Avoiding problems when stopping systemic glucocorticoid therapy

Why do this module?

Glucocorticoids are widely used in veterinary medicine and are one of the most commonly prescribed drug treatments (Lowe et al 2008). A study of three UK general veterinary practices found that 17% of cat and 15% of dog consultations resulted in treatment with systemic glucocorticoid therapy (O’Neill et al 2012). The drugs are used for their anti-inflammatory and immunosuppressive effects, to treat deficiencies (hypoadrenocorticism) and as anti-neoplastic treatments. As such, they are an important part of the veterinary therapeutic armoury. However, these drugs cause well-known unwanted effects, including suppression of the hypothalamic-pituitary-adrenal axis (HPA axis), which can lead to problems when the treatment is stopped.

This module was prompted by an enquiry from a small-animal vet, who asked if there is a standard protocol for withdrawing steroid therapy. It outlines the rationale and evidence on steroid withdrawal in cats and dogs and includes an example of a withdrawal protocol.

Hydrocortisone is the synthetic equivalent of the natural glucocorticoid cortisol (which also has mineralococorticoid properties). Other synthetic glucocorticoids are chemical modifications of cortisol with enhanced glucocorticoid and reduced mineralocorticoid effects. The drugs are available for use orally, parenterally and topically (in the eyes or ears, on the skin, or by inhalation).

The different drugs have different half-lives, durations of biological effect, and relative potencies (see the table). This must all be taken into account when calculating the dose as well as the effect on the HPA axis. The potency of a glucocorticoid is described relative to hydrocortisone, which is given an arbitrary value of 1 (Lowe et al 2008; BSAVA Formulary 2017; Plumb’s Veterinary Drugs 2017). The more potent a steroid as an anti-inflammatory, the more it will suppress the HPA axis (Behrend and Kemppainen 1997).

Relative potency of glucocorticoids

 
 

Oral prednisolone and methylprednisolone are short-acting glucocorticoids with a duration of action of 24–36 hours. This allows easy dose adjustment and alternate-day dosing when tapering, making them ideal for long-term treatment. Drugs formulated as highly water-soluble compounds for injection (e.g. methylprednisolone sodium succinate, dexamethasone sodium phosphate) have a duration of action similar to the base glucocorticoid and are suitable to use when starting treatment in patients too sick to take oral medications.

Drugs formulated as less water-soluble compounds for injection are longer-acting glucocorticoids. They include methylprednisolone acetate, dexamethasone isonicotinate and triamcinolone acetonide. They can have a continued clinical effect ranging from several days to several weeks (BSAVA Formulary 2017), making it impossible to adjust the dose. They are, therefore, only appropriate for systemic therapy if oral administration is too difficult, such as in fractious or roaming cats, or if the owner cannot administer tablets (e.g. because of arthritis).

Despite the widespread use of glucocorticoids, there is very little published evidence on optimal doses, dosing intervals or duration of treatment. Glucocorticoid doses need to be adjusted for each dog and cat because there is individual sensitivity to treatment.

Cats are considered to be more resistant than dogs to the effects of glucocorticoids and generally need higher doses (on a mg/kg basis). This may be explained in part by cats having fewer glucocorticoid receptors than dogs: they have around half the density of glucocorticoid receptors in the skin and liver compared to dogs and the receptors show lower binding affinity (van den Broek & Stafford 1992). While cats are less sensitive to steroid effects they can still develop serious adverse effects, such as diabetes mellitus, and they still show HPA axis suppression. It is important to dose overweight cats on the estimated ideal lean weight, because plasma prednisolone concentrations are around 2-fold higher in obese cats compared to normal weight cats given the same mg/kg dose (Trepanier 2015).

Large-breed dogs should be dosed towards the lower end of the recommended dose range because they tend to be more sensitive than small breeds to the unwanted effects of glucocorticoids. This may be due to relative overdosing when the dose is based on body weight rather than body surface area; some specialists recommend dosing medium to large dogs on a mg/m2 basis (BSAVA Formulary 2017).

The adrenal glands produce glucocorticoid hormones under the control of adrenocorticotropic hormone (ACTH) from the anterior pituitary, and corticotrophin-releasing hormone (CRH) from the hypothalamus. In turn, endogenous glucocorticoids provide negative feedback to turn off ACTH and CRH production, so creating a balance to meet the current needs of the animal. Treatment with glucocorticoids can lead to suppression of this system.

 
 

It appears that single doses of glucocorticoids, even in topical treatments, can affect the HPA axis.

  • Glucocorticoids (triamcinolone, fluocinonide or betamethasone) applied daily for 5 days to the skin of healthy dogs in larger amounts than would normally be used in clinical practice suppressed the HPA axis from day 2 of treatment, and there was still a measurable effect 3 weeks after stopping treatment with fluocinonide and betamethasone (Zenoble et al 1987).
  • Anti-inflammatory doses of oral prednisone (0.55mg/kg twice daily for 5 weeks) suppressed the HPA axis in healthy dogs at 14 days, and adrenal reserve was markedly reduced by day 28. The HPA axis had recovered by 2 weeks after stopping treatment (Moore and Hoenig 1992).
  • Oral prednisolone (1mg/kg on 9 alternate days) suppressed the HPA axis in healthy dogs after just one dose; alternate-day treatment did not prevent suppression, and HPA function returned to normal 1 week after stopping the drug (Brockus et al 1999).
  • Single doses of intravenous dexamethasone (0.1 mg/kg or more) suppressed the HPA axis for up to around 3 days in healthy dogs, with a longer duration of suppression with higher doses (Kemppainen et al 1989).

These studies suggest that the HPA axis in dogs is suppressed soon after starting treatment and takes a few weeks to recover after stopping. They also suggest that the longer the treatment period and the higher the dose, the greater the suppression and the longer the recovery period.

If glucocorticoids are stopped suddenly after a period of treatment, the risk, because of HPA suppression, is that the adrenal glands may not be able to respond appropriately to stimulation. This may lead to a relative deficiency in endogenous cortisol leading to signs of adrenal insufficiency. Clinical signs can be vague and include lethargy, weakness and inappetence, but signs similar to some immune-mediated diseases may also be seen, including fever, joint and muscle pain, and skin lesions (Behrend & Kemppainen 1997; Margolin et al 2006). Gastro-intestinal signs can also occur, and in people it has been shown that abrupt glucocorticoid withdrawal can cause vomiting through changes in gut motility (Phillips et al 1991).

The problems with glucocorticoid withdrawal can be avoided if the drugs are only used when they are clinically indicated and alternatives are unavailable or not suitable. Glucocorticoids should only be used long term where there is an established diagnosis of a disease that requires such treatment. Some of these are life-threatening, such as immune-mediated haemolytic anaemia and immune-mediated thrombocytopenia. Others are life-affecting, including inflammatory bowel disease and atopic skin disease. Generally, the more serious the disease, the higher the dose of glucocorticoid used and the longer the treatment duration; some diseases require lifelong therapy.

The longer the treatment duration, the slower the taper needed when the treatment is stopped. Most published advice suggests that systemic glucocorticoid therapy should be tapered if a patient has had more than 2 weeks’ therapy (Behrend & Kemppainen 1997, Feldman 2015). There are no published studies to determine the optimal steroid withdrawal schedule in veterinary patients. When glucocorticoids have been used at anti-inflammatory doses for a non-life-threatening disease the dose can be tapered more quickly.

When, and how quickly, to reduce the steroid dose must be decided for each patient taking into account the severity of the disease being treated, the dose and duration of the treatment, and the presence of adverse effects. The aim of tapering is to slowly reduce the dose incrementally, allowing the clinician to see evidence of any relapse of the treated disease. When tapering has started, the patient should be monitored regularly for any evidence of relapse and for signs of glucocorticoid withdrawal.

If a second immunosuppressive drug (e.g. azathioprine) is used in combination with the steroid it can provide a “steroid-sparing effect” (Whitley and Day 2011), allowing tapering of the steroid earlier in the course of the disease than if steroids are used alone, because the second immunosuppressant can help maintain remission. Some of the drugs used in this way are unlicensed uses of human medicines.

Should the animal undergo a stressful event (e.g. surgery, trauma, illness) during the tapering process, or before normal adrenal and pituitary function have returned, the dose of glucocorticoid should be increased (Plumb’s Veterinary Drugs 2017). An ACTH stimulation test can help identify animals with HPA suppression.

Example of a withdrawal protocol after immunosuppressive therapy with prednisolone (Feldman 2015, Behrend and Kemppainen 1997):

Induction:     1.0mg/kg twice daily for 10–28 days

Tapering:      0.75mg/kg twice daily or 1.5mg/kg once daily for 10–28 days

                      0.5mg/kg twice daily or 1mg/kg once daily for 10–28 days

                      0.25mg/kg twice daily or 0.5mg/kg once daily for 10–28 days

                       0.25 mg/kg once daily for 10–28 days

                       0.25mg/kg on alternate days for 21 days or more

Rapid discontinuation of glucocorticoid therapy might be desirable – for instance, if a patient on glucocorticoid therapy develops a disease (e.g. diabetes mellitus) in which glucocorticoids are contraindicated, or if the steroid treatment is causing intolerable adverse effects (e.g. excessive muscle wastage, iatrogenic Cushing’s). There is no published evidence on what to do in these cases. If rapid discontinuation is required in a patient previously on long-term therapy it would seem sensible to reduce to a daily physiological dose of an oral glucocorticoid (e.g. 0.2 mg/kg prednisolone) for a period of time to allow recovery of the HPA, or for 1–2 weeks, reducing to alternate-day treatment for 1–2 weeks, then stopping. Sick animals may need higher doses than this and the patient would need to be carefully monitored for signs of glucocorticoid withdrawal, such as vomiting or poor appetite. An alternative treatment may need to be started to treat the original disease.

When starting glucocorticoid therapy that is expected to continue for more than a couple of weeks, it is important to educate owners about the importance of not stopping medication suddenly and to warn them of the signs associated with rapid withdrawal. When explaining a tapering protocol it is helpful to give owners a written schedule to ensure they have clear instructions. As adrenal insufficiency can be life-threatening, tell owners what signs to look out for and that these may be subtle. Advise them to seek veterinary advice if they have concerns.

Evidence suggests that glucocorticoid therapy can suppress the HPA axis shortly after starting treatment. Published advice recommends tapering therapy before stopping if the patient has received systemic glucocorticoid therapy for longer than 2 weeks. Animals treated with immunosuppressive doses of a glucocorticoid should be weaned more slowly than animals on anti-inflammatory doses. Long-acting glucocorticoids should be avoided for long-term treatment unless there is no other option because they cause profound HPA axis suppression and their use precludes easy dose adjustment.

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References

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Brockus CW et al. Effect of alternate-day prednisolone administration on hypophyseal-adrenocortical activity in dogs. Am J Vet Res 1999; 60: 698–702.

BSAVA Small Animal Formulary 9th Ed, Gloucester BSAVA, 2017. pp 425–7.

Feldman EC et al. Canine and Feline Endocrinology, edition 4. St. Louis, Missouri: Elsevier Saunders, 2015; 555–77

Kemppainen RJ et al. Effects of single intravenously administered doses of dexamethasone on response to the adrenocorticotropic hormone stimulation test in dogs. Am J Vet Res 1989; 50: 1914–7.

Lowe AD et al. Glucocorticoids in the cat. Vet Dermatol 2008; 19: 340–7.

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Plumb’s Veterinary Drugs. Glucocorticoid agents. General information [online]. Available: https://www.plumbsveterinarydrugs.com/#!/appendix/4081. [Accessed 5 May 2017].

Trepanier L. Glucocorticoids. Clinician’s Brief [online], December 2015. Available: https://www.cliniciansbrief.com/sites/default/files/attachments/MEDS_Glucocorticoids.pdf. [Accessed 13 May 2017]

van den Broek AHM, Stafford WL. Epidermal and hepatic glucocorticoid receptors in cats and dogs. Res Vet Sci 1992; 52: 312-5.

Whitley NT, Day MJ. Immunomodulatory drugs and their application to the management of canine immune-mediated disease. J Small Anim Pract 2011; 52: 70–85.

Zenoble RD, Kemppainen RJ. Adrenocortical suppression by topically applied corticosteroids in healthy dogs. J Am Vet Med Assoc 1987; 191: 685–8