Exhibit 1012
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1012
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01800
`
`

`
`The Relative Potency of Oral Transmucosal Fentanyl Citrate
`Compared with Intravenous Morphine in the Treatment of
`Moderate to Severe Postoperative Pain
`
`J. Lance Lichtor, MD*, Ferne B. Sevarino, MD†, Girish P. Joshi, MBBS, MD, FFARCSI‡,
`Michael A. Busch, PhD§, Earl Nordbrock, PhD§, and Brian Ginsberg, MBBCH, DA, FAA储
`
`*Department of Anesthesiology, The University of Chicago, Chicago, Illinois; †Department of Anesthesiology, Yale
`University, New Haven, Connecticut; ‡Department of Anesthesiology, University of Texas Southwestern, Dallas, Texas;
`§Anesta Corporation, Salt Lake City, Utah; and 储Department of Anesthesiology, Duke University, Durham,
`North Carolina
`
`Pharmacokinetic studies have shown that oral trans-
`mucosal absorption of fentanyl is relatively rapid com-
`pared with gastrointestinal absorption, and it results in
`increased bioavailability. We designed this study to es-
`tablish the relative potency of oral transmucosal fenta-
`nyl citrate (OTFC) compared with IV morphine in 133
`postoperative patients. The morning after surgery, pa-
`tients randomly received one dose of either OTFC (200
`or 800 ␮g) and a placebo IV injection or IV morphine (2
`or 10 mg) and an oral transmucosal placebo unit. Pain
`intensity, pain relief, time to meaningful pain relief, and
`time to remedication were recorded. Median time to
`onset of relief was approximately 5 min for all groups.
`Over the first hour, little difference among treatment
`groups was seen for pain intensity and pain relief. By
`2 h after study drug administration, 800 ␮g of OTFC
`
`and 10 mg of IV morphine generally produced similar
`analgesia, which was better than the smaller doses. Du-
`ration of analgesia with the larger doses (800 ␮g of
`OTFC and 10 mg of morphine) was similar and longer
`that produced by the smaller doses. The larger doses of
`OTFC and morphine produced better and more sus-
`tained analgesia than 200 ␮g of OTFC or 2 mg of mor-
`phine. Implications: The relative potency of oral trans-
`mucosal fentanyl citrate (OTFC) to IV morphine was
`8 –14:1. In this postoperative setting, OTFC produced
`rapid pain relief similar to that produced by IV mor-
`phine. The larger doses of OTFC (800 ␮g) and morphine
`(10 mg) produced better and more sustained analgesia
`than 200 ␮g of OTFC or 2 mg of morphine.
`
`(Anesth Analg 1999;89:732–8)
`
`O ral transmucosal fentanyl citrate (OTFC) is a
`
`noninvasive delivery system for fentanyl (1).
`The OTFC unit consists of a sweetened matrix
`containing fentanyl that is attached to a handle. When
`OTFC is placed in the mouth and sucked by the pa-
`tient, the matrix dissolves and fentanyl is absorbed
`through the oral mucosa to provide fast-acting
`analgesia.
`
`This work was supported by a grant from Anesta Corp., Salt Lake
`City, UT.
`Presented in part at the 1996 APS meeting, Washington, DC; at
`the 1997 Congress of the European Federation of IASP Chapters,
`Barcelona, Spain; and at the 1997 annual meeting of the IARS, San
`Francisco, CA.
`Accepted for publication April 22, 1999.
`Address correspondence and reprint requests to Dr. J. Lance
`Lichtor, University of Chicago Hospital, Department of Anesthesia
`and Critical Care, 5841 S. Maryland Ave., Box 4028, Chicago, IL
`60637.
`
`OTFC is currently being studied as a treatment for
`breakthrough pain in patients with cancer (2). Break-
`through pain is a flare of severe pain that exceeds the
`analgesia from the long-acting medication that is ad-
`ministered at regular intervals to manage a patient’s
`persistent pain. OTFC is intended to be used in con-
`junction with a long-acting opioid to manage these
`flares of intense, often excruciating, pain. The utility of
`OTFC for managing postoperative pain is also being
`evaluated.
`It is important to understand the relative potency of
`new analgesics given via a new route of administra-
`tion. Therefore, the present study was designed to
`determine the relative potency of OTFC to IV mor-
`phine in postoperative patients. This population is
`ideal for studying analgesics because of the ability to
`find a relatively standardized pain model. The relative
`potency of new analgesics is often compared with
`morphine, because morphine is the standard of care in
`the treatment of pain. Ashburn et al. (3) evaluated
`
`732
`
`Anesth Analg 1999;89:732–8
`
`©1999 by the International Anesthesia Research Society
`0003-2999/99
`
`

`
`ANESTH ANALG
`1999;89:732–8
`
`LICHTOR ET AL.
`REGIONAL ANESTHESIA AND PAIN MANAGEMENT
`RELATIVE POTENCY OF ORAL TRANSMUCOSAL FENTANYL AND IV MORPHINE
`
`733
`
`multiple administrations of OTFC in patients recover-
`ing from total hip replacement or knee arthroplasty
`in a morphine patient-controlled analgesia (PCA)-
`sparing model and estimated that 1 mg of OTFC
`seemed to be as potent as 5 mg of IV morphine. Their
`study, however, did not formally evaluate the relative
`potency of OTFC. In the present randomized, double-
`blinded, parallel-group, four-point study, we evalu-
`ated the relative potency of OTFC and IV morphine
`after single-dose administrations.
`
`Methods
`After institutional approval, written informed consent
`was obtained from patients 18 –79 yr (ASA physical
`status I or II) scheduled for lower abdominal surgery
`in which PCA was planned for postoperative pain
`control. Excluded were patients with clinically signif-
`icant laboratory abnormalities, patients taking medi-
`cations that could confound the quantification of or
`need for analgesia, patients with a history of drug or
`alcohol abuse, and pregnant and lactating women.
`This
`randomized, double-blinded,
`four-point,
`parallel-group study took place at five different hos-
`pitals. Patients were randomly assigned to one of four
`active treatments: 200 ␮g of OTFC, 800 ␮g of OTFC,
`2 mg of IV morphine, or 10 mg of IV morphine. The
`800-␮g OTFC dose was selected because it had repeat-
`edly proved effective and safe. A pilot study compar-
`ing 200 and 400 ␮g of OTFC was conducted to deter-
`mine which of those doses should be used as the small
`OTFC dose in the four-point study. The 200-␮g dose
`was found to be the minimal effective dose and there-
`fore was used. Similarly, the doses of IV morphine
`used in the four-point study were determined in a
`separate pilot study. Doses of 2 and 10 mg of IV
`morphine were selected based on the results of this
`pilot study. Patients were assigned a sequential num-
`ber in the order they entered the study. Before the
`study, sequential numbers were randomly assigned to
`one of the four treatment groups, with randomization
`stratified in blocks of four so that exactly one sequence
`number in each block was assigned to each treatment
`group. Because of the different routes of administra-
`tion, a double-dummy blinding technique was used.
`Patients receiving OTFC also received a placebo IV
`injection; patients receiving IV morphine also received
`an oral transmucosal (OT) placebo. The packaging and
`appearance of the active and placebo OT units were
`indistinguishable, and the packaging for active and
`placebo IV injection was indistinguishable. Both the
`patient and investigator were blinded to study medi-
`cation given to the patient. Patients were instructed to
`suck on the OT unit actively and to consume it com-
`pletely within 15 min.
`
`Surgery and anesthesia were performed according
`to customary practice at each institution. Intraopera-
`tive medications were not restricted because the study
`would commence the day after surgery. Patients were
`allowed to recover for the remainder of the surgical
`day and the first night (minimum of 8 h before study
`start). After surgery and up until study start, patients
`had access to PCA morphine for pain control. At ap-
`proximately 6:00 am after surgery, PCA was discon-
`tinued. Patients who did not experience moderate to
`severe pain within 4 h after discontinuation of PCA
`did not qualify for the study. PCA morphine use from
`midnight through PCA termination was recorded. Pa-
`tients with nasogastric tubes had their nasogastric
`tube clamped immediately before study initiation.
`At the patient’s first request for analgesia for mod-
`erate to severe pain, the study medications were ad-
`ministered. Patients were given a stopwatch, which
`was started with the administration of study medica-
`tions, and they were asked to stop the watch when
`meaningful pain relief occurred. Study drug evalua-
`tions were made using 100-mm visual analog scales
`(VAS) that measured pain intensity (0 ⫽ no pain to
`100 ⫽ worst pain imaginable) and pain relief (0 ⫽ no
`pain relief to 100 ⫽ complete pain relief). Pain inten-
`sity was measured immediately before study drug
`administration (time 0); 15, 30, 45, and 60 min after
`start of study drug administration; and hourly for the
`next 5 h (total of 6 h). Pain relief was measured 15, 30,
`45, and 60 min after start of study drug administration
`and hourly for the next 5 h. Final pain intensity and
`pain relief scores were obtained on study termination.
`No attempts were made to obtain pain by evoked
`stimuli. At the end of the study, patients globally
`assessed drug efficacy using a 5-point scale (1 ⫽ poor,
`2 ⫽ fair, 3 ⫽ good, 4 ⫽ very good, and 5 ⫽ excellent).
`Duration of the study was a maximum of 6 h, or the
`time from the dose of test medication until patients
`requested additional analgesia. Patients were encour-
`aged to remain in the study for at least 1 h.
`A study nurse remained with the patients through-
`out the study. Pulse oximetry was monitored contin-
`uously, and vital signs (respiratory rate, heart rate,
`and blood pressure) were recorded at the same time as
`the VAS pain scores. Adverse events were recorded.
`Several measures of analgesia were derived from
`the data. Because pain intensity as measured by VAS
`varied among patients at study start, pain intensity
`difference (PID) was calculated. PID is the difference
`between pain intensity scores at baseline and at an
`observation point. The area under the PID curve was
`summed and weighted by the time interval between
`measurements to determine the summed pain inten-
`sity difference (SPID). The area under the pain relief
`curve, weighted for
`time, was also determined
`(TOTPAR). Scores were weighted to correct for differ-
`ences in time intervals between assessments (pain
`
`

`
`734
`
`LICHTOR ET AL.
`REGIONAL ANESTHESIA AND PAIN MANAGEMENT
`RELATIVE POTENCY OF ORAL TRANSMUCOSAL FENTANYL AND IV MORPHINE
`
`ANESTH ANALG
`1999;89:732–8
`
`measurements were taken every 15 min for the first
`hour and then hourly for the remaining 5 h). SPID was
`also normalized for each patient to express these
`scores as a percentage of the maximal possible score
`for each patient. Normalization helps to ensure that
`patients with higher pain intensity scores at baseline
`are not overrepresented compared with patients with
`lower baseline scores. For patients terminating the
`study before 6 h, the last observation was carried
`forward for pain intensity and pain relief scores.
`Two-way analysis of variance (treatment group,
`center, and treatment group by center) was used to
`compare the four treatment groups with respect to
`age, weight, baseline pain intensity scores, SPID, and
`TOTPAR at every time point. A Wilcoxon survival
`analysis was used to compare treatment groups for
`time in the study and time to meaningful relief. Sex
`and global assessment of pain relief were evaluated
`using a Cochran-Mantel-Haenszel test stratified by
`centers (4). The exact permutation test was used for
`the proportion of patients who remained in study at
`least 1 h. A two-sided P ⬍ 0.05 was considered statis-
`tically significant. The relative potency of OTFC to
`morphine was assessed by using a general
`linear
`model, regressing the dependent variable (SPID and
`TOTPAR) on log-transformed dose level, and it in-
`cluded a test for parallelism of the two dose-response
`curves (5).
`
`Results
`All 133 patients were included in safety analyses, but
`10 were excluded from efficacy analyses because of
`protocol violations. Five patients received a concomi-
`tant medication before study start that could have
`confounded the quantification of analgesia, two pa-
`tients did not consume at least 90% of the study drug,
`and three patients were enrolled at a site that did not
`have at least one evaluable patient in every treatment
`group. There were no significant differences among
`treatment groups for any demographic variable (Ta-
`ble 1). Mean consumption times of the OT unit across
`the groups was 14 –17 min (individual times were
`6 –31 min). Data from patients with consumption
`times ⬎20 min (n ⫽ 10) were excluded from some
`efficacy evaluations (time until meaningful relief, pro-
`portion of patients experiencing meaningful relief,
`global assessment, and pain intensity and pain relief
`scores before 60 min). Except for cumulative PCA use
`from 4 am to PCA discontinuation, there were no
`statistically significant treatment group differences
`(Table 2).
`There was no statistical difference in SPID scores
`among groups up to 60 min after study drug admin-
`istration, although, at 60 min, the difference between
`the two morphine groups approached significance
`
`(P ⫽ 0.07) (Fig. 1). At 120 min postdose and later, the
`average SPID scores in the 800 ␮g of OTFC and 10 mg
`of IV morphine (large dose) groups were statistically
`different from the average of the 200 ␮g of OTFC and
`2 mg of IV morphine (small dose) groups (P ⱕ 0.04 at
`each time point).
`In the first hour, 800 ␮g of OTFC produced less total
`pain relief (TOTPAR) than 200 ␮g of OTFC or 10 mg of
`IV morphine (P ⱕ 0.051 at each time point), whereas
`10 mg of morphine provided more pain relief than
`2 mg of morphine (P ⱕ 0.02 at each time point) (Fig. 2).
`By 2 h, TOTPAR scores for the large doses and small
`doses began to separate, with statistically significant
`differences between the large- and small-dose groups
`4, 5, and 6 h postadministration (P ⱕ 0.03).
`All four test medications had a rapid onset of action,
`and there was no significant difference among groups
`in time to onset of relief. Median time for onset of pain
`relief for either dose of OTFC was 4.2 min (range
`0.4 –32.3 min). Median time to relief was 5.4 min (0.2–
`13.7 min) for 2 mg of morphine and 3.8 min for 10 mg
`of morphine (0.2–34.3 min).
`The large-dose treatments produced the longest an-
`algesia and were very similar. Patients who received
`800 ␮g of OTFC remained in the study for a median of
`215 min, and patients who received 10 mg of mor-
`phine remained in the study for a median of 188 min
`(P ⫽ 0.69). Median times that patients receiving 200 ␮g
`of OTFC or 2 mg of morphine remained in the study
`were 145 and 130 min, respectively. Patients receiving
`800 ␮g of OTFC or 10 mg of morphine had a signifi-
`cantly longer time to remedication than patients re-
`ceiving either of the smaller doses (P ⱕ 0.04). Six
`patients remained in the study ⬍1 h. Of these patients,
`one had received 200 ␮g of OTFC, two had received
`800 ␮g of OTFC, and three had received 2 mg of
`morphine. The proportion of patients remaining in the
`study at least 1 h did not differ among treatment
`groups (P ⫽ 0.27).
`Patients provided a global assessment of their pain
`relief. Of patients receiving 200 or 800 ␮g of OTFC,
`77% or 74%, respectively, rated their pain relief as
`either very good or excellent, compared with 43% of
`patients receiving 2 mg of morphine and 64% of pa-
`tients receiving 10 mg of morphine. The median as-
`sessment by patients who received either dose of
`OTFC or 10 mg of IV morphine was 2 (very good). The
`median score by patients receiving 2 mg of morphine
`was 3 (good). There was no significant difference
`among treatment groups (Table 3).
`Relative potency estimates of OTFC to IV morphine
`are shown in Figure 3. Relative potency estimates
`were performed only when the test for parallelism
`was not statistically significant (P ⬎ 0.05) and only
`when the common slope was statistically significant
`(P ⬍ 0.05). Thus, relative potency was not calculated
`for pain relief before 3 h. Relative potency estimates
`
`

`
`ANESTH ANALG
`1999;89:732–8
`
`LICHTOR ET AL.
`REGIONAL ANESTHESIA AND PAIN MANAGEMENT
`RELATIVE POTENCY OF ORAL TRANSMUCOSAL FENTANYL AND IV MORPHINE
`
`735
`
`Table 1. Patient Characteristics
`
`Sex (male/female)
`Age (yr)
`Weight (kg)
`Surgical procedurea
`Hysterectomy (noncancer)
`Hysterectomy (cancer)
`Other gynecological
`Colorectal
`Other
`
`Oral transmucosal
`fentanyl citrate
`
`Morphine
`
`200 ␮g
`(n ⫽ 33)
`
`3:30
`42 ⫾ 10
`71 ⫾ 15
`
`16
`5
`9
`2
`2
`
`800 ␮g
`(n ⫽ 32)
`
`1:31
`41 ⫾ 8
`71 ⫾ 13
`
`19
`4
`8
`1
`1
`
`2 mg
`(n ⫽ 34)
`
`1:33
`43 ⫾ 10
`71 ⫾ 17
`
`18
`7
`7
`1
`1
`
`10 mg
`(n ⫽ 34)
`
`1:33
`47 ⫾ 9
`73 ⫾ 13
`
`18
`9
`5
`1
`2
`
`Values are mean ⫾ sd or n.
`n ⫽ 133.
`a Some patients underwent more than one surgical procedure.
`
`Table 2. Baseline Comparisonsa
`
`Cumulative PCA morphine use (mg)
`Total PCA morphine use (mg)
`Minutes from PCA off to baseline
`Pain intensity score
`PCA off
`Baseline
`
`Oral transmucosal
`fentanyl citrate
`
`Morphine
`
`200 ␮g
`(n ⫽ 30)
`
`10.1 ⫾ 7.4
`17.7 ⫾ 10.6
`47 ⫾ 37
`
`30 ⫾ 20
`51 ⫾ 24
`
`800 ␮g
`(n ⫽ 30)
`
`7.4 ⫾ 4.4*
`15.8 ⫾ 10.5
`39 ⫾ 35
`
`38 ⫾ 24
`54 ⫾ 22
`
`2 mg
`(n ⫽ 31)
`
`10.5 ⫾ 6.8
`18.1 ⫾ 10.4
`40 ⫾ 32
`
`36 ⫾ 22
`49 ⫾ 22
`
`10 mg
`(n ⫽ 32)
`
`8.9 ⫾ 5.1
`17.0 ⫾ 9.7
`57 ⫾ 52
`
`30 ⫾ 21
`49 ⫾ 20
`
`Values are mean ⫾ sd.
`* P ⫽ 0.02 versus 200 ␮g of oral transmucosal fentanyl citrate and 2 mg of morphine.
`a The data of 10 patients were considered unevaluable due to protocol violations and are not included.
`
`ranged from 10 to 14 for SPID scores and from 7.5 to 7.9
`for TOTPAR total pain relief scores. Time in study to
`remedication produced a relative potency estimate of 14.
`Oxygen desaturation clinically diagnosed as hy-
`poventilation occurred in one patient who received
`200 ␮g of OTFC and in one patient who received
`10 mg of morphine (Table 4). Both patients received
`supplemental oxygen. No patients had a serious drug-
`related adverse event. No patients terminated the
`study early because of adverse events.
`
`Discussion
`The primary purpose of this study was to determine
`the relative potency of OTFC to IV morphine. SPID
`scores were statistically higher for the large-dose
`groups than for the small-dose groups beginning at
`two hours. However, for pain relief, the difference was
`not statistically significant until four hours. Based on
`pain intensity scores beginning at two hours, pain
`relief scores beginning at three hours, and time until
`requested additional analgesia, the relative potency of
`OTFC to IV morphine was calculated to be 8 –14:1.
`
`The lack of difference before two hours between the
`large- and small-dose groups is likely due to study
`design. All patients had adequate analgesia with IV
`PCA before the study period and theoretically should
`have required only small doses of opioid to maintain
`plasma opioid levels in the analgesic range. Effective
`use of PCA results in the plasma level of the analgesic,
`morphine, being kept close to the minimal effective
`analgesic concentration. Austin et al. (6) demonstrated
`that only a small change in the plasma level of an opioid
`was associated with the transition from pain to analge-
`sia. Because only a small change in plasma concentration
`was required to produce analgesia in these patients, this
`analgesic threshold was exceeded by even the smaller
`doses of morphine and OTFC. The larger doses of mor-
`phine and OTFC theoretically exceeded this threshold
`and maintained the blood level above the threshold for a
`longer period. Although the pain relief scores of patients
`who received 200 ␮g of OTFC were significantly better
`than those of patients who received 800 ␮g of OTFC
`during the first hour, it is doubtful that this difference is
`clinically relevant. The residual amount of morphine
`that was undoubtedly present before either OTFC or IV
`
`

`
`736
`
`LICHTOR ET AL.
`REGIONAL ANESTHESIA AND PAIN MANAGEMENT
`RELATIVE POTENCY OF ORAL TRANSMUCOSAL FENTANYL AND IV MORPHINE
`
`ANESTH ANALG
`1999;89:732–8
`
`patients could indicate when they had achieved mean-
`patients could indicate when they had achieved mean-
`ingful pain relief. Both doses of OTFC produced an onset
`
`ingful pain relief. Both doses of OTFC produced an onsetingful pain relief. Both doses of OTFC produced an onset
`of meaningful relief similar to the onset reported with IV
`
`of meaningful relief similar to the onset reported with IVof meaningful relief similar to the onset reported with IV
`morphine, with at least 50% of patients in each group
`
`morphine, with at least 50% of patients in each groupmorphine, with at least 50% of patients in each group
`
`receiving relief by approximately 5 minutes and almostreceiving relief by approximately 5 minutes and almost
`receiving relief by approximately 5 minutes and almost
`all patients receiving relief by 10 minutes. This end point
`all patients receiving relief by 10 minutes. This end point
`may have had some limitations. The term “meaningful
`may have had some limitations. The term “meaningful
`
`relief” was left up to interpretation by patients. Somerelief” was left up to interpretation by patients. Some
`relief” was left up to interpretation by patients. Some
`
`patients reported onset of meaningful relief as early as 12patients reported onset of meaningful relief as early as 12
`patients reported onset of meaningful relief as early as 12
`
`seconds after the start of consumption of OTFC, at whichseconds after the start of consumption of OTFC, at which
`seconds after the start of consumption of OTFC, at which
`
`time only a fraction of the dose of drug would have beentime only a fraction of the dose of drug would have been
`time only a fraction of the dose of drug would have been
`absorbed into systemic circulation. Patients were not
`absorbed into systemic circulation. Patients were not
`asked to complete a VAS when meaningful relief was
`experienced. We used a single-dose model because it
`is a standard model used to investigate the efficacy of
`analgesics (7).
`Many factors are thought to have an effect on post-
`operative pain. These include weight, age, sex, sur-
`geon expertise, operative site, drugs used periopera-
`tively, and length of surgery. Variability among
`institutions was hopefully sufficient to remove sur-
`geon expertise, variability in surgical technique, per-
`haps drugs used perioperatively, and length of sur-
`gery as confounding factors. There were no significant
`differences in any measured variable among institu-
`tions. Although patient age and weight were similar
`across the different centers, both factors may influence
`postoperative pain sensation (8). Virtually all patients
`in this study were female. Sex as a factor in predicting
`postoperative pain is questionable. Some studies have
`shown, for example, that male patients have more
`pain and require more opioids than female patients
`(9). Other studies have found no correlation with sex
`(10). When other factors, such as age and weight, are
`taken into account, the effect of sex, even when sig-
`nificant, is trivial (7). Depression and personality may
`also have had an effect, although these were not mea-
`sured before the study.
`The side effects experienced by patients in all four
`groups were generally similar in frequency and na-
`ture, which suggests that neither OTFC nor morphine
`showed any particular advantage in this respect. In
`one patient who received the smaller dose of OTFC,
`oxygen desaturation, clinically diagnosed as hypoven-
`tilation, was easily managed with supplemental oxy-
`gen. This patient’s experience suggests that it may be
`necessary to monitor oxygen saturation when using
`this type of drug therapy. However, decreases in ox-
`ygen saturation may occur just as often using conven-
`tional means of pain control. Indeed, one patient re-
`ceiving 10 mg of morphine also experienced oxygen
`desaturation clinically diagnosed as hypoventilation.
`Hypoxemia has been reported with PCA opioid ad-
`ministration. For example, in cases of accidental over-
`dose, a decreased respiratory rate as slow as 3– 6
`breaths/min, and even apnea, occurred (10). Other
`than these rare cases, the frequency and severity of
`
`Figure 1. Mean pain intensity differences. *Two-way analysis of
`variance significant difference between large-dose groups (800 ␮g of
`oral transmucosal fentanyl citrate [OTFC] and 10 mg of morphine)
`and small-dose groups (200 ␮g of OTFC and 2 mg of morphine) at
`180 min (P ⫽ 0.007), 240 min (P ⫽ 0.009), and 360 min (P ⫽ 0.046).
`
`Figure 2. Pain relief scores. *Two-way analysis of variance signifi-
`cant difference between large-dose groups (800 ␮g of oral transmu-
`cosal fentanyl citrate [OTFC] and 10 mg of morphine) and small-
`dose groups (200 ␮g of OTFC and 2 mg of morphine) at 180 min
`(P ⫽ 0.003) and 240 min (P ⫽ 0.01). A higher pain relief score
`represents greater pain relief.
`
`Table 3. Global Assessment of Pain Relief Scores
`
`OTFC (␮g)
`200
`800
`Morphine (mg)
`2
`10
`
`Excellent
`
`Very good
`
`4 (15)
`7 (26)
`
`7 (23)
`7 (25)
`
`16 (62)
`13 (48)
`
`6 (20)
`11 (39)
`
`Values are n (%).
`OTFC ⫽ oral transmucosal fentanyl citrate.
`
`morphine was administered may have interacted with
`both fentanyl and morphine to artifactually make a
`given dose seem to be more potent than if its potency
`was assessed in the absence of residual morphine and
`metabolites. This should have a minimal effect on the
`relative potency of the two drugs.
`In many postoperative pain studies, onset of analgesia
`is determined indirectly by interpolations of VAS or
`verbal rating scales. This study used a stopwatch so that
`
`

`
`ANESTH ANALG
`1999;89:732–8
`
`LICHTOR ET AL.
`REGIONAL ANESTHESIA AND PAIN MANAGEMENT
`RELATIVE POTENCY OF ORAL TRANSMUCOSAL FENTANYL AND IV MORPHINE
`
`737
`
`Figure 3. Dose-effect curves of summed
`pain intensity differences (SPIDs). Values
`are mean ⫾ sem.
`
`Table 4. Most Common Study Drug-Associated Adverse Events
`
`Oral transmucosal
`fentanyl citrate
`
`Morphine
`
`200 ␮g
`(n ⫽ 33)
`
`12 (36)
`5 (15)
`5 (15)
`2 (6)
`1 (3)
`1 (3)
`1 (3)
`3 (9)
`4 (12)
`2 (6)
`
`800 ␮g
`(n ⫽ 32)
`
`2 mg
`(n ⫽ 34)
`
`3 (9)
`5 (16)
`1 (3)
`1 (3)
`4 (13)
`0 (0)
`1 (3)
`3 (9)
`2 (6)
`0 (0)
`
`9 (26)
`6 (18)
`6 (18)
`3 (9)
`0 (0)
`0 (0)
`1 (3)
`3 (9)
`7 (21)
`1 (3)
`
`10 mg
`(n ⫽ 34)
`
`11 (32)
`10 (29)
`8 (24)
`4 (12)
`6 (18)
`1 (3)
`6 (18)
`1 (3)
`2 (6)
`1 (3)
`
`Fever
`Nausea
`Pruritus
`Vomiting
`Dizziness
`Hypoventilation
`Taste aversion
`Urinary retention
`Abdominal pain
`Tachycardia
`
`Values are n (%).
`
`respiratory depression has been reported to be ex-
`tremely low. In a study using PCA administration,
`only 1.2% of 1333 respiratory rate chartings had values
`⬍16 breaths/min (11).
`We often found slow respiratory rates, although no
`incident was so severe as to require further interven-
`tion. Average respiratory rates were ⬎16 breaths/min
`at every observation time point. Because the smaller
`dose of OTFC was just as effective as the larger dose,
`it seems that that dose would also be preferable in
`terms of adverse respiratory side effects, although fur-
`ther study is warranted.
`In other studies with fentanyl, especially in small
`patient groups, nausea and vomiting was a common
`side effect (12). Fentanyl induces nausea and vomiting
`by affecting an area postrema of the medulla called the
`chemoreceptor trigger zone (13), but its effects cause
`less emesis than other opioid analgesics (14). This
`present study found nausea and vomiting in 10 of 65
`patients during OTFC administration, an incidence
`rate midrange between that found by Chudnofsky et
`al. (16) in their retrospective review of the use of IV
`fentanyl in the emergency department and that found
`
`by Lind et al. (13) in their evaluation of OTFC for
`analgesia and sedation in the emergency department.
`One patient who was nauseated before OTFC admin-
`istration felt less nausea after the drug was administered.
`In summary, OTFC is an effective analgesic, and its
`relative potency to IV morphine is 8 –14:1. The two
`doses of OTFC produced similar efficacy in the first
`two hours; however, the larger dose produced a more
`sustained effect. The onset of analgesia for OTFC was
`not different from that for IV morphine. These results
`are not surprising because all potent ␮-opioids (in-
`cluding fentanyl) have been associated with pain re-
`lief. The side effects were those expected with opioids.
`We conclude that the efficacy of OTFC is similar to
`that of IV morphine, although the safety of OTFC for
`treating postoperative pain has not been adequately
`evaluated. At this time, OTFC is specifically contrain-
`dicated for use in opioid nontolerant patients, includ-
`ing use in managing acute and postoperative pain.
`However, the potential for OTFC as a noninvasive
`PCA in the postoperative patient cannot be discounted
`and should be addressed in a controlled fashion to
`ensure that safety and efficacy variables are established.
`
`

`
`738
`
`LICHTOR ET AL.
`REGIONAL ANESTHESIA AND PAIN MANAGEMENT
`RELATIVE POTENCY OF ORAL TRANSMUCOSAL FENTANYL AND IV MORPHINE
`
`ANESTH ANALG
`1999;89:732–8
`
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