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Transdermal fentanyl in children with cancer pain: Feasibility, tolerability, and pharmacokinetic correlates
T
Transdermal fentanyl in children with cancer pain: Feasibility, tolerability, and pharmacokinetic correlates
John J. Collins, MBBS, FRACP, Ira J. Dunkel, MD, Suneel K. Gupta, PhD, Charles E. Inturrisi, PhD, Jeanne Lapin, RN, Leah N. Palmer, RN, BSN, Sharon M. Weinstein, MD, and Russell K. Portenoy, MD
Objectives: (1) To assess the feasibility and tolerability of the therapeutic transdermal fentanyl system (TTS-fentanyl) by using a clinical protocol developed for children with cancer pain. (2) To estimate the pediatric pharmacokinetic parameters of TTS-fentanyl. Methods: The drug was administered in open-label fashion; and measures of analgesia, side effects, and skin changes were obtained for a minimum of 2 doses (6 treatment days). Blood specimens were analyzed for plasma fentanyl concentrations. The pharmacokinetics of TTS-fentanyl were estimated by using a mixed effect modeling approach. Results: Treatment was well tolerated. Ten of the 11 patients who completed the 2 doses continued treatment with TTS-fentanyl. The duration of treatment ranged from 6 to 275 days. The time to reach peak plasma concentration ranged from 18 hours to >66 hours in patients receiving the 25 µg/h patch. Compared with published pharmacokinetic data from adults, the mean clearance and volume of distribution of transdermal fentanyl were the same, but the variability was less. Conclusions: Treatment of children with TTS-fentanyl is feasible and well tolerated and yields fentanyl pharmacokinetic parameter estimates similar to those for adults. A larger study is required to confirm these findings and further test the clinical protocol. (J Pediatr 1999;134:319-23)
From The Pain and Palliative Care Service and the Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York; Pain Service, MD Anderson Cancer Center, Houston, Texas; Department of Pharmacology, Cornell University (Medical College), New York, New York; and Alza Corporation, Palo Alto, California.
Supported in part by a grant from Janssen Pharmaceutica. Submitted for publication July 1, 1998; revision received Oct 13, 1998; accepted Dec 2, 1998. Reprint requests: John J. Collins, MBBS, FRACP, Physician, Vincent Farifax Pain Unit, The New Children’s Hospital, Westmead, New South Wales 2145, Australia. Copyright © 1999 by Mosby, Inc. 0022-3476/99/$8.00 + 0 9/21/96309
The transdermal therapeutic system for fentanyl, TTS-fentanyl, provides continuous systemic delivery of fentanyl and a duration of analgesia for each dose that can extend for up to 72 hours.1 This formulation has proved to be a useful alternative to the oral or parenteral administration of opioids in adults. TTS-fentanyl has been evaluated in adults as a treatment for postoperative pain2 and cancer pain.3-6 It is widely accepted as safe and effective for treatment of chronic pain in adults. To date, there has been no published evaluation of TTS-fentanyl in children
with chronic pain. The objectives of this study were: (1) to assess the feasibility and tolerability of TTS-fentanyl when administered with a standard clinical protocol to children with cancer pain and (2) to estimate the pediatric pharmacokinetic parameters of TTS-fentanyl. TTS-fentanyl
Therapeutic transdermal fentanyl system
METHODS This study was approved by the Institutional Review Boards of Memorial Sloan-Kettering Cancer Center and MD Anderson Cancer Center. The consent of a parent or parents and, when appropriate, assent of the child were obtained. Patients were eligible for the trial if they met eligibility criteria, including age >7 years but <18 years, weight of at least 10 kg, diagnosis of cancer, and cancer pain requiring opioid therapy at a minimum dose equivalent to oral morphine, 45 mg/day, with established opioid potencies. At enrollment, each patient’s medical history was reviewed, a physical examination was performed, and demographic and disease-related data were collected. On the day of recruitment into the study, the TTS-fentanyl system was applied by a member of the investigation team. The date and time of application of the system were recorded. The initial dose of TTS-fentanyl, weaning of previously used opi319
COLLINS ET AL
THE JOURNAL OF PEDIATRICS MARCH 1999
Table. Transdermal fentanyl in children: Patient demographics
Patient No.
Age (y)
Weight (kg)
Hodgkin’s lymphoma Osteogenic sarcoma
16.7
64.2
Bone pain
Alternative opioid
17.5
87
Phantom limb pain
3*
Myelodysplastic syndrome
10
22
4
12.5
39.4
17.9
91.2
Plexopathy
6
Ewing’s sarcoma Ewing’s sarcoma Medulloblastoma
Abdominal pain caused by GVHD and biliary colic Mucositis
Improved QOL if oral route eliminated Oral route not tolerated
16.5
40
Mucositis
7 8†
Rhabdomyosarcoma Chondrosarcoma
15.3 15.9
53 51.1
9
Osteogenic sarcoma Ewing’s sarcoma Acute lymphoblastic leukemia
15.1
42.1
Plexopathy Pleuritic chest pain Bone pain
7
22.5
Mucositis pain
9.2
35
Bone pain
12
Sarcoma
13.2
36.1
13†
Acute myelogenous leukemia
16.7
71.2
Vincristine neuropathy Bone pain
1 2
5†
10 11
Cancer type
Pain diagnosis
Indication for TTS-fentanyl
Oral route not tolerated New opioid trial indicated Oral route not tolerated Improved QOL Oral route not tolerated Oral route not tolerated Oral route not tolerated Improved QOL if oral route eliminated Oral route not tolerated New opioid trial indicated
QOL, Quality of life; GVHD, graft-versus-host disease.. *This patient was converted from a fentanyl infusion of 100 µg/h to TTS fentanyl 100 µg/h; the TTS-fentanyl dose was subsequently increased to 125 µg/h. †Patients 5, 8, and 13 did not contribute blood specimens.
oids, “rescue” dosing, dose titration, and side effect management were described in a clinical protocol, which was developed based on the use of TTS-fentanyl in adults1,4 and on clinical experience. At the completion of the study, patients were given the option of continuing treatment with TTSfentanyl. Patients were monitored daily by a physician or nurse during the initial application of the TTS-fentanyl system (the first 2 to 3 days) and then not less than every 3 days during the remainder of the study. Monitoring was performed through a visit or telephone contact. Patients were monitored until 320
therapy with the transdermal system was discontinued for clinical reasons or until a stable dose had been achieved for a minimum of 2 consecutive administrations (a total of 6 days for patients who changed the system every 3 days). Outcome data included daily patientrated scores on a visual analog scale for pain, patient-reported adverse events, investigator-rated compliance with therapy, parent-reported system adherence to the skin, and skin-related side effects. The visual analog scale had verbal anchors of “least possible pain” and “worst possible pain.” At the end of the study period (after 2 doses), a patient-
rated global assessment of the treatment was recorded, including the decision to continue. For patients who withdrew from the study, the date and reason for withdrawal were recorded. Patients were given the option of agreeing to blood sampling. No blood sampling was performed in children <10 kg in weight. Those who consented provided 3 to 6 3-mL blood samples. Samples were drawn at random times, always combined with routine blood collections to avoid the need for additional central venous line access. Specimens of blood, collected in sodium heparin tubes, were spun, frozen, and stored for subsequent analysis.
COLLINS ET AL
THE JOURNAL OF PEDIATRICS VOLUME 134, NUMBER 3 Plasma concentrations of fentanyl were measured by radioimmunoassay with a solid-phase procedure (Coat-ACount, Diagnostics Products Corp). Plasma samples (0.05 mL) and standards (0.025 to 0.375 ng/0.025 mL) were incubated for 60 minutes at room temperature with iodine 125—labeled fentanyl, and then the incubation liquid was removed by decantation. The samples were counted for 1 minute in the gamma counter. The interassay coefficient of variation was <10%. When a sample aliquot of 0.050 mL was used, the lower limit of sensitivity was 0.5 ng/mL. Commonly used analgesics do not cross-react in this assay, and norfentanyl has a cross-reactivity between 8% and 16%. All clinical data were tabulated. Outcome data including compliance, skin adherence, skin-related and patient-reported opioid side effects or opioid-related side effects (eg, itching, nausea, drowsiness), satisfaction with therapy and desire to continue therapy, adequacy of analgesia with the clinical protocol, and proportion of patients unable to use TTS-fentanyl were summarized by using descriptive statistics. The pharmacokinetics of TTS-fentanyl in children were investigated by using several variations of a basic onecompartment model used in adult studies.7 In brief, the one-compartment model was fitted to the data with an absorption rate constant (ka) for all doses and patients, with different clearance (CL/F) terms for all doses and a total of 7 structural parameters. Because of sparse sampling per patient during the early transdermal fentanyl application period, individual absorption rate constant values were not estimated. For the optimal model, the objective was found to be 70.9 with 7 parameters. Based on the previous modeling experiences7 and present data, a one-compartment model with first-order absorption was found to be an adequate approximation. It has been shown that there is a good in vitro to in vivo corre-
lation for TTS-fentanyl administered to adults.7 When this model was used in the METHOD-CONDITIONAL option in NONMEM, the mean volume was fixed to the adult mean volume value of 968, and both clearance (CL/F) and volume of distribution (V/F) were estimated for all patients. The clearance (CL/F) and volume of distribution (V/F) values for individual patients were estimated by using Bayesian method in NONMEM. A one-compartment model with firstorder absorption was used to verify this correlation. The individual pharmacokinetic parameters were regressed against each patient’s demographic parameters.
RESULTS Thirteen patients were recruited from the inpatient and outpatient services at Memorial Sloan-Kettering Cancer Center from January 1996 to June 1997 and at MD Anderson Cancer Center from June 1997 to December 1997 (Table). The median age was 15.3 years (range, 7 to 17.9 years). Four patients had hematologic malignancies, 1 had a brain tumor, and 8 had solid tumors. Of the 13 patients, 7 had active disease at the time of enrollment. The etiologies of the pain were mixed. The indication for TTS-fentanyl was either a need for non-oral opioid administration (eg, severe mucositis) or the clinical assessment that quality of life would be improved if the oral route were eliminated (eg, palliative pain management when patients do not desire intravenous analgesics). All patients had extensive prior opioid exposure. The doses of the opioids received immediately before the application of TTS-fentanyl were equivalent to oral morphine, 45 to 1080 mg per day. The starting TTS-fentanyl dose ranged from 25 µg/h to 300 µg/h. The mean number of additional “rescue” opioid doses per patient during the study ranged from nil to approximately 3 per day.
Clinical Outcomes Eleven of the 13 enrolled patients were evaluated for at least 2 doses (6 days) and completed the study. One patient discontinued the study on the second day of TTS-fentanyl administration because she disliked the sensation of the patch on her skin; the other patient discontinued because he attributed fever and dyspnea, which occurred 6 hours after the initial placement of the patch, to transdermal fentanyl. The duration of TTS-fentanyl treatment among those who continued ranged from 6 to 275 days, resulting in a total of 497 treatment-days. Three patients required TTS-fentanyl dose escalation during the study. The global impression of the utility of transdermal fentanyl in patients who completed the study was very good to excellent. Ten of the 11 patients continued treatment with transdermal fentanyl after the completion of the study; the one who did not had resolution of the underlying pain condition. The compliance with the protocol was excellent in all cases. The adherence of the system to the skin was acceptable. Only 2 patients required reinforcement with paper tape. Transdermal fentanyl was well tolerated in most cases. Side effects were mild. The one exception to this was a patient who had symptoms of akathisia and anxiety 6 hours after switching from intravenous fentanyl, 115 µg/h, to TTS-fentanyl, 100 µg/h. These symptoms were thought to be “withdrawallike” and abated after an additional 25 µg/h TTS-fentanyl was applied. Apart from mild spontaneously resolving skin erythema in some cases, there was no skin toxicity.
Fentanyl Pharmacokinetics Eleven patients contributed 57 random blood samples. Maximum plasma concentration (Cmax) values ranged from 0.91 µg/L (25 µg/h TTS-fentanyl) to 39.3 µg/L (200 µg/h). A model previously developed for transdermal fentanyl, a one-compartment 321
COLLINS ET AL
THE JOURNAL OF PEDIATRICS MARCH 1999
Figure. Observed and predicted plasma fentanyl concentrations after administration of transdermal fentanyl, 25 µg/h, for 72 hours in children.
model with first-order absorption, was fitted to these pediatric data.7 This model used the in vitro release rate as the input rate. The rate was scaled for different strengths. The Figure shows the observed and predicted plasma concentration time profiles obtained after the application of 25 µg/h TTS-fentanyl in the pediatric patients. This predicted curve for steadystate plasma profile demonstrates peak concentration at approximately 24 hours and a profile consistent with 72-hour administration in most cases. The time to reach peak plasma concentration ranged from 18 hours to >66 hours in patients receiving the 25 µg/h patch. The pediatric clearance values were slightly higher than those of the adult population in a previously published study.8 There was a larger difference in the volume of distribution when pediatric and adult data were compared, and there was greater variability in the adult population. The clearance values in the pediatric population were inversely related to body weight. This suggests that the lower the body weight, the higher the fentanyl clearance, and consequently, the lower the fentanyl plasma concentrations.
DISCUSSION The World Health Organization’s “analgesic ladder” approach to cancer 322
pain, which recommends the selection of analgesics according to pain severity, is effective for children,9-11 as well as adults. If the oral route is not available, an alternative route is needed. In the pediatric population this need for a non-oral route of opioid administration may be greater because the usual indications (inability to swallow or absorb the opioid drug) are supplemented by poor compliance with oral regimens among the very young. Non-oral routes of opioid administration may be problematic in children. Long-term rectal dosing may not be tolerated or feasible. Repeated intramuscular or subcutaneous injections are unacceptable, the intravenous route is only possible if a venous access device is available, and continuous subcutaneous infusion may be unavailable or difficult to sustain. Transdermal administration may be a useful method of delivering an opioid to children. Although TTS-fentanyl is commonly available and widely used in adults, there have been no studies of the safety, efficacy, tolerability, or pharmacokinetics of this formulation in children. According to the protocol developed for this study, TTS-fentanyl was indicated primarily because the oral route was not tolerated or there would likely be improvement in the quality of life if the oral route were eliminated. Although the study sample was small,
treatment with TTS-fentanyl according to this protocol was demonstrated to be both feasible and well tolerated. The utility of the clinical protocol was suggested by the observation that most patients continued to use the preparation after the 2-dose study period. The analgesia reported was acceptable in most cases, and the global impression of the preparation by patients was very good to excellent. In this pediatric sample, clearance and volume of distribution were similar to published adult values.8 Although the variability in these parameters was less than in adults, interindividual variation in kinetics was still substantial. The predicted plasma profile at steady state was also similar to that of adults,12 demonstrating peak effects at about 24 hours and a slow decline from the peak concentration. This profile was consistent with 72-hour dosing in most cases. This small open-label survey suggests that the treatment of children with TTS-fentanyl is feasible and well tolerated and yields pharmacokinetic parameter estimates similar to those for adults. Practitioners should be aware that supplementary analgesia is often needed until steady state is reached at an effective dose and that many days may be required to identify this dose. Supplemental doses (“rescue doses”) may also be needed to treat breakthrough pain, even after the correct dose is found and steady state has been approached. A larger study is required to confirm these observations and further test the clinical protocol developed for this population. We thank Dr Henry Kilham, Head, Vincent Fairfax Pain Unit, New Children’s Hospital, Sydney, Australia, for his constructive criticism of the manuscript and Marilyn Herleth, Beth Israel Medical Center, New York, for her technical assistance.
REFERENCES 1. Sandler A. Transdermal fentanyl: acute analgesic clinical studies. J Pain Symptom Manage 1992;7:S27-35.
COLLINS ET AL
THE JOURNAL OF PEDIATRICS VOLUME 134, NUMBER 3 2. Gourlay GK, Kowalski SR, Plummer JL, Cherry DA, Gaukroger P, Cousins MJ. The transdermal administration of fentanyl in the treatment of postoperative pain: pharmacokinetics and pharmacodynamic effects. Pain 1989;37:193-202. 3. Herbst LH, Strause LG. Transdermal fentanyl use in hospice home-care patients with chronic cancer pain. J Pain Symptom Manage 1992;7:S54-7. 4. Maves TJ, Barcellos WA. Management of cancer pain with transdermal fentanyl: phase IV trial, University of Iowa. J Pain Symptom Manage 1992; 7:S58-62. 5. Ahmedzai S, Brooks D. Transdermal fentanyl versus sustained-release oral morphine in cancer pain: preference, efficacy, and quality of life. The TTS-fen-
O
6.
7.
8.
9.
tanyl Comparative Trial Group. J Pain Symptom Manage 1997;13:254-61. Payne R, Mathias SD, Pasta DJ, Wanke LA, Williams R, Mahmoud R. Quality of life and cancer pain: satisfaction and side effects with transdermal fentanyl versus oral morphine. J Clin Oncol 1998;16:1588-93. Gupta SK, Southam M, Gale R. System functionality and physiochemical model of fentanyl transdermal system. J Pain Symptom Manage 1992;7: S17-26. Gupta SK, Yih B, Bernstein K. Population analysis to evaluate dose proportionality of the transdermal fentanyl system. Clin Pharm Ther 1995;57:180. Berde C, Ablin A, Glazer J, Miser A, Shapiro B, Weisman S, et al. American Academy of Pediatrics Report of the
Subcommittee on Disease-Related Pain in Childhood Cancer. Pediatrics 1990;86:818-25. 10. Miser AW. Management of pain associated with childhood cancer. In: Schecter NL, Berde CB, Yaster M, editors. Pain in infants, children, and adolescents. Baltimore: Williams and Wilkins; 1993. p. 411-23. 11. McGrath PJ, Beyer J, Cleeland C, Eland J, McGrath PA, Portenoy RK. American Academy of Pediatrics Report of the Subcommittee on Assessment and Methodologic Issues in the Management of Pain in Childhood Cancer. Pediatrics 1990;86:814-7. 12. Portenoy RK, Southam MA, Gupta SK, Lapin J, Layman M, Inturissi CE, et al. Transdermal fentanyl for cancer pain. Anesthesiology 1993;78:36-43.
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323
Transdermal fentanyl in children with cancer pain: Feasibility, tolerability, and pharmacokinetic correlates
John J. Collins, MBBS, FRACP, Ira J. Dunkel, MD, Suneel K. Gupta, PhD, Charles E. Inturrisi, PhD, Jeanne Lapin, RN, Leah N. Palmer, RN, BSN, Sharon M. Weinstein, MD, and Russell K. Portenoy, MD
Objectives: (1) To assess the feasibility and tolerability of the therapeutic transdermal fentanyl system (TTS-fentanyl) by using a clinical protocol developed for children with cancer pain. (2) To estimate the pediatric pharmacokinetic parameters of TTS-fentanyl. Methods: The drug was administered in open-label fashion; and measures of analgesia, side effects, and skin changes were obtained for a minimum of 2 doses (6 treatment days). Blood specimens were analyzed for plasma fentanyl concentrations. The pharmacokinetics of TTS-fentanyl were estimated by using a mixed effect modeling approach. Results: Treatment was well tolerated. Ten of the 11 patients who completed the 2 doses continued treatment with TTS-fentanyl. The duration of treatment ranged from 6 to 275 days. The time to reach peak plasma concentration ranged from 18 hours to >66 hours in patients receiving the 25 µg/h patch. Compared with published pharmacokinetic data from adults, the mean clearance and volume of distribution of transdermal fentanyl were the same, but the variability was less. Conclusions: Treatment of children with TTS-fentanyl is feasible and well tolerated and yields fentanyl pharmacokinetic parameter estimates similar to those for adults. A larger study is required to confirm these findings and further test the clinical protocol. (J Pediatr 1999;134:319-23)
From The Pain and Palliative Care Service and the Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York; Pain Service, MD Anderson Cancer Center, Houston, Texas; Department of Pharmacology, Cornell University (Medical College), New York, New York; and Alza Corporation, Palo Alto, California.
Supported in part by a grant from Janssen Pharmaceutica. Submitted for publication July 1, 1998; revision received Oct 13, 1998; accepted Dec 2, 1998. Reprint requests: John J. Collins, MBBS, FRACP, Physician, Vincent Farifax Pain Unit, The New Children’s Hospital, Westmead, New South Wales 2145, Australia. Copyright © 1999 by Mosby, Inc. 0022-3476/99/$8.00 + 0 9/21/96309
The transdermal therapeutic system for fentanyl, TTS-fentanyl, provides continuous systemic delivery of fentanyl and a duration of analgesia for each dose that can extend for up to 72 hours.1 This formulation has proved to be a useful alternative to the oral or parenteral administration of opioids in adults. TTS-fentanyl has been evaluated in adults as a treatment for postoperative pain2 and cancer pain.3-6 It is widely accepted as safe and effective for treatment of chronic pain in adults. To date, there has been no published evaluation of TTS-fentanyl in children
with chronic pain. The objectives of this study were: (1) to assess the feasibility and tolerability of TTS-fentanyl when administered with a standard clinical protocol to children with cancer pain and (2) to estimate the pediatric pharmacokinetic parameters of TTS-fentanyl. TTS-fentanyl
Therapeutic transdermal fentanyl system
METHODS This study was approved by the Institutional Review Boards of Memorial Sloan-Kettering Cancer Center and MD Anderson Cancer Center. The consent of a parent or parents and, when appropriate, assent of the child were obtained. Patients were eligible for the trial if they met eligibility criteria, including age >7 years but <18 years, weight of at least 10 kg, diagnosis of cancer, and cancer pain requiring opioid therapy at a minimum dose equivalent to oral morphine, 45 mg/day, with established opioid potencies. At enrollment, each patient’s medical history was reviewed, a physical examination was performed, and demographic and disease-related data were collected. On the day of recruitment into the study, the TTS-fentanyl system was applied by a member of the investigation team. The date and time of application of the system were recorded. The initial dose of TTS-fentanyl, weaning of previously used opi319
COLLINS ET AL
THE JOURNAL OF PEDIATRICS MARCH 1999
Table. Transdermal fentanyl in children: Patient demographics
Patient No.
Age (y)
Weight (kg)
Hodgkin’s lymphoma Osteogenic sarcoma
16.7
64.2
Bone pain
Alternative opioid
17.5
87
Phantom limb pain
3*
Myelodysplastic syndrome
10
22
4
12.5
39.4
17.9
91.2
Plexopathy
6
Ewing’s sarcoma Ewing’s sarcoma Medulloblastoma
Abdominal pain caused by GVHD and biliary colic Mucositis
Improved QOL if oral route eliminated Oral route not tolerated
16.5
40
Mucositis
7 8†
Rhabdomyosarcoma Chondrosarcoma
15.3 15.9
53 51.1
9
Osteogenic sarcoma Ewing’s sarcoma Acute lymphoblastic leukemia
15.1
42.1
Plexopathy Pleuritic chest pain Bone pain
7
22.5
Mucositis pain
9.2
35
Bone pain
12
Sarcoma
13.2
36.1
13†
Acute myelogenous leukemia
16.7
71.2
Vincristine neuropathy Bone pain
1 2
5†
10 11
Cancer type
Pain diagnosis
Indication for TTS-fentanyl
Oral route not tolerated New opioid trial indicated Oral route not tolerated Improved QOL Oral route not tolerated Oral route not tolerated Oral route not tolerated Improved QOL if oral route eliminated Oral route not tolerated New opioid trial indicated
QOL, Quality of life; GVHD, graft-versus-host disease.. *This patient was converted from a fentanyl infusion of 100 µg/h to TTS fentanyl 100 µg/h; the TTS-fentanyl dose was subsequently increased to 125 µg/h. †Patients 5, 8, and 13 did not contribute blood specimens.
oids, “rescue” dosing, dose titration, and side effect management were described in a clinical protocol, which was developed based on the use of TTS-fentanyl in adults1,4 and on clinical experience. At the completion of the study, patients were given the option of continuing treatment with TTSfentanyl. Patients were monitored daily by a physician or nurse during the initial application of the TTS-fentanyl system (the first 2 to 3 days) and then not less than every 3 days during the remainder of the study. Monitoring was performed through a visit or telephone contact. Patients were monitored until 320
therapy with the transdermal system was discontinued for clinical reasons or until a stable dose had been achieved for a minimum of 2 consecutive administrations (a total of 6 days for patients who changed the system every 3 days). Outcome data included daily patientrated scores on a visual analog scale for pain, patient-reported adverse events, investigator-rated compliance with therapy, parent-reported system adherence to the skin, and skin-related side effects. The visual analog scale had verbal anchors of “least possible pain” and “worst possible pain.” At the end of the study period (after 2 doses), a patient-
rated global assessment of the treatment was recorded, including the decision to continue. For patients who withdrew from the study, the date and reason for withdrawal were recorded. Patients were given the option of agreeing to blood sampling. No blood sampling was performed in children <10 kg in weight. Those who consented provided 3 to 6 3-mL blood samples. Samples were drawn at random times, always combined with routine blood collections to avoid the need for additional central venous line access. Specimens of blood, collected in sodium heparin tubes, were spun, frozen, and stored for subsequent analysis.
COLLINS ET AL
THE JOURNAL OF PEDIATRICS VOLUME 134, NUMBER 3 Plasma concentrations of fentanyl were measured by radioimmunoassay with a solid-phase procedure (Coat-ACount, Diagnostics Products Corp). Plasma samples (0.05 mL) and standards (0.025 to 0.375 ng/0.025 mL) were incubated for 60 minutes at room temperature with iodine 125—labeled fentanyl, and then the incubation liquid was removed by decantation. The samples were counted for 1 minute in the gamma counter. The interassay coefficient of variation was <10%. When a sample aliquot of 0.050 mL was used, the lower limit of sensitivity was 0.5 ng/mL. Commonly used analgesics do not cross-react in this assay, and norfentanyl has a cross-reactivity between 8% and 16%. All clinical data were tabulated. Outcome data including compliance, skin adherence, skin-related and patient-reported opioid side effects or opioid-related side effects (eg, itching, nausea, drowsiness), satisfaction with therapy and desire to continue therapy, adequacy of analgesia with the clinical protocol, and proportion of patients unable to use TTS-fentanyl were summarized by using descriptive statistics. The pharmacokinetics of TTS-fentanyl in children were investigated by using several variations of a basic onecompartment model used in adult studies.7 In brief, the one-compartment model was fitted to the data with an absorption rate constant (ka) for all doses and patients, with different clearance (CL/F) terms for all doses and a total of 7 structural parameters. Because of sparse sampling per patient during the early transdermal fentanyl application period, individual absorption rate constant values were not estimated. For the optimal model, the objective was found to be 70.9 with 7 parameters. Based on the previous modeling experiences7 and present data, a one-compartment model with first-order absorption was found to be an adequate approximation. It has been shown that there is a good in vitro to in vivo corre-
lation for TTS-fentanyl administered to adults.7 When this model was used in the METHOD-CONDITIONAL option in NONMEM, the mean volume was fixed to the adult mean volume value of 968, and both clearance (CL/F) and volume of distribution (V/F) were estimated for all patients. The clearance (CL/F) and volume of distribution (V/F) values for individual patients were estimated by using Bayesian method in NONMEM. A one-compartment model with firstorder absorption was used to verify this correlation. The individual pharmacokinetic parameters were regressed against each patient’s demographic parameters.
RESULTS Thirteen patients were recruited from the inpatient and outpatient services at Memorial Sloan-Kettering Cancer Center from January 1996 to June 1997 and at MD Anderson Cancer Center from June 1997 to December 1997 (Table). The median age was 15.3 years (range, 7 to 17.9 years). Four patients had hematologic malignancies, 1 had a brain tumor, and 8 had solid tumors. Of the 13 patients, 7 had active disease at the time of enrollment. The etiologies of the pain were mixed. The indication for TTS-fentanyl was either a need for non-oral opioid administration (eg, severe mucositis) or the clinical assessment that quality of life would be improved if the oral route were eliminated (eg, palliative pain management when patients do not desire intravenous analgesics). All patients had extensive prior opioid exposure. The doses of the opioids received immediately before the application of TTS-fentanyl were equivalent to oral morphine, 45 to 1080 mg per day. The starting TTS-fentanyl dose ranged from 25 µg/h to 300 µg/h. The mean number of additional “rescue” opioid doses per patient during the study ranged from nil to approximately 3 per day.
Clinical Outcomes Eleven of the 13 enrolled patients were evaluated for at least 2 doses (6 days) and completed the study. One patient discontinued the study on the second day of TTS-fentanyl administration because she disliked the sensation of the patch on her skin; the other patient discontinued because he attributed fever and dyspnea, which occurred 6 hours after the initial placement of the patch, to transdermal fentanyl. The duration of TTS-fentanyl treatment among those who continued ranged from 6 to 275 days, resulting in a total of 497 treatment-days. Three patients required TTS-fentanyl dose escalation during the study. The global impression of the utility of transdermal fentanyl in patients who completed the study was very good to excellent. Ten of the 11 patients continued treatment with transdermal fentanyl after the completion of the study; the one who did not had resolution of the underlying pain condition. The compliance with the protocol was excellent in all cases. The adherence of the system to the skin was acceptable. Only 2 patients required reinforcement with paper tape. Transdermal fentanyl was well tolerated in most cases. Side effects were mild. The one exception to this was a patient who had symptoms of akathisia and anxiety 6 hours after switching from intravenous fentanyl, 115 µg/h, to TTS-fentanyl, 100 µg/h. These symptoms were thought to be “withdrawallike” and abated after an additional 25 µg/h TTS-fentanyl was applied. Apart from mild spontaneously resolving skin erythema in some cases, there was no skin toxicity.
Fentanyl Pharmacokinetics Eleven patients contributed 57 random blood samples. Maximum plasma concentration (Cmax) values ranged from 0.91 µg/L (25 µg/h TTS-fentanyl) to 39.3 µg/L (200 µg/h). A model previously developed for transdermal fentanyl, a one-compartment 321
COLLINS ET AL
THE JOURNAL OF PEDIATRICS MARCH 1999
Figure. Observed and predicted plasma fentanyl concentrations after administration of transdermal fentanyl, 25 µg/h, for 72 hours in children.
model with first-order absorption, was fitted to these pediatric data.7 This model used the in vitro release rate as the input rate. The rate was scaled for different strengths. The Figure shows the observed and predicted plasma concentration time profiles obtained after the application of 25 µg/h TTS-fentanyl in the pediatric patients. This predicted curve for steadystate plasma profile demonstrates peak concentration at approximately 24 hours and a profile consistent with 72-hour administration in most cases. The time to reach peak plasma concentration ranged from 18 hours to >66 hours in patients receiving the 25 µg/h patch. The pediatric clearance values were slightly higher than those of the adult population in a previously published study.8 There was a larger difference in the volume of distribution when pediatric and adult data were compared, and there was greater variability in the adult population. The clearance values in the pediatric population were inversely related to body weight. This suggests that the lower the body weight, the higher the fentanyl clearance, and consequently, the lower the fentanyl plasma concentrations.
DISCUSSION The World Health Organization’s “analgesic ladder” approach to cancer 322
pain, which recommends the selection of analgesics according to pain severity, is effective for children,9-11 as well as adults. If the oral route is not available, an alternative route is needed. In the pediatric population this need for a non-oral route of opioid administration may be greater because the usual indications (inability to swallow or absorb the opioid drug) are supplemented by poor compliance with oral regimens among the very young. Non-oral routes of opioid administration may be problematic in children. Long-term rectal dosing may not be tolerated or feasible. Repeated intramuscular or subcutaneous injections are unacceptable, the intravenous route is only possible if a venous access device is available, and continuous subcutaneous infusion may be unavailable or difficult to sustain. Transdermal administration may be a useful method of delivering an opioid to children. Although TTS-fentanyl is commonly available and widely used in adults, there have been no studies of the safety, efficacy, tolerability, or pharmacokinetics of this formulation in children. According to the protocol developed for this study, TTS-fentanyl was indicated primarily because the oral route was not tolerated or there would likely be improvement in the quality of life if the oral route were eliminated. Although the study sample was small,
treatment with TTS-fentanyl according to this protocol was demonstrated to be both feasible and well tolerated. The utility of the clinical protocol was suggested by the observation that most patients continued to use the preparation after the 2-dose study period. The analgesia reported was acceptable in most cases, and the global impression of the preparation by patients was very good to excellent. In this pediatric sample, clearance and volume of distribution were similar to published adult values.8 Although the variability in these parameters was less than in adults, interindividual variation in kinetics was still substantial. The predicted plasma profile at steady state was also similar to that of adults,12 demonstrating peak effects at about 24 hours and a slow decline from the peak concentration. This profile was consistent with 72-hour dosing in most cases. This small open-label survey suggests that the treatment of children with TTS-fentanyl is feasible and well tolerated and yields pharmacokinetic parameter estimates similar to those for adults. Practitioners should be aware that supplementary analgesia is often needed until steady state is reached at an effective dose and that many days may be required to identify this dose. Supplemental doses (“rescue doses”) may also be needed to treat breakthrough pain, even after the correct dose is found and steady state has been approached. A larger study is required to confirm these observations and further test the clinical protocol developed for this population. We thank Dr Henry Kilham, Head, Vincent Fairfax Pain Unit, New Children’s Hospital, Sydney, Australia, for his constructive criticism of the manuscript and Marilyn Herleth, Beth Israel Medical Center, New York, for her technical assistance.
REFERENCES 1. Sandler A. Transdermal fentanyl: acute analgesic clinical studies. J Pain Symptom Manage 1992;7:S27-35.
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THE JOURNAL OF PEDIATRICS VOLUME 134, NUMBER 3 2. Gourlay GK, Kowalski SR, Plummer JL, Cherry DA, Gaukroger P, Cousins MJ. The transdermal administration of fentanyl in the treatment of postoperative pain: pharmacokinetics and pharmacodynamic effects. Pain 1989;37:193-202. 3. Herbst LH, Strause LG. Transdermal fentanyl use in hospice home-care patients with chronic cancer pain. J Pain Symptom Manage 1992;7:S54-7. 4. Maves TJ, Barcellos WA. Management of cancer pain with transdermal fentanyl: phase IV trial, University of Iowa. J Pain Symptom Manage 1992; 7:S58-62. 5. Ahmedzai S, Brooks D. Transdermal fentanyl versus sustained-release oral morphine in cancer pain: preference, efficacy, and quality of life. The TTS-fen-
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tanyl Comparative Trial Group. J Pain Symptom Manage 1997;13:254-61. Payne R, Mathias SD, Pasta DJ, Wanke LA, Williams R, Mahmoud R. Quality of life and cancer pain: satisfaction and side effects with transdermal fentanyl versus oral morphine. J Clin Oncol 1998;16:1588-93. Gupta SK, Southam M, Gale R. System functionality and physiochemical model of fentanyl transdermal system. J Pain Symptom Manage 1992;7: S17-26. Gupta SK, Yih B, Bernstein K. Population analysis to evaluate dose proportionality of the transdermal fentanyl system. Clin Pharm Ther 1995;57:180. Berde C, Ablin A, Glazer J, Miser A, Shapiro B, Weisman S, et al. American Academy of Pediatrics Report of the
Subcommittee on Disease-Related Pain in Childhood Cancer. Pediatrics 1990;86:818-25. 10. Miser AW. Management of pain associated with childhood cancer. In: Schecter NL, Berde CB, Yaster M, editors. Pain in infants, children, and adolescents. Baltimore: Williams and Wilkins; 1993. p. 411-23. 11. McGrath PJ, Beyer J, Cleeland C, Eland J, McGrath PA, Portenoy RK. American Academy of Pediatrics Report of the Subcommittee on Assessment and Methodologic Issues in the Management of Pain in Childhood Cancer. Pediatrics 1990;86:814-7. 12. Portenoy RK, Southam MA, Gupta SK, Lapin J, Layman M, Inturissi CE, et al. Transdermal fentanyl for cancer pain. Anesthesiology 1993;78:36-43.
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