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Effective Analgesic Score: A “Marker” of the Effects of Chemotherapy on Pain in Advanced Cancer Patients?
Vol. 34 No. 4 October 2007
Journal of Pain and Symptom Management
339
Letters
regimens administered are converted to oral morphine (intravenous morphine-oral morphine ratio 1:3; transdermal fentanyl oral morphine 1:100; and transdermal buprenorphine oral morphine 1:75). To score pain response correctly is a key point, not only for radiotherapy, but also for chemotherapy. The large majority of chemotherapy courses are administered to patients with metastatic disease; to score the effect on symptoms, in particular pain, is mandatory. In our unit, EAS is calculated and reported routinely in the charts of all patients receiving chemotherapy and pain therapy; it is evaluated at the start of chemotherapy and monitored monthly. To evaluate the effectiveness of EAS in scoring the effect of chemotherapy on reducing pain in cancer patients, we performed a retrospective analysis of data related to patients treated with chemotherapy for metastatic or
Effective Analgesic Score: A ‘‘Marker’’ of the Effects of Chemotherapy on Pain in Advanced Cancer Patients? To the Editor: Recently, Mercadante proposed an index, the Effective Analgesic Score (EAS), to monitor the effect of radiotherapy on pain caused by bone metastases.1 EAS is calculated on the basis of the following formula: PI(1 þ M/10). PI indicates the pain intensity evaluated with a Numerical Rating Scale 0e10, 1 indicates administration of anti-inflammatory drugs at full dosage on a regular basis (0 if anti-inflammatory drugs are not administered), and M indicates the dosage (milligrams) of oral morphine equivalents.1 To evaluate EAS, analgesic
Table 1 Characteristics of Patients Patient
Age (yr)
Sex
1 2
55 69
M F
3 4 5 6 7 8
56 36 59 53 57 39
M F F F F F
9 10 11
43 72 68
F M M
12 13 14 15
46 42 57 76
F M F M
Primary Tumor Rectum Abdominal liposarcoma Oral Breast Melanoma Breast Cervix Breast Ovary Lung Cancer of unknown primary site Pancreas Rectum Breast Prostate
Sites of Metastasis
KPS
Chemotherapy Regimes
Response to Chemotherapy
Lymph nodes
50 60
Irinotecan-5FU Epirubicin-ifosfamide
SD PD
Lymph nodes Lymph nodes, lung Lymph nodes, lung Lymph nodes, lung Lymph nodes, lung CSN, bone, and lung Peritoneal Bone Liver, lymph nodes
50 50 70 60 70 70
Paclitaxel Docetaxel-5FU CDDP-deticene CBDCA-gemcitabine Docetaxel-5FU Docetaxel-trastuzumab
RP SD SD SD SD SD
60 60 70
CBDCA-paclitaxel CDDP-vinorelbine CDDP-5FU
RC SD SD
Liver Lymph nodes Bone Bone, lung
80 80 80 50
Gemcitabine-5FU Oxaliplatin-irinotecan-5FU-bevacizumab Epirubicin-docetaxel Docetaxel
SD RP SD SD
KPS = Karnofsky Performance Status; SD = stable disease; PD = progressive disease; PR = partial response; CR = complete response; CDDP = cisplatin; CBDCA = carboplatin; CSN = cerebral.
Ó 2007 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
0885-3924/07/$esee front matter
340
Table 2 Characteristics of Pain, Dose of Oral Morphine Equivalents, and EAS
Patient
Mechanism of Pain
Pain Site
Breakthrough Pain
Dose of Oral Morphine Equivalents and Adjuvant Treatments
EAS0
EAS1
EAS2
EAS3
EAS4
No No
Morphine 300 mg Morphine 40 mg
3 30 ¼ 90 4 4 ¼ 16
2 30 ¼ 60 24¼8
3 9 ¼ 27 24¼8
03¼0 00¼0
03¼0 00¼0
Abdominal
No
Morphine 180 mg
4 18 ¼ 72
3 15 ¼ 45
3 15 ¼ 45
4 9 ¼ 36
3 9 ¼ 36
Right shoulder and arm
Yes
5 19 ¼ 95
1 18 ¼ 18
0 12 ¼ 0
06¼0
03¼0
Somatic and neuropathic Somatic and neuropathic
Right inguinal
No
5 4 ¼ 20
24¼8
02¼0
01¼0
01¼0
Chest and left arm
No
5 13 ¼ 65
1 12 ¼ 12
1 11 ¼ 11
2 10 ¼ 20
2 6 ¼ 12
7
Visceral
Abdominal
No
5 4 ¼ 20
13¼3
0 1,5 ¼ 0
00¼0
00¼0
8 9 10
Lumbar Abdominal Dorsal
Yes No Yes
4 6 ¼ 24 5 2 ¼ 10 4 7 ¼ 28
16¼6 12¼2 3 7 ¼ 21
03¼0 11¼1 4 5 ¼ 20
00¼0 00¼0 33¼9
00¼0 00¼0 33¼9
Lumbar
No
4 6 ¼ 24
16¼6
14¼4
02¼0
02¼0
12
Somatic Visceral Somatic and neuropathic Somatic and neuropathic Visceral
Abdominal
No
6 2.5 ¼ 15
21¼2
01¼0
00¼0
00¼0
13
Visceral
Perineal
No
3 28 ¼ 84
3 27 ¼ 81
1 13.5 ¼ 13.5
09¼0
03¼0
14
Somatic and neuropathic Somatic and neuropathic
Lumbar
Yes
Morphine 180 mg þ gabapentin þ FANS: ketorolac 20 mg Morphine 30 mg þ FANS: ketorolac 20 mg Morphine 120 mg þ gabapentin þ FANS: nimesulide 200 mg Morphine 30 mg þ FANS: nimesulide 200 mg Morphine 60 mg Morphine 20 mg Morphine 60 mg þ FANS: ketorolac 20 mg Morphine 60 mg: ketorolac 20 mg Morphine 15 mg þ FANS: nimesulide 200 mg Morphine 270 mg þ FANS: ketorolac 20 mg Morphine 360 mg
4 37 ¼ 148
4 36 ¼ 144
3 27 ¼ 81
2 18 ¼ 36
1 12 ¼ 12
Lumbar
Yes
4 12 ¼ 48
2 9 ¼ 18
16¼6
14¼4
12¼2
3 4 5 6
11
15
Morphine 90 mg þ gabapentin
Vol. 34 No. 4 October 2007
Inguinal Abdominal
Letters
Somatic Somatic and neuropathic Visceral and neuropathic Somatic and neuropathic
1 2
Vol. 34 No. 4 October 2007
locally advanced disease, receiving analgesic drugs for pain at the start of chemotherapy, observed from January 1 to December 31, 2006. Seventy-eight patients were observed. Seventeen patients who exhibited a reduction of opioid doses $50% during chemotherapy were selected; their characteristics are reported in Table 1. Data related to characteristics of pain, dose of oral morphine equivalents, and EAS at the start of chemotherapy (EAS 0) and over 4 months (EAS 1e4) are reported in Table 2. Our data support the hypothesis that EAS is easy to use in daily clinical practice and feasible to monitor the analgesic effects of chemotherapy; it could offer oncologists several advantages useful in both patient care and research. From a clinical point of view, EAS could be inserted in clinical decision making as a ‘‘marker’’ of clinical benefit. EAS was feasible in scoring effectiveness of chemotherapy regardless of the mechanisms of pain, or the presence of episodic pain and/or neuropathic pain. Interestingly, these data indicate that chemotherapy can reduce pain, even in cases of stable or progressive disease. This effect could be related to the impact of chemotherapy on the pattern of kinins, rather than a direct effect on mechanical pain inputs associated with the tumor mass. In similar cases, reduction of EAS could support the decision to continue chemotherapy even when it fails to reduce the progression of disease. Clinical benefit and/or pain response are often considered in evaluation of new drugs or new chemotherapy regimens without definitive consensus on method of evaluation. Some studies considered only patient-reported pain score;2,3 others record only the kind and doses of analgesic drugs;4 and some studies considered both these parameters but not in an integrated manner.5e8 EAS could overcome these methodological issues related to evaluation of effects of chemotherapy on pain. Moreover, incorporating EAS in evaluation of response to treatments gives a numerical value that can be compared easily among different clinical studies. In conclusion, EAS deserves further evaluation to confirm or refute its role in monitoring the effects of chemotherapy on pain. Because our results are based on a selected population evaluated in a retrospective way, it cannot be considered conclusive. Nevertheless, EAS
Letters
341
seems to be easy to implement in daily practice and useful both in patient care and research. If its feasibility is confirmed in larger, prospective, and controlled studies, oncologists could have a new ‘‘marker’’ to monitor the effect of disease-oriented treatment on pain and to compare the results of clinical studies. Giampiero Porzio, MD Federica Aielli, MD Lucilla Verna, MD Ghazaleh Shodia-E-Razavi, MD Supportive Care Task Force Medical Oncology Department University of L’Aquila L’Aquila, Italy Marianna Tudini, MD Katia Cannita, PhD Corrado Ficorella, MD Medical Oncology Department University of L’Aquila L’Aquila, Italy doi:10.1016/j.jpainsymman.2007.05.005
References 1. Mercadante S. Scoring the effect of radiotherapy for painful bone metastases. Support Care Cancer 2006;14:967e969. 2. Bottomley A, Gaafa R, Manegold C, et al. Short treatment-related symptoms and quality of life: results from an international randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an EORTC Lung Cancer Group and National Cancer Institute, Canada, Intergroup Study. J Clin Oncol 2006;24:1435e1442. 3. Vansteenkiste JF, Vanderbroek JE, Nackaerts KL, et al. Clinical-benefit response in advanced non-small-cell lung cancer: a multicentre prospective randomised phase III study of single agent gemcitabine versus cisplatin-vindesine. Ann Oncol 2001;12: 1221e1230. 4. Fossa` SD, Slee PH, Brausi M, et al. Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European Organization for Research and Treatment of Cancer Genitourinary Group. J Clin Oncol 2001;19:62e71. 5. Beer TM, Eilers KM, Garzotto M, et al. Quality of life and pain relief during treatment with calcitriol and docetaxel in symptomatic metastatic androgen-independent prostate cancer. Cancer 2004;15: 758e763. 6. Berry DL, Moinpour CM, Jiang CS, et al. Quality of life and pain in advanced stage prostate cancer: results of a Southwest Oncology Group randomized
342
trial comparing docetaxel and estramustine to mitoxantrone and prednisone. J Clin Oncol 2006;24: 2828e2835. 7. Ernst DS, Tannock IF, Winquist EW, et al. Randomized, double-blind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain. J Clin Oncol 2003;21:3335e3342. 8. Morant R, Bernhard J, Maibach R, et al. Response and palliation in a phase II trial of gemcitabine in hormone-refractory metastatic prostatic carcinoma. Ann Oncol 2000;11:183e188.
Treatment of Cancer Pain with Noninvasive Brain Stimulation To the Editor: Although therapeutics for the treatment of pain have developed considerably in the last few years, they still may fail to alleviate pain in cancer patients or become associated with significant undesirable side effects. Pain because of pancreatic cancer may be an example of such an instance. Patients with locally advanced or advanced pancreatic cancer often require increasing doses of opioid pain medications to control their pain. Although effective in pain control, opioids are often associated with adverse side effects: constipation, nausea, confusion, and drowsiness. Other treatment optionsdsuch as radiation or celiac plexus blockdmay not provide sustained pain relief.1e4 Recent advances in the techniques of noninvasive brain stimulation may offer alternative therapeutic options for pain control. We recently reported that transcranial direct current stimulation (tDCS), based on the application to the scalp of a weak direct current that flows between two relatively large electrodesd an anode and a cathode5dis a an effective method of reducing pain in patients with spinal cord injury and fibromyalgia.6,7 The present case provides proof-of-principle evidence that tDCS can exert clinically meaningful analgesic effects in patients with pain because of pancreatic cancer.
Case A 65-year-old woman was diagnosed with pancreatic cancer after one year of pain of
Letters
Vol. 34 No. 4 October 2007
increasing intensity in the upper abdominal area. The diagnosis of pancreatic cancer was made with a computed tomography scan of the abdomen, showing an image suggestive of a necrotic mass in the tail of the pancreas. A subsequent biopsy confirmed adenocarcinoma of the pancreas. Surgical treatment was not considered because of the local invasion and the presence of metastatic lesions. The patient began chemotherapy with gemcitabine, which resulted in a partial alleviation of her pain. However, after six months, her pain returned and codeine and paracetamol (acetaminophen) were initiated. At the time of the study, she was taking 180 mg of codeine per day (four times a day) and up to 2 g of paracetamol. With this treatment regimen, she had pain levels that varied, on average, from 1 to 6 on a scale from 0 to 10. She reported that her pain was especially severe when the effects of codeine were wearing off (two to four hours after the previous dose) (Fig. 1 shows her daily variation of pain). In addition, she reported severe constipation with this dosage of codeine. After giving written informed consent, the patient participated in a research protocol investigating the effects of noninvasive brain stimulation in patients with chronic pain. The protocol was approved by the local research ethics committee. She was blinded to the treatment condition, and received sham and active tDCS in a randomized order. We measured pain, cognitive effects, and side effects using the following instruments: numeric scales for pain, mood, and anxiety; MiniMental State Examination (MMSE); Stroop test; Forward and Backward Digit Span; and a questionnaire for adverse effects. During the day of stimulation, medication was withheld to evaluate her response without the effects of analgesics. We also asked her immediately after each tDCS session to guess which type of stimulation she received. She responded that she believed she received active stimulation in both situations (could not differentiate). Importantly, the rater was also blinded to the treatment received by the patient. Direct current was transferred by using a saline-soaked pair of surface sponge electrodes and delivered by a custom-developed, batterydriven, constant current stimulator with a maximum output of 10 mA and electrode size of
Journal of Pain and Symptom Management
339
Letters
regimens administered are converted to oral morphine (intravenous morphine-oral morphine ratio 1:3; transdermal fentanyl oral morphine 1:100; and transdermal buprenorphine oral morphine 1:75). To score pain response correctly is a key point, not only for radiotherapy, but also for chemotherapy. The large majority of chemotherapy courses are administered to patients with metastatic disease; to score the effect on symptoms, in particular pain, is mandatory. In our unit, EAS is calculated and reported routinely in the charts of all patients receiving chemotherapy and pain therapy; it is evaluated at the start of chemotherapy and monitored monthly. To evaluate the effectiveness of EAS in scoring the effect of chemotherapy on reducing pain in cancer patients, we performed a retrospective analysis of data related to patients treated with chemotherapy for metastatic or
Effective Analgesic Score: A ‘‘Marker’’ of the Effects of Chemotherapy on Pain in Advanced Cancer Patients? To the Editor: Recently, Mercadante proposed an index, the Effective Analgesic Score (EAS), to monitor the effect of radiotherapy on pain caused by bone metastases.1 EAS is calculated on the basis of the following formula: PI(1 þ M/10). PI indicates the pain intensity evaluated with a Numerical Rating Scale 0e10, 1 indicates administration of anti-inflammatory drugs at full dosage on a regular basis (0 if anti-inflammatory drugs are not administered), and M indicates the dosage (milligrams) of oral morphine equivalents.1 To evaluate EAS, analgesic
Table 1 Characteristics of Patients Patient
Age (yr)
Sex
1 2
55 69
M F
3 4 5 6 7 8
56 36 59 53 57 39
M F F F F F
9 10 11
43 72 68
F M M
12 13 14 15
46 42 57 76
F M F M
Primary Tumor Rectum Abdominal liposarcoma Oral Breast Melanoma Breast Cervix Breast Ovary Lung Cancer of unknown primary site Pancreas Rectum Breast Prostate
Sites of Metastasis
KPS
Chemotherapy Regimes
Response to Chemotherapy
Lymph nodes
50 60
Irinotecan-5FU Epirubicin-ifosfamide
SD PD
Lymph nodes Lymph nodes, lung Lymph nodes, lung Lymph nodes, lung Lymph nodes, lung CSN, bone, and lung Peritoneal Bone Liver, lymph nodes
50 50 70 60 70 70
Paclitaxel Docetaxel-5FU CDDP-deticene CBDCA-gemcitabine Docetaxel-5FU Docetaxel-trastuzumab
RP SD SD SD SD SD
60 60 70
CBDCA-paclitaxel CDDP-vinorelbine CDDP-5FU
RC SD SD
Liver Lymph nodes Bone Bone, lung
80 80 80 50
Gemcitabine-5FU Oxaliplatin-irinotecan-5FU-bevacizumab Epirubicin-docetaxel Docetaxel
SD RP SD SD
KPS = Karnofsky Performance Status; SD = stable disease; PD = progressive disease; PR = partial response; CR = complete response; CDDP = cisplatin; CBDCA = carboplatin; CSN = cerebral.
Ó 2007 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
0885-3924/07/$esee front matter
340
Table 2 Characteristics of Pain, Dose of Oral Morphine Equivalents, and EAS
Patient
Mechanism of Pain
Pain Site
Breakthrough Pain
Dose of Oral Morphine Equivalents and Adjuvant Treatments
EAS0
EAS1
EAS2
EAS3
EAS4
No No
Morphine 300 mg Morphine 40 mg
3 30 ¼ 90 4 4 ¼ 16
2 30 ¼ 60 24¼8
3 9 ¼ 27 24¼8
03¼0 00¼0
03¼0 00¼0
Abdominal
No
Morphine 180 mg
4 18 ¼ 72
3 15 ¼ 45
3 15 ¼ 45
4 9 ¼ 36
3 9 ¼ 36
Right shoulder and arm
Yes
5 19 ¼ 95
1 18 ¼ 18
0 12 ¼ 0
06¼0
03¼0
Somatic and neuropathic Somatic and neuropathic
Right inguinal
No
5 4 ¼ 20
24¼8
02¼0
01¼0
01¼0
Chest and left arm
No
5 13 ¼ 65
1 12 ¼ 12
1 11 ¼ 11
2 10 ¼ 20
2 6 ¼ 12
7
Visceral
Abdominal
No
5 4 ¼ 20
13¼3
0 1,5 ¼ 0
00¼0
00¼0
8 9 10
Lumbar Abdominal Dorsal
Yes No Yes
4 6 ¼ 24 5 2 ¼ 10 4 7 ¼ 28
16¼6 12¼2 3 7 ¼ 21
03¼0 11¼1 4 5 ¼ 20
00¼0 00¼0 33¼9
00¼0 00¼0 33¼9
Lumbar
No
4 6 ¼ 24
16¼6
14¼4
02¼0
02¼0
12
Somatic Visceral Somatic and neuropathic Somatic and neuropathic Visceral
Abdominal
No
6 2.5 ¼ 15
21¼2
01¼0
00¼0
00¼0
13
Visceral
Perineal
No
3 28 ¼ 84
3 27 ¼ 81
1 13.5 ¼ 13.5
09¼0
03¼0
14
Somatic and neuropathic Somatic and neuropathic
Lumbar
Yes
Morphine 180 mg þ gabapentin þ FANS: ketorolac 20 mg Morphine 30 mg þ FANS: ketorolac 20 mg Morphine 120 mg þ gabapentin þ FANS: nimesulide 200 mg Morphine 30 mg þ FANS: nimesulide 200 mg Morphine 60 mg Morphine 20 mg Morphine 60 mg þ FANS: ketorolac 20 mg Morphine 60 mg: ketorolac 20 mg Morphine 15 mg þ FANS: nimesulide 200 mg Morphine 270 mg þ FANS: ketorolac 20 mg Morphine 360 mg
4 37 ¼ 148
4 36 ¼ 144
3 27 ¼ 81
2 18 ¼ 36
1 12 ¼ 12
Lumbar
Yes
4 12 ¼ 48
2 9 ¼ 18
16¼6
14¼4
12¼2
3 4 5 6
11
15
Morphine 90 mg þ gabapentin
Vol. 34 No. 4 October 2007
Inguinal Abdominal
Letters
Somatic Somatic and neuropathic Visceral and neuropathic Somatic and neuropathic
1 2
Vol. 34 No. 4 October 2007
locally advanced disease, receiving analgesic drugs for pain at the start of chemotherapy, observed from January 1 to December 31, 2006. Seventy-eight patients were observed. Seventeen patients who exhibited a reduction of opioid doses $50% during chemotherapy were selected; their characteristics are reported in Table 1. Data related to characteristics of pain, dose of oral morphine equivalents, and EAS at the start of chemotherapy (EAS 0) and over 4 months (EAS 1e4) are reported in Table 2. Our data support the hypothesis that EAS is easy to use in daily clinical practice and feasible to monitor the analgesic effects of chemotherapy; it could offer oncologists several advantages useful in both patient care and research. From a clinical point of view, EAS could be inserted in clinical decision making as a ‘‘marker’’ of clinical benefit. EAS was feasible in scoring effectiveness of chemotherapy regardless of the mechanisms of pain, or the presence of episodic pain and/or neuropathic pain. Interestingly, these data indicate that chemotherapy can reduce pain, even in cases of stable or progressive disease. This effect could be related to the impact of chemotherapy on the pattern of kinins, rather than a direct effect on mechanical pain inputs associated with the tumor mass. In similar cases, reduction of EAS could support the decision to continue chemotherapy even when it fails to reduce the progression of disease. Clinical benefit and/or pain response are often considered in evaluation of new drugs or new chemotherapy regimens without definitive consensus on method of evaluation. Some studies considered only patient-reported pain score;2,3 others record only the kind and doses of analgesic drugs;4 and some studies considered both these parameters but not in an integrated manner.5e8 EAS could overcome these methodological issues related to evaluation of effects of chemotherapy on pain. Moreover, incorporating EAS in evaluation of response to treatments gives a numerical value that can be compared easily among different clinical studies. In conclusion, EAS deserves further evaluation to confirm or refute its role in monitoring the effects of chemotherapy on pain. Because our results are based on a selected population evaluated in a retrospective way, it cannot be considered conclusive. Nevertheless, EAS
Letters
341
seems to be easy to implement in daily practice and useful both in patient care and research. If its feasibility is confirmed in larger, prospective, and controlled studies, oncologists could have a new ‘‘marker’’ to monitor the effect of disease-oriented treatment on pain and to compare the results of clinical studies. Giampiero Porzio, MD Federica Aielli, MD Lucilla Verna, MD Ghazaleh Shodia-E-Razavi, MD Supportive Care Task Force Medical Oncology Department University of L’Aquila L’Aquila, Italy Marianna Tudini, MD Katia Cannita, PhD Corrado Ficorella, MD Medical Oncology Department University of L’Aquila L’Aquila, Italy doi:10.1016/j.jpainsymman.2007.05.005
References 1. Mercadante S. Scoring the effect of radiotherapy for painful bone metastases. Support Care Cancer 2006;14:967e969. 2. Bottomley A, Gaafa R, Manegold C, et al. Short treatment-related symptoms and quality of life: results from an international randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an EORTC Lung Cancer Group and National Cancer Institute, Canada, Intergroup Study. J Clin Oncol 2006;24:1435e1442. 3. Vansteenkiste JF, Vanderbroek JE, Nackaerts KL, et al. Clinical-benefit response in advanced non-small-cell lung cancer: a multicentre prospective randomised phase III study of single agent gemcitabine versus cisplatin-vindesine. Ann Oncol 2001;12: 1221e1230. 4. Fossa` SD, Slee PH, Brausi M, et al. Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European Organization for Research and Treatment of Cancer Genitourinary Group. J Clin Oncol 2001;19:62e71. 5. Beer TM, Eilers KM, Garzotto M, et al. Quality of life and pain relief during treatment with calcitriol and docetaxel in symptomatic metastatic androgen-independent prostate cancer. Cancer 2004;15: 758e763. 6. Berry DL, Moinpour CM, Jiang CS, et al. Quality of life and pain in advanced stage prostate cancer: results of a Southwest Oncology Group randomized
342
trial comparing docetaxel and estramustine to mitoxantrone and prednisone. J Clin Oncol 2006;24: 2828e2835. 7. Ernst DS, Tannock IF, Winquist EW, et al. Randomized, double-blind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain. J Clin Oncol 2003;21:3335e3342. 8. Morant R, Bernhard J, Maibach R, et al. Response and palliation in a phase II trial of gemcitabine in hormone-refractory metastatic prostatic carcinoma. Ann Oncol 2000;11:183e188.
Treatment of Cancer Pain with Noninvasive Brain Stimulation To the Editor: Although therapeutics for the treatment of pain have developed considerably in the last few years, they still may fail to alleviate pain in cancer patients or become associated with significant undesirable side effects. Pain because of pancreatic cancer may be an example of such an instance. Patients with locally advanced or advanced pancreatic cancer often require increasing doses of opioid pain medications to control their pain. Although effective in pain control, opioids are often associated with adverse side effects: constipation, nausea, confusion, and drowsiness. Other treatment optionsdsuch as radiation or celiac plexus blockdmay not provide sustained pain relief.1e4 Recent advances in the techniques of noninvasive brain stimulation may offer alternative therapeutic options for pain control. We recently reported that transcranial direct current stimulation (tDCS), based on the application to the scalp of a weak direct current that flows between two relatively large electrodesd an anode and a cathode5dis a an effective method of reducing pain in patients with spinal cord injury and fibromyalgia.6,7 The present case provides proof-of-principle evidence that tDCS can exert clinically meaningful analgesic effects in patients with pain because of pancreatic cancer.
Case A 65-year-old woman was diagnosed with pancreatic cancer after one year of pain of
Letters
Vol. 34 No. 4 October 2007
increasing intensity in the upper abdominal area. The diagnosis of pancreatic cancer was made with a computed tomography scan of the abdomen, showing an image suggestive of a necrotic mass in the tail of the pancreas. A subsequent biopsy confirmed adenocarcinoma of the pancreas. Surgical treatment was not considered because of the local invasion and the presence of metastatic lesions. The patient began chemotherapy with gemcitabine, which resulted in a partial alleviation of her pain. However, after six months, her pain returned and codeine and paracetamol (acetaminophen) were initiated. At the time of the study, she was taking 180 mg of codeine per day (four times a day) and up to 2 g of paracetamol. With this treatment regimen, she had pain levels that varied, on average, from 1 to 6 on a scale from 0 to 10. She reported that her pain was especially severe when the effects of codeine were wearing off (two to four hours after the previous dose) (Fig. 1 shows her daily variation of pain). In addition, she reported severe constipation with this dosage of codeine. After giving written informed consent, the patient participated in a research protocol investigating the effects of noninvasive brain stimulation in patients with chronic pain. The protocol was approved by the local research ethics committee. She was blinded to the treatment condition, and received sham and active tDCS in a randomized order. We measured pain, cognitive effects, and side effects using the following instruments: numeric scales for pain, mood, and anxiety; MiniMental State Examination (MMSE); Stroop test; Forward and Backward Digit Span; and a questionnaire for adverse effects. During the day of stimulation, medication was withheld to evaluate her response without the effects of analgesics. We also asked her immediately after each tDCS session to guess which type of stimulation she received. She responded that she believed she received active stimulation in both situations (could not differentiate). Importantly, the rater was also blinded to the treatment received by the patient. Direct current was transferred by using a saline-soaked pair of surface sponge electrodes and delivered by a custom-developed, batterydriven, constant current stimulator with a maximum output of 10 mA and electrode size of