THE MODULATION OF STRESS
ANSWERS
IN PATIENTS WITH CANCERS.
By Renato COCCHI, a neurologist and a
medical psychologist
Abstract
Patients with cancers undergoing
chemotherapic or radio treatments have at least three causes of stress. The
illness itself causes even an internal metabolic stress. Chemo- or
radiotherapies produce chemo-metabolic or physical stresses of external origin.
Finally the awareness of his/her illness elicits a psychological stress.
By itself the illness can act on
homeostasis and give a rise to stress reactions that modify serotoninergic
mechanisms too.
Therefore, it comes out the depressive mood
and decreasing of the serotoninergic antipain reaction starting from the Raphe.
Side-effects of chemo- and
radio-therapies are mainly stress reactions. Moreover they cause both making
worse the serotoninergic inhibition already present and a fall of the
cell-mediated immunity competence.
The secondary psychological stress then
manifests itself by increased depressive mood and increased falling of
nonspecific immunity reactions.
Psychotherapy can help in reducing the
psychological stress but usually it is partial intervention. When combined with
anxiolytic and pro-serotoninergic drugs it acts more favorably on the mood and
improves the serotoninergic antipain reaction.
By this way it can spare the doses of
exogenous opiates. There is more efficacy with a more complex approach acting
on stress neurochemical pathways (GABA, glutamate and related
neurotransmitters) and specifically on cell-mediated immunity. Such an approach
can use low doses of drugs by exploiting special synergies.
Since stress reactions are always
individualized ones, following genetic and acquired mechanisms, a therapy of
stress reactions modulation needs to be tailored to each patient.
Trials according to that approach and
lasting over ten years, even if in an anecdotal way, pointed up feasibility and
good efficacy. However I did public notice of them more than eight years ago.
Key Words: Cancer, Chemotherapy,
Radiotherapy, Stress reactions, Immunity, Drug modulation.
Before pointing up the relationship between
stress reactions and illnesses, I need defining stress itself.
Although I do not fully agree with it, this
is the more authoritative definition of stress. " .... it generally refers
to physical or psychological alterations capable of disrupting
homeostasis." (Cullinan et al., 1995).
Waiting for a more precise one, I proposed
this as an operational definition (Cocchi, 1996). "We can term stress a
set of relations linking external or internal stressors of physical, chemical,
biological / metabolic and psychological / social origin, to nonspecific
reactions of a living organism. These reactions come out from the modification
of homeostasis made by the stressor or stressors, and act as a common final
pathway.
Stress reactions can come out from external
stressors, or internal stressors or both. ..." The internal stressor most
likely we can imagine is an illness itself, from flu to dementias or cancers.
Nevertheless, the most frequent stress condition is a physiological one. I am
referring to the well-known premenstrual syndrome.
The premenstrual syndrome as a paradigm
of an internal metabolic stress.
During the 2nd World Congress on Stress held
in 1998 in Melbourne, I proposed the premenstrual syndrome as the most evident
example of an internal metabolic stress.
So since it owns the special feature of
being elicited by a normal functioning of the fertile woman's body (Cocchi,
1998).
The fall of the progesterone rate at the end
of menses luteinic phase alters the progesterone homeostasis by driving this
hormone below its lower homeostatic limit.
Such as any homeostatic impairment, this
fact too elicits stress reactions. As Mortola asserted (1992), all the 22
symptoms of the premenstrual syndrome are fully non-specific which means: none
has a direct link with the specific action of the progesterone.
As for myself I had some doubts about three
of them (Bloating, breast tenderness and swelling) which I excluded on my
research about nonspecific side-effects of drugs (Cocchi, 1998).
The same symptoms of the premenstrual
syndrome can arise in many other stress conditions in females but also in
males.
Although 90% of all women suffer from the
premenstrual syndrome, 10% if free of it (Mortola, 1997). This leads to the
inference that the premenstrual syndrome does not necessarily follow the fall
of progesterone, ie. There is not a direct relationship between these two
phenomena.
Those women with good ability to fight
stress feel very little the following of this metabolic stress. The others who
have more weak constitution, or more weak now because undergoing another
stress, or more than one, suffer from the premenstrual syndrome.
Whatever such stress derives from a normal
and physiological issue of the fertile woman, it is quite important, since it
is a facilitating factor for seizures in epileptic women.
The sum of stress and stress reactions
I think that the idea of internal stress is
not a new one, but simply something poorly defined, Nevertheless, it has its
own literature, at least as oxidative stress (Cristol et al. 1998; Jerca et al.
1996; Mocali et al. 1995; Thom et al. 1997; Yu, 1996).
The amount of stress reactions depends on
specific thresholds (ie. limits the crossing of which elicits stress reactions)
linked in its turn to genetic and acquired factors.
This means that we can see people more
suffering from stress or people less suffering from it. That is a genetically
high or a low threshold (as for cows, see the excellent research of
Garcia-Belenguer et al. 1996).
In spite of it genetic thresholds to stress
could have been lowered by a very stressful life event like a birth trauma
(Bergant et al. 1998).
There we can have a stable inhibition of the
hippocampal feedback to react to the suprarenal cortisol incretion as the hypothalamus-hypophysis-corticosuprarenal
axis's answer to the stress. So we can see excess sensitivity to stress or
excess stress reactions. (Sapolsky, 1987; McEwen and Sapolsky, 1995; Sapolsky,
1996; McIntosh, Cortopassi and Sapolsky 1998).
Coming back to women without any
premenstrual syndrome, when they have other stress factors, they can even start
to suffer from the premenstrual syndrome. Then the sum of stresses can cross a
high threshold too.
That is the well-known history of the
changing-the-weather advising corn. When the stress is rising as or becoming
bad weather the corn's pain usually not perceived because under its pain
gate-controlled threshold, begins to manifest itself. The stress factor could
be the ionic variation that precedes the bad weather. So the sum of
stresses - not perceived corn's pain and ionic variation - can cross the pain
threshold and the corn becomes painful.
Precise research did not find any
pathological modification of that corn to justify the state of painfulness
before the bad weather arrival.
On the other hand, mainly as for acute
stress, the power of the stressor is a significant variable. More powerful is
the stressor and more reduced will be the tolerance even in persons with a
natural good one.
When we have multiple stressors, the whole
stressing power is at least the sum of every power that act in the same time
(Pike et al. 1997).
Stress and illness.
In every illness we have to consider the sum
of three factors:
i. the causal agent;
ii. the organism's specific response;
iii. the organism's non-specific response,
which is a stress
response to the current illness (Loo and
Loo, 1986).
As for cancer we can say that the
nonspecific response refers to an internal stressor, the cancer itself as an
illness.
Now, in every illness the organism can set
off stress reactions. These are both primary stress reactions - due to the
homeostatic alteration the illness itself elicits -
and secondary psychological ones, from the
person's awareness of being ill. That last one can arise in a subsequent time.
As all stress reactions, they seem first to
go along the neurochemical pathway glutamate-GABA (Horger and Roth, 1996).
I mentioned above that stress reactions
differ from individual to individual and depend on constitutional, inherited
and acquired features.
Among which the particular time of the
biological cycle of a living organism could greatly affect them. Aging is the
more understandable example as a reduced ability to cope with
stress (You, 1996; Pike et al. 1997;
Friedman and Irwin, 1997; as for cows, see again Garcia-Belenguer et al. 1996).
Stress reactions and drugs
Stress reactions during cancer
chemotherapies, as for all stress reactions, modify antipain mechanisms. I
maintain first serotoninergic ones (Harvey et al., 1974), and opiatergic ones
too (Stout, Kilts and Nemeroff, 1995), making difficulties in managing antipain
therapy (Samain et al., 1970).
On the other hand even lighter drugs than
anticancer chemotherapies can elicit side-effects symptoms in sensitive
persons. These side-effects symptoms are symptoms of stress, as I proved in my
research (Cocchi 1998).
As a result of that research, in a hundred
drugs chosen in alphabetical order I found 13 out of 19 symptoms surely
nonspecific of the premenstrual syndrome. To avoid any bias, I excluded drugs
without oral via, compound drugs, corticosteroides, psychodrugs, drugs
specifically acting on the GI tract, drugs acting on ovaries, and
immune-suppressing ones.
What is very curious, but not a paradox
according to these premises, the same drug can elicit both insomnia and
sleepiness, of course not in the same person.
Modulation of stress reactions by drugs: A tentative rationale.
To make of drug therapies, we need a very
short and rough sum up of some neurochemical mechanisms involved in reactions
to chronic stress of a human body.
They are:
1. Direct acting on type A GABAergic
receptors; these last modify their conformation, by this way reducing type A
GABAergic inhibition (Horger and Roth, 1995);
2. Reduced need of GABA for type A GABAergic
inhibition and more GABA into the synaptic cleft (Cocchi, Patrucco, Zerbi,
1987);
3. Increased type B GABAergic inhibition
that, in its turn, inhibits brain acetylcholine (Scatton and Bartholini, 1980),
serotonin (Scatton et al., 1986);
As for acetylcholine, its reduced turnover
follows type B GABAergic receptors' stimulation (Williford et al, 1981; Goto et
al. 1985).
So, it seems to drive to a reduced brain
synthesis, by lowering blood-brain barrier transport of choline by reduced
high-affinity uptake (Hope, 1979; Cohen et al., 1995). There can happen also an
efflux of brain choline (Klein, Koppen and Loffelholz, 1990; Klein et al.
1992).
Although a low-affinity uptake starts
working (Hope, 1979) there is more choline supply for the synthesis of
peripheral acetylcholine. Its increasing in stress conditions has been
demonstrated as for the vagal district (Hata et al. 1986; Kita et al. 1986).
This could account, at least in part, for
increased strength of parasympathetic / vagal responses.
4. Compensatory incretion of peripheral
adrenaline (Zigmond, Finlay and Sved, 1995), and glucocorticoids (Sorg and
Kalivas,1995). The last affect also hippocampal memory sites (McEwen, 1995) and
cell-mediated immunity (Dhabhar et al. 1996; Haessig et al. 1996; Dantzer,
1997; Friedman and Irwin, 1997).
5. More GABA into the synaptic cleft
backwards reduces GAD activities (Baxter, 1976, Loescher 1980) with reduced
transformation of the glutamate into GABA.
6. Excess of the glutamate, besides being
excitatory and eventually neurotoxic (Rothman and Olney, 1986), seems to
increase mesoprefrontal dopamine (Horger and Roth, 1995).
Although controversial, the same appears to
happen for noradrenaline activity in Locus Coeruleus, the main brain site for
this neurotransmitter (Zigmond, Finlay and Sved, 1995).
The glutamergic stimulation of some
hypothalamic nuclei - mainly the dorso-medialis and the paraventricularis - in
its turn elicits nucleus dorsalis vagi and tracti solitarii nucleus responses.
So parasympathetic symptoms can increase (Kunos and Varga, 1995; Yoneda and
Tache', 1995; Brann, 1995; Pluzhnichenko, 1997).
7. The reduced turnover of the serotonin,
besides the fall of the mood, can inhibit the serotoninergic antipain mechanism
coming from the Raphe (Samain et al, 1970).
Of course, this is only a very simplistic
general frame, but it is a good point to start.
The choice of the drugs to modulate stress reactions.
There is a growing interest in the
modulation of stress reactions by drugs (Davidson, 1997).
This approach is mainly acting on GABA and
related mechanisms and it has also a direct effect on EEG. In aging people with
cognitive troubles I used QEEG as an objective control (Cocchi, 1996).
According to what I have just said, the main
focal points to act by drugs are:
1. Basic intervention:
- Increase type A GABAergic inhibition;
- Decrease type B GABAergic inhibition;
- Increase the GAD action.
By themselves those elicit also:
- Decreasing of the cortisolic
incretion and of the peripheral adrenergic compensation by reduced activation
of the hypothalamus-hypophysis-corticosuprarenal axis (Buckingham, 1998;
Schedlowski and Schmidt, 1996);
- Decreasing of the possible glutamate
excess because its larger transformation into GABA.
2. Accessory intervention:
- Increase brain acetylcholine synthesis, if
in need;
- Decrease both vagal outflow and increased
strength of vagal responses.
- Increase of the brain serotonin, which
improves the mood and potentiates the antipain serotoninergic response;
- Possible action on dopamine, which may
need expert professionals for evaluating the positive or negative direction of
current dopaminergic symptoms.
This is a very short and simplistic introduction,
but it is enough for a more comprehensive therapeutic approach.
Being a cascade of events having its
starting point on reduced type A GABAergic inhibition, theoretically we could
only prescribe a benzodiazepine as monotherapy (Schoch et al., 1985).
This is not the best way to afford it,
because we shall need high dosages, which in turns produce side effects like
sleepiness and muscle relaxation.
A high dosage monotherapy could induce a new
share of stress reactions to chemical stress due to the foreign nature of the
drug and/or its strong action (Antelman, 1988, Cocchi 1998; Covelli et al.
1998).
As I did, mainly in Down children and in
autistic children (Cocchi, 1996), we can do better using:
- A low dose benzodiazepine, to act on type
A GABAergic receptor. Benzodiazepines as antistress drugs lower the incretion
of the cortisol (Bruni et al. 1980; Viukari, 1983).
- A brain Ca-antagonist (nimodipine,
verapamil, etc.) for lowering the type B GABAergic inhibition ( Liron et al.,
1985; Borman, 1988). This reduction could positively act on brain acetylcholine
(ACh) turnover and could stop or at least lower the choline efflux from the
brain.
- Pyridoxine, acting as cofactor of all
decarboxylases, and of GAD too;
-If the case, we can add pyritinol, a good
increaser of brain ACh synthesis (Blusztajn and Martin, 1988; Greiner, Haase
and Seifried, 1988; Toledano and Bentura, 1994).
Increased synthesis of brain Ach drives the
synthesis of peripheral Ach to normal, by reducing the peripheral choline
supply, following its larger blood-brain barrier crossing.
- Nearly always serotoninergic mechanisms
need to be balanced too, to make the most of the antipain serotoninergic action
starting from the Raphe.
Here, one can add antidepressant drugs, from
tricyclics to SSRIs. If we also prefer increasing the serotonin synthesis, we
may add its 5-hydroxytriptophan, its direct precursor.
Pyridoxine as the catalyst of related
decarboxylarase, has already its room in that regimen.
- If necessary, as a function of the present
case and its current symptoms, we may act on dopamine. We can prescribe either
an antipsychotic drug like low doses haloperidol or perphenazine, or amantadine
as a dopamine agonist.
- Cutting down of stress reactions lowers
cortisol incretion and partly improves the depressed cell-mediated immunity
(Dhabar et al. 1996; Haessig et al. 1996).
- When GABA synthesis increases the brain
glutamate decreases with a lesser incretion of endogenous opiates (Stout, Kilts
and Nemeroff, 1995) already elicited by the illness itself.
In the same time there is reduced
hypothalamic stimulation of the dorsalis nucleus vagi and tracti solitarii
nucleus.
These are both the starting points of the
parasympathetic outflow in stress conditions (Brann, 1995).
Obviously a polytherapy like this is not
suitable to become standard protocol. That runs because of the individual
features of stress reactions both constitutional and linked to the peculiar
biological moment of the body life. Growing old reduces stress thresholds.
On the other hand, the brain does not work
by independent cause and effect relationships. New and expensive monotherapies
in Alzheimer's disease and related dementias are time-limited. It cannot be
different inasmuch as they are under pretence of acting on a single
neurotransmitter (the brain ACh) of a multivariable system like the brain is.
This so, in spite that since 1983 Costantinidis has reported at least 14
impaired neurotransmitters in dementias of aged persons.
Anyhow, the three-drugs regimen (a
benzodiazepine, a Ca-antagonist and pyridoxine) is working in must people and
can easily be fitted to every treated patient. In this way too it is necessary
to avoid that doses higher than individual thresholds become the origin of a
new share of stress. As for my experience, this approach is fully feasible and
I have it tried in many subjects (see: Cocchi. 1987-2000; Cocchi and Favuto,
1993; Crivelli, Donati and Cocchi, 1999). I never reported my trials in cancer
patients because when I had dared to mention it in a newspaper, a not
broad-minded oncologist of the Marche's region insulted and ill-treated me (Cocchi, 1992).
Conclusions.
This is a kind of theoretical report but
fully based on modulation of stress reactions since more than 20 years (Cocchi,
1981). It is quite enough for a therapeutic approach in a share very considered
by the Sudeuropean medical practice of the preantibiotic era and then
forgotten. Nobody seems to remember what clinicians of the first half XX
century called as the "individual field." It was nothing different
from the individual resistance to stress.
Should we remember the therapeutic regimen
to TB patients in the pre-sulphamidic and antibiotic era? The sanatorium
provided sun, pure air, adequate diet, etc. and that is a sound example of this
therapeutic approach.
Every illness is always a compromise between
an offensive ability and a defensive ability. So we can treat both the opposing
parties each independently from the other or both in the same time, when
possible. Surely we can ALWAYS treat any illness by modifying the
"individual field," in other terms by modulating stress reactions.
Often we deal with palliative interventions.
Who has an extrachromosome 21 shall have it for life. Cancer does not spare in
most cases. The Alzheimer's disease does not have any reversibility.
It remains that modulation of stress
reactions can improve the quality of the residual life, although short, in a
noticeable way. Perhaps this is not only a little step.
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Paper presented in Italian during the Congress: Tumore e psiche: Modelli integrati nel trattamento del paziente oncologico. Psicofarmacologia e terapia oncologica. Genova 8-9 Febbraio 2001
Printed in Italian in Ciliberti R., Pedrucci T (eds) Tumore e psiche: Modelli integrati nel trattamento del paziente oncologico. Psicofarmacologia e terapia oncologica.. Grafiche Amedeo, Chiusanico 2002: 128-135.:
Copyright by R.Cocchi. First posted on Internet on February, 2001.
Author's address: dr. Renato Cocchi, via Rabbe4no, 3
42100 Reggio Emilia (Italy)
renatococchi@libero.it
Drug modulation of stress reactions
World congresses on stress and other concresses
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