article

helpmeAB2018

article.pdf

ORIGINAL CONTRIBUTION

Patient-Controlled Transdermal Fentanyl Hydrochloride vs Intravenous Morphine Pump for Postoperative Pain A Randomized Controlled Trial Eugene R. Viscusi, MD Lowell Reynolds, MD Frances Chung, MD Linda E. Atkinson, PhD Sarita Khanna, PhD

P ATIENT-CONTROLLED ANALGE- sia (PCA) allows the patient to self-administer small doses of opioids, such as fentanyl, mor-

phine, hydromorphone, or meperi- dine, as needed to manage pain. A key principle of PCA use is that it is initi- ated after titration to patient comfort with loading doses of intravenous (IV) opioids.1 Thereafter, PCA is used to maintain a mild level of pain rather than total pain relief, allowing the patient to self-administer enough drug to achieve a comfortable balance between analge- sia and adverse effects.2-5 Existing PCA therapies infuse opioid analgesics through an IV line at a preset rate by electronic pumps or by disposable, fixed-volume devices when a patient ac- tivates a dosing button. Problems that compromise patient safety, such as pro- gramming errors, uncontrolled deliv- ery of syringe contents, and patient tam- pering, have been reported.6 Pump failures and syringe mix-ups are also possible.

To overcome these problems, a fen- tanyl hydrochloride patient-con- trolled transdermal system (PCTS) is under development as an alternative method that delivers small doses of fen- tanyl by iontophoresis with electro-

Author Affiliations and Financial Disclosures are listed at the end of this article. Corresponding Author: Eugene R. Viscusi, MD,

Department of Anesthesiology, Thomas Jefferson Uni- versity, 111 S 11th St, Suite G 8490, Philadelphia, PA 19107 ([email protected]).

Context Patient-controlled analgesia (PCA) with morphine is commonly used to pro- vide acute postoperative pain control after major surgery. The fentanyl hydrochloride patient-controlled transdermal system eliminates the need for venous access and com- plicated programming of pumps.

Objective To assess the efficacy and safety of an investigational patient-controlled iontophoretic transdermal system using fentanyl hydrochloride compared with a stan- dard intravenous morphine patient-controlled pump.

Design, Setting, and Patients Prospective randomized controlled parallel-group trial conducted between September 2000 and March 2001 at 33 North American hos- pitals, enrolling 636 adult patients who had just undergone major surgery.

Interventions In surgical recovery rooms, patients were randomly assigned to in- travenous morphine (1-mg bolus every 5 minutes; maximum of 10 mg/h) by a patient- controlled analgesia pump (n = 320) or iontophoretic fentanyl hydrochloride (40-µg infusion over 10 minutes) by a patient-controlled transdermal system (n = 316). Supple- mental analgesia (morphine or fentanyl intravenous boluses) was administered as needed before and for the first 3 hours after activation of the PCA treatments. Patients then used the PCA treatments without additional analgesics for up to 72 hours.

Main Outcome Measures The primary efficacy variable was patient global as- sessment of the method of pain control during the first 24 hours. Additional efficacy 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 visual analog scale (VAS), and patient global assessments at 48 and 72 hours. Adverse effects were also recorded.

Results Ratings of good or excellent after 24 hours of treatment for the method of pain control were given by 73.7% of patients (233/316) who used transdermal fen- tanyl PCA and 76.9% of patients (246/320) who used intravenous morphine PCA; treatment difference was –3.2% (95% confidence interval, –9.9% to 3.5%; P = .36). Early patient discontinuations (25.9% fentanyl vs 25.0% morphine; P = .78) and last pain intensity scores (32.7 fentanyl vs 31.1 morphine on the VAS; P = .45) were not different between the 2 treatments. With continued treatment for up to 48 or 72 hours, more than 80% of patient assessments in each treatment group were good or excellent. The incidence of opioid-related adverse events was similar between the groups.

Conclusion An investigational PCA transdermal system using iontophoresis to de- liver fentanyl provided postsurgical pain control equivalent to that of a standard in- travenous morphine regimen delivered by a PCA pump. JAMA. 2004;291:1333-1341 www.jama.com

transport delivery platform technol- ogy (E-TRANS; ALZA Corp, Mountain View, Calif ). The system uses a low- intensity direct current to move fen- tanyl from a hydrogel reservoir into the skin, where it then diffuses into the lo- cal circulation and is transported to the central nervous system. The self- adhesive unit, about the size of a credit card, is worn on the patient’s upper arm or chest, does not have the IV tubing, cables, and large pump of the IV PCA, and may facilitate patient mobility. The opioid analgesic fentanyl has a poten- tial advantage over morphine in that it does not have active metabolites that can accumulate over time.7

For these advantages to be realized, the delivery method must provide pain control that is comparable to that of cur- rent standard therapy. The purpose of this study was to establish that the trans- dermal PCA delivery system is equiva- lent to a standard morphine IV PCA regi- men in postoperative pain management.

METHODS Study Design

A prospective, randomized, parallel- group, unblinded, active-controlled study was conducted from September 2000 to March 2001 at 29 US and 4 Ca- nadian hospitals. Centers were re- cruited according to the knowledge of postoperative pain management of the local investigator and the proven abil- ity of staff to conduct research. The in- stitutional review board, research eth- ics board, or an independent centralized ethics review board approved the pro- tocol. Patients provided signed in- formed consent during the screening process.

Randomization A randomization schedule was cre- ated with computer-generated ran- dom numbers in a block size of 4 by us- ing all patients, regardless of center. The patients were stratified by type of sur- gery (stratum 1: orthopedic, upper ab- dominal, and thoracic; stratum 2: all other procedures, including lower ab- dominal). Separate lists were gener- ated for each stratum. The randomiza-

tion was developed to eliminate any bias on the part of the investigators and their staff and to balance the number of pa- tients between the 2 treatments and the surgery types. Eligible patients were as- signed a study treatment (fentanyl PCTS or IV PCA morphine) with an interac- tive voice response system randomiza- tion procedure.8 The investigators and their staff did not know the block size or the next treatment assignment be- fore randomization.

Patient-Controlled Transdermal System The fentanyl hydrochloride PCTS is manufactured to function within pre- set dosing specifications. It operates for 24 hours after the first dose is deliv- ered or delivers a maximum of 80 doses and shuts off. The dose, controlled by the amount of electrical current, is fixed to not exceed 40 µg, the dosing inter- val is 10 minutes, and each dose is a 10- minute infusion. Drug delivery begins when the electrical current is acti- vated by pressing the dosing button twice within 3 seconds. During deliv- ery of the dose, the fentanyl PCTS can- not deliver additional doses, and de- livery of the dose cannot be interrupted or extended.

The system provides an audible (beep) and visual indication (red light from a light-emitting diode) that a dose has begun. The light turns off momen- tarily when the dose has been com- pleted and then flashes to indicate the approximate number of doses deliv- ered. One flash represents delivery of 1 to 5 doses, 2 flashes represent deliv- ery of 6 to 10 doses, and so on. Be- cause the maximum number of doses allowed by the system is 80, the corre- sponding maximum number of flashes is 16. Alerts for nonfunctioning con- ditions are a short series of beeps (the fentanyl PCTS should be restarted) and continuous beeping (the system has shut down and should be removed). Thus, the audible and visual signals pro- vide information on dosing similar to that of standard IV PCA.

The PCA pumps were programmed to deliver a 1-mg dose as a bolus, with

a subsequent 5-minute lockout and a limit of 10 doses per hour (10 mg). The choice of the active comparator regi- men is supported by the research of Owen and colleagues,9 who showed an optimal balance between efficacy and adverse effects at an on-demand mor- phine dose of 1 mg compared with on- demand doses of 0.5 and 2 mg and us- ing a dosing interval of 5 minutes. Ginsberg et al10 demonstrated similar efficacy for PCA regimens incorporat- ing various lockout periods from 2 to 8 minutes. Because of the confound- ing logistics—patients would have to press 2 dosing buttons simulta- neously—the study was not blinded, which would have required an IV PCA pump and a fentanyl PCTS for each patient.

Patients Names of prospective participants were selected from hospital surgical sched- ules. The patients were approached by anesthesiologists or surgeons to ascer- tain interest in joining the study. Pa- tients (N = 726) were screened within 2 weeks before enrollment, written in- formed consent was obtained, and medical history and a physical exami- nation were conducted. Patients were instructed in the use of the fentanyl PCTS and IV PCA morphine pump and in the performance of the study assess- ments. Patients were aged at least 18 years; were American Society of Anes- thesiologists physical status I, II, or III (no, mild to moderate, or severe sys- temic disturbance, respectively); were scheduled to undergo general or re- gional anesthesia for major abdomi- nal, orthopedic, or thoracic surgery; and were expected to have moderate or se- vere pain requiring parenteral opioids for at least 24 hours after surgery.

Postoperative screening occurred when patients were admitted to the postanesthesia care unit (PACU; recov- ery room) after having undergone sur- gery. They were awake and breathing spontaneously, with a respiratory rate of 8/min to 24/min, arterial oxygen satu- ration by pulse oximetry (SpO2) of at least 90% (with or without supplemen-

PATIENT-CONTROLLED POSTOPERATIVE ANALGESIA: PATCH VS PUMP

tal oxygen), able to answer questions and follow commands, and had been in the PACU for at least 30 minutes and were comfortable or had been brought to comfort with bolus IV doses of al- lowed opiates.

Patients (FIGURE 1) were excluded be- cause they had received a long-lasting intraoperative regional analgesic or long- lasting intraspinal opioids, were ex- pected to have postoperative analgesia supplied by a continuous regional tech- nique, or were expected to require in- tensive care or would probably require additional surgical procedures within 36 hours. Postoperative patients were also excluded if they had received intraop- erative or postoperative administration of opioids other than morphine, fen- tanyl, sufentanil, or alfentanil (except up to 50 mg of meperidine for shivering), were intubated at final screening assess- ments, were known or suspected to be opioid tolerant, had a recent history of opioid dependence, or had active sys- temic skin disease or active local skin disease that would preclude fentanyl PCTS application to their arms or chest. Pregnant women or patients with coex- isting medical conditions likely to in- terfere with study procedures were not enrolled.

Study Protocol After surgery, patients were brought to the PACU and evaluated for the re- mainder of the study entry criteria (vi- tal signs, general postsurgical condi- tion). Patients were titrated to an acceptable level of comfort if needed with IV doses of morphine, fentanyl, sufentanil, or alfentanil. After patients had been in the PACU at least 30 min- utes and were awake, alert, and com- fortable, they marked their pain inten- sity on a 100-mm visual analog scale (VAS), and study staff recorded vital signs and SpO2. These assessments com- pleted the study entry criteria. Quali- fying patients were then randomized in a 1 to 1 ratio to fentanyl PCTS or IV PCA morphine pump within each stra- tum as defined by surgery type.

Pain intensity, vital signs, and oxy- gen saturation were assessed again, and

the time of this second set of assess- ments was the start of the treatment pe- riod, hour 0. Immediately, the fen- tanyl PCTS was applied or the IV PCA morphine pump was attached and en- abled, and the patient was considered to be enrolled (n = 636; Figure 1). The patient was again instructed about use of the PCA. Only the patient was to de- liver a dose of fentanyl or morphine. Supplemental medication (single or multiple IV bolus doses of fentanyl [fen- tanyl PCTS group] or morphine [IV PCA morphine group]) was available on request during the first 3 hours af- ter hour 0. Study measurements (vital signs, oximetry, number of doses de- livered, pain intensity scores by VAS) were taken at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after enrollment and every 4 hours thereafter up to 72 hours. Sleep- ing patients were not awakened for pain assessments. Patient global assess- ments were obtained at 24, 48, and 72 hours or when the patient discontin- ued study medication, whichever came first. At any time in the study, patients

who could not maintain pain relief at a comfortable level (with or without supplemental analgesia) were with- drawn from the trial to receive higher doses or additional analgesics to con- trol their pain. Study staff monitored pa- tients and recorded patient-reported adverse events, their severity and rela- tionship to study treatments, concomi- tant medications, and assessments of erythema at the application site.

Outcome Measures The patient global assessment at 24 hours was the primary efficacy end point. It consisted of a categorical evalu- ation (poor, fair, good, excellent) of the method of pain control. The patient was read aloud the following question by the investigator’s staff, and the response was recorded: “Overall, would you rate this method of pain control during the last 24 hours as being poor, fair, good, or excellent?” Assessments were also col- lected at 48- and 72-hour points for pa- tients who remained in the study. If the patient was withdrawn from the study

Figure 1. Flow of Patients Through the Trial

234 Completed Study 148 No Parenteral Opioid Required 43 Completed 72-Hour Treatment 43 Hospital Discharge <72 Hours

240 Completed Study 191 No Parenteral Opioid Required 28 Completed 72-Hour Treatment 21 Hospital Discharge <72 Hours

316 Included in Primary Analyses for Efficacy and Safety

320 Included in Primary Analyses for Efficacy and Safety

636 Randomized

82 Withdrew 48 Inadequate Analgesia 19 Adverse Event 7 Withdrew Consent

1 Protocol Violation 6 Other

1 Technical Failure

80 Withdrew 33 Inadequate Analgesia 19 Adverse Event 5 Withdrew Consent

3 Protocol Violation 19 Other

1 Technical Failure

90 Excluded 82 Did Not Meet Screening Criteria 8 Withdrew Consent

316 Assigned to Receive Fentanyl Hydrochloride PCTS

320 Assigned to Receive Intravenous PCA Morphine

726 Patients Screened

PCTS indicates patient-controlled transdermal system; PCA, patient-controlled analgesia.

PATIENT-CONTROLLED POSTOPERATIVE ANALGESIA: PATCH VS PUMP

before any 24-hour point, the assess- ment was completed at withdrawal, and this observation was carried forward to the next 24-hour point.

Pain intensity was measured on a 100-mm ungraded VAS that ranged from “no pain” (0 mm) to “worst pos- sible pain” (100 mm). If the patient was withdrawn from the study before a 24- hour point, the pain-intensity measure- ment was completed at withdrawal. Pa- tients were instructed to “Rate the pain you have at this time. On a scale of ‘no pain’ to ‘worst possible pain,’ rate where you feel your pain is at this moment.” The patient was to make a vertical mark on a 100-mm ungraded horizontal line anchored by “no pain” and “worst pos- sible pain” to indicate the amount of pain he or she was experiencing. If the patient was unable to make a mark, the investigator’s staff marked the line as directed by the patient. The number of patients whose pain control was inad- equate and who were withdrawn from the study was tabulated.

At specified times, the investigator’s staff recorded the number of light flashes displayed by the fentanyl PCTS, the number of bolus doses delivered dis-

played on the IV PCA morphine pump, and the supplemental IV bolus doses of fentanyl or morphine used. The fen- tanyl PCTS dose was estimated by using 5 times the number of flashes minus 2.

Respiratory rate was the primary mea- sure of systemic safety. Clinically rel- evant respiratory depression (CRRD) was defined as the simultaneous oc- currence of bradypnea (respiratory rate less than 8/min sustained for 1 minute) and excessive sedation (the patient is not easily aroused). Clinically rel- evant respiratory depression was treated by ensuring a patent airway and pro- viding supportive treatment to reestab- lish regular breathing (stimuli, IV naloxone). The patient could remain in study after 1 episode but would be with- drawn from study if 2 episodes oc- curred. Opioid analgesia was sus- pended until alertness and other vital signs were normal.

Statistical Analysis Demographic and clinical variables were summarized according to treat- ment group for all randomized pa- tients. Depending on the nature of the

variable, either the 2-sample t test (nu- meric data) or �2 test (categorical data) was used to compare treatment groups.

Treated patients were those who re- ceived fentanyl PCTS or IV PCA mor- phine and completed a patient global assessment. For the efficacy analyses, patients who completed at least 72 hours of treatment, did not require fur- ther parenteral opioid analgesia, or were discharged from the hospital were con- sidered to have completed the study. Pa- tients who required parenteral opioid analgesia after 24 hours could con- tinue in the study to a maximum of 72 hours of treatment.

The patient global assessment at 24 hours was the primary efficacy end point. The primary efficacy analysis was the construction of a 2-sided 95% con- fidence interval (CI) for the difference in success rate (proportion of excellent/ good) according to the 24-hour pa- tient global assessment data between the 2 treatment groups. The 2 treatments were considered therapeutically equiva- lent if the 95% CI of the difference in success rate fell within ±10% accord- ing to 2 one-sided tests with � = .025 and a maximum acceptable difference of 10%.

All data from all centers and surgery types were pooled. Center was not used as a stratification variable because of the large number of centers required for pa- tient enrollment. The mean of the last pain intensity score during the 24- hour treatment period(s) was ana- lyzed with a 2-way analysis of vari- ance model.

A sample size of 504 evaluable pa- tients (252 patients in each treatment group) was planned for this study to provide an 80% probability to demon- strate the therapeutic equivalence in proportion between 2 treatments.

RESULTS Of the 90 patients screened who did not enter the study, 82 did not meet the screening criteria and 8 met the screen- ing criteria but decided not to enroll in the study (Figure 1). Demographic val- ues were similar between the 2 treat- ment arms (TABLE 1). The patients were

Table 1. Demographics of Treated Patients

Characteristics Fentanyl PCTS

(n = 316) Intravenous PCA Morphine

(n = 320)

Sex, No. (%) Female 229 (72.5) 238 (74.4)

Male 87 (27.5) 82 (25.6)

Age, y Mean (SD) 51.2 (15.3) 50.2 (14.8)

Range 18-90 18-86

Race, No. (%) White 233 (73.7) 234 (73.1)

Black 55 (17.4) 62 (19.4)

Hispanic 22 (7.0) 16 (5.0)

Asian 3 (0.9) 4 (1.3)

Other 3 (0.9) 4 (1.3)

Body mass index, mean (SD)* 29.1 (6.7) 29.3 (6.9)

Range 16.0-56.7 15.4-62.0

Surgical procedure, No. (%) Lower abdominal 176 (55.7) 185 (57.8)

Orthopedic bone 116 (36.7) 111 (34.7)

Upper abdominal 16 (5.1) 15 (4.7)

Thoracic/chest 6 (1.9) 4 (1.3)

Other 2 (0.6) 5 (1.6) Abbreviations: PCA, patient-controlled analgesia; PCTS, patient-controlled transdermal system. *Body mass index was measured as weight in kilograms divided by height in meters squared.

PATIENT-CONTROLLED POSTOPERATIVE ANALGESIA: PATCH VS PUMP

predominantly female and white. The av- erage age of the patients was about 50 years. Surgical procedures were primar- ily lower abdominal, with the majority represented by gynecologic surgery or or- thopedic surgery (predominantly lower extremity and spinal procedures).

The 316 patients in the fentanyl PCTS group and the 320 patients in the IV PCA morphine group represent the patients in the intent-to-treat analyses for efficacy and safety (Figure 1). Of these treated patients, 82 (25.9%) with- drew early from fentanyl PCTS and 80 patients (25.0%) discontinued IV PCA morphine (P = .78; TABLE 2). Withdraw- als because of inadequate analgesia were fewer but not statistically significant in the IV PCA morphine group (10.3%) compared with the fentanyl PCTS group (15.2%; P = .07).

In the withdrawal category of “other,” a statistically significantly higher proportion of patients using IV PCA morphine (19 patients, 5.9%) dis- continued for this reason than pa- tients using fentanyl PCTS (6 pa- tients, 1.9%) (P = .009). The most common “other” reason for with- drawal in both treatment groups was be- cause the patient or investigator re- quested use of or a transfer to analgesic medications disallowed according to protocol (Table 2).

Efficacy Fentanyl hydrochloride PCTS and IV PCA morphine were therapeutically equivalent according to the primary end point of global ratings of method of pain control during the first 24-hour treat- ment period. The distribution of pa- tient ratings is displayed in TABLE 3; the overall distribution of the proportion of patients’ ratings of poor, fair, good, or excellent between the 2 treatments is not statistically different (P�.10). The primary analysis was applied to a com- bined rating of good and excellent, which was reported by 73.7% of pa- tients who received fentanyl PCTS and 76.9% of patients who received IV PCA morphine. The between-treatment dif- ference in the good/excellent rating was –3.2% (95% CI, –9.9% to 3.5%; P = .36),

which met the predefined statistical cri- terion for equivalence. With contin- ued treatment for up to 48 or 72 hours, more than 80% of patient assessments in each treatment group were good or excellent.

The mean of the last recorded pain intensity scores (assessed on a VAS of 0-100) within the first 24 hours for all treated patients was also statistically in- distinguishable between treatments,

supporting the equivalence of fen- tanyl PCTS relative to IV PCA mor- phine (TABLE 4). These mean scores were 32.7 for the fentanyl PCTS group and 31.1 for the IV PCA morphine group (P = .45). The pain intensity scores were also comparable at all as- sessed times during the 24 hours (Table 4), and the distribution of pain scores between the treatment groups at 3 and 24 hours was similar (FIGURE 2). The

Table 2. Early Discontinuations of Treated Patients From the Study*

Reason for Discontinuation

No. (%)

P Value

Fentanyl PCTS (n = 316)

Intravenous PCA Morphine

(n = 320)

All reasons 82 (25.9) 80 (25.0) .78

Inadequate analgesia 48 (15.2) 33 (10.3) .07

Adverse event 19 (6.0) 19 (5.9) .97

Other† 6 (1.9) 19 (5.9) .009

Patient/investigator requested or transferred to excluded pain medications

2 8

Patient dissatisfaction with method of pain control

1 0

Intravenous PCA line problems 0 5

Study staff unavailable for additional 24-h treatment periods

1 1

Did not require further parenteral analgesia 0 3

Low oxygen saturation reading because of inaccurate oximeter

1 0

Physician decision 0 1

Overuse of PCA 0 1

No fentanyl PCTS available 1 0

Withdrew consent 7 (2.2) 5 (1.6) .55

Suspected technical failure 1 (0.3) 1 (0.3) �.99

Protocol violation 1 (0.3) 3 (0.9) .32 Abbreviations: PCA, patient-controlled analgesia; PCTS, patient-controlled transdermal system. *Only the primary termination reason was used for this analysis. †“Other” reasons were analyzed as a single group.

Table 3. Patient Global Assessment of Pain Control Method*

Global Assessment of Method of Pain Control

No. (%)

Fentanyl PCTS (n = 316)

Intravenous PCA Morphine (n = 320)

Success 233 (73.7) 246 (76.9)

Excellent 122 (38.6) 108 (33.8)

Good 111 (35.1) 138 (43.1)

Failure 80 (25.3) 68 (21.3)

Fair 38 (12.0) 42 (13.1)

Poor 42 (13.3) 26 (8.1)

Data missing 3 (0.9) 6 (1.9) Abbreviations: PCA, patient-controlled analgesia; PCTS, patient-controlled transdermal system. *At 24 hours or early discontinuation, patients were asked, “Overall, would you rate this method of pain control during

the last 24 hours as being poor, fair, good, or excellent?” Data are reported for all treated patients. Overall distribu- tion of ratings between treatments for patients was P = .12. Missing data were added to the poor/fair category for the computation of P values and confidence intervals. The between-treatment difference in the good/excellent rat- ings was −3.2% (95% confidence interval, −9.9% to 3.5%) (P = .36). P values were obtained using a �2 test.

PATIENT-CONTROLLED POSTOPERATIVE ANALGESIA: PATCH VS PUMP

magnitude of these scores reflected a level to which patients commonly ti- trate themselves with opioid PCA.3-5

Fentanyl hydrochloride PCTS dos- ing was qualitatively similar to IV PCA morphine pump (TABLE 5). Patients in both treatment groups administered more doses per hour during the first 6 hours than in the subsequent 66 hours. The amount of fentanyl (1244 µg) and morphine (43.9 mg) was typical of re- ported opioid consumption during the first 24 hours after major surgery.11 The

percentage of the maximum possible doses used during the entire 72-hour study period was 22.0% for fentanyl PCTS and 17.2% for IV PCA mor- phine treatments. Supplemental IV opi- oid was allowed during the first 3 hours after treatment initiation to retitrate pa- tients to comfort. Both groups were similar in that their pain during the first 3 hours after treatment initiation re- quired administration of supplemen- tal analgesic to establish comfort. The proportion of patients who received

supplemental IV opioid was similar for both treatment groups (Table 5).

Safety The incidence of opioid-related ad- verse events was similar between the fentanyl PCTS and IV PCA morphine groups (TABLE 6). Other opioid- related adverse events that occurred less frequently in the PCTS group and IV PCA group were hypotension (1.3%, 1.9%, respectively), urinary retention (1.6%, 0.6%), hypoventilation (0.3%, 1.3%), and ileus (0.9%, 0.6%). Ad- verse events, most of which were con- sidered treatment-related, led to early discontinuations for 6% of patients per treatment group (Table 2). Two of 29 serious adverse events reported for 21 patients were considered to be related to study medication: a report of severe confusion that prolonged hospitaliza- tion was attributed to fentanyl PCTS treatment, and a report of CRRD was attributed to IV PCA morphine treat- ment. The CRRD was reported as a res- piratory adverse event (4/min, moder- ate sedation). The patient was given naloxone and was withdrawn from the study. No patient who received fen- tanyl PCTS developed CRRD.

Application site reactions (6.3%) re- ported as spontaneous adverse events

Figure 2. Distribution of Pain Intensity Scores at 3 Hours and Last Score

Pain Intensity Score

P at

ie n ts

, %

3-Hour VAS

<25 25 to <50 50 to <75 ≥75 Not Determined

Fentanyl PCTS

Intravenous PCA Morphine

Pain Intensity Score

Last VAS

<25 25 to <50 50 to <75 ≥75

Pain intensity scores measured on a 100-mm visual analog scale (VAS) with 0 = no pain to 100 = worst imag- inable pain. Distribution of pain scores was similar between the 2 treatment groups after 3 hours and at the last pain measurement recorded. PCTS indicates patient-controlled transdermal system; PCA, patient- controlled analgesia.

Table 4. Pain Intensity Scores by Time During the First 24 Hours of Treatment*

Hours After Enrollment

Fentanyl PCTS (n = 316) Intravenous PCA Morphine (n = 320)

No. of Patients in Study

No. (%) of Patients With VAS Data

VAS, Mean (SE)

No. of Patients in Study

No. (%) of Patients With VAS Data

VAS, Mean (SE)

0 316 314 (99.4) 43.3 (1.3) 320 317 (99.1) 44.5 (1.3)

0.5 316 269 (85.1) 41.7 (1.4) 320 264 (82.5) 43.1 (1.5)

1 316 262 (82.9) 40.4 (1.5) 320 254 (79.3) 40.8 (1.5)

2 314 272 (86.6) 38.2 (1.5) 320 260 (81.3) 38.5 (1.5)

3 311 264 (84.9) 34.9 (1.6) 317 249 (78.5) 34.5 (1.5)

4 303 252 (83.1) 33.5 (1.5) 315 253 (80.3) 33.3 (1.4)

6 291 256 (88.0) 33.8 (1.5) 309 270 (87.4) 31.6 (1.4)

8 288 227 (78.8) 31.2 (1.6) 304 223 (73.3) 30.8 (1.5)

12 280 213 (76.1) 30.0 (1.5) 300 215 (71.7) 29.1 (1.5)

16 276 214 (77.5) 29.3 (1.5) 297 241 (81.1) 30.6 (1.4)

20 271 244 (90.0) 27.5 (1.4) 289 264 (91.3) 29.4 (1.3)

24 260 252 (96.9) 24.3 (1.3) 270 253 (93.7) 27.3 (1.4)

Last recorded score† 316 32.7 (1.6) 320 31.1 (1.5) Abbreviations: PCA, patient-controlled analgesia; PCTS, patient-controlled transdermal system; VAS, visual analog scale. *Pain intensity was marked on a VAS from 0 (no pain) to 100 (worst pain imaginable). Only patients with a recorded score at the time point were included in the calculation of the

mean (patients were not awakened to obtain a pain score and such data were considered missing). †The last recorded score occurred at 24 hours or at early discontinuation of the treatment within the first 24 hours. P = .45 for the difference between the averages of the last pain

assessment, based on analysis of variance.

PATIENT-CONTROLLED POSTOPERATIVE ANALGESIA: PATCH VS PUMP

by fentanyl PCTS patients were mild to moderately severe in all but 1 case. Scheduled skin evaluations at 24 hours after system removal revealed ery- thema in approximately half (53.8%) of the fentanyl PCTS patients. Most of this erythema was mild, resembling sunburn or tanning marks. None re- quired treatment, and all resolved within 4 weeks.

COMMENT The fentanyl hydrochloride PCTS pro- vided PCA after major surgery that was therapeutically equivalent to a standard IV PCA morphine regimen, as judged by patient global assessments, the pre- defined primary end point. The other ef- ficacy variables—pain intensity scores and discontinuation for inadequate an- algesia—confirmed the primary effi- cacy variable. Within the subset of pa- tients who withdrew for inadequate analgesia, more patients were in the fen- tanyl PCTS group (15.2%) compared with the IV PCA group (10.3%; Table 2). However, pain intensity scores of the 2 treatments were comparable at each as- sessment (Table 4), and the dosing pat- tern of the 2 treatments with respect to frequency of dosing over time and the proportion of total available doses acti- vated was similar (Table 5). These data do not reveal a reason for the different withdrawal rate. Eight patients in the IV PCA group withdrew from the study to use study-prohibited analgesics com- pared with 2 in the fentanyl PCTS group (Table 2). It is possible that these pa- tients should have been attributed to withdrawal for inadequate analgesia.

Individualized dosing with PCA ad- dresses the subjective nature of a pa- tient’s ability to tolerate pain and his or her requirement for and response to opioids. PCA is initiated when pa- tients have been made comfortable. For postoperative patients, this initiation generally occurs after administration of loading doses of IV opioids,7 which re- sults in large interpatient variation (up to 5-fold) in plasma concentrations as- sociated with analgesic efficacy.7 There- fore, PCA delivery systems are ideally suited to provide safe and effective in-

dividualized treatment of acute pain, al- lowing self-titration in small-dose in- crements to maintain comfort.

The safety and efficacy of PCA with systemic opioids in the postoperative set- ting in general and with fentanyl spe- cifically have been widely reported for nearly 20 years, at doses ranging from 10 to 60 µg and lockout intervals rang- ing from 1 to 10 minutes.1,3-5,10,12-14 Fen- tanyl is considered to have 50 to 100 times the potency of morphine accord- ing to responses to IV bolus doses.15

With this conversion factor, the aver- age amount of fentanyl accessed by pa- tients in the first 24 hours of this study (1244 µg) would be equivalent to 62 to

124 mg morphine, which exceeds the amount of morphine (43.9 mg) ac- cessed by IV PCA patients (Table 5). This discontinuity may be because the number of fentanyl doses delivered is es- timated within a 1- to 5-dose range by observing the number of dosing flashes from the fentanyl PCTS, and the phar- macodynamic actions of a 10-minute in- fusion of 40 µg of fentanyl may be dif- ferent than an IV bolus of 40 µg of fentanyl.7 The 40-µg dose for the PCTS was selected after the study by Camu et al14 in which a 10-minute infusion of 40 µg yielded an optimal profile of pain re- lief and safety compared with infu- sions of 20 or 60 µg of fentanyl.

Table 5. Doses Used and Patients Requiring Supplemental Analgesia in the First 24 Hours*

Measure Fentanyl PCTS

(n = 316) Intravenous PCA Morphine

(n = 320)

Analgesic doses used in the first 24 hours, No.* Mean (SD) 33.4 (19.7) 45.9 (26.9)

Range 3-93† 0-129

No. of doses available/24 h 144 240

No. of doses/patient/h Mean 1.39 1.91

No. of doses available 6 10

Total opioid use in 24 h, mean (SD) 1244 (785.6) µg‡ 43.9 (26.6) mg

Supplemental IV opioid in the first 3 h Patients requiring

supplemental IV opioid, No. (%)§ 72 (22.8) 87 (27.2)

Total doses, No. 215 224 Abbreviations: PCA, patient-controlled analgesia; PCTS, patient-controlled transdermal system; IV, intravenous. *The total number of PCTS doses was estimated as 5 � the number of displayed flashes � 2. The total number of

PCA morphine doses was read directly from the pump. †Range of fentanyl �80 indicates use of 2 systems in 24 hours. ‡This amount equals 62-124 morphine equivalents based on fentanyl having a potency 50-100 times that of mor-

phine.19 §P = .20 by �2 test.

Table 6. Treatment-Related Adverse Events*

Adverse Event

No. (%)

Fentanyl PCTS (n = 316)

Intravenous PCA Morphine (n = 320)

Nausea 129 (40.8) 147 (45.9)

Headache 36 (11.4) 24 (7.5)

Vomiting 31 (9.8) 27 (8.4)

Pruritus 26 (8.2) 40 (12.5)

Application site reactions (erythema, itching, vesicles, other)

20 (6.3) 0

Constipation 12 (3.8) 7 (2.2)

Hypoxia 12 (3.8) 7 (2.2)

Fever 11 (3.5) 13 (4.1)

Dizziness 6 (1.9) 12 (3.8)

Somnolence 6 (1.9) 7 (2.2)

Anxiety 4 (1.3) 9 (2.8) Abbreviations: PCA, patient-controlled analgesia; PCTS, patient-controlled transdermal system. *Reported at a frequency of at least 2%. A patient may be reported in more than 1 category.

PATIENT-CONTROLLED POSTOPERATIVE ANALGESIA: PATCH VS PUMP

The inherent safety of PCA is that the dosing frequency is controlled as needed by the patient for pain relief, re- ducing the possibility of overdose as pain requirements are met. A meta- analysis of 15 randomized controlled studies showed that postoperative pa- tients using PCA obtained signifi- cantly better pain relief than those us- ing intramuscular analgesia, with no increase in adverse effects.16 The study also showed that patients using PCA in this setting tended to use less total opi- oid and had shorter hospital stays, al- though this trend was not statistically significant. The Acute Pain Manage- ment Panel, in its Clinical Practice Guideline for acute pain manage- ment,17 also notes that for patients who have had thoracic surgery, PCA re- sults in incrementally improved anal- gesia, increased patient satisfaction, and trends toward improved pulmonary function and earlier recovery or dis- charge compared with intramuscular or bolus IV injections.

Building on the PCA concept that has become the standard of care in many fa- cilities for the management of postop- erative and other acute pain, fentanyl PCTS was designed to provide a pre- programmed, self-contained, noninva- sive alternative to IV PCA. Key system design characteristics, the choice of the 40-µg dose on demand, the 10-minute dosing interval, and the 80-dose maxi- mum available from each system, were carefully selected according to the sub- stantial literature in this field and corroborated in phase 1 and 2 clinical trials.12,14 The fentanyl PCTS does not in- corporate a continuous infusion with the on-demand bolus doses because previ- ous studies indicate that a continuous basal infusion does not enhance effi- cacy during acute use.6,7 This inte- grated drug-device delivery system in- corporates design features that effectively prevent unintentional dosing during use, such as a recessed dosing button, double- push activation, and electronic lockout and disablement features.

Limitations of this study are the open design and lack of placebo control. The study was not blinded, because pa-

tients would have been required to push the buttons of the pump and transder- mal PCA system simultaneously when seeking pain medication and would shortly have determined which deliv- ery system contained opioid. Random- ized, blinded, placebo-controlled trials have been conducted that demon- strate the superiority of the fentanyl PCTS for pain control compared with a PCTS that did not deliver fentanyl.18

Another limitation is that no single morphine IV PCA regimen is “ap- proved” for postoperative analgesia, and the morphine IV PCA regimen chosen for this study was a fixed dose, whereas physicians tend to think of IV PCA as adjustable. Although current IV PCA pumps allow a wide variety of dosing regimens, the preferred doses re- ported in the literature are similar.6 In practice, clinicians seldom deviate from a narrow dose range similar to those used in this study. Patients with ex- treme opioid requirements may re- quire a customized regimen, but this is the exception. For example, fentanyl PCTS may not be appropriate for opi- oid-tolerant patients whose opioid dose requirement may be higher than that provided by the system. The fentanyl PCTS may also be criticized for lack of programming flexibility, but this fea- ture would introduce the risk of pro- gramming errors and dosing mis- takes.6 In addition, current approaches for acute pain management use adju- vant analgesics such as regional blocks, wound infiltration, or systemic non- steroidal anti-inflammatory drugs with PCA.19 Future fentanyl PCTS studies will need to address its use in a multi- modal analgesic setting.

An investigational PCA transder- mal system using iontophoresis to de- liver fentanyl provided postsurgical pain control equivalent to that of standard IV morphine delivered by a PCA pump. The PCTS offers the advantages of needle-free, preprogrammed opera- tion in a small, self-contained unit.

Author Affiliations: Department of Anesthesiology, Thomas Jefferson University, Philadelphia, Pa (Dr Vis- cusi); Loma Linda University–Center for Pain Man- agement, Loma Linda, Calif (Dr Reynolds); Depart-

ment of Anesthesiology, University of Toronto, Toronto Western Hospital, Ontario (Dr Chung); Statistics and Data Management (Dr Khanna) and Clinical Devel- opment (Dr Atkinson), ALZA Corporation, Mountain View, Calif. Financial Disclosures: Drs Atkinson and Khanna own stock in Johnson & Johnson, the parent company of ALZA Corporation (study sponsor). Author Contributions: Dr Viscusi had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Atkinson, Khanna. Acquisition of data: Viscusi, Reynolds, Chung. Analysis and interpretation of data: Viscusi, Atkin- son, Khanna. Drafting of the manuscript: Viscusi, Atkinson, Khanna. Critical revision of the manuscript for important in- tellectual content: Viscusi, Reynolds, Chung, Atkin- son, Khanna. Statistical expertise: Khanna. Obtained funding: Viscusi, Reynolds, Chung. Administrative, technical, or material support: Atkin- son, Khanna. Study supervision: Viscusi, Reynolds, Atkinson, Chung. Study Investigators: UnitedStates: Alabama: Sheffield: Helen Keller Hos- pital, Timothy Melson, MD; California: Sacramento: University of California Davis, Barth Wilsey, MD; Kan- sas: Kansas City: University of Kansas Medical Cen- ter, Anthony Kovac, MD; Kentucky: Lexington: Uni- versity of Kentucky Medical Center, Daniel Kenady, MD; Illinois: Chicago: Northwestern University, Shireen Ahmad, MD; University of Illinois–Chicago, Verna L. Baughman, MD; Neurosurgery Research Institute, Mar- tin Herman, MD, PhD; Rush-Presbyterian, St. Luke’s Medical Center, Timothy Lubenow, MD; Maine: Port- land: Maine Medical Center, Craig Curry, MD; Mas- sachussetts: Boston: Boston Medical Center, Eric Pierce, MD; Springfield: Baystate Medical Center, Robert Steinberg, MD; Missouri: Columbia: University of Mis- souri–Columbia, Robert Fisher, DO; New Jersey: Cam- den: Cooper Hospital/UMC, Michael Goldberg, MD; Ridgewood: Neurology Group of Bergen County, Ken- neth Levin, MD; Trenton: St. Francis Hospital, Jane Rohlf, MD; New York: Brooklyn: New York Method- ist Hospital, Joel Yarmush, MD; New York: Mt Sinai School of Medicine, Jeffrey H. Silverstein, MD; New York Presbyterian Hospital, Weill Medical College of Cornell University, Cynthia A. Lien, MD; Rochester: University of Rochester Medical Center, Sheldon Isaac- son, MD; North Carolina: Durham: Duke University Medical Center, Brian Ginsberg, MD; Pennsylvania: Hershey: Lancaster General Hospital, George Rung, MD; Tennessee: Memphis: Methodist Healthcare, Roger Cicala, MD; Nashville: Anesthesia Medical Group, Arthur Runyon-Hass, MD; Texas: Galveston: University of Texas at Galveston Medical Branch, Daneshvari Solanki, MD; Houston: Memo- rial Hospital, Harold Minkowitz, MD; University of Texas Medical School–Houston, Samia N. Kahlil, MD; San Marcos: Central Texas Medical Center, Ray- mond Brewer, MD; Canada: Nova Scotia: Halifax: Queen Elizabeth II Health Sciences Centre, Alex- ander John Clark, MD; Ontario: Kingston: Queens Uni- versity, Kingston General Hospital, Joel Parlow, MD; London: London Health Services Center, Neal Bad- ner, MD. Funding/Support: ALZA Corporation, Mountain View, Calif, supported the study in its entirety. Role of the Sponsor: The study was designed and ap- proved by the sponsor, ALZA Corporation. The con- duct of the study was monitored by an independent contract research organization that was responsible for verification of data and adherence to good clinical prac- tice guidelines. The company, ALZA, analyzed the data and approved the manuscript for regulatory accu- racy to ensure that any claims were justified by the

PATIENT-CONTROLLED POSTOPERATIVE ANALGESIA: PATCH VS PUMP

data. All authors contributed to the writing and re- view process and approved the final manuscript. To ensure accuracy and avoid any potential bias, a stat- istician (Brad Efron, PhD) who was not part of the study and who is not employed by ALZA had access to all of the data and performed an independent review. Dr Atkinson was responsible for the design and conduct of the trial and Dr Khanna was responsible for the de- sign, data management, and statistical analysis of the trial. Both authors are employees of the company. Drs Chung, Reynolds, and Viscusi do not have financial interests in ALZA or own stock in Johnson & Johnson, the parent corporation.

REFERENCES

1. Lehmann KA. Patient-controlled analgesia: an ef- ficient therapeutic tool in the postoperative setting. Eur Surg Res. 1999;31:112-121. 2. Sinatra R, Lodge K, Sibert K, et al. A comparison of morphine, meperidine, and oxymorphone as uti- lized in patient-controlled analgesia following cesar- ean delivery. Anesthesiology. 1989;70:585-590. 3. Glass PS, Estok P, Ginsberg B, Goldberg JS, Sladen RN. Use of patient-controlled analgesia to compare the efficacy of epidural to intravenous fentanyl ad- ministration. Anesth Analg. 1992;74:345-351. 4. Howell PR, Pavy T, McMorland G, Douglas JM. Pa- tient-controlled analgesia following caesarean sec-

tion under general anesthesia: a comparison of fen- tanyl with morphine. Can J Anaesth. 1995;42:41- 45. 5. Welchew EA. On-demand analgesia: a double- blind comparison of on-demand intravenous fen- tanyl with regular intramuscular morphine. Anaesthe- sia. 1983;38:19-25. 6. Macintyre PE. Safety and efficacy of patient- controlled analgesia. Br J Anaesth. 2001;87:36-46. 7. Peng PWH, Sandler AN. A review of the use of fen- tanyl analgesia in the management of acute pain in adults. Anesthesiology. 1999;90:576-599. 8. Byron B. Using IVRS in clinical trial management. Appl Clin Trials. October 2002:36-42. 9. Owen H, Plummer JL, Armstrong I, et al. Vari- ables of patient-controlled analgesia. Anaesthesia. 1989;44:7-10. 10. Ginsberg B, Gil KM, Muir M, et al. The influence of lockout intervals and drug selection on patient- controlled analgesia following gynecological sur- gery. Pain. 1995;62:95-100. 11. Woodhouse A, Hobbes AFT, Mather LE, Gibson M. A comparison of morphine, pethidine and fen- tanyl in the postsurgical patient-controlled analgesia environment. Pain. 1996;64:115-121. 12. Rowbotham DJ, Wyld R, Nimmo WS. A dispos- able device for patient-controlled analgesia with fen- tanyl. Anaesthesia. 1989;44:922-924. 13. American Pain Society. Principles of Analgesic Use

in the Treatment of Acute Pain and Cancer Pain. 4th ed. Glenview, Ill: American Pain Society; 1999. 14. Camu F, Van Aken H, Bovill JG. Postoperative an- algesic effects of three demand-dose sizes of fen- tanyl administered by patient-controlled analgesia. Anesth Analg. 1998;87:890-895. 15. Mather LE. Clinical pharmacokinetics of fentanyl and its newer derivatives. Clin Pharmcokinet. 1983; 8:422-446. 16. Ballantyne JC, Carr DB, Chalmers TC, Dear KBG, Mosteller F. Postoperative patient-controlled analge- sia: meta-analysis of initial randomized control trails. J Clin Anesth. 1993;5:182-193. 17. Acute Pain Management Panel. Acute Pain Man- agement: Operative or Medical Procedures and Trauma: Clinical Practice Guideline. Rockville, Md: Agency for Health Care Policy and Research, Public Health Service, US Dept of Health and Human Ser- vices; 1992. AHCPR publication 92-0032. 18. Chelly JE, Grass J, Houseman TW, Minkowitz H, Pue A. The safety and efficacy of a fentanyl patient- controlled transdermal system for acute postopera- tive analgesia: a multicenter, placebo-controlled trial. Anesth Analg. 2004;98:427-433. 19. Schumann R, Shikora S, Weiss JM, Wurm H, Stras- sels S, Carr DB. A comparison of multimodal peri- operative analgesia to epidural pain management af- ter gastric bypass surgery. Anesth Analg. 2003;96: 469-474.

In the degree in which I have been privileged to know the intimate secrets of hearts, I ever more realize how great a part is played in the lives of men and women by some little concealed germ of abnormality. For the most part they are occupied in the task of stifling and crushing those germs, treating them like weeds in their gardens. There is another and better way, even though more difficult and more perilous. Instead of trying to suppress the weeds that can never be killed, they may be cultivated into useful or beautiful flowers. For it is impossible to conceive any impulse in a human heart which cannot be transformed into Truth or into Beauty and into Love.

—Havelock Ellis (1859-1939)

PATIENT-CONTROLLED POSTOPERATIVE ANALGESIA: PATCH VS PUMP

Copyright of JAMA: Journal of the American Medical Association is the property of American Medical Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.