Breast Cancer Clinical Trial
Official title:
Exploratory Study on the Use of Pregabalin for the Treatment of Taxol Related Arthralgia-Myalgia
Paclitaxel is chemotherapeutic agent used in many of the most common anti-cancer regimens.
Its use is frequently associated with moderate to severe muscle and joint pain that may
persist for several days after the treatment. This side effect, known as "Arthralgia-Myalgia
Syndrome, has a significant impact on the quality of life and functional abilities of those
receiving the treatment, and is not alleviated by many of the interventions attempted for
that purpose.
Sporadic reports suggest that a drug called gabapentin may be effective in the management of
this adverse effect. Observations from our practice indicate that pregabalin, which
possesses similar biological activity to that of gabapentin, may also be useful in
preventing and treating paclitaxel associated myalgia - arthralgia.
The current study represents an initial evaluation of the hypothesis that pregabalin may be
beneficial in the management of the symptoms due to the "Arthralgia-Myalgia Syndrome". The
investigation will be carried out in the format of a small scale, randomized, placebo
controlled trial with patients receiving paclitaxel in the course of standard treatment for
breast cancer.
Taxane Related Arthralgia-Myalgia Syndrome:
Paclitaxel and docetaxel are the major representatives of the drug class of taxanes, agents
commonly used in the treatment of a variety of solid tumors. They interfere with the mitotic
process of dividing cells by stabilizing the microtubules and are the mainstay of treatment
in lung, breast, and ovarian cancer, among others. The adverse side effects associated with
taxane treatment frequently impair the quality of life of cancer patients and occasionally
impose discontinuation of the oncological treatment of choice (Forsyth, Balmaceda et al.
1997; Saibil, Fitzgerald et al. 2010).
The phenomenon of diffuse pain involving joints and muscles in the wake of treatment with
taxanes commonly referred to as Taxane related Arthralgia-Myalgia Syndrome (from here on
noted as TAMS) is well known and documented (Rowinsky, Chaudhry et al. 1993). It is common,
as apparent from a recent retrospective study of patients treated with regimens used for
breast cancer which revealed an 80% incidence of taxane related pain (Saibil, Fitzgerald et
al. 2010).
The pain may be localized, regional or diffuse, most commonly in the back, hips, shoulders,
thighs, legs and feet (Loprinzi, Maddocks-Christianson et al. 2007). It is usually depicted
as arthralgia-myalgia due to the difficulty to associate it clearly with either the joints
or the muscles (Loprinzi, Maddocks-Christianson et al. 2007). The nature of the sensation is
described as aching, deep pain, often with associated radiating, shooting, stabbing,
pulsating elements (Loprinzi, Maddocks-Christianson et al. 2007). The sensation is of unique
quality previously unencountered by those experiencing it, the description of which is not
compatible with established reports of neuropathic pain.
The syndrome may be of incapacitating intensity, capable of imposing days of bed restriction
on those suffering from it. This burden is often extended to significant others who have to
remain and care for the daily needs of those handicapped by the pain. Attempts of treatment
with steroids, non-steroid anti-inflammatory drugs and opioid analgesics frequently fail to
produce satisfactory results (Garrison, McCune et al. 2003).
Pregabalin - Basic Pharmacology and Potential for Treatment of TAMS:
Pregabalin is a small molecule with an established efficacy in the treatment of neuropathic
pain (Gajraj 2007). It is known to interact with the α2-δ subunit of voltage gated calcium
channels present in multiple tissues, most prominently in brain and muscle (Taylor,
Angelotti et al. 2007).
Pregabalin is rapidly absorbed via a specialized transport system, reaching a peak
concentration in the serum circa one hour after oral ingestion (Gajraj 2005).
Bioavailability exceeds 90% and the pharmacokinetic profile is linear throughout the
clinically relevant concentrations (Gajraj 2005). It does not bind significantly to proteins
in the blood stream, does not undergo any modification during its passage through the
organism, and is eliminated unchanged in the urine (Gajraj 2005). No significant
pharmacokinetic interactions have been reported to date (Gajraj 2007).
Currently pregabalin is being used in the treatment of neuropathic pain and as an
anti-epileptic agent (Gajraj 2007). Accumulated evidence is supportive of a high degree of
safety in its use, with the most common side effects constituting of mild to moderate degree
dizziness, somnolence, feeling drunk, fatigue and increased weight (Harmark, van Puijenbroek
et al. 2011).
Sporadic reports suggest that gabapentin may be effective in alleviating Taxol related
arthralgia-myalgia symptoms (Nguyen and Lawrence 2004). On grounds of similar
pharmacodynamics (Bryans and Wustrow 1999) it may be hypothesized that pregabalin also has
potential to alleviate the paclitaxel related arthralgia-myalgia. Furthermore, observations
from our clinical oncology service are supportive of this hypothesis.
Evaluation of the Taxane Related Arthralgia-Myalgia Syndrome:
Pain constitutes a major component of the Taxane related Arthralgia-Myalgia Syndrome (from
here on referred to as TAMS) (Garrison, McCune et al. 2003). We propose that pregabalin may
have a significantly beneficial effect on the pain secondary to this syndrome. Consequently,
evaluation of the pain before and after treatment with the study drug by means of a well
established pain scoring method is required.
Modern pain research acknowledges the subjective and complex nature of pain that complicates
its assessment. Furthermore, ethical imperatives place constraints on the comparative
control to serve the in evaluation of a novel analgesic intervention (Silverman, O'Connor et
al. 1993). One of the solutions to this issue, using normalized ordinal evaluations of pain
and analgesic drug consumption around a central value in a manner that also accounts for
changes in analgesic drug requirements (Silverman, O'Connor et al. 1993) will serve for
direct assessment of the study hypothesis.
The Integrated Assessment of Pain Score and Rescue Analgesic Treatment evaluation according
to Silverman et al will be augmented by raw pain assessment by means of a well established
pain scoring method (Farrar, Portenoy et al. 2000).
Bed restriction is a direct result of the TAMS that is often described by those suffering
from it. It is hereby proposed to monitor bed restriction by recording the number of hours
spent in horizontal position between the time of getting up from the night's sleep and the
hour of going to bed at the end of the day. The proposed measure will compare the number of
hours spent in the horizontal position on the day preceding the taxane treatment, and the
number of hours spent in that position on the day with the highest score of pain during the
week following treatment. The sample size is not calculated to serve the validation of this
novel measure, but an effort to assess its association with established quality-of-life
scores will be made.
The current proposal is focused on evaluating an intervention with potential to have a
positive impact on the quality of life of individuals receiving chemotherapy with taxanes.
The FACT-Taxane scale is a psychometric tool specifically developed to assess the impact of
taxane based treatment (Cella, Peterman et al. 2003). However, quality of life is a
composite measure, and requires a larger sample size to determine efficacy, and therefore it
will only serve as a secondary endpoint.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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