Managing Chronic Pain: Alternatives To The NSAIDs
Patricia Dowling Canada
While NSAIDs provide good relief of pain and inflammation, many small animal patients cannot tolerate the adverse side effects of these drugs. The following drug therapies may help practitioners improve quality of life for patients with chronic pain conditions.
Glucocorticoids are named for their influence on carbohydrate metabolism. Blood glucose concentration is increased, insulin effects are antagonized, and fatty acids and amino acids are mobilized for gluconeogensis (catabolic effect). By mobilizing glucose, steroids provide the body with the energy to combat stress. Glucocorticoids increase the number of circulating mature neutrophils. This effect is caused by a release of neutrophils from the marginal pool and a decreased migration into inflamed tissue. This is attributed to decreased adherence to vessel endothelium, decreased diapedesis from the vessels, and decreased response to chemotactic stimuli. Glucocorticoids decrease the numbers of lymphocytes in the peripheral circulation, depress lymphocyte activation and decrease participation of lymphocytes in inflammation. T cells are more affected than B cells.
Glucocorticoids improve microvascular integrity, decrease vessel permeability, and improve microvascular circulation. Some of the stabilizing effect on vessels may be attributable to an antagonism of vasoactive substances (e.g., histamine, 5-HT), or decreased synthesis of inflammatory mediators (e.g., prostaglandins, TNF). They also enhance vasoconstriction and increase blood pressure. There is some evidence for dual blockade of the arachidonic acid cascade, resulting in inhibition of prostaglandins, prostacyclin, thromboxane, and leukotrienes. It is difficult to separate the anti-inflammatory and immunosuppressive effects of glucocorticoids. Glucocorticoids suppress the ability of macrophages to engulf cells and process antigens necessary to stimulate an immune response. Although T-cells can be directly affected by glucocorticoids, B-cells can be affected and antibody synthesis decreased with high doses. Anti-inflammatory doses of glucocorticoids will not interfere with a normal immune response to vaccination.
Glucocorticoid therapy is directed at modifying the body’s response to inflammation; it is not directed at treating the underlying disease process. Therefore, the smallest dose that achieves the desired effect should be used to limit adverse side effects. Generally, anti-inflammatory doses are 10 times the physiological levels, immunosuppressive doses are twice the anti-inflammatory dose, and shock doses are five to 10 times the immunosuppressive dose. Product formulations have differences in onset and duration of action.
Adequan® is polysulfated glycosaminoglycan (PSGAG), made from an extract of cow lung and trachea that is then sulfated. The result is a large, charged molecule composed of galactosamine, glucosamine, and hexuronic acid. After administration, PSGAG binds to cartilage components. The precise mechanism of action of PSGAG in joints is unknown, but there are many studies demonstrating a beneficial effect of this product on damaged joints. Currently, PSGAG is thought to decrease destructive enzymes, act as an anti-inflammatory agent, and stimulate the normal production of hyaluronan and glycosaminoglycan. Adequan® is indicated for the treatment of degenerative joint diseases. In the US and Canada, Adequan is approved for use in dogs at 4.4 mg/kg IM twice weekly for four weeks. Although not approved, some practitioners use it in cats at 5–10 mg/cat IM. “Maintenance” therapy is not addressed by the manufacturer and has not been investigated in scientific studies, but veterinary practitioners have administered additional doses at intervals of weekly or monthly intervals with success in horses, dogs, and cats. Polysulfated glycosaminoglycan is related to the anti-clotting drug, heparin, and has some similar effects on blood clotting in horses. Although bleeding tendencies have been seen in people, prolonged administration of PSGAG in horses and dogs does not cause clinically apparent bleeding problems. It is probably best not to use PSGAG concurrently with aspirin in small animals.
Pentosan polysulfate is similar to polysulfated glycosaminoglycans (Adequan®), except that it is derived from beechwood hemicellulose rather than an animal product. The veterinary brand Cartrophen Vet® has similar anti-inflammatory action as Adequan®, but it is a less expensive product for dogs and is used extralabel in cats in Canada. Cartrophen Vet® is not available in the United States at this time, but the manufacturer is seeking approval in the US.
Pentosan is approved for use in women as Elmiron® for the treatment of interstitial cystitis (IC), as it is thought that a deficiency of the protective glycosaminoglycan layer in the bladder allows diffusion of irritating substances in urine. Inflammation of the bladder wall is thought to cause the clinical symptoms. Elmiron is an orally bioavailable pentosan that is thought to adhere to the bladder surface and supplement the natural glycosaminoglycan layer. Elmiron® is available in the US and Canada as a gelatin capsule and dosed in women at 100 mg PO q8h. In humans it has a urinary excretion t½ of 4.4 hours and is completely eliminated in 144 hours. Because this is a chronic, waxing and waning disease, pentosan must be given to women for a minimum of eight weeks to determine efficacy. Pentosan appears to be a possible treatment for IC in cats. The Elmiron® product is expensive (approximately $1/capsule) and it may be difficult to reformulate the capsule for a dose for a cat. Anecdotally, the canine product Cartrophen Vet® appears safe and effective in treating some cases of feline IC. The recommended dose for treatment of canine musculoskeletal pain and inflammation with Cartrophen Vet® is 3 mg/kg SC for a total of four injections, five to seven days apart. This dose has been widely used in cats in Canada, both for musculoskeletal problems and IC. Maintenance therapy is titrated to the individual patient, and some cats require monthly injections.
Pentosan is a heparin-like compound but its anticoagulant activity is weak (1/15 the activity of heparin). It has been available as a human product in Europe for over 30 years, with few adverse reactions. There are rare reports of bleeding complications in the human literature, so it probably should not be administered to cats who are on aspirin therapy or who are about to undergo surgery. The most commonly reported adverse effects in women are gastrointestinal discomfort, skin reactions and headache. No adverse reactions have been reported to the author from its use in cats.
These chondroprotective products (Cosequin®, Flex Free®, Xtra-Flex®, Glyco-flex®, etc.) are sold as nutritional supplements, or “nutriceuticals.” The classification of nutriceutical means that these products are not considered as “drugs” and do not have to meet the same standards of purity, efficacy, and safety that the Food and Drug Administration or Bureau of Veterinary Drugs would require of a drug for the treatment of degenerative joint disease. The nutriceuticals are promoted as oral supplements supplying the animal with the “building blocks” necessary for repair of damaged cartilage. However, the building blocks for production of joint cartilage are adequately supplied by most traditional diets. There are many anecdotal reports of improvement in clinical signs of lameness in humans and animals supplemented with nutriceuticals. Currently, there are few well-designed scientific studies proving that these products are effective. Some of the nutriceutical manufacturers are sponsoring such studies and results are pending. These products appear to be safe, may improve a lameness condition, but are somewhat expensive for long-term therapy. Because the nutriceuticals are not regulated by government agencies in the same manner as a drug would be, there is considerable variation in the composition and purity of the available products and standard doses have not been determined. Therefore, clinical results may vary considerably between different products. The chondroprotective nutriceuticals usually contain glucosamine salts and/or chondroitin sulfate.
Cartilage cells normally synthesize glucosamine from glucose and amino acids, however they can also use externally supplied, preformed glucosamine. Regardless of the source, the cartilage cells use glucosamine to synthesize glycosaminoglycans and hyaluronan. Glucosamine also regulates cartilage synthesis of proteoglycans and collagen. Chondrocytes make glucosamine from glucose. Glucosamine has mild anti-inflammatory action from scavenging free-radicals. Glucosamine is available as hydrochloride or sulfate formulations that appear equally effective. Chondroitin sulfate (CS) is long chain molecule composed of galactosamine sulfate and glucuronic acid units. It is the predominant glycosaminoglycan found in joint cartilage and is a natural component of other tissues, including tendons, bone, vertebral discs, heart, and cornea. Chondroitin sulfate stimulates glycosaminoglycan and proteoglycan synthesis in joint cartilage. It also inhibits destructive enzymes in joint fluid and cartilage and prevents thrombi formation in microvasculature.
Amitriptyline is a tricyclic antidepressant (TCA). The TCAs inhibit serotonin and norepinephrine reuptake and relieve primary anxiety or that secondary to disease. They also have anticholinergic, sedative, and hypotensive effects. They are used in animals as antidepressants, anxiolytics, for aggressive disorders, inappropriate elimination, sterotypies, narcolepsy, and incontinence. Relapse of a behavioural problem is common upon discontinuing medication. In humans, it was noticed that amitryptilline had analgesic properties and relieved the discomfort of interstitial cystitis in some women. It is not known how TCAs provide analgesia, as in humans, pain may be alleviated without causing a significant change in depression. Analgesic activity may be effected by changing concentrations of serotonin or by the effect of TCAs on endogenous opiod systems. The anticholinergic action of TCAs that increases urine retention may also reduce pain by diluting inflammatory mediators. In a recently published study, amitriptyline was found to be efficacious in the treatment of severe recurrent IC in nine of 15 cats at 10 mg/cat PO q24h for up to 12 months.
Amitriptyline is available as inexpensive, 10 mg tablets. Amitriptyline and the other TCAs are extensively metabolised by the liver and have very long elimination half-lives, so several weeks of treatment are required to achieve steady-state concentrations even though clinical signs may improve soon after starting therapy. Adverse side effects reported in cats included somnolence, weight gain, poor haircoat and decreased grooming, and transient cystic calculi developed in some cats. Some cats will be excessively sedated if given an entire 10 mg tablet, but because of their small size and enteric coating, the tablets are difficult to split into smaller doses. Adverse effects of amitriptyline in humans include sedation; orthostatic hypotension; anticholinergic effects (dry mouth, constipation, urine retention); and decreased seizure threshold. There are a large number of potential drug interactions with antihistamines, anticonvulsants, anesthetics, sympathomimetics, and thyroid hormones. Clients should be warned to be careful with the “candy-coated” little tablets, as there is no antidote for an overdose. Cardiac arrhythmias and central nervous system depression and seizures are the most serious adverse effects, and treatment is mainly symptomatic. Because of the long elimination t½, at least five days of electrocardiographic monitoring is recommended after an overdose. As the use of TCAs in veterinary medicine is a recent phenomenon, complications and adverse reactions are not well known. Patients on TCAs must be carefully monitored for cardiovascular complications if they must undergo general anaesthesia and surgery. Abrupt withdrawal of TCA therapy prior to a surgical procedure is not recommended, as a withdrawal syndrome is documented in humans and dosage reduction over two months is suggested.
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