Journal of Clinical Anesthesia (2005) 17, 328 – 330
Editorial
Botulinum toxin efficacy for the treatment of pain
There have been many reports in the literature on the
treatment of headache following the first published observa-
tion of successful myofascial pain and headache treatment
using botulinum neurotoxin [1]. This was followed by other
open label and case series of headache benefit with
botulinum neurotoxin [2-4]. One widely accepted premise
within evidence-based medicine, among others, supports the
idea that well-designed level I studies of sufficient power are
needed to best clarify issues of efficacy [5,6]. However, such
large studies are very expensive. Three interesting studies
have recently been reported. One open label study of
61 patients found that duration of migraine illness in years
was a predictor of botulinum toxin treatment response [7]. A
randomized, double-blind, placebo-controlled trial involving
355 patients given botulinum toxin type A for the treatment
of chronic daily headache showed a statistically significant
number of subjects experiencing a 50% or greater decrease in
headache frequency [8]. Another randomized, double-blind,
placebo-controlled trial looking at a subgroup of the same
355 patients studied by Mathew et al found a statistically
significant difference and improvement in baseline headache
frequency and severity between patients not on any
prophylactic medications receiving botulinum toxin treat-
ment and placebo treated groups [9].
But why publish another case report, such as the one in this
issue of the Journal of Clinical Anesthesia entitled, ‘‘Peri-
orbital Pain Associated with Spasms that Responded to
Botulinum Toxin Treatment and Microvascular Decompres-
sion Surgery: A Case Report?Q [10]. A thoughtful argument
has been made that until more definitive studies on efficacy
emerge, there should be a moratorium on publication of open-
label studies and case series involving botulinum toxin for the
treatment of headache pain [11].
However, while we wait for more definitive data on
botulinum toxin efficacy for the treatment of headache pain to
soon emerge, the case report by Iida et al. [10] serves as a
useful and timely reminder of the many controversies
surrounding the off-label use and publications of botulinum
toxin for pain. One of the earliest accepted observations of
0952-8180/$ – see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.jclinane.2005.02.006
head and neck pain reduction was consistently observed and
reported with the application of botulinum toxin in the
treatment of cervical dystonia [12]. Since then, many
positive, equivocal, and negative reports have been published
regarding a variety of pain disorders, sometimes in conflict
with one another.
The elements of controversy are complex and include
conflicting and contradictory methods, techniques, and
results. Perhaps there are clues that could explain the apparent
disparities among the positive, neutral, and negative reports
emerging. The differing results between studies could relate
to variations regarding mechanisms of pain, mechanisms of
treatment, methods of treatment, and the existence of
subpopulations and patient selection criteria, which could
influence the degree of efficacy or lack of efficacy.
Comparisons of reports and the ability to make definitive
conclusions on efficacy are hampered by these factors. Such
factors include case reports with differing presentations, bias,
and open-label use of botulinum toxin reporting benefit;
blinded and double-blinded randomized controlled trials
indicating either benefit or lack of benefit; the low power of
studies; and differences among reports regarding prepara-
tions, methods, and injection techniques of botulinum toxin.
Uncertainty as to the mechanisms for particular pain
disorders, the possible direct and indirect mechanisms
of action of botulinum toxin, in addition to the well-known
blockade of acetylcholine release at the presynaptic neuro-
muscular junction, the possible contribution toward efficacy
from other coexisting therapies when present, and placebo
and other possible physiological effects all add to confusion
and questions about prior published reports.
Many reports to date have suggested evidence for
headache pain benefit from botulinum toxin when compared
with other pharmaceuticals in the areas of cost, health care
facility use, prolonged improvement, minimal side effect
profile, prolonged pain benefit before and after clinical
muscle effects, and pain refractory to other therapies [5].
Neutral and negative results also have been published [11]. A
number of reviews and reports, including a randomized,
Editorial
double-blind, placebo-controlled study as well as a report of
efficacy [13,14], have shown minimal or no efficacy of
botulinum toxin for the treatment of migraine headaches.
Similar conflicting results between efficacy and lack of
efficacy for the treatment of tension headaches and chronic
daily headaches have been reported [15-19]. Two interesting
and opposing reviews provide additional insight into the
status of the current literature [5,11]. Comparing negative,
neutral, and positive results among seemingly similar
populations and diagnoses suggests other complexities and
confounding factors. Stating the obvious, although well-
designed level I studies are desired—and needed—the
western scientific gold standard may not be applied so
easily regarding pain and botulinum toxin efficacy.
Furthermore, there may be problems regarding selection
criteria, subpopulations, techniques, and known and
unknown physiological mechanisms. Basic and clinical
scientific understanding of the development, perpetuation,
nervous system changes and adaptations, genetic and gene
associations, interaction and communication between the
peripheral central nervous systems, and treatment of
chronic painful states has had a focus shift from symptom
control to the determination of mechanisms [20]. This
recognition acknowledges the inadequacies of developing
effective treatments for pain based solely on diagnosis. A
diagnosis does not necessarily determine the mechanism
or relative weight of mechanisms of associated pain
states [21,22].
Recent research has demonstrated a relationship between
botulinum toxin and regulation of calcitonin gene-related
peptide secretion from cultured rat trigeminal ganglia neu-
rons. The data demonstrated a decrease in the amount of
calcitonin gene-related peptide released from the cultured rat
trigeminal neurons [23]. The finding could have implications
in the treatment of migraine, trigeminal neuralgia, and other
pain disorders; however, the authors caution against an
automatic extension to human beings from the rat model.
Recent work has linked inflammation, the immune system,
and activation of glial cells as factors in the development,
perpetuation, and possible focus of treatment of chronic pain
states [24]. Glial proinflammatory cytokines appear to
mediate exaggerated pain states, one amplification point
occurring at the level of the activated glia in the spinal cord
[25]. Perhaps the varying interplay of peripheral and
central activation of inflammatory, proinflammatory, and
excitation phenomena may explain the varying results of
botulinum toxin application among subgroups of patients
within clinical diagnostic categories, and patient selection
criteria may be a factor in determining efficacy.
However, even with so many unknown factors implied in
the chronic pain state, it is still possible to draw reasonable
conclusions about specific therapeutic efficacy. An example
is the recently Food and Drug Administration–approved
indication for the management of diabetic peripheral neuro-
pathic pain, duloxetine HCl. There are many possible theories
to explain diabetic peripheral neuropathic pain, including
329
central sensitization, hyperexcitability, and decreased inhibi-
tion. One accepted pain inhibition theory is the pain
perception–modulating role in the brain, spinal cord, and
peripheral nervous systems of endogenous serotonin and
norepinephrine [26,27]. Targeting both of these endogenous
neurochemical modulators may lead to central pain inhibi-
tion. The dosage and efficacy of duloxetine HCl over placebo
were demonstrated in the treatment of diabetic neuropathic
pain1. The pain inhibitory effect of duloxetine HCl is
thought to be centrally mediated through potentiation of
serotonin and norepinephrine activity in the descending pain
pathways in the central nervous system.
Regarding the efficacy of botulinum toxin therapy for the
treatment of pain and headache, we should wait for the
results of randomized controlled trials with sufficient patient
numbers and power to confirm the many earlier observations
of therapeutic benefit reported in the literature. Given some
of the positive and negative contradicting results in the
literature thus far, the designing of future studies and
interpretation of data may be challenging.
Efficacy differences found among subpopulations
through patient selection criteria within pain disorders may
also assist in understanding the mechanisms contributing to
pain states as well as the possible therapeutic mechanisms
and bioeffects of botulinum toxin.
Martin A. Acquadro MD, DMD, FACP, FACPM
(Assistant Professor)
Harvard Medical School
Associate Anesthetist and Director of Cancer Pain
Department of Anesthesia and Critical Care
Massachusetts General Hospital
15 Parkman Street, #333
Boston, MA 02114, USA
E-mail address: macquadro@partners.org
Gary E. Borodic MD
(Assistant Professor, Surgeon)
Harvard Medical School
Boston, MA, USA
Department of Ophthalmology
Massachusetts Eye and Ear Infirmary
Boston, MA 02114, USA
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