Glucocorticoid epidural for sciatica: metabolic and endocrine sequelae

A. Ward, J. Watson, P. Wood1, C. Dunne2 and D. Kerr

Bournemouth Diabetes and Endocrine Centre, Royal Bournemouth Hospital,
1 Regional Endocrine Unit, Southampton General Hospital and
2 Department of Rheumatology, Christchurch Hospital, Christchurch, Dorset, UK


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objective. The study was designed to investigate the effect of epidural administration of glucocorticoid on insulin sensitivity.

Methods. Ten healthy individuals with sciatica underwent a short insulin tolerance test before and twice following (at 24 h and 1 week) a caudal epidural containing 80 mg triamcinolone. Fasting glucose, insulin and cortisol concentrations were also measured.

Results. The rate of glucose disappearance after insulin administration (kITT) fell from 3.6%/min before the epidural to 1.9%/min 24 h afterwards (P=0.001) and returned to pretreatment values by 1 week. Significantly raised fasting insulin and glucose levels also reflected impaired insulin sensitivity immediately after the epidural. Morning cortisol levels were suppressed after the epidural (49 nmol/l at 24 h and 95 nmol/l at 1 week vs 352 nmol/l at baseline; P<0.01).

Conclusions. Epidural administration of glucocorticoid results in potent suppression of insulin action and this should be taken into account when patients with diabetes require treatment for sciatica.

KEY WORDS: Glucocorticoid, Insulin sensitivity, Epidural, Adrenal suppression, Sciatica.


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Caudal epidural injections of glucocorticoid are widely used for the treatment of low back pain and sciatica due to herniated nucleus pulposus and a proportion of these patients will have diabetes. Oral or parenteral glucocorticoid administration can impair insulin sensitivity [1] and adversely affect glycaemic control in patients with diabetes. Although epidural glucocorticoid administration has been associated with suppression of the hypothalamic–pituitary–adrenal axis for up to 3 weeks [2], previous studies have failed to find any change in fasting blood glucose or lipid levels after a single epidural injection of dexamethasone [3]. However, we were recently involved in the case of a 65-yr-old man with type 2 diabetes on oral hypoglycaemic agents (HbA1c 7.5%), who presented with hyperosmolar non-ketotic hyperglycaemic coma 24 h after receiving 80 mg triamcinolone into the epidural space for low back pain and sciatica.

We undertook a pilot study to assess the effect of a single glucocorticoid epidural on insulin sensitivity in individuals with normal glucose tolerance.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Subjects and study design
Patients referred to the rheumatology out-patient service with sciatica who were otherwise well were invited to participate in the study. We recruited 10 subjects [six female, four male; mean age 43.4 yr (range 29–60); body mass index (BMI) 26.7 (range 21.1–33.4)]. There was no control group as it would have been unethical to treat patients with sciatica by epidural injection of local anaesthetic alone. Subjects were asked to attend on three occasions: 1 week before receiving 80 mg triamcinolone acetonide (Kenalog; Bristol-Myers-Squibb, Hounslow, UK) in 30 ml local anaesthetic (procaine) via the caudal epidural route, and 24 h and 1 week after the epidural. At each visit, a short insulin tolerance test was performed [4]. Informed consent was obtained from each subject at their first visit and the East Dorset Local Research Ethics Committee gave ethical approval for the study.

Short insulin tolerance test
Subjects attended at 8.00 a.m. after an overnight fast. A 21-gauge butterfly needle was inserted into an antecubital vein for administration of drugs and a further butterfly needle was inserted retrogradely into a vein on the hand for sampling. Samples were arterialized by placing the hand in a warming device. This has been shown to improve the agreement between the short insulin tolerance test and the euglycaemic–hyperinsulinaemic clamp, the gold standard for assessing insulin sensitivity [5]. After 20 min of rest, baseline samples were withdrawn for determination of glucose, insulin and cortisol. At time zero, 0.05 U/kg soluble human insulin (Actrapid; Novo Nordisk, Crawley, UK) was injected antecubitally and blood was then withdrawn every 2 min from 3 to 15 min. The test was terminated by injection of 20 ml 50% dextrose and the subject was given breakfast. Finishing the test at 15 min avoids the counter-regulatory hormone response interfering with the rate of glucose fall, from which insulin sensitivity is calculated.

Laboratory analyses
Whole-blood glucose was analysed at the bedside immediately using a YSI analyser [Yellow Springs Instruments, Yellow Springs, OH, USA; interassay coefficient of variation (CV) 1.22–1.65%)]. Serum cortisol was measured with an in-house radioimmunoassay using 125I tracer (interassay CV 7.4–10.3%) and serum insulin was measured by a time-resolved fluorescence immunometric assay (DELFIA, Perkin Elmer Life Sciences, Boston, MA, USA) using antibodies 3B1 and 14B (CV 4.6–7.3%).

Statistical analysis
Glucose, insulin and cortisol concentrations were log-transformed to achieve normality. Blood glucose falls linearly between 3 and 15 min after the insulin injection. The rate of glucose disappearance (kITT) over this time was calculated by linear regression and provided a measure of insulin sensitivity. Paired-sample t-tests were used to compare kITT and baseline glucose, insulin and cortisol measurements between visits using SPSS statistical software (SPSS, Chicago, IL, USA). Statistical significance was assigned to a P value of <0.05.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
All subjects completed the study without complications; in particular, none experienced symptomatic hypoglycaemia. Subject 10 did not attend on the third occasion for personal reasons. Table 1Go shows mean (S.D.) kITT, fasting blood glucose, fasting plasma insulin and fasting serum cortisol at the three time points in the study.


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TABLE 1. Mean (S.D.) insulin sensitivity (kITT) and fasting glucose, insulin and cortisol levels in 10 healthy individuals with sciatica measured before (Pre), 24 h after (Acute) and 1 week after (Post) a caudal epidural containing 80 mg triamcinolone acetonide

 
Insulin sensitivity (kITT) fell to nearly half the baseline value, from 3.7%/min to 1.9%/min (mean difference 1.8%/min; 95% CI 1.0–2.5, P=0.001), immediately after the epidural, but had returned to baseline by 1 week (Fig. 1Go). Fasting insulin levels reflected the fall in insulin sensitivity and rose from 11.6 to 16.2 mU/l (1.4-fold higher; 95% CI 1.0–1.9, P=0.03) immediately after the epidural and had fallen at 1 week. Fasting glucose showed a similar pattern, rising from 4.7 to 5.3 mmol/l (1.1-fold higher; 95% CI 1.0–1.2, P=0.003) at visit 2. Two subjects developed fasting hyperglycaemia in the diabetic range, with whole-blood glucose levels of 6.4 and 7.4 mmol/l at this time; the levels had normalized by the follow-up visit.



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FIG. 1. Insulin sensitivity in 10 healthy patients with sciatica expressed as the rate of glucose disappearance (kITT) during a short insulin tolerance test at baseline (PRE) and 24 h (ACUTE) and 1 week (POST) after an epidural injection of 80 mg triamcinolone acetonide. Data are mean±S.E.M. *P=0.001 for change vs baseline.

 
There was marked adrenal suppression at both visits after the glucocorticoid epidural. Fasting cortisol fell from 352 to 49 nmol/l (7.2-fold lower; 95% CI 4.0–12.9, P<0.001) within 24 h and was still low a week later, at 96 nmol/l (3.5-fold lower; 95% CI 1.6–7.8, P=0.007) (Fig. 2Go).



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FIG. 2. Fasting 9 a.m. serum cortisol levels in 10 healthy patients with sciatica before and after glucocorticoid epidural (time course as in Fig. 1). Results expressed as mean±S.E.M. *P<0.001, **P=0.007 vs baseline.

 


    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
This study has demonstrated a marked change in insulin sensitivity in individuals with normal glucose tolerance after caudal epidural administration of triamcinolone. Previously, Akinmokun et al. [5] reported a kITT of 4.1%/min in normal subjects (mean age 36 yr, BMI 24) and 2.0%/min in type 2 diabetes (mean age 52 yr, BMI 33). Thus, the mean insulin sensitivity in individuals in this study, 24 h after the epidural, was similar to that in seen in patients with type 2 diabetes and was sufficient to produce fasting hyperglycaemia in two patients. In the pre-epidural study, these two subjects had higher fasting blood glucose and lower kITT than the rest of the group, suggesting a degree of underlying insulin resistance. Although the reduction in insulin sensitivity is unlikely to be clinically relevant in normal individuals, it may have implications for the management of patients with back pain who already have abnormal glucose tolerance. It has been shown that glucocorticoids cause greater perturbations of blood glucose in such individuals due to relative insulin deficiency [6]. Patients with diabetes may not routinely be given advice on how to manage their condition after a glucocorticoid epidural and therefore are at risk of the potentially disastrous metabolic decompensation seen in our patient.

In this study, insulin sensitivity and fasting insulin and glucose levels were normal 1 week after a single epidural injection. However, as patients may receive a course of epidurals, sometimes as frequently as 1 week apart, the possibility of a cumulative effect on insulin sensitivity arises. The findings in this study are likely to be relevant to any glucocorticoid administered epidurally, as altered glucose homeostasis is a class effect for these agents and is of similar magnitude for clinically equivalent doses [7].

Our demonstration of adrenal suppression is confirmation of previous work which has documented impaired responsiveness to adrenocorticotrophic hormone (ACTH) and reduced ACTH and cortisol release during insulin-induced hypoglycaemia, in addition to suppressed 9 a.m. cortisol levels [8]. After lumbar epidural administration of 80 mg methylprednisolone acetate, plasma levels were undetectable throughout the 3 weeks of the study despite profound adrenal suppression. The authors suggested that the steroid was acting directly on central glucocorticoid receptors, presumably via cerebrospinal fluid (CSF) absorption [2]. Arachnoid villi are found in the epidural space and may allow passage of glucocorticoid into the subarachnoid space. Work in cats has demonstrated high uptake of labelled methylprednisolone into the hippocampus, among other areas, after intrathecal injection [9]. This is of note as it suggests easy transfer of glucocorticoid between CSF and neuronal tissue, and the hippocampus is an important feedback site for the hypothalamic–pituitary–adrenal axis.

No literature is available on plasma or CSF triamcinolone levels after administration via the epidural route. Comparable work on patients who have received intra-articular injections has shown detectable triamcinolone in the circulation for up to 4 weeks in association with hypothalamic–pituitary–adrenal axis suppression [10]. There is a rich plexus of veins in the sacral area and thus some systemic absorption after caudal epidural is likely. It is important to note that all the epidural injections in this study were administered by an experienced clinician and were atraumatic, suggesting that direct intravenous administration of glucocorticoid is unlikely. Some centres advocate the use of radiological guidance for needle placement to ensure glucocorticoid administration into the epidural space. However, failure to reach the epidural space would be more likely to weaken the results than to promote glucocorticoid side-effects.

It should be noted that neither triamcinolone nor methylprednisolone is licensed for epidural administration and the data sheet for methylprednisolone contains a specific warning against intrathecal use in the light of past complications. Whilst the epidural route is safer, the incidence of inadvertent dural puncture may be significant, particularly when the lumbar approach is used. The efficacy of epidural glucocorticoid in the treatment of sciatica is much debated in the literature and large studies are ongoing to address this question. The number of subjects in this study is small and it would be useful to include a measure of glucose tolerance or insulin sensitivity in these larger trials in the light of our results.

In summary, we suggest that patients with diabetes should be given specific advice on the management of their condition after glucocorticoid epidural in the form of a protocol jointly agreed by the rheumatology and diabetes teams. In addition, the possibility of impaired stress responses due to adrenal suppression should be borne in mind in any patient who has received a glucocorticoid epidural within the last month. Finally, when investigating a patient with insulin resistance or impaired glucose tolerance, a history of recent glucocorticoid exposure should include epidural administration.


    Acknowledgments
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The authors would like to thank Melanie Weiss and Jai Ingelby for their help with the studies and Holly Syddall for statistical support.


    Notes
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Correspondence to: D. Kerr, Bournemouth Diabetes and Endocrine Centre, Royal Bournemouth Hospital, Castle Lane East, Bournemouth BH7 7DW, UK. Back


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Munck A. Glucocorticoid inhibition of glucose uptake by peripheral tissues: old and new evidence, molecular mechanisms, and physiological significance. Persp Med Biol1971;14:265–9.
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  9. Lehrer GM, Maker HS, Weissbarth S. Brain uptake of methylprednisolone acetate. Arch Neurol1973;28:324–8.[ISI][Medline]
  10. Cook DM, Meikle AW, Bowman R. Systemic absorption of triamcinolone after a single intraarticular injection suppresses the pituitary–adrenal axis [abstract]. Clin Res1988;36:121A.
Submitted 20 March 2001; revised version accepted 6 July 2001.



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