Do NSAIDs really work for Laminitis - a homeopaths' view
A REVIEW OF NSAIDS IN EQUINE VETERINARY MEDICINE:
How reasoned is their use in laminitis cases?
By Edward De Beukelaer, Homeopath, reprinted here with permission
‘Nsaid’ is the abbreviation for Non-Steroidal Anti-Inflammatory Drugs. The name is given to a heterogeneous group of medicines that have an anti-inflammatory effect which differs from steroids. Their principal action is the inhibition of prostaglandins. Since prostaglandins play a central role in developing inflammatory reactions, their inhibition results in a diminution of this response to injury. It is customary in medicine to treat inflammation as unwelcome, although recently more and more papers question whether we should not treat inflammation as an important healing mechanism which should be respected. (Ref. 16)
While Nsaids have an anti-inflammatory effect, they are also thought to have a pain relieving effect, though this is less substantiated.
The objective of this review is to examine the science of Nsaids and their use in medicine, with particular attention to their use for laminitis in horses.
Nsaids and science
The bulk of scientific data on Nsaids relates to the interaction of these drugs in the physiological pathways and their clearance times in the blood. Clearance times are determined to establish minimum waiting periods between the last administration of a drug and the entry of an athlete (man or horse) into a competition or, in the case of a horse, its slaughter and subsequent eligibility for human consumption. Studies on clearance times offer little, if any, useful information about medical characteristics.
The most studied and best understood effect of Nsaids is to inhibit prostaglandin production. All articles on Nsaids start with a short introduction to these drugs in relation to the prostaglandin/inflammation cascade. There are many more pathways with which Nsaids interfere but usually the effect of this interference is not fully understood.
There are very few studies in which the effect of Nsaids is compared with other similar drugs, or evaluated against a placebo control. This is especially the case for laminitis. In ‘Equine Laminitis’ (Ref. 2), Chris Pollit wrote :
“However, the effectiveness of flunixin® or any NSAID as an anti-laminitis agent has never been tested.”
In Reference 17 is the statement:
“The aggressive use of Nsaids has recently been questioned in the treatment of laminitis because of complications of NSAID therapy in the horse and lack of histological evidence of inflammation in affected laminae.”
With regards to the long-term use of painkillers, the following observations can be found in both veterinary and human medical literature.
Ref. 5 (Veterinary): “Nsaids are also used for long-term therapy of chronic inflammation of both soft and hard tissues. In this circumstance, they provide symptomatic relief through their analgesic actions, but whether the progress of disease is altered is not known.”
Ref. 3 (Human):“Further studies should compare the benefit-risk ratios of Nsaids and analgesics for shoulder complaints in order to establish whether the use of Nsaids is more valuable than analgesics, despite the higher risk of adverse reactions from Nsaids.”
Ref. 4 (Human): “In conclusion, the evidence suggests that Nsaids are effective for short-term symptomatic relief in patients with acute low back pain. Sufficient evidence on chronic low back pain is still lacking.”
Ref. 1 (Veterinary) page 244: “ Presently, there is not an abundance of information on comparative aspects of potency, efficacy and tolerability of Nsaids, and the biologic reasons for clinical impressions of relative efficacy are yet to be defined.”
Ref. 1 (Veterinary) page 245: “Nsaids are used for a myriad of traumatic, inflammatory and septic conditions, and the general beneficial and deleterious effects are similar.”
Ref. 6 (Veterinary) “High doses of Phenylbutazone were not associated with greater analgesic effects on lameness scores than was the low dosage. Considering that toxicity of Phenylbutazone is related to dosage, the higher dosage may not be beneficial in chronically lame horses.”
Overall, apart from theoretical reasoning about their influence on pathophysiological pathways, there is no experiment-based justification for the popular use of anti-inflammatory treatment for lameness in the horse (and this, of course, includes laminitis). One information sheet goes even further, saying that, although there are differences between various anti-inflammatory drugs, in large studies they cannot be distinguished in their activity. It also states that there are individual differences between patients and that horses are particularly sensitive to Nsaids, i.e. are particularly likely to develop adverse reactions.
Ref. 7 (Veterinary) “There are dozens of Nsaids on the “human” market. When studied in large populations and evaluated “on average” they are therapeutically indistinguishable (A particular drug is not superior for a particular disease, though toxicity may vary). Interestingly, when special studies are carried out it can be demonstrated that one drug may be superior to others for a particular patient. Horses seem to suffer these side effects more commonly than other species.”
In an article on the scientific validation of medicines for lameness and joint disease in horses (Ref. 8), C.W. McIlwraith writes:
“The discussion of Nsaids is relatively non-controversial in the context of this representation.”
This contrasts with the in-depth examination he makes in this article into the use of steroids and other agents that claim efficacy on equine lameness.
This common opinion on Nsaids, especially Phenylbutazone, is illustrated in the following quote in ‘Adam’s Lameness’ (Ref. 9):
“Phenylbutazone is considered relatively non-toxic at doses of 2.2 mg/kg twice per day or less. … It definitely has a pronounced analgesic effect and although more marked anti-inflammatory effects have not yet been demonstrated, it is considered to work well clinically.”
The above observation in Adam’s book on lameness that ‘Phenylbutazone is considered relatively non-toxic’ illustrates most veterinarians’ attitude to the use of Nsaids in general. Most of the scientific studies on the toxicity of Phenylbutazone and other Nsaids relate to their occasional overdosing. These acute and often devastating side-effects appear at dose levels which are two to three times the recommended dose rates. However, one report (Ref. 10) mentions the appearance of right dorsal colitis in five horses after use of the recommended dose rates of Phenylbutazone for 5-30 days. No studies have been carried out to detect and document long-term toxicity and other side-effects. This explains the inclusion within the drug literature inserts for phenylbutazone medication in horses, of a caution with regard to its long-term use. (Ref. 11)
More recently, questions have been raised about the use of Nsaids by Dr. A. Blikslager and Dr. S. Jones:(2004)
Ref. 13 (Veterinary) Non-steroidal anti-inflammatory drugs (Nsaids) are the cornerstone of treatment for many painful conditions in horses, including arthritis, laminitis, and colic. Although these drugs are an important component of therapy for these disease syndromes, overuse and misuse of Nsaids can result in gastrointestinal injury, kidney damage and even death in horses. Researchers at North Carolina State University’s College of Veterinary Medicine have investigated these drugs in horses with colic-related intestinal injury. This research has uncovered previously unknown adverse effects: Nsaids actually retard healing of damaged gastrointestinal tissue.
….. However, because these drugs are absorbed systemically and are transported throughout the body via the bloodstream, they reach unintended targets where they can have adverse effects. Specifically, there is increasing evidence that two organ systems are particularly susceptible to these drugs: the gastrointestinal tract and the kidneys….
It is now widely recognized that Nsaids can cause side effects in the gastrointestinal tract, such as stomach ulcers, and, on rare occasions, potentially fatal conditions such as colitis (severe inflammation and injury of the colon)…… The kidneys may also suffer damage from these drugs, particularly when horses are dehydrated. Although studies have shown that these complications may be caused by excessive doses of Nsaids, some horses develop adverse effects when given normal doses.
New Research Raises Additional Concerns
Recent research conducted by Dr. Anthony Blikslager, Associate Professor of Equine Surgery, has yielded surprising results and highlights the complexity of NSAID use. Eight horses with intestinal injury of the small intestine were treated with Banamine®, which is very beneficial for controlling pain and reversing some of the systemic effects of absorption of bacterial toxins from the damaged intestine. Surprisingly, the drug slowed down the intestinal repair process as compared to horses which received no Banamine®, although Banamine® did improve the comfort level of the horses. (None of the horses showed colic signs as they all received the alternative narcotic pain medication butorphanol, trade name Torbugesic®.) Banamine® stopped the intestinal lining from re-sealing for at least 18 hours, which could result in increased endotoxin absorption. According to Dr. Blikslager, “This effect was unexpected because Banamine® is used for its ability to reduce the clinical signs of endotoxin absorption. Now, we need to assess the clinical importance of these findings, and look at safer drugs in the NSAID class.”
..When using systemic Nsaids, horse owners should make sure that they use these drugs in the safest possible manner. “The overall goal of pain management therapy’ said Dr. Blikslager “should be to use these drugs at the lowest possible dose for the shortest time possible.”
”Unfortunately, there are few outward signs of the initial adverse effects caused by systemic Nsaids. (Note: highlighting made by the author) However, if a horse is being treated with a systemic drug, like bute for lameness, and becomes uninterested in food and depressed, gastrointestinal damage could be the reason. The next level of severity would involve episodes of colic or diarrhea….
It is important to note that systemic Nsaids can be used very successfully, to the point where some horses with chronic lameness receive bute for extended periods of time, typically at a dose such as 1 gram once daily. However, even in these horses, it is worth considering giving horses time off from treatment, such as treating only before and after strenuous exercise on a limited number of days per week, or taking the horse off bute periodically to allow organ systems such as the gastrointestinal tract and kidneys to recover”
(End quote from research paper.)
This paper clearly states the concern that surrounds the use of Nsaids in horses. If we look at human medicine statistics in “Toxic and deathly Nsaids” (Ref. 12) there are many arguments supporting the need for more investigation into the long-term effects of Nsaids on animals in general and horses in particular. Another study points out that a conclusion reached by the Food and Drug Administration (PDA) does not coincide with published data.
Ref. 14: (Human)“PDA Reviews contain a substantial amount of unpublished data regarding NSAID-related dyspepsia that is of comparable quality to the published data. The conclusion reached by the PDA Review data is that use of Nsaids is not associated with dyspepsia, while that reached by published data is that use of Nsaids is associated with dyspepsia”
Dr. Blikslager (Ref. 13) referred to reduced bone and intestinal healing caused by Nsaids. Bandolier (Ref. 15), in a newsletter dated March 2004, also mentions several studies in animals indicating that Nsaids have a deleterious effect on bone healing. Although there is contradictory evidence, they suggest that dose and duration related issues have not been solved. An article (Ref. 16) on Nsaids and ligament injuries states:
“Since there is evidence that cell proliferation and division is associated with certain prostaglandins it may even be harmful to continue Nsaids for a long period of time.”
In this article, the potential benefits of NSAID medication for ligament injuries is seen as being less important than good management. Harder & An (Ref. 21) refer in their article to the mounting evidence indicating that Nsaids interfere with normal bone healing. These observations are in line with recent thoughts that inflammation is necessary for efficient healing.
Anti-inflammatory treatment in contemporary medicine.
The use of Nsaids is often described as ‘supportive’ (Ref. 1) for the treatment of lameness in horses. The term ‘supportive’ is open to anyone’s interpretation and cannot be described as scientific.
From reading the above mentioned papers, it becomes clear that there is no conclusive scientific evidence to support the use of Nsaids for the purpose of healing. Also, their use is mostly based on clinical impressions and not on controlled experiments
As a consequence, the only remaining reason for the use of Nsaids is in the hope of reducing pain. Pain is very much associated with suffering. We humans feel we suffer when we experience pain. When we can take away pain, it seems obvious that we take away suffering. As a consequence, painkillers are consumed in large quantities in our modern society, through over-the-counter sales and by prescription. The use of painkillers has become a trivial matter for many and borders on an epidemic. We persuade ourselves that we feel better when we take these medicines and therefore argue that they must be good for us. There is a widespread use of painkillers for sports injuries. Their apparent efficacy in this field has contributed to their image as useful medicines and made their automatic use for other indications more easily accepted and popular.
We extrapolate what we want and how we feel to the animals under our care. When we see an animal in pain, we reach for painkillers. As the main reason for the use of painkillers is the relief of suffering, we argue that the reason itself justifies their use. As it is not unusual to see an animal regaining liveliness, at least during the initial use of painkillers, such observations reinforce our belief that painkillers are beneficial. We should ask ourselves whether the results bear out the intention.
There is also considerable pressure on veterinarians from their clients and society in general to reduce the suffering of animals. The veterinary profession recognizes its duty to reduce suffering and promote the welfare of animals. The use of painkillers fulfils this duty because it is seen to prevent suffering.
The convenience of using painkillers, their apparent efficacy and a common short-term view of medicine has encouraged and endorsed their use by both the public and the medical professions, regardless of an increasing understanding that they carry a significant degree of toxicity.(Ref. 12)
Little consideration has been given to the long-term effects and consequences of analgesic treatment. Retired horses end up in a field or a ‘rescue’ home and do not benefit from any meta-analysis of the treatments they received during their working life. People tend to remember the horses that have done well for months and years on daily doses of phenylbutazone. They forget the others that did not do so well and fail to consider a possible relationship with the Nsaid treatment they received. Only acute illnesses (intoxications) are recorded. Insidious consequences of long-term treatment with Nsaids are difficult to establish.
Is the absence of proof of long-term side effects sufficient evidence that there is no risk? No! Absence of evidence is not evidence of absence. We should question why so many publications warn about the long-term use of anti-inflammatory treatments.
For potential long-term consequences of analgesic treatment in veterinary medicine we have to look to what information is available from human medicine. Although we cannot extrapolate the information on humans to horses without considering species differences, the overall negative view on long-term use of Nsaids in man is so overwhelming that we should be more cautious with long-term use of Nsaids in horses.
Pain relief, welfare and choice of therapy.
I will now restrict my attention to the use of Nsaids in laminitis.
There are sufficient doubts raised about the efficacy of Nsaids in reducing the inflammatory response of laminitis to justify concluding they have no benefit for this aspect of the condition. Also, questions are raised about the inappropriateness of interfering with the inflammatory process when tissues need repairing.
The only possible remaining benefit, therefore, is in the hope of reducing pain. Some say that Phenylbutazone is clinically very effective in achieving this (Ref. 9). Others assign it only very modest analgesic effects (Ref. 7). One study concludes that the dose rate does not correlate with different levels of pain relief for chronic lameness in horses. (Ref. 6). In a web site of the University of Minnesota (Ref. 22) it says:
‘Traditional drugs such as Banamine® or Phenylbutazone may not be sufficient for pain control in horses that are very ill.’
again suggesting some insufficiencies in pain relief of Nsaids.
The plethora of approaches to pain management in horses, mentioned in the following summary of a research paper, shows the complexity of the subject of pain.
(Ref. 24) “This preliminary study investigated the attitudes, and evaluated the current practice of a sample of the veterinary profession in the UK in relation to the management of pain in horses. In June 2001, a questionnaire was posted to 260 veterinarians in specialised equine practice, and 140 veterinarians in general practice with a significant equine caseload. There was a 25 per cent response rate to the questionnaire, which recorded information about the availability and prescription of analgesic drugs, the factors influencing the selection of analgesics and their administration, and estimates of the severity of pain associated with selected clinical conditions. There were considerable variations in the practices applied to manage pain in horses, implying that there are similar attitudinal barriers to the optimal management of pain in horses as have been identified in other domestic species.”
Pain relief for laminitis is usually given for long periods. The apparent need for such a strategy itself raises questions about the efficacy of the analgesic effect. The perceived need for long-term medication should also ring an alarm bell with regard to the risk of toxic side-effects. In the absence of good scientific support for the use of Nsaids, the presence of continuous warnings about their use from researchers, and the generally unsatisfactory results from the currently orthodox management of laminitis, it seems sensible to reconsider our whole approach to this devastating disease.
When conventionally, Nsaids are used, we know they do not offer complete pain relief for horses with chronic laminitis. They reduce the pain, ‘awaiting’ the moment the pain disappears. They also interfere with the inflammation process necessary for good healing and therefore usually prolong suffering because healing is slower or only partial.
Choices should be made without yielding to emotions but based on evidence and knowledge, and by looking beyond first impressions. The UFAW (Ref. 23) Chief Executive James K. Kirkwood writes the following:
“UFAW continues to play a leading role in advancing animal welfare by (I) promoting the science aimed at providing better understanding of the animal’s needs, physical and mental, (II) promoting high standards of animal care through disseminating information and facilitating discussion, and (III) making sure that in all our interactions with them, animal’s welfare interests are properly considered and addressed.”
We should also bear the definition of health by the WHO in mind:
“Health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity.”
Researchers are investigating the possible negative effects on healing of long-term painkiller use (Ref. 13, 15 ). During her work, aimed at returning the deformed hooves of chronically lame horses to a physiological shape, Dr. H. Strasser (Ref. 18) has recognised the negative effect of NSAID painkillers on this healing process and strongly discourages their use. Others (Ref. 19) have also discovered that good healing is possible only by stopping NSAID treatment. In his paper, (Ref. 20) S. Ralston suggests that:
“Alternative and adjunct therapy to traditional NSAID therapy should be explored, since the analgesic use of Nsaids, being prolonged, carries the risk of causing gastric ulceration.”
There is a general lack of interest and even hostility by the profession to the exploration of alternatives to conventional practice. Reasons for this are historical and human. Reasons given are lack of proof of efficacy. Discussions are fuelled by emotions and inflexible views. Considerations for the patient (horse) may come second to intellectual interests.
‘Primo non noncere’ is the oath we take before becoming a veterinary surgeon. Not harming means not using treatments that worsen the disease. First impressions are not the best parameters to judge whether an animal becomes worse. Decisions should be based on sound knowledge. Too often emotionally charged sensibilities come into play to decide what can be a valid treatment.
The conclusion must be that the use of Nsaids are defended on the basis of clinical impressions and habit only. There is no scientific data available to justify their use, especially in long-term problems. There is also a worrying lack of good data on their long term effects while questions are raised on their suspected long term side effects.
Emotionally charged arguments hamper the development of new alternative techniques. Economical factors determine which techniques will be researched or those which will be put to one side.
Treatment of laminitis is not making much progress regardless of large amounts of research.
Pain is often the sole parameter taken into account in deciding on animal welfare.
Alternative holistic views do not comply with the very technical and specialist dissecting approach of scientific medicine.
In such an environment it seems unlikely that various parties will come to agree on what constitutes best practice. Choices are made based on individual research, experience and convictions.
I like to thank W.R. Cook, FRCVS, PhD, professor of surgery Emeritus of Tufts University, Massachusetts, for his help in the realization of this report.
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5) The Merck Veterinary Manual 2003
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‘Non-steroidal Anti-inflammatory Drugs.’
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17) Belknap, Blikslager, Jennings., College of Veterinary Medicine, State University of North Carolina. ‘Laminar COX-1 and COX-2 protein expression in the developmental stage of laminitis: a case for use of COX-2 selective inhibitors?’ 50th Annual Convention of AAEP. 2004 Denver. Ithaca, New York.
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20) Ralston, R., Department of Animal Sciences. State University of New Jersey. ‘Care for the older horse: Diet and health.’ November 2001
21) Harder, A. T., An, Y. H., ’The mechanisms of the inhibitory effects of non-steroidal anti-inflammatory drugs on bone healing: a concise review.’ Journal of Clinical Pharmacology, 2003 43 :807.
23) The Universities Federation for Animal Welfare, Wheathampstead, Hertfordshire UK. ‘Annual report 2004-2005.’
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