Non steroidal anti-inflammatory drugs (NSAIDs) include any drug with anti-inflammatory properties that is not a steroid. They consist of several families of drugs under the collective grouping of NSAIDs. NSAIDs represent the most extensively used drugs of all time; in humans it is estimated that over 1 million aspirins are taken every hour globally (Lees, 2009). NSAIDs have been the mainstay of analgesic agents throughout history with the first reported uses being documented in ancient texts, including Hippocrates in the 5th century BC. The glycoside salicin was obtained from the leaves and bark of the willow tree (Salix spp.); when hydrolyzed this yields salicyl alcohol which is used to produce salicylic acid — when in its acetyl ester form this is better known as aspirin. The Bayer Pharmaceutical Company first produced this commercially in 1898 (Jeffreys, 2004). Today there are many different NSAIDs available and their use has expanded in the last 20 years as the veterinary profession has made a priority of the prevention of pain and management of welfare.
Inflammation and NSAIDs
Eicosanoids are a diverse group of inflammatory mediators including the prostaglandins (PG), thromboxanes (TX) and the leukotrienes. They are derived from the fatty phospholipid bilayer that forms the cell membrane and act locally at the site of production for a short duration (Adams, 2009). Eicosanoids play a role in all normal physiological homeostatic mechanisms in health and in disease: this creates a problem when aiming to target drugs to reduce pathological inflammation and pain components of inflammation without disrupting the normal ‘house-keeping’ role that these agents perform. These autacoids (locally produced hormone like substances) are not stored but manufactured in response to a range of pharmacological, physiological or pathological stimuli. Cellular phospholipids release arachidonic acid in response to acyl hydrolases such as phospholipase A2. Arachidonic acid is subject to rapid oxidative metabolism within the cell by different enzymic pathways. A cascade of eicosanoids are produced playing roles in health and disease through complex interplay between host factors and intracellular responses (Adams, 2009). The most important enzymes in this cascade process are cyclo-oxygenase (COX) and lipoxygenase (LOX) (Figure 1).
The initial step in the cascade to PG and thromboxane production is the oxidation and cyclization of arachidonic acid to PGG2 through the action of COX. PGG2 is relatively unstable and is rapidly transformed into different PGs depending on the presence or lack of certain enzymes. The cascade results in multiple eicosanoids being produced and the presence of COX is essential for all of the downstream products to be produced: targeting this step would be a prudent method to prevent the production of the unwanted PGs and TXs. This is exactly what the NSAIDs do. LOX also acts on arachidonic acid but results in the production of leukotrienes through a metabolic pathway separate to the COX enzymes. Some of the newer NSAIDs have activity on both LOX and COX.
Cyclo-oxygenase (COX)
COX exists as two major isoforms, one induced in inflammation and one continually present. COX-1 is considered the ‘house-keeping’ form of COX and is continually expressed in cells, producing PG used in the maintenance of homeostasis. These PGs play a role in autoregulation of renal blood flow, renin secretion, gastric mucosal blood flow, production of the mucus layer in the stomach, and modulation of gastric acid secretion to name a few. It was thought that the adverse effects of NSAIDs occur through inhibition of COX-1. However, it is now thought that COX-1 may play a role in inflammation as well, although COX-2 is still the principle enzyme involved in the inflammatory response (Dugdale, 2010); COX-3 is sometimes mentioned but is thought to be a subtype of COX-1. It is found in the brain of dogs and was thought to be a central mediator of pain, but is now generally grouped with COX-1 (Lees, 2010).
COX-2 is induced in inflammation and results in the production of the inflammatory PGs and TXs. COX-2 specific NSAIDs were once thought to be the holy grail of NSAID pharmaceuticals, however, it is now recognized that COX-2 plays a role in angiogenesis and healing, and can even have anti-inflammatory effects in the late stages of inflammation (Lees, 2009).
Overall most of the newer veterinary NSAIDs are COX-2 selective rather then wholly COX-2 specific (Dugdale, 2010), e.g. meloxicam. The COX-2 active sites are larger then COX-1 and the newer NSAIDs have larger, different structures to the ‘classical’ NSAIDS allowing them to limit their inhibition of COX-1 by steric hindrance (Maddison and Johnson, 2002; Lees, 2009). The term COXIBs is used for some of newer cyclo-oxygenase-2-inibitors.
Inflammatory PGs play an important role in inflammation, often working synergistically with other inflammatory mediators. For instance, PGE2 has a synergistic effect with histamine by increasing the pain response's intensity and duration: this is termed hyperalgesia. PGs act both peripherally and centrally in the pain pathways. Allodynia, the process where normally non-painful stimuli become painful, is thought to be due to the presence of PG. PGs can also dilate small arterioles, and in the presence of histamine and bradykinins, enhance the oedema seen in inflammation.
NSAID pharmacology
Pharmacology is the study of drug action on the body (pharmacodynamics) together with a study of the body's action on the drug (pharmacokinetics) (Murrell, 2010; Murrell, 2011). The classical NSAIDs all have similar pharmacological properties despite the variation in chemical structure (Table 1). The majority of the newer COXIBs, however, are sulphonamides or similar agents and are quite different to the classical NSAIDs. The following descriptions discuss the classical NSAIDs.
Table 1. Examples of the different groups of NSAIDs available
| Classical NSAIDs | New NSAIDs | |
|---|---|---|
| Carboxylic acids | Enolic acids | COXIBs |
| Salicylates | Pyrazolones | Tepoxalin |
| Aspirin (sodium salicylate) | Phenybutazone | Firocoxib |
| Acetic acids | Oxicams | |
| Diclofenac | Meloxicam | |
| Piroxicam | ||
| Propionic acids | ||
| Carprofen | ||
| Ketoprofen | ||
| Ibuprofen | ||
| Anthranilic acids | ||
| Tolfenamic acid | ||
| Flunixin | ||
Almost all NSAIDs are weak organic acids with a dissociation constant (pKa) ranging from 3.5 to 6.0. The dissociation constant is the pH where 50% of the NSAID exists in an ionized state and 50% in a non-ionized state (Murrell, 2011). Being a weak organic acid in the stomach they are generally well absorbed (as non-ionized molecules) in the low pH environment where they exhibit ‘ion trapping’ in the plasma (where they exist as the ionized form). Interestingly in herbivores some of the NSAIDs bind to hay and this reduces their bioavailabilty, although this is not seen with other foodstuffs (Lees, 2009).
Most NSAIDs are strongly bound (95–99%) to plasma proteins (the exception is aspirin with only 50–80% being plasma protein bound) (Lees, 2009). This means there is little passage from the plasma into the interstitial fluid, however, in inflammation the exudate that occurs contains a high concentration of NSAIDs due to the presence of leaked plasma proteins. In addition, in the presence of acidic, inflamed tissues the NSAIDs have good cellular penetration (less acidic intracellular environment). With certain NSAIDs the concentration in exudate can exceed that of plasma (Lees, 2009). Milk is generally alkaline and NSAIDs do not penetrate the mammary gland unless mastitis is present.
Table 2. Commonly used NSAID doses in veterinary practice
| NSAID | Dog | Cat | Horse | Cow | Rabbit | Feraret | Avin | Reptile |
|---|---|---|---|---|---|---|---|---|
| Carprofen | 4mg/kg SC then 2mg/kg bd | 4mg/kg od preoperative SC | 0.7mg/kg IV/PO od | 1.4mg/kg single dose | 4mg/kg SC then 1.5mg/kg bd PO | 1 mg/kg PO od | 2–4mg/kg bd-tds | l–4mg/kg then half the dose od |
| Meloxicam | 0.2mg/kg PO/SC then 0.1 mg/kg od PO | 0.1–0.2mg/kg SC or PO, then 0.05mg/kg PO for 14 days | 0.6mg/kg PO/IV | 0.5mg/kg single dose | 0.2mg/kg PO/SC od | 0.1–0.2mg/kg PO/SC od | O.lmg/kg od | 0.1–0.2mg/kg PO every 24 hours |
| Ketoprofen | 2mg/kg od up to 3 days | 2 mg/kg SC once then 1 mg/kg SC od for maximum of 4 days | 2.2mg/kg IV | 3 mg/kg 1 M/IV for 3 days | 1 mg/kg IM/SC od | — | 2 mg/kg od–tds | 2mg/kg od |
| Phenylbutazone | 2–20mg/kg bd | 6–8mg/kg IV/IM/PO bd | 4.4mg/kg IV then 2.2mg/kg bd for 2–5 days titrating the dose down thereafter | — | — | — | 20mg/kg tds | — |
| Flunxin | 1 mg/kg IV/IM 3 days | 1 mg/kg IV/IM for a single dose | 1.1 mg/kg IV/IM od | 2.2mg/kg od for up to 5 days | l–2mg/kg SC od | 0.3–0.5mg/kg PO/SC/IV od | 1 mg/kg od | — |
| Aspirin | 10mg/kg bd | l-25mg/kg eod | 25mg/kg PO tds | — | 10–25mg/kg PO tds–qds | 0.5-2 2 mg/kg PO od–tds | 5mg/kg tds | — |
| Tepoxalin | 10mg/kg PO od | — | — | — | — | — | — | — |
Note by author: Doses are subject to change and licensing restrictions and as such should be confirmed by clinicians before using the doses recommended here. SC, sub cutaneous; bd, twice daily; od, once daily; IV, intravenous; PO, per os; IM, intramuscular; tds, three times daily; eod, every other day; qds, four times daily
Most NSAIDs are metabolized by the liver to inactive metabolites, although aspirin and phenylbutazone have active metabolites. Some of the NSAIDs exist in enantiometric forms, e.g. carprofen and ketoprofen, which have differing rates of metabolism (Lees, 2009). Urine excretion is dependent on urine pH: herbivores with alkaline urine favour excretion while carnivores and omnivores with acidic urine do not. The high plasma protein binding is more important in preventing renal clearance, as only a small amount of drug is free in the circulation that can be renally excreted.
Anti-inflammatory and analgesia actions of NSAIDs
NSAIDs exhibit both central and peripheral actions. COX inhibition prevents vasodilation, histamine release and bradykinin production. This results in a reduction in erythema, oedema and exudation. NSAIDs also inhibit other chemotaxic and inflammatory mediators depending on the type of NSAID used (Dugdale, 2010). Changes also occur at a central level in the spinal cord in response to pain.
The analgesic properties of NSAIDs are much more effective if given prior to inflammation or pain. This seems obvious when looking at the pathway and can be compared to shutting the barn door after the animals have left: if the PGs are present all the NSAIDs will do is reduce the production of additional PGs, not prevent the changes that have occurred already. This is sometimes referred to as prevention of ‘wind-up’: physical changes occur in the neural pain transmission pathways once pain has been experienced, this makes it more difficult to manage analgesia effectively. Giving NSAIDs prior to predicted painful procedures, i.e. preemptively, prevents or reduces these physical changes in neural transmission in peripheral and central nerves and allows more efficient analgesia. Therefore it is imperative that these agents are given at the time of premedication or earlier if at all possible.
Side effects
The side effects seen with the use of NSAIDs ultimately result from inhibition of the house-keeping PGs. These include:
- Gastric ulceration following PGI2 and PGE inhibition, these PGs play a major role in maintaining the integrity of the mucus layer of the gastrointestinal tract. This can be exacerbated in some species, e.g. dogs, where the half life is prolonged by enterohe-patic recycling. Other factors that promote gastric ulceration include concurrent use of corticosteroids, dehydration, hypovolaemic shock and disruption to normal gut flow (Maddison and Johnson, 2002)
- Renal toxicity can occur following the loss of the autoregulation mechanisms that support blood flow through the kidney. This is regulated by the presence of PG. Renal papillary necrosis or ischaemia is more likely in dehydrated animals
- Hepatotoxicity is less common but is reported in some species
- Prolonged bleeding times due to inhibition of TX production: TX is a vasoconstrictor and mediator for platelet aggregation (Dugdale, 2010)
- Delayed parturition through the action on PG and possible foetal effects such as embryotoxicity and closure of the ducuts arteriosis (Dugdale, 2010)
- Exacerbation of clinical signs of asthma: it is hypothesized that the use of NSAIDs allows more arachidonic acid to go down the leukotriene cascade route which enhances bronchial reactivity and attracts more inflammatory cells (Dugdale, 2010).
Conclusion
NSAIDs are extremely useful therapeutic agents in the management of pain and ensuring the welfare for the patients under our care. They should be used as part of a considered, balanced, multi-modal analgesia programme that incorporates current and best practice in analgesia.