by
Aftab J. Ahmed, Ph.D.
Systemic Enzymes
in Fibromyalgia
Elusive as it is, fibromyalgia (FM) is equally baf-
fling, exasperating and challenging to physicians
and patients alike. Described commonly as diffuse,
nondescript pain with palpable stiffness in soft
tissue, syndromes associated with FM have been simultaneously
dismissed out of hand and deemed as a cause
célèbre. This divide may be inherent in attempts to
define, in a narrative, a disorder as intangible as FM.
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Fibromyalgia is a clinical
construct developed primarily
by rheumatologists and was
clinically first described in 1904.
To date its diagnosis is
ascertained largely by exclusion,
based on patient history and a
thorough physical examination.
The criteria set forth by the
American College of
Rheumatology (ACR) facilitate
diagnosis considerably,
which include presentation of
persistent musculoskeletal pain
for at least three months and
tenderness, or hypersensitivity,
on digital palpation in at least
11 of 18 anatomical points
(“tender points”) in the occipital,
neck, shoulder, thoracic and
lumbar spine, hip, elbow, and
among others, knees.
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The core symptom of FM is widespread
pain, perceived as arising from
the muscle, even though joint pain
may well be concomitant. Typically,
FM pain and stiffness have a diurnal
variation, whereby the symptoms are
least bothersome between late
morning and mid-afternoon hours.
Further, FM symptoms wax and wane
in intensity over days and weeks and
are subject to flare-up upon exertion,
systemic infections, soft tissue
injuries, non-restorative or lack of,
sleep and psychological and emotional
stress. The most telling of
symptoms is easy fatigability upon
even moderate exertion, which could
be potentially debilitating and, worse
yet, frustrate therapeutic outcomes.
While a clear cut cause has not yet
been identified, FM is usually
associated with physical trauma,
infections and psychological distress.
Interestingly, in some cases, physical
trauma or injury may not manifest
itself as FM until some time has
elapsed after an injury. Irrespective of the underlying
cause of FM, secondary manifestations of the disease
exacerbate the primary symptoms. As such, the
boundary between what triggers and perpetuates FM
becomes quite blurred indeed. This is because the
overlap between physical symptoms and psychological
components cannot be teased apart.
Accordingly, two different sets of factors aggravate
FM and complicate both its natural history and clinical course. On the one hand are components that predispose
to and precipitate FM whereas, on the other, are
perpetuating factors of the disease.The overlap and
interactions among these factors are nearly impossible
to dissect. For instance, restless legs syndrome (RSL)
may be presented with FM. While there is no evidence
that RLS necessarily follows or precedes FM, its concurrent
presentation is yet another complication that must
be reckoned with. By the same token, the normal tendency
while experiencing pain is to hold bands of achy
muscles in position to minimize discomfort. The
upshot is that the muscle in question becomes even
more taut, which invariably deepens the pain when it
inevitably has to be moved. Furthermore, psychogenic
factors could paradoxically “feed” FM symptoms, as the
sufferer attempts to alleviate them, inducing more
stress, which further intensifies the symptoms. Given
this multiplicity of factors, FM is being increasingly
described as a somatized (medically unexplained symptoms)
functional disorder.
This categorization should bode well for therapeutic
outcomes in FM. Presently, therapeutic/corrective regimens
predominantly focus on mitigating pain, be it with
non-steroidal anti-inflammatory drugs (NSAIDS), opioid
analgesics, muscle relaxants or antidepressants. The
focus on pain in FM is predicated both because it is widespread
and has changing areas of emphasis. Whereas the
severity of FM symptoms may fluctuate, it is seldom that
the disease completely remits. In short, the tangible projection
of FM is unrelenting, unresolved pain for duration,
which becomes refractory to intervention.
As a part of the chronic pain spectrum, FM is characterized
by non-malignant, persistent pain. In the general
population, two percent of people (both men and
women) are prone to FM syndromes. Analyses of published
reports suggest that among FM patients, 25.2 percent
of women and 6.8 percent of men had 11 or more
tender points, as defined by the ACR criteria.
Tellingly, pain-free subjects show a logarithmic (i.e.,
accentuated, almost startled) response to increase in
pain intensity disproportionate to the strength of the
pain-inducing stimulus. However FM patients have a
linear response, as pain perception increases commensurate
with the stimulus against a background of generalized pain. This bespeaks that the sensory switch of pain perception
has been thrown open and is not reversible. As such, FM
represents a syndrome in which pain is experienced independent
of physical damage and must be seen rather as an issue
of pain processing. This is a matter of some sensitivity for FM
sufferers, as the pain experienced is all too real. Nonetheless,
recent evidence has begun to shed light on the curious paradox
of chronic pain.
The mechanistic minutiae of pain notwithstanding, it is
well-known that some of the conditions associated with FM
such as irritable bowel syndrome and irritable bladder syndrome
have identical central mechanisms that amplify pain. Similarly,
pain perception is exacerbated in many cases of low back pain,
despite the lack of inflammation. Hence, FM is but one among
the numerous conditions resulting in chronic pain without any
obvious trigger. In fact, it could be argued that in conditions
with yet unexplained, somatic symptoms—for example,
chronic fatigue and cognitive dysfunction, to name merely two,
would likely be explicated by pain amplification mechanisms.
Yet such considerations do not exclude an organic basis for
FM. Thus FM patients consistently show low tryptophan levels,
an amino acid necessary for the production of serotonin, a neurotransmitter,
which affects numerous loci in the brain,
including the sleep locus. This explains non-restorative sleep in
FM sufferers and implies alterations in the hypopituitaryadrenal
axis. Also, the amounts of substance P, another neurotransmitter,
are increased in the cerebrospinal fluid of FM
patients. Substance P enhances pain perception by as much as
three times the normal levels. Furthermore, severe fatigue after
exercise, prolonged standing or stressful situations may subject
FM patients to neurally mediated hypotension.
In turn, this leads to the breakdown
of the muscle tissue, which contributes
to pain typically associated
with FM. Accordingly, if hypoxia
were reversed and the muscle could
produce sufficient energy, fatigue
and exhaustion in FM might be
meaningfully managed. Whereas
therapeutic regimens by and large
zero in on pain to ensure functionality
and personal autonomy, it is
equally necessary to target those
processes that aggravate the FM
symptomatology.
Since no pharmaceuticals yet
appear on the horizon to correct the
metabolic context of the disease,
nutritional intervention offers an alternative to at least keep the severity of symptoms in check.
Specifically, with respect to energy replenishment, the nutritive
malic acid could potentially help the muscle produce more
energy. A metabolite in the Kreb’s cycle, which funnels requisite
metabolites to mitochondria for energy production, malic acid
may have an important role in increasing cellular energy under
both aerobic and anaerobic conditions. As such, nutritive supplementation
with malic acid should increase its intracellular
levels to offset energy deficit due to exertion or physical activity.
Additionally, S-adenosylmethionine (SAMe), which alleviates
stress and anxiety, has been in use to help cope with FM.
In general, the importance of maintaining sundry nutritives
well within their requisite ranges cannot be emphasized enough.
For instance, magnesium is a mineral critical to muscle relaxation,
and may be beneficial, especially with concomitant restless
leg syndrome and/or easy fatigability. Likewise, vitamins B1
and B6 are usually low in FM sufferers as well as among those
with mild depression and their supplementation should be
useful.
The natural history of FM is somewhat singular in that conditions,
concurrent to and secondary ramifications of the disease
itself, become inextricably intertwined. These, in part at least,
make FM refractory to corrective regimens. Therefore, it stands
to reason that management of secondary presentations is just as
relevant in any therapeutic/corrective regimen.
Consequently, if these conditions
are adequately managed,
the course of FM may be signifi-
cantly improved. For instance,
irritable bowel syndrome (IBS) is
typically presented in some cases,
which is as intractable as FM
itself. As yet, no satisfactory therapies
are available to manage IBS,
let alone its simultaneous handling
with FM. Importantly, no
organic cause has yet been identi-
fied and, given the broad range of
its symptoms, IBS is a prototypical
case of a disease where structure
and function coalesce. As such, IBS is uniquely suited for nutritional intervention. One of
the hallmarks of IBS is an imbalance in the intestinal flora.
Accordingly, if the floral balance were to be restored, cases of
simultaneous FM-IBS presentation should become far more
amenable to favorable outcomes. Floral balance in the colon is
optimally restored with prebiotics, principally with inulin isolated
from the root of Jerusalem artichokes. In fact, the
Jerusalem artichoke inulin is a prebiotic par excellence in that it
isolates naturally with magnesium organically linked to it,
among other trace and essential minerals. What is more, oral
intake of inulin not only delivers these minerals effectively but it
also facilitates absorption of dietary and supplemental minerals
efficiently.
Among the nutritives, though, systemic enzymes in the
management of FM quite stand out. Their benefits rest on the
premise that (an) organic trigger(s) skew(s) the balance between
the pro- and anti-inflammatory cytokines. Independent reports
show that NSAIDS relieve FM symptoms, in at least a subset of
FM patients, suggesting that FM does not have to become a sentence
for a life of unremitting pain. In fact, evidence points to
sub-threshold inflammation as underlying FM, despite the fact
that clinical examination is not suggestive of frank inflammatory
response. This contention is corroborated by the observations
that pro-inflammatory cytokines interleukin( IL)-6 and
tumor necrosis factor-á (TNF-á) can cause heightened
sensitivity to pain. That is, overproduction of IL-6 and TNF-á
may be operative in perpetuation of FM. After
all, FM is commonly attendant to rheumatoid
arthritis, low-back pain, and osteoarthritis—all
conditions in which pro-inflammatory cytokines
are pivotal. Accordingly, modulation of such
cytokines promises to relieve discomfort associated
with FM.
Curiously, though, this approach has
received less attention than it merits. In part, it
may be for absence of means to directly interfere
with the levels of pro-inflammatory
cytokines. The challenge inherent in modulation
of cytokines is that they comprise a rather
large family of molecular messengers and their
relative amounts are up- or down-regulated in
concert with each other. Consequently, modulation
of but one cytokine would likely disturb
the exquisite balance among them—unless, of
course, their respective amounts are coordinately
regulated. Systemic enzymes, especially
the combination of bromelain, papain,
trypsin, chymotrypsin and pancreatin in the
German formulation, have been shown to
modulate the immune response and hence,
down-regulate pro-inflammatory cytokines
while, at the same time, upregulating antiinflammatory
cytokines.
Since IL-6 and TNF-á contribute to the
inflammatory response, their levels are modulated
sufficiently to take the edge out of the discomfort typical of FM. In fact, an
exploratory study, carried out in Germany,
suggests that dispensation of systemic enzymes
helps manage FM symptoms. To an extent, the
benefits of systemic enzymes administration
may also be attributed to the bioflavonoid,
rutin, contained in the systemic enzymes cocktail.
It is known that in syndromes such as FM,
chronic pain is accompanied with reduced
thalamic blood flow. Thus, systemic enzymes,
by virtue of their proteolytic (proteindegrading)
activity, facilitate robust blood
flow, whereas rutin also is instrumental in
strengthening the vessel wall integrity.
Cumulatively, then, this specific German systemic
enzyme gemisch, along with rutin,
should be beneficial as a nutritive regimen over
the long run.
In summary, then, as nutritives, systemic
enzymes in combination with rutin, are rather
effectively employed to nutritionally manage
FM symptoms, especially in conjunction with
low-impact exercise. Aerobic exercise in the
management of FM is strongly advised, as it
improves pain and disturbed sleep and also
reduces the tender points count. Of late, functional
exercise, in which the routine movements
are emphasized, has come in vogue, and
should be invaluable to FM sufferers. It is wellknown
that systemic enzymes accentuate the
benefits of physical exercise by both stimulating
more robust blood flow and indeed, by
strengthening the body’s own repair processes.
As alluded to above, the many syndromes
characterized by chronic pain—including but
not limited to chronic fatigue syndrome,
repetitive stress injuries and in fact, sports
injuries, such as tennis elbow and golfer’s
frozen shoulder, would eventually form a continuum
of conditions with a common final
pathway to pain perception. With specific reference
to FM, however, implementation of a
nutritive regimen centered around systemic
enzymes should encourage the body to marshal
its own healing resources. Over time then,
chronic pain lurking in the shadow of
fibromyalgia might be sufficiently dulled so as
not to be terribly intrusive.
References available upon request, send a SASE
to totalhealth.
Aftab J. Ahmed, Ph.D., is vice president of
research and development and business development,
Marlyn Nutraceuticals, Inc. Phoenix,
Arizona. E-mail:
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