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Transdermal fentanyl in the management of cancer pain in ambulatory patients: An open-label pilot study
VOL 12 No. 4 octotul1996
234 Joumal of fain and Symptom Manogmv~t
Transdermal Fentanyl in the Management of Cancer Pain in Ambulatory Patients: An Open-Label Pilot Study Julie E. Hammack, MD, James A. Mailliard, MD, Charles 1.. Loprinzi, MD, Raylene M. Rospond, PharmD, Judith R. O’Fallon, PhD, Mary B. Wilwerding, RN, Nicholas E Reuter, MD, John C. Michalak, MD, Pat Fidler, RN, and Angela W. Miser, MB, BS Map Clinic and Mayo Foundafion (I.EH., C.L.L., J.RO.. A.WM.). Rochuln; Minnesoln; N&n&z Onw& GnwpCreigh~on Lkivmity (I.A.M.. RM.R, M.B.U!, PE), Uniwrsily OJ Nthtuba Medical Gnrcr and AssocialeJ. Clmaha, Ntbmsk; St. Cloud Clinic oJlnlerna1 Medicine, Lki. (NXR), St Cloud, Minnesotq and S-land Hrmalology-Oncology A.socu&s (ICM.), Sioux Cify, Icwc
We per/mmed on @edabel pilot study lo dejne andgaii e$icaq nm@abiliQ, and tmidy OJ tmwiermal J&nyl in an ambuhztory pop&lion of palienls with cam pain. our 7-day shdy inclldaki 35 polienl.s, all of whom had failed * hid o/an opioid anolgaic conveniirmolly used fm modmate pain. Patients reuiwd eifhtr a 25 pg/hr or 50 pg/hr Jmtanyl tmnrdermol patchd+nd.ingon/.nior+oiddose.Painwasmmsured daily utilizing visual analogue (VAS) and cxlepi& (CAT) scales. Houn of nighttime sleep, qualityof hjii toxicities, and useoJrescue mediufion were aLw ass-d There was a 24%29% duction in mean VAS and CAT pain SC- as compmad with the baseline and D 25 % increase in mean harm of nighitime dep. F&nine penenl of those patients m-g (46 96 o/all study fatients) were d.$ed to my sati$ed with the ana&& prwided 6,ltvm&ndfenhnyl sir perrent of ull study fxzlimb were no1 al all saliqied wi!h Ore pah relief obhind Te were similar to lhase sem wilh other opioids. No -path! dtdoped wuere saiahn or respiratmy depression. The 25-50 pg/hr patch appzan to .!w II safe starting dosagz b ambulatory pient.5 Qnvtously tidng qbioids wnuenrimeally urad f&r moab& ~“n J Pain Symptom Manage 1996;12:234-240.
Iiliad& Fentanyl, a synthetic cogener of meperidine first synthesized in 1960.’ has gained wideAddmu npriti rcqucsh to: Julie E. Hammark, Mayo Clinic, 200 First Stmet S.W.. Rochester. 55905. USA Acc$uedfor@licatim~ &t&w 25.1995. CBU.S. Cancer Pain Relief comminee. 19% Pnbbhd by Ebeier, New Yor&, New York
UD, 4r?I
spread acceptance as an anesthetic agenr and peri-nperative analgesic.’ Compared to morphine, it is more lipophilic and 50-100 times more potent on inuavenous administration. The half-life of intravenous fentanyl varies from 3 to 12 hr. It is Ndcalkylared in the liver to inactive metabolites and the majority of an administered dose is excreted i-1 the urine.
0%539!24/%/$15.00 PI1 !so%H924(%)oG131-1
Adverse effects from fentanyl are like other opioids: sedation, encephalopathy, respiratory depression, constipation, nausea: miosis, and hypotension. IL does not cause histamine release, and itching is an uncommon side effect With mpid inttavenous administration. acute muscular rigidity has been observed. Transdermal drug administration is a relatively new method of drug delivery.’ Nitroglycerin, clonidine, and scopolamine are among the agents currently delivered via the tmnsdermal route. Transdermal analgesic delivery is desirable in those cancer pain patients who are unable LO Lake otally administered opioids. Ease of administration and plasma drug levels that fluctuate less than during repetitive administration of short-acting drugs also may make thii an attractive \ysLem in cancer pain management Becwse of its high potency and lipophilicity, fentanyl was deemed a good first opioid for tnnsdermal delivery. The tmmdermal thcmpcu tic system (TX) for fentanyi (Alza Corporation. Palo Alto; NDA 19813) is a thii (0.2 mm) skin patch containing fentanyl in a sealed drug reservoir. The reservoir is sandwiched between an occlusive backing layer (faces away from the skin) and an adhesive controlled-telease membmnethatisopposedtotheskin.Tbesystemi designed to release a desired pg/hr fentanyl dose over a 72-br period (25 pg/hr per 10 cm’). The epidermis and dermis absob fentaoyl. A drug depot develops in the skin’s upper layen and then difhnes into the systemic circ&don. When administered tmnsdermally. fentanyl is only 2630 Limes more potent than morphinec6 owing Lo the relatively lower bioavailability of this route. 6erum fentanyl concentrations are not measurable until 2 hr after application, and peak concentration requires 8-16 hr. Steady stax swum concenttations are reached within 24 hr. and the npparent elimination half-life after patch removal is toughly 12-36 hr.” Clinical studies with uansdeL7nal fenanyl have primarily involved two slibscts of patic-nts: postopemiw patienLs’*7-‘o and patients wi h cancerrrw ~~I!-ls.l!l The cancer pain tidies pub lisbed Lo date have suggested that ~nmsdermal fencmyl is efficacious and safe, with a side effect profile similar to other commonly used opioid
analgesics. Infodon on the use of tmnsdermal fentanyl in a wider communi~y-bmed setting with prcxhxninantly ambukuory cmcer patients is lacking, however. To clarify this use, we designed an open-label pilot study Lo define better the efficacy, acceptability. starting dosage range, and toxicity of tmnsdermal fentanyl in this population of cmcer pain patients
Patients were accrued from four North Central Cancer Treatment Group (NCCTG) institutions. All patients were 18 years or older, had biopsy-proven malignancy and chronic pain directly related Lo malignant disease. Eligible patients had an ECOC performance score of 3 or better and a life expectancy of at least 30 days. All patients must have failed an “adequate trial” of an opioid drug conventionally used for moderate pain (that is, codeine, oxycodone. or propoxyphene). with or without a nonsteroidal antiinflammatory drug (NSAID). An adequate ti was defined as administration of at least four doses per 24 hr of the opioid for a minimum of 3 days, with the four doses being equivalent in analgesic potency LO at least 45 mg of oral morphine sulfate per 24 hr (for example, I50 mg of codeine or 25 mg of oxycodone per day). Parirnts who had been receiving mixed agonist-antagonist opioid medications were excluded from the study, as were patients who had used an opioid conventionally used for severe pain (for example, morphine, hydromorphone, meprridine, or methadone) within the week Preceding enrollment Patients with severe renal or hepatic rnsufiiciency, as defined by Seturn creatinine greater than two times upper limits of normal (ULN j. aspartatc amino trausfcrase (AS) greater than five times ULN, or total biliruhin greater than three times UNL.. and patients with cardiac, respiratory. dermatologic, or neurologic dysfunction that would. in the invcsigd:ors’ judgmenk increase risk trom the cpioids. were excluded from tbc study. Pregnant OF lactating women were excluded from the su~dy. as were women of childbearing age not taking active measures Lo avoid pregnancy.
236
Hammock et a.!
Patients were ineligible if, during the 21 days prior to enrollment. they had received radiation therapy to the painful site or had begun a new chemotherapy regimen. Patients were also ineligible if radiation or initiation of a new chemotherapy protocol was anticipated during the study, After patient eligibility was established, patients were required to record their use of analgesic medications during the preceding 24 hr, their average pain severity during the previous day [using a o-4 categorical scale (CAT) and visual analogue scale (VAS)]. their current pain severity, the average number of hours of sleep during the 2-5 nights prior to study cnset, current symptoms, and a qualityof-IiTe assessment. Each patient signed an informed consent form. Patients whose prior daily optoid dose was 45-134 mg/day of oral morphine equivalent milligrams were assigned to receive the 25 pg/hr fentanyl patch and those receiving greater titan 135 mg/day of oral morphine equivalent milligrams were assigned the 50 pg/hr patch (no patient was receiving more than 150 mg/day of oral morphine equivalent milligrams). Fentanyl patches were applied to the anterior chest wall. Excessive chest hair was clipped with scissors, but never shaved. The patch was not applied LO an area of skin that had been recently radiated. Each system was removed and safely discarded every 72 hr and another w placed on an ahernate skin site on the chest wall. Patients discontinued the scheduled opioid/nonopioid medication at the beginning of the study but were allowed to take morphine sulfate immediate release (MSIR) (IO-30 mg orally every 3-i hr) or an alternative short-acting opioid (hydromorphone). with or without an NSAID or acetaminophen as needed for pain relief. The use of multiple opioid medications conventionally used for severe pain or the combination of opioids used conventionally for both moderate and severe pain as rescues wu not allowed. For 7 days after study entry, patients were asked LO complete daily questionnaires at roughly tbe same time each day to indicate paio severity over the preceding 24 hr. hours of sleep at night+ adverse symptoms and their se~edty. and rescue analgesic intake. A deep ing respiratory rate was obtained by the patient’s helper for the lint 3 nights of the
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study and recorded on the questionnaire. The level of pain was measured using both a CAT (O=none. l=mild, 2=moderate. S=severe. and 4=very severe) and a VAS (“no pain” on the left end of the line and “worst pain imaginable” on the right end). For each VAS completed by the patient, a VAS pain score was catrnlated by dividing the distance from the left of the VA!3 line LO the patient’s mark by the total length of the VAS line, and multiplying this fraction by 100 VA!3 pain scores of 0 and 100 correspond to “no pain” and “the worst pain imaginable,” respectively. After the 7 study days. quality of life and overall satisfaction with the system treatment v+as assessed. Quality of life was assessed utilizing a VAS with “lowest quality” at the left end corresponding to “complete physical dependence on others, seriously troubled mentally, unaware of surroundings and in a hopeless position.” “Highest quality.” at the right end of tbe VAS line corresponded to “physically and mentally independent, communicating well with others. able LO do most of the things enjoyed, pulling own weight, with a hopeful yet realistic attitude.” Overall satisfaction was msessed using a CAT (t&4) with 0 and 4 corresponding LO ‘*not at all satisfied” and “completely satisfied.” respectively. Patients were contacted by telephone every I-5 days during the 7-day study (pilot phase) LO assess pain control, toxicities, and questionnaire compliance. Patients were removed from the study and the fentanyl patch discontinued if unmanageable side effects occurred, if sufficient analgesia could not be achieved with the administered fentanyl and rescue medications as oudined. or if they received radiation. surgery, or new chemotherapy during the study period. Similarly, the receipt of an alternative opioid for severe pain or new adjtnant medication, anesthetic pain procedure (that is, nerve block), or neuroablative procedure was cause for removal from tbe study. Antiemetics, laxatives, and antibiotics were allowed and administered as clhticaffy indicated. AL the end of the study week, patients were allowed to register for a continuation phase LO receive transdermal fentanyf for an indefinite duration provided that they continued to experience pain directly resulting from active malignancy. The dose of fentanyl was titrated to control the patient’s pain. Patients were
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required to complete weekly questionnaires assess drug efficacy and toxicity.
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Between October 1991 and July 1992. 35 patients from four institutions in the NCCTG enlered the trial. The 35 patients tanged in age from 43 LO 81 years. with a median age of f54 yean. 3eventeen (49%) were women. All but two were Caucasian. The underlying malignancies and cancer pain diagnoses are listed in Tables 1 and 2. Four (11%) patients received a fentanyl dose of 50 pg/hr and the remaining 31 (89%) received 25 )rg/hr. Of the 35 patients on tie pi101 study, Ike were inevaiuabie. One (3%) did not respond to any questionnaires and four ( 1 I %) patients repotted only baseline data. One of these five patients died from his underlying disease during tbe ‘I-day study period; another developed . . cogmtne impairment not attributable to fenmnyl. One patient changed physicians and one patient did not complete the forms but went on the cxrtinuation study. No reason was given for the remaining patient going off study. Au five of these patients were assigned the 25 pg/hr dose of fentanyi. An additional five patients stopped using fentanyi during tbe 7day pilo~ study bui were still evahrable as they had completed the baseline and some of tie subsequenl questionnaires; all but one were assigned tbe 25 pg/hr dose of fencanyi. Two of these patients died from their cancers (one of whom was assigned the 50 pg/br dose of fentanyl). One developed severe constipation (presumably opioid-related). One patient
stopped the drug secondary LO inadequate analgesia and another patiem developed conbrsion and hallucinations. which were atuib uted to the fenumyl. Figure 1 presents the mean daily VAS pain scores across all 30 mahable patients b day (day 0, baseline). me mean VA.3 pain scores over the last 24 hr at baseline and a~ day 8 (end of study) were 56 and 41. reslxuively. Tine mnean CAT pain scores at baselire and rt the end of the study were 2.3 and 1.6, respectively. These data suggest that fenmnyl *as associated wilh a 24%-29% mean reductkn in the levels of pain compared to baseline. The pauern of rescue medication use during t K study is sbmm in Figure 2 and mean houn of nighttime sleep over the study period 2 ‘e shown in Figure 3. Fig. 2. Mean daily daschyby fug,'44 immediaterekare oral morphine or quivaknr). 5
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Patients were asked to t-ate their satisfaction with pain relief from transdermal fentanyl. Two (6%) were “not at all satisfied,” 9 (26%) were “somewhat satisfied.” 16 (46%) were “satisfied” to “completely satisfied.” Eight (23%) did not respond to the question.
Toxicity Only two patients discontinued drug during the May study secondary to fenumyl toxicity (see above), one due to constipation and another due to hallucinations. Both patients were receiving the 25 pg/hr dosage of fentanyl. In addition, two patients reported respiratory rates less ti I2 per minute but greater than 8 per minute. NC patient developed severe sedation (grade 3 or 4). The sedation and reduction in respiratory rate did not necessitate diiontinuation of the drug in any patient Seventeen percent of the 89 evaluable patients experienced moderate to severe hallucinations. Skin toxicity (erythema, papules, itching) was mild and acceptable in both the pilot and continuation phases of the study. In the 25 pg/hr group, two patients reported mild itching, one reported mild erythema. oae reported mild papules/ pustules, and one reported papules/pustules on greater than 50% of the skin occluded by the patch. In the 50 pg/hr group, one patient repted eryhema on greater than 59% of the ccchKled area. Patients receiving the 50 pg/hr dosage of fentanyl had significantly higher grades of constipation than those receiving 25 pg/hr (P < 0.008). Because patients were deterministiCaky assigned to the dose levels based on their prior analgesic regimen, however, other fac-
Canslipation misring none mild mcxAentc vy(‘re Dizzilwsr missing none mild moderate severe Hallucinarions mirring none mild modcme se”crc Impaired lhinking mixsing none mild modcraw sa2wre Nauua mAng none mild moderate *evere Swealing mikng “0°C mild modcratc severe
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ton besides fentanyl dose could account this difference. Other reported toxicities their seve!-ities are listed in Table 3.
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Twenty-five patients (71%) entered the continuation phase of the study. Twenty-two of these patients were originally at the 25 pg/hr fentanyl dose and three were originally at the 50 pg/hr dose. Patients stayed in the continuation phase of the study for a median of 48 days (range, 7-295 days) after the end of the pilot study. The dosages in the continuation phase ranged from 25 pg.‘h to 206 pg/hr (median, 75 g/hr). Dose titration was at the discretion of the treating physician. Toxicities during the continuation phase were similar to those found during the pilot. Constipation. nausea, and vomiting continued to be the
VoL 12 No. 4 Octc&-r 19%
i’?a-
Fentanyl JOT Cancer Pain Man-
commonest advctsc effects. Two patients discontinued fentanyl during the continuation phase due to perceived drug toxicity, specifically sedation and “impaired thinking.” Other reasons given for going off study included .leath from underlying disease (nine patients), rapidly escalating pain necessitating opioid infusions (five patients), inability to afford the patches (six patients), and radiation therapy or planned surgery (three patients). Pain severity, quality-of-life measurements, and hours of sleep did not change significantly during the continuation phase of the study. The mean VAS at day 49 was 46.
We studied the efficacy and side elfect profile of nansdermal fentanyl in an ambulatory population of cancer pain patients pt~dously receiving only an opioid conventionalIy used for moderate pain. The underlying malignancies in our patients were those commonly associated with cancer-related pain and their pain di ,,FPwere typical for this group of patients. Ttansdennal fentanyl was well tolerated in our patients. Toxicities were similar to those seen with other opioid medications. Significant toxicities induded nausea, which was moderate to severe in 45% of patients, and constipation, which was moderate to severe in 6S%. It is suspetted that some of the reported nausea may have resulted from the patients’ underlying dis ease and not as a side effect of fentanyl per se. Notably, nausea has been reported in as many as 50% of advanced cancer patients receiving a placeLmiR Furthermore, the patients’ opioid rescue medications could have been responsible for some of these toxicities Stool softeners were not a requirement at the start of our study and were used only at the discretion of the patients’ physicians. As with other opioids. prevention of constipation may be optimized by starting a stool softener or other laxative coincident with fentanyl. One study has suggested that transdermal fentanyl may produce less constipation than morphine.‘” In the pilot phase, 59% (I6 patients) of those responding were satisfied to very satis fled with the analgesia and side effect profile of transdermal fentanyl. Mean VA!I pain scores for the group decreased from 56 to 41 over the 7day study period, and patients experi-
239
enced pain reductions of 24%~29% compared to baseline. Mean hours of sleep increased from 5.5 hr to 7 hr during the study, constituting a 25% increase in the mean houn of sleep. Improvement in pain and sleep could not be attributed solely to increased use of rescue medications. After the second day on study, the average use of rescue medications decreased. Because steady state blood levels of fentanyl may take 17-24 hr to be achieved after tt-ansdermal application, the apparent increase in rescue medication use m the first 2 days of the study likely represents the lag time in achieving analgesic serum levels with transdermal fentanyl. Even during this transition period, the total average &uy oral opioid used was less than that used on the day prior to commencing the study. In summary, we found that transdermal fentanyl appeared to be useful and safe in a general population of cancer pain patielus previously receiving an opioid for moderate pain. The 25-50 pg/h! patch appears to be a safe starting dosage in these patients, but I:kely will require upward titration to obtain optimal analgesia in most patients. Data from the continuation phase of this study confirms longterm analgesia and acceptable toxicity of transdermal fentanyl in our patients. Transdcrmal fentanyl is more expensive than other commonly used opioids with a similar side effect profile. Transdermal fentanyl may, however, be a useful alternative in patients unable to tolerate oral medications or as a second-line or third-line agent in those with unmanageable adverse elIects from other high-potency opioids.
This study was conducted as a collaborative trial of North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service grants CA-25224, CA-37464, CA-15083, CA-35103, and CA-52352 from the National Cancer Institute, Department of Health and Human Services. Additional participating institutions include: Cedar Rapids Oncology Project CCOP, Cedar Rapids, L4 52463 (Martin Wiesenfeld. MD) and Rapid City Regional Oncology Group, Rapid City, SD 59709 (Larry P. Ebbert, MD)
240
w
HeV
1. Jawen PAJ. A review of the chemical features awxiated with strong morphine-hke activity. Br J Anaesth 1962;34260. 2 Bailey PL, Stanley TH. Nvcotic ;ntrawnous anesthetics. In: Miller RD. cd. Anesthesia. New York: Churchill Livingstone. 1990~281-366. 3. Wcster RC, Maiih HI. Cutaneous phamac* khcticJ: 10 steps to perc”ta”cous atmrplion. Drug Metab Rev 198$14:16%205. 4. Gxuiay CR, Rowakki !%R, PlummerJl et al. The efficacy of tmnsdermal fenenyl in the treatment of postoperative pain: a doubleblind comparison of fentanyl and placebo systems. Pain 1990; 40~21-28. 5. Varvcl JR, Shafer SL. Hwang SS. et al. Absorp lion characteristics of transdermally administered fectanyl. Anesth,siology 1992;70:928-934. 6. Lehman” KA. Zech D. Transdermal clinic&l pharmacology. J Pain Symptom 199!2;7(wppl 3):!X-S16.
fentanyl: Manage
7. PI&a PM, Linford J, Rramer TH. et al. Transdermal therapeutic -em (fentanyl) for postoperative pain: an efficacy, toxicity, and pharmacokinetic trial. Anesthesiology 1986$5A210. 8. Halley FO. Van Steennis C. Transdermal administration of fentanyl for postopetatiw analgesia. Anesthesiology 1986;65A548. 9. Caplan P& Ready LB, Obson CL. et al. Transdermal delivery of fentanyl for postoperative pain control. Anesthesiology 1986$5Al96.
10. Nimmo WS. Duthie DJR Plasma fentanyl concentrations after tnnsdermal or N infusion of fentanyl. Anesthesiology 1986;65:A559. 11. Simmons MA. Payne R. Richenbacher J. et al. TTS (fentanyl) in the management of pain in patients with cancer. Pm Am Sw Clin Oncology 1989;8:234. 12. Slowr R. Tnnsdermal fentanyl: clinic al trial at the University of Colorado Health Scienws Center. J Pain Symptom Manage 1992;7(suppl 5):X5-$47. 13. Maws TJ. Barcellos WA. Managemen* of cancer pain with transdermal fentanyl: phase N trial, University of Iowa. J. Pain Symptom Manage 1992: 7(suppl 3):S58-S62. 14. Miser AW, Narang PK. Dothage 5.4. et al. Ttans dcrmal fentanyl for pain control in patients with cancer. Fain 1992;37:15-21. 15. Zrch D, Crond S. Lynch J. et al. Transdermal fentayl and initial dose&ding with patientsxonuollcd analgesia in cancer pain. Pain 1992;5029%302. 16. Portertoy RK Cancer pain: epidemiology syndromes. Cancer 1989$X2298-2507.
and
17. Payne R. Cancer pain: anatomy, ph+&qy, pharmacology. Cancer l-63:22662274.
and
18. ffirdinal CC. Loptinzi CL, Schaid DJ. et al. A controlled trial of cyproheptadine in cancer patients with anorexia and/or cachexia. Cancer 1990;65:2657-2662. 19. Ahmedzai S, Alkn E. Fallon M, et al. Transdermal fentanyi in cancer pain. J Drug Llev 1994;6:93-97.
234 Joumal of fain and Symptom Manogmv~t
Transdermal Fentanyl in the Management of Cancer Pain in Ambulatory Patients: An Open-Label Pilot Study Julie E. Hammack, MD, James A. Mailliard, MD, Charles 1.. Loprinzi, MD, Raylene M. Rospond, PharmD, Judith R. O’Fallon, PhD, Mary B. Wilwerding, RN, Nicholas E Reuter, MD, John C. Michalak, MD, Pat Fidler, RN, and Angela W. Miser, MB, BS Map Clinic and Mayo Foundafion (I.EH., C.L.L., J.RO.. A.WM.). Rochuln; Minnesoln; N&n&z Onw& GnwpCreigh~on Lkivmity (I.A.M.. RM.R, M.B.U!, PE), Uniwrsily OJ Nthtuba Medical Gnrcr and AssocialeJ. Clmaha, Ntbmsk; St. Cloud Clinic oJlnlerna1 Medicine, Lki. (NXR), St Cloud, Minnesotq and S-land Hrmalology-Oncology A.socu&s (ICM.), Sioux Cify, Icwc
We per/mmed on @edabel pilot study lo dejne andgaii e$icaq nm@abiliQ, and tmidy OJ tmwiermal J&nyl in an ambuhztory pop&lion of palienls with cam pain. our 7-day shdy inclldaki 35 polienl.s, all of whom had failed * hid o/an opioid anolgaic conveniirmolly used fm modmate pain. Patients reuiwd eifhtr a 25 pg/hr or 50 pg/hr Jmtanyl tmnrdermol patchd+nd.ingon/.nior+oiddose.Painwasmmsured daily utilizing visual analogue (VAS) and cxlepi& (CAT) scales. Houn of nighttime sleep, qualityof hjii toxicities, and useoJrescue mediufion were aLw ass-d There was a 24%29% duction in mean VAS and CAT pain SC- as compmad with the baseline and D 25 % increase in mean harm of nighitime dep. F&nine penenl of those patients m-g (46 96 o/all study fatients) were d.$ed to my sati$ed with the ana&& prwided 6,ltvm&ndfenhnyl sir perrent of ull study fxzlimb were no1 al all saliqied wi!h Ore pah relief obhind Te were similar to lhase sem wilh other opioids. No -path! dtdoped wuere saiahn or respiratmy depression. The 25-50 pg/hr patch appzan to .!w II safe starting dosagz b ambulatory pient.5 Qnvtously tidng qbioids wnuenrimeally urad f&r moab& ~“n J Pain Symptom Manage 1996;12:234-240.
Iiliad& Fentanyl, a synthetic cogener of meperidine first synthesized in 1960.’ has gained wideAddmu npriti rcqucsh to: Julie E. Hammark, Mayo Clinic, 200 First Stmet S.W.. Rochester. 55905. USA Acc$uedfor@licatim~ &t&w 25.1995. CBU.S. Cancer Pain Relief comminee. 19% Pnbbhd by Ebeier, New Yor&, New York
UD, 4r?I
spread acceptance as an anesthetic agenr and peri-nperative analgesic.’ Compared to morphine, it is more lipophilic and 50-100 times more potent on inuavenous administration. The half-life of intravenous fentanyl varies from 3 to 12 hr. It is Ndcalkylared in the liver to inactive metabolites and the majority of an administered dose is excreted i-1 the urine.
0%539!24/%/$15.00 PI1 !so%H924(%)oG131-1
Adverse effects from fentanyl are like other opioids: sedation, encephalopathy, respiratory depression, constipation, nausea: miosis, and hypotension. IL does not cause histamine release, and itching is an uncommon side effect With mpid inttavenous administration. acute muscular rigidity has been observed. Transdermal drug administration is a relatively new method of drug delivery.’ Nitroglycerin, clonidine, and scopolamine are among the agents currently delivered via the tmnsdermal route. Transdermal analgesic delivery is desirable in those cancer pain patients who are unable LO Lake otally administered opioids. Ease of administration and plasma drug levels that fluctuate less than during repetitive administration of short-acting drugs also may make thii an attractive \ysLem in cancer pain management Becwse of its high potency and lipophilicity, fentanyl was deemed a good first opioid for tnnsdermal delivery. The tmmdermal thcmpcu tic system (TX) for fentanyi (Alza Corporation. Palo Alto; NDA 19813) is a thii (0.2 mm) skin patch containing fentanyl in a sealed drug reservoir. The reservoir is sandwiched between an occlusive backing layer (faces away from the skin) and an adhesive controlled-telease membmnethatisopposedtotheskin.Tbesystemi designed to release a desired pg/hr fentanyl dose over a 72-br period (25 pg/hr per 10 cm’). The epidermis and dermis absob fentaoyl. A drug depot develops in the skin’s upper layen and then difhnes into the systemic circ&don. When administered tmnsdermally. fentanyl is only 2630 Limes more potent than morphinec6 owing Lo the relatively lower bioavailability of this route. 6erum fentanyl concentrations are not measurable until 2 hr after application, and peak concentration requires 8-16 hr. Steady stax swum concenttations are reached within 24 hr. and the npparent elimination half-life after patch removal is toughly 12-36 hr.” Clinical studies with uansdeL7nal fenanyl have primarily involved two slibscts of patic-nts: postopemiw patienLs’*7-‘o and patients wi h cancerrrw ~~I!-ls.l!l The cancer pain tidies pub lisbed Lo date have suggested that ~nmsdermal fencmyl is efficacious and safe, with a side effect profile similar to other commonly used opioid
analgesics. Infodon on the use of tmnsdermal fentanyl in a wider communi~y-bmed setting with prcxhxninantly ambukuory cmcer patients is lacking, however. To clarify this use, we designed an open-label pilot study Lo define better the efficacy, acceptability. starting dosage range, and toxicity of tmnsdermal fentanyl in this population of cmcer pain patients
Patients were accrued from four North Central Cancer Treatment Group (NCCTG) institutions. All patients were 18 years or older, had biopsy-proven malignancy and chronic pain directly related Lo malignant disease. Eligible patients had an ECOC performance score of 3 or better and a life expectancy of at least 30 days. All patients must have failed an “adequate trial” of an opioid drug conventionally used for moderate pain (that is, codeine, oxycodone. or propoxyphene). with or without a nonsteroidal antiinflammatory drug (NSAID). An adequate ti was defined as administration of at least four doses per 24 hr of the opioid for a minimum of 3 days, with the four doses being equivalent in analgesic potency LO at least 45 mg of oral morphine sulfate per 24 hr (for example, I50 mg of codeine or 25 mg of oxycodone per day). Parirnts who had been receiving mixed agonist-antagonist opioid medications were excluded from the study, as were patients who had used an opioid conventionally used for severe pain (for example, morphine, hydromorphone, meprridine, or methadone) within the week Preceding enrollment Patients with severe renal or hepatic rnsufiiciency, as defined by Seturn creatinine greater than two times upper limits of normal (ULN j. aspartatc amino trausfcrase (AS) greater than five times ULN, or total biliruhin greater than three times UNL.. and patients with cardiac, respiratory. dermatologic, or neurologic dysfunction that would. in the invcsigd:ors’ judgmenk increase risk trom the cpioids. were excluded from tbc study. Pregnant OF lactating women were excluded from the su~dy. as were women of childbearing age not taking active measures Lo avoid pregnancy.
236
Hammock et a.!
Patients were ineligible if, during the 21 days prior to enrollment. they had received radiation therapy to the painful site or had begun a new chemotherapy regimen. Patients were also ineligible if radiation or initiation of a new chemotherapy protocol was anticipated during the study, After patient eligibility was established, patients were required to record their use of analgesic medications during the preceding 24 hr, their average pain severity during the previous day [using a o-4 categorical scale (CAT) and visual analogue scale (VAS)]. their current pain severity, the average number of hours of sleep during the 2-5 nights prior to study cnset, current symptoms, and a qualityof-IiTe assessment. Each patient signed an informed consent form. Patients whose prior daily optoid dose was 45-134 mg/day of oral morphine equivalent milligrams were assigned to receive the 25 pg/hr fentanyl patch and those receiving greater titan 135 mg/day of oral morphine equivalent milligrams were assigned the 50 pg/hr patch (no patient was receiving more than 150 mg/day of oral morphine equivalent milligrams). Fentanyl patches were applied to the anterior chest wall. Excessive chest hair was clipped with scissors, but never shaved. The patch was not applied LO an area of skin that had been recently radiated. Each system was removed and safely discarded every 72 hr and another w placed on an ahernate skin site on the chest wall. Patients discontinued the scheduled opioid/nonopioid medication at the beginning of the study but were allowed to take morphine sulfate immediate release (MSIR) (IO-30 mg orally every 3-i hr) or an alternative short-acting opioid (hydromorphone). with or without an NSAID or acetaminophen as needed for pain relief. The use of multiple opioid medications conventionally used for severe pain or the combination of opioids used conventionally for both moderate and severe pain as rescues wu not allowed. For 7 days after study entry, patients were asked LO complete daily questionnaires at roughly tbe same time each day to indicate paio severity over the preceding 24 hr. hours of sleep at night+ adverse symptoms and their se~edty. and rescue analgesic intake. A deep ing respiratory rate was obtained by the patient’s helper for the lint 3 nights of the
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study and recorded on the questionnaire. The level of pain was measured using both a CAT (O=none. l=mild, 2=moderate. S=severe. and 4=very severe) and a VAS (“no pain” on the left end of the line and “worst pain imaginable” on the right end). For each VAS completed by the patient, a VAS pain score was catrnlated by dividing the distance from the left of the VA!3 line LO the patient’s mark by the total length of the VAS line, and multiplying this fraction by 100 VA!3 pain scores of 0 and 100 correspond to “no pain” and “the worst pain imaginable,” respectively. After the 7 study days. quality of life and overall satisfaction with the system treatment v+as assessed. Quality of life was assessed utilizing a VAS with “lowest quality” at the left end corresponding to “complete physical dependence on others, seriously troubled mentally, unaware of surroundings and in a hopeless position.” “Highest quality.” at the right end of tbe VAS line corresponded to “physically and mentally independent, communicating well with others. able LO do most of the things enjoyed, pulling own weight, with a hopeful yet realistic attitude.” Overall satisfaction was msessed using a CAT (t&4) with 0 and 4 corresponding LO ‘*not at all satisfied” and “completely satisfied.” respectively. Patients were contacted by telephone every I-5 days during the 7-day study (pilot phase) LO assess pain control, toxicities, and questionnaire compliance. Patients were removed from the study and the fentanyl patch discontinued if unmanageable side effects occurred, if sufficient analgesia could not be achieved with the administered fentanyl and rescue medications as oudined. or if they received radiation. surgery, or new chemotherapy during the study period. Similarly, the receipt of an alternative opioid for severe pain or new adjtnant medication, anesthetic pain procedure (that is, nerve block), or neuroablative procedure was cause for removal from tbe study. Antiemetics, laxatives, and antibiotics were allowed and administered as clhticaffy indicated. AL the end of the study week, patients were allowed to register for a continuation phase LO receive transdermal fentanyf for an indefinite duration provided that they continued to experience pain directly resulting from active malignancy. The dose of fentanyl was titrated to control the patient’s pain. Patients were
Breast Lung Gauroiirnlinal My&ma Other
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required to complete weekly questionnaires assess drug efficacy and toxicity.
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Between October 1991 and July 1992. 35 patients from four institutions in the NCCTG enlered the trial. The 35 patients tanged in age from 43 LO 81 years. with a median age of f54 yean. 3eventeen (49%) were women. All but two were Caucasian. The underlying malignancies and cancer pain diagnoses are listed in Tables 1 and 2. Four (11%) patients received a fentanyl dose of 50 pg/hr and the remaining 31 (89%) received 25 )rg/hr. Of the 35 patients on tie pi101 study, Ike were inevaiuabie. One (3%) did not respond to any questionnaires and four ( 1 I %) patients repotted only baseline data. One of these five patients died from his underlying disease during tbe ‘I-day study period; another developed . . cogmtne impairment not attributable to fenmnyl. One patient changed physicians and one patient did not complete the forms but went on the cxrtinuation study. No reason was given for the remaining patient going off study. Au five of these patients were assigned the 25 pg/hr dose of fentanyi. An additional five patients stopped using fentanyi during tbe 7day pilo~ study bui were still evahrable as they had completed the baseline and some of tie subsequenl questionnaires; all but one were assigned tbe 25 pg/hr dose of fencanyi. Two of these patients died from their cancers (one of whom was assigned the 50 pg/br dose of fentanyl). One developed severe constipation (presumably opioid-related). One patient
stopped the drug secondary LO inadequate analgesia and another patiem developed conbrsion and hallucinations. which were atuib uted to the fenumyl. Figure 1 presents the mean daily VAS pain scores across all 30 mahable patients b day (day 0, baseline). me mean VA.3 pain scores over the last 24 hr at baseline and a~ day 8 (end of study) were 56 and 41. reslxuively. Tine mnean CAT pain scores at baselire and rt the end of the study were 2.3 and 1.6, respectively. These data suggest that fenmnyl *as associated wilh a 24%-29% mean reductkn in the levels of pain compared to baseline. The pauern of rescue medication use during t K study is sbmm in Figure 2 and mean houn of nighttime sleep over the study period 2 ‘e shown in Figure 3. Fig. 2. Mean daily daschyby fug,'44 immediaterekare oral morphine or quivaknr). 5
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238
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Patients were asked to t-ate their satisfaction with pain relief from transdermal fentanyl. Two (6%) were “not at all satisfied,” 9 (26%) were “somewhat satisfied.” 16 (46%) were “satisfied” to “completely satisfied.” Eight (23%) did not respond to the question.
Toxicity Only two patients discontinued drug during the May study secondary to fenumyl toxicity (see above), one due to constipation and another due to hallucinations. Both patients were receiving the 25 pg/hr dosage of fentanyl. In addition, two patients reported respiratory rates less ti I2 per minute but greater than 8 per minute. NC patient developed severe sedation (grade 3 or 4). The sedation and reduction in respiratory rate did not necessitate diiontinuation of the drug in any patient Seventeen percent of the 89 evaluable patients experienced moderate to severe hallucinations. Skin toxicity (erythema, papules, itching) was mild and acceptable in both the pilot and continuation phases of the study. In the 25 pg/hr group, two patients reported mild itching, one reported mild erythema. oae reported mild papules/ pustules, and one reported papules/pustules on greater than 50% of the skin occluded by the patch. In the 50 pg/hr group, one patient repted eryhema on greater than 59% of the ccchKled area. Patients receiving the 50 pg/hr dosage of fentanyl had significantly higher grades of constipation than those receiving 25 pg/hr (P < 0.008). Because patients were deterministiCaky assigned to the dose levels based on their prior analgesic regimen, however, other fac-
Canslipation misring none mild mcxAentc vy(‘re Dizzilwsr missing none mild moderate severe Hallucinarions mirring none mild modcme se”crc Impaired lhinking mixsing none mild modcraw sa2wre Nauua mAng none mild moderate *evere Swealing mikng “0°C mild modcratc severe
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: I
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ton besides fentanyl dose could account this difference. Other reported toxicities their seve!-ities are listed in Table 3.
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Phase
Twenty-five patients (71%) entered the continuation phase of the study. Twenty-two of these patients were originally at the 25 pg/hr fentanyl dose and three were originally at the 50 pg/hr dose. Patients stayed in the continuation phase of the study for a median of 48 days (range, 7-295 days) after the end of the pilot study. The dosages in the continuation phase ranged from 25 pg.‘h to 206 pg/hr (median, 75 g/hr). Dose titration was at the discretion of the treating physician. Toxicities during the continuation phase were similar to those found during the pilot. Constipation. nausea, and vomiting continued to be the
VoL 12 No. 4 Octc&-r 19%
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Fentanyl JOT Cancer Pain Man-
commonest advctsc effects. Two patients discontinued fentanyl during the continuation phase due to perceived drug toxicity, specifically sedation and “impaired thinking.” Other reasons given for going off study included .leath from underlying disease (nine patients), rapidly escalating pain necessitating opioid infusions (five patients), inability to afford the patches (six patients), and radiation therapy or planned surgery (three patients). Pain severity, quality-of-life measurements, and hours of sleep did not change significantly during the continuation phase of the study. The mean VAS at day 49 was 46.
We studied the efficacy and side elfect profile of nansdermal fentanyl in an ambulatory population of cancer pain patients pt~dously receiving only an opioid conventionalIy used for moderate pain. The underlying malignancies in our patients were those commonly associated with cancer-related pain and their pain di ,,FPwere typical for this group of patients. Ttansdennal fentanyl was well tolerated in our patients. Toxicities were similar to those seen with other opioid medications. Significant toxicities induded nausea, which was moderate to severe in 45% of patients, and constipation, which was moderate to severe in 6S%. It is suspetted that some of the reported nausea may have resulted from the patients’ underlying dis ease and not as a side effect of fentanyl per se. Notably, nausea has been reported in as many as 50% of advanced cancer patients receiving a placeLmiR Furthermore, the patients’ opioid rescue medications could have been responsible for some of these toxicities Stool softeners were not a requirement at the start of our study and were used only at the discretion of the patients’ physicians. As with other opioids. prevention of constipation may be optimized by starting a stool softener or other laxative coincident with fentanyl. One study has suggested that transdermal fentanyl may produce less constipation than morphine.‘” In the pilot phase, 59% (I6 patients) of those responding were satisfied to very satis fled with the analgesia and side effect profile of transdermal fentanyl. Mean VA!I pain scores for the group decreased from 56 to 41 over the 7day study period, and patients experi-
239
enced pain reductions of 24%~29% compared to baseline. Mean hours of sleep increased from 5.5 hr to 7 hr during the study, constituting a 25% increase in the mean houn of sleep. Improvement in pain and sleep could not be attributed solely to increased use of rescue medications. After the second day on study, the average use of rescue medications decreased. Because steady state blood levels of fentanyl may take 17-24 hr to be achieved after tt-ansdermal application, the apparent increase in rescue medication use m the first 2 days of the study likely represents the lag time in achieving analgesic serum levels with transdermal fentanyl. Even during this transition period, the total average &uy oral opioid used was less than that used on the day prior to commencing the study. In summary, we found that transdermal fentanyl appeared to be useful and safe in a general population of cancer pain patielus previously receiving an opioid for moderate pain. The 25-50 pg/h! patch appears to be a safe starting dosage in these patients, but I:kely will require upward titration to obtain optimal analgesia in most patients. Data from the continuation phase of this study confirms longterm analgesia and acceptable toxicity of transdermal fentanyl in our patients. Transdcrmal fentanyl is more expensive than other commonly used opioids with a similar side effect profile. Transdermal fentanyl may, however, be a useful alternative in patients unable to tolerate oral medications or as a second-line or third-line agent in those with unmanageable adverse elIects from other high-potency opioids.
This study was conducted as a collaborative trial of North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service grants CA-25224, CA-37464, CA-15083, CA-35103, and CA-52352 from the National Cancer Institute, Department of Health and Human Services. Additional participating institutions include: Cedar Rapids Oncology Project CCOP, Cedar Rapids, L4 52463 (Martin Wiesenfeld. MD) and Rapid City Regional Oncology Group, Rapid City, SD 59709 (Larry P. Ebbert, MD)
240
w
HeV
1. Jawen PAJ. A review of the chemical features awxiated with strong morphine-hke activity. Br J Anaesth 1962;34260. 2 Bailey PL, Stanley TH. Nvcotic ;ntrawnous anesthetics. In: Miller RD. cd. Anesthesia. New York: Churchill Livingstone. 1990~281-366. 3. Wcster RC, Maiih HI. Cutaneous phamac* khcticJ: 10 steps to perc”ta”cous atmrplion. Drug Metab Rev 198$14:16%205. 4. Gxuiay CR, Rowakki !%R, PlummerJl et al. The efficacy of tmnsdermal fenenyl in the treatment of postoperative pain: a doubleblind comparison of fentanyl and placebo systems. Pain 1990; 40~21-28. 5. Varvcl JR, Shafer SL. Hwang SS. et al. Absorp lion characteristics of transdermally administered fectanyl. Anesth,siology 1992;70:928-934. 6. Lehman” KA. Zech D. Transdermal clinic&l pharmacology. J Pain Symptom 199!2;7(wppl 3):!X-S16.
fentanyl: Manage
7. PI&a PM, Linford J, Rramer TH. et al. Transdermal therapeutic -em (fentanyl) for postoperative pain: an efficacy, toxicity, and pharmacokinetic trial. Anesthesiology 1986$5A210. 8. Halley FO. Van Steennis C. Transdermal administration of fentanyl for postopetatiw analgesia. Anesthesiology 1986;65A548. 9. Caplan P& Ready LB, Obson CL. et al. Transdermal delivery of fentanyl for postoperative pain control. Anesthesiology 1986$5Al96.
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and
17. Payne R. Cancer pain: anatomy, ph+&qy, pharmacology. Cancer l-63:22662274.
and
18. ffirdinal CC. Loptinzi CL, Schaid DJ. et al. A controlled trial of cyproheptadine in cancer patients with anorexia and/or cachexia. Cancer 1990;65:2657-2662. 19. Ahmedzai S, Alkn E. Fallon M, et al. Transdermal fentanyi in cancer pain. J Drug Llev 1994;6:93-97.