Download S8A OPIOIDS: WHICH, WHY, HOW, AND WHAT’S NEW

Survey
yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project

Document related concepts

Harm reduction wikipedia , lookup

Canine parvovirus wikipedia , lookup

Dental emergency wikipedia , lookup

Transcript
Western Veterinary Conference 2013
S8A
OPIOIDS: WHICH, WHY, HOW, AND WHAT’S NEW
Mark E. Epstein, DVM, Dipl. ABVP (Canine/Feline), Dipl. AAPM, CVPP
International Veterinary Academy of Pain Management
TotalBond Veterinary Hospitals & Carolinas Animal Pain Management
Gastonia & Charlotte, NC, USA
Synthetic opioids are powerful, useful tools to manage pain for one simple reason: Receptors
for naturally-occurring opioids (endorphins, enkephalins) are distributed ubiquitously
throughout the body and can be found in both central and peripheral tissues. Several opioid
different receptor types and subtypes have been isolated, each with a variant effect. The
historic categorization of mu, kappa, delta, and sigma opioid receptor subtypes have been reclassed according to a rubric aligned with gene expression. However for the sake of our
discussions, this manuscript to familiar and traditional Greek-letter categories and in particular
mu and kappa receptors as these are the two that are manipulated in animals to provide
analgesia.
Activation of a mu-opioid receptor inhibits presynaptic release (especially in the dorsal horn of
the spinal cord) and postsynaptic response (especially in the dorsal root ganglion) to excitatory
neurotransmitters. The proposed mechanism includes opioid receptor coupling with the
membrane-associated G protein; this leads to decreased intracellular formation of cAMP which
diminishes calcium channel phosphorylation (closing off the voltage-gated calcium channel)
and opens potassium channels enhancing potassium influx. The resulting effect is
hyperpolarization of the neuron and blockade of Substance P release. Nociceptive
transmission is thus greatly impeded.1
Opioid tolerance and resistance occurs when signaling cascades force calcium channels to
remain open despite the presence of opioid. Additionally, glial cells, once thought to merely
provide supporting roles in the spinal cord but are now known to be highly interactive with
nociceptors, dysregulate opioids…and unfortunately, opioids activate glial cells. Therefore in
an important sense, the pain we perceive is a balancing act between the activity of the opioids
and the activity of glia.
A number of different opioid drugs are available which vary in their relative potency and
receptor affinity.
PURE MU-AGONISTS:
Morphine remains the prototype opioid and the opioid in widest use; it has no ceiling effect on
analgesia or respiratory depression, elicits histamine release, and causes vomiting at low
doses (higher doses, IV doses, and chronic use do not elicit vomiting, presumptively by
interaction with mu receptors in the antiemetic center2). Cats lack glucoronate metabolism,
resulting in minimal production of the analgesic M6G metabolite3, therefore morphine may not
be the ideal opioid for use in this species.
Oxymorphone (Numorphan®) and hydromorphone (Dilaudid®) do not elicit histamine release
(therefore may be wiser choice in cases of hypovolemia e.g. trauma, dehydration), and nausea
may be less pronounced, but they have a much shorter duration of action than morphine. In
cats, hydromorphone may have a longer duration of action (>7 hours in a thermal threshold
model4 ) and is implicated more than other opioids in episodes of hyperthermia in this species.5
Methadone may also be an attractive opioid alternative in animals,6 in part due to its additional
effect as an NMDA antagonist and evidence of effectiveness in rodent models of neuropathic
pain.7 The parenteral preparation is favored by some veterinarians as a pre-medication due to
its low AE profile (minimal if any nausea, no histamine release) and prolonged sedative
properties. Orally, however, in contradistinction to humans, it appears to have low oral
bioavailability and rapid clearance.8
Fentanyl is a short-acting opioid preparation (Sublimaze®) with a potency of 80-100x that of
morphine. It has a very short half-life that limits most of its use as an intravenous constant rate
infusion.
Meperidine (Demerol®) is a weak mu-agonist (approx. ¼ the potency of morphine) but more
importantly carries a very short duration of action in the dog (less than 1 hour)9. These
features have limited its use in animals.
Commercial oral opioid preparations are widely available, and while there is often a significant
first-pass effect limiting bioavailability10, these drugs are not without their utility. Hydrocodone,
codeine (both alone and in combination with acetaminophen), hydromorphone (Dilaudid®) and
sustained-released forms of oral opioids include morphine (MSContin®), oxycodone
(Oxycontin®), and oxymorphone (Opana ER®)11 are all available by prescription. PK data
exists for some of these formulations12,13,14,15,16 but PD (efficacy) data is currently lacking in
dogs and cats. Oral methadone in humans has much higher bioavailability (>70%) than does
morphine (<20%), but in dogs the oral bioavailability of methadone appears to be very low.17
Transmucosal preparations such as fentanyl buccal tablets and suckers (Actiq®, Fentora®) do
exist, but pharmacokinetics and pharmacodynamics in dogs and cats is less established and
the limitation of administration to dogs and cats of this kind of delivery system is self-evident.
Rectal suppository opioid formulations may also be prescribed, but appear to provide little
advantage in bioavailability over the oral route in the dog.18
Tramadol has also become a popular adjunct to chronic pain management in both human19,20
and veterinary medicine because of its effectiveness as a weak opioid, and norepinephrine
and serotonin (an inhibitory neurotransmitters) agonist. However, conversion to the active mu
agonist M1 metabolite appears to be minimal in the dog21, indicating most of its activity in this
species may be derived from its seritoninergic and noradrenergic activity. Per-rectal
administration does not appear to offer an advantage in this regard.22 In contradistinction, cats
do appear to manufacture the M1 metabolite with a sustained half-life,23 and the clinical utility
as an adjunct to NSAID during ovariohysterectomy has been established.24 Tapentadol
(Nucytna®) is a new centrally acting analgesic with a dual mode of action similar to tramadol:
mu-opioid receptor agonism and inhibition of norepinephrine reuptake. However, it is the
parent compound, not a metabolite, that provides for both of these effects, and thus may offer
an alternative superior to tramadol in dogs. Unfortunately recent data from the U.S. reveals it
in dogs to have low bioavailability,25 and poor performance on a tail-flick model of evaluating
analgesic effect.26 Its future utility in veterinary medicine is unknown. Tramadol (and
tapentadol) should not be used with other serotoninergic medications such as tricyclic
antidepressants, SNRI’s, and amitraz-containing compounds.
PARTIAL MU AGONIST
Buprenorphine (Buprenex®) is a partial agonist on the mu receptor though it has greater
affinity than morphine (and will displace it if given together, although this effect may be
clinically significant only at higher doses). It does have a ceiling effect meaning the analgesic
effect does not become more pronounced at higher doses (and may actually become
diminished at higher doses as it displaces endogenous opioids off mu receptors). A great
benefit of the drug in veterinary medicine is that its pKa (8.4) closely matches the pH of the
feline oral mucosa (9.0), which allows for nearly complete absorption when given buccally in
that species27, with kinetics nearly identical to IV and IM administration,28 and eliciting very
little sedation. Transmucosal absorption in the dog appears to be much lower than in cats
(approx. 40%29 ), indicating the utility of TM buprenorphine was limited, albeit present and
similar to humans, in this species.
AGONIST-ANTAGONIST
Butorphanol is a weak mu antagonist and a kappa agonist; while it will weakly block the muopioid receptor (reversing the effects of any of the mu-agonists, if present), the kappa agonism
will promote the release of inhibitory neurotransmitters such as GABA. Its very short duration
of action in the dog (approx. 30-40 min, though sedation may be longer) makes it a poor
choice for an analgesic in this species for any kind of significant or prolonged pain states,
though used parenterally it has utility as an adjunct with other medications such as alpha-2
agonists. It comes as both a parenteral and oral formulation. Nalbuphine is an injectable muantagonist, kappa agonist (and currently not controlled). One recent study in humans reports
success with repeated weekly injections in relieving patients previously suffering from
refractory chronic pain.30
ANTAGONIST
Naloxone (Narcan®) is a potent mu-opioid receptor antagonist, traditionally used to achieve
rapid reversal of opioid overdose or opioid-induced severe adverse effects. However, the
reversal of opioid AE in veterinary patients is often accomplished instead with the use of a
partial mu agonist such as buprenorphine or a mu-antagonist/kappa agonist such as
butorphanol; this allows the AE to diminish while maintaining a degree of analgesia.
Interestingly however, in humans, micro-doses (as low as 0.01 – 0.05 mcg/kg IV) of naloxone
have been used to improve the analgesia provided by buprenorphine.31
SUSTAINED AND EXTENDED-DURATION OPIOIDS
There is an increasing interest in sustained-release and/or long-acting parenteral formulations
and technologies in humans and animals, several of which have been investigated and one of
which has recently received FDA approval. In animals, the efficacy, durability, and tolerability
of liposome-encapsulated (LE) hydromorphone has been demonstrated in dogs, with adequate
serum levels up to 4 days32 and superior analgesic effect 12 hours post-ovariohysterectomy
compared to subcutaneous morphine.33 This same formulation, route, and dose demonstrated
favorable pharmacokinetics and tolerability in rhesus macaques when compared to
subcutaneous or intravenous hydromorphone.34 Similar studies with LE oxymorphone and
hydromorphone have been performed in laboratory animals demonstrating durability,
tolerability, and effectiveness (rhesus macaques35 and rodents36,37,38). No commercial LEopioid product is available on the market.
Fentanyl has been available in the U.S. as a transdermal patch formulation since 2005, labeled
in humans for breakthrough cancer pain, and has been studied (and used off-label) in dogs,
cats, and rabbits. Results have demonstrated utility in these species39,40 but also wide
variability in serum concentrations.41,42,43 More recently, a long-acting fentanyl product with a
novel delivery system was approved in dogs for 3 days peri-operative pain (Recuvyra®,
Elanco). This product makes use of patented Metered Dose Transdermal Spray (MDTS)
technology and is labeled to provide plasma levels of fentanyl adequate to provide analgesia
for 72 hours.
Buprenorphine is recently available for humans as a transdermal patch (Transtec®, BuTrans®,
Buprederm®). Rabbits and rodents achieved rapid plasma levels (1-24 hours) with peak
analgesic activity with the tail-flick and writhing model at 3-4 hours and sustained for 72 hours
of the study.44 However in one feline study using a 35 mcg/h patch, plasma levels were
negligible and there were no changes in thermal thresholds.45 The experience in dogs is
somewhat better. In one canine study utilizing a 70 mcg/h patch resulted in sustained plasma
concentrations of 0.7-1.8 ng/ml within 36 hours of application.46 Another canine study utilizing
a 52.5 mcg/h found peak plasma levels of 1.54 ng/ml and analgesic efficacy to be non-inferior
to iv buprenorphine in mechanical & thermal thresholds within 36 hours of application and
lasting until the patch was removed; however there was some inconsistency as 3 of the 10
dogs had recorded negligible plasma levels.47 An additional clinical canine study found the 70
mcg/kg patch to be non-inferior to SC buprenorphine post-ovariohysterectomy.48
Buprenorphine is also available in a compounded (non-FDA approved) sustained-release
formulation. Unpublished PK data in dogs report plasma levels adequate for analgesia for
over 72 hours,49 but there are anecdotal reports of prolonged and in some cases dramatic
sedation especially at the higher end of the dosage range in larger dogs.50 Unpublished PK
data in cats superior maintenance of plasma levels adequate for analgesia over 3 days when
compared to repeated OTM dosing.51,52 One published PD study in cats found SR
buprenorphine to be non-inferior to Q 12 H OTM dosing for three days postovariohysterectomy, with minimal adverse effects.53 Similar positive outcomes have been
observed in unpublished studies with non-human primates54 and rodents,55 and in one
published rat study.56
Tips for Use of Opioids:
Pre-operatively, opioids are customarily combined with an anxiolytic (tranquilizer/sedative) to
create a profoundly relaxed, stress-free, comfortable, and anesthetic-sparing state. The
choice of opioid, route, dose, and duration of administration is dependent upon clinical
preferences and patients’ individual needs…keeping in mind that the multi-modal approach is
designed, among other things, to be opioid-sparing. This is precisely because it is a settled
matter in human medicine that best way to avoid opioid AE’s is to minimize, insofar as
possible, the use of opioids (especially post-operatively). However, such wide biologic
variation exists in patient response to disease, trauma, surgery, pain, and drug intervention,
that one must prepared to encounter, recognize, and treat opioid AE’s.
In humans, the top 7 opioid AE’s include: Constipation, persistent nausea, dizziness/vertigo,
somnolesence/drowsiness, vomiting, dry skin/pruritis, and myoclonus/urinary retention. In
animals we do not have these metrics, but in an anecdotal, informal poll, the most frequently
perceived adverse effects were reported to be: Dysphoria (41%), nausea/constipation (15%),
ileus/constipation (13%), ineffectiveness (7%), respiratory depression (3%). 20% of DVM’s
reported not having observed adverse effects.57
Oral opioids: Veterinarians also tend not to prescribe oral opioids because of a perception that
there is minimal bioavailability and/or mu-agonist activity, but as discussed above with
hydrocodone and codeine, this is not the case; hydrocodone doses are reported at 0.22–0.5
mg/kg, and codeine at approx. 1 mg/kg.58 In this instance the author typically prescribes the
formulations in combination with acetaminophen: acetaminophen 325 mg + hydrocodone 5
mg or acetaminophen + codeine 15 mg (#2) for large dogs >70 lb and proportionately lower
doses for smaller dogs. These are Class III scheduled drugs.
Opioids for all their effectiveness may create clinical challenges as well. In the acute setting,
opioid-induced dysphoria, hyperalgesia, and respiratory depression may be encountered;
recognizing (note: opioids cause mydriasis in cats,59 miosis in other species) and having
strategies for counteracting their signs will minimize the complications that they present.60 In
the chronic setting, currently infrequently utilized in veterinary medicine (arguably
inappropriately so), the most commonly reported in humans by far is constipation; but
abnormal pain sensitivity, hormonal changes, and immune modulation are also reported
though their mechanisms are not fully established.61
Fortunately, novel Peripherally Acting Mu Opioid Receptor Antagonists (PAMOR) are in the
final stages of development; taken with an oral opioid, PAMORs will permit the central
analgesic effect of the opioid but block their effect on gastrointestinal motility. Additionally,
microdoses of the mu-antagonist naloxone added to patient morphine PCA have diminished
opioid-associated adverse events.62 Such medications hold great promise in minimizing
constipation and other peripheral AE’s, which commonly forces the withholding of opioids.63
A final word is warranted on newly-illuminated confounders to opioid effectiveness and the
development of opioid tolerance and resistance. Several drugs are being actively investigated
for their anti-glial activity, and we can likely expect to see them in common use with opioids.
Drug
Other Names
Potency*
morphine
Generic
1
codeine
Generic
1/10
hydrocodone
Vicodin, generic w/ acetaminophen
6x
oxycodone
Percocet, oxy-Contin
3-6x
oxymorphone
Numorphan
10x
hydromorphone
Dilaudid, generic
8x
meperidine
Demerol
1/6
propoxyphene
Darvon
1/3-1/6
buprenorphine
Buprenex
25x
fentanyl
Sublimaze
100x
butorphanol
Torbugesic, Stadol
5x
*Potency is compared to morphine.
Drug
Single Dose
Dog
Cat
hydromorphone
0.05-0.2mg/kg SQ, IM, IV
0.05-0.2mg/kg SQ, IM, IV
morphine
0.1-1.0 mg/kg SQ, IM, IV
0.1-1.0 mg/kg SQ, IM, IV
buprenorphine
0.01-0.02 mg/ kg SQ, IM, IV
0.01-0.02 mg/ kg SQ, IM, IV
butorphanol
0.2-0.4mg/kg SQ, IM, IV
0.2-0.4mg/kg SQ, IM, IV
methadone
0.1 – 1.0 mg/kg SQ, IM, IV
0.05 – 0.5 mg/kg SQ, IM, IV
fentanyl
0.1-0.7 ug/kg/min
0.1-0.7 ug/kg/min
morphine
2-6 ug/kg/min
2-4 ug/kg/min
Opioids
CRI
Transdermal
fentanyl patch
1-2 ug/kg/hr
1-2 ug/kg/hr
Transmucosal
buprenorphine
0.01-0.02 mg/kg
(between teeth & gum)
0.01-0.02 mg/kg
(between teeth & gum)
hydromorphone
0.1 mg/kg
0.1 mg/kg
Oral
tramadol
1-5 mg/kg PO
1-3 mg/kg PO
hydromorphone
0.1 mg/kg PO
0.05 mg/kg PO
codeine
1.1-2.2 mg/kg PO
hydrocodone
0.5 mg/kg PO
Contraindicated in
acetaminophencontaining products
Adopted From: Your Patient Is Still In Pain--Now What? "Rescue Analgesia" (S7AP) WVC 2009 Posner LP,
DVM, DACVA; Papich, DVM, DACVCP
Referrences
1
Barkin RL, Iusco M, Barkin SJ. Opioids used in primary care for the management of pain: a pharmacologic,
pharmacotherapeutic, and pharmacodynamics overview, In: Weiner’s Pain Management, A Practical Guide for
Clinicians 7th ed., Boswell MV, Cole BE (Ed), Taylor & Francis, Boca Raton FL 2006, p. 791
2
Scotto di Fazano C, Vergne P, et al. Preventive therapy for nausea and vomiting in patients on opioid therapy for
non-malignant pain in rheumatology Therapie 2002; 57:446-449
3
Taylor PM, Robertson SA, Morphine, pethidine and buprenorphine disposition in the cat, J. Vet. Pharmacol.
Therap. 24, 391±398, 2001
4
Wegner K, Roberston SA, Kollias-Baker C, Sams RA, Muir WW. Pharmacokinetic and pharmacodynamic
evaluation of intravenous hydromorphone in cats. J Vet Pharmacol Therap 2004; 27: 329-336.
5
Niedfeldt RL, Robertson SA. Postanesthetic hyperthermia in cats: a retrospective comparison between
hydromorphone and buprenorphine. Vet Anaesth Analg. 2006 Nov;33(6):381-9.
6
Helle KE, Hao, et al. Comparative actions of the opioid analgesics morphine, methadone, and codeine in rat
models of peripheral and central neuropathic pain. J Pain. August 2005;116(3):347-58.
7
Helle KE, Hao, et al. Comparative actions of the opioid analgesics morphine, methadone, and codeine in rat
models of peripheral and central neuropathic pain. J Pain. August 2005;116(3):347-58.
8
Kukanich B, Lascelles BD, Aman AM, Mealey KL, Papich MG. J Vet Pharmacol Ther. 2005 Oct;28(5):461-6. The
effects of inhibiting cytochrome P450 3A, p-glyco-protein, and Gastric acid secretion on the oral bioavailability of
methadone in dogs.
9
Ritschel WA, Neub M, Denson DD. Meperidine pharmacokinetics following intravenous, peroral, and buccal
administration in beagle dogs. Methods Find Exp Clin Pharmacol 1987 Dec. 9, (9)12:811-5
10
Kukanich B. Lascelles BD, Papich MG. Pharmakokinetics of morphine and plasma concentrations of morphine6-glucoronide following morphine administration to dogs. J Vet Pharmacol Ther 2005;28:371-6.
11
Matsumoto AK. Oral extended-release oxymorphone: a new choice for chronic pain relief, Expert Opinion
Pharmacother, 2007 Jul; 8(10): 1515-27
12
Aragon CL, Read MR, Gaynor JS, et al. Pharmacokinetics of an immediate and extended release oral
morphine formulation utilizing the spheroidal oral drug absorption system in dogs. J Vet Pharmacol Ther. 2009
Apr;32(2):129-36
13
Doohoo S, Tasker RA, Donald A. Pharmacokinetics of parenteral and oral sustained-release morphine sulphate
in dogs. J Vet Pharmacol Ther. 1994 Dec;17(6):426-33
14
Doohoo SF, Tasker, RA. Pharmacokinetics of oral morphine sulfate in dogs: a comparison of sustained release
and conventional formulations. Can J Vet Res. 1997 Oct;61(4):251-5.
15
KuKanich B. Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and
codeine-6-glucuronide in healthy Greyhound dogs. J Vet Pharmacol Ther. 2010 Feb;33(1):15-21.
16
Kuckanich B, Paul J. Pharmacokinetics of Hydrocodone and Its Metabolite Hydromorphone After Oral
Hydrocodone Administration to Dogs ACVIM 2010
17
Kukanich B, Lascelles BD, Aman AM, Mealey KL, Papich, et al J Vet Pharmacol Ther. 2005 Oct;28(5):461-6.
The effects of inhibiting cytochrome P450 3A, p-glyco-protein, and Gastric acid secretion on the oral bioavailability
of methadone in dogs.
18
Barnhart MD, et al. Pharmaokinetics, pharmacodynamics, and analgesic effects of morphine after rectal,
intramuscular, and intravenous administration in dogs. Am J Vet Res 2000; 61:24-28.
19
Wilder-Smith CH, Hill L, Spargo K, et al. Treatment of severe pain from osteoarthritis with slow-release
tramadol or dihydrocodeine in combination with NSAID's: a randomised study comparing analgesia,
antinociception and gastrointestinal effects. Pain 2001;91:23-31.
20
Katz WA. Pharmacology and clinical experience with tramadol in osteoarthritis. Drugs 1996;52 Suppl 3:39-47
21
McMIllan CJ, Livingston A, Clark CR et al. Pharmacokinetics of intravenous tramadol in dogs. Can J Vet Res.
2008 Jul;72(4):325-31.
22
Giorig M, Del Carlo S. Saccomanni G. Pharmacokinetics of tramadol and its major metabolites following rectal
and intravenous administration in dogs. N Z Vet J. 2009 Jun;57(3):146-52.
23
Pyependop BH, Ilkiw JE. Pharmacokinetics of tramadol, and its metabolite O-desmethyl-tramadol, in cats. J
Vet Pharmacol Ther. 2008 Feb;31(1):52-9.
24
Brondani JI, Loureiro Luna SP, Beier SL, Minto BW, Padovani CR. Analgesic efficacy of perioperative use of
vedaprofen, tramadol or their combination in cats undergoing ovariohysterectomy. J Feline Med Surg. 2009
Jun;11(6):420-9
25
http://www.accessdata.fda.gov/drugsatfd ... rmR_P2.pdf p. 60-62
26
http://www.tga.gov.au/pdf/auspar/auspar-palexia.pdf p. 9
Lascelles BD, Robertson SA, Taylor PM, et al. Proceedings of the 27th Annual Meeting of the American
College of Veterinary Anesthesiologists, Orlando, Florida, October 2002
28
Robertson SA, Taylor PM, Sear JW. Systemic uptake of buprenorphine by cats after oral mucosal
administration. Vet Rec. May 2003;152(22):675-8
29
Abbo LA, Ko JC, Maxwell LK, et al. Pharmacokinetics of buprenorphine following intravenous and oral
transmucosal administration in dogs. Vet Ther 208; 9(2):83:93
30
Howard, Nalbuphine in the Successful Long-Term Daily Management of Chronic Severe Pain: a First Report
Am J Pain Mgmt 16(1) Jan 2006
31
LaVincenta SF, White JM, Somogyi AA, et al. Enhanced buprenorphine analgesia with the addition of ultra-lowdose nalaxone in healthy subjects. Clin Pharm & Ther 83:144-52, 2008
32
Smith LJ, KuKanich B, Hogan BK, Brown C, Heath TD, Krugner-Higby LA. Pharmacokinetics of a controlledrelease liposome-encapsulated hydromorphone administered to healthy dogs. J Vet Pharmacol Ther. 2008
Oct;31(5):415-22.
33 2
Krugner-Higby L, Smith, L, Schmidt B, Wunsch L, Smetana A, Brown C, Heath TD. Experimental
Pharmacodynamics and Analgesic Efficacy of Liposome-Encapsulated Hydromorphone in Dogs. J Am Anim Hosp
Assoc 2011; 47:185–195.6
34
Krugner-Higby L, KuKanich B, Schmidt B, Heath TD, Brown C. Pharmacokinetics and behavioral effects of
liposomal hydromorphone suitable for perioperative use in rhesus macaques. Psychopharmacology (Berl). 2011
Aug;216(4):511-23.
35
Krugner-Higby L, KuKanich B, Schmidt B, Heath TD, Brown C, Smith LJ. Pharmacokinetics and behavioral
effects of an extended-release, liposome-encapsulated preparation of oxymorphone in rhesus macaques. J
Pharmacol Exp Ther. 2009 Jul;330(1):135-41.
36
Krugner-Higby L, Smith L, Clark M, Heath TD, Dahly E, Schiffman B, Hubbard-VanStelle S, Ney D, Wendland
A. Liposome-encapsulated oxymorphone hydrochloride provides prolonged relief of postsurgical visceral pain in
rats. Comp Med. 2003 Jun;53(3):270-9.
37
Clark MD, Krugner-Higby L, Smith LJ, Heath TD, Clark KL, Olson D. Evaluation of liposome-encapsulated
oxymorphone hydrochloride in mice after splenectomy. Comp Med. 2004 Oct;54(5):558-63.
38
Smith LJ, Krugner-Higby L, Clark M, Wendland A, Heath TD. A single dose of liposome-encapsulated
oxymorphone or morphine provides long-term analgesia in an animal model of neuropathic pain. Comp Med.
2003 Jun;53(3):280-7.
39
Kyles AE, Hardie EM, Hansen BD, Papich MG. Comparison of transdermal fentanyl and intramuscular
oxymorphone on post-operative behaviour after ovariohysterectomy in dogs. Res Vet Sci. 1998 NovDec;65(3):245-51.
40
Glerum LE, Egger CM, Allen SW, Haag M. Analgesic effect of the transdermal fentanyl patch during and after
feline ovariohysterectomy. Vet Surg. 2001 Jul-Aug;30(4):351-8.
41
Egger CM Plasma fentanyl concentrations in awake cats and cats undergoing anesthesia and
ovariohysterectomy using transdermal administration, Vet Aneasth Analg 2003 30:229-36
42
Kyles AE, Papich M, Hardie EM. Disposition of transdermally administered fentanyl in dogs. Am J Vet Res
1996 57: 715-719
43
Lee DD, Papich MG, Hardie EM. Comparison of pharmacokinetics of fentanyl after intravenous and
transdermal administration in cats. Am J Vet Res 2000; 61 (6): 672-677.
44
Park I, Kim D, Song J, In CH, Jeong SW, Lee SH, Min B, Lee D, Kim SO. Buprederm, a new transdermal
delivery system of buprenorphine: pharmacokinetic, efficacy and skin irritancy studies. Pharm Res. 2008
May;25(5):1052-62.
45
Murrell JC, Robertson SA, Tyalor PM, McCown JL, Bloomfield M, Sear JW. Use of a transdermal matrix patch
of buprenorphine in cats: preliminary pharmacokinetic and pharmacodynamic data. Vet Rec. 2007 Apr
28;160(17):578-83
46
Andaluz A, Moll X, Ventrua R, Abellan R, Fresno L, Garcia F. 2009. Plasma buprenorphine concentrations
after the application of a 70-ug/h transdermal patch in dogs. Preliminary report 2009.. J Vet Pharmacol Ther
32:503-505.
47
Pieper K, Schuster T, Levionnois O, Matis U, Bergadano A. Antinociceptive efficacy and plasma
concentrations of transdermal buprenorphine in dogs. Vet J. 2011 Mar;187(3):335-41
27
48
Moll X, Fresno L, Garcia F, Prandi, Andaluz A. Comparison of subcutaneous and transdermal administration of
buprenorphine for pre-emptive analgesia in dogs undergoing elective ovariohysterectomy. Vet J. 2011
Jan;187(1):124-8.
49
SR Veterinary Technologies. [Internet]. 2010. [Cited July 2012]. Available at:
http://www.wildpharm.com/documents/Buprenorphine_info_sheet.pdf
50
Veterinary Information Network Anesthesia & Analgesia Message Boards, International Veterinary Academy of
Pain Management Listserve Forum
51
SR Veterinary Technologies, Comparison of sustained-release buprenorphine and transmucosal buprenorphine
in cats. Clinical Research Bulletin, Jan 2011; Apr 2011
52
SR Veterinary Technologies, Irritability and pharmacokinetics of two sustained release buprenorphine
formulations (buprenorphine HCl SR TRI and buprenorphine HCl SR NMP) in Cats, March 2012
53
Catbagan DL, Quimby JM, Mama KR, Rychel JK, Mich PM. Comparison of the efficacy and adverse effects of
sustained-release buprenorphine hydrochloride following subcutaneous administration and buprenorphine
hydrochloride following oral transmucosal administration in cats undergoing overariohysterectomy. Am J Vet
Res. 2011 Apr;72(4):461-6.
54
Wildlife Pharmaceuticals, internal research.
55
SR Veterinary Technologies, Pharmacokinetic properties of novel sustained release buprenorphine and
meloxicam formulations in rats. Clinical Research Bulletin 2011
56
Foley PL, Liang H, Crichlow AR. Evaluation of a sustained-release formulation of buprenorphine for analgesia
in rats. J Am Assoc Lab Anim Sci. 2011 Mar;50(2):198-204.
57
Epstein, ME “Opioids: A Practical Guide and New Developments.” North American Veterinary Conference,
2012
58
Plumb’s Veterinary Drug Handbook, 7th Ed. Plumb DC. PharmaVet Inc., Stockholm, WA; Wiley Blackwell,
Ames IA. 2011
59
Robertson SA. Pain management in the cat. In: Gaynor JS, Muir WM ed (s) Handbook of Veterinary Pain
Management., Mosby, St. Louis, MO: 2009 p. 415-436.
60
Carr, DB (Ed.) Opioid Side Effects, In: IASP Pain Clinical Updates, April 2007 XV:2
61
Carr, DB (Ed.) Opioid Side Effects, In: IASP Pain Clinical Updates, April 2007 XV:2
62
Cepeda MS, Alvarez H, Morales O, et al. Addition of ultralow dose naloxone to postoperative morphine PCA:
unchanged analgesia and opioid requirements but decreased incidence of opioid side effects. Pain 107:41-46,
2004
63
Gervitz C. Update on the management of opioid-induced constipation, Topics In Pain Management, Oct. 2007
23(3): 1-5