|
Question Posted November 1, 2004
What is the correct dosage for oral tramadol in dogs? Would you use it in a dog with elevated liver enzymes?
We have a couple of cases that might benefit from it- an ortho case that is on steroids and therefore can't take NSAID's for pain mgt and a Leukemia case that is becoming painful.
I know we have discussed tramadol before but I can't find any notes that I saved.
I appreciate any/all input.
Patty
Response 1
See below; but I reccommend you read the whole paper J Vet Pharmacol Ther. 2004 Aug;27(4):239-46. Pharmacokinetics of tramadol and the metabolite O-desmethyltramadol in dogs. KuKanich B, Papich MG. Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606, USA. butch_kukanich@ncsu.edu Tramadol is an analgesic and antitussive agent that is metabolized to O-desmethyltramadol (M1), which is also active. Tramadol and M1 exert their mode of action through complex interactions between opiate, adrenergic, and serotonin receptors. The pharmacokinetics of tramadol and M1 were examined following intravenous and oral tramadol administration to six healthy dogs, as well as intravenous M1 to three healthy dogs. The calculated parameters for half-life, volume of distribution, and total body clearance were 0.80 +/- 0.12 h, 3.79 +/- 0.93 L/kg, and 54.63 +/- 8.19 mL/kg/min following 4.4 mg/kg tramadol HCl administered intravenously. The systemic availability was 65 +/- 38% and half-life 1.71 +/- 0.12 h following tramadol 11 mg/kg p.o. M1 had a half-life of 1.69 +/- 0.45 and 2.18 +/- 0.55 h following intravenous and oral administration of tramadol. Following intravenous M1 administration the half-life, volume of distribution, and clearance of M1 were 0.94 +/- 0.09 h, 2.80 +/- 0.15 L/kg, and 34.93 +/- 5.53 mL/kg/min respectively. Simulated oral dosing regimens at 5 mg/kg every 6 h and 2.5 mg/kg every 4 h predict tramadol and M1 plasma concentrations consistent with analgesia in humans; however, studies are needed to establish the safety and efficacy of these doses. Sheilah Robertson
Response 2
You said any and all, so here goes :-)
I use tramadol extensively at 2-5mg/kg q12h, depending on the patient and its response. In a few cases I have gone to 2-3mg/kg q8h for short periods of time with pretty good results, base on owner replies. I definitely reach for it
in painful patients that are on corticosteroids, assuming the analgesia from
the tramadol combined with the antiinflammatory effect of the steroid will
both be beneficial.
I have used tramadol in a few patients with elevated liver enzymes, with no apparent ill effects, but I might hesitate if clinical liver disease was present.
R. L. Headley
Response 3
Greetings - I use the same dose as does Dick. Supposedly can go as high as
2-4mg/kg, but, wouldn't w/ a liver case. You may consider adding amantadine, if
chronic pain (2.2-4.4 mg/kg). Have used this combo on both dogs and cats w/
liver "issues" and djd. This combo is magical. Works great on those post-declaw
chronic limpers.
Kathy Morris-Stilwell
Response 4
The key question is whether the patient's CYP450 enzyme activity is compromised. That must not always be the case in patients with elevated liver enzymes but likely is. As the papers of Linz et al. (1981) and Wu et al. (2001) (see abstracts below) demonstratetramadol undergoes in animals extensive phase I (= CYP450) metabolism in the liver. Hence, you must assume that when this enzyme activity is decreased plasma half-lives of tramadol and its (partially active metabolites [e.g. M1]) are prolonged. Since tramadol seems to be metabolized much more rapidly in animals than in man, there are appreciable differences between man and animals in the amount of tramadol excreted unchanged in the urine (about 30% and 1% of the p.o. dose, respectively). Consequently, tramadol administration in humans with liver disease may be less problematic than in animals. Thus, it is difficult to project experiences with tramadol in human patients with hepatic disease to animals with hapatopathies. Wu WN. McKown LA. Gauthier AD. Jones WJ. Raffa RB. Institution Division of Preclinical Development, The R.W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477, USA. Title Metabolism of the analgesic drug, tramadol hydrochloride, in rat and dog. Source Xenobiotica. 31(7):423-41, 2001 Jul. Abstract 1. Metabolism of the analgesic agent, tramadol hydrochloride, was investigated after a single oral administration of 14C-tramadol to four rats (50)mgkg(-1) and two dogs (20)mg kg(-1). 2. Recovery of total radioactivity in rat and dog urine samples over 24 h was 73 and 65% of the radioactive dose, respectively. 3. Unchanged tramadol and a total of 24 metabolites, consisting of 16 Phase I metabolites and eight conjugates (seven glucuromides, one sulphate), were isolated and tentatively identified, which accounted for > 52% of the dose in urine of both species. 4. Of the metabolites, five (M1-5) were previously identified. 5. The metabolites were formed via the following six metabolic pathways: O-demethylation, N-demethylation, cyclohexyl oxidation, oxidative N-dealkylation, dehydration and conjugation. 6. Pathways 1-3 appear to be major steps, forming seven O-desmethyl/N-desmethyl and hydroxy-cyclohexyl metabolites in major quantities. 7. Pathways 1-3 in conjunction with pathway 6 produced four glucuronides along with four minor conjugates. 8. In addition, the in vitro metabolism of tramadol was conducted using rat hepatic S9 fraction in the presence of an NADPH-generating system. Unchanged tramadol (30% of the sample) plus nine metabolites, M1-7, tramadol-N-oxide (M31) and OH-cyclohexyl-M1 (M32), were profiled and tentatively identified based on MS and MS/MS data.
Lintz W. Erlacin S. Frankus E. Uragg H.
Title
[Biotransformation of tramadol in man and animal.
Source
Arzneimittel-Forschung (Drug Research) 31(11):1932-43, 1981.
Abstract
Following p.o. administration of 14C-labelled
rac.-1-(e)-(m-methoxyphenyl)-2-(e)-dimethylaminomethyl-cyclohexan-1-(a)-ol
hydrochloride (tramadol hydrochloride, CG 315, Tramal) to mice, hamsters,
rats, guinea pigs, rabbits, dogs and man the metabolic pathways were
investigated and the results compared. After synthesis of the reference
substances the metabolites were identified by co-chromatography using both
TLC (thin-layer chromatography) and HPLC (high-performance liquid
chromatography) methods, by co-crystallization and by gas
chromatography-mass spectrometry. In all species the main metabolic
pathways are N- and O-demethylation (phase I reactions) and conjugation of
O-demethylated compounds (phase II reactions). 11 metabolites are known, 5
arising by phase I reactions (M1 to M5) and 6 by phase II reactions
(glucuronides and sulfates of M1, M4 and M5). The 5 phase I metabolites are
mono-O-demethyl-tramadol (M1), mono-N-demethyl-tramadol (M2),
di-N-demethyl-tramadol (M3), tri-N,O-demethyl-tramadol (M4) and
di-N,O-demethyl-tramadol (M5). The biotransformation scheme of tramadol is
qualitatively identical in man, dog, rabbit, guinea pig, rat, hamster and
mouse. In all species M1 and M1-conjugates, M5 and M5-conjugates and M2 are
the main metabolites, whereas M3, M4 and M4-conjugates were only formed in
minor quantities. Following p.o. administration to man and animals
14C-tramadol are rapidly and almost completely absorbed. The unchanged drug
and metabolites are mainly excreted via kidneys. The cumulative renal
excretion of total radioactivity accounts for approximately 90% in man and
varies from 86 to 100% in mouse, hamster, rat, guinea pig, rabbit and dog;
the residual of the applied radioactivity appears in the feces. Apparently
tramadol is metabolized much more rapidly in animals than in man. For that
reason there are appreciable differences between man and animals in the
amount of tramadol excreted unchanged in the urine (about 30% and 1% of the
p.o. dose, respectively). After incubation with beta-glucuronidase and
arylsulfatase at least 81% of the excreted radioactivity could be extracted
from the urine of man animals (with the exception of the guinea pig and the
rabbit). In man all extractable metabolites were identified.
Bernd Driessen
Response 5
Tramadol at 2 -4or5 mg/kg plus amantadine is currently controlling intractable pain in a cauda equina syndrome pt of mine. Magical!
Sharon Jensen