Guide
to Pudendal Neuralgia and PNE from Ava
The Core Group would like to extend its gratitude to Ava for writing
this in-depth analysis which covers a broad spectrum of topics related to
Pudenal Neuralgia and PNE. Our
membership will find this document to be a great asset as they attempt to sort
out many of the nuances of this baffling medical problem.
We would like to point out that all of the posts on this forum are for
informational purposes only and the information contained in this “Guide to
Pudendal Neuralgia and PNE from Ava” has come directly from Ava and not from
The Core Group.
As always, we advise our members to rely on the advice of their doctors
before making any decisions regarding information they have gleaned from any
website.
Once again, we would like to express our deepest thanks to Ava for the
time and the solid research that she has put into preparing this document and
for sharing all of her ideas with us, both on the forum and in this document.
The Core Group
Table of
Contents
A. The application of
logic to PNE issues
B. On opinions given on
the forum
C. Assisting others by
sharing information
II. On PNE
A. Mechanisms of nerve
injury
B. Path of the pudendal
nerve and sites of possible entrapment
III. On
pudendal neuralgia following vaginal or abdominal hysterectomy
IV. On reasons for failed pudendal
decompression surgery
V. On diagnostic testing
A. Practical guide
B. PNMLT
1.
neurophysiology
2. analogy
3.
sensitivity and specificity
4. validity
of intra-operative and post-operative PNMLT
5. reasons
for PNMLT despite concerns over validity
5. Botox and
the PNMLT
6. nerve
testing of the penis
C. MR neurography
D. Nerve blocks
E. Botox (diagnostic)
VI. On the processes involved in pain
A. The mechanism of
central sensitization
B. Activation of opiate
receptors following surgical event
C. Nociceptive versus
neuropathic pain
D. The four horsemen of
pain
VII. On
pharmaceuticals
A. Valium and other
benzodiazepams
B. Indocid suppositories
and NSAIDs
C. Narcotic analgesics
D. Neurontin
E. Cymbalta
F. AV411
G. PARP-1
H. minocin
I. Quinamm
J. Tylenol
K. Effectiveness of current medications for
neuropathic pain
L. On the pharmaceutical industry
VIII. On the use of medications in combination to
address neuropathic pain
IX. On
acupuncture
X. On spinal cord stimulators
XI. On
lumbar disc herniation
XII. On MRI, CT and discography for lumbar disc
diagnosis
XIII. On alternative medicine
XIV. On prolotherapy and SIJD
XV. On a proposal to evaluate responses to
neuropathic analgesics
A. The application of logic to PNE issues
Several have
written that it is difficult for the non-science trained individual to
understand the basis for some of these arguments. Yet in order for us to apply
logic to PNE, it is important that the process begins. Otherwise it is like the
Japanese film Rashomon, where the same event is viewed from diametrically
different positions, thus the interpretations from the varying position is
wildly disparate. So I would like for those who want not only to understand but
to participate to begin with the anatomy of the nerve. Take your hand and
palpate your sacrum. Imagine the sacral plexus originating from the cord,
forming on the other side of the bone you are touching. Imagine the nerve as it
courses along the inside of the gluteus maximum muscle...feel the muscle,
imagine the course of the nerve. Trace the course of the nerve a little further
each day, rehearsing three or four times what you know. There are many books
and drawings to guide you, but none more powerful than your own imagination of
the nerve in your own body. In 30 days or less you will know the nerve and all
adjacent anatomical structures, and you will find confidence in this knowledge.
Not only that, you will have begun to penetrate the layers and layers of
mundane that science requires in order to begin a pursuit of the profound.
While the value of this forum is already immeasurable, suppose we were to link
in series the processing capabilities of all 780 or so minds, these being all
well informed, and then perhaps produce the single original thought that would
turn the tide. Yes, we have talked about the paucity of diagnostic modalities
and their limitations, and the doubts that arise because such modalities are
used in a way that conflicts with science, but I believe we can do better than
that. It is important to realize that the law of diminishing returns applies to
doubts as well.
We have talked about the frailties of the PNMLT, the neuropathological basis
for those frailties, and the fact that a post op or intra-operative PNMLT
cannot be valid. But what would be the solution... those are the questions we
should be debating. Since the degeneration regeneration process compromises
velocity and latency in post release testing, what means, theoretical or
otherwise, might be devised. In terms of nerve testing, the one which gave the
most desirable clinical information would be that test which measured what the
dendrite was saying to the cord. Is the cord being told that pain is present or
not? We can now measure the quantity, osmolality, osmolarity, and particulate
size of a liquid passing through a tube without actually sampling the tube. Is
it possible to do the same in terms of measuring impulse propagation along the
axon? Or perhaps we can find greater reliability in measuring velocity and
latency
in unmyelinated axons in the pudendal nerve. This has not been discussed for
obvious reasons, but the pudendal nerve, like all peripheral nerves, has axons
that are mylenated to different degrees as well as axons that have not been
myelinated at all. Again, since the thicker, heavier myelinated axons are what
transmit the impulse quickest, they are the axons carrying the impulse that is
measured in the PNMLT. When damaged, they transmit slower. Neuropathy shows us
why, and that these changes persist. But suppose we were able to subject the
pudendal nerve to a test of unmyelinated axons only, or if we devise an impulse
that would not transmit in the myelin sheath but instead be transmitted in the
same manner that unmyelinated axons transmit.
If we look at the mechanics of entrapment, then apply the same physics to the
cellular level, one sees why injury occurs initially to the sheath of
myelinated axons within the nerve. A force applied to a structure of many
consistencies will first affect those parts of the structure that provide the
least resistance, unless the architecture of the structure is designed to
diffuse such as force. It was never necessary for such an architectural
modification in peripheral nerves...protection came from location and outside
structures... the nerve never had to evolve a mechanism to protect itself from
compression.
This gives rise to the possibility of another means of testing for PNE, one
that would give correct data (excluding the uncertainty principle) either
pre-op or post-op as to persistent entrapment.... peripheral nerve impedance
testing. In the time before telephones were owned by customers, but were
instead rented from the phone company, electrical tests were developed to
monitor if phones had been added illegally to your service. The phone company
would dial your number and measure impedance on your line. One phone ringing
gave a certain impedance, 2 phones another level, 3 phones more, and so on. If
you were paying for 2 phones, but impedance testing revealed three, then your
bill would be adjusted. Customers could defeat impedance testing by clipping
the wires to the ringer, but most did not have that savvy. If equipment of
exquisite sensitivity could be developed, we would not have to apply a stimulus
to the rectum. Instead we would measure the response of the nerve to a
carefully measured stimulus applied proximally. If the nerve was firing above
baseline (there would always be some level of activity, but this could be
quantified and standardized in animal and human models), this would suggest
entrapment. It is possible that if the sensitivity of the readings was great,
the degree of impedance could correlate in a linear or sigmoid fashion, again
carefully quantified, with degree of entrapment. Impedance would not be a
measure of velocity or latency and therefore unaffected by the state of the
myelin sheath. A person still symptomatic but with baseline impedance would not
have persistent PNE, but rather the pain would have to come from either the
cord or cortex level. A post release but still symptomatic patient whose
impedance was elevated into the levels associated with entrapment could have
persistent PNE, but then again, other sources of stimuli to the nerve (other
pathological processes) would have to be ruled out.
But we should never be satisfied with nerve testing alone, even if we reach the
point where velocity, latency and impedance could be measured with a high
degree of sensitivity and specificity, and that correlation to entrapment was
impeachable. We need to be able to see the nerve in much the same manner that a
cardiologist can visualize the coronary anatomy via catheterization. We are not
far from the point that magnetic resonance imaging could measure the
configuration of the pudendal nerve at each millimeter along its path. Then in
most cases of true PNE the exact anatomical location of entrapment could be
pinpointed. At present this is more a software problem than a hardware one. In
my opinion Bill and Melinda Gates are an extraordinary couple, and I certainly
do not wish PNE upon them. But I am willing to bet my husband's every last
nickel that if one or the other of them had developed PNE a year or so ago,
reliable nerve testing would now be available to us, and software would have
been developed that allowed precise visualization of the pudendal and other
nerves. Such diagnostic modalities might seem far-fetched to our doubters , but
these modalities are far more realistic than an MRI scan or lithotripsy was two
decades ago.
But while we can look to the future, we live in the present, and many patients
with PNE still have pain. Again, I contend that if one can be cured, something
has to be responsible for dismal results in those still suffering. Do we simply
accept these treatment failures as a part of doing business, or do we figure
out why they happened and what can be done, both to prevent future failures and
to give relief to those who live with that failure every day. To do so we have
to look at what we are doing and the basis for doing it. Take diagnostic blocks
for instance. When your phone goes out of service and a repairman is summoned,
he does not check the cable closest to the central office first. He goes to the
protector outside your home, and checks to see if there is a dial tone. If not,
he goes to the pedestal where the drop to your house connects to the residential
cable, and then works his way back to the switching equipment.
If there is a dial tone at the pedestal, then the problem is in the wire
overhead or buried underground to your individual dwelling. You may be tempted
to argue that when an electrician comes to your house to check out a faulty
outlet, he first goes to the electrical panel. There are both therapeutic and
diagnostic implications for this exception. First, the electrician does not
wish to be electrocuted, so he turns off power to the outlet before repair.
Second, he does not trace the pathway of power in a logical sense, at least not
initially, because he does not have to go back to his truck, drive three miles,
climb a pole and sort through hundreds of cable pairs to find yours in order to
do so. To the telephone repairman it is much more efficient, time and energy
wise, to apply logic to the problem presented than it is to do so to the
electrician's problem. One will generally find logic applied to those
activities where substantial resources can be saved through its application,
but will not necessarily find logic applied where its application will make no
difference. With nerve testing, it seems logical to test at every point
possible. A positive block at Colles' fascia says that a decompression
procedure only to Alcock's canal will not help that patient. The more
information that is available prior to surgery, especially given the pitfalls
of current testing, and very especially given that re-operation entails
difficulties of its own, is the only responsible manner in which to approach
PNE.
B. On opinions given on the forum
In a recent
edition of the Bay City Journal, a
Because one sits in the bleachers and catches the home run ball does not
automatically make that individual a professional batting coach. Because one
has been so fortunate as to recover completely following pudendal decompression
does not qualify that person to teach neurosurgery. Such behavior in and of
itself does not concern me. What does concern me is that the innocent, truly
searching human who, in the midst of the misery of pudendal neuropathy, will
grasp at anything, perhaps even suppositions found here but grounded in neither
reason nor fact. This site seeks to do much, but what it does not seek to do is
mislead. Those who contribute have a duty to qualify remarks, especially when
remarks are submitted in quantity.
Let's look at two examples of misleading information. The first is rather
harmless, the second potentially less so. In the same post in which she calls
me “patronizing”, one member writes: “You also say that vaginal birth injures
tissues and the only issue is to what degree. I know plenty of women who had no
tearing, no pain afterwards, and no dysfunction. So I further disagree that
injury always happens.”
While we should appreciate disagreement, such dispute should be substantive.
Granted the member may not have immediate access to an obstetrical textbook,
but the internet lists more than 54,000 sites in which pelvic floor dysfunction
and pelvic injury following normal labor is discussed. One such site is: http://www.cmaj.ca/cgi/content/full/166/3/337.
That injury occurs during normal uncomplicated labor is not a subject of debate
among obstetricians, so one wonders why it should be debated here. Yes, we all
know women who show no flagrant signs of postpartum injury. I was one, and
fortunately so are most women. But this does not diminish the credibility of
the science, nor does it require the imposition of reverse logic. Instead, it
is most logical to propose that woman cannot go through all the tremendous
physiological changes that occur during pregnancy and delivery without some
injury to supporting structures, mucous membranes, pelvic muscles, or the
cervix. That one might recover quickly and without noticeable residual effect
is not only a testament to God’s creation of woman, but it is also the result
of a process of healing that has evolved a maturity and serenity over time.
When we tell our men folk of the terrible pain that accompanies labor and
delivery, and when we laugh in comparing this pain to everyday agonies that
accompany the exercise of manhood, are we honest with them? Is the pain of
labor and delivery that severe? If so, as we often say it is, what do you think
our axons were telling us with all that afferent sensory stimulation.... does
this pain come to celebrate the expectant birth? Doesn't it seem much more
logical that our sensory apparatus throughout the pelvis is screaming
"injury" to the cord?
The other example is this. A member wrote: “Scans such as MRI don't show
nerves, so it is not surprising that you had the experience that you did.” I
found this quote particularly interesting since today I was examining a L4/5
nerve root on an MRI scan. The neurosurgical resident standing beside me
remarked: "Interesting the displacement...more posterior than lateral.
Should be easier to get at". "Nonsense", I rebutted. "That
nerve is only in your imagination. It can't be seen on scan." I had
learned this medical fact on the forum.
What if a guest had read her statement of fact, decided against an MRI on the
basis of that post, and died 8 months later from an osteoblastic malignancy
that would have been picked up by scan? The same with our new mother. What if
her pelvic pain was from a deep perineal abcess that resulted from fecal
contamination of the deep wound that occurred during delivery. At 5 weeks an
undiagnosed abcess is low on the index of suspicion, but it still ranks far
above PNE. Every bout of short term perineal and pelvic pain is not going to be
PNE, nor is it going to be readily amendable to PT. Given the brief interval
between delivery and pain, it is the obstetrician who should determine the
merits of a PT evaluation.
More importantly, this young lady's doctor has had 10 - 11 months to get to
know his patient well, maybe even longer. We have 2 or 3 paragraphs. What makes
better sense... to let the doctor give guidance, or some far away internet
user.
C. Assisting others by sharing
information
Karen's last post
is not just thoughtful and sincere, but it is filled with the elegance of
wisdom and experience. One must do exactly as she suggests if they are to
expect even a small measure of satisfaction from a visit to their physician.
For if the symptom complex is outside of that physician's level of expertise
and knowledge, even if the symptoms appear to be due to a process within that
physician's specialty, it is highly doubtful that physician will take the time
that evening to search for answers. Karen knows as well as I that this is not
the way it should be, and I would wage large sums that it is not the manner in
which she confronts puzzling issues in her own patients. But we all know, that
for the most part, this is the way it is when most patients go to doctors. The
posts I am honored to add to this forum are done with the intent of teaching, but
also to explore the many sides of pudendal neuropathy. The more energy and
effort each of us puts into thought brings us closer to answers that make
sense. These answers then provide patients with information with which to make
choices about diagnostic modalities and treatments in the search for relief
from a terrible pain. Those who use this forum for information are lucky to
have insightful members like Karen and Les and Celeste and Greg and Callie and
Marianne and all the other ones (who also deserve individual mention) who are
constantly monitoring and offering helpful comments. They are lucky as well to
have the occasional antagonist, like L.G., whose experiences are invaluable in
relating the not-so-good sides of current care. If anything, this forum is
fair, giving credibility to all sides. As for me, it led me to
II. On PNE
A. Mechanism of nerve injury
Nerves can be
damaged in any number of scenarios, by compression, entrapment, or disruption
of their usual anatomic pathway. Also by toxins, by viruses (herpes zoster), by
trauma, by surgery, by autoimmune disease, by diabetes (diabetic peripheral
neuropathy), even by vitamin deficiency (B-12). But while the number of disease
processes that can affect the nervous system in some way is large, the types of
pathology that can affect an individual nerve alone is limited. This not only
narrows the probabilities with respect to injury in PNE, but it is extremely
helpful in understanding the cellular mechanisms involved. By doing so, one can
make appropriate decisions regarding the efficacy of different treatment
strategies, and thereby one's willingness to undertake them. If a strategy
makes sense on a biochemical and cellular physiology level, then it is far more
likely to be successful. Conversely, if such strategy fails to meet that
criteria, while it may be advocated strongly by some, and there may be isolated
cases of success (which may or may not have anything to do with the applied
treatment), it is doubtful such strategies will measure up when compared to
placebo. Just like football, the basics of tackling and blocking, while hardly
glamorous, are usually what eventually determine outcome. As one who, like
others, suffered for years, it is outcome and outcome and outcome that
interests me most. When one considers the possible etiologies of individual or
paired neuropathy, they may at the outset eliminate severance, which elicits an
entirely different response at the cellular level than one will find in PNE.
Yet in numerous places in the forum axonal re-growth is discussed and projected
as a mechanism to explain delayed response. Again, severance is not the injury
in PNE and axonal re-growth not the cellular response. In severance, the
partially or completely interrupted axon has to first seal its interrupted cell
membrane, but this occurs in the first hours following injury. Then the repair
process is initiated and supervised from the nucleus residing in the cell body.
The problem with the now linearly expanding axon is that while the DNA can
direct every tiny facet of axonal restructuring within the cell, it has almost
no information on how to proceed outside the cell, so that usually in the case
of total severance the nerve really does not know where to go or what
structures, synapses or receptors to innervate. The re-growth of axons of a non
completely severed nerve have the luxury of following the course of those not
severed, so the chance of re-innervation is far greater. But the forum
addressed notion of measured millimeters per week of axonal re-growth has
little applicability to the neuropathology involved in PNE. Besides severance,
individual or paired neuropathy can result from blunt trauma, or from
structural abnormalities, usually acquired. It is this we will focus on.....
B. Path of Pudendal Nerve and
sites of possible entrapment
When the pudendal
nerve leaves the sacral plexus, it travels posterior to the coccygeus muscle
and sacrospinus ligament, and anterior to the gluteus maximus muscle and the
sacrotuberous ligament. It then continues inferior-medially, remaining
posterior-lateral to the levator ani muscle, but generally before entering
Alcock's canal gives off the inferior rectal nerve. The clinical implications here
have importance. Since my surgery involved division of the sacrotuberous
ligaments bilaterally, and much of my pain was rectal in the beginning, careful
dissection prior to Alcock's canal would play a role in recovery. Alcock's
canal is basically composed of an extension of the obturator internus fascia,
again clinically important. Fascia, like other collagen vasular tissues, can
undergo pathologic change, and in doing so, adhere, entrap, compress or
otherwise compromise the transiting nerve. Shortly after exiting Alcock's canal
the pudendal nerve gives off the perineal nerve which must pass through the
superficial perineal fascia (except for a single rectal branch) before reaching
its area of responsibility. Whereas the transit through Alcock's canal is
parallel to fascia, the transit of the perineal nerve through Colles' fascia is
perpendicular, giving rise to an additional consideration of restriction. The
pudendal nerve itself must also pass through Colles' fascia, enter the
urogenital diaphragm and become renamed (dorsal nerve of the penis in the male,
labial nerve in the female). Even as the pudendal nerve becomes another there
is ample opportunity for restriction. While I do not know the step by step
moves of the surgical procedures involved in PNE surgery, I am aware of those
descriptions, and especially the fact that visual exposure is very limited. I
am unsure of dissection to the level of Colles' fascia, but I do intend to
review operative notes to study the extent of dissection. If one were to compare
this to a hundred pair telephone cable, with each set of wires leading off to
homes of Family A, the Family B, then Family C, and so on and so on until the
last pair of ten or so wires went to the homes of Families Y and Z.
If the main cable is disrupted somewhere between the switching equipment in the
central office but before the first wires are given off to Family A, then all
the wires will be affected and no family would have phone service. But if the
cable is disrupted after giving off service to Families A-J, but before service
to Families K and after, then only Families K through Z will be out of service.
Given the many variations in human bodies, the different courses an artery or
vein might take, even the fact that the appendix can generally be found in one
of four positions, or especially the different but complex relationships of the
cystic artery, the right hepatic artery and the cystic duct in different
individuals, one can reasonably suppose that branches from the pudendal nerve
come off in different places in different individuals, and while these branches
usually innervate the same structures, the courses to those structures is also
variable. More than supposition, anatomical dissection shows this to be true in
the case of every nerve. Also, it is not reasonable to suppose that every true
case of PNE is due to compression, entrapment, stretching, or irritation at the
same location along the pudendal nerve's course. All of this has strong
clinical implications in answering such questions as to relief of some symptoms
and not others, partial relief of all symptoms but not complete relief, as well
as the one we pray for, relief of all symptoms. Nor is it necessarily
reasonable to assume that restriction and damage, if caused by displacement,
hypertrophy, inflammation or otherwise, cannot be the result of two sites or
more, especially given that the processes involved may be regional, involving
an area the size of a tennis ball, rather than an area the size of a marble. If
the nerve is then freed at one point but not the other, especially if the freed
point is the proximal one, then one would expect relief in the posterior
perineum but not the anterior one.
III. On
pudendal neuralgia following vaginal or abdominal hysterectomy
1.
Vaginal
hysterectomy involves the cutting and ligature of the uterosacral and cardinal
ligaments, as well as freeing the uterus from its close attachment to the
levator ani muscle, but the surgical field should never reach as far as the
sacrotuberous ligaments. These should remain unharmed by surgery, with
exceptions. Those being the development of scarring and adhesions, or
post-operative infection moving laterally to involve these structures. With
hysterectomy, by whatever approach, there is some residual weakening of the
pelvic floor musculature, but usually this can be minimized by careful
operative technique and post op strengthening therapies. Pelvic pain can come
from so many sources, and the symptoms might seem to be pudendal in
distribution. Because there is a great deal of nerve overlap, and because
sympathetic fibers also play a role in sensory innervation to this area, and
because of the radiating nature of pain along sensory dermatomes, it is
imperative that consideration be given to the myriad pelvic pain pathologies
that are not PNE. For those interested in a more technical description, or at
the least, a partial listing of the possibilities, try this link: http://www.foamix.co.il/eMedicine.htm
2.
Here I've quoted,
and wonder which of the three procedures you had:
"The 3 common vaginal procedures to suspend the prolapsed vaginal apex are
sacrospinous ligament fixation, modified McCall culdoplasty, and iliococcygeus
fascia suspension. As originally described by Amreich and modified by Richter
and Nichols, sacrospinous ligament fixation is usually performed on the
patient's right side to avoid the rectosigmoid (Nichols, 1982). The vaginal
apex is attached, using permanent sutures, to the sacrospinous ligament. A
thorough knowledge of pelvic anatomy is critical in order to avoid
complications. [b][u]Take care to place the sutures 1-2 cm medial to the
ischial spine to avoid injury to the pudendal bundle and the inferior gluteal
vessels. [/u][/b]Place the suture through—rather than around—the ligament.
Excellent results have been reported for correcting vaginal vault prolapse
using fixation to the sacrospinous ligament. However, in 1992, Shull and
colleagues reported a predisposition for recurrence of anterior vaginal wall
relaxation after sacrospinous ligament fixation.
The McCall culdoplasty may be used to correct apical descent or as prophylaxis
against future prolapse (McCall, 1957). This procedure uses the uterosacral
ligaments, which, if strong, are shortened and reattached to the vaginal cuff
after completion of the vaginal hysterectomy. In the authors' opinion,
attaching the prolapsed vagina to stretched prolapsed uterosacral ligaments is
of little value. The surgeon must be bold enough to grasp the uterosacrals near
the sacrum, where they are usually strong and undetached, but careful enough to
respect and avoid the neighboring ureters. Intraoperative cystourethroscopy is
therefore essential to be sure the ureters have not been ligated or kinked.
The iliococcygeus fascia suspension provides effective cuff suspension, since
it attaches the apex to the obturator internus fascia and iliococcygeus fascia
with less risk of neurovascular damage than does the sacrospinous ligament
fixation (Shull et al, 1993). Alternatively, the authors have described placing
the suture through the iliococcygeus and the periosteum at the ischial spine,
where it is attached (Scotti et al, 1998)."
How did Nates determine that you had axonal loss and demyelination in all
branches of the pudendal? Without cadaver dissection and study, that would be a
remarkable feat. And such is not done in other peripheral neuropathies.
Here you go under the knife without past history of pudendal pain, only to
waken with symptoms. Either the dorsal lithotomy position of your body during
surgery caused pudendal damage, which is possible but would hardly persist, or
a branch of your pudendal caught a suture during the procedure. As eloquently
as you write and as well as your posts indicate you think you must realize
nerve entrapment from an ill-placed suture to be by far the most likely
explanation for your neuropathy. Nerve tissue has almost no structure, with
less resistance to pressure than does jello. It is extremely fragile, and for that
reason as we were created it was done in such a fashion so as to afford nerves
and the nervous system the finest protections available to a body. Even the
endings of axons that branch up to the skin surfaces do not run along the
surface where they could suffer insult. Instead they course deep, then turn
towards the surface they innervate. Larger nerves are hidden behind bone and
cartilage at every site possible, or tucked deep behind muscle. A nerve has
absolutely no defense against a suture.The PNMLT does not measure conduction
through individual branches. The peroneal branch could not be accessed through
the rectum, nor the dorsal nerve of the clitorus. The inferior rectal branch,
which comes off the pudendal prior to its passage through Alcock's canal, is
the tract along which the electrical impulses from PNMLT tranverse. If you were
told that the PNMLT measured individual branches, and that a determination
could be made based on PNMLT that each of these branches were diseased in some
way, then you were misled.
Then you were told that the pudendal nerve, on its exploration, "the
fibers appeared in shreds". Unless the surgeon opened the epineurium of
the nerve, which I greatly doubt he did, because it would serve no utility and
increase the possibility of both trauma to the nerve as well as vascular
injury, then he could not see the nerve bundles. Since axons are microscopic,
he could not have legitimately referred to those. And since nerve bundles of
axons are then lumped together and covered with epineurium, he could not see
those either.
The wonderful vibes from the tribal group are fine, Amanada. I would join with
the Cherokee every night for ritualistic dance if it would work. Your best
interests may be paramount, but knowledge and skill must accompany. Ketamine
put you at risk with zero possibility of lasting difference. Intrathecal drugs
the same. If the purpose was to aid in diagnosis then such modalities can be
justified. But when the theory says "no" in fifteen different ways,
its not going to work. Just like it didn't. Bedside manners are much
appreciated by patients, as well as the caring and concern from staff. But
neither of these factor into outcomes when the pathology is real.
No one looked at your pudendal and saw a nerve in shreds. No one tested each
individual branch of the pudendal. Your entrapment neuropathy is most likely
far distal to Alcock's, has not been seen, and has not been helped.
3.
Not the pudendal,
but some of its tributaries are very close to the wound margins. That's the
point with Amanda. Most likely her entrapment is far distal to Alcock's canal.
That is why surgery failed her, but also why nerve blocks and other modalities
proximal to the entrapment have achieved some short term results. I have
previously noted four sites of possible entrapment along the course of the
pudendal and its branches, and the arrangement of the entrapment structure in
relation to nerve. So while the PT is right... we do not always follow Gray's
anatomy... neuropathic pain from distal pudendal nerve branch injury is quite
possible with vaginal hysterectomies, and in fact, probably occurs more
frequently than thought.
IV. On reasons
for failed pudendal decompression surgery
1.
Like others who
have commented, I am sympathetic to your continuing symptoms and pray you can
find relief. I am fairly confident based on your aggressive approach (early
diagnosis and prompt decision to travel for surgery) that you are still
searching for help. The information I am providing is based on common sense and
after thorough review of other neuropathic conditions and the results of
procedures to remedy those maladies. In addition, I have recently had PNE
surgery in
2.
My words are not
intended to supply "sweet comfort", but rather to apply analytical
logic to the question of PNE, and to do so in such a way that others can make
informed choices. Where there are pitfalls I have made an effort to note them...
such as the sensitivity and specificity of the PNMLT. Yes, in theory it should
supply accurate data each and every time, but the fact that it does not does
not relegate it to worthlessness. When this series of posts began I noted that
I also have an MD son who has done hundreds of nerve decompression procedures.
I am somewhat surprised that no one has latched onto this. But the role that it
played in my decision to undergo surgery was large, and that reason is solely
about outcome. During a multi-year period of time in the 1980s he performed 365
carpal tunnel release procedures, and then staff carefully studied the short
and long term results. As many of you know, CTS supposedly involves entrapment
of the median nerve at the wrist from hyperplasia of the flexor retinaculum,
which is due to numerous etiologies, from thyroid disease to occupational ones.
The median nerve is much like the pudendal, and like the sciatic... the same
things I wrote about before... arrangement of axons, sensory and motor components,
etc. In fact, the median is a tad larger, and while they have not been actually
counted, there are probably more sensory receptors in the distal digits than in
the perineum (which doesn't seem true but makes sense from an evolutionary
standpoint). At 1, 4, and 8 years not a single patient had recurrence of
symptoms. At 2 weeks following each of 365 releases not a single patient had
pain. How can such results be explained? First, apply logic to the
neuropathologies involved in true entrapment, and one can see that if a single
patient can be cured, then (if the diagnosis is correct) it follows that all
patients can be cured. The rate limiting factor is simply the extent and
fastidiousness of the dissection. In this, I must boast, there was probably none
better... in religious and sometimes extreme preparation, in focused dissection
far more proximal and distal (even to the mid-metacarpals) than was customary.
The approach was clear... initial exploration provides clear planes of
dissection (virgin tissue), and most likely it is this one single occasion in
which cure will be the outcome...so make the very most of it. Granted this was
in a decade when there was little issue with such things as compensation
neurosis and the long term use of narcotics to address chronic pain. Such
iatrogenic addictions take from many patients the ability to determine for
themselves if pain is still real. My decision to travel to
When it is not, I refer back to past comments. I would like to say that in a
previous description of the course of the pudendal nerve I wrote of its
perpendicular penetration of Colles's fascia, another site of possible
entrapment. The body's response to dissection at this point would be much like
the response of the tympanic membrance to myringotomy, it would attempt to
rapidly seal (over 4-5 weeks). That is why all children undergoing
myringotomies also get tubes. Tubes are nothing fancy, just cm long tubes of plastic
perhaps 3 to 4 mm in diameter. They are quickly placed in the surgical
laceration in the tympanic membrane in order to keep the TM from healing itself
and sealing. A very similar tube could be used to protect the pudendal nerve at
Colles' fascia... the only adjustment would have to be for size and perhaps
length, and to also make a slit down the length of the tube so that it could be
easily fitted around the nerve. I also see in the next 5 years the development
of much more minute endoscopic equipment that could be used for more distal
dissection in PNE and other entrapment syndromes such as the anterior cutaneous
nerve entrapment syndrome. It would probably be preferable to combine an open
procedure with an endoscopic one which would allow dissection to be carried
into places now perhaps unreachable.
V. On
diagnostic testing
A. Practical guide
1.
Yesterday I suggested that millimeter by millimeter visualization of the
pudendal nerve, and thereby the likely probability of pinpointing entrapment,
might be possible in the near future with enhanced MRI software. This morning I
discovered (by way of the forum), that in three places in the
the specific anatomical slicing presented by imaging. I read the latest article
prepared by those who promote the current technology, and you may find this at:
http://www.neurography.com/images/NeurolClinics-Neurography.pdf.
I also reviewed the 2005 American Medical Association's medical policy and
technology assessment committee on Magnetic Resonance Neurography, which says:
"MR neurography refers to modifications of MRI using special software and
hardware upgrades, which have been proposed for the diagnosis of peripheral
nerve disorders. The development of MR neurography enables direct high
resolution longitudinal and cross-sectional images of peripheral nerves such
that the morphology of the nerve can be visualized. Published literature
regarding MR neurography primarily consists of small case series of
heterogeneous patients. There is inadequate data regarding the diagnostic
performance of MR neurography, in terms of defining the normal range of
morphologies, the sensitivity and specificity of identification of
abnormalities in comparison to other diagnostic tests, and the impact on the
management of the patient." As this modality becomes more refined and
tested it will become an important tool in both the diagnosis and pre and post
surgical management of the PNE patient.
But for many considering surgery, and for those post surgical patients who have
not found freedom from pain as the outcome, modalities that are down the road
have little importance on May 8, 2006. There seems no clear cut guide of how to
proceed for the symptomatic but undiagnosed. And the post surgical patient with
pain is faced with an even more vexing puzzle.
Here I would like to present a modest guideline for the patient with suspected
PNE to follow before surgery is entertained, leaving it for each of you to
agree, disagree or add, all of which should contribute to our understanding.
1. You must first rule out those conditions, local, regional or systemic, which
would mimic PNE but which would not be remedied by a decompression procedure:
a. the following labs:
CBC, sedimentation rate,
C-reactive protein, Thyroid Stimulating
Hormone assay (TSH), Prostatic
Specific Antigen assay (if male),
Anti-Nuclear Antibody Assay
(ANA), CMP (complete metabolic
panel) Rheumatoid factor,
Fasting blood sugars for three successive days,
Urinalysis, CEA
b. the following imaging studies:
X-rays of the pelvis and
lumboscaral spine
CT scan of the pelvis
MRI of the lumbosacral spine
c. a complete physical exam, including a detailed neurological exam
2. If this testing is all normal, then consider each of the modalities which
are useful in varying degrees to diagnose entrapment of the pudendal nerve:
a. The PNMLT has a low level of specificity but a moderate level of sensitivity
in the diagnosis of entrapment. The test measures a function of nerve velocity
called latency. Entrapped nerves conduct an nerve impulse slower than a normal
nerve. The purpose of the test is to measure impulse conduction along the nerve
in order to compare latency to standard. In balance, there is considerable
controversy concerning the reliability of this test, but it is this member's
opinion that testing is worthwhile.
b. Magnetic resonance neurography is considered "investigational/not
medically necessary" by the American Medical Association, but the
literature suggests that improvements in both imaging and interpretation are
being made on a regular basis. Information for patients can be viewed at www.neurography.com.
It is this member's opinion that current testing is valuable in that there is a
greater than 50-50 probability results might provide significant information to
the neurosurgeon. In addition, since it is doubtful diagnostic modalities will
be developed because of concern over PNE alone, participation in developing
technologies will increase both the credibility of PNE as a syndrome as well as
expand the knowledge base upon which future PNE patients might rely.
c. CT guided injections are diagnostic blocks of the pudendal nerve at specific
locations which help determine the location of pathology. They are not specific
for PNE, but their sensitivity for pathology is high. It is possible to be even
more selective and block at each anatomically conceivable area of entrapment.
The development of this capability would be straight-forward and highly
recommended. Also recommended is a practice of careful sensory testing
following diagnostic blocks. Far more information could be obtained from
vibratory testing and two point discrimination, then carefully documented, than
the current practice of checking results by phone. The applicability of such
information in determining other sites of possible entrapment after failed
procedures could be significant.
3. If such testing suggests PNE, then the decision for surgery should be well
informed. Many physicians are skillful, but it is the wise physician who
appreciates the partnership with their patient that knowledge will bring. You
will have reached this point only because you have suffered much. To guide you
out of entrapment your surgeon will need both wisdom and skill. Make your
choices well informed ones. Speaking for many others in this forum, we wish you
the very best.
4. If pain is totally relieved from Botox, then the pain is not neuropathic
from pudendal entrapment at Alcock's. The pelvic floor muscles innervated by
the pudendal can spasm and thus place compressive forces on pudendal branches
feeding them. If this persisted to such a point that the nerve branch was
injured, the pain would be neuropathic, but again, the site of injury would not
be at Alcocks. The sole mechanism of action of Botox is at the neuromuscular
junction, the site at which the nerve passes on to muscle instructions that
have been received from the cord. The action of Botox at this site is quite
well understood, blocking the transfer of information from the nerve to the
muscle, resulting in muscle paralysis. The paralysis is flaccid, not rigid. The
muscle becomes totally relaxed, unable to contract without orders from the
cord. Only if the pudendal passed though a muscle that was in a state of
constant or almost constant contraction, which it does not, could muscle be
held liable for neuropathy (except for tiny branches, which could be liable).
If pain is relieved from Botox, then PT is not only advisable, it is necessary
in order to prepare the pelvis for the time when the effects of Botox have worn
off. Only when Botox affords no relief, and PT causes additional pudendal
distribution symptoms, is PT inadvisable.
While Botox works at the junction between muscle and nerve, it does not affect
sensory afferents coming from muscle, or from areas surrounding muscle. A
pathological process affecting the pelvis in the area infiltrated with Botox
would nonetheless generate transduction forces that would be interpreted and
recognized as pain. A nerve block, however, defeats transmission in the area of
administration, so that any nociception, whether nociceptive or neuropathic,
whether from laceration, fracture, tumor, or nerve entrapment, regardless of
etiology, would not reach the cord or brain.
I believe this allows us to suggest the following: do not entertain PNE
decompression until you have undergone a trail of Botox therapy. If your pain
is musculoskeletal, and relieved by Botox, you will not find relief from
surgical decompression at Alcock's. Instead, all efforts.... PT, medication
(including Botox) ... should be focused on achieving muscle relaxation on
command. This needs to be added to the recommendations to the patient with PNE
symptoms.
2.
This is in
response to your request for information on the utility of the above specified
laboratory tests in eliminating pathology that might mimic true pudendal nerve
entrapment. Your question involved the context of pathology that would not
otherwise be revealed by scanning modalities. In another thread you patiently
explained to me the difficulties involved in deciphering medical terminology.
Unfortunately, as I explained later, it is only possible to dissect this
terminology but so far. Here I will attempt to do just that. But keep in mind
that at 75 this mind is approaching senility, and could lapse into much too
technical a discourse. If that happens, please query me on a single item or
two, and I will explain more carefully.
Some of the testing recommended could reveal disease both in lab results and on
imaging studies as well as on either alone. For example, carcinoma of the
prostate that was metastatic both to bone as well as adjacent tissue would most
likely result in an elevated PSA, an elevated alkaline phosphatase on the
metabolic panel, as well as bony lesions on X-rays of the pelvis, and soft
tissue masses on pelvic CT. Still, the PSA could be elevated in the absence of
other findings, and while elevations do not necessarily mean cancer, they would
demand thoughtful evaluation of the prostate. Since the prostate is located in
an area that has sensory innervation by the pudendal, PNE would have to take
second place until significant prostatic pathology was eliminated as the source
of pain. Likewise, I think that it is important for all clinicians to realize,
especially those who diagnose and treat PNE, that the presence of disease such
as prostatic carcinoma does not totally exclude the possibility, however
remote, that the patient with unresolved pain could also be suffering from a
disease such as PNE.
You are aware that disease affecting peripheral nerves can be intrinsic to the
nerve, extrinsic to the nerve, or both. Even more confusing, within the nerve
disease can be either intrinsic or extrinsic to the axons. There are many
diseases that will affect the nerve either at its origin, down its path, or
within its own cellular processes, and do so in such a way that the result is
pain. The acronym TITMEND, though not all-inclusive, is useful as a guide to
etiologic categorization: toxic, infectious, traumatic, metabolic,
endocrinologic, neoplastic, or degenerative. Within one or the other of these
categories can one find the cause of most disease, and in each of these
categories one can find disease processes that would affect the pudendal nerve.
But for example of the utility of lab testing for disease that would not be
evidenced by scanning, let us consider the case of diabetic peripheral
neuropathy. It is quite well recognized in medical communities that most folks
with type two diabetes are actually diabetic for 4 to 7 years before diagnosis,
and 5 million is the figure generally given for the number of undiagnosed
diabetics in our population. In addition, almost 10% of these undiagnosed
diabetics are felt to already have neuropathies due to their diabetes before
they are diagnosed. That means that 500,000 Americans have peripheral
neuropathies due to a condition yet undiagnosed. Even this does not fully
portray the possibilities for non entrapment pudendal neuropathy due to
diabetes. People whose fasting blood sugars run between 100 and 125 are
considered pre-diabetic, and studies show this group of Americans to be at risk
for neuropathy as well. The lab test... fasting blood sugars times 3...is given
as a recommendation because diabetes and pre-diabetes is prevalent in our
society, it is often asymptomatic, and the statistical probabilities of it
producing neuropathy is far greater than entrapment. Granted that long standing
sitting pain should have led to an earlier work-up to exclude such a
possibility, but it is this member’s contention that all avenues should be
explored and re-explored before the commitment to surgery.
Several members with recognized diabetes have written about suspected PNE. For
them diagnostic testing in the form of nerve blocks and PNMLT have little
promise. Blocking the pudendal would temporarily relieve the distress of almost
any illness affecting it, including a neuropathy due to diabetes. Studies on
the validity of PNMLT in the diabetic, to my knowledge, are unavailable if
performed. And if so, they most likely represent such small numbers that little
confidence can be found in their results. The known diabetic with sitting pain
has to rely solely on the wisdom of the recommendation of his/her physician, but
so often this is insufficient.
3.
In chess one
weighs the statistical probabilities of every move in anticipation of your
opponents. Yes, diabetic neuropathy usually affects the distal extremities
first, and a research article I gave web directions to above partially explains
why. But diabetic neuropathy affecting the extremities first is not always the
case. Given the large numbers of people with undiagnosed diabetes, the fact
that they may not be having the typical symptoms of fatique, urinary frequency
and nocturia et al, there is still a greater likelihood that isolated pudendal
area pain could be diabetic neuropathy than it could be PNE. Before this forum
I knew of no patients with PNE, but I knew several with isolated diabetic
pudendal neuropathy. For the cost saver a FBS can at times be free.... the
health department, the knowledgeable diabetic neighbor with a glucometer, and
sometimes the local pharmacy does free glucose testing.
As far as using the CEA to rule in or out an occult malignancy before
entertaining PNE surgery, there are certainly no double-blind studies to
support it. Yet if one were to accept the premise of ruling out all disease
that has a greater statistical probability of causing pudendal pain than PNE,
this test would have efficacy. Perhaps not to some, but to the clinician who is
a grandmaster at clinical thought and diagnosis, this is the way they would
proceed.
I have argued that it is necessary to take the disease and all its diagnostic
and therapeutic remedies to the cellular and biochemical level in order to
prove or disprove utility. But to do so in a discussion of proposed testing
would require an investment of time for explanation that I anticipate most
members would neither appreciate or understand.
B. PNMLT
1. Neurophysiology
There remain many
unanswered questions in the field of peripheral nerve injury and nerve
regeneration. Yet some assumptions can be made with a good degree of medical
certainty. These assumptions rest on an understanding of latency and the current
state of knowledge with respect to neuronal healing. Although this may not be
new information or helpful to you, I am going to assume otherwise, and give the
basis for my answer to your question. Any peripheral nerve, the pudendal nerve
included, is comprised of axons of varying diameters. As you well know, the
nerve cell has many structures, but is divided into three parts... the cell
body, (which contains the nucleus, mitochondria, golgi apparatus and ribosomes)
the dendritic process, and the axon. The axon in the pudendal nerve is part of
the single nerve cell whose cell body resides in the spinal cord. Multiple
axons from multiple cells form a nerve bundle, and many bundles make up the
pudendal nerve. Injury to axons within the pudendal nerve results in a dropout
of the total number of axons stimulated by the PNMLT and thus you have a
decrease in the amplitude of the evoked electrical response, called the
compound motor action potential. What nerve latency is, in essence, is a
reflection of the pattern of activation of the separate axons that make up the
pudendal nerve. The axons in the nerve that are myelenated the heaviest are the
axons that deliver the compound action potential the fastest, thus it are these
fibers that determine the nerve velocity and also the latency. Nerves transmit
via their myelin sheaths, and the thicker the myelin the faster the
transmission. Latencies that are prolonged have occurred because faster
myelinated axons have dropped out (due to injury such as compression), and thus
what is recorded are slower velocities because most of the nerves now have
reduced myelin and thus slower velocities of conduction.
That is why, in general, higher numbers in the PNMLT reflect more significant
disease in the nerve. Very interesting, recent work has shown that chronic
nerve compression injury does not produce immediate axonal pathology but in
fact is a Schwann cell mediated disease, and chronic nerve compression induces
both Schwann cell proliferation and apoptosis before the onset of axonal
degeneration. Since PNE is usually longstanding, it is important to evaluate
what happens to the nerve after Schwann cell proliferation, and indeed, these
are the changes that produce the abnormal PNMLT. Evaluation of the thickness of
myelin and the diameter of axons in chronic compression indicate an alteration
in the myelin structure, specifically a dramatic increase in the number of
axons with thin myelin sheaths. Measurement of the myelin thickness shows not
only a greater than 600% increase in the number of axons that are thin (less
than 5 nm thickness) but also a proportionate decrease in the number of axons
with thick myelin sheaths so characteristic of a normal pudendal nerve. This
takes us to the critical point in the answer. A nerve chronically compressed
has many axons that have undergone a process of demyelination and then
remyelination at the site of injury, and the remyelination is not nearly as
thick as prior to compression. Therefore, with respect to a followup PNMLT
following initial surgery, one would expect persistent latency and abnormal
numbers, even though the compression has been either relieved, partially
relieved, or unrelieved.
The degree of remyelination, however, should have little to no impact on
residual pain.
2. Analogy
Like the PNMLT, in car racing the fastest time is the one that wins the prize.
There are many different cars (axons) on the racetrack (the peripheral nerve).
Generally speaking, some cars and drivers are more capable than others, and
these are the ones that can be predicted to win.
Suppose that a substance had been invented that could coat the cars, making
them less resistant to air, the result being faster times. Also suppose that
only a percentage of car owners could afford this substance, so that some of
the cars in the race were coated and some were not. There would be a far
greater likelihood that one of these coated cars would cross the finish line
first, and in fact, that coated cars would win every race. Coated nerves
(myelinated ones) transmit impulses faster than unmyelinated ones, and win the
race in PNMLT. It is the winning time that is recorded, not the average time
from each of the contestants. The winning time is then compared to what the
usual winning time should be (in a normal pudendal nerve). We know that rain
affects the condition of the racetrack so that slower times can be predicted.
Similarly we know that some conditions affect conduction in normal nerves,
these being such things as age, temperature, even whether or not the nerve is
located in the upper or lower extremity
(http://jnnp.bmjjournals.com/cgi/content/full/70/3/372).
What the PNMLT measures is the fastest time from the winning car and then
compares this number to what is expected of winning times in usual and normal
races on the pudendal nerve. If there has been a terrorist event (pudendal
neuropathy is sort of like long standing nerve terrorism) at the race track,
where an explosion or other insult caused debris to be thrown onto the track,
or perhaps displaced the wall surrounding the track so that the space available
for driving was limited in this area, then the race cars would have to slow
down when they approached this area, and the winning time from the race
affected by terrorism would be slower than a race that had not been affected
(normal race).
The race cars that have been coated to make them less resistant to air and thus
faster are the cars that win the race. Therefore these are the cars that
determine the value of the PNMLT. But these are not the race cars that carry
the pain impulse around the tract. Coated cars carry instructions to muscle.
The uncoated cars are carrying pain stimuli. We assume, and probably rightfully
so, that the terrorist event affects all cars on the race track, so measuring
the speed of the fastest cars against what is normal allows us to suppose that
uncoated cars are likewise affected. You can find far more detailed information
at: http://www.uphs.upenn.edu/ortho/oj/1999/html/oj12sp99p45.html.
3. Sensitivity and
specificity
Sensitivity and specificity are two critical measures in determining the
utility of any diagnostic procedure. In the case of nerve electrophysiologic
studies like the PNMLT, sensitivity refers the procedure’s ability to detect
the presence of sensory abnormalities in a group of patients. If the patients
being tested are at high risk for neuropathy, such as patients with advanced
diabetes, then the sensitivity would be expected to be high. Testing a group of
randomly selected diabetic children, however, would naturally include some that
have not yet developed neuropathy and yield a correspondingly lower level of
detection sensitivity.
A test that is “too” sensitive, however, can result in false positive measures
that wrongly identify a healthy patient as having an abnormality.
Specificity is the statistic that expresses the ability of a diagnostic
procedure to correctly identify healthy (control) subjects. A specificity of
100% means that there were no false positive measures in the healthy group.
Diagnostic tests balance sensitivity against specificity, so that the maximum
number of abnormalities are detected with the fewest number of false positives.
The following table presents sensitivity and specificity measures drawn from
eight different studies. With the exception of Study #4, each study used
randomly selected patients for whom a clinical finding of sensory impairment
was not a selection criterion. As a consequence, the sensitivities will vary
depending upon the patient population selected. Statistical analyses presented
in these cited studies all revealed statistically significant differences
between patients and control subjects.
Sensitivity 94% Specificity 100% n = 33 diabetic patients and 54 controls
Sensitivity 77% Specificity 100% n= 29 dialysis patients and 137 controls
Sensitivity 84% Specificity 88% n = 70 radiculopathy patients *
Sensitivity 23% Specificity 100% n = 92 diabetic children and 80 controls
Sensitivity 50% Specificity 95% n = 16 Fabry’s disease patients and 50 controls
Sensitivity 54% Specificity 95% n = 2360 diabetic patients *
Sensitivity 60% Specificity 95% n = 73 diabetic patients and 47 controls
Sensitivity 93% Specificity 100% n = 10 syringomyelia patients and 15 controls
Statistical Analyses of CPT vs NCV Sensitivity
1. Ro, L.S., Chen, S.T., Tang, L.M., Hsu, W.C., Chang, H.S., Huang, C.C.
Current Perception Threshold Testing in Fabry’s Disease. Muscle & Nerve,
Volume 22: 1531-1537, 1999. Appendix E., Reference 15.
A chi-square SPSS statistical analysis was conducted to compare the detection
sensitivity of neuropathy by sNCT/CPT and NCV tests in this study. The CPT
detected neuropathy in 50% of the patients. The NCV detected neuropathy in 0%
of the patients. There was a significant superiority of the detection
sensitivity of the sNCT/CPT electrodiagnostic test over the NCV test in this
study (p<0.001, df=1).
2. Katims, J.J., Rouvelas, P., Sadler, B.T.,
A chi-square SPSS statistical analysis was conducted to compare the detection
of neuropathy by sNCT/CPT measure and NCV measures in the median nerve and in
the peroneal nerve. The tests were equally sensitive in their detection
sensitivity for neuropathy (p<0.193, df =1, median nerve and p<0.707, df
= 1, peroneal nerve).
3.
A chi-square SPSS statistical analysis was conducted to compare the detection
of neuropathy by sNCT/CPT measure and NCV measures in the median nerve and in
the peroneal nerve. The tests were equally sensitive in their detection
sensitivity for neuropathy (p<0.119, median nerve and p<0.701, peroneal
nerve).
4. Kurozawa, Y., Nasu, Y. Current Perception Thresholds in Vibration-Induced
Neuropathy. Archives of Environmental Health, Volume 56(3):254-256, 2001.
A. A chi-square SPSS statistical analysis was conducted to compare the
detection of stage 3 vibration neuropathy by sNCT/CPT measure and NCV measures.
The tests were equally sensitive in their detection sensitivity for this stage
of vibration neuropathy (p<0.308, df = 1).
B. A chi-square SPSS statistical analysis was conducted to compare the
detection of stage 2 vibration neuropathy by sNCT/CPT measure and NCV measures.
There was a significant superiority of the detection sensitivity of the
sNCT/CPT electrodiagnostic test over the NCV test in the detection of this
stage of neuropathy(p<0.000, df=1).
5. Rendell, M.S., Katims, J.J., Richter, R., Rowland, F. A comparison of nerve
conduction velocities and current perception thresholds as correlates of
clinical severity of diabetic sensory neuropathy. Journal of Neurology,
Neurosurgery and Psychiatry, Volume 52:502-511, 1989. Appendix E., Reference 5.
A. Among the diabetic subjects in this study classified by both Physical Score
and Symptom Score as normal, the 5 Hz CPT measures were the most “effective
discriminator” of these “normal” patients in comparison with the NCV and other
measures in the study (p<0.05, Tables 6 and 7). This finding is a indication
of the specificity of the CPT evaluation based on clinical findings.
B. Lower extremity sensory NCV measures were unable to discriminate between the
normal and abnormal subjects as classified by both Physical Score and Symptom
Score. All three frequency CPT measures were able to discriminate between these
same two groups of subjects. The significance of these observations ranged from
p<0.01 (5 Hz and 250 Hz) to p<0.05 (2 kHz). This finding demonstrates
that the CPT evaluation is a more effective discriminator than the sensory NCV.
See Table 7.
C. A strong correlation is defined as a correlation coefficient > 0.5.
Correlations of the upper and lower extremity Physical and Symptom Scores with
the CPT and sensory NCV measures were significant, with p values ranging from
0.001 to 0.05. The strongest correlation was observed with physical evaluation
and the 250 Hz CPT from the lower extremity (Spearman correlation coefficient =
0.57, p<0.001). The sensory NCV from the same extremity showed a very weak
correlation (Spearman correlation coef. = 0.15, p<0.05). See Tables 4 and 5.
D. When the electrodiagnostic measures were further divided into “Relatively
Abnormal” and “Very Abnormal Groups”, the sensory NCV was unable to
discriminate between the normal and relatively abnormal groups Physical or
Symptom scores in either the upper or the lower extremity. In contrast, the CPT
measures were able to discriminate between the normal and relatively abnormal
groups Physical or Symptom scores in either extremity (p<0.01). These
findings indicate that the sensory NCV is not effective for discriminating
moderate neuropathy, but is effective for discriminating severe neuropathy. In
contrast the CPT measures are effective for discriminating both moderate
neuropathy, and severe neuropathy.
6. Masson, E.A., Veves, A., Fernando, D., Boulton, A.J.M. Current perception
thresholds: a new, quick, and reproducible method for the assessment of
peripheral neuropathy in diabetes mellitus. Diabetologia, Volume 32:724-728,
1989.Appendix E., Reference 7.
A. This publication does not permit a direct comparison of the detection
sensitivities of the sNCT/CPT and the NCV measures.
B. A significant correlation between the 2000 Hz CPT measures and the
NCVmeasures (Spearman correlation coefficient -0.66, p<0.005) was reported
inTable 2.
C. A significant correlation between the 5 Hz CPT measures and the
thermalmeasures (Spearman correlation coef .34, p<0.005) was reported in
Table 2.
D. No significant correlation was observed between the NCV and the thermal
endorgan sensory threshold test as reported in Table 2. This was expected as
the NCV is a large fiber test and thermal end-organ stimulation is conducted by
the small fibers. As neuropathies can selectively effect the large or small
diameter nerve fibers the ability of the sNCT evaluation to test the function
of both sub-populations of nerve fibers makes this test a more effective tool
for the evaluation of neuropathy than the NCV test.
Based on the above publications the sensitivity of the sensory nerve conduction
velocity testing for the detection of polyneuropathy is between 0% and 79%.
One must also take into account these studies were undertaken in world class
electrophysiologic laboratories and performed by highly skilled technicians
under strict quality assurance standards and supervision.
This data confirms conclusions drawn in posts previously presented. The PNMLT
is a modality we have, and gives information which must be viewed in light of
results from the remaining arms of the diagnostic triad. Alone it has little
value. Intra-operatively and post-operatively it has no value. To answer the
question of a patient with a normal PNMLT yet with severe pain having a greater
likelihood of poor outcome from surgical decompression versus a patient with an
abnormal PNMLT, this type of conclusion cannot be reached. It cannot be reached
based upon theoretical approach, and there are no controlled studies which
would allow one to dispute such theory. In fact, such a statement is contrary
to theory. Let me explain. High numbers on the PNMLT should reflect disease
involvement of an increasing number of heavily myelinated axons, while normal
numbers reflect such axons are as yet uninvolved in the compression neuropathy
(or there is no neuropathy). Differentiation of pain into categories like
severe does not reflect on transduction forces nor on transmission, but instead
is a very poor indication of disease severity because it involves some
modulation but is mostly a matter of perception. Several considerations must be
made in the patient with a normal PNMLT and in severe pudendal distribution
pain. If the CT guided (where we can reasonably assume the analgesic has
reached the pudendal) nerve block gives the patient immediate relief of pain,
and the duration of such analgesia is consistent with the labeled duration of
effect of the analgesic, then it can be concluded with a reasonable degree of
certainty that the pudendal nerve is indeed responsible for delivering
nociceptive input to the spinal cord. This conclusion can be made whether the
PNMLT is normal or not.
A second CT guided block (and indeed, a third or fourth) should achieve the
same results as the first. If not, one of the following must apply: (1) for
whatever reason, the analgesic did not reach the pudendal nerve, (2) the
analgesic was mislabeled, thus no analgesic reached the nerve, (3) the response
to the first injection was a placebo one, (4) the neuropathy has extended
proximally to involve the nerve between the site of the first injection and the
spinal cord, (5) since the time of the first injection another disease process
has involved the pudendal nerve proximal to the site of the initial injection.
It has been alleged that degree of PNMLT abnormality correlates with prognosis
and well as severity of compression. There are no controlled studies to support
this view. Moreover, carefully designed, placebo controlled studies of
commonplace compression neuropathies generally find no correlation between
degree of entrapment as visualized on MRI with severity of symptoms,
probability of analgesia following decompression, or degree of abnormality on
electrophysiologic testing. Given the limitations of PNML testing, it is not
reasonable to offer the results of this test as a prognostic indicator of
surgical decompression.
4.
Validity of intra- operative and post operative PNMLT
The axons injured
by compression or some other structural reason do not form new axons. The ones
you have at birth are with you all through life, and the very same axons that
formed the pudendal nerve when you were seventeen and seemingly indestructible
are still there... in bundles that form the pudendal nerve. The myelin sheath
that coats each axon degenerates and then regenerates once injured. There may
be several episodes of degeneration and regeneration, but in almost all cases
the regenerated myelin sheath is thin, unlike the sheath of a healthy nerve.
Since thickness of the sheath determines velocity of conduction of the nerve
impulse, a thin sheath conducts slower than a thick one. It is likely, and
appears to be so both in research and cadaver dissections, that the axon will
never regain its original myelin thickness. Therefore, yes, Greg, you are
right. Dr. Ansell's belief is more than that. It is correct based upon fairly
extensive neurophysiologic studies. Latency will not change during surgical
decompression, and I'm certain that it is easy for you to see this given the
nature of latency as previously described and the cellular changes that are
responsible for delayed conduction. The severity of pain during my illness made
it clear that hyperbole and subjectivity is not the way to approach PNE.
Providers and patients need to make decisions based on the most current
evidence-based, non-biased science, and such science is generally repetitive,
for researchers as well as those who depend on research find comfort when
results are reproducible. It is important to realize, as I wrote before...
demyelination with insufficient remyelination does not account for persistent
symptoms in supposedly decompressed patients. Once again I allege the only
reasonable probabilities for this: incorrect diagnosis, insufficient
decompression, or established central pathways at the cord or cortex level that
take time to resolve despite the absence of stimuli. The latter would explain
progressive improvement in a subset of post-operative patients, and I am aware
of several medications that would speed this along.
5. Reasons for PNMLT
despite concerns over validity
As I have written
before, the sensitivity of the diagnostic triad leaves much to be desired. The
same is true of its specificity. But suppose we were to dismiss the PNMLT
altogether. This would be much like dismissing the upper GI series, which
misses 65% of endoscopically proven gastric ulcers, or even the CXR, which
misses most bronchogenic carcinoma until the tumor has had 5 years to double
and spread to regional nodes. Or we could dismiss the PSA, since levels of 4 to
8 are gray and may or may not suggest disease, or could be the result of
tobacco dependence. No, what we do is take the modalities that are available to
us and constantly refine them, improving technical skills as well as
technology, until new modalities become available. Just like baking a cake,
sometimes it is easier and more efficient to adjust a recipe than to start from
scratch. What is known to each of us is that resources for PNE are few and far
between. We have no lobby of Hollywood stars pleading with Congress for
research monies, as did the sufferers of AIDS. Our numbers are relatively few
and hardly spark the interests of a pharmaceutical industry whose focus is the
bottom line. Although my state has huge, reputable medical centers, I, like
others, have had to travel out of state to see a physician who has even heard
of PNE. So while PNMLT is not a panacea, it is a modality we have. The future
may bring new technologies that are far more reliable, but these will be only
as good as their operators. Colonoscopy misses 5% of colorectal tumors, but in
the hand of others, and on a good day, the miss rate is zero. If a technology
and its results can be correlated with gross and microscopic pathology, then it
is much more likely to be successful in diagnosis, as well as in monitoring
improvement. Nerve conduction technology should improve dramatically in the next
decade.
Intervertebral disc herniation should be ruled out before PNE surgery is
contemplated, and an MRI is the most reliable method to do so. In addition,
pelvic pathology that could produce a pudendal neuralgia, either from
compression or invasion of the nerve, should also be ruled out, and a pelvic CT
scan should suffice. I had both before making the first trip to Houston. At 75,
most of my discs were bulging (discs dehydrate with age and uniformly bulge),
but there was no encroachment on the neural canal.
In fact, we could pull 100 asymptomatic folks out of the isles of Walmart, do
MRIs of their lumbosacral spine, and more than 30% would have significant disc
disease. Like PNMLT, MRIs are not a panacea for diagnosis.
But I promised to write about nerve injury, those "damaged" and those
compressed. For the sake of an intellectual exercise I will write about the
sciatic nerve rather than the pudendal. Both are peripheral nerves, with the
same configurations, same arrangement of axons, same location of cell bodies
within the cord, same type of synapses both dendritic and axonal. Except for
size, location, areas innervated, and location of cord synapses, they are the
same. We do ourselves and others disservice by thinking somehow the pudendal
nerve is subject to a disease process that affects that nerve alone. All
peripheral nerves can suffer compression and are subject to disease. While the
structure or lesion precipitating compression may be different, the changes
that take place in the nerve are the same. The same is true of systemic
diseases affecting peripheral nerves. But since polyneuropathy is essentially
ruled out in most of our cases, especially given the duration of symptoms, I
will avoid a discussion of those injuries and the neuropatholgies involved.
Rather I will focus, or attempt to do so, on disease and how it affects a
single sciatic nerve. In essence, that is what has happened to us.
6. Botox and the
PNMLT
Botox should not
affect the PNMLT. Botox affects the neuromuscular junction at the efferent
nerve ending, working to block any impulse from the brain from reaching the
muscle. In theory this blocks all the impulses flowing from the cord to muscle
while the cord is in a hyper-excitable state from chronic pain.
The PNMLT measures impulse conduction along afferent axons. The neuromuscular
junction is not involved in this measurement, nor any synapse.... therefore
Botox will not affect it.
7. Nerve testing of
penis
Electrophysiologic
testing of the penis, with either positive or negative results, have about as
much efficacy in ruling in or out pudendal neuropathy (of whatever cause) as
does measuring the growth of one's eyebrows.
This test (see: http://www.hawaii.edu/hivandaids/Innervation_of_the_Human_Glans_Penis.pdf#search='nerve%20conduction%20studies%20in%20penis'
)
measures conduction through a very short length of nerve (dorsal nerve of the
penis). Pudendal neuropathy does not arise from entrapment along the dorsal
nerve of the penis. PNE could be present while such a test was positive or
negative. PNE could be absent while such a test was positive or negative. There
is no validity of such a test to PNE. Surely your doctor did not intend to rule
out PNE with nerve testing of the penis ???
C. MR Neurography
Does MR
neurography have application to PNE, either for pre-operative determination of
location and degree of entrapment, or for post-operative determination of
successful decompression? In another post I have written:
"Magnetic resonance neurography is considered "investigational/not
medically necessary" by the American Medical Association, but the
literature suggests that improvements in both imaging and interpretation are
being made on a regular basis. Information for patients can be viewed at www.neurography.com.
It is this member's opinion that current testing is valuable in that there is a
greater than 50-50 probability results might provide significant information to
the neurosurgeon. In addition, since it is doubtful diagnostic modalities will
be developed because of concern over PNE alone, participation in developing
technologies will increase both the credibility of PNE as a syndrome as well as
expand the knowledge base upon which future PNE patients might rely."
Yet this dismisses other considerations, each of which suggests less
reliability, but which in fairness must also be presented.
1. If the CAUSATIVE MECHANISMS involved in PNE are consistent with those of
nearly all other cases of nerve entrapment syndromes in the human body, and are
also consistent with the vision of injury expressed to me by Dr. Renney during
my original visit to Houston, then the mechanism and thus the injury will most
likely not be seen on MR neurography. I have previously written that the
causative mechanism is most likely as follows: "at least one side of the
compressive surface is mobile, so that chronic injury to the pudendal involves
either a repetitive slapping insult, or a
sliding-rubbing-against-sharp-or-tight-edges type of insult"., neither of
which would likely be demonstrated with current MR neurography technology. This
is not to say that as software is further refined, so that the nerve could be
actually visualized during movement, and thus a more reliable indication of
pathology would result.
2. Visualization of pudendal nerve injury might be solely positional
(POSITIONAL ENTRAPMENT), in which case the above described software modifications
might help. And also answer for us the question of whether or not the constant
pain that is the hallmark of long standing and unresolved pudendal neuropathy
represents central sensitization with continuing but intermittent injury or
rather a progression to continuous injury. In such case where injury is solely
positional, then only a procedure performed with the patient in that position
would demonstrate an abnormality in the nerve.
3. While those who have reason to seek neurography for failed lumbar spine
surgery number in the hundreds of thousands, the number of patients seeking MR
neurography for pudendal neuropathy would be few. As such, the repetition of
study that gives boost to improvement in clinical skills in both analysis and
interpretation of results is not going to be present at any of the three
centers where this software is available in the US. Moreover, the length of
nerve that must be examined in failed lumbar procedure is short. In contrast,
the pudendal courses over a wide area, and as I have written before, there are
four possible sites of entrapment.
4. Finally, the demonstration of a compressed segment of pudendal nerve on MR
neurography might be meaningless unless studies had shown in a statistically
significant number of patients that such a lesion corresponded to anatomical
findings at the time of surgery and surgical decompression of this MR
neurography demonstrated segment resulted in relief of pain. Given the usual
duration of symptoms in PNE and the role of central sensitization in
perpetuating pain long after the injury to the nerve has been removed, it is
doubtful that such rigorous scrutiny could ever be applied to PNE and MR
neurography.
D. Nerve blocks
1.
Karen is correct
in that the duration of analgesia from a nerve block should be equal to the
expected duration of effect of the analgesic, but no longer. If the analgesic
is marcaine, the analgesia may last several days. If the analgesic is
xylocaine, the concentration of drug selected can be varied, but the effect
should last no longer than 12 hours at the extreme.
Several studies have demonstrated that the prolonged and very occasional
permanent effect of a nerve block to the median nerve was not due to the
anti-inflammatory nature of the attendant corticosteroid but was rather due to
a reduction in constriction of the nerve.
Apparently steroids injected locally help break down adipose tissue (fat). In
these studies it was shown that a reduction in the amount of fat beneath the
transverse carpal ligament (which was entrapping the median nerve) relieved the
entrapment to such an extent that neuropathy resolved. Generally speaking,
steroids have no effect on scar or fibrotic tissue, unless that fibrous tissue
is acutely inflamed, such as an acute tendonitis, or a active collagen vascular
disease process. Since there is very little fat, if at all, in Alcock's,
combinations of local anesthetics with corticosteroids injected into this area
will have no consequence other than the transient analgesia expected of the
anesthetic.
If pain is totally relieved from Botox, then the pain is not neuropathic from
pudendal entrapment at Alcock's. The pelvic floor muscles innervated by the
pudendal can spasm and thus place compressive forces on pudendal branches
feeding them. If this persisted to such a point that the nerve branch was
injured, the pain would be neuropathic, but again, the site of injury would not
be at Alcocks. The sole mechanism of action of Botox is at the neuromuscular
junction, the site at which the nerve passes on to muscle instructions that
have been received from the cord. The action of Botox at this site is quite
well understood, blocking the transfer of information from the nerve to the
muscle, resulting in muscle paralysis. The paralysis is flaccid, not rigid. The
muscle becomes totally relaxed, unable to contract without orders from the
cord. Only if the pudendal passed though a muscle that was in a state of
constant or almost constant contraction, which it does not, could muscle be
held liable for neuropathy (except for tiny branches, which could be liable).
If pain is relieved from Botox, then PT is not only advisable, it is necessary
in order to prepare the pelvis for the time when the effects of Botox have worn
off. Only when Botox affords no relief, and PT causes additional pudendal
distribution symptoms, is PT inadvisable.
While Botox works at the junction between muscle and nerve, it does not affect
sensory afferents coming from muscle, or from areas surrounding muscle. A
pathological process affecting the pelvis in the area infiltrated with Botox
would nonetheless generate transduction forces that would be interpreted and
recognized as pain. A nerve block, however, defeats transmission in the area of
administration, so that any nociception, whether nociceptive or neuropathic,
whether from laceration, fracture, tumor, or nerve entrapment, regardless of
etiology, would not reach the cord or brain.
I believe this allows us to suggest the following: do not entertain PNE
decompression until you have undergone a trial of Botox therapy. If your pain
is musculoskeletal, and relieved by Botox, you will not find relief from
surgical decompression at Alcock's. Instead, all efforts.... PT, medication
(including Botox) ... should be focused on achieving muscle relaxation on
command. This needs to be added to the recommendations to the patient with PNE
symptoms.
2.
I want to run some
things by you. Since your son has had both an MRI and a CT, and I presume were
normal, I would also like to presume that work up included blood tests to rule
out systemic disease.
You've seen a urologist, so testicular malignancy, the most common cancer in a
male that age, has been ruled out. To me that is a critical determination. You
write that you were given a diagnosis of prostatitis. Since antibiotics were
prescribed, I presume the diagnosis was bacterial prostatitis. I also presume
that the urinalysis showed leukocytes, and a positive result was received on
urine culture. These are essential for such a diagnosis. The urine specimen
should have included premassage and postmassage of the prostate. This test is
known as the 2-glass test. If the 2 glass test was positive, the culture of
prostatic fluid positive, then the diagnosis of prostatitis was not false. If
these tests were negative, or worse... not done... then the diagnosis is
suspect, and could certainly be false.
Then the visit to the neurologist, and on to Dr. Antolak. You are certainly
putting in the effort, and I admire that. You were told to be patient
"that the effects of the injection may not be noticable for 5-6
weeks". First, the failure to obtain immediate and complete though
temporary analgesia after the injection of 6 cc of marcaine is a major red
flag, and lowers the index of suspicion with respect to PNE. Second, much of
what Dr. Antolak told you is suspect. The literature does not support his
contention that the effects of steroid injection may not be noticable for 5-6
weeks, nor does clinical practice in other areas of nerve entrapment. Placebo
has a response rate of 47%, so a response rate as given by Dr. Antolak (15-70%)
could easily be placebo. In fact, symptomatic improvement as measured in 5 or
10 minute intervals of sitting is no reasonable measure of treatment efficacy.
You were told your son "has damaged a nerve that will require many months
to heal". Just the simple fact that there was no immediate analgesia with
a potent nerve block should give pause to such a remark. You have a normal
PNMLT, a negative response to nerve block, and yet the doctor is telling you
the problem is neuropathy. "pain under his stomach" is a little
difficult for me to locate, but from reading your posts in total it is not
apparent the distribution of symptoms is predominantly pudendal. And you were
told there is a cumulative effect over time, but there is nothing in the
literature, clinical studies or pathology models, to support such a statement.
You've heard the saying: two heads are better than one. The most effective way
to address a chronic pain state is with an interdisciplinary team approach. A
psychiatric evaluation should be a part of any such team effort. Chronic pain
is both influenced by emotions and precipitates emotions, some of them
destructive. Someone needs to explore work history, social history, drug
history, school history, for all of these histories might give important clues.
The team approach needs to be guided by what movements the physical therapist
says he can and cannot make. It needs to be guided by response to medication
that target specific generators of pain, whether nociceptive or neuropathic,
for that response, or lack of response, also gives clues. It might be helpful
to bring in an occupational therapist as well. You need a physician to head
such a team that is willing to listen, to search the literature, and to make
sense. When a physician tells a patient that they need look no further (but
offers no results that would stand up to scruity) and advises that you bide
your time (although his treatments to date have resulted in essentially zero
response), that patient needs to take a hard look at what is going on.
3.
Across many topics
on the forum the issue of nerve blocks is raised. Some members wonder about
side effects, others the probability of cure. Questions abound, and responses
usually reflect what physicians have said to patients or family members. It is
apparent that there is a lot of false information out there, giving false hope,
which, when deflated, then causes suspicion of other modalities which might be
effective.
Karen has made it clear, and I totally agree, that the nerve block should be
considered a diagnostic tool only. Patients should not go into the test
expecting anything other. If the nerve block gives permanent analgesia from
pudendal pain, then you can bless the heavens, for you did not have PNE in the
first place.
But answering this question about nerve blocks generates many others. Greg
writes that he knows people who have improved following nerve block.
What is the length of action of steroids, and are they washed away by
increasing the blood flow during physical therapy? These are just two of a
myriad of questions surrounding a pudendal block.
In my opinion the two most important questions are these: Aside from the use of
a local anesthetic to determine if the persisting pain is carried to the cord
via the pudendal nerve, thereby possibly indicating the pudendal itself as the
instigator (although again, any structure or tissue innervated by the pudendal
past the point of block could also be giving rise to these pain messages), what
does the added steroid tell us? Could the steroid itself be damaging to the
nerve rather than helpful, and if so, is this harm the mechanism of a post
block pain flare?
Steroids are added to the CT guided mix based on two assumptions: either direct
pressure or ischemia on the pudendal nerve produces a localized inflammatory
process, or an on-going inflammatory process causes swelling of structures
adjacent to the nerve and this is a possible mechanism of compression. If one
attempts to justify either of these assumptions in the area of pudendal
neuropathy, there is nowhere to look. To my knowledge there is no careful study
at necropsy, no biospy samples taken at the time of surgical decompression,
that demonstrate beyond a doubt the presence of an inflammatory response.
Chuck's field of study would allow him to provide greater insight on this
issue, but he will tell you that when there is on-going inflammation certain
cellular elements are involved. Absent these cellular elements, there is no
inflammation. No inflammation, and the use of a steroid is like attempting to
pound a square peg into a round hole. In PNE we have no studies to tell us
either way.
So lets look at a kindred condition, another entrapment neuropathy, and see
what research tells us there.
Investigation 1: In 160 random necropsy examinations, Lindblom and Rexed found
60 nerve root compressions. Forty four nerve root segments were examined
histologically by serial section (specimens selected from 17 cases with the
most severe macroscopic deformation). The most common findings were atrophic
pressure effects sometimes with increased connective tissue, with "diffuse
degenerations mixed with regenerative processes . . .especially in the ventral
root fibers." No cellular infiltrates were found except for some red blood
cells in one ventral root.
Investigation 2: Lindahl and Rexed reported small nerve biopsies of "the
dorsal part of the nerve root" of 10 patients operated on for sciatica
from herniated disc. They identified no pathology in five, degenerated fibres
and dural thickening from pressure effects in three, "cell infiltrates
here and there" in one, and "excessive cell infiltration . . .with a
preponderance of the mononuclear type" in only one.
Investigation 3: The inflammation theory is further questioned by Gibbs who
wrote concerning the thousands of nerve roots he has inspected at disc surgery,
"There is . . .a normal vascularisation of the dura covering the nerve
root, but it would be rare, if ever, to observe an increase in the blood supply
even under the magnification that we so frequently use. The nerve roots of the
cauda equina (intrathecal) are frequently swollen by passive congestion because
the drainage to the extradural veins is blocked . . .from the herniated
nucleus. Passive congestion alone does not constitute inflammation."
Investigation 4: Bogduk summarised, "Authors . . .have argued by inference
that this (inflammation) must be the pathology they treat with epidural
steroids. However, no clinical studies have demonstrated how inflammatory
radiculopathies are distinguished from noninflammatory radiculopathies before
treatment with epidural steroids."
Investigation 5: Nelson and Landau at the
"Intraspinal steroid therapy is not effective therapy for back pain or
radicular syndromes because steroid formulations, placebos, and sham injections
have similar outcomes."
This type of information is consistent across the medical literature ... no
operative descriptions of nerve roots showing capillary dilatation, no biopsy
reports demonstrating leukocyte infiltration or other cellular elements one
would expect to find with an on-going inflammatory process. In addition, I can
find no necropsy reports that support the inflammatory assumptions.
There are, however, reasonable explanations for the transient improvements seen
following pudendal blocks containing steroids, as well as explanations for the
post injection pain exacerbations. When methylprednisolone acetate (MPA), a
common steroid used in injections, was applied to the plantar nerve of a rat,
there was an immediate blockade of unmyelinated nociceptive C fibers that
cleared when the MPA was removed. Transitory amelioration of symptoms in a
patient post injection can also be explained by a chemical blockade along with
destruction of C fiber axons and nerve terminals by the polyethelene glycol and
the benzyl alcohol contained in several steroid formulations. It is reasonable
to speculate that when one receives a CT guided steroid/xylocaine mix into the
area of the pudendal nerve at Alcocks, the effects of xylocaine are immediate
but last no longer than a few hours, but the blockade induced by the steroid
and attendant preservatives prolongs the already existing state of analgesia
for additional hours, until both the xylocaine first and associated mix last
are then metabolized. Leaving ... a nerve with chemical injury to nociceptive
fibers, and thus the flare.
Certain conclusions can be drawn with evidence based certitude:
1. If pudendal neuropathy follows other entrapment models, and we have no
reason to think it doesn't, then the use of steroids for therapeutic purposes
is not effective, and not without risks.
2. Since there is no evidence to justify steroid injections into the region of
Alcocks, no limitations should be imposed with respect to beginning physical
therapy following CT guided nerve block. A patient's pain and tolerance should
be the limiting factors.
3. Pudendal block with a steroid mix may result in increased pain, early or
late. There may also be serious complications including permanent neurological
deficits.
4. Patients should be informed that there is no evidence, in theory or in
practice, that a pudendal block can provide permanent relief of pain.
VII. On the
processes involved in pain
A. The mechanism of central sensitization
Once when we were
diving off
I would prefer to write a more technical discourse, explaining kappa opiate
receptors, sodium channels in axons, as so forth, but that style of writing,
and the accompanying content, has been discouraged in this forum. So here I
will attempt to describe the basics in terms of the totality, and what it means
to PNE sufferers with respect to surgery, post operative expectations, and the
implications for additional testing.
Generally speaking, by the time one reaches the point of surgical
decompression, pain has become the dominant feature of life, and fear of pain
permeates most of one’s choices. Activities once taken for granted have now
become impossible. Relationships with spouses, children, friends and co-workers
suffer as well, for chronic pain predisposes to the same irritations it causes,
as well as to a whole host of emotional liabilities. Well described on this
forum are experiences that mimic mine, trips to numerous physicians,
unnecessary surgeries, the trials and failures of a myriad different drugs. So
that when, by whatever means ... forum, physician, therapist, or word of mouth
... PNE is suggested, expectations are raised and hope becomes real. Despite
the controversy surrounding pudendal neuropathy and entrapment, and despite the
significant probability that you might remain unchanged or worse following
surgery, you have finally found some possibility of remedy. So, like the end
stage cancer patient who travels to
All this time your neurological clock is being reset. In many ways different,
but in other ways similar to the neural pathways established from cocaine use,
where a certain stimuli, a street corner where the drug was purchased, a face
that resembles the dealer, even a smell somewhat akin to the burning of the
drug, all evoke an intense neural reaction in the brain. But in chronic pain
there is more than memory to evoke responses, more than established pathways to
re-create misery. The switching equipment at all levels ... in the cortex, in
the thalamus, at the cord level, and at the periphery ... becomes distorted in
many ways, anatomically, biochemically, and functionally. Just like an old
pre-electric typewriter, where pounding repetitively on the same key, faster
and faster, will ultimately result in the key becoming frozen and stuck at the
ribbon. So that while you no longer pound the key, or even touch it, the key
remains depressed, and the pain continues.
Here it is more than just perception. In fact perception has some function but
it is minor compared to modulation. In the nervous system, the higher centers
usually rule. There are exceptions, like id and ego, reflex arcs, and
bronchodilatation following fright, but the pain experience, especially the chronic
one, is ruled from above. Chronic pain distorts the manner in which the nervous
system responds to that pain, the manner in which it accepts the persisting
message of pain from the injured tissue (pudendal nerve), even the manner in
which the nerve attempts to inform the cord, and thereby the brain, of pain.
And the mechanisms that are inherent to pain resolution and relief become
distorted as well. One such mechanism are opiate receptors, and these are
located throughout the brain and the spinal cord. They were not put where they
are so as to be responsive to Oxycontin (although they are), but rather to be
responsive to opiates that your body produces in response to pain (endorphins).
In chronic pain one finds a significant reduction in the number of opiate
receptors in the cord. In the case of a severed nerve almost all the cord
opiate receptors disappear. Yet changes in number and activity of opiate
receptors is just one of the many neural mechanisms that become involved in
perpetuating pain long after the stimulus for pain has been removed.
Yet surgery produces transitory relief for many. As written above, surgery is
controlled tissue injury. When the buttocks are incised, the gluteus teased
apart and retracted, the sacrotuberous ligament divided, Alcock’s canal
opened... all this tissue insult is perceived as harm by the immune system. The
body’s response is immediate and usually vigorous.
There is an immediate inflammatory response whose purpose is to seal and heal
damaged tissue, and to fight and destroy the hopefully small numbers of
bacteria left behind from the procedure. Many different types of cells are
enlisted to aid in this reconstructive process, and many different types of
enzymes, hormones, catalysts, and other chemicals play a role as well. Very
important is the fact that, almost like turning on a light switch, opiate
receptors now become active in the pudendal nerve. Although they are hiding in
the reef during all these months and years of chronic pain, the occasion of
tissue damage from decompression surgery is the spider carcass prompting their
activity. Endothelial cells lining small vessels begin making endorphins, which
bind to these now active opiate receptors. Post operative medications, usually
opiates, now also have peripheral receptors on the nerve with which to bind.
The anti-nociceptive effects, both central and peripheral, are relief of pain.
But as soon as the body determines repair of damage to be complete (a time span
of 2 to 4 weeks), regardless of the state of entrapment, relieved or otherwise,
peripheral opiate receptors in the axon terminals become inactive. If the
entrapment was indeed the source of persistent pain, and was relieved by
surgery, then a great deal of activity must take place before the central mechanisms
can acknowledge the lack of pain stimuli and once again reset. Some wonder, in
the case of pain of many years duration,
if the key can ever be completely unstuck. Many animals are being tortured at
this very moment to try and answer that question for us.
B. Activation of opiate receptors
following surgical event
The events that occur in injured tissue as described in the post above are
localized events. An injury to the left forearm does not provoke the activation
of opiate receptors in the sciatic nerve innervating the leg. If otherwise,
where injury of even the most modest degree were to provoke the whole body
activation of opiate receptors on all peripheral nerves, as well as the
transport of opiate receptors from the cord down along the axon to the nerve
terminal, and in addition, the release of endorphins from a variety of
circulating lymphocytes, macrophages, and the endothelial cell wall... then
what would happen is that millions of Americans would be going around stabbing
themselves on a very frequent basis ...just to enjoy the neuro-chemical
response. In fact, a whole growth industry of devices for producing and
maintaining peripheral and some central analgesia from self-injurious behavior
would be on the stock exchange. No, one cannot expect a peripheral nerve's
attempt to provide analgesia to an area superinfected from an ingrown toenail
to then somehow radiate that analgesic response towards the scrotum or rectum.
And even though the inherent analgesia provided by endorphins coupling with now
active receptors in inflamed tissue does not remedy all the pain, it is
remarkable to observe the course of an ingrown toenail, where for sometimes
weeks tissue injury is occurring but there is no
perception of pain. Basically, the nociception from that tissue injury has been
suppressed at the local level by the mechanism being discussed.
The application of an opoid agonist (like morphine) along nerves in uninjured
tissue does not elicit any analgesic effect, reinforcing the concept that
inflammation, such as that which follows surgical decompression, promotes
accessibility and effective coupling of endorphins to opiate receptors in
peripheral nerve endings. Granted, clinical relief is very seldom complete. One
experiences nociceptive pain after a stabbing, or after a fracture, or
following any type of surgery. But what is happening is that the body is doing
its utmost to minimize that pain, so that we can only guess and suppose what
pain might be like as a consequence of these injuries if peripheral mechanisms
were absent. That is, unless you suffer from neuropathic pain, in which case
you already have some idea, for these peripheral mechanisms are not available
to address your suffering.
The actual mechanism by which opiate analgesic receptors become active in the
pudendal nerve following decompression surgery might be of some interest. On
the day of decompression surgery, and for perhaps the following 48 hours, the
inflammatory response generated by surgery causes a disruption of the
perineurium which is critical for the access of endorphins to the now
activating opiate receptors on the pudendal nerve.
These already peripherally located receptors are mostly delta opiate receptors,
and these almost immediately develop a high level of activity, for their
numbers are not yet great, but the result is that they yield significant
analgesic effects despite being, at least in those hours, only a small fraction
of soon to be occupied receptors. At this same time the pudendal nerve sensory
axons are delivering to the peripheral nerve terminals via axonal transport a
sizable number of kappa and mu opiate receptors. This migration down the nerve
occurs 2-3 days following decompression surgery. The sum of the activity of
these receptors, in combining with both endorphins and exogenously administered
analgesics, is the relief of pain. Interestingly, unlike opiate receptors in
the central nervous system, peripheral receptors do not appear to develop
tolerance to opiates, a fact that later could have broad clinical applications.
Currently some parts of the pharmaceutical industry are looking at ways to
perhaps synthetically activate peripheral receptors without the now-necessary
tissue injury and inflammatory response. If this could be accomplished, as well
as develop opiates with high affinities that could not cross the blood brain
barrier, then the result of which would be the ability to provide analgesia to
almost all injury in the body, including neuropathic pain, and without the
attendant complications of addiction, respiratory depression and the otherwise
that caution opiate prescribing.
C. Nociceptive versus neuropathic
pain
1.
In terms of
classifying pain generators, they can be either nociceptive, neuropathic,
psychogenic, or a combination of any two or three. For example, there is
probably a neuropathic component to every nociceptive event. They can also be
idiopathic, meaning there is no explanation of the mechanism involved. Lets
begin here with an explanation of what each of these pain generators represent.
Suppose a carpenter driving a nail missed the nail entirely and instead the
hammer stuck his finger. Or suppose a butcher was careless, applied too much
force to the blade, and on cutting through the meat also cut into his finger.
Both of these events would result in the release of phospholipids and other
substances that would initiate a cascade of biochemical reactions termed a
nociceptive response. Clinically, pain can be labeled "nociceptive"
if it can be inferred that the pain is related to the degree of receptor
stimulation by processes causing tissue injury. Nociceptive pain involves the
normal activation of the nociceptive system by noxious stimuli. Nociception
consists of four processes: transduction, transmission, perception, and
modulation.
Normal somatosensory processing involves interaction between afferent systems
activated by tissue injury and accompanying inflammation. The primary afferent
system includes nociceptors (A-delta and C- fibers), signal processing in the
dorsal horn of the spinal cord, ascending neural pathways, and thalamic and
other specialized brain structures. Peripheral nociceptors are lightly
myelinated or non-myelinated ends of primary afferent nociceptive (sensory
neurons). Peripheal nociceptors have various response characteristics and they
can be found in skin, muscle, joints, and some visceral tissues.
The nociceptive process begins with transduction (depolarization) at the
peripheral nociceptors in response to noxious stimuli. Transmission is the
process by which these stimuli proceed along primary afferent nociceptive axons
to the spinal cord and then on to higher centers. Only when the impulses reach
the brain are they intellectually recognized as pain. This is perception.
The ultimate perception of pain depends on both activity in this afferent
system and its modulation at multiple levels of the nervous system. Pain
modulation is determined by activity in
the endorphinergic system and other pain modulating systems. In the
endorphinergic system, analgesia is mediated by the binding of endogenous
opioid compounds to special subsets of receptors: mu, delta, and kappa.
Endorphins are widely distributed and closely associated with systems known to
regulate homeostasis, response to stress, and pain. In this very complex
system, other neurotransmitters, such as serotonin and norepinephrine also play
a role in the endogenous pain modulating system.
Nociceptive pain can be acute (short-lived, remitting) or persistent
(long-lived, chronic), and may primarily involve injury to somatic or visceral
tissues. Pain due to activation of somatic primary afferents is termed somatic
pain and is typically localized and described as aching, squeezing, stabbing,
or throbbing. Arthritis and metastatic bone pain are examples of somatic pain.
Pain arising from stimulation of afferent receptors in the viscera is referred
to as visceral pain. Visceral pain caused by obstruction of hollow viscus is
poorly localized (because most viscera do not contain nociceptors) and is often
described as cramping and gnawing, with a daily pattern of varying intensity.
When organ capsules are involved, the pain may be described as sharp, stabbing
or throbbing, descriptors similar to those associated with somatic pain.
Nociceptive pain of any type can be referred and some referral patterns are
clinically relevant. For example, injury to the hip joint may be referred to
the knee and bile duct blockage may produce pain near the right shoulder blade.
Pain is also distinguished by its location.
Nociceptive pain may involve acute or chronic inflammation. The physiology of
inflammation is complex. In addition to an immune component, retrograde release
of substances from C polymodal nociceptors also may be involved. This
“neurogenic inflammation” involves the release of the endogenous pain
facilitory chemical known as substance P, as well as serotonin, histamine,
acetylcholine, and bradykinin. These substances activate and sensitize other
nociceptors. Prostaglandins produced at the site of injury act to further enhance
the nociceptive response to inflammation by lowering the threshold to noxious
stimulation. Chronic inflammation with nociceptive stimulation may be the
source of persistent pain.
From reading your latest posts I gather that you have found new employ. Suppose
the hiring package included an immediate vacation for two, all expense paid, to
the
Neuropathic pain is the label applied to pain syndromes inferred to result from
direct injury or dysfunction of the sensory axons in the peripheral or central
nervous system (CNS). These changes may be caused by injury to either neural or
non-neural tissues. Although neuropathic pain is influenced by ongoing tissue injury,
there is an assumption that the fundamental mechanisms sustaining the pain have
become independent of the initial injury or damage. Neuropathic pain has varied
characteristics, but is frequently described as a continuous burning pain,
shock-like or paresthetic. The pain may or may not be lacerating. Neuropathic
pain syndromes may be associated with referred pain, allodynia (pain induced by
non-noxious stimuli, e.g. light touch), hyperalgesia (increased response to a
noxious stimuli), or hyperpathia (exaggerated responses to painful stimuli,
with continuing sensation of pain after the stimulation has ceased).
Neuropathic pain syndromes can be subclassified according to broad sets of
inferred mechanisms. Some neuropathic pain syndromes are presumed to involve a
predominating peripheral generator (e.g. compressive or entrapment
neuropathies, plexopathies, radiculopathies and polyneuropathies). Other
syndromes appear to depend on processes that reside in the spinal cord, brain
or both (e.g., pain due to spinal cord injury or post-stroke pain)
Some of the neurophysiologic and neuroanatomic changes that may occur in
peripherally-generated neuropathic pain are understood. Injury to peripheral
neural axons can result in abnormal nerve regeneration in the weeks to months
following injury. The damaged axon may grow multiple nerve sprouts, some of
which form neuromas. These nerve sprouts, including those forming neuromas, can
generate spontaneous activity, which peaks in intensity several weeks after
injury. Unlike normal axons, these structures are more sensitive to physical
distention, which is clinically associated with tenderness and the appearance
of Tinel’s sign (i.e., sensation of tingling or “pins and needles” when the
area is tapped or manipulated). After a period of time, atypical connections
may develop between nerve sprouts or demyelinated axons in the region of the
nerve damage, permitting “cross-talk” between somatic or sympathetic efferent
nerves and nociceptors. Dorsal root fibers may also sprout following injury to
peripheral nerves. The specific changes associated with centrally-generated
pain syndromes are not known.
Suppose that in England the universal response of the populace to even the most
minor of injuries (superficial scratch) was to scream and cry, to summon an
ambulance, to be hospitalized, to be given workers compensation for 6 months,
and to be given opiates in large doses for no less than a month. Socioeconomic
conditioning, local expectations of gender, exposure to similar illness in
others... these and many other factors influence response to and interpretation
of pain.
The patient’s psychological state contributes significantly to pain perception
and associated suffering. Physicians and other healthcare personnel need to
maintain a willingness to believe the patient’s self-report of pain and to
investigate its cause; concurrently, the presence of anxiety, depression, or
other affective or psychological disorders should also be assessed so that
appropriate supportive care and/or pharmacotherapy can be instituted. In some
cases, evidence that the pain itself is sustained by psychological factors can
be inferred. This phenomenon is known generically as “psychogenic” pain.
Specific diagnoses, as described in the Diagnostic and Statistical Manual of
the American Psychiatric Association can also be applied. When reasonable
inferences about the sustaining pathophysiology of a pain syndrome cannot be
made, it is best to label the pain as “idiopathic.”
In medicine questions are like revolutions... once one gets started it is
difficult to find an end. But I believe we are well on our way to understand
pain and the mechanisms which produce it. There are a lot of research issues
that are hovering around just outside the realm of PNE. For example:
"PUDENDAL URETHRAL SENSORY NERVE STIMULATION FOR BLADDER EVACUATION
Another emerging application of pudendal nerve stimulation is electrical
activation of urethral sensory nerve fibers to elicit bladder contraction and
voiding (19). This approach is based on the augmenting reflex whereby fluid
flow in the urethra initiates bladder contractions in the quiescent bladder and
augments ongoing contractions in the active bladder (20,21). Pre-clinical
studies in animals demonstrated that bladder contractions may be generated by
electrical stimulation of the urethral sensory branch of the pudendal nerve
(19,22), and that the urethro-bladder reflex was preserved following acute
spinal transection (19-22). The excitatory urethro-bladder reflex was found to be
strongly state-dependent (19,23). When the bladder is at low volumes,
electrical stimulation of the urethral sensory branch does not cause excitation
of the bladder but evokes an increase in urethral sphincter activity. When the
bladder is at higher volumes, electrical stimulation of the urethral sensory
branch of the pudendal nerve leads to excitation of the bladder (24) and
micturition-like increases in bladder pressure (19,22), and prolonged
stimulation leads to long-term augmentation of the urethro-bladder reflex (25).
These results challenge the traditional view that coordinated voiding requires
intact spinal-brainstem-spinal reflex loops (2) and suggest that the
inter-neuronal circuitry required to elicit coordinated bladder evacuation
exists within the spinal cord. This may provide a new approach to restoration
of bladder evacuation following SCI."
"DEMYELINATING NEUROPATHY AND NEUROPATHIC PAIN IN PERIAXIN-DEFICIENT MICE.
Brophy P.J., Gillespie C.S., Griffiths I.R.(1), Ure J.(2), Cottrell D.F., Fleetwood-Walker
S.M., Sherman D.L., Smith A.(2) University of Edinburgh, Edinburgh EH9 lQH, UK,
(1)University of Glasgow, Glasgow G61 IQH, UK, (2)University of Edinburgh EH9
3JQ, UK.
The Periaxin gene is specifically expressed in myelinating Schwann cells. Mice
lacking a functional Periaxin gene develop a neuropathy characterized by focal
hypermyelination and segmental demyelination in the peripheral nervous system
(PNS). The mice display allodynia, a painful response to normally innocuous
stimuli, at an early age and by six to eight months they exhibit severe
functional impairment. All peripheral myelinated nerves examined are severely
affected. We conclude that the periaxins play an essential a role in
stabilizing the interaction of the axon with myelin-forming Schwann cells. We
also suggest that these animals will be useful models for studying late-onset
forms of demyelinating neuropathy, particularly where neuropathic pain is
associated with demyelination."
And then there are those recent articles which suggest what we have already
said in other posts in this forum. In this case that entrapment might not be
localized to a single site, but that indeed, the underlying mechanism of injury
to tissue may involve not only different sites, but may involve different
tissues at the same site.
"SWELLING DISTAL IN THE FOREARM AND PAINFUL MEDIAN NERVE COMPRESSION
Dammers J., Veering M.M. Department of Neurology, Medical Centre Alkmaar, The
Netherlands
In Cambridge ('97) we presented the results of our double blind placebo
controlled study on corticosteroid injection in carpal tunnel syndrome. 1) Our
results (50% responders after one year) were better than generally met. We
think that our good result is due to the fact that we give an injection 4 cm
proximal to the carpal tunnel. In 66% of the cases we observe a swelling on the
volar side of the forearm, proximal to the carpal tunnel. After one or two
injections we see this swelling diminish. This is due to the fact that
corticosteroids have lipolytic properties. Echography and MRI-imaging of these
swellings do not show any other structures than subcutaneus fat and muscle.
Local swelling after Colles fracture, ganglion, arthritis and tendonitis are
well known causes of CTS. Apart from these, two other types of local swelling
(fat and muscle) do exist, but no mention of these is made in literature. We
studied 200 persons, patients and accompanying persons visiting our out-patient
department, on the incidence of these local swellings. This can be an fatty
structure subcutaneous, on the volar side of the distal forearm. More often we
see a swelling which is predominantly caused by pronator quadratus muscle. We
consider this a swelling when it protrudes above the level of the tendons of
the flexor muscles. This swelling disappears by forcefully closing of the fist,
by pressure of the tendons, becoming a swelling again when the person pronates
the fist against resistance. We asked 200 persons between 20 and 90 years (mean
age 53, 82 male, 118 female) to have their forearm inspected. We tried to
discover by history and neurological examination if they suffered CTS. This was
the case in 33 women, 11 men. (p<0.015). Pronator quadratus muscle
hypertrophia was seen in 70.29%. 54 Female and 16 male (p<0.001).
Correlation of pronator muscle hypertrophia and CTS was highly significant.
Fatty swellings subcutaneous were met in 12 cases, correlation with CTS was
high, (p<0.09). Women do have more often than man local swelling. This often
leads to CTS, especially in women because of their smaller canals and
menopausal accumulation of fat. A narrow carpal tunnel and subcutaneous fat and
muscle cause distal median nerve compression. In 95% of the cases it positively
reacts on an injection of corticosteroids, the way we inject it and gives long-lasting
results of about 50% after a year. Conclusion: painful distal median nerve
compression is not only caused by a narrow tunnel. Beside well known local
swellings, pronator quadratus muscle hypertrophia and/or local fat are
pathogenic as well. Lipolysis by locally applied steroids is probably the
reason injections give longstanding results in about 50% of "CTS"
patients
1. Dammers J, Prins J, Veering MM, Vermeulen M. Corticosteroids close to the
carpal tunnel. A double blind study with encouraging outcome. Abstract
Peripheral Nerve Society Meeting.
In fairness, I think it is important to mention that the perfect results
previously presented in median nerve surgery probably had something to do with
patient selection. This is not to say patients were turned down, but is to say
that most patients with CTS had not been symptomatic for years and years. Also,
many were symptomatic only at night or with certain activities. In addition,
many obtained partial or complete relief of pain with upper extremity
splinting. Most of us refrain from activities that produce severe pain,
although with PNE it is almost impossible to not sit at sometime during the day
NEUROPATHIC PAIN AFTER CCI IS PERMANENTLY REVERSED BY GABA THERAPY
Eaton M.J., Karmally S., Martinez M.A., Plunkett J.A., Cejas P., Lopez T. The
Miami Project to Cure Paralysis, University of Miami School of Medicine,
Little is known about the endogenous spinal mechanisms of the altered sensory
behaviors related to unilateral chronic constriction injury (CCI) of the
sciatic nerve and the development of neuropathic pain. Cellular therapy that is
able to reverse chronic pain after CCI, also reverses the loss of GABA in the
endogenous GABA interneurons of the dorsal horn. The neuronal cell line,
33G120.17, transfected with rat GAD67 cDNA (glutamate decarboxylase for GABA
synthesis) was used as a subarachnoid graft in a model of chronic neuropathic
pain induced by CCI. When 33G10.17 cells were transplanted one week after CCI,
they survived greater than seven weeks on the pia matter around the spinal cord
and synthesized GABA. Furthermore, the tactile and cold allodynia and tactile
and thermal hyperalgesia induced by CCI was significantly reduced during the
two to seven week period after grafts of 33G10.17 cells. The maximal effect on
chronic pain behaviors with the GABAergic grafts occurred two to three weeks
after transplantation. To investigate whether the induction of chronic
neuropathic pain is sensitive to GABA levels, a single dose of intrathecal (IT)
GABA was substituted for cells grafts, one week after CCI. Both thermal and
tactile sensory behaviors were potently reversed for at least 4-5 weeks after
IT GABA. These data suggest that altered spinal GABA levels contribute to the
induction and maintenance of chronic neuropathic pain and that cell therapy can
prevent or relieve that pain. This work was supported by the Miami Project; NIH
#36438-02; and The State of
Here we have an approach that in the near future might have important
applications to those with persistent neuropathic pain following decompression.
We have research that suggests axons delivering a pain stimuli along the
pudendal nerve actually may come off the nerve at a point entirely different
than what was previously supposed.
"CUTANEOUS BRANCHING STRUCTURE OF PHYSIOLOGICALLY IDENTIFIED NOCICEPTORS
Meyer R.A., Peng Y.B., Ringkamp M.,
Little is known about the branching structure of physiologically identified
cutaneous nociceptors. We used electrophysiological. techniques to locate the
position of the branch point where daughter fibers innervating two separate
locations in the receptive field join the parent axon. Single-fiber recording
techniques were used to investigate 32 Ad and 10 C-fiber nociceptors
innervating the hairy skin of the monkey. Electrodes for transcutaneous
stimulation were fixed at two separate locations inside the receptive field.
Distinct steps in latency of the recorded action potential (AP) were observed
as the electrical stimulus intensity increased in the receptive field
indicating discrete sites for AP initiation. The number of discrete latencies
at each stimulation location ranged from 1 to 9 for the Ad fibers and 2 to 6
for the C fibers. The mean size of the latency step was larger in the Ad fibers
(9.9 ± 1.0 ms) than in the C fibers (4.0 ± 1.0 ms). Collision experiments were
performed to determine the connectivity between one AP initiation site from each
location in the receptive field. To correct for changes in electrical
excitability following AP propagation, collision experiments between the two
skin locations and between each skin location and a nerve trunk electrode were
necessary. For nine branch points from 7 Ad fibers, the mean distance between
the skin and the branch point was 54 ± 10 mm. For one C-fiber, the branch point
was 94 mm from the skin. These results indicate that some nociceptive afferents
branch quite proximal to their peripheral receptive field. Furthermore, these
results demonstrate that collision techniques can be used to study the
functional anatomy of identified nociceptive afferent terminals."
This would support my prior contention that careful sensory testing , mapping
and documentation prior to and following diagnostic blocks might have important
clinical implications both to that individual patient as well as to the entire
class of those with PNE.
Finally for those who have stayed with this discussion, I believe not only that
we are making progress, but that a remedy can be found for all. It is in this
area that the forum and its members could have their greatest utility. I have
written about, and all members know first-hand, how difficult it is to find a
doctor... any doctor... who has even heard of PNE. Let's suppose that a
suffering person has learned, through intense investigation on the internet of
perineal pain, that PNE as a syndrome does exist. That person then goes back to
the same doctor who has treated this person's painful-sitting unsuccessfully
for years, and presents the physician with a copy of symptoms taken from the
tipna website. Suppose this doctor is not so hurried, so uncaring, so
money-conscious, so lacking in intellectual curiosity that he reads the material
and begins his own search. He queries a search engine to look up PNE on
emedicine, and finds no such entry. He then queries "chronic pelvic
pain", to find:
Neurologic disorders
Neuralgia/cutaneous nerve entrapment (surgical scar in the lower part of the
abdomen; usually iliohypogastric, ilioinguinal, genitofemoral, and lateral
femoral cutaneous nerves)
Shingles (herpes zoster infection)
Degenerative joint disease
Disk herniation
Spondylosis
Abdominal epilepsy
Abdominal migraine
Neoplasia of spinal cord or sacral nerve
but there is no mention of the pudendal nerve or its possible entrapment. It is
then likely this patient's physician will turn a blind eye to the literature
brought in by the patient, and proceed along the same course that has endured
no relief.
I have published on many occasions, as have my children, and there are members
of this forum who have writing skills and knowledge superior to mine. If these
talents were harnessed in a different topic section on this site, so that we
could begin to compose a document of sufficient clarity and information to
warrant publication on emedicine, I wage a result would be to create an index
of suspicion for PNE all across our world.
The mechanism by which the forum would undertake to do so could be debated, but
I suggest we start with history of PNE, and proceed, as does every other
emedicine summary, through causes, testing and so forth until we reach a
section on treatment.
A member or members who are physicians (Karen for instance) could edit/monitor
this topic. As information regarding the history of PNE was assimilated, they
would be responsible for its organization and summary. The summation would be
presented to the forum where members would have opportunity to make amendments,
which could be voted upon. Then the history section could be voted upon, and
having then completed
one section of our proposed publication, we could move on to the next. Finally
we would not only have a document rich in information and perspective, this
would represent, for the first time in history, an occasion where sufferers,
both past and present, were able to affect a change in the medical literature.
A number of journals would consider it. In addition, the forum’s document could
be simplified so that it could also be made available to non-medical
publications. The simple novelty of its creation and the quality of
presentation would inspire interest from any number of national health and home
based magazines. I recognize that some may feel the mere presence of the TIPNA
site is sufficient, but I call to their attention the plight of many older and
elderly, who do not have use of a computer, who do know understand search
engines and the ease of use, who could not fathom what topic to enter if
computer access was available, and if fortunate enough to have it done for
them, could not understood what they read. All they really understand is pain,
and for this they depend on their doctor, who frequently lets them down.
2.
I have doubts
about my ability, or anyone's, to produce an explanation of what takes place in
the generation of pain, and therefore how to affect it, in a writing style that
would be acceptable to all. I think it is important that an explanation of
these concepts be available to those who wonder. But the terminology involved
can be simplified but so far. For example, some have supposed on this forum
that the injury to their pudendal nerve is not entrapment or compression but
rather "pinching". I have attempted to explain that regardless of
mode, the response of the nerve to injury can be graded, and that with each
increase in severity of pathology the nervous system reacts in progressively
different ways. Most nerve entrapment syndromes, the pudendal included, result
from long standing injury to the nerve as it passes through an osseoligamentous
tunnel and the compression is usually between bony surfaces and ligamentous
ones.
In almost all cases of entrapment at least one side of the compressive surface
is mobile, so that the long standing injury to the nerve involves either a
repetitive "slap" against the nerve or a "rubbing" type
abrasion against sharp or tight edges. This partially explains the symptomatic
benefit of standing, that is, until nerve damage reaches a point that standing
is of no benefit. But whatever the mechanism, the changes that take place in
the nerve are progressive along a pattern that we can identify... things like
edema, structural alterations in the myelin sheath, ischemic changes from
disruption of capillary blood circulation, and so forth. So regardless of
mechanism of injury we rate damage to the nerve by the pathologic changes that
are taking place in it because of the injury. We do that because that allows us
to predict what the nerve's response is going to be. Or more accurately, what
the nervous system's response is going to be. If recent research has taught us
anything at all, it is that peripheral and central neural mechanisms are not
mutually exclusive. In fact, long standing injury to a peripheral nerve like
the pudendal is associated with an extensive amount of interaction between both
the central and the peripheral nervous system that reinforce the pathology
involved and contribute to your state of chronic pain.
Most of the people who use this forum either have or have had neuropathic pain.
I doubt many of your doctors can describe the fail-safe mechanisms that
perpetuate neuropathic pain, nor do they have a clue as to peripheral and
central hyperexcitability. Hopefully just your use of the word "nociceptive"
during your office visit with your provider is likely to generate additional
thought in that provider's mind, as well as some inclination to review the
literature.
Pain as we evolved served and continues to serve a useful purpose. It is a
normal reaction of the sensory system to noxious stimuli and it alerts the
individual of possible or actual damage to the body. This highly evolved
protective function ... making us aware of injury or disease ....usually remits
when the illness is cured and healing is complete. The pain that is present
when tissue is injured is called nociceptive pain, and this pain is
characterized by the peripheral sensitization of nociceptors. Nocicepetors are
like a sensory organ located at the very tips of sensory axons. Because these axons
are conveying information from the periphery to the central nervous system,
they are termed afferent axons. Primary afferent nociceptors are carrying the
message of tissue injury from the site of injury to the spinal cord.
If your skin suffered second degree sunburn, the primary afferent nociceptors,
the sensory axons working to provide an alert system to the body in that
area.... these nociceptors would be sensitized. They would exhibit an increased
impulse frequency to the same stimulus, producing hyperalgesia, which is
defined as an increased pain response to a stimuli. Rub you hand across your
second degree sunburn and you will rapidly recognize that it does not feel the
same as it did before the burn. The pain you now feel from a normal stimuli,
rubbing your hand across skin, is hyperalgesia.
Unfortunately nociception can persist long after tissue injury, long
after the body's need to be signaled and warned, and long after it has any
useful function.
D. The four horsemen of pain
Thus far I have
attempted to describe in some detail the course that the pudendal nerve takes
as it leaves the spinal cord and sacral plexus and travels towards its motor
and sensory destinations. I have written about possible sites of entrapment
along this course, the changes in the nerve itself that entrapment might bring,
how these changes would affect the PNMLT, the possibility of picking up the
site of entrapment on MR neurography, and how tissue injury, in the form of
decompression surgery, causes opiate receptors on the pudendal nerve's sensory
terminals to become active. I have written that the recurrence of neuropathic
pain shortly following decompression surgery is not the result of re-entrapment
but rather a continuum of the original pain state, albeit briefly modified by
the analgesic properties inherent to peripheral nerves during inflammation.
Mostly this recurrence is due to ineffective modulation and unregulated
transduction. In order to fully understand these events, and to understand the
approach we need to take with respect to medication, one must have a basic
appreciation of the four physiologic processes that together cause you to hurt
or not to hurt. Each of these processes can be pharmacologically manipulated,
and the manner in which that is done, and the approach that can be successful,
is the subject of this and future discussion.
These four processes are the 4 horsemen of pain: (1) TRANSDUCTION is the
translation of physical energy (noxious stimuli) into electric activity at the
peripheral nociceptor.
(2) TRANSMISSION is the propagation of nerve impulses through the nervous
system. (3) MODULATION occurs through the descending endogenous analgesic
systems, which modify nociceptive transmission. These endogenous systems
(opioid, serotonergic and noradrenergic) modulate nociception through
inhibition of the spinal dorsal horn (T) cells. (4) PERCEPTION is the final
process resulting from successful transduction, transmission and modulation and
integration of thalamocortical, reticular and limbic function to produce the
final conscious subjective and emotional experience of pain.
This is what I propose. That we view with favor the models set forth for
effective chemotherapy in some malignancies, as has been done with antiviral
therapy for HIV infected patients, as we do in addressing other infectious
diseases like tuberculosis, and like we do everywhere when we find current
strategies lacking. That instead of attacking the cancer cell only at its cell
wall, we devise treatments that attack it anywhere we can. That instead of
approaching TB with an antibiotic that works some of the time, we use
combinations of antibiotics whose sum effect is to work all of the time. That
is where we should be with neuropathic pain, but as yet no such path has been
marked.
I say we should begin to mark such a path. That we take each stage in the pain
process, understand it as fully as the research allows, and develop a
multi-drug strategy which attacks pain at each level simultaneously, thereby
increasing our chances of reversing hyperalgesia and enhancing our opportunity
for relief. To do so will require a knowledge of each stage of the pain process
as well as an understanding of the mechanism of action of each drug we add to
our armamentarium. What I propose to do is describe each of these processes in
a separate post or topic, including in that post each medication known to alter
the pathologies involved. Then we shall propose calculated analgesia, where
medications are considered in such a manner so as to balance our approach to
pain.
We are certain that following pudendal nerve injury sensitization of central
neurons takes place with alterations in their firing characteristics, and this
is something we must do something about. We know that when the pudendal nerve endures
prolonged entrapment, the resultant repetitive impulses fired to the cord
causes the nerves in that area to undergo synaptic modifications, with changes
in their receptive fields. This is something we must address if the problem is
going to be fixed. We know that chronic pain causes a marked depletion in the
neurotransmitters within the inhibitory descending pain pathways (whose
function are to reduce pain), so that complete relief of pain will never occur
until these pathways regain their regulatory activity. For chronic pain and
pudendal neuropathy is attributable to the malfunctioning ... to the
pathological malfunctioning ... of a damaged nervous system at all of its
levels.
What I wonder is this... if we do not drive the train together, who is going to
drive it for us? Look about, search the literature. There are no recent
relevant studies on PNE. And in most cases the pharmaceutical literature on
chronic pain is nothing more than falsified data touting medications that
destroy via addiction while using the subterfuge of pain relief. If one buys
into that ploy they are never going to get well. But if one makes the effort to
understand why they hurt, the same nervous system that causes pain may also
give up the solution to wellness.
VI. On pharmaceuticals
A. Valium and other benzodiazepams
1.
Valium is a member
of the drug class benzodiazepam. It works to address your pain because
benzodiazepam receptors are located on the alpha subunit of the GABA receptor
on postsynaptic nerve endings within the spinal cord. As such, when this
receptor is occupied by a benzodiazepam such as Valium, the chloride-channel
gating effect of GABA is enhanced, so that the now increased chloride channel
conductance within the cord axon leads to hyperpolarization of the cell and
decreased (inhibition) transmission of the painful stimuli upward. Since
transmission of noxious stimuli is thus delayed at the cord level, the signals
reaching the cortex (where perception of pain creates the real event for your
consciousness) do not carry the same effect they would carry if not delayed.
2.
As we have
discussed, benzodiazepam agonists (Valium, Tranxene) and other agonist at the
benzodiazepam site achieve their therapeutic effects by enhancing the actions
of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) at its
receptor. The benzodiazepams have a binding site on the GABA receptor, which
forms a channel through the membrane and opens and closes to control chloride
flow into the cell. When Valium or Tranxene sits on this receptor site, GABA
produces a more rapid pulsatile opening of the channel, and the flow of
chloride is increased. The central GABA receptor, known as the GABAA receptor,
consists of at least four subunits; three of these—alpha, beta, and gamma—each
contains three to six variants. The multiplicity of variants suggests that
there are a number of different GABA receptors, but the subunit makeup of the
native receptor has not yet been determined.
Two GABA receptors have been identified anatomically and pharmacologically.
These receptors—variably called type I and type II, benzodiazepine I and
benzodiazepine II, or omega I and omega II—are located throughout much of the
central nervous system (CNS). The omega I site has been associated with the
alpha-1 subunit, whereas the omega II site appears to be heterogeneous, located
on receptors with alpha-2, alpha-3, and alpha-5 subunits. The ratio of omega I
to omega II binding sites is greater in the cerebellar and cerebral cortices,
whereas omega II sites predominate in the spinal cord. Therefore these are the
sites that should hold our attention. Unfortunately, pharmacological studies
indicate that the 1,4-benzodiazepams bind with relative nonselectivity to both
omega I and omega II sites. The triazolobenzodiazepams tend to have a greater
affinity for omega I and II receptors than do the other benzos, and they are
more potent. Zopiclone, despite its unusual chemical structure, has a binding
profile much like that of the classic benzos. Zolpidem, however, binds with
much greater affinity to the omega I site and there is evidence that abecarnil
may have some specificity for the omega I site as well, therefore these benzos
are of less interest to us.
Most of the benzodiazepams currently available for therapeutic use are
considered to be full agonists at the benzodiazepam site. By definition a full
benzodiazepam agonist is a drug that produces the maximum effect in all
biological assays, although it occupies less than the maximum number of
benzodiazepam receptors. Since we are looking for maximal effect in omega II
sites, even with unoccupied receptors, we need a full agonist. Recently,
partial agonists at the benzodiazepam site have been identified; a partial
benzodiazepam agonist is a drug that produces less effect than a full agonist
when it occupies the same number of benzodiazepam receptors. Benzodiazepam
antagonists are drugs with affinity for the benzodiazepam modulatory site but
no efficacy. A unique aspect of the benzodiazepam-related modulatory site on the
GABAA receptor is that it is bi-directional; there are agents that bind here
that decrease the effects of GABA at its site on this receptor, and thus have
effects opposite to those of classical benzodiazepams. Confused? As we progress
further up the cord, to the midbrain and the cortex, things get even more
confusing.
3.
Just like with
modification of pain, any muscle relaxant effect would be at the cord or cortex
level via the mechanism given above. Muscles themselves do not respond directly
to medications that supposedly relax them. The only direct manner in which to
affect muscle activity is to deprive the muscle of substrate (oxygen, glucose,
etc.), or to amend the neuromuscular junction, where acetylcholine alone is the
neurotransmitter. What Valium does is to reduce the excitability of dorsal horn
cells in the spinal cord, probably depress excitability in the thalamus, and
depress excitability at different sites throughout the cortex. The muscle is
not truly relaxed, nor is it changed in any way from Valium. The commands that
your brain gives to muscle are relaxed, at least until they reach the point
where the efferent axon leaves the spinal cord. From that point on there is no
effect from the benzodiazepams, or from muscle relaxants such as Baclofen or
Soma.
There is clinical relevance. If we could determine that minimum dosing of
benzodiazepams would result in occupation of alpha subunits without the
bothersome central sedation, then a long acting benzo (minus the cocktail
effect of rapid onset) would be one piece in our model of maximum analgesia for
neuropathic pain. We need to affect modulation of central processing of pain
with at least three medications with differing mechanisms of action. The best
benzo might be one of those.
4.
Benzodiazepam
Comparative Time Half-life
dose to peak
plasma
level
------------------------------------------------------------------------------------
Alprazolam .5 1 - 2 9 - 20
Bromazepam 3.0 .5 - 4 8 - 30
Chlordiazepoxide 25 1 - 4 24 - 100
Clonazepam .25 1 - 4 19 - 60
Clorazepate 10 variable 1.3 - 120 * (unreliable absorption)
Diazepam 5 1 - 2 30 - 200 *
Estazolam 1 .5 - .6 8 - 24
Flurazepam 15 .5 - 1 40 - 250 *
Halazepam 40 1 - 3 30 - 96 *
Ketazolam 7.5 3.2 30 - 200
Lorazepam 1 2 4 8 - 24
Nitrazepam 2.5 .5 - 7 15 - 48
Oxazepam 15 2 - 3 3 - 25
Prazepam 10 2.5 - 6 30 - 100
Quazepam 7.5 1.5 39 - 120 *
Temazepam 10 2.5 3 - 25
Triazolam .25 1 - 2 1.5 - 5
* metabolites
Karen, if we were looking only at half-life, that might would be the case. But
as you recognize, 30 to 200 hours is much too variable a period of time. We
need control, and Valium (diazepam) does not allow it. In addition, we need a
benzo with a slow and gradual onset of action. Valium is enjoyed because of its
cocktail effect, that is, most of the drug hits fairly quickly. We are looking
for receptor site occupancy in the cord, not the cerebral events.
The occasional pre-sedation is not harmful in the least, nor does it trigger
reward pathways. I apologize for misleading. Frequent use over a period of a
few weeks is the problem, enhancing dopaminergic pleasure responses that are
quite separate from the feeling of analgesia.
B. Indocid suppositories
Yogi, famous Yankee catcher and word artist, said: in theory there is no difference
between theory and practice, but in practice there is. If an Indocid
suppository were to provide relief from chronic perineal or pelvic pain, then
in theory (and probably practice) that pain would not be neuropathic. Indocid
is indocin, a non selective non-steroidal antiinflammatory drug in the same
class with Motrin. It acts through inhibition of the cyclooxygenase enzymes
that produce the inflammatory prostaglandins. These types of drugs work on
nociceptive pain, but not on neuropathic pain. If someone obtained persistent
and substantial relief from the NSAIDs, regardless of mode of insertion (oral,
rectal, intra vaginal, intra urethral, intra nasal, whatever), then the index
of suspicion with respect to PNE could be lowered.
To summarize:
There are 5 generators of pain... nociceptive, neuropathic, psychogenic, mixed,
or idiopathic. A traumatic event is primarily nociceptive. Pain that persists
is most likely neuropathic, though could be psychogenic, nociceptive or a
combination of all three. Since we know that the action of all the NSAIDs,
including Indocin, is to inhibit the action of the COX (cyclooxygenase)enzyme
that helps initiate and propagate the nociceptive response, we can conclude
that if analgesia is obtained from these medications, then the generator is
nociceptive. NSAIDs (like Indocid) have no theoritical basis for relieving pain
when the generator is neuropathic. If the generator is psychogenic, any
analgesic response to NSAIDs would be a placebo one. As far as the B & O,
opium provides analgesia to different degrees regardless of pain generator, so
its utility in ruling in or out a specific pain generator is nil.
C. Narcotic analgesics
1.
Strategies in
terms of medication, especially when those medications have the ability to be
so disruptive, or to cause behavior changes, or to put one out on a highway
where the medication affected inability to operate a motor vehicle places
others at risk.... these strategies for medication selection need to be
evidence based. The following letter to the state board highlights that need,
and was written by one of my children.
"Decision making in the practice of medicine should not be based on
unfounded dogma. Theories, however well-intentioned, simply do not determine
outcomes. The happenings set in motion by a particular unproven plan of care
will rarely be those narrowly intended, are intrinsically unpredictable, and
will usually ramify far beyond the anticipation of the instigator. This appears
to be the case with respect to chronic opiate use in treating chronic
non-malignant pain.
The use of opiates in chronic non-malignant pain is profoundly messy, and the
practice of medicine suffers from no more controversial an issue. The last ten
years
have been one of opioid zealotry, with the liberalization of prescribing
opiates quickly moving from the realm of scientific discourse into one
emotionally charged and highly politicized. Even today most scientific studies
in this area are rated poor by design and measurement of outcomes, and the
majority receive funding from a pharmaceutical industry that profits indirectly
from study results. Until there are well designed randomized double blinded
studies available for review by the medical community, the use of opiates to
treat chronic benign pain remains unproved.
Few would argue that opiates are powerful and effective analgesics.
Indisputable is the fact that they are effective in acute traumatic and
post-operative pain states that are primarily nociceptive. The failure to
address pain in these circumstances can have multiple negative effects on
patients, delaying recovery as well as depressing immune function. It is
equally clear that aggressive management of pain is appropriate in terminal
conditions such as cancer, and that ineffective management can be considered
inhumane. What remains at issue is whether or not these drugs are appropriate,
effective, and commensurate with functional recovery and rehabilitation in
chronic non-terminal conditions. There are basic clinical questions that
surround the long term use of these medications in benign conditions, and
little to no quality unbiased science to provide answers.
A few randomized and controlled studies are available to give guidance on the
short term use of opiates, but there are no published studies of sufficient
length to be clinically relevant to the question of long-term, perhaps even
lifetime, opiate use. At present what
is considered appropriate research outcomes is the reflected biases of study
designers. Rehabilitation oriented clinicians tend to emphasize objective
functional outcomes,
whereas medication oriented physicians tend towards subjective, palliative
outcomes.
I have written to the Board on several occasions stressing that a physician's
reluctance to employ opiates in treating chronic benign pain should not be
considered "under-treatment", and that such caution not represent
"lack of knowledge". Those of us who spend our evenings searching the
literature for better ways to care for our patients
and find no valid data to support the current opiate fad are probably far more
knowledgeable than the majority of providers who prescribe opiates for any and
all chronic benign pain.
Early in medical school we learn that medicine is both an art and a science, an
understanding daily reinforced with patient encounters. A small part of the art
is the attention we focus while listening, the determinations we make by
skillful exam, the comfort we give to the sick or dying with their knowledge
that we will be there for
them and that we care. It is the science upon which we depend to make treatment
decisions. That science can be qualified by its design, and what is considered
the "best" science are well-designed, randomized, double-blind
studies.
Unfortunately even the best science is subject to manipulation. Corporate needs
affect study results and deeply shadows the validity of a substantial part of
medical treatment research. I have enclosed a study from The American Journal
of Psychiatry which should give pause in reviewing treatment options for
psychiatric medication. The questionable validity of results, which suggests
improper data management in randomized, double-blind studies procured by
pharmaceutical interests, is not a phenomena isolated to psychiatry. Sworn
testimony before the U.S. Senate in 2002 revealed that Purdue Pharma, the maker
of Oxycontin, engaged in an extensive and sophisticated non-branded promotion
of opiates to treat chronic non-malignant pain, that it sponsored thousands of
seminars for physicians in which the benefits were unsubstantiated and
overstated and the risks trivialized, that it used marketing data to determine
which physicians would prescribe opioids most “liberally” and “least
discriminately” and targeted these physicians, and that from 1996 to 2000 the use
of other opioids grew 23% while Oxycontin prescriptions increased 1800% in the
same period. Most of the current science and the contributions to the
literature, the overwhelming majority rated poor to fair, has been funded by
Purdue Pharma or Purdue Frederick, and/or the authors are employees of either.
Opioids are not a panacea for pain. Some studies indicate a lack of response in
up to 38% of patients, even with liberal use. As the Board recognizes, one
factor that has been shown to be a determinate of response is the generator of
the pain, whether it is predominantly neuropathic or nociceptive. The animal
literature provides persuasive evidence that opioids have little to no effect
in certain neuropathic models, although there are exceptions. Likewise there is
compelling evidence from human clinical research to suggest opioids are less
effective in neuropathic conditions. Unfortunately most studies fail to
differentiate between types of pain and lump a variety of painful conditions
together. Moreover, studies that rely on outcomes by way of patient validation
of pain through scoring depend on individual patient's response to pain. This
response has been influenced in no small degree by social conditioning and
expectations, as well as other factors. The only study in the past 5 years that
has been rated better than fair in design (funded by Purdue Pharma and one
author employed by them) looked at the difference between a long acting opiate
and placebo during 6 weeks of therapy, and the numeric analogue pain score
difference, ruled statistically significant, was 1.2 points (4.1 to 5.3 for
placebo). There is even evidence that opioids may make certain pain states
worse by causing hyperalgesia. Almost any physician has experienced the sadness
of treating a terminal cancer patient on high dose narcotics and can remember
the pain that even light touch could cause in areas of the patient's body
spared the disease.
To date there are no studies of adequate quality or sufficient power to arrive
at evidence based conclusions about the incidence and prevalence of
psychological dependency, addiction and abuse in the chronic benign pain
population. In fairness this is partially the result of a lack of uniform
terminology... a situation recently remedied, at least in part, by definitions
given by a consensus group (and adopted by the NCMB) to physical dependency,
addiction, and pseudo-addiction. Notably absent from this effort, again
reflecting bias, is a definition of psychological dependency. Psychological
dependency is an emotional state of craving for a drug for its euphorigenic
effects or to avoid negative effects associated with withdrawal. In some cases
it may be a consequence of the fear of uncontrolled pain rather than the
pursuit of euphoria or the avoidance of abstinence. This type of dependency
occurs at variable rates dependent on the specific characteristics of the
clinical situation and is a salient consideration in studying and managing
patients who present on opioids.
The NCMB defines addiction as the compulsive use of a substance resulting in
physical, psychological or social harm to the user and continued use despite
that harm. The pharmaceutical literature argues that addiction is probably a
rare phenomena in most chronic pain conditions, yet one can find numerous
examples of social harm (imprisonment), and realize that the presence of
psychiatric diagnoses, particularly personality disorders, as well as certain
sociologic milieu can make abuse and addiction far more likely. The first
scientific study to give us unbiased, hard data on prevalence of addiction,
dependency and pseudo-addiction is underway (and NIH funded): http://www.fammed.wisc.edu/research/projects/opioid/html.
The development of tolerance with chronic opioid use is one of the most
controversial issues, and again, there are no quality studies to lend
credibility to anything we have been told. It is clear that tolerance develops
to some degree in animal models, in treating cancer pain, in treating post
surgical pain, and in street use. It is therefore reasonable to assume that
tolerance will develop in all chronic dosing. In addition, in some clinical
circumstances there may be a worsening of the disease with an accompanying
change in nociceptive activity causing an increased requirement for opioids,
mimicking tolerance and perhaps disguising the exacerbating illness. Any future
study into tolerance must assess the potential of disease progression on
results, although this may be extremely difficult to do in light of the many
nebulous diagnoses encountered in chronic pain management.
It is clear that any patient presenting with a history of long term narcotics
for the treatment of various alleged chronic pain states has increased disease
conviction, a somatic preoccupation, and an externalized locus of control, all
of which lead to increased opioid seeking behavior in the absence of increased
nociceptive input. Indeed, some of the strongest arguments against chronic narcotic
therapy comes from the neurobehavioral arena, and psychiatric diagnoses are
important factors to consider before initiating opiates short-term. Narcotics
can worsen depression, and psychological functioning has been shown to improve
following opioid detoxification. The argument that effective analgesia improves
depression has never been proven, and several studies have demonstrated that
psychological functioning worsens with opiate therapy.
Part of the chronic benign pain controversy stems from divergent goals and
philosophies of physicians. If the doctor's goal is to satisfy and palliate,
chronic opioid therapy is an expedient way to achieve it. If the primary goal
is to treat the underlying process and restore the patient to optimal
functioning with integration into the family structure and community as well as
a return to work, opioids may be contraindicated. The chronic use of opiates
can place serious and perhaps insurmountable restrictions on vocational and
psychological rehabilitation. Patients on opioids have a far higher rate of
unemployment than chronic pain patients using non-opiate therapies. It is the
opinion of this physician that maximal self-actualization and optimal
functional recovery are far more valuable to a patient, concurring or
otherwise, than simple long-term palliation.
The proper goal of pain management is not to completely rid the patient of
pain. The goal is to reduce the intensity to the point that it does not inhibit
function, and this is generally achieved with a 55-65% pain reduction. There
are many non-opioid therapies available that have benefit (by randomized double
blind studies and in my experience as
a clinician) in chronic benign pain. Neuropathic pain in particular is
responsive in significant degree to the tricyclics and certain anticonvulsants.
We are not without tools to work with.
Data driven prescribing favors the use of non-opioids to address chronic benign
pain.
The science at this date is clear, and can be reviewed by the Board by going
to:
http://www.oregon.gov/DAS/OHPPR/HRC/docs/OPIOID_EPC.pdf.
As the studies are reviewed, please make note of their funding sources.
This is my third letter to the Board on the subject of opiates in treating
chronic benign pain. I have called opioid zealotry a passing fad, and said that
chronic opioid use robs patients of the ability to determine for themselves if
pain is still real. I have voiced concerns that hundreds of thousands of North
Carolinians are abusing prescription drugs, and how those drugs get on the
street. I have asked the Board to place common sense restrictions on opiate
prescribing. Today I reiterate the science.
Our profession is an honorable one, driven by ethics, empathy and good will.
Our goal is to help, our creed to do no harm. We ensure that the things we do
are helpful, not harmful, by studying them beforehand. We try to do that in as
honest and forthcoming a manner possible by designing carefully controlled
studies, independent of outside influences, and to do so repetitiously, because
we find comfort in our treatment strategies when findings and results are
reproducible.
But it is here, in treating chronic non-malignant pain with dangerous and
powerful medication, that we have no valid science. Yet this course of care has
been set in motion, has the very apparent approval of the Board, and unarguably
has ramifications already far beyond the anticipation of its instigators. I
have written to the Board concerning these ramifications, the role of
physicians, and how that role allows the public to question the ethics of our
profession. I respectfully request an evidence based reconsideration of your
position. "
And then we find those researchers who question many facets of the chronic pain
question. From a leading researcher in the field of neurosurgery in the
American northwest:
"Patients with CPSMV (Ochoa, 1993) often receive a flawed diagnosis. The
somatosensory, somatomotor, and vasomotor clinical manifestations usually
associated with chronic pain in CPSMV patients are, by nature, neurologic, and
therefore call for specialized history and physical evaluation of the nervous
system. Moreover, the laboratory testing required to determine the actual
source of those manifestations must address neurophysiologic parameters. These
elementary requirements for proper identification of a pathophysiologic basis
for CPSMV are too often not observed. Typically, CPSMV patients assessed by
clinicians go without the benefit of formal neurologic evaluation. Some of the
"gold standard" diagnostic tests used for differential diagnosis rely
weakly on subjective reports from the patients. Many patients express
substantial relief of the pain, muscle weakness, spasms, or sensory loss following
medical interventions pursued with a diagnostic intent. These include somatic
nerve blocks, selective sympathetic blocks, the application of skin patches or
stimulators, or a simple inert ritual. It is clear that, to a major extent, the
subjective and psychophysical effects of such interventions are due to the
placebo phenomenon (Verdugo and Ochoa, 1994). Necessary placebo control for
these interventions is usually not implemented because the clinician is either
unaware of its high prevalence or mistakenly believes that it might be
unethical (Ochoa, 1995).
The signs and symptoms collectively referred to as CPSMV are nonspecific and
reflect a heterogeneous variety of medical entities. Chronic pains in CPSMV
patients originate from any of several distinct primary health disorders that
might be due to a variety of etiologies. Clear understanding of the diverse
causes and types of CPSMV is essential for scientifically rational clinical and
laboratory investigation of the whole spectrum of neurologic and psychiatric
disorders that may underlie the condition (Ochoa, 1993, 1997; See also Mailis,
1995).
My strong contention is that many CPMSV patients experience pain emanating from
a primary psychopathologic origin rather than a neuropathologic origin. The psychogenesis
is usually through conversion-somatization, a phenomenon understood as
unconscious attempts to relieve intolerable stress through the development of
somatic symptoms (Cheyne, 1733; Hart, 1979; Lipowski, 1988; Ron, 1994; Ford,
1995). Characteristically, these symptoms are related to and under the
potential influence of brain function: somatomotor, vasomotor, somatosensory,
or the special senses. When these patients are not properly typified through
rigorous differential neurologic diagnosis, they are harmed by omission of
accurate diagnosis and treatment and by commission of unnecessary and sometimes
harmful medical interventions (Ron, 1994; Ochoa, 1996). This group of
psychopathologic ("neuropathic pain") patients also includes the illegitimate
conscious malingerers and individuals with Münchausen's syndrome (Faust, 1995;
Folks, 1995). A critique of dogmas promulgated through the book Reflex
Sympathetic Dystrophy: a Reappraisal, edited by Jänig and Stanton Hicks, was
recently reviewed for the journal Brain. The reviewer emphasized the
misunderstanding of reflex sympathetic dystrophy (RSD) and pointed the finger
at the subterfuge of its new taxonomic disguise: "complex regional painful
syndrome" (CRPS), the inevitable iatrogenesis generated by such a
diagnostic term, the placebo artifact incurred in diagnostic blocks, and the
fallacy of automatically adjudicating to physical suffering the psychiatric
dysfunction commonly associated with RSD."
2.
It is one thing to
recommend marijuana, or a long acting opiate, on the basis of individual
experience, which all then know must be taken with a grain of salt. But
comments such as "the pure opiates like oxycontin are safe for long term
use..." are not substantiated by the literature, except for that put out
by Purdue Pharma, which has engaged in repeated corrupt misbehaviors with
respect to marketing oxycontin to physicians. In addition, the amount of
acetaminophen in the synthetic narcotics like Ultracet is not troubling at 1 po
qid dosing. Tylenol is the most frequently taken medication on this planet...
has been for years. The current rumblings about toxicity at 4 Gm per day are
probably warranted, but few users of combination drugs reach that level of
dosing. Besides, millions of people have taken 4 Gms per day OTC without
medical follow-up and case reports of these folks turning yellow are few and
far between ... and usually associated with dosing that exceeds the recommended
norms.
The goal of pain management is not to alleviate pain... it is to reduce it to a
level that is commensurate with function. Usually that is achieved with a
50-55% reduction in pain. If one takes oxycontin tid (which exceeds its dosing
half-life) and requires additional oxy for "breakthrough" pain (which
is inconsistent with neuropathic models), what happens, in just a short while,
is that patient becomes an addict and unable to truely determine the level of
discomfort. That patient also now has a powerful exogenous reason not to get
well, or to pursue other treatment modalities.
The proper approach to neuropathic pain is a stepped program that is guided (by
an interdisciplinary team approach) towards (1) identifying the etiology (2)
continuing to rule out a malignant or life threatening pathology that may hide
in the maze of neuropathic pain (3) lifestyle modifications (4) physical and
occupational therapies (5) psychological assessment and reassessment (6) an
evidence based approach to medications for neuropathic pain.
If one cares to examine the evidence with respect to opiates for chronic
non-malignant pain, they may do so at:
http://www.oregon.gov/DAS/OHPPR/HRC/docs/OPIOID_EPC.pdf.
D. Neurontin
Neurontin is not
addictive, at least no more than aspirin. Like Greg wrote, many patients are
taking a lot more than you. When compared against other AEDs in non-biased
studies, except for those neuropathies due to herper zoster, diabetes, and
trigeminal neuralgia, the drug did not pass muster. There has been a lot of
bad-information put out by the folks that make and profit from Neurontin. Many
in the medical community are not sure what to believe about this drug.
http://www.kglg.com/case/case.asp?lngCaseId=2457
and
http://www.kaisernetwork.org/daily_reports/rep_index.cfm?hint=3&DR_ID=18008
are links to information regarding allegations of improper marketing, false
indications for use, etc.
The manufacturer recommends that when discontinuing Neurontin it be done so
over a period of not less than one week. This has nothing to do with withdrawal
in the normal sense. Abrupt discontinuation in a person chronically taking a
large dose could precipitate seizures, even in those patients who have never
had one. You may review this at:
www.pfizer.com/pfizer/download/uspi_neurontin.pdf
E. Cymbalta
Rick argues that
Cymbalta takes weeks before it provides maximum analgesia, while D.G. argues
the reverse... about a day. In truth there are but two studies out there to
guide us, and these were funded by the manufacturer. Such a pharmaceutically
funded study has a 5 times greater chance of being favorable to a drug than a
well-controlled unbiased study. But lets give EI Lilly the benefit of the
doubt. Lets suppose that the billions to be made in addressing neuropathic pain
and depression had no effect on study design, data development, or reporting of
results. Let's assume that, at least for once, truth and altruism were the dual
goals of this research. What can that science (the only science we have) tell
us about Cymbalta.
First we must also assume that the mechanism of nerve injury in DPN (diabetic
peripheral neuropathy) is similar to the nerve injury that occurs in PNE,
because both of these studies looked at the management of DPN alone. The total
number of patients involved in both studies was 791, which in my opinion is
sufficient for statistical analysis. To be included in the study the patient
had to have painful neuropathy for at least 6 months, and be either a Type I or
Type 2 diabetic. In addition to receiving Cymbalta, patients in both studies
were allowed up to 4 Gm. of Tylenol per day for pain. The amount that the
different patients took did not figure into the statistical analysis, so right
up front one can see that the patient who took two 500 mg. tylenol 4 times a day
would probably have a better pain score than the one who took cymbalta alone.
So again, we must assume this did not affect the data. Both studies compared
Cymbalta 60 mg q day, Cymbalta 60 mg. bid, and placebo.
These were the results:
(1) Some patients experienced a decrease in pain as early as week 1.
(2) 68% of patients had a 10% reduction in pain from baseline with Cymbalta 60
mg. q day, and 66% with Cymbalta 60 mg. bid., while 60 % of patients given
placebo had a 10 % reduction in pain from baseline.
(3) 48 % of patients on Cymbalta 60 mg. q day, and 47 % on Cymbalta 60 mg. bid
had a 50 % reduction in pain from baseline, while 27% of patients given placebo
had a 50% reduction in pain from baseline.
(4) 18% of patients on Cymbalta 60 mg. q day, and 17 % on Cymbalta 60 mg. bid
had a 90 % reduction in pain from baseline, while 6 % of patients on placebo
had a 90 % reduction in pain from baseline.
Therefore, for the benefit of the forum, it is reasonable to conclude that: (a)
analgesia can be expected (68%) in the first two weeks following initiation of
Cymbalta, but it is uncommon indeed for analgesia to arrive in the first few
days;
(b) there appears to be no difference in analgesic efficacy with 60 mg. once a
day or 60 mg. twice a day.
(c) there is a significant placebo effect to pain relief with almost any
modality.
F. Avigen AV411
Avigen has some
explaining to do to the medical community and to the FDA if it is hoping to
address neuropathic pain by suppressing certain inflammatory cytokines.
Neuropathic pain is not inflammatory. Nociceptive pain is partially generated
as an inflammatory response to injury. Nerve pain can be both nociceptive and
neuropathic if the process of injury is on-going, but generally the balance
tends towards a neuropathic generator. This glial attenuator, AV411, could be
beneficial in rheumatoid states and even in sarcoidosis. It might reduce or
alleviate pain from an acute insult to the body by stalling the inflammatory
cascade. But it will not address nerve pain if the generator is entirely
neuropathic. One cannot suppress what is not happening in the first place. Just
like immunosuppression with steroids when there is no immune system activation.
I admit the company is banking on glial cell activity in the CNS, but this is
not proven science.
Don't trust any of these pharmaceuticals, especially one that says it wants to
join the big boys.
While AV411 has been used in Japan for over a decade to treat asthma, and has
been recently approved for such use in Korea, there have been no reports in the
medical literature from those nations where neuropathic pain has improved in
patients taking this drug.
For a vigorous but biased opinion of the drug, go to:
http://www.jmdutton.com/research/avgn/reports/avgn_report_061206.pdf
G. PARP-1
Yes, we certainly
would like to consider any neurotrophic med as a possible combination. I think
the PARP-1 inhibition may result in lower rates of inflammation in certain
areas of the brain, and therefore have the possibility of affecting those
diseases in which inflammation is the initiating step or propagating component,
like the neurodegenerative diseases mentioned. The modulation of neuropathic pain
does not involve inflammatory events. It is a complex yet straightforward
arrangement of circuits, intended to mollify pain impulses after they arrive at
the cord but before they reach the cognitive areas where these impulses can be
perceived as pain. It is as though God felt we could not handle pain impulses
in their raw state, but rather man needed an inherent system of filters through
which pain must pass before becoming recognized as pain. This would alter the
intensity, and in some cases where pain impulses were minimal, these impulses
would be dismissed by filters before reaching the cortex. With the neuropathic
pain of PNE, these filters get overwhelmed, but unfortunately not clogged.
At each end of the filter system are relay stations. At each relay station are
certain designated messengers whose duty is to take the impulse arriving, cross
the track, and pass that information on to the axon which will be traveling
through these filters to the subcortical level (in the midbrain). The thing about
these messengers is that they sometimes are given messages that have been
altered, they sometimes have to approach more than one axon, they often have to
compete with other messengers for the axon's attention. Each and every pain
impulse delivers this confusion to the cord, which it attempts to sort out with
the use of interneurons. But in neuropathic pain many of these interneurons are
so worn out in the struggle that they actually die. Still, this entire process
of filter and relay has no inflammatory component within the central nervous
system (although acute pain in the peripheral body is mediated by
inflammation). It is more a matter of overload and disrupted pathways, pathways
attempting to modulate a stimulus far too intense or too durable for their capabilities,
pathways attempting to include more interneurons by expanding their receptive
fields but still losing to the on-going neuropathic input. We need meds that
affect these filters, that give encouragement to the appropriate messengers and
slay those messengers which are mediating the upward pain signal. We need
electricians, not fire fighters.
H. Minocin
Minocycline is
currently marketed as Minocin, and is useful in the treatment of acne vulgaris.
Teenagers with acne are usually given Minocin 50 mg. bid times 30 days, and it
is effective (temporarily) except in recalcitrant cases. Fairly safe at that
dose, and recently prescribed quite often, since it doesn't stain the teeth in
teenagers like the tetracyclines.
The stated supposed mechanism of action with respect to neurodegenerative
disorders means that while the drug may turn out to be (we'll see) effective in
PD and AD, even Huntington's, it's not going to be of use in modifying central
pain mechanisms nor in remedying neurapraxis in Alcock's from true pudendal
entrapment. If it does prove useful, it will do so as a centrally acting
adjunct (to other medication) rather than a drug that alone cures.
I. Quinamm
Yes, Quinamm is
effective in leg cramps, probably even better than the reported 50%. Frankly, I
don't know of a single patient in whom it doesn't work. But the mechanism of
painful nocturnal calf cramping and subsequent pain is quite different from the
pain generators in PNE. Or in any muscle activity that could be responsible for
pressure on a pudendal nerve branch. Calf pain during intense muscle
contraction or tetany is mostly due to the inability of the circulatory system
in that part of the extremity to meet the oxygen requirements of the overactive
muscle. The muscles in the area are large and thick, and the vascular supply
probably the least of any part of the body, especially when recumbent. A
tissue, like muscle, that is working hard but poorly fed (anaerobic metabolism)
begins to generate the ATP (the cellular gasoline I talked about in a post
yesterday) via gluconeogenesis alone, resulting in the production of large
amounts of lactic acid, the presence of which is extremely painful. Lactic acid
is the generator of pain in states like angina where oxygen requirements are
not met by oxygen supply (to the myocardium). By increasing the refractory
period for muscle contraction, as Casparios has written, Quinamm also reduces
muscle work, thus muscle oxygen requirements, and thus the available oxygen is
sufficient to allow the Kreb's cycle to work. And no lactic acid is produced.
The pelvic floor muscles are generally broad and thin, and the vascular supply
more than ample, regardless of body position. Ball your hand into a fist,
squeeze tightly without letting up. Unless you have diffuse atherosclerotic
disease, or subclavian steal syndrome, despite the self-induced tetany, you
will have no pain. Interestingly, Quinamm does work peripherally on muscle
itself whereas most "muscle relaxants", ie Baclofen, work centrally
(most are thought to work in the thalamus). So the idea is good, but in
practice it won't work. Then again, almost anything has a placebo effect.
J. Tylenol
As you are aware,
Tylenol arthritis has 650 mg. of acetaminophen per dose, so the four you take
would total less than 3 Gm per day. The study Karen has posted looked at liver
numbers in patients on 4 Gms per day.
Tylenol has always been a classic example of a predictable hepatotoxin when
taken at super-therapeutic doses. The high limit of therapeutic dosing, until
now, has been 4 Gm. The above study calls into question lots of prior work on
dose-effect of Tylenol and what is a safe dose under most circumstances. Most
likely this work will be questioned until other randomized studies give the
same results. Still, one must view 4 Gm of Tylenol with caution. It has always
seemed too much to me.
As with many areas of pharmacology, toxicity is not a straight line, but rather
a sigmoidal one. Therefore, I feel the 2.6 G. you take in the 4 Tylenol
arthritis caps are safe for you, unless you are taking other medications that
may also be potentially hepatotoxic, or use alcohol frequently. It would be a
good idea to have periodic liver function testing done, maybe twice yearly if
your numbers remain normal. Here is a link to Tylenol toxicity, which may have
to be revised somewhat in light of the information Karen has shared.
http://www.emedicine.com/emerg/topic819.htm
K. Effectiveness of current medications for
neuropathic pain
DRUGS FOR PAIN IN
POLYNEUROPATHY. HOW EFFECTIVE ARE THEY?
Sindrup S.H., Jensen T.S. Depts. of Neurology, Odense and Aarhus University
Hospitals, Denmark.
Drugs from several different classes have been shown to relieve pain in polyneuropathy.
We performed a systematic review to identify placebo-controlled clinical trials
on oral drugs in painful polyneuropathy and calculated for each drug class the
numbers needed to treat (NNT) to obtain one patient with >/=50% pain relief
(1/[>/=50% reliefactive/totalactive - >/=50% reliefactive/
totalplacebo]).
Drug NNT(95 % CI)
Antidepressants
Tricyclic 3(2.4-4.0)
Tricyclic, optimal dose 1.4(1.1-1.9)
Sel. serotonin reuptake inhibit. 6.7 (3.4-435)
NMDA-antagonist
Dextromethorphan 1.9 (1.1-3.7)
Sodium channel blockers
Phenytoin 2.1(1.5-3.6)
Carbamazepine 3.3(2-9.4)
Mexiletine 10 (3-infinity)
Calcium channel blocker
Gabapentin 3.7 (2.4-8.3)
Tramadol (atypical opioid) 3.4 (2.3-6.4)
L-dopa 3.4 (1.5-infiniti)
Tricyclic antidepressants appear to be the most effective drugs. Selective
serotonin reuptake inhibitors and mexiletine are clearly less efficacious,
whereas the response on dextromethorphan, gabapentin, and tramadol is in the
same range as the tricyclics.
L. On the pharmaceutical industry
Perhaps even more
disconcerting is the relationship of pharmaucetical industry sponsorship and
results found in supposedly controlled clinical trials. The American Journal of
Psychiatry (October 2005) examined funding source and author financial conflict
of interest in all clinical trials published in the four leading psychiatric
journals (Am J of Psych, Archives of Gen Psy, Jour of Clin Psychopharmacology,
J of Clin Psy) between 2001 and 2003. 397 trials were identified. 239 received
funding from a pharmaceutical company. 162 of these trials were supposedly
randomized, double blind, placebo-controlled (the best biased free studies we
can devise). In these 162 trials it was discovered that those studies which
were funded by the pharmaceutical industry were 500% more likely to report a
drug to be superior to placebo than a study not industry funded.
IX. On the use
of medications in combination to address neuropathic pain
1.
I like transdermal delivery systems. Avoids many side effects, especially
gastrointestinal. Also, it avoids the first pass through the liver, which in
many instances, tries to modify the drug (or metabolize it). Every medication
taken per orum get absorbed into the blood stream in the small intestine, and
all that blood must first pass through the liver before reaching the tissue to
which it is targeted. A transdermal delivered medication goes first through the
heart and then to the tissue to which it is targeted.
An NMDA receptor antagonist that does so by ion channel blockade is a novel
approach, and in theory might work. Apparently early trials are promising. If
it works in vitro, then clinical efficacy will depend on concentration required
to achieve this blockade, the bioavailablity of the drug at the level delivered
by the transderm system, and whether or not nociceptive impulses find a way to
override NMDA antagonism.
Which brings up an interesting thought. We suppose our damaged pudendal nerve
is generating pain impulses (transduction) that travel along sensory afferents
in the pudendal (transmission) to reach the cord. Here these impulses are
subjected to the defensive interplay of a part of the spinothallamic tract,
which attempts to modulate pain so that the impulses traveling to the brain
(and telling it of pain) are weakened (lessened, modulated). A lot of
medications that members take ... most, in fact... Lyrica, Cymbalta, narcotics,
synthetic narcotics like tramadol, the benzodiazeams, neurontin, the
tricyclics, and on and on ... all of these medications act at either the cord
level or the cortex level to increase modulation of pain impulses or to
diminish the perception of these impulses
once they reach the cortex.
What I wonder is this: all of us have taken a medication that gave us some
degree of relief from pain, only to become less effective with time. In such
case we often conclude that either our disease is worsening, or the medication
has lost its efficacy. What if what is really happening is that the body,
having set a certain level of nociceptive stimuli as normal (this is a bit
different than the concept of central sensitization), begins to channel these
nociceptive impulses through receptors that are unaffected by the medication,
that is, receptors that use an alternate neurotransmitter. The switching
equipment simply re-routs the signal so that it can be maintained.
The body is constantly doing such with respect to other disease processes.
Inside the carotid artery in your neck are tiny baroreceptors that are
essentially responsible for maintaining the body's blood pressure. When you
develop hypertension, over time, these baroreceptors re-set, and work to
counter the effects of anti-hypertensive medications. If one takes a single
blood pressure lowering agent, say a beta blocker, this drug works by reducing
cardiac output (lowers the stroke volume of the heart as well as the heart
rate). If the trottle on a pump is pulled to slow, and the pump then pumps less
water into a pipe, the pressure in the pipe will fall. The baroreceptors then
attempt to compensate and pull the blood pressure back to higher number by
increasing peripheral arterial resistance. In this counter-move, by reducing
the diameter of the pipe, the pressure will rise. Endocrinologists and family
docs have learned that the best way to manage blood pressure is to use smaller
amounts of more medications, each targeted to address a specific item in
control, some reduce the volume in the pipe, some slow the pump, some dilate
the pipe.
So what if no single medication will work well, for long, with central pain,
regardless of medication, and no matter what new drugs researchers come up
with. Since pain pathways are far more complicated than baroreceptors in the
neck, the body may have multiple ways to defeat any neuropathic analgesic. It may
not be a matter of finding a drug that will close a single receptor, and thus a
single pain pathway. We are eventually going to have to deal with all
receptors, and all their combined neurotransmitters.
2.
The NEJM is one of
the world's leading medical publications, each entry carefully peer-reviewed.
In the Netherlands neuropathy was addressed by comparing combinations with a
single agent and placebo. Combinations won out. While the number of patients in
the study was statistically significant, as well as the differences in scores,
in my opinion this is far too small a model. Moreover, measurement of
effectiveness was short term. Those of us with entrapment neuropathies have
pain for longer than 5 weeks, and these types of studies need to also tell us
what happens in terms of effectiveness down the road.
We will find answers in combination therapy, but we will not find the answer we
need in two drugs. I suppose one could take morphine at such a dose that almost
all senses are extinguished, but that is not what we need, nor what shall be
proposed. We need a strategy based on carefully researched neuropharmacology at
the cellular and synaptic level.
While this study does prove a point, I wonder how many of the patients enlisted
in the study had prior experience with opiates, how many had needle tracts, and
how did they arrive at pain scores of 5.72. I know what a 10 is, and a 2, but I
have trouble telling between a 5 and a 6 and a 7. I know this is an
international forum, and that others deserve due respect. But this article
comes from the Netherlands of all places. The NEJM must have been under some
political pressure from the Bush administration (maybe in exchange for some
troops to Iraq) to publish it.
3.
Yes, Karen, I
think it is relevant. The effect was central, not peripheral. Remember
transduction, the first phase of the pain process. Here the injury, especially
if acute, is translated by receptors on the nerve ending into an electrical
discharge that moves along the sensory axon (transmission) to the cord. Versed
and Demerol do not affect transduction in neuropathic pain, nor do they affect
peripheral transmission. Once the impulse arrives at the cord, many games are
played with it before it is further transmitted upward along the spinothallamic
tract. In neuropathic conditions the defending team is weakened, the offense
team strengthened, and the signal reaching upwards is thus magnified versus a
normal pain impulse traveling north.
Versed, like the other benzos, attaches to the alpha subunit of the GABA
receptor, reducing excitation. This weakens the pain signal that has been
ineffectively modulated. Demerol works on all the central opiate receptors
throughout the cord and cortex. Both drugs have a rapid onset of action, and
both are rapidly metabolized. Yes, you received fairly immediate relief, but
you were also playing with reward pathways, which are dangerous. The best
benzo, and I believe one needs to be incorporated into any management strategy
for neuropathic pain, would be one with a constant blood level, no cocktail
effect, and slowly metabolized.
How many of you would be willing to accept a 75% reduction in pain, and live
with the remaining 25%? What I'm afraid is going on centrally in terms of
achieving total analgesia is that the line between dosing and clinical response
is not a straight one, but rather sigmoidal. What this means is that in
proposing a medication strategy, I believe I can get us to the point of
reducing pain by 75% with a minimum of side effects. But further analgesia
would require dosing far out of proportion to what is necessary to get us to
75%. I have been looking at all inhibitory and excitatory neurotransmitters,
especially glutamate and g-aminobutyric acid (GABA). GABA is our friend, by far
the most important inhibitory neurotransmitter. The difficulties in devising
strategy are compounded by the multiplicity of variations in sites GABA will
affect. And by the confusing role of some neurtransmitters. Norepinephrine, for
example, is an excitatory transmitter in some clinical states, but in pain
states it becomes inhibitory. So the very same chemical used to confer
information from nerve cell to nerve cell changes its color depending on the
information it wishes to convey.
Our optimum strategy, the one that will give us relief from most of our pain,
and do so across the board, and in Ireland as well as Columbus, Ohio, is a mix
that does the following (1) inhibits serotonin and norepinephine re-uptake at
the synapse, thus making more available for transmission (2) increase the
effectiveness of GABA receptors, where the combined effect of these meds is
much stronger than the sum of their combined effects (3) maximize opiate
receptor function with a bare minimum of medication. To do will require 4
drugs, all universally available to my knowledge, in low doses, on a careful
schedule. Think of how blood pressure control is achieved, by using lower doses
of multiple meds to both avoid side effects and fool the body's compensatory
mechanisms. In neuropathic pain, we can be successful if we do the same, and
are willing to accept a significant reduction in pain as the goal rather than
the elimination of pain.
X. On
acupuncture
Like you, I am not
sold on acupuncture. But our knowledge of how this modality works has increased
a good bit in the last 20 years. I wanted to give you a view of the current
science on acupuncture versus what one might read on various forums.
Early on the placebo effect was dismissed as the main mechanism of action.
Animals are not capable of demonstrating the placebo effect, yet, veterinary
medicine uses acupuncture as an effective means of pain relief in treatment.
Also, the analgesia from acupuncture can be blocked by certain drugs and
reversed by administering the opiate-receptor antagonist naloxone. This
indicates that a physiologic mechanism is involved in producing acupuncture
analgesia rather than a placebo one.
When an acupuncture needle is inserted into a traditional acupuncture point,
afferent sensory axons are stimulated (transduction), which results in a nerve
impulse being sent to the spinal cord. Here, endorphogenic cells are stimulated
to release endorphins (brain chemicals) such as enkephalin and dynorphin. These
substances provide local inhibition (blocking) of the incoming pain signal.
In addition to causing effects in the spinal cord, the nerve impulse produced
by the acupuncture needle is also transmitted to the periaqueductal gray area
of the mid-brain, where enkephalin is released. Enkephalin, in turn, brings
about the release of the monoamine neurotransmitters serotonin and
norepinephrine in the spinal cord. These monoamines play a role in suppressing
the transmission of the pain impulse. In addition to its role in reducing pain,
serotonin is involved in producing an antidepressant effect in the brain. In
fact, many of the newest antidepressant drugs work by prolonging the effect of
serotonin in the brain.
A third effect brought about by acupuncture is the release of beta-endorphin
and Adreno-Cortico-Tropic Hormone (ACTH) from the pituitary gland into the
bloodstream and cerebrospinal fluid. These endorphins produce system-wide pain
relief, remote from the area where the acupuncture needle was inserted. ACTH,
in turn, activates the adrenal gland to release cortisol into the bloodstream.
Cortisol is a naturally occurring steroid substance that has anti-inflammatory
properties. The net result of these 3 areas being stimulated is an inhibition
of the incoming pain sensation locally, a general, morphine-like,
pain-relieving effect throughout the body, an anti-inflammatory effect, and a
general sense of improved well-being.
Depending on which acupuncture points are chosen, whether they are near the
painful site or farther away, determines which of the 3 pathways mentioned are
primarily activated. Placing needles near the painful site brings about a more
intense pain relief, because it activates all 3 centers (spinal cord, midbrain,
and pituitary gland). Local needling also maximizes inhibition of the incoming
pain signal at the segmental region of the spinal cord. Needling acupuncture
points distant to the painful area predominantly affects the mid-brain and
pituitary gland. In general, a combination of local and distant acupuncture
points are used together during a treatment, in order to maximize the effects
at all 3 centers.
Like all treatment modalities, acupuncture does not work some of the time.
Skill of the acupuncturist, the gate theory of pain, and many other factors are
going to determine whether or not there is benefit. It is certainly a low risk
procedure, and for someone from Hong Kong, like fabexpress, information on
acupuncture should abound.
X. On spinal
cord stimulators
Your second question relates to spinal cord stimulators and the likelihood of
additional interventional modalities to treat neuropathic pain in the future.
Below I present three articles, and at the end of these I will summarize.
The Cochrane database is the Consumer Reports of medicine. Cochrane looks at
all the evidence that is out there, grades and rates the quality of that data,
and performs peer reviewed statistical analysis that can be trusted, for these
people are as unbiased as any in science.
Article 1:
The Cochrane Database of Systematic Reviews 2006 Issue 2
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley &
Sons, Ltd.
There is insufficient evidence to assess the benefits and harms of spinal cord
stimulation for the relief of chronic pain.
Spinal cord stimulation (SCS) is a form of therapy used to treat certain types
of chronic pain. It involves an electrical generator that delivers pulses to a
targeted spinal cord area. The exact mechanism of action of SCS is poorly
understood. We undertook a review of the available evidence and found two
randomized controlled trials of this intervention. One trial studied the
effects of SCS for Failed Back Surgery Syndrome and the other was a trial of
patients with Complex Regional Pain Syndrome Type 1 (reflex sympathetic
dystrophy). We concluded that SCS might be effective for certain patients but
there is little evidence available to assess the benefits and harms of this
treatment.
Background
Spinal cord stimulation (SCS) is a form of therapy used to treat certain types
of chronic pain. It involves an electrical generator that delivers pulses to a
targeted spinal cord area. The leads can be implanted by laminectomy or
percutaneously and the source of power is supplied by an implanted battery or
by an external radio-frequency transmitter. The exact mechanism of action of SCS
is poorly understood.
Objectives
To assess the efficacy and effectiveness of spinal cord stimulation in
relieving certain kinds of pain, as well as the complications and adverse
effects of this procedure.
Search strategy
We searched MEDLINE and EMBASE to September 2003; the Cochrane Central Register
of Controlled Trials (CENTRAL) (Issue 3, 2003); textbooks and reference lists
in retrieved articles. We also contacted experts in the field of pain and the
main manufacturer of the stimulators.
Selection criteria
We included trials with a control group, either randomized controlled trials
(RCTs) or non-randomized controlled clinical trials (CCTs), that assessed
spinal cord stimulation for chronic pain.
Data collection and analysis
Two independent reviewers selected the studies, assessed study quality and
extracted the data. One of the assessors of methodological quality was blinded
to authors, dates and journals. The data were analyzed using qualitative
methods (best evidence synthesis).
Main results
Two RCTs (81 patients in total) met our inclusion criteria. One was judged as
being of high quality (score of 3 on Jadad scale) and the other of low quality
(score of 1 on Jadad scale). One trial included patients with Complex Regional
Pain Syndrome Type I (reflex sympathetic dystrophy) and the other patients with
Failed Back Surgery Syndrome. The follow-up periods varied from 6 to 12 months.
Both studies reported that SCS was effective, however, meta-analysis was not
undertaken because of the small number of patients and the heterogeneity of the
study population.
Authors' conclusions
Although there is limited evidence in favor of SCS for Failed Back Surgery
Syndrome and Complex Regional Pain Syndrome Type I, more trials are needed to
confirm whether SCS is an effective treatment for certain types of chronic
pain. In addition, there needs to be a debate about trial designs that will
provide the best evidence for assessing this type of intervention.
Article 2
Presented as an advertisement by the Interventional Pain Center at MGH,
certainly a world-class hospital. Note the sentence “there is substantial
scientific evidence on the efficacy of spinal cord stimulation”, and compare
this to the unbiased Cochrane review.
Spinal cord stimulation is the most common mode of neuromodulation used in
managing chronic low back pain. It is minimally invasive and reversible as
opposed to nerve ablation.
The basic scientific background of the initial spinal cord stimulation trials
was based on the gate control theory of Melzack and Wall. It has been
demonstrated in multiple studies that dorsal horn neuronal activity caused by
peripheral noxious stimuli could be inhibited by concomitant stimulation of the
dorsal columns. Various other mechanisms, which may play a significant role in
the mechanism of action of spinal cord stimulation, include the suppressive
effect of spinal cord stimulation on tactile allodynia, increased dorsal horn
inhibitory action of gamma-aminobutyric acid (GABA), prevention or abolition of
peripheral ischemia, and effects on human brain activity.
Spinal cord stimulation is indicated in low back pain with radiculopathy,
failed back surgery syndrome, complex regional pain syndrome, peripheral
vascular disease, and ischemic heart disease. There is substantial scientific
evidence on the efficacy of spinal cord stimulation for treatment of low back
and lower extremity pain of neuropathic nature. Clinical studies revealed a
success rate of from 50% to 70% with spinal cord stimulation, with decreased pain
intensity scores, functional improvement and decreased medication usage.
This review discusses multiple aspects of spinal cord stimulation, including
pathophysiology and mechanism of action, rationale, indications, technique,
clinical effectiveness, and controversial aspects.
Article 3: Dr. Saff gives a balanced approach, explains the pros and cons, and
presents a reasonable approach to interventional technology applications.
INTERVENTIONAL THERAPY FOR NEUROPATHIC PAIN
Gary N. Saff, MD
Assistant Clinical Professor of Anesthesiology
St. Luke’s Roosevelt Hospital
There exists a vast array of interventional therapies for the treatment of
painful
peripheral neuropathies; however, the majority of these pain syndromes can be
successfully managed with the more conservative oral analgesics and adjuvants.
Even in my practice at a tertiary interventional pain management center, I
usually have success with an aggressive trial of various oral medications. For
patients that fail the oral medication trials, either due to inefficacy or
intolerable side effects, we proceed with interventions that should be familiar
to most anesthesiologists specializing in pain management. These techniques
include local anesthetic blocks, implanted spinal cord stimulators, and
implanted intrathecal catheters. These interventional therapies are ideally
performed by an anesthesiologist because the skills required for nerve blocks,
spinal, and epidural injections are performed routinely in the operating room.
More importantly, the treatments of complications from these procedures (apnea,
seizures, and hemodynamic instability) should be well within the
anesthesiologist’s skill and
comfort level.
Somatic blocks may be performed peripherally (interscalene, axillary,
popliteal, femoral) or neuraxially (spinal, epidural). In addition, sympathetic
blocks (stellate ganglion, lumbar sympathetic) can be used to treat small fiber
pain syndromes that may be associated with an autonomic component. Narcotics,
local anesthetics, and various analgesic adjuvants may be part of the
injection. The toxicity of these medications is minimal when properly placed.
However, if the needle is accidentally placed in a vessel during a procedure
such as an interscalene block, then even ¼ cc of local anesthetic would cause a
seizure requiring the physician to perform airway management techniques. Due to
metabolism and redistribution of the injected medication, these nerve blocks
will have a finite life span, however may help break a "pain flare"
and spinal cord "wind-up" process in someone whose pain is otherwise
well controlled.
Spinal cord stimulation is based on the Gate Control Theory whereby the
stimulation of large myelinated fibers receives preferential processing in the
CNS (central nervous system) over afferent input from the smaller A-delta and C
fibers. This procedure is best reserved for patients with distal limb pain
syndromes, unilateral over bilateral. The procedure is similar to the placement
of an epidural catheter; however, this device delivers an electric current,
which the patient often perceives as a "tingling" and more pleasant
sensation than the previous pain. The specific lead conformation, rate, amps,
and bandwidth can be altered to obtain maximal pain control. A percutaneous
trial should be performed in the sterile atmosphere of an operating room. One
hour or less is all the time that is required unless the area of pain is
difficult to "capture". It is not a
painful procedure and the patient is only lightly sedated so as to maintain a dialogue
with the physician as to where the stimulation is perceived. For lower
extremity pain, the epidural needle (15 gauge) is placed at a gradual angle of
less than 30 degrees at the T12-L2 area with the stimulator lead threaded to
the T6-T10 area to obtain simulation in the relevant part of the lower
extremity. Upper extremity pain involves epidural needle placement at C7-T3 and
stimulator lead threaded to the C3-C6 levels. Sometimes dual bilateral leads
are required to obtain bilateral or proximal extremity and back stimulation.
This procedure is performed on a trial basis lasting several days as an
inpatient or outpatient. The trial electrical generator box, the size of a deck
of cards, is
kept externally and can be worn on the belt. If successful, the leads are
internalized and connected to an internal battery device the size of a
pacemaker or to an external battery device which sends transcutaneous current
to an antennae and stimulator system. Percutaneous leads are not much larger
than the diameter of a paperclip. For more difficult or broader coverage, a
neurosurgeon is required to make a small laminotomy for placement of a
"paddle" shaped lead. The system can bereprogrammed through a control
device transcutaneously. The patient also has some limited control over the
stimulation with a less complex control device for home use. Spinal cord
simulator long-term studies reveal 50% persistent satisfactory pain relief at 2
years. I have found that choosing an ideal candidate takes clinical experience
and seasoning on behalf of the physician. Complications include infection, lead
migration or failure, pulse generator/receiver failure, loss of pain relief,
uncomfortable stimulation, allergic response, nerve injury, and paralysis.
To summarize, interventional techniques mainly consist of nerve blocks, spinal
cord stimulation, and intrathecal pump placement only after aggressive trials
of oral medications have failed. The most benign of these procedures is nerve
blocks, which have a finite duration, though are helpful in pain flares in
which case we see prolonged analgesia in excess of the duration of the block.
Spinal cord stimulators and intrathecal pumps can also give excellent results
and are indicated in the treatment of painful peripheral neuropathies. Of
utmost importance in these technologies is a thorough trial of the temporary
percutaneous stimulator lead or neuraxial medication infusion before
the decision to implant hardware can be justified. Psychiatric clearance should
be performed routinely in anyone suffering with chronic pain. The patient
population’s response to painful peripheral neuropathy is so vast and complex
that making strict protocols and performing well-controlled scientific studies
almost becomes an impossibility. Hence, there is wide variation in the practice
of this type of pain management as well as there being plenty of exciting
opportunities for new studies in the future.
As existing interventional technologies improve and new ones come on line, I
suspect the prudent physician will use these to augment and compliment
medication regimes, rather than rely on a modality such as the cord stimulator
alone to hold the line against pain. If, for example, a certain generated pulse
arriving by artificial means to the cord would activate opiate receptors and
cause the release of endogenous endorphins, and a second generated pulse of
differing frequency, wavelength, signal strength etc would synergistically
affect modulation pathways, then the chances would be very good that a low dose
benzodiazepine alone but in concert with these given pulses would provide the
severely compromised neuropathic pain patient with complete analgesia as well
as full functional recovery.
XII. On lumbar
disc herniation
It appears that
what you are saying, Katy, is that you have symptoms suggestive of an L5/S1
disc herniation, but no clear compression, entrapment, or other neural
compromise on MRI. Then your symptoms progressed to include the perineum, and
the sacral roots were then diagnosed as responsible. It also appears you are
saying that you have been told that the symptoms from the L5/S1 dermatone, even
with a negative MRI, are the result of inflammatory cytokines, and that you
have also been told that these inflammatory components then made their way inferiorly
to affect S2-S4. So that now you have symptoms relating to L5-S1 and perineal
pain attributed to pudendal neuropathy arising at S2-4. Is that correct?
If so, you have received good advice from the members of the forum, and your
questions have given rise to those from others who suffer similarly. Karen has
suggested a diskogram, and indeed, it the modality of choice in a patient with
a normal MRI but continuing radicular symptoms. You meet both criteria for such
a study: duration of pain and failure of multiple modalities to address that
pain.
Even with a negative MRI and negative diskogram, you can still hurt from
nociceptors located in the annulus fibrosis at L5/S1. You do not need nerve
compression to elicit either an inflammatory event (with inflammatory
cytokines) at that level nor a neuropathic response. Neuropathic pain can set
up from any on-going pain generator if the cord is exposed to sufficient
nociceptive signals over a sufficient period of time. So because you might have
a normal MRI, and indeed, the diskogram recommmended by Karen may also be
negative, but you still could have a pathological reason for pain. Only this
reason is not amenable to surgery, so do not go under the knife in an attempt
to rid yourself of pain.
With respect to the movement of cytokines from L5/S1 to involve the sacral
plexus and origins of the pudendal, this is most unlikely. In fact, because of
the arrangement of fascial planes, meninges, and other connective tissue
placement, this sort of shared involvement from a single process, especially
over time, would be nearly impossible. You may have a disease process that is
involving multiple levels, or you may have both a neuropathic process at L5/S1
and another process involving the pudendal. A CT guided block of the pudendal
would tell you whether the nerve itself was involved or whether the process was
originating at the cord or sacral level. Although the sacrum is indeed fused,
it is also possible for tumors, bone cysts, and some degenerative states to
affect the nerve exits in much the same way as a ruptured disc might affect the
lumbar spine.
XIII. MRI, CT
and discography for lumbar disc diagnosis
Computerized tomography (CT scan) can be used to identify symmetric uniform
degenerative changes of the disk that result in a diffuse annular disk bulge,
seen as diffuse peripheral extension of disk material. The margin of the
annular bulge is usually smooth in contour but may be asymmetric. Overlapping
3- to 5-mm axial sections in 3-mm increments with multiplanar reformations is
the optimal protocol. Sagittal reformations or CT scans may demonstrate loss of
disk height. An intradisk vacuum phenomenon is seen commonly as focal or linear
areas of markedly diminished density within the intervertebral disk.
CT also may demonstrate endplate degenerative changes, including sclerosis and
cortical irregularity with erosions. CT allows for visualization of disk
degeneration, bulging, and herniations but not with the detail of MRI.
Degeneration of the intervertebral disk and endplate commonly is observed at
autopsy and in imaging studies in asymptomatic patients. In the lumbar spine,
CT scans are abnormal in 35% of asymptomatic volunteers of all ages and in 50%
of persons aged 40 years or older.
MRI is currently the criterion standard imaging modality for detecting disk
pathology. MRI has demonstrated degenerative changes in 3 times as many motion
segments as contrast-enhanced CT scan. MRI uses a magnetic field to obtain
direct multiplanar images with excellent soft-tissue contrast, and MRI provides
superb resolution and precise localization of intervertebral disks.
On MRI, degeneration of the intervertebral disk results in diminished signal
intensity on T1- and T2-weighted images. These signal intensity changes are due
to diminished water and glycosaminoglycan content and increased collagen
content of the intervertebral disk. Sagittal images provide the best depiction
of the loss of intervertebral disk height. Bulging of the disk annulus can be
demonstrated on axial and sagittal images. Posterior extension of the disk
annulus by >1.5 mm is invariably correlated with radial tears of the disk
annulus. Furthermore, tears of the annulus fibrosus can be visualized as HIZ
lesions (HIZL).
In vitro, MRI can demonstrate radial tears of the disk annulus. The sensitivity
of MRI is 67% compared with diskography in detecting radial annular tears.
Focal enhancement of radial tears may be seen on gadolinium-enhanced
T1-weighted MRIs. This enhancement has been attributed to granulation tissue in
the tear. A vacuum phenomenon is demonstrated as an area without signal
intensity in the intervertebral disk; this is best appreciated on sagittal
T1-weighted images. MRI shows notable abnormalities in approximately 30% of
asymptomatic people of all ages, and in 57% of those aged 60 years or older.
Disk degeneration or a bulging intervertebral disk is observed in 35% of
subjects aged 20-39 years and in nearly 100% of those aged 60-80 years.
An important component of the degenerative process of the lumbar intervertebral
disk is degeneration of the cartilaginous endplate. The cartilaginous endplate
cannot be discretely identified on MRI because of its thinness and the
chemical-shift artifacts at the endplate; however, MRI demonstrates reactive
changes in the bone marrow due to the degenerative process in the
diskovertebral joint associated with chronic repetitive stress. Disruption and
fissuring of the endplate with granulation tissue and reactive woven bone
result in endplate changes where vascularized fibrous tissue replaces adjacent
marrow.
Type 1 endplate changes are characterized by decreased signal intensity on
T1-weighted images and increased signal intensity on T2-weighted images.
Disruption of the endplate with replacement of the hematopoietic elements in
the adjacent marrow by fat result in type 2 changes. Consequently, type 2
endplate changes are nearly isointense with fat, have hyperintensity on
T1-weighted images and isointensity or slight hypointensity on T2-weighted
images. Type 1 changes appear to convert to type 2 changes over time. Extensive
bony sclerosis with thickening of subchondral trabeculae results in type 2
endplate changes. Type 3 changes have decreased signal intensity on both T1-
and T2-weighted images.
MRI and CT scanning have considerable false-positive rates and less frequent
false-negative results.
Plain radiographs, myelography (of value only in patients with nerve
impingement on moving or standing), enhanced or nonenhanced CT, and nuclear
imaging cannot depict painful disks. MRI is helpful in showing changes in
signal intensity generated by the nucleus pulposus and, occasionally, in
adjacent vertebral bodies; however, the same types of MRI changes can be seen
in lifelong asymptomatic individuals.
Both April and Schellhaus have suggested that HIZL observed on MRI may be a
marker of a painful disk. However, findings from 4 independent studies of the
clinical usefulness of HIZL as an indicator of a symptomatic disk are not
supportive of this conclusion.
Provocation of concordant pain with lumbar diskography has been well
demonstrated. The key feature of diskography is the patient's response to disk
stimulation and not the appearance of the disk. Results of physiologic testing
explicitly determine whether a disk is painful. Specificity of diskography in
this regard has been well established by the work of Walsh et al. Because the
only available diagnostic intervention that identifies a symptomatic disk is
provocative diskography, this diagnostic tool should be ordered (or at least
considered) before surgery.
Diskography remains controversial; some spinal physicians do not acknowledge
its reliability or validity. Their contention primarily rests in a desire to
prevent inappropriate surgery because of a potential to abuse diskography
combined with the view, albeit unsubstantiated, that IDD represents a
constellation of symptoms rather than a specific diagnosis. The value of
diskography is debatable. Actual demonstration of disk disruption has been
shown to be no more important than pain reproduction.
Electrodiagnostic testing (nerve conduction studies and electromyography) is
warranted when their results may change the patient's therapy. In particular,
electrodiagnostic testing is indicated (1) if patients have symptoms suggestive
of cauda equina syndrome and their imaging studies are not diagnostic; (2) if
imaging studies show an abnormality not consistent with the symptoms; (3) if
such studies appear to be normal despite clinical suspicions; (4) if the
clinician suspects focal nerve entrapment, polyneuropathy, or myopathic
condition; and (5) if the clinician needs to identify which of several anatomic
lesions in the spine is the cause of radicular symptoms.
If a malignancy is suggested, laboratory studies, including determination of
the complete blood count, erythrocyte sedimentation rate, and alkaline
phosphatase levels and serum protein electrophoresis, may be helpful.
Conversely, if a rheumatologic etiology is considered, tests for antinuclear
antibody, rheumatoid factor, uric acid, and HLA-B27 levels may be beneficial.
XIV. On alternative
medicine
Taking Marie is a
matter of faith, not a matter of science. In fact, there is no such thing as
alternative medicine. It is a misnomer. So long as one understands that the effects
of energy release (or whatever seemingly notable phrase is coined to give such
sham therapies distinction and acceptance) is merely the same placebo one to be
expected of a visit to a palm reader, one may throw away their monies at $80 an
hour by reasoned choice. In the real world what these sessions do is alter
perception of pain, and thus, to a much lesser extent, modulation of pain. But
the pathology does not change, nor do the pain generators, nor is there a
change in the movement of impulses signaling injury to the cord. One merely
expects to get better, having traveled long distances and spent sizable sums,
and therefore... perhaps... the mind is convinced some change has occurred.
I have a higher power as well, Christine. I go to Christ, and he is with me
through all this. God provides his own placebo effect. But we do not call this
science. We know how energy is produced by the body, the biochemical cycles
that take glucose and run it through gluconeogenesis and the Kreb's cycle to
provide our cells with adenosine triphosphotase. We know exactly how this
cellular gasoline drives all the body's processes, including transduction and
transmission in the pudendal nerve.
We know how inflammation makes heat and erythema. We know the genes that are responsible
for Huntington's. What we don't know, because it is not possible to know, is
how moving one's hands over another body can release energy. It might can be
said to happen... one can say almost anything has happened, including the
removal of potentially malignant cells (and see, you did not develop cancer)...
but no one has yet developed a tool to measure such "energy". What
would happen to you, Christine, if Marie made a mistake and released too much
energy? Would you turn into a pumpkin, or perhaps have a recurrence of PNE? No,
I'm sure Marie has the ability to move her hands in such a manner that the
energy released is within the acceptable therapeutic limits, neither toxic nor
insufficient. And that when she pulls you over onto her, at this point nerve
healing could not possibly fail to occur.
My grandson says: whatever floats your boat. So perhaps that's applicable here.
Only let's make it clear. Despite tens of thousands of studies, all conducted
by alternative medicine proponents and none double blind, placebo controlled,
the only efficacy to these types of therapies is the patient's faith in
achieving a placebo effect.
XV. On
prolotherapy and SIJD
This information
might be relevant to your discussions regarding prolotherapy, tightening ligaments,
SIJD, and relief of pain. In addition, the mechanism of action of prolotherapy
in SIJD is discussed.
The key element in sacroiliac dysfunction diagnosis is pain. Many authors have
attempted to define a typical pain pattern associated with the SIJD. Several of
these reports describe patients reporting pain in one or both buttocks at or
near the posterior superior iliac spine (PSIS). However, pain radiating to the
hip, posterior thigh, or even calf has been described.
Patients often relate that pain especially worsens when sitting for long
periods or performing twisting or rotary motions.
Pain quality: Pain is described as a dull ache or sharp, stabbing, or
knifelike.
Pain distribution: Reported distributions are the buttocks, back of the thigh,
and upper back; it can be unilateral or bilateral.
Pain that is worse in the morning (morning stiffness) and resolves with
exercise: This pattern is consistent with an inflammatory disease.
Palpation may be the most reliable indication of SIJ pain. The patient usually
places a thumb directly onto one particular spot in the dimple of the PSIS
(sacral sulcus). The patient can usually precisely reproduce the pain over that
one spot (Fortin finger sign). More diffuse back or buttock and leg pain should
prompt the clinician to question the diagnosis of SIJ dysfunction.
Upon neurologic examination, motor strength, sensory examination, and reflexes
in the lower extremities should all prove normal. However, sometimes strength
examination proves challenging and the patient may exhibit weaknesses because
of pain inhibition or frank muscle imbalance that developed during episodes of
pain and relative inactivity. True neurogenic weakness, numbness, or loss of
reflex should alert the clinician to consider nerve root injury or pathology
other than a mechanical dysfunction.
It is a simple matter to perform pain provocation tests for SIJD. Distraction
can be performed to the anterior sacroiliac ligaments by applying pressure to
the anterior superior iliac spine (iliac gapping test). Apply compression to
the joint with the patient lying on his or her side. Pressure is applied
downwards to the uppermost iliac crest (iliac compression test). The goal of
the Gaenslen test is to apply torsion to the joint. With one hip flexed onto
the abdomen, the other leg is allowed to dangle off the edge of the table.
Pressure should then be directed downward on the leg in order to achieve hip
extension and stress the SIJ. For the flexion, abduction, and external rotation
(FABER or Patrick) test, the examiner externally rotates the hip while the
patient lies supine. Then, downward pressure is applied to the knee. In all
tests, pain in the typical area raises suspicion for an SIJ lesion.
Unfortunately, although systematic, these tests have not proven reliable in
controlled studies. Dreyfuss and colleagues studied 12 SIJ tests in relation to
fluoroscopically guided SIJ injection. They were unable to find even one of
these tests to be highly sensitive or specific for diagnosing SIJ pain.
Many patients state that the pain began spontaneously, while others can cite a
specific inciting event. Bernard and Kirkaldy-Willis reported that 58% of
patients diagnosed with SIJ pain based on clinical examination findings had
some inciting traumatic injury.
Factors that specifically increase the likelihood of mechanical injury to the
SIJ have not been identified. Pregnancy is one particular condition attributed
to SIJ dysfunction. Yet certain biomechanical or muscle length imbalances may
ultimately predispose a person to sacroiliac dysfunction and pain. Likely, this
is a result of altered gait patterns and repetitive stress to the SIJ and
related structures. These conditions exist in persons with leg-length
inequality, scoliosis, a history of polio, poor-quality footwear, and hip
osteoarthritis.
The use of imaging studies when evaluating sacroiliac pathology is a source of
controversy among clinicians because whether normal and abnormal radiographic
studies can help differentiate symptomatic versus non-symptomatic patients is
unclear. This is probably due to the great variability in joint anatomy between
patients. Additional disagreement exists on the significance of inflammatory
findings and degenerative findings (sclerosis) being diagnostic of pain within
the joint. The usual SIJ examination is performed using anteroposterior
pelvis/lumbar spine radiography. Sclerosis or obliteration of the SIJ can be
observed in older patients. Patients with AS usually have normal radiography
findings; in older patients with this disease, the joint can appear fused.
CT scanning can often be used to document reactive spurring, sclerosis, or even
subluxation. Many clinicians believe reactive spurring is due to prolonged
abnormal motion within the joint.
Some clinicians view enhancement observed in the SIJ unilaterally in a patient
with suspected SIJ conditions as an indicator of SIJ dysfunction or
inflammation. In 1996, Slipman et al found nuclear imaging under these
circumstances to be very low in sensitivity but high in specificity for
sacroiliac-mediated pain. Painful SIJs were confirmed with an intra-articular
injection of anesthetic. Therefore, bone scanning was of little value in the
diagnostic algorithm for SIJ pain.
Adding single-photon emission CT scanning may increase the sensitivity of
nuclear imaging for SIJ injuries; however, this has not been studied.
MRI is not generally used for evaluating the SIJ, although it can be a valuable
tool to help exclude disk herniation (especially at L5-S1) as part of the SIJ
dysfunction differential diagnosis. MRI can occasionally show inflammatory
signs within the SIJ. MRI can also be used to investigate pelvic stress
fracture, femoral neck stress fracture, or femoral head avascular necrosis.
Physical therapy focuses on pain control in the acute phase. Modalities such as
ultrasonography with or without phonophoresis, deep and superficial heat, and
superficial cold treatments can reduce pain. Neural therapies such as deep
tissue massage, myofascial release, and muscle energy stretching techniques can
also help. Pelvic myofascial stretching in the neutral spine position can be
used for immediate, short-term relief of discomfort. By identifying activities
that aggravate the condition, the physician or therapist can have the patient
avoid these activities.
Although in the acute-phase muscle spasms may prevent frank manipulation, less
aggressive techniques such as muscle energy stretching can be very helpful.
Patients may experience difficulty or even worsening symptoms with physical
therapy treatments in certain cases. In these patients, reevaluate the
diagnosis and consider other diagnostic possibilities (eg, infection,
inflammatory disease, malignancy, neural [lumbosacral root] injury). Patients
with acute inflammatory disorders or infections should not usually be
administered heat treatments. Patients who cannot perform physical therapy may
also have a functional component to their disorder or an underlying
psychological disorder, which needs to be addressed.
Surgical intervention is rarely used for nontraumatic SIJ pain. Surgery is
considered only in patients with chronic pain that has lasted for years, has
not been effectively treated by other means, and has led to an extremely poor
quality of life. The procedure is a fusion across the joint; however, although
the surgery has been reported to result in benefit in selected cases or small
case series, no randomized controlled study has shown reliable pain reduction
with SIJ fusion.
In the acute phase, sometimes a local trigger point injection into the muscle
can relieve symptoms.
If the pain does not resolve well in the first 2-3 weeks, an intra-articular
injection under fluoroscopic guidance should be considered. SIJ injection is
frequently performed with a mixture of anesthetic and steroid, as described by
Fortin in 1994 and others. When the actual source of the patient’s discomfort
is unclear, postinjection pain reduction offers significant diagnostic
information. Fluoroscopic guidance is important because, while a local blind
injection into the area of maximal pain can be temporarily effective, the
needle rarely enters the joint. CT scanning or MRI can also be used to guide
injections into the SIJ, with excellent reliability.
Günaydin and colleagues reported that 20 of 31 patients reported subjective
improvement after the first injection and 9 of 15 patients reported subjective
improvement after the second injection. The improvement lasted for a mean of
8.7 and 16.1 months for each group, respectively.
Luukkainen and colleagues reported that periarticular injection of
methylprednisolone may be effective in the treatment of pain in the region of
the SIJ in nonspondyloarthropathy patients from a study of 24 consecutive
patients. Although these studies are promising, they are not randomized
placebo-controlled studies. Therefore, before efficacy can be established,
randomized placebo-controlled studies must be undertaken.
Even if the injections do relieve the pain, the relief from the injections
alone is very often short-lived. Therefore, using the injections only as part
of an interdisciplinary rehabilitation program is important. The pain relief
offers a window of opportunity to increase the rehabilitation. The point in the
course of recovery when a second or even third injection should be attempted is
unclear. Most clinicians wait 2-4 weeks before proceeding with a repeat
injection.
Manipulation has been reported in multiple studies as effective treatment for
acute lower back pain. However, studies specifically on SIJ syndrome are less
abundant. The SIJ is accessible to manipulation treatments and these may be
extremely effective. As with other passive modalities, these treatments should
be coupled with an extensive active rehabilitative program. Manipulation following
intra-articular injection has been reported anecdotally to be beneficial in
selected cases.
In chronic conditions, some practitioners believe that SIJ pain is due to
hypermobility of the joint, which occurs because of laxity in the ligamentous
complex. Prolotherapy is a series of saline and glucose injections applied to
the SIJ ligaments to cause an inflammatory reaction, which results in scarring
and tightening of the ligaments and a reduction in pain. However, no
satisfactory outcome investigations have been performed on prolotherapy for
this condition.
A newer procedure, radiofrequency denervation, has recently been advocated for
the treatment of especially recalcitrant sacroiliac dysfunction. The procedure
was thought to be ineffective for SIJ pain because the innervation to the joint
is so diffuse. However, Gevargez and colleagues recently reported that 3 months
after the procedure, 13 patients (34.2%) were completely free of pain. Twelve
patients (31.6%) reported substantial pain reduction, 7 patients (18.4%) had
slight pain reduction, and 3 patients (7.9%) had no pain reduction. No
longer-term follow-up data are available; further study is needed.
The recovery phase cannot proceed without an active, aggressive rehabilitation
program. Often, SIJ injury leaves patients with significant deconditioning and
muscle imbalances. These functional muscular deficits were sometimes present
before the injury and may have predisposed the patient to injury. Some muscles
are known to be functioning in a tight or shortened position, such as the hip
flexors, hamstrings, tensor fascia lata, obturator internus, and rectus
femoris. Other muscles are weak or inhibited, such as the gluteal and abdominal
muscles.
The initial goal of physical therapy should be to correct any mechanical or
leg-length asymmetries (eg, orthotic/shoe lift), stretching overly tight
lumbopelvic muscles, and strengthening weak and inhibited muscles. All of this
should begin in the neutral spine position or a pelvic position, which minimizes
acute discomfort. Then the patient should be asked to take on more challenging
tasks while progressing through the program. Stabilization exercises are
performed with the patient in a more dynamic, functional position and often
include balance and proprioceptive activities. Strengthening of the core
muscles surrounding the spine can be achieved in various ways. Recently,
Pilates training has become very popular for this purpose. Finally, the patient
should graduate to sport- or work-specific training designed to return the
patient to his or her prior level of functioning.
In patients who develop chronic injuries, an SIJ belt can provide compression
and feedback to the gluteal muscles. Patients with ligamentous hypermobility
can especially benefit from this apparatus because the belt can reduce SIJ
rotation. The belt differs from a generalized lumbar orthosis because it is
much thinner and thus secures across the anterior superior iliac spines.
The outcome in this disease is usually good if properly diagnosed and treated.
XV. On a proposal to evaluate responses to
neuropathic analgesics
1.
Medicine does
approach the unknown with trial and error, but it is my hope we can
significantly reduce any dependence on trail and error with a two pronged
approach to neuropathy and pharmacological modulation. Let me present the idea
and see if there is agreement.
Approach 1. Theory. A review and assessment of each step in the pain process,
an understanding of the mechanisms involved with each step, especially the
cellular and molecular basis for each... from which we devise a medication
strategy which attacks at multiple levels simultaneously. This approach is
based on the assumption that the combined effect of medications will be far
greater than the sum of each medication, an assumption we can pose with some
confidence because in most research models this is what is found.
Approach 2. Clinical results. This approach requires the participation of forum
members, providing fairly detailed information regarding their personal
experiences with medications. We need to know drug, dose, pain response on the
visual analogue scale, duration of therapy, response graded by time over the
course of therapy, combination therapies, side effects, and reasons for
discontinuing medications. Each drug can then be scored. From a large pool with
vastly different treatment histories, where providers have many different
approaches, and where there is no outside financial influence, we should be
able to arrive at helpful conclusions regarding meds. Remember, it is doubtful
that any one of us has had a treatment plan based on combinations the work
might suggest, so prior failure of one or two agents in an individual patient
should not cast doubt on the ability of these drugs, when used to augment and
supplement the actions of other drugs, carefully targeted, to work.
Then we compare both, our molecular based strategy with our clinical
conclusions. If they are close then we may have hit the jackpot. Even if they
are not close, look at how far we will have come. Besides, we already know that
clinical responses might be significantly different if the right mixes can be
found. While Approach 2 provides a clinical check and balance, it is not an
absolute one. Yes, necessity is a mother of invention. What deserves
inventiveness more than neuropathic pain?
2.
Yes, those are the
types of questions. But unlike so many analysis based on case histories in the
medical literature, this one needs to be valid. The way that we are starting
out helps make it so because we have no preconceived notion, and therefore a
bias, to prove. Instead we are only looking for the truth ... which medications
have worked best among a very diverse treatment population. Validity does not
come easy, but it is not only possible, it is imperative to finding dependable
answers.
It is probably best that we divide labors and efforts into cells. Those members
with data assembly skills, like Amanda, can work on the clinical studies side
of the equation. Members whose interests lie in the fundamentals can contribute
to the research side. Everyone who has or have had pain needs to help with
information.
As I have written, we could score medications based on response to neuropathic
pain in our forum group. For these scores to be valid, the pain scale upon
which we depend for comparison must be carefully explained and well understood.
Data should also be given validity ratings. By that, I mean that a member who
has no other medical condition other than PNE, who is post decompression
surgery, who takes a single drug and achieves a 40 % reduction in pain within
two weeks, with substantial analgesia lasting for months, the data from that
member would receive a validity rating of A. A member who has many co-existing
illnesses, and takes all manner of drugs that are independent of the
medications taken for pain, then depending on those drugs and those conditions,
the data from that member might have to be rated with a "B" validity.
That in no way, shape or form demeans the value of the data, for it is as
valuable to us as any other. But in order to maintain validity, we must
consider the impact of other drugs and illnesses on the true effectiveness of
the analgesics taken at the same time. I will attempt to explain why this
matters in our search for the truth.
Most drugs are bound to plasma proteins once they enter the blood through the
walls of the small intestine. Plasma proteins then act as carriers, toting
medications to the site for which they are intended. The degree to which all drugs
bind to these transport proteins is variable ... some drugs are very tightly
bound during transport, others barely at all. (There is little magic to this.
The Physician Desk Reference gives the state of plasma binding in its
description of the pharmacology of every drug explained in the book). Basically
there are two types of transport proteins, albumin and globulins. For the most
part, drugs that are acidic bind to albumin while those that are basic in pH
bind to globulins, although there are some drugs that bind to both.
You are wondering what could this possibly have to do with the effectiveness of
a drug for pain. In order for a drug to get to the cord, or the brain, it has
to cross a membrane, called the blood-brain barrier. Drugs that are bound to
these plasma proteins cannot cross the blood brain barrier, therefore they are
pharmacologically inept. You can take as many as you want, but unless they are
freed from plasma binding, you will not get a clinical response. So if a member
has a medical condition that changes the amount of circulating transport
proteins, or is taking a medication that affects the number of binding sites
available for the transport of other drugs, such as the analgesic, or the
membrane stabilizer, so that the medication cannot get to its site of action,
then the true effectiveness of that medication would not be completely valid as
reported. The degree of validity would depend on the circumstances.
Drug binding is affected not only by other medications, but also by things like
pregnancy. Older folks like myself have decreased protein concentrations and
thus the drug available for activity at the receptor is increased. Diseases
like renal failure, liver failure and uncontrolled diabetes lead to changes in
the ratios of bound and free drug. Other medications taken by a member might
compete with the analgesic for binding sites and either decrease or increase
the amount of drug that makes it across the blood brain barrier.
Central to truth is validity of data. Central to validity is obtaining
information on medical history and other medications.
As far as dose response, we could provide a time line, sectioned into each
month, looking at a time frame going back as far as data can be considered
reliable (by memory). The time line would give room for dose adjustments,
medication additions and eliminations
Med
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Response
On the response side of the line members would be encouraged to provide not
only pain scores, but some indication of the effect of medications on daily
function. Important to our overall strategy is reducing pain while permitting
functional recovery.
3.
As proposed, the
work on neurotransmitters and nociceptive modulating receptor sites is
on-going. Phase two requires input from a good many folks on the forum (or
guests) who have neuropathic pain. The strategy of phase two is to rate pain
response to various medications, determine if these numbers are statistically
significant, and construct a combination medication package which can then be
compared to the cellular model with respect to efficacy.
As discussed in a post above, it is important that the data receive quality of
data scoring as well as analgesia scoring. In order for that to occur without
bias, a protocol will be developed to use in the analysis of data. In order to
protect the confidentiality of members contributing data, I suggest that Karen
and Greg select three members of TIPNA whose integrity is beyond doubt (and
would have the confidence of members). The data to be requested from forum
members who choose to contribute to this study would then be PMed to one of
these three members, who in turn would de-personalize the information (by
giving it a number rather than a name). Then the information would be forwarded
for analysis.
A separate topic will be created so that members can follow results as data is
accumulated. The topic will be edited weekly with new and total numbers.
Members should not view this topic until after they have completed the
questions and PMed either of the three members selected for de-personaliztion
of data (in order to prevent bias in answers). It would probably be best to
wait until the end to present data to the forum, but an up to date accounting
of data received might spur more interest in contributing.
The following is a list of proposed questions. Readers are encouraged to
suggest additions or modifications.
1. Please list your given diagnoses and approximate date of diagnosis (any
chronic medical conditions):
(Reason for question: some medical illnesses affect absorption, transportation,
and or metabolism/elimination of medication, so these may affect quality of
data scoring.)
2. Please give the diagnosis of the illness that is felt responsible for your
neuropathic pain:
3. Please list any surgical procedures you have had and the approximate date of
the procedure:
(Reason: some surgical procedures (eg.subtotal gastrectomy) may affect the
manner in which medications are absorbed or metabolized, thus affecting quality
of data scoring.)
4. Give the approximate date of onset of this illness (first symptoms):
5. Give your age/sex:
6. Give those factors which you feel may be responsible for this illness (eg.
vaginal hysterectomy, cycling, etc):
7. Please give a history of your use of medications taken to address pain
(since the date of onset of illness given above). Please include the dose of
medication, any dose adjustments, any untoward side effects that required the
dose be reduced or the medication discontinued. Please include any other
medications taken at the same time as the medications for analgesia, including
the dose, the reason for the medication, and whether or not the medication was
continued or discontinued.
Please rate your pain and response to medications based on the visual analogue
scale as given below:
no worst
pain pain imagined
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0 1 2 3 4 5 6 7 8 9 10