trial comparing docetaxel and estramustine to mi-toxantrone and prednisone. J Clin Oncol 2006;24:2828e2835.

7. Ernst DS, Tannock IF, Winquist EW, et al. Ran-domized, double-blind, controlled trial of mitoxan-trone/prednisone and clodronate versusmitoxantrone/prednisone and placebo in patientswith hormone-refractory prostate cancer and pain.J Clin Oncol 2003;21:3335e3342.

8. Morant R, Bernhard J, Maibach R, et al. Re-sponse and palliation in a phase II trial of gemcita-bine in hormone-refractory metastatic prostaticcarcinoma. Ann Oncol 2000;11:183e188.

342 Vol. 34 No. 4 October 2007Letters

Treatment of Cancer Pain withNoninvasive Brain Stimulation

To the Editor:Although therapeutics for the treatment of

pain have developed considerably in the lastfew years, they still may fail to alleviate pain incancer patients or become associated with signif-icant undesirable side effects. Pain because ofpancreatic cancer may be an example of suchan instance. Patients with locally advanced or ad-vanced pancreatic cancer often require increas-ing doses of opioid pain medications to controltheir pain. Although effective in pain control,opioids are often associated with adverse sideeffects: constipation, nausea, confusion, anddrowsiness. Other treatment optionsdsuch asradiation or celiac plexus blockdmay not pro-vide sustained pain relief.1e4

Recent advances in the techniques of nonin-vasive brain stimulation may offer alternativetherapeutic options for pain control. Werecently reported that transcranial direct cur-rent stimulation (tDCS), based on the applica-tion to the scalp of a weak direct current thatflows between two relatively large electrodesdan anode and a cathode5dis a an effectivemethod of reducing pain in patients with spi-nal cord injury and fibromyalgia.6,7 The pres-ent case provides proof-of-principle evidencethat tDCS can exert clinically meaningful anal-gesic effects in patients with pain because ofpancreatic cancer.

CaseA 65-year-old woman was diagnosed with

pancreatic cancer after one year of pain of

increasing intensity in the upper abdominalarea. The diagnosis of pancreatic cancer wasmade with a computed tomography scan ofthe abdomen, showing an image suggestiveof a necrotic mass in the tail of the pancreas.A subsequent biopsy confirmed adenocarci-noma of the pancreas. Surgical treatment wasnot considered because of the local invasionand the presence of metastatic lesions. The pa-tient began chemotherapy with gemcitabine,which resulted in a partial alleviation of herpain. However, after six months, her painreturned and codeine and paracetamol (acet-aminophen) were initiated. At the time ofthe study, she was taking 180 mg of codeineper day (four times a day) and up to 2 g of par-acetamol. With this treatment regimen, shehad pain levels that varied, on average, from1 to 6 on a scale from 0 to 10. She reportedthat her pain was especially severe when the ef-fects of codeine were wearing off (two to fourhours after the previous dose) (Fig. 1 showsher daily variation of pain). In addition, she re-ported severe constipation with this dosage ofcodeine.

After giving written informed consent, thepatient participated in a research protocolinvestigating the effects of noninvasive brainstimulation in patients with chronic pain.The protocol was approved by the local re-search ethics committee. She was blinded tothe treatment condition, and received shamand active tDCS in a randomized order. Wemeasured pain, cognitive effects, and sideeffects using the following instruments: nu-meric scales for pain, mood, and anxiety; Mini-Mental State Examination (MMSE); Strooptest; Forward and Backward Digit Span; anda questionnaire for adverse effects. During theday of stimulation, medication was withheld toevaluate her response without the effects ofanalgesics. We also asked her immediately aftereach tDCS session to guess which type of stim-ulation she received. She responded that shebelieved she received active stimulation inboth situations (could not differentiate). Im-portantly, the rater was also blinded to thetreatment received by the patient.

Direct current was transferred by using a sa-line-soaked pair of surface sponge electrodesand delivered by a custom-developed, battery-driven, constant current stimulator with a max-imum output of 10 mA and electrode size of

Vol. 34 No. 4 October 2007 343Letters

Fig. 1. Daily mean variation of pain levels as indexed by visual analog scale. Arrows indicate the time of medica-tions intake (6 AM, 12 PM, 6 PM, and 12 AM). The patient was taking 45 mg of codeine and 500 mg of paracetamol.

35 cm2. The anode electrode was placed overC3 (using EEG 10/20 systemdcorrespondingto the primary motor cortex)6 and the cathodeelectrode was placed over the contralateralsupraorbital area.

During sham stimulation, the patient had nochange in pain levels and pain worsened twohours after the tDCS (increase of two points).However, after active stimulation, she reportedthat she was pain free (her pain decreased fromfour to zero) and the benefit lasted for severalhours. The effect was particularly remarkableas she reported that she usually could not toler-ate skipping one dose of her medication formore than four hours (Fig. 2).

There were no adverse effects. After shamstimulation, her MMSE did not change, digitspan forward did not change, digit span

backward increased one sequence (two tothree), and Stroop colors performance execu-tion time decreased from 25.63 to 22.89 sec-onds. After active stimulation, MMSE, digitspan forward and backward did not change,and Stroop colors execution time also de-creased from 23.06 to 20.56 seconds. Therewere no changes in mood and anxiety after ei-ther sham or active stimulation.

CommentThis case report shows that active, but not

sham, tDCS can acutely alleviate pain becauseof advanced pancreatic cancer. In addition, wealso showed that, in this patient, this treat-ment was not associated with adverse events,cognitive changes, or mood changes. We pre-viously showed that another technique of

Fig. 2. Pain levels during treatment with sham and active tDCS. During treatment with tDCS, medications werewithheld.

344 Vol. 34 No. 4 October 2007Letters

noninvasive brain stimulation (repetitivetranscranial magnetic stimulation) can alsosignificantly suppress chronic visceral pain inpatients with chronic pancreatitis.8

Prior work done in patients with chronicpancreatic inflammation suggests that sus-tained chronic visceral pain from pancreaticdisease affects: 1) the interaction and modifi-cation of various somatic sensory modalitiesbetween the ascending pathways;9,10 2) the ac-tivation of spinal gating mechanisms throughthe dorsal column neural synapses;11 and 3)reorganization in the cortical representationof visceral sensation, including a suppressionof local GABAergic and a potentiation of glu-tamatergic activity. In fact, chronic pancreatitispatients report a decrease in pain when givenketamine, a noncompetitive antagonist of glu-tamatergic N-methyl-D-aspartate (NMDA) re-ceptors.12 NMDA receptors enhance brainexcitability, can control synapse maturation,and modulate other receptors, such as thegamma-aminobutyric acid type A (GABA-A)receptors.13

The rationale of using the primary motor cor-tex as the target comes from studies using epi-dural motor cortex stimulation,14,15 suggestingthe potential therapeutic utility of motor cortexstimulation. Upregulation of motor cortex ex-citability might modulate pain perceptionthrough indirect effects via neural networkson pain-modulating areas, such as thalamic nu-clei, as suggested by neuroimaging.14

Several limitations should be discussed.First, this is a report of one case only. However,we believe this is important to report to en-courage future research in this area. Second,we did not measure the long-term effects ofthis therapy. Therefore, it is unclear whetherthe effects would be long-lasting if severalsessions of tDCS are applied; this should befurther explored. We previously showed thatfive consecutive sessions of tDCS in chronicpain because of spinal cord injury results inpain alleviation that lasts five days6; however,mechanisms of pain in pancreatic cancer arecertainly different.

AcknowledgmentsThis work was supported by a grant from

the National Pancreas Foundation and the

Harvard-Thorndike General Clinical ResearchCenter at BIDMC (NCRR MO1 RR01032dCREFF/BIDMC).

Gisele Silva, MD, PhDDepartment of NeurologyFederal University of Sao PauloSao Paulo, Brazil

Rebecca Miksad, MDDepartment of OncologyBeth Israel Deaconess Medical CenterHarvard Medical SchoolBoston, Massachusetts, USA

Steven D. Freedman, MD, PhDPancreas CenterDepartment of MedicineBeth Israel Deaconess Medical CenterHarvard Medical SchoolBoston, Massachusetts, USA

Alvaro Pascual-Leone, MD, PhDBerenson-Allen Center for NoninvasiveBrain StimulationDepartment of NeurologyBeth Israel Deaconess Medical CenterHarvard Medical SchoolBoston, Massachusetts, USA

Sanjay Jain, MD, PhDDepartment of OncologyBeth Israel Deaconess Medical CenterHarvard Medical SchoolBoston, Massachusetts, USA

Daniela L. Gomes, MDDepartment of NeurologyFederal University of Sao PauloSao Paulo, Brazil

Edson J. Amancio, MD, PhDCentro de Neurocirugia Funcional e DorHospital 9 de JulhoSao Paulo, Brazil

Paulo S. Boggio, PhDCentro de Ciencias Biologicas e da SaudeUniversidade Presbiteriana MackenzieSao Paulo, Brazil

Claudio F. Correa, MD, PhDCentro de Neurocirugia Funcional e DorHospital 9 de JulhoSao Paulo, Brazil

Felipe Fregni, MD, PhDBerenson-Allen Center forNoninvasive Brain StimulationDepartment of NeurologyBeth Israel Deaconess Medical CenterHarvard Medical SchoolBoston, Massachusetts, USA

doi:10.1016/j.jpainsymman.2007.06.002

Palliative Medicine and IntensiveCare MedicinedTwo Sidesof the Same Coin?

To the Editor:Intensive care medicine and palliative medi-

cine both deal with the limits of life-sustainingcare. Decision making in matters of life anddeath is one of the greatest challenges for physi-cians, because it may be an area of conflict withregard to aspects of patient autonomy, medicalprognosis, and the ethics of medical care.

Superficially, palliative medicine and inten-sive care medicine seem to be at the oppositeends of care; one is known as ‘‘talking medi-cine’’ and the other as ‘‘apparatus medicine.’’In palliative medicine, symptom control andalleviation of suffering are the focus of careto achieve or maintain the best possible qualityof life in patients with incurable, advanced,and life-limiting diseases. Even though appro-priate symptom control may result in prolon-gation of life, this is not a major goal oftreatment and, therefore, can be seen as oneof the essential differences between palliativeand intensive care medicine. Palliative medi-cine regards dying as a natural process and nei-ther seeks to prolong life nor to hasten death.However, palliative medicine cares for a muchlarger target group than the dying; a greatnumber of palliative patients benefit from pal-liative care measures for a period of months oreven years.

In intensive care medicine, the main focus ofcare lies on prolongation of life and restorationof health, whenever possible; symptom controland alleviation of suffering are also essentialaspects of intensive care unit treatment.1

It is not unusual that decisions in intensivecare medicine must be made in an instant, par-ticularly when dealing with an emergency

Vol. 34 No. 4 October 2007 345Letters

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