Download Lidocaine 5 % patches as an effective short-term co

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DOI 10.1007/s00520-013-1948-7
SPECIAL ARTICLE
Lidocaine 5 % patches as an effective short-term co-analgesic
in cancer pain. Preliminary results
Cristina Garzón-Rodríguez & Miquel Casals Merchan &
Agnes Calsina-Berna & Eugenia López-Rómboli & Josep Porta-Sales
Received: 20 August 2012 / Accepted: 13 August 2013
# Springer-Verlag Berlin Heidelberg 2013
Abstract
Purpose To analyze the short-term efficacy and patients’ subjective perception of the use of lidocaine 5 % patches for
painful scars (post-thoracotomy and post-mastectomy) and
pain caused by chest wall tumors.
Methods This is a prospective, descriptive, non-controlled,
non-randomized, open-label study of patients seen in the
palliative care outpatient clinic. Demographic data, variables
relating to the severity of the pain, and concomitant therapy
both at the start and end of treatment, the need for interventional anesthetic techniques (IAT), patients’ subjective perception and treatment-related side effects were all recorded.
Results Twenty patients were included with a mean follow-up
of 29.2 days. The treatment led to a statistically significant
clinical improvement in pain severity. There was no clinically
significant opioid dose escalation during the treatment period.
Only three patients required IAT to relieve the pain. Sixty five
percent of patients were very satisfied with the therapy. No
systemic or local adverse events were reported.
Conclusions The addition of lidocaine 5 % patches is effective in the short term for the treatment of neuropathic cancer
pain accompanied by allodynia, whether deriving from a
painful scar or chest wall tumor. These findings need to be
This paper was presented as a poster at the MASCC/ISOO 2012. International Symposium on Supportive Care in Cancer New York City on
June 28–30 2012.
C. Garzón-Rodríguez (*) : A. Calsina-Berna : E. López-Rómboli :
J. Porta-Sales
Palliative Care Service, Institut Català d’Oncologia, Bellvitge
Biomedical Research Institute (IDIBELL), L’Hospitalet de
Llobregat, Spain
e-mail: [email protected]
M. Casals Merchan
Anesthesiology and Pain Clinic, Bellvitge Biomedical Research
Institute (IDIBELL), L’Hospitalet de Llobregat, Spain
confirmed by randomized controlled trials with larger
samples.
Keywords Neuropathic pain . Lidocaine 5 % patch . Painful
scar . Cancer
Introduction
Pain is a common entity in cancer patients, with a prevalence
ranging from 30 % at the time of diagnosis to 90 % in
advanced stages of the disease [1]. Pain is often of mixed
etiology, with nociceptive and neuropathic components. Various reports have shown the prevalence of the neuropathic
component in patients with cancer pain to be between 17 [2]
and 39.7 % [3].
Neuropathic pain is caused by an injury or malfunction in
the central or peripheral nervous system [4]. In patients with
cancer, it is mainly the result of nerve damage or compression
caused by tumor growth and can be difficult to manage [1, 5].
Two instances commonly associated with difficult-tocontrol neuropathic pain are pain following surgery (essentially post-thoracotomy and post-mastectomy) and the pain
caused by chest wall involvement in lung cancer [6, 7].
Post-thoracotomy pain is defined as a burning sensation or
dysesthesia in the incision area which persists for more than
2 months after the procedure [8]. Some studies report the
incidence to be 30–40 %, while others put the range from
11–80 %, with 2–10 % of patients suffering severe or disabling pain [8, 9]. The discomfort often persists 3–6 months
after surgery [9] and beyond, causing restrictions to the daily
lives of 50 % of patients [10]. The precise mechanism of
action is not known, but the most likely cause is damage to
intercostal nerves [7, 8]. Although different thoracotomy techniques have been compared, none has been shown to reduce
the incidence [8].
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Post-mastectomy pain has been described as a sharp stabbing
or burning sensation in the chest, arm and axilla, exacerbated by
shoulder movements. The incidence is estimated to be anywhere
between 4 and 56 % [11] with 5–10 % of cases complaining of
severe pain [9] associated with reduced quality of life [11].
Apart from interventional anesthetic techniques (IAT), a
number of drugs are used in the attempt to tackle neuropathic
pain which, through their mechanism of action, have been
shown to reduce nervous system excitability, either by suppressing the mechanisms that increase or trigger painful stimuli or by
potentiating the mechanisms that inhibit the transmission or
perception of the stimulus. The recommended therapeutic arsenal includes anticonvulsants, opioids, and antidepressants [12].
Topical lidocaine in the form of patches has been shown to be
effective in the treatment of postherpetic neuralgia and other
painful peripheral neuropathies [13–15]. Lidocaine patches
probably work through non-selective blockade of sodium channels in the damaged nociceptors. They were developed in 1989
and consist of a 10×14 cm patch with an adhesive layer of
lidocaine 5 % (700 mg/patch) which is placed on the area to be
treated for 12 h a day. However, when applied in cancer patients
with neuropathic pain of varying etiology, results have been
conflicting. A retrospective audit in a comprehensive cancer
center [16] analyzed 97 lidocaine patch prescriptions issued
between August 2001 and January 2009. According to their
medical records, the patients had some type of neuropathic pain
(postherpetic neuralgia, pain directly caused by tumor invasion,
post surgical pain and mixed pain: nociceptive and neuropathic
pain). Most of the patients had been treated with analgesics and
co-analgesics. Treatment duration varied from a few days to
several months. Approximately 25 % of the patients experienced
a clear benefit in terms of their pain. The presence of allodynia
seemed to be a predictive factor of good analgesic response.
A phase III, double-blind, crossover, multicenter study [17]
which compared the use of lidocaine with placebo in postsurgical pain in cancer patients failed to demonstrate beneficial
effects in terms of pain reduction. Of the 28 patients randomized, only 18 completed the two treatment phases. The study
was closed prematurely due to recruitment difficulties.
The primary objective of this study was to evaluate the
short-term efficacy of the application of lidocaine 5 % patches
in the treatment of cancer pain with a neuropathic component,
associated either with painful scar or superficial pain secondary to a chest wall tumor.
The secondary objectives were to evaluate the patients’
perception of the treatment and tolerance or the development
of treatment-derived adverse effects.
Materials and methods
This is a prospective, descriptive, non-controlled, nonrandomized, open-label study of the compassionate use of
lidocaine 5 % patches as co-analgesic in patients with cancer
pain secondary to painful scar or chest wall tumor.
Patients diagnosed with cancer and seen in the palliative
care outpatient clinic were included after giving their consent.
The patients were instructed to apply up to a maximum of three
patches at a time to cover the painful area for 12 h each day.
The main cause of the pain symptoms was painful scar
(mastectomy or thoracotomy) or chest pain secondary to
tumor infiltration (ribcage or subcutaneous tissue). There
had to be a neuropathic component plus allodynia, with a
PainDETECT score >18 [18].
On inclusion, the average pain had to be >4/10 on the
verbal numerical scale (VNS) and patients had to already be
prescribed at least one co-analgesic at therapeutic doses for
neuropathic pain (corticosteroid, antidepressant, and/or anticonvulsant) prior to the addition of the lidocaine patches (See
Fig. 1).
The variables recorded were related to epidemiological data
about the cancer, concomitant treatment, morphine equivalent
daily dose of opioids, the need for IAT during follow-up, local
adverse effects of the treatment with the patch and patient
global subjective perception, which was assessed with a simple
question and ordinal response “Have you noticed any improvement in the pain since the treatment with the lidocaine patch?”;
with the response categories of “none,” “mild,” or “significant”.
The severity of the background, average, and breakthrough
pain was assessed by a VNS from 0 to 10 (0 = no pain at all
and 10 = the worst pain imaginable).
Modification of the opioid dose was permitted during the
follow-up period but the doses of co-analgesics had to remain
stable. Patients could be included if they were already on specific
treatment for their cancer, but if such treatment was started
during the follow-up period the patient had to be excluded.
The SPSS 18 statistics package was used to analyze the
data. The demographic data and the rest of the variables were
analyzed with simple descriptive statistics: quantitative variables with mean and standard deviation and categorical variables as percentage. The Wilcoxon signed-rank nonparametric test was used to compare the different pain scores
between the baseline assessment and the end of follow-up.
Results
Between March and September 2011, 20 patients were included. The average age was 62 years and 55 % of the sample was
male. The most common type of carcinoma was lung cancer
(55 %) and 40 % of the patients were receiving a course of
chemotherapy. The average duration of the treatment was
29.2 days (SD 26.4, range 3–90 days). Five patients
discontinued the treatment after less than 10 days due to lack
of efficacy and one patient due to clinical deterioration and the
need for hospital admission.
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Fig. 1 Flow chart for identifying
appropriate patients for the
treatment
Patient with pain
VNS >4/10
YES
C
O
N
S
I
D
E
R
Skin area well
demarcated?
YES
NO
Neuropathic origin
PAIN DETECT >18
YES
O
T
H
E
R
NO
Neuropathy involving
superficial tissues?
YES
NO
T
H
E
R
A
P
Y
Presence of allodynia
YES
NO
Already receiving coanalgesics at
therapeutic doses?
YES
NO
Initiate treatment with
lidocaine 5% patches
Consider therapeutic
doses first
All the patients were receiving treatment with opioids at the
time of inclusion with a mean oral morphine equivalent daily
dose of 125 mg/day (SD 120) range (20–560 mg), 70 % were
taking antiepileptic treatment (gabapentin, pregabalin) as coanalgesic, 45 % were on corticosteroids and 5 % on antidepressants (tricyclics, venlafaxine, or duloxetine); 45 % were
receiving a combined treatment with two co-analgesics.
Only three patients required an IAT during the follow-up
period for control of refractory pain. These patients were the
ones receiving higher daily doses of morphine (200, 240, and
560 mg/day, respectively) and they were on a combination of
two co-analgesics, which could indicate that their pain was
more difficult to control. None of the three felt significant
improvement or satisfaction with the use of the lidocaine
patch.
There was a clinically and statistically significant improvement in all the subjective pain assessment parameters (see
Fig. 2). The mean VNS in breakthrough pain before the
treatment was 7.1 (SD 1.89) and the mean at the end of
follow-up was 4.25 (SD 1.83) (P <0.05). The average pain
score on the VNS went down from 5.20 at screening (SD 1.32)
to 3 (SD 1.37) (P <0.05) at the end of follow-up. There was a
significant reduction in the number of breakthrough pain/day
from 2.75 (SD 2.24) to 1.75 (SD 1.71) (P <0.05). A significant
increase was also found between the initial opioid dose and the
dose at the end of the follow-up period (see Fig. 3).
The majority of the patients (65 %) were very satisfied with
the treatment. There was no statistically significant difference
between satisfied and non-satisfied patients when analyzing
the morphine increase (15.7 vs. 10 mg) (P =0.1) and none had
received IAT; in other words, we cannot attribute the perception of improvement to the increase in opioids or the use of
IAT. No local or systemic treatment-derived adverse effects
were reported.
Discussion
The results of this study showed that the addition of lidocaine
5 % patches could be effective in the short term for the
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Fig. 2 Average, worst, and breakthrough pain evolution in each patient and their mean improvement during the study
treatment of neuropathic cancer pain, whether deriving from
painful scar or chest wall tumor. The underlying mechanisms
responsible for the symptom relief produced by topical lidocaine in patients with allodynia are not fully understood.
Lidocaine acts through blockage of abnormally functioning
Fig. 3 Morphine equivalent daily dose (in milligrams) evolution in each
patient during the study
(sensitized) sodium channels in dermal nociceptors, thereby
reducing ectopic discharges. Reduction of afferent ectopic
activity may reduce central sensitization [19].
These results are similar to those obtained for superficial
neuropathic pain following surgery; Hans G et al. [20]
conducted a prospective open-label study including 40 patients with severe neuropathic pain secondary to surgical
trauma and non-surgical trauma. Approximately 52.5 % of
the patients benefited from the treatment with lidocaine, with
the severity of their pain on a VNS diminishing from 7.2 at
screening to <5 at the end of the study. As in our case, the
authors put emphasis on precise selection of the patients in
whom, in addition to suffering from neuropathic pain, the pain
had to be well localized, superficial, and involve positive
symptoms such as allodynia and hyperalgesia. The authors
of the retrospective audit [16] also state that the presence of
allodynia could be considered as a predictive factor for response. They included a wide variety of causes of pain syndrome but the groups that benefited most were those with
postherpetic neuralgia and painful scar; hence, once more, we
are talking about the same two characteristics: well localized
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and superficial. We are unable to conclude whether or not
topical lidocaine would be effective in other cases of neuropathic or mixed etiology pain or in cases where the pain is of
deeper origin (e.g., pleural involvement only).
The severity of the pain was analyzed using a VNS, thus
measuring the background, average, and breakthrough pain.
However, no instruments were used that were specifically
designed to assess the emotional dimension, quality of life or
sleep, or degree to which the pain interfered with daily activities.
This may constitute a limitation since there are other studies
[17] which failed to demonstrate improvement with the lidocaine patch in terms of pain severity, but did find a reduction in
the extent to which the pain interfered with daily activities.
There is also a lack of consensus on the optimum duration
of treatment with the patch. The onset of action is relatively
rapid (hours). Fleming and O’Connor [16] suggested continued use of the patch for at least 10 days before assuming lack
of clinical benefit. Cheville et al. [17], however, question the
4-week treatment period they used in their study, suggesting
that the negative results obtained may have been related to the
small simple size and the fact that 1 month of follow-up was
insufficient.
The mean duration of treatment in our case was 29 days, with
a range from 3 to 90 days. The reasons for withdrawal were lack
of efficacy (n =5), the need for hospital admission or deterioration due to progression of the underlying disease (n =1).
Another factor we took into account before considering
applying the patches in an indication other than that authorized (compassionate use) was their safety. Blood levels of the
lidocaine 5 % patch are minimal when applied at a maximum
dose of three patches a day for 12 h, and even when four
patches a day are applied for 18 h. The systemic circulation
reaches only 1/10 of the concentration required in the treatment of cardiac arrhythmias [21]. As found previously by
other authors [14–17], none of the withdrawals from our study
were attributable to local or systemic undesirable effects.
There are limitations in terms of extrapolating our results;
this was a non-controlled, open-label study in which opioid
titration, continuation of chemotherapy if it had been started
prior to inclusion, and interventional anesthetic techniques for
pain control were all permitted during the treatment period.
These factors mean that the results should be interpreted with
caution. Although it was permitted to change the opioid dose
during the observation period, the actual increase (final dose
minus initial dose) in the mean oral morphine equivalent daily
dose was 15 mg, which is low in terms of being attributable to
the clinical improvement in the patients.
Conclusions
The addition of lidocaine 5 % patches could be effective in the
short term for the treatment of neuropathic cancer pain
accompanied by allodynia, whether deriving from painful scar
or chest wall tumor. Patient satisfaction with the patches was
high and the incidence of adverse effects negligible. Randomized, controlled clinical trials are needed with a larger number
of patients in order to analyze the role of topical lidocaine in
the treatment of neuropathic pain in cancer patients.
Funding None.
Conflict of interests The authors have no conflict of interest to declare.
Financial disclosure None.
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