15 Jul 2019
Ian Self discusses management and, using various case examples, treatment options in canine and feline patients.
Ian Self
Job Title
Image © Africa Studio / Adobe Stock
As veterinary professionals we are very aware of the presence of acute pain in our patients.
Acute pain is provoked by a specific disease or injury, serves a useful biological purpose, is associated with skeletal muscle spasm and sympathetic nervous system activation, and is self-limiting (Grichnik and Ferrante, 1991). It is a necessary evolutionary trait, allowing localisation of trauma/injury and assessment of the likely severity of the inciting cause, plus associated behavioural changes to limit further damage.
Chronic pain, however, is often difficult to recognise, mainly due to the insidious nature of its onset, plus the signs demonstrated by patients experiencing it, which are easily mistaken for other conditions or primary behavioural alterations.
The definition of chronic pain has traditionally been based on time (typically between three and six months). However, perhaps, a better definition would be pain that extends beyond the expected period of healing. This indicates chronic pain is pathological in nature and serves no useful biological purpose. Nevertheless, definitions are not always helpful to us as clinicians – for example, OA pain that is chronic in nature, yet appropriate to the disease, especially during “flare-ups”. In this case, it is appropriate to say OA pain is nociceptive (caused by inflamed or damaged tissue activating nociceptors), despite the chronic nature of the condition, and the pain is “appropriate” to the condition. Chronic (pathological) pain, though, is neuropathic (caused by damage to or malfunction of the nervous system).
Accepting chronic pain is pathological, we need to examine the causes and, therefore, where we may intervene to limit its development. Chronic pain may arise from:
One or more mechanisms of central sensitisation may contribute to any type of persistent pain, and the aforementioned situations may lead to activation of the N-methyl D-aspartate (NMDA) receptor in the dorsal horn of the spinal cord, release of substance P, tumour necrosis factor and prostaglandins within the dorsal horn, a failure of inhibitory interneurone activity, reduced descending noxious inhibitory control or glial cell activation – all mechanisms cited in the development of pathological pain. It is, therefore, important to recognise multimodal treatment of chronic pain should not only involve analgesic therapy, but also an assessment of the underlying cause to limit these mechanisms.
Assessment of chronic pain is often reported to be more difficult compared to acute pain. This is likely due to the (normally) slow onset of the pain, which allows behavioural adaptation – allowing the ability to cope with increasing levels of pain and, therefore, maintain normal function for as long as possible. In addition, chronic or pathological pain can be caused by a wide variety of conditions with different mechanisms of producing the pain – consider pain in an old dog suffering from OA (inflammatory pain) versus pain in a dog with a renal tumour stretching the renal capsule (“visceral” pain).
Despite the problems, several validated scales do exist for assessment of OA pain (White and Hunt, 2019), and the author finds several of these scales useful for other types of chronic pain. Available scales include:
In cats, no universally accepted validated scales exist for OA or chronic pain; however, the following are examples of published scales:
It is vital to recognise total elimination of pain is rarely, if at all, possible. Arguably, the concept of improved quality of life or reduction in “suffering” should be considered as a primary goal when treating patients with chronic pain conditions, with the emphasis on the impact of the pain on the individual’s daily life and allowing the patient to cope with its condition. Validated quality of life scales, such as the online Vetmetrica HRQOL system (www.newmetrica.com), are likely to become increasingly important when dealing with patients experiencing chronic pain.
Several pharmacological treatment options exist when dealing with chronic pain (Self, 2019), and NSAIDs are the most commonly prescribed medications for treating chronic pain in companion animals.
Despite minimal evidence on the use of paracetamol in dogs, in the author’s experience, it appears to provide appropriate analgesia for chronic pain conditions when administered at appropriate doses. A licensed form of paracetamol exists for use in dogs, which also contains codeine. Paracetamol should be avoided in cats.
Gabapentin and pregablin can be useful adjuncts in managing chronic pain, although side effects include sedation – particularly when treatment has started.
Amantadine and memantine are NMDA antagonists that can be used alone for treating chronic pain or in conjunction with NSAIDs in dogs with chronic OA pain refractory to NSAIDs alone (Lascelles et al, 2008). Various doses have been reported.
Amitriptyline is a tricyclic antidepressant (TCA) used in humans for controlling neuropathic pain and has been used to treat neuropathic pain in dogs. It should not be used with tramadol or other drugs that inhibit serotonin and norepinephrine uptake.
Tramadol is an atypical synthetic opioid (KuKanich and Papich 2004); however, a large variability in uptake exists and the author finds it has extremely limited efficacy in the treatment of chronic pain in dogs, and its main effect appears to be behavioural alteration rather than analgesia. However, it appears more efficacious in cats. The author would not use tramadol alone for treating chronic pain.
Steroids can be of use if the chronic pain has an inflammatory component, but are not a commonly used first-line treatment because of the side effects associated with long-term use. Similarly, long-term administration of opioids in cases of chronic pain is uncommon because of the side effects caused by these drugs, although may be of use in a multimodal approach in cases of flare-ups.
Other less common drugs used include bisphosphonates for treatment of osteosarcoma-associated pain, the orally administered opioid tapentadol and transdermal fentanyl preparations for “breakthrough” pain treatment. In cases of severe flare-ups, the author would consider hospitalisation and the IV administration of opioids, ketamine/lidocaine combination infusions and, if applicable, local anaesthetic techniques.
A number of pain treatments are emerging. A liposome formulation of bupivacaine (local anaesthetic) that offers postoperative relief for up to 72 hours, has recently been licensed in the US for dogs and cats. Interest also exists in sustained release depot formulations of opioids, such as buprenorphine, although none are, as yet, commercially available.
Intra-articular treatments for OA aim to encourage healing of damaged tissue directly and autologous conditioned serum, platelet rich plasma and cultured bone marrow-derived stem cells have all been reported. Grapiprant is a novel NSAID of the piprant class that acts via antagonism of the EP4 receptor, the primary mediator of canine OA pain (Kirkby-Shaw et al, 2015).
Finally, some clinical work exists examining the use of monoclonal antibody (mAb) therapies targeting chronic pain and species-specific anti-nerve growth factor (NGF) mAbs have been developed for the management of OA-associated pain in dogs and cats; early clinical trials show anti-NGF therapy appears very effective (Enomoto et al, 2019).
Physical therapies, such as physiotherapy, hydrotherapy, massage and acupuncture, have potential to play a large role in ensuring patient comfort, although precise approaches fall outside the scope of this article.
Environmental management is also vital – ensuring the patient can perform normal functions as easily as possible should be discussed extensively with the owners, including sleeping, exercise and toileting regimes.
Nutraceuticals have potential to influence the progress of disease. The main evidence in cases of OA points to a benefit of oral supplementation with omega-3 fatty acids found in some fish oils and green-lipped mussel extracts (Roush et al, 2010; Bui and Bierer, 2001).
When considering cases of chronic pain, such as OA, it is important to manage the expectations of the owner and ensure he or she is involved in the decision-making process. Many chronic pain patients will be faced with their disease for life and will require continuous treatment, with the associated care and financial inputs from the owner.
Various approaches have been cited, but the author adopts the following general approach to these cases:
The following examples are based on patients presented to the chronic pain management clinic and illustrate the author’s approach when dealing with chronic pain, together with justifications for the choice of treatment.
These cases do not represent recommendations for similar cases, as each case must be assessed individually.
Harris, a 14-year-old shih-tzu, was presented for management of pain relating to ongoing OA.
He was being managed with gabapentin, robenacoxib and occasional tramadol (used when exhibiting flare-ups). He was also on a joint supplement and taken for hydrotherapy as necessary.
The main presenting concerns of the owners were the side effects of medication for his condition, especially when he received flare-up doses of the tramadol and gabapentin, at which point he was reported to be very “wobbly” (a common side effect of both medications). They were also quite interested in introducing other alternative therapies into his pain management regime, such as acupuncture.
On clinical examination, Harris had a grade one systolic murmur, with enlarged submandibular lymph nodes and a slightly tense abdomen. He had typical gait changes associated with OA, showing a slightly spread gait to equalise forces on his joints.
Focusing on pain, a reasonable range of movement was visible in both hip joints. However, a 4/5 pain response was seen on the right hip and 2/5 response in the left hip. He also appeared to be offloading his right hindlimb lameness through the spine to his left forelimb, leading to a definite pain panniculus response over the lumbar spinal region; a common finding in chronic OA cases.
Both elbow joints had pronounced effusion, but with minimal pain on palpation. Nevertheless, Harris appeared to be very happy and bright in himself, and the owners were already applying environmental modifications (for example, memory foam beds, ramps on stairs, frequent shorter walks and consistent exercise regime). Clinical examination was otherwise unremarkable.
The author discussed the most recent evidence that tramadol is a very poor analgesic agent in dogs and, certainly in Harris’ case, seemed to be only sedating him. It was decided to aim to stop tramadol over the following visits once his overall analgesia had improved.
Following discussions the following plan was agreed:
On re-examination, the owners’ impressions were that the paracetamol had made little difference. However, on examination, Harris was significantly less painful on epaxial muscle palpation, so it was recommended Harris continued with the paracetamol regime either given once or twice daily depending on need. In addition, therapy with amantadine was started at 75mg once daily to provide background, central analgesia and phasing out the gabapentin after two weeks of amantadine therapy. After a further two weeks, the owner reported Harris was having prolonged periods of improved relief on the new regime.
The plan going forward was to reduce and eventually stop the tramadol (which evidence has suggested has minimal to zero analgesic effect in dogs), and review in three to four months.
Johnny, a 10-year-old Jack Russell terrier, was presented with a 9-year history of self-trauma along the tail and around the tail head. He had hemi tail amputation at a year due to a “nerve problem” but, unfortunately, no more details or images were available from that period.
The owners reported Johnny would suddenly attack his tail several times daily, and he would also wake up to attack it, indicating a sensory component to the problem, although the owners agreed, undoubtedly, a behavioural component existed. The tail biting occurred regularly and the owners reported they couldn’t leave Johnny alone in the house without placing a muzzle.
On clinical examination, heart rate was 68, but no murmurs or abnormal lung sounds were detected. Johnny had bilateral luxating patellae and some discomfort when hips were manipulated, but otherwise no abnormalities were detected.
At this stage, von Frey filament sensory testing was carried out and Johnny was found to be markedly sensitive down to 0.4g filament to approximately 7.5cm away from tail base in every direction – manifest as a pronounced dip and struggling, plus growling. This indicated marked allodynia (pain response to a non-painful stimulus) as a normal response is around 2g filament based on previous experience with similar dogs.
The owners were informed that trying to abolish nine years of hyperalgesia and sensitisation was likely to be very difficult; the emphasis would be long-term management rather than a cure.
Options offered include:
The owners opted to start paracetamol at 15mg/kg twice daily (approx 100mg twice daily).
Two weeks later, clinical examination heart rate was unremarkable. Unfortunately, the owners did not feel the paracetamol made any appreciable difference to the tail-biting behaviour. Therefore, the owners opted for acupuncture (generally good effects for hyperalgesia, plus as a behaviour modifier via endogenous endorphin release). In addition, gabapentin was started at 100mg twice daily for three weeks to treat neuropathic pain, although this makes it less likely we can isolate the effects of both components in terms of any improvement noted. Acupuncture was performed for another three weeks at weekly intervals (normal induction regime) needling between the shoulder blades, left and right epaxials at the thoracolumbar and lumbar areas (four sites), and two points centrally deep over the sacrum. This was well-tolerated.
After four weeks Johnny had shown variable response to acupuncture. Some weeks he improved for two or three days after the session, but on one occasion no response was seen – this is unusual, but probably reflected the complicated nature of this case.
Despite the variable clinical response, von Frey filament testing at this stage showed much reduced response around the tail head responding to 4g filament – a significant improvement.
At this stage, it was agreed to continue the gabapentin, but to introduce amitriptyline 10mg twice daily. Some evidence exists for direct (NMDA receptor antagonist) analgesic effects, in addition to the potential behaviour-modifying effects.
After three weeks of treatment it was agreed Johnny was as good as could be expected with the analgesia regime. The owners reduced both drugs to once daily, but would give twice daily as needed if required – at that stage giving 100mg gabapentin once daily in the evening and 10mg amitriptyline once daily in the evening – and reported this allowed Johnny a good night’s sleep.
The plan going forward was to discharge Johnny back to the care of the referring vet, but to see Johnny every year as it was felt an acceptable level of quality of life had been reached, with minimal tail biting and no further need for muzzles when left alone.
