Do NSAIDs such as Rimadyl make arthritis worse ?

[guest]

ASSESSING THE EFFICACY OF PERIOPERATIVE ORAL CARPROFEN AFTER CRANIAL
CRUCIATE SURGERY USING NONINVASIVE, OBJECTIVE PRESSURE PLATFORM GAIT
ANALYSIS
1: Vet Surg. 2004 May-Jun;33(3):286-92.
Horstman CL, Conzemius MG, Evans R, Gordon WJ.
Orthopedic Research Laboratory, Department of Veterinary Clinical
Sciences, Iowa State University, Ames, IA, USA. chrishorstman@yahoo.com
OBJECTIVE: To document, using pressure platform gait analysis, the
effect of perioperative oral carprofen on limb function and pain after
cranial cruciate ligament surgery in dogs. STUDY DESIGN: Blinded,
prospective clinical investigation. ANIMALS: Twenty dogs with naturally
occurring unilateral cranial cruciate disease. PROCEDURE: Physiologic
indices, subjective pain scoring, and pressure platform gait analyses
were performed before and 24, 48, and 72 hours after surgery.
Correlations were assessed between methods of evaluation and the data
was compared across treatment groups. RESULTS: No strong correlations
were noted between physiologic data, subjective scoring systems, or gait
analysis data at a walk or stance. Although average measures of limb
function were nearly twice as large in dogs treated with carprofen, no
significant differences between groups over time were identified. No
significant differences were noted in any other measure of pain or limb
function. Power analysis of peak vertical force at a walk indicated that
significant difference would have been detected had the number of dogs
in each group been increased to 35. CONCLUSION: When limb function was
assessed with pressure platform gait analysis no statistical difference
was noted between groups with respect to PVF and VI at a walk or stance,
although average ground reaction forces for dogs in the carprofen group
were greater than the traditional pain management group at all time
points. CLINICAL RELEVANCE: Oral carprofen appears to provide some
benefit for the treatment of postoperative orthopedic pain.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 15104637 [PubMed - indexed for MEDLINE]

*Notes: No significant differences between groups over time were
identified. No significant differences were noted in any other measure
of pain or limb function. When limb function was assessed with pressure
platform gait analysis no statistical difference was noted between
groups.


EFFECTS OF POSTOPERATIVE ADMINISTRATION OF KETOPROFEN OR CARPROFEN ON
SHORT- AND LONG-TERM RESULTS OF FEMORAL HEAD AND NECK EXCISION IN DOGS
1: J Am Vet Med Assoc. 2003 Oct 1;223(7):1006-12.
Grisneaux E, Dupuis J, Pibarot P, Bonneau NH, Charette B, Blais D.
Departement de Sciences Cliniques, Faculte de Medecine Veterinaire,
Universite de Montreal, Saint-Hyacinthe, QC, Canada J2S 7C6.
OBJECTIVE: To determine whether postoperative administration of
ketoprofen or carprofen had any effects on short- or long-term results
of femoral head and neck excision (FHNE) in dogs. DESIGN: Prospective
randomized controlled trial. ANIMALS: 40 client-owned, large-breed dogs
undergoing FHNE and 15 healthy large-breed dogs used as controls for hip
joint angle measurements and force plate analyses. PROCEDURE: Dogs
undergoing FHNE were treated with ketoprofen, carprofen, or a placebo
for 21 days after surgery. Hip joint abduction and extension angles were
measured at the end of surgery and 120 days later. Lameness scores were
assigned, and force plate analyses were performed on days 3, 15, and
120. RESULTS: There were no significant differences among treatment
groups in regard to hip joint angles or lameness scores. Force plate
analysis revealed that dogs in all 3 treatment groups bore consistently
less weight on the operated limb than did control dogs for the duration
of the study. Dogs receiving ketoprofen had greater peak propulsive
force at a walk on day 3 and greater peak vertical force at a walk on
day 15 than did dogs receiving the placebo. Treatment of an acute
condition and preservation of the lesser trochanter, but not
postoperative analgesic administration, were positively associated with
ground reaction forces on day 120. Owners of 12 of 31 dogs indicated
that the dog's gait worsened for a few days after discontinuation of
analgesic administration. CONCLUSIONS AND CLINICAL RELEVANCE:
Administration of ketoprofen or carprofen after surgery was not
associated with long-term results of FHNE, probably because of the
impact of other factors. Because some owners noticed worsening of the
lameness following cessation of analgesic administration in the present
study, it is possible that longer administration would have improved
long-term results.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 14552490 [PubMed - indexed for MEDLINE]

*Notes: There were no significant differences among treatment groups in
regard to hip joint angles or lameness scores.


EFFECT OF PERIOPERATIVE ORAL CARPROFEN ON POSTOPERATIVE PAIN IN DOGS
UNDERGOING SURGERY FOR STABILIZATION OF RUPTURED CRANIAL CRUCIATE
LIGAMENTS
1: Vet Ther. 2002 Winter;3(4):425-34.
Gaynor JS, Brevard S, Mallinckrodt C, Baker G, Wander K.
Department of Clinical Sciences, Colorado State University, Fort
Collins, CO 80523, USA.
A randomized, placebo-controlled, parallel study was conducted to
investigate the effectiveness of oral carprofen for the control of
postoperative pain in dogs undergoing knee surgery for stabilization of
ruptured cranial cruciate ligaments. Dogs were randomly assigned to
treatment with carprofen (n = 10) or placebo (n = 9). Pain was assessed
at 1, 2, 4, 6, 24, and 48 hours and 10 and 21 days postoperatively.
Eight of 10 dogs treated with carprofen and five of nine dogs treated
with placebo were given at least one dose of morphine as rescue therapy.
The mean relative dose of morphine given at 1 hour (P =.01) and 24 hours
(P =.02) after surgery was greater for dogs treated with carprofen than
for dogs given a placebo. There were no significant postoperative
differences in cortisol levels or any measured variable. It appears that
the scoring system used was not sensitive enough to detect differences
in pain between a known analgesic and a placebo.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 12584680 [PubMed - indexed for MEDLINE]

*Notes: There were no significant postoperative differences in cortisol
levels or any measured variable.


CLINICAL EFFICACY AND PHARMACOKINETICS OF CARPROFEN IN THE TREATMENT OF
DOGS WITH OSTEOARTHRITIS
1: Vet Rec. 2002 Jun 1;150(22):684-9.
Lipscomb VJ, AliAbadi FS, Lees P, Pead MJ, Muir P.
Department of Small Animal Medicine and Surgery, The Royal Veterinary
College, University of London, Hatfield, Herts.
Six medium to large breed dogs with osteoarthritis were treated with 2
mg/kg of racemic carprofen, mixed with their morning feed, daily for 28
days. The treatment significantly (P < 0.01) reduced their mean lameness
score, measured on a visual analogue scale, and there was a trend (P =
0.11) for the peak vertical forces exerted on a forceplate to be
increased in the most severely affected limb. The plasma
concentration-time relationships of the S(+) and R(-) enantiomers were
studied for 24 hours after the first dose and after seven days and 28
days. There were no significant differences between the mean
pharmacokinetic parameters measured on the three occasions, suggesting
that carprofen was not accumulated and that tolerance to the drug did
not develop. Although the pharmacokinetic parameters of the S(+) and
R(-) enantiomers were generally very similar, there were wide variations
both between and within dogs.
Publication Types:
Clinical Trial
PMID: 12074237 [PubMed - indexed for MEDLINE]

*Notes: The increase in peak vertical forces as measured by forceplate
analysis was not statistically significant.


ASSESSING THE EFFICACY OF PERIOPERATIVE CARPROFEN ADMINISTRATION IN
DOGS UNDERGOING SURGICAL REPAIR OF A RUPTURED CRANIAL CRUCIATE LIGAMENT
1: J Am Anim Hosp Assoc. 2000 Sep-Oct;36(5):448-55.
Comment in:
J Am Anim Hosp Assoc. 2001 Mar-Apr;37(2):115.
Reese CJ, Trotter EJ, Short CE, Erb HN, Barlow LL.
Companion Animal Hospital, Department of Clinical Sciences, College of
Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA.
Twenty-one otherwise healthy dogs that presented for surgical repair of
a ruptured cranial cruciate ligament were blindly and randomly given
either carprofen (2.2 mg/kg body weight, orally) or a placebo beginning
12 hours preoperatively and continuing every 12 hours for a total of
three doses. The patients were assessed for postoperative pain using a
subjective pain score and given oxymorphone (0.1 mg/kg body weight,
intramuscularly) every four hours if the pain score was 2 or greater.
Blood samples were also collected to determine serum cortisol levels.
There was a significant increase in serum cortisol levels in the
immediate postoperative period in both the placebo group and the
carprofen group (p less than 0.05). There was no significant difference
in the percentage of increase in serum cortisol levels between the two
groups. No correlation was evident between the serum cortisol levels and
the corresponding pain scores in either group. This subjective method of
assessing postoperative pain was not accurate and should not be relied
upon for determination of postoperative analgesic administration.
Perioperative oral administration of carprofen did not appear to be
effective in controlling postoperative pain in these patients.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 10997522 [PubMed - indexed for MEDLINE]

*Notes: There was no significant difference in the percentage of
increase in serum cortisol levels between the two groups. Perioperative
oral administration of carprofen did not appear to be effective in
controlling postoperative pain in these patients.


RANDOMIZED, CONTROLLED TRIAL OF THE EFFICACY OF CARPROFEN, A
NONSTEROIDAL ANTI-INFLAMMATORY DRUG, IN THE TREATMENT OF OSTEOARTHRITIS
IN DOGS
1: J Am Vet Med Assoc. 1995 Mar 15;206(6):807-11.
Vasseur PB, Johnson AL, Budsberg SC, Lincoln JD, Toombs JP, Whitehair
JG, Lentz EL.
Department of Surgical and Radiological Science, School of Veterinary
Medicine, University of California, Davis 95616, USA.
Seventy dogs were included in a randomized, controlled, multicenter
trial to test the efficacy of carprofen (2.2 mg/kg of body weight, PO, q
12 h) for relief of clinical signs associated with osteoarthritis.
Thirty-six dogs received carprofen, and 34 received a placebo. Response
of the dogs was evaluated by comparing results of force plate
examination and a graded lameness examination performed before and
immediately after 2 weeks of treatment, and by obtaining a subjective
assessment of the dog's posttreatment condition from owners and
participating veterinarians. A physical examination, CBC, serum
biochemical analyses, urinalysis, and fecal occult blood test were
performed before and after treatment to monitor safety. For force plate
evaluation, the odds ratio was 3.3, meaning that a dog treated with
carprofen was 3.3 times more likely to have a positive response than was
a dog treated with the placebo. For evaluation by a veterinarian, the
odds ratio was 3.5, and for owner evaluation, the odds ratio was 4.2.
Institution where dogs were treated did not have a significant effect on
results. A variety of reactions that may have been related to the
medication (placebo or carprofen) were recorded; however, none were
considered serious. Serum alanine aminotransferase activity was high in
3 dogs (2 that received placebo and 1 that received carprofen) at the
conclusion of treatment; none of the 3 dogs were clinically ill. Ten
dogs (5 that received placebo and 5 that received caprofen) had negative
pretreatment and positive posttreatment fecal occult blood test results.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 7759332 [PubMed - indexed for MEDLINE]

*Notes: This trial was reported as part of the Food and Drug
Administration Freedom of Information Summary NADA 141-053 (original)
for Rimadyl (carprofen). On day 15, the improvement rate for dogs
receiving carprofen as evaluated using force plate was not statistically
significant. In both the evaluations of the lameness scores from Day 1
to Day 15, there was no statistically significant improvement with
carprofen.

[guest]

COX-2 SELECTIVE NSAID COMMENTS

The human cox-2 inhibitors are, at this time, under the microscope. It
has become quite obvious that all is not known about the effects of
cox-2 inhibition in humans. This inquiry into the safety of cox-2
specific NSAIDs should be extended to include the cox-2 specific
veterinary NSAIDs. Much less is known about the effects of cox-2
inhibition in canines.

The veterinary cox-2 inhibitors include the mildly cox-2 selective
carprofen (Rimadyl) and meloxicam (Metacam) as well as the cox-2
selective NSAIDs of the coxib class deracoxib (Deramaxx) and firocoxib
(Previcox). (1) Firocoxib is the most cox-2 selective veterinary NSAID
approved to date. (2)

All of the concerns about human drug approval, adverse drug events, and
monitoring of the safety of cox-2 inhibitors exist and are magnified in
veterinary medicine. This is primarily due to differences in pre and
post-approval drug clinical trials, in the reporting of ADEs, in
diagnostic procedures for pets and humans, in the treatment of illness
available for pets and humans and the clients' ability to pay, and the
value placed on human life as opposed to the value of the lives of
animals. Also, the veterinarian serves a dual role as both physician and
pharmacist.

There are considerable differences between pre-approval and
post-approval clinical trials for canine NSAIDs and human NSAIDs.
Pre-approval clinical trials for veterinary drugs are small, short and
use only healthy subjects.
Almost eight years has passed since the first veterinary cox-2 inhibitor
was brought to market. We now have at least 4 cox-2 inhibitors. Still,
no good information exists as to dog breed differences in metabolism,
effects on aged or unhealthy dogs, concomitant drug use, and
consequences of long term use. Nevertheless, these drugs are commonly
dispensed to dogs of all breeds, all ages, and in varying states of
health, often for chronic, daily, long term use.

While it is sometimes the case that problems with human drugs are not
identified until the drug is brought to market and used by extremely
large numbers of people, this is always the case with veterinary drugs
due to their very limited and small trials. According to veterinary
clinical pharmacologist Dawn Boothe: "Prelicensing and other
experimental studies focus on dose-dependent effects and target a
relatively small test population. It is not until a drug is placed in
widespread clinical use that we see the idiosyncratic and other more
subtle toxicities that are potentially serious." (3)

One of the problems in identifying Vioxx as a possible contributor to
heart attack and stroke in humans was that these events commonly occur
in the general population. Many cox-2 inhibitor adverse reactions in
dogs may be being passed off as common occurrences of old age. Only
through huge long-running post-approval clinical trials was the possible
connection between Vioxx and heart problems discovered. These types of
trials are not conducted with veterinary drugs.
Intensive monitoring within hospitals and analysis of health registers
post drug approval is uncommon in veterinary medicine. (24)

There are also differences in the reporting of adverse drug events
(ADEs) between veterinary and human drugs. It has been estimated that
only about 1/10 of dog adverse reactions to medication are reported as
compared to reporting of human adverse reactions. Veterinary clinical
pharmacologist Mark Papich states that "the true incidence of adverse
drug effects in domestic animals is not known because most are not
reported". (17)

In addition, major differences exist in diagnostic procedures for
canines and humans. For example, while it is extremely common for
physicians to diagnose heart attacks and strokes, it is uncommon for
veterinarians to do so. Most veterinarians do not order MRIs or CT scans
that are very common diagnostic tools for humans, and many veterinary
clients could not pay for them anyway. According to FDA CVM: "Additional
limitations in veterinary pharmacovigilance include the cost and
availability of diagnostic tests and the lack of comprehensive
postmortem information". (21)

Humans survive many cox-2 inhibitor related adverse reactions due to
their ability to voice discomfort and to obtain medical treatment which
is most often paid for by insurance benefits.
For example, a human can voice stomach discomfort to his physician while
a dog obviously cannot, and according to veterinary clinical
pharmacologist Dawn Boothe: "Unfortunately, there is no sensitive
indicator of gastrointestinal bleeding in dogs and damage may be quite
extensive before signs are evident." (16) Therefore even the most common
NSAID side effect of gastrointestinal damage is likely to be quite
serious in canines. Many dogs who experience gastrointestinal damage,
kidney failure, or liver toxicity from cox-2 inhibitors are euthanized
because their owners cannot travel, many times out of state, to an
advanced veterinary medical care facility for necessary diagnostics, nor
pay for extended intensive medical treatment. Additionally, many
treatments available to humans are still investigational for pets.

Great value is placed upon human life while animals are still generally
legally considered property. Therefore physicians are subject to much
liability whenever drugs are used improperly while veterinarians are
subject to virtually none.

Finally, while in human medicine there exists the pharmacist to provide
drug information and answer specific consumer questions about product
use, no such intermediary exists in veterinary medicine.

A brief summary of a few of the highlights of the history of the
veterinary cox-2 inhibitor Rimadyl will serve to illustrate most of the
above. In short term clinical trials for Rimadyl, the number of reports
of adverse reactions were minimal. Most commonly reported were vomiting,
lethargy, and appetite change. While an increase in serum activity of
ALT was the most frequently reported clinicopathologic change,
investigators did not relate any clinical signs to the elevations in
ALT. It was reported that clinicopathologic abnormalities and mild
adverse effects were the same for the carprofen group and the placebo
control group. (4)(5) According to the FDA CVM, based on studies that
were submitted for the drug approval process, "the risk of Rimadyl was
thought to be negligible". (6).

Rimadyl hit the market in 1997 and was directly advertised to consumers
through television commercials (featuring the recovery of old dogs from
lameness) as well as full-page magazine ads, print stories, and radio
reports. Consequently, it was widely used very quickly. By 1999 the CVM
estimated that Rimadyl had been given to 2.5 million dogs. (6)

A brief chronology of select Rimadyl post-approval events 1997 to 2002:

May 1997 - CVM asked Pfizer to change the adverse drug reaction section
of the label due to ADE reports received and asked Pfizer to send a
"Dear Doctor" letter to veterinarians about Rimadyl's adverse effects.
(6)

September 1997 - An extensive adverse reaction section was included in
Rimadyl labeling. The existing possibility of a fatal outcome was
included. (6)

1998 - 39% (no. 3626) of ALL ADE reports received by FDA CVM involved
Rimadyl. About 13% involved death of the dog. (6)

April 28, 1999 - Dog owner Bob Sinclair spoke about Rimadyl and animal
drug issues at the FDA Stakeholders meeting in Overland Park, Kansas.
(22) (23)

Spring 1999 - Death was added to the adverse reactions section of the
Rimadyl label. (6)

June 24, 1999 - Concerned consumers met with Pfizer officials and were
presented with an advance proof print of a new Rimadyl Consumer
Information Page. (7)

October 1999 - Jean Townsend of Johns Island, South Carolina brought a
class action lawsuit against Pfizer alleging that neither she nor her
vet were adequately warned of the possible adverse consequences of
Rimadyl use. (8)

December 1, 1999 - The FDA CVM issued a Rimadyl Update. CVM stated that
dog owners who had reported ADEs directly to the agency said they were
not aware of any potential Rimadyl adverse effects. CVM advised: "As a
NSAID with potentially serious side effects, however, the use of Rimadyl
should be carefully considered before being incorporated in any
therapeutic plan. Moreover, dog owners should have an active role in
making that decision." (6)

March 9, 2000 - Another "Dear Doctor" letter was sent by Pfizer to
veterinarians. Among other things, this letter informed veterinarians of
an Owner Information Sheet to be attached, along with the product
insert, to each bottle of Rimadyl Caplets and Rimadyl Chewable Tablets.
Veterinarians were also informed that new bottles of Rimadyl would be
offered in 2 week, 1 month, and 3 month supplies so that vets would be
able to dispense full bottles with the drug information attached. In
addition Pfizer stated: "Pfizer, in conjunction with the FDA CVM,
encourages veterinarians to provide owners with information about both
risks and benefits associated with all potential therapeutic options."
(9)

December 13, 2002 - Pfizer was asked by the Division of Surveillance FDA
CVM to immediately stop dissemination of certain promotional materials
judged to be misleading. (10)

Currently, the Rimadyl label includes the following adverse reactions
based on voluntary post-approval drug reporting, listed in decreasing
order of frequency by body system:
Gastrointestinal: Vomiting, diarrhea, constipation, inappetence, melena,
hematemesis, gastrointestinal ulceration, gastrointestinal bleeding,
pancreatitis.
Hepatic: Inappetence, vomiting, jaundice, acute hepatic toxicity,
hepatic enzyme elevation, abnormal liver function test(s),
hyperbilirubinemia, bilirubinuria, hypoalbuminemia.
Approximately one-fourth of hepatic reports were in Labrador Retrievers.
Neurologic: Ataxia, paresis, paralysis, seizures, vestibular signs,
disorientation.
Urinary: Hematuria, polyuria, polydipsia, urinary incontinence, urinary
tract infection, azotemia, acute renal failure, tubular abnormalities
including acute tubular necrosis, renal tubular acidosis, glucosuria.
Behavioral: Sedation, lethargy, hyperactivity, restlessness,
aggressiveness.
Hematologic: Immune-mediated hemolytic anemia, immune-mediated
thrombocytopenia, blood loss anemia, epistaxis.
Dermatologic: Pruritus, increased shedding, alopecia, pyotraumatic moist
dermatitis (hot spots), necrotizing panniculitis/vasculitis, ventral
ecchymosis.
Immunologic or hypersensitivity: Facial swelling, hives, erythema.
In rare situations, death has been associated with some of the adverse
reactions listed above. (11)

This is quite an extensive list for a drug whose risk was thought to be
negligible based on pre-approval trials. As of January 3, 2005, the
cumulative total of Rimadyl possible ADE reports as posted on the CVM
website was 12,919. 2,349 involved death of the dog. (12)

Problems continue to surround the use of Rimadyl and the other
veterinary cox-2 inhibitors. A two year review of the consumer messages
to the FDA CVM hotline which appeared in JAVMA News on January 15, 2004
revealed the following:
"Frequent comments from pet owners who contact the CVM hotline include
these:
* They did not receive a client information sheet when one was available
for a drug that was prescribed for their pet.
* The medication they received from their veterinarian was not dispensed
in the CVM-approved container but was broken into aliquots that were
taken home without the client information sheet or approved label.
* The veterinarian did not conduct or recommend blood testing before and
after prescribing the drug, even though baseline testing and/or periodic
monitoring was recommended on the label. Common examples include
heartworm products and nonsteroidal, anti-inflammatory drugs.
* After reading client information sheets and labels on the Internet
about a drug prescribed for their pet, they discovered that their pet
may have fallen into a category of animal for which a precaution or
contraindication existed."
Article author Dr. Victoria Hampshire of the FDA CVM reminded
practitioners that, "Drugs that come with client information sheets are
intended to be dispensed in the manufacturer's container, with the
sheets accompanying the prescription." (13)

The almost uniform failure of veterinarians to provide the Client
Information Sheets for the veterinary cox-2 inhibitors led to the
publishing of two additional articles by FDA CVM in 2004 bringing this
to the attention of the veterinary community. In a FDA Veterinarian
article "Adverse Drug Experience Reports Lead to Label Changes, Other
Actions for Safer Animal Drugs", Dr. Thomas Moskal advised veterinarians
to communicate risk information for NSAIDs to clients and to be sure
that the dog owner receives the Client Information Sheet. (14) In the
article "Minimizing the risk factors of the veterinary NSAIDs" which
appeared in JAVMA News April 15, 2004 Dr. Moskal stated: "Drug risk
information is communicated to veterinary practitioners and to the
public through the product labeling...Drugs that come with Client
Information Sheets are intended to be dispensed to clients with the
Client Information Sheet accompanying the prescription." (15)

Companion animals cannot verbally notify owners when they are
experiencing an adverse reaction to a cox-2 inhibitor. The pet owner who
sees the dog every day must detect any problems, but can only do so if
he or she knows what to watch for.
Veterinarians have failed in their role as physician by failing to
obtain informed consent when prescribing NSAIDs, and they have failed in
their role as pharmacists by not providing adequate consumer drug
information. Dogs have become family members in most households, and are
cared for as such. Dog owners should not be left reeling in shock and
burdened by extreme guilt when their beloved canine companion suffers or
dies from the use of a cox-2 inhibitor, because THEY HAD NO IDEA.

The FDA should not only request, but must enforce, that the FDA
recommended and approved Client Information Sheets currently existing
for the veterinary NSAIDs be given to pet owners. Pet owners are
currently seeking legislation state by state mandating full disclosure
of the risks of veterinary drugs such as the cox-2 inhibitors. They
should not have to do so. The existing Medication Guide Rule which
enforces the providing of FDA prepared Medication Guides for certain
human drugs should be amended to include veterinary drugs with FDA
mandated and approved Client Information Sheets, or a Veterinary
Medication Guide Rule should be implemented.

In addition, the current labels and Client Information Sheets for all of
the veterinary NSAIDs should be posted on the FDA website, so that
individuals seeking information on the internet do not have to wade
through annals of promotional materials at the drug company websites to
find FDA approved documents. Currently, the only US information for
firocoxib (Previcox) available on the internet at this time is the
Freedom of Information Summary (18), which contains a paucity of
information. Neither the Previcox label nor the Client Information Sheet
may be accessed at the FDA website or elsewhere. A consumer must file a
formal, written FOI request and pay a fee to obtain the Previcox label
and CIS. (25) Also, consumers should be able to view the causality
assessment scores for veterinary NSAID ADE data posted on the FDA CVM
website.

Of the cox-2 selective veterinary NSAIDs carprofen (Rimadyl), meloxicam
(Metacam), deracoxib (Deramaxx), and firocoxib (Previcox), the most is
currently known about carprofen, and therefore I have focused on its
history in this discussion. The other three drugs are much less well
known because they are much newer drugs.

The coxib Deramaxx, approved August 21, 2002, is thus far responsible
for 2400 possible ADEs. 550 involved death of the dog. (12) No data for
the coxib Previcox, approved July 21, 2004 (18) has been posted on the
FDA CVM website to date. (12) Previcox is the more extreme cox-2
inhibitor. In in vitro canine whole blood assays, Previcox exhibits
approximately 380-fold selectivity for cox-2 over cox-1. (2) Deramaxx is
structurally related to Celebrex, while Previcox is structurally related
to Vioxx. (26)

Current evidence suggests that cox-2 is produced constitutively in the
brain, spinal cord, kidney, ovary, uterus, placenta, thymus, bone,
cartilage, synovia, endothelia, prostrate, and lung. (27)
It is responsible for homeostatic mechanisms in the body and plays an
important part in healing. (16) More research is needed regarding the
safety of currently available cox-2 inhibitors on the kidney and other
organs. According to veterinary clinical pharmacologist Mark Papich:
"Some of the prostaglandins that play an important role in salt and
water regulation and hemodynamics in the kidney are synthesized by cox-2
enzymes." (19) Prostaglandins mediated by cox-2 are induced when
gastrointestinal erosion occurs. Veterinary clinical pharmacologist Dawn
Boothe states that "cox-2 appears to be the isoform mediating repair of
damaged tissues with expression being greatest within the first 10 days
of damage". (16)

A study released January 17, 2005 found that when mice that are
genetically prone to hardening of the arteries were treated with a cox-2
inhibitor, their condition worsened. (20) Several studies have linked
the human cox-2 inhibitor Vioxx to increased risk of heart attack and
stroke. There is concern regarding this with the cox-2 inhibitors
Celebrex and Bextra. Indeed, this is the reason the current meetings are
taking place. There is no evidence that this is not a concern in dogs,
only evidence that such is much less likely to be detected through the
voluntary ADE reporting system, for reasons already mentioned in these
comments.
In light of the history of carprofen and the current concerns about
extreme cox-2 inhibition in humans as well as in animals, one wonders
why the extreme cox-2 inhibitor firocoxib (Previcox) was approved as
recently as July 2004.

A panel should be convened to discuss the safety of the veterinary
NSAIDs and how to improve the current circumstances. This panel should
include consumer representatives. Much human suffering is also
associated with the sickness and loss of beloved canine companions.

Thank you for considering these comments.

References

(1) Papich, Mark. Nonsteroidal Anti-Inflammatory Drugs. Antech
Diagnostics News, January 2005.
http://www.antechdiagnostics.com/client ... n05_01.htm.
(2) http://www.emea.eu.int/vetdocs/PDFs/EPA ... 04.en6.pdf
(3) Boothe, Dawn M. Clinical Perspectives on Current and Future Options
in Canine NSAID Therapy. Advances No. 3, Pfizer Animal Health -
Practical information about the art, science, and research of veterinary
medicine. May 2002.
(4) Holtsinger RH, Parker RB, Bealse BS, et al. The therapeutic efficacy
of carprofen (Rimadyl) in 209 clinical cases of canine degenerative
joint disease. Vet Comp Orthop Traumatol 1995; 5: 140-144.
(5) Vasseur PB, Johnson AL, Budsberg SC, et al. Randomized controlled
trial of the efficacy of carprofen, a nonsteroidal anti-inflammatory
drug, in the treatment of osteoarthritis in dogs. J Am Vet Med Assoc
1995; 206: 807-811.
(6) CVM Update. http://www.fda.gov/cvm/index/updates/rimadyl2.html
(7) http://www.escribe.com/pets/doghealth2/m423.html
(8) http://www.hometown.aol.com/sn1154/rim1.html
(9)
http://www.fda.gov/cvm/index/safety/4045.pdf
(10)
http://www.fda.gov/cvm/index/regulatory/w121302pz.pdf
(11)
http://www.rimadyl.com/PAHimages/compli ... liance.pdf
(12) http://www.fda.gov/cvm/index/ade/ade_cum.htm
(13) Hampshire, Victoria. Emerging issues regarding informed consent.
JAVMA News, 01/15/04.
(14) Moskal, Thomas J. Adverse Drug Experience Reports Lead to Label
Changes, Other Actions for Safer Animal Drugs. FDA Veterinarian,
March/April 2004. http://www.fda.gov/cvm/index/fdavet/fdavettoc.html
(15) Moskal, Thomas J. Minimizing the risk factors associated with
veterinary NSAIDs FDA-CVM offers suggestions based on postmarketing
experience. JAVMA News, April 15, 2004.
http://avma.org/onlnews/javma/apr04/040415g.asp
(16) Boothe, Dawn. The new nonsteroidal anti-inflammatory drugs. The
Central Veterinary Conference, Aug. 2004.
(17) Papich Mark. Adverse drug reactions of clinical significance. The
Central Veterinary Conference, Aug. 28-31, 2003.
(18) http://www.fda.gov/cvm/efoi/section2/141-230.pdf
(19) Papich, Mark. Anti-inflammatory drugs: how to sort out the choices.
The Central Veterinary Conference, Aug. 28-31, 2003.
(20)
http://sfgate.com/cgi-bin/article.cgi?f ... AS4VO1.DTL
(21)
http://www.fda.gov/cvm/index/vmac/CVMFo ... cument.pdf
(22)
http://www.escribe.com/pets/doghealth2/m19225.html
(23)
http://www.fda.gov/ohrms/dockets/docket ... r00003.txt
(24) Maddison, Jill. Adverse Drug Reactions. Ettinger's Textbook of
Veterinary Internal Medicine Fifth Edition, Vol. 1. Pennsylvania,
Saunders, 2000.
(25) Personal correspondence with Linda Grassie, FDA CVM.
(26)
http://www.terrabase-inc.com/cox-inhibitors.html
(27) Dowling, Patricia. Nonsteroidal Anti-Inflammatory Drugs. The
Central Veterinary Conference, Aug. 2004.

[guest]

Here's what it says in the 'New and unusual causes of acute renal failure in dogs and cats' chapter in the 2004 Vet Clinics Issue on Nephrology: 'Dogs are probably more susceptible to renal damage and ARF caused by NSAIDs or COX-2 inhibitors than are people because of differences in renal anatomy, distribution of COX-2 in renal tissues, and expression of COX-2 in volume-depleted states. Species with unipapillary kidneys, such as dogs, are more sensitive to NSAID-induced renal toxicity than are people, who are a multipapillary species. There are also species differences in renal medullary distribution of COX-1 and COX-2. The papillary tip has comparatively low renal oxygen tension, so it is more susceptible to injury than other parts of the kidney. Dogs exhibit one or both COX isoforms in the papillary interstitial cells, which are a rich source of prostaglandins. Interstitial cells are the first cell type to undergo renal papillary necrosis caused by NSAIDs and are proably the most susceptible cell in the renal papilla because of their expression of COX isoforms...Contstitutive expression of COX-2 at several sites in dogs indicates that this isoform is involved in regulation of normal renal functions in these species, and is also indicated by its upregulation in volume-depleted dogs. COX-2 may also play an important role in amintaining renal blood flow in volume-depleted dogs...Normal healthy dogs given carprofen or ketoprofen had a significant decrease in serum creatinine clearance for the 24-hr period from 24 to 48 hours after drug administration compared with control dogs (Forsyth SF, Guilford WG, Pefeiffer DU: 'Effect of NSAID administration on creatinine clearnace in healthy dogs undergoing anesthesia and surgery.' JSAP 2000;41(12)547-50).

One could argue that there isn't a safer NSAID to administer to a dog pre-op. I think we get away with it in young spays/declaws because they have lots of nephrons. I think when we have a mored aged animal with potential hypotension during the procedure, then we interfere with the COX-2 function and autoregulation of the kidneys' blood pressure via prostaglandin inhibition, we can have problems. I'd vote for avoiding NSAIDs at all pre-op--use something else like narcotics or tramadol or ketamine to induce followed by an MLK drip, etc.

[guest]

http://www.newschannel6.tv/news/default ... ws&id=7358

Class Action Lawsuit Against Pfizer Over Drug
Friday, March 18, 2005


Thousands of pet owners across the country claim the popular K-9 drug Rimadyl killed their pets and a Longview Attorney has filled suit.
Kelly Heitkamp is filling a class action suit against Pfizer, the maker of the drug that is used as a pain reliever for dogs but can cause serious side effects.
The Food and Drug Administration has received more than 12-thousand complaints.
Heitkamp says in more than 23-hundred of those cases, the dogs died.
Pfizer is also the maker of Celebrex, which has taken a lot heat from the FDA about the increased chances of heart problems among its users.

[guest]

Superiority of the gastroduodenal safety profile of licofelone over rofecoxib, a COX-2 selective inhibitor, in dogs.
J Vet Pharmacol Ther 28[1]:81-6 2005 Feb

Moreau M, Daminet S, Martel-Pelletier J, Fernandes J, Pelletier JP
The Companion Animal Research Group, Faculty of Veterinary Medicine, University of Montreal, St Hyacinthe, QC, Canada.
This study assessed the gastroduodenal safety profile of licofelone, a new nonsteroidal anti-inflammatory drug with dual inhibitory activity against 5-lipoxygenase and cyclo-oxygenase (COX), by using endoscopic evaluations and by comparing licofelone to rofecoxib, a selective COX-2 inhibitor. Twenty-one dogs underwent blinded gastroduodenoscopies, during which the mucosa of the gastroduodenal tract was assessed and scored. Blood analyses were monitored on days 0 (baseline), 14, 28, 42, and 56. Examinations to detect fecal occult blood were performed daily. Dogs were randomly assigned to three groups that received either a placebo, licofelone at a dose of 2.5 mg/kg twice daily, or rofecoxib at a dose of 0.5 mg/kg daily, respectively. Significant differences between the groups in gastric (P = 0.003), duodenal (P = 0.009), and gastroduodenal (P = 0.002) endoscopic lesion scores were observed at day 56. Rofecoxib-treated dogs had more lesions in all areas when compared with placebo-treated dogs, more duodenal lesions when compared with licofelone-treated dogs and more lesions than they had at baseline. In contrast to licofelone, rofecoxib was found to induce significant gastric and gastroduodenal lesions in dogs that lacked pre-existing lesions at baseline. Blood analyses and fecal examinations did not reveal abnormalities in any of the experimental groups. Treatment with licofelone was well tolerated and was shown to be safer than rofecoxib in terms of upper gastrointestinal damage. In this way, this study demonstrates the gastroduodenal safety profile of licofelone for chronic treatment.

[Guest]

[guest]

From today's Chicago Tribune:

http://www.chicagotribune.com/features/health/
chi-0512130248dec13,1,1552035.story

I'm including the entire column since not everyone is able to access
the Trib's site.



Trial and error

With some drug researchers hiding crucial data in clinical trials,
there is a way to get better science on drug safety

Merrill Goozner

December 13, 2005

The specter of researchers hiding damaging data when drug companies
financed their clinical trials is once again haunting the medical
publishing establishment. Last week, the editors of the New England
Journal of Medicine accused Merck-funded researchers of not reporting
three deaths in the trial that led to the approval of Vioxx, the pain
reliever subsequently pulled from the market because it caused heart
attacks in some patients.

Medical editors are once again scrambling for better ways to manage
these conflicts of interest. The editors of the Journal of the
American Medical Association have taken the extraordinary step of
requiring every industry-funded researcher who submits a study based
on a clinical trial to hire an independent statistician to analyze
the data. They also demanded that the principal investigator vouch
for the integrity of the data and the accuracy of the data analysis--
an approach that's comparable to what corporate accountants now face
in the wake of the Enron Corp. scandal.

Unfortunately, piling new disclosure rules on medical researchers
will not address the core problem. When industry has exclusive
control over studies of its new drugs and medical devices, the most
important questions usually do not get asked.

Most trials aimed at gaining Food and Drug Administration approval
for a new product compare it to a placebo. Instead of asking whether
it is better than what is already out there, they ask if it is better
than nothing. As often as not, it is. In some cases the clinical
trial protocol designed by industry-funded researchers compares the
new drug to a rival drug but at doses designed to put it in the best
light. That was the case with Vioxx, whose original trial compared it
to high doses of naproxen to show that it caused less stomach
distress. When the data showed Vioxx patients with four (now five)
times more heart attacks, the Merck-funded researchers waved off that
red flag by claiming naproxen probably was cardio-protective.

Merck defended its study last week by saying all the data had been
turned over to the FDA, which still approved the drug. And in that
sense, the company was right. The original study never tested enough
people to definitively prove the drug caused heart problems--or,
conversely, to show that it was safe.

Less than a year after the original trial was published,
cardiologists at the Cleveland Clinic published an analysis
questioning the safety of not only Vioxx, but the entire class of so-
called Cox-2 inhibitors (Celebrex and Bextra are the other two
approved drugs in the class). They called for a major new trial large
enough to test that hypothesis. That trial was never done. Instead,
industry funded hundreds of studies testing the Cox-2s for every
imaginable ache and pain, which appeared in every conceivable medical
specialty journal as part of the drug companies' overall marketing
campaign.

The way to get better science in front of regulators and physicians
(who rely on the medical literature) is to have an independent body
take control of FDA registration trials. The drug and medical device
industries already pay user fees to the FDA to hasten reviews of
their new product applications. The user fee law is up for renewal
next year. Why not expand those fees to include paying the government
to conduct the final product registration trials?

It could be done through a new institute in the National Institutes
of Health, which could contract with investigators at universities,
independent research institutes, or the private firms that have
sprung up in recent years to conduct clinical trials. The most
important thing is that the trials be designed to answer the right
questions--is the new product truly safe and how does its
effectiveness compare to what's already out there. Regulators are
facing tougher and tougher calls on drug safety. The government next
year begins paying a large share of the nation's drug tab through
insurance companies, which will influence which drugs seniors buy
through their co-pays. Americans will be better off if those
decisions are not based on information provided by a medical
literature written by researchers in industry's back pocket.

----------

Merrill Goozner, author of "The $800 Million Pill," directs the
Integrity in Science project at the Center for Science in the Public
Interest.