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Transdermal fentanyl for chronic cancer pain: Detailed case reports and the influence of confounding factors
vol. ?JVO.3 (Suy.@.) April 1992
journal of Pain and SymptomManagement S51
Richard B. Patt, hEI, and Laura A. Hogan, RM UniversiQ ofRochester SchoolofMediGine and De&k&y, Pain Treatment Center,Rochester,.iQw T&-k
Abstract P&t-s wereenteredintoan open label s&y to evaluate the ejicag of transdernzalfentanylas an analgesic for chroniccancer pain. The clinical courseof 3p~tient-s is de&bed as well as an emphasis on the apparent &&rue of confoundingfmtors, i.e., factors unique to each patient that appeared to aflect that individual’s a+za&esicrequireme&. Qur anecdotal c&&a! experiencewe.& &cacious, and safe means ofp~aco@ic
that ~~~alf~~uy~
k an acceptable,
managementforpatients wikh chroniccancer pain. Our results
reinforcethe concept that cancerpa;l is a dynamic, multiply &&mined process and that, as a result, the #ect.s
ofa sing,&?interventionare d#icalt
to a&yze. J Pain Symptom Manage 1992;?:S51-S53.
Advanced cancerpain, fmtanyl, ana&+x, transdennal delivg, assessment
Patients were entered into an open-label study to evaluate the efficacy of transdermal fentanyl as an analgesic for chronic cancer pain. The clinical course of 3 patients is described, as well as our preliminary impressions based on these limited clinical data. Special reference is made to the apparent influence of confounding factors, i.e., factors unique to each patient, that appeared to affect that individual’s analgesic requirements.
CaSe CaseStudy1 Thk was a 48-yr-old woman with breast cancer diagnosed in December 1988. She had undergone Au&.ss rep&t requeststo: Richard B. Pan, MD, Pain Treatment Center, University of Rochester Medical Center, Department of AnesthesiologyBox 604, 601 Ehnwood Avenue,Rochester, NY 14642. 0 U.S. Cancer Pain Relief Committee, 1992 Published by Elsetier, New York, New York
lumpectomy, axillary node dissection, chemotherapy, and radiation therapy. Known extent of disease included widely disseminated bone metastases. The patient described constant tingling and tender, aching pain over the chest wall accompanied by hyperesthesia and aching pain in the right forearm and low back. Possible Confound&g Factor. High doses of steroids that were prescribed during treatment regimen. I%vious Treatment. The patient’s pretreatment regimen included ibuprofen 800 mg 3 times/day, amitriptyline 10 mg HS, sustained-release morphine 30 mg 3 times/day, and Percocet l-2 tablets every 3-4 hr. course of ~e~~~t. ~~th~~t a~~~~~g the existing regimen, transdermal fentanyl was initiated at 25 pg/hr and was increased to 50 pg/hr 24 hr later. Sustained-release morphine was discontinued over treatment days 3 and 4. Of note is that the patient
08853924/92/$5.00
s52
Patt aud Hogan
complained of increased pain after starting tmnsdermalfentanyl. Prednisone 40 mg/day was started on treatment day 13 and continued through treatment day 44. A stable dose of f’entanyl WAS maintained until day 31 when, during prednisone taper, it was increased to 100 pg/hr, then 125 pg/hr in response to increased pain. Results.At 2 wk, pain was markedly reduced (from 75/ 100 mm to 2/ 100 mm), and marked relief of pain (97/ 100 mm) was noted. Concurrently, the patient subscribed to a marked reduction in the quality of her mood (from 781100 mm to 21100 mm), and a generalized trend toward increased distress (depressive thoughts, fear, and stress) was observed despite improved pain control. At 4 wk (coinciding with prednisone taper), pain levels were persistently low (9 mm), and a moderately high level of relief (57 mm) was maintained. Mood returned to near baseline (57 mm). Shortly aflterward, prednisone was discontinued, and the dose of fentanyl was titrated upward with return of comfort. Patch was “wonderful compared to constantly taking pills.” Case St&y 2 This 58-yr-old woman was diagnosed with lung cancer in November 1989 and had received radiation therapy and chemotherapy. The known extent of disease included pulmonary nodules, malignant pleural effusion, and pleural invasion versus chest wall disease on recent scintigram. She complained of constant, vague chest-wall pain of a sharp, stabbing, and numb quality. Posdh Confoundiq Factors. Addiction to amphetamines in distant past and distant history of alcohol abuse. Freuiou~Trealment.The patient’s pretreatment regimen included choline magnesium trisalicylate 750 mg 3 times/day, sustained-release morphine 75 mg 3 times/day, immediate-release morphine elixir 60 mg every 2-3 hr as needed, and metoclopramide 10 mg 4 times/day. coarse of Treatment. Without altering the existing regimen, treatment with transdermal fentanyl was irdhed at 25 pgh and was increased to 50 pg/hr 24 hr later. of note is that the patient complained of increased pain after starting transdermal fentanyl. Sustained-release morphine was discontinued
&I. 7No. 3 (St&id) April 1992
over treatment days 3 and 4. Fentanyl was gradually titrated upward to 125 ag/hr by day 28, and to 250 ug/hr by day 45. The patient continued to use immediate-release morphine for breakthrough pain (5 doses/day). &st&. Reports of pain were variable from day to day, but a pattern toward the use of fewer “rescue” doses emerged. The patient reported increased fimctional ability, an increased desire for socialization, decreased drowsiness, and improved sleep with less disruption related to pain. The patient reported less personal hardship related to her cancer and that the cancer was less disruptive to family members. Mood improved significantly, with markedly less fear of the future. Despite an absence of significant changes in pain levels, overall the patient was very pleased with the medication and preferred to continue treatment. Case &udy 3 Thii was a 72-yr-old man with adenocarcinoma of the rectosigmoid colon treated with surgical restction and radiotherapy. Massive local recurrence of hi disease had destroyed much of his sacrum, rendering him bedbound and incontinent of urine and feces. He described deep, aching rectal pain with constant, stabbing pain radiating to the posterior calves. Possible Confounding Factor. Initial unrealistic anticipation of remission yielding to depression over impending death and concern over wife’s inability to cope with the future. Frwious Treatment. In the 2 mo prior to his entering the study, pain was well controlled on low doses of oral opioids, but as nerve invasion progressed he required rapid dose increases of opioids, which resulted in delirium. A subarachnoid alcohol block was performed with return of comfort, permitting a sign&ant reduction in opioid requirements and resolution of mental status changes. At the time he was entered into the study he was receiving sustained-release morphine 30 mg 3 times/day, immediate-release morphine tablets 30-45 mg every 2-3 hr, and methylphenidate 15 mg every morning. Course of Treatment. Without any change in the existing medication regimen, treatment was initiated with transdermal fentanyl at 25 pg/hr, which
B’ol.7.X0.3 (Su@) April 1992
Transdennal Fentanylfo Chonic Cancer Pain
was increased to 50 pg/hr 24 hr later. Sustainedrelease morphine was discontinued on treatment day 3. Fentanyl was increased gradually by 25+g/hr increments to 150 pg/hr by day 48 and continued to be supplemented with occasional doses of immediate-release morphine for breakthrough.
s53
TableI Factors Threshold lowered
Threshold rsllsed
Discomfort InSOm& Fatigue Anxiety
Relief of symptoms Sleep Rest Sympathy Understmding Companionship Diversional activity Reduction in anxiety Elevation in mood Analgesics Amxiolytics Antidepressants
Fear
f&p
Results.The patient reported a gradually declining state of health. Pain increased mildly and concentration was mildly impaired, but the patient preferred the new treatment. Cancer was rated as beiig less disruptive to family members. He reported feeling more discouraged and subscribed to an increased
fear of the future and a reduced
eshold
Sadness Depression Boredom Introversion Mental isolation Social al3andonment
Modilied from Twycross RG, Lack Sk Therapeutics in terminal cancer. Edinburgh: Churchill Livingstone, 1986.
ability to cope with stress. He also reported reduced confidence
in the course of treatment,
b&g
less
willing to spend time with others, and being more discouraged
with life overall.
Overall, patients expressed a high degree of satisfaction with treatment. In the 2 patients with stable clinical courses (Cases 1 and 2), pain decreased over the study interval. The third patient became preoccupied with considerations of impending death and reported mildly increased pain as well as decrements in level of function and mood. One of the patients, who experienced the most markedly decreased pain, concurrently reported dramatic disturbances in mood, which corresponded to the addition of high doses of prednisone. Mood returned toward baseline and pain began to increase once prednisonc was discontinued, suggesting an influence of intercurrent therapy on results. The less stable (and more depressed) patient reported no significant changes in concurrent symptoms. The 2 stable patients reported markedly enhanced sleep due to less nocturnal pain, as well as less personal and family hardship and less constipation. Nausea did not increase, nor did new side effects occur in any patients. No respiratory depression was reported.
Our anecdotal cImical experience suggests that transdermal fentanyl is a highly acceptable, efficacious, and safe means of pharmacologic management for patients with chronic cancer pain. Our
results reinforce the concept that cancer pain is a dynamic, multiply detezmined process, and that, as a result, the effects of a single intervention are diEcult to analyze. Investigators have pointed out the influence of a variety of factors on patients’ reports of pain and response to therapy (see Tables 1 and 2). Careful monitoring of our patients suggested that external events (for example, depression over impending death, the administration of exogenous steroids, and history of addiction) have the potential to markedly influence the results of testing. Another potentially confounding factor relates to the design of this open-label study: The simple fact that patients were entered into the study, were subjected to a higher level of monitoring, and that, therefore, aggressive dose titration was more likely to occur may have influenced the quality of symptom control pre- and posttreatment. This observation makes pre- and posttreatment comparisons unwise. Despite these difliculties, however, we have formed a favorable impression of the role of transdermal fentanyl in the management of selected patients with cancer pain. Tile 2 Indicators Suggested to Predict Outcome of Cancer Pain Management Neuropathic pain Incident pain Opioid tolerance High psychological distr~s Prior drug or alcohol abuse Modilied from Bruela E, .MxMii K, HansonJ, MacDonaldN. The Edmonton staging system for cancer pain: preliminary report. Pain 1989;37:203.
journal of Pain and SymptomManagement S51
Richard B. Patt, hEI, and Laura A. Hogan, RM UniversiQ ofRochester SchoolofMediGine and De&k&y, Pain Treatment Center,Rochester,.iQw T&-k
Abstract P&t-s wereenteredintoan open label s&y to evaluate the ejicag of transdernzalfentanylas an analgesic for chroniccancer pain. The clinical courseof 3p~tient-s is de&bed as well as an emphasis on the apparent &&rue of confoundingfmtors, i.e., factors unique to each patient that appeared to aflect that individual’s a+za&esicrequireme&. Qur anecdotal c&&a! experiencewe.& &cacious, and safe means ofp~aco@ic
that ~~~alf~~uy~
k an acceptable,
managementforpatients wikh chroniccancer pain. Our results
reinforcethe concept that cancerpa;l is a dynamic, multiply &&mined process and that, as a result, the #ect.s
ofa sing,&?interventionare d#icalt
to a&yze. J Pain Symptom Manage 1992;?:S51-S53.
Advanced cancerpain, fmtanyl, ana&+x, transdennal delivg, assessment
Patients were entered into an open-label study to evaluate the efficacy of transdermal fentanyl as an analgesic for chronic cancer pain. The clinical course of 3 patients is described, as well as our preliminary impressions based on these limited clinical data. Special reference is made to the apparent influence of confounding factors, i.e., factors unique to each patient, that appeared to affect that individual’s analgesic requirements.
CaSe CaseStudy1 Thk was a 48-yr-old woman with breast cancer diagnosed in December 1988. She had undergone Au&.ss rep&t requeststo: Richard B. Pan, MD, Pain Treatment Center, University of Rochester Medical Center, Department of AnesthesiologyBox 604, 601 Ehnwood Avenue,Rochester, NY 14642. 0 U.S. Cancer Pain Relief Committee, 1992 Published by Elsetier, New York, New York
lumpectomy, axillary node dissection, chemotherapy, and radiation therapy. Known extent of disease included widely disseminated bone metastases. The patient described constant tingling and tender, aching pain over the chest wall accompanied by hyperesthesia and aching pain in the right forearm and low back. Possible Confound&g Factor. High doses of steroids that were prescribed during treatment regimen. I%vious Treatment. The patient’s pretreatment regimen included ibuprofen 800 mg 3 times/day, amitriptyline 10 mg HS, sustained-release morphine 30 mg 3 times/day, and Percocet l-2 tablets every 3-4 hr. course of ~e~~~t. ~~th~~t a~~~~~g the existing regimen, transdermal fentanyl was initiated at 25 pg/hr and was increased to 50 pg/hr 24 hr later. Sustained-release morphine was discontinued over treatment days 3 and 4. Of note is that the patient
08853924/92/$5.00
s52
Patt aud Hogan
complained of increased pain after starting tmnsdermalfentanyl. Prednisone 40 mg/day was started on treatment day 13 and continued through treatment day 44. A stable dose of f’entanyl WAS maintained until day 31 when, during prednisone taper, it was increased to 100 pg/hr, then 125 pg/hr in response to increased pain. Results.At 2 wk, pain was markedly reduced (from 75/ 100 mm to 2/ 100 mm), and marked relief of pain (97/ 100 mm) was noted. Concurrently, the patient subscribed to a marked reduction in the quality of her mood (from 781100 mm to 21100 mm), and a generalized trend toward increased distress (depressive thoughts, fear, and stress) was observed despite improved pain control. At 4 wk (coinciding with prednisone taper), pain levels were persistently low (9 mm), and a moderately high level of relief (57 mm) was maintained. Mood returned to near baseline (57 mm). Shortly aflterward, prednisone was discontinued, and the dose of fentanyl was titrated upward with return of comfort. Patch was “wonderful compared to constantly taking pills.” Case St&y 2 This 58-yr-old woman was diagnosed with lung cancer in November 1989 and had received radiation therapy and chemotherapy. The known extent of disease included pulmonary nodules, malignant pleural effusion, and pleural invasion versus chest wall disease on recent scintigram. She complained of constant, vague chest-wall pain of a sharp, stabbing, and numb quality. Posdh Confoundiq Factors. Addiction to amphetamines in distant past and distant history of alcohol abuse. Freuiou~Trealment.The patient’s pretreatment regimen included choline magnesium trisalicylate 750 mg 3 times/day, sustained-release morphine 75 mg 3 times/day, immediate-release morphine elixir 60 mg every 2-3 hr as needed, and metoclopramide 10 mg 4 times/day. coarse of Treatment. Without altering the existing regimen, treatment with transdermal fentanyl was irdhed at 25 pgh and was increased to 50 pg/hr 24 hr later. of note is that the patient complained of increased pain after starting transdermal fentanyl. Sustained-release morphine was discontinued
&I. 7No. 3 (St&id) April 1992
over treatment days 3 and 4. Fentanyl was gradually titrated upward to 125 ag/hr by day 28, and to 250 ug/hr by day 45. The patient continued to use immediate-release morphine for breakthrough pain (5 doses/day). &st&. Reports of pain were variable from day to day, but a pattern toward the use of fewer “rescue” doses emerged. The patient reported increased fimctional ability, an increased desire for socialization, decreased drowsiness, and improved sleep with less disruption related to pain. The patient reported less personal hardship related to her cancer and that the cancer was less disruptive to family members. Mood improved significantly, with markedly less fear of the future. Despite an absence of significant changes in pain levels, overall the patient was very pleased with the medication and preferred to continue treatment. Case &udy 3 Thii was a 72-yr-old man with adenocarcinoma of the rectosigmoid colon treated with surgical restction and radiotherapy. Massive local recurrence of hi disease had destroyed much of his sacrum, rendering him bedbound and incontinent of urine and feces. He described deep, aching rectal pain with constant, stabbing pain radiating to the posterior calves. Possible Confounding Factor. Initial unrealistic anticipation of remission yielding to depression over impending death and concern over wife’s inability to cope with the future. Frwious Treatment. In the 2 mo prior to his entering the study, pain was well controlled on low doses of oral opioids, but as nerve invasion progressed he required rapid dose increases of opioids, which resulted in delirium. A subarachnoid alcohol block was performed with return of comfort, permitting a sign&ant reduction in opioid requirements and resolution of mental status changes. At the time he was entered into the study he was receiving sustained-release morphine 30 mg 3 times/day, immediate-release morphine tablets 30-45 mg every 2-3 hr, and methylphenidate 15 mg every morning. Course of Treatment. Without any change in the existing medication regimen, treatment was initiated with transdermal fentanyl at 25 pg/hr, which
B’ol.7.X0.3 (Su@) April 1992
Transdennal Fentanylfo Chonic Cancer Pain
was increased to 50 pg/hr 24 hr later. Sustainedrelease morphine was discontinued on treatment day 3. Fentanyl was increased gradually by 25+g/hr increments to 150 pg/hr by day 48 and continued to be supplemented with occasional doses of immediate-release morphine for breakthrough.
s53
TableI Factors Threshold lowered
Threshold rsllsed
Discomfort InSOm& Fatigue Anxiety
Relief of symptoms Sleep Rest Sympathy Understmding Companionship Diversional activity Reduction in anxiety Elevation in mood Analgesics Amxiolytics Antidepressants
Fear
f&p
Results.The patient reported a gradually declining state of health. Pain increased mildly and concentration was mildly impaired, but the patient preferred the new treatment. Cancer was rated as beiig less disruptive to family members. He reported feeling more discouraged and subscribed to an increased
fear of the future and a reduced
eshold
Sadness Depression Boredom Introversion Mental isolation Social al3andonment
Modilied from Twycross RG, Lack Sk Therapeutics in terminal cancer. Edinburgh: Churchill Livingstone, 1986.
ability to cope with stress. He also reported reduced confidence
in the course of treatment,
b&g
less
willing to spend time with others, and being more discouraged
with life overall.
Overall, patients expressed a high degree of satisfaction with treatment. In the 2 patients with stable clinical courses (Cases 1 and 2), pain decreased over the study interval. The third patient became preoccupied with considerations of impending death and reported mildly increased pain as well as decrements in level of function and mood. One of the patients, who experienced the most markedly decreased pain, concurrently reported dramatic disturbances in mood, which corresponded to the addition of high doses of prednisone. Mood returned toward baseline and pain began to increase once prednisonc was discontinued, suggesting an influence of intercurrent therapy on results. The less stable (and more depressed) patient reported no significant changes in concurrent symptoms. The 2 stable patients reported markedly enhanced sleep due to less nocturnal pain, as well as less personal and family hardship and less constipation. Nausea did not increase, nor did new side effects occur in any patients. No respiratory depression was reported.
Our anecdotal cImical experience suggests that transdermal fentanyl is a highly acceptable, efficacious, and safe means of pharmacologic management for patients with chronic cancer pain. Our
results reinforce the concept that cancer pain is a dynamic, multiply detezmined process, and that, as a result, the effects of a single intervention are diEcult to analyze. Investigators have pointed out the influence of a variety of factors on patients’ reports of pain and response to therapy (see Tables 1 and 2). Careful monitoring of our patients suggested that external events (for example, depression over impending death, the administration of exogenous steroids, and history of addiction) have the potential to markedly influence the results of testing. Another potentially confounding factor relates to the design of this open-label study: The simple fact that patients were entered into the study, were subjected to a higher level of monitoring, and that, therefore, aggressive dose titration was more likely to occur may have influenced the quality of symptom control pre- and posttreatment. This observation makes pre- and posttreatment comparisons unwise. Despite these difliculties, however, we have formed a favorable impression of the role of transdermal fentanyl in the management of selected patients with cancer pain. Tile 2 Indicators Suggested to Predict Outcome of Cancer Pain Management Neuropathic pain Incident pain Opioid tolerance High psychological distr~s Prior drug or alcohol abuse Modilied from Bruela E, .MxMii K, HansonJ, MacDonaldN. The Edmonton staging system for cancer pain: preliminary report. Pain 1989;37:203.