Therapeutic Review

Therapeutic Review

Tramadol

Debbie Myers, DVM

T

ramadol is an opioid that has been used for
the past two decades to manage pain in hu-
mans. This drug is a synthetic analog of co-

deine and is not currently classified as a con-
trolled substance.

1

Tramadol follows a two-compart-

ment model with one distribution phase and one
elimination phase.

1

The first mode of tramadol an-

esthesia is as an opioid that has moderate affinity at
mu (

␮) receptors and weaker affinity for delta (␦)

and kappa (

␬) receptors. The second way tramadol

inhibits pain is via the drug’s influence on the de-
scending pain inhibitory systems. Tramadol influ-
ences these systems by preventing reuptake and en-
hancing the release of serotonin and norepineph-
rine. Both of these neurotransmitters inhibit the
transmission of painful stimuli. The dose required to
inhibit neurotransmitter reuptake and cause opioid
receptor analgesia is the same.

Tramadol has good tissue affinity and the ability to

cross the blood-brain barrier and placental barrier.

2-5

This drug has been found to produce numerous pos-
itive responses in vertebrates, including analgesia for
moderate to severe pain; antitussive,

2

antidepressant,

6,7

anti-inflammatory,

3

and immunostimulatory effects;

5

micturition control;

8,9

an ability to lower glucose in

diabetics;

10

the reduction of the minimum alveolar

concentration of isoflurane necessary to maintain an-
esthesia;

11,12

and local anesthetic effects.

3

Tramadol is primarily metabolized by the cyto-

chrome P-450 enzyme system in the liver, where it
undergoes biotransformation to its many metabo-
lites.

3,5

During oral administration, 90% of tramadol

is excreted by the kidneys and the remaining 10% is
excreted via the feces.

3

The excretion of tramadol

may be decreased in patients with renal compro-
mise; however, tramadol does not decrease renal
blood flow and is considered safe for the kid-
neys.

3,5,13

Tramadol is primarily administered orally,

but can be given subcutaneously, intravenously, rec-
tally, or intramuscularly.

3,5

In humans, tramadol is rapidly and almost com-

pletely absorbed after oral administration, and ap-
proximately 70% of the drug is bioavailable. In a

rodent model, tramadol was found to be well distrib-
uted into the lungs, spleen, liver, kidney, and brain.

5

After multiple doses per day, bioavailability increases
to about 90% to 100%. It has been suggested that
this increased bioavailability is attributed to first-pass
liver metabolism. Similar results, with minor differ-
ences, have been reported when the drug is admin-
istered via the parenteral routes.

3,5

In humans, oral

and intravenous tramadol at 2 mg/kg provides anal-
gesia superior to that of a placebo, with peak anal-
gesia at 3 hours and a total effect lasting 6 hours.

5

Approximately 30% of the analgesic effect of tram-
adol in humans can be reversed with naloxone be-
cause of the drug’s dual modalities of pain relief
(opioid receptor binding, serotonin/norepineph-
rine reuptake inhibition).

5,14

Tramadol does not appear to cause the significant

adverse effects common to opioids, including respi-
ratory depression, constipation, or sedation. How-
ever, one study evaluating tramadol usage in cats
(1-4 mg/kg) did find a dose-dependent depressant
effect on ventilation and an increase in the apneic
threshold.

15

Naloxone was found to completely re-

verse the respiratory depression, indicating the de-
pressive effects are mediated by opioid receptors.

15

No other species studied thus far have shown any
negative respiratory effects to the author’s knowl-
edge. Tramadol appears to produce only minor de-
laying effects on the gastrointestinal transit time and
causes less gastrointestinal irritation than the non-
steroidal anti-inflammatory drugs that inhibit pros-
taglandin synthesis.

3,5,13

Nonsteroidal anti-inflamma-

tory drugs have also been found to increase blood
pressure in patients on hypertensive drugs,

16

From the Louisiana State University, School of Veterinary Med-

icine, Baton Rouge, LA 70803 USA

Address correspondence to: Debbie Myers, DVM, Louisiana

State University, School of Veterinary Medicine, Baton Rouge, LA
70803. E-mail: [e-mail]

© 2005 Elsevier Inc. All rights reserved.
1055-937X/05/1404-$30.00
doi:10.1053/j.saep.2005.09.010

284

Seminars in Avian and Exotic Pet Medicine, Vol 14, No 4 (October), 2005: pp 284 –287

whereas tramadol has not shown any negative hemo-
dynamic effects and would be an alternative for pa-
tients with hypertension or other cardiac risk fac-
tors.

3,5,14,16,17

Tramadol has been shown to lower the

seizure threshold in several species but, usually only
at high doses.

3,5,18

Therefore, individual patient fac-

tors must always be taken into account when using
this drug. Furthermore, because of tramadol’s ability
to decrease plasma glucose by enhancing glucose
uptake, caution is advised in ferrets suspected of
insulinoma.

10

As tramadol has become a staple for analgesia in

human and small animal medicine, there has been
growing interest in assessing the value of this drug in
nontraditional species. To date, pharmacokinetic
studies have been performed in fish, amphibians,
hamsters, mice, rabbits, and rats. These preliminary
reports have provided some important data on the
usefulness of tramadol in these species, and will be
discussed in more detail in this article. However, to
fully comprehend the potential effects of tramadol,
or any opioid, in a vertebrate, one must first charac-
terize the different types of opioid receptors found
in a given species.

Opioid receptors are generally divided into three

major classes:

␮, ␬, and sigma (␴) with delta (␦)

receptors representing a minor class. Mu opioid re-
ceptors have been found in many different species,
including bovids,

19,20

chickens,

12,20

pigs,

21

bull-

frogs,

20,22

bass, sharks, hagfish,

20

goldfish,

22

rats,

mice, hamsters, grassfrogs,

23

turtles,

24-27

carp,

28

rab-

bits,

1,4

dogs, cats, and humans. In mammals,

␮ re-

ceptors are associated with pain relief, while

␴ and ␬

opioid receptors modulate pain at spinal and su-
praspinal sites. Mu and

␬ receptors have also been

found to provide analgesia and central nervous sys-
tem depression in mammals during anesthesia. A
direct benefit of this can be seen when combining an
opioid with an inhalant anesthetic, because the con-
centration of the inhalant required for anesthesia
can be decreased when combined with an opioid.
The presence of

␮ receptors in a number of differ-

ent exotic species, in combination with the analgesic
properties of tramadol at the

␮ receptors, suggests

that this compound may prove valuable in managing
pain in exotic species.

The majority of the research evaluating the effects

of tramadol in exotic species has been focused on
lagomorphs and rodents. Rabbits appear to tolerate
doses of tramadol up to 10 mg/kg intravenously.
The drug begins to disappear from the plasma after
8 hours, with a distribution of 7.31 minutes and an
elimination half-life of 63.2 minutes. Tramadol in
rabbits follows a two-compartment model.

1

Studies

evaluating the analgesic effects of tramadol in rats,
mice, and hamsters have found that a wide range of
doses (0.5-20 mg/kg) are well tolerated.

Preliminary work being done in amphibians by

Dr. Shekher Mohan at Oklahoma State University
suggests that in the leopard frog (Rana pipiens), opi-
oid agonists produce their antinociceptive effects at
a single type of opioid receptor, coined the “unire-
ceptor.” The unireceptor may be a generic opioid
receptor that has binding affinity for

␮, ␦, and ␬

opioids.

23

Thus, one can hypothesize based on cur-

rent and past amphibian studies that tramadol may
produce analgesia in at least some amphibians. One
of the difficulties with evaluating pain in different
species is finding an appropriate model for eliciting
and measuring pain. In anurans, the acetic acid test
has been used in the past with good results. This
model could potentially be used to evaluate the ef-
ficacy of tramadol in anurans.

Fish have become important animal models in

research. Historically, very little concern has been
given to the idea of managing pain in fish. Some
scientists argue that fish do not have the necessary
neurologic hardware to feel pain, whereas others will
suggest that the biochemical pathways important in
transmitting and interpreting pain in higher verte-
brates are present in fish. Obviously, additional re-
search is needed to elucidate the truth in this matter.
However, in the meantime, it might be prudent to
acknowledge that fish may sense pain and therefore
treat accordingly. One experiment evaluating opi-
oids in carp (Cyprinus carpio) found that tramadol at
levels between 10 to 100 nmol/g body weight pro-
vided dose-dependent analgesia, with the higher
doses providing more rapid and long-lasting (

⬎2

hours) analgesia. The authors suggested that the
fish, like higher vertebrates, developed a prolonged
analgesia in response to a

␮ opioid receptor ago-

nist.

28

Similar results have been described in other

fish.

20

However, the effect may not be found in all

teleosts, because researchers examining goldfish
found that tramadol had a low affinity at

␮ receptor

sites.

22

The provision of analgesics to reptiles is a recent

event. Historically, reptiles, like fish and amphibians,
have been considered too “primitive” in the ability to
interpret pain. The stoic nature of these animals in
response to noxious stimuli has helped reinforce this
unsubstantiated mindset. However, like other lower
vertebrates, these animals do have the biochemical
pathways necessary to interpret pain and should be
managed in a proper manner. To better understand
the potential value of opioids (for example, tram-
adol) in reptiles, research is needed to characterize

Therapeutic Review

285

the different types of opioid receptors found in these
animals. Initial research suggests that turtles have
both

␮ and ␦ receptors. However, ␦ receptors were

found in higher numbers in turtles compared with
rats (a predominately

␮ receptor species).

22,25-27

Al-

though tramadol primarily works at

␮ receptors in

mammals, it does have weak affinity for

␦ receptors

and may have some clinical value in turtles.

Opioids have been found to produce analgesia in

avian species, but the results have been variable and
conflicting. In pigeons, for example,

␮ and ␬ ago-

nists produce analgesia. However, unlike in mam-
mals, it is not possible to differentiate between the
two agonists in the pigeon. It has been suggested
that pigeons may have a common mechanism of
action for the two drug classes.

29

If this is the case,

then it is possible that tramadol may have some
clinical value in these birds. Buprenorphine, a par-
tial

␮ agonist with some ␬ antagonist properties, has

been shown to have no clinical effect on African gray
parrots even at high doses,

29

whereas butorphanol, a

strong

␬ agonist and weak ␮ antagonist, has been

found to decrease the minimum alveolar concentra-
tion of isoflurane required for anesthesia in cocka-
toos and African grey parrots but not Blue-Fronted
Amazon parrots or turkeys.

28

Variability in response

to the opioids between birds within the same order
suggests that analgesic dosing may need to be based
on a genera to genera basis. Further work to char-
acterize the different types of opioid receptors found
in different species of birds is needed before the true
value of opioids (for example, tramadol) can be
determined.

Tramadol has been found to be a very useful

method of analgesia for mild to severe pain in nu-
merous species. Tramadol may also have additional
value beyond analgesia as mentioned previously.
Further research to evaluate the drug’s effectiveness
in controlling pain responses in exotic animal med-
icine should be pursued.

References

1.

Kueuk A, Kadioglu Y, Celebi F: Investigation of the
pharmacokinetics and determination of tramadol in
rabbit plasma by a high performance liquid chroma-
tography-diode array detector method using liquid-
liquid extraction. J Chromatogr B 816:203-208, 2005

2.

Kukanich B, Papich MG: Pharmacokinetics of tram-
adol and the metabolite O-desmethyl tramadol in
dogs. J Vet Pharmacol Therap 27:239-246, 2004

3.

Leppert W, Luczak J: The role of tramadol in cancer
pain treatment—a review. Support Care Cancer 13:
5-17, 2005

4.

Alici HA, Ozmen I, Cesur M, et al: Effect of the spinal
drug tramadol on the fatty acid composition of rabbit

spinal cord and brain. Biol Pharm 26:1403-1406,
2003

5.

Grono S, Sablotzki A: Clinical pharmacology of tra-
madol. Clin Pharmacokinet 43:879-923, 2004

6.

Yalein I, Aksu F, Belzung C: Effects of desipramine
and tramadol in a chronic mild stress model in mice
are altered by yohimbine but not by pindolol. Eur
J Pharmacol 514:165-174, 2005

7.

Faron-Gorecka A, Kuoemider M, Inan SY, et al: Long-
term exposure of rats to tramadol alters brain dopa-
mine and alpha adrenoreceptor function that may
be related to anti-depressant potency. Eur J Pharma-
col 501:103-110, 2004

8.

Anderson KE: New pharmacologic targets for the
treatment of overactive bladder: an update. Urology
63:32-41, 2004

9.

Panuita RK, Pehrson R, Christoph T, et al: Actions of
tramadol on micturition in awake freely moving rats.
Br J Pharmacol 139:741-748, 2003

10.

Cheng JT, Liu IM, Chi TC, et al: Plasma glucose-
lowering effect of tramadol in streptozotocin-in-
duced diabetic rats. Diabetes 50:2815-2826, 2001

11.

Wolff MH, Leather HA, Wouters PF: Effects of tram-
adol on minimum alveolar concentration (MAC) of
isoflurane in rats. Br J Anaesth 83:780-783, 1999

12.

Concannon KT, Dodam JR, Hellyer PW: Influence of
a mu- and kappa-opioid agonist on isoflurance min-
imal anesthetic concentration in chickens. Am J Vet
Res 56:806-811, 1995

13.

Nagoka E, Minami K, Shiga Y, et al: Tramadol has no
effect on cortical renal blood flow— despite in-
creased serum catecholamine levels—in anesthetized
rats: implications for analgesia in renal insufficiency.
Anesth Analg 94:619-625, 2002

14.

Natalini CC, Robinson EP: Evaluation of the analge-
sic effects of epidurally administered morphine, al-
fentanil, butorphanol, tramadol and U504884 in
horses. Am J Vet Res 61:1579-1587, 2000

15.

Teppema LJ, Nieuwenhuijs D, Olievier CN, et al:
Respiratory depression by tramadol in the cat: in-
volvement of opioid receptors. Anesthesiology 98:
420-427, 2003

16.

Ruoff GE: The impact of NSAID drugs on hyperten-
sion: alternative analgesia for patients at risk. Clin
Ther 20:376-387, 1998

17.

Natalini CC, Robinson EP: Effects of epidural opioid
analgesics on heart rate, arterial blood pressure, re-
spiratory rate, body temperature, and behavior in
horses. Vet Ther 4:364-375, 2003

18.

Potschka H, Friderichs E, Loscher W: Anticonvulsant
and proconvulsant effects of tramadol, its enatiomers
and its M1 metabolite in the rat kindling model of
epilepsy. Br J Pharmacol 131:203-212, 2000

19.

Sagata K, Minami K, Yanagihara N, et al: Tramadol
inhibits norepinephrine transporter function at de-
sipramine-binding sites in cultured bovine adrenal
medullary cells. Anesth Analg 94-901-906, 2002

20.

Li X, Keith DE Jr, Evans CJ: Mu opioid receptor-like
sequences are present throughout vertebrate evolu-
tion. J Mol Evol 43:179-184, 1996

21.

Merritt-Charles L, Chen D, Legall C, et al: Provision
of anesthesia for porcine cardiac transplantation at
the veterinary school in Trinidad and Tobago. West
Indian Med J 52:95-98, 2003

22.

Jozefowski S, Plytyez B: Characterization of opiate

286

Therapeutic Review

binding sites on the goldfish (Carassius auratus L.)
pronephric leukocytes. Pol J Pharmacol 49:229-237,
1997

23.

Shekher M, Martin K, Brasal C, et al. Oklahoma
State University Center for Health Sciences.

http://www.healthsciences.okstate.edu/college/dept/
basic/pharmphys/arllab.htm.

Accessed August 8, 2005.

24.

Vitanova L, Popova E, Kupenova P, et al: Compara-
tive studies on the effects of some enkephalin ago-
nists on the ERG of frog and turtle. Comp Biochem
Physiol C 97:93-98, 1990

25.

Johnson SM, Wilkerson JE, Wenninger MR, et al:
Role of synaptic inhibition in turtle respiratory

rhythm generation. J Physiol 544(Pt. 1):253-265,
2002

26.

Bakalkin GYa, Pivovarov AS, Kobylyansky AG, et al:
Lateralization of opioid receptors in turtle visual cor-
tex. Brain Res 480:268-276, 1989

27.

Xia Y, Haddad GG: Major differences in the expres-
sion of delta- and mu-opioid receptors between turtle
and rat brain. J Comp Neurol 436:202-210, 2001

28.

Chorvova LS, Lapshin DN: Opioid modulation of
pain threshold in fish. Dokl Biol Sci 375:590-1,
2000

29.

Machin KL: Controlling avian pain. Compendium
April:299-307, 2005

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