Altered Pain Thresholds and the Perception of Chronic
Pain
by Daniel J. Murphy, DC, FACO
Most lay
people consider the perception of pain to be a bad thing. Yet, as
professionals, we acknowledge that, although pain can be a bad thing,
pain can also be an important friend who warns and protects us from
adverse occurrences to our bodily tissues. Chronic pain, however,
appears to serve no useful purpose and results in an abnormal
psychological profile.1 It
is understood that an individual’s perception of spinal pain cannot be
ascribed solely to spinal mechanical abnormalities seen on radiographs
or even MRIs.2, 3, 4, 5, 6, 7, 8 Individuals who experience identical
nociceptive environmental stresses will often have a large variation in
their perception of pain.Why is it that some individuals with marked
spinal mechanical abnormalities
might
perceive little or no pain while others with minor mechanical
abnormalities might perceive significant pain? There is no simple or
single answer to such a question for either an individual or especially
for a group of individuals. However, several recent studies add to our
understanding of such questions. Prior to reviewing these studies one
should recall the following from Kandell et al.:9
Opiates are endogenous peptides that cause powerful analgesia by
acting
directly
on the central nervous system (rather than on pain receptors in the
periphery).
There are three classes of endogenous [endogenous means the
body
makes them on its own, naturally] opioid peptides, of which the best
known are the enkephalins. Opioid peptide chemicals, like morphine, bind
to opioid peptide receptor sites, and cause powerful analgesia.
[The opioid peptide receptor site on the neuron where these
opioid chemicals
attach
are made of protein. Recall that a section of a chromosome that encodes
for a specific function is called a gene, and is made up of DNA. DNA
transcripts
RNA and RNA transcribes protein. Consequently, the quantum of
opioid
peptide receptor sites one has are genetically encoded and therefore
inherited
traits.]
There are three major classes of opiate receptors: mu, delta, and
kappa. It
is
the mu opiate receptor, or muOR, that we will review below. High levels
of muOR are found in the periaqueductal gray of the midbrain and in the
dorsal horn of the spinal cord. Opiates chemicals attach to opiate
receptor sites (like muOR) and cause hyperpolarization of nociceptive
membrane potentials,
making
them harder to depolarize (harder to reach excitation threshold and
to
fire an action potential).
[The
muOR is a protein. Different individuals express the gene that
transcripts the muOR protein differently. If one’s genetic expression
is such
that
they make fewer muOR, they cannot inhibit pain as efficiently as
others,
consequently they experience and perceive pain more greatly.]
In the summer of 1999, Uhl, Sora, and Wang10 published an article
where
they
review recent work at their lab and the lab of others who are
investigating the genetic basis for mouse and human differences in pain
perception. They note that there are differences between human
individuals and between mouse strains in levels of mu opiate receptor (muOR)
genetic expression, and therefore, in responses to painful stimuli.
Support
for their ideas comes from analyses of the human and murine
(mouse/rodent family) muOR genes.
Data
from animal models provide powerful information for the understanding of
genetic bases for individual differences in levels of human muOR gene
expressions, and consequently in their perception of pain. If one has
more
muOR,
then one perceives less pain. Studies on mice show that the lack of muOR
results in increased perception of pain. This means that a lack of muOR
renders
one closer to threshold, making it easier to fire the nociceptor and to
perceive pain. Or, it is more easy to fire a nociceptive neuron if its
inhibitory muOR is missing.
These authors note that nociceptive thresholds vary in gene
dose-dependent
fashions
in mice. Mice with no muORs
have lower excitation nociceptive
thresholds
(easier to reach threshold) than mice with 50% of normal receptor
densities.
Mice with 50% quantum of receptors have lower excitation nociceptive
thresholds (easier to reach threshold) than mice with an intact quantum
muORs.
These mice studies provide powerful models for possible sources
and consequences of genetic variation in humans. Studies of human twins
document
that
individual differences in several types of pain are likely to have
substantial
genetic determinants. Humans differ from one another in muOR densities.
This has been shown in postmortem brain samples and in vivo
positron-emission
tomography analyses. The studies show 30-50% or even
larger
ranges of individual human differences in muOR densities.
These authors state:
“Elucidation of the genetic bases for these differences in
receptor expression
would
thus represent a substantial advance in our understanding of
individual
differences in nociceptive behaviors and drug responses.”
“Levels
of expression of many, if not most, human genes differ from individual
to individual.”
They
conclude: Studies strongly support the possibility that muOR gene
alleles
(allele is a noun, which means a mutation expression form of a gene
responsible
for hereditary variation) would be strong candidates for contributing to
individual differences in human nociception.
I believe that this article is hugely relevant to chiropractic.
It indicates that an individual’s perception of nociception is unique
and is dependent upon one’s gene expression through inherited DNA.
In the whiplash arena, there are some individuals who have
voluntarily
subjected
themselves up to thousands of whiplash collisions, apparently
without
suffering any pain. Based upon this article, one could argue that such
individuals are genetic mutants who cannot be used to represent the
genetic expression of nociception for all of society who are involved in
such collisions.
In trauma, overall, one would expect the area of injury to have
an altered pain threshold as a consequence of altered local chemistries,
inflammation, etc. Chiropractors classically assess local pain
thresholds with a pressure threshold meter, often called an algometer.
However, the genetic quantum of
muOR would affect the individual systemically, not just locally at the
site
of
trauma. Consequently, individuals with reduced quantum of muOR would
have a systemically reduced nociceptive thresholds. Therefore, one would
have to evaluate the patient’s nociceptive thresholds, with an
algometer, at
non-injured
locations in an effort to assess systemic nociceptive thresholds, and
compare it to a matched asymptomatic control group. Conceptually, this
could be used to indirectly assess the genetic quantum of muORs for the
individual. I am aware of three studies published this year (1999) that
have done such a systemic algometer assessment on pain patients, as
follows:
In October of 1999, Clauw et al.11 examined the association
between
experimental
pain sensitivity (tenderness) and baseline reports of pain and
physical
function in a group of consecutive patients with chronic low back
pain.
All participants underwent a dolorimeter (algometer) examination to
assess
tenderness throughout the body, including four areas considered to be
control
points (bilateral thumbnail and forehead).
These
authors note that most patients with chronic low back pain do not have
an
identifiable structural or mechanical cause for their pain, and that
structural abnormalities are inconsistently correlated with the pain or
disability that an individual experiences. They state:
“Population
based studies have demonstrated that pain sensitivity varies
tremendously in the general population, with some individuals exhibiting
a high pain threshold (as measured by tenderness in response to
cutaneous pressure), and others a low pain threshold."
“Individuals with a low pain threshold frequently experience chronic
widespread or regional pain, even in the absence of any accompanying
structural abnormality.”
They
found that patients with diminished ability to function and greater
clinical
pain tended to have a lower pain threshold at control points and were
thus
more globally tender. These findings suggest that the experimental
assessment
of tenderness and clinical pain are associated. This study highlights
the relevance of tenderness and underscores the need to include this
concept in the assessment of chronic low back pain.
The next article was published in November, 199912 on chronic
whiplash
pain
patients. The authors examined the muscular sensibility in areas within
and outside the region involved in a whiplash trauma, and compared them
to
sex
and age matched control subjects. The authors used an algometer and the
infusion
of hypertonic saline into selected muscles and measured patient
response
with a visual analogue scale (VAS).
The pressure pain thresholds were significantly lower in whiplash
chronic
pain
patients compared with controls. Chronic whiplash patients have a
significantly
lower pain threshold as measured with an algometer at both the
area
of injury and at non-injured areas, as compared to controls.
Infusion of hypertonic saline caused significantly higher VAS
scores with
longer
duration of pain in whiplash chronic pain patients compared to
control
subjects. Chronic whiplash patients have a significantly greater area of
pain (distal and proximal), intensity of pain, and duration of pain
following the injection of a hypertonic saline solution at both the area
of injury and at
non-injured
areas, as compared to controls.
In this study, muscular hyperalgesia and large referred pain
areas were
found
in patients with chronic whiplash syndrome compared to control subjects
both within and outside the traumatized area. These findings suggest a
generalized central hyperexcitability in patients suffering from chronic
whiplash
syndrome.
They state:
“In the present study, we have found muscular hyperalgesia to
painful muscle
stimulation
not only in the neck and shoulder region, but also in distant
areas
in which the patient does not normally experience pain. This finding
could
be a manifestation of a generalized central hyperexcitability and
support the hypothesis that central pathogenetic mechanisms are involved
in the whiplash syndrome.”
Lastly, in the most recent issue of the European Spine Journal,13
another
whiplash
study using an algometer assessment was published. In this study
on chronic whiplash pain sufferers, pain intensity was evaluated by
means of a
visual
analogue scale and muscular tenderness was assessed by pressure
algometry
at 14 standard global locations in 22 patients, and compared to
matched
controls.
The results indicate that muscular tenderness by algometry showed
the
whiplash
chronic pain patient group had a significantly lower pressure pain
threshold (PPT) compared with controls.
In summary:
Spinal structural abnormalities on radiographs and MRI are
commonplace, yet not well correlated with the perception of pain. Those
who perceive pain
are
those with altered thresholds, caused by a variety of reasons, including
genetic
reasons. These studies present evidence that pain thresholds can be
altered
because of the genetic expression of mu opiate receptors for a
particular individual, indicating that those with low pain thresholds
are genetic variants. One can attempt to identify such individuals with
a global assessment of pain thresholds with an algometer. Reduced global
pain thresholds are associated with a genetic reduction of the quantum
of mu opiate receptors, in a similar fashion that one might be
genetically encoded with a reduced quantum of hair follicles. A trivial
environmental stress on such individuals might reach nociceptive
threshold and be perceived as painful. In an individual with a greater
quantum of muOR, such a trivial
environmental
stress would not reach threshold and would, therefore, not be perceived
as painful.
References:
1.
Wallis, B. J., S. M. Lord, et al. (1997). “Resolution of psychological
distress of whiplash patients following treatment by radiofrequency
neurotomy: a randomized, double-blind, placebo-controlled trial.” Pain
73: 15-22.
2.
Boden SD, et al. Abnormal magnetic-resonance scans of the lumbar spine
in asymptomatic subjects. A prospective investigation. J Bone Joint Surg
Am. 1990 Mar;72(3):403-8.
3.
Boden SD, et al. Abnormal magnetic-resonance scans of the cervical spine
in asymptomatic subjects. A prospective investigation. Bone Joint Surg
Am. 1990 Sep;72(8):1178-84.
4.
Jensen MC; Brant-Zawadzki MN; Obuchowski N; Modic MT; Malkasian D; Ross
JS. Magnetic resonance imaging of the lumbar spine in people without
back pain. N Engl J Med 1994 Jul 14;331(2):69-73
5.
Lee CK, Vessa P, Lee JK. Chronic disabling low back pain syndrome caused
by internal disc derangements. The results of disc excision and
posterior lumbar interbody fusion. Spine 1995 Feb 1;20(3):356-61
6.
Schellhas KP, Smith MD, Gundry CR, Pollei SR. Cervical discogenic pain.
Prospective correlation of magnetic resonance imaging and discography in
asymptomatic subjects and pain sufferers. Spine 1996 Feb 1;21(3):300-11;
discussion 311-2
7.
Savage RA, et al. The relationship between the magnetic resonance
imaging appearance of the lumbar spine and low back pain, age and
occupation in males. Eur Spine J. 1997;6(2):106-14.
8.
Matsumoto M, Fujimura Y, Suzuki N, Nishi Y, Nakamura M, Yabe Y, Shiga H.
MRI of cervical intervertebral discs in asymptomatic subjects. J Bone
Joint Surg Br. 1998 Jan;80(1):19-24.
9.
Kandel ER, et.al., Principles of Neural Science, 1991, pp. 394-397)
10.
George R Uhl, Ichiro Sora, Zaijie Wang. The mu opiate receptor as a
candidate gene for pain: polymorphisms, variations in expression,
nociception, and opiate responses. Proc Natl Acad Sci U S A 1999 Jul
6;96(14):7752-5
11.
Daniel J Clauw, David Williams, William Lauerman, Marisa Dahlman, Angela
Aslami, Alf L Nachemson, Arthur I Kobrine, Sam W Wiesel. Pain
sensitivity as a correlate of clinical status in individuals with
chronic low back pain. Spine 1999 Oct 1;24(19):2035-41
12.
Mona Koelbaek Johansen; Thomas Graven-Nielsen; Anders Schou Olesen; Lars
Arendt-Nielsen. Generalized muscular hyperalgesia in chronic whiplash
syndrome. Pain 1999 Nov 1;83(2):229-234
13.
Helene Olivegren, Nicklas Jerkvall, Ylva Hagstrom, Jane Carlsson. The
long-term prognosis of whiplash-associated disorders. Eur Spine J
1999;8(5):366-70
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