, VAS scores were converted to 10-point scle by dividing the VAS score by 10. Sfety Anlyses Dt from ll rndomized spine surgery ptients in the 2 studies were included in the sfety nlyses. Adverse events were recorded nd ctegorized ccording to the MedDRA system clssifiction nd included ny systemic event tht led to n interruption in nlgesi dministrtion. Opioid-relted dverse events included tchycrdi, ileus, nuse, vomiting, constiption, somnolence, confusionl stte, urinry retention, dyspne, hypoventiltion, hypoxi, pruritus, nd hypotension. Sttisticl Anlyses Anlyses presented in the current rticle were performed post hoc on the pooled subgroup of ptients who hd spinl surgeries in the 2 previously reported studies compring fentnyl ITS to morphine IV PCA. 19,21 Descriptive sttistics were summrized for continuous vribles. Frequencies nd percentges were presented for ctegoricl vribles, such s PGA of pin control. Comprisons of the continuous vribles were performed using t test; ctegoricl vribles were compred using Results Of the 1296 ptients included in the originl trils, 170 underwent spine surgery procedures. Of these spine surgery ptients, 90 were rndomized to the fentnyl ITS group nd 80 were rndomized to the IV PCA morphine group. The 2 groups were similr in ge nd sex. Men ge ws 52.8 yers (±13.66 yers) nd 49.9 yers (±15.71 yers) for fentnyl ITS nd IV PCA morphine ptients, respectively. Both groups lso hd similr rtio of men to women, with 41 men nd 49 women in the fentnyl ITS group nd 37 men nd 43 women in the IV PCA morphine group. The mjority of ptients in both groups completed the study (71.1% vs 78.8% for fentnyl ITS nd IV PCA morphine, respectively). The results of ptient nd investigtor globl ssessments of pin control re provided in Tble 1 nd Tble 2. Among ll ptients (N=170) included in this study, 87 in the fentnyl ITS group nd 80 in the IV PCA morphine group hd complete dt for efficcy evlution. Ptients rted their pin control methods similrly cross the 2 nlgesic groups; no significnt differences were found between the percentges of ptients in the fentnyl ITS nd IV PCA morphine groups who rted their pin control method s excellent or excellent or good. However, when compring investigtors rtings of pin control, significntly more rted fentnyl ITS s excellent t the finl ssessment s compred to IV PCA morphine (P<.01). Other secondry outcome mesures re shown in Tble 3. Men pin intensity scores were similr between the fentnyl ITS nd IV PCA morphine groups, s were rtes of rescue mediction dministrtion nd erly withdrwl from the study. Adverse events re presented in Tble 4. Overll, 74.4% of the fentnyl ITS group nd 77.5% of the IV PCA morphine group experienced n dverse event (P=.721). The most common dverse event for both the fentnyl ITS nd IV PCA morphine groups ws nuse (37.8% vs 47.5%; P=.217) followed by vomiting (17.8% vs 15%; P=.682) nd hedche (13.3% vs 7.5%; P=.318). Opioid-specific dverse event rtes were similr between the 2 nlgesic groups (54.4% for fentnyl ITS vs 63.8% for IV PCA morphine; SEPTEMBER 2015 Volume 38 Number 9 e821

4 P=.275). The only significnt differences in dverse events between the 2 groups were the rte of ppliction site erythem Tble 2 Globl Assessment of Pin Control Method: Rted s Excellent Postsurgery Time Fentnyl ITS (n=87) IV PCA Morphine Ptient ssessment: 24 h 23 (26.4) 18 (22.5).3550 Ptient ssessment: 48 h 25 (28.7) 13 (16.3).0909 Ptient ssessment: 72 h 12 (13.8) 6 (7.5).4094 Ptient: finl ssessment 33 (37.9) 21 (26.3).1374 Investigtor: finl ssessment 38 (43.7) 18 (22.5).0123 Abbrevitions: ITS, iontophoretic trnsderml system; IV, intrvenous; PCA, ptientcontrolled nlgesi. Outcome Mesure Men Finl Pin Intensity Rting, 0-10 scle Tble 1 Globl Assessment of Pin Control Method: Rted s Excellent or Good Postsurgery Time Fentnyl ITS (n=87) Tble 3 Secondry Outcome Mesures Fentnyl ITS (n=87) IV PCA Morphine Ptient ssessment: 24 h 59 (67.8) 60 (75.0).4396 Ptient ssessment: 48 h 52 (59.8) 39 (48.8).1526 Ptient ssessment: 72 h 26 (29.9) 23 (28.8).6796 Ptient: finl ssessment 63 (72.4) 61 (76.3).7875 Investigtor: finl ssessment 67 (77.0) 62 (77.5) Abbrevitions: ITS, iontophoretic trnsderml system; IV, intrvenous; PCA, ptientcontrolled nlgesi. IV PCA Morphine (27.8% for fentnyl ITS vs 0% IV PCA morphine; P<.0001) nd ppliction site pruritus (6.7% for fentnyl ITS vs 0% for Rescue mediction given, 17 (19.5) 14 (17.5).8427 Abbrevitions: ITS, iontophoretic trnsderml system; IV, intrvenous; PCA, ptientcontrolled nlgesi. IV PCA morphine; P=.030). The rections were typiclly mild to moderte with spontneous resolution. Discussion In the current nlyses, the uthors evluted the use of fentnyl ITS for postopertive pin mngement in spine surgery ptients from 2 phse III pivotl clinicl trils. Included ptients were from 2 prior prospective multi-site rndomized clinicl trils of ptients undergoing mjor surgicl procedures. These clinicl trils compred the efficcy nd sfety of fentnyl ITS to tht of IV PCA morphine. 19,21 Although the results of the 2 clinicl trils demonstrted the noninferiority of fentnyl ITS to the current gold stndrd, the ptient popultion included in the trils ws heterogeneous nd the studies did not tke into ccount the potentil for different pin mngement needs mong surgicl groups. Thus, the purpose of the current nlysis ws to specificlly determine whether fentnyl ITS is n pproprite lterntive to IV PCA morphine in spine surgery postopertive cre. Regrding the primry outcome mesure, the uthors found tht fentnyl ITS ws s therpeuticlly effective s IV PCA morphine in helping ptients chieve excellent or good pin control fter spine surgery. In fct, higher percentge of fentnyl ITS ptients rted their method of pin control s excellent t ll postopertive ssessment time points (26.4% vs 22.5%, 28.7% vs 16.3%, 13.8% vs 7.5%, nd 37.9% vs 26.3%, respectively), but the differences did not rech sttisticl significnce. Investigtors lso ssessed the method of pin control used in their ptients, nd significntly more rted fentnyl ITS s excellent thn they did those tking IV PCA morphine. Other secondry outcomes were lso comprble between the fentnyl ITS nd IV PCA morphine groups. Finl ptient ssessments of pin intensity were similr, with both groups reporting men pin score of 3.2. The mjority of fentnyl e822 Copyright SLACK Incorported

5 Event Tble 4 Adverse Events in >2% of Ptients Fentnyl ITS (n=90) IV PCA Morphine Any AE reported 67 (74.4) 62 (77.5).721 Opioid-relted AE b 49 (54.4) 51 (63.8).2745 MedDRA system orgn clss Eye disorders Diplopi 0 2 (2.5).220 Gstrointestinl disorders Abdominl pin 2 (2.2) 3 (3.8).667 Constiption 6 (6.7) 4 (5.0).751 Fltulence 2 (2.2) 1 (1.3) Nuse 34 (37.8) 38 (47.5).217 Vomiting 16 (17.8) 12 (15.0).682 Generl disorders nd dministrtion site conditions Appliction site erythem 25 (27.8) 0 <.0001 Appliction site edem 3 (3.3) Appliction site pruritus 6 (6.7) Appliction site vesicles 2 (2.2) Chest pin 0 2 (2.5).220 Injection site inflmmtion 0 2 (2.5).220 Injection site rection 0 3 (3.8).102 Pin 2 (2.2) 1 (1.3) Pyrexi 8 (8.9) 8 (10.0) Infections nd infesttions Phryngitis 5 (5.6) 2 (2.5).449 Event Tble 4 (cont d) Adverse Events in >2% of Ptients Nervous system disorders Fentnyl ITS (n=90) IV PCA Morphine Dizziness 2 (2.2) 4 (5.0).422 Hedche 12 (13.3) 6 (7.5).318 Hypertoni 2 (2.2) Presthesi 2 (2.2) 3 (3.8).667 Somnolence 3 (3.3) 2 (2.5) Tremor 2 (2.2) Psychitric disorders Anxiety 3 (3.3) 3 (3.8) Confusionl stte 3 (3.3) 2 (2.5) Renl nd urinry disorders Urinry retention 2 (2.2) 4 (5.0).4219 Respirtory, thorcic, nd medistinl disorders Dyspne 2 (2.2) 1 (1.3) Hypoventiltion 1 (1.1) 2 (2.5).602 Hypoxi 2 (2.2) 2 (2.5) Skin nd subcutneous tissue disorders Pruritus 4 (4.4) 7 (8.8).352 Vsculr disorders Hypotension 2 (2.2) 2 (2.5) Abbrevitions: AE, dverse event; ITS, iontophoretic trnsderml system; IV, intrvenous; PCA, ptient-controlled nlgesi. b Tretment-emergent opioid-relted dverse events re defined s tchycrdi, ileus, nuse, vomiting, constiption, somnolence, confusionl stte, urinry retention, dyspne, hypoventiltion, hypoxi, pruritus, nd hypotension. ITS ptients did not require dditionl rescue medictions, nd the rtes of rescue medictions given were not different from those of ptients treted with IV PCA morphine (19.5% nd 17.5%, respectively). Withdrwl rtes were lso similr between groups, with most ptients remining in the study for the entire postopertive tretment period (71.1% fentnyl ITS nd 78.8% IV PCA morphine). When compring the sfety profiles of fentnyl ITS nd IV PCA morphine, the overll rte of dverse events ws similr between the 2 groups. Regrdless of tretment method, the most commonly reported dverse events were those typiclly ssocited with opioid dministrtion, such s nuse, vomiting, nd hedche. Other opioid-relted dverse events, such s confusion, ileus, nd hypotension, were low in both groups nd not sttisticlly different. Respirtory function ws primry sfety outcome in the 2 originl clinicl trils. In the spine surgery popultion evluted in the current nlyses, the incidence of hypoventiltion ws low, with 1 cse in the fentnyl ITS group nd 2 in the IV PCA morphine group. The only significnt difference seen between the groups with respect to dverse events ws higher rte of ppliction site rections in the fentnyl ITS ptients. These rections were typiclly mild to moderte t the site where the ITS device ws plced on the skin. The rections resolved shortly fter removl of the ITS device nd did not require further tretment. As described erlier, ITS devices must be SEPTEMBER 2015 Volume 38 Number 9 e823

6 replced fter 24 hours of use, or 80 dministered doses. The new system should be pplied to different skin site to void locl site rections. The current nlysis is limited by the open design nd lck of plcebo nd blinding in the originl clinicl trils. However, prior rndomized, blinded, plcebocontrolled clinicl trils hve shown the superiority of fentnyl ITS for pin control s compred to control ITS device tht did not deliver fentnyl. 23 Another limittion of the clinicl trils is the fct tht not ll prticipting hospitls used the sme IV PCA morphine settings due to vrying regultions nd procedures in different countries. On the other hnd, this limittion mkes the studies more comprble to rel-world uses of PCA in clinicl prctice. The ITS device itself cn lso been seen s limited by its lck of progrmming flexibility. However, this is lso one of the primry dvntges of the system becuse it elimintes the potentil for progrmming errors nd dosing mistkes. Conclusion Overll, the efficcy nd sfety results seen in spine surgery ptients in the current study re consistent with the previous findings of phse III trils tht showed fentnyl ITS to be superior to plcebo 23,24 nd eqully efficcious s IV PCA morphine This nlysis dds to the literture by demonstrting tht fentnyl ITS is n pproprite nd sfe option for postopertive pin control mngement of spine surgery ptients. The fentnyl ITS system provides t lest equivlent efficcy for postopertive pin control without the limittions of PCA use. Specificlly, the ITS does not require (1) ny progrmming, (2) ny mixing/preprtion of medictions, (3) ny motorized equipment tht could fil, (4) ny seprte power source, (5) ny IV ccess or venipuncture, or (6) ny IV tubing. These fctors mke the ITS drmticlly less time-consuming for nursing nd phrmcy stff nd llow for incresed postopertive freedom of the spine surgery ptients. Thus, it hs the potentil to reduce cost, reduce resource utiliztion, nd improve ptient stisfction while providing effective postopertive nlgesi. References 1. Breivik H. Postopertive pin mngement: why is it difficult to show tht it improves outcome? Eur J Anesthesiol. 1998; 15(6): Breivik H, Stubhug A. Mngement of cute postopertive pin: still long wy to go! Pin. 2008; 137(2): Crr DB, Gouds LC. Acute pin. Lncet. 1999; 353(9169): Gottschlk A, Freitg M, Tnk S, et l. Qulity of postopertive pin using n intropertively plced epidurl ctheter fter mjor lumbr spinl surgery. Anesthesiology. 2004; 101(1): Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgicl pin: risk fctors nd prevention. Lncet. 2006; 367(9522): Yukw Y, Kto F, Ito K, Tershim T, Horie Y. A prospective rndomized study of preemptive nlgesi for postopertive pin in the ptients undergoing posterior lumbr interbody fusion: continuous subcutneous morphine, continuous epidurl morphine, nd diclofenc sodium. 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