Papich (1997) discusses the use of NSAIDs focusing on their low to moderate intensity analgesic properties and concludes that they are effective, inexpensive and long acting. This makes them desirable within veterinary practices, and they are commonly chosen for their use or management of somatic or integumental pain (Flaherty and MacGillivray, 2007).
NSAIDs mostly work peripherally in the body when administered; this peripheral response inhibits the formation of some of the substances that are involved in the inflammatory response.
When pain occurs inflammation and swelling become activated at the site of pain, and these are the major causes of pain (Hall et al, 2001). When tissues are damaged this causes pain (Figure 1). Pain can be described as physiological, such as a burn or cut to the skin, and in this instance a noxious stimulus is transmitted to the nociceptors to evoke a response, i.e. pain. Pathological pain can be described as tissue damage that has already occurred. This is normally present in an anaesthetized animal undergoing surgery. Pathological and physiological pain can be categorized further according to where the pain response is occurring: somatic; visceral; or neuropathic pain.
Somatic pain — this occurs because of the stimulation of pain nociceptors in the skin, superficial muscles, anywhere that pain is caused by external stimuli. The degree of pain experienced is high and normally localized to one specific point, where the tissue is damaged and inflammation has occurred.
Visceral pain — this arises from stimulation of pain nociceptors within the abdominal or thoracic organs. It is normally diseased organs that cause the pain but the intensity is not the same as somatic pain. The level of pain is determined by how many pain nociceptors are affected at any one point.
Neuropathic pain — this is generated by damage to any part of the central nervous system or peripheral nerves. The level of pain experienced can be excruciating and also long lasting. When the nerves are damaged or severed nociceptors input signals into the spinal cord, eventually if pain is left untreated stimulation of other pain receptors occurs, this excites other neighboring nerves and fibres such as mechanoreceptors and sympathetic nerves. This amplifies the pain further. Neuropathic pain can be severe and difficult to control.
When NSAIDs are administered they inhibit inflammatory mediator substances, it is these inflammatory mediator substances that cause the inflammation and swelling thus causing the pain the animal experiences. Inflammatory mediator substances include the cyclo-oxygenases (COX), which are enzymes that are involved in the pain process, and it is these enzymes that synthesize prostaglandins that are responsible for pain and swelling. By blocking COX enzymes, NSAIDs inhibit prostaglandin production, thus reducing pain.
Prostaglandin's role
There are several prostaglandins involved within the pain process, and these are formed when the COX acts on arachidonic acid. The regulatory and reactionary responses of prostaglandins accounts for the commonly associated side effects seen with NSAIDs.
There are two main COX isoenzymes COX–1 and COX–2. Research has identified COX-4 and more recently COX–5, however, the discussion of the side effects for this article have been concentrated on the common relevant COX–1 and 2 enzymes.
NSAIDS produce analgesia by blocking the conversion of arachidonic acid to prostaglandins. It is prostaglandins that play a key role in producing pain once a noxious stimulus has occurred. They are inflammatory mediators, they sensitize pain fibres producing pain and act on the spinal cord to up regulate pain signals. By blocking or preventing prostaglandin production the patient will experience less pain. NSAIDs reduce or inhibit these prostaglandin-mediated responses.
If a medication is administered that blocks prostaglandin production then a reduction in pain should result, however prostaglandins also have other roles within the body. They help maintain renal perfusion and have a role in the production of mucus in the stomach preventing gastric ulceration. When NSAIDs are administered these will also be affected.
There are two types of COX enzymes:
- COX–1 — these produce ‘good’ prostaglandins. These enzymes form prostaglandins that are stimulated almost constantly within the body and are mainly involved in the secretion of stomach mucus production, water excretion by the kidneys and the formation of platelets.
- COX–2 — these produce ‘bad’ prostaglandins. COX-2 is the principle enzyme involved in the inflammatory response (Dugdale, 2010). Therefore NSAIDs should inhibit the COX–2 enzyme thus reducing pain.
It is the newer NSAIDs that target this enzyme more specifically to limit the inhibition of the COX-1 enzymes, therefore limiting the unwanted side effects that may be seen with NSAID administration.
Common NSAIDs that are available for use in small animals in the UK:
- Ketoprofen
- Carprofen
- Meloxicam
- Firocoxib
- Mavacoxib
- Robenacoxib
- Tepoxalin
- Phenylbutazone
- Cimicoxib.
Side effects of NSAIDs
The specificity of each of the NSAIDs regarding the action of inhibition of COX enzymes can determine the undesirable effects that occur. Some NSAIDs have undesirable side effects more than other NSAIDs. Although NSAIDs have a similar mechanism of action, individuals who do not respond to one NSAID may respond to another (Dhikav et al, 2002).
It is generally the older NSAIDs that are more specific to the COX-1 enzyme. This inhibition of Cox–1 results in blocking the formation of good prostaglandins causing the side affects that are most common, such as gastric and renal problems. Newer NSAIDs have been manufactured to have a greater specificity for COX-2, providing fewer undesirable side effects. This is particularly true relating to Carprieve (carprofen) that preferentially inhibits COX-2 enzyme, thereby limiting the production of prostaglandins involved in inflammation (Ramsey, 2011). Other non-COX mediated mechanisms are suspected to contribute to the anti-inflammatory effect but these have not yet been identified.
Case study 1.Hera, a 6-year-old Bullmastiff presented for evaluation of a right pelvic limb lameness. On clinical examination there was mild tibial thrust with tibial compression testing on the right stifle. Mild medial buttressing and effusion was also palpable within the joint. Stifle radiographs confirmed a right cranial cruciate deficiency and surgical management with Tibial Plateau Levelling Osteotomy (TPLO) was advised, and surgery was scheduled. Following induction of anaesthesia Hera received an injection of carprofen at 2 mg/kg. This was given prior to noxious stimuli to reduce peripheral sensitization and to coincide with an opioid, and a femoral and sciatic nerve block to provide balanced analgesia. A right TPLO was performed using a Slocum technique, and recovery from anaesthesia was uneventful. Hera remained in hospital overnight. She was pain scored every 4–6 hours and given analgesia when required. The following morning Hera was bright, alert and responsive, had eaten breakfast and was using the limb. Following further examination from the veterinary surgeon it was decided that Hera could be discharged. Hera was discharged later that day with post-operative care instructions and a course of carprofen at a dose of 75 mg twice daily for 5 days, then once daily for 9 days. Hera was scheduled for a follow up examination 6 weeks post surgery, but the owners were advised to contact the surgery if they had any concerns. At the 6 week examination the owner reported that Hera was progressing well. Hera was using the limb well and the owners were pleased with her progress.
The body's action on NSAIDs
The body's action on NSAIDs varies widely between species, which affects their efficacy and the degree of side effects. The most common side effects of prostaglandin inhibition are the gastric and renal manifestations, which may lead to secondary anaemia and hypoproteinaemia. Benson (2000) has reported impaired platelet function and delayed parturition with NSAID use, with nephropathy occurring in patients with hypovolaemia, congestive heart failure and other cardiovascular impairments. These side effects may be related to the inhibition of renal prostaglandins. Renal prostaglandins are responsible for potent an-tihypertensive and vasodepressor activity within the body. NSAIDS can have a variety of effects on renal function, these are directly related to NSAID-induced inhibition of renal synthesis of prostaglandins.
This finding may be significant as relative or absolute hypovolaemia is not uncommon in the postoperative period, and concerns regarding this risk of toxicity have precluded the use of many NSAIDs in pre-emptive analgesia in the past. The side effects are however dependant on the doses administered and consultation with the veterinary surgeon must be sought before any administration of NSAIDs.
It is, however, considered good practice to administer NSAIDs, or any analgesics before the pain process has been initiated. This can determine the efficacy of the medication administered. If the pain process has begun it limits that ability of the analgesic to have an effect, i.e. once the prostaglandins are present, the anaglesic can only prevent additional prostaglandins being produced. Therefore it is considered best practice to use NSAIDs as part of the patient's pre-operative medication. Used pre-emptively or as part of a multi-modal analgesic regimen, carprofen has been found to be safe and effective (Lascelles et al, 2005; Deneuche et al, 2004; Slingsby and Waterman-Pearson, 2002; Bostrom et al, 2006).
Carprofen
Carprofen is generally considered relatively prostaglandin sparing (Grant, 2006). This means that it is a relatively weak inhibitor of COX, however it does have a greater specificity for COX-2 rather than COX-1 meaning that it does have, clinically, a very good safety profile with very few negative consequences for the patient receiving it.
Carprofen is licensed in the UK for pre-operative use in cats and dogs and has a long-term use license in dogs. It is used in cats and dogs for its potent anti-inflammatory effects and antipyretic effects and is indicated for the control of pain and reduction of in-flammation and fever (Tennant, 1999).
In addition, efficacy of carprofen in the post-operative period can be maximized — it is more effective when used in synergy, producing a synergistic effect (Flaherty and MacGillivray, 2007). Ketoprofen and carprofen, for example, have been shown to provide the best post-operative analgesia when combined with an opioid (Pibarot et al, 1997).
Case study 2.Manny, a 9-month-old German Shepherd Dog was presented for evaluation of hip dysplasia. The owner reported that Manny was exercising normally when he became lame following a walk and a swelling was detected over the right hip region. Clinical examination revealed a lateral deviation of the right greater trochanter. There was discomfort with bilateral hip extension and a decreased range of motion on bilateral hip extension. The changes were more severe in the right hip. The cause of the abnormalities in the right pelvic limb was right hip luxation and concurrent hip dysplasia. In Manny's case it was decided to proceed with total hip replacement of the right pelvic limb. Due to the nature of the surgery it was paramount that Manny received adequate analgesia pre, peri and post operatively. An opioid was combined into his premed, carprofen was administered at a dose of 2 mg/kg and an epidural was utilized. Surgery was successful and Manny recovered from anaesthesia uneventfully. For the following 24 hours Manny was assessed for pain using the Glasgow Composite Pain Score System. Pain assessment revealed that Manny did not require further analgesia overnight. Carprofen was prescribed for a further 2 weeks at a dose of 75 mg twice daily for 5 days, then 75 mg once daily for 9 days. During the hospitalization period Manny was starting to use the right pelvic limb well and was subsequently discharged 2 days post surgery. Manny was re assessed 4 weeks following surgery. The owners reported steady progress and Manny had shown no signs of discomfort, and was using the limb.
Carprofen use in dogs
Slingsby and Waterman-Pearson (1998) have shown that when carprofen was used in combination with pethidine in dogs post operatively, enhanced analgesic effects were noted compared with using either drug alone. Its use is also longer in duration than most analgesics, with its half life in dogs being approximately 8 hours with duration lasting 24 hours (Grant, 2006). Its length of duration in comparison with other analgesics is of benefit because it can be administered less frequently. Extensive research has been performed with regards to carprofen's use in treatment of orthopaedic-related pain. Laredo (2004) discusses carprofen's effective use in orthopedic analgesia and its great success alongside meloxicam. Carprofen has also been proven to improve articular cartilage degeneration after acute joint inflammation was induced; one study actually found an improvement 12 weeks post cranial cruciate ligament rupture and the patients generally had smaller and less severe cartilage lesions in comparison to untreated dogs (Pelletier, 2000).
Its use in cats
Injections of carprofen are licensed in cats for single use and tablets are not. Caution should be exercised when employing NSAIDs in cats (Grant, 2006). Cats differ from dogs in relation to the pharmacodynamics of NSAIDs with prolonged half lives and the potential for toxicity in feline patients. Additionally, very few studies have been performed examining the feline response to this group of analgesics. One of the few NSAIDs that appears to be well tolerated in cats is meloxicam, and meloxicam, unlike carprofen, can be used long term in cats. However, there are some older studies examining the efficacy of meloxicam in the prevention of acute pain in cats undergoing ovariohysterectomy (Slingsby and Waterman-Pearson, 2002). In the study by Slingsby and Waterman-Pearson (2002) of 80 cats undergoing flank ovario-hysterectomy, patients were assigned to carprofen or meloxicam before surgery. Pain was assessed using a visual analogue scale (VAS) over 20 hours and there was no significant difference between pain measured in both groups. Two cats in the meloxicam group and one cat in the carprofen group required rescue analgesia. In one study there were 10 cats per group, with different groups being given a single injection of carprofen, meloxicam, ketoprofen, or tolfenamic acid (Slingsby and Waterman-Pearson, 2000). Pain was assessed using a VAS and there was no difference between groups. One cat in each of the meloxicam, tolfenamic acid and ketoprofen groups required rescue analgesia. These studies show that there is no difference between meloxicam and the other NSAIDs studied in the prevention of post-surgical pain.
Cracknell (2007) also recommends carprofen for its use in small mammals, avian and reptiles in the pre-or post-operative period for the treatment of pain.
Contraindications of NSAIDs
There are a number of contraindications for NSAIDs:
- Cardiac impairment
- Renal impairment
- Hepatic impairment
- Blood dyscrasias
- Dehydrated patients
- Hypovolaemic patients
- Hypotensive patients
- Dogs under 6 weeks of age
- Patients with gastrointestinal bleeding
- Do not use with highly protein bound drugs, e.g. cardiac drugs (propanalol, frusemide), anticonvul-sants (diazepam), albumin (Booth, 2001)
- Do not administer different NSAIDS within 24 hours of administration
Case study 3.Blue, a 6-year-old German Shepherd Dog presented following investigations for a hard swelling over the caudal left thoracic wall. The investigations had diagnosed the presense of a chondroma/chondrosarcoma. Further investigation was necessary to assess Blue for possible surgery. Following magnetic resonance imaging (MRI) scan, Blue was scheduled for surgery for left thoracic wall resection. Pre-emptive and balanced analgesia was provided due to the complexity and invasive nature of the surgery. An opioid was combined in the premed, carprofen was administered at a dose of 4 mg/kg and an epidural was administered. En – bloc resection of ribs 7–10 and myocutaneous flap of the latissimus dorsi muscle was performed to reconstruct the thoracic wall and surrounding skin deficits. A chest drain was also placed prior to closure of the chest wall. Blue recovered from anaesthesia uneventfully. He was pain scored every 4 hours and analgesia was provided by a transdermal patch, and carprofen at a dose of 75 mg twice daily. For the first 24 hours after surgery Blue's demeanour was unsettled and his pain score revealed the necessity for further opioid analgesia. The following day Blue was ambulatory and eating. The chest drain remained in situ for a further 24 hours and analgesia continued via the transdermal patch and carprofen. Blue made steady progress and remained hospitalized for 1 week. Postoperative care of the wound and minimal exertion was necessary to aid in Blue's recovery. He was discharged and re examination arranged for 1 week. The following week, Blue returned to clinic. His wound was healing well and the owner reported that Blue was recovering well from surgery.
Client compliance
No analgesic will achieve optimum effect if client compliance is poor. This includes administration techniques, which may be considered the vital part in achieving the optimum effects of the medication, and timings of administration may be considered important with respect to the medication's duration of action. Compliance decreases over time and requires sustained communication between patients and veterinary staff (Guenther, 2006). Guenther (2006) reveals that similarly, client compliance is a critically important part of the success of long-term management of pain-related problems in animals.
The client should be educated about the medication requirements during the explanation of the patient's problems. It is also important to discuss the client's understanding of the pathogenesis of the disease and the patient's anticipated progression. This is to inform and equip the client with skills to monitor their pet for signs of improvement or deterioration and so that they can assess the efficacy of the prescribed medication. Innes (2006) additionally raises the important point of educating the client with regards to the fluctuation of any clinical signs, and anticipated benefits and potential complications of all management and medications. Using this knowledge, the veterinary surgeon and owner must establish and agree realistic expectations for the patient. These expectations should be revisited, evaluated and possibly adjusted over time based on the patient's response to the medication. If NSAIDs are administered incorrectly they can have adverse effects on the physical status of the patient and provide little or no analgesic effect (Fox, 2006).
Carprieve
Carprieve presents in 20 mg, 50 mg, and 100 mg capsules for oral use and a long-acting injection (Figure 2). Carprieve favoured tablets have been launched by Norbrook Laboratories to help make dosing dogs a stress-free experience for dog and owner (Norbrook, 2011).
Carprieve offers COX-2 preferential pain release, with the favoured tablets mainly indicated for chronic inflammation, such as degenerative joint disease in dogs, as well as post-operative pain management. The new tablets are pork liver favoured and highly palatable. Tests have shown that 75% of dogs will take them voluntarily (Norbrook, 2011). This should dramatically improve client administration techniques promoting optimum effects of the medication.
Carprieve has no UK license for cats and is con-traindicated in them and the inadvertent administration of oral carprofen tablets may induce life-threatening conditions in this species.
Conclusion
NSAIDS are commonly chosen in veterinary practices for the treatment of somatic and integumental pain (Flaherty and MacGillivray, 2007). Their versatility is a possible reason why they are commonly selected as they can be used successfully in treating pain pre-operatively, intra-operatively, post-operatively and additionally used in long-term treatment in dogs. The duration of action is the longest in analgesia medications (Grant, 2006), requiring less frequent administration than most other analgesics. This should improve owner compliance and help to keep the costs to a minimum. Which NSAID to choose is ultimately the veterinary surgeon's decision but this may be based on any concurrent NSAIDs the patient has received within a 24 hour period, the specification towards COX enzymes, interactions with other medications, contraindications and expected side effects of the medication. Client compliance must also be considered with administration benefits of the medication being made a priority factor. Good client compliance will clearly improve the effects of the medication ensuring it reaches its optimum effect for the patient (Innes, 2006). An NSAID that is seen by the client to be effective, without side effects and easy to administer may improve client confidence in its administration, ultimately providing the optimum effect for the patient.
Key Points
- NSAIDS are commonly chosen for their analgesic properties.
- NSAIDS produce analgesia by conversion of arachidonic acid to prostaglandins.
- Newer NSAIDS are more specifically selective on COX-2 inhibition.
- Carprofen (Carprieve) has a greater specificity for COX-2, giving it a greater safety profile.
- No analgesic will achieve optimum effects if client compliance is poor.