ORIGINAL CONTRIBUTION Patient-Controlled Transdermal Fentanyl Hydrochloride vs Intravenous Morphine Pump for Postoperative Pain A Randomized Controlled Trial Eugene R. Viscusi, MD Context Patient-controlled analgesia (PCA) with morphine is commonly used to pro- Lowell Reynolds, MD vide acute postoperative pain control after major surgery. The fentanyl hydrochloride Frances Chung, MD patient-controlled transdermal system eliminates the need for venous access and com- plicated programming of pumps. Linda E. Atkinson, PhD Objective To assess the efficacy and safety of an investigational patient-controlled Sarita Khanna, PhD iontophoretic transdermal system using fentanyl hydrochloride compared with a stan- dard intravenous morphine patient-controlled pump. ATIENT-CONTROLLED ANALGE- Design, Setting, and Patients Prospective randomized controlled parallel-group sia (PCA) allows the patient to trial conducted between September 2000 and March 2001 at 33 North American hos- self-administer small doses of pitals, enrolling 636 adult patients who had just undergone major surgery. opioids, such as fentanyl, mor- Interventions In surgical recovery rooms, patients were randomly assigned to in- Pphine, hydromorphone, or meperi- travenous morphine (1-mg bolus every 5 minutes; maximum of 10 mg/h) by a patient- dine, as needed to manage pain. A key controlled analgesia pump (n=320) or iontophoretic fentanyl hydrochloride (40-µg principle of PCA use is that it is initi- infusion over 10 minutes) by a patient-controlled transdermal system (n=316). Supple- ated after titration to patient comfort mental analgesia (morphine or fentanyl intravenous boluses) was administered as needed with loading doses of intravenous (IV) before and for the first 3 hours after activation of the PCA treatments. Patients then opioids.1 Thereafter, PCA is used to used the PCA treatments without additional analgesics for up to 72 hours. maintain a mild level of pain rather than Main Outcome Measures The primary efficacy variable was patient global as- total pain relief, allowing the patient to sessment of the method of pain control during the first 24 hours. Additional efficacy self-administer enough drug to achieve measures were the proportion of patients discontinuing the study because of inad- equate analgesia for any reason, patient-reported pain intensity scores on a 100-mm a comfortable balance between analge- 2-5 visual analog scale (VAS), and patient global assessments at 48 and 72 hours. Adverse sia and adverse effects. Existing PCA effects were also recorded. therapies infuse opioid analgesics Results Ratings of good or excellent after 24 hours of treatment for the method of through an IV line at a preset rate by pain control were given by 73.7% of patients (233/316) who used transdermal fen- electronic pumps or by disposable, tanyl PCA and 76.9% of patients (246/320) who used intravenous morphine PCA; fixed-volume devices when a patient ac- treatment difference was –3.2% (95% confidence interval, –9.9% to 3.5%; P=.36). tivates a dosing button. Problems that Early patient discontinuations (25.9% fentanyl vs 25.0% morphine; P=.78) and last compromise patient safety, such as pro- pain intensity scores (32.7 fentanyl vs 31.1 morphine on the VAS; P=.45) were not gramming errors, uncontrolled deliv- different between the 2 treatments. With continued treatment for up to 48 or 72 ery of syringe contents, and patient tam- hours, more than 80% of patient assessments in each treatment group were good or pering, have been reported.6 Pump excellent. The incidence of opioid-related adverse events was similar between the failures and syringe mix-ups are also groups. possible. Conclusion An investigational PCA transdermal system using iontophoresis to de- To overcome these problems, a fen- liver fentanyl provided postsurgical pain control equivalent to that of a standard in- tanyl hydrochloride patient-con- travenous morphine regimen delivered by a PCA pump. trolled transdermal system (PCTS) is JAMA. 2004;291:1333-1341 www.jama.com under development as an alternative Author Affiliations and Financial Disclosures are listed Department of Anesthesiology, Thomas Jefferson Uni- method that delivers small doses of fen- at the end of this article. versity, 111 S 11th St, Suite G 8490, Philadelphia, PA tanyl by iontophoresis with electro- Corresponding Author: Eugene R. Viscusi, MD, 19107 ([email protected]). ©2004 American Medical Association. All rights reserved. (Reprinted) JAMA, March 17, 2004—Vol 291, No. 11 1333 Downloaded From: https://jamanetwork.com/ on 10/01/2021 PATIENT-CONTROLLED POSTOPERATIVE ANALGESIA: PATCH VS PUMP transport delivery platform technol- tion was developed to eliminate any bias a subsequent 5-minute lockout and a ogy (E-TRANS; ALZA Corp, Mountain on the part of the investigators and their limit of 10 doses per hour (10 mg). The View, Calif). The system uses a low- staff and to balance the number of pa- choice of the active comparator regi- intensity direct current to move fen- tients between the 2 treatments and the men is supported by the research of tanyl from a hydrogel reservoir into the surgery types. Eligible patients were as- Owen and colleagues,9 who showed an skin, where it then diffuses into the lo- signed a study treatment (fentanyl PCTS optimal balance between efficacy and cal circulation and is transported to the or IV PCA morphine) with an interac- adverse effects at an on-demand mor- central nervous system. The self- tive voice response system randomiza- phine dose of 1 mg compared with on- adhesive unit, about the size of a credit tion procedure.8 The investigators and demand doses of 0.5 and 2 mg and us- card, is worn on the patient’s upper arm their staff did not know the block size ing a dosing interval of 5 minutes. or chest, does not have the IV tubing, or the next treatment assignment be- Ginsberg et al10 demonstrated similar cables, and large pump of the IV PCA, fore randomization. efficacy for PCA regimens incorporat- and may facilitate patient mobility. The ing various lockout periods from 2 to opioid analgesic fentanyl has a poten- Patient-Controlled 8 minutes. Because of the confound- tial advantage over morphine in that it Transdermal System ing logistics—patients would have does not have active metabolites that The fentanyl hydrochloride PCTS is to press 2 dosing buttons simulta- can accumulate over time.7 manufactured to function within pre- neously—the study was not blinded, For these advantages to be realized, set dosing specifications. It operates for which would have required an IV PCA the delivery method must provide pain 24 hours after the first dose is deliv- pump and a fentanyl PCTS for each control that is comparable to that of cur- ered or delivers a maximum of 80 doses patient. rent standard therapy. The purpose of and shuts off. The dose, controlled by this study was to establish that the trans- the amount of electrical current, is fixed Patients dermal PCA delivery system is equiva- to not exceed 40 µg, the dosing inter- Names of prospective participants were lent to a standard morphine IV PCA regi- val is 10 minutes, and each dose is a 10- selected from hospital surgical sched- men in postoperative pain management. minute infusion. Drug delivery begins ules. The patients were approached by when the electrical current is acti- anesthesiologists or surgeons to ascer- METHODS vated by pressing the dosing button tain interest in joining the study. Pa- Study Design twice within 3 seconds. During deliv- tients (N=726) were screened within A prospective, randomized, parallel- ery of the dose, the fentanyl PCTS can- 2 weeks before enrollment, written in- group, unblinded, active-controlled not deliver additional doses, and de- formed consent was obtained, and study was conducted from September livery of the dose cannot be interrupted medical history and a physical exami- 2000 to March 2001 at 29 US and 4 Ca- or extended. nation were conducted. Patients were nadian hospitals. Centers were re- The system provides an audible instructed in the use of the fentanyl cruited according to the knowledge of (beep) and visual indication (red light PCTS and IV PCA morphine pump and postoperative pain management of the from a light-emitting diode) that a dose in the performance of the study assess- local investigator and the proven abil- has begun. The light turns off momen- ments. Patients were aged at least 18 ity of staff to conduct research. The in- tarily when the dose has been com- years; were American Society of Anes- stitutional review board, research eth- pleted and then flashes to indicate the thesiologists physical status I, II, or III ics board, or an independent centralized approximate number of doses deliv- (no, mild to moderate, or severe sys- ethics review board approved the pro- ered. One flash represents delivery of temic disturbance, respectively); were tocol. Patients provided signed in- 1 to 5 doses, 2 flashes represent deliv- scheduled to undergo general or re- formed consent during the screening ery of 6 to 10 doses, and so on. Be- gional anesthesia for major abdomi- process. cause the maximum number of doses nal, orthopedic, or thoracic surgery; and allowed by the system is 80, the corre- were expected to have moderate or se- Randomization sponding maximum number of flashes vere pain requiring parenteral opioids A randomization schedule was cre- is 16. Alerts for nonfunctioning con- for at least 24 hours after surgery. ated with computer-generated ran- ditions are a short series of beeps (the Postoperative screening occurred dom numbers in a block size of 4 by us- fentanyl PCTS should be restarted) and when patients were admitted to the ing all patients, regardless of center. The continuous beeping (the system has postanesthesia care unit (PACU; recov- patients were stratified by type of sur- shut down and should be removed).