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4 Effective Pain Management T his chapter presents an overview of the basic clinical strategies, both pharmacologic and nonpharmacologic, for managing pain in labora- tory animals. Topics include preventive analgesia, consequences of unrelieved pain, and ethical considerations relating to pain as a subject of study. Available information on pain management of nonmammalian spe- cies is also presented. INTRODUCTION The regulatory review process (see Appendix B) requires that investiga- tors adequately control pain in research animals, unless procedures that may cause more than momentary or slight pain are justified for scientific reasons and approved by the IACUC. In order to treat or prevent pain, it is necessary to evaluate its source and intensity (for additional discussion see Chapter 3). As a rule, pain is likely to occur in proportional terms as a result of tissue injuryâmore extensive tissue damage results in greater pain and thus a need for a stronger analgesic regimen. While certain conditions reliably cause severe pain (e.g., acute nerve compression, burns, spastic contraction of smooth muscle) and inflammation often contributes to the worsening of pain, scientists do not fully understand how much pain to expect in various animal species. Information about the cause and effect of surgery or disease and pain in clinical veterinary medicine is largely based on observation and anecdote and tends to focus on commonly treated spe- cies, such as dogs, cats, and horses. Table 1-1 of Chapter 1 lists examples 1
2 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS of typically painful conditions that occur either spontaneously or as a result of experimental procedure. CLINICAL VETERINARY PAIN MANAGEMENT The principles of clinical veterinary pain management and prevention, summarized in Boxes 4-1 and 4-2, are comparatively easy to apply in clini- cally familiar species such as dogs and cats, for which ranges of doses and drug combinations are relatively well known. However, the application of the principles discussed below to other laboratory animal species is a matter of trial and error until adequate scientific information is available to establish evidence-based guidelines, including information on the feasibil- ity of various routes of administration (e.g., oral bioavailability, palatability, transdermal preparations). Readers are encouraged to seek publications (including the American College of Veterinary Anesthesiologistsâ Position Paper on the Treatment of Pain [ACVA 1998]), reports, books, and the vet- erinary literature for specific information on available drugs, doses, routes of administration, side effects, contraindications, and the like that may be useful for dogs, cats, rabbits, and other species used as research animals. BOX 4-1 Current Guidelines for Clinical Veterinary Pain Management â¢ Sedation does not provide pain relief and may mask the animalâs response to pain. â¢ Use of analgesic and adjunct drugs should be at effective plasma/tissue con- centrations especially when the nociceptive barrage and pain are greatest (i.e., after surgery or injury). â¢ Use of more than one type of management strategy (e.g., multimodal anal- gesia [targeting multiple pain mechanisms with the use of local anesthetics and opioids] or anxiolytics when postsurgical pain is likely to be moderate to severe) is recommended. â¢ Avoidance of peaks and valleys in analgesic dosing (best accomplished by the administration of continuous or overlapping regimes) when postsurgical pain is expected to be severe maintains animal well-being. â¢ Monitoring, at appropriate intervals, of the effectiveness of analgesics admin- istered is crucial. â¢ If there is doubt about the source of an animalâs clinical signs, administration of an additional dose of analgesicâdependent on the drug, species, and often the individual animalâcan help determine whether pain was the cause (while this is not commonly done in laboratory animal medicine, this method of pain control/alleviation in nonrodent species is common in clinical veterinary prac- tice in a patient-specific manner).
3 EFFECTIVE PAIN MANAGEMENT BOX 4-2 Additional Considerations for the Prevention and Management of Pain in Laboratory Animals â¢ Pain in animals is often unrecognized and undertreated. â¢ If a procedure is considered painful in humans, it should be assumed to be painful in laboratory animals, regardless of their age or species. â¢ Adequate treatment of pain may be associated with decreased complications, lower mortality, reduced variability in experimental data, and improved scien- tific outcomes. â¢ The appropriate use of environmental, nonpharmacologic, or pharmacological interventions, as well as the selection of humane endpoints in animal experi- mentation, can prevent or reduce animal pain in most experimental designs without compromising the scientific validity of the research, except where pain is the subject of research. â¢ Researchers, veterinarians, and animal care professionals should be respon- sible for learning about the assessment, prevention, and management of pain in laboratory animals. â¢ Veterinarians and animal care professionals should develop IACUC-approved educational guidelines and protocols for the management of pain in laboratory animals at their institution. Some ranges for effective doses of analgesics in rats and mice (i.e., doses that reduce experimental measures of pain and/or reach tissue con- centrations believed to be effective in other species) are available through literature search. However, strain differences in animalsâ responses to anal- gesics and anesthetics are an important factor to consider (Mogil et al. 2005; Terner et al. 2003; Wilson et al. 2003a,b). STRATEGIES FOR MANAGING PAIN IN LABORATORY ANIMALS Effective management of pain in laboratory animals often begins with general (surgical) anesthesia, but also includes local anesthetics, analgesics, anxiolytics, and sedatives as well as nonpharmacological methods (includ- ing minimization of tissue trauma). Pain management goals range from total elimination (as, for example, during general anesthesia for a surgical procedure) to pain that is tolerated without compromising the animalâs well-being. General Anesthesia When animals are anesthetized for procedures that would otherwise cause pain, it is important to maintain an appropriate depth of anesthesia.
4 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS A wide range of indices have been developed to assess depth of anesthe- sia in animals and humans (Appadu and Vaidya 2008; Bruhn et al. 2006; Franks 2008; John and Prichep 2005; Lu et al. 2003; Murrell and Johnson 2006; Otto 2008; Whelan and Flecknell 1992); these include autonomic responses such as changes in heart rate and blood pressure, alterations in the EEG or other measures of CNS function, or changes in somatic reflex responses to noxious stimuli. During anesthesia not accompanied by neu- romuscular blocking agents, depression of somatic reflex responses is the most widely used method for ensuring an appropriate depth of anesthesia. In all animal species, absence of the pedal withdrawal reflex indicates a surgical plane of anesthesia (i.e., anesthesia that is deep enough to elimi- nate the experience of pain and thus allow surgery to take place). Although this is an easily assessed index, it is important to use a stimulus that is suf- ficiently noxious but not so strong as to produce tissue damage. In some species, other reflexes, such as the response to applying a clamp to the nasal septum (pigs) or pinching the ears (rabbit, guinea pig), are also useful but reliance on these responses has been criticized (Antognini et al. 2005) because animals may lose consciousness at much lighter anesthesia planes, in which case the persistence of reflexes would not indicate pain perception (see also Box 1-3 in Chapter 1). Doses of anesthetic agents sufficient to sup- press spinal reflexes may therefore be greater than those required to carry out surgery humanely; if these reflexes are not suppressed, surgery will be hampered by the animalsâ repeated reflex movements. Although the use of neuromuscular blocking agents (which prevent neurotransmitters from act- ing on their receptors in skeletal muscles) could prevent such movements, it would also require intubation and mechanical ventilation of the animal. For practical reasons, suppression of withdrawal responses remains the most useful means of ensuring loss of both awareness and responses to surgical stimuli. The ideal general anesthetic should rapidly and/or smoothly induce muscle relaxation and a surgical plane of anesthesia, and should be readily controllable and reversible. There are two categories of general anesthetics used in laboratory animal medicine: volatile inhalants (e.g., isoflurane) and injectable drugs (e.g., barbiturates, other sedative-hypnotic agents such as propofol, or combinations of drugs such as propofol-fentanyl). The latter category also includes total intravenous anesthesia (TIVA). TIVA techniques may be useful in laboratory animal settings where the equipment required for inhalant anesthesia is not practical or possible (e.g., near MRI units). Other injectable general anesthetic drugs still in use due to their unique application in specialized studies include Î±-chloralose, tribromoethanol, and urethane. These drugs have certain specific applications but may not be appropriate for situations in which animals will recover (Gaertner et al. 2008; Karas and Silverman 2006; Koblin 2002; Meyer and Fish 2005) as,
EFFECTIVE PAIN MANAGEMENT after surgery, with anesthetic withdrawal and recovery, the animals will experience pain unless they receive analgesics. Sedation/Anxiolysis Sedatives and anxiolytics are adjuncts to general anesthetics and are also used in pain management strategies. These two distinct classes of drugs are often used in combination to modulate, block, or relieve pain. Terminol- ogy varies but a general distinction between the sedative-hypnotic agents and anxiolytics is often useful. Sedative-hypnotic drugs (e.g., barbiturates and drugs with significant sedating properties such as Î±2-adrenoreceptor agonists) produce dose-dependent states of CNS depression that vary from somnolence to general anesthesia and even death. Anxiolytics are drugs that reduce anxiety or fear (e.g., benzodiazepines) and can induce sleep. Some anxiolytic drugs, previously termed âtranquilizersâ (e.g., phenothiazines like acepromazine and butyrophenones like haloperidol and droperidol), produce a state of relaxation and indifference to external stimuli and, in elevated doses, can induce an undesirable cataleptic state rather than gen- eral anesthesia. Of the above drugs and classes, only the Î±2-adrenoreceptor agonists have analgesic efficacy. Neither barbiturates nor anxiolytics are analgesic; barbiturates may in fact contribute to a hyperalgesic state, while phenothiazines and butyrophenones are generally considered devoid of analgesic efficacy. Readers are referred to the section âModulatory Influ- ences on Pain: Anxiety, Fear, and Stressâ in Chapter 2 for a discussion of the relationship of anxiety and pain. Neuroleptanalgesia is an intense analgesic and amnesic state produced by the combination of an opioid analgesic and a neuroleptic drug (this description is adapted from the American Heritage Medical Dictionary 2007). The neuroleptic drug component is a phenothiazine or butyrophe- none (or possibly an anxiolytic) and the analgesic is a potent and efficacious opioid that also acts as a major tranquilizer (i.e., anxiolytic). Butorphanol- acepromazine, fentanyl-fluanisone (HypnormÂ®1), and oxymorphone- midazolam are examples of commonly used veterinary neuroleptanalgesic combinations. Neuroleptanalgesic combinations by themselves are not suffi- cient for most surgical interventions. However, the use of drugs with sedative or tranquilizing properties (neurolepts as well as Î±2-adrenoreceptor agonists) combined with opioids, ketamine, or tiletamine-zolazepam (TelazolÂ®) can cause states ranging from modified consciousness (e.g., reduction of anxiety or âconscious sedationâ) to complete unconsciousness (general anesthesia). Table 4-1 summarizes the analgesic properties of selected drugs, includ- 1 Hypnorm is not available in the United States (as of August 2009).
6 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS TABLE 4-1 Analgesic Properties of Selected Anesthetic Drugs and Adjuncts Analgesic Drug Class Efficacy Î±2-Adrenoreceptor agonists Analgesic/sedative-hypnotic Yes Barbiturates Sedative-hypnotic No Benzodiazepines Anxiolytic No Butyrophenones Neuroleptic/anxiolytic No Chloralose, chloral hydrate Sedative-hypnotic No Halogenated inhalant anesthetics General anesthetic No Ketamine Dissociative, NMDA antagonist Yes Nitrous oxide General anesthetic (human); general Yes anesthetic adjunct only in animals Opioids Analgesic Yes Phenothiazines Neuroleptic/anxiolytic No Propofol Sedative-hypnotic No (TelazolÂ®) Tiletamine-zolazepam Combination of a dissociative/ Yes NMDA receptor antagonist and a benzodiazepine anxiolytic Tribromoethanol Sedative-hypnotic No Urethane (e.g., ethyl carbamate) Not classified No NOTE: Drugs with inherent analgesic effects may contribute to postoperative pain control but are not sufficient to exert such control in and of themselves. ing tranquilizers, sedatives, and anesthetics, commonly used in laboratory animals. Analgesia Conventional analgesic drug classes include opioids, NSAIDs, and local anesthetics. Although analgesia is defined as âlack of pain,â complete elimi- nation of pain in awake animals is commonly neither achievable nor desir- able. Pain has a protective role as it usually serves to limit further injury; for example, humans with no skin sensation are prone to undetectable injury or infection. But in some instances animals with untreated severe pain may struggle or self-mutilate and exacerbate or cause additional injury to them- selves. With most analgesic techniques, however, residual pain naturally limits activity, although it is not a restraint mechanism and should not be used to restrain animals.
EFFECTIVE PAIN MANAGEMENT The goal of analgesic drug intervention is to achieve a balanced state during which an animal is neither substantially hindered by pain nor adversely affected by the side effects of analgesics. Often the use of a single analgesic is sufficient. An emerging practice for the prevention or treatment of established pain in both human and veterinary patients, however, is the combined use of two or more types of analgesics, or âmultimodal analgesiaâ (Buvanendran and Kroin 2007; Corletto 2007; Hellyer et al. 2007; Kehlet et al. 2006; Lemke 2004; White 2005; White et al. 2007). Multimodal post- surgical analgesia may be regarded as overly complicated, but cited benefits include more effective and efficient analgesia and possible dose reduction of one or more individual drugs. In theory, treatment of patients with nonopioid analgesics to reduce the overall requirement for opioids would result in fewer opioid-induced side effects. The concept, known as âopioid sparing,â is a desirable goal because extended or high-dose opioid therapy is often accompanied by unwanted side effects (e.g., sedation, constipation, urinary retention, or analgesic tol- erance) that prolong or complicate convalescence (Kehlet 2004; White et al. 2007). Synergy (i.e., greater analgesia than predicted from a simple additive effect of the combination of two drugs acting with different mechanisms) has been demonstrated in numerous experimental animal models (e.g., Price et al. 1996; Kolesnikov et al. 2000; Matthews and Dickenson 2002; Qiu et al. 2007) as well as with combinations of opioids, NSAIDs, local anesthetics, Î±2-agonists, ketamine, tramadol, and gabapentin (Guillou et al. 2003; Koppert et al. 2004; Reuben and Buvanendran 2007; White et al. 2007). Multimodal analgesia using âadjuvant analgesicsâ (i.e., antidepres- sants, antiepileptic drugs, NMDA antagonists, or transdermal lidocaine) may also be an effective alternative for the treatment of refractory chronic pain unresponsive to the administration of a single agent (Knotkova and Pap- pagallo 2007). Table 4-2 summarizes pharmacologic methods for treating pain of various intensities. Advanced Analgesic Techniques The ability to provide analgesia to laboratory animals is limited by the lack of information about species-specific drug effects and doses. It is perhaps useful to understand the state-of-the-art techniques currently used in clinical (i.e., nonlaboratory) veterinary medicine as a potential objective for laboratory animal pain medicine; identification of the most useful tech- niques may lead to important innovations to help overcome barriers to the provision of analgesia. Needless to say, size, species, and technical aspects will continue to be limiting factors for many techniques. Box 4-3 provides a summary of analgesic techniques and their limitations.
8 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS TABLE 4-2 Pharmacologic Approach to Pain Management Based on Predicted Intensity Pain Intensity Analgesic Approach Low Single-agent therapy acceptable NSAIDs, local anesthetic infiltration, or opioid agonist-antagonists (butorphanol, buprenorphine) Moderate Multimodal analgesia to be considered NSAIDs in combination with adjuncts such as local anesthetics, opioid agonist-antagonists (buprenorphine), tramadol, Î±2-agonists, NMDA antagonists High Multimodal analgesia recommended mu-opioid agonists (morphine, hydromorphone, fentanyl, methadone) + one or more of the following: NSAIDs, local anesthetics, Î±2-agonists, antiepileptic drugs, NMDA antagonists Advanced analgesic techniques: epidural administration of local anesthetics with or without opioids and constant rate infusions Nonpharmacologic Methods Nonpharmacologic approaches to pain management are appropriate when the use of pharmacological methods is contraindicated, when effec- tive analgesic drugs are not available, or to complement drug therapy. Non- pharmacologic methods include preventive strategies that help minimize causative factors for pain, through, for example, appropriate animal han- dling and minimization of tissue trauma during surgery. Such techniques are important because both long-duration surgery and extensive tissue manipu- lation (e.g., rib retraction, prolonged tourniquet-induced limb ischemia, disproportionately long incision relative to animal size) result in increased postoperative pain. Training in proper surgical techniques coupled with knowledge of comparative anatomy is necessary to appreciate the distinct needs of each animal species before, during, and after surgery and to uphold the 3Rs principle of refinement. Moreover, nonphysiologic restraint or surgical positioning of animals may exert undue pressure on joints, nerves, or soft tissues and cause significant postprocedural pain. These sources of pain are avoidable if investigators and animal care personnel are trained to understand that any form of tissue pressure, damage, or ischemia is a potential cause of pain (Martini et al. 2000; LASA 1990). Minimally invasive surgery techniques (e.g., fiberoptic technologies) reduce tissue injury and are associated with reduced postsurgical pain, stress response, and convalescence time compared to open or scalpel surgery (reviewed by Karas et al. 2008).
EFFECTIVE PAIN MANAGEMENT BOX 4-3 Advanced Analgesic Techniques â¢ Low-dose epidural administration of opioids or opioid-local anesthetic com- binations can result in analgesia whose quality is similar to if not better than that achieved with systemic administration. This method depends on technical expertise and may be challenging to implement in very small animals. Epidural administration of drugs has not been studied in nonmammalian vertebrates. â¢ Local anesthetics can be injected into joints, wounds, and body cavities (ab- dominal or pleural) by continuous or intermittent injection through intra-wound catheters, greatly reducing the need for systemic administration of other anal- gesics (Liu et al. 2006). The relatively short duration of the action of local an- esthetics may limit their utility in situations where redosing is difficult. Lidocaine is used intravenously to provide analgesia after tissue injury (Omote 2007). â¢ Oral administration of some analgesics is feasible (e.g., NSAIDs, opioids, gabapentin), but for some drugs (opioids) first-pass (species-dependent) me- tabolism limits bioavailability, necessitating dose adjustment, use of a different route of administration, or selection of another drug. Compounding of drugs into palatable forms that animals are willing to consume is possible, but without data to support a particular method, one must be concerned about absorption, shelf life, and efficacy. â¢ Dilution of injectable analgesics to make them easier to use or to improve provision in very small animals must be done with the understanding that formulations may not work as well and that shelf life is not predictable. â¢ Continuous infusion of certain types of analgesics (e.g., opioids, ketamine, Î±2-adrenoreceptor agonists) avoids âpeaks and valleysâ in drug concentration and may provide better coverage for moderate to severe pain. Transdermal preparations are available in formulations suitable for larger animals and may be useful in producing uninterrupted analgesia. Sustained-release formula- tions make it possible to avoid periods of inadequate drug administration. For further consultation please see Carroll 2008; Flecknell 2009; Gaynor and Muir 2002; Hellyer et al. 2007; Krugner-Higby et al. 2008; Lamont and Mathews 2007; Robertson 2005; Tranquilli et al. 2007; Valverde and Gunkel 2005. METHODS FOR THE PREVENTION OR MANAGEMENT OF PAIN While classic pharmacologic treatment requires drugs with specific analgesic properties, unconventional drugs, such as antiepileptics, can also be effective. And when anxiety contributes to pain, drugs with anxiolytic properties can be added. Analgesics A thorough review of the effects and doses of analgesic drugs is beyond the scope of this work (for comprehensive reviews see Carroll 2008; Fleck-
80 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS nell and Waterman-Pearson 2000; Gaynor and Muir 2002; Hawk et al. 2005; Lamont and Mathews 2007; Robertson 2005; Valverde and Gunkel 2005). Instead, this section provides an overview of analgesic drugs that are currently used or may become useful in laboratory animal medicine. Opioids Opioid analgesics are important drugs for surgical analgesia and/or therapeutic management of moderate to severe pain in humans and certain animal species. There are two general categories of such analgesics (Ross et al. 2006; Stefano et al. 2005; Waldhoer et al. 2004): opioid receptor ago- nists (e.g., morphine, hydromorphone, fentanyl) and mixed opioid recep- tor agonist/antagonists (e.g., buprenorphine, butorphanol); the latter group possesses (in a single molecule) agonist efficacy at one of the three types of opioid receptor and antagonist efficacy at a different opioid receptor. A third group of endogenous opioid peptides (e.g., endorphins, enkeph- alins, and dynorphins) are produced by the body and also act on opioid receptors. It is a misconception, however, to assume that the only role of endogenous opioid peptides is to produce analgesia; they have multiple, nonanalgesic functions depending on where in the body they are produced and released. Given the existence of three distinct opioid receptors, all located in variable densities in various tissues, differences in the selectivity and affinity of opioid drugs and endogenous opioid peptides are believed to account for many of the variations in the effect profile of opioids (Fields 2004; Waldhoer et al. 2004). And because opioid receptors are subject to regulation (e.g., by phosphorylation or endocytosis), the effects of both endogenous and exogenous opioids can be influenced by the âstateâ of the receptor. Changes such as these presumably account for the phenomenon of analgesic tolerance, a reduction in the analgesic effectiveness of a given dose of drug after repeated administration. Opioids are the most efficacious analgesics available, but their use is accompanied by undesirable effects that include an increase in smooth muscle tone and reduction in propulsive motility of the gastrointestinal tract (leading to constipation), cough suppression, respiratory depression, behavioral changes (euphoria and dysphoria, excitement, or increased loco- motion), and physiological dependence. In addition to their presence on neurons both in the nociceptive pathway (see Chapter 2) and elsewhere in the body (e.g., the gastrointestinal tract), opioid receptors are found on cells of the immune system and opioid effects on immune function vary from stimulation to inhibition (Stefano et al. 2005; Page et al. 2001). In rats and other rodents, pica (the ingestion of nonedible substances, such as bedding) and the consumption of large volumes of food have been noted with the use of the partial opioid receptor agonist/weak antagonist buprenorphine (Aung
81 EFFECTIVE PAIN MANAGEMENT et al. 2004; Bosgraaf et al. 2004; Clark et al. 1997; Yamamoto et al. 2004). Concern about the undesirable side effects of opioids is frequently cited as a reason for not using them, but for limited or short-term therapy the side effects are often either manageable or not a problem. Dose regimens of opioid analgesics for dogs, cats, horses, rats, mice, a few species of birds, and sheep have been reported. When such regimens are based on experimental evidence, it frequently derives from an analge- siometric testing method (such as thermal threshold; Johnson et al. 2007; Robertson et al. 2005a,b; Waterman et al. 1991; Wilson et al. 2003a,b). Doses for other mammals currently listed in formularies are based on extrapolation. Relatively little is known about the efficacy, drug choices, or side effects of opioids in amphibians, reptiles, invertebrates, and most birds. In addition to classical intravenous, intramuscular, and intraperitoneal routes of administration, many opioids are also substantially bioavailable by nasal, sublingual, or rectal routes (Lindhardt et al. 2000; Robertson et al. 2005a). Oral administration of opioids in mammals often diminishes their bioavailability, making this method of delivery less effective. Addi- tionally, long-duration formulations of opioids have been investigated in animal models and, although not yet commercially available, may repre- sent a future method to provide sustained analgesia in laboratory animals (Krugner-Higby et al. 2008; Smith et al. 2004). Because of the relative safety of opioids, information about effective dose ranges and novel methods of administration would be useful. Research is needed to determine ranges and methods for most laboratory animal species. Tramadol Tramadol2 is a centrally acting synthetic analgesic used to treat post- operative and chronic pain in humans. It has a multimodal action: it is an opioid receptor agonist and it inhibits norepinephrine and serotonin reuptake from neurons where those amines are released, including in the spinal cord where both norepinephrine and serotonin can contribute to the modulation of nociception (Grond and Sablotzki 2004). An active (M1) metabolite of tramadol binds with high affinity to mu-opioid receptors; indeed it has more affinity for the opioid receptor than the parent drug. The use of tramadol has recently increased significantly in veterinary medicine. However, in humans and dogs (and possibly other species) with an inherited 2 Draft FDA guidance on tramadol is available at www.fda.gov/downloads/Drugs/Guidance- ComplianceRegulatoryInformation/Guidance/ucm090703.pdf (accessed July 28, 2009).
82 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS deficiency of cytochrome P450 2D6 the M1 metabolite is not produced and the drug is therefore less effective (KuKanich and Papich 2004; Stamer et al. 2003). Oral tablets as well as a combination with acetaminophen are currently commercially available in the United States, whereas the paren- teral formulation is not. The inability to administer tramadol by injection may limit its usefulness in animals, as clinical experience has shown that its bitter taste makes it aversive to dogs, cats, primates, and rats. The paren- teral formulation, if obtained, can be given by intramuscular, intravenous, subcutaneous, or intraperitoneal injection. Affaitati and colleagues (2002) found that subcutaneous injection of tramadol in a rat model of ureteral calculosis reduced signs consistent with visceral pain. Tramadol analgesia is enhanced when combined with other types of analgesics (KuKanich and Papich 2004). Doses in dogs and cats, and possibly in rats and mice, may be estimated from published pharmacokinetic data and dose response studies, but in general more research on the effects of and methods to administer tramadol is needed for laboratory animal species. NSAIDs Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat post- operative chronic and inflammatory pain in humans and animal species. NSAIDs are classified as âantihyperalgesicsâ rather than as true analgesics since they do not increase the pain threshold in normal, uninjured subjects (Ghilardi et al. 2004; Yaksh et al. 1998). This very useful class of drug inhib- its various isoforms of cyclooxygenase (COX), thus reducing the production of prostaglandins (Samad et al. 2002), a key component of the inflammatory reaction. Prostaglandin inhibition either at the site of tissue injury or cen- trally at the spinal cord can modulate pain. At least three isoforms of COX have been identified and drugs that selectively inhibit the various isoforms have been created in the search for an effective drug with few side effects. Commercially available selective COX-2-inhibiting NSAIDs are very impor- tant drugs for pain management in dogs. Despite increased cardiovascular risk in adult human populations, adverse cardiovascular effects of COX-2 selective NSAIDs have not been reported in veterinary species. However, because of their inhibition of COX isoforms, NSAIDs are capable of causing injury through their effects on vari- ous organ systems. These effects include gastric ulceration and perforation, acute renal failure, and decreased coagulation due to inhibition of platelet aggregation. In animals for which therapeutic dose ranges have been determined, NSAIDs can be used as relatively long-acting (12-24 hour) agents for momentary, procedural, and persistent or chronic pain. They can also be combined with other analgesics in a multimodal approach. Pharmacoki-
83 EFFECTIVE PAIN MANAGEMENT netics are known for some NSAIDs in dogs, ruminants, horses, rats, mice, and several species of fowl (Baert and De Backer 2003; Busch et al. 1998; Engelhardt et al. 1996; Lascelles et al. 2007; Lees 2003; Lees et al. 2004; Tranquilli et al. 2007). Effectiveness has been demonstrated â¢ in soft tissue models of pain in dogs, cats, rats, and mice (Kroin et al. 2006; Lascelles et al. 2007; Leece et al. 2005; Roughan and Flecknell 2001, 2004; Whiteside et al. 2004; Wright-Williams et al. 2007); â¢ for orthopedic pain in dogs, cats, fowl, mice, rats, and horses (Barton et al. 2007; Danbury et al. 2000; Hocking et al. 2005; El Mouedden and Meert 2007; Lascelles et al. 2007; Luger et al. 2002; Valverde and Gunkel 2005); â¢ in rat neuropathic pain models (Lynch et al. 2004); and â¢ in visceral pain models in mice and rats (Engelhardt et al. 1995; Millecamps et al. 2004; Miranda et al. 2006). The efficacy of NSAIDs in nonmammalian, nonavian species is unknown. Local Anesthetics Local anesthetics are effective both in awake or sedated animals to reduce momentary, non-tissue-damaging pain (e.g., needle biopsy) and in anesthetized animals as supplements during surgical procedures (Robertson 2005; Valverde and Gunkel 2005; White 2005). Their effect is due to the reversible binding of neuronal sodium channels and the ensuing inhibition of neural conduction (Valverde and Gunkel 2005); by decreasing sensory input, local anesthetics inhibit peripheral and central sensitization (White 2005). The chief disadvantages of local anesthesia/analgesia are that certain techniques (e.g., epidural or regional nerve blocks) require technical exper- tise and even long-acting local anesthetics have relatively short durations of effect (4-6 hours, depending on the site). Local anesthetics also have antimicrobial and anti-inflammatory properties, which may limit the ben- efits of their intermediate-term use in studies of inflammation (Cassuto et al. 2006). Potential advantages of local anesthetic use include the opportunity to reduce general anesthetic doses (thus reducing anesthetic-induced car- diovascular depression), comfortable awakening from surgery, and excellent postoperative analgesia without unwanted side effects (e.g., sedation and ileus; Robertson 2005; Valverde and Gunkel 2005; White 2005). Local anesthetic techniques have been reported for most domestic ani- mals and, if not, may be extrapolated from studies done in rodents.
84 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS NMDA Receptor Antagonists Ketamine, a dissociative anesthetic, and several other unrelated drugs (such as memantine) modify nociceptive signal transmission and block the induction and maintenance of central sensitization by blocking N-methyl-D- aspartate (NMDA) receptors (Himmelseher and Durieux 2005). As a âcentral sensitization modulator,â ketamine acts by reversing allodynia, hyperalge- sia, and opioid tolerance rather than as an analgesic. However, at low and subanesthetic doses it exhibits analgesic properties, hence its use for the management of pain in a variety of situations (Visser and Schug 2006). For example, studies in animals (horses, dogs, mice, rats) and humans have shown that low doses of ketamine (and other NMDA receptor antagonists) reduce the required concentration of inhalant anesthetics during surgical procedures, contribute to opioid sparing, prevent opioid tolerance, reduce acute somatic and visceral pain, and aid in the treatment of neuropathic pain (Anand et al. 2007; De Kock and Lavandâhomme 2007; Himmelseher and Durieux 2005; Knotkova and Pappagallo 2007; Lu et al. 2003; Muir et al. 2003; Price et al. 1996; Richebe et al. 2005; Strigo et al. 2005; Valverde and Gunkel 2005). Ketamine is extensively used in anesthetic regimens for animals. High doses in combination with another anesthetic drug (e.g., xylazine) are commonly used to anesthetize a variety of laboratory animals (particularly rodents). The optimum duration of ketamine administration for effective postsurgical pain management is unknown, although it may be that intra- operative dosing with extension into the postanesthetic period is optimal (Himmelseher and Durieux 2005). Further studies are needed to determine whether this speculative benefit of ketamine is valid. Î±2-Adrenoreceptor Agonists Drugs that act on Î±2-adrenergic receptors (Î±2-adrenoreceptor agonists) in the dorsal horn of the spinal cord produce analgesia accompanied by cardiovascular depression and sedation (Kamibayashi and Maze 2000). In human patients those side effects can be particularly limiting, but in stable veterinary patients some degree of sedation is often useful. In equine and small animal practice âmicrodoseâ administration of Î±2-adrenoreceptor agonists (detomidine and medetomidine in horses, medetomidine in dogs and cats) is used clinically to enhance pain relief as well as reduce anxiety in trauma and surgical patients. One of the major advantages of this class of drugs is the ease with which the sedative effects are reversed (although the reversal also applies to any analgesic effect). Inhibition of both postop- erative/postprocedural and neuropathic pain by Î±2-adrenoreceptor agonists has been shown in many animal models, but the clinical consequences of
8 EFFECTIVE PAIN MANAGEMENT this outcome are unknown (Murrell and Hellebrekers 2005). High doses of Î±2-adrenoreceptor agonists used as presurgical sedatives or in anesthetic regimes may confer a degree of perioperative analgesia in laboratory ani- mals, but this remains to be demonstrated. Unconventional Analgesics: Antiepileptic Drugs Anticonvulsants or antiepileptic drugs (AEDs) act to reduce neuronal hyperexcitability, and there is currently intense interest in their use for both surgical âprotective premedicationâ and chronic cancer pain states as they appear to have antihyperalgesic properties. Two AEDs, gabapentin and a new chemically related congener, pregabalin, are approved for chronic pain management in humans (particularly neuropathic pain such as postherpetic neuralgia), and gabapentin is being investigated for treatment of surgical pain as well (Dahl et al. 2004; Mathiesen et al. 2007). There are numerous reports of the efficacy of these two AEDs to reduce the sensitized state of postoperative/postprocedural and persistent pain in animal models (e.g., Blackburn-Munro and Erichsen 2005). Gabapentin is synergistic with other analgesics and is currently used (empirically) for chronic pain management in dogs and cats. The Role of Anxiolytic Drugs in Pain Management Fear or anxiety-related stress may enhance pain (see Chapter 1 and âModulatory Influences on Pain: Anxiety, Fear, and Stressâ in Chapter 2). Studies have shown that pain is both a cause of and worsened by anxiety (Linton 2000; Morley et al. 1999; Munro et al. 2007; Panksepp 1980; Perkins and Kehlet 2000; Ploghaus et al. 2001). Drugs with anxiolytic properties in animals include phenothiazines, which can be either short- (e.g., acepromazine) or long-acting (e.g., zuclopenthixol, fluphenazine); butyrophenones (e.g., azaperone, haloperidol); and benzodiazepines (e.g., diazepam). Evidence is mounting that antiepileptic drugs may also have anxiolytic properties at lower doses than those that provide analgesia or antiseizure effects (Munro et al. 2007). Measures to reduce fear and anxiety, whether pharmacological or nonpharmacological, should be considered important in the reduction of pain. Confounding and Beneficial Effects of Anesthetics and Analgesics The laboratory animal, whether used as a whole animal or as a source of tissue for in vitro preparations, is susceptible to an array of influences on its normal function. Clearly, any drug-induced or unintended physiologic state (e.g., pain, dehydration, acid base imbalance) in an animal model may
86 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS affect the outcome. Anesthesia and analgesia are integrally involved in the humane care of laboratory animals, but they are also essential tools that can contribute to the success of an experiment. It is essential that the investigator understand how such drugs may affect an animal so that experiments can be designed to minimize, balance, or control for confounding variables. Selected situations are illustrated below. Neurotoxicity The developing CNS is exquisitely sensitive to its internal milieu (Bhutta and Anand 2002). Although the immature brain undergoes some degree of baseline neurodegeneration by apoptotic processes as part of normal development (Kuan et al. 2000), exposure to certain drugs (including those for therapeutic or anesthetic use) or stressors (e.g., noxious stimuli, maternal deprivation, hypoglycemia, hypoxia, ischemia) during this critical window leads to pathological neurodegeneration. The neurotoxic effect of CNS depressants on the developing brain was heralded by the Olney group, which reported accelerated neurodegenera- tion in rat pups exposed to NMDA receptor antagonists, Î³-aminobutyric acid (GABA) agonists, and anticonvulsant drugs (Bittigau et al. 2002; Ikonomi- dou et al. 1999, 2000). Similarly, Slikker and colleagues (2007) reported increased neurodegeneration in fetal and postnatal (day 5) rhesus monkeys exposed to ketamine for 24 hours, but not after 6 hours, confirming that ketamine dose and duration both play important roles in ketamine-induced neurodegeneration (Hayashi et al. 2002; Anand et al. 2007). Since many anesthetic drugs or adjuncts are either NMDA receptor antagonists (e.g., ketamine) or GABAA receptor agonists (benzodiazepines, barbiturates, and volatile anesthetics), prolonged administration of these drugs during the perinatal period may have significant consequences on brain development and function (Loepke and Soriano 2008). Initially, it was thought that anesthetic and anticonvulsant drugs (and ethanol) simply accelerate the normal âpruningâ or apoptotic process. How- ever, permanent changes in brain histology and in behavioral and locomo- tor performance have recently been reported in mature rats exposed to isoflurane and midazolam during infancy (Jevtovic-Todorovic et al. 2003). The revelation that anesthetic drugs are neurotoxic suggests a link to the neurodegenerative sequelae of fetal alcohol syndrome. However, no phe- notype of âfetal or neonatal anesthesia syndromeâ has been demonstrated (Soriano et al. 2005). This issue is of paramount interest to pediatric anes- thesiology and intensive care researchers who study the safety of fetal and neonatal anesthesia (Anand and Soriano 2004; Todd 2004). Anesthetic-induced neurotoxicity is not limited to the young (Anand 2007); several investigators have demonstrated both transient and long-term cognitive dysfunction in older rats (12-24 months). Exposure to isoflurane
8 EFFECTIVE PAIN MANAGEMENT and nitrous oxide resulted in improved spatial memory in young rats but impaired it in aged rats for at least 3 weeks, indicating that anesthetics can influence memory for much longer than the pharmacokinetic properties of the drug suggest and may adversely affect memory processes in the elderly (Culley et al. 2003, 2004). Furthermore, isoflurane induces beta-amyloid protein deposition and apoptotic cell death, similar to the neurodegenera- tive process observed in Alzheimerâs disease (Xie et al. 2007). Accordingly, research that requires administering anesthesia prior to assessment of cog- nitive function should take into account the long-term effects of anesthetic exposure. Neuroprotection Anesthetic drugs have been shown to impart neuroprotective effects as well. In contrast to the neurotoxic effect of NMDA receptor antagonists described above, ketamine and memantine also protect neurons from exci- totoxic injury. Anand and colleagues (2007) examined the effect of a low (sedative) dose of ketamine on P7 rat pups subjected to repetitive inflam- matory pain (such pain increases neuronal excitation and cell death in developmentally regulated cortical and subcortical areas). Ketamine at a dose of 5 mg/kg (i.e., a quarter of the dose that induces neurodegeneration in unstimulated rat pups) attenuated cell death and provided some degree of neuroprotection. Memantine has been shown to reduce cognitive decline in patients with Alzheimerâs disease (Tariot et al. 2004). Xenon, an inert gas that is a weak NMDA receptor antagonist and thus displays some anesthetic properties, and dexmedetomidine, an Î±2-adrenoreceptor agonist, decreased the infarct volume in P7 rat pups after experimental focal cerebral ischemia (Ma et al. 2007). Furthermore, the coadministration of xenon prevented isoflurane-induced neurodegeneration during a 6-hour exposure to 0.75% isoflurane in neonatal rats (ibid.). Reports also indicate that the inhalant anesthetic isoflurane is neuro- protective during hypoxia-ischemia in in vivo and in vitro animal models of the developing brain (Loepke et al. 2002; McAuliffe et al. 2007; Zhao and Zuo 2004) and during focal cerebral ischemia. Sakai and colleagues (2007) demonstrated that isoflurane provided long-term protection (for 1 month) in terms of reduced injury after experimental stroke (for a review of the preconditioning neuroprotective effects of inhalant anesthetics see Wang et al. 2008). Cardioprotection During cardiac surgery, or in models designed to study cardiovascular disorders, consideration is often given to the fact that ischemia and reper- fusion of the ischemic heart can induce myocardial injury and cell death.
88 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS Anesthetic or analgesic drugs used during procedures may exert important effects on the models (Riess et al. 2004; Suleiman et al. 2008). Brief epi- sodes of nonlethal ischemia (which may be intentional or unintentional, as in the case of excessive depth of anesthesia, hypotension, or tachycardia) activate mechanisms that lead to protection of cardiac myocytes from further injury (Post and Heusch 2002; Suleiman et al. 2008; Weber et al. 2005). This phenomenon is known as cardiac preconditioning. Protection against myocardial damage after ischemic insult is also a well-known effect of volatile (inhalant) anesthetics; and opioids (those acting at delta-opioid receptors) and potentially other anesthetics or analgesics may have similar properties (Barry and Zuo 2005; Peart et al. 2005). The timing of drug administration (before, during, or after ischemia) determines whether an intervention has an effect and if so the degree of cardioprotection (Schipke et al. 2006; Weber et al. 2005). Other anesthetic agents (e.g., propofol, ketamine, thiopental) may also have myocardial preconditioning or protective effects (Suleiman et al. 2008). The molecular events surrounding myocardial damage and conditioning effects of ischemia and drug therapy have been reviewed (Peart et al. 2005). The triggering of a pro-inflammatory state by surgery, anesthetics, or devices, as well as poten- tial anti-inflammatory effects of drugs may all play a role in the outcome of cardiac procedures (Suleiman et al. 2008). It appears that the method with which animals are anesthetized and treated for pain may influence experi- mental findings in cardiac-surgical or cardiac-disease models, but these interactions are extremely complex and not fully delineated. Immunosuppression and Reduction of the Inflammatory Response Experimental in vivo models of cancer, infectious diseases, trauma (including surgery), hypoxia, ischemia, or toxicity activate a complex orchestration of inflammation, cellular defenses, and repair mechanisms. Inflammation is part of the immune response, a âfirst responderâ that pro- tects the animal from invading organisms or insults and modulates cellular and homeostatic events. Most, if not all, modern anesthetic agents can alter certain inflammatory markers of immune function in in vitro and in vivo models both in humans and in animal models (Galley et al. 2000; Hom- burger and Meier 2006; Kona-Boun et al. 2005; Lemaire and van der Poll 2007; Schneemilch et al. 2005). However, general anesthesia is not the pri- mary determinant of immune status, for its effect is substantially augmented by the concomitant stress response and surgical tissue injury. Immune func- tion is influenced by an interaction between doses and timing as well as nondrug factors such as pain, psychologic state, perioperative blood loss, or hypothermia (Galley et al. 2000; Homburger and Meier 2006; Padgett
8 EFFECTIVE PAIN MANAGEMENT and Glaser 2003; Vallejo et al. 2003). Indeed, some authors suggest that the actual clinical significance of anesthetic-induced immunosuppression is minor (Galley et al. 2000). Analgesic agents also affect immune function. But although opioids cause immunosuppression this effect may be highly dependent on the situation. Morphine, for example, induces changes in natural killer cell activity, inflammatory cytokine production, and mitogen-induced lympho- cyte proliferation that lead to immunosuppression in both in vitro and in vivo models (Page 2005; Roy et al. 2005). Conversely, in the context of surgical or cancer pain models, treatment with various opioid analgesics (fentanyl, morphine, tramadol) paradoxically seems to improve immune system function, by inhibiting metastatic spread of cancer cells and limiting tumor growth (Gaspani et al. 2002; Page et al. 2001; Sacerdote et al. 2000; Sasamura et al. 2002). In animal models, there appear to be differences between opioid agents, with buprenorphine contributing less to immune dysfunction than fentanyl (Franchi et al. 2007; Martucci et al. 2004). There is speculation that opioids may be less immunosuppressive when they are given in the context of pain than in in vitro or in vivo animal models without pain (Page 2005). The immune system effects of perioperative and/or chronic opioids may therefore depend on the specific opioid (e.g., buprenorphine versus fentanyl) and on the relationship between the dose and the amount of pain. Other analgesics (e.g., local anesthetics, ketamine) have been shown to play a role in modulating inflammatory or immune system function (Beilin et al. 2007; Cassuto et al. 2006; Homburger and Meier 2006). Experiments that focus on inflammation or immune function as an outcome measure should require in-depth knowledge of the relevant contributions of analge- sic and anesthetic drugs. Implication or exclusion of analgesic drugs in the experimental design may be appropriate only if other factors that affect the inflammatory response or immune function are well controlled. Nonpharmacologic Management of Pain Most nonpharmacologic methods to treat pain predominantly address acute and chronic musculoskeletal pain conditions. Techniques may include electrostimulation, local tissue cooling (cryotherapy), heat, and manual therapy. These techniques are time- and thus cost-intensive and may require specialized training. As research into mechanisms and efficacy continues, the reader is encouraged to search for more up-to-date information. Electrotherapy and electrostimulation techniques are commonly used to treat pain in humans; modalities include transcutaneous electrical nerve stimulation (TENS), interferential therapy, and electroacupuncture. Although
0 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS animal models have shown a reduction in primary and secondary hyper- algesia after TENS treatments (Ainsworth et al. 2006; Hingne and Sluka 2007), definitive support for the use of TENS in laboratory animal medicine is lacking. Similarly, although acupuncture is commonly used in the man- agement of human musculoskeletal pain (e.g., osteoarthritis, intervertebral disk disease, rheumatoid arthritis), its effectiveness in managing animal pain has not been adequately studied. Cryotherapy, typically used in situations of brief injury or active inflam- mation, is probably one of the most easily applicable techniques in a labo- ratory animal facility, requiring little training or cost. It can be achieved using crushed ice, frozen gel packs, frozen alcohol/water slushes, special- ized cryotherapy units, or cold sprays. However, despite its common use with acute injury, there is little definitive evidence of a pain-relieving benefit for acute or chronic pain (Greenstein 2007). It is important to seek further guidance prior to its use. The benefit of therapeutic heating, produced by either deep (therapeutic ultrasound) or superficial (moist hot packs, immersion baths, infrared light) methods has not yet been proven for laboratory animals. Manual modalities include joint manipulation/mobilization and mas- sage. Although studies have demonstrated the efficacy of such therapies in humans, physical manipulation (e.g., chiropractic adjustment) in animals requires advanced training and is still poorly understood. Limited forms of massage therapy for animals may enhance comfort in joint or muscle pain (especially in animals immobilized by their physiologic state or in restraint devices) although basic training is necessary. At the very least, massage or other hands-on therapies promote bonding between handler and animal in amenable species, can be calming, and may further accustom animals to being touched. Other Nonpharmacologic Measures to Improve Comfort Environmental and physical factors can exacerbate pain that results from disease or injury. Nonpain sources of discomfort or distress, such as nausea, hunger, dehydration, dizziness, or weakness, should always be considered (McMillan 2003). Changes in environment, such as deeper or softer bedding, alternative feeding strategies, dim lights, or warmer tempera- tures may improve the comfort of debilitated animals or those with lower pain thresholds. The use of other appropriate supportive measures, such as parenteral fluid supplementation and wound care, are critical adjuncts to optimize animal comfort and welfare.
1 EFFECTIVE PAIN MANAGEMENT PRACTICAL APPLICATIONS AND CONSIDERATIONS FOR PAIN MANAGEMENT Minimization of Momentary, Non-Tissue-Damaging Pain Procedures of short duration that do not cause significant tissue damage may nonetheless cause transient pain that is aversive to animals. Examples of such procedures include the placement of intravenous catheters; injec- tion or sampling with large gauge needles; removal of staples, sutures, chest tubes, and abdominal drains; and oral gavage. Especially when vigorous movement in response to a painful stimulus is likely, techniques that reduce pain might also reduce the potential for injury from struggling and enhance the accuracy of the procedure as well as the safety of the handler. Pharma- cologic measures for the minimization of such brief types of pain include general anesthesia, sedation, and local anesthesia. In small animals (e.g., rodents, piglets, cats) brief episodes of inhalant anesthesia may be induced via mask or chamber using isoflurane or sevo- flurane followed by mask maintenance and recovery in a protected environ- ment. Major advantages of this approach include rapid onset and recovery times as well as multiple administrations without lingering drug effects. However, in certain species (e.g., ruminants) mask induction of inhalant anesthesia is not appropriate due to risk of regurgitation and aspiration or, in very large animals and primates, size and restraint challenges. Sedation and neuroleptanalgesia may be useful for minimizing minor procedural pain; examples of such uses include the administration of intra- venous propofol during aspiration of vitreous fluid from the eyes of dogs, or a combination of opioid/Î±2-adrenoreceptor agonist administration before ultrasound-guided needle biopsy in dogs or ruminants. Animals under pro- longed sedation may require additional support (e.g., observation, thermal supplementation, protection from physical harm during recovery) but with many current techniques recovery may be hastened with pharmacologic reversal of the drug (e.g., opioid receptor or Î±2-adrenoreceptor antagonists). However, pain and distress may return when pharmacologic reversal of these drugs is used to awaken animals, so in some cases it may be prefer- able to allow spontaneous recovery. Topical application of local anesthetic preparations or a short, 1- to 2-minute application of ice or vapocoolant spray to the site may greatly reduce the pain of injection or other superficial pain-producing procedures; studies in cats and humans show reduced pain during minor procedures fol- lowing topical application of local anesthetics (Gibbon et al. 2003; Howard 2005; Luhmann et al. 2004; Wagner et al. 2006; Weise and Nahata 2005). And local application of lidocaine, for example, may even reduce pain produced by more invasive techniques, such as biopsy or bone marrow
2 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS aspiration. Disadvantages of topical local anesthetics include prolonged (20-60 minutes) delay in effect when applied to intact epithelium, propen- sity for removal by the animal, lack of information about concentration (dose) and efficacy for many animal species, and expense. Furthermore, the injection of local anesthetics often causes an acute burning sensation (30 sec to 1 min), which can be alleviated by buffering the drug solution with sodium bicarbonate (Burgher and McGuirk 1998; Burns et al. 2006), administering sedation or a topical anesthetic, or applying local cooling with ice or vapocoolants (Luhmann et al. 2004; Ong et al. 2000). Topical lidocaine gel or solution warmed to body temperature is well absorbed through mucosal surfaces (but not through intact mammalian skin) and is an effective means to reduce the pain of urethral or nasal cannulation and of many ocular procedures. The benefit of nonpharmacologic measures to minimize the brief but potentially distressing pain of minor procedures in animals is frequently underestimated, but there is evidence of its effectiveness in human neonatal and adult medicine (Golianu et al 2007; Houck and Sethna 2005). Tech- niques such as topical cooling, physical distraction, and training might be easily incorporated to reduce brief aversive pain. Ice Studies in human pediatric and adult medicine show that the applica- tion of ice reduces brief pain associated with intramuscular and intradermal injection of drugs and local anesthetics (Farion et al. 2008; Hasanpour et al. 2006; Hayward et al. 2006; Kuwahara and Skinner 2001; Yoon et al. 2008). Although the usefulness of ice application has not been studied in labora- tory animals, it should be considered a helpful method for the alleviation of brief pain in laboratory animals. Physical Distraction and Training Examples of physical distraction techniques to manage brief pain in animals include the use of a twitch, snare, or âshoulder rollâ in horses and livestock, the gentle scruffing of cats, and the gentle pinch of a skin fold in dogs, all of which presumably activate mechanoreceptors and modulate nociceptive transmission. The mechanism of action is not yet clear, but sug- gestions include the release of endogenous opioid peptides in response to stress or the âgate control theoryâ (for more information see Lagerweij et al. 1984 or Dickenson 2002). Randomized controlled studies in humans support the application of various mechanical stimuli for reducing procedural pain. Methods exam- ined include pressure to the site of intramuscular injection of a large volume (Barnhill et al. 1996), and leg massage and facilitated tucking or swaddling
3 EFFECTIVE PAIN MANAGEMENT prior to heel stick in preterm infants/neonates (Corff et al. 1995; Howard 2005; Jain et al. 2006). However, the amount of pressure applied can make the difference between a pain-reducing and a pain-producing stimulus; a useful guideline for large laboratory animals is that pressure not exceed that which the handler could apply comfortably to his or her own body. Positive reinforcement training of certain socialized species can greatly reduce the need for forcible restraint during brief painful procedures. Ani- mals acclimated to injection or venipuncture or trained to enter a restraint device (e.g., a chair or sling; Laule et al. 2003; Rennie and Buchanan-Smith 2006; Wolfensohn 2004) may willingly submit to mildly painful procedures in return for a reward (e.g., food, release, physical contact). In contrast, the stress of restraint and/or separation from cage or herd mates may increase fear and anxiety, which in turn can enhance pain (see Chapter 2). For ani- mals acclimated to handling, the presence of a familiar individual (human or conspecific) is often beneficial, and soft verbal encouragement from relaxed, nonthreatening handlers is arguably an important stress reduction measure. Interventions for Postoperative/Postprocedural and Chronic Pain This section deals primarily with the management of pain generated by procedures that cause tissue damage (e.g., surgery) and by disease-related and chronic conditions. Considerations regarding pain-related research are discussed in Appendix A, while Box 1-1 defines the various categories of pain as used in this report. Postprocedural and Postsurgical Pain Substantial tissue damage from surgery or other procedures causes postprocedural pain that increases as inflammation develops in the injured tissues. The intensity of postoperative/-procedural pain usually peaks within 4 to 24 hours, after which, as tissues heal, it subsides and resolves at a vari- able rate dependent on several factors but principally on the extent of tissue insult. The mainstay of management of postoperative/-procedural pain of moderate to severe intensity in both human and veterinary clinical medi- cine is systemic administration of opioid receptor agonists (e.g., morphine, fentanyl) or mixed agonists/antagonists (e.g., buprenorphine). As previously discussed, NSAIDs can be effective for the management of mild to moder- ate pain; however, because they lack true analgesic efficacy, they are fre- quently combined with opioids and other drugs. Other analgesic or adjunct drugs (see below) commonly used to manage postoperative/-procedural pain include local anesthetics, ketamine, Î±2-adrenoreceptor agonists, and, increasingly, tramadol and gabapentin. Cryotherapy is an example of a potentially beneficial nonpharmacologic adjunct to analgesia.
4 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS One standard postoperative care approach following very painful sur- geries is the initial administration of a high-efficacy opioid receptor ago- nist to provide surgical-level analgesia for a period of time, followed by a mixed opioid agonist/antagonist (e.g., buprenorphine) or other drug (e.g., tramadol). Alternatively, adoption of a multimodal analgesic regime may be appropriate (e.g., opioid-NSAID, opioid-ketamine, or some other com- bination). As the intensity of pain decreases, the pain management strategy (e.g., type and frequency of analgesic drug administration) can be modified. Following a change in analgesic strategy, observations for effectiveness must continue. The last step is to taper these high-efficacy opioid follow- on strategies to a single agent as the intensity of pain lessens. Similarly, when analgesics are discontinued altogether, observations must continue regularly, albeit less frequently, to determine whether termination of pain management is appropriate. The time course of postoperative/-procedural pain may vary considerably not only between species but also between individuals. There is considerable concern that improperly managed postopera- tive/-procedural pain can evolve into much longer-lasting, even chronic pain. Drugs that function primarily as antihyperalgesics (e.g., NMDA recep- tor antagonists and COX-2 inhibitors) are under evaluation to prevent what is sometimes referred to as the chronification of pain (Samad et al. 2001, 2002). Sickness Syndrome An unintended and underappreciated consequence of invasive pro- cedures is âsickness syndrome.â This syndrome occurs when animals are exposed to potent stimulators of the immune/inflammatory response (e.g., endotoxins, antigenic vaccines, certain cancer states, CNS trauma, reper- fusion injury, clinical sepsis), as the resulting proinflammatory cytokines can âfacilitateâ or enhance pain (Cleeland et al. 2003; Romanovsky 2004; Watkins and Maier 2005; Wieseler-Frank et al. 2005). In addition to fever, the animal exhibits generalized clinical signs of hyperalgesia, malaise, inappetence, somnolence, and other signs that may have evolved as a protective mechanism to induce the animal to rest or sleep (Dantzer and Kelley 2007; Wieseler-Frank et al. 2005). In âsickness syndromeâ cytokines can also activate glia in the CNS and contribute to the maintenance of gen- eralized central sensitization (Wieseler-Frank et al. 2005). Because many laboratory animal models include some degree of strong immune stimula- tion associated with the above conditions, it is important to appreciate that sick animals may be more sensitive to external noxious and nonnoxious stimuli. Interventions to reduce these hyperalgesic states are experimental and include strategies to reverse glial activation (see ShÃ¤fers et al. 2004;
EFFECTIVE PAIN MANAGEMENT Watkins and Maier 2005). A decision to withhold analgesics in an appar- ently âsickâ animal should take into account the potentially significant impact of âsickness syndrome,â and in any case nonpharmacologic meth- ods to manage painâsuch as a protective environment (shelter, dim light, warmth, bedding), protection from conspecifics, and âhospiceâ husbandry measuresâare strongly recommended. Preemptie Analgesia The typical approach to treating postoperative pain, whether in animals or humans, is to give analgesics during or immediately after surgery, but the possibility that treatment before surgery can influence postoperative pain has received considerable attention following Woolfâs observation of central hyperexcitability associated with postinjury pain (Woolf 1983). Bach and colleagues (1988) reported that aggressive analgesic treatment (daily morphine administration to the spinal cord) before limb amputation in humans significantly reduced the development of phantom limb pain in the first year after surgery. This observation has been confirmed, largely in animals, suggesting that the use of âpreemptive analgesiaâ before surgery can reduce the magnitude of hypersensitivity and pain that normally occur after surgery (Bromley 2006; Gonzalez et al. 2000; Lascelles et al. 1995, 1997; Reichert et al. 2001). The effectiveness of preemptive analgesia is presumed to reflect the prevention or attenuation of peripheral and central sensitization, both of which would normally develop during and after a surgical procedure. Tissue and nerve damage activate and sensitize peripheral nociceptors, awaken sleeping nociceptors, and produce central sensitization (an increase in the excitability of central neurons; see Chapter 2). In some respects, the consequence of central sensitization is the biochemical establishment of a âmemoryâ of the injury, in which activation of the NMDA receptor is impli- cated. The behavioral consequence of central sensitization is that normally innocuous stimuli can induce pain (allodynia) and noxious stimuli evoke greater than normal pain (hyperalgesia). In the short term, the hypersensitiv- ity that results is adaptive, as it compels the animal to protect the injured part of the body. However, because central sensitization is associated with multiple molecular, structural, and neurophysiological changes in CNS neu- rons and glia, it may also be maladaptive if these changes persist beyond the period of expected postoperative pain (perhaps becoming independent of the original injury) or contribute to the development of a chronic pain state (Romero-Sandoval et al. 2008; Watkins and Maier 2005; Woolf 2007). Because tissue injury produces central sensitization, it may seem appro- priate to use preemptive analgesia in surgical cases, treating the animals before surgery with drugs that prevent nociceptor and central sensitization.
6 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS However, most such drugs are experimental and are rarely, if ever, used in the management of pain, as they are not yet approved for clinical use and indeed may even be contraindicated. There are some exceptions; for example, the NMDA receptor antagonist ketamine, local anesthetics, and NSAIDs, especially COX-2 inhibitors, have been demonstrated to have some utility in rodents. The discussion above suggests that preemptive analgesia should be considered in the course of regular surgical procedures, provided the drugs do not interfere with the experimental protocol. Unfortunately, the initial enthusiasm for preemptive analgesia in humans has decreased because most evidence does not indicate that it offers significantly greater control of postoperative hypersensitivity and pain than other appropriate postopera- tive strategies for pain management. Accordingly, the likelihood is small that preemptive analgesia significantly contributes to a reduction of the hypersensitivity and pain that occur in the weeks to months after surgery (Grape and TramÃ¨r 2007). It is therefore not at all clear that its use should be recommended or required in the laboratory. However, although preemptive strategies may not help much, they probably will not hurt. To the extent that they do not interfere with the science that justified the surgical procedure they should be considered, but the evidence for their essential contribution in experimental animals remains limited. It bears reiterating that animals will experience pain after surgery if they have not received an analgesic either before or during the procedure. If analgesics are not given until after surgery, there will be a delay until the drug reaches effective analgesic concentrations in brain tissue. Deci- sions about the management of pain in the recovering animal should take into account the properties of the anesthetic drug(s) used, the anticipated intensity and type of pain caused by the procedure, and the interaction of administered analgesics with anesthetics. For example, buprenorphine given during ketamine-medetomidine anesthesia in rats resulted in the death of some animals, but ketamine-medetomidine anesthesia alone did not (presumably the buprenorphine suppressed the CNS/respiration even further; Hedenqvist et al. 2000). NSAIDs and local anesthetics do not generally interfere with opioid-induced CNS depression or the action of other anesthetics, but NSAIDs may take 30 or more minutes to be effec- tive whereas local anesthetics act rapidly. A âsparingâ effect of many types of pre- or intraoperative analgesics may enable and require a reduction in doses of general anesthesia, which can be a desirable goal as many general anesthetics depress cardiac output and respiratory drive. Thus the timing of initiation of analgesia is important not only for managing pain at recovery but also for reducing the likelihood of transition of postopera- tive/-procedural hyperalgesia to a chronic state (Dahl and Moiniche 2004; Kissin 2005; Pogatzki-Zahn and Zahn 2006).
EFFECTIVE PAIN MANAGEMENT Chronic Pain Chronic pain (persistent or chronic pain is discussed in Box 1-1 and Appendix A) in laboratory animals may develop as a consequence of experimental procedures (e.g., device implantation), induced diseases (e.g., cancer, diabetes), or husbandry problems. Animals in chronic pain may experience constant, episodic, or escalating pain accompanied by âbreak- throughâ episodes of more severe pain. Manipulations that are minimally painful in healthy animals may cause significant pain in those already experiencing pain; thus, for example, handling or husbandry procedures may be painful and should be modified accordingly (e.g., with the use of less invasive sampling techniques, administration of additional analgesia prior to handling). When determining treatments, assessment methods, and endpoints, the etiology of chronic pain is important. Chronic pain can be inflammatory, visceral, neuropathic, or cancer-related (Bennett et al. 2006). Drug classes commonly used to manage chronic pain include NSAIDs, opioids, trama- dol, antiepileptics, antidepressants, and, to a lesser extent, NMDA receptor antagonists and local anesthetics. Nondrug therapies can also be helpful. Depending on the type of pain, animals may need different dosages or types of analgesia. For example, mice with bone cancer need and can tolerate tenfold higher doses of morphine than mice with inflammatory pain (caused by complete Freundâs adjuvant or formalin injection) at a similar location of the body (El Mouedden and Meert 2007; Luger et al. 2002). In mice the CNS-depressant effects of morphine (determined through performance in motor coordination assays) are less of an impediment when pain is greater; in contrast, in rats with bone cancer morphine analgesia was accompanied by sedation (Medhurst et al. 2002). Some analgesic drug classes that are effective for inflammatory and neuropathic pain are not effective in bone cancer models (El Mouedden and Meert 2007; Luger et al. 2002; Medhurst et al. 2002; Shaiova 2006). When pain is expected to increase over time, the frequency of obser- vations and possible interventions should also increase. The potential for tolerance, dependence, and withdrawal must also be considered when designing pain management strategies. Consequences of Unrelieed Pain It is likely that unalleviated pain will influence the outcome of a research project in a number of ways. Significant unrelieved pain is a stressor that, if the animal cannot adapt to it, causes distress and negative physiologic consequences, not the least of which is immune dysfunction (Bartolomucci 2007; Blackburn-Munro and Blackburn-Munro 2001; Carr and Goudas
8 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS 1999; Padgett and Glaser 2003; Ulrich-Lai et al. 2006), especially with respect to experimental metastatic models (Gaspani et al. 2002; Page et al. 2001; Sasamura et al. 2002). Unrelieved pain also has specific effects on animal behavior (Karas et al. 2008), such as reductions in food and water intake or body weight (a surrogate marker of oral intake) demonstrated in a number of animal models, including rats, mice, rabbits, and swine (Fleck- nell et al. 1999; Harvey-Clark et al. 2000; Karas et al. 2001, 2007; Liles et al. 1998; Malavasi et al. 2006; Shavit et al. 2005). In many instances, the administration of analgesics reduces the magnitude of these changes (Flecknell et al. 1999; Harvey-Clark et al. 2000; Karas et al. 2001; Liles et al. 1998; Malavasi et al. 2006). Other adverse effects of pain and the morbidity it causes (e.g., ileus, impaired respiratory function and tissue oxygenation) have been reviewed for human patients (Akca et al. 1999; Anand 1993; Bonnet and Marret 2005; Kehlet 2004; Mattei and Rombeau 2006) and it is likely that similar pain-induced morbidity occurs in animals as well. It is therefore reasonable to argue that pain relief is good not only for animal welfare but also for the quality of scientific data. Animal Welfare Considerations of Research with Persistent Pain Models Research on pain as a study subject is described in Appendix A. Because of the painful nature of these models and the underlying assumption that analgesics may interfere with the research outcomes, it is important to con- sider the following questions: â¢ Is it possible to objectively assess discomfort and/or spontaneous pain or recognize the differences between these and the implica- tions for animal welfare? â¢ Is the presence of some (or any) spontaneous pain acceptable in order to meet experimental objectives? The fact that these models have been developed and are in common use indicates that investigators, IACUCs, and veterinarians agree that the presence of ongoing discomfort and/or spontaneous pain can be accept- able if warranted by experimental objectives. However, methods to assess spontaneous pain (or âpain at restâ) have not been universally validated. Professional judgment and limited evidence based on the monitoring of a variety of animal behaviors (e.g., food and water ingestion, sleeping, noctur- nal activity, sexual activity; see Chapter 3) suggest that, with the exception of the immediate postprocedural period, rodents grow and gain weight and appear to resume normal species-specific behaviors in models of inflamma- tory, incisional, and even most peripheral neuropathic pain (for references
EFFECTIVE PAIN MANAGEMENT related to specific pain models see Appendix A). But most of these studies have been relatively unsophisticated (e.g., measures are subjective, observ- ers are not blinded), and most speciesâ spontaneous pain-related behaviors have not been studied. Moreover, the question arises whether to treat what appears to be spontaneous pain in such models, as central nervous system and invasive cancer pain models typically increase in pain intensity and are irreversible. Because drug treatment to reduce pain may interfere with the underlying mechanisms that are the focus of study in these and other models (and thus increase animal use by resulting in an invalid experiment), the provision of humane care without compromising experimental objectives could place the investigator and care providers at odds. Clearly, if the focus of study is the biology of pain, treatment of a presumptive spontaneous condition will interfere with the objectives of the experiment (if, however, reducing a presumptive pain condition does not compromise the goals of the study, then treatment is appropriate). The problem, of course, is that many of the drugs used to treat pain also have effects unrelated to pain, as for example the inhibition of cyclooxygenase with NSAIDs. It is not known to what extent blocking these enzymes by pain-relieving drugs will interfere with the primary objective of the experiment (e.g., tumor development) and there is very little evidence to guide either investigators or care providers. There is accumulating evidence that many of these models are useful to the study of pain mechanisms and pain management and thus their con- tinued use is valid. However, based on the discussion in Chapter 3 and the approach advocated in US Government Principle #4, animals in persistent pain models should be assumed to be in pain most of the time. They may also experience significant pain upon movement, thus severely affecting their quality of life. Therefore, such studies should be planned conscien- tiously and judiciously to obtain the maximum amount of data from the minimum number of animals and to use and explore alternatives as much as possible. Further, the committee strongly supports the application of humane endpoints in these studies and refers the reader to Chapter 5 for additional information. ANALGESIA IN SELECTED NONMAMMALIAN SPECIES Most information about analgesia is available only for certain mamma- lian species, and it is reasonable to consider extrapolation between similar mammals. It is beyond the scope of this document to provide the full range of information currently available in veterinary formularies and handbooks of veterinary anesthesia and analgesia. The following sections describe what is known about pain or analgesic treatment in several nonmammalian verte- brates whose use in biomedical research is increasing. Until more informa-
100 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS tion about these species is available, this report can be used as a source of reference for investigators, veterinarians, and animal care personnel. Fish It has been reported that the nociceptive sensory system in teleost fish is strikingly similar to the mammalian system and that fish show complicated aversive behavioral and physiological responses to noxious stimuli (Sned- don et al. 2003a,b). These responses were alleviated by morphine (Sneddon 2003), but whether fish are capable of pain perception as opposed to only nociception remains uncertain (Sneddon 2006). The fish brain is activated during noxious stimulation (Dunlop and Lam- ing 2005; Nordgreen et al. 2007; Reilly et al. 2008a) and there are species- specific differences in response to the same noxious event in common carp (Cyprinus carpio), zebrafish (Danio rerio), and rainbow trout (Oncorhynchus mykiss; Reilly et al. 2008b; also see Chapter 3 and ILAR 2009 for a more extensive discussion of pain perception in fish). Rainbow trout and zebrafish typically respond to noxious events by reducing activity and frequency of swimming; noxious stimulation also causes a rapid rise in respiration rate to almost double that of normal rates. Common carp do not exhibit the same responses, but do show anomalous behaviors associated with loss of equilibrium or ârockingâ on their pectoral fins on the substrate. Rainbow trout exhibit these behaviors as well, but in addition rub the stimulated area on the gravel bottom or sides of the tank. Such anomalous behaviors are not observed in zebrafish. Therefore, more species may have to be assessed before reliable criteria can be developed for recognizing pain or discomfort in fish. There is little information regarding dosage and route of analgesia in fish; only three analgesicsâmorphine, ketoprofen, and butorphanolâhave been assessed so far. Morphine at a wide range of investigational doses (2.5-30 mg/kg i.m.3) has been shown to reduce nociceptive responses in rainbow trout at the lowest effective dose of 5 mg/kg i.m. (Sneddon 2003). Butorphanol, investigated in chain dogfish (Scyliorhinus retifer) and koi carp (C. carpio), was ineffective in the elasmobranch dogfish (dose range 0.25-5 mg/kg; Davis et al. 2006). In contrast, it was effective in diminishing postsurgical changes in behavior and physiology in the teleost bony carp at a dose of 0.4 mg/kg i.m. (Harms et al. 2005). The NSAID ketoprofen (1-4 mg/kg) also had no effect in the dogfish; however, both ketoprofen and butorphanol were given via immersion, and drug uptake through the gills may not have occurred since morphine uptake via this route of administra- 3 The doses of analgesic drugs discussed in the text are for investigational not clinical use unless otherwise indicated.
101 EFFECTIVE PAIN MANAGEMENT tion is quite time consuming (Newby et al. 2006). In contrast, ketoprofen appeared to reduce inflammation of the muscles in koi carp but some aberrant postoperative behaviors were still observed after administration (2 mg/kg i.m.). Much research is needed in this area to determine optimum doses and efficacy of different analgesics. Amphibians Basic research has significantly delineated the anatomy, mechanisms, and regulation of pain in the Northern grass frog, Rana pipiens, and this species has been proposed as a model for opioid research (Stevens 2004). The analgesic efficacy and duration of action of opioids, Î±2-adrenoreceptor agonists, and numerous nonopioid analgesics in amphibians have been reported (Mohan and Stevens 2006; Stevens et al. 2001; Willenbring and Stevens 1997). Species differences in the distribution of nociceptors between R. pipiens and rodents have also been described (Stevens 2004). However, there are no reports of clinical studies using objectively established indices of pain in amphibians or of pharmacological studies in either R. pipiens or laboratory Xenopus. Comparison of limited lethality data in R. pipiens sug- gests that the safety index for these agents is quite narrow (Green 2003). Based primarily on the animalâs wiping behavior after the application of acetic acid to its skin, scientists have tested a few analgesic agents and their doses (Terril-Robb et al. 1996; Stevens et al. 2001; Machin 2001; Smith 2007). More studies of specific techniques are needed. Reptiles Information about efficacy, pharmacokinetics, and adverse effects of analgesics in reptiles is extremely limited. Indeed, there is no toxicity infor- mation to guide local anesthesia/analgesia dosing for reptiles; many authors advise adoption of the dose limits for dogs and cats. In a 2004 survey of 367 veterinary practitioners who treat reptiles, 98% of the respondents indicated that they believed that âreptiles feel painâ; approximately 40% reported the use of empirical or extrapolated methods to prevent or manage pain in their reptiles (Read 2004). The most commonly used drugs were opioids, NSAIDs, and local anesthetics. Evidence for opioid analgesic efficacy in reptiles is found in less than a handful of reports (Mosley 2005). In a recently published study in the red-eared slider (turtle), Sladky and colleagues (2007) reported that sub- cutaneous butorphanol administration at 2.8 or 28 mg/kg did not provide analgesia in a thermal latency assay. In contrast, morphine produced long- lasting (24-hour) increases in response latency and concomitant âmarked and prolongedâ respiratory depression. In green iguanas butorphanol was
102 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS not shown to reduce isoflurane anesthetic requirements; it also did not adversely affect cardiovascular function (Mosley et al. 2003, 2004). Tuttle and colleagues (2006) investigated the pharmacokinetics of the NSAID ketoprofen in the green iguana and determined that, based on the drugâs long elimination half-life, the standard practice of daily dosing might be excessive, although a 10-day course of carprofen or meloxicam admin- istration in the green iguana did not reveal any detrimental effects on the animalâs hemogram and chemistry (Trnkova et al. 2007). Birds Therapeutic interventions to address pain in birds are based predomi- nantly on studies of fowl (ducks, chickens, turkeys) and various psittacine (parrot) species. The most commonly studied analgesic drugs are NSAIDs and opioids; pharmacokinetic information (to guide dose and duration) is available for certain NSAIDs, but information on the effectiveness of other pain management strategies is limited to professional opinion and best practices. NSAID efficacy studies were conducted with analgesiometric testing (thermal threshold), scoring of clinical parameters (weight bearing, lameness, other behaviors), and/or assessment of self-administration of an analgesic drug. Citations are listed for each type of study described below. Most clinical parameter and self-assessment testing was conducted in fowl species with naturally occurring or experimental induction of arthri- tis, or following partial beak amputation (Gustafson et al. 2007). While a dose-response curve is usually a component of these studies, the duration of analgesic action is not easily extrapolated from the results. On the other hand, most of the efficacy studies using analgesiometry were conducted with opioids in perching birds (psittacine species; see text below). These later studies allow an understanding of the duration of the drugs tested, but the type of pain studied (withdrawal threshold to a momentary noxious stimulus) is probably not representative of either postsurgical or chronic pain, so it is important to recognize that the dose and duration information that they convey may differ (i.e., the dose may be higher or lower than needed) in the context of clinical pain in birds. Because class Aves includes species with extremely variable physiological adaptation strategies in which only limited types of pain have been studied, it is probably not feasible to simply extrapolate from the doses described in the literature for the use of analgesics in different bird species. Little to no information on dosing, effi- cacy, and adverse effects is available for many bird species used in labora- tory animal science (e.g., song birds). Studies of surgical analgesia in birds are needed, and beak amputation in fowl may represent an ideal model as it has been reported for birds of varying ages and species. Studies of opioids in parrots and chickens (Gentle et al. 1999; Paul-
103 EFFECTIVE PAIN MANAGEMENT Murphy et al. 1999; Sladky et al. 2007) indicate that opioids acting at the mu-opioid receptor are either not effective in birds or are much less so than in mammals, whereas butorphanol, a kappa agonist opioid with antagonist efficacy at the mu-opioid receptor, is considered the opioid of choice for acute and chronic pain management in birds (Paul-Murphy et al. 1999; Sladky et al. 2007). A chief disadvantage cited for the use of butorphanol in birds is its apparent short duration, requiring frequent redosing. Sladky and colleagues (2007) found long-lasting (up to 5 days) antinociception (to a heat stimulus) and persistent serum concentrations in Hispaniolan parrots given a liposomal encapsulated formulation of butorphanol (10-15 mg/kg) intramuscularly. Morphine has been shown to produce analgesia in certain strains of chickens at much lower doses (15 vs. 100 mg/kg) than in other strains; it is unknown if such strain differences occur in other species (Gen- tle et al. 1999). A possibly confounding factor is the sedation caused by high doses of some opioids. Opioids are primarily administered intramuscularly; one study showed that intra-articular injection of various doses of morphine, fentanyl, and buprenorphine in chickens did not have an appreciable anal- gesic effect (ibid.). The best evidence for opioid analgesia in birds currently supports drugs acting at the kappa receptor, but more work is needed to determine optimal administration schedules and specific doses. NSAIDs are the most extensively studied drugs in birds in terms of pharmacology and efficacy, but their use nonetheless requires piecing together the available information to guide dosing. Carprofen has been shown to reduce clinical signs of both naturally occurring and experimen- tally induced articular pain in chickens (Danbury et al. 2000; Hocking et al. 2005; Mc Geown et al. 1999); Mc Geown and colleagues (1999) showed that the time lame chickens required to complete an obstacle course was reduced by roughly 50% 90 minutes after intramuscular administration of 1 mg/kg carprofen. In contrast, the minimum effective intramuscular dose of carprofen in a urate model of articular pain in chickens was 30 mg/kg (although mortality was also observed at this dose; Hocking et al. 2005). Naturally lame chickens were found to selectively consume carprofen in feed whereas healthy individuals avoided the medicated feed (Danbury et al. 2000). The authors calculated that the amount of oral carprofen birds consumed to achieve adequate serum levels was approximately 10 times the recommended oral dose for dogs. This study suggests that the dose required depends on the intensity of pain and also points out likely differ- ences in oral bioavailability of this drug in chickens compared with dogs. A degree of clinical efficacy has been demonstrated for both flunixin and ketoprofen. Hocking and colleagues (2005) found minimum effective doses of intramuscular flunixin (12 mg/kg) and ketoprofen (3 mg/kg) in a urate arthritis chicken model and indicated that the flunixin dose was similar to, and the ketoprofen dose greater than, doses of the drugs recom-
104 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS mended for horses and cattle. Although these results establish drug efficacy, they raise concerns about toxicity, including death, and suggest the need to study lower doses. Machin and colleagues (2001) studied intramuscular ketoprofen (5 mg/ kg) in isoflurane-anesthetized mallard ducks and concluded that responses to a noxious stimulus (pressure by clamp) were reduced by ketoprofen 30 to 90 minutes after administration. As NSAIDs have not been reliably found to reduce the minimal alveolar concentration of inhalant anesthetics in mammalian species, the results of this study must be interpreted cautiously. Neither phenylbutazone nor acetaminophen showed analgesic activity in lame chickens (Hocking et al. 2005). Moreover, the efficacy of three anti- inflammatory corticosteroids (betamethasone, dexamethasone, and meth- ylprednisone) was evident from an assay in lame chickens. The authors indicated that the doses used were comparable to those used in mammals for management of pain behaviors (Hocking et al. 2001). Limited pharmacokinetic data on NSAIDs in birds are available. Baert and DeBacker (2003) compared the pharmacokinetic properties of flunixin, salicylate, and meloxicam in five species of birds (chickens, ostriches, ducks, turkeys, and pigeons) and found that parameters varied by drug and species, and that the typical correlation of elimination half-life with body weight was not evident. Although elimination half-life is important in deter- mining the steady-state serum concentration of a drug, serum concentrations of NSAIDs do not necessarily determine the duration of analgesia. Machin and colleagues (2001) examined plasma thromboxane (TBX) levels follow- ing 5 mg/kg of either ketoprofen or flunixin administration in mallard ducks and found that TBX concentrations were suppressed for about 12 hours by both drugs; because intramuscular injection sites in flunixin-treated ducks showed histopathologic evidence of necrosis, the authors caution against this route of injection in these animals. Adverse effects of NSAIDs in birds have been reported, so these drugs must be used with appropriate caution. Urate accumulation (visceral gout), renal necrosis, and liver damage occur in vultures with oral exposure to the NSAID diclofenac, and the syndrome has been reproduced in domes- tic chickens (Naidoo et al. 2007). A single dose of ketoprofen (2-5 mg/kg) given to male eider ducks was implicated in deaths from renal damage (Mulcahy et al. 2003). Gastrointestinal damage may also occur in addition to nephropathy, as in mammals, although this is not as well studied. LIMITATIONS OF AVAILABLE INFORMATION Pain in animals may not be effectively managed in many situations because of a lack of information about how to recognize and treat it, although controlled studies of analgesia are available for popular veterinary
10 EFFECTIVE PAIN MANAGEMENT species, primarily for postsurgical and chronic osteoarthritis pain. Some evidence has accumulated in support of pain management strategies for limited types of postoperative and postprocedural pain in some strains of laboratory rodents (e.g., for laparotomy; Karas et al. 2001; Krugner-Higby et al. 2003; Roughan and Flecknell 2001, 2004; Wright-Williams et al. 2007). However, appropriate analgesic treatment for the myriad common surgical approaches in rats, mice, and most laboratory mammals, as well as for chronic, disease-, or cancer-related pain, is mostly extrapolated from research in which pain is the subject of study. In practical terms, analgesia in rabbits, guinea pigs, rodents other than rats and mice, primates, sheep, calves, goats, and swine remains a purely empirical exercise based on anecdote, experience, and best practice. Even less is known about non- mammalian vertebrates, although recent evidence suggests that pain in amphibians and fish may in many ways be analogous to that of mammals (Sneddon 2004; Stevens et al. 1994; Stoskopf 1994). However, this inter- pretation is controversial because amphibians lack the cerebral and limbic cortical components widely believed necessary for the appreciation of pain (Stevens 2004). In addition to the absence of scientific evidence, making it difficult to measure the intensity and expected frequency of pain and the efficacy of analgesics in many laboratory species, there are circumstances in which the withholding of analgesic drugs is necessary. One example is pain-related research in which the use of anesthetic and analgesic drugs may not be appropriate because they may interfere with behavioral or other endpoints to be assessed and validated as the focus of the study. Also, many anesthetic and analgesic drugs have inherent properties (protective or toxic) that must be understood and accounted for (e.g., by means of appropriate control groups). Last, anesthetics and analgesics can lead to end-organ injury, either directly through toxic effects or indirectly through impaired vital organ function. Thus, while the specific choice of anesthetics or analgesics is important, so is the manner in which they are used. Investigators should bear in mind that withholding analgesics after surgery or other invasive pro- cedures associated with anticipated moderate to severe pain may confound the results with unwanted variables of immobility, weight loss, and other consequences of stress and pain. The effective reduction and management of pain in laboratory animals to optimize both their well-being and the quality of the research is still fraught with limitations. However, extrapolation of techniques from other species, accounting for differences in physiology between them, and atten- tion to the vast scientific literature that uses animal models can improve the ability to manage pain in animals in the laboratory.
106 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS CONCLUSIONS AND RECOMMENDATIONS 1. Treatment of postprocedural, persistent, and chronic pain requires a basic understanding of its etiology, strategies, and time course. Anticipation of the potential intensity of pain is important in design- ing the appropriate approach to its prevention or management. 2. The amount of pain experienced by laboratory animals can be reduced through the use of preventive or therapeutic strategies or their combination. Such therapeutic measures include the use of general and local anesthetics, analgesics, and anxiolytics as well as nonpharmacologic methods. 3. Although regulations require treatment for only nonbrief pain, ani- mals subjected to multiple episodes of momentary pain may benefit from measures to alleviate such pain. 4. Limitations to effective pain management include (1) a lack of knowledge of drug effects and doses in many mammalian and, especially, nonmammalian species; and (2) potential confounding effects of analgesics and anesthetics on study variables. 5. In studies where the use of certain analgesics appears to be contra- indicated, investigators should be mindful that unwanted variables from pain-induced perturbation of homeostatic mechanisms can affect the animal model. REFERENCES ACVA (American College of Veterinary Anesthesiologists). 1998. American College of Veteri- nary Anesthesiologistsâ Position Paper on the Treatment of Pain in Animals. Available at www.acva.org/professional/Position/pain.html. Accessed January 5, 2009. Affaitati G, Giamberardino MA, Lerza R, Lapenna D, De Laurentis S, Vecchiet L. 2002. Effects of tramadol on behavioural indicators of colic pain in a rat model of ureteral calculosis. Fundam Clin Pharmacol 16(1):23-30. Ainsworth L, Budelier K, Clinesmith M, Fiedler A, Landstrom R, Leeper BJ, Moeller L, Mutch S, OâDell K, Ross J, Radhakrishnan R, Sluka KA. 2006. Transcutaneous electrical nerve stimulation (TENS) reduces chronic hyperalgesia induced by muscle inflammation. Pain 120(1-2):182-187. Akca O, Melischek M, Scheck T, Hellwagner K, Arkilic CF, Kurz A, Kapral S, Heinz T, Lack- ner FX, Sessler DI. 1999. Postoperative pain and subcutaneous oxygen tension. Lancet 354(9172):41-42. American Heritage Medical Dictionary. 2007. Boston: Houghton Mifflin. Anand KJS. 1993. Relationships between stress responses and clinical outcome in newborns, infants, and children. Crit Care Med 21:S358-S359. Anand KJS. 2007. Anesthetic neurotoxicity in newborns: Should we change clinical practice? Anesthesiology 107:2-4. Anand KJS, Soriano SG. 2004. Anesthetic agents and the immature brain: Are these toxic or therapeutic? Anesthesiology 101(2):527-530.
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