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4
Effective Pain Management
T
his chapter presents an overview of the basic clinical strategies, both
pharmacologic and nonpharmacologic, for managing pain in labora-
tory animals. Topics include preventive analgesia, consequences of
unrelieved pain, and ethical considerations relating to pain as a subject of
study. Available information on pain management of nonmammalian spe-
cies is also presented.
INTRODUCTION
The regulatory review process (see Appendix B) requires that investiga-
tors adequately control pain in research animals, unless procedures that
may cause more than momentary or slight pain are justified for scientific
reasons and approved by the IACUC. In order to treat or prevent pain, it
is necessary to evaluate its source and intensity (for additional discussion
see Chapter 3). As a rule, pain is likely to occur in proportional terms as a
result of tissue injury—more extensive tissue damage results in greater pain
and thus a need for a stronger analgesic regimen. While certain conditions
reliably cause severe pain (e.g., acute nerve compression, burns, spastic
contraction of smooth muscle) and inflammation often contributes to the
worsening of pain, scientists do not fully understand how much pain to
expect in various animal species. Information about the cause and effect of
surgery or disease and pain in clinical veterinary medicine is largely based
on observation and anecdote and tends to focus on commonly treated spe-
cies, such as dogs, cats, and horses. Table 1-1 of Chapter 1 lists examples
1
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2 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS
of typically painful conditions that occur either spontaneously or as a result
of experimental procedure.
CLINICAL VETERINARY PAIN MANAGEMENT
The principles of clinical veterinary pain management and prevention,
summarized in Boxes 4-1 and 4-2, are comparatively easy to apply in clini-
cally familiar species such as dogs and cats, for which ranges of doses and
drug combinations are relatively well known. However, the application
of the principles discussed below to other laboratory animal species is a
matter of trial and error until adequate scientific information is available to
establish evidence-based guidelines, including information on the feasibil-
ity of various routes of administration (e.g., oral bioavailability, palatability,
transdermal preparations). Readers are encouraged to seek publications
(including the American College of Veterinary Anesthesiologists’ Position
Paper on the Treatment of Pain [ACVA 1998]), reports, books, and the vet-
erinary literature for specific information on available drugs, doses, routes
of administration, side effects, contraindications, and the like that may be
useful for dogs, cats, rabbits, and other species used as research animals.
BOX 4-1
Current Guidelines for Clinical Veterinary Pain Management
• Sedation does not provide pain relief and may mask the animal’s response to
pain.
• Use of analgesic and adjunct drugs should be at effective plasma/tissue con-
centrations especially when the nociceptive barrage and pain are greatest (i.e.,
after surgery or injury).
• Use of more than one type of management strategy (e.g., multimodal anal-
gesia [targeting multiple pain mechanisms with the use of local anesthetics
and opioids] or anxiolytics when postsurgical pain is likely to be moderate to
severe) is recommended.
• Avoidance of peaks and valleys in analgesic dosing (best accomplished by the
administration of continuous or overlapping regimes) when postsurgical pain
is expected to be severe maintains animal well-being.
• Monitoring, at appropriate intervals, of the effectiveness of analgesics admin-
istered is crucial.
• If there is doubt about the source of an animal’s clinical signs, administration
of an additional dose of analgesic—dependent on the drug, species, and often
the individual animal—can help determine whether pain was the cause (while
this is not commonly done in laboratory animal medicine, this method of pain
control/alleviation in nonrodent species is common in clinical veterinary prac-
tice in a patient-specific manner).
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3
EFFECTIVE PAIN MANAGEMENT
BOX 4-2
Additional Considerations for the Prevention and
Management of Pain in Laboratory Animals
• Pain in animals is often unrecognized and undertreated.
• If a procedure is considered painful in humans, it should be assumed to be
painful in laboratory animals, regardless of their age or species.
• Adequate treatment of pain may be associated with decreased complications,
lower mortality, reduced variability in experimental data, and improved scien-
tific outcomes.
• The appropriate use of environmental, nonpharmacologic, or pharmacological
interventions, as well as the selection of humane endpoints in animal experi-
mentation, can prevent or reduce animal pain in most experimental designs
without compromising the scientific validity of the research, except where pain
is the subject of research.
• Researchers, veterinarians, and animal care professionals should be respon-
sible for learning about the assessment, prevention, and management of pain
in laboratory animals.
• Veterinarians and animal care professionals should develop IACUC-approved
educational guidelines and protocols for the management of pain in laboratory
animals at their institution.
Some ranges for effective doses of analgesics in rats and mice (i.e.,
doses that reduce experimental measures of pain and/or reach tissue con-
centrations believed to be effective in other species) are available through
literature search. However, strain differences in animals’ responses to anal-
gesics and anesthetics are an important factor to consider (Mogil et al. 2005;
Terner et al. 2003; Wilson et al. 2003a,b).
STRATEGIES FOR MANAGING PAIN IN LABORATORY ANIMALS
Effective management of pain in laboratory animals often begins with
general (surgical) anesthesia, but also includes local anesthetics, analgesics,
anxiolytics, and sedatives as well as nonpharmacological methods (includ-
ing minimization of tissue trauma). Pain management goals range from
total elimination (as, for example, during general anesthesia for a surgical
procedure) to pain that is tolerated without compromising the animal’s
well-being.
General Anesthesia
When animals are anesthetized for procedures that would otherwise
cause pain, it is important to maintain an appropriate depth of anesthesia.
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4 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS
A wide range of indices have been developed to assess depth of anesthe-
sia in animals and humans (Appadu and Vaidya 2008; Bruhn et al. 2006;
Franks 2008; John and Prichep 2005; Lu et al. 2003; Murrell and Johnson
2006; Otto 2008; Whelan and Flecknell 1992); these include autonomic
responses such as changes in heart rate and blood pressure, alterations in
the EEG or other measures of CNS function, or changes in somatic reflex
responses to noxious stimuli. During anesthesia not accompanied by neu-
romuscular blocking agents, depression of somatic reflex responses is the
most widely used method for ensuring an appropriate depth of anesthesia.
In all animal species, absence of the pedal withdrawal reflex indicates a
surgical plane of anesthesia (i.e., anesthesia that is deep enough to elimi-
nate the experience of pain and thus allow surgery to take place). Although
this is an easily assessed index, it is important to use a stimulus that is suf-
ficiently noxious but not so strong as to produce tissue damage. In some
species, other reflexes, such as the response to applying a clamp to the
nasal septum (pigs) or pinching the ears (rabbit, guinea pig), are also useful
but reliance on these responses has been criticized (Antognini et al. 2005)
because animals may lose consciousness at much lighter anesthesia planes,
in which case the persistence of reflexes would not indicate pain perception
(see also Box 1-3 in Chapter 1). Doses of anesthetic agents sufficient to sup-
press spinal reflexes may therefore be greater than those required to carry
out surgery humanely; if these reflexes are not suppressed, surgery will be
hampered by the animals’ repeated reflex movements. Although the use of
neuromuscular blocking agents (which prevent neurotransmitters from act-
ing on their receptors in skeletal muscles) could prevent such movements,
it would also require intubation and mechanical ventilation of the animal.
For practical reasons, suppression of withdrawal responses remains the most
useful means of ensuring loss of both awareness and responses to surgical
stimuli.
The ideal general anesthetic should rapidly and/or smoothly induce
muscle relaxation and a surgical plane of anesthesia, and should be readily
controllable and reversible. There are two categories of general anesthetics
used in laboratory animal medicine: volatile inhalants (e.g., isoflurane) and
injectable drugs (e.g., barbiturates, other sedative-hypnotic agents such as
propofol, or combinations of drugs such as propofol-fentanyl). The latter
category also includes total intravenous anesthesia (TIVA). TIVA techniques
may be useful in laboratory animal settings where the equipment required
for inhalant anesthesia is not practical or possible (e.g., near MRI units).
Other injectable general anesthetic drugs still in use due to their unique
application in specialized studies include α-chloralose, tribromoethanol,
and urethane. These drugs have certain specific applications but may not
be appropriate for situations in which animals will recover (Gaertner et al.
2008; Karas and Silverman 2006; Koblin 2002; Meyer and Fish 2005) as,
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EFFECTIVE PAIN MANAGEMENT
after surgery, with anesthetic withdrawal and recovery, the animals will
experience pain unless they receive analgesics.
Sedation/Anxiolysis
Sedatives and anxiolytics are adjuncts to general anesthetics and are
also used in pain management strategies. These two distinct classes of drugs
are often used in combination to modulate, block, or relieve pain. Terminol-
ogy varies but a general distinction between the sedative-hypnotic agents
and anxiolytics is often useful. Sedative-hypnotic drugs (e.g., barbiturates
and drugs with significant sedating properties such as α2-adrenoreceptor
agonists) produce dose-dependent states of CNS depression that vary from
somnolence to general anesthesia and even death. Anxiolytics are drugs that
reduce anxiety or fear (e.g., benzodiazepines) and can induce sleep. Some
anxiolytic drugs, previously termed “tranquilizers” (e.g., phenothiazines
like acepromazine and butyrophenones like haloperidol and droperidol),
produce a state of relaxation and indifference to external stimuli and, in
elevated doses, can induce an undesirable cataleptic state rather than gen-
eral anesthesia. Of the above drugs and classes, only the α2-adrenoreceptor
agonists have analgesic efficacy. Neither barbiturates nor anxiolytics are
analgesic; barbiturates may in fact contribute to a hyperalgesic state, while
phenothiazines and butyrophenones are generally considered devoid of
analgesic efficacy. Readers are referred to the section “Modulatory Influ-
ences on Pain: Anxiety, Fear, and Stress” in Chapter 2 for a discussion of
the relationship of anxiety and pain.
Neuroleptanalgesia is an intense analgesic and amnesic state produced
by the combination of an opioid analgesic and a neuroleptic drug (this
description is adapted from the American Heritage Medical Dictionary
2007). The neuroleptic drug component is a phenothiazine or butyrophe-
none (or possibly an anxiolytic) and the analgesic is a potent and efficacious
opioid that also acts as a major tranquilizer (i.e., anxiolytic). Butorphanol-
acepromazine, fentanyl-fluanisone (Hypnorm®1), and oxymorphone-
midazolam are examples of commonly used veterinary neuroleptanalgesic
combinations. Neuroleptanalgesic combinations by themselves are not suffi-
cient for most surgical interventions. However, the use of drugs with sedative
or tranquilizing properties (neurolepts as well as α2-adrenoreceptor agonists)
combined with opioids, ketamine, or tiletamine-zolazepam (Telazol®) can
cause states ranging from modified consciousness (e.g., reduction of anxiety
or “conscious sedation”) to complete unconsciousness (general anesthesia).
Table 4-1 summarizes the analgesic properties of selected drugs, includ-
1 Hypnorm is not available in the United States (as of August 2009).
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6 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS
TABLE 4-1 Analgesic Properties of Selected Anesthetic Drugs and
Adjuncts
Analgesic
Drug Class Efficacy
α2-Adrenoreceptor agonists Analgesic/sedative-hypnotic Yes
Barbiturates Sedative-hypnotic No
Benzodiazepines Anxiolytic No
Butyrophenones Neuroleptic/anxiolytic No
Chloralose, chloral hydrate Sedative-hypnotic No
Halogenated inhalant anesthetics General anesthetic No
Ketamine Dissociative, NMDA antagonist Yes
Nitrous oxide General anesthetic (human); general Yes
anesthetic adjunct only in animals
Opioids Analgesic Yes
Phenothiazines Neuroleptic/anxiolytic No
Propofol Sedative-hypnotic No
(Telazol®)
Tiletamine-zolazepam Combination of a dissociative/ Yes
NMDA receptor antagonist and a
benzodiazepine anxiolytic
Tribromoethanol Sedative-hypnotic No
Urethane (e.g., ethyl carbamate) Not classified No
NOTE: Drugs with inherent analgesic effects may contribute to postoperative pain control but
are not sufficient to exert such control in and of themselves.
ing tranquilizers, sedatives, and anesthetics, commonly used in laboratory
animals.
Analgesia
Conventional analgesic drug classes include opioids, NSAIDs, and local
anesthetics. Although analgesia is defined as “lack of pain,” complete elimi-
nation of pain in awake animals is commonly neither achievable nor desir-
able. Pain has a protective role as it usually serves to limit further injury; for
example, humans with no skin sensation are prone to undetectable injury
or infection. But in some instances animals with untreated severe pain may
struggle or self-mutilate and exacerbate or cause additional injury to them-
selves. With most analgesic techniques, however, residual pain naturally
limits activity, although it is not a restraint mechanism and should not be
used to restrain animals.
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EFFECTIVE PAIN MANAGEMENT
The goal of analgesic drug intervention is to achieve a balanced state
during which an animal is neither substantially hindered by pain nor
adversely affected by the side effects of analgesics. Often the use of a single
analgesic is sufficient. An emerging practice for the prevention or treatment
of established pain in both human and veterinary patients, however, is the
combined use of two or more types of analgesics, or “multimodal analgesia”
(Buvanendran and Kroin 2007; Corletto 2007; Hellyer et al. 2007; Kehlet
et al. 2006; Lemke 2004; White 2005; White et al. 2007). Multimodal post-
surgical analgesia may be regarded as overly complicated, but cited benefits
include more effective and efficient analgesia and possible dose reduction
of one or more individual drugs.
In theory, treatment of patients with nonopioid analgesics to reduce the
overall requirement for opioids would result in fewer opioid-induced side
effects. The concept, known as “opioid sparing,” is a desirable goal because
extended or high-dose opioid therapy is often accompanied by unwanted
side effects (e.g., sedation, constipation, urinary retention, or analgesic tol-
erance) that prolong or complicate convalescence (Kehlet 2004; White et al.
2007). Synergy (i.e., greater analgesia than predicted from a simple additive
effect of the combination of two drugs acting with different mechanisms)
has been demonstrated in numerous experimental animal models (e.g.,
Price et al. 1996; Kolesnikov et al. 2000; Matthews and Dickenson 2002;
Qiu et al. 2007) as well as with combinations of opioids, NSAIDs, local
anesthetics, α2-agonists, ketamine, tramadol, and gabapentin (Guillou et al.
2003; Koppert et al. 2004; Reuben and Buvanendran 2007; White et al.
2007). Multimodal analgesia using “adjuvant analgesics” (i.e., antidepres-
sants, antiepileptic drugs, NMDA antagonists, or transdermal lidocaine) may
also be an effective alternative for the treatment of refractory chronic pain
unresponsive to the administration of a single agent (Knotkova and Pap-
pagallo 2007). Table 4-2 summarizes pharmacologic methods for treating
pain of various intensities.
Advanced Analgesic Techniques
The ability to provide analgesia to laboratory animals is limited by
the lack of information about species-specific drug effects and doses. It is
perhaps useful to understand the state-of-the-art techniques currently used
in clinical (i.e., nonlaboratory) veterinary medicine as a potential objective
for laboratory animal pain medicine; identification of the most useful tech-
niques may lead to important innovations to help overcome barriers to the
provision of analgesia. Needless to say, size, species, and technical aspects
will continue to be limiting factors for many techniques. Box 4-3 provides
a summary of analgesic techniques and their limitations.
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8 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS
TABLE 4-2 Pharmacologic Approach to Pain Management Based on
Predicted Intensity
Pain Intensity Analgesic Approach
Low Single-agent therapy acceptable
NSAIDs, local anesthetic infiltration, or opioid agonist-antagonists
(butorphanol, buprenorphine)
Moderate Multimodal analgesia to be considered
NSAIDs in combination with adjuncts such as local anesthetics, opioid
agonist-antagonists (buprenorphine), tramadol, α2-agonists, NMDA
antagonists
High Multimodal analgesia recommended
mu-opioid agonists (morphine, hydromorphone, fentanyl, methadone)
+ one or more of the following: NSAIDs, local anesthetics, α2-agonists,
antiepileptic drugs, NMDA antagonists
Advanced analgesic techniques: epidural administration of local anesthetics
with or without opioids and constant rate infusions
Nonpharmacologic Methods
Nonpharmacologic approaches to pain management are appropriate
when the use of pharmacological methods is contraindicated, when effec-
tive analgesic drugs are not available, or to complement drug therapy. Non-
pharmacologic methods include preventive strategies that help minimize
causative factors for pain, through, for example, appropriate animal han-
dling and minimization of tissue trauma during surgery. Such techniques are
important because both long-duration surgery and extensive tissue manipu-
lation (e.g., rib retraction, prolonged tourniquet-induced limb ischemia,
disproportionately long incision relative to animal size) result in increased
postoperative pain. Training in proper surgical techniques coupled with
knowledge of comparative anatomy is necessary to appreciate the distinct
needs of each animal species before, during, and after surgery and to
uphold the 3Rs principle of refinement. Moreover, nonphysiologic restraint
or surgical positioning of animals may exert undue pressure on joints,
nerves, or soft tissues and cause significant postprocedural pain. These
sources of pain are avoidable if investigators and animal care personnel are
trained to understand that any form of tissue pressure, damage, or ischemia
is a potential cause of pain (Martini et al. 2000; LASA 1990). Minimally
invasive surgery techniques (e.g., fiberoptic technologies) reduce tissue
injury and are associated with reduced postsurgical pain, stress response,
and convalescence time compared to open or scalpel surgery (reviewed by
Karas et al. 2008).
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EFFECTIVE PAIN MANAGEMENT
BOX 4-3
Advanced Analgesic Techniques
• Low-dose epidural administration of opioids or opioid-local anesthetic com-
binations can result in analgesia whose quality is similar to if not better than
that achieved with systemic administration. This method depends on technical
expertise and may be challenging to implement in very small animals. Epidural
administration of drugs has not been studied in nonmammalian vertebrates.
• Local anesthetics can be injected into joints, wounds, and body cavities (ab-
dominal or pleural) by continuous or intermittent injection through intra-wound
catheters, greatly reducing the need for systemic administration of other anal-
gesics (Liu et al. 2006). The relatively short duration of the action of local an-
esthetics may limit their utility in situations where redosing is difficult. Lidocaine
is used intravenously to provide analgesia after tissue injury (Omote 2007).
• Oral administration of some analgesics is feasible (e.g., NSAIDs, opioids,
gabapentin), but for some drugs (opioids) first-pass (species-dependent) me-
tabolism limits bioavailability, necessitating dose adjustment, use of a different
route of administration, or selection of another drug. Compounding of drugs
into palatable forms that animals are willing to consume is possible, but without
data to support a particular method, one must be concerned about absorption,
shelf life, and efficacy.
• Dilution of injectable analgesics to make them easier to use or to improve
provision in very small animals must be done with the understanding that
formulations may not work as well and that shelf life is not predictable.
• Continuous infusion of certain types of analgesics (e.g., opioids, ketamine,
α2-adrenoreceptor agonists) avoids “peaks and valleys” in drug concentration
and may provide better coverage for moderate to severe pain. Transdermal
preparations are available in formulations suitable for larger animals and may
be useful in producing uninterrupted analgesia. Sustained-release formula-
tions make it possible to avoid periods of inadequate drug administration. For
further consultation please see Carroll 2008; Flecknell 2009; Gaynor and Muir
2002; Hellyer et al. 2007; Krugner-Higby et al. 2008; Lamont and Mathews
2007; Robertson 2005; Tranquilli et al. 2007; Valverde and Gunkel 2005.
METHODS FOR THE PREVENTION OR MANAGEMENT OF PAIN
While classic pharmacologic treatment requires drugs with specific
analgesic properties, unconventional drugs, such as antiepileptics, can also
be effective. And when anxiety contributes to pain, drugs with anxiolytic
properties can be added.
Analgesics
A thorough review of the effects and doses of analgesic drugs is beyond
the scope of this work (for comprehensive reviews see Carroll 2008; Fleck-
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80 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS
nell and Waterman-Pearson 2000; Gaynor and Muir 2002; Hawk et al.
2005; Lamont and Mathews 2007; Robertson 2005; Valverde and Gunkel
2005). Instead, this section provides an overview of analgesic drugs that are
currently used or may become useful in laboratory animal medicine.
Opioids
Opioid analgesics are important drugs for surgical analgesia and/or
therapeutic management of moderate to severe pain in humans and certain
animal species. There are two general categories of such analgesics (Ross
et al. 2006; Stefano et al. 2005; Waldhoer et al. 2004): opioid receptor ago-
nists (e.g., morphine, hydromorphone, fentanyl) and mixed opioid recep-
tor agonist/antagonists (e.g., buprenorphine, butorphanol); the latter group
possesses (in a single molecule) agonist efficacy at one of the three types of
opioid receptor and antagonist efficacy at a different opioid receptor.
A third group of endogenous opioid peptides (e.g., endorphins, enkeph-
alins, and dynorphins) are produced by the body and also act on opioid
receptors. It is a misconception, however, to assume that the only role of
endogenous opioid peptides is to produce analgesia; they have multiple,
nonanalgesic functions depending on where in the body they are produced
and released. Given the existence of three distinct opioid receptors, all
located in variable densities in various tissues, differences in the selectivity
and affinity of opioid drugs and endogenous opioid peptides are believed
to account for many of the variations in the effect profile of opioids (Fields
2004; Waldhoer et al. 2004). And because opioid receptors are subject
to regulation (e.g., by phosphorylation or endocytosis), the effects of both
endogenous and exogenous opioids can be influenced by the “state” of the
receptor. Changes such as these presumably account for the phenomenon
of analgesic tolerance, a reduction in the analgesic effectiveness of a given
dose of drug after repeated administration.
Opioids are the most efficacious analgesics available, but their use is
accompanied by undesirable effects that include an increase in smooth
muscle tone and reduction in propulsive motility of the gastrointestinal
tract (leading to constipation), cough suppression, respiratory depression,
behavioral changes (euphoria and dysphoria, excitement, or increased loco-
motion), and physiological dependence. In addition to their presence on
neurons both in the nociceptive pathway (see Chapter 2) and elsewhere in
the body (e.g., the gastrointestinal tract), opioid receptors are found on cells
of the immune system and opioid effects on immune function vary from
stimulation to inhibition (Stefano et al. 2005; Page et al. 2001). In rats and
other rodents, pica (the ingestion of nonedible substances, such as bedding)
and the consumption of large volumes of food have been noted with the use
of the partial opioid receptor agonist/weak antagonist buprenorphine (Aung
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81
EFFECTIVE PAIN MANAGEMENT
et al. 2004; Bosgraaf et al. 2004; Clark et al. 1997; Yamamoto et al. 2004).
Concern about the undesirable side effects of opioids is frequently cited as
a reason for not using them, but for limited or short-term therapy the side
effects are often either manageable or not a problem.
Dose regimens of opioid analgesics for dogs, cats, horses, rats, mice, a
few species of birds, and sheep have been reported. When such regimens
are based on experimental evidence, it frequently derives from an analge-
siometric testing method (such as thermal threshold; Johnson et al. 2007;
Robertson et al. 2005a,b; Waterman et al. 1991; Wilson et al. 2003a,b).
Doses for other mammals currently listed in formularies are based on
extrapolation. Relatively little is known about the efficacy, drug choices,
or side effects of opioids in amphibians, reptiles, invertebrates, and most
birds.
In addition to classical intravenous, intramuscular, and intraperitoneal
routes of administration, many opioids are also substantially bioavailable
by nasal, sublingual, or rectal routes (Lindhardt et al. 2000; Robertson
et al. 2005a). Oral administration of opioids in mammals often diminishes
their bioavailability, making this method of delivery less effective. Addi-
tionally, long-duration formulations of opioids have been investigated in
animal models and, although not yet commercially available, may repre-
sent a future method to provide sustained analgesia in laboratory animals
(Krugner-Higby et al. 2008; Smith et al. 2004).
Because of the relative safety of opioids, information about effective
dose ranges and novel methods of administration would be useful. Research
is needed to determine ranges and methods for most laboratory animal
species.
Tramadol
Tramadol2 is a centrally acting synthetic analgesic used to treat post-
operative and chronic pain in humans. It has a multimodal action: it is
an opioid receptor agonist and it inhibits norepinephrine and serotonin
reuptake from neurons where those amines are released, including in the
spinal cord where both norepinephrine and serotonin can contribute to
the modulation of nociception (Grond and Sablotzki 2004). An active (M1)
metabolite of tramadol binds with high affinity to mu-opioid receptors;
indeed it has more affinity for the opioid receptor than the parent drug. The
use of tramadol has recently increased significantly in veterinary medicine.
However, in humans and dogs (and possibly other species) with an inherited
2 Draft FDA guidance on tramadol is available at www.fda.gov/downloads/Drugs/Guidance-
ComplianceRegulatoryInformation/Guidance/ucm090703.pdf (accessed July 28, 2009).
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