574260

case-report2015
PMJ0010.1177/0269216315574260Palliative MedicineNizard et al.

Case Report

Palliative Medicine

Interest of repetitive transcranial 2015, Vol. 29(6) 564568

The Author(s) 2015
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DOI: 10.1177/0269216315574260

motor cortex in the management pmj.sagepub.com

of refractory cancer pain in

palliative care: Two case reports

Julien Nizard1, Amlie Levesque1, Nathalie Denis1,

Edwige de Chauvigny1, Aurlie Lepeintre1, Sylvie Raoul2,
Jean-Jacques Labat1, Samuel Bulteau3, Benot Maillard1,
Kevin Buffenoir2, Gilles Potel1, Jean-Pascal Lefaucheur4
and Jean Paul Nguyen2

Abstract
Background: Non-drug treatments should be systematically associated to the medical analgesic treatment during the terminal phase
of cancer.
Cases presentation: Patient 1, a 23-year-old woman, presented an adenocarcinoma of the rectum, with liver and lung metastases.
Pain was initially treated by oral morphine and a combination of pregabalin and amitriptyline. Ketamine and intrathecal administration
of morphine were both ineffective. Patient 2, a 69-year-old woman, presented a cutaneous T-cell lymphoma. She was admitted to
the palliative care unit with mixed pain related to cutaneous lymphomatous infiltration. World Health Organization (WHO) step 3
analgesics had not been tolerated.
Cases management: Both patients received five consecutive 20-min sessions of repetitive transcranial magnetic stimulation to the
right motor cortex.
Cases outcome: Patient 1 experienced a marked improvement of her pain over the days following the first repetitive transcranial
magnetic stimulation session. Medical treatment was able to be rapidly decreased by about 50%, which restored an almost normal
level of consciousness and lucidity. Patient 2s pain was also markedly decreased over the days following these five consecutive
sessions, and repetitive transcranial magnetic stimulation also appeared to have had a beneficial effect on the patients anxiety
and mood.
Conclusion: In the context of palliative care of cancer patients experiencing refractory pain that is difficult to control by the usual
treatments, motor cortex repetitive transcranial magnetic stimulation, due to its noninvasive nature, can be used as an adjuvant
therapy to improve various components of pain, including the emotional components. By reducing the doses of analgesics, repetitive
transcranial magnetic stimulation decreases the severity of their adverse effects and improves the patients quality of life.

Keywords
Refractory pain, cancer pain, quality of life, repetitive transcranial magnetic stimulation, rTMS

1Pain-Palliative-Support Corresponding author:

Care and Ethics, UIC 22 and Laboratoire de
Julien Nizard, Pain-Palliative-Support Care and Ethics, UIC 22 and
Thrapeutique (EA3826), University Hospital, CHU Nord Lannec,
Laboratoire de Thrapeutique (EA3826), University Hospital, CHU
Nantes, France
2Neurosurgery Department, University Hospital, Nantes, France Nord Lannec, 44093 Nantes cedex 1, France.
3Psychiatry Department, University Hospital, Nantes, France Email: julien.nizard@univ-nantes.fr
4EA 4391 and Department of Physiology, Faculty of Medicine Henri

Mondor, Crteil, France

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Nizard et al. 565

What is already known about this topic?

Terminal cancer patients often experience pain that is difficult to treat.
High doses of analgesics may be insufficient to relieve pain or may induce unacceptable adverse effects, especially
drowsiness.
Non-drug treatments, especially physical and psycho-corporal therapies, should be systematically associated.
At the present time, two indications present a sufficient level of evidence to formally adopt the therapeutic indication for
the use of repetitive transcranial magnetic stimulation (rTMS), in clinical practice: neuropathic pain and major depressive
disorders.
To our knowledge, no study has been previously published about rTMS in the context of palliative care of cancer pain
patients.

What this paper adds?

We report the two first cases of patients in whom refractory cancer pain was markedly improved by a series of five sessions
of rTMS of the motor cortex.
By reducing the doses of analgesics, rTMS decreases the severity of their adverse effects, which can lead to a marked
improvement in the quality of life of the patient.

Implications for practice, theory or policy

In the context of palliative care of cancer pain patients at the end of life, motor cortex rTMS can be used as add-on therapy
likely to improve various components of pain, including the emotional-affective components such as depression.
Randomized controlled trials, comparing active stimulation and sham stimulation, are needed.

Background
Cancer pain may correspond to nociceptive pain, generally
relieved by the administration of opioid analgesics, neuro-
pathic pain, requiring the use of specific medications such
as anticonvulsants or antidepressants, and often mixed
pain. Pain can become difficult to control at the terminal
phase of cancer due to the mixed nature of the pain and the
need to administer high-dose drug combinations, often
accompanied by drowsiness, which contributes to deterio-
ration of the quality of the end of life. Non-drug treat-
ments, especially physical and psycho-corporal therapy,
should be systematically associated. We report two clinical
cases in which five sessions of repeated transcranial mag-
netic stimulation induced marked relief of the patients
pain and allowed a considerable reduction of their analge-
sic drug treatment. To our knowledge, no study has been
previously published about repetitive transcranial mag-
netic stimulation (rTMS) on the context of palliative care.
Case report 1
Case presentation
A woman in her early 20s presented an adenocarcinoma of
the rectum, treated by radiotherapy and abdominopelvic
resection, followed by chemotherapy. She presented local
disease progression despite this treatment, with the discov-
ery of peritoneal carcinomatosis with liver and lung metas-
tases. The patients health status gradually deteriorated
with increasing abdominal and pelvic pain, which partly
corresponded to nociceptive pain, due to compression by
the tumour, and partly to possible neuropathic pain,1 as a
consequence of surgery and radiotherapy (with a DN4
score, a screening instrument used to measure neuropathic
pain,2 of 7/10.). This pain was initially treated by oral mor-
phine and a combination of pregabalin and amitriptyline.
The patient continued to experience pain despite this treat-
ment with a numerical rating scale (NRS) varying between
8 and 10/10. She also suffered from drowsiness and intel-
lectual slowing that confined her to bed.
Case management
Patient 1 was admitted to the Palliative Care Unit. Initiation
of N-methyl d-aspartate (NMDA) receptor antagonist (ket-
amine) treatment failed to decrease pain or the doses of
major opioids. Intrathecal administration of morphine was
also ineffective. Introduction of midazolam was minimally
effective and accentuated the patients drowsiness. The
Medication Quantification Scale (MQS) score (used to
quantify analgesic and co-analgesic consumption in chronic
pain patients according to drug class, and daily therapeutic
dose)3 was then 126. In view of the patients limited life
expectancy (less than 3months), the neurosurgeon con-
tacted did not propose any specific treatment (neither an
invasive neurostimulation, nor a destructive procedure).
A therapeutic trial of motor cortex stimulation by
rTMS was proposed, as we had already obtained good
results in two cases of refractory pelvic and perineal pain.4

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566 Palliative Medicine 29(6)
The patient received five 20-min sessions of stimulation
of the right motor cortex, in the zone corresponding to the
representation of the perineal region4 with the following
parameters: 20 trains of 10s at 10Hz to 80% of the resting
motor threshold with an inter-train interval of 50s (2000
stimuli).
Case outcomes
The patient experienced a marked improvement of her pain
over the days following the first rTMS session. Medical
treatment was able to be rapidly decreased by about 40%
(MQS score decreased to 56), which restored an almost nor-
mal level of consciousness and lucidity. She was also able to
resume walking. In parallel, we observed a reduction of her
anxiety and depression symptoms, confirmed by the liaison
psychiatrist. Four other rTMS sessions were performed to
maintain this result. Progress of her disease led to her death
6weeks later.
Case report 2
Case presentation
A woman in her late 60s presented a cutaneous T-cell lym-
phoma. She had received chemotherapy, together with
symptomatic treatment for intense refractory pruritus. The
patients quality of life had gradually become worse, with
deterioration of her cutaneous state and body image.
The patient was admitted to the Palliative Care Unit
while complaining of the inefficacy of the various symp-
tomatic treatments that she had taken on pruritus and dif-
fuse pain of the limbs. Her mean pain was initially scored
as 7/10 on the NRS, related to cutaneous lymphomatous
infiltration, with a marked neuropathic component
(DN4: 5/10). It was refractory to step 2 analgesics, and
step 3 had been poorly tolerated previously. Amitriptyline
had been stopped because it was only minimally effec-
tive and poorly tolerated. The liaison psychiatrist con-
sidered that the patient presented a major depressive
disorder and proposed a treatment with a selective sero-
tonin reuptake inhibitor (SSRI) antidepressant (escitalo-
pram). The initial MQS score of 12 was relatively low in
this second case. In view of the repeated treatment fail-
ures and a serious cutaneous adverse drug reaction dur-
ing the last cycle of chemotherapy, the patient refused all
new drug treatments.
Case management
The multidisciplinary medical and nursing team proposed
the various complementary non-drug treatments available
in the unit, and then rTMS, with the same protocol: five
consecutive daily 20-min sessions of right motor cortex
stimulation, with the same parameters.
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Case outcomes
The NRS markedly decreased on the days following these
five consecutive sessions, from 7 to 2/10 (Figure 1). Drug
treatment after these five sessions decreased to paraceta-
mol 1.5g daily and maintenance of escitalopram. The
MQS score therefore decreased to 4.
Although admission to the palliative care unit per se
helped to improve the patients mood, rTMS also appeared
to have a beneficial effect on her mood. The Hospital
Anxiety Depression (HAD) scale decreased from 9/21
(before the first rTMS session) to 1/21 for anxiety score,
and from 7 to 3/21 for depression score. This appeared to
be clinically relevant for the liaison psychiatrist and was
confirmed by elements of the psychiatric interview.
However, the course of rTMS was administered after
3weeks of treatment with escitalopram, a period corre-
sponding to the usual onset of action of this molecule.
Nine days after stopping rTMS, pain recurred, and the
patient immediately requested another rTMS session. It
was performed, and the patient was able to be discharged
to a retirement home. Weekly maintenance rTMS sessions
were planned.
Discussion
Pain related to cancer progression often raises complex
management problems. High doses of analgesics and co-
analgesics and combined management of the nociceptive,
neuropathic and visceral components are often necessary
to relieve the patients pain. Although it is often difficult to
clearly distinguish the respective roles of these various
components, the nociceptive component is generally well
controlled by the use of step 3 opioids. Despite various
modes of administration, some patients experience severe
adverse effects of these treatments, and some patients con-
tinue to experience nociceptive pain that is relatively
refractory to morphine.5 Similarly, treatment of some
forms of neuropathic pain may require the use of high
doses of anticonvulsants and antidepressants, resulting in
major drowsiness, further decreasing the patients quality
of life. In terminal patients experiencing mixed pain, the
combination of several therapeutic classes with potentia-
tion of their respective adverse effects often results in
severe drowsiness and a very marked impairment of qual-
ity of life.6 Patient 1 presented all of these aspects, while
the iatrogenic effects of drug treatment were no longer the
primary complaint in Patient 2.
In this setting of patients with refractory cancer pain,
the currently available treatments are usually invasive,
raising legitimate questions concerning their benefit/risk
balance for the patient. In contrast, the main advantage of
repeated transcranial magnetic stimulation, a relatively
new approach for the treatment of pain disorders,7 is its
noninvasive nature. The use of rTMS, as adjuvant therapy
Nizard et al. 567

Figure 1. Course of the numerical rating scale (NRS) of pain (solid line) and treatment (Medication Quantification Scale (MQS))
(dotted line) between January 20 and March 16 (a: patient 1) and between February 25 and May 5 (b: patient 2). (a) Evolution of the
NRS and MQS in Patient 1. For greater simplicity, MQS was calculated with a decimal (12.6 instead of 126 on January 20). Sessions
performed on 31/1, 3/2, 6/2, 7/2 and 8/2. (*Start of treatment with midazolam; **Discontinuation of treatment with midazolam;
***Wedding; ****Discharge from the palliative care unit; 3/3: Return to the palliative care unit; 12/3: Onset of terminal phase;
*****Death). (b) Evolution of the NRS in patient 2. Initial MQS score of 12 was relatively low in this second case, and decreased to
4 after rTMS. (*Admission in palliative care unit; **Admission in rest house; ***Death.)
rTMS: repetitive transcranial magnetic stimulation.

in the context of multidisciplinary management provided
by a palliative care unit, appeared to be a potentially useful
approach, with a favourable benefit/risk balance.
rTMS has been shown to be effective on both chronic
pain and depression. It is generally associated with
excellent safety and the rare adverse effects are usually
only minor, and mainly consist of transient headache.8
The rTMS target generally used to treat depression is the
dorsolateral prefrontal cortex, when the target for the
treatment of chronic pain is the precentral motor cortex,
rather than somatosensory cortical areas. The relevance
of this target has been confirmed by many studies that
have provided convincing evidence for the efficacy and
the mechanisms of action of invasive and noninvasive
motor cortex stimulation.7
The analgesic efficacy of high frequency (>5Hz)
rTMS of the motor cortex on neuropathic pain has now
been clearly established, with a level of evidence of A8
(several convincing class I and II randomized controlled
trials), while the level of evidence remains B/C for non-
cancer/non-neuropathic pain (complex regional pain syn-
drome (CRPS), fibromyalgia, etc.).
It has also been regularly observed that even in the case
of bilateral or midline pain, as in the present cases, stimu-
lation on only one side could be sufficient.8 A concomitant
improvement of pain and depression, corresponding to the

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568 Palliative Medicine 29(6)
affective component of pain, has already been observed in
chronic pain patients treated by motor cortex stimulation,8
probably due to functional interactions between the motor
cortex and the cingulate, orbitofrontal and prefrontal corti-
ces involved in the emotional component of pain.
This combined effect could be particularly useful in the
context of the end of life. In the present cases, rTMS ses-
sions over 1week allowed a significant pain improvement
and/or reduction of analgesics, allowing the patient to
recover a sufficient level of consciousness, lucidity and
motivation to complete a complex sociofamilial project.
As this study was based on only two open-label cases
with no comparison with the sham technique, it is obvi-
ously impossible to draw any conclusions on the efficacy of
rTMS in this indication (the effect of rTMS may consist of
a placebo effect), or to define its potential role, in the pallia-
tive setting, in patients with refractory pain. However, due
to its potentially favourable benefit/risk balance, this tech-
nique appears to be a promising adjuvant therapy in selected
patients, in which short-lasting pain relief is required.
Several potential obstacles, more specific to this popu-
lation, must be taken into account. The accessibility of the
machine can constitute a problem for these patients, who
are often difficult to transport. Nevertheless, some
machines are relatively easy to use, and can be taken to the
patients bedside.
In the specific setting of palliative care units, adapted
protocols could be proposed with, for example, three ses-
sions on 3 consecutive days, rather than five, which would
allow more patients to benefit from rTMS. Inversely, for
patients in a palliative setting, but not at the end of life, it
would appear legitimate to propose maintenance sessions
in order to maintain the analgesic effect of rTMS in the
medium term.
Conclusion
In the context of palliative care of cancer pain patients at
the end of life, motor cortex rTMS, a noninvasive and very
well-tolerated technique, with a limited efficacy over time
appears to be a highly relevant technique. Although the
place of rTMS with respect to other treatment options still
needs to be defined, it can be used as adjuvant therapy, as
part of global palliative care, as it is likely to improve vari-
ous components of pain, including the emotional-affective
components. In addition, by reducing the doses of analge-
sics, rTMS decreases the severity of their adverse effects,
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which can lead to a marked improvement in the patients
quality of life. We are currently conducting a prospective
open-label study to support the proof of concept and feasi-
bility of rTMS in this specific setting, before envisaging a
randomized controlled trial comparing active stimulation
and sham stimulation.
Acknowledgements
We confirm that Ethical Committee approval was sought and
that guidelines on patient consent have been met. Both Patient 1
and 2 gave their permission for their cases to be written for
publication.
Declaration of conflicting interests
The authors have no conflicts of interest to declare.
Funding
This research received no specific grant from any funding agency
in the public, commercial or not-for-profit sectors.
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