ttp://www.bsava.com
REVIEW
Therapeutic options for the treatment of chronic pain in dogs P. D. MacFarlane, A. S. Tute* and B. Alderson† Langford Veterinary Services, The University of Bristol, Langford BS40 5DU *Gable Cross Veterinary Rehabilitation, Gable Cross Farm, Lowcross, Tilston, Cheshire SY14 7DW †The University of Liverpool, Leahurst, Neston, Wirral CH64 7TE
Chronic pain is a widely recognised problem in humans and is being increasingly recognised as a significant problem in dogs. Whilst a large number of therapies are described and utilised to treat chronic pain in dogs, there is a severe shortage of evidence to guide practitioners in selection of treatments. Until more evidence becomes available, practitioners should adopt a cautious approach, utilising licensed treatments first when possible. Non-pharmacological therapies should be incorporated into the chronic pain management plan whenever possible. Given the probable prevalence of chronic pain in dogs there is an urgent need for research to identify effective treatments. Journal of Small Animal Practice (2014) 55, 127–134 DOI: 10.1111/jsap.12176 Accepted: 11 November 2013; Published online: 28 January 2014
INTRODUCTION Chronic pain is a widely recognised problem in humans with an estimated global incidence between 10 and 25% (Goldberg & McGee 2011). The incidence of chronic pain in dogs is unknown, but is being increasingly recognised as a significant problem. Chronic pain is usually defined as such by having persisted for more than 3 to 6 months (Taylor 2005). It may be associated with an on-going disease process for example osteoarthritis or neoplasia, but can also be linked to an apparently resolved condition, for example post-surgical chronic pain or neuropathic pain because of damage to neural tissue (Taylor 2005). Whilst by definition chronic pain must persist for some time, in certain conditions for example osteoarthritis or oncological pain, it is probable that the chronic nature of the pain is well established by the time the condition is diagnosed. Many specific chronic pain conditions are recognised in humans and there are often defined diagnostic criteria for each. However, these may be difficult or impossible to apply in companion animals as they may require a detailed description of the patient’s pain experience (IASP 2011). Some of the descriptors associated with these pain states such as the “burning” sensation often associated with neuropathic pain in humans, may be difficult to recognise in dogs. Chronic pain states are characterised by changes in the normal function of neural systems that detect stimuli, the processing of and cognitive response to these stimuli (Voscopoulos & Lema 2010). The precise neural changes seen vary with the specific type of chronic pain state encountered (Voscopoulos & Lema Journal of Small Animal Practice
•
Vol 55
•
March 2014
•
2010) and so it is likely that therapeutic interventions which are effective in one situation may not be as effective in others. It is beyond the scope of this article to describe the wide range of chronic pain states recognised in humans, the assessment of pain or to detail every therapy that may be used. Rather it aims to give a brief overview of some of the underlying pathological changes seen in chronic pain states and the more commonly employed treatment modalities.
PATHOPHYSIOLOGY OF CHRONIC PAIN In the normally functioning nervous system noxious stimuli are detected by an extremely complex system of nociceptive neurons, which transmit information to the dorsal horn of the spinal cord (Willis & Westlund 1997). At this level, signals from nociceptive neurons may be transmitted directly to the brain, or be integrated along with inputs from sensory neurons and descending modulatory neurons in order to aid discrimination between noxious and non-noxious stimuli (Willis & Westlund 1997). Further processing occurs at the level of the brain stem and within the brain itself before the noxious stimuli can be perceived as “pain” in the cerebral cortex (Voscopoulos & Lema 2010). Each component of this system is “plastic” – that is exposure to a noxious stimulus may lead to changes in the neurological and emotional response to subsequent nociceptive stimuli (Voscopoulos & Lema 2010). In some situations such as acute soft tissue injury, these changes may be considered “protective” and are expected to return to normal once healing has occurred. Most
© 2014 British Small Animal Veterinary Association
127
P. D. MacFarlane et al.
commonly this is manifested as increased sensitivity to noxious stimuli (hyperalgesia) or a normally non-noxious stimuli being perceived as painful (allodynia) (IASP 2011). If after an acute injury hyperalgesia and allodynia do not resolve or if a chronic disease process is driving pain, then they can be considered maladaptive. Once the nervous system has become sensitised, it may not respond as expected to analgesic medications. Sensitisation may occur in both the neural pathways associated with a damaged tissue (segmental) and in those, which are not associated with the damaged tissue (extra-segmental). Peripherally sensitisation occurs via a number of mechanisms. Many of these are mediated by inflammation which expands the pool of receptors in nociceptive nerve terminals and increases the nerves responsiveness to stimuli, including recruiting so called “silent nociceptors” (Voscopoulos & Lema 2010). During their course to the dorsal horn of the spinal cord it is possible for “cross-excitation” to occur between neurons, and this may be another mechanism via which peripheral sensitisation may occur (D’Mello & Dickinson 2008). The dorsal horn of the spinal cord is a key component of the nociceptive nervous system (Voscopoulos & Lema 2010). Here inputs from nociceptors and other sensory neurons are integrated with descending modulatory impulses in the wide dynamic range (WDR) neurons (D’Mello & Dickinson 2008). This is a key site for sensitisation as if the WDR neurons response to stimuli is altered then both hyperalgesia and allodynia may arise. Key to this process is the N-methyld-aspartate (NMDA) receptor which will only open after high levels of stimulation but which once opened will allow prolonged depolarisation of the neuron (Petrenko et al. 2003). The resulting influx of calcium into cells leads to a host of alterations to cellular behaviour including altering the expression of receptors, altering both the expression and sensitivity of receptors and also changing the pattern of intracellular response to future stimulation (Petrenko et al. 2003). Signals transmitted up the spinal cord towards the brain are further processed in the brainstem before onward transmission (Voscopoulos & Lema 2010). Within the brain itself a large number of distinct systems are engaged in the recognition and response to noxious stimuli, until finally in the cerebrum the conscious sensation of noxious stimuli as the emotional state of pain occurs (Voscopoulos & Lema 2010). Descending modulatory neurons extend from the brain and brainstem to the dorsal horn of the spinal cord (Heinricher et al. 2009). These may be both inhibitory (decreasing the sensitivity of nociceptive systems) and facilitatory (increasing sensitivity). The inhibitory pathway is largely mediated via the neurotransmitter norepinephrine, whereas the facilitatory pathway is principally affected by serotonin (D’Mello & Dickinson 2008). The fact that the brain can modulate what is transmitted as noxious stimuli and that pain is an emotional state supports the observation that those humans with depression are more likely to experience chronic pain (Taylor 2005). Although the scientific study of emotional states in animals is difficult (Mendl et al. 2009) it is possible that a dog’s “emotional” state could also affect its susceptibility to chronic pain state. The association between depression and chronic pain in humans may be a direct result 128
of the effects of depression or because the tendency to develop depression is likely to correlate with other negative affective states, for example, pain catastrophising (an exaggerated emotional response to pain or the fear of pain) (Quartana et al. 2009).
MUSCULOSKELETAL ADAPTATION IN CHRONIC PAIN STATES Along with the well-documented neurological changes seen in chronic pain states, a number of musculoskeletal adaptations are observed. Animals in pain often adopt some degree of antalgic posture and gait, a form of postural guarding. This altered posture may lead to the development of new pain foci as tissues are abnormally loaded, sometimes referred to as secondary pain generators (Allen & Koshi 2005). This is thought to be a key process in the development of some chronic back pain in humans (O’Sullivan 2005). Chronic musculoskeletal problems and pain often have acute exacerbations reflecting the impact of normal activity on chronically adapted soft tissue structures. Inactivity often leads to weight gain and obesity and this has been identified as a potential risk factor in the development and progression of osteoarthritis and pain in certain joints (Kealy et al. 1997, 2000, Impellizeri et al. 2000, German 2006), creating a vicious cycle of weight gain, pain and further reduction in activity. The progression of arthritis may be due to the mechanical effects of increased mass (Marshall et al. 2010) or by a metabolic link (Ehling et al. 2006). Once altered musculoskeletal function is established it is unlikely that pharmacological intervention alone will be effective in relieving the chronic pain state (Brandt 1997). In humans, chronic pain is known to have a significant negative impact on quality of life (Breivik et al. 2006). There is also evidence that dogs with neuropathic pain have diminished quality of life (Rutherford et al. 2012).
THERAPIES IN CHRONIC PAIN In human pain medicine, a large number of treatments are used for managing patients with chronic pain states including medication, physical therapy, surgical interventions, acupuncture and various forms of cognitive therapy; these various therapies are best deployed as part of a multi-disciplinary approach (Stein & Kopf 2010). Some of these therapies have been adopted for the treatment of chronic pain in dogs and this review describes the theoretical mode of action and available evidence for treatments which are widely used, or, have evidence to support their use. Pharmacotherapy in the treatment of chronic pain Drug therapy should ideally be based on the mechanisms underlying the chronic pain, for example, the use of non-steroidal anti-inflammatory drugs (NSAIDs) to treat inflammatory pain. Unfortunately, it is often the case that the precise underlying pathology in any given case is unknown. It should therefore be recognised that occasionally therapeutic trials will be required and
Journal of Small Animal Practice
•
Vol 55
•
March 2014
•
© 2014 British Small Animal Veterinary Association
Therapeutic options for chronic pain in dogs
owners should be counselled that a given therapy may or may not be effective. Therapeutic trials usually consist of administration of a drug for 2 to 4 weeks as for many medications the onset of effects may be slow (Lascelles et al. 2008). It is self-evident that drug treatment for chronic pain tends to be given over prolonged periods. It is possible that this may lead to variations in the pharmacokinetics of the drug over time (Miyake et al. 1990) and so it is possible that dosages may need to be adjusted to maintain efficacy or to address changes in the underlying disease process. With the exception of the NSAIDs, few of the drugs used to treat chronic pain in companion animals are licensed and so their use must be justified under the cascade in the UK (Veterinary Medicines Directorate 2013a) and informed client consent sought. The use of schedule two and three opiates might be considered in some cases and the appropriate legislation must be complied with (Veterinary Medicines Directorate 2013b). Given the wide range of therapies suggested for the treatment of chronic pain, and the general paucity of evidence relating to their use, it can be difficult to decide which drug to administer when. A commonly used concept to address this problem in human medicine is the “pain ladder” introduced by the World Health organisation in 1987 for treating cancer pain. The ladder has three steps starting with NSAID’s or paracetamol; then the addition of weak opioids (e.g. codeine) and finally their substitution with strong opioids (e.g. morphine). At any stage adjunctive drugs such as anti-convulsants may be added if it is felt they may be appropriate. This scheme has been adopted and adapted for other pain states (Vargas-Schaffer 2010) including chronic pain, and acute pain – in the latter case often starting at the top of the ladder and working down once pain is controlled. Non-steroidal anti-inflammatory drugs The NSAIDs are widely used to treat some forms of chronic pain, notably osteoarthritis and they are unusual in a veterinary context in that their use is supported by a large body of evidence, much of which has been recently reviewed (Lascelles et al. 2005, Sanderson et al. 2009, Innes et al. 2010b). There are many licensed NSAIDs available on the veterinary market, but none has so far been demonstrated to be better or safer than any other in clinical trials and selection is often based on personal preference, licensing and ease of dosing (Innes et al. 2010a). Anecdotally, the response to the different drugs varies between individuals and often swapping from one NSAID to another may result in improved pain management although it is not known why this is the case. It is usual to recommend a “washout” period when changing from one NSAID to another, although the length of this washout period has not been established; 5 to 7 days is considered to be a conservative estimate (Kukanich et al. 2012). Paracetamol Paracetamol has been widely used in human medicine for over 50 years, and yet its precise mechanism of action is still unclear. It appears increasingly likely that it has multiple modes of action, both centrally and peripherally (Raffa 2001). Although it is often grouped with the NSAIDs, paracetamol has little or no effect on cyclooxygenase (COX-1 and COX-2), and its concurrent use Journal of Small Animal Practice
•
Vol 55
•
March 2014
•
with NSAIDs and steroids is widely advocated in human pain medicine (Ong et al. 2010). Paracetamol undergoes hepatic metabolism via a number of pathways including glucuronidation, sulphation and N-hydroxylation. An intermediate metabolite in the latter pathway is NAPQI, which is toxic. In humans and dogs, paracetamol toxicity is only seen when high doses are given, however, in cats toxicity may be encountered at low doses and paracetamol should not be administered to this species. It is largely devoid of gastrointestinal and renal side effects. There is no published evidence to support the use of paracetamol for chronic pain in dogs. It is available as a licensed preparation compounded with codeine (Pardale V). The license states that therapy should be limited to 5 days and that it should not be co-administered with NSAIDs. Tramadol Tramadol is a synthetic analogue of codeine and is a centrally acting analgesic drug with actions at adrenergic, serotonin and opioid receptors (Kukanich & Papich 2004). A recently published placebo-controlled study has identified a positive effect of tramadol on pain in dogs with osteoarthritis (Malek et al. 2012). There is a very large variability in uptake following oral administration in dogs (Kukanich & Papich 2004). Human sustained release preparations may not produce effective plasma concentrations in dogs (Giorgi et al. 2009). The M1 metabolite is responsible for a large proportion of the analgesia in humans (Smith 2011). Dogs do not produce as much of the M1 metabolite as humans and therefore the opioid analgesia component of tramadol in dogs may not be as efficacious (Kukanich & Papich 2004). In humans who are poor tramadol metabolisers the serotonin and adrenergic analgesia is enhanced, whereas that due to opioid effects is diminished (Rollason et al. 2008). Thus the analgesia produced by tramadol in dogs may be via its effects on serotonin and norepinephrine reuptake, rather than by any opioid effect (McMillan et al. 2008). Side effects that are most commonly reported in dogs are salivation, vomiting, sedation and seizures (Grubb 2010). Tramadol lowers the seizure threshold, therefore it should be used with caution in dogs with a history of seizures. The drug has a bitter taste and is often resented by dogs. Very rarely serotonin syndrome can be seen as behavioural changes, neuromuscular hyperactivity and autonomic activation; this is more likely when it is coadministered with drugs that inhibit the reuptake of serotonin such as the tricyclic antidepressants, for example clomipramine (Ener et al. 2003). Opioids Opioids are commonly used in the treatment of chronic pain in humans (Jensen et al. 2009). There is no published data with regard to the clinical efficacy or safety of the long-term use of opioids in veterinary species. Human prolonged-release preparations may not be suitable for use in dogs as oral absorption is poor, effective plasma concentrations may not be reached or dosing intervals may not be prolonged when compared to conventional formulations (Dohoo & Tasker 1997). However, when administered sublingually buprenorphine has reasonable bioavailability in dogs (Ko et al. 2011) and could be considered for long-term
© 2014 British Small Animal Veterinary Association
129
P. D. MacFarlane et al.
dosing. Whilst there is anecdotal evidence to suggest that this may be an effective strategy, there does not appear to be any trial data to support its use. However, in humans, sublingual buprenorphine is well established as a treatment option for cancer-related chronic pain (Pergolizzi et al. 2008). Transdermal fentanyl patches could also be considered for long-term pain treatment – although little is known of their pharmacokinetics after 72 hours (Hofmeister & Egger 2004) or at what frequency patches need to be replaced. Recently, a liquid transdermal fentanyl perpetration has been launched onto the UK market. The data sheet of this product stipulates that dogs weighing more than 20 kg should be hospitalised for 48 hours after its application. The lack of pharmacokinetic data related to repeated dosing of this product should preclude its chronic use until its safety in this application has been established. Pentazocine is a synthetic opioid with partial agonist activity at both µ and κ receptors (Shu et al. 2011). It has been shown to be effective in acute pain in dogs (Taylor & Houlton 1984) but there are no studies investigating its use in chronic pain despite its widespread use. Opioids have the potential to cause respiratory depression, bradycardia and sedation, although rarely except in cases of accidental overdose, which has been reported in conjunction with the ingestion of fentanyl patches (Schmiedt & Bjorling 2007). NMDA receptor antagonists Amantadine: Amantadine was first recognised as an antiviral agent (Davies et al. 1964) and then was found to be useful in the treatment of Parkinson’s disease (Schwab et al. 1969). It is an NMDA antagonist and has been used in the treatment of various chronic pain conditions in humans, including neuropathic pain, as it does not elicit the adverse psychomotor effects of ketamine. In one study, amantadine, administered to dogs already receiving meloxicam, led to further improvement in pain relief when compared to placebo; the difference in pain score becoming significant after 21 days of amantadine administration (Lascelles et al. 2008). Amantadine has good oral bioavailability in dogs and is metabolised in the liver and excreted in the urine (Bleidner et al. 1965). Common side effects in dogs appear to be agitation and diarrhoea; however, in the authors’ experience these tend to resolve after a few days. More severe side effects include seizures (Grubb 2010).
was reported (Cashmore et al. 2009) and also in Cavalier King Charles spaniels with clinical signs associated with Chiari-like malformation and syringomyelia (Plessas et al. 2012). Gabapentin: Gabapentin is an antiepileptic drug that was found to be effective in humans as an analgesic for neuropathic pain, probably due to actions at voltage-gated calcium channels in the brain and spinal cord (Moore et al. 2011). Gabapentin is highly bioavailable in dogs and is metabolised in the liver and excreted via the kidney, therefore in cases with hepatic or renal disease dosing regimes should be altered (Radulovic et al. 1995). The most common side effect is sedation, however, decreasing the dose will stop this and the dose can often be increased again without sedation (Grubb 2010). Vomiting may also occur. When stopping gabapentin the dose should be stepped down over several days as stopping abruptly may cause seizures (Mathews 2008). Pregabalin and carbamazepine: Pregabalin and carbamazepine have similar mechanisms of action to gabapentin and their pharmacokinetics have been reported in the dog (Frey & Löscher 1980, Salazar et al. 2009). Pregabalin is more expensive than gabapentin and there is currently no evidence for any advantages in efficacy over gabapentin. Bisphosphonates Bisphosphonates, such as pamidronate, inhibit osteoclast activity, which may have a role in the pain associated with bone malignancy. Two studies of the use of pamidronate in dogs have shown improvements in pain control (Fan et al. 2005, 2007). Approximately 1·0 mg/kg is administered as an intravenous infusion over 2 hours, and may be repeated every 28 days. Significant improvement in signs of pain may be seen in approximately 30 to 40% of cases with bone malignancy (Fan et al. 2005, 2007). When combined with standardised palliative therapy, pamidronate did not result in an extended duration of subjective pain relief, however, it may have resulted in a better quality of analgesia (Fan et al. 2009).
Ketamine: There is extensive human literature regarding the use of ketamine for various types of chronic pain states (Quibell et al. 2011) and it may be given at subanaesthetic doses via the oral, subcutaneous or intravenous route. There is only anecdotal evidence relating to the use of ketamine for chronic pain in dogs and the side effects may limit its usefulness in this situation in dogs (Mathews 2008).
Tricyclic antidepressants The tricyclic antidepressants are widely used in humans (Dharmshaktu et al. 2012), acting as serotonin and norepinephrine re-uptake inhibitors, enhancing descending inhibition of nociception. There are no controlled trials of their use in dogs but amitriptyline has been reported to be beneficial in a case series of three dogs with neuropathic pain (Cashmore et al. 2009). Amitriptyline should be used cautiously in dogs with conduction abnormalities as it may cause ECG changes and, at higher doses, ventricular arrhythmias (Reich et al. 2000). It should not be used with tramadol, St. John’s wort and other drugs that act via serotonin and norepinephrine reuptake, as they may have interactions that lead to serotonin syndrome (Ener et al. 2003).
Anticonvulsant drugs There are no controlled trials documenting the use of anticonvulsant drugs for the control of chronic pain in dogs. In one case report of neuropathic pain in dogs a positive effect of gabapentin
Steroids If pain has an inflammatory component then the potent antiinflammatory action of glucocorticoids may be of benefit. In addition, glucocorticoids may modulate nociceptive processing
130
Journal of Small Animal Practice
•
Vol 55
•
March 2014
•
© 2014 British Small Animal Veterinary Association
Therapeutic options for chronic pain in dogs
in the dorsal horn (McEwen & Kalia 2010). However, they may also potentiate neuropathic pain via complex mechanisms involving the hypothalamic-pituitary-adrenal axis (McEwen & Kalia 2010) and so must be employed cautiously and with consideration of the type of pain present. A licensed veterinary compound of prednisolone and cinchophen is available in the UK for the treatment of osteoarthritis in the dog. This product has been shown to give equivalent analgesia to phenylbutazone in dogs with osteoarthritis (McKellar et al. 1991). The concurrent use of glucocorticoids and NSAIDs should be avoided because of the increased risk of gastrointestinal ulceration. Central muscle relaxants There is no evidence to support the use of muscle-relaxants in dogs with chronically painful conditions. Muscle relaxants are not usually considered as analgesics; however, the use of drugs to relax muscles, in combination with conventional analgesics may reduce anxiety-induced pain and skeletal muscle pain. Many different drugs have been used in humans and none has been shown to be superior (Elenbaas 1980). Anecdotally, diazepam is often used in dogs, especially following spinal surgery to reduce the pain associated with muscle spasm. Pentosan polysulphate Pentosan polysulphate is a semi-synthetic glycosaminoglycan, the mechanism of action for analgesia is currently unknown and there are many proposed mechanisms. It has very poor bioavailability via the oral route and may take several months to achieve the desired effect (Ghosh 1999). It is licensed for use for the treatment of lameness and pain of degenerative joint disease/osteoarthrosis (non-infectious arthrosis) in the skeletally mature dog. In dogs, it has been investigated for use in osteoarthritis with varying results. Systemic administration of four subcutaneous injections at 7-day intervals of 3·0 mg/kg reduced lameness and pain compared to baseline (assessed by veterinarian examination including stiffness, weakness and pain on joint manipulation, subjective lameness scores and an owner questionnaire) (Read et al. 1996). The oral formulation did not improve the clinical or radiographic signs of osteoarthritis in dogs following cranial cruciate ligament surgery but did alter the biochemical markers in the synovial fluid (Innes et al. 2000). The data sheet for pentosan polysulphate states that it should not be used in conjunction with NSAIDs as there may be potentiation of the anticoagulant activity (NOAH 2013). Neutraceuticals These are a group of food supplements, which are purported to be able to modify disease processes or act as analgesics. There are several compounds available in the veterinary market and many more marketed for humans, which could be utilised in dogs. There is extremely sparse evidence relating to the use of nutritional supplements for chronic pain, other than osteoarthritis, in the human literature (Gagnier 2008). There is some evidence from well-conducted, placebocontrolled clinical trials supporting the use of several of these compounds in osteoarthritis in dogs including elk velvet antler Journal of Small Animal Practice
•
Vol 55
•
March 2014
•
(Moreau et al. 2003, 2004), food containing green-lipped mussel, (Sanderson et al. 2009), green-lipped mussel (Bierer & Bui 2002, Bui & Bierer 2003) and omega-3 fatty acids (Roush et al. 2004). There is limited evidence comparing them to pharmaceutical preparations. One study in dogs with clinical signs of chronic osteoarthritis compared glucosamine/chondroitin sulphate with carprofen; glucosamine/chondroitin sulphate improved some of the clinical signs of lameness by day 70 (compared to day 14 with carprofen) (McCarthy et al. 2007). Non-pharmacological therapies The importance of non-pharmacological therapies is emphasised by the fact that the National Institute of Clinical Excellence (NICE) consider education, exercise and weight loss as core treatments for osteoarthritis with pharmaceutical treatment being considered only in addition to core treatment (NICE 2008). Weight control Moderate (6 to 8%) weight loss in dogs with osteoarthritis has been shown to reduce pain scores (Marshall et al. 2010). Dietary management and lifestyle alterations may lead to significant weight loss in clinical canine cases (German et al. 2007). Therapeutic exercise (see later) also would be expected to contribute to weight reduction programmes. Massage Massage includes a variety of soft tissue manipulations whose physiological and psychological effects are used to reduce pain and alter mechanical stress caused by myofascial tissue disorders. There is evidence in humans that massage may increase the range of joint motion (Sefton et al. 2011) and decrease pain scores (Cherkin et al. 2001). Physiological effects include tissue repair and pain modulation (Wright & Sluka 2001), mediated by improved local circulation and lymphatic drainage, segmental inhibitory mechanisms, and, activation of descending pain inhibitory systems (Furlan et al. 2002, Sutton 2004). Owners of dogs experiencing chronic pain often reduce tactile contact, including patting and stroking, for fear of causing further pain or distress. It is possible that re-introducing tactile stimulation, through massage and touch by the owner, may aid in desensitising animals with allodynia to irritating somato-sensory input (Allen 2006). Myofascial release and trigger point therapy Physical trauma results in fascial strains, which tighten over time, resulting in a loss of normal flexibility. Movements and postures become painful, further trauma may ensue and pain may be experienced at sites distant from the original insult (Sutton 2004, Barnes 2009). Diagnostic criteria for myofascial trigger points have been described in dogs (Frank 1999). They include identifying discrete painful nodules 0·5 to 4·0 cm in diameter within muscle bellies (Janssens 1991). When palpated they lead to reproducible pain which may be experienced locally or at a distance. If treatment is targeted at the region at which the pain is experienced there may not be resolution of the initiating painful stimulus (Janssens
© 2014 British Small Animal Veterinary Association
131
P. D. MacFarlane et al.
1991). Palpation of these points may be extremely painful, leading to biting even in very well-trained animals. In one case series resolution of pain was observed in 60% of patients using either dry needling or intra-trigger point injection of 1% lidocaine (Janssens 1991). Passive stretching and passive range of motion exercises Many dogs suffering from chronic pain associated with osteoarthritis have restricted range of joint motion. This may be due to a combination of postural guarding and reduced activity levels causing soft tissue shortening and fibrosis, and avoidance of moving into painful positions (Johnston 1997, Millis & Levine 1997, Allen & Koshi 2005). Regular movement, throughout the available joint range, is important for maintaining a full range of motion and for the health of articular and peri-articular structures. Passive stretching (PS) and passive range of motion (PROM) exercises are particularly useful immediately after surgery to prevent some of the effects of disuse and immobilisation discussed above. They improve the extensibility of muscles and soft tissues, improve joint range, prevent adhesions, promote synovial fluid production and diffusion and improve cartilage lubrication and health (Millis & Levine 1997, Allen & Koshi 2005). Therapeutic exercise A wide range of exercise programmes, including hydrotherapy, are described in the human literature and many are associated with decreased pain scores. However, it is not possible to distinguish between different modalities on the impact of chronic pain states in humans (Turk et al. 2011). Good quality rest is important to patients with chronic pain states but excessive rest will lead to exacerbation of musculoskeletal pain (Gibbs & Klinger 2011). Therapeutic exercise aims to improve muscle strength (to support painful joints including those of the spinal column), proprioception (to provide dynamic stability and reduce risk of injury), active range of joint motion, cardiorespiratory strength and endurance (to minimise anaerobic respiration) and controlling body weight, with the ultimate aim of returning the dog to full, or as near full and active function as possible (Hamilton et al. 2004). Acupuncture and electroacupuncture Traditional Chinese acupuncture and the western approach are both used in human medicine. Evidence supporting the superiority of one form over the other is lacking, however, the use of acupuncture is accepted by NICE in a limited number of conditions in humans (NICE 2009). Pain modulating effects are thought to be mediated principally at the segmental level, with needle stimulation of afferent nerves resulting in action potentials entering the dorsal horn of the spinal cord (Wang et al. 2008). Descending inhibitory systems may also play a role in the analgesia provided by acupuncture. Central regulatory effects mediated by the limbic system, which plays a central role in the affective and cognitive dimensions of 132
pain, may be responsible for general calming effects as well as an improved sense of well-being reported in human patients (Wang et al. 2008, Fang et al. 2009). Gold bead implantation at acupuncture sites has been used for long-term analgesia in dogs with hip dysplasia with variable results (Bolliger et al. 2002, Jaeger et al. 2005, 2006, 2007). Transcutaneous electrical nerve stimulation (TENS) Like acupuncture, TENS relies on sensory nerve depolarisation to suppress pain at spinal cord level (Steiss & Levine 2005) and it is widely used in humans. Johnson & Levine (2004) highlighted several contraindications including, but not confined to, direct exposure to cardiac pacemakers, the abdominal area in pregnant bitches, malignancy at or near the site of treatment, seizure disorders and situations where active movement is contraindicated. Palliative radiotherapy Palliative radiotherapy is well established for the palliative treatment of pain associated with osteosarcoma in dogs with very few side effects reported in these cases (Ramirez et al. 1999). Radiotherapy has also been shown to be an effective treatment for osteoarthritis (Ruppert et al. 2004) in dogs. The mechanism via which radiotherapy alleviates pain in osteoarthritis is still being investigated in animal models, but a decrease in inflammation and joint swelling appears to be central to its effect (Calabrese & Calabrese 2012). Radiotherapy has limited availability for veterinary patients and may be associated with serious acute and late side effects (Arthur et al. 2008). Until further studies are conducted evaluating its efficacy and safety for treating osteoarthritis, its use should not be widely advocated. Environmental modification There is evidence from studies in humans that environmental modification may be of benefit. Supportive bedding (Jacobson et al. 2010) aids sleep and sleep deprivation is linked to increased pain perception. There is limited evidence that bedding type can affect the progression of osteoarthritis in dogs (Rogachefsky et al. 2004). In human patients with osteoarthritis associated pain difficulty with accessibility, limiting activity, can aggravate the condition (Gibbs & Klinger 2011) and in the authors’ opinion considering the effects of factors such as smooth floors, steep steps and high car tail gaits on a dog’s ability to exercise is important in order to maximise mobility levels.
SUMMARY Whilst a large number of therapies are described and utilised to treat chronic pain in dogs, there is a severe shortage of evidence to guide practitioners in selection of treatments. Until more evidence becomes available practitioners should adopt a cautious approach, utilising licensed treatments first when possible. Non-pharmacological therapies should be incorporated into the chronic pain management plan. Given the probable prevalence of chronic pain in dogs there is an urgent need for research to identify effective treatment.
Journal of Small Animal Practice
•
Vol 55
•
March 2014
•
© 2014 British Small Animal Veterinary Association
Therapeutic options for chronic pain in dogs
Acknowledgements The authors acknowledge Sue Dawson for her help. Conflict of interest None of the authors of this article has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper. References Allen, R. J. (2006) Physical agents used in the management of chronic pain by physical therapists. Physical Medicine and Rehabilitation Clinics of North America 17, 315-345 Allen, R. J. & Koshi, L. R. (2005) Chronic limb pain developing from reduced mobility. In: Physical therapy: annual conference and exposition of the American Physical Therapy Association. Boston, MA, June 9, 2005 Arthur, J. J., Kleiter, M. M., Thrall, D. E., et al. (2008) Characterization of normal tissue complications in 51 dogs undergoing definitive pelvic region irradiation. Veterinary Radiology & Ultrasound 49, 85-89 Barnes, J. F. (2009) Myofascial release: the missing link in traditional treatment. In: Therapies in Rehabilitation: Evidence for Efficacy in Therapy, Prevention and Wellness. 3rd edn. Ed C. M. Davis. SLACK Inc, Thorofare, NJ, USA. pp 89-112 Bierer, T. L. & Bui, L. M. (2002) Improvement of arthritic signs in dogs fed greenlipped mussel (Perna canaliculus). The Journal of Nutrition 132, 1634S-1636S Bleidner, W. E., Harmon, J. B., Hewes, W. E., et al. (1965) Absorption, distribution and excretion of amantadine hydrochloride. The Journal of Pharmacology and Experimental Therapeutics 150, 484-490 Bolliger, C., DeCamp, C. E., Stajich, M., et al. (2002) Gait analysis of dogs with hip dysplasia treated with gold bead implantation acupuncture. Veterinary and Comparative Orthopaedics and Traumatology 15, 116-122 Brandt, K. D. (1997) Putting some muscle into osteoarthritis. Annals of Internal Medicine 127, 154-156 Breivik, H., Collett, B., Ventafridda, V., et al. (2006), Survey of chronic pain in Europe: Prevalence, impact on daily life, and treatment. European Journal of Pain 10, 287-333 Bui, L. M. & Bierer, T. L. (2003) Influence of green lipped mussels (Perna canaliculus) in alleviating signs of arthritis in dogs. Veterinary Therapeutics 4, 397-40 Calabrese, E. J. & Calabrese, V. (2012) Reduction of arthritic symptoms by low dose radiation therapy (LD-RT) is associated with an anti-inflammatory phenotype. International Journal of Radiation Biology 89, 278-286 Cashmore, R. G., Harcourt-Brown, T. R., Freeman, P. M., et al. (2009) Clinical diagnosis and treatment of suspected neuropathic pain in three dogs. Australian Veterinary Journal 87, 45-50 Cherkin, D. C., Eisenberg, D., Sherman, K. J., et al. (2001) Randomised trial comparing Traditional Chinese Medical Acupuncture, therapeutic massage and selfcare education for chronic low back pain. Archives of Internal Medicine 161, 1081-1088 Cummings, W. A., & Filshie J. (2008) An overview of Western medical acupuncture in Western Medical Acupuncture Davies, W. Z., Grunert, R. R., Haff, R., et al. (1964) Antiviral activity of 1- adamantanamine (amantadine). Science 144, 862-863 Dharmshaktu, P., Tayal, V. & Kalra, B. S. (2012) Efficacy of antidepressants as analgesics : a review. Journal of Clinical Pharmacology 52, 6-17 D’Mello, R. & Dickinson, A. H. (2008) Spinal cord mechanisms of pain. British Journal of Ananesthesia 101, 8-16 Dohoo, S. E. & Tasker, R. A. (1997) Pharmacokinetics of oral morphine sulfate in dogs: a comparison of sustained release and conventional formulations. Canadian Journal of Veterinary Research 61, 251-255 Ehling, A., Schäffler, A., Herfarth, H., et al. (2006) The potential of adiponectin in driving arthritis. Journal of Immunology 176, 4468-4478 Elenbaas, J. K. (1980) Centrally acting oral skeletal muscle relaxants. American Journal of Hospital Pharmacy 37, 1313-1323 Ener, R. A., Meglathery, S. B., Decker, W. A. V. (2003) Serotonin syndrome and other serotonergic disorders. Pain Medicine 4, 63-74 Fan, T. M., deLorimier, L. P., Charney, S. C., et al. (2005) Evaluation of intravenous pamidronate administration in 33 cancer-bearing dogs with primary or secondary bone involvement. Journal of Veterinary Internal Medicine 19, 74-80 Fan, T. M., deLorimier, L. P., O’Dell-Anderson, K., et al. (2007) Single-agent pamidronate for palliative therapy of canine appendicular osteosarcoma bone pain. Journal of Veterinary Internal Medicine 21, 431-439 Fan, T. M., Charney, S. C., deLorimier, L. P., et al. (2009) Double-blind placebocontrolled trial of adjuvant pamidronate with palliative radiotherapy and intravenous doxorubicin for canine appendicular osteosarcoma bone pain. Journal of Veterinary Internal Medicine 23, 152-160 Fang, J., Jin, Z., Wang, Y., et al. (2009) The salient characteristics of the central effects of acupuncture needling: Limbic-paralimbic-neocortical network modulation. Human Brain Mapping 30, 1196-1206 Fox, S. M. (2010) Chronic Pain in Small Animal Medicine. Manson Publishing, London.
Journal of Small Animal Practice
•
Vol 55
•
March 2014
•
Frank, E. M. (1999) Myofascial trigger point diagnostic criteria in the dog. Journal of Musculoskeletal Pain 7, 231-237 Frey, H. H. & Löscher, W. (1980) Pharmacokinetics of carbamazepine in the dog. Archives Internationales de Pharmacodynamie et de Therapie 243, 180-191 Furlan, A. D., Brosseau, L., Innamura, M., et al. (2002) Massage for low-back pain: a systematic review within the framework of the cochrane collaboration back review group. Spine 27, 1896-1910 Gagnier, J. J. (2008) Evidence-informed management of chronic low back pain with herbal, vitamin, mineral, and homeopathic supplements. The Spine Journal 8, 70-79 German A. J. (2006) The growing problem of obesity in dogs and cats. The Journal of Nutrition 136, 1940S-1946S. German, A. J., Holden, S. L., Bissot, T., et al. (2007) Dietary energy restriction and successful weight loss in obese client-owned dogs. Journal of Veterinary Internal Medicine 21, 1174-1180 Gibbs, L. B. & Klinger, L. (2011) Rest is a meaningful occupation for women with osteoarthritis: occupation, participation and health. OTJR: Occupation, Participation and Health 31, 143-150 Giorgi, M., Saccomanni, G., Lebkowska-Wieruszewska, B., et al. (2009) Pharmacokinetic evaluation of tramadol and its major metabolites after single oral sustained tablet administration in the dog: a pilot study. The Veterinary Journal 180, 253-255 Goldberg, D. S. & McGee, S. J. (2011) Pain as a global public health priority. BMC Public Health 11, 770-775 Ghosh, P. (1999) The pathobiology of osteoarthritis and the rationale for the use of pentosan polysulfate for its treatment. Seminars in Arthritis and Rheumatism 28, 211-266 Grubb, T. (2010) What do we really know about the drugs we use to treat chronic pain? Topics in Companion Animal Medicine 25, 10-19 Hamilton, S., Millis, D. L., Taylor, R. A., et al. (2004) Therapeutic exercises. In: Canine Rehabilitation and Physical Therapy. Eds D. L. Millis, D. Levine and R. A. Taylor. Saunders, St Louis, MO, USA Heinricher, M. M., Tavares, I., Leith, J. L., et al. (2009) Descending control of nociception: specificity, recruitment and plasticity. Brain Research Reviews. 60, 214-225 Hofmeister, E. H. & Egger, C. (2004) Transdermal fentanyl patches in small animals. Journal of the American Animal Hospital Association 40, 468-478 Impellizeri, J. A., Tetrick, M. A. & Muir, P. (2000) Effect of weight reduction on clinical signs of lameness in dogs with hip osteoarthritis. Journal of the American Veterinary Medical Association 216, 1089-1091 Innes, J. F., Barr, A. R. S. & Sharif, M. (2000) Efficacy of oral calcium pentosan polysulphate for the treatment of osteoarthritis of the canine stifle joint secondary to cranial cruciate ligament deficiency. Veterinary Record 146, 433-437 Innes, J. F., Clayton, J. & Lascelles, B. D. X. (2010a) Review of the safety and efficacy of long-term NSAID use in the treatment of canine osteoarthritis. Veterinary Record 166, 226-230 Innes, J. F., O’Neill, T. & Lascelles, B. D. X. (2010b) Use of non-steroidal antiinflammatory drugs for the treatment of canine osteoarthritis. In Practice 32, 126-137 International Association for the Study of Pain. (2011) Classification of Chronic Pain Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 2nd edn. (Revised). http://www.iasp-pain.org/Content/NavigationMenu/Publications/ FreeBooks/Classification_of_Chronic_Pain/default.htm. Accessed February 9, 2013 Jacobson, B.H., Boolani, A., Dunklee, G., et al. (2010) Effect of prescribed sleep surfaces on back pain and sleep quality in patients diagnosed with low back and shoulder pain. Applied Ergonomics 42, 91-97 Jaeger, G. T., Larsen, S. & Moe, L. (2005) Stratification, blinding and placebo effect in a randomized, double blind placebo-controlled clinical trial of gold bead implantation in dogs with hip dysplasia. Acta Veterinaria Scandinavica 46, 57-68 Jaeger, G. T., Larsen, S., Søli, N., et al. (2006) Double-blind, placebo- controlled trial of the pain-relieving effects of the implantation of gold beads into dogs with hip dysplasia. Veterinary Record 158, 722-726 Jaeger, G. T., Larsen, S., Søli, N., et al. (2007) Two years follow-up study of the pain-relieving effect of gold bead implantation in dogs with hip-joint arthritis. Acta Veterinaria Scandinavica 49, 9 Janssens, L. A. A. (1991) Trigger points in 48 dogs with myofascial pain syndromes. Veterinary Surgery 20, 274-278 Jensen, T. S., Madsen, C. S. & Finnerup, N. B. (2009) Pharmacology and treatment of neuropathic pains. Current Opinion in Neurology 22, 467-474 Johnson, J. & Levine, D. (2004) Electrical stimulation In: Canine Rehabilitation and Physical Therapy. Eds D. L. Millis, D. Levine and R. A. Taylor. Saunders, St Louis, MO, USA. Johnston, S. A. (1997) Osteoarthritis. Joint anatomy, physiology, and pathobiology. The Veterinary Clinics of North America. Small Animal Practice 27, 699-723 Kealy, R. D., Lawler, D. F., Ballam, J. M., et al. (1997) Five-year longitudinal study on limited food consumption and development of osteoarthritis in coxofemoral joints of dogs. Journal of the American Veterinary Medical Association 210, 222-225 Kealy, R. D., Lawler, D. F., Ballam, J. M., et al. (2000) Evaluation of the effect of limited food consumption on radiographic evidence of osteoarthritis in dogs. Journal of the American Veterinary Medical Association 217, 1678-1680
© 2014 British Small Animal Veterinary Association
133
P. D. MacFarlane et al.
Ko, J. C., Freeman, L. J., Barletta, M., et al. (2011) Efficacy of oral transmucosal and intravenous administration of buprenorphine before surgery for postoperative analgesia in dogs undergoing hysterectomy. Journal of the American Veterinary Medical Association 238, 318-328 KuKanich, B. & Papich, M. G. (2004) Pharmacokinetics of tramadol and the metabolite O-desemthyltramadol in dogs. Journal of Veterinary Pharmacology and Therapeutics 27, 239-246 KuKanich, B., Bidgood, T. & Knesl, O. (2012), Clinical pharmacology of nonsteroidal anti-inflammatory drugs in dogs. Veterinary Anaesthesia and Analgesia 39, 69-90 Lascelles, B. D. X., McFarland J. M. & Swann, H. (2005) Guidelines for safe and effective use of NSAIDs in dogs. Veterinary Therapeutics 6, 237-251 Lascelles, B. D. X., Gaynor, J. S., Smith, E. S., et al. (2008) Amantadine in a multimodal analgesic regimen for alleviation of refractory osteoarthritis pain in dogs. Journal of Veterinary Internal Medicine 22, 53-59 Malek, S., Sample, S. J., Schwartz, Z., et al. (2012) Effect of analgesic therapy on clinical outcome measures in a randomized controlled trial using client-owned dogs with hip osteoarthritis. BMC Veterinary Research 8, 185-202 Marshall, W. G., Hazewinkel, H. A. W., Mullen, D., et al. (2010) The effect of weight loss on lameness in obese dogs with osteoarthritis. Veterinary Research Communications 34, 241-253 Mathews, K. A. (2008) Neuropathic pain in dogs and cats: if only they could tell us if they hurt. Veterinary Clinics of North America: Small Animal Practice Update on Pain Management 38, 1365-1414 McCarthy, G., O’Donovan, J., Jones, B., et al. (2007) Randomised double-blind, positive-controlled trial to assess the efficacy of glucosamine/chondroitin sulfate for the treatment of dogs with osteoarthritis. The Veterinary Journal 174, 54-61 McEwen, B. S. & Kalia, M. (2010) The role of corticosteroids and stress in chronic pain conditions. Metabolism 59, S9-S15 McKellar, Q. A., Pearson, T., Galbraith, E. A., et al. (1991) Pharmacokinetics and clinical efficacy of a cinchophen and prednisolone combination in the dog. Journal of Small Animal Practice 32, 53-58 McMillan, C., Livingston, A., Clark, C. R., et al. (2008) Pharmacokinetics of intravenous tramadol in dogs. Canadian Journal of Veterinary Research 72, 325-331 Mendl, M., Burman, O. H. P., Parker, R. M. A., et al. (2009) Cognitive bias as an indicator of animal emotion and welfare: emerging evidence and underlying mechanisms. Applied Animal Behaviour Science 118, 161-181 Millis, D. L. & Levine, D. (1997) The role of exercise and physical modalities in the treatment of osteoarthritis. The Veterinary Clinics of North America Small Animal Practice 27, 913-930 Moore, R. A., Wiffen, P. J., Derry, S., et al. (2011) Gabapentin for chronic neuropathic pain and fibromyalgia in adults. The Cochrane Library 3, 1-91 Moreau, M., Dupuis, J., Bonneau, N. H., et al. (2003) Clinical evaluation of a neutraceutical, carprofen and meloxicam for the treatment of dogs with osteoarthritis. Vet Record 152, 323-329 Moreau, M., Dupuis, J., Bonneau, N. H., et al. (2004) Clinical evaluation of a powder of quality elk velvet antler for the treatment of osteoarthritis in dogs. The Canadian Veterinary Journal 45, 133-139 Miyake, K., Fukuchi, H., Kitaura, T., et al. (1990) Pharmacokinetics of amitriptyline and its demethylated metabolite in serum and specific brain regions of rats after acute and chronic administration of amitriptyline. Journal of Pharmaceutical Sciences 79, 288-291 National Institute for Health and Clinical Excellence Clinical. (2008) Osteoarthritis: The care and management of osteoarthritis in adults. Guideline 59, February 2008 National Institute for Health and Clinical Excellence Clinical. (2009) Low back pain: early management of persistent non-specific low back pain. Full guideline, May 2009 National Office of Animal Health. (2013) http://www.noahcompendium.co.uk/Arthro pharm_(Europe)_Limited/Cartrophen_Vet_100mg_ml_Solution_for_Injection/ -26938.html. Accessed August 2, 2013. O’Sullivan, P. (2005) Diagnosis and classification of chronic low back pain disorders: maladaptive movement and motor control impairments as underlying mechanism. Manual Therapy 10, 242-255 Ong, C. K. S., Seymour, R. A., Lirk, P., et al. (2010) Combining paracetamol (acetaminophen) with nonsteroidal antiinflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain. Anesthesia & Analgesia 110, 1170-1179 Pergolizzi, J., Böger, R. H., Budd, K., et al. (2008) Opioids and the management of chronic severe pain in the elderly: consensus statement of an international expert panel with focus on the six clinically most often used World Health Organization step III Opioids (Buprenorphine, Fentanyl, Hydromorphone, Methadone, Morphine, Oxycodone). Pain Practice 8, 287-313 Petrenko, A. B., Yamakura, T., Baba, H., et al. (2003) The role of N- methyl-D-Aspartate (NMDA) receptors in pain: a review. Anesthesia & Analgesia 97, 1108-1116 Plessas, I. N., Rusbridge, C., Driver, C. J., et al. (2012) Long-term outcome of Cavalier King Charles spaniel dogs with clinical signs associated with Chiari-like malformation and syringomyelia. Veterinary Record 171, 501-505 Quartana, P. J., Campbell, C. M. & Edwards, R. R. (2009) Pain catastrophizing: a critical review. Expert Review of Neurotherapeutics 9, 745-758 Quibell, R., Prommer, E. E., Mihalyo M., et al. (2011) Ketamine. Journal of Pain and Symptom Management 41, 640-649
134
Radulovic, L. L., Türck, D., von Hodenberg, A., et al. (1995) Disposition of gabapentin (neurontin) in mice, rats, dogs, and monkeys. Drug Metabolism and Disposition 23, 441-448 Raffa, R. B. (2001) Pharmacology of oral combination analgesics: rational therapy for pain. Journal of Clinical Pharmacy and Therapeutics 26, 257-264 Ramirez, O., Dodge, R. K., Page, R. L., et al. (1999) Palliative radiotherapy of appendicular osteosarcoma in 95 dogs. Veterinary Radiology & Ultrasound 40, 517-522 Read, R. A., Cullis-Hill, D. & Jones M. P. (1996) Svsternic use J of pentosan polysulphate in the treatment of osteoarthritis. Journal of Small Animal Practice 37, 108-114 Reich, M. R., Ohad, D. G., Overall, K. L., et al. (2000) Electrocardiographic assessment of antianxiety medication in dogs and correlation with serum drug concentration. Journal of the American Veterinary Medical Association 216, 1571-1575 Richardson, D. C., Leventhal, P. S. & Hahn, K. A. (2010) Multicenter veterinary practice assessment of the effects of omega-3 fatty acids on osteoarthritis in dogs. Journal of the American Veterinary Medical Association 236, 59-66 Rogachefsky, R. A., Altman, R. D., Markov, M. S., et al. (2004) Use of a permanent magnetic field to inhibit the development of canine osteoarthritis. Bioelectromagnetics 25, 260-270 Rollason, V., Samer, C., Piguet, V., et al. (2008) Pharmacogenetics of analgesics: Toward the individualization of prescription. Pharmacogenomics 9, 905-933 Roush, J. K., Dodd, C. E., Fritsch, D. A., et al. (2004) Radiotherapy of osteoarthritis. Indication, technique and clinical results. Orthopade 33, 56-62 Rutherford, L., Wessmann, A., Rusbridge, C., et al. (2012) Questionnaire-based behaviour analysis of Cavalier King Charles spaniels with neuropathic pain due to Chiari-like malformation and syringomyelia. The Veterinary Journal 194, 294-298 Salazar, V., Dewey, C. W., Schwark, W., et al. (2009) Pharmacokinetics of singledose oral pregabalin administration in normal dogs. Veterinary Anaesthesia and Analgesia 36, 574-580 Sanderson, R. O., Beata, C., Flipo, R. M., et al. (2009) Systematic review of the management of canine osteoarthritis. Veterinary Record 164, 418-424 Schmiedt, C. W. & Bjorling, D. E. (2007) Accidental prehension and suspected transmucosal or oral absorption of fentanyl from a transdermal patch in a dog. Veterinary Ananesthesia and Analgeisa 34, 70-73 Schwab, R. S., England, A. C. Jr, et al. (1969) Amantadine in the treatment of Parkinson’s disease. Journal of the American Medical Association 208, 1168-1170 Sefton, J. M., Yarar, C., Carpenter, D. M., et al. (2011) Physiological and clinical changes after therapeutic massage of the neck and shoulders. Manual Therapy 16, 487-494 Shu, H., Hayashida, M., Arita, H., et al. (2011) Pentazocine-induced antinociception is mediated mainly by µ-opioid receptors and compromised by µ-opioid receptors in mice. The Journal of Pharmacology and Experimental Therapeutics 338, 579-587 Smith, H. S. (2011) The metabolism of opioid agents and the clinical impact of their active metabolites. Clinical Journal of Pain 27, 824-838 Stein, C. & Kopf, A. (2010) Anesthesia and treatment of Chronic Pain. In: Miller’s Anaesthesia. 7th edn. Eds R. D. Miller, L. I. Eriksson, L. A. Fleisher, J. P. Wiener-Kronish and W. L. Young. Churchill Livingstone, Elsevier, Philadelphia, PA, USA. pp 1797-1818 Steiss, J. E. & Levine, D. (2005) Physical agent modalities. Veterinary Clinics of North America Small Animal Practice 35, 1317-1333 Sutton, A. (2004) Massage. In: Canine Rehabilitation and Physical Therapy. Eds D. L. Millis, D. Levine and R. A. Taylor. Saunders, St Louis, MO, USA. pp 303-323 Taylor, R. R. (2005) Pain: subtypes, prevalence, and associated conditions In: Cognitive Behavioral Therapy for Chronic Illness and Disability. Springer Science and Media Inc, New York, NY, USA. pp 237-255 Taylor, P. M. & Houlton, J. E. F. (1984) Post-operative analgesia in the dog: a comparison of morphine, buprenorphine and pentazocine. Journal of Small Animal Practice 25, 437-451 Turk, D. C., Wilson H. D. & Cahana, A. (2011) Treatment of chronic non-cancer pain. The Lancet 377, 2226-2235 Vargas-Schaffer, G. (2010) Is the WHO analgesic ladder still valid? Twenty-four years of experience. Canadian Family Physician 56, 514–517 Veterinary Medicines Directorate. (2013a) Administration of a veterinary medicinal product outside the terms of a marketing authorization http://www.legislation. gov.uk/uksi/2011/2159/schedule/4/made. Accessed February 9, 2013 Veterinary Medicines Directorate. (2013b) Controlled drugs legislation. http:// www.vmd.defra.gov.uk/vet/controlled-drug.aspx. Accessed February 9, 2013 Voscopoulos, C. & Lema, M. (2010) When does acute pain become chronic?British Journal of Ananesthesia 105, 169-185 Wang, S. -M., Kain, Z. N. & White P. (2008) Acupuncture analgesia: I. The scientific basis. Anesthesia & Analgesia 106, 602-610 Willis, W. D. & Westlund, K. N. (1997) Neuroanatomy of the pain system and the pathways that modulate pain. Journal of Clinical Neurophysiology 14, 2-31 Wright, A. & Sluka, K. A. (2001) Nonpharmacological treatments for musculoskeletal pain. The Clinical Journal of Pain 17, 33-46 World Health Organization. (1987) Traitement de la douleur cancéreuse. Geneva, Switzerland: World Health Organization.
Journal of Small Animal Practice
•
Vol 55
•
March 2014
•
© 2014 British Small Animal Veterinary Association
REVIEW
Therapeutic options for the treatment of chronic pain in dogs P. D. MacFarlane, A. S. Tute* and B. Alderson† Langford Veterinary Services, The University of Bristol, Langford BS40 5DU *Gable Cross Veterinary Rehabilitation, Gable Cross Farm, Lowcross, Tilston, Cheshire SY14 7DW †The University of Liverpool, Leahurst, Neston, Wirral CH64 7TE
Chronic pain is a widely recognised problem in humans and is being increasingly recognised as a significant problem in dogs. Whilst a large number of therapies are described and utilised to treat chronic pain in dogs, there is a severe shortage of evidence to guide practitioners in selection of treatments. Until more evidence becomes available, practitioners should adopt a cautious approach, utilising licensed treatments first when possible. Non-pharmacological therapies should be incorporated into the chronic pain management plan whenever possible. Given the probable prevalence of chronic pain in dogs there is an urgent need for research to identify effective treatments. Journal of Small Animal Practice (2014) 55, 127–134 DOI: 10.1111/jsap.12176 Accepted: 11 November 2013; Published online: 28 January 2014
INTRODUCTION Chronic pain is a widely recognised problem in humans with an estimated global incidence between 10 and 25% (Goldberg & McGee 2011). The incidence of chronic pain in dogs is unknown, but is being increasingly recognised as a significant problem. Chronic pain is usually defined as such by having persisted for more than 3 to 6 months (Taylor 2005). It may be associated with an on-going disease process for example osteoarthritis or neoplasia, but can also be linked to an apparently resolved condition, for example post-surgical chronic pain or neuropathic pain because of damage to neural tissue (Taylor 2005). Whilst by definition chronic pain must persist for some time, in certain conditions for example osteoarthritis or oncological pain, it is probable that the chronic nature of the pain is well established by the time the condition is diagnosed. Many specific chronic pain conditions are recognised in humans and there are often defined diagnostic criteria for each. However, these may be difficult or impossible to apply in companion animals as they may require a detailed description of the patient’s pain experience (IASP 2011). Some of the descriptors associated with these pain states such as the “burning” sensation often associated with neuropathic pain in humans, may be difficult to recognise in dogs. Chronic pain states are characterised by changes in the normal function of neural systems that detect stimuli, the processing of and cognitive response to these stimuli (Voscopoulos & Lema 2010). The precise neural changes seen vary with the specific type of chronic pain state encountered (Voscopoulos & Lema Journal of Small Animal Practice
•
Vol 55
•
March 2014
•
2010) and so it is likely that therapeutic interventions which are effective in one situation may not be as effective in others. It is beyond the scope of this article to describe the wide range of chronic pain states recognised in humans, the assessment of pain or to detail every therapy that may be used. Rather it aims to give a brief overview of some of the underlying pathological changes seen in chronic pain states and the more commonly employed treatment modalities.
PATHOPHYSIOLOGY OF CHRONIC PAIN In the normally functioning nervous system noxious stimuli are detected by an extremely complex system of nociceptive neurons, which transmit information to the dorsal horn of the spinal cord (Willis & Westlund 1997). At this level, signals from nociceptive neurons may be transmitted directly to the brain, or be integrated along with inputs from sensory neurons and descending modulatory neurons in order to aid discrimination between noxious and non-noxious stimuli (Willis & Westlund 1997). Further processing occurs at the level of the brain stem and within the brain itself before the noxious stimuli can be perceived as “pain” in the cerebral cortex (Voscopoulos & Lema 2010). Each component of this system is “plastic” – that is exposure to a noxious stimulus may lead to changes in the neurological and emotional response to subsequent nociceptive stimuli (Voscopoulos & Lema 2010). In some situations such as acute soft tissue injury, these changes may be considered “protective” and are expected to return to normal once healing has occurred. Most
© 2014 British Small Animal Veterinary Association
127
P. D. MacFarlane et al.
commonly this is manifested as increased sensitivity to noxious stimuli (hyperalgesia) or a normally non-noxious stimuli being perceived as painful (allodynia) (IASP 2011). If after an acute injury hyperalgesia and allodynia do not resolve or if a chronic disease process is driving pain, then they can be considered maladaptive. Once the nervous system has become sensitised, it may not respond as expected to analgesic medications. Sensitisation may occur in both the neural pathways associated with a damaged tissue (segmental) and in those, which are not associated with the damaged tissue (extra-segmental). Peripherally sensitisation occurs via a number of mechanisms. Many of these are mediated by inflammation which expands the pool of receptors in nociceptive nerve terminals and increases the nerves responsiveness to stimuli, including recruiting so called “silent nociceptors” (Voscopoulos & Lema 2010). During their course to the dorsal horn of the spinal cord it is possible for “cross-excitation” to occur between neurons, and this may be another mechanism via which peripheral sensitisation may occur (D’Mello & Dickinson 2008). The dorsal horn of the spinal cord is a key component of the nociceptive nervous system (Voscopoulos & Lema 2010). Here inputs from nociceptors and other sensory neurons are integrated with descending modulatory impulses in the wide dynamic range (WDR) neurons (D’Mello & Dickinson 2008). This is a key site for sensitisation as if the WDR neurons response to stimuli is altered then both hyperalgesia and allodynia may arise. Key to this process is the N-methyld-aspartate (NMDA) receptor which will only open after high levels of stimulation but which once opened will allow prolonged depolarisation of the neuron (Petrenko et al. 2003). The resulting influx of calcium into cells leads to a host of alterations to cellular behaviour including altering the expression of receptors, altering both the expression and sensitivity of receptors and also changing the pattern of intracellular response to future stimulation (Petrenko et al. 2003). Signals transmitted up the spinal cord towards the brain are further processed in the brainstem before onward transmission (Voscopoulos & Lema 2010). Within the brain itself a large number of distinct systems are engaged in the recognition and response to noxious stimuli, until finally in the cerebrum the conscious sensation of noxious stimuli as the emotional state of pain occurs (Voscopoulos & Lema 2010). Descending modulatory neurons extend from the brain and brainstem to the dorsal horn of the spinal cord (Heinricher et al. 2009). These may be both inhibitory (decreasing the sensitivity of nociceptive systems) and facilitatory (increasing sensitivity). The inhibitory pathway is largely mediated via the neurotransmitter norepinephrine, whereas the facilitatory pathway is principally affected by serotonin (D’Mello & Dickinson 2008). The fact that the brain can modulate what is transmitted as noxious stimuli and that pain is an emotional state supports the observation that those humans with depression are more likely to experience chronic pain (Taylor 2005). Although the scientific study of emotional states in animals is difficult (Mendl et al. 2009) it is possible that a dog’s “emotional” state could also affect its susceptibility to chronic pain state. The association between depression and chronic pain in humans may be a direct result 128
of the effects of depression or because the tendency to develop depression is likely to correlate with other negative affective states, for example, pain catastrophising (an exaggerated emotional response to pain or the fear of pain) (Quartana et al. 2009).
MUSCULOSKELETAL ADAPTATION IN CHRONIC PAIN STATES Along with the well-documented neurological changes seen in chronic pain states, a number of musculoskeletal adaptations are observed. Animals in pain often adopt some degree of antalgic posture and gait, a form of postural guarding. This altered posture may lead to the development of new pain foci as tissues are abnormally loaded, sometimes referred to as secondary pain generators (Allen & Koshi 2005). This is thought to be a key process in the development of some chronic back pain in humans (O’Sullivan 2005). Chronic musculoskeletal problems and pain often have acute exacerbations reflecting the impact of normal activity on chronically adapted soft tissue structures. Inactivity often leads to weight gain and obesity and this has been identified as a potential risk factor in the development and progression of osteoarthritis and pain in certain joints (Kealy et al. 1997, 2000, Impellizeri et al. 2000, German 2006), creating a vicious cycle of weight gain, pain and further reduction in activity. The progression of arthritis may be due to the mechanical effects of increased mass (Marshall et al. 2010) or by a metabolic link (Ehling et al. 2006). Once altered musculoskeletal function is established it is unlikely that pharmacological intervention alone will be effective in relieving the chronic pain state (Brandt 1997). In humans, chronic pain is known to have a significant negative impact on quality of life (Breivik et al. 2006). There is also evidence that dogs with neuropathic pain have diminished quality of life (Rutherford et al. 2012).
THERAPIES IN CHRONIC PAIN In human pain medicine, a large number of treatments are used for managing patients with chronic pain states including medication, physical therapy, surgical interventions, acupuncture and various forms of cognitive therapy; these various therapies are best deployed as part of a multi-disciplinary approach (Stein & Kopf 2010). Some of these therapies have been adopted for the treatment of chronic pain in dogs and this review describes the theoretical mode of action and available evidence for treatments which are widely used, or, have evidence to support their use. Pharmacotherapy in the treatment of chronic pain Drug therapy should ideally be based on the mechanisms underlying the chronic pain, for example, the use of non-steroidal anti-inflammatory drugs (NSAIDs) to treat inflammatory pain. Unfortunately, it is often the case that the precise underlying pathology in any given case is unknown. It should therefore be recognised that occasionally therapeutic trials will be required and
Journal of Small Animal Practice
•
Vol 55
•
March 2014
•
© 2014 British Small Animal Veterinary Association
Therapeutic options for chronic pain in dogs
owners should be counselled that a given therapy may or may not be effective. Therapeutic trials usually consist of administration of a drug for 2 to 4 weeks as for many medications the onset of effects may be slow (Lascelles et al. 2008). It is self-evident that drug treatment for chronic pain tends to be given over prolonged periods. It is possible that this may lead to variations in the pharmacokinetics of the drug over time (Miyake et al. 1990) and so it is possible that dosages may need to be adjusted to maintain efficacy or to address changes in the underlying disease process. With the exception of the NSAIDs, few of the drugs used to treat chronic pain in companion animals are licensed and so their use must be justified under the cascade in the UK (Veterinary Medicines Directorate 2013a) and informed client consent sought. The use of schedule two and three opiates might be considered in some cases and the appropriate legislation must be complied with (Veterinary Medicines Directorate 2013b). Given the wide range of therapies suggested for the treatment of chronic pain, and the general paucity of evidence relating to their use, it can be difficult to decide which drug to administer when. A commonly used concept to address this problem in human medicine is the “pain ladder” introduced by the World Health organisation in 1987 for treating cancer pain. The ladder has three steps starting with NSAID’s or paracetamol; then the addition of weak opioids (e.g. codeine) and finally their substitution with strong opioids (e.g. morphine). At any stage adjunctive drugs such as anti-convulsants may be added if it is felt they may be appropriate. This scheme has been adopted and adapted for other pain states (Vargas-Schaffer 2010) including chronic pain, and acute pain – in the latter case often starting at the top of the ladder and working down once pain is controlled. Non-steroidal anti-inflammatory drugs The NSAIDs are widely used to treat some forms of chronic pain, notably osteoarthritis and they are unusual in a veterinary context in that their use is supported by a large body of evidence, much of which has been recently reviewed (Lascelles et al. 2005, Sanderson et al. 2009, Innes et al. 2010b). There are many licensed NSAIDs available on the veterinary market, but none has so far been demonstrated to be better or safer than any other in clinical trials and selection is often based on personal preference, licensing and ease of dosing (Innes et al. 2010a). Anecdotally, the response to the different drugs varies between individuals and often swapping from one NSAID to another may result in improved pain management although it is not known why this is the case. It is usual to recommend a “washout” period when changing from one NSAID to another, although the length of this washout period has not been established; 5 to 7 days is considered to be a conservative estimate (Kukanich et al. 2012). Paracetamol Paracetamol has been widely used in human medicine for over 50 years, and yet its precise mechanism of action is still unclear. It appears increasingly likely that it has multiple modes of action, both centrally and peripherally (Raffa 2001). Although it is often grouped with the NSAIDs, paracetamol has little or no effect on cyclooxygenase (COX-1 and COX-2), and its concurrent use Journal of Small Animal Practice
•
Vol 55
•
March 2014
•
with NSAIDs and steroids is widely advocated in human pain medicine (Ong et al. 2010). Paracetamol undergoes hepatic metabolism via a number of pathways including glucuronidation, sulphation and N-hydroxylation. An intermediate metabolite in the latter pathway is NAPQI, which is toxic. In humans and dogs, paracetamol toxicity is only seen when high doses are given, however, in cats toxicity may be encountered at low doses and paracetamol should not be administered to this species. It is largely devoid of gastrointestinal and renal side effects. There is no published evidence to support the use of paracetamol for chronic pain in dogs. It is available as a licensed preparation compounded with codeine (Pardale V). The license states that therapy should be limited to 5 days and that it should not be co-administered with NSAIDs. Tramadol Tramadol is a synthetic analogue of codeine and is a centrally acting analgesic drug with actions at adrenergic, serotonin and opioid receptors (Kukanich & Papich 2004). A recently published placebo-controlled study has identified a positive effect of tramadol on pain in dogs with osteoarthritis (Malek et al. 2012). There is a very large variability in uptake following oral administration in dogs (Kukanich & Papich 2004). Human sustained release preparations may not produce effective plasma concentrations in dogs (Giorgi et al. 2009). The M1 metabolite is responsible for a large proportion of the analgesia in humans (Smith 2011). Dogs do not produce as much of the M1 metabolite as humans and therefore the opioid analgesia component of tramadol in dogs may not be as efficacious (Kukanich & Papich 2004). In humans who are poor tramadol metabolisers the serotonin and adrenergic analgesia is enhanced, whereas that due to opioid effects is diminished (Rollason et al. 2008). Thus the analgesia produced by tramadol in dogs may be via its effects on serotonin and norepinephrine reuptake, rather than by any opioid effect (McMillan et al. 2008). Side effects that are most commonly reported in dogs are salivation, vomiting, sedation and seizures (Grubb 2010). Tramadol lowers the seizure threshold, therefore it should be used with caution in dogs with a history of seizures. The drug has a bitter taste and is often resented by dogs. Very rarely serotonin syndrome can be seen as behavioural changes, neuromuscular hyperactivity and autonomic activation; this is more likely when it is coadministered with drugs that inhibit the reuptake of serotonin such as the tricyclic antidepressants, for example clomipramine (Ener et al. 2003). Opioids Opioids are commonly used in the treatment of chronic pain in humans (Jensen et al. 2009). There is no published data with regard to the clinical efficacy or safety of the long-term use of opioids in veterinary species. Human prolonged-release preparations may not be suitable for use in dogs as oral absorption is poor, effective plasma concentrations may not be reached or dosing intervals may not be prolonged when compared to conventional formulations (Dohoo & Tasker 1997). However, when administered sublingually buprenorphine has reasonable bioavailability in dogs (Ko et al. 2011) and could be considered for long-term
© 2014 British Small Animal Veterinary Association
129
P. D. MacFarlane et al.
dosing. Whilst there is anecdotal evidence to suggest that this may be an effective strategy, there does not appear to be any trial data to support its use. However, in humans, sublingual buprenorphine is well established as a treatment option for cancer-related chronic pain (Pergolizzi et al. 2008). Transdermal fentanyl patches could also be considered for long-term pain treatment – although little is known of their pharmacokinetics after 72 hours (Hofmeister & Egger 2004) or at what frequency patches need to be replaced. Recently, a liquid transdermal fentanyl perpetration has been launched onto the UK market. The data sheet of this product stipulates that dogs weighing more than 20 kg should be hospitalised for 48 hours after its application. The lack of pharmacokinetic data related to repeated dosing of this product should preclude its chronic use until its safety in this application has been established. Pentazocine is a synthetic opioid with partial agonist activity at both µ and κ receptors (Shu et al. 2011). It has been shown to be effective in acute pain in dogs (Taylor & Houlton 1984) but there are no studies investigating its use in chronic pain despite its widespread use. Opioids have the potential to cause respiratory depression, bradycardia and sedation, although rarely except in cases of accidental overdose, which has been reported in conjunction with the ingestion of fentanyl patches (Schmiedt & Bjorling 2007). NMDA receptor antagonists Amantadine: Amantadine was first recognised as an antiviral agent (Davies et al. 1964) and then was found to be useful in the treatment of Parkinson’s disease (Schwab et al. 1969). It is an NMDA antagonist and has been used in the treatment of various chronic pain conditions in humans, including neuropathic pain, as it does not elicit the adverse psychomotor effects of ketamine. In one study, amantadine, administered to dogs already receiving meloxicam, led to further improvement in pain relief when compared to placebo; the difference in pain score becoming significant after 21 days of amantadine administration (Lascelles et al. 2008). Amantadine has good oral bioavailability in dogs and is metabolised in the liver and excreted in the urine (Bleidner et al. 1965). Common side effects in dogs appear to be agitation and diarrhoea; however, in the authors’ experience these tend to resolve after a few days. More severe side effects include seizures (Grubb 2010).
was reported (Cashmore et al. 2009) and also in Cavalier King Charles spaniels with clinical signs associated with Chiari-like malformation and syringomyelia (Plessas et al. 2012). Gabapentin: Gabapentin is an antiepileptic drug that was found to be effective in humans as an analgesic for neuropathic pain, probably due to actions at voltage-gated calcium channels in the brain and spinal cord (Moore et al. 2011). Gabapentin is highly bioavailable in dogs and is metabolised in the liver and excreted via the kidney, therefore in cases with hepatic or renal disease dosing regimes should be altered (Radulovic et al. 1995). The most common side effect is sedation, however, decreasing the dose will stop this and the dose can often be increased again without sedation (Grubb 2010). Vomiting may also occur. When stopping gabapentin the dose should be stepped down over several days as stopping abruptly may cause seizures (Mathews 2008). Pregabalin and carbamazepine: Pregabalin and carbamazepine have similar mechanisms of action to gabapentin and their pharmacokinetics have been reported in the dog (Frey & Löscher 1980, Salazar et al. 2009). Pregabalin is more expensive than gabapentin and there is currently no evidence for any advantages in efficacy over gabapentin. Bisphosphonates Bisphosphonates, such as pamidronate, inhibit osteoclast activity, which may have a role in the pain associated with bone malignancy. Two studies of the use of pamidronate in dogs have shown improvements in pain control (Fan et al. 2005, 2007). Approximately 1·0 mg/kg is administered as an intravenous infusion over 2 hours, and may be repeated every 28 days. Significant improvement in signs of pain may be seen in approximately 30 to 40% of cases with bone malignancy (Fan et al. 2005, 2007). When combined with standardised palliative therapy, pamidronate did not result in an extended duration of subjective pain relief, however, it may have resulted in a better quality of analgesia (Fan et al. 2009).
Ketamine: There is extensive human literature regarding the use of ketamine for various types of chronic pain states (Quibell et al. 2011) and it may be given at subanaesthetic doses via the oral, subcutaneous or intravenous route. There is only anecdotal evidence relating to the use of ketamine for chronic pain in dogs and the side effects may limit its usefulness in this situation in dogs (Mathews 2008).
Tricyclic antidepressants The tricyclic antidepressants are widely used in humans (Dharmshaktu et al. 2012), acting as serotonin and norepinephrine re-uptake inhibitors, enhancing descending inhibition of nociception. There are no controlled trials of their use in dogs but amitriptyline has been reported to be beneficial in a case series of three dogs with neuropathic pain (Cashmore et al. 2009). Amitriptyline should be used cautiously in dogs with conduction abnormalities as it may cause ECG changes and, at higher doses, ventricular arrhythmias (Reich et al. 2000). It should not be used with tramadol, St. John’s wort and other drugs that act via serotonin and norepinephrine reuptake, as they may have interactions that lead to serotonin syndrome (Ener et al. 2003).
Anticonvulsant drugs There are no controlled trials documenting the use of anticonvulsant drugs for the control of chronic pain in dogs. In one case report of neuropathic pain in dogs a positive effect of gabapentin
Steroids If pain has an inflammatory component then the potent antiinflammatory action of glucocorticoids may be of benefit. In addition, glucocorticoids may modulate nociceptive processing
130
Journal of Small Animal Practice
•
Vol 55
•
March 2014
•
© 2014 British Small Animal Veterinary Association
Therapeutic options for chronic pain in dogs
in the dorsal horn (McEwen & Kalia 2010). However, they may also potentiate neuropathic pain via complex mechanisms involving the hypothalamic-pituitary-adrenal axis (McEwen & Kalia 2010) and so must be employed cautiously and with consideration of the type of pain present. A licensed veterinary compound of prednisolone and cinchophen is available in the UK for the treatment of osteoarthritis in the dog. This product has been shown to give equivalent analgesia to phenylbutazone in dogs with osteoarthritis (McKellar et al. 1991). The concurrent use of glucocorticoids and NSAIDs should be avoided because of the increased risk of gastrointestinal ulceration. Central muscle relaxants There is no evidence to support the use of muscle-relaxants in dogs with chronically painful conditions. Muscle relaxants are not usually considered as analgesics; however, the use of drugs to relax muscles, in combination with conventional analgesics may reduce anxiety-induced pain and skeletal muscle pain. Many different drugs have been used in humans and none has been shown to be superior (Elenbaas 1980). Anecdotally, diazepam is often used in dogs, especially following spinal surgery to reduce the pain associated with muscle spasm. Pentosan polysulphate Pentosan polysulphate is a semi-synthetic glycosaminoglycan, the mechanism of action for analgesia is currently unknown and there are many proposed mechanisms. It has very poor bioavailability via the oral route and may take several months to achieve the desired effect (Ghosh 1999). It is licensed for use for the treatment of lameness and pain of degenerative joint disease/osteoarthrosis (non-infectious arthrosis) in the skeletally mature dog. In dogs, it has been investigated for use in osteoarthritis with varying results. Systemic administration of four subcutaneous injections at 7-day intervals of 3·0 mg/kg reduced lameness and pain compared to baseline (assessed by veterinarian examination including stiffness, weakness and pain on joint manipulation, subjective lameness scores and an owner questionnaire) (Read et al. 1996). The oral formulation did not improve the clinical or radiographic signs of osteoarthritis in dogs following cranial cruciate ligament surgery but did alter the biochemical markers in the synovial fluid (Innes et al. 2000). The data sheet for pentosan polysulphate states that it should not be used in conjunction with NSAIDs as there may be potentiation of the anticoagulant activity (NOAH 2013). Neutraceuticals These are a group of food supplements, which are purported to be able to modify disease processes or act as analgesics. There are several compounds available in the veterinary market and many more marketed for humans, which could be utilised in dogs. There is extremely sparse evidence relating to the use of nutritional supplements for chronic pain, other than osteoarthritis, in the human literature (Gagnier 2008). There is some evidence from well-conducted, placebocontrolled clinical trials supporting the use of several of these compounds in osteoarthritis in dogs including elk velvet antler Journal of Small Animal Practice
•
Vol 55
•
March 2014
•
(Moreau et al. 2003, 2004), food containing green-lipped mussel, (Sanderson et al. 2009), green-lipped mussel (Bierer & Bui 2002, Bui & Bierer 2003) and omega-3 fatty acids (Roush et al. 2004). There is limited evidence comparing them to pharmaceutical preparations. One study in dogs with clinical signs of chronic osteoarthritis compared glucosamine/chondroitin sulphate with carprofen; glucosamine/chondroitin sulphate improved some of the clinical signs of lameness by day 70 (compared to day 14 with carprofen) (McCarthy et al. 2007). Non-pharmacological therapies The importance of non-pharmacological therapies is emphasised by the fact that the National Institute of Clinical Excellence (NICE) consider education, exercise and weight loss as core treatments for osteoarthritis with pharmaceutical treatment being considered only in addition to core treatment (NICE 2008). Weight control Moderate (6 to 8%) weight loss in dogs with osteoarthritis has been shown to reduce pain scores (Marshall et al. 2010). Dietary management and lifestyle alterations may lead to significant weight loss in clinical canine cases (German et al. 2007). Therapeutic exercise (see later) also would be expected to contribute to weight reduction programmes. Massage Massage includes a variety of soft tissue manipulations whose physiological and psychological effects are used to reduce pain and alter mechanical stress caused by myofascial tissue disorders. There is evidence in humans that massage may increase the range of joint motion (Sefton et al. 2011) and decrease pain scores (Cherkin et al. 2001). Physiological effects include tissue repair and pain modulation (Wright & Sluka 2001), mediated by improved local circulation and lymphatic drainage, segmental inhibitory mechanisms, and, activation of descending pain inhibitory systems (Furlan et al. 2002, Sutton 2004). Owners of dogs experiencing chronic pain often reduce tactile contact, including patting and stroking, for fear of causing further pain or distress. It is possible that re-introducing tactile stimulation, through massage and touch by the owner, may aid in desensitising animals with allodynia to irritating somato-sensory input (Allen 2006). Myofascial release and trigger point therapy Physical trauma results in fascial strains, which tighten over time, resulting in a loss of normal flexibility. Movements and postures become painful, further trauma may ensue and pain may be experienced at sites distant from the original insult (Sutton 2004, Barnes 2009). Diagnostic criteria for myofascial trigger points have been described in dogs (Frank 1999). They include identifying discrete painful nodules 0·5 to 4·0 cm in diameter within muscle bellies (Janssens 1991). When palpated they lead to reproducible pain which may be experienced locally or at a distance. If treatment is targeted at the region at which the pain is experienced there may not be resolution of the initiating painful stimulus (Janssens
© 2014 British Small Animal Veterinary Association
131
P. D. MacFarlane et al.
1991). Palpation of these points may be extremely painful, leading to biting even in very well-trained animals. In one case series resolution of pain was observed in 60% of patients using either dry needling or intra-trigger point injection of 1% lidocaine (Janssens 1991). Passive stretching and passive range of motion exercises Many dogs suffering from chronic pain associated with osteoarthritis have restricted range of joint motion. This may be due to a combination of postural guarding and reduced activity levels causing soft tissue shortening and fibrosis, and avoidance of moving into painful positions (Johnston 1997, Millis & Levine 1997, Allen & Koshi 2005). Regular movement, throughout the available joint range, is important for maintaining a full range of motion and for the health of articular and peri-articular structures. Passive stretching (PS) and passive range of motion (PROM) exercises are particularly useful immediately after surgery to prevent some of the effects of disuse and immobilisation discussed above. They improve the extensibility of muscles and soft tissues, improve joint range, prevent adhesions, promote synovial fluid production and diffusion and improve cartilage lubrication and health (Millis & Levine 1997, Allen & Koshi 2005). Therapeutic exercise A wide range of exercise programmes, including hydrotherapy, are described in the human literature and many are associated with decreased pain scores. However, it is not possible to distinguish between different modalities on the impact of chronic pain states in humans (Turk et al. 2011). Good quality rest is important to patients with chronic pain states but excessive rest will lead to exacerbation of musculoskeletal pain (Gibbs & Klinger 2011). Therapeutic exercise aims to improve muscle strength (to support painful joints including those of the spinal column), proprioception (to provide dynamic stability and reduce risk of injury), active range of joint motion, cardiorespiratory strength and endurance (to minimise anaerobic respiration) and controlling body weight, with the ultimate aim of returning the dog to full, or as near full and active function as possible (Hamilton et al. 2004). Acupuncture and electroacupuncture Traditional Chinese acupuncture and the western approach are both used in human medicine. Evidence supporting the superiority of one form over the other is lacking, however, the use of acupuncture is accepted by NICE in a limited number of conditions in humans (NICE 2009). Pain modulating effects are thought to be mediated principally at the segmental level, with needle stimulation of afferent nerves resulting in action potentials entering the dorsal horn of the spinal cord (Wang et al. 2008). Descending inhibitory systems may also play a role in the analgesia provided by acupuncture. Central regulatory effects mediated by the limbic system, which plays a central role in the affective and cognitive dimensions of 132
pain, may be responsible for general calming effects as well as an improved sense of well-being reported in human patients (Wang et al. 2008, Fang et al. 2009). Gold bead implantation at acupuncture sites has been used for long-term analgesia in dogs with hip dysplasia with variable results (Bolliger et al. 2002, Jaeger et al. 2005, 2006, 2007). Transcutaneous electrical nerve stimulation (TENS) Like acupuncture, TENS relies on sensory nerve depolarisation to suppress pain at spinal cord level (Steiss & Levine 2005) and it is widely used in humans. Johnson & Levine (2004) highlighted several contraindications including, but not confined to, direct exposure to cardiac pacemakers, the abdominal area in pregnant bitches, malignancy at or near the site of treatment, seizure disorders and situations where active movement is contraindicated. Palliative radiotherapy Palliative radiotherapy is well established for the palliative treatment of pain associated with osteosarcoma in dogs with very few side effects reported in these cases (Ramirez et al. 1999). Radiotherapy has also been shown to be an effective treatment for osteoarthritis (Ruppert et al. 2004) in dogs. The mechanism via which radiotherapy alleviates pain in osteoarthritis is still being investigated in animal models, but a decrease in inflammation and joint swelling appears to be central to its effect (Calabrese & Calabrese 2012). Radiotherapy has limited availability for veterinary patients and may be associated with serious acute and late side effects (Arthur et al. 2008). Until further studies are conducted evaluating its efficacy and safety for treating osteoarthritis, its use should not be widely advocated. Environmental modification There is evidence from studies in humans that environmental modification may be of benefit. Supportive bedding (Jacobson et al. 2010) aids sleep and sleep deprivation is linked to increased pain perception. There is limited evidence that bedding type can affect the progression of osteoarthritis in dogs (Rogachefsky et al. 2004). In human patients with osteoarthritis associated pain difficulty with accessibility, limiting activity, can aggravate the condition (Gibbs & Klinger 2011) and in the authors’ opinion considering the effects of factors such as smooth floors, steep steps and high car tail gaits on a dog’s ability to exercise is important in order to maximise mobility levels.
SUMMARY Whilst a large number of therapies are described and utilised to treat chronic pain in dogs, there is a severe shortage of evidence to guide practitioners in selection of treatments. Until more evidence becomes available practitioners should adopt a cautious approach, utilising licensed treatments first when possible. Non-pharmacological therapies should be incorporated into the chronic pain management plan. Given the probable prevalence of chronic pain in dogs there is an urgent need for research to identify effective treatment.
Journal of Small Animal Practice
•
Vol 55
•
March 2014
•
© 2014 British Small Animal Veterinary Association
Therapeutic options for chronic pain in dogs
Acknowledgements The authors acknowledge Sue Dawson for her help. Conflict of interest None of the authors of this article has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper. References Allen, R. J. (2006) Physical agents used in the management of chronic pain by physical therapists. Physical Medicine and Rehabilitation Clinics of North America 17, 315-345 Allen, R. J. & Koshi, L. R. (2005) Chronic limb pain developing from reduced mobility. In: Physical therapy: annual conference and exposition of the American Physical Therapy Association. Boston, MA, June 9, 2005 Arthur, J. J., Kleiter, M. M., Thrall, D. E., et al. (2008) Characterization of normal tissue complications in 51 dogs undergoing definitive pelvic region irradiation. Veterinary Radiology & Ultrasound 49, 85-89 Barnes, J. F. (2009) Myofascial release: the missing link in traditional treatment. In: Therapies in Rehabilitation: Evidence for Efficacy in Therapy, Prevention and Wellness. 3rd edn. Ed C. M. Davis. SLACK Inc, Thorofare, NJ, USA. pp 89-112 Bierer, T. L. & Bui, L. M. (2002) Improvement of arthritic signs in dogs fed greenlipped mussel (Perna canaliculus). The Journal of Nutrition 132, 1634S-1636S Bleidner, W. E., Harmon, J. B., Hewes, W. E., et al. (1965) Absorption, distribution and excretion of amantadine hydrochloride. The Journal of Pharmacology and Experimental Therapeutics 150, 484-490 Bolliger, C., DeCamp, C. E., Stajich, M., et al. (2002) Gait analysis of dogs with hip dysplasia treated with gold bead implantation acupuncture. Veterinary and Comparative Orthopaedics and Traumatology 15, 116-122 Brandt, K. D. (1997) Putting some muscle into osteoarthritis. Annals of Internal Medicine 127, 154-156 Breivik, H., Collett, B., Ventafridda, V., et al. (2006), Survey of chronic pain in Europe: Prevalence, impact on daily life, and treatment. European Journal of Pain 10, 287-333 Bui, L. M. & Bierer, T. L. (2003) Influence of green lipped mussels (Perna canaliculus) in alleviating signs of arthritis in dogs. Veterinary Therapeutics 4, 397-40 Calabrese, E. J. & Calabrese, V. (2012) Reduction of arthritic symptoms by low dose radiation therapy (LD-RT) is associated with an anti-inflammatory phenotype. International Journal of Radiation Biology 89, 278-286 Cashmore, R. G., Harcourt-Brown, T. R., Freeman, P. M., et al. (2009) Clinical diagnosis and treatment of suspected neuropathic pain in three dogs. Australian Veterinary Journal 87, 45-50 Cherkin, D. C., Eisenberg, D., Sherman, K. J., et al. (2001) Randomised trial comparing Traditional Chinese Medical Acupuncture, therapeutic massage and selfcare education for chronic low back pain. Archives of Internal Medicine 161, 1081-1088 Cummings, W. A., & Filshie J. (2008) An overview of Western medical acupuncture in Western Medical Acupuncture Davies, W. Z., Grunert, R. R., Haff, R., et al. (1964) Antiviral activity of 1- adamantanamine (amantadine). Science 144, 862-863 Dharmshaktu, P., Tayal, V. & Kalra, B. S. (2012) Efficacy of antidepressants as analgesics : a review. Journal of Clinical Pharmacology 52, 6-17 D’Mello, R. & Dickinson, A. H. (2008) Spinal cord mechanisms of pain. British Journal of Ananesthesia 101, 8-16 Dohoo, S. E. & Tasker, R. A. (1997) Pharmacokinetics of oral morphine sulfate in dogs: a comparison of sustained release and conventional formulations. Canadian Journal of Veterinary Research 61, 251-255 Ehling, A., Schäffler, A., Herfarth, H., et al. (2006) The potential of adiponectin in driving arthritis. Journal of Immunology 176, 4468-4478 Elenbaas, J. K. (1980) Centrally acting oral skeletal muscle relaxants. American Journal of Hospital Pharmacy 37, 1313-1323 Ener, R. A., Meglathery, S. B., Decker, W. A. V. (2003) Serotonin syndrome and other serotonergic disorders. Pain Medicine 4, 63-74 Fan, T. M., deLorimier, L. P., Charney, S. C., et al. (2005) Evaluation of intravenous pamidronate administration in 33 cancer-bearing dogs with primary or secondary bone involvement. Journal of Veterinary Internal Medicine 19, 74-80 Fan, T. M., deLorimier, L. P., O’Dell-Anderson, K., et al. (2007) Single-agent pamidronate for palliative therapy of canine appendicular osteosarcoma bone pain. Journal of Veterinary Internal Medicine 21, 431-439 Fan, T. M., Charney, S. C., deLorimier, L. P., et al. (2009) Double-blind placebocontrolled trial of adjuvant pamidronate with palliative radiotherapy and intravenous doxorubicin for canine appendicular osteosarcoma bone pain. Journal of Veterinary Internal Medicine 23, 152-160 Fang, J., Jin, Z., Wang, Y., et al. (2009) The salient characteristics of the central effects of acupuncture needling: Limbic-paralimbic-neocortical network modulation. Human Brain Mapping 30, 1196-1206 Fox, S. M. (2010) Chronic Pain in Small Animal Medicine. Manson Publishing, London.
Journal of Small Animal Practice
•
Vol 55
•
March 2014
•
Frank, E. M. (1999) Myofascial trigger point diagnostic criteria in the dog. Journal of Musculoskeletal Pain 7, 231-237 Frey, H. H. & Löscher, W. (1980) Pharmacokinetics of carbamazepine in the dog. Archives Internationales de Pharmacodynamie et de Therapie 243, 180-191 Furlan, A. D., Brosseau, L., Innamura, M., et al. (2002) Massage for low-back pain: a systematic review within the framework of the cochrane collaboration back review group. Spine 27, 1896-1910 Gagnier, J. J. (2008) Evidence-informed management of chronic low back pain with herbal, vitamin, mineral, and homeopathic supplements. The Spine Journal 8, 70-79 German A. J. (2006) The growing problem of obesity in dogs and cats. The Journal of Nutrition 136, 1940S-1946S. German, A. J., Holden, S. L., Bissot, T., et al. (2007) Dietary energy restriction and successful weight loss in obese client-owned dogs. Journal of Veterinary Internal Medicine 21, 1174-1180 Gibbs, L. B. & Klinger, L. (2011) Rest is a meaningful occupation for women with osteoarthritis: occupation, participation and health. OTJR: Occupation, Participation and Health 31, 143-150 Giorgi, M., Saccomanni, G., Lebkowska-Wieruszewska, B., et al. (2009) Pharmacokinetic evaluation of tramadol and its major metabolites after single oral sustained tablet administration in the dog: a pilot study. The Veterinary Journal 180, 253-255 Goldberg, D. S. & McGee, S. J. (2011) Pain as a global public health priority. BMC Public Health 11, 770-775 Ghosh, P. (1999) The pathobiology of osteoarthritis and the rationale for the use of pentosan polysulfate for its treatment. Seminars in Arthritis and Rheumatism 28, 211-266 Grubb, T. (2010) What do we really know about the drugs we use to treat chronic pain? Topics in Companion Animal Medicine 25, 10-19 Hamilton, S., Millis, D. L., Taylor, R. A., et al. (2004) Therapeutic exercises. In: Canine Rehabilitation and Physical Therapy. Eds D. L. Millis, D. Levine and R. A. Taylor. Saunders, St Louis, MO, USA Heinricher, M. M., Tavares, I., Leith, J. L., et al. (2009) Descending control of nociception: specificity, recruitment and plasticity. Brain Research Reviews. 60, 214-225 Hofmeister, E. H. & Egger, C. (2004) Transdermal fentanyl patches in small animals. Journal of the American Animal Hospital Association 40, 468-478 Impellizeri, J. A., Tetrick, M. A. & Muir, P. (2000) Effect of weight reduction on clinical signs of lameness in dogs with hip osteoarthritis. Journal of the American Veterinary Medical Association 216, 1089-1091 Innes, J. F., Barr, A. R. S. & Sharif, M. (2000) Efficacy of oral calcium pentosan polysulphate for the treatment of osteoarthritis of the canine stifle joint secondary to cranial cruciate ligament deficiency. Veterinary Record 146, 433-437 Innes, J. F., Clayton, J. & Lascelles, B. D. X. (2010a) Review of the safety and efficacy of long-term NSAID use in the treatment of canine osteoarthritis. Veterinary Record 166, 226-230 Innes, J. F., O’Neill, T. & Lascelles, B. D. X. (2010b) Use of non-steroidal antiinflammatory drugs for the treatment of canine osteoarthritis. In Practice 32, 126-137 International Association for the Study of Pain. (2011) Classification of Chronic Pain Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 2nd edn. (Revised). http://www.iasp-pain.org/Content/NavigationMenu/Publications/ FreeBooks/Classification_of_Chronic_Pain/default.htm. Accessed February 9, 2013 Jacobson, B.H., Boolani, A., Dunklee, G., et al. (2010) Effect of prescribed sleep surfaces on back pain and sleep quality in patients diagnosed with low back and shoulder pain. Applied Ergonomics 42, 91-97 Jaeger, G. T., Larsen, S. & Moe, L. (2005) Stratification, blinding and placebo effect in a randomized, double blind placebo-controlled clinical trial of gold bead implantation in dogs with hip dysplasia. Acta Veterinaria Scandinavica 46, 57-68 Jaeger, G. T., Larsen, S., Søli, N., et al. (2006) Double-blind, placebo- controlled trial of the pain-relieving effects of the implantation of gold beads into dogs with hip dysplasia. Veterinary Record 158, 722-726 Jaeger, G. T., Larsen, S., Søli, N., et al. (2007) Two years follow-up study of the pain-relieving effect of gold bead implantation in dogs with hip-joint arthritis. Acta Veterinaria Scandinavica 49, 9 Janssens, L. A. A. (1991) Trigger points in 48 dogs with myofascial pain syndromes. Veterinary Surgery 20, 274-278 Jensen, T. S., Madsen, C. S. & Finnerup, N. B. (2009) Pharmacology and treatment of neuropathic pains. Current Opinion in Neurology 22, 467-474 Johnson, J. & Levine, D. (2004) Electrical stimulation In: Canine Rehabilitation and Physical Therapy. Eds D. L. Millis, D. Levine and R. A. Taylor. Saunders, St Louis, MO, USA. Johnston, S. A. (1997) Osteoarthritis. Joint anatomy, physiology, and pathobiology. The Veterinary Clinics of North America. Small Animal Practice 27, 699-723 Kealy, R. D., Lawler, D. F., Ballam, J. M., et al. (1997) Five-year longitudinal study on limited food consumption and development of osteoarthritis in coxofemoral joints of dogs. Journal of the American Veterinary Medical Association 210, 222-225 Kealy, R. D., Lawler, D. F., Ballam, J. M., et al. (2000) Evaluation of the effect of limited food consumption on radiographic evidence of osteoarthritis in dogs. Journal of the American Veterinary Medical Association 217, 1678-1680
© 2014 British Small Animal Veterinary Association
133
P. D. MacFarlane et al.
Ko, J. C., Freeman, L. J., Barletta, M., et al. (2011) Efficacy of oral transmucosal and intravenous administration of buprenorphine before surgery for postoperative analgesia in dogs undergoing hysterectomy. Journal of the American Veterinary Medical Association 238, 318-328 KuKanich, B. & Papich, M. G. (2004) Pharmacokinetics of tramadol and the metabolite O-desemthyltramadol in dogs. Journal of Veterinary Pharmacology and Therapeutics 27, 239-246 KuKanich, B., Bidgood, T. & Knesl, O. (2012), Clinical pharmacology of nonsteroidal anti-inflammatory drugs in dogs. Veterinary Anaesthesia and Analgesia 39, 69-90 Lascelles, B. D. X., McFarland J. M. & Swann, H. (2005) Guidelines for safe and effective use of NSAIDs in dogs. Veterinary Therapeutics 6, 237-251 Lascelles, B. D. X., Gaynor, J. S., Smith, E. S., et al. (2008) Amantadine in a multimodal analgesic regimen for alleviation of refractory osteoarthritis pain in dogs. Journal of Veterinary Internal Medicine 22, 53-59 Malek, S., Sample, S. J., Schwartz, Z., et al. (2012) Effect of analgesic therapy on clinical outcome measures in a randomized controlled trial using client-owned dogs with hip osteoarthritis. BMC Veterinary Research 8, 185-202 Marshall, W. G., Hazewinkel, H. A. W., Mullen, D., et al. (2010) The effect of weight loss on lameness in obese dogs with osteoarthritis. Veterinary Research Communications 34, 241-253 Mathews, K. A. (2008) Neuropathic pain in dogs and cats: if only they could tell us if they hurt. Veterinary Clinics of North America: Small Animal Practice Update on Pain Management 38, 1365-1414 McCarthy, G., O’Donovan, J., Jones, B., et al. (2007) Randomised double-blind, positive-controlled trial to assess the efficacy of glucosamine/chondroitin sulfate for the treatment of dogs with osteoarthritis. The Veterinary Journal 174, 54-61 McEwen, B. S. & Kalia, M. (2010) The role of corticosteroids and stress in chronic pain conditions. Metabolism 59, S9-S15 McKellar, Q. A., Pearson, T., Galbraith, E. A., et al. (1991) Pharmacokinetics and clinical efficacy of a cinchophen and prednisolone combination in the dog. Journal of Small Animal Practice 32, 53-58 McMillan, C., Livingston, A., Clark, C. R., et al. (2008) Pharmacokinetics of intravenous tramadol in dogs. Canadian Journal of Veterinary Research 72, 325-331 Mendl, M., Burman, O. H. P., Parker, R. M. A., et al. (2009) Cognitive bias as an indicator of animal emotion and welfare: emerging evidence and underlying mechanisms. Applied Animal Behaviour Science 118, 161-181 Millis, D. L. & Levine, D. (1997) The role of exercise and physical modalities in the treatment of osteoarthritis. The Veterinary Clinics of North America Small Animal Practice 27, 913-930 Moore, R. A., Wiffen, P. J., Derry, S., et al. (2011) Gabapentin for chronic neuropathic pain and fibromyalgia in adults. The Cochrane Library 3, 1-91 Moreau, M., Dupuis, J., Bonneau, N. H., et al. (2003) Clinical evaluation of a neutraceutical, carprofen and meloxicam for the treatment of dogs with osteoarthritis. Vet Record 152, 323-329 Moreau, M., Dupuis, J., Bonneau, N. H., et al. (2004) Clinical evaluation of a powder of quality elk velvet antler for the treatment of osteoarthritis in dogs. The Canadian Veterinary Journal 45, 133-139 Miyake, K., Fukuchi, H., Kitaura, T., et al. (1990) Pharmacokinetics of amitriptyline and its demethylated metabolite in serum and specific brain regions of rats after acute and chronic administration of amitriptyline. Journal of Pharmaceutical Sciences 79, 288-291 National Institute for Health and Clinical Excellence Clinical. (2008) Osteoarthritis: The care and management of osteoarthritis in adults. Guideline 59, February 2008 National Institute for Health and Clinical Excellence Clinical. (2009) Low back pain: early management of persistent non-specific low back pain. Full guideline, May 2009 National Office of Animal Health. (2013) http://www.noahcompendium.co.uk/Arthro pharm_(Europe)_Limited/Cartrophen_Vet_100mg_ml_Solution_for_Injection/ -26938.html. Accessed August 2, 2013. O’Sullivan, P. (2005) Diagnosis and classification of chronic low back pain disorders: maladaptive movement and motor control impairments as underlying mechanism. Manual Therapy 10, 242-255 Ong, C. K. S., Seymour, R. A., Lirk, P., et al. (2010) Combining paracetamol (acetaminophen) with nonsteroidal antiinflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain. Anesthesia & Analgesia 110, 1170-1179 Pergolizzi, J., Böger, R. H., Budd, K., et al. (2008) Opioids and the management of chronic severe pain in the elderly: consensus statement of an international expert panel with focus on the six clinically most often used World Health Organization step III Opioids (Buprenorphine, Fentanyl, Hydromorphone, Methadone, Morphine, Oxycodone). Pain Practice 8, 287-313 Petrenko, A. B., Yamakura, T., Baba, H., et al. (2003) The role of N- methyl-D-Aspartate (NMDA) receptors in pain: a review. Anesthesia & Analgesia 97, 1108-1116 Plessas, I. N., Rusbridge, C., Driver, C. J., et al. (2012) Long-term outcome of Cavalier King Charles spaniel dogs with clinical signs associated with Chiari-like malformation and syringomyelia. Veterinary Record 171, 501-505 Quartana, P. J., Campbell, C. M. & Edwards, R. R. (2009) Pain catastrophizing: a critical review. Expert Review of Neurotherapeutics 9, 745-758 Quibell, R., Prommer, E. E., Mihalyo M., et al. (2011) Ketamine. Journal of Pain and Symptom Management 41, 640-649
134
Radulovic, L. L., Türck, D., von Hodenberg, A., et al. (1995) Disposition of gabapentin (neurontin) in mice, rats, dogs, and monkeys. Drug Metabolism and Disposition 23, 441-448 Raffa, R. B. (2001) Pharmacology of oral combination analgesics: rational therapy for pain. Journal of Clinical Pharmacy and Therapeutics 26, 257-264 Ramirez, O., Dodge, R. K., Page, R. L., et al. (1999) Palliative radiotherapy of appendicular osteosarcoma in 95 dogs. Veterinary Radiology & Ultrasound 40, 517-522 Read, R. A., Cullis-Hill, D. & Jones M. P. (1996) Svsternic use J of pentosan polysulphate in the treatment of osteoarthritis. Journal of Small Animal Practice 37, 108-114 Reich, M. R., Ohad, D. G., Overall, K. L., et al. (2000) Electrocardiographic assessment of antianxiety medication in dogs and correlation with serum drug concentration. Journal of the American Veterinary Medical Association 216, 1571-1575 Richardson, D. C., Leventhal, P. S. & Hahn, K. A. (2010) Multicenter veterinary practice assessment of the effects of omega-3 fatty acids on osteoarthritis in dogs. Journal of the American Veterinary Medical Association 236, 59-66 Rogachefsky, R. A., Altman, R. D., Markov, M. S., et al. (2004) Use of a permanent magnetic field to inhibit the development of canine osteoarthritis. Bioelectromagnetics 25, 260-270 Rollason, V., Samer, C., Piguet, V., et al. (2008) Pharmacogenetics of analgesics: Toward the individualization of prescription. Pharmacogenomics 9, 905-933 Roush, J. K., Dodd, C. E., Fritsch, D. A., et al. (2004) Radiotherapy of osteoarthritis. Indication, technique and clinical results. Orthopade 33, 56-62 Rutherford, L., Wessmann, A., Rusbridge, C., et al. (2012) Questionnaire-based behaviour analysis of Cavalier King Charles spaniels with neuropathic pain due to Chiari-like malformation and syringomyelia. The Veterinary Journal 194, 294-298 Salazar, V., Dewey, C. W., Schwark, W., et al. (2009) Pharmacokinetics of singledose oral pregabalin administration in normal dogs. Veterinary Anaesthesia and Analgesia 36, 574-580 Sanderson, R. O., Beata, C., Flipo, R. M., et al. (2009) Systematic review of the management of canine osteoarthritis. Veterinary Record 164, 418-424 Schmiedt, C. W. & Bjorling, D. E. (2007) Accidental prehension and suspected transmucosal or oral absorption of fentanyl from a transdermal patch in a dog. Veterinary Ananesthesia and Analgeisa 34, 70-73 Schwab, R. S., England, A. C. Jr, et al. (1969) Amantadine in the treatment of Parkinson’s disease. Journal of the American Medical Association 208, 1168-1170 Sefton, J. M., Yarar, C., Carpenter, D. M., et al. (2011) Physiological and clinical changes after therapeutic massage of the neck and shoulders. Manual Therapy 16, 487-494 Shu, H., Hayashida, M., Arita, H., et al. (2011) Pentazocine-induced antinociception is mediated mainly by µ-opioid receptors and compromised by µ-opioid receptors in mice. The Journal of Pharmacology and Experimental Therapeutics 338, 579-587 Smith, H. S. (2011) The metabolism of opioid agents and the clinical impact of their active metabolites. Clinical Journal of Pain 27, 824-838 Stein, C. & Kopf, A. (2010) Anesthesia and treatment of Chronic Pain. In: Miller’s Anaesthesia. 7th edn. Eds R. D. Miller, L. I. Eriksson, L. A. Fleisher, J. P. Wiener-Kronish and W. L. Young. Churchill Livingstone, Elsevier, Philadelphia, PA, USA. pp 1797-1818 Steiss, J. E. & Levine, D. (2005) Physical agent modalities. Veterinary Clinics of North America Small Animal Practice 35, 1317-1333 Sutton, A. (2004) Massage. In: Canine Rehabilitation and Physical Therapy. Eds D. L. Millis, D. Levine and R. A. Taylor. Saunders, St Louis, MO, USA. pp 303-323 Taylor, R. R. (2005) Pain: subtypes, prevalence, and associated conditions In: Cognitive Behavioral Therapy for Chronic Illness and Disability. Springer Science and Media Inc, New York, NY, USA. pp 237-255 Taylor, P. M. & Houlton, J. E. F. (1984) Post-operative analgesia in the dog: a comparison of morphine, buprenorphine and pentazocine. Journal of Small Animal Practice 25, 437-451 Turk, D. C., Wilson H. D. & Cahana, A. (2011) Treatment of chronic non-cancer pain. The Lancet 377, 2226-2235 Vargas-Schaffer, G. (2010) Is the WHO analgesic ladder still valid? Twenty-four years of experience. Canadian Family Physician 56, 514–517 Veterinary Medicines Directorate. (2013a) Administration of a veterinary medicinal product outside the terms of a marketing authorization http://www.legislation. gov.uk/uksi/2011/2159/schedule/4/made. Accessed February 9, 2013 Veterinary Medicines Directorate. (2013b) Controlled drugs legislation. http:// www.vmd.defra.gov.uk/vet/controlled-drug.aspx. Accessed February 9, 2013 Voscopoulos, C. & Lema, M. (2010) When does acute pain become chronic?British Journal of Ananesthesia 105, 169-185 Wang, S. -M., Kain, Z. N. & White P. (2008) Acupuncture analgesia: I. The scientific basis. Anesthesia & Analgesia 106, 602-610 Willis, W. D. & Westlund, K. N. (1997) Neuroanatomy of the pain system and the pathways that modulate pain. Journal of Clinical Neurophysiology 14, 2-31 Wright, A. & Sluka, K. A. (2001) Nonpharmacological treatments for musculoskeletal pain. The Clinical Journal of Pain 17, 33-46 World Health Organization. (1987) Traitement de la douleur cancéreuse. Geneva, Switzerland: World Health Organization.
Journal of Small Animal Practice
•
Vol 55
•
March 2014
•
© 2014 British Small Animal Veterinary Association
