Tanya Duke-Novakovski
Morphine was first isolated in 1804 by the German pharmacist, Friedrich Sert¨urner, who also reported its respiratory depressant effects. Codeine was isolated in 1832 and papaverine in 1848.
Although it is possible to synthesize morphine, it is easier to derive it from the dried latex obtained from the opium poppy (Papaver somniferum). Legal production is controlled by the United Nations Single Convention on Narcotic Drugs and other international drug treaties. Innovative ways to extract morphine from the poppy devel-oped during World War II due to demands for potent analgesics.
Morphine remains the opioid to which all others are compared.
TERMINOLOGY
“Opium” is derived from Greek and means “juice.” The poppy plant is a source of 20 alkaloids of opium and contains up to 12%
morphine. Other naturally occurring alkaloids include codeine, the-baine, papaverine, and noscapine. An “opiate” is derived from opium. An “opioid” refers to all exogenous substances whether natural or synthetic that can bind to opioid receptors and produce a morphine-like effect. Opioids can produce analgesia without loss of touch, proprioception, or consciousness. Opioids are commonly classified into opioid agonists, agonist–antagonists, and antagonists (Figure 4.1).
STRUCTURE OF OPIOIDS
Two distinct chemical classes exist: phenanthrenes and benzyliso-quinolines. The phenanthrene group includes morphine, codeine, and thebaine, and other clinically useful opioids. There is a close relationship between the stereochemical structure and the potency of opioids and, in most cases, it is the levorotatory isomer that is most active.
Semisynthetic opioids are based on morphine. Substitution of a hydroxyl group for a methyl group on carbon 3 results in methyl-morphine or codeine. Substitution of acetyl groups on carbons 3 and 6 results in diacetylmorphine (heroin). Thebaine does not have much opioid activity, but is the precursor for etorphine.
Synthetic opioids contain the phenanthrene nucleus but are not derived from opium. These include levorphanol, methadone deriva-tives, benzomorphan derivatives (pentazocine), and phenylpiperi-dine derivatives (meperiphenylpiperi-dine (pethiphenylpiperi-dine), fentanyl). The main
dif-ferences among these drugs are potency and rate of equilibration between the plasma and the site of drug effect (biophase).
OPIOID RECEPTORS
Opioid receptors belong to the large guanine (G) protein-coupled receptor family, which also includes muscarinic, adrenergic, gamma-aminobutyric acid (GABAB), and somatostatin receptors.
Opioid G-protein receptors consist of seven transmembrane units, with the inner end of the protein unit connected to cell signal-ing cascades that close voltage-sensitive calcium channels, stimu-late potassium efflux, and reduce cyclic adenosine monophosphate production. These actions generally decrease neuronal excitability through hyperpolarization of the cell, and inhibit release of neu-rotransmitters, including acetylcholine, dopamine, norepinephrine, substance P, and GABA.
Opioid receptors have been subclassified intoor OP3 or MOP receptors,or OP2 or KOP receptors,␦or OP1 or DOP recep-tors, and nociceptin/orphanin FQ peptide receptors (FQ or NOP), also referred to as ORL-1 receptors. These different classifica-tions arise from traditional pharmacology nomenclature (Greek symbols), International Union of Pharmacology Recommendations (OP 1–3 classification) and molecular biology nomenclature (MOP, KOP, DOP, NOP). The Greek names will be used to describe recep-tor types throughout this chapter.
The opioid receptor system is integral to regulation of appetite, thermoregulation, stress responses, respiratory control, and pain (Pattinson, 2008). Endogenous endorphins activate the -opioid receptor, enkephalins activate the- and␦-opioid receptors, dynor-phins activate-receptors, and nociceptin/orphanin peptides acti-vate the FQ/ORL-1 receptor.
The-opioid receptors are principally involved in spinal (sub-stantia gelatinosa) and supraspinal (periaqueductal gray area, amyg-dala, corpus striatum, and hypothalamus) analgesia. Activation of
1is speculated to produce profound analgesia, whereas stimula-tion of2receptors results in respiratory depression (hypoventila-tion), vagal effects (bradycardia), and physical dependence. Seda-tion is also a prominent effect of-opioid receptor activation and can be useful for premedication, chemical restraint/immobilization techniques, and for providing postoperative sedation. Common exogenous-opioid agonists used in veterinary medicine include
Pain Management in Veterinary Practice, First Edition. Edited by Christine M. Egger, Lydia Love and Tom Doherty.
C2014 John Wiley & Sons, Inc. Published 2014 by John Wiley & Sons, Inc.
41
(a) (b)
(c) (d)
Agonist opioid (Morphine)
Partial agonist opioid (Buprenorphine)
Partial activation of μ-receptor
Partial agonist
Log dose
Opioid Agonist–Antagonist (Butorphanol)
Antagonist
No activation of receptors Opioid antagonist
(Naloxone)
Increase Log dose Increase
Log dose Increase AnalgesiaIncrease
AnalgesiaIncrease AnalgesiaIncrease
AnalgesiaIncrease
Log dose Increase
Agonist opioid
Agonist + partial agonist
Agonist opioid Agonist
opioid Agonist
Agonist
Agonist + antagonist
Agonist–
antagonist (κ-interaction)
Agonist + agonist–
antagonist (blocking action
at μ-receptor) Activation of κ-receptor
but occupation without action at the μ-receptor
Agonist
Agonist Both receptors
activated Opioid actions μ
κ
μ κ
μ κ
μ κ
μ κ μ
κ
μ κ
μ κ
Figure 4.1. Opioid receptor interactions. A lock-and-key analogy is used to illustrate different drug interactions at l- andj-receptors. A relative dose–response curve for analgesic potency is diagrammed. (a) An opioid agonist stimulates bothl- andj-receptors, resulting in increased analgesic effect with increased dose. (b) A partial agonist weakly stimulates thel-receptor to achieve a reduced maximum analgesic effect compared with a full agonist. A large dose of a partial agonist will block the receptor actions of the full agonist and this moves its dose–response curve to the right and depresses the maximal analgesic response. Buprenorphine, a commonly used partial agonist, has very strong receptor binding so that even with very large doses of an agonist, the limited analgesic effect of buprenorphine predominates. (c) Complete opioid antagonists possess no intrinsic activity but block thel- andj-receptors. Because of the competitive nature of the binding at the receptors, more agonist is required in the presence of antagonist to produce its full analgesic effect. (d) Agonist–antagonists have mixed activity at the two receptor types. Most, such as nalbuphine or butorphanol, have agonist activity atj-receptors and antagonist activity atl-receptors. In the presence of a fulll-agonist, these opioids tend to act as antagonists and increase the dose of full agonist required to achieve maximum analgesic effect. (Modified from Maddison.
J., Page, S., and Church, D.Small Animal Clinical Pharmacology, Elsevier 2008, p. 312. with permission.)
4 / Opioids 43 morphine, L-methadone, meperidine (pethidine), fentanyl,
sufen-tanil, alfensufen-tanil, remifensufen-tanil, etorphine, and carfentanil. Buprenor-phine is a partial-agonist, occupying but not fully activating the receptor. Naloxone is a specific antagonist with high affinity for the -opioid receptor, but with no intrinsic activity. Naltrexone also has antagonist activity, but with a longer duration compared to naloxone.
-Receptors mediate spinal analgesia, mild sedation, and miosis, and cause less respiratory depression and vagally mediated brady-cardia than-receptor activation. Dysphoria and diuresis may occur through activation of calcium-channel-linked receptors.-opioid agonists are usually reserved for mild to moderate pain.-agonists may not be as useful as-opioid agonists for controlling severe forms of pain, but can help to alleviate visceral pain (Kalpravidh et al., 1984a, 1984b; Muir & Robertson, 1985; Houghton et al., 1991; Ide et al., 2008). Opioid agonist–antagonists stimulate -opioid receptors, are antagonistic to the-opioid receptor and, in veterinary medicine, include pentazocine, nalbuphine, and butor-phanol. Buprenorphine exhibits antagonism at-receptors.
␦-Receptors may modulate-opioid receptors. There are no spe-cific␦-opioid agonists in use in veterinary medicine.
The function of the FQ peptide/ORL-1 receptor is still under intense research (Chiou et al., 2007). Spinally localized antinoci-ceptive and supraspinally mediated pronociantinoci-ceptive effects have been documented (Rizzi et al., 2006).
PERIPHERAL OPIOID EFFECTS
Peripheral analgesic effects of opioids may be due to activation of opioid receptors located on primary afferent neurons. Inflamma-tion increases synthesis, axonal transport, and expression of opioid receptors on nociceptive afferents. Activation of these receptors decreases the release of excitatory neurotransmitters.
BASIC OPIOID PHARMACOKINETICS
Opioids are generally metabolized through the hepatic microsomal enzyme system, and metabolites are eliminated through biliary or renal excretion. There are differences in the metabolism of opioids among species, and some metabolites are active.
The lungs play an important role in the pharmacokinetics of opioids and may act as a “sink” or play an active role in metabolism.
Most drugs handled by the lungs are basic amines with a pKa greater than 8. Opioids taken up by the lungs include fentanyl, sufentanil, alfentanil, meperidine, methadone, morphine, and codeine. The first pass uptake of fentanyl and sufentanil into the lungs is large, with 75% and 61% of the administered dose of fentanyl and sufentanil remaining in the lungs, respectively. Pulmonary uptake of alfentanil is around 10% of the administered dose (Boer, 2003). Morphine is taken up and bound in very limited amounts, but not metabolized.
Meperidine and methadone are significantly taken up into the lungs, but meperidine is not metabolized, and methadone metabolism is minimal.
Buprenorphine, butorphanol, alfentanil, sufentanil, and methadone pharmacokinetics do not appreciably change in humans with renal failure, but hydromorphone can accumulate and toxicity has been reported. Tramadol and sufentanil are reportedly safe to administer to patients with renal dysfunction, but respiratory depression from tramadol accumulation was observed in a human
patient with renal failure. Fentanyl may accumulate in critically ill patients, but appears to be safe in patients with mild renal impairment. Patients with renal failure may be more prone to the respiratory depressant effects of potent opioids, with the exception of remifentanil. Metabolism of morphine is altered in patients with renal failure, resulting in accumulation of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G); thus, care should be taken with repeat dosing of morphine. Meperidine is not affected by renal failure, but the metabolite normeperidine is not excreted as efficiently and is proconvulsant.
Age-related changes in opioid metabolism occur, and meperidine elimination half-life increases in dogs older than 10 years of age (63 minutes compared to 37 minutes, after IV injection; 146 min-utes compared to 51 minmin-utes, after intramuscular (IM) injection) (Waterman & Kalthum, 1989, 1992).
SIDE EFFECTS OF OPIOIDS
Opioids are widely used in pain management regimens, but they do have side effects that may require attention. Some side effects could be considered useful, such as sedation in the perioperative period.
Drug-specific side effects will be discussed in the individual drug sections.
Respiratory System
Dose-dependent respiratory center depression is observed with
-opioid agonists in particular. The2-opioid receptors decrease the responsiveness of neurons in the medullary respiratory center to carbon dioxide, and the corresponding decrease in pH and hyper-capnia results. Coadministration of opioids with other anesthetic agents and sedatives can compound the depressant effects to the point where hypoventilation occurs or ventilation ceases. Patients may require artificial ventilatory support and oxygen therapy. Stim-ulation of-opioid receptors does not have as profound an effect on the respiratory system (MacCrackin et al., 1994). Humans are more susceptible to opioid-induced respiratory depression compared to animals (Pattinson, 2008). Veterinarians must be aware of the sen-sitivity of humans to respiratory depression when sending patients home with fentanyl patches (Martin et al., 2006; Schmiedt & Bjor-ling, 2007), or when other opioid medications are prescribed for owners to administer to their pets (Lust et al., 2011; George et al., 2010; Haymarle et al., 2010).
Pain stimulates the respiratory center and can offset the respi-ratory depression caused by opioids. If breakthrough pain is con-trolled using another drug or technique, concurrent opioid-induced respiratory depression becomes more evident and should be antic-ipated. An excellent review of the effects of opioids and details of their action on the respiratory center is available (Pattinson, 2008).
Cardiovascular System
Opioids are often used in patients with cardiovascular instability as these drugs, at clinical doses, have minimal effects on cardiac out-put, cardiac rhythm, and arterial blood pressure. The-opioid ago-nists cause bradycardia through stimulation of the vagal nucleus, and this is the most noticeable clinical effect. The increased vagal tone can be reversed with anticholinergic drugs. Rapid IV adminis-tration of high doses of morphine, and especially meperidine, will cause histamine release, vasodilation, and hypotension (Kalthum
& Waterman, 1988). Potent-opioid agonists can be used in some
44 Section 2 / Pharmacology of Analgesic Drugs clinical situations to decrease heart rate and ventricular
arrhythmo-genicity.
Gastrointestinal System and Emesis
-Agonist opioids cause emesis by direct stimulation of dopamine receptors in the chemoreceptor trigger zone (CRTZ), located out-side the blood–brain barrier in the area postrema of the medulla.
Apomorphine acts at this site and dopamine antagonists can help prevent emesis. More lipid-soluble opioids are thought to act on the vomiting center inside the blood–brain barrier and have an inhibitory effect (Blancquaert et al., 1986). There is individual vari-ability in the emetic response and species differences exist. Horses, rabbits, ruminants, and swine do not vomit after-opioid agonist administration. Cats and dogs do vomit, but dogs appear to be more sensitive to opioid-induced emesis. Interestingly, dogs usually do not vomit when opioids are administered IV or when -opioid agonists are administered to dogs in pain. Whether or not emesis occurs is the final result of excitatory actions on the CRTZ and inhibitory actions on the vomiting center, and is related to the dose and lipophilicity of the drug. High doses of morphine and clinical doses of fentanyl do not produce emesis in dogs, whereas clini-cal doses of morphine do cause emesis (Blancquaert et al., 1986).
The use of antidopaminergic drugs, such as acepromazine, prior to administration of opioids decreases the incidence of vomiting (Valverde et al., 2004). There are also differences among individ-ual opioids in dogs. Morphine and hydromorphone appear to cause emesis more often compared to meperidine, methadone, tramadol, and fentanyl (Valverde et al., 2004; Monteiro et al., 2008, 2009).
Other gastrointestinal effects are mediated through - and ␦ -opioid receptors located within the mesenteric plexus of the gastrointestinal tract (GIT). Stimulation of these receptors causes defecation in dogs, and occasionally causes defecation in cats. Fol-lowing this initial effect, there is reduced propulsion that can lead to ileus and constipation. Horses and ruminants are particularly sen-sitive to these effects, and this has led to reluctance to use opioids for postoperative analgesia in these species. Some studies indicate that morphine administration increases the risk of ileus, but other studies do not support the correlation (Doherty, 2009). It appears that using morphine infusions intra-operatively does not increase the risk of postoperative colic in horses, although administration for longer than 24 hours may do so (Boscan et al., 2006a). Dogs and cats appear to succumb to the GIT effects with longer-term opioid treatment regimens and side effects may be managed with stool softeners and, if possible, physical activity such as walking.
Acute postoperative ileus in cats and dogs can be managed with drugs, such as metoclopramide (Graves et al., 1989), that stimulate propulsion. In horses, methynaltrexone, a peripherally acting opi-oid antagonist, reversed the effects of morphine on gut motility, but does not have prokinetic effects per se (Boscan et al., 2006b).
In humans, morphine and fentanyl increase the tone of the sphinc-ter of Oddi, leading to increased bile duct pressure ranging from 99% with fentanyl to 53% with morphine and 61% with meperidine.
The incidence of clinical problems in humans is 3% with use of fen-tanyl (Radnay et al., 1980). There are anatomical differences among species that may complicate the extrapolation of findings in studies using primates to canines or felines. In humans, denial of potent analgesics for fear of promoting pancreatitis or cholangitis is now considered unwise. It is also unknown how the effects on bile duct pressure relate to the pancreatic duct (Thompson, 2001). Despite
no proof that-opioid agonists aggravate pancreatitis in veterinary medicine, there are still reports that morphine should be avoided and meperidine or buprenorphine used instead (Zoran, 2006). In treating severe pain from pancreatitis, potent opioids should not be withheld (Dyson, 2008).
- Opioid-induced increased pyloric sphincter tone may create problems during endoscopy or foreign body removal, though this is anecdotal. One study evaluated ease of passage of the endoscope into the duodenum with hydromorphone or butorphanol in cats, and found no differences between opioids (Smith et al., 2004a).
Butorphanol can be used to reverse the-opioid effects during the procedure if problems are observed (MacCrackin et al., 1994).
In dogs, gastroesophageal reflux under anesthesia can cause post-operative esophageal strictures (Wilson & Walshaw, 2004) or lead to aspiration if the airway is unprotected (Java et al., 2009). Meperi-dine was shown to reduce the incidence of gastroesophageal reflux compared to morphine (Wilson et al., 2007). If regurgitation occurs, esophageal lavage should be performed and the airway protected.
Thermoregulatory Center
Opioids act at the thermoregulatory center in the hypothalamus and effects on thermoregulation are clinically observable. Hyperthermia after opioid administration has been reported in cats (Wesley &
Cumby, 1978; Posner et al., 2010), horses (Carregaro et al., 2006;
Thomasy et al., 2006), swine (Bossone & Hannon, 1991), and ruminants (Caulkett et al., 2000; Uhrig et al., 2007), and may be partly linked to increased locomotor activity in these species. In one study, the resulting hypermetabolic state was probably due to using greater doses of morphine than are used clinically (Bossone
& Hannon, 1991).
In cats, the increase in body temperature is normally mild (Gel-lasch et al., 2002) but recently, hydromorphone was implicated in an increase in temperature greater than 41.7◦C (107◦F) (Niedfeldt &
Robertson, 2006; Posner et al., 2007). A controlled study examined these effects in more detail and found that all-opioid agonists and partial-opioid agonists can produce a mild to moderate increase in body temperature, which did not appear to be dose dependent.
The authors caution that greater doses than those studied may still have a significant effect (Posner et al., 2010). Sedative doses of ketamine may also increase body temperature, but ketamine did not appear to exaggerate the effects of the coadministered opioid (Posner et al., 2010).
Panting is a well-recognized side effect of administration of -opioid agonists to dogs, due to lowering of the thermoregulatory set point, and the incidence can be reduced by 20–30% with coad-ministration of acepromazine (Smith et al., 2001; Monteiro et al., 2008). Hypothermia appears to be more common than hyperther-mia in canines with administration of opioids, and the combination of opioid and acepromazine can further promote the decrease in body temperature (Monteiro et al., 2008, 2009).
Shivering
Opioid receptors appear to be involved in the act of shivering. IV administration of-opioid agonists, such as low-dose meperidine and tramadol, have been used to limit postoperative shivering unre-lated to hypothermia in patients where the subsequent increased metabolic demand may give cause for concern (Mohta et al., 2009).
Human patients are more likely to shiver with the sudden with-drawal of remifentanil, and pre-emptive ketamine administration
4 / Opioids 45 can prevent this (Nakasuji et al., 2010). No reports on these effects
of remifentanil have been published in the veterinary literature.
Antitussive Actions
Depression of the cough reflex is an effect of opioid administration.
Vagal afferent information is normally processed in the brainstem, and the cough reflex is coordinated through efferent nerve activ-ity. The presence of a true cough reflex center is in dispute, but stimulation of the medulla or nucleus tractus solitarius can elicit a cough. Opioids, such as morphine, suppress these areas. Butor-phanol was originally marketed as an antitussive in dogs before it became popular as an analgesic, and is still used for this purpose (Cavanagh et al., 1976; Westermann et al., 2005). Butorphanol has 100 times the antitussive effect of codeine and 4 times that of mor-phine (Cavanagh et al., 1976). Codeine and hydrocodone are used specifically for suppression of the cough reflex in humans, but 0.6 mg/kg codeine had no antitussive effect in horses when given orally (Westermann et al., 2005).
Euphoria and Dysphoria
Sedation is the typical response to opioids observed in pain-free dogs, monkeys, and humans, but excitement or euphoria can be observed in pain-free mice, cats, horses, goats, sheep, pigs, and cows. Euphoria, in dogs, is described as excessive wakefulness and vocalization; whereas, in cats, euphoria causes rolling, “knead-ing,” and extreme friendliness. Dysphoria in dogs causes agitation, excitement, restlessness, excessive vocalization, and disorientation.
In cats, dysphoria causes fearful and apparent hallucinatory behav-ior, open-mouth breathing, agitation, vocalization, and pacing.
The use of opioids for pain control has been limited in species that exhibit dysphoria. Pain-free horses have increased locomotor activity and an excited look about them when given potent opioids (Pascoe et al., 1991). The dysphoric or euphoric response may not be observed if the patient was in pain before opioid administration.
The final response may be linked with the distribution of-,␦-, and-opioid receptors and subtypes within the central nervous system. Interestingly, within the species that are normally expected to respond to opioids with excitement are individuals that do not respond at all and appear normal. This has been observed with mice, cats, and horses. Stimulation of the-opioid receptor is known to produce dysphoria in most species.
Central dopamine release has been linked with increased opioid-induced locomotor activity in horses, and can be reversed using dopamine antagonists such as acepromazine (Tobin, 1978). A study investigating individual D1and D2receptor antagonists in horses treated with alfentanil failed to reduce locomotor activity and, in fact, the dopamine antagonists, including azaperone, also stimu-lated increased locomotor activity (Pascoe & Taylor, 2003). The authors concluded that opioid-induced dopamine release did not cause the excitatory behavior observed in horses. However, the general sedative effects of acepromazine and␣-2-adrenergic ago-nists have been used successfully with- and-opioid agonists in clinical situations to provide chemical restraint in horses and cats without producing excitement.
Opioids stimulate the oculomotor nucleus leading to miosis.
Species that respond to opioids with sedation will exhibit miosis, but the release of catecholamines in species which respond to opioids with excitement tends to override the stimulation of the
oculomo-tor center, and mydriasis is the final effect observed (Wallenstein &
Wang, 1979).
Urinary System
-opioid agonists cause inhibition of sacral parasympathetic ner-vous system outflow. This inhibition causes detrusor muscle relax-ation, an increase in bladder capacity, and urinary retention, and this is especially evident when opioids are used spinally or epidurally.
Increased antidiuretic hormone and plasma natriuretic peptide con-centrations with-agonists can cause decreased urine production.
-opioid agonists can decrease antidiuretic hormone release and cause diuresis.
Immunomodulatory Effects
Immunosuppressive properties of opioids are related more to their molecular structure than their antinociceptive potency. Morphine, fentanyl, codeine, and methadone are more immunosuppressive than hydromorphone, tramadol, oxycodone, and hydrocodone.
Buprenorphine and-opioid antagonists may enhance the immune system or have no effect. The -opioid receptor modifies cen-tral actions of the neuroendocrine axis, leading to a reduction in natural killer T-cell activity, lymphocyte proliferation, and inter-feron activity. Direct stimulation of-opioid and␦-opioid recep-tors on B lymphocytes, monocytes, and macrophages is pri-marily responsible for peripheral immunosuppression. Opioids generally induce the release of catecholamines that act on primary and secondary lymphoid organs to depress cell function. Morphine generally increases proinflammatory cytokine and decreases anti-inflammatory cytokine production in a dose-dependent manner.
However, opioids should be used if analgesic effects are required, because ongoing, untreated pain will detrimentally modulate the immune system more significantly than do opioids (Odunayo et al., 2010).
SPECIFIC-AGONISTS
Studies examining the pharmacokinetics of opioids in cats, dogs, and horses are summarized in Tables 4.1, 4.2, 4.3, and 4.4.
Morphine
Morphine has a pKa of 7.9, with 23% in the nonionized form at pH 7.4, and is approximately 30–40% protein bound. Morphine is a full agonist and acts at-,␦-, and-opioid receptors. Due to its relative hydrophilicity, morphine makes a slow transition into the central nervous system; however, the lag time is clinically not a deterrent and morphine has an action of 3–4 hours duration.
Generally, morphine is conjugated to M3G and M6G, although there may be alternative pathways in cats, possibly forming ethereal sulfates (Taylor et al., 2001). M6G has similar properties as mor-phine and contributes to analgesia, whereas M3G has little affinity for-opioid receptors and can produce excitatory effects. In dogs, concentrations of M6G after IV injection of morphine are much lower than those in humans (KuKanich et al., 2005a). Because M6G likely does not contribute significantly to the analgesic effects in dogs, the question arises as to the correct dosing schedule for dogs, and this has not yet been ascertained. To maintain the known anal-gesic plasma concentrations of morphine for humans (20 ng/mL) the dosing schedule of 0.5 mg/kg given IV or IM every 2 hours was
Table4.1.Summaryofstudiesexaminingthepharmacokineticsofopioidsinthecat.Furtherdetailscanbeobtainedfromthereferencesused(some dataexpressedwithstandarddeviationwhereavailable) DrugDose(mg/kg)RouteTmax(min)Clearance mL/min/kg Volumeof distribution atsteady state(L/kg)
Mean elimination half-life (hormin)Bioavailability (%)Reference Alfentanil0.05IVNA11.6±3.24.9±1.62.0hNAPascoeetal.,1993a Buprenorphine0.01IVNA16.77.17.0hNATayloretal.,2001 Buprenorphine0.01IM3.023.78.96.3hNATayloretal.,2001 Buprenorphine0.02IVNA9.34.86.2hNARobertsonetal.,2005b Buprenorphine0.02Buccal30.0NANANA116.3Robertsonetal.,2005b Butorphanol0.4IM21.012.9±57.6±6.36.3±2.3hNAWellsetal.,2008 Butorphanol0.4Buccal66.035.3±6.515.6±4.75.2±5.7h37.2Wellsetal.,2008 Fentanyl0.0072± 0.0012IVNA19.8±2.72.6±0.32.4±0.6minNALee,2000 Fentanyl0.01IV2.0NANANANARobertsonetal.,2005a Hydromorphone0.1IVNA24.63.01.7hNAWegneretal.,2004 Meperidine5.0IM10.020.85.23.6hNATayloretal.,2001 Morphine0.2IVNA24.12.61.3hNATayloretal.,2001 Morphine0.2IM15.013.91.71.6hNATayloretal.,2001 Remifentanil1.0g/kg/minInfusion5.07667.6317.4minNAPypendopetal.,2008a Tramadol2.0IVNA20.8±3.23.3±0.132.2±0.3hNAPypendop&Ilkiw,2007 Tramadol5.0Oral40±14NANA3.4±0.1h93±7Pypendop&Ilkiw,2007 Tramadol2.0IVNA14.9±6.11.9±0.41.9±0.7hNACagnardietal.,2011 NA,notavailableorapplicable;IV,intravenous;IM,intramuscular.
46
Table4.2.Summaryofstudiesexaminingthepharmacokineticsofopioidsinthedog.Furtherdetailscanbeobtainedfromthereferencesused (somedataexpressedwithstandarddeviationwhereavailable) DrugDose (mg/kg)RouteTmax
Clearance (mL/min/kg)
Volumeof distributionat steadystate (L/kg)Elimination half-lifeBioavailability (%)Referenceused Alfentanil1.6mg/ kg/minInfusionNA29.8±14.50.56±0.219.9±0.9minNAHokeetal.,1997 Buprenorphine0.015IV2(2–5)min5.4±1.91.6±0.34.5±2.2hNAKrotschecketal.,2008 Buprenorphine0.02IVNA∼23.5∼6.04.4±1.4hNAAndaluzetal.,2009a Buprenorphine0.02IVNA22.2±0.30.42±0.217.3±0.8minNAPieper,2011 Butorphanol0.25SC28.7±13min5.83±2.28.4±3.11.7±0.4hNAPfefferetal.,1980 Butorphanol0.25IM42.2±13min5.68±1.57.5±2.41.5±0.2hNAPfefferetal.,1980 Butorphanol0.25Epidural13.9min33.74.393.2hNATroncyetal.,1996 Codeine0.734IVNA303.2NANAKuKanich,2009 Codeine1.43Oral55.0minNANANA4.0KuKanich,2009 Fentanyl0.01IVNA77.95.045.7minNASanoetal.,2006 Hydromorphone0.1IVNA106.284.240.33minNAKuKanichetal.,2008a Hydromorphone0.1SC11.4min57.43.290.40minNAKuKanichetal.,2008a Methadone0.4IVNA27.9±7.39.2±3.33.9±1.0hNAIngvast-Larssonetal.,2010 Methadone0.5IVNA56.0±9.47.8±1.91.5±0.2hNAKuKanich&Borum,2008c Methadone0.4SC1.26±1.2hNANA10.7±4.3h79±22Ingvast-Larssonetal.,2010 Meperidine2.0IVNA77±8.33.1±0.636.6±6.0minNAKalthum&Waterman,1988 Meperidine2.0SC20.0minNANA57.6±7.6min0.11–0.13Waterman&Kalthum,1989 Morphine0.5IVNA85.27.21.6hNABarnhartetal.,2000 Morphine1.0IM5.0min91.26.81.4h119Barnhartetal.,2000 Morphine2.0Rectal5.0min88.46.11.1h16.5Barnhartetal.,2000 Morphine0.5IVNA62.5±10.44.6±0.21.2±0.2hNAKuKanichetal.,2005a Oxymorphone0.1IVNA52.34.10.48minNAKuKanichetal.,2008b Oxymorphone0.1SC13min48.34.20.59minNAKuKanichetal.,2008b Remifentanil0.5g/ kg/minInfusionNA63.1±18.10.22±0.15.6±0.6minNAHokeetal.,1997 Tramadol4.4IVNA54.6±8.23.8±0.90.8±1.2hNAKuKanich&Papich,2004 Tramadol11.0Oral1.04±0.5h52.3±24NA1.7±0.12h65±38KuKanich&Papich,2004 Tramadol4.0IVNA35.6±3.03.4±0.51.4±0.4hNAMcMillanetal.,2008 NA,notavailableorapplicable;IV,intravenous;IM,intramuscular;SC,subcutaneous.
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