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http://www.fda.gov/cder/foi/label/2003/21168se5-007_depakote_lbl.pdf

http://www.support4hope.com/medications/mood_stabilizers/divalproex_de
pakote.htm
Mood stabilizer: divalproex, Depakote
Generic Name: divalproex
Brand Name(s): Depakote
Common Use: Mood stabilizer
Divalproex sodium has anticonvulsant properties, and is chemically
related to valproic acid. Although its mechanism of action has not
yet been established, it has been suggested that its activity is
related to increased brain levels of gamma-aminobutyric acid (GABA).
The effect on the neuronal membrane is unknown. It dissociates into
valproic acid in the gastrointestinal tract.
Acute Mania:
Divalproex is indicated in the treatment of the manic episodes
associated with bipolar disorder (DSM-III-R). The effectiveness of
divalproex in long-term use, that is for more than 3 weeks, has not
been systematically evaluated in controlled trials. Dilvalproex is
not indicated for use as a mood stabilizer in patients under 18 years
of age.
Contraindications
Patients with hepatic disease or significant dysfunction.
Hypersensitivity to the drug.
Adverse Side Effects
Gastrointestinal:
Nausea, vomiting and indigestion are the most commonly reported side
effects at the initiation of therapy. These effects are usually
transient and rarely require discontinuation of therapy. Diarrhea,
abdominal cramps and constipation have also been reported. Anorexia
with some weight loss and increased appetite with some weight gain
have also been seen.
CNS:
Sedative effects have been noted in patients receiving valproic acid
alone but are found most often in patients on combination therapy.
Sedation usually disappears upon reduction of other antiepileptic
medication. Ataxia, headache, nystagmus, diplopia, asterixis, "spots
before the eyes", tremor (may be dose-related), dysarthria,
dizziness, and incoordination have rarely been noted. Rare cases of
coma have been reported in patients receiving valproic acid alone or
in conjunction with phenobarbital.
Dermatologic:
Transient increases in hair loss have been observed. Skin rash,
photosensitivity, generalized pruritus, erythema multiforms, Stevens-
Johnson syndrome and petechiae have rarely been noted.
Endocrine:
There have been reports of irregular menses and secondary amenorrhea,
breast enlargement, galactorrhea and parotid gland swelling in
patients receiving valproic acid. Abnormal thyroid function tests
have been reported (see Precautions).
Psychiatric:
Emotional upset, depression, psychosis, aggression, hyperactivity and
behavioral deterioration have been reported.
Musculoskeletal:
Weakness has been reported.
Special Senses:
Hearing loss, either reversible or irreversible, has been reported
however, a cause and effect relationship has not been established.
Other:
Edema of extremities has been reported.
Bipolar Disorder:
The incidence of adverse events has been ascertained based on data
from 2 short-term (21 day) placebo-controlled clinical trials of
divalproex in the treatment of acute mania, and from 2 long-term (up
to 3 years) retrospective open trials.
Most Commonly Observed:
During the short-term placebo-controlled trials, the 6 most commonly
reported adverse events in patients (N=89) exposed to divalproex were
nausea (22%), headache (21%), somnolence (19%), pain (15%), vomiting
(12%), and dizziness (12%).
In the long-term retrospective trials (634 patients exposed to
divalproex), the 6 most commonly reported adverse events were
somnolence (31%), tremor (29%), headache (24%), asthenia (23%),
diarrhea (22%) and nausea (20%).
Associated With Discontinuation of Treatment:
In the placebo-controlled trials, adverse events which resulted in
valproate discontinuation in at least 1% of patients were nausea (4%)
abdominal pain (3%), somnolence (2%) and rash (2%). In the long-term
retrospective trials, adverse events which resulted in valproate
discontinuation in at least 1% of patients were alopecia (2.4%),
somnolence (1.9%), nausea (1.7%) and tremor (1.4%). The time to onset
of these events was generally within the first 2 months of initial
exposure to valproate. A notable exception was alopecia, which was
first experienced after 3 to 6 months of exposure by 8 of the 15
patients who discontinued valproate in response to the event.
Overdose
Naloxone has been reported to reverse the CNS depressant effects of
valproic acid overdosage. Because naloxone could theoretically also
reverse the antiepileptic effects of divalproex, it should be used
with caution in patients with epilepsy.
Since divalproex tablets are enteric-coated, the benefit of gastric
ravage or emesis will vary with the time since ingestion. General
supportive measures should be applied with particular attention to
the prevention of hypovolemia and the maintenance of adequate urinary
output.

http://www.rxabbott.com/br/dep/dep001.htm
DEPAKOTE (divalproex sodium) is indicated for the treatment of the
manic episodes associated with bipolar disorder. A manic episode is a
distinct period of abnormally and persistently elevated, expansive,
or irritable mood. Typical symptoms of mania include pressure of
speech, motor hyperactivity, reduced need for sleep, flight of ideas,
grandiosity, poor judgment, aggressiveness, and possible hostility.
The efficacy of DEPAKOTE was established in 3-week trials with
patients meeting DSM-III-R criteria for bipolar disorder who were
hospitalized for acute mania.
Safety
The only adverse event that was reported by significantly more
patients receiving DEPAKOTE compared to placebo was vomiting (P
<0.05).1,2
Other common adverse events vs placebo were nausea (22% vs 15%),
somnolence (19% vs 12%), and dizziness (12% vs 4%).1
Hepatic failure resulting in fatalities has occurred in patients
receiving valproic acid and its derivatives. Patients should be
monitored closely for the appearance of nonspecific symptoms which
may precede hepatotoxicity. Liver function tests should be performed
prior to therapy and at frequent intervals thereafter, especially
during the first 6 months. DEPAKOTE should not be administered to
patients with hepatic disease or significant hepatic dysfunction.2
Valproic acid may produce teratogenic effects in the offspring of
human females receiving the drug during pregnancy.2
Cases of life-threatening pancreatitis have been reported in adults
and children receiving valproate, either initially or after several
years of use. Some cases were described as hemorrhagic with a rapid
progression from onset to death. Patients should be warned that
symptoms of pancreatitis require prompt medical evaluation. If
pancreatitis is diagnosed, valproate should be discontinued.2
Valproate is contraindicated in patients with known urea cycle
disorders (UCD), a group of uncommon genetic abnormalities.
Hyperammonemic encephalopathy, sometimes fatal, has been reported
following initiation of valproate therapy in patients with known or
suspected UCDs. Patients who develop symptoms of unexplained
hyperammonemic encephalopathy while receiving valproate therapy
should receive prompt treatment (including discontinuation of
valproate). 2
The frequency of adverse effects (particularly elevated liver enzymes
and thrombocytopenia) may be dose-related.2
Some elderly dementia patients taking valproate in a clinical trial
experienced somnolence, sometimes requiring discontinuation. In some
of these patients, there was associated reduced nutritional intake,
weight loss, and a trend to have a lower baseline albumin
concentration, higher BUN, and lower valproate clearance.2

http://www.nami.org/Template.cfm?
Section=About_Medications&template=/ContentManagement/ContentDisplay.c
fm&ContentID=7389
What is Depakote?
Depakote (divalproex sodium), marketed by Abbott Laboratories, is a
prescription medication that has been proven effective in the
treatment of manic episodes associated with bipolar disorder, also
known as manic depression.
What is bipolar disorder?
Bipolar disorder is a neurobiological brain disorder (mental illness)
characterized by cyclic mood swings of extreme highs called mania and
intense lows known as depression. Bipolar disorder affects more than
two million Americans each year, but patients with this disorder can
lead fulfilling lives when they receive proper treatment.
Unfortunately, some two-thirds of those afflicted don't receive
treatment.
Medication is an essential part of successful treatment for bipolar
disorder, and Depakote is the newest medication approved to treat
mania. With the proper dosage, Depakote can reduce manic symptoms,
shorten hospitalization, help prevent future manic episodes, and make
it possible for an individual to live productively in the community.
When was Depakote introduced to the U.S.?
Depakote has been marketed in the United States since 1983. Until it
was approved for use in treating bipolar disorder on June 1, 1995, it
was used exclusively in the treatment of epilepsy. This new use of
Depakote for the manic episodes of bipolar disorder is a breakthrough
in medicine because it is the first medication approved for the
symptoms of mania in 25 years.
What is the standard dose of Depakote?
Depakote is available in three tablet strengths, which are
administered orally. The recommended initial dose is 750 mg daily
taken in divided doses. (The starting dose should be reduced in
elderly patients.) Dosages usually begin low and may be increased by
the doctor until the patient reaches the point where the lowest
therapeutic dose produces the desired clinical effect.
Is there anyone that shouldn't take Depakote?
Depakote should not be given to patients with liver disease or
significant liver dysfunction to avoid liver failure. Pregnant women
should not take Depakote because of the possible harm it can cause
the fetus.
Caution should be taken when Depakote is administered with other
medications, including aspirin. Patients must be sure to report all
other medications -- prescribed and over-the-counter -- that they are
taking to the doctor prescribing Depakote. Depakote should also be
given with caution to nursing mothers.
What are the side effects of Depakote?
There are significant risks for pregnant patients that should be
discussed with the doctor in each case. If you are already pregnant
and on Depakote, do not discontinue it abruptly. Call you doctor to
discuss the situation.
Liver problems, which can be severe, may develop on Depakote,
especially in the first six months of treatment. Problems with white
blood cell count and blood platelets, which can also be severe, may
also develop on this medication. Blood tests to monitor liver
function and blood cells are an important part of treatment with
Depakote, and they serve to make this treatment acceptably safe.
Rarely, a potentially fatal abnormality involving the pancreas call
pancreatitis can occur.
Other common side effects are nausea, drowsiness, and dizziness; but
for some patients these conditions lessen or go away over time.
Because Depakote may cause drowsiness, patients receiving this
medication should not engage in hazardous activities or operate motor
vehicles while undergoing treatment until the drowsiness subsides.
Some adverse effects on skin and hair may also occur, including rash,
hair loss, and itching.
Patients taking stronger doses of Depakote may experience more side
effects, so it is important to weigh the benefits of a higher dose
against the possibility of greater adverse reactions to the drug.
How long does it take to work, and should Depakote be taken for long
periods of time?
In clinical studies, patients have been found to respond to the
effects of Depakote after just ten days of treatment. In these
studies Depakote was found to be safe in treating a sample of 360
patients for more than three months. As with any medication,
physicians who prescribe Depakote for extended periods of time should
continually reevaluate the patient and the drug's overall short- and
long-term effects.
What are the advantages of Depakote?
Depakote is a major advance in the treatment of manic episodes
associated with bipolar disorder. It is an effective and well-
tolerated treatment that offers hope for many consumers. There are a
number of anti-depressant medications available for treating the
depressive episodes of bipolar disorder, but there are only four
approved by the FDA for treating mania: lithium, chlorpromazine
(Thorazine), Depakote, and Zyprexa.
Reviewed by Jack Gorman, M.D., Chair NAMI Scientific Council, Sept
2002

http://www.rxabbott.com/br/dp/dp001.htm
DEPAKOTE is indicated for prophylaxis of migraine headaches. There is
no evidence that DEPAKOTE is useful in the acute treatment of
migraine headaches. Because valproic acid may be a hazard to the
fetus, DEPAKOTE should be considered for women of childbearing
potential only after this risk has been thoroughly discussed with the
patient and weighed against the potential benefits of treatment.
Adverse events in
than placebo:
Gastrointestinal System
nausea (31% vs 10%)
dyspepsia (13% vs 9%)
diarrhea (12% vs 7%)
vomiting (11% vs 1%)
abdominal pain (9% vs 4%)
increased appetite (6% vs 4%)
Nervous System
asthenia (20% vs 9%)
somnolence (17% vs 5%)
dizziness (12% vs 6%)
tremor (9% vs 0%)
Other
weight gain (8% vs 2%)
back pain (8% vs 6%)
alopecia (7% vs 1%)
Hepatic failure resulting in fatalities has occurred in patients
receiving valproic acid and its derivatives. Patients should be
monitored closely for the appearance of nonspecific symptoms which
may precede hepatotoxicity. Liver function tests should be performed
prior to therapy and at frequent intervals thereafter, especially
during the first 6 months. Depakote should not be administered to
patients with hepatic disease or significant hepatic dysfunction.
Cases of life-threatening pancreatitis have been reported in adults
and children receiving valproate, either initially or after several
years of use. Some cases were described as hemorrhagic with a rapid
progression from onset to death. Patients should be warned that
symptoms of pancreatitis require prompt medical evaluation. If
pancreatitis is diagnosed, valproate should be discontinued.
The frequency of adverse effects (particularly elevated liver enzymes
and thrombocytopenia) may be dose-related.
Valproic acid may produce teratogenic effects in the offspring of
human females receiving the drug during pregnancy. An information
leaflet is available for patients who could become pregnant.
The use of Depakote tablets for migraine prophylaxis in women of
childbearing potential requires that the benefits of use be weighed
against the risk of injury to the fetus.
Some elderly dementia patients taking valproate in a clinical trial
experienced somnolence, sometimes requiring discontinuation. In some
of these patients, there was associated reduced nutritional intake,
weight loss and a trend to have a lower baseline albumin
concentration, a higher BUN, and lower valproate clearance.
There is insufficient information available to discern the safety and
effectiveness of Depakote for the prophylaxis of migraines in
patients over 65.
References:
1. DEPAKOTE (divalproex sodium) package insert, Abbott Laboratories.

http://www.drspock.com/discussion/message/0%2C1812%2C49849%2C00.html
http://www.reglan-lawsuit.com/side-effects.htm
http://www.edifyingspectacle.org/weblog/archives/gallimaufry/migraine_
headaches_reglan.php
http://homepage.mac.com/mattocks/morfz/cisavsreg.html
http://www.yourownhealth.com/reference/REGLAN.asp
http://www.utmem.edu/transplant/propulsid.htm
http://www.druginfonet.com/index.php?pageID=faq/faqregla.htm

http://www.neonatology.org/ref/meds/med64.html
Generic Name Metoclopramide
Brand Name Reglan
Indications Facilitate gastric emptying and GI motility.
Dose 0.03-0.1 mg/kg/dose given q 8 hrs PO or IV, may increase
frequency to q 6 hrs. Warning: IV solution is light-sensitive.
Route IV, PO
Levels and Metabolism Absorbed well from GI tract. Variable first-
pass metabolism by liver. Significant fraction excreted unchanged in
urine. Lipid-soluble; large volume of distribution.
Action Derivative of procainamide. Exact mechanism of action is
unknown, however it has both dopamine receptor blocking activity and
peripheral cholinergic effects.
Toxicity Intended for short-term use (several weeks) only. Dystonic
reactions and extrapyramidal signs may be seen with prolonged use. GI
obstruction, hemorrhage. Seizures.
Contraindications Intended for short-term use only. See toxicity.
References Young & Mangum, Neo FAX, p. 158, 1993.
Gomella, Neonatology, p. 473, 1992.

http://www.medhelp.org/perl6/gastro/archive/2950.html
Subject: Reglan
Topic Area: Digestive
Forum: The Gastroenterology and Liver Diseases Forum
Question Posted By: Christine on Thursday, September 10, 1998
My doctor just prescribed Reglan for my symptoms of fullness,
belching, etc. I read from someone that Reglan has "serious" side
effects and that "it enters the brain and can cause irreversabile
side effects." This person was not a doctor. Is this true? I don't
see many people using this medication--mostly I see Propulsid used.
Can you tell me a bit about Reglan and why it doesn't seem to be too
popular.
Christine
Dear Christine,
Metaclopramide (Reglan) is not often used as a first line drug
because of its side effect profile. It works as a peripheral and
central dopamine antagonist and a cholinergic agonist. It causes an
increase in lower esophageal sphincter pressure and accelerates
gastric emptying. Side effects include: fatigue, lethargy and
psychotropic and extrapyramidal side effects as well as galactorrhea
(milk discharge from the breasts) secondary to increased prolactin
levels. The fatigue, lethargy and drowsiness occurs because
metaclopramide crosses the blood brain barrier to affect the central
nervous system. Extrapyramidal side effects are abnormal movements
and muscle spasms that can be quite troublesome, but usually subside
with discontinuation of the drug. Side effects have been reported in
up to 30% of patients. Tardive dyskinesia is a movement disorder
which can occur with long-term use of metaclopramide. It can persist
even after the drug is discontinued. The frequency of side effects
can be decreased by decreasing the dose, giving a larger dose only
before troubling meals or at bedtime or using a sustained release
tablet. I hope you find this information helpful.
This response is being provided for general informational purposes
only and should not be considered medical advice or consultation.
Always check with your personal physician when you have a question
pertaining to your health.
If you would like to be seen at our institution please call 1-800-653-
6568 our Referring Physicians' Office and make an appointment to see
Dr. Muszkat, one of our experts in Gastroenterology.
HFHSM.D.-ym
*Keywords: metaclopramide, side effects

http://www.drugintel.com/reglan_tardive_dyskinesia.htm
Reglan (Metoclopamide) Prescription Drug Reglan / Metoclopramide
attracts Personal Injury Lawsuits; Lawyers focus on Tardive
Dyskinesia.
Are warnings on the drug label adequate for the frequently permanent
Metoclopramide / Reglan Side Effects of Tardive Dyskinesia?
Coverage beginning: 30 May 2003
Reglan (Metoclopramide) is used to treat Gastroesophageal Reflux
Disease (Gerd; Heartburn; Acid Reflux Disease). Minor Side Effects
and Side Effects that are transient and disappear with time are
listed below. The Reglan Side Effect of greatest concern to
DrugIntel include Tardive Dyskinesia, a Side Effect that can be
permanent.
Reglan (Metoclopramide)
Drug names
Gastroesophageal Reflux Disease (Gerd); Anti-Emetic (Anti-Nausea)
Medical usage
Extrapyramidal Side Effects - Acute Dystonia, Parkinson-like
Extrapyramidal Symptoms; and Tardive Dyskinesia
Adverse Reactions
Trade Name Reglan: A.H. Robins (American Home Products / Wyeth)
Generic Metoclopramide: Baxter, Gensia (GensiaSciCor; Abbott;
Faulding / Mayne Pharmaceutical
Companies
Acute Dystonia - rapid onset and usually reversible symptoms
comparable to Tardive Dyskinesia and Huntington Disease. Usually
reversible.
Extrapyramidal Symptoms: Comparable to Parkinson Disease. Usually
reversible.
Tardive Dyskinesia: Involuntary Movements especially of Face, Mouth,
and Tongue; Tics; Grimaces of the Face. Can include Tardive Thought
Disorder. Tardive Dyskinesia can be a permanent Side Effect which
worsens, rather than disappears, when treatment with Reglan or
Metoclopramide is stopped.
Patient presentation
Active litigation ongoing; contact info@...
Litigation status
Further info
Liability of the manufacturers of Reglan (Metoclopramide) is argued
by Lawyers based on several points:
Use of Reglan (Metoclopramide) for longer than 12 weeks may
constitute an Off-Label Use (not approved by Fda).
Estimates of Incidence of Tardive Dyskinesia furnished by the
manufacturer(s) may be lower than the actual rate.
Prophylaxis by use of antihistamine drugs may not be efficacious,
credible, or practical.
For further Information concerning Attorneys specializing in Reglan
(Metoclopramide) Side Effects / Personal Injury / Medical Malpractice
Lawsuits, contact DrugIntel.
Since Tardive Dyskinesia may be a lifelong Adverse Reaction to Reglan
(Metoclopramide), there have been a number of cases, but the expected
deluge has not yet materialized. The deluge is expected due to the
recent replacement by Reglan of Propulsid (cisapride), a drug
Recalled by Fda. The Propulsid Recall was due to QT prolongation
(Arrhythmia) by the drug.
Therapeutic Treatment of Tardive Dyskinesia caused by Reglan
(Metoclopramide). There are new Treatments for Tardive Dyskinesia
emerging from experimental development. Write to DrugIntel for
details.
Side Effects of Prescription Drug Reglan (Metaclopramide) include:
Depression
Fatigue
Lethargy
Galactorrhea (milk discharge from the breasts secondary to elevated
prolactin levels)
Extrapyramidal Symptoms:
Dystonic Reactions
Muscle Spasm
Involuntary Movements of the Limbs
Facial Grimacing
Acute Extrapyramidal Dystonic Reactions usually occur within 48 hours
after starting Reglan (Metoclopramide) administration, if they will
occur. Parkinsonian type Extrapyramidal Symptoms (Eps) can occur
within the first 6 months after starting the drug. Tardive Dyskinesia
can occur after brief periods on Reglan (Metoclopramide) but are more
likely to occur with increased duration of treatment.
Omeperazole (Prilosec) is generally a well tolerated drug, and is
widely considered a safer alternative to Reglan (Metoclopramide).
Omeperazole has now been used in Europe for prolonged periods for
patients with Gastroesophageal Reflux Disease without apparent
serious consequences.
Reglan (Metoclopramide) Prescription for Infants: Extra dangers
exist for infants because their Blood Brain Barrier is less well
formed than for adults, the first line of defense against
Metoclopramide. Reglan (Metoclopramide) use during Pregnancy to
treat Nausea is highly risky, in our opinion (see details).
Nissen Fundoplication (Surgery) for the treatment of Gastroesophageal
Reflux Disease (Gerd) is an option for patients who continue to have
Acid Reflux Symptoms despite medical therapy and adherence to Diets
and other measures designed to limit Reflux Disease. It is also
indicated in young patients who are concerned about being on
medications for the rest of their lives. Surgery carries its own
risks and potential complications. Extensive testing prior to surgery
is recommended to exclude an Esophageal Motility Disorder and to
confirm the diagnosis of Gastroesophageal Reflux Disease (Gerd).
Neuroleptic drugs used to treat Schizophrenia are well-known to cause
Tardive Dyskinesia: Zyprexa, Seroquel, Risperdal, Geodon, Clozapine,
Thorazine, Serentil, Mellaril, Prolixin, Haldol, Loxitane, Moban,
Trilafon, Orap, Navane, and Stelazine.
Others are used to control Gastrointestinal Disorders that can cause
Tardive Dyskinesia include Compazine and Propulsid. All have a
common mechanism of action, blocking dopamine receptors.
Tardive Dyskinesia Symptoms: Tardive Dyskinesia is characterized by
repetitive, involuntary, purposeless movements. Features of the
disorder may include grimacing, tongue protrusion, lip smacking,
puckering and pursing, and rapid eye blinking. Rapid movements of the
arms, legs, and trunk may also occur. Impaired movements of the
fingers may appear as though the patient is playing an invisible
guitar or piano. Tardive Dyskinesia is very different from Obsessive
Compulsive Disorder (OCD) in which individual movements do have
purpose.

http://www.rxlist.com/cgi/generic2/metoclo_wcp.htm
WARNINGS
Mental depression has occurred in patients with and without prior
history of depression.Symptoms have ranged from mild to severe and
have included suicidal ideation and suicide. Metoclopramide should be
given to patients with a prior history of depression only if the
expected benefits outweigh the potential risks.
Extrapyramidal symptoms, manifested primarily as acute dys-tonic
reactions, occur in approximately 1 in 500 patients treated with the
usual adult dosages of 30 to 40 mg/day of metoclopramide.These
usually are seen during the first 24 to 48 hours of treatment with
metoclopramide, occur more frequently in pediatric patients and adult
patients less than 30 years of age and are even more frequent at
higher doses. These symptoms may include involuntary movements of
limbs and facial grimacing, torticollis, oculogyric crisis, rhythmic
protrusion of tongue, bulbar type of speech, trismus, or dystonic
reactions resembling tetanus.Rarely, dystonic reactions may present
as stridor and dyspnea, possibly due to laryngospasm.If these
symptoms should occur, inject 50 mg diphenhydramine hydrochloride
intramuscularly, and they usually will subside. Benztropine mesylate,
1 to 2 mg intramuscularly, may also be used to reverse these
reactions. Parkinsonian-like symptoms have occurred, more commonly
within the first 6 months after beginning treatment with meto-
clopramide, but occasionally after longer periods. These symptoms
generally subside within 2 to 3 months following discontinuance of
metoclopramide. Patients with preexisting Parkinson's disease should
be given metoclopramide cautiously, if at all, since such patients
may experience exacerbation of parkinsonian symptoms when taking
metoclopramide.
Tardive Dyskinesia
Tardive dyskinesia, a syndrome consisting of potentially
irreversible, involuntary, dyskinetic movements may develop in
patients treated with metoclopramide. Although the prevalence of the
syndrome appears to be highest among the elderly, especially elderly
women, it is impossible to predict which patients are likely to
develop the syndrome. Both the risk of developing the syndrome and
the likelihood that it will become irreversible are believed to
increase with the duration of treatment and the total cumulative dose.
Less commonly, the syndrome can develop after relatively brief
treatment periods at low doses; in these cases, symptoms appear more
likely to be reversible.
There is no known treatment for established cases of tardive
dyskinesia although the syndrome may remit, partially or completely,
within several weeks-to-months after metoclo-pramide is withdrawn.
Metoclopramide itself, however, may suppress (or partially suppress)
the signs of tardive dyskine-sia, thereby masking the underlying
disease process. The effect of this symptomatic suppression upon the
long-term course of the syndrome is unknown. Therefore, the use of
metoclopramide for the symptomatic control of tardive dyski-nesia is
not recommended.
Neuroleptic Malignant Syndrome (NMS)
There have been rare reports of an uncommon but potentially fatal
symptom complex sometimes referred to as Neuroleptic Malignant
Syndrome (NMS) associated with metoclopramide. Clinical
manifestations of NMS include hyperthermia, muscle rigidity, altered
consciousness, and evidence of autonomic instability (irregular pulse
or blood pressure, tachycardia, diaphoresis and cardiac arrhythmias).
The diagnostic evaluation of patients with this syndrome is
complicated. In arriving at a diagnosis, it is important to identify
cases where the clinical presentation includes both serious medical
illness (e.g., pneumonia, systemic infection, etc.) and untreated or
inadequately treated extrapyramidal signs and symptoms (EPS).Other
important considerations in the differential diagnosis include
central anticholinergic toxicity, heat stroke, malignant
hyperthermia, drug fever and primary central nervous system (CNS)
pathology.
The management of NMS should include 1) immediate discontinuation of
metoclopramide and other drugs not essential to concurrent therapy,
2) intensive symptomatic treatment and medical monitoring, and 3)
treatment of any concomitant serious medical problems for which
specific treatments are available. Bromocriptine and dantrolene
sodium have been used in treatment of NMS, but their effectiveness
have not been established (see ADVERSE REACTIONS).
PRECAUTIONS
General
In one study in hypertensive patients, intravenously administered
metoclopramide was shown to release catecholamines; hence, caution
should be exercised when metoclopramide is used in patients with
hypertension.
Because metoclopramide produces a transient increase in plasma
aldosterone, certain patients, especially those with cirrhosis or
congestive heart failure, may be at risk of developing fluid
retention and volume overload.If these side effects occur at any time
during metoclopramide therapy, the drug should be discontinued.
INFORMATION FOR PATIENTS
Metoclopramide may impair the mental and/or physical abilities
required for the performance of hazardous tasks such as operating
machinery or driving a motor vehicle.The ambulatory patient should be
cautioned accordingly.

http://www.rxlist.com/cgi/generic2/metoclo_ad.htm
Metoclopramide
SIDE EFFECTS
In general, the incidence of adverse reactions correlates with the
dose and duration of metoclopramide administration.The following
reactions have been reported, although in most instances, data do not
permit an estimate of frequency:
CNS Effects
Restlessness, drowsiness, fatigue, and lassitude occur in
approximately 10% of patients receiving the most commonly prescribed
dosage of 10 mg q.i.d. (see PRECAUTIONS). Insomnia, headache,
confusion, dizziness, or mental depression with suicidal ideation
(see WARNINGS) occur less frequently. The incidence of drowsiness is
greater at higher doses.There are isolated reports of convulsive
seizures without clearcut relationship to metoclopramide. Rarely,
hallucinations have been reported.
Extrapyramidal Reactions (EPS)
Acute dystonic reactions, the most common type of EPS associated with
metoclopramide, occur in approximately 0.2% of patients (1 in 500)
treated with 30 to 40 mg of metoclopramide per day. Symptoms include
involuntary movements of limbs, facial grimacing, torticollis,
oculogyric crisis, rhythmic protrusion of tongue, bulbar type of
speech, trismus, opisthotonus (tetanus-like reactions), and, rarely,
stridor and dyspnea possibly due to laryngospasm;ordinarily these
symptoms are readily reversed by diphenhydramine (see WARNINGS).
Parkinsonian-like symptoms may include bradykinesia, tremor, cogwheel
rigidity, mask-like facies (see WARNINGS).
Tardive dyskinesia most frequently is characterized by involuntary
movements of the tongue, face, mouth, or jaw, and sometimes by
involuntary movements of the trunk and/or extremities; movements may
be choreoathetotic in appearance (see WARNINGS).
Motor restlessness (akathisia) may consist of feelings of anxiety,
agitation, jitteriness, and insomnia, as well as inability to sit
still, pacing, foot tapping. These symptoms may disappear
spontaneously or respond to a reduction in dosage.
Neuroleptic Malignant Syndrome
Rare occurrences of neuroleptic malignant syndrome (NMS) have been
reported. This potentially fatal syndrome is comprised of the symptom
complex of hyperthermia, altered consciousness, muscular rigidity,
and autonomic dysfunction (see WARNINGS).
Endocrine Disturbances
Galactorrhea, amenorrhea, gynecomastia, impotence secondary to
hyperprolactinemia (see PRECAUTIONS).Fluid retention secondary to
transient elevation of aldosterone (see CLINICAL PHARMACOLOGY).
Cardiovascular
Hypotension, hypertension, supraventricular tachycardia, bradycardia,
fluid retention, acute congestive heart failure and possible AV block
(see CONTRAINDICATIONS and PRECAUTIONS).
Gastrointestinal
Nausea and bowel disturbances, primarily diarrhea.
Hepatic
Rarely, cases of hepatotoxicity, characterized by such findings as
jaundice and altered liver function tests, when metoclo-pramide was
administered with other drugs with known hepa-totoxic potential.
Renal
Urinary frequency and incontinence.
Hematologic
A few cases of neutropenia, leukopenia, or agranulocytosis, generally
without clearcut relationship to metoclopramide. Methemoglobinemia,
in adults and especially with overdosage in neonates (see
OVERDOSAGE). Sulfhemoglobinemia in adults.
Allergic Reactions
A few cases of rash, urticaria, or bronchospasm, especially in
patients with a history of asthma.Rarely, angioneurotic edema,
including glossal or laryngeal edema.
Miscellaneous
Visual disturbances.Porphyria.
DRUG INTERACTIONS
The effects of metoclopramide on gastrointestinal motility are
antagonized by anticholinergic drugs and narcotic analgesics.
Additive sedative effects can occur when metoclopramide is given with
alcohol, sedatives, hypnotics, narcotics, or tranquilizers.
The finding that metoclopramide releases catecholamines in patients
with essential hypertension suggests that it should be used
cautiously, if at all, in patients receiving monoamine oxi-dase
inhibitors.
Absorption of drugs from the stomach may be diminished (e.g.,
digoxin) by metoclopramide, whereas the rate and/or extent of
absorption of drugs from the small bowel may be increased (e.g.,
acetaminophen, tetracycline, levodopa, ethanol, cyclosporine).
Gastroparesis (gastric stasis) may be responsible for poor diabetic
control in some patients. Exogenously administered insulin may begin
to act before food has left the stomach and lead to hypoglycemia.
Because the action of metoclopramide will influence the delivery of
food to the intestines and thus the rate of absorption, insulin
dosage or timing of dosage may require adjustment.
Carcinogenesis,Mutagenesis,Impairment of Fertility
A 77-week study was conducted in rats with oral doses up to about 40
times the maximum recommended human daily dose. Metoclopramide
elevates prolactin levels and the elevation persists during chronic
administration. Tissue culture experiments indicate that
approximately one-third of human breast cancers are prolactin-
dependent in vitro, a factor of potential importance if the
prescription of metoclopramide is contemplated in a patient with
previously detected breast can-cer.Although disturbances such as
galactorrhea, amenorrhea, gynecomastia, and impotence have been
reported with pro-lactin-elevating drugs, the clinical significance
of elevated serum prolactin levels is unknown for most patients. An
increase in mammary neoplasms has been found in rodents after chronic
administration of prolactin-stimulating neuroleptic drugs and
metoclopramide. Neither clinical studies nor epidemiologic studies
conducted to date, however, have shown an association between chronic
administration of these drugs and mammary tumorigenesis;the available
evidence is too limited to be conclusive at this time.
An Ames mutagenicity test performed on metoclopramide was negative.
Pregnancy Category B
Reproduction studies performed in rats, mice and rabbits by the I.V.,
I.M., S.C., and oral routes at maximum levels ranging from 12 to 250
times the human dose have demonstrated no impairment of fertility or
significant harm to the fetus due to metoclo-pramide.There are,
however, no adequate and well-controlled studies in pregnant
women.Because animal reproduction studies are not always predictive
of human response, this drug should be used during pregnancy only if
clearly needed.
Nursing Mothers
Metoclopramide is excreted in human milk.Caution should be exercised
when metoclopramide is administered to a nursing mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been
established (see OVERDOSAGE).
Care should be exercised in administering metoclopramide to neonates
since prolonged clearance may produce excessive serum concentrations
(see CLINICAL PHARMACOLOGYPharmacokinetics).In addition, neonates
have reduced levels of NADH-cytochrome b5 reductase which, in
combination with the aforementioned pharmacokinetic factors, make
neonates more susceptible to methemoglobinemia (see OVER-DOSAGE).
The safety profile of metoclopramide in adults cannot be extrapolated
to pediatric patients. Dystonias and other extrapyramidal reactions
associated with metoclopramide are more common in the pediatric
population than in adults. (See WARNINGS and ADVERSE REACTIONS
Extrapyramidal Reactions.) Geriatric Use
Clinical studies of reglan® did not include sufficient numbers of
subjects aged 65 and over to determine whether elderly subjects
respond differently from younger subjects.
The risk of developing parkinsonian-like side effects increases with
ascending dose.Geriatric patients should receive the lowest dose of
reglan® that is effective. If parkinsonian-like symptoms develop in a
geriatric patient receiving reglan®, reglan® should generally be
discontinued before initiating any specific anti-parkinsonian agents
(see WARNINGS and DOSAGE AND ADMINISTRATION For the Relief of
Symptomatic Gastroesophageal Reflux).
The elderly may be at greater risk for tardive dyskinesia (see
WARNINGS Tardive Dyskinesia).
Sedation has been reported in reglan® users. Sedation may cause
confusion and manifest as over-sedation in the elderly (see CLINICAL
PHARMACOLOGY, PRECAUTIONS Information for Patients and ADVERSE
REACTIONS CNS Effects). reglan® is known to be substantially
excreted by the kidney, and the risk of toxic reactions to this drug
may be greater in patients with impaired renal function (see DOSAGE
AND ADMINISTRATION USE IN PATIENTS WITH RENAL OR HEPATIC
IMPAIRMENT).
For these reasons, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased renal function,
concomitant disease, or other drug therapy in the elderly (see DOSAGE
AND ADMINISTRATION For the Relief of Symptomatic Gastroesophageal
Reflux and USE IN PATIENTS WITH RENAL OR HEPATIC IMPAIRMENT). Other
Special Populations
Patients with NADH-cytochrome b5 reductase deficiency are at an
increased risk of developing methemoglobinemia and/or
sulfhemoglobinemia when metoclopramide is administered.In patients
with G6PD deficiency who experience metoclo-pramide-induced
methemoglobinemia, methylene blue treatment is not recommended (see
OVERDOSAGE).

http://www.reglan-lawsuit.com/
Reglan Lawsuit
Background Information on Reglan
Reglan (metoclopramide) is most commonly prescribed to patients
suffering from gastroesophageal reflux. The FDA has approved the
pharmaceutical for short-term use (4 to 12 weeks) and only when
conservative treatment fails.
Reglan Side Effects
In spite of the fact that the FDA has approved Reglan only for short-
term use, approximately one-third of patients are being prescribed
the medication for 12 months or longer. Long-term use can cause
serious side effects, including tardive dyskinesia, a neurological
disorder which causes involuntary movements of the tongue, mouth,
face, lips and sometimes arms, trunk or legs.
Although the labeling for Reglan and generic metoclopramide mentions
tardive dyskinesia, the labeling suggests that it rarely occurs.
Notwithstanding this statement by these drug companies, two studies
have determined the prevalence of tardive dyskinesia is between 27
percent and 29 percent in long-term users.
If you have taken this pharmaceutical for an extended period of time,
you may be at a greater risk of developing tardive dyskinesia.
About Your Health
If you or a loved one has used Reglan or metoclopramide, promptly
consult your doctor for an evaluation.
Your Legal Rights
If you have been injured by Reglan or metoclopramide, you may be
entitled to compensation.
Our firm is representing patients who have been injured by the use of
Reglan or generic metoclopramide. You should contact us to discuss
your legal rights.
Why You Should Contact Us Now
Martin & Jones has teamed with Medical Legal Consultants of
Washington (MLCW) to handle lawsuits involving Reglan. MLCW has
successfully litigated a number of claims against manufacturers and
distributors of Reglan and generic metoclopramide.
Martin & Jones has been actively involved in medical device and
pharmaceutical litigation since 1982. The firm has successfully
represented more than 1,500 individuals who were injured by either
medical devices or defective medications. We have a reputation for
taking on tough, serious cases and have successfully represented
individuals in claims against 30 of the 100 largest corporations in
America.
Medical Legal Consultants of Washington began handling drug-induced
tardive dyskinesia cases in 1985. Since that time, they have
established their reputation as one of the leading law firms in this
specialized field.
This important relationship brings together two of the national
leaders in pharmaceutical litigation. With a wealth of experience
acquired over the past three decades, Martin & Jones and Medical
Legal Consultants of Washington are committed to providing the
highest standard of representation possible for Reglan patients
throughout the country.
If you have been harmed by the use of Reglan or generic
metoclopramide, you may be entitled to compensation. You should
immediately contact an attorney experienced in Reglan litigation.
We Can Help You
Litigating against large companies, like the manufacturers and
distributors of Reglan and generic metoclopramide, can be time-
consuming, complex and expensive. Both Martin & Jones and MLCW have a
long, successful track record in such cases, and have the expertise
and resources needed to appropriately evaluate and successfully
pursue Reglan claims.
We are representing Reglan and metoclopramide victims throughout the
United States. We can help you, too, wherever you live. For more
information, please call us toll-free at 1-800-662-1234 or complete
our online contact form.
If you have taken Reglan or metoclopramide and are experiencing
health problems, please contact us for free information about your
legal rights.

http://content.health.msn.com/hw/drug_data/d03833a1?
bn=depakote&orgpath=/hw/drug_data/d03833a1&printing=true
Depakote, Depakote ER, Depakote Sprinkles
What is the most important information I should know about divalproex
sodium?
In rare cases, divalproex sodium has caused liver failure, sometimes
resulting in death. Children younger than 2 years of age, especially
those taking multiple seizure medicines, those with metabolic
diseases, those with mental retardation, and those with organic brain
disease are at the highest risk of liver failure. Notify your doctor
immediately if you develop loss of seizure control, weakness,
fatigue, swelling of the face, vomiting, or loss of appetite. These
symptoms may be early signs of liver damage.
In rare cases, divalproex sodium has also caused severe, even fatal,
cases of pancreatitis (inflammation of the pancreas). Some of the
cases have progressed rapidly from initial symptoms to death. Cases
have been reported soon after starting treatment with divalproex
sodium, as well as after several years of use. Notify your doctor
immediately if you develop nausea, vomiting, abdominal pain, or loss
of appetite. These symptoms may be early signs of pancreatitis.
Do not stop taking this medication if you have a seizure disorder,
even if you feel better. It is important to continue taking
divalproex sodium to prevent the seizures from recurring.
Do not crush, chew, or break the capsules or delayed- or extended-
release tablets (Depakote, Depakote ER). Swallow them whole.
Carry or wear a medical identification tag to let others know that
you are taking this medicine in the case of an emergency.
Divalproex sodium may interact with other drugs that cause
drowsiness, including alcohol, antidepressants, antihistamines, pain
relievers, anxiety medicines, and muscle relaxants. Dangerous
sedation, dizziness, or drowsiness may occur if divalproex sodium is
taken with alcohol or any of these medications. Talk to your doctor
before taking divalproex sodium in combination with alcohol or any
other medicines, including herbal products.
What is divalproex sodium?
Divalproex sodium affects chemicals in the body that may be involved
in causing seizures, migraines, and mania. The exact way that it
works is unknown.
Divalproex sodium is used to treat various types of seizure
disorders, to prevent migraine headaches, and to control mania
associated with bipolar disorder.
Divalproex sodium may also be used for purposes other than those
listed in this medication guide.
What should I discuss with my healthcare provider before taking
divalproex sodium?
Do not take divalproex sodium if you have liver disease or a urea
cycle disorder.
Divalproex sodium is in the FDA pregnancy category D. This means
that it is known to be harmful to an unborn baby. Malformations of
the face and head, heart, and nervous system have been reported. Do
not take divalproex sodium without first talking to your doctor if
you are pregnant or could become pregnant during treatment.
Divalproex sodium passes into breast milk and may affect a nursing
infant. Do not take divalproex sodium without first talking to your
doctor if you are breast-feeding a baby.
Children younger than 2 years of age are at an increased risk for
liver damage, especially if divalproex sodium is taken with other
seizure medicines.
How should I take divalproex sodium?
Take divalproex sodium exactly as directed by your doctor. If you do
not understand these directions, ask your pharmacist, nurse, or
doctor to explain them to you.
Take each dose with a full glass of water.
Take divalproex sodium with food if it causes stomach upset.
Do not crush, chew, or break the capsules or delayed- or extended-
release tablets (Depakote, Depakote ER). Swallow them whole.
The sprinkle capsules can either be swallowed whole or opened and
sprinkled onto some soft food such as applesauce or pudding.
Your doctor may want you to have blood tests during treatment. It is
important for your doctor to know how much medication is in your
blood and how well your liver is working.
Carry or wear a medical identification tag to let others know that
you are taking this medicine in the case of an emergency.
Do not stop taking this medication if you have a seizure disorder,
even if you feel better. It is important to continue taking
divalproex sodium to prevent the seizures from recurring.
Store divalproex sodium at room temperature away from moisture and
heat.
What happens if I miss a dose?
Take the missed dose as soon as you remember. However, if it is
almost time for the next dose, skip the dose you missed and take only
the next regularly scheduled dose. Do not take a double dose of this
medication.
What happens if I overdose?
Seek emergency medical attention.
Symptoms of a divalproex sodium overdose include unconsciousness,
sleepiness or drowsiness, faint or no heartbeat, decreased breathing,
or stopped breathing.
What should I avoid while taking divalproex sodium?
Divalproex sodium may interact with other drugs that cause
drowsiness, including alcohol, antidepressants, antihistamines, pain
relievers, anxiety medicines, and muscle relaxants. Dangerous
sedation, dizziness, or drowsiness may occur if divalproex sodium is
taken with alcohol or any of these medications. Talk to your doctor
before taking divalproex sodium in combination with alcohol or any
other medicines, including herbal products.
Use caution when driving, operating machinery, or performing other
hazardous activities. Divalproex sodium may cause dizziness or
drowsiness. If you experience dizziness or drowsiness, avoid these
activities.
What are the possible side effects of divalproex sodium?
In rare cases, divalproex sodium has caused liver failure, sometimes
resulting in death. Children younger than 2 years of age, especially
those taking multiple seizure medicines, those with metabolic
diseases, those with mental retardation, and those with organic brain
disease are at the highest risk of liver failure. Notify your doctor
immediately if you develop loss of seizure control, weakness,
fatigue, swelling of the face, vomiting, or loss of appetite. These
symptoms may be early signs of liver damage.
In rare cases, divalproex sodium has also caused severe, even fatal,
cases of pancreatitis (inflammation of the pancreas). Some of the
cases have progressed rapidly from initial symptoms to death. Cases
have been reported soon after starting treatment with divalproex
sodium, as well as after several years of use. Notify your doctor
immediately if you develop nausea, vomiting, abdominal pain, or loss
of appetite. These symptoms may be early signs of pancreatitis.
If you experience any of the following serious side effects, stop
taking divalproex sodium and seek emergency medical attention:
an allergic reaction (difficulty breathing; closing of your throat;
swelling of your lips, tongue, or face; or hives);
a rash;
unexplained lethargy (fatigue), vomiting, or changes in mental status;
unusual bleeding or bruising; or
double vision or back-and-forth movements of the eyes.
Other, less serious side effects may also occur. Continue to take
divalproex sodium and notify your doctor if you experience
tremor (shaking);
weight gain;
menstrual changes;
hair loss;
drowsiness or weakness;
depression or other psychiatric changes;
headache; or
low red blood cells (anemia).
Side effects other than those listed here may also occur. Talk to
your doctor about any side effect that seems unusual or that is
especially bothersome.
What other drugs will affect divalproex sodium?
Other drugs used to treat seizures such as phenytoin (Dilantin),
carbamazepine (Tegretol), phenobarbital (Luminal, Solfoton),
felbamate (Felbatol), lamotrigine (Lamictal), clonazepam (Klonopin),
and others may increase or decrease the effects of divalproex sodium
and may themselves have increased or decreased effectiveness. Tell
your doctor about all other medications that you are taking.
Before taking divalproex sodium, tell your doctor if you are taking
warfarin (Coumadin) or aspirin. Divalproex sodium may interact with
these medications and affect the clotting of your blood. You may
require a dosage adjustment or special monitoring during treatment if
you are taking either of these drugs.
Divalproex sodium may interact with other drugs that cause
drowsiness, including alcohol, antidepressants, antihistamines, pain
relievers, anxiety medicines, and muscle relaxants. Dangerous
sedation, dizziness, or drowsiness may occur if divalproex sodium is
taken with alcohol or any of these medications. Talk to your doctor
before taking divalproex sodium in combination with alcohol or any
other medicines.
Drugs other than those listed here may also interact with divalproex
sodium. Talk to your doctor and pharmacist before taking any
prescription or over-the-counter medicines, including herbal products.
Where can I get more information?
Your pharmacist has additional information about divalproex sodium
written for health professionals that you may read.
What does my medication look like?
Divalproex sodium is available with a prescription under the brand
name Depakote. Other brand or generic formulations may also be
available. Ask your pharmacist any questions you have about this
medication, especially if it is new to you.
Depakote 125 mg--oval, salmon-pink tablets
Depakote 250 mg--oval, peach-colored tablets
Depakote 500 mg--oval, lavender-colored tablets
Depakote Sprinkle 125 mg--blue-and-white capsules
Depakote ER 55 mg-gray tablets
Brand Names:
Depakote
Depakote ER
Depakote Sprinkles

Reminder Reminder from the Calendar of ThePancreatitisPlace
Hosted Chat - ReeAnn
Sunday May 16, 2004
7:00 pm - 9:00 pm
This event repeats every week.
The next reminder for this event will be sent in 23 hours, 3 minutes.
Event Location: AOL's TPP Chat room
Notes:
ReeAnn ~ Owner will host a chat in AOLs TPP Chat room. You will need AOL or free AIM (www.aim.com) to access this Chat room. Please email us for the link.
DeniseHallock@...
MsReeAnnBetts@...

Dear Robert And Denise
MY THOUGHTS AND PRAYRES GO OUT TO TAMMY
ONE DAY
AT A TIME
DAVE

She is awake but remebering is still a problems, please excuse as we
must be by her side. We will not be able to attend tonights panc pals
meeting.
God Bless,
Robert
Founder "All Diabetic International"

Dearest Robert,
Thank God she came out of the coma!!! She is definitely in my
thoughts and prayers today. You and Denise give each other a BIG HUG
too! (That's from me) And tell Tammy we will be praying for her and
keeping her in our thoughts!
God Bless Y'all :)
~Polly~

Hey Kimber,
This is actually my PCP that is doing this. I've always known
that his been on the "extreme" goofy side as far as doctors go, but I
knew he'd help with pain if I were to ever need it, and there's few
doctors around here that will deal with the state medicaid program.
I missed my appt. this week with the GI that sent me down to IU
Medical. Too many other things going on. hehee
Anyway.... maybe I should reschedule that just to see what "he" has
to say. Or get another opinion from some other one. How do you find
one that just specializes with Panc.?
I know the doctor that did the ERCP doesn't believe it's pancretits
b/c of the blood tests too. But his partner also said it's not
completely ruled out either. The UI GI said he would be willing to
do that procedure again, along with doing some special kind of MRCP.
Anyone know of this? I'm not sure I want to trust him again. But he
did call me to see how I was doing.
Another question too....why go through all this??? So they can
possibly give me CP dx. and THEN....I can be treated for the nausea,
pain vomiting, etc.????? and treat the pain when I need to be????? I
don't know what to do. I know that if I wouldn't have been there
alone... I might have stayed down there for the week like they
wanted me too. But how is one suppose to make that decision in the
hospital, by themselves, all drugged up???? After being awake for
most of the procedure???
I am so greatful to those from here that did call to see how I was
doing. After the shock wore off, I wondered if I was dreaming. Then
I realized.... WOW! there are some really cool people out there.
heheee ((((((huggz to ya)))))))
I honestly don't know what to do at this point. Trying to figure out
what to do with my son too. I really need him to go some where so I
can concentrate on getting my health back and wont be under so much
stress everyday. Especially with me going off of these pain meds
I've been on for the last 5 months. We are considering a Military
school, and I think he's kind of liking the idea too, so....we'll see.
I'm just trying to keep praying about it. I just know I'm very very
sick...and really....really .... tired of it all!! With the help of
my friends...and their prayers....I will get bye :o) 'Cause I'm
gonna try with a little help from my friends!! And I'll get bye with
a little help from my friends! :o)
I really do want to be off of the pain meds if I can for several
reasons, besides for the way that everyone treats you when you're on
them..... I just know that's why I was still awake during the ERCP.
Having me quit all my meds 24-48 hours prior probably put my CNS in
shock without have all those downer effect ones in my body. Heck
they give me more versaid to knock me out for an MRI than they did
for the ERCP. Oh well. Next time... if there is a next time....I
WILL BE COMPLETELY OUT!!!
I told my PCP that we all know that no test are completely
conclusive. He said yes they are. Before I went to that appt., I
wanted everyone to send me an email letting me know about the normal
blood enzyme tests yet are still dx. with pancreatitis. ...but I
didn't get a chance to write. But would still like to send all them
too him just so he knows. My regular email isn't connecting today

Hi all,
It has been a long day. My daughter slipped into a coma Thursday. I
was at the hospital all day with her. God was looking out for her and
returned her to me. I was talking to her and she came through. I was
telling her that I loved her and she said I love you to. She slowing
is remembering, Thank God!!! Please remember her in your prayers.
This is Tammy my baby daughter 21 years old.
God Bless,
Robert
Founder "All Diabetic International"

Hi Everyone!
Sorry I haven't written in so long. Well, since the ERCP procedure
probably. Things have been one constant crisis after another. I guess I've
been so overwhelmed with everything that I didn't know what all to write, or how
to even write it.
After that horrifying experience at IU Medical, my doctor has been really shitty
with me about the pain meds. He says I have no problem, it's all in my mind, I
need to go see a shrink.... LOL... I said I do! Have been for over a year on a
weekly basis!
In the meantime, I still get extremely nauseated and still have been using the
$5 a piece suppositories to shove up one end to calm down the other.
(BOY.....My mind has a wild imagination, doesn't it?!) I walk around belching
really loud.... all the time.... and the stomach gets to hurting under my ribs,
where it always has, really bad sometimes. Amongst other things.
The steroids they have me on for addisons disease is swelling my legs up so bad
that it's hard to walk. And causing other problems. The doc did put me on a
water pill and potasium. He said the lack of potasium could be causing the pain
in my legs. Although those with addisons disease aren't supposed to be on
those. Oh well. They are helping with the leg swelling today. My ankles had
been getting as big as my knees! I definitely need to find me an
endocrinologist to get that mess straightened out next.
Yesterday after going to the doctors to get the remainder of a script for pain
suckers that I didn't get filled last Friday because there was no one in the
office to call in an authorization, so I only got 10 and paid cash for
them(EXPENSIVE!!) ...and was told I could stop back in the office anytime and
get a script for the other 5.
Well....they changed their mind!! He said I need to go to a pain managment
clinic. I literally FREAKED OUT!!! Just as the nurse was telling me this, he
started walking through. I stopped him and begged him not to do this to me
right now. He said I'm sorry, I can't see any reason from the tests you've had
run that you need to be on something like this. I was breaking down
hysterically...and said "FINE....FORGET IT....I'm f*ckin' ending it ALL tonight!
I said "you have no idea what you're doing to me right now! I've been ready to
end it just because of all the stress I've been under already, and now this! I
CANT TAKE IT..... IT'S OVER!
...and then I started to walk away. He stopped me and said then let me treat
you for your nerves. I said I already am, they just put me on xanax last week.
He said that's good. I told him that he promised me ...on many occasions that
he would wean me off of this med when he wanted me to go off. That's why I
hesitated going on it in the first place. I even asked him last week if he
would take me off of it slower this time so I dont end up with so much rebound
pain and he said that'd be ok.
After some talking, he agreed to wean me off of it. He's giving me several
weeks to taper off. To drop the mcg in the pain patch down by 25 every 15 days.
Something like that. I'm on 75mcg's right now. So.... I'm not sure how this is
all going to go. I do want to be off the pain meds becuase I know they mess
with my emotions, but I've gone off enough times to know it really sucks at
first. And who knows what's going to happen as far as getting so sick again
that I start throwing up all the time and can't handle the pain. Hopefullly, I
won't have that problem and I'll learn other ways to deal with the pain.
I honestly feel like I've been having a nervous breakdown. If this isn't
one..... I hope to God I never have one. After that wonderful ERCP, 7 days
later....my 13 year old son decided to hop in my car when I was at the
chiropractors office(a week ago yesterday), and take off in it with his friend
and head to Virginia. Yep! They ran away. They drove from 2:15pm until 11pm.
They made it all the way to the Kentucky/Virginia state line. My son ended up
calling me several times to say he was sorry and I convinced him I there's no
way I'd call the cops and get him in anymore trouble. I talked him to getting a
hotel room so he wouldn't be driving through the mountains at night. Then he
called me from the hotel and he gave me the # where he was staying so I could
call him back. ...Needless to say what I did with the phone number!!!
I had to go down there over the weekend and go to court to get him on Monday.
He had to stay in a juivenille facility that weekend. Monday, we go to court
here and see what happens. I honestly never thought my son would ever do
anything like that since he doesn't even like being home by himself. But I
guess one never knows. I do know the stress had been getting too overwhelming
for him too, and I probably should have read the signs....but we all know ya
miss a lot of things when you're chronically ill.
I'm glad he's alive and back in one piece, and his dad is staying here helping
me out with him until Monday. Not sure if they're going to put him back in a
center or not. A lot of it depends on how he behaves for me. Well....That's
the story. Just wanted to let you guys know(that don't already know) why I've
been out of touch. LOL....And Out of Mind!!!! I'm very greatful that you guys
are here for me :) Thank you :)
Well...today....just trying to take it easy. One day at a time, right?! Trust
in the Lord! That's what I'm working on.
Sorry I haven't been there for you guys or kept in touch much lately. You're
all in my thoughts and prayers :)
Gentle Huggz,
~Polly~

Polly, if your doctor is treating you so badly, have you thought about
going to a different doctor? I've never been one to believe "it's all in
your head" when it comes to these problems. Is your current doctor a
pancreas specialist or just a regular GI? I highly recommend a pancreas
specialist as they usually know more about the disease then the regular
GI's do.
Kimber
--
Kimber Allen
Vallejo, CA
hominid2@...
Note: All advice given is personal opinion, not equal to that of a licensed
physician or health care professional.

Hey Robert
Some time back someone posted info on reglan, I should have
printed it out but didnt.I have a friend that has a 1yr child who has
been on reglan for 8 mon now. The baby is having alot of problems and
i dont know if thier related to the reglan or not. I know its alot of
work but if you can repost that info i can pass it on to her.
Thanks!
ONE DAY AT A TIME
Dave

Sally,
if he's not willing to learn anything new, then it's definitely time to
get a new doctor. The best doctors I know are willing to learn new
things, even things from the internet from their patients.
Kimber
--
Kimber Allen
Vallejo, CA
hominid2@...
Note: All advice given is personal opinion, not equal to that of a licensed
physician or health care professional.

http://www.keepkidshealthy.com/cgi-bin/MasterPFP.cgi
Acute Pancreatitis
Acute pancreatitis is rare in children, and although often caused by
alcohol consumption and gall stones, in children it usually occurs
with blunt trauma to the abdomen. Viruses can also cause pancreatitis
in children, including mumps and chickenpox.
Symptoms of pancreatitis include epigastric abdominal pain, fever and
persistent vomiting. The pain is usually severe.
Diagnosis of pancreatitis is by testing the blood for an elevation in
the enzymes amylase and lipase. An ultrasound and/or CT scan may show
an enlarged pancreas, abscesses or swelling. Recurrent cases of
pancreatitis may need an endoscopic retrograde
cholangiopancreatography (ERPC).
Routine treatments include intravenous fluids, medications to manage
pain, and nasogastric suction for persistent vomiting. Children
usually recover in two to four days.
Cystic fibrosis is a common cause of chronic pancreatitis in
children.
This article can be found on the web at:
http://www.keepkidshealthy.com/welcome/conditions/pancreatitis.html

http://www.med-help.net/Pancreatitis.html
Pancreatitis: Inflamation fo the pancreas. May results from edema,
necrosis, or hemorrhage. In this disorder, the enzymes normally
excreted by the pancreas attack and digest the surrounding pancreatic
tissue. Pancreatitis occurs in acute and chronic forms. Prognosis is
good when pancreatitis follows biliary tract disease but poor when it
follows alcoholism. mortality rises as high as 60% when pancreatits
is associated with necrosis and hemorrhage.
Cause: Most commonly caused by biliary tract disease and alcoholism,
pancreatitis also results from pancreatic carcinoma; certain drugs,
such as glucocorticoids and chlorothiazide. Less commonly, the
disorderresults from metabolic and endocrine disorders, vascular
disease, viral infections, or pregnancy.
Symptoms:
Epigastic pain
Vomiting
Extreme pain
Abdominal rigidity
Diminished bowel activity
Extreme malaise
Restlessness
Mottled skin
Tachycardia
Low grade fever
Cold, sweaty extremities
Treatment:
Maintain circulation and fluid volume
Relieve pain
Decreased pancreatic secretions.
Antibiotic therapy
I.V. replacement of electrolytes and proteins.

http://www.gastrojournal.org/scripts/om.dll/serve?
article=a0059901252&nav=full
Toward understanding (and management) of painful chronic pancreatitis
Painful chronic pancreatitis is poorly understood, and its management
is controversial. There is an increasing appreciation that pain
patterns differ among the types of chronic pancreatitis and may be
due to different mechanisms. Contributing to the treatment
controversy is the paucity of information about basic mechanisms
producing pain, lack of information about the character of pain, and
when to intervene with treatment and what treatment(s) to use. It is
increasingly apparent that the nature of the pain (e.g., constant vs.
intermittent and severity) confounds response to treatment. The
treatment controversy is further fueled because there are few
controlled trials.
Some differences in pain patterns among three forms of chronic
pancreatitis (early-onset idiopathic, alcoholic, and late-onset
idiopathic) are the age at onset (mean ages of 21, 45, and 55 years,
respectively) and the incidence and severity of pain.1 At the
beginning of disease, pain is present in approximately 75% of
patients with alcoholic chronic pancreatitis, 50% of patients with
late-onset idiopathic chronic pancreatitis, and all patients with
early-onset idiopathic chronic pancreatitis. Pain is less severe in
the late-onset idiopathic group. Overall, ~40% of patients with
alcoholic pancreatitis and ~60% of patients with idiopathic chronic
pancreatitis require surgery to relieve pain. The remainder can be
treated with medical, nonsurgical treatments. Pain eventually
decreases in 75% of the patients with or without surgery.
These differences in pain patterns must affect response to pain
management, but this has not been addressed adequately. In this issue
of GASTROENTEROLOGY, Amman et al.2 report the characteristics of pain
and associate them with underlying clinical causes and outcome (with
or without surgery) in 207 patients with alcoholic chronic
pancreatitis. They identified two pain patterns in their prospective
longitudinal study. All patients had short episodes of pain, usually
less than 10 days' duration, that were separated by pain-free
intervals of months to years. This pain pattern was the only pain
pattern in 44% of the patients, and none of these patients underwent
surgery for pain relief. By contrast, 56% of patients had episodes of
constant pain defined as "prolonged periods of persistent (daily)
pain ... occurring 2 or more days per week for at least 2 months."
All these patients underwent surgery, and most had a complication
(pancreatic pseudocysts or cholestasis) that was amenable to surgical
correction that induced pain relief. Sixty-six percent had a cyst(s),
and 16% had biliary obstruction. Cysts were treated by a drainage
procedure, lateral pancreaticojejunostomy, or resection. The
proportion of cysts in Ammann's series (~40%) is somewhat higher than
reported by others (~25%).1,3 The first operation occurred within 6
years of onset of disease. Thirty-four percent of patients underwent
a second surgical procedure; this was late in the course of disease,
5½ to 7 years after the first procedure, and usually done to relieve
biliary obstruction.
In contrast to other studies, only 14% of patients who underwent the
first surgical procedure did not have a correctable complication.
Another surprising finding in Ammann's series is the apparent absence
of inflammatory masses as a cause of pain. Others found that about
30% of patients with painful chronic pancreatitis have enlargement of
the pancreatic head caused by inflammation4 that is superimposed on a
background of classical findings of chronic pancreatitis.5 These
investigators claim that the inflammatory mass causes pain by
involving pancreatic nerves and producing bile duct, pancreatic duct,
or duodenal obstruction.5 Because of these findings, operations have
been devised to remove inflammatory masses.6,7 Ammann's group
performed none of these operations, and only two pancreatic head
resections (Whipple) were performed at the time of the first surgery
and two at the second.
Ammann et al. only evaluated patients with alcoholic chronic
pancreatitis who were not addicted to narcotics. Therefore, their
findings cannot be applied to patients with other forms of chronic
pancreatitis, including those with an inflammatory mass, or patients
addicted to narcotics who have other forms of chronic pancreatitis.
The number of patients in their entire series who were addicted to
narcotics was small (10 patients, ~5%), probably less than in other
studies. Further studies are needed to understand the pain
characteristics and underlying clinical causes in these groups of
patients.
Amman et al. also reinforce their previous finding8 that progression
to pain relief occurred in all patients. They also emphasize that
progression to calcification, diabetes, or exocrine insufficiency is
similar whether or not patients underwent surgery. Last, continued
alcohol abuse occurred in ~75% of operated and nonoperated patients
and was associated with higher unemployment and mortality but not
pain reduction. Thus, Amman and, in general, Lankisch et al.9 agree
that abstinence from alcohol does not affect pain, but other
advantages accrue.
All groups agree that there is an inexorable march to calcification
and exocrine and endocrine insufficiency. However, the association
between the cessation of pain and onset of calcification and exocrine
and endocrine insufficiency is controversial. Seemingly, as Amman et
al. now point out, the character of the pain is more important than
this association in predicting natural history of pain. Fifty percent
of patients with intermittent pain, without a pseudocyst or
cholestasis, had pain relief within 6 years of onset of disease and
for patients with chronic pain undergoing surgery, usually for these
complications.
Amman's study has several important clinical messages. First, many
patients with chronic pain caused by alcoholic chronic pancreatitis
who are not addicted to narcotics have complications that, if
corrected, will produce pain relief. In addition, contrary to popular
belief, in this and another series,1 ~50% of patients with chronic
alcoholic pancreatitis had pain that was managed by nonsurgical
treatment and, presumably, could be managed without endoscopic
treatments. Data from other prospective control and anecdotal
treatment studies indicate that chronic pain, as defined by Amman et
al., occurs in a minority of patients with chronic pancreatitis. For
example, in a recent multicenter trial of octreotide for painful
chronic pancreatitis,10 several centers could muster only 85 patients
over a year who met the criteria similar to Amman's. This difficulty
in accrual suggests that even in centers with an interest in
pancreatic diseases there are few patients meeting criteria of
chronic pain. In anecdotal reports of pain treatment, many treated
patients had no pain or had intermittent pain. Cremer's group11 noted
that 7 (10%) of 70 patients (25 included from an earlier study12)
undergoing extracorporeal shock wave and endoscopic removal of
pancreatic stones never had pain and 40% had only one pain attack in
the year before treatment.
Given these observations, how can we assess attempts to alleviate
pancreatic pain? Many strategies that have been applied to this
problem were recently reviewed in an AGA Medical Position Statement13
and Technical Review.3 The treatments covered in these publications
will not be discussed, except for endoscopic therapies, because they
provide a format for commentary that outlines problems in evaluating
current approaches to therapy. However, given the different patterns
of pain and perhaps different etiologies according to the type of
pancreatitis, no definite conclusions will ever be gained about
therapy without properly conducted trials.
First it is important to realize that the natural history of pain
confounds response to therapy. In Ammann's study, ~50% had
intermittent pain and had a favorable course without surgery. If
these patients had been submitted to a specific treatment
(endoscopic, surgical, pancreatic enzymes, etc.), the favorable
response would have been attributed to the therapy. For example,
there are two major endoscopic approaches: clearing stones from the
pancreatic duct and/or stenting the pancreatic duct. Interestingly,
by using the former approach, Cremer's group11 reported that the best
results (longest pain-free intervals) occurred in the patients who
had no pain or few attacks of pain before endoscopic therapy. By
performing a multivariate analysis of their data, they found that the
best predictor of a long pain-free interval was infrequent attacks of
pain before therapy. This analysis led them to state that "the best
results are obtained if endoscopic therapy is performed early," it
is "often effective for years," and "propose endoscopic management
early in the course of calcifying pancreatitis." Instead, an equally
plausible explanation of their results is that the patients
who "responded" to therapy would not have had attacks of pain
regardless of treatment.
Similarly, these investigators interpreted results of their previous
uncontrolled studies12,14 that clearing of stones from the pancreatic
produced pain relief in ~70% of patients. It is difficult to judge
the effect of treatment in these studies because up to 71% of
patients had relapsing pain and intervals between pain episodes
varied from months to years. In addition, the frequency of the
painful attacks before treatment is not stated, the mean follow-up
after treatment was short, and some patients had no or few attacks of
pain. In another retrospective study, Smits et al.15 found
that "endoscopic treatment of pancreatic stones is a valid approach
in patients with pancreatic lithiasis." However, they did not clear
stones in 11 of the 53 patients and 3 of these 11 patients (27%) had
complete symptom relief; only 4 of 11 (36%) needed surgery; and 23%
had treatment-related complications (bleeding, exacerbation of
pancreatitis, perforation, pancreatic abscess, stent clogging).
Sherman et al.16 also noted that despite failure to clear stones with
endoscopic therapy in 6 of 32 patients, these patients had less pain
after the procedure. In contrast to the authors' interpretations, the
data of Amman et al. lend support to the interpretation that in
patients with intermittent pain, the natural history of the pain
rather than treatment governs outcome and investigation of this
problem requires a control group.
Second, it is important to recognize that unproven treatments may be
associated with significant complications and are expensive. For
example, stenting the pancreatic duct, another proposed endoscopic
treatment for pain, has an overall technical success of 85%, but pain
reduction occurs in only 54% of the patients17-20 and leads to
parenchymal changes and permanent pancreatic ductal changes in a
significant number of patients.21 Smith et al.22 noted incomplete
resolution of ductal changes in 32% and no change in 5% of the
patients after a mean of 192 days and concluded that stenting of the
pancreatic duct was an experimental procedure. Of note, Cremer11
hospitalizes patients 14 ± 14 days after the initial treatment, a
very large expense. In these days of cost containment and evidence-
based medicine, expense is another reason to call for appropriately
designed prospective treatment trials for the different patterns of
pain within the forms of painful chronic pancreatitis.
The data of Amman et al. suggest that the two patterns of pain are
produced by different mechanisms. The intermittent pattern may be
produced by the underlying chronic pancreatitis, whereas chronic pain
may be caused by complications of chronic pancreatitis (pseudocysts
and biliary tract obstruction). Within this hypothesis is the idea
that the intermittent episodes of pain are triggered by activation of
the mechanisms underlying the development of chronic pancreatitis.
For example, excluding hereditary and metabolic
(hypertriglyceridemia, hypercalcemia) causes of pancreatitis, there
are probably at least two general forms of chronic pancreatitis,
early- and late-onset with different basic (? genetic) mechanisms.
Furthermore, the late-onset disease may be modified by environmental
factors such as alcohol that induce disease earlier. This hypothesis
would also explain why only a subset of alcoholics develop chronic
pancreatitisonly those with a genetic predisposition.
Additional evidence for the molecular basis of pain is the recent
discoveries of gene mutations of hereditary pancreatitis23,24 and
cystic fibrosis transmembrane conductance regulator (CFTR) gene
mutations that occur in ~20%33% of patients with idiopathic chronic
and acute recurrent pancreatitis.25,26 The findings in hereditary
pancreatitis support the general hypothesis that recurrent attacks of
pain are due to recurrent episodes of inflammation/necrosis;
intrapancreatic activation of trypsin may be responsible.
Interestingly, in preliminary reports, ~25% of patients with
recurrent pancreatitis and pancreas divisum have CFTR mutations27
compared with ~0%5% in biliary acute pancreatitis,28 chronic
pancreatitis associated with alcohol,29 and the general population.
One interpretation of these data is that alleged causes of
pancreatitis such as pancreas divisum and sphincter of Oddi
dysfunction do not cause pancreatitis, but are innocent bystanders.
Pain in these conditions may be related to underlying genetic-
cellular mechanisms rather than common anomalies. Patients with CFTR
mutations are young and likely represent a subpopulation of patients
we previously described as having early-onset idiopathic chronic
pancreatitis.
The cause of pain is uncertain. There are at least two, but not
necessarily mutually exclusive, hypotheses under investigation.
Bockman et al.5 showed that in chronic pancreatitis perineural
inflammation disrupted perineural neural sheaths and hypothesized
that the exposure of the unprotected nerves to bioactive substances
triggers pain. A second hypothesis that painful chronic pancreatitis
is caused by increased pancreatic ductal and parenchymal pressure
producing a compartment syndrome that induces ischemia is supported
by experimental studies performed by Karanjia et al.30,31 They showed
increased interstitial and perfusion pressures and decreased blood
flow in feline chronic pancreatitis.30 These abnormalities were
reversed substantially by surgical incision of the gland and draining
the pancreatic duct, but were affected minimally by stenting the
pancreatic duct.31 Thus, incision of the gland rather than ductal
drainage may be more important in relieving pain and reducing
pancreatic secretion will reduce pressure and alleviate pain. This
hypothesis forms the rationale for treatments that may reduce
pancreatic secretion such as octreotide, specific diets, and
pancreatic enzyme therapy. Whether these treatments reduce secretion
in chronic pancreatitis and effectively ameliorate pain is either
unknown or insufficiently studied.
Patients with chronic alcoholic pancreatitis undergoing pancreatic
head resection for an inflammatory mass have perineural inflammation
and, within the nerves, neurotransmitters associated with pain
transmission such as substance P and calcitonin gene-regulated
peptide.32 Immune cell infiltration and growth-associated protein
4333 also correlate with pain intensity. Discussion of pancreatic
inflammatory masses is incomplete without the admonition that
pancreatic cancer may masquerade as this lesion. There is a 2% per
decade cumulative risk for developing pancreatic cancer in chronic
pancreatitis34; in hereditary pancreatitis, the cumulative risk
approximates 40% by age 70.35
In patients without an inflammatory mass, pain may be induced by
ongoing or intermittent episodes of clinical (increased amylase
levels or imaging evidence, but no mass) or subclinical episodes of
necrosis and inflammation (without biochemical or imaging evidence)
or fibrosis. In both groups of patients, pain may be associated with
mediators of inflammation or fibrosis. For example, cytokines such as
interleukins 6 and 8 are important in acute pancreatitis,36
chemokines such as MOB-1, an -chemokine, and MCP-1, a -chemokine, and
tumor necrosis factor may be involved. Whether fibrosis by itself
produces pain is unknown, but in chronic pancreatitis the link
between fibrosis and pain likely is related to pancreatic stellate
cells. These cells are the pancreatic representatives of hepatic
stellate cells, which are involved in hepatic fibrosis.
Pancreatic stellate cells are perivascular37 and derived from vitamin
Acontaining cells that can acquire a myofibroblast phenotype.38,39
Wells and Crawford suggested in a recent editorial in
GASTROENTEROLOGY,40 that these cells, because of their contractile
potential and perivascular location, could cause microvascular
ischemia and pain. Pancreatic stellate cells are stimulated by
transforming growth factor 1 and basic fibroblast growth factor and,
to a lesser extent, platelet-derived growth factor and transforming
growth factor .38 During regeneration of the pancreas due to acute
pancreatitis and during fibrosis in chronic pancreatitis,38,41 this
stimulation produces collagen I and III, laminin, and fibronectin.
Furthermore, there is a link among the extracellular matrix,
specifically fibronectin, inflammatory cytokines,42 lipid
peroxidation,43 and activated stellate cells in experimental hepatic
fibrogenesis. If these findings are corroborated in pancreatic
fibrogenesis, there is the tantalizing possibility that in the future
treatment of painful alcoholic and "idiopathic" chronic pancreatitis
may be directed toward correcting abnormalities at the cellular level
such as modulating inflammation or fibrosis.
In summary, painful chronic pancreatitis has variable expression, and
intermittent and chronic pain are probably caused by different
mechanisms. Because intervals between attacks of intermittent pain
vary and may be a year or more, it is impossible to evaluate the
results of a treatment in these patients unless a randomized,
controlled trial is performed. Treatments such as "early endoscopic
therapy" advocated by enthusiasts for apparently minimally
symptomatic or even asymptomatic patients should not be carried out
unless we have scientific evidence that it is better than no
treatment. Trials either should be confined to one of the patterns of
pain (intermittent or constant) or patients should be stratified for
different patterns of pain.
The example of clearing the pancreatic duct of stones illustrates the
difficulty of evaluating pain relief without performing a randomized
controlled trial, mainly because many patients have relapsing pain.
This example also serves to caution against accepting unproven,
potentially dangerous therapy without scientific validation and is
applicable to all other unproven treatments. Is it time for a
moratorium on unproven treatments for painful chronic pancreatitis?
Unproven, potentially harmful and expensive treatments should only be
used in the context of a scientific clinical trial designed to prove
or disprove efficacy. It may be more appropriate to address more
fundamental reasons for pain and begin trials of novel treatments
directed toward the increasing evidence that pain is the result of
intrapancreatic inflammation/fibrosis.

http://www.aafp.org/afp/990501ap/2507.html

http://www.emedicine.com/med/topic1721.htm
Pancreatitis, Chronic
Background: The term chronic pancreatitis is commonly defined as a
continuing inflammatory disease of the pancreas, characterized by
irreversible morphological change and typically causing pain and/or
permanent loss of function. The author considers this terminology
somewhat misleading. Because lack of histology and bias toward
overreliance on imaging technology have limited the understanding of
pancreatic disease, chronic pancreatitis usually is envisioned as an
atrophic fibrotic gland with dilated ducts and calcifications. Yet,
clearly, findings on conventional imaging studies may be normal in
chronic pancreatitis, and discrepancies can be found when
sophisticated diagnostic tests compare structure and function.
In the author's opinion, viewing inflammatory diseases of the
pancreas in a manner analogous to the hepatobiliary system is more
appropriate. Similar to cirrhosis of the liver, a variety of diseases
may affect the parenchyma or ductal system to varying degrees,
eventually resulting in fibrosis of the pancreas. However, until
physicians are able to identify individual diseases, chronic
pancreatitis should be thought of as a heterogeneous group of
diseases.
Pathophysiology: Several concepts should be considered regarding the
pathophysiology of chronic pancreatitis. Alcohol is the dominant
etiologic factor and the most widely studied. Although a linear
relationship exists between the amount of alcohol ingested and the
risk of developing chronic pancreatitis, the fact that fewer than 10%
of people with alcoholism actually develop the disease is not
understood.
In the affected gland, alcohol appears to increase protein secretion
from acinar cells while decreasing fluid and bicarbonate production
from ductal epithelial cells. The resulting viscous fluid results in
proteinaceous debris becoming inspissated within the lumen, causing
ductular obstruction, upstream acinar atrophy, and fibrosis. GP2,
which is secreted from the acinar cell and homologous to a protein
involved in renal tubular casts, is an integral component of these
ductal plugs. Lithostathine (formerly pancreatic stone protein),
which also is produced by acinar cells, accounts for about 5% of
secretory protein and inhibits the growth of calcium carbonate
crystals. Abnormal lithostathine S1, whether inherited or acquired
through trypsin digestion, appears to play a role in stone formation;
it is insoluble at the neutral pH of pancreatic juice and is the
major constituent of pancreatic stones.
A competing theory suggests that the persistent demands of
metabolizing alcohol (and probably other xenobiotics, such as drugs,
tobacco smoke, environmental toxins, and pollution) causes oxidative
stress within the pancreas and may lead to cellular injury and organ
damage, especially in the setting of malnutrition. Both oxidative and
nonoxidative pathways metabolize ethanol. Alcohol dehydrogenase
oxidatively metabolizes ethanol first to acetaldehyde and then to
acetate. When the alcohol concentration increases, cytochrome P-450
2E1 is induced to meet the metabolic demands. Although these
reactions occur principally in the liver, further increases in
ethanol concentration induce pancreatic cytochrome P-450 2E1, and the
level of acetate within the pancreas begins to approach that observed
in the liver. Reactive oxygen species produced by this reaction may
overwhelm cellular defenses and damage important cellular processes.
In an effort to explain why so few people with alcoholism actually
develop chronic pancreatitis, researchers have studied genetic
polymorphisms of ethanol-oxidizing enzymes; to date, none have
correlated with a susceptibility to alcohol-induced pancreatitis.
Although nonoxidative metabolism of ethanol is a minor pathway, the
fatty acid ethyl esters produced by this reaction may cause cellular
injury and are synthesized in the pancreas to a greater extent than
in other organ systems. Whatever the etiology of chronic
pancreatitis, pancreatic fibrogenesis appears to be a typical
response to injury. This involves a complex interplay of growth
factors, cytokines, and chemokines, leading to deposition of
extracellular matrix and fibroblast proliferation. In pancreatic
injury, local expression and release of transforming growth factor
beta (TGF-beta) stimulates the growth of cells of mesenchymal origin
and enhances synthesis of extracellular matrix proteins, such as
collagens, fibronectin, and proteoglycans.
Recent evidence indicates involvement of distinct chemokines in the
initiation and perpetuation of chronic pancreatitis. In contrast to
healthy pancreatic tissues, pancreatic lobules in mild-to-moderate
chronic pancreatitis express monocyte chemotactic protein-1 (MCP-1)
messenger RNA (mRNA) in centroacinar ducts, endothelial cells,
fibroblasts, macrophages, T cells, and, occasionally, in nerves. In
more advanced disease, interleukin (IL)8 and extractable nuclear
antigen (ENA)78 mRNA is detected in centroacinar cells. Further
research is needed to understand the complexity of this area, and,
hopefully, research will lead to new treatment approaches. While
alcohol greatly influences understanding of pathophysiology,
approximately 30% of cases are idiopathic, and 10% of cases are due
to rare diseases. The pathophysiology of these will be addressed
separately.
Frequency:
In the US: Based on estimates from hospital discharge data in the
United States, approximately 87,000 cases of pancreatitis occur
annually.
Internationally: Comparing the hospital admissions data from several
cities around the globe, the overall frequency is similar. Expressed
as number of cases per 1000 hospital admissions, the value for
Marseille is 3.1, for Cape Town is 4.4, Sao Paulo is 4.9, and for
Mexico City is 4.4. When the data from several centers are compared
over time, the incidence of chronic pancreatitis from 1945-1985
appears to be increasing.
Mortality/Morbidity: No data exist on the extent of the disability
resulting from benign pancreatic diseases.
Race: Hospitalization rates for blacks are 3 times higher than for
whites in the United States.
Sex:
In population studies, males are affected more commonly than females
(6.7 versus 3.2 per 100,000 population).
Differences in the hospitalization rates of patients with chronic
pancreatitis exist with respect to sex. Rates in males peak at age 45-
54 years and then decline, and female rates reach a plateau, which
remains stable after age 35 years.
Sex differences with respect to etiology also exist. alcohol-induced
illness is more prevalent in males, idiopathic and hyperlipidemic-
induced pancreatitis is more prevalent in females, and equal sex
ratios are observed in chronic pancreatitis associated with
hereditary pancreatitis.
Age: In aggregate, the mean age at diagnosis is 46 years, plus or
minus 13 years. In idiopathic chronic pancreatitis, a bimodal age
distribution has been reported, designated as early-onset form
(median age 19.2 y) and late-onset form (median age 56.2 y).
CLINICAL Section 3 of 11
Author Information Introduction Clinical Differentials Workup
Treatment Medication Follow-up Miscellaneous Pictures Bibliography
History: For most patients with chronic pancreatitis, abdominal pain
is the presenting symptom. Either the patient's age or the etiology
of the disease has some influence on the frequency of this
presentation. Ninety-six percent of those with early-onset idiopathic
pancreatitis present with abdominal pain, compared with 77% with
alcohol-induced disease and 54% with late-onset idiopathic chronic
pancreatitis.
Clinically, the patient experiences intermittent attacks of severe
pain, often in the mid or left upper abdomen and occasionally
radiating in a bandlike fashion or localized to the mid back. The
pain may occur either after meals or independently of meals, but it
is not fleeting or transient and tends to last at least several
hours. Unfortunately, patients often are symptomatic for years before
the diagnosis is established; the average time from the onset of
symptoms until a diagnosis of chronic pancreatitis was 62months,, add
or subtract 4 months. The delay in diagnosis is even longer in people
without alcoholism, in whom the average time is 81 months from onset
of symptoms to diagnosis.
The natural history of pain in chronic pancreatitis is highly
variable. Most patients experience intermittent attacks of pain at
unpredictable intervals, while a minority of patients experience
chronic pain. In most patients, pain severity either decreases or
resolves over 5-25 years. Nevertheless, ignoring pain relief with the
expectation that the disease eventually will resolve itself is
inappropriate. In alcohol-induced disease, eventual cessation of
alcohol intake may reduce the severity of pain. Variability in the
pain pattern contributes to the delay in diagnosis and makes
determining the effect of any therapeutic intervention difficult.
Other symptoms associated with chronic pancreatitis include diarrhea
and weight loss. This may be due either to fear of eating (eg,
postprandial exacerbation of pain) or due to pancreatic exocrine
insufficiency and steatorrhea.
A small percentage of patients (7%) have painless chronic
pancreatitis and present with signs or symptoms of pancreatic
exocrine or endocrine insufficiency.
Physical:
In most instances, the standard physical examination does not help to
establish a diagnosis of chronic pancreatitis; however, a few points
are noteworthy.
During an attack, patients may assume a characteristic position in an
attempt to relieve their abdominal pain (eg, lying on the left side,
flexing the spine and drawing the knees up toward the chest).
Funduscopic examination may reveal a milky white hue in the retinal
blood vessels when hyperlipidemia is present.
Occasionally, a tender fullness or mass may be palpated in the
epigastrium, suggesting the presence of a pseudocyst or an
inflammatory mass in the abdomen. Patients with advanced disease (ie,
patients with steatorrhea) exhibit decreased subcutaneous fat,
temporal wasting, sunken supraclavicular fossa, and other physical
signs of malnutrition.
A few patients with severe, intractable pain exhibit a characteristic
mottled erythema or hyperpigmentation over their abdomens or backs;
on further questioning, these patients will reveal that they
sustained burns to the skin while applying hot water bottles, heating
pads, or electric pads over the area in an attempt to relieve pain.
Causes: Although the author believes pancreatic fibrosis (cirrhosis)
is a more appropriate term than chronic pancreatitis, parenchymal and
ductal causes have yet to be differentiated. Therefore, the
heterogeneous etiology of chronic pancreatitis will be categorized
and discussed from the viewpoint of pathogenesis.
The cause of chronic pancreatitis usually is metabolic in nature.
Excessive alcohol consumption is the most common cause, accounting
for about 60% of all cases. Because fewer than 10% of people with
alcoholism develop the disease, other factor(s) must place these
individuals at risk. Recently, a mutation in the gene encoding the
serine protease inhibitor, Kazal type 1, was identified in patients
with chronic pancreatitis. The N34S mutation was detected in 5.8% of
274 patients with alcoholic chronic pancreatitis compared to 1.0% of
people with alcoholism without pancreatitis. Although all patients
were heterozygous for the mutation, it provides evidence for
abnormalities in the pancreatic protease/protease inhibitor system
playing a role in the pathogenesis of alcoholic chronic pancreatitis.
Several inherited disorders also are considered metabolic in origin.
Hereditary pancreatitis is an autosomal dominant disorder with an 80%
penetrance, accounting for about 1% of cases. Research of families
with hereditary pancreatitis has led to the identification of several
mutations in the cationic trypsinogen gene on chromosome 7. These
mutations apparently render the activated enzyme resistant to second-
line proteolytic control mechanisms. Mutations were found in the
pancreatic secretory serine protease inhibitor Kazal type 1 (SPINK1)
gene in 18 of 96 patients with idiopathic or hereditary chronic
pancreatitis.
Cystic fibrosis, one of the most common genetic abnormalities, is an
autosomal recessive disorder accounting for a small percent of
patients with chronic pancreatitis. The cystic fibrosis transmembrane
regulator (CFTR) gene transcribes a protein important in regulating
chloride transport across cellular membranes. Several hundred
mutations of the CFTR gene have been identified, and the clinical
manifestation of any given mutation depends on how severely it
affects the protein's ability to regulate chloride transport. This
leads to clinical manifestations ranging from severe chronic
pancreatitis associated with classic pulmonary disease to chronic
pancreatitis associated with relatively normal respiratory function.
Hyperlipidemia (usually type I and type V) also may cause chronic
pancreatitis; however, it usually presents with repeated attacks of
acute pancreatitis.
Hypercalcemia due to hyperparathyroidism now is a rare cause of
chronic pancreatitis, probably because automation of serum
chemistries reveals hypercalcemia before it results in pancreatitis.
Nutritional, or tropical, chronic pancreatitis is rare in the United
States, but it is an important cause of disease in other parts of the
world.
Medications are an infrequent, or possibly underrecognized, cause of
chronic pancreatitis.
Idiopathic chronic pancreatitis, which accounts for approximately 30%
of cases, has been subdivided into early-onset and late-onset forms
arbitrarily. While the cause is not yet known, some evidence points
to atypical genetic mutations in CFTR, cationic trypsinogen, and
possibly other proteins.
Obstruction of the flow of pancreatic juice can cause chronic
pancreatitis. Obstructive forms account for less than 10% of cases
and may be congenital or acquired.
Congenital abnormalities, such as pancreas divisum and annular
pancreas divisum, are uncommon (even rare) causes of chronic
pancreatitis and usually require an additional factor to induce
chronic pancreatitis. For example, while pancreas divisum usually
does not cause chronic pancreatitis, patients with divisum and minor
papilla stenosis are at risk. In these patients, clear evidence of
disease exists in the dorsal pancreas, whereas the ventral pancreas
is normal histologically.
Acquired obstructive forms typically result from blunt abdominal
trauma or accidents involving motor vehicles, bicycles, horses, and,
on occasion, severe falls. In these cases, the pancreas is whiplashed
against the spine, causing trauma to the ductal system, resulting in
a stricture close to the surgical genu. In rare instances, chronic
inflammatory conditions affecting the duodenum, or primarily the
duodenal papilla, can induce fibrosis and papillary stenosis in a
subset of patients, leading to chronic pancreatitis.
Autoimmune pancreatitis is uncommon and accounts for less than 1% of
cases of chronic pancreatitis. Autoimmune pancreatitis may be primary
pancreatitis, which is associated with hypergammaglobulinemia,
eosinophilia, diffuse swelling of the pancreas, positive fluorescent
antinuclear antibody (FANA), anticarbonic anhydrase II, and
antilactoferrin antibodies. Secondary forms of autoimmune chronic
pancreatitis are associated with primary biliary cirrhosis, primary
sclerosing cholangitis, and Sjögren syndrome
Lab Studies:
Blood tests
Elevations of serum amylase and lipase are found only during acute
attacks of pancreatitis, usually early in the course of the disease.
In the later stages of chronic pancreatitis, atrophy of the
pancreatic parenchyma can result in serum enzyme levels within the
reference range, even during acute attacks of pain.
While low concentrations of serum trypsin are relatively specific for
advanced chronic pancreatitis, they are not sensitive enough to be
helpful in most patients with mild-to-moderate disease.
Laboratory studies to identify causative factors include serum
calcium and triglyceride levels.
When common etiologies are not found, research protocols are
available to test for genetic mutations in cationic trypsinogen and
CFTR.
Fecal tests
Because maldigestion and malabsorption do not occur until more than
90% of the pancreas has been destroyed, steatorrhea is a
manifestation of advanced chronic pancreatitis, and neither
qualitative nor quantitative fecal fat analysis can detect early
disease.
Assays of fecal chymotrypsin and human pancreatic elastase 1 have the
same limitations but are useful in confirming advanced chronic
pancreatitis with exocrine insufficiency.
Pancreatic function tests
Direct tests: These tests are the most sensitive and can be used to
detect chronic pancreatitis at its earliest stage; however, they are
somewhat invasive, labor intensive, and expensive.
Determination in duodenal aspirates: Intubation of the duodenum
usually is performed with a Dreiling tube, which allows for separate
aspiration of gastric and duodenal contents. The methodology varies
depending on the specific laboratory; however, the authors generally
use exogenous secretin with cerulein or cholecystokinin to achieve
maximal stimulation of the pancreas. The output of pancreatic
bicarbonate, protease, amylase, and lipase then is measured in the
duodenal aspirates. This test currently only is available in
specialized centers. While the greatest sensitivity can be obtained
in prolonged infusions of secretagogue to uncover a decreased
pancreatic secretory reserve, it is impractical for general clinical
use.
Determination in pancreatic juice: This test generally is performed
in conjunction with an endoscopic retrograde cholangiopancreatography
(ERCP). The pancreatic duct is freely cannulated, an exogenous
secretagogue is administered as above, and the pancreatic juice then
is aspirated out of the duct as it is produced. The output of
pancreatic bicarbonate, protease, amylase, and lipase are measured.
This test is gaining popularity because most patients undergo ERCP at
some point in their evaluation.
Indirect tests: Noninvasive tests of pancreatic function have been
developed for detecting chronic pancreatitis. In principle, these
tests work via oral administration of a complex substance that is
hydrolyzed by a specific pancreatic enzyme to release a marker
substance. The intestine absorbs the marker, which then is measured
in the serum or urine. These tests are capable of detecting moderate-
to-severe chronic pancreatitis. The presence of renal, intestinal,
and liver disease may interfere with the accuracy of these tests.
Neither currently is freely available in the United States.
Imaging Studies:
Diagnosis of chronic pancreatitis requires morphologic abnormalities
to appear on imaging procedures. Although advances in technology have
improved the ability to detect these changes, most imaging procedures
cannot depict early chronic pancreatitis because the structural
changes they rely on are associated with moderate-to-advanced disease.
Abdominal x-ray: Pancreatic calcifications, often considered
pathognomonic of chronic pancreatitis, are observed in approximately
30% of cases. Paired anteroposterior (AP) and oblique views are
preferred because the vertebral column otherwise could obscure small
flecks of calcium. The calcifications form within the ductal system
initially in the head, and later in the body and tail, of the gland.
Once considered a late complication of the disease, recent evidence
has demonstrated that calcifications may regress spontaneously over
time. Some have suggested that the disappearance of calcifications on
abdominal film is associated with the development of malignancy.
Computed tomography scan: Computed axial tomography scan has the
advantage of providing images of the pancreas of which interpretation
is relatively intuitive. Although it excels at depicting the
morphologic changes of advanced chronic pancreatitis described above,
the subtle abnormalities of early-to-moderate chronic pancreatitis
are beyond its resolution, and a normal finding on this study does
not rule out chronic pancreatitis. This study is indicated to look
for complications of the disease and is useful in planning surgical
or endoscopic intervention.
Endoscopic retrograde cholangiopancreatography: ERCP provides the
most accurate visualization of the pancreatic ductal sys