Lesley J. Smith
Beginning in January 2001, the United States Congress declared the Decade of Pain Control and Research. However, the under-treatment of hospitalized human patients remains a significant clin-ical problem (Taylor et al., 2008). This issue likely can be extrapo-lated to veterinary medicine as well. Barriers to effective analgesia are varied, and are probably more challenging in veterinary patients than in human patients due to the inability to offer patient-controlled analgesia (PCA) to the veterinary patient population.
An “ideal” analgesic would be effective against a broad range of pain types, have a rapid onset and controllable duration, be free of adverse effects such as respiratory depression and sedation, lack clinically problematic metabolites, and be readily accessible and cost-effective. Perhaps most importantly in veterinary medicine, the “ideal” analgesic would also be easy and safe to administer, with a dosing interval that is extended enough to be convenient for the practitioner as well as to the owner at home. Lastly, the “ideal”
analgesic in veterinary medicine would be available in a formulation that prevents accidental access by children or illicit use by humans.
Many of the currently available analgesics in the veterinary world meet some of these criteria, but no currently available analgesic meets all of the above stipulations.
One of the barriers to finding the “ideal” analgesic is a current deficiency in drug delivery technology. Many of the available anal-gesics are effective, for example, opioids, but are not formulated in delivery systems that provide steady-state analgesia or extended duration in veterinary patients. In the last decade, the pharmaceuti-cal industry has made a focused effort to improve drug delivery sys-tems by incorporating known analgesics, for example, morphine, into novel delivery matrices. This focus has been largely driven by the human analgesic market, and many of these technologies are essentially variations on PCA. Thus, many of the newly mar-keted novel delivery systems are not practical for use in veterinary medicine. This chapter will not review variations of PCA in novel delivery systems (e.g., iontophoretic transdermal self-delivery sys-tems), because they are likely not practical or relevant to veterinary medicine.
This review will summarize the most relevant novel analgesic delivery systems or methods that are currently marketed for human application, with a focus on application in veterinary medicine, where appropriate. Some of the delivery systems that will be dis-cussed are not yet commercially available, but show promise in
research studies. Because this chapter is focused on delivery sys-tems, the analgesic merit of the actual drugs incorporated into those delivery systems will not be covered in depth.
TOPICAL DRUG DELIVERY SYSTEMS
Topical analgesics deliver the drug locally when they are applied directly over the area of interest. In most cases, low to clinically insignificant serum concentrations of the drug are attained, making topical systems relatively free of adverse effects. Formulations have been developed to improve absorption across human skin using penetration enhancers (Brown et al., 2006). Because these topical agents are designed for penetration of human skin, their efficacy in veterinary patients is uncertain, and many products have yet to be tested or studied in the veterinary population.
Eutectic Mixture of Local Anesthetics
One product that has received acceptance in veterinary medicine as a topical local anesthetic is eutectic mixture of local anesthetics (EMLA) cream. This formulation is a eutectic mixture of lido-caine and prilolido-caine that is effective in facilitating catheter place-ment in pediatric and adult humans (Taddio, 2001). Application of EMLA cream to the skin allows for a high concentration of the local anesthetic drugs at the site of catheter placement without systemic absorption. Two studies have been reported in cats on the use of EMLA cream. In one study, healthy cats (n=10) had 1 mL of EMLA cream applied to a shaved site over the jugular vein and wrapped with an occlusive bandage that was left in place for 1 hour (Gibbon et al., 2003). No cat in that study had measureable serum concentrations of local anesthetic and no methemoglobin was detected. Six cats were amenable to jugular catheter placement without sedation, and the other four cats required sedation, but had been apprehensive and difficult to handle prior to any interven-tion (Gibbon et al., 2003). In a second study, EMLA was assessed in clinically ill cats presented to a veterinary teaching hospital, and in need of jugular catheter placement (Wagner et al., 2006).
EMLA was applied, as in the previous study, and 60% of cats had jugular catheters placed without sedation, whereas 38% required sedation. While these data did not reach statistical significance (p= 0.06) a larger number of animals may have been needed to demon-strate a positive effect of EMLA cream. In the author’s experience,
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.
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116 Section 2 / Pharmacology of Analgesic Drugs application of EMLA to shaved skin of dogs, followed by a 20–
30 minute period during which the area is covered with a simple occlusive dressing (e.g., TegadermR covered with VetwrapR) in order to ensure continued contact of EMLA with the skin, substan-tially reduces struggling during catheter placement in unsedated or lightly sedated animals.
Needle-free Powder Lidocaine
A novel, needle-free powder lidocaine delivery system was recently developed for use in catheter placement in children. This prefilled system delivers dry powder lidocaine monohydrate through the epi-dermis by sealing the device against the skin and then pressing a button that releases pressurized helium from a microcylinder, caus-ing a 0.5 mg cassette of lidocaine to rupture with velocities sufficient to penetrate the skin. In one study, the use of this device resulted in significant reductions in reported pain on venipuncture (p<0.001), with no observable adverse effects on the overlying skin (Zempsky et al., 2008). While this system has potential application to vet-erinary patients, the company has since filed for bankruptcy, so a commercial product may not be forthcoming.
Lidocaine Patch
Like topical creams and gels, the concept behind the lidocaine patch is that the drug is absorbed across the skin for local deliv-ery to a painful area, with minimal systemic uptake or risk of adverse effects. Lidocaine is a sodium channel blocker that is most effective against rapidly firing ectopic impulses that are generated from injured neurons. In neuropathic pain states, such as diabetic neuropathy or post-herpetic neuralgia, ectopic impulse generation from sensory nerves is a hallmark of the painful condition. The Lidoderm 5% patchR (Endo Pharmaceuticals, Newark, DE) was recently approved by the FDA for the treatment of post-herpetic neuralgia (Galer et al., 2002). A recent PubMed search by the author could not identify any studies on the analgesic efficacy of the lidocaine patch in companion animals. One study demonstrated a lack of systemic absorption of lidocaine (as measured by ELISA) after two lidocaine 5% patches were placed on the carpi of healthy horses, but analgesia was not evaluated in that study (Bidwell et al., 2007). Similarly, pharmacokinetic studies in dogs (Ko et al., 2007) and cats (Ko et al., 2008) indicate minimal systemic absorption from lidocaine patches.
Nonsteroidal Anti-inflammatory Drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed analgesics whose mechanism is to inhibit the cyclooxy-genase (COX) class of enzymes, thereby reducing prostaglandin
production and reducing inflammation at sites of tissue injury. Many topical NSAIDs have been developed in human medicine, and the primary advantage is that peak plasma concentrations of the drug
are<10% of those that occur after oral intake of NSAIDs,
there-fore reducing the adverse effect profile associated with this class of drugs. Topical NSAIDs that have been developed in the form of cream, drops, foam, gel, ointments, patches, or sprays include diclofenac, ibuprofen, salicylic acid, ketorolac, flurbiprofen, fel-binac, ketoprofen, indomethacin, and piroxicam (Stanos, 2009). In a review of 86 trials of topical NSAIDs, it was found that the treat-ment was superior to a placebo for the relief of acute musculoskele-tal pain (Moore et al., 1998). In veterinary medicine, the only com-mercially available topical NSAID is SurpassR (Boerhinger Ingel-heim Vetmedica, Saint Joseph, MO) (Figure 9.1). Surpass is a 1%
diclofenac cream that has been shown to be effective against pain in horses with osteoarthritis when applied directly over the affected joint (Lynn et al., 2004). Other studies have confirmed the anal-gesic efficacy of SurpassR in experimentally induced osteoarthritis (Frisbie et al., 2009), and in horses with inflammation and under-going regional limb perfusion (Levine et al., 2009). Application of SurpassR to the skin does result in measureable urinary and serum concentrations of diclofenac for up to 10 days; thus, its use should be undertaken with knowledge of the clearance times in horses that are in active competition (Anderson et al., 2005) and that may be tested for NSAID administration.
Topical Capsaicin Cream
Capsaicin, derived from red chili peppers, has long been reported to have analgesic properties (Turnbull, 1850). More recently, cap-saicin has been shown to have analgesic benefits in various types of neuropathic pain states (The Capsaicin Study Group, 1991; Ellison et al., 1997). Capsaicin is an agonist at transient receptor poten-tial vanilloid type 1 (TRPV1) receptors, which are ligand-gated cation channels, expressed both centrally and peripherally, that respond to mechanical, thermal, and chemical stimuli, initiating action potentials along sensory neurons and ascending spinal tracts (Palazzo et al., 2010). Prolonged activation leads to downregula-tion of receptors and cytotoxicity of sensory neurons expressing TRPV1 channels. Activation of TRPV1 receptors by capsaicin ini-tially results in sensory neuronal depolarization, and the sensa-tions of heat, burning, stinging, or itching. High concentrasensa-tions of capsaicin or repeated applications, however, produce a persistent local effect on cutaneous nociceptors, described as defunctional-ization, that results in reduced spontaneous activity and a loss of responsiveness to a wide range of sensory stimuli (Anand &
Bley, 2011).
Figure 9.1. Surpass, 1% topical diclofenac (With permission from Boehringer Ingelheim Vetmedica, Inc.)
9 / Novel Methods of Analgesic Drug Delivery 117 In a review paper by Rains and Bryson (1995), depending on
the methodology, 28–55% of people with osteoarthritis reported a reduction in the visual analogue scale pain score after capsaicin cream was applied topically 3–4 times daily to the arthritic area.
Capsaicin cream (EquiblokR) has recently gained some popularity for the treatment of localized osteoarthritis in horses. The equine commercial capsaicin product contains 0.2% capsaicin, whereas the human product contains 0.075%. Despite being more concen-trated, there is no evidence that the 0.2% capsaicin cream penetrates equine skin. Repeated topical application may cause skin irritation.
Eye irritation can occur if the horse rubs its face near the area of application. There are no scientifically controlled published studies of the effectiveness of topical capsaicin cream for pain in horses with osteoarthritis.
TRANSDERMAL DELIVERY SYSTEMS
Unlike topical drug delivery systems, transdermal drug delivery centers on systemic uptake of the drug to create its analgesic effects.
Because of systemic uptake, dose-dependent adverse effects are of similar concern as for intravenous or other parenteral routes of administration. However, transdermal delivery systems offer the advantages of convenient “at home” catheter-free drug delivery, as well as an extended duration of effective use.
Fentanyl Patch
Fentanyl is a potentagonist opioid that has a well-established place in treating moderate-to-severe pain. Some unique properties of fentanyl include its high lipophilicity, which allows for rapid penetration into the central nervous system (CNS) and, therefore, a rapid onset of effect. Because of its high lipophilicity, however, fentanyl is rapidly redistributed to muscle and fat, which act as storage sites for a later re-release back into the plasma. Like other
opioids, fentanyl causes sedation in many veterinary patients, and dysphoria, nausea, constipation, urinary retention, and dose-dependent respiratory depression in some others. Fentanyl’s high lipid solubility and low molecular weight make it ideal for transder-mal delivery (Roy & Flynn, 1990). The traditional fentanyl patch, which is now available as a generic product in 12.5, 25, 50, and 100
g/h delivery sizes of fentanyl, is a four-layer system. The outer layer is an impermeable polyester/ethylene coating that protects the patch, the second layer is the drug reservoir and contains fentanyl gelled in hydroxyethyl cellulose, the layer behind the drug reser-voir is a rate-control membrane which is an ethylene-vinyl acetate copolymer that is more impermeable to fentanyl than skin and thus ensures the slow release of fentanyl across the membrane, and the last layer is a protective peel adhesive that is removed immediately prior to patch placement.
Recently, a novel matrix delivery system for fentanyl has been described that has release kinetics very similar to the reservoir sys-tem. In this system, fentanyl is incorporated directly into dipropy-lene glycol droplets that are within the adhesive coating (Sathyan et al., 2005). This more recent version of the fentanyl patch carries less likelihood for abuse due to the higher difficulty in access-ing the fentanyl within the patch. In veterinary patients, however, the cost of this patch compared to the traditional reservoir system is likely to outweigh any theoretical advantages with respect to illicit use.
Many studies have been conducted on the efficacy and safety of the fentanyl patch in veterinary patients, and an exhaustive review
of the literature is beyond the scope of this chapter. A few key points to mention are that systemic absorption of fentanyl from the patch varies with species, and effective plasma concentrations may not be reached for 6–24 hours (Egger et al., 2003; Hofmeister & Egger, 2004; Egger et al., 2007). Inter-individual absorption of fentanyl within species is also highly variable, so placement of a fentanyl patch does not guarantee that effective serum concentrations of fentanyl will be attained in that patient. Another point is that, at least in humans and cats, there is still a subcutaneous (SC) depot of fentanyl (approximately 30% of the total delivered dose) after the patch is removed that will continue to be absorbed for several hours (Portenoy et al., 1993; Lee et al., 2000). In addition, there is a risk of toxicity if a patch is ingested, and there is a case report describing profound sedation in a dog that ingested a fentanyl patch (Schmiedt & Bjorling, 2007).
There is a novel ‘patchless’ topical preparation of fentanyl (RecuvyraR) for application between the shoulder blades of dogs 2–4 hours prior to surgery. It is claimed that one application of RecuvyraR provides long-acting, continuous systemic delivery of fentanyl for up to 4 days (Linton et al., 2012). See Chapter 21 for further discussion of RecuvyraR.
Buprenorphine Patch
The buprenorphine patch has been evaluated to a limited extent in veterinary patients. This patch (Purdue Pharma, Cranberry NJ) was recently approved by the FDA for the treatment of moderate to severe pain in people. The patch is commercially available in sizes that deliver 35, 52.5, or 70 g/h. Like the fentanyl patch, the buprenorphine patch should deliver drug at a relatively con-stant rate in a convenient formulation without the risk of first-pass metabolism. Buprenorphine is considered a partialagonist whose analgesic properties have been evaluated in dogs and cats; however, a review of this extensive body of literature is beyond the scope of this chapter. Murrell et al. (2007) evaluated serum concentrations and thermal threshold as an analgesic test in healthy cats that had a 35g /h buprenorphine patch placed on the shaved skin of their lateral thorax. In that study, they found that buprenorphine absorp-tion was variable among cats, but all cats had measureable drug concentrations in serum by 6 hours after patch placement, accom-panied by mild sedation or euphoria (Murrell et al., 2007). The mean peak buprenorphine concentration was 10 ng/mL, but several cats exceeded that peak at individual time points and buprenorphine con-centrations remained well above zero for more than 24 hours after the patch was removed (Murrell et al., 2007). In the Murrell et al.
(2007) study, despite buprenorphine drug concentrations in the ther-apeutic range, there was no analgesic effect as evidenced by thermal threshold testing. This may have been because the test model was not appropriate or it may be that release rates of buprenorphine from the patch are slow enough to delay transfer into the CNS for effective analgesia. A recent study in dogs also reported variable serum drug concentrations after a 70 g/h buprenorphine patch was placed on a shaved area of the ventral abdomen in healthy beagles (Andaluz et al., 2009). In that study, drug concentrations increased during the first 36 hours after patch placement and peaked between 0.7 and 1.0 ng/mL (Figure 9.2). One dog had extremely low drug concentrations throughout the sampling period. These authors did not attempt to evaluate analgesia. From limited data available, it appears that the buprenorphine patch deserves further clinical investigation into its analgesic properties and assessment of inter-individual variability in drug absorption from the patch.
118 Section 2 / Pharmacology of Analgesic Drugs
Dog 1 Dog 2 Dog 3 Dog 4
0 0 1 2
20 40 60
Time (h)
80 100 120
Buprenorphine (ng/mL)
Figure 9.2. Plasma buprenorphine concentrations (ng/mL) in dogs after placement of a 70lg/h transdermal
buprenorphine patch (From Andaluz, A., Moll, X., Ventura, R., Abell ´an, R., Fresno, L., & Garc´ıa, F. (2009) Plasma buprenorphine concentrations after the application of a 70 lg/hour transdermal patch in dogs. Preliminary report.
Journal of Veterinary Pharmacology and Therapeutics, 32(5), 503–505. With permission.)
TRANSMUCOSAL DRUG DELIVERY
Like transdermal delivery systems, transmucosal drug delivery offers ease of drug administration while achieving therapeutic serum concentrations of the drug. Therefore, adverse effects of sys-temic drug administration pertain to transmucosal routes of deliv-ery. Of available analgesics perhaps fentanyl and buprenorphine have been the most intensively studied for transmucosal adminis-tration.
Oral Transmucosal Fentanyl
A fentanyl lozenge (FentoraR, Cephalon Inc., Frazer PA), which delivers 200, 400, 600, 800, 1200, or 1600g of fentanyl in a sugar base, has been developed for use in people. After the lozenge is placed in the mouth, approximately 25% of the total fentanyl avail-able is absorbed almost immediately across the buccal mucosa, leading to a 10–15 minute onset of effect and peak plasma fen-tanyl concentrations. The remaining amount of the drug is swal-lowed with saliva, and is subsequently slowly absorbed from the GI tract to maintain fentanyl at therapeutic concentrations for about 2 hours (Zhang et al., 2002). This product has not been evalu-ated in companion animal patients, and is unlikely to be practical given the need for contact time between the lozenge and the oral mucosa, which is approximately 14–25 minutes, in order to com-pletely dissolve the lozenge (Fentora Package Insert, December 2011).
Similarly, a fentanyl buccal tablet is newly available (EffentoraR) that uses an effervescent technology to enhance fentanyl uptake by transiently changing oral pH. This product provides almost imme-diate therapeutic concentrations with a higher peak serum concen-tration of drug than achieved with the lozenge. Like the fentanyl lozenge, this product is not likely to be practical in veterinary species. Both the fentanyl buccal tablet and the fentanyl lozenge
are intended for use in severe breakthrough pain in people who are already on a background regular dose of an opioid.
Oral Transmucosal Buprenorphine
Buprenorphine has been extensively studied in cats as an oral trans-mucosal analgesic, but the studies in dogs are limited. Buprenor-phine has close to 100% bioavailability when administered trans-mucosally to cats. Higher bioavailability in cats compared to other species is at least partially explained by differences in oral pH.
Oral pH of cats has been reported to range from 8 to 9, whereas humans have an oral pH ranging from 5.4 to 7.5. Buprenorphine is a weak base with a pKa of 8.24. Therefore, a high percentage of the drug would exist in the unionized form in the feline oral cavity, enhancing its absorption.
The adverse effects (e.g., mania, excitement, hyperthermia) reported in cats treated with fullopioid agonists are not as severe with buprenorphine. In cats, buprenorphine usually causes euphoria (purring, rolling, rubbing, and kneading with their forepaws) but rarely vomiting, nausea, or dysphoria (Robertson et al., 2003). Mild hyperthermia has been reported in cats after buprenorphine admin-istration (Posner et al., 2010). Using a thermal and mechanical threshold-testing device, subcutaneous administration of buprenor-phine resulted in slow onset, quick offset, and minimal antinocicep-tion in the cat (Steagall et al., 2007). Using the same thermal device method, Robertson et al. (2003) showed that oral transmucosal administration of buprenorphine in cats was as effective as the IV route (Robertson et al., 2003). In a clinical study of cats undergoing ovariohysterectomy, however, Giordano et al. (2010) showed that cats given buprenorphine by the IV and IM routes had significantly lower dynamic interactive visual analog scale pain scores than those given the drug by the SC and oral transmucosal routes. Also, in the latter two groups, there was a significantly higher incidence of treatment failure when compared with the IV and IM groups (Giordano et al., 2010). In the Giordano study (2010), cats were premedicated with medetomidine, and buprenorphine was admin-istered soon after anesthetic induction. The absorption of a drug through the oral transmucosal route is dependent on the regional blood flow, local temperature, and mucosal integrity. It is possi-ble that medetomidine could have caused local vasoconstriction, thereby contributing to poor systemic uptake of buprenorphine and therefore the poor analgesic effect observed after oral transmu-cosal administration. In that study, the dose of buprenorphine (0.01 mg/kg) was rather low, so it is possible that, had a larger dose been used, better analgesia would have been observed by the oral transmucosal route.
A recent study examined oral transmucosal buprenorphine in dogs (Abbo et al., 2008). In that study, 0.02 mg/kg or 0.12 mg/kg of buprenorphine were given by either the IV or oral transmucosal routes to healthy dogs. Bioavailability of buprenorphine after oral transmucosal administration was 38%+12% after the 0.02 mg/kg dose, and 47%+ 16% after the 0.12 mg/kg dose (Abbo et al., 2008). Peak plasma drug concentrations were similar between 0.02 mg/kg buprenorphine IV and 0.12 mg/kg buprenorphine transmu-cosal (Abbo et al., 2008). Given the relatively large volume of buprenorphine that would need to be administered to a dog to achieve a dose of 0.12 mg/kg transmucosally, and given the rela-tively low bioavailability reported in that study, oral transmucosal buprenorphine is probably not a practical or cost-effective analgesic option for dogs.
9 / Novel Methods of Analgesic Drug Delivery 119 Oral Transmucosal Methadone
Methadone has physicochemical properties similar to buprenor-phine, with a similar pK and, therefore, potentially similar bioavail-ability when administered via the oral transmucosal route. There are limited studies available as to the feasibility of using this opioid for analgesia via this route. One recent study demonstrated that methadone was indeed bioavailable after oral transmucosal admin-istration in cats (Ferreira et al., 2011). These authors demonstrated that 0.6 mg/kg of oral transmucosal methadone resulted in peak plasma concentrations 2 hours after administration, with greater sedation as compared with a lower dose (0.3 mg/kg) given IV.
The cats treated with oral transmucosal methadone were notably sedated for greater than 4 hours, and had evidence of analgesia for a similar time period, as assessed by mechanical pressure applied to the carpi. While these results are promising with respect to the use of methadone by this route in cats, further studies would be needed to prove that clinical analgesia (e.g., post-ovariohysterectomy) is achieved.
EXTENDED RELEASE ORAL OPIOIDS
Oral opioid formulations, both short- and long-acting forms, are the mainstay of pain medication for human beings. Some long-acting forms of morphine sulfate have been available in the United States for many years. The forms marketed as MS ContinR(Perdue Fred-erick, Stamford, CT) and OramorphR (Roxane Pharmaceuticals, Columbus, OH) must be swallowed whole without being chewed or broken. If the pills are broken before reaching the stomach there is a potential for an overdose requiring treatment with reversal agents such as naloxone. This potentially makes dosing at appro-priate mg/kg doses difficult in smaller veterinary patients.
KapanolR (GlaxoSmithKline, Australia) is a long-acting, gran-ular formulation of morphine developed for administration every 12–24 hours to humans. The Kapanol granules can be swallowed in a single dose within the gelatin capsule or the granules may be dispersed in liquid or semisolid food material, such as apple-sauce, and then swallowed without chewing (Broomhead et al., 1997). A dispersible granular formulation of a long-acting opioid medication could potentially be administered to veterinary patients in small amounts of highly palatable soft foods or Pill PocketsR; however, there is the risk that the animal may chew the granules and receive a very high dose. Currently, Kapanol is not available in the United States; however, two granular formulations of extended-release morphine sulfate have recently been approved for use by the FDA in the United States (Caldwell et al., 2002; Caldwell, 2004).
AvinzaR (Ligand Pharmaceuticals, San Diego, CA) is a novel mor-phine formulation that contains both immediate release granules and extended release granules. When extended release granules in Avinza come into contact with gastrointestinal fluid, they swell and release morphine into the gastrointestinal tract (Caldwell, 2004).
KadianR, another recently approved extended-release oral mor-phine product (Actavis Inc., Fort Lee, NJ), is similar to Kapanol in its extended release technology and its pharmacokinetics in human beings (Broomhead et al., 1997).
Most extended release oral opioid formulations have not been extensively studied in controlled clinical trials in veterinary patients. Although occasionally prescribed for post-operative or chronic pain in veterinary species, the actual efficacy of these oral formulations is questionable. In an early study using healthy
bea-gles, Dohoo & Tasker (1997) evaluated the pharmacokinetics of MS Contin as an oral sustained release morphine product. Dogs that were given 15 mg tablets of MS Contin (approximately a 1.5 mg/kg dose) attained serum concentrations that were approximately 3% of those attained after the same dose was administered IV (Dohoo &
Tasker, 1997). In addition, the authors did not find a sustained serum concentration after MS Contin and drug concentrations tended to decrease well below non-therapeutic values by 200 minutes after drug administration (Dohoo & Tasker, 1997). The assay used in that study likely detected metabolites of morphine as well as the parent drug, so the relative area under the curve for morphine may have been falsely increased. The calculated bioavailability of MS Contin in dogs was 15%–17%, likely due to significant first-pass metabolism and large variability in absorption among individual animals. A similar study by KuKanich et al (2005) found that approximately 1.5 mg/kg of extended-release morphine adminis-tered orally to dogs resulted in very low serum concentrations of the drug that were nondetectable by 4 hours after drug adminis-tration (Figure 9.3). Differences between data in these two studies might be related to methodology in assaying morphine; however, both studies point to the impracticality and low therapeutic value in pursuing oral extended release morphine for analgesic purposes in dogs.
AvinzaR oral pharmacokinetics has also been examined in dogs.
AvinzaR, as mentioned previously, has both immediate release and sustained release granules containing morphine. In a study using healthy Labrador dogs, this formulation of oral morphine was dosed at either 1 mg/kg or 2 mg/kg (Aragon et al., 2009). All dogs had detectable serum concentrations of morphine 3 hours after drug administration; however, 24 hours post-drug, only 5/14 dogs
Figure 9.3. Plasma morphine concentrations (ng/mL) in dogs after oral administration of an extended release morphine sulphate preparation (From KuKanich, B., Lascelles, B.D.X., & Papich, M.G. (2005) Pharmacokinetics of morphine and plasma concentrations of
morphine-6-glucuronide following morphine administration to dogs.Journal of Veterinary Pharmacology and Therapeutics, 28, 371–376. With permission.)
120 Section 2 / Pharmacology of Analgesic Drugs continued to have measureable serum morphine concentrations
(Aragon et al., 2009). There was a large amount of variability among dogs with respect to serum concentration versus time curves, and the authors concluded that oral morphine in this formulation was poorly and unpredictably absorbed (Aragon et al., 2009). Again, this was likely due to first-pass metabolism, which is more promi-nent in dogs than in other species, including humans. In that study, because of the inconsistent nature of morphine’s absorption and the low (below therapeutic) serum concentrations observed at many time points, the authors concluded that this oral morphine formula-tion was not useful for analgesic purposes in dogs. It is possible that veterinary species, other than dogs, with less first-pass metabolism may benefit from oral extended-release opioid formulations, but studies are lacking.
POLYMER GELS Hydromorphone
Formulations of hydromorphone have been made using impregna-tion of the drug into water-soluble polymer gels that can be sub-cutaneously implanted for continuous drug delivery up to 4 weeks (Lesser et al., 1996). Drug formulations in polymerized gels have much longer kinetics (up to 4 weeks for rabbits in vivo for a hydro-morphone preparation) than either traditional oral or parenteral forms of the same drugs (Lesser et al., 1996). These extremely long release kinetics are achieved at the cost of peak therapeutic concentrations in serum. Polymer gels also require minor surgery to place and replace the gel for animals undergoing treatment of chronic pain.
Buprenorphine
A commercial sustained release preparation of buprenorphine is currently available and marketed directly for veterinary use (Buprenorphine SRR). This product is likely a variation on poly-mer gel technology, although the patent is still pending. The drug is imbedded in a matrix of DL-lactide-co-caprolactone, which is a water-insoluble matrix that precipitates in body fluids thereby leav-ing a reservoir of the drug to be released (Dunn et al., 1996). Accord-ing to the manufacturer, Buprenorphine SRR can be administered subcutaneously every 72 hours to provide analgesia (Zoopharm Inc., Buprenorphine SRR package insert, January 2012). Although limited in number, studies have demonstrated promise for the use of Buprenorphine SRR for the treatment of mild-to-moderate pain.
A study in rats demonstrated 2–3 days of analgesia after SC admin-istration of buprenorphine SR, using both a thermal model and a tibial defect model in which weight-bearing was used to assess analgesia (Foley et al., 2011). Limited pharmacokinetic analysis with three rats showed that measureable serum concentrations of buprenorphine were attained at 72 hours after the higher dose was administered (1.2 mg/kg). In a study of cats undergoing ovariohys-terectomy, Catbagan et al. (2011) demonstrated similar analgesic efficacy of oral transmucosal buprenorphine (0.02 mg/kg) adminis-tered twice daily to Buprenorphine SRR administered once at pre-medication (0.12 mg/kg). Ten to 11 cats were studied in each group and side effects were similar. There was no difference between groups with respect to VAS score, Colorado State University Pain Score, or von Frey filament size threshold at any time point (Cat-bagan et al., 2011). All cats were also administered meloxicam,
so analgesia was not solely due to buprenorphine in either group.
The analgesic use of Buprenorphine SRR in dogs or other species has not been examined in a controlled, nonbiased published study, but its use warrants further investigation. While Buprenorphine SRR holds promise as a viable and convenient extended-release opioid for use in veterinary medicine, this opioid is not consid-ered to provide profound analgesia as may be necessary for major surgical pain.
LIPOSOME-ENCAPSULATED OPIOIDS
Encapsulation into liposomes is a method of preparing long-acting formulations of opioid drugs. Multivesicular liposome-encapsulated preparations of morphine produce significant blood concentrations for 6 days after a single SC injection in mice (Kim et al., 1993). Similar preparations have been shown to produce sig-nificant blood concentrations and analgesic effects after epidural administration in rats and dogs (Kim et al., 1996; Yaksh et al., 1999).
Liposomes release their contents in a number of ways, which may be broadly categorized as either release through efflux or release through liposome degradation in the biological milieu. Degrada-tion of the liposome structure may occur through a number of mechanisms, such as lipases present in tissue fluid and uptake by phagocytic cells. Liposome degradation is affected by the lipid composition, the physical characteristics, and the method of man-ufacture. Efflux of liposome contents occurs directly through the liposome membrane without degradation of the membrane itself, and depends on the ability of the drug to partition through the mem-brane. This partitioning of the drug is primarily influenced by the polarity and molecular weight of the drug, and secondarily by the lipid composition and structure of the liposomes.
Epidural Administration
In 2004, the FDA approved an extended-release liposome-encapsulated formulation of morphine for epidural use in peo-ple (DepodurR, EKR Therapeutics Inc., Cedar Knolls NJ) (Figure 9.4). This technology utilizes a proprietary carrier, DepofoamR, that allows slow release of morphine across multiple lipid bilay-ers. DepodurR provides up to 48 hours of analgesia after epidural administration without the need for an indwelling epidural catheter.
In a human clinical trial, people undergoing hip replacement were given 5 mg of standard morphine or 10, 15, 20, 25, or 30 mg doses of DepodurR epidurally prior to surgery, and their use of post-operative PCA with fentanyl was recorded (Viscusi et al., 2006).
Patients that were given the epidural extended-release morphine had 3–6 times longer before first use of PCA, and lower overall fen-tanyl usage (Figure 9.5) (Viscusi et al., 2006). In a second trial, 200 patients undergoing hip arthroplasty were given epidural extended-release morphine at doses of 15, 20, or 30 mg or placebo (Viscusi et al., 2005). Intraoperative opioid dosing with fentanyl was stan-dardized to 250g. The mean time to the first request for additional analgesia was 21.1 hours in the patients that were given epidural extended-release morphine compared with 3.1 hours in those that received the placebo, and the cumulative fentanyl usage was sig-nificantly lower in all patients given the extended-release epidural morphine formulation (Viscusi et al., 2005). While DepodurR obvi-ates the need for an indwelling epidural catheter, there are some disadvantages to its use including the current price of this product.